Method for preparing maribavir

Abstract

The present disclosure discloses compositions comprising maribavir, methods for providing the same, and compositions that provide intermediates useful in providing maribavir.

Description

[Technical Field]

[0001] The present invention relates to compounds useful as antiviral agents, pharmaceutical compositions thereof, and methods for preparing such compounds and compositions. [Background technology]

[0002] Cytomegalovirus (CMV) is a member of the herpesvirus family. Human cytomegalovirus (HCMV) infection is common, with serological evidence of prior infection in 40% to 100% of various adult populations. However, severe HCMV disease occurs almost exclusively in individuals with compromised or immature immune systems. Cytomegalovirus remains a significant problem for patients undergoing various types of transplants, including hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT), which are associated with the use of intensive immunosuppressive chemotherapy. Summary of the Invention

[0003] Maribavir is a benzimidazole riboside and an orally available antiviral drug for CMV. Maribavir is also known by the trade name LIVTENCITY™. Maribavir is a compound having the following chemical structure: (2S,3S,4R,5S)-2-(5,6-dichloro-2-(isopropylamino)-1H-benzo[d]imidazol-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol: [ka] is a potent, orally available antiviral agent for the treatment of CMV infection and disease in transplant recipients. Transplant recipients are at significant risk for CMV infection.

[0004] The synthesis of maribavir is described in US 6,077,832 ("the '832 patent") in Examples 1, 2, and 5. The synthesis, shown in Scheme 1 below, consists of three chemical transformation steps with a total yield of approximately 27%. [ka]

[0005] The synthesis shown in Scheme 1 first involves coupling 2-bromo-5,6-dichlorobenzimidazole with 1,2,3,5-tetra-O-acetyl-L-ribofuranose. Next, the acetyl group on the ribofuranose moiety is removed, followed by the introduction of isopropylamine to yield maribavir. Notably, the first step also produced the alpha anomer in approximately 6% yield (see Example 1 of the '832 patent).

[0006] The synthesis of maribavir is also described in WO 2001 / 077083 ('083 publication) in Examples 1-4 and 7. The synthesis, shown in Scheme 2 below, consists of five chemical transformations with a total yield of approximately 18-20%. [ka]

[0007] The synthesis in Scheme 2 follows a similar route as provided in Scheme 1 as disclosed in the '832 patent, but replaces some of the reagents in the first step. Additionally, the '083 publication also discloses a two-step process to provide 2-bromo-5,6-dichlorobenzimidazole.

[0008] U.S. Pat. No. 6,617,315 ("the '315 patent") discloses an alternative route: synthesizing 2-(alkylamino)-1H-benzimidazole using 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate as a desulfurizing agent, coupling the 2-(alkylamino)-1H-benzimidazole with 1,2,3,5-tri-O-acetyl-ribofuranose, and deprotecting the 2-(alkylamino)-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl-1H-benzimidazole). See General Procedures I, II, and III in columns 27-28 of the '315 patent. Specifically, the '315 patent discloses the synthesis of the acetyl-protected intermediate in Scheme 3 in Examples 24 and 25. [ka]

[0009] These two steps have a combined yield of approximately 49%. Notably, the '315 patent does not exemplify the deacetylation of 5,6-dichloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazole to obtain maribavir. While the synthesis disclosed in the '315 patent appears to be a significant improvement over the syntheses described in the '832 patent and the '083 publication, the yield of maribavir is still expected to be less than 49% (e.g., 37%, assuming a 75% yield for the deacetylation exemplified in the '832 patent and the '083 publication).

[0010] Thus, in some embodiments, the present invention encompasses the recognition that the synthesis of maribavir can be modified to increase the overall yield. In some embodiments, maribavir or a pharmaceutically acceptable salt thereof is prepared according to Scheme 4 or Scheme 5, as set forth below: [ka] [ka]

[0011] In some embodiments, the present disclosure provides an improved synthesis of maribavir in Scheme 5, where the overall yield is at least 45%. It will be appreciated that the physical and / or chemical properties of particular intermediate compounds (e.g., compounds 2-3 or 5-8), solvents and / or reagents, and reaction conditions may contribute to the overall yield of maribavir and / or help control impurities, particularly when scaling up the synthesis.

[0012] Additionally or alternatively, the present disclosure also recognizes that acceptable quality maribavir is important for proper milling and formulation into tablets. For example, in some embodiments, a specific polymorphic form of maribavir (e.g., Form VI disclosed in U.S. Pat. No. 6,482,939) that is free of other crystalline forms, solvates, or hydrates is desired. In some embodiments, the present disclosure provides methods for preparing a specific polymorphic form of maribavir (e.g., Form VI disclosed in U.S. Pat. No. 6,482,939) that is free of other crystalline forms, solvates, or hydrates. Additionally or alternatively, in some embodiments, a specific size distribution of maribavir is important for tablet manufacture. In some embodiments, the present disclosure provides methods for preparing maribavir with a specific particle size distribution that is amenable to milling and formulation into tablets. Additionally or alternatively, in some embodiments, a specific size distribution of maribavir is amenable to the manufacture of oral solid dosage forms. In some embodiments, the present disclosure provides methods for preparing maribavir with a specific particle size distribution that is amenable to formulation into oral solid dosage forms. Additionally or alternatively, in some embodiments, the particular size distribution of maribavir may affect the bioavailability of maribavir. In some embodiments, the present disclosure provides a solid oral formulation comprising maribavir polymorphic Form VI having a particular particle size distribution (e.g., d(50) of about 50 to about 400 μm). In some embodiments, the present disclosure provides a method for crystallizing maribavir polymorphic Form VI having a particular particle size distribution (e.g., d(50) of about 50 to about 400 μm).

[0013] Additionally or alternatively, the present disclosure recognizes the importance of minimizing certain impurities when manufacturing pharmaceutical products. For example, impurity profiles should be consistent to maintain consistency of efficacy and minimize potential side effects. In some embodiments, when the synthesis of a pharmaceutical product consists of multiple steps, it is understood that impurities formed in an early step may remain through subsequent steps and form additional impurities. Therefore, reducing impurities at each step (e.g., step 1, 2, or 3) of the synthesis of maribavir is important to maintain the consistency of the manufactured pharmaceutical product.

[0014] Thus, in some embodiments, the present disclosure provides compositions comprising maribavir or a pharmaceutically acceptable salt thereof, and methods for preparing the same. In some embodiments, the provided compositions comprise maribavir and one or more compounds selected from the following: [ka] or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, provided compositions are prepared according to the methods disclosed herein (e.g., steps 1-3). In some embodiments, provided compositions contain at least 90%, 95%, 99%, 99.5%, or 99.9% by weight of maribavir. In some embodiments, provided compositions contain maribavir that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that a composition or compound does not contain significant amounts of contaminants. Such contaminants may include starting materials, residual solvents, or other impurities that may result from the preparation and / or isolation of maribavir. In some embodiments, provided compositions contain maribavir or a pharmaceutically acceptable salt thereof and compounds 2, 3, and / or 4 in an amount of less than 0.10% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions contain maribavir or a pharmaceutically acceptable salt thereof and compounds 2, 3, and / or 4 in an amount of less than 0.10% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions comprise maribavir or a pharmaceutically acceptable salt thereof and compounds 2, 3, and / or 4 in an amount of less than 0.10% (a / a HPLC) relative to maribavir. In some embodiments, provided compositions comprise maribavir or a pharmaceutically acceptable salt thereof and compounds 2, 3, and / or 4 in an amount undetectable by HPLC. In some embodiments, provided compositions comprise maribavir as Form VI, as described in U.S. Pat. No. 6,482,939. In some embodiments, provided compositions comprise at least 90%, 95%, 99%, 99.5%, or 99.9% by weight of Form VI maribavir. In some embodiments, provided compositions comprise maribavir substantially free of other polymorphic forms described in, for example, U.S. Pat. No. 6,482,939, U.S. Pat. No. 8,546,344, or U.S. Pat. No. 11,130,777. In some embodiments, provided compositions comprise maribavir having a particular size distribution as defined and described herein.Impurities (e.g., intermediates, enantiomeric impurities) can potentially affect the quality of drug substances and drug products and may represent a risk to drug safety. Patient safety may be affected if certain impurities are present in amounts above the qualification limit. There is an unknown risk to drug safety for unknown impurities. [Brief explanation of the drawings]

[0016] [Figure 1] 1 shows a plot of the purity of compound 2 as a function of input quality after filtration of recrystallized compound 2 (i.e., before the washing step). [Figure 2] 1 shows a plot of compound 2 (HPLC purity) versus recrystallization temperature and observed crystallization temperature (H=high temperature (T>90° C.) and L=low temperature (T<40° C.)). [Figure 3] Figure 1 shows an interval plot of Compound 2 versus recrystallization temperature. Pooled standard deviations are used to calculate the intervals. [Figure 4] 1 shows a contour plot of the purity of Compound 2 examining the effect of recrystallization temperature and observed crystallization temperature. DETAILED DESCRIPTION OF THE INVENTION

[0017] definition Compounds of the present invention include those generally described above, and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 thIn addition, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry," 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, which are incorporated herein by reference in their entireties.

[0018] The terms "aliphatic" or "aliphatic group," as used herein, refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocycle," "carbocyclic," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation but is not aromatic, having one point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "carbocyclic" (or "alicyclic" or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0019] The term "halogen" means F, Cl, Br or I.

[0020] The term "aryl," used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having 5 to 14 total ring members, in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the invention, "aryl" refers to an aromatic ring system; exemplary groups include phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0021] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, groups having 6, 10, or 14 pi-electrons shared in a cyclic arrangement, and groups having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and the quaternized form of any basic nitrogen. Exemplary heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-," as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring. Exemplary groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0022] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and that, in addition to carbon atoms, has one or more, preferably 1 to 4, heteroatoms as defined above. The term "nitrogen," when used in reference to a ring atom of a heterocycle, includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N-substituted pyrrolidinyl).

[0023] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclic alkyl" refers to a heterocycle-substituted alkyl group, where the alkyl and heterocyclic moieties independently are optionally substituted.

[0024] As described herein, compounds may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more of the hydrogens of a given moiety of a compound have been replaced with a suitable substituent. "Substituted" applies to one or more of the hydrogens that are explicit or implied from the structure (e.g., [ka] At least [ka] refers to, [ka] At least [ka] (refers to "optionally substituted"). Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned in this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to a compound that remains substantially unchanged when subjected to conditions that allow for the production, detection, and, in certain embodiments, recovery, purification, and use of the compound for one or more of the purposes disclosed herein.

[0025] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen, -(CH2) 0‐4 R°, -(CH2) 0‐4 OR°, -O(CH2) 0‐4 R o,-O-(CH2) 0‐4 C(O)OR°, -(CH2) 0‐4 CH(OR°)2, -(CH2) 0‐4 SR°, -(CH2) 0‐4 Ph (optionally substituted with R°), —(CH2) 0‐4 O(CH2) 0-1 Ph (optionally substituted with R°), -CH=CHPh (optionally substituted with R°), -(CH2) 0‐4 O(CH2) 0-1 -pyridyl (optionally substituted by R°), -NO2, -CN; -N3, -(CH2) 0‐4 N(R°)2, -(CH2) 0‐4 N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2) 0‐4 N(R°)C(O)NR°2, -N(R°)C(S)NR°2, -(CH2) 0‐4 N(R°)C(O)OR°, -N(R°)N(R°)C(O)R°, -N(R°)N(R°)C(O)NR°2, -N(R°)N(R°)C(O)OR°, -(CH2) 0‐4 C(O)R°, -C(S)R°, -(CH2) 0‐4 C(O)OR°, -(CH2) 0‐4 C(O)SR°, -(CH2) 0‐4 C(O)OSiR°3, ‐(CH2) 0‐4 OC(O)R°, ‐OC(O)(CH2) 0‐4 SR°, SC(S)SR°, ‐(CH2) 0‐4 SC(O)R°, -(CH2) 0‐4 C(O)NR°2, -C(S)NR°2, -C(S)SR°, -SC(S)SR°, -(CH2) 0‐4 OC(O)NR°2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -C(NOR°)R°, -(CH2) 0‐4 SSR°, ‐(CH2) 0‐4 S(O)2R°, -(CH2) 0‐4 S(O)2OR°, -(CH2) 0‐4 OS(O)2R°, -S(O)2NR°2, -(CH2) 0‐4S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(OR°)R°, -C(NH)NR°2, -P(O)2R°, -P(O)R°2, -OP(O)R°2, -OP(O)(OR°)2, SiR°3, -(C 1‐4 Linear or branched alkylene)O‐N(R°)2, or -(C 1‐4 straight or branched chain alkylene)C(O)O—N(R°), where each R° is optionally substituted as defined below and independently represents hydrogen, C 1‐6 Aliphatic, -CH2Ph, -O(CH2) 0‐1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially saturated, or aryl ring having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, when R° is present independently, together with the intervening atom(s) is a 3-12 membered saturated, partially saturated, partially unsaturated, or aryl monocyclic or bicyclic ring, optionally substituted as defined below.

[0026] Suitable monovalent substituents for R° (or the ring formed by R° together with the intervening atoms when there are two R° independently) are independently halogen, —(CH2), 0-2 R · ,-(Halo R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · , -(CH2) 0-2 CH(OR · )2, -O(HaloR · ), -CN, -N3, -(CH2) 0-2 C(O)R · , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · , -(CH2) 0-2 SR · , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · , -(CH2) 0-2 NR· 2, -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · 、 -(linear or branched chain C 1-4 alkylene)C(O)OR · or -SSR · and each R · is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens and, independently, C 1-4 Aliphatic group, -CH2Ph, -O(CH2) 0-1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0027] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S- is mentioned, R * are independently hydrogen, C, optionally substituted as defined below, 1-6 and an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbon atoms of the "optionally substituted" groups of compounds of Formula I and subgenus thereof include -O(CR * 2) 2-3 O- and R * are independently hydrogen, C, optionally substituted as defined below,1-6 It is selected from an aliphatic group, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0028] R * Suitable substituents for the aliphatic group include halogen, -R · ,-(Halo R · ), -OH, -OR · , -O(HaloR · ), -CN, -C(O)OH, -C(O)OR · , -NH2, -NHR · , -NR · 2 or -NO2, where each R · is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens and, independently, C 1-4 Aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R † )S(O)2R † are listed, and each R † are independently hydrogen, optionally substituted as defined below, C 1-6an aliphatic group, an unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † When there are two independent occurrences of R†, R† together with the intervening atom(s) form an unsubstituted 3- to 12-membered monocyclic or bicyclic saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0030] R † Suitable substituents for the aliphatic group are independently halogen, -R · ,-(Halo R · ), -OH, -OR · , -O(HaloR · ), -CN, -C(O)OH, -C(O)OR · , -NH2, -NHR · , -NR · 2 or -NO2, and each R · is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens and, independently, C 1-4 Aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0031] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the normal scope of sound medical judgment, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0032] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+ (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate with counterions such as, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0033] As used herein in reference to a value, the term "about" refers to a value that is similar relative to the referenced value. Generally, a person of ordinary skill in the art familiar with the context will understand the relevant degree of variation that "about" encompasses in that context. For example, in some embodiments, the term "about" can encompass a range of values ​​of (i.e., ±) 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the reference value. For example, a dose containing "about 200 mg" of maribavir encompasses any amount of maribavir within the range of 180 mg to 220 mg.

[0034] As used herein, the terms "administering" or "administration" generally refer to administering a composition to a subject to achieve delivery of an active agent to a desired site (e.g., in some embodiments, a site of disease or injury, and / or a site of a responsive process, cell, tissue, etc.). As will be understood by those of skill in the art upon reading this disclosure, in some embodiments, one or more specific routes of administration may be possible and / or feasible and / or useful in practicing the present disclosure. In some embodiments, administration may be oral. In some embodiments, administration may include only a single dose. In some embodiments, administration may involve the application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., multiple doses separated by time) and / or periodic (e.g., individual doses separated by a period of time) dosing.

[0035] As used herein, the term "treat" or "treating" refers to partially or completely alleviating, inhibiting, improving, and / or reducing one or more symptoms of a disorder or condition. As used herein, the terms "treatment," "treat," and "treating" refer to partially or completely alleviating, inhibiting, improving, and / or reducing a disorder or condition, or one or more symptoms of a disorder or condition, as described herein. In some embodiments, treatment may occur after one or more symptoms appear. In some embodiments, the term "treating" includes halting the progression of a disease or disorder. Treatment may also be continued after symptoms have been cured, for example, to prevent or delay recurrence. Thus, in some embodiments, the term "treating" includes preventing the recurrence or recurrence of a disease or disorder.

[0036] Unit ratios such as L / kg, kg / kg, etc. are expressed relative to the mass (kilograms) of the limiting reagent for each reagent / component / etc. described (e.g., in each of steps 1, 2, or 3 as defined and described herein).

[0037] The compounds provided may be synthesized according to the schemes described herein. The reagents and conditions described are for illustrative purposes only and are not intended to be limiting. As will be appreciated by those skilled in the art, various analogs can be prepared by modifying the synthetic reactions, such as by using different starting materials, different reagents, and different reaction conditions (e.g., temperature, solvent, concentration, etc.).

[0038] It will be understood that any intermediate shown in Scheme 4 or 5 may be isolated and / or purified prior to each subsequent step. Alternatively, any intermediate shown in Scheme 4 or 5 may be utilized in a subsequent step without isolation and / or purification. Such telescoping of steps is contemplated in the present disclosure.

[0039] In some embodiments, the compounds described herein can be purified by any means known in the art. In some embodiments, purification of the compounds described herein comprises filtration, chromatography, distillation, crystallization, or a combination thereof. In some embodiments, chromatography comprises high-performance liquid chromatography (HPLC). In some embodiments, chromatography comprises normal-phase, reverse-phase, or ion-exchange elution on a cartridge equipped with a suitable sorbent medium. Purification via chromatographic methods typically utilizes one or more solvents known to those skilled in the art or determined by routine experimentation.

[0040] Step 1 In some embodiments, the present disclosure provides compound 2a: [ka] or a salt thereof, wherein R 1 and R 2 is as defined and described herein.

[0041] In some embodiments, the present disclosure provides Compound 2: [ka] or a salt thereof.

[0042] As shown in Schemes 4 and 5, Step 1 is the first of three steps for preparing maribavir as disclosed herein. Any by-products formed in Step 1 may be present in the provided composition and may further react to form additional by-products and / or reduce the overall yield or quality of maribavir. In some embodiments, the present disclosure provides methods for preparing Compound 2 or a salt thereof with reduced and / or low levels of impurities. While not wishing to be bound by theory, a low volume of reaction solvent (e.g., 1,4-dioxane) may allow efficient conversion to Compound 2 with reduced and / or low levels of impurities. Additionally or alternatively, without wishing to be bound by theory, the provided crystallization step(s) may result in Compound 2 with reduced and / or low levels of impurities.

[0043] In some embodiments, the present disclosure provides a method for treating a rhodopsin-related malabsorption disorder comprising administering to a patient a therapeutically effective amount of Compound 2, or a salt thereof, in combination with one or more of the following compounds: [ka] or a salt thereof.

[0044] In some embodiments, provided compositions include compound 2 or a salt thereof, and compounds 9, 10, 11, and / or 12 or salts thereof in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions include compound 2 or a salt thereof, and compounds 9, 10, 11, and / or 12 or salts thereof in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir.

[0045] In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 9 or a salt thereof. In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 9 or a salt thereof, in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 9 or a salt thereof, in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 9 or a salt thereof, in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. 1 1 H NMR).

[0046] In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 10 or a salt thereof. In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 10 or a salt thereof, in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 10 or a salt thereof, in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 10 or a salt thereof, in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. 1 1 H NMR).

[0047] In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 11 or a salt thereof. In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 11 or a salt thereof, in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 11 or a salt thereof, in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 11 or a salt thereof, in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. 1 1 H NMR).

[0048] In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 12 or a salt thereof. In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 12 or a salt thereof, in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 12 or a salt thereof, in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 2 or a salt thereof, and Compound 12 or a salt thereof, in an amount of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. 1 1 H NMR).

[0049] In some embodiments, such compositions comprising Compound 2 or a salt thereof are prepared as described herein. In some embodiments, the present disclosure also provides the recognition that certain reagents (and amounts thereof) and / or reaction conditions may provide Compound 2 or a salt thereof of improved quality (e.g., with high purity and / or minimal by-products) and / or may improve the yield of Compound 2 or a salt thereof. In some embodiments, such improvements in the yield or quality of Compound 2 or a salt thereof may also improve the yield or quality of maribavir. Without wishing to be bound by theory, the present disclosure provides the recognition that the incorporation of crystallization and / or recrystallization into Step 1 may improve yield, purity, and / or reduce the formation of by-products (e.g., Compounds 9, 10, 11, and 12).

[0050] In some embodiments, compound 2a or a salt thereof is prepared as shown in step 1 of Scheme 4. In some embodiments, in step 1, compound 2a or a salt thereof is prepared by reacting: (a) Compound 5a [ka] or a salt thereof (wherein Each R 2 are independently halogens), Compounds 6a and 7a [ka] or a salt thereof under suitable reaction conditions to provide compound 2a, or a pharmaceutically acceptable salt thereof, 1 independently, C 1~6an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 3- to 7-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] Generally, as defined above, each R 2 is independently halogen. In some embodiments, each R 2 is independently fluoro or chloro. In some embodiments, R 2 is fluoro). In some embodiments, R 2 is chloro.

[0052] As generally defined above, each R 1 independently, C 1~6 is an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 3- to 7-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 1 is C 1~6 is an optionally substituted group selected from aliphatic or 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R 1 is an arbitrarily substituted C 1~6 In some embodiments, R 1 is an arbitrarily substituted C 1~3 In some embodiments, R 1 is optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, or t-butyl. In some embodiments, R 1 is methyl, ethyl, n-propyl, isopropyl, or t-butyl. In some embodiments, R1 is isopropyl. In some embodiments, R 1 is an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R 1 is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0053] In some embodiments, compound 2 or a salt thereof is prepared as shown in step 1 of Scheme 5. In some embodiments, in step 1, compound 2 or a salt thereof is prepared by reacting: (a) Compound 5: [ka] or its salt Compounds 6 and 7: [ka] or its salts to provide compound 2 under suitable reaction conditions.

[0054] In some embodiments, step 1 further comprises one or more of the following compounds: [ka] or a salt thereof.

[0055] In some embodiments, step 1 is performed at a concentration of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% w / w relative to compound 2 (e.g., by HPLC or 1In some embodiments, step 1 provides a composition comprising about 1.1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or about 0.02% w / w (e.g., by HPLC or 1 In some embodiments, step 1 provides a composition comprising Compound 9 at a concentration of less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% a / a relative to Compound 2 (e.g., by HPLC or 1 In some embodiments, step 1 provides a composition comprising about 1.1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or about 0.02% w / w of Compound 9 relative to Compound 2 (e.g., by HPLC or 1 In some embodiments, step 1 provides a composition comprising compound 9, wherein compound 9 or a salt thereof is purified by (e.g., HPLC or 1 1 H NMR) is undetectable.

[0056] In some embodiments, step 1 provides a composition comprising less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (w / w HPLC) of compound 10 relative to compound 2. In some embodiments, step 1 provides a composition comprising about 0.63%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.11%, about 0.1%, about 0.08%, or about 0.05% (w / w HPLC) of compound 10 relative to compound 2. In some embodiments, step 1 provides a composition comprising less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) of compound 10 relative to compound 2. In some embodiments, step 1 provides a composition comprising about 0.63%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.11%, about 0.1%, about 0.08%, or about 0.05% (a / a HPLC) of Compound 10. ... 1 1 H NMR) is undetectable.

[0057] In some embodiments, step 1 provides a composition comprising less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (w / w HPLC) of compound 11 relative to compound 2. In some embodiments, step 1 provides a composition comprising about 1.00%, about 0.5%, about 0.1%, about 0.05%, or about 0.02% (w / w HPLC) of compound 11 relative to compound 2. In some embodiments, step 1 provides a composition comprising less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) of compound 11 relative to compound 2. In some embodiments, step 1 provides a composition comprising about 1.00%, about 0.5%, about 0.1%, about 0.05%, or about 0.02% (a / a HPLC) of compound 11. In some embodiments, step 1 provides a composition comprising about 1.00%, about 0.5%, about 0.1%, about 0.05%, or about 0.02% (a / a HPLC) of compound 11. In some embodiments, step 1 provides a composition wherein compound 11 or a salt thereof is present (e.g., by HPLC or 1 1 H NMR) is undetectable.

[0058] In some embodiments, step 1 provides a composition comprising less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (w / w HPLC) of compound 12 relative to compound 2. In some embodiments, step 1 provides a composition comprising about 1.00%, about 0.5%, about 0.1%, about 0.05%, or about 0.02% (w / w HPLC) of compound 12 relative to compound 2. In some embodiments, step 1 provides a composition comprising less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) of compound 12 relative to compound 2. In some embodiments, step 1 provides a composition comprising about 1.00%, about 0.5%, about 0.1%, about 0.05%, or about 0.02% (a / a HPLC) of compound 12. In some embodiments, step 1 provides a composition comprising about 1.00%, about 0.5%, about 0.1%, about 0.05%, or about 0.02% (a / a HPLC) of compound 12. In some embodiments, step 1 provides a composition wherein compound 12 or a salt thereof is present (e.g., by HPLC or 1 1 H NMR) is undetectable.

[0059] In some embodiments, Step 1 provides a composition shown in any one of Tables 4-1 to 4-6 in Example 4.

[0060] In some embodiments, compound 6 or a salt thereof is present in an amount of about 0.50 to 1.50 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 0.70 to 1.30 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 0.70 to 1.10 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 0.70 to 0.90 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 0.90 to 1.30 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 1.10 to 1.30 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 0.80 to 1.20 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 0.95 to 1.10 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 1.00 to 1.10 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 0.95 to 1.05 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 0.90 to 1.09 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 1.00 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 0.99, 1.00, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, or 1.09 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 1.02 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 1.04 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 6 or a salt thereof is present in an amount of about 1.06 equivalents relative to compound 5 or a salt thereof.

[0061] In some embodiments, compound 7 or a salt thereof is present in an amount of about 0.50 to 1.50 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 7 or a salt thereof is present in an amount of about 0.70 to 1.30 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 7 or a salt thereof is present in an amount of about 0.70 to 1.10 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 7 or a salt thereof is present in an amount of about 0.70 to 0.90 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 7 or a salt thereof is present in an amount of about 0.90 to 1.30 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 7 or a salt thereof is present in an amount of about 0.95 to 1.15 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 7 or a salt thereof is present in an amount of about 0.90 to 1.20 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 7 or a salt thereof is present in an amount of about 1.00 to 1.15 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 7 or a salt thereof is present in an amount of about 1.03 to 1.13 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 7 or a salt thereof is present in an amount of about 1.05 to 1.10 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 7 or a salt thereof is present in an amount of about 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, or 1.12 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 7 or a salt thereof is present in an amount of about 1.06 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 7 or a salt thereof is present in an amount of about 1.08 equivalents relative to compound 5 or a salt thereof. In some embodiments, compound 7 or a salt thereof is present in an amount of about 1.10 equivalents relative to compound 5 or a salt thereof.

[0062] In some embodiments, the reaction conditions include a solvent. In some embodiments, the solvent is or comprises acetone, acetonitrile, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, pyridine, sulfolane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, tert-butyl methyl ether, or cyclopentyl methyl ether. In some embodiments, the solvent is or comprises acetone. In some embodiments, the solvent is or comprises acetonitrile. In some embodiments, the solvent is or comprises 1,2-dimethoxyethane. In some embodiments, the solvent is or comprises N,N-dimethylformamide. In some embodiments, the solvent is or comprises N,N-dimethylacetamide. In some embodiments, the solvent is or comprises N-methylpyrrolidinone. In some embodiments, the solvent is or comprises dimethyl sulfoxide. In some embodiments, the solvent is or comprises ethyl acetate. In some embodiments, the solvent is or comprises isopropyl acetate. In some embodiments, the solvent is or comprises pyridine. In some embodiments, the solvent is or comprises sulfolane. In some embodiments, the solvent is or comprises tetrahydrofuran. In some embodiments, the solvent is or comprises 2-methyltetrahydrofuran. In some embodiments, the solvent is or comprises toluene. In some embodiments, the solvent is or comprises benzene. In some embodiments, the solvent is or comprises α,α,α-trifluorotoluene. In some embodiments, the solvent is or comprises chlorobenzene. In some embodiments, the solvent is or comprises xylene. In some embodiments, the solvent is or comprises tert-butyl methyl ether.In some embodiments, the solvent is or comprises cyclopentyl methyl ether, hi some embodiments, the solvent is or comprises 1,4-dioxane.

