Process for preparation of Maripasvir

Abstract

Compositions comprising Maripasvir, methods of providing the compositions, and compositions of intermediates useful for providing Maripasvir are disclosed.

Description

This application is a divisional application of the Chinese patent application with application number 202380037727.4 (application date: October 11, 2023, invention name: method for preparing maribavir). Technical Field

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

[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 the adult population. However, severe HCMV disease occurs almost exclusively in individuals with compromised or immature immune systems. CMV remains a significant problem for patients undergoing all types of transplantation, including hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT), associated with the use of potent immunosuppressive chemotherapy. Summary of the invention

[0003] Maribavir is a benzimidazole riboside that is an oral antiviral drug against CMV. Maribavir is also known by its trade name LIVTENCITY TM Maribavir ((2S,3S,4R,5S)-2-(5,6-dichloro-2-(isopropylamino)-1H-benzo[d]imidazol-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol) is a compound with the following chemical structure: It is a potent, orally bioavailable antiviral agent used to treat CMV infection and disease in transplant recipients, who are at significant risk for CMV infection.

[0004] The synthesis of maribavir is described in Examples 1, 2 and 5 of US Pat. No. 6,077,832 (the '832 patent). As shown in Scheme 1 below, the synthesis consists of three chemical transformation steps with an overall yield of about 27%. Solution 1

[0005] The synthesis described in Scheme 1 first couples 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 and then the isopropylamine is installed to provide maribavir. Notably, the first step also produces the α anomer in about 6% yield (see the '832 patent, Example 1).

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

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

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

[0009] The total yield of these two steps is about 49%. It is noteworthy that the '315 patent does not exemplify the deacetylation of 5,6-dichloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetyl-β-1-ribofuranosyl)-1H-benzimidazole to obtain maribavir. Although the synthesis disclosed in the '315 patent appears to be a significant improvement over the synthesis described in the '832 patent and the '083 publication, the yield of maribavir is still expected to be less than 49% (e.g., 37% when assuming a deacetylation yield of 75% as 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 below: Solution 4 Solution 5

[0011] In some embodiments, the present invention provides an improved synthesis of maribavir in Scheme 5 with an overall yield of at least 45%. It should be understood that certain intermediate compounds (e.g., 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 invention also provides the following recognition: Maribavir with acceptable quality is important for proper grinding and formulation into tablets. For example, in some embodiments, a specific polymorphic form of maribavir (e.g., Form VI disclosed in US6,482,939) is required, free of other crystalline forms, solvates or hydrates. In some embodiments, the present invention provides a method for preparing a specific polymorphic form of maribavir (e.g., Form VI disclosed in US6,482,939) free of other crystalline forms, solvates or hydrates. Additionally or alternatively, in some embodiments, the specific particle size distribution of maribavir is important for tablet preparation. In some embodiments, the present invention provides a method for preparing maribavir with a specific particle size distribution suitable for grinding and formulation into tablets. Additionally or alternatively, in some embodiments, the specific particle size distribution of maribavir is important for the preparation of oral solid dosage forms. In some embodiments, the present invention provides a method for preparing maribavir with a specific particle size distribution suitable for formulation into oral solid dosage forms. Additionally or alternatively, in some embodiments, a specific particle size distribution of maribavir can affect the bioavailability of maribavir. In some embodiments, the present invention provides a solid oral dosage form comprising maribavir polymorphic form VI having a specific particle size distribution (e.g., d(50) between about 50 and about 400 μm). In some embodiments, the present invention provides a method for crystallizing maribavir polymorphic form VI having a specific particle size distribution (e.g., d(50) between about 50 and about 400 μm).

[0013] Additionally or alternatively, the present invention provides the following recognition: when manufacturing a drug product, it is important to minimize certain impurities. For example, the impurity profile should remain consistent to maintain consistency of efficacy and minimize potential adverse reactions. In some embodiments, when the synthesis of a drug product consists of multiple steps, it should be understood that impurities formed in early steps can form additional impurities by subsequent steps. Therefore, it is important to reduce impurities at each step (e.g., step 1, 2 or 3) of the synthesis of maribavir to maintain the consistency of the produced drug product.

[0014] Therefore, in some embodiments, the present invention provides a composition comprising maribavir or a pharmaceutically acceptable salt thereof and a method for preparing the same. In some embodiments, the composition provided comprises maribavir and one or more compounds selected from the following: or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the composition provided is prepared according to the method disclosed herein (e.g., steps 1-3). In some embodiments, the composition provided comprises at least 90%, 95%, 99%, 99.5% or 99.9% of maribavir by weight. In some embodiments, the composition provided comprises maribavir substantially free of impurities. As used herein, the term "substantially free of impurities" means that the composition or compound does not contain a significant amount of foreign matter. Such foreign matter may include starting materials, residual solvents, or other impurities that may be produced by the preparation and / or separation of maribavir. In some embodiments, the composition provided comprises maribavir or a pharmaceutically acceptable salt thereof and a compound 2, 3, and / or 4 in an amount less than 0.10% (w / w HPLC) relative to maribavir. In some embodiments, the composition provided comprises maribavir or a pharmaceutically acceptable salt thereof and a compound 2, 3, and / or 4 in an amount less than 0.10% (w / w HPLC) relative to maribavir. In some embodiments, the compositions provided include maribavir or a pharmaceutically acceptable salt thereof and an amount of compound 2, 3, and / or 4 less than 0.10% (a / a HPLC) relative to maribavir. In some embodiments, the compositions provided include maribavir or a pharmaceutically acceptable salt thereof and an amount of compound 2, 3, and / or 4 that is not detectable by HPLC. In some embodiments, the compositions provided include maribavir in Form VI, as described in US6,482,939. In some embodiments, the compositions provided include at least 90%, 95%, 99%, 99.5%, or 99.9% of Form VI maribavir by weight. In some embodiments, the compositions provided include maribavir substantially free of other polymorphic forms, for example, as described in US6,482,939, US8,546,344, or US11,130,777. US8,546,344 or US11,130,777. In some embodiments, the compositions provided include maribavir having a specific particle size distribution as defined and described herein. Impurities (such as intermediates, enantiomeric impurities) may affect the quality of the raw materials and drug products and may pose a risk to the safety of drug products. If the amount of certain impurities is higher than the qualified limit, it may have an impact on patient safety. Unknown impurities pose an unknown risk to the safety of drug products. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 A graph showing the purity of Compound 2 as a function of feed mass after recrystallization of Compound 2 by filtration (ie, before the washing steps) is shown.

[0017] Figure 2 Compound 2 (HPLC purity) is plotted versus recrystallization temperature and observed crystallization temperature (H = high temperature, where T>90°C; L = low temperature, where T<40°C).

[0018] Figure 3 An interval plot is shown for compound 2 versus recrystallization temperature. The pooled standard deviation was used to calculate the interval.

[0019] Figure 4 Depicted are contour plots of Compound 2 purity examining the effect of recrystallization temperature and observed crystallization temperature. DETAILED DESCRIPTION definition

[0020] The compounds of the present invention include those generally described above, and are further described by the classes, subclasses, and specific species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present invention, chemical elements are determined according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th edition). In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th edition, Smith, MB and March, J. ed., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0021] As used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., unbranched) or branched substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a monocyclic hydrocarbon or bicyclic hydrocarbon (also referred to herein as "carbocycle", "carbocyclic", "alicyclic" or "cycloalkyl") that is completely saturated or contains one or more unsaturated units, but is not aromatic, and has a single 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 other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "carbocycle" (or "alicyclic" or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic, and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, substituted or unsubstituted straight or branched chain alkyl, alkenyl, alkynyl, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0022] The term "halogen" means F, Cl, Br or I.

[0023] The term "aryl" as used alone or as part of a larger moiety in "aralkyl", "aralkyloxy" or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, and exemplary groups include phenyl, biphenyl, naphthyl, anthracenyl, etc., which may carry 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, etc.

[0024] 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; having 6, 10 or 14 p electrons shared in a cyclic array; and 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 any quaternized form of basic nitrogen. Exemplary heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. As used herein, the terms "heteroaryl" and "heteroaryl-" also include groups in which a heteroaryl ring is fused to one or more aryl, alicyclic or heterocyclic rings, wherein the group or point of attachment is on the heteroaryl ring. Exemplary groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido [2,3-b] -1,4-oxazine-3 (4H) -one. The heteroaryl group 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 optionally substituted rings. The term "heteroaralkyl" refers to an alkyl substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0025] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic group" and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety which is saturated or partially unsaturated and has one or more, preferably 1-4, heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when applied to a ring atom of a heterocycle includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (eg, N-substituted pyrrolidinyl).

[0026] The heterocyclic ring may be attached to its side group at any heteroatom or carbon atom to produce a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepine, pyrrolidine, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepine, pyrrolidine, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, pyrrolidine, tetrahydroquinolinyl, pyrrolidine ... Oxazepine Thiazepine The term "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic group" are used interchangeably herein and also include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl, wherein the group or point of attachment is on the heterocyclyl ring. The heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl substituted with a heterocyclyl, wherein the alkyl and heterocyclyl moieties are independently optionally substituted.

[0027] As described herein, compounds may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogen atoms of the designated moiety of the compound are replaced with a suitable substituent. "Substituted" applies to one or more hydrogen atoms in a structure, whether explicit or implicit (e.g., At least and At least ). Unless otherwise indicated, 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 particular group, the substituent may be the same or different at each position. The combinations of substituents contemplated by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow it to be produced, detected, and in certain embodiments, recovered, purified, and used for one or more purposes disclosed herein.

[0028] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently halogen; -(CH2) 0- 4R o ; -(CH2) 0-4 OR o ; -O(CH2) 0-4 R o ; -O-(CH2) 0-4 C(O)ORo ; -(CH2) 0-4 CH(OR o )2; -(CH2) 0-4 SR o ; -(CH2) 0-4 Ph, which can be o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be o Substitution; -CH=CHPh, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2; -(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2; -(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ; -(CH2) 0-4 C(O)R o ;-C(S)R o ; -(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 C(O)SR o ; -(CH2) 0-4 C(O)OSiR o 3; -(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0- 4SR-;SC(S)SRo ; -(CH2) 0-4 SC(O)R o ; -(CH2) 0-4 C(O)NR o 2; -C(S)NR o 2; -C(S)SR o ;-SC(S)SR o ; -(CH2) 0-4 OC(O)NR o 2; -C(O)N(OR o )R o ; -C(O)C(O)R o ; -C(O)CH2C(O)R o ;-C(NOR o )R o ; -(CH2) 0- 4SSR o ; -(CH2) 0-4 S(O)2R o ; -(CH2) 0-4 S(O)2OR o ; -(CH2) 0-4 OS(O)2R o ; -S(O)2NR o 2; -(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ; -C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o )2;SiR o 3;-(C 1-4 Straight or branched alkylene)ON(R o )2; or -(C 1-4 Straight or branched alkylene)C(O)ON(R o )2, where each R o may be substituted as defined below and are independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2-(5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of R o Together with its intervening atoms, it forms a 3-12 membered saturated, partially unsaturated or aromatic mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0029] R o (or two independent occurrences of R o Suitable monovalent substituents on the ring formed by the ring and its spacer atom are independently halogen, -(CH2) 0-2 R · 、-(halogen R · )、-(CH2) 0-2 OH, -(CH2) 0-2 OR · 、-(CH2) 0-2 CH(OR · )2; -O(halogen R · )、-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- 2SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · 、-(CH2) 0-2 NR · 2. -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · 、-(C 1-4 Straight or branched alkylene)C(O)OR · or -SSR · , where each R · unsubstituted or, when preceded by "halo", substituted only by one or more halogens, and independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0030] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =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-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6 aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bonded to the ortho-substitutable carbon of the "optionally substituted" group of the compounds of Formula I and its subgenuses include: -O(CR * 2) 2-3 O-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0031] R * Suitable substituents on the aliphatic group include halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · unsubstituted or, when preceded by "halo", substituted only by one or more halogens, and independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0032] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or Each of these are independently hydrogen, C which may be substituted as defined below1-6 aliphatic, 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, notwithstanding the above definition, two independent occurrences of Together with its intervening atoms, it forms an unsubstituted 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0033] Suitable substituents on the aliphatic group are independently halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · unsubstituted or, when preceded by "halo", substituted only by one or more halogens, and independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0034] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with 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) formed salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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, valerate, and the like.