[0063] In some embodiments, the solvent is present in an amount of about 1.0 L / kg to about 20.0 L / kg. In some embodiments, the solvent is present in an amount of about 5.0 L / kg to about 20.0 L / kg. In some embodiments, the solvent is present in an amount of about 5.0 L / kg to about 15.0 L / kg. In some embodiments, the solvent is present in an amount of about 5.0 L / kg to about 12.0 L / kg. In some embodiments, the solvent is present in an amount of about 5.0 L / kg to about 10.0 L / kg. In some embodiments, the solvent is present in an amount of about 5.0 L / kg to about 8.0 L / kg. In some embodiments, the solvent is present in an amount of about 5.0 L / kg to about 6.0 L / kg. In some embodiments, the solvent is present in an amount of about 1.0 L / kg to about 5.0 L / kg. In some embodiments, the solvent is present in an amount of about 2.0 L / kg to about 5.0 L / kg. In some embodiments, the solvent is present in an amount of about 3.0 L / kg to about 5.0 L / kg. In some embodiments, the solvent is present in an amount of about 4.0 L / kg to about 5.0 L / kg. In some embodiments, the solvent is present in an amount of about 2.0 L / kg to about 8.0 L / kg. In some embodiments, the solvent is present in an amount of about 3.0 L / kg to about 7.0 L / kg. In some embodiments, the solvent is present in an amount of about 4.0 L / kg to about 6.0 L / kg. In some embodiments, the solvent is present in an amount of about 1.0 L / kg, 2.0 L / kg, 3.0 L / kg, 4.0 L / kg, 5.0 L / kg, 6.0 L / kg, 7 L / kg, 8 L / kg, 9 L / kg, or 10 L / kg. In some embodiments, the solvent is present in an amount of about 5.0 L / kg. In some embodiments, the solvent is present in an amount of about 4.0 L / kg. In some embodiments, the solvent is present in an amount of about 6.0 L / kg.

[0064] In some embodiments, the reaction conditions include heating to a temperature T7. In some embodiments, the temperature T7 is from about 50°C to about 150°C. In some embodiments, the temperature T7 is from about 50°C to about 130°C. In some embodiments, the temperature T7 is from about 50°C to about 110°C. In some embodiments, the temperature T7 is from about 50°C to about 100°C. In some embodiments, the temperature T7 is from about 60°C to about 150°C. In some embodiments, the temperature T7 is from about 80°C to about 150°C. In some embodiments, the temperature T7 is from about 100°C to about 150°C. In some embodiments, the temperature T7 is about 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C, or 150°C. In some embodiments, the temperature T7 is about 90°C. In some embodiments, the temperature T7 is about 95°C. In some embodiments, the temperature T7 is about 100°C. In some embodiments, the temperature T7 is about 105°C. In some embodiments, the temperature T7 is about 110°C. In some embodiments, the temperature T7 is about 115°C. In some embodiments, the temperature T7 is about 120°C.

[0065] In some embodiments, the reaction conditions include maintaining the reaction at a temperature T7 for a period of time. In some embodiments, the period is at least 12 hours. In some embodiments, the period is at least 24 hours. In some embodiments, the period is at least 48 hours. In some embodiments, the period is about 2 hours to about 20 hours. In some embodiments, the period is about 3 hours to about 20 hours. In some embodiments, the period is at least about 4 hours to about 20 hours. In some embodiments, the period is about 5 hours to about 20 hours. In some embodiments, the period is about 7.5 hours to about 20 hours. In some embodiments, the period is about 10 hours to 20 hours. In some embodiments, the period is about 11 hours to 20 hours. In some embodiments, the period is about 12 hours to 20 hours. In some embodiments, the period is about 13 hours to 20 hours. In some embodiments, the period is about 14 hours to about 20 hours. In some embodiments, the period is about 14 hours to about 19 hours. In some embodiments, the period is about 14 hours to about 18 hours. In some embodiments, the period is about 14 hours to about 17 hours. In some embodiments, the period is about 14 hours to about 16 hours. In some embodiments, the period is about 14 hours to about 15 hours.

[0066] In some embodiments, for example, after the reaction has taken place, step 1 further comprises (b) cooling the reaction mixture.

[0067] In some embodiments, after heating to temperature T7, the reaction conditions further include cooling to temperature T8. In some embodiments, temperature T8 is from about 50°C to about 110°C. In some embodiments, temperature T8 is from about 50°C to about 100°C. In some embodiments, temperature T8 is from about 50°C to about 90°C. In some embodiments, temperature T8 is from about 50°C to about 85°C. In some embodiments, temperature T8 is from about 50°C to about 80°C. In some embodiments, temperature T8 is from about 65°C to about 110°C. In some embodiments, temperature T8 is from about 75°C to about 110°C. In some embodiments, temperature T8 is from about 60°C to about 100°C. In some embodiments, temperature T8 is from about 70°C to about 90°C. In some embodiments, temperature T8 is from about 75°C to about 85°C. In some embodiments, temperature T8 is from about 75°C to about 80°C. In some embodiments, temperature T8 is about 80°C to about 85°C. In some embodiments, temperature T8 is about 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 105°C, or 110°C. In some embodiments, temperature T8 is about 80°C. In some embodiments, temperature T8 is about 75°C. In some embodiments, temperature T8 is about 85°C.

[0068] In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 2°C / hr to about 20°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 2°C / hr to about 17.5°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 2°C / hr to about 15°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 2°C / hr to about 12.5°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 2°C / hr to about 10°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 2°C / hr to about 7.5°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 5°C / hr to about 20°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 7.5°C / hr to about 20°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 10°C / hr to about 20°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 4°C / hr to about 17.5°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 4°C / hr to about 15°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 4°C / hr to about 12.5°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 5°C / hr to about 10°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 6°C / hr to about 8°C / hr. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 2.0°C / hr, 3.0°C / hr, 4.0°C / hr, 5.0°C / hr, 6.0°C / hr, 7.0°C / hr, 8.0°C / hr, 9.0°C / hr, or 10.0°C / hr. 8に Cooling. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 6.5°C / hour. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 6.5°C / hour. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 7.0°C / hour.

[0069] In some embodiments, the reaction (e.g., the presence of Compound 5 or Compound 2) is monitored for completion by HPLC. In some embodiments, the reaction is monitored for the presence of Compound 5 or Compound 2 (e.g., a / a by HPLC).

[0070] In some embodiments, the reaction is determined to be complete when less than 25% a / a of Compound 5 or a salt thereof (e.g., by HPLC) is detected. In some embodiments, the reaction is determined to be complete when less than 10% a / a of Compound 5 or a salt thereof (e.g., by HPLC) is detected. In some embodiments, the reaction is determined to be complete when less than 5% a / a of Compound 5 or a salt thereof (e.g., by HPLC) is detected. In some embodiments, the reaction is determined to be complete when less than 4% a / a of Compound 5 or a salt thereof (e.g., by HPLC) is detected. In some embodiments, the reaction is determined to be complete when less than 3% a / a of Compound 5 or a salt thereof (e.g., by HPLC) is detected. In some embodiments, the reaction is determined to be complete when less than 2% a / a of Compound 5 or a salt thereof (e.g., by HPLC) is detected. In some embodiments, the reaction is determined to be complete when less than 1% a / a of Compound 5 or a salt thereof (e.g., by HPLC) is detected.

[0071] In some embodiments, step 1 further comprises (c) crystallizing compound 2 or a salt thereof (e.g., from the reaction mixture). In some embodiments, the present disclosure recognizes that crystallization can provide a high yield and / or purity of compound 2 or a salt thereof, and / or can provide compound 2 or a salt thereof with low or undetectable levels of by-products (e.g., compounds 9, 10, 11, or 12, or salts thereof), particularly when the reaction is scaled up. Without wishing to be bound by theory, it is believed that compound 2 or a salt thereof crystallizes at a different temperature than the by-products (e.g., compounds 9, 10, 11, or 12, or salts thereof). Thus, without wishing to be bound by theory, performing crystallization at a particular temperature and / or controlling the cooling rate of the reaction can provide a high yield and / or purity of compound 2 or a salt thereof, and / or can provide compound 2 or a salt thereof with, for example, reduced or undetectable levels of by-products (e.g., compounds 9, 10, 11, or 12, or salts thereof).

[0072] In some embodiments, crystallizing Compound 2 or a salt thereof includes providing a first mixture, the first mixture comprising Compound 2 or a salt thereof and a first solvent. In some embodiments, the first mixture is provided at a temperature T8.

[0073] In some embodiments, the primary solvent is or comprises acetone, acetonitrile, dichloromethane, 1,2-dichloroethane, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, pyridine, sulfolane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, tert-butyl methyl ether, or cyclopentyl methyl ether. In some embodiments, the primary solvent is or comprises acetone. In some embodiments, the primary solvent is or comprises acetonitrile. In some embodiments, the primary solvent is or comprises dichloroethane. In some embodiments, the primary solvent is or comprises 1,2-dichloroethane. In some embodiments, the primary solvent is or comprises 1,2-dimethoxyethane. In some embodiments, the primary solvent is or comprises N,N-dimethylformamide. In some embodiments, the primary solvent is or comprises N,N-dimethylacetamide. In some embodiments, the primary solvent is or comprises N-methylpyrrolidinone. In some embodiments, the primary solvent is or comprises dimethyl sulfoxide. In some embodiments, the primary solvent is or comprises ethyl acetate. In some embodiments, the primary solvent is or comprises isopropyl acetate. In some embodiments, the solvent is or comprises pyridine. In some embodiments, the primary solvent is or comprises sulfolane. In some embodiments, the solvent is or comprises tetrahydrofuran. In some embodiments, the primary solvent is or comprises 2-methyltetrahydrofuran. In some embodiments, the primary solvent is or comprises toluene. In some embodiments, the primary solvent is benzene. In some embodiments, the primary solvent is or comprises α,α,α-trifluorotoluene.In some embodiments, the primary solvent is or comprises chlorobenzene. In some embodiments, the primary solvent is or comprises xylene. In some embodiments, the primary solvent is or comprises tert-butyl methyl ether. In some embodiments, the primary solvent is or comprises cyclopentyl methyl ether. In some embodiments, the primary solvent is or comprises 1,4-dioxane.

[0074] In some embodiments, the primary solvent is present in an amount of about 1.0 L / kg to 10.0 L / kg of solute. In some embodiments, the primary solvent is present in an amount of about 1.0 L / kg to 8.0 L / kg of solute. In some embodiments, the primary solvent is present in an amount of about 1.0 L / kg to 6.0 L / kg of solute. In some embodiments, the primary solvent is present in an amount of about 1.0 L / kg to 4.0 L / kg of solute. In some embodiments, the primary solvent is present in an amount of about 2.0 L / kg to 10.0 L / kg of solute. In some embodiments, the primary solvent is present in an amount of about 4.0 L / kg to 10 L / kg of solute. In some embodiments, the primary solvent is present in an amount of about 6.0 L / kg to 10 L / kg of solute. In some embodiments, the primary solvent is present in an amount of about 2.0 L / kg to 8.0 L / kg of solute. In some embodiments, the primary solvent is present in an amount of about 4.0 L / kg to 6.0 L / kg of solute. In some embodiments, the primary solvent is present in an amount of about 1.0 L / kg, 2.0 L / kg, 3.0 L / kg, 4.0 L / kg, 5.0 L / kg, 6.0 L / kg, 7.0 L / kg, 8.0 L / kg, 9.0 L / kg, or 10.0 L / kg. In some embodiments, the primary solvent is present in an amount of about 3.0 L / kg of solute. In some embodiments, the primary solvent is present in an amount of about 4.0 L / kg of solute. In some embodiments, the primary solvent is present in an amount of about 4.9 L / kg of solute. In some embodiments, the primary solvent is present in an amount of about 5.0 L / kg of solute. In some embodiments, the primary solvent is present in an amount of about 6.0 L / kg of solute.

[0075] In some embodiments, crystallizing Compound 2 or a salt thereof comprises adding seed crystals to the primary mixture. In some embodiments, the seed crystals are added in an amount of about 0.01 wt % to about 5.0 wt % of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.1 wt % to about 5.0 wt % of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.1 wt % to about 4.0 wt % of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.1 wt % to about 3.0 wt % of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.1 wt % to about 2.0 wt % of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.1 wt % to about 1.5 wt % of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.10 wt% to about 1.00 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.1 wt% to about 0.75 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.1 wt% to about 0.50 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.1 wt% to about 0.40 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.1 wt% to about 0.30 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.1 wt% to about 0.25 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.20 wt% to about 1.00 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.25 wt% to about 1.00 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.50 wt% to about 1.00 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.10 wt%, 0.15 wt%, 0.20 wt%, 0.25 wt%, 0.30 wt%, 0.35 wt%, 0.40 wt%, 0.45 wt%, or 0.50 wt% of Compound 5 or a salt thereof.

[0076] In some embodiments, the seed crystals are added in an amount of about 0.05 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.10 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.15 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.20 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.25 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.30 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.35 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.45 wt% of Compound 5 or a salt thereof. In some embodiments, the seed crystals are Compound 2 or a salt thereof.

[0077] In some embodiments, crystallization of Compound 2 or a salt thereof comprises cooling the primary mixture to a temperature T9. In some embodiments, the temperature T9 is from about 0°C to about 50°C. In some embodiments, the temperature T9 is from about 0°C to about 45°C. In some embodiments, the temperature T9 is from about 0°C to about 40°C. In some embodiments, the temperature T9 is from about 0°C to about 35°C. In some embodiments, the temperature T9 is from about 0°C to about 30°C. In some embodiments, the temperature T9 is from about 0°C to about 25°C. In some embodiments, the temperature T9 is from about 10°C to about 50°C. In some embodiments, the temperature T9 is from about 15°C to about 50°C. In some embodiments, the temperature T9 is from about 20°C to about 50°C. In some embodiments, the temperature T9 is from about 25°C to about 50°C. In some embodiments, the temperature T9 is from about 15°C to about 40°C. In some embodiments, the temperature T9 is from about 20°C to about 35°C. In some embodiments, temperature T9 is about 18°C ​​to about 32°C. In some embodiments, temperature T9 is about 20°C to about 35°C. In some embodiments, temperature T9 is about 25°C to about 30°C. In some embodiments, temperature T9 is about 26°C to about 28°C. In some embodiments, temperature T9 is about 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, or 32°C. In some embodiments, temperature T9 is about 24°C. In some embodiments, temperature T9 is about 25°C. In some embodiments, temperature T9 is about 26°C. In some embodiments, temperature T9 is about 27°C. In some embodiments, temperature T9 is about 29°C. In some embodiments, temperature T9 is about 30°C. In some embodiments, temperature T9 is about 31°C.

[0078] In some embodiments, the first mixture is cooled at a rate of about 2.0°C / hr to about 20°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 4.0°C / hr to about 20°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 6°C / hr to about 20°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 8°C / hr to about 20°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 2.0°C / hr to about 15°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 2.0°C / hr to about 10°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 2.0°C / hr to about 8.0°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 4.0°C / hr to about 12.0°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 5.0°C / hr to about 12.0°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 5.0°C / hr to about 10.0°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 5.0°C / hr to about 8.0°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 6.0°C / hr to about 7.0°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 2.0°C / hr, 3.0°C / hr, 4.0°C / hr, 5.0°C / hr, 6.0°C / hr, 7.0°C / hr, 8.0°C / hr, 9.0°C / hr, or 10.0°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 5.5°C / hr. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 6.0° C. / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 6.5° C. / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 7.0° C. / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 7.5° C. / hour.

[0079] In some embodiments, step 1 further comprises the step of (d) recrystallizing compound 2 or a salt thereof (e.g., from the reaction mixture). In some embodiments, the present disclosure provides the recognition that recrystallization can provide a high yield and / or purity of compound 2 or a salt thereof, and / or can provide compound 2 or a salt thereof with reduced or low levels of by-products (e.g., compounds 9, 10, 11, or 12 or salts thereof), for example, particularly when the reaction is scaled up. In some embodiments, the recrystallization conditions provided herein can provide a high yield and / or purity of compound 2 or a salt thereof, and / or can provide compound 2 or a salt thereof with reduced or undetectable levels of by-products (e.g., compounds 9, 10, 11, and / or 12 or salts thereof), for example.

[0080] In some embodiments, recrystallizing Compound 2 or a salt thereof includes (i) providing a first mixture, the first mixture comprising Compound 2 or a salt thereof and a first solvent, wherein the first solvent is as described above and herein.

[0081] In some embodiments, the primary mixture is provided at a temperature T9, where temperature T9 is as described above and herein.

[0082] In some embodiments, the primary solvent is as described above and herein.

[0083] In some embodiments, the recrystallization of compound 2 or a salt thereof further comprises (ii) adding a secondary solvent to the primary mixture to form a secondary mixture. In some embodiments, the secondary solvent is or comprises chloroform, hexane, pentane, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, the secondary solvent is or comprises chloroform. In some embodiments, the secondary solvent is or comprises hexane. In some embodiments, the secondary solvent is or comprises pentane. In some embodiments, the secondary solvent is or comprises diethyl ether. In some embodiments, the secondary solvent is or comprises ethyl acetate. In some embodiments, the secondary solvent is or comprises isopropyl acetate. In some embodiments, the secondary solvent is or comprises tert-butyl methyl ether. In some embodiments, the secondary solvent is or comprises cyclopentyl methyl ether. In some embodiments, the secondary solvent is or comprises toluene. In some embodiments, the secondary solvent is or comprises benzene. In some embodiments, the secondary solvent is or comprises α,α,α-trifluorotoluene. In some embodiments, the secondary solvent is or comprises chlorobenzene. In some embodiments, the secondary solvent is or comprises xylene. In some embodiments, the secondary solvent is or comprises dichloromethane.

[0084] In some embodiments, the secondary solvent is present in an amount of about 1 L / kg to about 20 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 2 L / kg to about 20 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 6 L / kg to about 20 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 10 L / kg to about 20 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 2 L / kg to about 18 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 2 L / kg to about 14 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 2 L / kg to about 10 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 4 L / kg to about 18 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 6 L / kg to about 14 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 8 L / kg to about 12 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 9 L / kg to about 11 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 5 L / kg, 6 L / kg, 7 L / kg, 8 L / kg, 9 L / kg, 10 L / kg, 11 L / kg, 12 L / kg, 13 L / kg, 14 L / kg, or 15 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 8 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 9 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 10 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 11 L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 12 L / kg of solute.

[0085] In some embodiments, the recrystallization of compound 2 or a salt thereof further comprises (iii) holding the secondary mixture at a temperature T9 for a period of time, and optionally stirring. In some embodiments, the secondary mixture is stirred at a temperature T9 for a period of time. In some embodiments, the period of time is at least 1 hour. In some embodiments, the period of time is at least 3 hours. In some embodiments, the period of time is at least 6 hours. In some embodiments, the period of time is about 1 hour to about 8 hours. In some embodiments, the period of time is about 2 hours to about 6 hours. In some embodiments, the period of time is about 2 hours to about 5 hours. In some embodiments, the period of time is about 2 hours to about 4 hours. In some embodiments, the period of time is about 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours. In some embodiments, the period of time is about 1 hour. In some embodiments, the period of time is about 2 hours. In some embodiments, the period of time is about 3 hours. In some embodiments, the period of time is about 4 hours. In some embodiments, the period of time is about 5 hours.

[0086] In some embodiments, step 1 further comprises (e) filtering the reaction mixture, the first mixture, or the second mixture to obtain a filtered mixture.

[0087] In some embodiments, the secondary mixture is heated to a temperature T 10 In some embodiments, the solution is filtered at a temperature T 10 In some embodiments, the temperature T 10 In some embodiments, the temperature T 10 In some embodiments, the temperature T 10 In some embodiments, the temperature T 10 In some embodiments, the temperature T 10 In some embodiments, the temperature T 10 In some embodiments, the temperature T 10In some embodiments, the temperature T 10 In some embodiments, the temperature T 10 In some embodiments, the temperature T 10 In some embodiments, the temperature T 10 In some embodiments, the temperature T 10 is about 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, or 32°C. In some embodiments, the temperature T 10 is about 24° C. In some embodiments, the temperature T 10 is about 26° C. In some embodiments, the temperature T 10 is about 27° C. In some embodiments, the temperature T 10 is about 28° C. In some embodiments, the temperature T 10 is approximately 30°C.

[0088] In some embodiments, step 1 further comprises (f) washing the (e.g., filtered or secondary) mixture to provide a final mixture.

[0089] In some embodiments, washing includes washing solvent 1. In some embodiments, washing includes adding washing solvent 1 to, for example, the filtration mixture. In some embodiments, washing solvent 1 is or includes acetone, acetonitrile, dichloromethane, 1,2-dichloroethane, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, pyridine, sulfolane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, tert-butyl methyl ether, or cyclopentyl methyl ether. In some embodiments, washing solvent 1 is or includes acetone. In some embodiments, washing solvent 1 is or includes acetonitrile. In some embodiments, washing solvent 1 is or includes dichloromethane. In some embodiments, washing solvent 1 is or includes 1,2-dichloroethane. In some embodiments, washing solvent 1 is or comprises 1,2-dimethoxyethane. In some embodiments, washing solvent 1 is or comprises N,N-dimethylformamide. In some embodiments, washing solvent 1 is or comprises N,N-dimethylacetamide. In some embodiments, washing solvent 1 is or comprises N-methylpyrrolidinone. In some embodiments, washing solvent 1 is or comprises dimethyl sulfoxide. In some embodiments, washing solvent 1 is or comprises ethyl acetate. In some embodiments, washing solvent 1 is or comprises isopropyl acetate. In some embodiments, washing solvent 1 is or comprises pyridine. In some embodiments, washing solvent 1 is or comprises sulfolane. In some embodiments, washing solvent 1 is or comprises tetrahydrofuran. In some embodiments, washing solvent 1 is or comprises 2-methyltetrahydrofuran.In some embodiments, washing solvent 1 is or comprises toluene. In some embodiments, washing solvent 1 is or comprises benzene. In some embodiments, washing solvent 1 is or comprises α,α,α-trifluorotoluene. In some embodiments, washing solvent 1 is or comprises chlorobenzene. In some embodiments, washing solvent 1 is or comprises xylene. In some embodiments, washing solvent 1 is or comprises tert-butyl methyl ether. In some embodiments, washing solvent 1 is or comprises cyclopentyl methyl ether. In some embodiments, washing solvent 1 is or comprises 1,4-dioxane. In some embodiments, washing solvent 1 is or comprises dichloromethane. In some embodiments, washing solvent 1 comprises 1,4-dioxane and dichloromethane.

[0090] In some embodiments, the amount of washing solvent 1 is 0.30 L / kg to 5.00 L / kg. In some embodiments, washing solvent 1 is in an amount of about 1.0 L / kg to about 5.00 L / kg. In some embodiments, washing solvent 1 is in an amount of about 1.50 L / kg to about 5.00 L / kg. In some embodiments, washing solvent 1 is in an amount of about 2.50 L / kg to about 5.00 L / kg. In some embodiments, washing solvent 1 is in an amount of 0.30 L / kg to 4.50 L / kg. In some embodiments, washing solvent 1 is in an amount of about 0.50 L / kg to about 3.00 L / kg. In some embodiments, washing solvent 1 is in an amount of about 0.50 L / kg to about 2.50 L / kg. In some embodiments, washing solvent 1 is in an amount of about 0.50 L / kg to about 2.00 L / kg. In some embodiments, washing solvent 1 is in an amount of about 1.50 L / kg to about 4.00 L / kg. In some embodiments, washing solvent 1 is in an amount of about 2.25 L / kg to about 3.00 L / kg. In some embodiments, washing solvent 1 is in an amount of about 2.50 L / kg to about 2.75 L / kg. In some embodiments, washing solvent 1 is in an amount of about 0.50 L / kg, 1.05 L / kg, 1.65 L / kg, 2.00 L / kg, 2.25 L / kg, 2.50 L / kg, or 2.70 L / kg. In some embodiments, washing solvent 1 is in an amount of about 0.50 L / kg. In some embodiments, washing solvent 1 is in an amount of about 1.65 L / kg. In some embodiments, washing solvent 1 is in an amount of about 2.00 L / kg. In some embodiments, washing solvent 1 is in an amount of about 2.25 L / kg. In some embodiments, Wash Solvent 1 is in an amount of about 2.50 L / kg. In some embodiments, Wash Solvent 1 is in an amount of about 2.75 L / kg.

[0091] In some embodiments, cleaning solvent 1 contains 1,4-dioxane in an amount of about 0.4 L / kg to about 1.5 L / kg. In some embodiments, cleaning solvent 1 contains 1,4-dioxane in an amount of about 0.4 L / kg to about 1.3 L / kg. In some embodiments, cleaning solvent 1 contains 1,4-dioxane in an amount of about 0.4 L / kg to about 1.0 L / kg. In some embodiments, cleaning solvent 1 contains 1,4-dioxane in an amount of about 0.6 L / kg to about 1.5 L / kg. In some embodiments, cleaning solvent 1 contains 1,4-dioxane in an amount of about 0.8 L / kg to about 1.5 L / kg. In some embodiments, cleaning solvent 1 contains 1,4-dioxane in an amount of about 0.6 L / kg to about 1.3 L / kg. In some embodiments, cleaning solvent 1 contains 1,4-dioxane in an amount of about 0.8 L / kg to about 0.9 L / kg. In some embodiments, wash solvent 1 comprises 1,4-dioxane in an amount of about 0.60 L / kg, 0.70 L / kg, 0.80 L / kg, 0.90 L / kg, or 1.00 L / kg. In some embodiments, wash solvent 1 comprises 1,4-dioxane in an amount of about 0.60 L / kg. In some embodiments, wash solvent 1 comprises 1,4-dioxane in an amount of about 0.70 L / kg. In some embodiments, wash solvent 1 comprises 1,4-dioxane in an amount of about 0.80 L / kg. In some embodiments, wash solvent 1 comprises 1,4-dioxane in an amount of about 0.90 L / kg. In some embodiments, wash solvent 1 comprises 1,4-dioxane in an amount of about 1.00 L / kg.

[0092] In some embodiments, cleaning solvent 1 comprises dichloromethane in an amount of about 1.0 L / kg to about 3.2 L / kg. In some embodiments, cleaning solvent 1 comprises dichloromethane in an amount of about 1.0 L / kg to about 3.0 L / kg. In some embodiments, cleaning solvent 1 comprises dichloromethane in an amount of about 1.0 L / kg to about 2.5 L / kg. In some embodiments, cleaning solvent 1 comprises dichloromethane in an amount of about 1.0 L / kg to about 2.0 L / kg. In some embodiments, cleaning solvent 1 comprises dichloromethane in an amount of about 1.5 L / kg to about 3.0 L / kg. In some embodiments, cleaning solvent 1 comprises dichloromethane in an amount of about 1.25 L / kg to about 2.0 L / kg. In some embodiments, cleaning solvent 1 comprises dichloromethane in an amount of about 1.5 L / kg to about 1.7 L / kg. In some embodiments, wash solvent 1 comprises dichloromethane in an amount of about 1.35 L / kg, 1.45 L / kg, 1.55 L / kg, 1.65 L / kg, 1.75 L / kg, or 1.85 L / kg. In some embodiments, wash solvent 1 comprises dichloromethane in an amount of about 1.35 L / kg. In some embodiments, wash solvent 1 comprises dichloromethane in an amount of about 1.45 L / kg. In some embodiments, wash solvent 1 comprises dichloromethane in an amount of about 1.55 L / kg. In some embodiments, wash solvent 1 comprises dichloromethane in an amount of about 1.64 L / kg. In some embodiments, wash solvent 1 comprises dichloromethane in an amount of about 1.75 L / kg.

[0093] In some embodiments, wash solvent 1 comprises 1,4-dioxane in an amount of about 0.4 L / kg to about 1.5 L / kg and dichloromethane in an amount of about 1.0 L / kg to about 3.2 L / kg. In some embodiments, wash solvent 1 comprises 1,4-dioxane in an amount of about 0.8 L / kg to about 0.9 L / kg and dichloromethane in an amount of about 1.5 L / kg to about 1.7 L / kg. In some embodiments, wash solvent 1 comprises 1,4-dioxane in an amount of about 0.60 L / kg, 0.70 L / kg, 0.80 L / kg, 0.90 L / kg, or 1.00 L / kg and dichloromethane at about 1.40 L / kg, 1.50 L / kg, 1.60 L / kg, 1.70 L / kg, or 1.80 L / kg. In some embodiments, wash solvent 1 comprises 1,4-dioxane in an amount of about 0.86 L / kg and dichloromethane in an amount of about 1.64 L / kg.

[0094] In some embodiments, washing solvent 1 is provided at about 0°C to 50°C. In some embodiments, washing solvent 1 is provided at about 0°C to 40°C. In some embodiments, washing solvent 1 is provided at about 0°C to 30°C. In some embodiments, washing solvent 1 is provided at about 10°C to 50°C. In some embodiments, washing solvent 1 is provided at about 20°C to 50°C. In some embodiments, washing solvent 1 is provided at about 30°C to 50°C. In some embodiments, washing solvent 1 is provided at about 10°C to 40°C. In some embodiments, washing solvent 1 is provided at about 18°C ​​to 32°C. In some embodiments, washing solvent 1 is provided at about 20°C to 30°C. In some embodiments, washing solvent 1 is provided at about 23°C to 27°C. In some embodiments, washing solvent 1 is provided at about 20°C, 22°C, 24°C, 25°C, 26°C, 28°C, or 30°C. In some embodiments, washing solvent 1 is provided at about 23°C. In some embodiments, Wash Solvent 1 is provided at about 25° C. In some embodiments, Wash Solvent 1 is provided at about 27° C. In some embodiments, Wash 1 includes, for example, agitating the filtered mixture. In some embodiments, Wash 1 further includes removing Wash Solvent 1.

[0095] In some embodiments, washing includes wash 2. In some embodiments, wash 2 includes adding wash solvent 2, for example, to the filtered mixture. In some embodiments, wash solvent 2 is or includes chloroform, hexane, pentane, 1,4-dioxane, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, wash solvent 2 is or includes chloroform. In some embodiments, wash solvent 2 is or includes hexane. In some embodiments, wash solvent 2 is or includes pentane. In some embodiments, wash solvent 2 is or includes diethyl ether. In some embodiments, wash solvent 2 is ethyl acetate. In some embodiments, wash solvent 2 is or includes isopropyl acetate. In some embodiments, wash solvent 2 is or includes tert-butyl methyl ether. In some embodiments, wash solvent 2 is or includes cyclopentyl methyl ether. In some embodiments, wash solvent 2 is or comprises toluene. In some embodiments, wash solvent 2 is or comprises benzene. In some embodiments, wash solvent 2 is or comprises α,α,α-trifluorotoluene. In some embodiments, wash solvent 2 is or comprises chlorobenzene. In some embodiments, wash solvent 2 is or comprises xylene. In some embodiments, wash solvent 2 is or comprises 1,4-dioxane.

[0096] In some embodiments, wash solvent 2 is provided in an amount of about 0.5 L / kg to about 5.0 L / kg. In some embodiments, wash solvent 2 is present in an amount of about 0.5 L / kg to about 4.0 L / kg. In some embodiments, wash solvent 2 is present in an amount of about 0.5 L / kg to about 3.0 L / kg. In some embodiments, wash solvent 2 is provided in an amount of about 1.0 L / kg to 5.0 L / kg. In some embodiments, wash solvent 2 is provided in an amount of about 2.5 L / kg to 5.0 L / kg. In some embodiments, wash solvent 2 is provided in an amount of about 1.0 L / kg to 4.0 L / kg. In some embodiments, wash solvent 2 is provided in an amount of about 1.0 L / kg to 3.0 L / kg. In some embodiments, wash solvent 2 is provided in an amount of about 2.0 L / kg to 2.5 L / kg. In some embodiments, wash solvent 2 is provided in an amount of about 2.3 L / kg to 2.7 L / kg. In some embodiments, wash solvent 2 is provided in an amount of about 1.0 L / kg, 1.5 L / kg, 2.0 L / kg, 2.5 L / kg, 3.0, 3.5, 4.0, 4.5, or 5.0 L / kg. In some embodiments, wash solvent 2 is present in an amount of about 2.0 L / kg. In some embodiments, wash solvent 2 is present in an amount of about 2.5 L / kg. In some embodiments, wash solvent 2 is present in an amount of about 3.0 L / kg.

[0097] In some embodiments, washing solvent 2 is provided at about 0°C to 50°C. In some embodiments, washing solvent 2 is provided at about 0°C to 40°C. In some embodiments, washing solvent 2 is provided at about 0°C to 30°C. In some embodiments, washing solvent 2 is provided at about 10°C to 50°C. In some embodiments, washing solvent 2 is provided at about 20°C to 50°C. In some embodiments, washing solvent 2 is provided at about 30°C to 50°C. In some embodiments, washing solvent 2 is provided at about 10°C to 40°C. In some embodiments, washing solvent 2 is provided at about 18°C ​​to 32°C. In some embodiments, washing solvent 2 is provided at about 20°C to 30°C. In some embodiments, washing solvent 2 is provided at about 23°C to 27°C. In some embodiments, washing solvent 2 is provided at about 20°C, 22°C, 24°C, 25°C, 26°C, 28°C, or 30°C. In some embodiments, washing solvent 2 is provided at about 23°C. In some embodiments, Wash Solvent 2 is provided at about 25° C. In some embodiments, Wash Solvent 2 is provided at about 27° C. In some embodiments, Wash 2 includes, for example, agitating the filtered mixture. In some embodiments, Wash 2 further includes removing Wash Solvent 2.

[0098] In some embodiments, wash 3 includes wash 3 or wash 4. In some embodiments, wash 3 or wash 4 is the same as wash 2. In some embodiments, wash 3 includes adding wash solvent 3, for example, to the filtration mixture. In some embodiments, wash solvent 3 is or includes chloroform, hexane, pentane, 1,4-dioxane, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, wash solvent 3 is or includes chloroform. In some embodiments, wash solvent 3 is or includes hexane. In some embodiments, wash solvent 3 is or includes pentane. In some embodiments, wash solvent 3 is or includes diethyl ether. In some embodiments, wash solvent 3 is or includes ethyl acetate. In some embodiments, wash solvent 3 is or includes isopropyl acetate. In some embodiments, wash solvent 3 is or includes tert-butyl methyl ether. In some embodiments, washing solvent 3 is or comprises cyclopentyl methyl ether. In some embodiments, washing solvent 3 is or comprises toluene. In some embodiments, washing solvent 3 is or comprises benzene. In some embodiments, washing solvent 3 is or comprises α,α,α-trifluorotoluene. In some embodiments, washing solvent 3 is or comprises xylene. In some embodiments, washing solvent 3 is or comprises chlorobenzene. In some embodiments, washing solvent 3 is or comprises 1,4-dioxane.

[0099] In some embodiments, the wash solvent 3 is provided in an amount of about 0.5 L / kg to 5.0 L / kg. In some embodiments, the wash solvent 3 is provided in an amount of about 0.5 L / kg to 4.0 L / kg. In some embodiments, the wash solvent 3 is provided in an amount of about 0.5 L / kg to 3.0 L / kg. In some embodiments, the wash solvent 3 is provided in an amount of about 1.0 L / kg to 5.0 L / kg. In some embodiments, the wash solvent 3 is provided in an amount of about 2.5 L / kg to 5.0 L / kg. In some embodiments, the wash solvent 3 is provided in an amount of about 1.0 L / kg to 4.0 L / kg. In some embodiments, the wash solvent 3 is provided in an amount of about 1.0 L / kg to 3.0 L / kg. In some embodiments, the wash solvent 3 is provided in an amount of about 1.5 L / kg to 3.0 L / kg. In some embodiments, the wash solvent 3 is provided in an amount of about 2.0 L / kg to 2.8 L / kg. In some embodiments, wash solvent 3 is provided in an amount of about 2.3 L / kg to 2.7 L / kg. In some embodiments, wash solvent 3 is provided in an amount of about 1.0 L / kg, 1.5 L / kg, 2.0 L / kg, 2.5 L / kg, or 3.0 L / kg. In some embodiments, wash solvent 3 is present in an amount of about 2.0 L / kg. In some embodiments, wash solvent 3 is present in an amount of about 2.5 L / kg. In some embodiments, wash solvent 3 is present in an amount of about 3.0 L / kg.

[0100] In some embodiments, washing solvent 3 is provided at about 0°C to 50°C. In some embodiments, washing solvent 3 is provided at about 0°C to 40°C. In some embodiments, washing solvent 3 is provided at about 0°C to 30°C. In some embodiments, washing solvent 3 is provided at about 10°C to 50°C. In some embodiments, washing solvent 3 is provided at about 20°C to 50°C. In some embodiments, washing solvent 3 is provided at about 30°C to 50°C. In some embodiments, washing solvent 3 is provided at about 10°C to 40°C. In some embodiments, washing solvent 3 is provided at about 20°C to 30°C. In some embodiments, washing solvent 3 is provided at about 22°C to 28°C. In some embodiments, washing solvent 3 is provided at about 24°C to 26°C. In some embodiments, washing solvent 3 is provided at about 20°C, 22°C, 24°C, 25°C, 26°C, 28°C, or 30°C. In some embodiments, washing solvent 3 is provided at about 25°C. In some embodiments, Wash 3 includes, for example, agitating the filtered mixture. In some embodiments, Wash 3 further includes removing Wash Solvent 3.

[0101] In some embodiments, washing 4 comprises adding a washing solvent 4, for example, to the filtered mixture. In some embodiments, washing solvent 4 is or comprises chloroform, hexane, pentane, 1,4-dioxane, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, washing solvent 4 is or comprises chloroform. In some embodiments, washing solvent 4 is or comprises hexane. In some embodiments, washing solvent 4 is or comprises pentane. In some embodiments, washing solvent 4 is or comprises diethyl ether. In some embodiments, washing solvent 4 is or comprises ethyl acetate. In some embodiments, washing solvent 4 is or comprises isopropyl acetate. In some embodiments, washing solvent 4 is or comprises tert-butyl methyl ether. In some embodiments, washing solvent 4 is or comprises cyclopentyl methyl ether. In some embodiments, washing solvent 4 is or comprises toluene. In some embodiments, washing solvent 4 is or comprises benzene. In some embodiments, washing solvent 4 is or comprises α,α,α-trifluorotoluene. In some embodiments, washing solvent 4 is or comprises chlorobenzene. In some embodiments, washing solvent 4 is or comprises xylene. In some embodiments, washing solvent 4 is or comprises 1,4-dioxane.

[0102] In some embodiments, the wash solvent 4 is provided in an amount of about 0.5 L / kg to 5.0 L / kg. In some embodiments, the wash solvent 4 is provided in an amount of about 0.5 L / kg to 4.0 L / kg. In some embodiments, the wash solvent 4 is provided in an amount of about 0.5 L / kg to 3.0 L / kg. In some embodiments, the wash solvent 4 is provided in an amount of about 1.0 L / kg to 5.0 L / kg. In some embodiments, the wash solvent 4 is provided in an amount of about 2.5 L / kg to 5.0 L / kg. In some embodiments, the wash solvent 4 is provided in an amount of about 1.0 L / kg to 4.0 L / kg. In some embodiments, the wash solvent 4 is provided in an amount of about 1.0 L / kg to 3.0 L / kg. In some embodiments, the wash solvent 4 is provided in an amount of about 1.5 L / kg to 3.0 L / kg. In some embodiments, the wash solvent 4 is provided in an amount of about 2.0 L / kg to 2.8 L / kg. In some embodiments, wash solvent 4 is provided in an amount of about 2.3 L / kg to 2.7 L / kg. In some embodiments, wash solvent 4 is provided in an amount of about 2.4 L / kg to 2.5 L / kg. In some embodiments, wash solvent 4 is provided in an amount of about 1.0 L / kg, 1.5 L / kg, 2.0 L / kg, 2.5 L / kg, or 3.0 L / kg. In some embodiments, wash solvent 4 is present in an amount of about 2.0 L / kg. In some embodiments, wash solvent 4 is present in an amount of about 2.5 L / kg. In some embodiments, wash solvent 4 is present in an amount of about 3.0 L / kg.

[0103] In some embodiments, the wash solvent 4 is provided at about 0°C to 50°C. In some embodiments, the wash solvent 4 is provided at about 0°C to 40°C. In some embodiments, the wash solvent 4 is provided at about 0°C to 30°C. In some embodiments, the wash solvent 4 is provided at about 10°C to 20°C. In some embodiments, the wash solvent 4 is provided at about 20°C to 50°C. In some embodiments, the wash solvent 4 is provided at about 30°C to 50°C. In some embodiments, the wash solvent 4 is provided at about 10°C to 40°C. In some embodiments, the wash solvent 4 is provided at about 18°C ​​to 32°C. In some embodiments, the wash solvent 4 is provided at about 20°C to 30°C. In some embodiments, the wash solvent 4 is provided at about 23°C to 27°C. In some embodiments, the wash solvent 4 is provided at about 20°C, 22°C, 24°C, 25°C, 26°C, 28°C, or 30°C. In some embodiments, the wash solvent 4 is provided at about 25°C. In some embodiments, Wash 4 includes, for example, agitating the filtered mixture. In some embodiments, Wash 4 further includes removing Wash Solvent 4.

[0104] In some embodiments, washing comprises Wash 5. In some embodiments, Wash 5 comprises adding a wash solvent 5, for example, to the filtered mixture. In some embodiments, wash solvent 5 is or comprises chloroform, hexane, pentane, 1,4-dioxane, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, wash solvent 5 is or comprises chloroform. In some embodiments, wash solvent 5 is or comprises hexane. In some embodiments, wash solvent 5 is or comprises pentane. In some embodiments, wash solvent 5 is or comprises diethyl ether. In some embodiments, wash solvent 5 is or comprises ethyl acetate. In some embodiments, wash solvent 5 is or comprises isopropyl acetate. In some embodiments, wash solvent 5 is or comprises cyclopentyl methyl ether. In some embodiments, wash solvent 5 is or comprises toluene. In some embodiments, washing solvent 5 is or comprises benzene. In some embodiments, washing solvent 5 is or comprises α,α,α-trifluorotoluene. In some embodiments, washing solvent 5 is or comprises chlorobenzene. In some embodiments, washing solvent 5 is or comprises xylene. In some embodiments, washing solvent 5 is or comprises tert-butyl methyl ether.

[0105] In some embodiments, the wash solvent 5 is provided at 0.5 L / kg to 4.0 L / kg. In some embodiments, the wash solvent 5 is provided in an amount of about 0.5 L / kg to 3.0 L / kg. In some embodiments, the wash solvent 5 is provided in an amount of about 0.5 L / kg to 2.0 L / kg. In some embodiments, the wash solvent 5 is provided at 1.0 L / kg to 4.0 L / kg. In some embodiments, the wash solvent 5 is provided at 1.5 L / kg to 4.0 L / kg. In some embodiments, the wash solvent 5 is provided at 2.0 L / kg to 4.0 L / kg. In some embodiments, the wash solvent 5 is provided at 1.5 L / kg to 2.5 L / kg. In some embodiments, the wash solvent 5 is provided at 1.8 L / kg to 2.2 L / kg. In some embodiments, wash solvent 5 is provided in an amount of about 1.0 L / kg, 1.5 L / kg, 2.0 L / kg, 2.5 L / kg, 3.0, 3.5, or 4.0 L / kg. In some embodiments, wash solvent 5 is present in an amount of about 1.5 L / kg. In some embodiments, wash solvent 5 is present in an amount of about 2.0 L / kg. In some embodiments, wash solvent 5 is present in an amount of about 2.5 L / kg.

[0106] In some embodiments, the washing solvent 5 is provided at about 0°C to 50°C. In some embodiments, the washing solvent 5 is provided at about 0°C to 40°C. In some embodiments, the washing solvent 5 is provided at about 0°C to 30°C. In some embodiments, the washing solvent 5 is provided at about 20°C to 50°C. In some embodiments, the washing solvent 5 is provided at about 30°C to 50°C. In some embodiments, the washing solvent 5 is provided at about 10°C to 40°C. In some embodiments, the washing solvent 5 is provided at about 18°C ​​to 32°C. In some embodiments, the washing solvent 5 is provided at about 20°C to 30°C. In some embodiments, the washing solvent 5 is provided at about 23°C to 37°C. In some embodiments, the washing solvent 5 is provided at about 20°C, 22°C, 24°C, 25°C, 26°C, 28°C, or 30°C. In some embodiments, the washing solvent 5 is provided at about 25°C. In some embodiments, washing 5 comprises, for example, agitating the filtered mixture. In some embodiments, washing 5 further comprises removing the washing solvent 5 .

[0107] In some embodiments, washing comprises Wash 6. In some embodiments, Wash 6 comprises adding Wash Solvent 6, for example, to the filtered mixture. In some embodiments, Wash Solvent 6 is or comprises pentane, hexane, or heptane. In some embodiments, Wash Solvent 6 is or comprises n-pentane, n-hexane, or n-heptane. In some embodiments, Wash Solvent 6 is or comprises pentane. In some embodiments, Wash Solvent 6 is or comprises n-pentane. In some embodiments, Wash Solvent 6 is or comprises hexane. In some embodiments, Wash Solvent 6 is or comprises n-hexane. In some embodiments, Wash Solvent 6 is or comprises heptane. In some embodiments, Wash Solvent 6 is or comprises n-heptane.

[0108] In some embodiments, wash solvent 6 is provided at 0.5 L / kg to 4.0 L / kg. In some embodiments, wash solvent 6 is provided at 0.5 L / kg to 3.0 L / kg. In some embodiments, wash solvent 6 is provided at 1.0 L / kg to 4.0 L / kg. In some embodiments, wash solvent 6 is provided at 1.5 L / kg to 4.0 L / kg. In some embodiments, wash solvent 6 is provided at 2.0 L / kg to 4.0 L / kg. In some embodiments, wash solvent 6 is provided at 2.25 L / kg to 3.0 L / kg. In some embodiments, wash solvent 6 is provided at 2.3 L / kg to 2.75 L / kg. In some embodiments, wash solvent 6 is provided in an amount of about 1.0 L / kg, 1.5 L / kg, 2.0 L / kg, 2.5 L / kg, or 3.0 L / kg. In some embodiments, wash solvent 6 is present in an amount of about 2.0 L / kg. In some embodiments, the wash solvent 6 is present in an amount of about 2.5 L / kg. In some embodiments, the wash solvent 6 is present in an amount of about 3.0 L / kg.

[0109] In some embodiments, the washing solvent 6 is provided at about 0°C to 50°C. In some embodiments, the washing solvent 6 is provided at about 0°C to 40°C. In some embodiments, the washing solvent 6 is provided at about 0°C to 30°C. In some embodiments, the washing solvent 6 is provided at about 10°C to 20°C. In some embodiments, the washing solvent 6 is provided at about 20°C to 50°C. In some embodiments, the washing solvent 6 is provided at about 30°C to 50°C. In some embodiments, the washing solvent 6 is provided at about 10°C to 40°C. In some embodiments, the washing solvent 6 is provided at about 18°C ​​to 32°C. In some embodiments, the washing solvent 6 is provided at about 20°C to 30°C. In some embodiments, the washing solvent 6 is provided at about 23°C to 27°C. In some embodiments, the washing solvent 6 is provided at about 20°C, 22°C, 24°C, 25°C, 26°C, 28°C, or 30°C. In some embodiments, the washing solvent 6 is provided at about 25°C. In some embodiments, washing 6 includes, for example, agitating the filtered mixture. In some embodiments, washing 6 further includes removing washing solvent 6.

[0110] In some embodiments, step 1 further comprises (g) dehydrating, drying, and / or isolating compound 2 or a salt thereof.

[0111] Step 2 In some embodiments, the present disclosure provides compound 3a: [ka] or a salt thereof, wherein R 1 and R 2 , P.G. 1 , and X are as defined and described herein.

[0112] In some embodiments, the present disclosure provides compound 3: [ka] or a salt thereof.

[0113] As shown in Schemes 4 and 5, Step 2 is the second of three steps for preparing maribavir disclosed herein. Any by-products formed in Step 2 may be present in the provided composition and may further react to form additional by-products and / or reduce the overall yield or quality of maribavir. In some embodiments, the present disclosure provides methods for preparing compound 3, or a salt thereof, with reduced and / or low levels of impurities.

[0114] In some embodiments, the present disclosure provides a method for producing a compound of formula (I) comprising administering to a subject a compound of formula (I) ... or a salt thereof, and [ka] or a salt thereof.

[0115] It will be understood that compound 14 may exist in a mixture of α and β isomers, with the β isomer predominating, and compound 15 may be a mixture of four stereoisomers: β,β isomer, α,β isomer, β,α isomer, and α,α isomer.

[0116] In some embodiments, provided compositions comprise compound 3 or a salt thereof, and compounds 2, 8, 13, 14, and / or 15 or a salt thereof in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions comprise compound 3 or a salt thereof, and compounds 2, 8, 13, 14, and / or 15 or a salt thereof in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir.

[0117] In some embodiments, provided compositions include compound 3 or a salt thereof, and compounds 13, 14, and / or 15 or salts thereof in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions include compound 3 or a salt thereof, and compounds 13, 14, and / or 15 or salts thereof in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir.

[0118] In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 2 or a salt thereof. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 2 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 2 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 2 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. 1 1 H NMR).

[0119] In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 8 or a salt thereof. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 8 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 8 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 8 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. 1 1 H NMR).

[0120] In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 13 or a salt thereof. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 13 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 13 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 13 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. 1 1 H NMR).

[0121] In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 14 or a salt thereof. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 14 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 14 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 14 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. 1H NMR). In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 15 or a salt thereof. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 15 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 15 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. In some embodiments, provided compositions comprise Compound 3 or a salt thereof, and Compound 15 or a salt thereof, in an amount of less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. 1 1 H NMR).

[0122] In some embodiments, such compositions comprising compound 3 or a salt thereof are prepared as described herein. In some embodiments, the present disclosure also provides the recognition that certain reagents (and amounts thereof) and / or reaction conditions may provide compound 3 or a salt thereof of improved quality (e.g., with high purity and / or minimal by-products) and / or may improve the yield of compound 3 or a salt thereof. In some embodiments, such improvements in the yield or quality of compound 3 or a salt thereof may also improve the yield or quality of maribavir. Without wishing to be bound by theory, the present disclosure provides the recognition that the incorporation of crystallization (e.g., including salt formation) into Step 2 may improve the yield and / or reduce the formation of by-products (e.g., compounds 2, 8, 13, 14, and / or 15, or salts thereof).

[0123] In some embodiments, compound 3a or a salt thereof is prepared as shown in step 2 of Scheme 4. In some embodiments, in step 2, compound 3a or a salt thereof is prepared by reacting: (a) Compound 2a: [ka] or a salt thereof (wherein Each R 1 and R 2 is defined above and as described herein), and Compound 8a: [ka] or a salt thereof (wherein Each PG 1 are independently suitable oxygen protecting groups), under suitable reaction conditions to provide compound 3a or a salt thereof.

[0124] Generally, as defined above, each PG 1 are independently suitable oxygen protecting groups. A variety of methods and conditions for protecting and deprotecting alcohols are known in the chemical arts. For example, suitable protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Green and P.G.M. Butts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference in its entirety. In some embodiments, PG 1is acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl ether (MEM), dimethoxytrityl (DMT), methoxymethyl ether (MOM), methoxytrityl (MMT), p-methoxybenzyl ether (PMB), p-methoxyphenyl ether (PMP), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), tetrahydrofuran (THF), silyl ether (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), tri-isopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethyl), methyl ether, or ethoxyethyl ether. In some embodiments, each PG 1 are the same. In some embodiments, each PG 1 is acetyl (Ac).

[0125] In some embodiments, X represents a salt of compound 3a. Suitable salts are well known in the art; see, for example, generally, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M.B. Smith and J. March, 5th Edition, John Wiley & Sons, 2001. In some embodiments, X is camphorsulfonic acid (CSA), benzenesulfonic acid (PhSO3H), methanesulfonic acid (MsOH), toluenesulfonic acid (TsOH), 1,5-naphthalenedisulfonic acid (napsylic acid), 1,2-ethanedisulfonic acid (edisic acid), ethanesulfonic acid (esic acid), 4-chlorobenzenesulfonic acid (closic acid), 6,7-dihydroxycoumarin-4-methanesulfonic acid (cromesic acid), or trifluoromethanesulfonic acid (HOTf) salt. In some embodiments, X is HF, HCl, HBr, or HI. In some embodiments, X is HCl. In some embodiments, X is HBr.

[0126] In some embodiments, compound 3 or a salt thereof is prepared as shown in step 2 of Scheme 5. In some embodiments, in step 2, compound 3 or a salt thereof is prepared by reacting: (a) Compound 2: [ka] or a salt thereof, and Compound 8: [ka] or a salt thereof, under suitable reaction conditions to provide compound 3 or a salt thereof.

[0127] In some embodiments, step 2 comprises reacting the compound: [ka] and one or more salts thereof.

[0128] In some embodiments, step 2 provides a composition comprising less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (w / w HPLC) of Compound 2 relative to Compound 3. In some embodiments, step 2 provides a composition comprising about 0.12%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.05%, or about 0.02% (w / w HPLC) of Compound 2 relative to Compound 3. In some embodiments, step 2 provides a composition comprising less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) of Compound 2 relative to Compound 3. In some embodiments, step 2 provides a composition comprising about 0.12%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.05%, or about 0.02% (a / a HPLC) of compound 2 relative to compound 3. ... 1 1 H NMR) is undetectable.

[0129] In some embodiments, step 2 provides a composition comprising less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (w / w HPLC) of compound 8 relative to compound 3. In some embodiments, step 2 provides a composition comprising about 1%, about 0.75%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or about 0.02% (w / w HPLC) of compound 8 relative to compound 3. In some embodiments, step 2 provides a composition comprising less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) of compound 8 relative to compound 3. In some embodiments, step 2 provides a composition comprising about 1%, about 0.75%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or about 0.02% (a / a HPLC) of compound 8 relative to compound 3. ... 1 1 H NMR) is undetectable.

[0130] In some embodiments, step 2 provides a composition comprising less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (w / w HPLC) of compound 13 relative to compound 3. In some embodiments, step 2 provides a composition comprising about 1%, about 0.75%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or about 0.02% (w / w HPLC) of compound 13 relative to compound 3. In some embodiments, step 2 provides a composition comprising less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) of compound 13 relative to compound 3. In some embodiments, step 2 provides a composition comprising about 1%, about 0.75%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or about 0.02% (a / a HPLC) of compound 13 relative to compound 3. In some embodiments, step 2 provides a composition comprising less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, ... 1 1 H NMR) is undetectable.

[0131] In some embodiments, step 2 provides a composition comprising less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (w / w HPLC) of compound 14 relative to compound 3. In some embodiments, step 2 provides a composition comprising about 1%, about 0.75%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or about 0.02% (w / w HPLC) of compound 14 relative to compound 3. In some embodiments, step 2 provides a composition comprising less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) of compound 14 relative to compound 3. In some embodiments, step 2 provides a composition comprising about 1%, about 0.75%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or about 0.02% (a / a HPLC) of compound 14 relative to compound 3. In some embodiments, step 2 provides a composition comprising compound 14 or a salt thereof (e.g., by HPLC or 1 1 H NMR) is undetectable.

[0132] In some embodiments, step 2 provides a composition comprising less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (w / w HPLC) of compound 15 relative to compound 3. In some embodiments, step 2 provides a composition comprising about 1%, about 0.75%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or about 0.02% (w / w HPLC) of compound 15 relative to compound 3. In some embodiments, step 2 provides a composition comprising less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.02% (a / a HPLC) of compound 15 relative to compound 3. In some embodiments, step 2 provides a composition comprising about 1%, about 0.75%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or about 0.02% (a / a HPLC) of compound 15 relative to compound 3. In some embodiments, step 2 provides a composition comprising less than 7%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.4%, ... 1 1 H NMR) is undetectable.