[0035] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1–4 Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations, which are formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

[0036] The term "about" is used herein to refer to a value that is similar to the value mentioned in the context. Generally, those skilled in the art who are familiar with the context will understand the relevant degree of variation covered by "about" in this context. For example, in some embodiments, the term "about" can be covered in (i.e. ±) 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the value referred to. For example, a dose of "about 200 mg" of maribavir covers any amount of maribavir within the range of 180 mg to 220 mg.

[0037] As used herein, the term "administration" or "application" generally refers to administering a composition to a subject to achieve delivery of an active agent to a site of interest (e.g., a target site, which in some embodiments may be a site of disease or injury, and / or a site of a responsive process, cell, tissue, etc.). As will be understood by those skilled in the art reading the present invention, in some embodiments, one or more specific routes of administration may be feasible and / or useful in the practice of the present invention. In some embodiments, administration may be oral. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve administration of a fixed number of doses. In some embodiments, administration may involve intermittent administration (e.g., multiple doses separated in time) and / or periodic administration (e.g., a single dose separated by the same time period).

[0038] As used herein, the term "treatment" refers to partially or completely alleviating, suppressing, improving and / or relieving one or more symptoms of a disease or condition or a disease or condition. As used herein, the terms "treatment", "treat" and "treating" refer to partially or completely alleviating, suppressing, improving and / or relieving one or more symptoms of a disease or condition or a disease or condition as described herein. In some embodiments, treatment can be given after one or more symptoms have developed. In some embodiments, the term "treatment" includes stopping the progress of a disease or condition. Treatment can also be continued after symptoms subside, for example to prevent or delay its recurrence. Therefore, in some embodiments, the term "treatment" includes preventing the deterioration or recurrence of a disease or condition.

[0039] It should be understood that the unit ratios of L / kg, kg / kg, etc. are expressions for the mass (in kilograms) of each reagent / component, etc. relative to the limiting reagent (e.g., the reagent in each of steps 1, 2 or 3 as defined and described herein).

[0040] The provided compounds can be synthesized according to the schemes described herein. The reagents and conditions described are intended to be exemplary and not restrictive. As will be appreciated by those skilled in the art, various analogs can be prepared by varying the synthetic reactions, for example using different starting materials, different reagents and different reaction conditions (e.g., temperature, solvent, concentration, etc.).

[0041] It should be understood that any intermediate described in Scheme 4 or 5 may be isolated and / or purified prior to each subsequent step. Alternatively, any intermediate described in Scheme 4 or 5 may be used in a subsequent step without isolation and / or purification. The present invention encompasses telescoping of such steps.

[0042] In some embodiments, the compounds described herein can be purified by any means known in the art. In some embodiments, the purification of compounds described herein includes filtration, chromatography, distillation, crystallization or a combination thereof. In some embodiments, chromatography includes high performance liquid chromatography (HPLC). In some embodiments, chromatography includes normal phase, reverse phase or ion exchange elution on a column comprising a suitable adsorption medium. Purification by chromatography generally uses one or more solvents, which are known to those skilled in the art or determined by routine experiments. Step 1

[0043] In some embodiments, the present invention provides an improved synthesis of compound 2a: or a salt thereof, wherein R 1 and R 2 As defined and described herein.

[0044] In some embodiments, the present invention provides an improved synthesis of Compound 2: or a salt thereof.

[0045] 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, may further react to form additional by-products, and / or may reduce the overall yield or quality of maribavir. In some embodiments, the present invention provides a method for preparing compound 2 or a salt thereof having reduced and / or low levels of impurities. Without wishing to be bound by a particular theory, a lower volume of reaction solvent (e.g., 1,4-dioxane) may allow for more efficient conversion to compound 2, resulting in reduced and / or low levels of impurities. Additionally or alternatively, without wishing to be bound by a particular theory, the provided crystallization step may produce compound 2 having reduced and / or low levels of impurities.

[0046] In some embodiments, the present invention provides a composition comprising Compound 2 or a salt thereof and one or more of the following compounds: or a salt thereof.

[0047] In some embodiments, the compositions provided include compound 2 or a salt thereof, and compound 9, 10, 11 and / or 12 or a salt thereof, in an amount relative to maribavir of less than 1.00%, 0.5%, 0.1%, 0.05% or 0.02% (w / w HPLC). In some embodiments, the compositions provided include compound 2 or a salt thereof, and compound 9, 10, 11 and / or 12 or a salt thereof, in an amount relative to maribavir of less than 1.00%, 0.5%, 0.1%, 0.05% or 0.02% (a / a HPLC).

[0048] In some embodiments, the compositions provided include Compound 2, or a salt thereof, and Compound 9, or a salt thereof. In some embodiments, the compositions provided include Compound 2, or a salt thereof, and Compound 9, or a salt thereof, in an amount less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, the compositions provided include Compound 2, or a salt thereof, and Compound 9, or a salt thereof, in an amount less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. In some embodiments, the compositions provided include Compound 2, or a salt thereof, wherein Compound 9, or a salt thereof, is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0049] In some embodiments, the compositions provided include Compound 2, or a salt thereof, and Compound 10, or a salt thereof. In some embodiments, the compositions provided include Compound 2, or a salt thereof, and Compound 10, or a salt thereof, in an amount less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, the compositions provided include Compound 2, or a salt thereof, and Compound 10, or a salt thereof, in an amount less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. In some embodiments, the compositions provided include Compound 2, or a salt thereof, wherein Compound 10, or a salt thereof, is undetectable (e.g., by HPLC or 1 HNMR measurement).

[0050] In some embodiments, the compositions provided include Compound 2, or a salt thereof, and Compound 11, or a salt thereof. In some embodiments, the compositions provided include Compound 2, or a salt thereof, and Compound 11, or a salt thereof, in an amount less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, the compositions provided include Compound 2, or a salt thereof, and Compound 11, or a salt thereof, in an amount less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. In some embodiments, the compositions provided include Compound 2, or a salt thereof, wherein Compound 11, or a salt thereof, is undetectable (e.g., by HPLC or 1 HNMR measurement).

[0051] In some embodiments, the compositions provided include Compound 2, or a salt thereof, and Compound 12, or a salt thereof. In some embodiments, the compositions provided include Compound 2, or a salt thereof, and Compound 12, or a salt thereof, in an amount less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (w / w HPLC) relative to maribavir. In some embodiments, the compositions provided include Compound 2, or a salt thereof, and Compound 12, or a salt thereof, in an amount less than 1.00%, 0.5%, 0.1%, 0.05%, or 0.02% (a / a HPLC) relative to maribavir. In some embodiments, the compositions provided include Compound 2, or a salt thereof, wherein Compound 12, or a salt thereof, is undetectable (e.g., by HPLC or 1 HNMR measurement).

[0052] In some embodiments, such compositions comprising compound 2 or a salt thereof are prepared as described herein. In some embodiments, the present invention also provides the following recognition: certain reagents (and their amounts) and / or reaction conditions can provide a compound 2 or a salt thereof with improved quality (e.g., with higher purity and / or minimal by-products), and / or 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 can also improve the yield or quality of maribavir. Without wishing to be bound by a particular theory, the present invention provides the following recognition: combining crystallization and / or recrystallization into step 1 can improve yield, purity and / or reduce the formation of by-products (e.g., compounds 9, 10, 11, and 12).

[0053] 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 a method comprising the following steps: (a) Compound 5a: or a salt thereof, wherein Each R 2 are independently halogen; With compounds 6a and 7a: or a salt thereof, wherein Each R 1 are independently selected from C 1-6 an optionally substituted group of an aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic group, a 3- to 7-membered saturated or partially unsaturated heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, a phenyl group, or a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; The reaction is carried out under suitable reaction conditions to obtain compound 2a or a salt thereof.

[0054] As generally defined above, each R 2 is independently halogen. In some embodiments, each R 2 is independently fluoro or chloro. 2 is fluorine. In some embodiments, each R 2 It's chlorine.

[0055] As generally defined above, each R 1 are independently selected from C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated carbocyclic group, 3- to 7-membered saturated or partially unsaturated heterocyclic group 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, each R 1 are independently selected from C 1-6 aliphatic or 3- to 7-membered saturated or partially unsaturated carbocyclic group. 1 is an optionally substituted C 1-6 In some embodiments, R 1 is an optionally substituted C 1-3 In some embodiments, R 1 is optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl. 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl. 1 In some embodiments, R 1 is an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl group. 1is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0056] 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 a method comprising the following steps: (a) Compound 5: or a salt thereof, With compounds 6 and 7: or a salt thereof, The reaction is carried out under suitable reaction conditions to obtain compound 2 or a salt thereof.

[0057] In some embodiments, step 1 further provides one or more of the following compounds: or a salt thereof.

[0058] In some embodiments, step 1 provides a method comprising: 1 HNMR measurement) is less than 1.00%, 0.5%, 0.1%, 0.05% or 0.02% w / w of Compound 9. In some embodiments, step 1 provides a composition comprising a relative amount of Compound 2 (e.g., by HPLC or 1 H NMR measurement) 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. In some embodiments, step 1 provides a composition comprising relative to Compound 2 (e.g., by HPLC or 1 HNMR measurement) is less than 1.00%, 0.5%, 0.1%, 0.05% or 0.02% a / a of Compound 9. In some embodiments, step 1 provides a composition comprising a relative amount of Compound 2 (e.g., by HPLC or 1 H NMR measurement) 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% a / a of Compound 9. In some embodiments, step 1 provides a composition wherein Compound 9 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0059] 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 relative to compound 2. In some embodiments, step 1 provides a composition wherein compound 10 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0060] 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 relative to compound 2. In some embodiments, step 1 provides a composition wherein compound 11 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0061] 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 relative to compound 2. In some embodiments, step 1 provides a composition wherein compound 12 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0062] In some embodiments, step 1 provides a composition as provided in any one of Tables 4-1 to 4-6 in Example 4.

[0063] In some embodiments, compound 6 or its salt is present in an amount of about 0.50 to 1.50 equivalents relative to compound 5 or its salt. In some embodiments, compound 6 or its salt is present in an amount of about 0.70 to 1.30 equivalents relative to compound 5 or its salt. In some embodiments, compound 6 or its salt is present in an amount of about 0.70 to 1.10 equivalents relative to compound 5 or its salt. In some embodiments, compound 6 or its salt is present in an amount of about 0.70 to 0.90 equivalents relative to compound 5 or its salt. In some embodiments, compound 6 or its salt is present in an amount of about 0.90 to 1.30 equivalents relative to compound 5 or its salt. In some embodiments, compound 6 or its salt is present in an amount of about 1.10 to 1.30 equivalents relative to compound 5 or its salt. In some embodiments, compound 6 or its salt is present in an amount of about 0.80 to 1.20 equivalents relative to compound 5 or its salt. In some embodiments, compound 6 or its salt is present in an amount of about 0.95 to 1.10 equivalents relative to compound 5 or its salt. In some embodiments, compound 6 or its salt is present in an amount of about 1.00 to 1.10 equivalents relative to compound 5 or its salt. In some embodiments, compound 6 or its salt is present in an amount of about 0.95 to 1.05 equivalents relative to compound 5 or its salt. In some embodiments, compound 6 or its salt is present in an amount of about 0.90 to about 1.09 equivalents relative to compound 5 or its salt. In some embodiments, compound 6 or its salt is present in an amount of about 1.00 equivalents relative to compound 5 or its salt. In some embodiments, compound 6 or its salt 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 its salt. In some embodiments, compound 6 or its salt is present in an amount of about 1.02 equivalents relative to compound 5 or its salt. In some embodiments, compound 6 or its salt is present in an amount of about 1.04 equivalents relative to compound 5 or its salt. 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.