[0133] In some embodiments, Step 2 provides a composition shown in any one of Tables 4-7 to 4-11 of Example 4.

[0134] In some embodiments, step 2 provides compound 3 as a camphorsulfonic acid (CSA), benzenesulfonic acid (PhSO3H), methanesulfonic acid (MsOH), toluenesulfonic acid (TsOH), 1,5-naphthalenedisulfonic acid (napsylic acid), 1,2-ethanedisulfonic acid (edisic acid), ethanesulfonic acid (esic acid), 4-chlorobenzenesulfonic acid (closic acid), 6,7-dihydroxycoumarin-4-methanesulfonic acid (cromesic acid), or trifluoromethanesulfonic acid (HOTf) salt. In some embodiments, step 2 provides compound 3 as a hydrogen halide salt. In some embodiments, step 2 provides compound 3 as an HCl salt. In some embodiments, step 2 provides compound 3 as an HBr salt.

[0135] In some embodiments, compound 2 or a salt thereof is provided in an amount of about 0.50 to 1.50 equivalents relative to compound 8 or a salt thereof. In some embodiments, compound 2 or a salt thereof is provided in an amount of about 0.75 to 1.25 equivalents relative to compound 8 or a salt thereof. In some embodiments, compound 2 or a salt thereof is provided in an amount of about 0.90 to 1.51 equivalents relative to compound 8 or a salt thereof. In some embodiments, compound 2 or a salt thereof is provided in an amount of about 0.99 to 1.01 equivalents relative to compound 8 or a salt thereof. In some embodiments, compound 2 or a salt thereof is provided in an amount of about 0.90, 0.95, 1.0, 1.05, or 1.10 equivalents relative to compound 8 or a salt thereof. In some embodiments, compound 2 or a salt thereof is provided in an amount of about 0.90 equivalents relative to compound 8 or a salt thereof. In some embodiments, compound 2 or a salt thereof is provided in an amount of about 0.95 equivalents relative to compound 8 or a salt thereof. In some embodiments, compound 2 or a salt thereof is provided in an amount of about 1.0 equivalent relative to compound 8 or a salt thereof. In some embodiments, Compound 2 or a salt thereof is provided in an amount of about 1.05 equivalents relative to Compound 8 or a salt thereof. In some embodiments, Compound 2 or a salt thereof is provided in an amount of about 1.10 equivalents relative to Compound 8 or a salt thereof.

[0136] In some embodiments, compound 8 or a salt thereof is provided in an amount of about 0.50 to 2.0 equivalents relative to compound 2 or a salt thereof. In some embodiments, compound 8 or a salt thereof is provided in an amount of about 1.00 to 1.50 equivalents relative to compound 2 or a salt thereof. In some embodiments, compound 8 or a salt thereof is provided in an amount of about 1.10 to 1.40 equivalents relative to compound 2 or a salt thereof. In some embodiments, compound 8 or a salt thereof is provided in an amount of about 1.1, 1.2, 1.3, 1.4, or 1.5 equivalents relative to compound 2 or a salt thereof. In some embodiments, compound 8 or a salt thereof is provided in an amount of about 1.0 equivalent relative to compound 2 or a salt thereof. In some embodiments, compound 8 or a salt thereof is provided in an amount of about 1.1 equivalents relative to compound 2 or a salt thereof. In some embodiments, compound 8 or a salt thereof is provided in an amount of about 1.2 equivalents relative to compound 2 or a salt thereof. In some embodiments, compound 8 or a salt thereof is provided in an amount of about 1.3 equivalents relative to compound 2 or a salt thereof. In some embodiments, compound 8 or a salt thereof is provided in an amount of about 1.4 equivalents relative to compound 2 or a salt thereof.

[0137] In some embodiments, the reaction conditions include a solvent. In some embodiments, the solvent is or includes acetone, acetonitrile, dichloromethane, 1,2-dichloroethane, 1,2-dimethoxyethane, 1,4-dioxane, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, tert-butyl methyl ether, or cyclopentyl methyl ether. In some embodiments, the solvent is or includes acetone. In some embodiments, the solvent is or includes acetonitrile. In some embodiments, the solvent is or includes dichloromethane. In some embodiments, the solvent is or includes 1,2-dichloroethane. In some embodiments, the solvent is or includes 1,2-dimethoxyethane. In some embodiments, the solvent is or includes isopropyl acetate. In some embodiments, the solvent is or includes tetrahydrofuran. In some embodiments, the solvent is or includes 2-methyltetrahydrofuran. In some embodiments, the solvent is or includes toluene. In some embodiments, the solvent is or comprises benzene. In some embodiments, the solvent is or comprises α,α,α-trifluorotoluene. In some embodiments, the solvent is or comprises chlorobenzene. In some embodiments, the solvent is or comprises xylene. In some embodiments, the solvent is or comprises tert-butyl methyl ether. In some embodiments, the solvent is or comprises cyclopentyl methyl ether. In some embodiments, the solvent is or comprises 1,4-dioxane. In some embodiments, the solvent is ethyl acetate.

[0138] In some embodiments, the solvent is present in an amount of about 2.8 kg / kg to about 16.0 kg / kg. In some embodiments, the solvent is present in an amount of about 2.8 kg / kg to about 14.0 kg / kg. In some embodiments, the solvent is present in an amount of about 2.8 kg / kg to about 10.0 kg / kg. In some embodiments, the solvent is present in an amount of about 2.8 kg / kg to about 8.0 kg / kg. In some embodiments, the solvent is present in an amount of about 3.6 kg / kg to about 10.0 kg / kg. In some embodiments, the solvent is present in an amount of about 4.4 kg / kg to about 10.0 kg / kg. In some embodiments, the solvent is present in an amount of about 5.2 kg / kg to about 10.0 kg / kg. In some embodiments, the solvent is present in an amount of about 5.2 kg / kg to about 8.0 kg / kg. In some embodiments, the solvent is present in an amount of about 5.5 kg / kg to about 7.5 kg / kg. In some embodiments, the solvent is present in an amount of about 6.0 kg / kg to about 7.4 kg / kg. In some embodiments, the solvent is present in an amount of about 6.5 kg / kg to about 7.3 kg / kg. In some embodiments, the solvent is present in an amount of about 6.0 kg / kg to about 7.5 kg / kg. In some embodiments, the solvent is present in an amount of about 6.5 kg / kg, 6.6 kg / kg, 6.7 kg / kg, 6.8 kg / kg, 6.89 kg / kg, 7.0 kg / kg, 7.1 kg / kg, or 7.2 kg / kg. In some embodiments, the solvent is present in an amount of about 6.7 kg / kg. In some embodiments, the solvent is present in an amount of about 6.8 kg / kg. In some embodiments, the solvent is present in an amount of about 6.89 kg / kg. In some embodiments, the solvent is present in an amount of about 7.0 kg / kg. In some embodiments, the solvent is present in an amount of about 7.1 kg / kg.

[0139] In one embodiment, the reaction conditions include a drying agent. In some embodiments, the drying agent is or comprises N,O-bis(trimethylsilyl)-acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)acetamide, or molecular sieves. In some embodiments, the drying agent is or comprises N,O-bis(trimethylsilyl)-acetamide. In some embodiments, the drying agent is or comprises N,O-bis(trimethylsilyl)-trifluoroacetamide. In some embodiments, the solvent is or comprises N-(trimethylsilyl)acetamide. In some embodiments, the drying agent is or comprises molecular sieves.

[0140] In some embodiments, the desiccant is present in an amount of about 0.25 to about 1.50 equivalents. In some embodiments, the desiccant is present in an amount of about 0.55 to about 1.25 equivalents. In some embodiments, the desiccant is present in an amount of about 0.25 to about 1.00 equivalents. In some embodiments, the desiccant is present in an amount of about 0.25 to about 0.75 equivalents. In some embodiments, the desiccant is present in an amount of about 0.50 to about 1.00 equivalents. In some embodiments, the desiccant is present in an amount of about 0.45 to about 0.75 equivalents. In some embodiments, the desiccant is present in an amount of about 0.50 to about 0.65 equivalents. In some embodiments, the desiccant is present in an amount of about 0.55 to about 0.63 equivalents. In some embodiments, the desiccant is present in an amount of about 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, or 0.65 equivalents. In some embodiments, the desiccant is present in an amount of about 0.56 equivalents. In some embodiments, the desiccant is present in an amount of about 0.58 equivalents. In some embodiments, the desiccant is present in an amount of about 0.59 equivalents. In some embodiments, the desiccant is present in an amount of about 0.593 equivalents. In some embodiments, the desiccant is present in an amount of about 0.60 equivalents. In some embodiments, the desiccant is present in an amount of about 0.62 equivalents. In some embodiments, the desiccant is present in an amount of about 0.65 equivalents.

[0141] In some embodiments, the reaction conditions include stirring for a period of time. In some embodiments, the reaction is stirred for about 25 minutes to about 5 days. In some embodiments, the reaction is stirred for about 25 minutes to about 1 day. In some embodiments, the reaction is stirred for about 25 minutes to about 12 hours. In some embodiments, the reaction is stirred for about 25 minutes to about 6 hours. In some embodiments, the reaction is stirred for about 25 minutes to about 3 hours. In some embodiments, the reaction is stirred for at least 15 minutes. In some embodiments, the reaction is stirred for about 25 minutes. In some embodiments, the reaction is stirred for about 45 minutes. In some embodiments, the reaction is stirred for at least 60 minutes. In some embodiments, the reaction is stirred for about 120 minutes.

[0142] In some embodiments, the deprotection reaction conditions include a solvent. In some embodiments, the catalyst is or includes tert-butyldimethylsilyl triflate, triethylsilyl triflate, or trimethylsilyl triflate. In some embodiments, the catalyst is or includes tert-butyldimethylsilyl triflate. In some embodiments, the catalyst is or includes triethylsilyl triflate. In some embodiments, the catalyst is or includes trimethylsilyl triflate.

[0143] In some embodiments, the catalyst is present in a catalytic amount. In some embodiments, the catalyst is present in an amount of about 0.05 to about 0.90 equivalents relative to compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.05 to about 0.80 equivalents relative to compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.05 to about 0.70 equivalents relative to compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.05 to about 0.60 equivalents relative to compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.05 to 0.50 equivalents relative to compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.05 to 0.40 equivalents relative to compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.10 to about 0.60 equivalents relative to compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.20 to about 0.60 equivalents relative to compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.30 to about 0.60 equivalents relative to Compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.25 to 0.40 equivalents relative to Compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.30 to about 0.38 equivalents relative to Compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.32 to about 0.366 equivalents relative to Compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.34 to about 0.35 equivalents relative to Compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, or 0.38 equivalents relative to Compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.32 equivalents relative to Compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.33 equivalents relative to Compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.34 equivalents relative to Compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.349 equivalents relative to Compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.35 equivalents relative to Compound 2 or its salt.In some embodiments, the catalyst is present in an amount of about 0.36 equivalents relative to Compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.37 equivalents relative to Compound 2 or its salt. In some embodiments, the catalyst is present in an amount of about 0.38 equivalents relative to Compound 2 or its salt.

[0144] In some embodiments, suitable reaction conditions are at a temperature T a In some embodiments, the method comprises providing compounds 2 and 8 at a temperature T a In some embodiments, the temperature T a In some embodiments, the temperature T a In some embodiments, the temperature T a In some embodiments, the temperature T a In some embodiments, the temperature T a In some embodiments, the temperature T a In some embodiments, the temperature T a In some embodiments, the temperature T a In some embodiments, the temperature T a is about 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, or 25°C. In some embodiments, the temperature T a is about 20° C. In some embodiments, the temperature T a is about 21° C. In some embodiments, the temperature T a is about 22° C. In some embodiments, the temperature T a is about 23° C. In some embodiments, the temperature T a is about 24° C. In some embodiments, the temperature T a is approximately 25°C.

[0145] In some embodiments, step 2 includes (b) heating at a temperature T bIn some embodiments, the reaction conditions further include heating to a temperature T b In some embodiments, the heating step includes heating the b In some embodiments, the temperature T b In some embodiments, the temperature T b In some embodiments, the temperature T b In some embodiments, the temperature T b In some embodiments, the temperature T b In some embodiments, the temperature T b In some embodiments, the temperature T b In some embodiments, the temperature T b In some embodiments, the temperature T b In some embodiments, the temperature T b is about 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, 79°C, or 80°C. In some embodiments, the temperature T b is about 74°C. In some embodiments, the temperature T b is about 75° C. In some embodiments, the temperature T b is about 76°C. In some embodiments, the temperature T b is about 77°C. In some embodiments, the temperature T b is about 78°C. In some embodiments, the temperature T b is about 79°C. In some embodiments, the temperature T b is approximately 80°C.

[0146] In some embodiments, the reaction conditions include heating the reaction mixture to a temperature T bIn some embodiments, the period is from about 1 hour to about 48 hours. In some embodiments, the period is from about 2 hours to about 36 hours. In some embodiments, the period is from about 3 hours to about 24 hours. In some embodiments, the period is from about 4 hours to about 12 hours. In some embodiments, the period is about 5 hours. In some embodiments, the period is at least 2 hours. In some embodiments, the period is at least 4 hours. In some embodiments, the period is at least 6 hours. In some embodiments, the period is at least 8 hours. In some embodiments, the period is at least 12 hours. In some embodiments, the period is at least 24 hours.

[0147] In some embodiments, for example, the reaction is heated to a temperature T b After proceeding at this temperature for a period of time, step 2 (c) brings the reaction mixture to a temperature T c In some embodiments, the method further comprises cooling to a temperature T c In some embodiments, the temperature T c In some embodiments, the temperature T c In some embodiments, the temperature T c In some embodiments, the temperature T c In some embodiments, the temperature T c In some embodiments, the temperature T c In some embodiments, the temperature T c In some embodiments, the temperature T c In some embodiments, the temperature T c In some embodiments, the temperature T c In some embodiments, the temperature T c In some embodiments, the temperature Tc is about 19°C, 20°C, 21°C, 22°C, 23°C, or 24°C. In some embodiments, the temperature T c is about 19° C. In some embodiments, the temperature T c is about 20° C. In some embodiments, the temperature T c is about 21° C. In some embodiments, the temperature T c is about 22° C. In some embodiments, the temperature T c is about 23° C. In some embodiments, the temperature T c is approximately 24°C.

[0148] In some embodiments, the reaction (e.g., the presence of Compound 3 or Compound 2) is monitored for completion by HPLC. In some embodiments, the reaction is monitored for the presence of Compound 3. In some embodiments, the reaction is monitored for the presence of Compound 2 in an amount of about 50.0% (a / a) or less (e.g., by HPLC measurement). In some embodiments, the reaction is monitored for the presence of Compound 2 in an amount of about 25.0% (a / a) or less (e.g., by HPLC measurement). In some embodiments, the reaction is monitored for the presence of Compound 2 in an amount of about 15.0% (a / a) or less (e.g., by HPLC measurement). In some embodiments, the reaction is monitored for the presence of Compound 2 in an amount of about 10.0% (a / a) or less (e.g., by HPLC measurement). In some embodiments, the reaction is monitored for the presence of Compound 2 in an amount of about 5.0% (a / a) or less (e.g., by HPLC measurement). In some embodiments, the reaction is monitored for the presence of Compound 2 in an amount of about 4.0% (a / a) or less (e.g., by HPLC measurement). In some embodiments, the reaction is monitored for the presence of Compound 2 in an amount of about 3.0% (a / a) or less (e.g., by HPLC measurement). In some embodiments, the reaction is monitored for the presence of Compound 2 in an amount of about 2.0% (a / a) or less (e.g., by HPLC measurement). In some embodiments, the reaction is monitored for the presence of Compound 2 in an amount of about 1.0% (a / a) or less (e.g., by HPLC measurement).

[0149] In some embodiments, step 2 further comprises (d) washing and / or quenching the reaction mixture, e.g., to provide a first resultant mixture. In some embodiments, step 2 further comprises washing the reaction mixture. In some embodiments, step 2 further comprises quenching the reaction mixture.

[0150] In some embodiments, the wash and / or quench comprises a base wash 1. In some embodiments, the base wash 1 is or comprises washing the reaction mixture with an aqueous base. In some embodiments, the aqueous base is or comprises LiOH, NaOH, KOH, Li2CO3, Na2CO3, K2CO3, LiHCO3, NaHCO3, or KHCO3. In some embodiments, the aqueous base is or comprises KHCO3.

[0151] In some embodiments, the concentration of the aqueous base solution is about 5% to about 30% by weight. In some embodiments, the concentration of the aqueous base solution is about 10% to about 25% by weight. In some embodiments, the concentration of the aqueous base solution is about 15% to about 25% by weight. In some embodiments, the concentration of the aqueous base solution is about 10%, 15%, 20%, 25%, 30%, or 35% by weight. In some embodiments, the concentration of the aqueous base solution is about 10% by weight. In some embodiments, the concentration of the aqueous base solution is about 15% by weight. In some embodiments, the concentration of the aqueous base solution is about 20% by weight. In some embodiments, the concentration of the aqueous base solution is about 25% by weight. In some embodiments, the concentration of the aqueous base solution is about 30% by weight. In some embodiments, the concentration of the aqueous base solution is about 35% by weight. In some embodiments, the aqueous base solution is monitored for potassium bicarbonate (e.g., from about 0.811 kg / kg to about 1.02 kg / kg, e.g., 1.02 kg / kg) and water (e.g., from about 3.672 kg / kg to about 4.488 kg / kg, e.g., 4.08 kg / kg). In some such embodiments, these amounts are split between two separate aqueous base washes.

[0152] In some embodiments, base wash 1 is performed at a temperature T d In some embodiments, the temperature T d In some embodiments, the temperature T d In some embodiments, the temperature T d In some embodiments, the temperature T d In some embodiments, the temperature T d In some embodiments, the temperature T d is about 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, or 23°C. In some embodiments, the temperature T d is about 18° C. In some embodiments, the temperature T d is about 20° C. In some embodiments, the temperature T d is approximately 22°C.

[0153] In some embodiments, Base Wash 1 further comprises adding water to the reaction mixture. In some embodiments, the additional water is provided in an amount of about 2 kg / kg to about 6 kg / kg. In some embodiments, the additional water is provided in an amount of about 3.672 kg / kg to about 4.488 kg / kg. In some embodiments, the additional water is provided in an amount of about 3, 3.5, 4, 4.5, 5, 5.5, or 6 kg / kg. In some embodiments, solvent is provided in an amount of about 4.488 kg / kg.

[0154] In some embodiments, the wash and / or quench includes a brine wash 2. In some embodiments, the brine wash 2 includes washing the reaction mixture with brine (i.e., an aqueous NaCl solution). In some embodiments, the aqueous NaCl solution is about 1% to 100% NaCl by weight. In some embodiments, the aqueous NaCl solution is about 1% to 50% NaCl by weight. In some embodiments, the aqueous NaCl solution is about 1% to 10% NaCl by weight. In some embodiments, the aqueous NaCl solution is about 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, or 25% NaCl by weight. In some embodiments, the aqueous NaCl solution is prepared from NaCl (e.g., about 0.41 kg / kg to 0.69 kg / kg, e.g., 0.628 kg / kg) and water (e.g., about 1.835 kg / kg to about 2.243 kg / kg, e.g., 2.039 kg / kg).

[0155] In some embodiments, the brine wash 2 is performed at a temperature T d The process proceeds as follows.

[0156] In some embodiments, each of Base Wash 1 and Brine Wash 2 independently comprises stirring for a period of time. In some embodiments, the period is from about 5 minutes to about 5 days. In some embodiments, the period is from about 5 minutes to about 1 day. In some embodiments, the period is from about 5 minutes to about 12 hours. In some embodiments, the period is from about 5 minutes to about 6 hours. In some embodiments, the period is from about 5 minutes to about 3 hours. In some embodiments, the period is at least 5 minutes. In some embodiments, the period is at least 15 minutes. In some embodiments, the period is at least 45 minutes. In some embodiments, the period is at least 60 minutes. In some embodiments, the period is at least 120 days.

[0157] In some embodiments, Brine Wash 2 comprises allowing the reaction mixture or first resulting mixture to settle for a period of time. In some embodiments, the period is between about 1 minute and 60 minutes. In some embodiments, the period is between about 10 minutes and 30 minutes. In some embodiments, the period is greater than about 20 minutes.

[0158] In some embodiments, step 2 further comprises a step of distillation and / or solvent exchange of the reaction mixture or the first resulting mixture to provide a second resulting mixture comprising compound 3, or a pharmaceutically acceptable salt thereof, and a solvent.

[0159] In some embodiments, the distillation and / or solvent exchange comprises (i) removing a solvent (e.g., a reaction solvent as described above and herein) from the reaction mixture and / or first resulting mixture. In some embodiments, removing a solvent (e.g., a reaction solvent as described above and herein) comprises heating the reaction mixture and / or first resulting mixture to a temperature T e In some embodiments, the heating step includes heating the material to a temperature T e In some embodiments, the temperature T e In some embodiments, the temperature T e In some embodiments, the temperature T e In some embodiments, the temperature T e In some embodiments, the temperature T e In some embodiments, the temperature T e In some embodiments, the temperature T e In some embodiments, the temperature T e In some embodiments, the temperature T e is about 60° C. or less. In some embodiments, the temperature T e is less than or equal to 45° C. In some embodiments, the temperature T eis below 40°C.

[0160] In some embodiments, the reaction mixture and / or the first resulting mixture is heated to a temperature T e In some embodiments, the period is until a certain amount of solvent is recovered from the reaction mixture or first resulting mixture. For example, in some embodiments, the volume of recovered solvent is about 388 L to about 430 L, e.g., about 409 L.

[0161] In some embodiments, the distillation and / or solvent exchange comprises (ii) adding a distillation solvent to the reaction mixture or the first resulting mixture. In some embodiments, the distillation solvent is or comprises chloroform, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, the distillation solvent is or comprises chloroform. In some embodiments, the distillation solvent is or comprises diethyl ether. In some embodiments, the distillation solvent is or comprises ethyl acetate. In some embodiments, the distillation solvent is or comprises isopropyl acetate. In some embodiments, the distillation solvent is or comprises cyclopentyl methyl ether. In some embodiments, the distillation solvent is or comprises toluene. In some embodiments, the distillation solvent is or comprises benzene. In some embodiments, the distillation solvent is or comprises α,α,α-trifluorotoluene. In some embodiments, the distillation solvent is or comprises chlorobenzene. In some embodiments, the distillation solvent is or comprises xylene. In some embodiments, the distillation solvent is or comprises dichloromethane. In some embodiments, the distillation solvent is or comprises tert-butyl methyl ether.

[0162] In some embodiments, a quantity of distillation solvent is charged to a solution containing Compound 3 or a salt thereof. In some embodiments, the quantity of distillation solvent is about 100 kg to about 1000 kg. In some embodiments, the quantity of distillation solvent is about 100 kg to about 800 kg. In some embodiments, the distillation solvent is present in an amount of about 100 kg to about 600 kg. In some embodiments, the quantity of distillation solvent is about 100 kg to about 400 kg. In some embodiments, the quantity of distillation solvent is about 200 kg to about 1000 kg. In some embodiments, the quantity of distillation solvent is about 300 kg to about 1000 kg. In some embodiments, the quantity of distillation solvent is about 400 kg to about 1000 kg. In some embodiments, the quantity of distillation solvent is about 200 kg to about 600 kg. In some embodiments, the quantity of distillation solvent is about 300 kg to about 500 kg. In some embodiments, the quantity of distillation solvent is about 350 kg to about 450 kg. In some embodiments, the amount of distillation solvent is about 367 kg to about 407 kg. In some embodiments, the amount of distillation solvent is about 375 kg to about 400 kg. In some embodiments, the amount of distillation solvent is about 375 kg, 382 kg, 387 kg, 392 kg, or 400 kg. In some embodiments, the amount of distillation solvent is about 375 kg. In some embodiments, the amount of distillation solvent is about 387 kg. In some embodiments, the amount of distillation solvent is about 400 kg.

[0163] In some embodiments, the distillation solvent is heated to a temperature T f In some embodiments, the solution is added at a temperature T f In some embodiments, the temperature T f In some embodiments, the temperature T f In some embodiments, the temperature T f In some embodiments, the temperature T f In some embodiments, the temperature T f In some embodiments, the temperature Tf In some embodiments, the temperature T f In some embodiments, the temperature T f In some embodiments, the temperature T f In some embodiments, the temperature T f is about 18°C, 19°C, 20°C, 21°C, 22°C, or 23°C. In some embodiments, the temperature T f is about 18° C. In some embodiments, the temperature T f is about 20° C. In some embodiments, the temperature T f is about 21° C. In some embodiments, the temperature T f is approximately 22°C.

[0164] In some embodiments, the second resulting mixture is heated to a temperature T f (as described above and herein).

[0165] In some embodiments, step 2 further comprises (f) crystallizing compound 3 or a pharmaceutically acceptable salt thereof (e.g., from the reaction mixture, the first resulting mixture, or the second resulting mixture). In some embodiments, the crystallization comprises the formation of a salt of compound 3 (e.g., a salt described above and herein).

[0166] In some embodiments, crystallization comprises providing a crystallization mixture comprising Compound 3, or a pharmaceutically acceptable salt thereof, and a crystallization solvent. In some embodiments, the crystallization solvent is or comprises chloroform, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, the crystallization solvent is or comprises chloroform. In some embodiments, the crystallization solvent is or comprises diethyl ether. In some embodiments, the crystallization solvent is or comprises ethyl acetate. In some embodiments, the crystallization solvent is or comprises cyclopentyl methyl ether. In some embodiments, the crystallization solvent is or comprises toluene. In some embodiments, the crystallization solvent is or comprises benzene. In some embodiments, the crystallization solvent is or comprises α,α,α-trifluorotoluene. In some embodiments, the crystallization solvent is or comprises chlorobenzene. In some embodiments, the crystallization solvent is or comprises xylene, in some embodiments, the crystallization solvent is or comprises dichloromethane, in some embodiments, the crystallization solvent is or comprises isopropyl acetate.

[0167] In some embodiments, the crystallization mixture further comprises an acid. In some embodiments, the acid is camphorsulfonic acid (CSA), benzenesulfonic acid (PhSO3H), methanesulfonic acid (MsOH), toluenesulfonic acid (TsOH), 1,5-naphthalenedisulfonic acid (napsylic acid), 1,2-ethanedisulfonic acid (edisic acid), ethanesulfonic acid (esic acid), 4-chlorobenzenesulfonic acid (closic acid), 6,7-dihydroxycoumarin-4-methanesulfonic acid (cromesic acid), or trifluoromethanesulfonic acid (HOTf). In some embodiments, the acid is hydrochloric acid ("HCl").

[0168] In some embodiments, the crystallization mixture comprises compound 3 as a salt of an acid described above and herein. In some embodiments, the crystallization mixture comprises compound 3 as a halide salt. In some embodiments, the crystallization mixture further comprises compound 3 as an HCl salt. In some embodiments, the crystallization mixture further comprises compound 3 as an HBr salt.

[0169] In some embodiments, the acid is provided in an amount of about 0.5 to 1.5 equivalents relative to Compound 3 or its salt. In some embodiments, the acid is present in an amount of about 0.75 to 1.5 equivalents relative to Compound 3 or its salt. In some embodiments, the acid is present in an amount of about 0.95 to 1.5 equivalents relative to Compound 3 or its salt. In some embodiments, the acid is provided in an amount of about 1.05 to 1.5 equivalents relative to Compound 3 or its salt. In some embodiments, the acid is provided in an amount of about 0.5 to 1.25 equivalents relative to Compound 3 or its salt. In some embodiments, the acid is provided in an amount of about 0.5 to 1.15 equivalents relative to Compound 3 or its salt. In some embodiments, the acid is provided in an amount of about 0.5 to 1.05 equivalents relative to Compound 3 or its salt. In some embodiments, the acid is provided in an amount of about 0.6 to 1.4 equivalents relative to Compound 3 or its salt. In some embodiments, the acid is provided in an amount of about 0.8 to 1.2 equivalents relative to Compound 3 or its salt. In some embodiments, the acid is provided in an amount of about 0.95 to 1.05 equivalents relative to compound 3 or its salt. In some embodiments, the acid is present in an amount of about 0.95, 0.98, 1.01, 1.03, 1.04, 1.05, 1.06, or 1.07 equivalents relative to compound 3 or its salt. In some embodiments, the acid is present in an amount of about 1.01 equivalents relative to compound 3 or its salt. In some embodiments, the catalyst is present in an amount of about 1.037 equivalents relative to compound 3 or its salt. In some embodiments, the catalyst is present in an amount of about 1.05 equivalents relative to compound 3 or its salt.