[0064] In some embodiments, compound 7 or its salt is present in an amount of about 0.50 to 1.50 equivalents relative to compound 5 or its salt. In some embodiments, compound 7 or its salt is present in an amount of about 0.70 to 1.30 equivalents relative to compound 5 or its salt. In some embodiments, compound 7 or its salt is present in an amount of about 0.70 to 1.10 equivalents relative to compound 5 or its salt. In some embodiments, compound 7 or its salt is present in an amount of about 0.70 to 0.90 equivalents relative to compound 5 or its salt. In some embodiments, compound 7 or its salt is present in an amount of about 0.90 to 1.30 equivalents relative to compound 5 or its salt. In some embodiments, compound 7 or its salt is present in an amount of about 0.95 to 1.15 equivalents relative to compound 5 or its salt. In some embodiments, compound 7 or its salt is present in an amount of about 0.90 to 1.20 equivalents relative to compound 5 or its salt. In some embodiments, compound 7 or its salt is present in an amount of about 1.00 to 1.15 equivalents relative to compound 5 or its salt. In some embodiments, compound 7 or its salt is present in an amount of about 1.03 to about 1.13 equivalents relative to compound 5 or its salt. In some embodiments, compound 7 or its salt is present in an amount of about 1.05 to 1.10 equivalents relative to compound 5 or its salt. In some embodiments, compound 7 or its salt 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 its salt. In some embodiments, compound 7 or its salt is present in an amount of about 1.06 equivalents relative to compound 5 or its salt. In some embodiments, compound 7 or its salt is present in an amount of about 1.08 equivalents relative to compound 5 or its salt. In some embodiments, compound 7 or its salt is present in an amount of about 1.10 equivalents relative to compound 5 or its salt.

[0065] In some embodiments, the reaction conditions include solvents. In some embodiments, the solvent is or includes acetone, acetonitrile, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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 includes acetone. In some embodiments, the solvent is or includes acetonitrile. In some embodiments, the solvent is or includes 1,2-dimethoxyethane. In some embodiments, the solvent is or includes N,N-dimethylformamide. In some embodiments, the solvent is or includes N,N-dimethylacetamide. In some embodiments, the solvent is or includes N-methylpyrrolidone. In some embodiments, the solvent is or includes dimethyl sulfoxide. In some embodiments, the solvent is or includes 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. In some embodiments, the solvent is or comprises 1,4-dioxane.

[0066] In some embodiments, the solvent is present in an amount of about 1.0L / kg to about 20.0L / kg. In some embodiments, the solvent is present in an amount of about 5.0L / kg to about 20.0L / kg. In some embodiments, the solvent is present in an amount of about 5.0L / kg to about 15.0L / kg. In some embodiments, the solvent is present in an amount of about 5.0L / kg to about 12.0L / kg. In some embodiments, the solvent is present in an amount of about 5.0L / kg to about 10.0L / kg. In some embodiments, the solvent is present in an amount of about 5.0L / kg to about 8.0L / kg. In some embodiments, the solvent is present in an amount of about 5.0L / kg to about 6.0L / kg. In some embodiments, the solvent is present in an amount of about 1.0L / kg to about 5.0L / kg. In some embodiments, the solvent is present in an amount of about 2.0L / kg to about 5.0L / kg. In some embodiments, the solvent is present in an amount of about 3.0L / kg to about 5.0L / kg. In some embodiments, the solvent is present in an amount of about 4.0L / kg to about 5.0L / kg. In some embodiments, the solvent is present in an amount of about 2.0L / kg to about 8.0L / kg. In some embodiments, the solvent is present in an amount of about 3.0L / kg to about 7.0L / kg. In some embodiments, the solvent is present in an amount of about 4.0L / kg to about 6.0L / kg. In some embodiments, the solvent is present in an amount of about 1.0L / kg, 2.0L / kg, 3.0L / kg, 4.0L / kg, 5.0L / kg, 6.0L / kg, 7L / kg, 8L / kg, 9L / kg or 10L / kg. In some embodiments, the solvent is present in an amount of about 5.0L / kg. In some embodiments, the solvent is present in an amount of about 4.0L / kg. In some embodiments, the solvent is present in an amount of about 6.0L / kg.

[0067] In some embodiments, the reaction conditions include heating to a temperature T7. In embodiments, the temperature T7 is between about 50°C and about 150°C. In embodiments, the temperature T7 is between about 50°C and about 130°C. In embodiments, the temperature T7 is between about 50°C and about 110°C. In embodiments, the temperature T7 is between about 50°C and about 100°C. In embodiments, the temperature T7 is between about 60°C and about 150°C. In embodiments, the temperature T7 is between about 80°C and about 150°C. In embodiments, the temperature T7 is between about 100°C and 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.

[0068] In some embodiments, the reaction conditions include maintaining the reaction at temperature T7 for a period of time. In some embodiments, the period of time is at least 12 hours. In some embodiments, the period of time is at least 24 hours. In some embodiments, the period of time is at least 48 hours. In some embodiments, the period of time is between about 2 hours to about 20 hours. In some embodiments, the period of time is between about 3 hours to about 20 hours. In some embodiments, the period of time is between about 4 hours to about 20 hours. In some embodiments, the period of time is between about 5 hours to about 20 hours. In some embodiments, the period of time is between about 7.5 hours to about 20 hours. In some embodiments, the period of time is between about 10 hours to about 20 hours. In some embodiments, the period of time is between about 11 hours to about 20 hours. In some embodiments, the period of time is between about 12 hours to about 20 hours. In some embodiments, the period of time is between about 13 hours to about 20 hours. In some embodiments, the period of time is between about 14 hours to about 20 hours. In some embodiments, the period of time is between about 14 hours to about 19 hours. In some embodiments, the time period is between about 14 hours to about 18 hours. In some embodiments, the time period is between about 14 hours to about 17 hours. In some embodiments, the time period is between about 14 hours to about 16 hours. In some embodiments, the time period is between about 14 hours to about 15 hours.

[0069] In some embodiments, for example, after carrying out the reaction, step 1 further comprises (b) cooling the reaction mixture.

[0070] In some embodiments, after heating to temperature T7, the reaction conditions further include cooling to temperature T8. In some embodiments, temperature T8 is between about 50°C and about 110°C. In some embodiments, temperature T8 is between about 50°C and about 100°C. In some embodiments, temperature T8 is between about 50°C and about 90°C. In some embodiments, temperature T8 is between about 50°C and about 85°C. In some embodiments, temperature T8 is between about 50°C and about 80°C. In some embodiments, temperature T8 is between about 65°C and about 110°C. In some embodiments, temperature T8 is between about 75°C and about 110°C. In some embodiments, temperature T8 is between about 60°C and about 100°C. In some embodiments, temperature T8 is between about 70°C and about 90°C. In some embodiments, temperature T8 is between about 75°C and about 85°C. In some embodiments, temperature T8 is between about 75°C and about 80°C. In some embodiments, temperature T8 is between about 80°C and 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.

[0071] In some embodiments, the reaction mixture is cooled to a temperature T8 at a rate of about 2°C / hour to about 20°C / hour. In some embodiments, the reaction mixture is cooled to a temperature T8 at a rate of about 2°C / hour to about 17.5°C / hour. In some embodiments, the reaction mixture is cooled to a temperature T8 at a rate of about 2°C / hour to about 15°C / hour. In some embodiments, the reaction mixture is cooled to a temperature T8 at a rate of about 2°C / hour to about 12.5°C / hour. In some embodiments, the reaction mixture is cooled to a temperature T8 at a rate of about 2°C / hour to about 10°C / hour. In some embodiments, the reaction mixture is cooled to a temperature T8 at a rate of about 2°C / hour to about 7.5°C / hour. In some embodiments, the reaction mixture is cooled to a temperature T8 at a rate of about 5°C / hour to about 20°C / hour. In some embodiments, the reaction mixture is cooled to a temperature T8 at a rate of about 7.5°C / hour to about 20°C / hour. In some embodiments, the reaction mixture is cooled to a temperature T8 at a rate of about 10°C / hour to about 20°C / hour. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 4°C / hour to about 17.5°C / hour. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 4°C / hour to about 15°C / hour. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 4°C / hour to about 12.5°C / hour. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 5°C / hour to about 10°C / hour. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 6°C / hour to about 8°C / hour. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 2.0°C / hour, 3.0°C / hour, 4.0°C / hour, 5.0°C / hour, 6.0°C / hour, 7.0°C / hour, 8.0°C / hour, 9.0°C / hour or 10.0°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 6.5°C / hour. In some embodiments, the reaction mixture is cooled to temperature T8 at a rate of about 7.0°C / hour.

[0072] In some embodiments, the completion of the reaction (e.g., the presence of Compound 5 or Compound 2) is monitored by HPLC. In some embodiments, the presence of Compound 5 or Compound 2 is monitored in the reaction (e.g., a / a by HPLC).

[0073] In some embodiments, when less than 25% a / a of compound 5 or its salt is detected (e.g., by HPLC), the reaction is determined to be complete. In some embodiments, when less than 10% a / a of compound 5 or its salt is detected (e.g., by HPLC), the reaction is determined to be complete. In some embodiments, when less than 5% a / a of compound 5 or its salt is detected (e.g., by HPLC), the reaction is determined to be complete. In some embodiments, when less than 4% a / a of compound 5 or its salt is detected (e.g., by HPLC), the reaction is determined to be complete. In some embodiments, when less than 3% a / a of compound 5 or its salt is detected (e.g., by HPLC), the reaction is determined to be complete. In some embodiments, when less than 2% a / a of compound 5 or its salt is detected (e.g., by HPLC), the reaction is determined to be complete. In some embodiments, when less than 1% a / a of compound 5 or its salt is detected (e.g., by HPLC), the reaction is determined to be complete.

[0074] In some embodiments, step 1 further includes step (c) compound 2 or its salt (for example, from reaction mixture) crystallization. In some embodiments, the present invention provides the following understanding: crystallization can provide higher yield and / or purity of compound 2 or its salt, and / or provide compound 2 or its salt, for example, with low level or undetectable level of by-product (for example compound 9,10,11 or 12 or its salt), especially when the reaction is scaled up (scaled-up). It is not desirable to be bound by a particular theory, and it is believed that compound 2 or its salt is crystallized at a temperature different from the by-product (for example compound 9,10,11 or 12 or its salt). Therefore, it is not desirable to be bound by a particular theory, and it is believed that crystallization and / or control of the cooling rate of the reaction at a specific temperature can provide compound 2 or its salt with higher yield and / or purity, and / or provide compound 2 or its salt, for example, with reduced or undetectable level of by-product (for example compound 9,10,11 or 12 or its salt).

[0075] In some embodiments, the crystallization of compound 2 or a salt thereof comprises providing a primary mixture, wherein the primary mixture comprises compound 2 or a salt thereof and a primary solvent. In some embodiments, the primary mixture is provided at a temperature T8.

[0076] 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-methylpyrrolidone, 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 dichloromethane. 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-methylpyrrolidone. 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.

[0077] In some embodiments, the primary solvent is present in an amount of about 1.0L / kg to 10.0L / kg solute. In some embodiments, the primary solvent is present in an amount of about 1.0L / kg to 8.0L / kg solute. In some embodiments, the primary solvent is present in an amount of about 1.0L / kg to 6.0L / kg solute. In some embodiments, the primary solvent is present in an amount of about 1.0L / kg to 4.0L / kg solute. In some embodiments, the primary solvent is present in an amount of about 2.0L / kg to 10.0L / kg solute. In some embodiments, the primary solvent is present in an amount of about 4.0L / kg to 10L / kg solute. In some embodiments, the primary solvent is present in an amount of about 6.0L / kg to 10L / kg solute. In some embodiments, the primary solvent is present in an amount of about 2.0L / kg to 8.0L / kg solute. In some embodiments, the primary solvent is present in an amount of about 4.0L / kg to 6.0L / kg solute. In some embodiments, the primary solvent is present in an amount of about 1.0L / kg, 2.0L / kg, 3.0L / kg, 4.0L / kg, 5.0L / kg, 6.0L / kg, 7.0L / kg, 8.0L / kg, 9.0L / kg or 10.0L / kg. In some embodiments, the primary solvent is present in an amount of about 3.0L / kg, 4.0L / kg, 5.0L / kg, 6.0 or 7.0L / kg. In some embodiments, the primary solvent is present in an amount of about 3.0L / kg solute. In some embodiments, the primary solvent is present in an amount of about 4.0L / kg solute. In some embodiments, the primary solvent is present in an amount of about 4.9L / kg solute. In some embodiments, the primary solvent is present in an amount of about 5.0L / kg solute. In some embodiments, the primary solvent is present in an amount of about 6.0L / kg solute.

[0078] In some embodiments, the crystallization of compound 2 or its salt includes adding seed crystals to the primary mixture. In some embodiments, seed crystals are added in an amount of about 0.01% by weight to about 5.0% by weight of compound 5 or its salt. In some embodiments, seed crystals are added in an amount of about 0.1% by weight to about 5.0% by weight of compound 5 or its salt. In some embodiments, seed crystals are added in an amount of about 0.1% by weight to about 4.0% by weight of compound 5 or its salt. In some embodiments, seed crystals are added in an amount of about 0.1% by weight to about 3.0% by weight of compound 5 or its salt. In some embodiments, seed crystals are added in an amount of about 0.1% by weight to about 2.0% by weight of compound 5 or its salt. In some embodiments, seed crystals are added in an amount of about 0.1% by weight to about 1.5% by weight of compound 5 or its salt. In some embodiments, seed crystals are added in an amount of about 0.10% by weight to about 1.00% by weight of compound 5 or its salt. In some embodiments, seed crystals are added in an amount of about 0.1% by weight to about 0.75% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.1% to about 0.50% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.1% to about 0.40% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.1% to about 0.30% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.1% to about 0.25% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.20% to about 1.00% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.25% to about 1.00% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.50% to about 1.00% by weight of compound 5 or its salt. In some embodiments, the seeds are added in an amount of about 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, or 0.50% by weight of Compound 5 or a salt thereof.

[0079] In some embodiments, the seed crystals are added in an amount of about 0.05% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.10% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.15% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.20% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.25% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.30% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.35% by weight of compound 5 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.45% by weight of compound 5 or its salt. In some embodiments, the seed crystals are compound 2 or its salt.

[0080] In some embodiments, the crystallization of compound 2 or its salt comprises cooling the primary mixture to a temperature T9. In some embodiments, the temperature T9 is between about 0°C and about 50°C. In some embodiments, the temperature T9 is between about 0°C and about 45°C. In some embodiments, the temperature T9 is between about 0°C and about 40°C. In some embodiments, the temperature T9 is between about 0°C and about 35°C. In some embodiments, the temperature T9 is between about 0°C and about 30°C. In some embodiments, the temperature T9 is between about 0°C and about 25°C. In some embodiments, the temperature T9 is between about 10°C and about 50°C. In some embodiments, the temperature T9 is between about 15°C and about 50°C. In some embodiments, the temperature T9 is between about 20°C and about 50°C. In some embodiments, the temperature T9 is between about 25°C and about 50°C. In some embodiments, the temperature T9 is between about 15°C and about 40°C. In some embodiments, the temperature T9 is between about 20°C and about 35°C. In some embodiments, the temperature T9 is between about 18°C ​​and about 32°C. In some embodiments, the temperature T9 is between about 20°C and about 35°C. In some embodiments, the temperature T9 is between about 25°C and about 30°C. In some embodiments, the temperature T9 is between about 26°C and about 28°C. In some embodiments, the 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, the temperature T9 is about 24°C. In some embodiments, the temperature T9 is about 25°C. In some embodiments, the temperature T9 is about 26°C. In some embodiments, the temperature T9 is about 27°C. In some embodiments, the temperature T9 is about 29°C. In some embodiments, the temperature T9 is about 30°C. In some embodiments, the temperature T9 is about 31°C.

[0081] In some embodiments, the primary mixture is cooled at a rate of about 2.0°C / hour to about 20°C / hour. In some embodiments, the primary mixture is cooled to temperature T9 at a rate of about 4.0°C / hour to about 20°C / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 6°C / hour to about 20°C / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 8°C / hour to about 20°C / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 2.0°C / hour to about 15°C / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 2.0°C / hour to about 10°C / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 2.0°C / hour to about 8.0°C / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 4.0°C / hour to about 12.0°C / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 5.0°C / hour to about 12.0°C / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 5.0°C / hour to about 10.0°C / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 5.0°C / hour to about 8.0°C / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 6.0°C / hour to about 7.0°C / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 2.0°C / hour, 3.0°C / hour, 4.0°C / hour, 5.0°C / hour, 6.0°C / hour, 7.0°C / hour, 8.0°C / hour, 9.0°C / hour or 10.0°C / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 5.5°C / hour. In some embodiments, the reaction mixture is cooled to temperature T9 at a rate of about 6.0°C / hour. In some embodiments, the primary 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.

[0082] In some embodiments, step 1 further comprises step (d) recrystallizing compound 2 or a salt thereof (e.g., from a reaction mixture or a primary mixture). In some embodiments, the present invention provides the following understanding: recrystallization can provide a higher yield and / or purity of compound 2 or a salt thereof, and / or provide compound 2 or a salt thereof, for example, with a reduced or undetectable level of by-products (e.g., compounds 9, 10, 11 and / or 12 or a salt thereof), particularly when the reaction is scaled up. In some embodiments, the recrystallization conditions provided herein can provide a higher yield and / or purity of compound 2 or a salt thereof, and / or provide compound 2 or a salt thereof, for example, with a reduced or undetectable level of by-products (e.g., compounds 9, 10, 11 and / or 12 or a salt thereof).

[0083] In some embodiments, the recrystallization of Compound 2 or a salt thereof comprises (i) providing a primary mixture, wherein the primary mixture comprises Compound 2 or a salt thereof and a primary solvent, wherein the primary solvent is as described above and herein.

[0084] In some embodiments, the primary mixture is provided at temperature T9, wherein temperature T9 is as described above and herein.

[0085] In some embodiments, the primary solvent is as described above and herein.

[0086] In some embodiments, the recrystallization of compound 2 or its salt 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, 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 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.

[0087] In some embodiments, the secondary solvent is present in an amount of about 1L / kg to about 20L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 2L / kg to about 20L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 6L / kg to about 20L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 10L / kg to about 20L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 2L / kg to about 18L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 2L / kg to about 14L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 2L / kg to about 10L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 4L / kg to about 18L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 6L / kg to about 14L / kg of solute. In some embodiments, the secondary solvent is present in an amount of about 8L / kg to about 12L / kg solute. In some embodiments, the secondary solvent is present in an amount of about 9L / kg to about 11L / kg solute. In some embodiments, the secondary solvent is present in an amount of about 5L / kg, 6L / kg, 7L / kg, 8L / kg, 9L / kg, 10L / kg, 11L / kg, 12L / kg, 13L / kg, 14L / kg or 15L / kg solute. In some embodiments, the secondary solvent is present in an amount of about 8L / kg solute. In some embodiments, the secondary solvent is present in an amount of about 9L / kg solute. In some embodiments, the secondary solvent is present in an amount of about 10L / kg solute. In some embodiments, the secondary solvent is present in an amount of about 11L / kg solute. In some embodiments, the secondary solvent is present in an amount of about 12L / kg solute.

[0088] In some embodiments, the recrystallization of compound 2 or its salt further comprises (iii) maintaining and optionally stirring the secondary mixture at temperature T9 for a period of time. In some embodiments, the secondary mixture is stirred at 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 between about 1 hour to about 8 hours. In some embodiments, the period of time is between about 2 hours to about 6 hours. In some embodiments, the period of time is between about 2 hours to about 5 hours. In some embodiments, the period of time is between 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.

[0089] In some embodiments, step 1 further comprises the step (e) filtering (eg, the reaction mixture, the primary mixture, or the secondary mixture) to provide a filtered mixture.

[0090] In some embodiments, at temperature T 10 The secondary mixture is filtered. In some embodiments, the temperature T 10 Between about 0°C and about 60°C. In some embodiments, the temperature T 10 Between about 0°C and about 50°C. In some embodiments, the temperature T 10 Between about 0°C and about 40°C. In some embodiments, the temperature T 10 Between about 0°C and about 30°C. In some embodiments, the temperature T 10 Between about 10°C and about 60°C. In some embodiments, the temperature T 10 Between about 20°C and about 60°C. In some embodiments, the temperature T 10 Between about 10°C and about 50°C. In some embodiments, the temperature T 10 Between about 15°C and about 45°C. In some embodiments, the temperature T 10 Between about 20°C and about 40°C. In some embodiments, the temperature T 10 Between about 25°C and about 35°C. In some embodiments, the temperature T 10 Between about 24°C and about 32°C. In some embodiments, the temperature T 10 Between about 26°C and about 28°C. In some embodiments, the temperature T10 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 about 30°C.

[0091] In some embodiments, step 1 further comprises the step (f) washing (eg, the filtered mixture or the secondary mixture) to provide a final mixture.

[0092] In some embodiments, washing includes washing solvent 1. In some embodiments, washing solvent 1 includes adding washing solvent 1 to, for example, a filtered mixture. In some embodiments, washing solvent 1 is or comprises acetone, acetonitrile, dichloromethane, 1,2-dichloroethane, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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 comprises acetone. In some embodiments, washing solvent 1 is or comprises acetonitrile. In some embodiments, washing solvent 1 is or comprises dichloromethane. In some embodiments, washing solvent 1 is or comprises 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-methylpyrrolidone. 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, wash solvent 1 is or comprises xylene. In some embodiments, wash solvent 1 is or comprises tert-butyl methyl ether. In some embodiments, wash solvent 1 is or comprises cyclopentyl methyl ether. In some embodiments, wash solvent 1 is or comprises 1,4-dioxane. In some embodiments, wash solvent 1 is or comprises dichloromethane. In some embodiments, wash solvent 1 comprises 1,4-dioxane and dichloromethane.

[0093] In some embodiments, the amount of washing solvent 1 is 0.30L / kg to 5.00L / kg. In some embodiments, the amount of washing solvent 1 is 1.0L / kg to 5.00L / kg. In some embodiments, the amount of washing solvent 1 is 1.50L / kg to 5.00L / kg. In some embodiments, the amount of washing solvent 1 is 2.50L / kg to 5.00L / kg. In some embodiments, the amount of washing solvent 1 is 0.30L / kg to 4.50L / kg. In some embodiments, the amount of washing solvent 1 is 0.50L / kg to 3.00L / kg. In some embodiments, the amount of washing solvent 1 is 0.50L / kg to 2.50L / kg. In some embodiments, the amount of washing solvent 1 is 0.50L / kg to 2.00L / kg. In some embodiments, the amount of washing solvent 1 is 1.50L / kg to 4.00L / kg. In some embodiments, the amount of washing solvent 1 is 2.25L / kg to 3.00L / kg. In some embodiments, the amount of washing solvent 1 is 2.50L / kg to 2.75L / kg. In some embodiments, the amount of washing solvent 1 is about 0.50L / kg, 1.05L / kg, 1.65L / kg, 2.00L / kg, 2.25L / kg, 2.50L / kg or 2.70L / kg. In some embodiments, the amount of washing solvent 1 is about 0.50L / kg. In some embodiments, the amount of washing solvent 1 is about 1.65L / kg. In some embodiments, the amount of washing solvent 1 is about 2.00L / kg. In some embodiments, the amount of washing solvent 1 is about 2.25L / kg. In some embodiments, the amount of washing solvent 1 is about 2.50L / kg. In some embodiments, the amount of washing solvent 1 is about 2.75L / kg.

[0094] In some embodiments, the wash solvent 1 comprises 1,4-dioxane in an amount of about 0.4L / kg to about 1.5L / kg. In some embodiments, the wash solvent 1 comprises 1,4-dioxane in an amount of about 0.4L / kg to about 1.3L / kg. In some embodiments, the wash solvent 1 comprises 1,4-dioxane in an amount of about 0.4L / kg to about 1.0L / kg. In some embodiments, the wash solvent 1 comprises 1,4-dioxane in an amount of about 0.6L / kg to about 1.5L / kg. In some embodiments, the wash solvent 1 comprises 1,4-dioxane in an amount of about 0.8L / kg to about 1.5L / kg. In some embodiments, the wash solvent 1 comprises 1,4-dioxane in an amount of about 0.6L / kg to about 1.3L / kg. In some embodiments, the wash solvent 1 comprises 1,4-dioxane in an amount of about 0.8L / kg to about 0.9L / kg. In some embodiments, the 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, the wash solvent 1 comprises 1,4-dioxane in an amount of about 0.60 L / kg. In some embodiments, the wash solvent 1 comprises 1,4-dioxane in an amount of about 0.70 L / kg. In some embodiments, the wash solvent 1 comprises 1,4-dioxane in an amount of about 0.80 L / kg. In some embodiments, the wash solvent 1 comprises 1,4-dioxane in an amount of about 0.90 L / kg. In some embodiments, the wash solvent 1 comprises 1,4-dioxane in an amount of about 1.00 L / kg.