[0170] In some embodiments, the acid is provided as hydrochloric acid. In some embodiments, the acid is provided as a solution of hydrochloric acid in ethyl acetate. In some embodiments, the acid is provided as an aqueous solution of hydrochloric acid. In some embodiments, the acid is provided as a solution of hydrochloric acid in methanol. In some embodiments, the acid is provided as a solution of hydrochloric acid in dioxane. In some embodiments, the acid is provided as a solution of hydrochloric acid in diethyl ether.

[0171] In some embodiments, the crystallization mixture is heated to a temperature Tg In some embodiments, the temperature T g In some embodiments, the temperature T g In some embodiments, the temperature T g In some embodiments, the temperature T g In some embodiments, the temperature T g In some embodiments, the temperature T g In some embodiments, the temperature T g In some embodiments, the temperature T g is about 18°C, 20°C, 22°C, or 24°C. In some embodiments, the temperature T g is about 20° C. In some embodiments, the temperature T g is about 22° C. In some embodiments, the temperature T g is approximately 24°C.

[0172] In some embodiments, crystallization comprises adding an acid to the crystallization mixture over a period of time. In some embodiments, the period is from about 5 to about 120 minutes. In some embodiments, the period is from about 5 to about 90 minutes. In some embodiments, the period is from about 5 to about 60 minutes. In some embodiments, the period is from about 5 to about 30 minutes. In some embodiments, the period is from about 15 to about 120 minutes. In some embodiments, the period is from about 30 to about 120 minutes. In some embodiments, the period is at least 15 minutes. In some embodiments, the period is at least 30 minutes. In some embodiments, the period is at least 60 minutes. In some embodiments, the period is at least 120 minutes. In some embodiments, the period is about 15 minutes. In some embodiments, the period is about 30 minutes. In some embodiments, the period is about ... crystallization is carried out at a temperature T g adding an acid to the crystallization mixture at a temperature T g is as described above and herein.

[0173] In some embodiments, seed crystals are added to the crystallization mixture. In some embodiments, the seed crystals are Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.01% to about 0.12% w / w relative to Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.01% to about 0.10% w / w relative to Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.01% to about 0.08% w / w relative to Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.01% to about 0.07% w / w relative to Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.01% to about 0.06% w / w relative to Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.03% to about 0.10% w / w relative to Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.04% to about 0.10% w / w of Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.05% to about 0.10% w / w of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.06% to about 0.10% w / w of Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.03% to about 0.08% w / w of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.05% to about 0.07% w / w of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.04%, 0.05%, 0.06%, 0.07%, or 0.08% w / w of Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.04% w / w of Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.05% w / w of Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.06% w / w of Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.07% w / w of Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.08% w / w of Compound 2 or a salt thereof.

[0174] In some embodiments, the seed crystals are provided in a seed crystal solvent (e.g., a crystallization solvent described above and herein). In some embodiments, the seed crystal solvent is or comprises an amount of about 0 kg to about 0.41 kg. In some embodiments, the seed crystal solvent suspension is or comprises an amount of about 0 kg to about 0.31 kg. In some embodiments, the seed crystal solvent suspension is or comprises an amount of about 0 kg to about 0.21 kg. In some embodiments, the seed crystal solvent suspension is or comprises an amount of about 0 kg to about 0.16 kg. In some embodiments, the seed crystal solvent suspension is or comprises an amount of about 0 kg to about 0.11 kg. In some embodiments, the seed crystal solvent suspension is or comprises an amount of about 0 kg to about 0.60 kg. In some embodiments, the seed crystal solvent suspension is or comprises an amount of about 0.10 kg to about 0.21 kg. In some embodiments, the seed crystal solvent suspension is or comprises an amount of about 0.16 kg to about 0.21 kg. In some embodiments, the seed crystal solvent suspension is or comprises an amount of about 0.10 kg, 0.15 kg, 0.20 kg, or 0.25 kg. In some embodiments, the seed crystal solvent suspension is or comprises an amount of about 0.10 kg. In some embodiments, the seed crystal solvent suspension is or comprises an amount of about 0.15 kg. In some embodiments, the seed crystal solvent suspension is or comprises an amount of about 0.20 kg. In some embodiments, the seed crystal solvent suspension is or comprises an amount of about 0.25 kg.

[0175] In some embodiments, the crystallization mixture is heated to a temperature T g Aging is performed for a certain period of time at temperature T gare as described above and herein. In some embodiments, the period is about 5 to about 300 minutes. In some embodiments, the period is about 5 to about 240 minutes. In some embodiments, the period is about 10 to about 180 minutes. In some embodiments, the period is about 30 to about 120 minutes. In some embodiments, the period is about 60 to about 100 minutes. In some embodiments, the period is about 30, 60, 90, or 120 minutes. In some embodiments, the period is about 90 minutes. In some embodiments, the period is at least 10 minutes. In some embodiments, the period is at least 30 minutes. In some embodiments, the period is at least 60 minutes. In some embodiments, the period is at least 90 minutes. In some embodiments, the crystallization mixture is aged for a period of at least 120 minutes.

[0176] In some embodiments, the crystallization mixture is heated to a temperature T iIn some embodiments, the period is about 15 minutes to about 240 minutes. In some embodiments, the period is about 15 minutes to about 200 minutes. In some embodiments, the period is about 15 minutes to about 180 minutes. In some embodiments, the period is about 15 minutes to about 150 minutes. In some embodiments, the period is about 15 minutes to about 120 minutes. In some embodiments, the period is about 15 minutes to about 90 minutes. In some embodiments, the period is about 30 minutes to about 180 minutes. In some embodiments, the period is about 60 minutes to about 180 minutes. In some embodiments, the period is about 90 minutes to about 180 minutes. In some embodiments, the period is about 30 minutes to about 150 minutes. In some embodiments, the period is about 60 minutes to about 120 minutes. In some embodiments, the period is about 80 minutes to about 100 minutes. In some embodiments, the period is about 90 minutes. In some embodiments, the period is about 100 minutes. In some embodiments, the period is about 120 minutes. In some embodiments, the period is about 150 minutes. In some embodiments, the period is at least 30 minutes. In some embodiments, the period is at least 60 minutes. In some embodiments, the period is at least 90 minutes. In some embodiments, the period is at least 120 minutes.

[0177] In some embodiments, the temperature T i In some embodiments, the temperature T i In some embodiments, the temperature T i In some embodiments, the temperature T i In some embodiments, the temperature T i In some embodiments, the temperature T i In some embodiments, the temperature T i In some embodiments, the temperature T i In some embodiments, the temperature T iIn some embodiments, the temperature T i In some embodiments, the temperature T i In some embodiments, the temperature T i is about −2° C., 0° C., 2° C., 4° C., or 6° C. In some embodiments, the temperature T i is about −2° C. In some embodiments, the temperature T i is about 0° C. In some embodiments, the temperature T i is about 2° C. In some embodiments, the temperature T i is approximately 4°C.

[0178] In some embodiments, the crystalline compound is heated to a temperature T i In some embodiments, the period is about 30 minutes to 7 days. In some embodiments, the period is about 30 minutes to 1 day. In some embodiments, the period is about 30 minutes to 12 hours. In some embodiments, the period is about 30 minutes to 6 hours. In some embodiments, the period is about 30 minutes to 3 hours. In some embodiments, the period is about 30 minutes to 2 hours. In some embodiments, the period is about 30 minutes. In some embodiments, the period is about 60 minutes. In some embodiments, the period for which the crystallization mixture is aged is about 90 minutes. In some embodiments, the period for which the crystallization mixture is aged is about 120 minutes. In some embodiments, the period is at least 30 minutes. In some embodiments, the period is at least 60 minutes. In some embodiments, the period is at least 90 minutes. In some embodiments, the period is at least 120 minutes. In some embodiments, the period is at least about 5 minutes. In some embodiments, the period is less than 7 days.

[0179] In some embodiments, step 2 further comprises (g) optionally filtering or washing the crystallization mixture to obtain a filtered mixture. In some embodiments, step 2 further comprises filtering the crystallization mixture to obtain a filtered mixture. In some embodiments, step 2 further comprises washing the crystallization mixture to obtain a filtered mixture.

[0180] In some embodiments, the filtration is performed at a temperature T i is performed at temperature T i is as described above and herein.

[0181] In some embodiments, the filtration is carried out over a period of time. In some embodiments, the period is from about 10 minutes to about 4 days. In some embodiments, the period is from about 10 minutes to 1 day. In some embodiments, the period is from about 10 minutes to about 12 hours. In some embodiments, the period is from about 10 minutes to about 6 hours. In some embodiments, the period is from about 10 minutes to about 1 hour. In some embodiments, the period is from about 10 minutes to about 30 minutes. In some embodiments, the period is at least 10 minutes. In some embodiments, the period is at least 20 minutes. In some embodiments, the period is at least 30 minutes. In some embodiments, the period is at least 60 minutes.

[0182] In some embodiments, washing comprises Wash A. In some embodiments, Wash A comprises washing with Wash Solvent A. In some embodiments, Wash Solvent A is or comprises chloroform, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, Wash Solvent A is or comprises chloroform. In some embodiments, Wash Solvent A is or comprises diethyl ether. In some embodiments, Wash Solvent A is or comprises ethyl acetate. In some embodiments, Wash Solvent A is or comprises cyclopentyl methyl ether. In some embodiments, Wash Solvent A is or comprises toluene. In some embodiments, Wash Solvent A is or comprises benzene. In some embodiments, Wash Solvent A is or comprises α,α,α-trifluorotoluene. In some embodiments, Wash Solvent A is or comprises chlorobenzene. In some embodiments, Wash Solvent A is or comprises xylene. In some embodiments, wash solvent A is or comprises dichloromethane, hi some embodiments, wash solvent A is or comprises isopropyl acetate.

[0183] In some embodiments, washing solvent A is present in an amount of about 0.30 kg / kg to about 5.0 kg / kg. In some embodiments, washing solvent A is present in an amount of about 0.30 kg / kg to about 4.0 kg / kg. In some embodiments, washing solvent A is present in an amount of about 0.30 kg / kg to about 3.0 kg / kg. In some embodiments, washing solvent A is present in an amount of about 0.30 kg / kg to about 2.0 kg / kg. In some embodiments, washing solvent A is present in an amount of about 0.50 kg / kg to about 5.0 kg / kg. In some embodiments, washing solvent A is present in an amount of about 1.00 kg / kg to about 5.0 kg / kg. In some embodiments, washing solvent A is present in an amount of about 1.25 kg / kg to about 5.0 kg / kg. In some embodiments, washing solvent A is present in an amount of about 0.25 kg / kg to about 4.0 kg / kg. In some embodiments, wash solvent A is present in an amount of about 0.50 kg / kg to about 3.0 kg / kg. In some embodiments, wash solvent A is present in an amount of about 0.69 kg / kg to about 2.5 kg / kg. In some embodiments, wash solvent A is present in an amount of about 0.95 kg / kg to about 1.75 kg / kg. In some embodiments, wash solvent A is present in an amount of about 1.25 kg / kg to about 1.5 kg / kg. In some embodiments, wash solvent A is present in an amount of about 1.15 kg / kg, 1.25 kg / kg, 1.35 kg / kg, 1.55 kg / kg, or 1.75 kg / kg. In some embodiments, wash solvent A is present in an amount of about 1.15 kg / kg. In some embodiments, the solvent is present in an amount of about 1.35 kg / kg. In some embodiments, the solvent is present in an amount of about 1.55 kg / kg.

[0184] In some embodiments, the wash solvent A is heated to a temperature T i where Ti is as described above and herein.

[0185] In some embodiments, after addition of wash solvent A, the filtration mixture is stirred for a period of time. In some embodiments, the period is about 5 minutes to about 60 minutes. In some embodiments, the period is about 5 minutes to about 45 minutes. In some embodiments, the period is about 5 minutes to about 30 minutes. In some embodiments, the period is about 5 minutes to about 15 minutes. In some embodiments, the period is about 5 minutes or longer. In some embodiments, the period is about 10 minutes or longer. In some embodiments, the period is about 15 minutes or longer. In some embodiments, the period is about 20 minutes or longer. In some embodiments, the period is about 30 minutes or longer. In some embodiments, the period is about 60 minutes or longer.

[0186] In some embodiments, washing comprises Wash B. In some embodiments, Wash B comprises washing with Wash Solvent B. In some embodiments, Wash Solvent B is or comprises chloroform, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, Wash Solvent B is or comprises chloroform. In some embodiments, Wash Solvent B is or comprises diethyl ether. In some embodiments, Wash Solvent B is or comprises ethyl acetate. In some embodiments, Wash Solvent B is or comprises cyclopentyl methyl ether. In some embodiments, Wash Solvent B is or comprises toluene. In some embodiments, Wash Solvent B is or comprises benzene. In some embodiments, Wash Solvent B is or comprises α,α,α-trifluorotoluene. In some embodiments, Wash Solvent B is or comprises chlorobenzene. In some embodiments, Wash Solvent B is or comprises isopropyl acetate. In some embodiments, wash solvent B is or comprises dichloromethane. In some embodiments, wash solvent B is or comprises isopropyl acetate. In some embodiments, wash solvent B is or comprises tert-butyl methyl ether.

[0187] In some embodiments, wash solvent B is present in an amount of about 0.50 kg / kg to 4.0 kg / kg. In some embodiments, wash solvent B is present in an amount of about 0.50 kg / kg to 3.0 kg / kg. In some embodiments, wash solvent B is present in an amount of about 0.50 kg / kg to 2.0 kg / kg. In some embodiments, wash solvent B is present in an amount of about 1.0 kg / kg to 4.0 kg / kg. In some embodiments, wash solvent B is present in an amount of about 1.50 kg / kg to 4.0 kg / kg. In some embodiments, wash solvent B is present in an amount of about 1.75 kg / kg to 4.0 kg / kg. In some embodiments, wash solvent B is present in an amount of about 1.0 kg / kg to 3.0 kg / kg. In some embodiments, wash solvent B is present in an amount of about 1.25 kg / kg to 2.55 kg / kg. In some embodiments, wash solvent B is present in an amount of about 1.50 kg / kg to 2.05 kg / kg. In some embodiments, wash solvent B is present in an amount of about 1.75 kg / kg to 1.85 kg / kg. In some embodiments, wash solvent B is present in an amount of about 1.65 kg / kg, 1.70 kg / kg, 1.75 kg / kg, 1.80 kg / kg, or 1.85 kg / kg. In some embodiments, wash solvent B is present in an amount of about 1.65 kg / kg. In some embodiments, wash solvent B is present in an amount of about 1.70 kg / kg. In some embodiments, wash solvent B is present in an amount of about 1.75 kg / kg. In some embodiments, wash solvent B is present in an amount of about 1.80 kg / kg. In some embodiments, wash solvent B is present in an amount of about 1.85 kg / kg.

[0188] In some embodiments, the wash solvent B is at a temperature T i where Ti is as described above and herein.

[0189] In some embodiments, after addition of Wash Solvent B, the filtration mixture is stirred for a period of time, for example, as described above and herein for Wash A.

[0190] In some embodiments, the wash comprises Wash C. In some embodiments, Wash C is the same as Wash B as described above and herein.

[0191] In some embodiments, step 2 further comprises (h) drying the filtered mixture.

[0192] In some embodiments, drying comprises heating the filtered mixture to a temperature T m In some embodiments, the heating step includes heating the material to a temperature T m In some embodiments, the temperature T m In some embodiments, the temperature T m In some embodiments, the temperature T m In some embodiments, the temperature T m In some embodiments, the temperature T m In some embodiments, the temperature T m In some embodiments, the temperature T m is less than about 10°C, or about 10°C. In some embodiments, the temperature T m is less than about 20° C. or about 20° C. In some embodiments, the temperature T m is less than about 25° C. or about 25° C. In some embodiments, the temperature T m is less than about 30° C. or about 30° C. In some embodiments, the temperature T m is less than about 35° C. or about 35° C. In some embodiments, the temperature T m is less than about 40° C. or about 40° C. In some embodiments, the temperature T m is less than about 100° C. or about 100° C. In some embodiments, the filtered mixture is stirred for a period of time.

[0193] In some embodiments, the filtered mixture is heated to a temperature T mIn some embodiments, the period is until minimal condensation is visible in the filter dryer.

[0194] In some embodiments, the filtered mixture is heated to a temperature T m (as described above and herein).

[0195] In some embodiments, the filtered mixture is heated to a temperature T n In some embodiments, the drying is carried out at a temperature T n In some embodiments, the temperature T n In some embodiments, the filtered mixture is heated to a temperature T of about 60°C to about 80°C. n In some embodiments, the filtered mixture is dried at a temperature T n In some embodiments, the filtered mixture is dried at a temperature T n In some embodiments, the filtered mixture is dried at a temperature T n In some embodiments, the filtered mixture is dried at a temperature T n In some embodiments, the filtered mixture is dried at a temperature T of less than or about 45° C. n In some embodiments, the filtered mixture is dried at a temperature T n In some embodiments, the filtered mixture is dried at a temperature T n In some embodiments, the filtered mixture is dried at a temperature T n In some embodiments, the filtered mixture is dried at a temperature T n In some embodiments, the filtered mixture is dried at a temperature T n It is dried in.

[0196] In some embodiments, the filtered mixture is heated to a temperature Tn The solution is held at room temperature for a period of time. In some embodiments, the period is until the total solvent content is below 1.5% w / w (e.g., by GCHS measurement). In some embodiments, the period is until the total solvent content is below 1.3% w / w (e.g., by GCHS measurement). In some embodiments, the period is until the total solvent content is below 1.1% w / w (e.g., by GCHS measurement). In some embodiments, the period is until the total solvent content is below 0.8% w / w (e.g., by GCHS measurement). In some embodiments, the period is until the total solvent content is below 0.5% w / w (e.g., by GCHS measurement). In some embodiments, the period is until the total solvent content is below 0.2% w / w (e.g., by GCHS measurement). In some embodiments, the period is until the total solvent content is below 0.1% w / w (e.g., by GCHS measurement).

[0197] In some embodiments, the filtered mixture is heated to a temperature T n In some embodiments, the period is until the water content is below 1.5% w / w (e.g., by Karl Fischer measurement). In some embodiments, the period is until the water content is below 1.3% w / w (e.g., by Karl Fischer measurement). In some embodiments, the period is until the water content is below 1.1% w / w (e.g., by Karl Fischer measurement). In some embodiments, the period is until the water content is below 0.8% w / w (e.g., by Karl Fischer measurement). In some embodiments, the period is until the water content is below 0.5% w / w (e.g., by Karl Fischer measurement). In some embodiments, the period is until the water content is below 0.2% w / w (e.g., by Karl Fischer measurement). In some embodiments, the period is until the water content is below 0.1% w / w (e.g., by Karl Fischer measurement).

[0198] Step 3 In some embodiments, the present disclosure provides Compound 1: [ka] or a pharmaceutically acceptable salt thereof, wherein each R 1 and R 2 is as defined above and described herein.

[0199] In some embodiments, the present disclosure provides maribavir: [ka] or a pharmaceutical salt thereof.

[0200] As shown in Scheme 4, Step 3 is the last of three steps for preparing maribavir disclosed herein. Any by-products (or derivatives thereof) formed in Steps 1, 2, or 3 may be present in the provided maribavir-containing compositions and / or may reduce the overall yield or quality of maribavir. In some embodiments, the present disclosure provides methods for preparing maribavir or a pharmaceutically acceptable salt thereof containing reduced and / or low levels of impurities (e.g., those described herein).

[0201] In some embodiments, the present disclosure provides a combination of maribavir or a pharmaceutically acceptable salt thereof, and: [ka] or salts thereof.

[0202] In some embodiments, provided compositions comprising maribavir are as described herein.

[0203] In some embodiments, the present disclosure also provides the recognition that certain reagents (and amounts thereof) and / or reaction conditions may provide maribavir or its salts of improved quality (e.g., with high purity and / or minimal by-products) and / or may improve the yield of maribavir or its salts. Without wishing to be bound by a particular theory, the present disclosure provides the recognition that the incorporation of crystallization into Step 3 may improve the yield and / or reduce the formation of by-products (e.g., compounds 2, 3, or 4 or their salts). In some embodiments, the present disclosure provides the recognition that the amount of maribavir or its salts and / or water in the crystallization mixture may affect the yield and / or quality (e.g., particle size distribution) of maribavir. Additionally or alternatively, the present disclosure provides the recognition that the incorporation of phase separation and / or extraction into Step 3 at a particular pH may improve the yield and / or reduce the formation of by-products (e.g., compounds 2, 3, or 4 or their salts).

[0204] In some embodiments, Compound 1, or a pharmaceutical salt thereof, is prepared as shown in Step 3 of Scheme 4. In some embodiments, in Step 3, Compound 1, or a pharmaceutical salt thereof, is prepared by reacting: (a) Compound 3a: [ka] or a salt thereof (wherein Each R 1 , R 2 , X, and PG 1 is as defined above and described herein) under suitable reaction conditions to provide maribavir or a pharmaceutically acceptable salt thereof, to provide maribavir or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, maribavir or a pharmaceutical salt thereof is prepared as shown in Step 3 of Scheme 5. In some embodiments, in Step 3, maribavir or a pharmaceutical salt thereof is prepared by reacting: (a) Compound 3: [ka] or a salt thereof, It is prepared by a process comprising reacting under suitable reaction conditions to provide maribavir or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, step 3 comprises one or more of the following compounds: [ka] or a salt thereof.

[0207] In some embodiments, step 2 provides a composition comprising 0.01-0.10% (w / w HPLC) of compound 2 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.01-0.05% (w / w HPLC) of compound 2 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.02-0.05% (w / w HPLC) of compound 2 relative to maribavir. In some embodiments, step 2 provides a composition comprising 1%, 0.5%, 0.1%, 0.05%, 0.02%, or less than 0.01% (w / w HPLC) of compound 2 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.01-0.10% (a / a HPLC) of compound 2 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.01-0.05% (a / a HPLC) of compound 2 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.02-0.05% (a / a HPLC) of compound 2 relative to maribavir. In some embodiments, step 2 provides a composition comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% (a / a HPLC) of compound 2 relative to maribavir. In some embodiments, step 2 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (a / a HPLC) of compound 2 relative to maribavir. In some embodiments, step 2 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (w / w HPLC) of compound 2 relative to maribavir. In some embodiments, step 3 provides a composition comprising compound 2 or a salt thereof (e.g., by HPLC or 1 1 H NMR) is undetectable.

[0208] In some embodiments, step 2 provides a composition comprising 0.01-0.10% (w / w HPLC) of compound 3 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.01-0.05% (w / w HPLC) of compound 3 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.02-0.05% (w / w HPLC) of compound 3 relative to maribavir. In some embodiments, step 2 provides a composition comprising 1%, 0.5%, 0.1%, 0.05%, 0.02%, or less than 0.01% (w / w HPLC) of compound 3 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.01-0.10% (a / a HPLC) of compound 3 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.01-0.05% (a / a HPLC) of compound 3 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.02-0.05% (a / a HPLC) of compound 3 relative to maribavir. In some embodiments, step 2 provides a composition comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% (a / a HPLC) of compound 3 relative to maribavir. In some embodiments, step 2 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (a / a HPLC) of compound 3 relative to maribavir. In some embodiments, step 2 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (w / w HPLC) of compound 3 relative to maribavir. In some embodiments, step 3 provides a composition comprising compound 3 or a salt thereof (e.g., by HPLC or 1 1 H NMR) is undetectable.

[0209] In some embodiments, step 2 provides a composition comprising 0.01-0.10% (w / w HPLC) of compound 4 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.01-0.05% (w / w HPLC) of compound 4 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.02-0.05% (w / w HPLC) of compound 4 relative to maribavir. In some embodiments, step 2 provides a composition comprising 1%, 0.5%, 0.1%, 0.05%, 0.02%, or less than 0.01% (w / w HPLC) of compound 4 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.01-0.10% (a / a HPLC) of compound 4 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.01-0.05% (a / a HPLC) of compound 4 relative to maribavir. In some embodiments, step 2 provides a composition comprising 0.02-0.05% (a / a HPLC) of compound 4 relative to maribavir. In some embodiments, step 2 provides a composition comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% (a / a HPLC) of compound 4 relative to maribavir. In some embodiments, step 2 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (a / a HPLC) of compound 4 relative to maribavir. In some embodiments, step 2 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (w / w HPLC) of compound 4 relative to maribavir. In some embodiments, step 3 provides a composition comprising compound 4 or a salt thereof (e.g., by HPLC or 1 1 H NMR) is undetectable.

[0210] In some embodiments, step 3 provides a composition comprising 0.01-0.10% (w / w HPLC) of compound 2 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.01-0.05% (w / w HPLC) of compound 2 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.02-0.05% (w / w HPLC) of compound 2 relative to maribavir. In some embodiments, step 3 provides a composition comprising 1%, 0.5%, 0.1%, 0.05%, 0.02%, or less than 0.01% (w / w HPLC) of compound 2 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.01-0.10% (a / a HPLC) of compound 2 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.01-0.05% (w / w HPLC) of compound 2 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.02-0.05% (a / a HPLC) of compound 2 relative to maribavir. In some embodiments, step 3 provides a composition comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% (a / a HPLC) of compound 2 relative to maribavir. In some embodiments, step 3 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (a / a HPLC) of compound 2 relative to maribavir. In some embodiments, step 3 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (w / w HPLC) of compound 2 relative to maribavir. In some embodiments, step 3 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (w / w HPLC) of compound 2 relative to maribavir. In some embodiments, step 3 provides a composition wherein compound 2 or a salt thereof is present (e.g., by HPLC or 1 1 H NMR) is undetectable.

[0211] In some embodiments, step 3 provides a composition comprising 0.01-0.10% (w / w HPLC) of compound 3 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.01-0.05% (w / w HPLC) of compound 3 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.02-0.05% (w / w HPLC) of compound 3 relative to maribavir. In some embodiments, step 3 provides a composition comprising 1%, 0.5%, 0.1%, 0.05%, 0.02%, or less than 0.01% (w / w HPLC) of compound 3 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.01-0.10% (a / a HPLC) of compound 3 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.01-0.05% (a / a HPLC) of compound 3 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.02-0.05% (a / a HPLC) of compound 3 relative to maribavir. In some embodiments, step 3 provides a composition comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% (a / a HPLC) of compound 3 relative to maribavir. In some embodiments, step 3 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (a / a HPLC) of compound 3 relative to maribavir. In some embodiments, step 3 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (w / w HPLC) of compound 3 relative to maribavir. In some embodiments, step 3 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (w / w HPLC) of compound 3 relative to maribavir. In some embodiments, step 3 provides a composition wherein compound 3 or a salt thereof is present (e.g., by HPLC or 1 1 H NMR) is undetectable.

[0212] In some embodiments, step 3 provides a composition comprising 0.01-0.10% (w / w HPLC) of compound 4 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.01-0.05% (w / w HPLC) of compound 4 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.02-0.05% (w / w HPLC) of compound 4 relative to maribavir. In some embodiments, step 3 provides a composition comprising 1%, 0.5%, 0.1%, 0.05%, 0.02%, or less than 0.01% (w / w HPLC) of compound 4 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.01-0.10% (a / a HPLC) of compound 4 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.01-0.05% (a / a HPLC) of compound 4 relative to maribavir. In some embodiments, step 3 provides a composition comprising 0.02-0.05% (a / a HPLC) of compound 4 relative to maribavir. In some embodiments, step 3 provides a composition comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% (a / a HPLC) of compound 4 relative to maribavir. In some embodiments, step 3 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (a / a HPLC) of compound 4 relative to maribavir. In some embodiments, step 3 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (w / w HPLC) of compound 4 relative to maribavir. In some embodiments, step 3 provides a composition comprising about 1%, about 0.5%, about 0.1%, about 0.05%, about 0.02%, or about 0.01% (w / w HPLC) of compound 4 relative to maribavir. In some embodiments, step 3 provides a composition wherein compound 4 or a salt thereof is present (e.g., by HPLC or 1 1 H NMR) is undetectable.

[0213] In some embodiments, Step 3 provides a composition provided in any one of Tables 4-12 to 4-21 of Example 4.

[0214] In some embodiments, the reaction conditions include a solvent. In some embodiments, the solvent is or includes methanol, ethanol, isopropanol, tert-butanol, tert-butyl methyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, or water. In some embodiments, the solvent is or includes methanol. In some embodiments, the solvent is or includes ethanol. In some embodiments, the solvent is or includes isopropanol. In some embodiments, the solvent is or includes tert-butanol. In some embodiments, the solvent is or includes dimethyl sulfoxide. In some embodiments, the solvent is or includes dimethylformamide. In some embodiments, the solvent is or includes tetrahydrofuran. In some embodiments, the solvent is or includes cyclopentyl methyl ether. In some embodiments, the solvent is or includes 2-methyltetrahydrofuran. In some embodiments, the solvent is or includes water. In some embodiments, the solvent is or includes tert-butyl methyl ether. In some embodiments, the solvent comprises methanol and tert-butyl methyl ether.

[0215] In some embodiments, the solvent is provided in an amount of about 1 L / kg to about 12 L / kg. In some embodiments, the solvent is provided in an amount of about 2 L / kg to about 12 L / kg. In some embodiments, the solvent is provided in an amount of about 4 L / kg to about 12 L / kg. In some embodiments, the solvent is provided in an amount of about 1 L / kg to about 8 L / kg. In some embodiments, the solvent is provided in an amount of about 1 L / kg to about 6 L / kg. In some embodiments, the solvent is provided in an amount of about 1 L / kg to about 4 L / kg. In some embodiments, the solvent is provided in an amount of about 3 L / kg to about 9 L / kg. In some embodiments, the solvent is provided in an amount of about 4 L / kg to about 8 L / kg. In some embodiments, the solvent is provided in an amount of about 5 L / kg to about 7 L / kg. In some embodiments, the solvent is provided in an amount of about 1 L / kg, 2 L / kg, 3 L / kg, 4 L / kg, 5 L / kg, 6 L / kg, 7 L / kg, 8 L / kg, 9 L / kg, 10 L / kg, 11 L / kg, or 12 L / kg. In some embodiments, the solvent is provided in an amount of about 3 L / kg. In some embodiments, the solvent is provided in an amount of about 4 L / kg. In some embodiments, the solvent is present in an amount of about 5 L / kg. In some embodiments, the solvent is provided in an amount of about 6 L / kg. In some embodiments, the solvent is provided in an amount of about 7 L / kg.

[0216] In some embodiments, methanol is provided in an amount of about 0.10 L / kg to about 2.0 L / kg. In some embodiments, methanol is provided in an amount of about 0.25 L / kg to about 2.0 L / kg. In some embodiments, methanol is provided in an amount of about 0.50 L / kg to about 2.0 L / kg. In some embodiments, methanol is provided in an amount of about 0.10 L / kg to about 1.5 L / kg. In some embodiments, methanol is provided in an amount of about 0.10 L / kg to about 1.0 L / kg. In some embodiments, the solvent is provided in an amount of about 0.10 L / kg to about 0.5 L / kg. In some embodiments, methanol is provided in an amount of about 0.20 L / kg to about 1.0 L / kg. In some embodiments, the solvent is provided in an amount of about 0.3 L / kg to about 0.7 L / kg. In some embodiments, the solvent is provided in an amount of about 0.4 L / kg to about 0.6 L / kg. In some embodiments, methanol is provided in an amount of about 0.2 L / kg, 0.3 L / kg, 0.4 L / kg, 0.5 L / kg, 0.6 L / kg, 0.7 L / kg, or about 0.8 L / kg. In some embodiments, methanol is provided in an amount of about 0.3 L / kg. In some embodiments, the solvent is provided in an amount of about 0.4 L / kg. In some embodiments, the solvent is provided in an amount of about 0.5 L / kg. In some embodiments, methanol is provided in an amount of about 0.6 L / kg. In some embodiments, the solvent is provided in an amount of about 0.7 L / kg.

[0217] In some embodiments, tert-butyl methyl ether is provided in an amount of about 2 L / kg to about 12 L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 4 L / kg to about 12 L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 6 L / kg to about 12 L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 2 L / kg to about 8 L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 2 L / kg to about 6 L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 3 L / kg to about 7 L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 4 L / kg to about 6 L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 3 L / kg, 4 L / kg, 5 L / kg, 6 L / kg, or about 7 L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 3 L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 4 L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 5 L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 6 L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 7 L / kg.

[0218] In some embodiments, methanol is provided in an amount of about 0.10 L / kg to about 2.0 L / kg, and tert-butyl methyl ether is provided in an amount of about 2 L / kg to about 12 L / kg. In some embodiments, methanol is provided in an amount of about 0.4 L / kg to about 0.6 L / kg, and tert-butyl methyl ether is provided in an amount of about 4 L / kg to about 6 L / kg. In some embodiments, methanol is provided in an amount of about 0.34 L / kg to about 0.56 L / kg, and tert-butyl methyl ether is provided in an amount of about 3.65 L / kg to about 6.35 L / kg. In some embodiments, methanol is provided in an amount of about 0.48 L / kg, and tert-butyl methyl ether is provided in an amount of about 5.3 L / kg.

[0219] In some embodiments, the reaction conditions include a base. In some embodiments, the base is or includes LiOH, NaOH, or KOH. In some embodiments, the base is LiOH. In some embodiments, the base is NaOH. In some embodiments, the base is KOH. In some embodiments, the base is an aqueous LiOH solution. In some embodiments, the base is an aqueous NaOH solution. In some embodiments, the base is an aqueous KOH solution. In some embodiments, the aqueous base solution is about 5% to about 50%. In some embodiments, the aqueous base solution is about 10% to about 50%. In some embodiments, the aqueous base solution is at about 15°C to about 50°C. In some embodiments, the aqueous base solution is at about 20°C to about 50°C. In some embodiments, the aqueous base solution is at about 25°C to about 50°C. In some embodiments, the aqueous base solution is at about 30% to about 50%. In some embodiments, the aqueous base solution is at about 5°C to about 45°C. In some embodiments, the aqueous base solution is at about 5°C to about 40°C. In some embodiments, the aqueous base solution is at about 5°C to about 35°C. In some embodiments, the aqueous base solution is at about 5% to about 30%. In some embodiments, the aqueous base solution is at about 20°C to about 45°C. In some embodiments, the aqueous base solution is at about 25°C to about 40°C. In some embodiments, the aqueous base solution is at about 28% to about 34%. In some embodiments, the aqueous base solution is at about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% w / w. In some embodiments, the aqueous base solution is at about 5% w / w. In some embodiments, the aqueous base solution is at about 10% w / w. In some embodiments, the aqueous base solution is at about 10% w / w. In some embodiments, the aqueous base solution is at about 15% w / w. In some embodiments, the aqueous base solution is at about 25% w / w. In some embodiments, the aqueous base solution is at about 30% w / w. In some embodiments, the aqueous base solution is at about 35% w / w. In some embodiments, the aqueous base is about 40% w / w. In some embodiments, the base is LiOR, NaOR, or KOR, where R is an optionally substituted C 1-6In some embodiments, the base is an alkoxide, such as LiOR, NaOR, or KOR, where R is an optionally substituted C 1-6 It is aliphatic. In some embodiments, the base is an alkoxide, such as LiOR, NaOR, or KOR, where R is methyl. In some embodiments, the base is an alkoxide, such as LiOR, NaOR, or KOR, where R is ethyl. In some embodiments, the base is an alkoxide, such as LiOR, NaOR, or KOR, where R is propyl. In some embodiments, the base is an alkoxide, such as LiOR, NaOR, or KOR, where R is butyl. In some embodiments, the base is an alkoxide, such as LiOR, NaOR, or KOR, where R is pentyl. In some embodiments, the base is an alkoxide, such as LiOR, NaOR, or KOR, where R is hexyl. In some embodiments, the base is LiOMe. In some embodiments, the base is NaOMe. In some embodiments, the base is KOMe. In some embodiments, the base is LiOEt. In one embodiment, the base is NaOEt. In some embodiments, the base is KOEt. In some embodiments, the base is LiOtBu. In one embodiment, the base is NaOtBu. In some embodiments, the base is KOtBu.

[0220] In some embodiments, the reaction conditions include carrying out the reaction at a temperature T1 (e.g., heating to a temperature T1). In some embodiments, the temperature T1 is about 0°C to 60°C. In some embodiments, the temperature T1 is about 20°C to 60°C. In some embodiments, the temperature T1 is about 24°C to 45°C. In some embodiments, the temperature T1 is about 24°C to 40°C. In some embodiments, the temperature T1 is about 24°C to 35°C. In some embodiments, the temperature T1 is about 24°C to 30°C. In some embodiments, the temperature T1 is about 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, or 35°C. In some embodiments, the temperature T1 is about 30°C.

[0221] In some embodiments, the reaction is allowed to proceed for a period of time. In some embodiments, the reactants are stirred for a period of time. In some embodiments, the period is greater than 1 hour. In some embodiments, the period is greater than 4 hours. In some embodiments, the period is greater than 8 hours. In some embodiments, the period is from about 2 to about 8 hours. In some embodiments, the period is from about 1 to about 12 hours. In some embodiments, the period is from about 2.5 to about 4 hours. In some embodiments, the period is less than 4 hours. In some embodiments, the period is less than 2 hours. In some embodiments, the period is less than 1 hour.

[0222] In some embodiments, the reaction conditions include cooling the reaction mixture to a temperature T2. In some embodiments, the temperature T2 is from about 0°C to about 60°C. In some embodiments, the temperature T2 is from about 0°C to about 50°C. In some embodiments, the temperature T2 is from about 0°C to about 40°C. In some embodiments, the temperature T2 is from about 0°C to about 30°C. In some embodiments, the temperature T2 is from about 10°C to about 60°C. In some embodiments, the temperature T2 is from about 20°C to about 60°C. In some embodiments, the temperature T2 is from about 20°C to about 30°C. In some embodiments, the temperature T2 is from about 15°C to about 25°C. In some embodiments, the temperature T2 is from about 20°C to about 25°C. In some embodiments, the temperature T2 is about 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, or 25°C. In some embodiments, the temperature T2 is about 21°C. In some embodiments, the temperature T2 is about 22° C. In some embodiments, the temperature T2 is about 23° C.

[0223] In some embodiments, the reaction is monitored for completion (e.g., the presence of maribavir or Compound 3). In some embodiments, the reaction is monitored (e.g., by HPLC) for the presence of maribavir or Compound 3. In some embodiments, the reaction is monitored (e.g., by HPLC) for the presence of maribavir in an amount greater than 95.0% a / a. In some embodiments, the reaction is monitored (e.g., by HPLC) for the presence of maribavir in an amount greater than 96.0% a / a. In some embodiments, the reaction is monitored (e.g., by HPLC) for the presence of maribavir in an amount greater than 97.0% a / a. In some embodiments, the reaction is monitored (e.g., by HPLC) for the presence of maribavir in an amount greater than 97.5% a / a. In some embodiments, the reaction is monitored (e.g., by HPLC) for the presence of maribavir in an amount greater than 98.0% a / a. In some embodiments, the reaction is monitored (e.g., by HPLC) for the presence of maribavir in an amount greater than 98.1% a / a. In some embodiments, the reaction is monitored (e.g., by HPLC) for the presence of maribavir in an amount greater than 98.2% a / a. In some embodiments, the reaction is monitored (e.g., by HPLC) for the presence of maribavir in an amount greater than 98.3% a / a. In some embodiments, the reaction is monitored (e.g., by HPLC) for the presence of maribavir in an amount greater than 98.4% a / a. In some embodiments, the reaction is monitored (e.g., by HPLC) for the presence of maribavir in an amount greater than 98.5% a / a. In some embodiments, the reaction is monitored (e.g., by HPLC) for the presence of maribavir in an amount greater than 99.0% a / a.

[0224] In some embodiments, step 3 further comprises (b) phase separating and / or extracting the maribavir or a pharmaceutically acceptable salt thereof from the reaction mixture to provide a first resultant mixture.

[0225] In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adding a first phase separation solvent. In some embodiments, the first phase separation solvent is or comprises chloroform, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, the first phase separation solvent is or comprises chloroform. In some embodiments, the first phase separation solvent is or comprises diethyl ether. In some embodiments, the first phase separation solvent is or comprises ethyl acetate. In some embodiments, the first phase separation solvent is or comprises isopropyl acetate. In some embodiments, the first phase separation solvent is or comprises cyclopentyl methyl ether. In some embodiments, the first phase separation solvent is or comprises toluene. In some embodiments, the first phase separation solvent is or comprises benzene. In some embodiments, the first phase separation solvent is or comprises α,α,α-trifluorotoluene. In some embodiments, the first phase separation solvent is or comprises chlorobenzene. In some embodiments, the first phase separation solvent is or comprises xylene. In some embodiments, the first phase separation solvent is or comprises dichloromethane. In some embodiments, the first phase separation solvent is or comprises tert-butyl methyl ether.

[0226] In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adding a second phase separation solvent. In some embodiments, the second phase separation solvent is aqueous sodium chloride, aqueous lithium chloride, aqueous calcium chloride, or aqueous potassium chloride. In some embodiments, the second phase separation solvent is aqueous sodium chloride. In some embodiments, the second phase separation solvent is aqueous lithium chloride. In some embodiments, the second phase separation solvent is aqueous calcium chloride. In some embodiments, the second phase separation solvent is aqueous potassium chloride.

[0227] In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 4.0 to about 14.0. In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 6.0 to about 10.0. In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 6.0 to about 9.0. In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 6.0 to about 8.0. In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 6.0 to about 7.5. In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 6.0 to about 7.0. In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 6.5 to about 10.0. In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 7.5 to about 10.0. In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 6.8 to about 7.5. In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, or 8.0. In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 6.8. In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 7.0.In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 7.2. In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 7.4. In some embodiments, phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 7.6.

[0228] In some embodiments, step 3 further comprises (c) distilling and / or solvent exchanging the reaction mixture or the first resulting mixture to provide a second resulting mixture comprising maribavir or a pharmaceutically acceptable salt thereof and a solvent.

[0229] In some embodiments, the reaction mixture or first resulting mixture comprises a first solvent. In some embodiments, the first solvent is or comprises chloroform, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, the first solvent is or comprises chloroform. In some embodiments, the first solvent is or comprises diethyl ether. In some embodiments, the first solvent is ethyl acetate. In some embodiments, the first solvent is or comprises isopropyl acetate. In some embodiments, the first solvent is or comprises cyclopentyl methyl ether. In some embodiments, the first solvent is or comprises toluene. In some embodiments, the first solvent is or comprises benzene. In some embodiments, the first solvent is or comprises α,α,α-trifluorotoluene. In some embodiments, the first solvent is or comprises chlorobenzene. In some embodiments, the first solvent is or comprises xylene. In some embodiments, the first solvent is or comprises dichloromethane. In some embodiments, the first solvent is or comprises tert-butyl methyl ether. In some embodiments, the first solvent is removed from the reaction mixture or the first resulting mixture. In some embodiments, the first solvent is removed by distillation.

[0230] In some embodiments, a second solvent is added to the reaction mixture or the first resulting mixture. In some embodiments, the second solvent is or comprises isopropyl alcohol, methanol, ethanol, n-propanol, n-butanol, sec-butanol, tert-butanol, chloroform, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, the second solvent is or comprises methanol. In some embodiments, the second solvent is or comprises ethanol. In some embodiments, the second solvent is or comprises n-propanol. In some embodiments, the second solvent is or comprises n-butanol. In some embodiments, the second solvent is or comprises sec-butanol. In some embodiments, the second solvent is or comprises tert-butanol. In some embodiments, the second solvent is or comprises chloroform. In some embodiments, the second solvent is or comprises diethyl ether. In some embodiments, the second solvent is or comprises ethyl acetate. In some embodiments, the second solvent is or comprises isopropanol. In some embodiments, the second solvent is or comprises cyclopentyl methyl ether. In some embodiments, the second solvent is or comprises toluene. In some embodiments, the second solvent is or comprises benzene. In some embodiments, the second solvent is or comprises α,α,α-trifluorotoluene. In some embodiments, the second solvent is or comprises chlorobenzene. In some embodiments, the second solvent is or comprises xylene. In some embodiments, the second solvent is or comprises dichloromethane. In some embodiments, the second solvent is tert-butyl methyl ether.In some embodiments, the second solvent is or comprises isopropyl acetate.

[0231] In some embodiments, the second resulting mixture contains less than 1.0% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the second resulting mixture contains less than 0.75% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the second resulting mixture contains less than 0.50% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the second resulting mixture contains less than 0.25% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the second resulting mixture contains less than 1.0% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the second resulting mixture contains less than 0.2% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the second resulting mixture contains less than 0.09% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the second resulting mixture contains less than 0.05% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the second resulting mixture contains an undetectable amount of water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the amount of water in the second resulting mixture is 1 In some embodiments, the amount of water in the second resulting mixture is measured by Karl Fischer.

[0232] In some embodiments, the second resulting mixture comprises about 10-30% w / w maribavir or a pharmaceutically acceptable salt thereof (e.g.,1 H NMR measurements). In some embodiments, the second resulting mixture comprises about 13-25% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the second resulting mixture comprises about 15-22% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the second resulting mixture comprises about 16-20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the second resulting mixture comprises about 17-20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the second resulting mixture comprises about 17-19% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the second resulting mixture contains about 15%, 16%, 17%, 18%, 19%, 20%, 21%, or 22% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the second resulting mixture comprises about 15% w / w maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the second resulting mixture comprises about 16% w / w maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the second resulting mixture comprises about 17% w / w maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the second resulting mixture comprises about 18% w / w maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the second resulting mixture comprises about 19% w / w maribavir or a pharmaceutically acceptable salt thereof (e.g., 1H NMR measurements). In some embodiments, the second resulting mixture comprises about 20% w / w maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the second resulting mixture comprises about 21% w / w maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the second resulting mixture comprises about 22% w / w maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements).

[0233] In some embodiments, step 3 further comprises (d) crystallizing maribavir or a pharmaceutically acceptable salt thereof (from the reaction mixture, the first obtained mixture, or the second obtained mixture).

[0234] In some embodiments, crystallization involves providing a crystallization mixture containing maribavir or a pharmaceutically acceptable salt thereof and a primary solvent. In some embodiments, the primary solvent is or comprises chloroform, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, the primary solvent is or comprises chloroform. In some embodiments, the primary solvent is or comprises diethyl ether. In some embodiments, the primary solvent is or comprises ethyl acetate. In some embodiments, the primary solvent is or comprises cyclopentyl methyl ether. In some embodiments, the primary solvent is or comprises toluene. In some embodiments, the primary solvent is or comprises benzene. In some embodiments, the primary solvent is or comprises α,α,α-trifluorotoluene. In some embodiments, the primary solvent is or comprises chlorobenzene. In some embodiments, the primary solvent is or comprises xylene. In some embodiments, the primary solvent is or comprises dichloromethane, hi some embodiments, the primary solvent is or comprises isopropyl acetate.

[0235] In some embodiments, the crystallization mixture contains less than 0.2% w / w water (e.g., 1 In some embodiments, the crystallization mixture contains less than 0.09% w / w water (e.g., 1 In some embodiments, the crystallization mixture contains less than 1.0% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the crystallization mixture contains less than 0.75% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the crystallization mixture contains less than 0.50% w / w water (e.g.,1 H NMR or Karl Fischer measurements). In some embodiments, the crystallization mixture contains less than 0.25% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the crystallization mixture contains less than 1.0% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the crystallization mixture contains less than 0.2% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the crystallization mixture contains less than 0.09% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the crystallization mixture contains less than 0.05% w / w water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the second resulting mixture contains an undetectable amount of water (e.g., 1 H NMR or Karl Fischer measurements). In some embodiments, the amount of water in the crystallization mixture is 1 1 H NMR. In some embodiments, the amount of water in the crystallization mixture is measured by Karl Fischer.

[0236] Without wishing to be bound by any particular theory, it is believed that a concentration of maribavir or a pharmaceutically acceptable salt thereof that is too low may result in the possible dissolution of the seed crystals, potentially affecting the yield and / or particle size of maribavir. It is also believed that a concentration of maribavir or a pharmaceutically acceptable salt thereof that is too high may result in spontaneous crystallization and / or affect the particle size of maribavir. In some embodiments, the crystallization mixture comprises about 10-30% w / w maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the crystallization mixture comprises about 13-25% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1H NMR measurements). In some embodiments, the crystallization mixture comprises about 15-22% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the crystallization mixture comprises about 16-20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the crystallization mixture comprises about 17-20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the crystallization mixture comprises about 17-19% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the crystallization mixture contains about 15%, 16%, 17%, 18%, 19%, 20%, 21%, or 22% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the crystallization mixture comprises about 15% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the crystallization mixture comprises about 16% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the crystallization mixture comprises about 17% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the crystallization mixture comprises about 18% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the crystallization mixture comprises about 19% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the crystallization mixture comprises about 20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements). In some embodiments, the crystallization mixture comprises about 21% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1H NMR measurements). In some embodiments, the crystallization mixture comprises about 22% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 H NMR measurements).

[0237] In some embodiments, the crystallization further comprises heating the crystallization mixture to a temperature T3. In some embodiments, the temperature T3 is greater than about 60°C. In some embodiments, the temperature T3 is greater than about 25°C. In some embodiments, the temperature T3 is less than about 100°C. In some embodiments, the temperature T3 is between about 50°C and about 150°C. In some embodiments, the temperature T3 is between about 50°C and about 100°C. In some embodiments, the temperature T3 is between about 50°C and about 90°C. In some embodiments, the temperature T3 is between about 50°C and about 85°C. In some embodiments, the temperature T3 is between about 60°C and about 110°C. In some embodiments, the temperature T3 is between about 70°C and about 110°C. In some embodiments, the temperature T3 is between about 80°C and about 110°C. In some embodiments, the temperature T3 is between about 60°C and about 100°C. In some embodiments, the temperature T3 is between about 70°C and about 90°C. In some embodiments, the temperature T3 is about 74°C to about 90°C. In some embodiments, the temperature T3 is about 77°C to about 88°C. In some embodiments, the temperature T3 is about 82°C to about 86°C. In some embodiments, the temperature T3 is about 83°C to about 85°C. In some embodiments, the temperature T3 is about 77°C, 78°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C, 85°C, 86°C, 87°C, or 88°C. In some embodiments, the temperature T3 is about 81°C. In some embodiments, the temperature T3 is about 82°C. In some embodiments, the temperature T3 is about 83°C. In some embodiments, the temperature T3 is about 84°C. In some embodiments, the temperature T3 is about 85°C. In some embodiments, the temperature T3 is about 86°C.

[0238] In some embodiments, a secondary solvent is added to the crystallization mixture. In some embodiments, the secondary solvent is or includes chloroform, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, the secondary solvent is or includes chloroform. In some embodiments, the secondary solvent is or includes diethyl ether. In some embodiments, the secondary solvent is or includes ethyl acetate. In some embodiments, the secondary solvent is or includes isopropyl acetate. In some embodiments, the secondary solvent is or includes cyclopentyl methyl ether. In some embodiments, the secondary solvent is or includes benzene. In some embodiments, the secondary solvent is or includes α,α,α-trifluorotoluene. In some embodiments, the secondary solvent is or includes chlorobenzene. In some embodiments, the secondary solvent is or includes xylene. In some embodiments, the secondary solvent is or includes dichloromethane. In some embodiments, the secondary solvent is or comprises toluene.

[0239] In some embodiments, after the addition of the secondary solvent, the crystallization mixture is aged for 10 minutes to 2 hours. In some embodiments, after the addition of the secondary solvent, the crystallization mixture is aged for 10 minutes to 1.5 hours. In some embodiments, after the addition of the secondary solvent, the crystallization mixture is aged for 10 minutes to 1 hour. In some embodiments, after the addition of the secondary solvent, the crystallization mixture is aged for 10 minutes to 45 minutes. In some embodiments, after the addition of the secondary solvent, the crystallization mixture is aged for 10 minutes to 30 minutes. In some embodiments, after the addition of the secondary solvent, the crystallization mixture is aged for less than about 2 hours. In some embodiments, after the addition of the secondary solvent, the crystallization mixture is aged for less than 60 minutes. In some embodiments, after the addition of the secondary solvent, the crystallization mixture is aged for less than 30 minutes. In some embodiments, after the addition of the secondary solvent, the crystallization mixture is aged for less than 10 minutes. In some embodiments, after the addition of the secondary solvent, the crystallization mixture is aged for less than 5 minutes. In some embodiments, after the addition of the secondary solvent, the crystallization mixture is aged for at least 30 minutes.

[0240] In some embodiments, seed crystals are added to the crystallization mixture. Without wishing to be bound by any particular theory, it is believed that if the amount of seed crystals is too low, it may allow spontaneous / uncontrolled crystallization, which may affect particle size. Furthermore, it is believed that if the amount of seed crystals is too high, it may have a negative effect on particle size.

[0241] In some embodiments, the seed crystals are maribavir or a pharmaceutically acceptable salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.01% to about 0.50% w / w of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.01 wt% to about 0.15 wt% of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.15% to about 0.30% w / w of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.05% to about 0.30% w / w of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.10% to about 0.20% w / w of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.12% to about 0.18% w / w of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.14% to about 0.16% w / w of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.13% w / w of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.14% w / w of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.15% w / w of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.16% w / w of Compound 3 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.17% w / w of Compound 3 or a salt thereof.

[0242] Without wishing to be bound by any particular theory, it is believed that the size of the seed crystals may affect the particle size of the maribavir (e.g., too small a seed crystal may result in a smaller particle size of the maribavir, while too large a seed crystal may result in a larger particle size of the maribavir). In some embodiments, the size of the seed crystals may be characterized by their d(50) value or specific surface area ("SSA") value. In some embodiments, the size of the seed crystals may be characterized by their d(50) value. It is understood that the "d(50) value" refers to the median particle size of a sample (e.g., 50% of the particles are smaller than the d(50) value and 50% of the particles are larger than the d(50) value). In some embodiments, the seed crystals comprise a d(50) value of about 1.00 μm to about 10.00 μm. In some embodiments, the seed crystals comprise a d(50) value of about 1.00 μm to about 9.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 1.00 μm to about 8.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 1.00 μm to about 7.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 1.00 μm to about 6.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 1.00 μm to about 5.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 1.00 μm to about 4.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 1.00 μm to about 3.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 2.00 μm to about 10.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 3.00 μm to about 10.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 4.00 μm to about 10.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 5.00 μm to about 10.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 6.00 μm to about 10.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 7.00 μm to about 10.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 1.25 μm to about 9.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 1.75 μm to about 8.00 μm.In some embodiments, the seed crystal comprises a d(50) value of about 2.25 μm to about 7.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 2.75 μm to about 6.25 μm. In some embodiments, the seed crystal comprises a d(50) value of about 3.00 μm to about 6.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 1.25 μm, about 1.75 μm, about 2.25 μm, about 2.75 μm, about 3.00 μm, about 4.00 μm, about 5.00 μm, about 6.00 μm, about 6.25 μm, 7.00 μm, about 8.00 μm, about 9.00 μm, or about 10.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 1.25 μm. In some embodiments, the seed crystal comprises a d(50) value of about 1.75 μm. In some embodiments, the seed crystal comprises a d(50) value of about 2.25 μm. In some embodiments, the seed crystal comprises a d(50) value of about 2.75 μm. In some embodiments, the seed crystal comprises a d(50) value of about 3.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 4.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 5.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 6.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 6.25 μm. In some embodiments, the seed crystal comprises a d(50) value of about 7.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 8.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 9.00 μm. In some embodiments, the seed crystal comprises a d(50) value of about 10.00 μm.

[0243] In some embodiments, after the seed crystals are added, the crystallization mixture is aged for about 15 minutes to about 120 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for about 30 minutes to about 90 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for about 30 minutes to about 60 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for about 60 minutes to about 90 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for about 90 minutes to about 120 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for at least about 5 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for at least about 15 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for at least about 30 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for at least about 60 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for at least about 90 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for at least about 120 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for about 30 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for about 60 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for about 90 minutes. In some embodiments, after the seed crystals are added, the crystallization mixture is aged for about 120 minutes.