[0095] In some embodiments, washing solvent 1 comprises dichloromethane in an amount of about 1.0L / kg to about 3.2L / kg. In some embodiments, washing solvent 1 comprises dichloromethane in an amount of about 1.0L / kg to about 3.0L / kg. In some embodiments, washing solvent 1 comprises dichloromethane in an amount of about 1.0L / kg to about 2.5L / kg. In some embodiments, washing solvent 1 comprises dichloromethane in an amount of about 1.0L / kg to about 2.0L / kg. In some embodiments, washing solvent 1 comprises dichloromethane in an amount of about 1.5L / kg to about 3.0L / kg. In some embodiments, washing solvent 1 comprises dichloromethane in an amount of about 1.25L / kg to about 2.0L / kg. In some embodiments, washing solvent 1 comprises dichloromethane in an amount of about 1.5L / kg to about 1.7L / kg. In some embodiments, the washing solvent 1 comprises dichloromethane in an amount of about 1.35L / kg, 1.45L / kg, 1.55L / kg, 1.65L / kg, 1.75L / kg or 1.85L / kg. In some embodiments, the washing solvent 1 comprises dichloromethane in an amount between about 1.35L / kg. In some embodiments, the washing solvent 1 comprises dichloromethane in an amount between about 1.45L / kg. In some embodiments, the washing solvent 1 comprises dichloromethane in an amount between about 1.55L / kg. In some embodiments, the washing solvent 1 comprises dichloromethane in an amount between about 1.64L / kg. In some embodiments, the washing solvent 1 comprises dichloromethane in an amount between about 1.75L / kg.

[0096] In some embodiments, the washing solvent 1 comprises 1,4-dioxane in an amount of about 0.4L / kg to about 1.5L / kg and dichloromethane in an amount of about 1.0L / kg to about 3.2L / kg. In some embodiments, the washing solvent 1 comprises 1,4-dioxane in an amount of about 0.8L / kg to about 0.9L / kg and dichloromethane in an amount of about 1.5L / kg to about 1.7L / kg. In some embodiments, the washing solvent 1 comprises 1,4-dioxane in an amount of about 0.60L / kg, 0.70L / kg, 0.80L / kg, 0.90L / kg or 1.00L / kg and dichloromethane in an amount of about 1.40L / kg, 1.50L / kg, 1.60L / kg, 1.70L / kg or 1.80L / 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.

[0097] In some embodiments, wash solvent 1 is provided between about 0°C and 50°C. In some embodiments, wash solvent 1 is provided between about 0°C and 40°C. In some embodiments, wash solvent 1 is provided between about 0°C and 30°C. In some embodiments, wash solvent 1 is provided between about 10°C and 50°C. In some embodiments, wash solvent 1 is provided between about 20°C and 50°C. In some embodiments, wash solvent 1 is provided between about 30°C and 50°C. In some embodiments, wash solvent 1 is provided between about 10°C and 40°C. In some embodiments, wash solvent 1 is provided between about 18°C ​​and 32°C. In some embodiments, wash solvent 1 is provided between about 20°C and 30°C. In some embodiments, wash solvent 1 is provided between about 23°C and 27°C. In some embodiments, wash solvent 1 is provided at about 20°C, 22°C, 24°C, 25°C, 26°C, 28°C, or 30°C. In some embodiments, wash solvent 1 is provided at or about 23°C. In some embodiments, wash solvent 1 is provided at or about 25° C. In some embodiments, wash solvent 1 is provided at or about 27° C. In some embodiments, wash 1 comprises stirring, for example, the filtered mixture. In some embodiments, wash 1 further comprises removing wash solvent 1.

[0098] In some embodiments, washing includes washing 2. In some embodiments, washing 2 includes adding washing solvent 2 to, for example, the filtered mixture. In some embodiments, washing solvent 2 is or comprises chloroform, hexane, pentane, 1,4-dioxane, 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 2 is or comprises chloroform. In some embodiments, washing solvent 2 is or comprises hexane. In some embodiments, washing solvent 2 is or comprises pentane. In some embodiments, washing solvent 2 is or comprises ether. In some embodiments, washing solvent 2 is or comprises ethyl acetate. In some embodiments, washing solvent 2 is or comprises isopropyl acetate. In some embodiments, washing solvent 2 is or comprises tert-butyl methyl ether. In some embodiments, washing solvent 2 is or comprises cyclopentyl methyl ether. In some embodiments, washing solvent 2 is or comprises toluene. In some embodiments, washing 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.

[0099] In some embodiments, washing solvent 2 is provided in an amount of about 0.5L / kg to 5.0L / kg. In some embodiments, washing solvent 2 is provided in an amount of about 0.5L / kg to 4.0L / kg. In some embodiments, washing solvent 2 is provided in an amount of about 0.5L / kg to 3.0L / kg. In some embodiments, washing solvent 2 is provided in an amount of about 1.0L / kg to 5.0L / kg. In some embodiments, washing solvent 2 is provided in an amount of about 2.5L / kg to 5.0L / kg. In some embodiments, washing solvent 2 is provided in an amount of about 1.0L / kg to 4.0L / kg. In some embodiments, washing solvent 2 is provided in an amount of about 1.0L / kg to 3.0L / kg. In some embodiments, washing solvent 2 is provided in an amount of about 2.0L / kg to 2.5L / kg. In some embodiments, washing solvent 2 is provided in an amount of about 2.3L / kg to 2.7L / kg. In some embodiments, washing solvent 2 is provided in an amount of about 1.0L / kg, 1.5L / kg, 2.0L / kg, 2.5L / kg, 3.0L / kg, 3.5L / kg, 4.0L / kg, 4.5L / kg or 5.0L / kg. In some embodiments, washing solvent 2 is provided in an amount of about 2.0L / kg. In some embodiments, washing solvent 2 is provided in an amount of about 2.5L / kg. In some embodiments, washing solvent 2 is provided in an amount of about 3.0L / kg.

[0100] In some embodiments, the wash solvent 2 is provided between about 0°C and 50°C. In some embodiments, the wash solvent 2 is provided between about 0°C and 40°C. In some embodiments, the wash solvent 2 is provided between about 0°C and 30°C. In some embodiments, the wash solvent 2 is provided between about 10°C and 50°C. In some embodiments, the wash solvent 2 is provided between about 20°C and 50°C. In some embodiments, the wash solvent 2 is provided between about 30°C and 50°C. In some embodiments, the wash solvent 2 is provided between about 10°C and 40°C. In some embodiments, the wash solvent 2 is provided between about 18°C ​​and 32°C. In some embodiments, the wash solvent 2 is provided between about 20°C and 30°C. In some embodiments, the wash solvent 2 is provided between about 23°C and 27°C. In some embodiments, the wash solvent 2 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 2 is provided at or about 23°C. In some embodiments, wash solvent 2 is provided at or about 25° C. In some embodiments, wash solvent 2 is provided at or about 27° C. In some embodiments, wash 2 further comprises stirring, for example, the filtered mixture. In some embodiments, wash 2 further comprises removing wash solvent 2.

[0101] In some embodiments, washing includes washing 3 or washing 4. In some embodiments, washing 3 or washing 4 is the same as washing 2. In some embodiments, washing 3 includes adding washing solvent 3 to the filtered mixture, for example. In some embodiments, washing solvent 3 is or comprises chloroform, hexane, pentane, 1,4-dioxane, ethyl ether, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α, α, α-trifluorotoluene, chlorobenzene, xylene, chlorobenzene or dichloromethane. In some embodiments, washing solvent 3 is or comprises chloroform. In some embodiments, washing solvent 3 is or comprises hexane. In some embodiments, washing solvent 3 is or comprises pentane. In some embodiments, washing solvent 3 is or comprises ethyl ether. In some embodiments, washing solvent 3 is or comprises ethyl acetate. In some embodiments, washing solvent 3 is or comprises isopropyl acetate. In some embodiments, washing solvent 3 is or comprises 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, the wash solvent 3 is or comprises benzene. In some embodiments, the wash solvent 3 is or comprises α,α,α-trifluorotoluene. In some embodiments, the wash solvent 3 is or comprises xylene. In some embodiments, the wash solvent 3 is or comprises chlorobenzene. In some embodiments, the wash solvent 3 is or comprises 1,4-dioxane.

[0102] In some embodiments, washing solvent 3 is provided in an amount of about 0.5L / kg to 5.0L / kg. In some embodiments, washing solvent 3 is provided in an amount of about 0.5L / kg to 4.0L / kg. In some embodiments, washing solvent 3 is provided in an amount of about 0.5L / kg to 3.0L / kg. In some embodiments, washing solvent 3 is provided in an amount of about 1.0L / kg to 5.0L / kg. In some embodiments, washing solvent 3 is provided in an amount of about 2.5L / kg to 5.0L / kg. In some embodiments, washing solvent 3 is provided in an amount of about 1.0L / kg to 4.0L / kg. In some embodiments, washing solvent 3 is provided in an amount of about 1.0L / kg to 3.0L / kg. In some embodiments, washing solvent 3 is provided in an amount of about 1.5L / kg to 3.0L / kg. In some embodiments, washing solvent 3 is provided in an amount of about 2.0L / kg to 2.8L / kg. In some embodiments, washing solvent 3 is provided in an amount of about 2.3L / kg to 2.7L / kg. In some embodiments, washing solvent 3 is provided in an amount of about 1.0L / kg, 1.5L / kg, 2.0L / kg, 2.5L / kg, 3.0L / kg. In some embodiments, washing solvent 3 is provided in an amount of about 2.0L / kg. In some embodiments, washing solvent 3 is provided in an amount of about 2.5L / kg. In some embodiments, washing solvent 3 is provided in an amount of about 3.0L / kg.

[0103] In some embodiments, the wash solvent 3 is provided between about 0°C and 50°C. In some embodiments, the wash solvent 3 is provided between about 0°C and 40°C. In some embodiments, the wash solvent 3 is provided between about 0°C and 30°C. In some embodiments, the wash solvent 3 is provided between about 10°C and 50°C. In some embodiments, the wash solvent 3 is provided between about 20°C and 50°C. In some embodiments, the wash solvent 3 is provided between about 30°C and 50°C. In some embodiments, the wash solvent 3 is provided between about 10°C and 40°C. In some embodiments, the wash solvent 3 is provided between about 20°C and 30°C. In some embodiments, the wash solvent 3 is provided between about 22°C and 28°C. In some embodiments, the wash solvent 3 is provided between about 24°C and 26°C. In some embodiments, the wash solvent 3 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 3 is provided at or about 25°C. In some embodiments, washing 3 further comprises stirring the, for example, filtered, mixture. In some embodiments, washing 3 further comprises removing the wash solvent 3.

[0104] In some embodiments, washing 4 comprises adding a washing solvent 4 to, for example, a filtered mixture. In some embodiments, washing solvent 4 is or comprises chloroform, hexane, pentane, 1,4-dioxane, 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 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, wash solvent 4 is or comprises α,α,α-trifluorotoluene. In some embodiments, wash solvent 4 is or comprises chlorobenzene. In some embodiments, wash solvent 4 is or comprises xylene. In some embodiments, wash solvent 4 is or comprises 1,4-dioxane.

[0105] In some embodiments, washing solvent 4 is provided in an amount of about 0.5L / kg to 5.0L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 0.5L / kg to 4.0L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 0.5L / kg to 3.0L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 1.0L / kg to 5.0L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 2.5L / kg to 5.0L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 1.0L / kg to 4.0L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 1.0L / kg to 3.0L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 1.5L / kg to 3.0L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 2.0L / kg to 2.8L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 2.3L / kg to 2.7L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 2.4L / kg to 2.5L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 1.0L / kg, 1.5L / kg, 2.0L / kg, 2.5L / kg, 3.0L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 2.0L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 2.5L / kg. In some embodiments, washing solvent 4 is provided in an amount of about 3.0L / kg.