[0244] In some embodiments, an additional secondary solvent is added to the crystallization mixture. In some embodiments, the additional secondary solvent is added in an amount of about 5 / 1 to about 1 / 5 (kg / kg) of the total primary solvent. In some embodiments, the additional secondary solvent is added in an amount of about 2 / 1 to about 1 / 2 (kg / kg) of the total primary solvent. In some embodiments, the additional secondary solvent is added in an amount of about 24 / 7 to about 2 / 7 (kg / kg) of the total primary solvent. In some embodiments, the additional secondary solvent is added in an amount of about 16 / 7 to about 4 / 7 (kg / kg) of the total primary solvent. In some embodiments, the additional secondary solvent is added in an amount of about 8 / 7 (kg / kg) of the total primary solvent. In some embodiments, the additional secondary solvent is added in an amount of about 9 / 7 (kg / kg) of the total primary solvent. In some embodiments, the additional secondary solvent is added in an amount of about 10 / 7 (kg / kg) of the total primary solvent. In some embodiments, the additional secondary solvent is added in an amount of about 11 / 7 (kg / kg) of the total primary solvent. In some embodiments, the additional secondary solvent is added in an amount of about 12 / 7 (kg / kg) of the total primary solvent. In some embodiments, the additional secondary solvent is added in an amount of about 13 / 7 (kg / kg) of the total primary solvent. In some embodiments, the additional secondary solvent is added in an amount of about 15 / 7 (kg / kg) of the total primary solvent.

[0245] In some embodiments, after adding the additional secondary solvent, the crystallization mixture is stirred for a period of time. In some embodiments, the period is at least 30 minutes. In some embodiments, the period is at least 60 minutes. In some embodiments, the period is about 15 minutes to 120 minutes. In some embodiments, the period is about 15 minutes to 90 minutes. In some embodiments, the period is about 15 minutes to 60 minutes. In some embodiments, the period is about 30 minutes to 90 minutes. In some embodiments, the period is about 45 minutes to 90 minutes. In some embodiments, the period is about 60 minutes to 90 minutes. In some embodiments, the period is about 15 minutes. In some embodiments, the period is about 30 minutes. In some embodiments, the period is about 45 minutes. In some embodiments, the period is about 60 minutes. In some embodiments, the period is about 90 minutes.

[0246] In some embodiments, after the additional secondary solvent is added, the crystallization mixture is stirred at a temperature T3. In some embodiments, the temperature T3 is from about 50°C to about 150°C. In some embodiments, the temperature T3 is from about 50°C to about 100°C. In some embodiments, the temperature T3 is from about 50°C to about 90°C. In some embodiments, the temperature T3 is from about 50°C to about 80°C. In some embodiments, the temperature T3 is from about 70°C to about 115°C. In some embodiments, the temperature T3 is from about 80°C to about 115°C. In some embodiments, the temperature T3 is from about 60°C to about 105°C. In some embodiments, the temperature T3 is from about 70°C to about 95°C. In some embodiments, the temperature T3 is from about 75°C to about 90°C. In some embodiments, the temperature T3 is from about 77°C to about 88°C. In some embodiments, the temperature T3 is from about 81°C to about 87°C. In some embodiments, the temperature T3 is about 81°C to about 86°C. In some embodiments, the temperature T3 is about 80°C, 81°C, 82°C, 84°C, 85°C, 86°C, 87°C, 88°C, 89°C, or 90°C. In some embodiments, the temperature T3 is about 83°C. In some embodiments, the temperature T3 is about 84°C. In some embodiments, the temperature T3 is about 85°C.

[0247] In some embodiments, the crystallization mixture is cooled to a temperature T4. In some embodiments, the temperature T4 is about -20°C to about 25°C. In some embodiments, the temperature T4 is about -15°C to about 20°C. In some embodiments, the temperature T4 is about -15°C to about 15°C. In some embodiments, the temperature T4 is about -15°C to about 10°C. In some embodiments, the temperature T4 is about -15°C to about 5°C. In some embodiments, the temperature T4 is about -15°C to about 0°C. In some embodiments, the temperature T4 is about -5°C to about 25°C. In some embodiments, the temperature T4 is about -0°C to about 25°C. In some embodiments, the temperature T4 is about 5°C to about 25°C. In some embodiments, the temperature T4 is about 10°C to about 25°C. In some embodiments, the temperature T4 is about -10°C to about 20°C. In some embodiments, temperature T4 is about -5°C to about 15°C. In some embodiments, temperature T4 is about 0°C to about 10°C. In some embodiments, temperature T4 is about 3°C ​​to about 7°C. In some embodiments, temperature T4 is about 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or 10°C. In some embodiments, temperature T4 is about 4°C. In some embodiments, temperature T4 is about 5°C. In some embodiments, temperature T4 is about 6°C.

[0248] In some embodiments, the crystallization mixture is cooled to temperature T4 over a period of about 0.5 hours to about 8 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over a period of about 1 hour to about 5 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over a period of about 2 hours to about 4 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over a period of at least 1 hour. In some embodiments, the crystallization mixture is cooled to temperature T4 over a period of at least 3 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over a period of about 0.5, 1, 2, 3, 4, 5, 6, 7, or 8 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over a period of about 2 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over a period of about 3 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over a period of about 4 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over a period of about 6 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over a period of about 8 hours.

[0249] In some embodiments, the crystalline compound is stirred at temperature T4 for a period of time. In some embodiments, the period is about 3 hours to about 30 hours. In some embodiments, the period is about 3 hours to about 18 hours. In some embodiments, the period is about 3 hours to about 15 hours. In some embodiments, the period is about 3 hours to about 12 hours. In some embodiments, the period is about 3 hours to about 8 hours. In some embodiments, the period is about 3 hours to about 5 hours. In some embodiments, the period is less than about 18 hours. In some embodiments, the period is less than about 12 hours. In some embodiments, the period is less than about 6 hours. In some embodiments, the period is less than about 3 hours.

[0250] In some embodiments, step 3 further comprises (e) optionally filtering or washing the crystallization mixture to provide a filtered mixture. In some embodiments, step 3 further comprises filtering the crystallization mixture to provide a filtered mixture. In some embodiments, step 3 further comprises washing the crystallization mixture to provide a filtered mixture. In some embodiments, the crystallization mixture is washed with chloroform, diethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluorotoluene, chlorobenzene, xylene, or dichloromethane. In some embodiments, the crystallization mixture is washed with chloroform. In some embodiments, the crystallization mixture is washed with diethyl ether. In some embodiments, the crystallization mixture is washed with ethyl acetate. In some embodiments, the crystallization mixture is washed with isopropyl acetate. In some embodiments, the crystallization mixture is washed with cyclopentyl methyl ether. In some embodiments, the crystallization mixture is washed with benzene. In some embodiments, the crystallization mixture is washed with α,α,α-trifluorotoluene. In some embodiments, the crystallization mixture is washed with chlorobenzene. In some embodiments, the crystallization mixture is washed with xylene. In some embodiments, the crystallization mixture is washed with dichloromethane. In some embodiments, the crystallization mixture is washed with toluene.

[0251] In some embodiments, the crystallization wash solvent is provided in an amount of about 0.30 L / kg to about 2.00 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.30 L / kg to about 1.50 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.30 L / kg to about 1.25 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.30 L / kg to about 1.00 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.30 L / kg to about 0.9 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.50 L / kg to about 2.00 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.75 L / kg to about 2.00 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.85 L / kg to about 2.00 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.30 L / kg to about 2.00 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.40 L / kg to about 1.75 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.50 L / kg to 1.50 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.60 L / kg to about 1.25 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.67 L / kg to about 1.00 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.75 L / kg to about 0.90 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.80 L / kg to about 0.85 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.60 L / kg, 0.65 L / kg, 0.70 L / kg, 0.75 L / kg, 0.80 L / kg, 0.84 L / kg, 0.90 L / kg, or 0.95 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.75 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.80 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.84 L / kg. In some embodiments, the crystallization wash solvent is provided in an amount of about 0.90 L / kg.In some embodiments, the crystallization wash solvent is provided in an amount of about 0.95 L / kg.

[0252] In some embodiments, the crystallization wash solvent is provided at a temperature of about -20°C to about 60°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about -10°C to about 30°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about -10°C to about 20°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about -10°C to about 10°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about -5°C to about 40°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about 0°C to about 40°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about 5°C to about 40°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about -5°C to about 30°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about -5°C to about 20°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about 0°C to about 20°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about 0°C to about 15°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about 0°C to about 10°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about 2°C to about 8°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about 4°C to about 6°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, or 9°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about 4°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about 5°C. In some embodiments, the crystallization wash solvent is provided at a temperature of about 6°C.

[0253] In some embodiments, the crystallization wash solvent is provided over a period of time that is less than 5 days. In some embodiments, the crystallization wash solvent is provided over a period of time that is about 1 minute to about 5 days. In some embodiments, the crystallization wash solvent is provided over a period of time that is about 1 minute to about 24 hours. In some embodiments, the crystallization wash solvent is provided over a period of time that is about 1 minute to about 12 hours. In some embodiments, the crystallization wash solvent is provided over a period of time that is about 1 minute to about 8 hours. In some embodiments, the crystallization wash solvent is provided over a period of time that is about 1 minute to about 6 hours. In some embodiments, the crystallization wash solvent is provided over a period of time that is about 1 minute to about 4 hours. In some embodiments, the crystallization wash solvent is provided over a period of time that is about 1 minute to about 2 hours. In some embodiments, the crystallization wash solvent is provided over a period of time that is about 1 minute to about 1 hour. In some embodiments, the crystallization wash solvent is provided for a period of time, the period being about 1 minute to about 45 minutes. In some embodiments, the crystallization wash solvent is provided for a period of time, the period being about 1 minute to about 30 minutes. In some embodiments, the crystallization wash solvent is provided for a period of time, the period being about 1 minute to about 30 minutes. In some embodiments, the crystallization wash solvent is provided for a period of time, the period being about 15 minutes. In some embodiments, the crystallization wash solvent is provided for a period of time, the period being at least 15 minutes. In some embodiments, the crystallization wash solvent is provided for a period of time, the period being at least 30 minutes. In some embodiments, the crystallization wash solvent is provided for a period of time, the period being at least 60 minutes. In some embodiments, the crystallization wash solvent is provided for a period of time, the period being at least 90 minutes. In some embodiments, the crystallization wash solvent is provided for a period of time, the period being at least 1 day.

[0254] In some embodiments, step 3 further comprises (f) drying the filtered mixture.

[0255] In some embodiments, drying comprises heating the filtered mixture to a temperature T5 without stirring for a period of time. In some embodiments, the temperature T5 is from about 20°C to about 100°C. In some embodiments, the temperature T5 is from about 20°C to about 70°C. In some embodiments, the temperature T5 is from about 20°C to about 50°C. In some embodiments, the temperature T5 is from about 30°C to about 80°C. In some embodiments, the temperature T5 is from about 40°C to about 80°C. In some embodiments, the temperature T5 is from about 50°C to about 80°C. In some embodiments, the temperature T5 is from about 35°C to about 60°C. In some embodiments, the temperature T5 is from about 40°C to about 50°C. In some embodiments, the temperature T5 is 20°C or less. In some embodiments, the temperature T5 is about 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, or 100°C or less. In some embodiments, the temperature T5 is 40° C. or less. In some embodiments, the temperature T5 is 50° C. or less. In some embodiments, the temperature T5 is 60° C. or less.

[0256] In some embodiments, the filtered compound is held at temperature T5 for a period of time. In some embodiments, the period is at least 1 hour. In some embodiments, the period is at least 2 hours. In some embodiments, the period is at least 3 hours. In some embodiments, the period is at least 4 hours. In some embodiments, the period is at least 5 hours. In some embodiments, the period is at least 6 hours. In some embodiments, the period is at least 7 hours. In some embodiments, the period is at least 8 hours. In some embodiments, the period is at least 9 hours. In some embodiments, the period is at least 10 hours.

[0257] In some embodiments, drying comprises heating the filtered mixture to a temperature T6 without stirring for a period of time. In some embodiments, the temperature T6 is from about 20°C to about 100°C. In some embodiments, the temperature T6 is from about 40°C to about 100°C. In some embodiments, the temperature T6 is from about 20°C to about 80°C. In some embodiments, the temperature T6 is from about 20°C to about 70°C. In some embodiments, the temperature T6 is from about 20°C to about 60°C. In some embodiments, the temperature T6 is from about 30°C to about 60°C. In some embodiments, the temperature T6 is from about 40°C to about 60°C. In some embodiments, the temperature T6 is from about 45°C to about 55°C. In some embodiments, the temperature T6 is from about 45°C to about 50°C. In some embodiments, the temperature T6 is 25°C, 30°C, 40°C, 45°C, 50°C, 55°C, 60°C or less. In some embodiments, the temperature T6 is 90°C or less. In some embodiments, temperature T6 is 70° C. or less. In some embodiments, temperature T6 is 60° C. or less. In some embodiments, temperature T6 is 55° C. or less. In some embodiments, temperature T6 is 50° C. or less. In some embodiments, temperature T6 is 45° C. or less. In some embodiments, temperature T6 is 40° C. or less.

[0258] In some embodiments, the filtered compound is held at temperature T6 for a period of time. In some embodiments, the period is about 1 hour to 5 days. In some embodiments, the period is about 1 hour to 2 days. In some embodiments, the period is about 1 hour to 1 day. In some embodiments, the period is about 1 hour to 12 hours. In some embodiments, the period is about 1 hour to 6 hours. In some embodiments, the period is at least 1 hour. In some embodiments, the period is at least 2 hours. In some embodiments, the period is at least 3 hours. In some embodiments, the period is at least 4 hours. In some embodiments, the period is at least 5 hours. In some embodiments, the period is at least 6 hours. In some embodiments, the period is until the filtered mixture appears dry.

[0259] In some embodiments, the period is until about 100 ppm to about 1600 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until about 100 ppm to about 1400 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until about 100 ppm to about 1200 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until about 100 ppm to about 1000 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until about 100 ppm to about 800 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until about 100 ppm to about 700 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until about 300 ppm to about 1400 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until about 500 ppm to about 1400 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until about 700 ppm to about 1400 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until about 300 ppm to about 1200 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until about 500 ppm to about 1000 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until about 600 ppm to about 800 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until about 650 ppm to about 750 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until less than 1500 ppm of toluene is present (e.g., GCHS measurement). In some embodiments, the period is until less than about 1200 ppm toluene is present (e.g., GCHS measurement). In some embodiments, the period is until less than about 1000 ppm toluene is present (e.g., GCHS measurement).In some embodiments, the period is until less than 800 ppm toluene is present (e.g., GCHS measurement). In some embodiments, the period is until less than about 700 ppm toluene is present (e.g., GCHS measurement). In some embodiments, the period is until less than about 600 ppm toluene is present (e.g., GCHS measurement). In some embodiments, the period is until less than about 500 ppm toluene is present (e.g., GCHS measurement). In some embodiments, the period is until less than about 400 ppm toluene is present (e.g., GCHS measurement). In some embodiments, the period is until less than about 300 ppm toluene is present (e.g., GCHS measurement).

[0260] In some embodiments, the period is until about 1000 ppm to about 10,000 ppm of isopropyl acetate is present (e.g., GCHS measurements). In some embodiments, the period is until about 1000 ppm to about 8,000 ppm of isopropyl acetate is present (e.g., GCHS measurements). In some embodiments, the period is until about 1000 ppm to about 6,000 ppm of isopropyl acetate is present (e.g., GCHS measurements). In some embodiments, the period is until about 1000 ppm to about 5,000 ppm of isopropyl acetate is present (e.g., GCHS measurements). In some embodiments, the period is until about 1000 ppm to about 4,000 ppm of isopropyl acetate is present (e.g., GCHS measurements). In some embodiments, the period is until about 1000 ppm to about 3,000 ppm of isopropyl acetate is present (e.g., GCHS measurements). In some embodiments, the period is until about 3,000 ppm to about 10,000 ppm of isopropyl acetate is present (e.g., GCHS measurements). In some embodiments, the period is until about 4,000 ppm to about 10,000 ppm of isopropyl acetate is present (e.g., GCHS measurements). In some embodiments, the period is until about 5,000 ppm to about 10,000 ppm of isopropyl acetate is present (e.g., GCHS measurements). In some embodiments, the period is until about 2,000 ppm to about 8,000 ppm of isopropyl acetate is present (e.g., GCHS measurements). In some embodiments, the period is until about 3,000 ppm to about 6,000 ppm of isopropyl acetate is present (e.g., GCHS measurements). In some embodiments, the period is until about 4,000 ppm to about 5,000 ppm of isopropyl acetate is present (e.g., GCHS measurements). In some embodiments, the period is until less than about 10,000 ppm isopropyl acetate is present (e.g., as measured by GCHS). In some embodiments, the period is until less than about 8,000 ppm isopropyl acetate is present (e.g., as measured by GCHS). In some embodiments, the period is until less than about 6,000 ppm isopropyl acetate is present (e.g., as measured by GCHS).In some embodiments, the period is until less than about 5,000 ppm isopropyl acetate is present (e.g., as measured by GCHS). In some embodiments, the period is until less than about 4,000 ppm isopropyl acetate is present (e.g., as measured by GCHS). In some embodiments, the period is until less than about 3,000 ppm isopropyl acetate is present (e.g., as measured by GCHS). In some embodiments, the period is until less than about 2,000 ppm isopropyl acetate is present (e.g., as measured by GCHS). In some embodiments, the period is until less than about 1,000 ppm isopropyl acetate is present (e.g., as measured by GCHS).

[0261] In some embodiments, step 3 provides unmilled maribavir or a pharmaceutically acceptable salt thereof. In some embodiments, step 3 further comprises (g) milling the unmilled maribavir or a pharmaceutically acceptable salt thereof to obtain milled maribavir or a pharmaceutically acceptable salt thereof. In some embodiments, milling comprises formulating into tablets (e.g., 200 mg tablets).

[0262] Formulations and Compositions In some embodiments, provided compositions comprise at least 90% maribavir by weight. In some embodiments, provided compositions comprise at least 95% maribavir by weight. In some embodiments, provided compositions comprise at least 99% maribavir by weight. In some embodiments, provided compositions comprise at least 99.5% maribavir by weight. In some embodiments, provided compositions comprise at least 99.6% maribavir by weight. In some embodiments, provided compositions comprise at least 99.7% maribavir by weight. In some embodiments, provided compositions comprise at least 99.8% maribavir by weight. In some embodiments, provided compositions comprise at least 99.9% maribavir by weight.

[0263] In some embodiments, the provided compositions contain maribavir that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the composition or compound does not contain significant amounts of foreign matter. Such foreign matter may include starting materials, residual solvents, or other impurities that may result from the preparation and / or isolation of maribavir.

[0264] In some embodiments, the disclosure provides a composition comprising maribavir and one or more compounds selected from Compound 2, Compound 3, and Compound 4. In some embodiments, such a composition comprises 0.01-0.05% (w / w) of Compound 2, 0.01-0.05% (w / w) of Compound 3, and / or 0.01-0.05% (w / w) of Compound 4. In some embodiments, such a composition comprises 0.01-0.05% (a / a) of Compound 2, 0.01-0.05% (a / a) of Compound 3, and / or 0.01-0.05% (a / a) of Compound 4, as measured by HPLC. In some embodiments, the disclosure provides a composition comprising maribavir and 0.01-0.5% ent-maribavir (i.e., D-maribavir). [ka]

[0265] In some embodiments, the present disclosure provides a composition described in any of Tables 4-12 to 4-20 of Example 4.

[0266] In some embodiments, Steps 1-3 provide a particular polymorphic form of maribavir. In some embodiments, Steps 1-3 provide Form VI of maribavir (e.g., at least 90%, 95%, or 99% by weight of Form VI of maribavir), as described in U.S. Pat. No. 6,482,939. In some embodiments, Steps 1-3 provide Form VI of maribavir that is substantially free of other polymorphic forms of maribavir. As used herein, the term "polymorphic form" includes solvates and hydrates.

[0267] In some embodiments, provided compositions comprise maribavir Form VI (e.g., at least 90%, 95%, or 99% by weight of maribavir Form VI) as described in U.S. Pat. No. 6,482,939. In some embodiments, provided compositions comprise maribavir Form VI (e.g., at least 90%, 95%, or 99% by weight of maribavir Form VI) as described in U.S. Pat. No. 6,482,939, and another polymorphic form of maribavir, such as those described in U.S. Pat. No. 6,482,939, U.S. Pat. No. 8,546,344, or U.S. Pat. No. 11,130,777. In some embodiments, provided compositions comprise maribavir Form VI as described in U.S. Pat. No. 6,482,939, and an isopropyl acetate solvate of maribavir (e.g., as described in U.S. Pat. No. 6,482,939, U.S. Pat. No. 8,546,344, or U.S. Pat. No. 11,130,777). In some embodiments, provided compositions comprise maribavir Form VI and less than 10%, 5%, 1%, or 0.5% by weight of another polymorphic form of maribavir (e.g., those described in U.S. Pat. No. 6,482,939, U.S. Pat. No. 8,546,344, or U.S. Pat. No. 11,130,777). In some embodiments, provided compositions comprise maribavir Form VI and less than 10%, 5%, 1%, or 0.5% by weight of another polymorphic form of maribavir (e.g., those described in U.S. Pat. No. 6,482,939, U.S. Pat. No. 8,546,344, or U.S. Pat. No. 11,130,777). In some embodiments, provided compositions comprise maribavir Form VI substantially free of other polymorphic forms, e.g., those described in U.S. Pat. No. 6,482,939, U.S. Pat. No. 8,546,344, or U.S. Pat. No. 11,130,777.

[0268] In some embodiments, maribavir (eg, Form VI) is milled (eg, hammer milled) and formulated into tablets (eg, 200 mg tablets).

[0269] Particle size distribution ("PSD") is a measurement that defines the number of particles present according to size. It is understood that PSD is a valuable indicator of quality and performance and is necessary to ensure consistent pharmaceutical manufacturability. For example, PSD can affect the ease of handling when formulating compounds and excipients (e.g., tableting). Consistent formulation is important to ensure that the active drug is delivered to the correct location in the body, at the correct concentration, and at the correct rate. In some embodiments, the present disclosure provides compositions of maribavir and methods for producing compositions containing maribavir using a PSD that results in consistent tablet formulation. In some embodiments, Steps 1, 2, 3, and / or milling (e.g., hammer milling) provide maribavir with a PSD that enables the production of tablets with uniformity. In some embodiments, Step 3 provides maribavir Form VI particles with a desired PSD. In some embodiments, the present disclosure provides compositions containing maribavir Form VI particles with a PSD of about 100 to about 400 μm. In some embodiments, the present disclosure provides compositions comprising maribavir Form VI particles having a PSD of d(50) of about 100 to about 400 μm, wherein such maribavir Form VI is produced by using maribavir seeds having a PSD of d(50) of about 1 to about 10 μm. In some embodiments, the present disclosure provides methods for producing maribavir Form VI particles by using maribavir Form VI seeds having a PSD of d(50) of about 1 to about 10 μm.

[0270] In some embodiments, maribavir or a pharmaceutically acceptable salt thereof has a PSD of d(50) of about 50 to about 500 μm. In some embodiments, maribavir or a pharmaceutically acceptable salt thereof has a PSD of d(50) of about 100 to about 400 μm. In some embodiments, maribavir or a pharmaceutically acceptable salt thereof has a PSD of d(50) of about 170 to about 350 μm. In some embodiments, maribavir or a pharmaceutically acceptable salt thereof has a PSD of d(50) of about 170 to about 226 μm. In some embodiments, maribavir or a pharmaceutically acceptable salt thereof has a PSD of d(50) of about 227 to about 280 μm. In some embodiments, maribavir or a pharmaceutically acceptable salt thereof has a PSD of d(50) of about 281 to about 336 μm.

[0271] In some aspects, the present disclosure provides a composition comprising maribavir or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a composition made by the methods (e.g., steps 1-3) disclosed herein. In some embodiments, the present disclosure provides a composition comprising maribavir or a pharmaceutically acceptable salt thereof, and: [ka] or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the present disclosure provides a composition comprising 0.01 to 0.10% (w / w HPLC) of compound 2 relative to maribavir. In some embodiments, the present disclosure provides a composition comprising 0.01 to 0.05% w / w (e.g., as measured by HPLC) of compound 2 relative to maribavir. In some embodiments, the present disclosure provides a composition comprising 0.02 to 0.05% w / w (e.g., as measured by HPLC) of compound 2 relative to maribavir. In some embodiments, the present disclosure provides a composition comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% w / w (e.g., as measured by HPLC) of compound 2 relative to maribavir. In some embodiments, the present disclosure provides a composition comprising 0.01 to 0.10% a / a (e.g., as measured by HPLC) of compound 2 relative to maribavir. In some embodiments, the present disclosure provides a composition comprising 0.01 to 0.05% a / a (e.g., as measured by HPLC) of compound 2 relative to maribavir. In some embodiments, the disclosure provides compositions comprising Compound 2 at 0.02-0.05% a / a (e.g., as measured by HPLC) relative to maribavir. In some embodiments, the disclosure provides compositions comprising Compound 2 at less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% a / a (e.g., as measured by HPLC) relative to maribavir. In some embodiments, the disclosure provides compositions wherein Compound 2 or a salt thereof is less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% a / a (e.g., as measured by HPLC) relative to maribavir. 1 1 H NMR) is undetectable.

[0273] In some embodiments, the present disclosure provides a composition comprising 0.01 to 0.10% (w / w HPLC) of compound 3 relative to maribavir. In some embodiments, the present disclosure provides a composition comprising 0.01 to 0.05% w / w (e.g., as measured by HPLC) of compound 3 relative to maribavir. In some embodiments, the present disclosure provides a composition comprising 0.02 to 0.05% w / w (e.g., as measured by HPLC) of compound 3 relative to maribavir. In some embodiments, the present disclosure provides a composition comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% w / w (e.g., as measured by HPLC) of compound 3 relative to maribavir. In some embodiments, the present disclosure provides a composition comprising 0.01 to 0.10% a / a (e.g., as measured by HPLC) of compound 3 relative to maribavir. In some embodiments, the present disclosure provides a composition comprising 0.01 to 0.05% a / a (e.g., as measured by HPLC) of compound 3 relative to maribavir. In some embodiments, the disclosure provides compositions comprising compound 3 at 0.02-0.05% a / a (e.g., as measured by HPLC) relative to maribavir. In some embodiments, the disclosure provides compositions comprising compound 3 at less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% a / a (e.g., as measured by HPLC) relative to maribavir. In some embodiments, the disclosure provides compositions wherein compound 3 or a salt thereof is present at a concentration (e.g., as measured by HPLC or 1 1 H NMR) is undetectable.

[0274] In some embodiments, the present disclosure provides a composition comprising compound 4 at 0.01 to 0.10% (w / w HPLC) relative to maribavir. In some embodiments, the present disclosure provides a composition comprising compound 4 at 0.01 to 0.05% w / w (e.g., as measured by HPLC) relative to maribavir. In some embodiments, the present disclosure provides a composition comprising compound 4 at 0.02 to 0.05% w / w (e.g., as measured by HPLC) relative to maribavir. In some embodiments, the present disclosure provides a composition comprising compound 4 at 1%, 0.5%, 0.1%, 0.05%, 0.02%, or less than 0.01% w / w (e.g., as measured by HPLC) relative to maribavir. In some embodiments, the present disclosure provides a composition comprising compound 4 at 0.01 to 0.10% a / a (e.g., as measured by HPLC) relative to maribavir. In some embodiments, the present disclosure provides a composition comprising compound 4 at 0.01 to 0.05% a / a (e.g., as measured by HPLC) relative to maribavir. In some embodiments, the disclosure provides compositions comprising compound 4 at 0.02-0.05% a / a (e.g., as measured by HPLC) relative to maribavir. In some embodiments, the disclosure provides compositions comprising compound 4 at less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% a / a (e.g., as measured by HPLC) relative to maribavir. In some embodiments, the disclosure provides compositions wherein compound 4 or a salt thereof is present at a concentration (e.g., as measured by HPLC or 1 1 H NMR) is undetectable.