[0106] In some embodiments, the wash solvent 4 is provided between about 0°C and 50°C. In some embodiments, the wash solvent 4 is provided between about 0°C and 40°C. In some embodiments, the wash solvent 4 is provided between about 0°C and 30°C. In some embodiments, the wash solvent 4 is provided between about 10°C and 20°C. In some embodiments, the wash solvent 4 is provided between about 20°C and 50°C. In some embodiments, the wash solvent 4 is provided between about 30°C and 50°C. In some embodiments, the wash solvent 4 is provided between about 10°C and 40°C. In some embodiments, the wash solvent 4 is provided between about 18°C ​​and 32°C. In some embodiments, the wash solvent 4 is provided between about 20°C and 30°C. In some embodiments, the wash solvent 4 is provided between about 23°C and 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 or about 25°C. In some embodiments, washing 4 further comprises stirring the, for example, filtered, mixture. In some embodiments, washing 4 further comprises removing the wash solvent 4.

[0107] In some embodiments, washing comprises washing 5. In some embodiments, washing 5 comprises adding a washing solvent 5 to, for example, a filtered mixture. In some embodiments, washing solvent 5 is or comprises chloroform, hexane, pentane, 1,4-dioxane, ethyl 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 5 is or comprises chloroform. In some embodiments, washing solvent 5 is or comprises hexane. In some embodiments, washing solvent 5 is or comprises pentane. In some embodiments, washing solvent 5 is or comprises ethyl ether. In some embodiments, washing solvent 5 is or comprises ethyl acetate. In some embodiments, washing solvent 5 is or comprises isopropyl acetate. In some embodiments, washing solvent 5 is or comprises cyclopentyl methyl ether. In some embodiments, washing 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, the wash solvent 5 is or comprises chlorobenzene. In some embodiments, the wash solvent 5 is or comprises xylene. In some embodiments, the wash solvent 5 is or comprises tert-butyl methyl ether.

[0108] In some embodiments, washing solvent 5 is provided in an amount of 0.5L / kg to 4.0L / kg. In some embodiments, washing solvent 5 is provided in an amount of 0.5L / kg to 3.0L / kg. In some embodiments, washing solvent 5 is provided in an amount of 0.5L / kg to 2.0L / kg. In some embodiments, washing solvent 5 is provided in an amount of 1.0L / kg to 4.0L / kg. In some embodiments, washing solvent 5 is provided in an amount of 1.5L / kg to 4.0L / kg. In some embodiments, washing solvent 5 is provided in an amount of 2.0L / kg to 4.0L / kg. In some embodiments, washing solvent 5 is provided in an amount of 1.5L / kg to 2.5L / kg. In some embodiments, washing solvent 5 is provided in an amount of 1.8L / kg to 2.2L / kg. In some embodiments, washing solvent 5 is provided in an amount of about 1.0L / kg, 1.5L / kg, 2.0L / kg, 2.5L / kg, 3.0L / kg, 3.5L / kg or 4.0L / kg. In some embodiments, the wash solvent 5 is provided in an amount of about 1.5 L / kg. In some embodiments, the wash solvent 5 is provided in an amount of about 2.0 L / kg. In some embodiments, the wash solvent 5 is provided in an amount of about 2.5 L / kg.

[0109] In some embodiments, the wash solvent 5 is provided between about 0°C and 50°C. In some embodiments, the wash solvent 5 is provided between about 0°C and 40°C. In some embodiments, the wash solvent 5 is provided between about 0°C and 30°C. In some embodiments, the wash solvent 5 is provided between about 20°C and 50°C. In some embodiments, the wash solvent 5 is provided between about 30°C and 50°C. In some embodiments, the wash solvent 5 is provided between about 10°C and 40°C. In some embodiments, the wash solvent 5 is provided between about 18°C ​​and 32°C. In some embodiments, the wash solvent 5 is provided between about 20°C and 30°C. In some embodiments, the wash solvent 5 is provided between about 23°C and 37°C. In some embodiments, the wash 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 wash solvent 5 is provided at or about 25°C. In some embodiments, washing 5 further comprises stirring the filtered mixture, for example. In some embodiments, washing 5 further comprises removing the wash solvent 5 .

[0110] In some embodiments, washing further comprises washing 6. In some embodiments, washing 6 comprises adding a washing solvent 6 to the filtered mixture, for example. In some embodiments, washing solvent 6 is or comprises pentane, hexane, or heptane. In some embodiments, washing solvent 6 is or comprises n-pentane, n-hexane, or n-heptane. In some embodiments, washing solvent 6 is or comprises pentane. In some embodiments, washing solvent 6 is or comprises n-pentane. In some embodiments, washing solvent 6 is or comprises hexane. In some embodiments, washing solvent 6 is or comprises n-hexane. In some embodiments, washing solvent 6 is or comprises heptane. In some embodiments, washing solvent 6 is or comprises n-heptane.

[0111] In some embodiments, washing solvent 6 is provided in an amount of 0.5L / kg to 4.0L / kg. In some embodiments, washing solvent 6 is provided in an amount of 0.5L / kg to 3.0L / kg. In some embodiments, washing solvent 6 is provided in an amount of 1.0L / kg to 4.0L / kg. In some embodiments, washing solvent 6 is provided in an amount of 1.5L / kg to 4.0L / kg. In some embodiments, washing solvent 6 is provided in an amount of 2.0L / kg to 4.0L / kg. In some embodiments, washing solvent 6 is provided in an amount of 2.25L / kg to 3.0L / kg. In some embodiments, washing solvent 6 is provided in an amount of 2.3L / kg to 2.75L / kg. In some embodiments, washing solvent 6 is provided in an amount of about 1.0L / kg, 1.5L / kg, 2.0L / kg, 2.5L / kg or 3.0L / kg. In some embodiments, washing solvent 6 is provided in an amount of about 2.0L / kg. In some embodiments, the wash solvent 6 is provided in an amount of about 2.5 L / kg. In some embodiments, the wash solvent 6 is provided in an amount of about 3.0 L / kg.

[0112] In some embodiments, the wash solvent 6 is provided between about 0°C and 50°C. In some embodiments, the wash solvent 6 is provided between about 0°C and 40°C. In some embodiments, the wash solvent 6 is provided between about 0°C and 30°C. In some embodiments, the wash solvent 6 is provided between about 10°C and 20°C. In some embodiments, the wash solvent 6 is provided between about 20°C and 50°C. In some embodiments, the wash solvent 6 is provided between about 30°C and 50°C. In some embodiments, the wash solvent 6 is provided between about 10°C and 40°C. In some embodiments, the wash solvent 6 is provided between about 18°C ​​and 32°C. In some embodiments, the wash solvent 6 is provided between about 20°C and 30°C. In some embodiments, the wash solvent 6 is provided between about 23°C and 27°C. In some embodiments, the wash 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 wash solvent 6 is provided at or about 25°C. In some embodiments, washing 6 further comprises stirring the, for example, filtered, mixture. In some embodiments, washing 6 further comprises removing the wash solvent 6.

[0113] In some embodiments, step 1 further comprises step (g) dehydrating, drying and / or isolating compound 2 or a salt thereof. Step 2

[0114] In some embodiments, the present invention provides an improved synthesis of compound 3a: or a salt thereof, wherein R 1, R 2 PG 1 and X are as defined and described herein.

[0115] In some embodiments, the present invention provides an improved synthesis of compound 3: or a salt thereof.

[0116] As shown in Schemes 4 and 5, step 2 is the second of three steps for preparing maribavir as disclosed herein. Any byproducts formed in step 2 may be present in the provided compositions, may further react to form additional byproducts, and / or may reduce the overall yield or quality of maribavir. In some embodiments, the present invention provides methods for preparing compound 3 or a salt thereof with reduced and / or low levels of impurities.

[0117] In some embodiments, the present invention provides a composition comprising compound 3 or a salt thereof and one or more of the following compounds: or a salt thereof.

[0118] It should be understood that compound 14 may exist as a mixture of α and β isomers, with the β isomer being predominant. It should also be understood that compound 15 may be a mixture of four stereoisomers: β,β isomer; α,β isomer; β,α isomer; and α,α isomer.

[0119] In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 2, 8, 13, 14 and / or 15 or a salt thereof, in an amount relative to maribavir 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). In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 2, 8, 13, 14 and / or 15 or a salt thereof, in an amount relative to maribavir 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).

[0120] In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 13, 14 and / or 15 or a salt thereof, in an amount relative to maribavir 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). In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 13, 14 and / or 15 or a salt thereof, in an amount relative to maribavir 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).

[0121] In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 2 or a salt thereof. In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 2 or a salt thereof, in an amount relative to maribavir 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). In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 2 or a salt thereof, in an amount relative to maribavir 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). In some embodiments, the compositions provided include compound 3 or a salt thereof, wherein compound 2 or a salt thereof is undetectable (e.g., by HPLC or 1 HNMR measurement).

[0122] In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 8 or a salt thereof. In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 8 or a salt thereof, in an amount relative to maribavir 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). In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 8 or a salt thereof, in an amount relative to maribavir 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). In some embodiments, the compositions provided include compound 3 or a salt thereof, wherein compound 8 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0123] In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 13 or a salt thereof. In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 13 or a salt thereof, in an amount relative to maribavir 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). In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 13 or a salt thereof, in an amount relative to maribavir 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). In some embodiments, the compositions provided include compound 3 or a salt thereof, wherein compound 13 or a salt thereof is undetectable (e.g., by HPLC or 1 HNMR measurement).

[0124] In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 14 or a salt thereof. In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 14 or a salt thereof, in an amount relative to maribavir 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). In some embodiments, the compositions provided include compound 3 or a salt thereof, and compound 14 or a salt thereof, in an amount relative to maribavir 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). In some embodiments, the compositions provided include compound 3 or a salt thereof, wherein compound 14 or a salt thereof is undetectable (e.g., by HPLC or 1HNMR). In some embodiments, the compositions provided comprise compound 3 or a salt thereof, and compound 15 or a salt thereof. In some embodiments, the compositions provided comprise compound 3 or a salt thereof, and compound 15 or a salt thereof, in an amount relative to maribavir 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). In some embodiments, the compositions provided comprise compound 3 or a salt thereof, and compound 15 or a salt thereof, in an amount relative to maribavir 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 / aHPLC). In some embodiments, the compositions provided comprise compound 3 or a salt thereof, wherein compound 15 or a salt thereof is undetectable (e.g., by HPLC or 1 HNMR measurement).

[0125] In some embodiments, such compositions comprising compound 3 or a salt thereof are prepared as described herein. In some embodiments, the present invention also provides the following recognition: certain reagents (and their amounts) and / or reaction conditions can provide a compound 3 or a salt thereof with improved quality (e.g., with higher purity and / or very few by-products), and / or improve the yield and / or purity of compound 3 or a salt thereof. In some embodiments, such improvements in the yield or quality of compound 3 or a salt thereof can also improve the yield or quality of maribavir. Without wishing to be bound by a particular theory, the present invention provides the following recognition: incorporating crystallization (e.g., including salt formation) into step 2 can improve the yield and / or reduce the formation of by-products (e.g., compounds 2, 8, 13, 14 and / or 15 or their salts).

[0126] 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 a method comprising the following steps: (a) providing compound 2a: or a salt thereof, wherein Each R 1 and R 2 As defined above and described herein; and Compound 8a: or a salt thereof, wherein Each PG 1 is independently a suitable oxygen protecting group; The reaction is carried out under suitable reaction conditions to obtain compound 3a or a salt thereof.

[0127] As generally defined above, each PG 1 is independently a suitable oxygen protecting group. Various methods and conditions for protecting and deprotecting alcohols are known in the chemical arts. For example, methods and conditions for protecting and deprotecting alcohols are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Green and P.GMWuts, 3rd edition, John Wiley & Sons, 1999, the entire contents of which are incorporated herein by reference. In some embodiments, PG 1 is 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), triisopropylsilyloxymethyl (TOM) and triisopropylsilyl (TIPS) ether), methyl ether or ethoxyethyl ether. In some embodiments, each PG 1 In some embodiments, each PG 1 It is acetyl (Ac).

[0128] In some embodiments, X represents a salt of compound 3a. Suitable salts are well known in the art, for example, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, MB 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-naphthalene disulfonic acid (napsylicacid), 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.

[0129] 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 a method comprising the following steps: (a) providing compound 2: or a salt thereof, and Compound 8: or a salt thereof, The reaction is carried out under suitable reaction conditions to obtain compound 3 or a salt thereof.

[0130] In some embodiments, step 2 further provides one or more of the following compounds: or a salt thereof.

[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 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. In some embodiments, step 2 provides a composition wherein compound 2 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[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 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. In some embodiments, step 2 provides a composition wherein compound 8 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0133] 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 wherein compound 13 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0134] 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 wherein compound 14 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0135] 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 wherein compound 15 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0136] In some embodiments, step 2 provides a composition as provided in any one of Tables 4-7 to 4-11 in Example 4.

[0137] In some embodiments, step 2 provides compound 3 as camphorsulfonic acid (CSA), benzenesulfonic acid (PhSO3H), methanesulfonic acid (MsOH), toluenesulfonic acid (TsOH), 1,5-naphthalene disulfonic acid (naphthalene disulfonic acid), 1,2-ethanedisulfonic acid (ethanedisulfonic acid), ethanesulfonic acid (ethanesulfonic acid), 4-chlorobenzenesulfonic acid (chlorobenzenesulfonic acid), 6,7-dihydroxycoumarin-4-methanesulfonic acid (cromesic acid) or trifluoromethanesulfonic acid (HOTf) salt. In some embodiments, step 2 provides compound 3 as a hydrohalide 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.

[0138] In some embodiments, compound 2 or its salt is provided in an amount of about 0.50 to about 1.50 equivalents relative to compound 8 or its salt. In some embodiments, compound 2 or its salt is provided in an amount of about 0.75 to about 1.25 equivalents relative to compound 8 or its salt. In some embodiments, compound 2 or its salt is provided in an amount of about 0.90 to about 1.51 equivalents relative to compound 8 or its salt. In some embodiments, compound 2 or its salt is provided in an amount of about 0.99 to about 1.01 equivalents relative to compound 8 or its salt. In some embodiments, compound 2 or its salt is provided in an amount of about 0.90, 0.95, 1.0, 1.05 or 1.10 equivalents relative to compound 8 or its salt. In some embodiments, compound 2 or its salt is provided in an amount of about 0.90 equivalents relative to compound 8 or its salt. In some embodiments, compound 2 or its salt is provided in an amount of about 0.95 equivalents relative to compound 8 or its salt. In some embodiments, compound 2 or its salt is provided in an amount of about 1.0 equivalents relative to compound 8 or its salt. 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.

[0139] In some embodiments, compound 8 or its salt is provided in an amount of about 0.50 to about 2.0 equivalents relative to compound 2 or its salt. In some embodiments, compound 8 or its salt is provided in an amount of about 1.00 to about 1.50 equivalents relative to compound 2 or its salt. In some embodiments, compound 8 or its salt is provided in an amount of about 1.10 to about 1.40 equivalents relative to compound 2 or its salt. In some embodiments, compound 8 or its salt is provided in an amount of about 1.1, 1.2, 1.3, 1.4 or 1.5 equivalents relative to compound 2 or its salt. In some embodiments, compound 8 or its salt is provided in an amount of about 1.0 equivalents relative to compound 2 or its salt. In some embodiments, compound 8 or its salt is provided in an amount of about 1.1 equivalents relative to compound 2 or its salt. In some embodiments, compound 8 or its salt is provided in an amount of about 1.2 equivalents relative to compound 2 or its salt. In some embodiments, compound 8 or its salt is provided in an amount of about 1.3 equivalents relative to compound 2 or its salt. In some embodiments, compound 8 or its salt is provided in an amount of about 1.4 equivalents relative to compound 2 or its salt.

[0140] In some embodiments, the reaction conditions include solvents. In some embodiments, the solvent is or comprises 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 comprises acetone. In some embodiments, the solvent is or comprises acetonitrile. In some embodiments, the solvent is or comprises dichloromethane. In some embodiments, the solvent is or comprises 1,2-dichloroethane. In some embodiments, the solvent is or comprises 1,2-dimethoxyethane. In some embodiments, the solvent is or comprises isopropyl acetate. 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. In some embodiments, the solvent is or comprises 1,4-dioxane. In some embodiments, the solvent is ethyl acetate.

[0141] In some embodiments, the solvent is present in an amount of about 2.8kg / kg to about 16.0kg / kg. In some embodiments, the solvent is present in an amount of about 2.8kg / kg to about 14.0kg / kg. In some embodiments, the solvent is present in an amount of about 2.8kg / kg to about 10.0kg / kg. In some embodiments, the solvent is present in an amount of about 2.8kg / kg to about 8.0kg / kg. In some embodiments, the solvent is present in an amount of about 3.6kg / kg to about 10.0kg / kg. In some embodiments, the solvent is present in an amount of about 4.4kg / kg to about 10.0kg / kg. In some embodiments, the solvent is present in an amount of about 5.2kg / kg to about 10.0kg / kg. In some embodiments, the solvent is present in an amount of about 5.2kg / kg to about 8.0kg / kg. In some embodiments, the solvent is present in an amount of about 5.5kg / kg to about 7.5kg / kg. In some embodiments, the solvent is present in an amount of about 6.0kg / kg to about 7.4kg / kg. In some embodiments, the solvent is present in an amount of about 6.5kg / kg to about 7.3kg / kg. In some embodiments, the solvent is present in an amount of about 6.0kg / kg to about 7.5kg / kg. In some embodiments, the solvent is present in an amount of about 6.5kg / kg, 6.6kg / kg, 6.7kg / kg, 6.8kg / kg, 6.89kg / kg, 7.0kg / kg, 7.1kg / kg or 7.2kg / kg. In some embodiments, the solvent is present in an amount of about 6.7kg / kg. In some embodiments, the solvent is present in an amount of about 6.8kg / kg. In some embodiments, the solvent is present in an amount of about 6.89kg / kg. In some embodiments, the solvent is present in an amount of about 7.0kg / kg. In some embodiments, the solvent is present in an amount of about 7.1kg / kg.

[0142] In some embodiments, the reaction conditions include a desiccant. In some embodiments, the desiccant is or comprises N,O-bis(trimethylsilyl)-acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)acetamide, molecular sieves. In some embodiments, the desiccant is or comprises N,O-bis(trimethylsilyl)-acetamide. In some embodiments, the desiccant is or comprises N,O-bis(trimethylsilyl)trifluoroacetamide. In some embodiments, the desiccant is or comprises N-(trimethylsilyl)acetamide. In some embodiments, the desiccant is or comprises molecular sieves.

[0143] 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.

[0144] 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 at least 25 minutes. In some embodiments, the reaction is stirred for at least 45 minutes. In some embodiments, the reaction is stirred for at least 60 minutes. In some embodiments, the reaction is stirred for at least 120 minutes.

[0145] In some embodiments, the reaction conditions include catalysts. In some embodiments, the catalyst is or includes tert-butyldimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate or trimethylsilyl trifluoromethanesulfonate. In some embodiments, the catalyst is or includes tert-butyldimethylsilyl trifluoromethanesulfonate. In some embodiments, the catalyst is or includes triethylsilyl trifluoromethanesulfonate. In some embodiments, the catalyst is or includes trimethylsilyl trifluoromethanesulfonate.

[0146] 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 about 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 about 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 about 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 a salt thereof. In some embodiments, the catalyst is present in an amount of about 0.36 equivalents relative to compound 2 or a salt thereof. In some embodiments, the catalyst is present in an amount of about 0.37 equivalents relative to compound 2 or a salt thereof. In some embodiments, the catalyst is present in an amount of about 0.38 equivalents relative to compound 2 or a salt thereof.

[0147] In some embodiments, suitable reaction conditions include at a temperature T a Compounds 2 and 8 are provided. In some embodiments, the temperature T aBetween about 0°C and about 50°C. In some embodiments, the temperature T a Between about 0°C and about 35°C. In some embodiments, the temperature T a Between about 0°C and about 25°C. In some embodiments, the temperature T a Between about 10°C and about 50°C. In some embodiments, the temperature T a Between about 15°C and about 50°C. In some embodiments, the temperature T a Between about 5°C and about 35°C. In some embodiments, the temperature T a Between about 10°C and about 30°C. In some embodiments, the temperature T a Between about 19°C and about 25°C. In some embodiments, the temperature T a Between about 21°C and about 23°C. 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 about 25°C.

[0148] In some embodiments, step 2 further comprises step (b) heating to a temperature T b In some embodiments, the reaction conditions include heating to a temperature T b In some embodiments, the temperature T b Between about 20°C and about 150°C. In some embodiments, the temperature T b Between about 20°C and about 120°C. In some embodiments, the temperature T b Between about 20°C and about 100°C. In some embodiments, the temperature T b Between about 20°C and about 80°C. In some embodiments, the temperature T b Between about 40°C and about 150°C. In some embodiments, the temperature T b Between about 60°C and about 150°C. In some embodiments, the temperature T b Between about 40°C and about 120°C. In some embodiments, the temperature T b Between about 60°C and about 90°C. In some embodiments, the temperature T bBetween about 65°C and about 80°C. In some embodiments, the temperature T b Between about 72°C and about 79°C. 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 about 80°C.

[0149] In some embodiments, the reaction conditions include at a temperature T b Aging and / or stirring the reaction mixture for a period of time. In some embodiments, the time period is about 1 hour to about 48 hours. In some embodiments, the time period is about 2 hours to about 36 hours. In some embodiments, the time period is about 3 hours to about 24 hours. In some embodiments, the time period is about 4 hours to about 12 hours. In some embodiments, the time period is about 5 hours. In some embodiments, the time period is at least 2 hours. In some embodiments, the time period is at least 4 hours. In some embodiments, the time period is at least 6 hours. In some embodiments, the time period is at least 8 hours. In some embodiments, the time period is at least 12 hours. In some embodiments, the time period is at least 24 hours.

[0150] In some embodiments, for example, after allowing the reaction to proceed at a temperature T b After a period of time, step 2 further comprises the step (c) of cooling the reaction mixture to a temperature T c In some embodiments, the temperature T c Between about 0°C and about 70°C. In some embodiments, the temperature T c Between about 0°C and about 60°C. In some embodiments, the temperature T c Between about 0°C and about 50°C. In some embodiments, the temperature T c Between about 0°C and about 40°C. In some embodiments, the temperature T c Between about 0°C and about 30°C. In some embodiments, the temperature T c Between about 10°C and about 60°C. In some embodiments, the temperature Tc Between about 20°C and about 60°C. In some embodiments, the temperature T c Between about 10°C and about 50°C. In some embodiments, the temperature T c Between about 19°C and about 55°C. In some embodiments, the temperature T c Between about 15°C and about 40°C. In some embodiments, the temperature T c Between about 16°C and about 30°C. In some embodiments, the temperature T c Between about 20°C and about 25°C. In some embodiments, the temperature T c 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 about 24°C.

[0151] 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 less than or equal to about 50.0% (a / a) (e.g., measured by HPLC). In some embodiments, the reaction is monitored for the presence of compound 2 in an amount less than or equal to about 25.0% (a / a) (e.g., measured by HPLC). In some embodiments, the reaction is monitored for the presence of compound 2 in an amount less than or equal to about 15.0% (a / a) (e.g., measured by HPLC). In some embodiments, the reaction is monitored for the presence of compound 2 in an amount less than or equal to about 10.0% (a / a) (e.g., measured by HPLC). In some embodiments, the reaction is monitored for the presence of compound 2 in an amount less than or equal to about 5.0% (a / a) (e.g., measured by HPLC). In some embodiments, the reaction is monitored for the presence of compound 2 in an amount less than or equal to about 4.0% (a / a) (e.g., measured by HPLC). In some embodiments, the reaction is monitored for the presence of Compound 2 in an amount less than or equal to about 3.0% (a / a) (e.g., as measured by HPLC). In some embodiments, the reaction is monitored for the presence of Compound 2 in an amount less than or equal to about 2.0% (a / a) (e.g., as measured by HPLC). In some embodiments, the reaction is monitored for the presence of Compound 2 in an amount less than or equal to about 1.0% (a / a) (e.g., as measured by HPLC).