[0275] Medication regimen Provided herein are methods of treating a patient suffering from CMV, comprising administering maribavir to the patient (e.g., by administering a composition comprising and / or delivering maribavir described herein). In some embodiments, the provided methods comprise orally administering to the patient about 400 mg of maribavir twice daily. In some embodiments, the provided methods comprise orally administering to the patient about 200 mg of maribavir twice daily.

[0276] Maribavir can be administered with or without food. In some embodiments, maribavir is administered as a 200 mg tablet. In some embodiments, maribavir is administered as a 400 mg tablet. In some embodiments, maribavir is administered as a 200 mg oral solid composition. In some embodiments, maribavir is administered as a 400 mg oral solid composition.

[0277] In some embodiments, the disclosure provides a method of treating a patient having post-transplant CMV infection or disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily, wherein the maribavir is administered as an oral solid composition comprising: (i) maribavir Form VI having a d(50) PSD of less than about 400 μm; (ii) less than 0.05% Compound 2 or a salt thereof; (iii) less than 0.05% Compound 3 or a salt thereof; (iv) less than 0.05% Compound 4 or a salt thereof; and (v) a pharmaceutically acceptable excipient. In some embodiments, the disclosure provides a method of treating a patient having post-transplant CMV infection or disease who is intolerant to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily, wherein the maribavir is administered as an oral solid composition comprising: (i) maribavir Form VI having a d(50) PSD of less than about 400 μm; (ii) less than 0.05% Compound 2 or a salt thereof; (iii) less than 0.05% Compound 3 or a salt thereof; (iv) less than 0.05% Compound 4 or a salt thereof; and (v) a pharmaceutically acceptable excipient. In some embodiments, the disclosure provides a method of treating a patient having post-transplant CMV infection or disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily, wherein the maribavir is administered as an oral solid composition comprising: (i) maribavir Form VI having a d(50) PSD of less than about 400 μm; (ii) less than 0.05% Compound 2 or a salt thereof; (iii) less than 0.05% Compound 3 or a salt thereof; (iv) less than 0.05% Compound 4 or a salt thereof; (v) less than 0.05% D-maribavir or a salt thereof; and (v) a pharmaceutically acceptable excipient.In some embodiments, the disclosure provides a method of treating a patient having post-transplant CMV infection or disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily, wherein the maribavir is administered as an oral solid composition comprising: (i) maribavir Form VI having a d(50) PSD of less than about 400 μm, (ii) less than 0.05% Compound 2 or a salt thereof, (iii) less than 0.05% Compound 3 or a salt thereof, (iv) less than 0.05% Compound 4 or a salt thereof, and (v) a pharmaceutically acceptable excipient; and the patient is administered an immunosuppressant that is a CYP3A4 and / or P-gp substrate, including tacrolimus, cyclosporine, sirolimus, and everolimus. In some embodiments, the disclosure provides a method for controlling drug concentrations of maribavir and an immunosuppressant in a patient with post-transplant CMV infection or disease, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily, wherein the maribavir is administered as an oral solid composition comprising: (i) maribavir Form VI having a d(50) PSD of less than about 400 μm; (ii) less than 0.05% Compound 2 or a salt thereof; (iii) less than 0.05% Compound 3 or a salt thereof; (iv) less than 0.05% Compound 4 or a salt thereof; and (v) a pharmaceutically acceptable excipient; and the patient is administered an immunosuppressant.In some embodiments, the disclosure provides a method for controlling drug concentrations of maribavir and an immunosuppressant in a patient with post-transplant CMV infection or disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily, wherein the maribavir is administered as an oral solid composition comprising: (i) maribavir Form VI having a d(50) PSD of less than about 400 μm; (ii) less than 0.05% Compound 2 or a salt thereof; (iii) less than 0.05% Compound 3 or a salt thereof; (iv) less than 0.05% Compound 4 or a salt thereof; and (v) a pharmaceutically acceptable excipient; and the patient is administered an immunosuppressant that is a CYP3A4 and / or P-gp substrate, including tacrolimus, cyclosporine, sirolimus, and everolimus. In some embodiments, the disclosure provides a method of treating a patient having post-transplant CMV infection or disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily, wherein the maribavir is administered as an oral solid composition comprising: (i) maribavir Form VI having a d(50) PSD of less than about 400 μm; (ii) less than 0.05% Compound 2 or a salt thereof; (iii) less than 0.05% Compound 3 or a salt thereof; (iv) less than 0.05% Compound 4 or a salt thereof; and (v) a pharmaceutically acceptable excipient; wherein the patient is administered an immunosuppressant that is a CYP3A4 and / or P-gp substrate, including tacrolimus, cyclosporine, sirolimus, and everolimus, and the level of the immunosuppressant in the patient is monitored following administration of the maribavir.In some embodiments, the disclosure provides a method of treating a patient having post-transplant CMV infection or disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 800 mg twice daily, wherein the maribavir is administered as an oral solid composition comprising: (i) maribavir Form VI having a d(50) PSD of less than about 400 μm; (ii) less than 0.05% Compound 2 or a salt thereof; (iii) less than 0.05% Compound 3 or a salt thereof; (iv) less than 0.05% Compound 4 or a salt thereof; and (v) a pharmaceutically acceptable excipient; wherein the patient is receiving carbamazepine prior to administration of the maribavir. In some embodiments, the disclosure provides a method of treating a patient having post-transplant CMV infection or disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 1200 mg twice daily, wherein the maribavir is administered as an oral solid composition comprising: (i) maribavir Form VI having a d(50) PSD of less than about 400 μm; (ii) less than 0.05% Compound 2 or a salt thereof; (iii) less than 0.05% Compound 3 or a salt thereof; (iv) less than 0.05% Compound 4 or a salt thereof; and (v) a pharmaceutically acceptable excipient; wherein the patient has received phenytoin or phenobarbital prior to administration of the maribavir. In some embodiments, the disclosure provides a method of treating a patient having post-transplant CMV infection or disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily for six months or more, wherein the maribavir is administered as an oral solid composition comprising: (i) maribavir Form VI having a d(50) PSD of less than about 400 μm; (ii) less than 0.05% Compound 2 or a salt thereof; (iii) less than 0.05% Compound 3 or a salt thereof; (iv) less than 0.05% Compound 4 or a salt thereof; and (v) a pharmaceutically acceptable excipient.In some embodiments, the disclosure provides a method of treating a patient having post-transplant CMV infection or disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily for 12 months or more, wherein the maribavir is administered as an oral solid composition comprising: (i) maribavir Form VI having a d(50) PSD of less than about 400 μm; (ii) less than 0.05% of Compound 2 or a salt thereof; (iii) less than 0.05% of Compound 3 or a salt thereof; (iv) less than 0.05% of Compound 4 or a salt thereof; and (v) a pharmaceutically acceptable excipient. In some embodiments, the disclosure provides a method of treating a patient having post-transplant CMV infection or disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily, wherein the maribavir is administered as an oral solid composition comprising: (i) maribavir Form VI having a d(50) PSD of less than about 50 to about 400 μm; (ii) less than 0.1% of Compound 2 or a salt thereof; (iii) less than 0.15% of Compound 3 or a salt thereof; (iv) less than 0.1% of Compound 4 or a salt thereof; and (v) a pharmaceutically acceptable excipient. In some embodiments, the disclosure provides a method of treating a patient having post-transplant CMV infection or disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily, wherein the maribavir is administered as an oral solid composition comprising: (i) maribavir Form VI having a d(50) PSD of less than about 50 to about 400 μm; (ii) less than 0.1% of an intermediate impurity; (iii) less than 0.1% of an enantiomeric impurity; (iv) less than 0.1% of an unspecified impurity; and (v) a pharmaceutically acceptable excipient.

[0278] Enumeration of Embodiments 1. A composition comprising: (i) Mariba Building: [ka] or a pharmaceutically acceptable salt thereof, and (ii) One or more of the following: compound 2, [ka] or a pharmaceutically acceptable salt thereof, compound 3, [ka] or a pharmaceutically acceptable salt thereof, or Compound 4: [ka] or a pharmaceutically acceptable salt thereof.

[0279] 2.Compound 2: [ka] or a pharmaceutically acceptable salt thereof.

[0280] 3. The composition of embodiment 2, comprising 0.01 to 0.10% w / w (e.g., as measured by HPLC) of compound 2 relative to maribavir.

[0281] 4. The composition of embodiment 2 or 3, comprising 0.01 to 0.05% w / w (e.g., as determined by HPLC) of compound 2 relative to maribavir.

[0282] 5. The composition of any one of embodiments 2-4, comprising 0.02-0.05% w / w (e.g., HPLC measurement) of compound 2 relative to maribavir.

[0283] 6. The composition of embodiment 2, comprising Compound 2 at less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% w / w (e.g., as measured by HPLC) relative to maribavir.

[0284] 7. The composition of embodiment 2, comprising 0.01 to 0.10% a / a (e.g., HPLC measurement) of compound 2 relative to maribavir.

[0285] 8. The composition of embodiment 2 or 7, comprising 0.01 to 0.5% a / a (e.g., as measured by HPLC) of compound 2 relative to maribavir.

[0286] 9. The composition of any one of embodiments 2 or 7-8, comprising 0.02-0.05% a / a (e.g., HPLC measurement) of compound 2 relative to maribavir.

[0287] 10. The composition of embodiment 2, comprising Compound 2 at less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% a / a relative to maribavir (e.g., as measured by HPLC).

[0288] 11.Compound 3: [ka] or a pharmaceutically acceptable salt thereof.

[0289] 12. The composition of embodiment 11, comprising 0.01 to 0.10% w / w (e.g., as determined by HPLC) of compound 3 relative to maribavir.

[0290] 13. The composition of embodiment 11 or 12, comprising 0.01 to 0.5% w / w (e.g., as measured by HPLC) of compound 3 relative to maribavir.

[0291] 14. The composition of any one of embodiments 11-13, comprising 0.02-0.05% w / w (e.g., HPLC measurement) of compound 3 relative to maribavir.

[0292] 14. The composition of embodiment 11, comprising compound 3 at less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% w / w (e.g., as measured by HPLC) relative to maribavir.

[0293] 15. The composition of embodiment 11, comprising 0.01 to 0.10% a / a (e.g., HPLC measurement) of compound 3 relative to maribavir.

[0294] 16. The composition of embodiment 11 or 15, comprising 0.01 to 0.5% a / a (e.g., as measured by HPLC) of compound 3 relative to maribavir.

[0295] 17. The composition of any one of embodiments 11 or 15-16, comprising 0.02-0.05% a / a (e.g., HPLC measurement) of compound 3 relative to maribavir.

[0296] 18. The composition of embodiment 11, comprising compound 3 at less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% a / a relative to maribavir (e.g., as measured by HPLC).

[0297] 19. Compound 4: [ka] or a pharmaceutically acceptable salt thereof.

[0298] 20. The composition of embodiment 19, comprising 0.01 to 0.10% w / w (e.g., as determined by HPLC) of compound 4 relative to maribavir.

[0299] 21. The composition of embodiment 19 or 20, comprising 0.01 to 0.5% w / w (e.g., as measured by HPLC) of compound 4 relative to maribavir.

[0300] 22. The composition of any one of embodiments 19-21, comprising 0.02-0.05% w / w (e.g., as measured by HPLC) of compound 4 relative to maribavir.

[0301] 23. The composition of embodiment 19, comprising compound 4 at less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% w / w (e.g., as measured by HPLC) relative to maribavir.

[0302] 24. The composition of embodiment 19, comprising 0.01 to 0.10% a / a (e.g., HPLC measurement) of compound 4 relative to maribavir.

[0303] 25. The composition of embodiment 19 or 24, comprising 0.01 to 0.5% a / a (e.g., as measured by HPLC) of compound 4 relative to maribavir.

[0304] 26. The composition of any one of embodiments 19 or 24-25, comprising 0.02-0.05% a / a (e.g., as measured by HPLC) of compound 4 relative to maribavir.

[0305] 27. The composition of embodiment 19, comprising compound 3 at less than 1%, 0.5%, 0.1%, 0.05%, 0.02%, or 0.01% a / a relative to maribavir (e.g., as measured by HPLC).

[0306] 28. The composition of any one of embodiments 1 to 27, comprising maribavir having a particle size distribution (PSD) d(50) of about 170 to about 350 μm (e.g., about 170 to about 226 μm, about 227 to about 280 μm, or about 281 to about 336 μm).

[0307] 29. The composition of any one of embodiments 1 to 28, further comprising a pharmaceutically acceptable excipient.

[0308] 30. An oral solid formulation of maribavir comprising the composition of any of embodiments 1-29.

[0309] 31. The oral solid formulation of embodiment 31, wherein the formulation is a tablet.

[0310] 32. The oral solid formulation of embodiment 30 or 31, comprising about 200 mg of maribavir.

[0311] 33. The composition of any one of embodiments 1 to 29 or the oral solid dosage form of any one of embodiments 30 to 32, wherein the maribavir is prepared by a process of any one of embodiments 37 to 186.

[0312] 34. A method for treating a patient suffering from a cytomegalovirus (CMV) infection, comprising administering to the patient a pharmaceutical composition according to any one of embodiments 1 to 29 or an oral solid formulation according to any one of embodiments 30 to 33.

[0313] 35. The method of embodiment 34, wherein the patient is a transplant recipient.

[0314] 36. The method of embodiment 34 or 35, wherein the patient is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet.

[0315] 37. Mariba Building: [ka] or a pharmaceutically acceptable salt thereof, comprising: (a) Compound 3: [ka] or a salt thereof, reacting under suitable reaction conditions to provide maribavir or a pharmaceutically acceptable salt thereof.

[0316] 38. A method for preparing a composition according to any one of embodiments 1 to 32, comprising: (a) Compound 3: [ka] or a salt thereof, reacting under suitable reaction conditions to provide maribavir or a pharmaceutically acceptable salt thereof.

[0317] 39. The method of embodiment 37 or 38, wherein the reaction conditions comprise a solvent.

[0318] 40. The method of embodiment 39, wherein the solvent is or comprises methanol.

[0319] 41. The method of embodiment 39, wherein the solvent is or comprises MTBE.

[0320] 42. The method of any one of embodiments 39-41, wherein the solvent comprises methanol and MTBE.

[0321] 43. The method of embodiment 42, wherein methanol is provided in an amount of about 0.34 L / kg to about 0.56 L / kg, and MTBE is provided in an amount of about 3.65 L / kg to about 6.35 L / kg.

[0322] 44. The method of embodiment 42 or 43, wherein methanol is provided in an amount of about 0.48 L / kg and MTBE is provided in an amount of about 5.3 L / kg.

[0323] 45. The method of any one of embodiments 37-43, wherein the reaction conditions comprise a base.

[0324] 46. ​​The method of embodiment 45, wherein the base is NaOH.

[0325] 47. The method of embodiment 45 or 46, wherein the base is aqueous NaOH.

[0326] 48. The method of any one of embodiments 37-47, wherein the reaction comprises heating to a temperature T1.

[0327] 49. The method of embodiment 48, wherein the temperature T1 is about 24°C to 45°C.

[0328] 50. The method of embodiment 48 or 49, wherein the temperature T1 is about 30°C.

[0329] 51. The method of any one of embodiments 37-50, wherein the reaction is allowed to proceed for a period of time.

[0330] 52. The method of embodiment 51, wherein the reaction is stirred for a period of time.

[0331] 53. The method of embodiment 51 or 52, wherein the period is from about 2.5 to about 4 hours.

[0332] 54. The method of any one of embodiments 37-53, wherein the reaction conditions include cooling the reaction mixture to a temperature T2.

[0333] 55. The method of embodiment 54, wherein the temperature T2 is about 22°C.

[0334] 56. The method of any one of embodiments 37-55, wherein the reaction is monitored for the presence of maribavir in an amount greater than 98.3% a / a by HPLC.

[0335] 57. The method of any one of embodiments 37 to 56, further comprising the step of (b) phase separating and / or extracting maribavir or a pharmaceutically acceptable salt thereof from the reaction mixture to provide a first resultant mixture.

[0336] 58. The method of embodiment 57, wherein the phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof comprises adding a first phase separation solvent.

[0337] 59. The method of embodiment 58, wherein the first phase separation solvent is MBTE.

[0338] 60. The method of any one of embodiments 57-59, wherein the phase separation and / or extraction comprises adding a second phase separation solvent.

[0339] 61. The method of embodiment 60, wherein the second phase separation solvent is aqueous sodium chloride.

[0340] 62. The method of any one of embodiments 57-61, wherein the phase separation and / or extraction comprises adjusting the pH of the reaction mixture to about 6.0 to about 10.0.

[0341] 63. The method of any one of embodiments 57-62, wherein the phase separation and / or extraction comprises adjusting the pH of the reaction mixture to about 6.8 to about 7.5.

[0342] 64. The method of any one of embodiments 37 to 63, further comprising the step of: (c) distilling and / or solvent exchanging the reaction mixture or the first resulting mixture to provide a second resulting mixture comprising maribavir or a pharmaceutically acceptable salt thereof.

[0343] 65. The method of embodiment 64, wherein the reaction mixture or first resulting mixture comprises a first solvent.

[0344] 66. The method of embodiment 65, wherein the first solvent is TBME.

[0345] 67. The method of any one of embodiments 65-67, wherein the first solvent is removed from the reaction mixture or first resulting mixture.

[0346] 68. The method of embodiment 67, wherein the first solvent is removed by distillation.

[0347] 69. The method of any one of embodiments 63-68, wherein a second solvent is added to the reaction mixture or the first resulting mixture.

[0348] 70. The method of embodiment 69, wherein the second solvent is isopropyl acetate.

[0349] 71. The method of any one of embodiments 64-70, wherein the second resulting mixture comprises isopropyl acetate.

[0350] 72. The second resulting mixture contains less than 0.2% w / w water (e.g., 1 72. The method of any one of embodiments 64-71, comprising measuring the solubility of ...

[0351] 73. The second resulting mixture contains less than 0.09% w / w water (e.g., 1 73. The method of any one of embodiments 64-72, comprising measuring the solubility of ...

[0352] 74. The second resulting mixture contains about 17-20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 74. The method of any one of embodiments 64-73, comprising measuring the concentration of 1H NMR signals.

[0353] 75. The second resulting mixture contains about 17-19% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 75. The method of any one of embodiments 64-74, comprising H NMR measurements.

[0354] 76. The method of any one of embodiments 37-75, further comprising: (b) crystallizing maribavir or a pharmaceutically acceptable salt thereof (e.g., from the reaction mixture, the first obtained mixture, or the second obtained mixture).

[0355] 77. The method of embodiment 76, wherein the crystallization comprises providing a crystallization mixture comprising maribavir or a pharmaceutically acceptable salt thereof, and a primary solvent.

[0356] 78. The method of embodiment 77, wherein the primary solvent is isopropyl acetate.

[0357] 79. The resulting crystallized mixture contains less than 0.2% w / w water (e.g., 1 79. The method of any one of embodiments 76-78, comprising measuring the solubility of the fluorine-containing compound by H NMR or Karl Fischer measurements.

[0358] 80. The crystallization mixture contains less than 0.09% w / w water (e.g., 1 80. The method of any one of embodiments 76-79, comprising measuring the solubility of the fluorine-containing compound by H NMR or Karl Fischer measurements.

[0359] 81. The crystallization mixture contains about 17-20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 81. The method of any one of embodiments 76-80, comprising measuring the concentration of 1H NMR signals.

[0360] 82. The resulting crystallized mixture contains about 17-19% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., 1 82. The method of any one of embodiments 76-81, comprising measuring the concentration of 1H NMR signals.

[0361] 83. The method of any one of embodiments 76-82, wherein the crystallization further comprises heating the crystallization mixture to a temperature T3.

[0362] 84. The method of embodiment 83, wherein the temperature T3 is from about 77°C to about 88°C.

[0363] 85. The method of embodiment 83 or 84, wherein the temperature T3 is about 84°C.

[0364] 86. The method of any one of embodiments 76-85, wherein a secondary solvent is added to the crystallization mixture.

[0365] 87. The method of embodiment 86, wherein the secondary solvent is toluene.

[0366] 88. The method of any one of embodiments 86-87, wherein after the addition of the secondary solvent, the crystallization mixture is aged for less than about 30 minutes.

[0367] 89. The method of any one of embodiments 76-88, wherein seed crystals are added to the crystallization mixture.

[0368] 90. The method of embodiment 89, wherein the seed crystals are maribavir or a pharmaceutically acceptable salt thereof.

[0369] 91. The method of embodiment 89 or 90, wherein the seed crystals are added in an amount of about 0.05% to 0.30 w / w relative to compound 3 or its salt.

[0370] 92. The method of any one of embodiments 89-91, wherein the seed crystals are added in an amount of about 0.15% w / w relative to compound 3 or a salt thereof.

[0371] 93. The method of any one of embodiments 89-92, wherein the seed crystal size (d(50)) is about 2.25-7.00 μm.

[0372] 94. The method of any one of embodiments 89-93, wherein the seed crystal size (d(50)) is about 2.75-6.25 μm.

[0373] 95. The method of any one of embodiments 89-94, wherein the crystallization mixture is aged for about 30 minutes after the seed crystals are added.

[0374] 96. The method of any one of embodiments 76-95, wherein additional secondary solvent is added to the crystallization mixture.

[0375] 97. The method of embodiment 96, wherein the additional second solvent is added in an amount of about 1 1 / 7 (kg / kg) of the total amount of the first solvent.

[0376] 98. The method of embodiment 96 or 97, wherein the crystallization mixture is stirred for a period of time after the additional second solvent is added.

[0377] 99. The method of embodiment 98, wherein the period is about 1 hour.

[0378] 100. The method of embodiment 98 or 99, wherein after the additional secondary solvent is added, the crystallization mixture is stirred at a temperature T3.

[0379] 101. The method of embodiment 100, wherein the temperature T3 is from about 77°C to about 88°C.

[0380] 102. The method of embodiment 100 or 101, wherein the temperature T3 is about 84°C.

[0381] 103. The method of any one of embodiments 76-102, wherein the crystallization mixture is cooled to a temperature T4.

[0382] 104. The method of embodiment 103, wherein the temperature T4 is from about 3°C ​​to about 7°C.

[0383] 105. The method of embodiment 103 or 104, wherein the temperature T4 is about 5°C.

[0384] 106. The method of any one of embodiments 103-105, wherein the crystallization mixture is cooled to a temperature T4 over a period of about 3 hours.

[0385] 107. The method of any one of embodiments 103-106, wherein the crystallization mixture is stirred at a temperature T4 for a period of time.

[0386] 108. The method of embodiment 107, wherein the period is from about 3 to about 18 hours.

[0387] 109. The method of any one of embodiments 76-108, further comprising the step of: (e) optionally filtering or washing the crystallization mixture to provide a filtered mixture.

[0388] 110. The method of embodiment 109, comprising filtering the crystallization mixture to provide the filtered mixture.

[0389] 111. The method of embodiment 109 or 110, comprising washing the crystallization mixture to provide the filtered mixture.

[0390] 112. The method of embodiment 111, wherein the crystallization mixture is washed with toluene.

[0391] 113. The method of any one of embodiments 76-112, further comprising the step of: (f) drying the filtered mixture.

[0392] 114. The method of embodiment 113, wherein the drying comprises heating the filtered mixture to a temperature T5 without stirring for a period of time.

[0393] 115. The method of embodiment 114, wherein the temperature T5 is 40°C or less.

[0394] 116. The method of embodiment 114 or 115, wherein said period is at least 5 hours.

[0395] 117. The method of any one of embodiments 113-116, wherein the drying comprises heating the filtered mixture to a temperature T6 without stirring for a period of time.

[0396] 119. The method of embodiment 117, wherein the temperature T6 is 50°C or less.

[0397] 120. The method of embodiment 117 or 118, wh...

Claims

1. 1. A method of treating a patient having post-transplant cytomegalovirus (CMV) infection and / or disease, comprising orally administering to the patient maribavir or a pharmaceutically acceptable salt thereof in an amount of 400 mg twice daily, wherein maribavir: (i) Maribavir: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, and (ii) one or more of the following: Compound 2, 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, Compound 3, 【Chemistry 3】 or a pharmaceutically acceptable salt thereof, or Compound 4: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof The method is administered as a pharmaceutical composition comprising:

2. The method of claim 1 , wherein the patient is a transplant recipient.

3. 3. The method of claim 1 or 2, wherein the patient has undergone hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT).

4. 4. The method of any one of claims 1 to 3, wherein the CMV infection and / or disease is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet.

5. 4. The method of any one of claims 1 to 3, wherein the CMV infection and / or disease is intolerant to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet.

6. The method of any one of claims 1 to 5, wherein the pharmaceutical composition comprises less than 0.1% w / w of compound 2 or a salt thereof relative to maribavir (e.g., as measured by HPLC), less than 0.1% w / w of compound 3 or a salt thereof relative to maribavir (e.g., as measured by HPLC), and / or less than 0.1% w / w of compound 4 or a salt thereof relative to maribavir (e.g., as measured by HPLC).

7. 7. The method of any one of claims 1 to 6, wherein the maribavir is Form VI having a PSD of d(50) less than about 400 μm.

8. The method of any one of claims 1 to 7, wherein the pharmaceutical composition contains less than 0.1% D-maribavir or a salt thereof.

9. The method of any one of claims 1 to 8, wherein the patient is administered an immunosuppressant selected from CYP3A4 and / or P-gp substrates.

10. 10. The method of claim 9, wherein the CYP3A4 and / or P-gp substrate is selected from tacrolimus, cyclosporine, sirolimus, and everolimus, and the method comprises monitoring immunosuppressant drug levels throughout the course of treatment with maribavir.

11. The method of any one of claims 1 to 10, wherein the patient is administered an immunosuppressant drug.

12. A method for preparing maribavir polymorphic Form VI, comprising crystallizing maribavir Form VI from a crystallization mixture comprising maribavir or a pharmaceutically acceptable salt thereof and isopropyl acetate.

13. The crystallization mixture contains less than 0.2% w / w water (e.g., １ 13. The method of claim 12, wherein the hydroxyl group is hydroxypropyltrimonial, ...

14. The crystallization mixture contains less than 0.09% w / w water (e.g., １ 14. The method of claim 12 or 13, wherein the hydroxyl group is hydroxypropyltrimonial, ...

15. The crystallization mixture comprises about 17-20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., １ 15. The method of any one of claims 12 to 14, wherein the hydroxyl group is hydroxypropyltrimonial, ...

16. The crystallization mixture comprises about 17-19% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., １ 16. The method of any one of claims 12 to 15, wherein the hydroxyl group is hydroxypropyltrimonial, ...

17. The method of any one of claims 12 to 16, wherein seed crystals are added to the crystallization mixture.

18. 18. The method of claim 17, wherein the seed crystals are maribavir or a pharmaceutically acceptable salt thereof.

19. 13. The method of claim 12, comprising reacting compound 3 or a salt thereof under suitable reaction conditions to provide maribavir or a pharmaceutically acceptable salt thereof, wherein seed crystals are added in an amount of about 0.05% to 0.30% w / w relative to compound 3 or a salt thereof.

20. The method according to any one of claims 12 to 19, wherein the seed crystals are added in an amount of about 0.15% w / w relative to compound 3 or a salt thereof.

21. 21. The method of any one of claims 12 to 20, wherein the seed crystal size (d(50)) is about 2.25 to 7.00 μm.

22. 22. The method of any one of claims 12 to 21, wherein the seed crystal size (d(50)) is about 2.75 to 6.25 μm.

23. 1. A method for preparing maribavir or a salt thereof, comprising: (a) Compound 5: 【Chemistry 5】 or its salt Compounds 6 and 7: 【Chemistry 6】 under suitable reaction conditions to provide compound 2 or a salt thereof.

24. Mariba Building 【Chemistry 7】 or a pharmaceutically acceptable salt thereof, comprising: (a) Compound 3: 【Chemistry 8】 or a salt thereof, reacting under suitable reaction conditions to provide maribavir or a pharmaceutically acceptable salt thereof; Compound 3 or a salt thereof is: (a) Compound 2: 【Chemistry 9】 or a salt thereof, under suitable reaction conditions to provide compound 3 or a pharmaceutically acceptable salt thereof; Compound 2 or a salt thereof is: (a) Compound 5: 【Chemistry 10】 or a salt thereof, Compounds 6 and 7: 【Chemistry 11】 under suitable reaction conditions to provide compound 2 or a salt thereof.

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