[0152] In some embodiments, step 2 further comprises step (d) washing and / or quenching the reaction mixture, for example to provide a first resulting mixture. In some embodiments, step 2 further comprises the step of washing the reaction mixture. In some embodiments, step 2 further comprises the step of quenching the reaction mixture.

[0153] In some embodiments, washing and / or quenching comprises base wash 1. In some embodiments, base wash 1 is or comprises washing the reaction mixture with an aqueous base (aqueous base solution). In some embodiments, the aqueous base (aqueous base solution) is or comprises LiOH, NaOH, KOH, Li2CO3, Na2CO3, K2CO3, LiHCO3, NaHCO3 or KHCO3. In some embodiments, the aqueous base (aqueous base solution) is or comprises KHCO3.

[0154] In some embodiments, the aqueous alkali (alkaline aqueous solution) concentration is about 5% by weight to about 30% by weight alkali. In some embodiments, the aqueous alkali (alkaline aqueous solution) concentration is about 10% by weight to 25% by weight alkali. In some embodiments, the aqueous alkali (alkaline aqueous solution) concentration is about 15% by weight to about 25% by weight alkali. In some embodiments, the aqueous alkali (alkaline aqueous solution) concentration is about 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight or 35% by weight alkali. In some embodiments, the aqueous alkali (alkaline aqueous solution) concentration is about 10% by weight alkali. In some embodiments, the aqueous alkali (alkaline aqueous solution) concentration is about 15% by weight alkali. In some embodiments, the aqueous alkali (alkaline aqueous solution) concentration is about 20% by weight alkali. In some embodiments, the aqueous alkali (alkaline aqueous solution) concentration is about 25% by weight alkali. In some embodiments, the aqueous alkali (alkaline aqueous solution) concentration is about 30% by weight alkali. In some embodiments, the aqueous alkali (alkaline aqueous solution) concentration is about 35% by weight alkali. In some embodiments, the aqueous base (alkaline aqueous solution) comprises potassium bicarbonate (e.g., between about 0.811 kg / kg and 1.02 kg / kg, such as 1.02 kg / kg) and water (e.g., between about 3.672 kg / kg and about 4.488 kg / kg, such as 4.08 kg / kg). In some such embodiments, these amounts are divided into two separate washes with an aqueous base (alkaline aqueous solution).

[0155] In some embodiments, the alkaline washing 1 is carried out at a temperature T d In some embodiments, the temperature T d Between about 0°C and about 50°C. In some embodiments, the temperature T d Between about 0°C and about 40°C. In some embodiments, the temperature T d Between about 10°C and about 40°C. In some embodiments, the temperature T d Between about 10°C and about 30°C. In some embodiments, the temperature T d Between about 15°C and about 25°C. 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 about 22°C.

[0156] In some embodiments, the alkali wash 1 further comprises adding water to the reaction mixture. In some embodiments, additional water is provided in an amount of about 2 kg / kg to about 6 kg / kg. In some embodiments, additional water is provided in an amount of about 3.672 kg / kg to about 4.488 kg / kg. In some embodiments, 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, additional water is provided in an amount of about 4.488 kg / kg.

[0157] In some embodiments, washing and / or quenching include brine washing 2. In some embodiments, brine washing 2 includes washing the reaction mixture with brine (i.e., NaCl aqueous solution). In some embodiments, the NaCl aqueous solution is about 1% to 100% NaCl by weight. In some embodiments, the NaCl aqueous solution is about 1% to 50% NaCl by weight. In some embodiments, the NaCl aqueous solution is about 1% to 10% NaCl by weight. In some embodiments, the NaCl aqueous solution is about 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20% or 25% NaCl by weight. In some embodiments, the NaCl aqueous solution is prepared by NaCl (e.g., between about 0.41kg / kg and 0.69kg / kg, such as 0.628kg / kg) and water (e.g., between about 1.835kg / kg and about 2.243kg / kg, such as 2.039kg / kg).

[0158] In some embodiments, the brine wash 2 is at a temperature T as described above and herein. d conduct.

[0159] In some embodiments, alkali washing 1 and brine washing 2 each independently include stirring for a period of time. In some embodiments, the time period is between about 5 minutes to about 5 days. In some embodiments, the time period is between about 5 minutes to about 1 day. In some embodiments, the time period is between about 5 minutes to about 12 hours. In some embodiments, the time period is between about 5 minutes to about 6 hours. In some embodiments, the time period is between about 5 minutes to about 3 hours. In some embodiments, the time period is at least 5 minutes. In some embodiments, the time period is at least 15 minutes. In some embodiments, the time period is at least 45 minutes. In some embodiments, the time period is at least 60 minutes. In some embodiments, the time period is at least 120 minutes.

[0160] In some embodiments, the brine wash 2 includes allowing the reaction mixture or the first resulting mixture to settle for a period of time. In some embodiments, the period of time is between about 1 minute and 60 minutes. In some embodiments, the period of time is between about 10 minutes and 30 minutes. In some embodiments, the period of time is greater than 20 minutes.

[0161] In some embodiments, step 2 further comprises step (e) distilling the reaction mixture or the first resulting mixture and / or exchanging the solvent 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.

[0162] In some embodiments, the distillation and / or solvent exchange comprises (i) removing the solvent (e.g., a reaction solvent as described above and herein) from the reaction mixture and / or the first resulting mixture. In some embodiments, removing the solvent (e.g., a reaction solvent as described above and herein) comprises heating the reaction mixture and / or the first resulting mixture to a temperature T e In some embodiments, the temperature T e Between about 0°C and about 100°C. In some embodiments, the temperature T e Between about 0°C and about 60°C. In some embodiments, the temperature T e Between about 0°C and about 40°C. In some embodiments, the temperature T e Between about 10°C and about 60°C. In some embodiments, the temperature T e Between about 20°C and about 60°C. In some embodiments, the temperature T e Between about 30°C and about 60°C. In some embodiments, the temperature T e Between about 20°C and about 50°C. In some embodiments, the temperature T e Between about 30°C and about 40°C. In some embodiments, the temperature T e Between about 40°C and about 50°C. In some embodiments, the temperature T e is less than or equal to about 60° C. In some embodiments, the temperature T e is less than or equal to about 45°C. In some embodiments, the temperature T e is less than or equal to about 40°C.

[0163] In some embodiments, the reaction mixture and / or the first resulting mixture is maintained at a temperature T eContinue for a period of time. In some embodiments, the time period is until a certain volume of solvent is collected from the reaction mixture or the first resulting mixture. For example, in some embodiments, the collected volume of the solvent is between about 388L and about 430L, such as about 409L.

[0164] In some embodiments, 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, 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 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.

[0165] In some embodiments, the solution containing compound 3 or its salt is charged with a certain amount of distillation solvent. In some embodiments, the amount of distillation solvent is between about 100kg and about 1000kg. In some embodiments, the amount of distillation solvent is between about 100kg and about 800kg. In some embodiments, the amount of distillation solvent is between about 100kg and about 600kg. In some embodiments, the amount of distillation solvent is between about 100kg and about 400kg. In some embodiments, the amount of distillation solvent is between about 200kg and about 1000kg. In some embodiments, the amount of distillation solvent is between about 300kg and about 1000kg. In some embodiments, the amount of distillation solvent is between about 400kg and about 1000kg. In some embodiments, the amount of distillation solvent is between about 200kg and about 600kg. In some embodiments, the amount of distillation solvent is between about 300kg and about 500kg. In some embodiments, the amount of distillation solvent is between about 350kg and about 450kg. In some embodiments, the amount of distillation solvent is between about 367kg and 407kg. In some embodiments, the amount of distillation solvent is between about 375kg and about 400kg. In some embodiments, the amount of distillation solvent is about 375kg, 382kg, 387kg, 392kg or 400kg. In some embodiments, the amount of distillation solvent is about 375kg. In some embodiments, the amount of distillation solvent is about 387kg. In some embodiments, the amount of distillation solvent is about 400kg.

[0166] In some embodiments, at temperature T f Add distillation solvent. In some embodiments, the temperature T f Between about 0°C and about 50°C. In some embodiments, the temperature T f Between about 0°C and about 40°C. In some embodiments, the temperature T f Between about 0°C and about 30°C. In some embodiments, the temperature T f Between about 0°C and about 20°C. In some embodiments, the temperature T f Between about 10°C and about 40°C. In some embodiments, the temperature T f Between about 15°C and about 40°C. In some embodiments, the temperature T f Between about 20°C and about 40°C. In some embodiments, the temperature T f Between about 10°C and about 35°C. In some embodiments, the temperature T f Between about 15°C and about 30°C. In some embodiments, the temperature T f Between about 18°C ​​and about 23°C. In some embodiments, the temperature T fis 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 about 22°C.

[0167] In some embodiments, the second resulting mixture is at a temperature T f (as described above and herein) with stirring.

[0168] In some embodiments, step 2 further comprises the following steps: (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, crystallization comprises forming a salt of compound 3 (e.g., a salt as described above and herein).

[0169] 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, ethyl 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 ethyl 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.

[0170] 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-naphthalene disulfonic acid (naphthalene disulfonic acid), 1,2-ethanedisulfonic acid (ethanedisulfonic acid), ethanesulfonic acid (ethanesulfonic acid), 4-chlorobenzenesulfonic acid (chlorobenzenesulfonic acid), 6,7-dihydroxycoumarin-4-methanesulfonic acid (cromesic acid) or trifluoromethanesulfonic acid (HOTf). In some embodiments, the acid is hydrochloric acid ("HCl").

[0171] 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 hydrohalide salt. In some embodiments, the crystallization mixture comprises compound 3 as an HCl salt. In some embodiments, the crystallization mixture comprises compound 3 as an HBr salt.

[0172] In some embodiments, the acid is provided in an amount of about 0.5 to 1.5 equivalents relative to compound 3 or a salt thereof. In some embodiments, the acid is provided in an amount of about 0.75 to 1.5 equivalents relative to compound 3 or a salt thereof. In some embodiments, the acid is provided in an amount of about 0.95 to 1.5 equivalents relative to compound 3 or a salt thereof. In some embodiments, the acid is provided in an amount of about 1.05 to 1.5 equivalents relative to compound 3 or a salt thereof. In some embodiments, the acid is provided in an amount of about 0.5 to 1.25 equivalents relative to compound 3 or a salt thereof. In some embodiments, the acid is provided in an amount of about 0.5 to 1.15 equivalents relative to compound 3 or a salt thereof. In some embodiments, the acid is provided in an amount of about 0.5 to 1.05 equivalents relative to compound 3 or a salt thereof. In some embodiments, the acid is provided in an amount of about 0.6 to 1.4 equivalents relative to compound 3 or a salt thereof. In some embodiments, the acid is provided in an amount of about 0.8 to 1.2 equivalents relative to compound 3 or a salt thereof. 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 acid is present in an amount of about 1.037 equivalents relative to compound 3 or its salt. In some embodiments, the acid is present in an amount of about 1.05 equivalents relative to compound 3 or its salt.

[0173] In some embodiments, the acid provided is a hydrochloric acid solution. 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.

[0174] In some embodiments, the crystallization mixture is at a temperature T g In some embodiments, the temperature T g Between about 0°C and about 50°C. In some embodiments, the temperature T gBetween about 10°C and about 50°C. In some embodiments, the temperature T g Between about 20°C and about 50°C. In some embodiments, the temperature T g Between about 0°C and about 30°C. In some embodiments, the temperature T g Between about 5°C and about 40°C. In some embodiments, the temperature T g Between about 10°C and about 30°C. In some embodiments, the temperature T g Between about 15°C and about 25°C. 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 about 24°C.

[0175] In some embodiments, crystallization comprises adding an acid to the crystallization mixture over a period of time. In some embodiments, the period of time is between about 5 and about 120 minutes. In some embodiments, the period of time is about 5 minutes to about 90 minutes. In some embodiments, the period of time is about 5 minutes to about 60 minutes. In some embodiments, the period of time is about 5 minutes to about 30 minutes. In some embodiments, the period of time is about 15 minutes to about 120 minutes. In some embodiments, the period of time is about 30 minutes to about 120 minutes. In some embodiments, the period of time is at least 15 minutes. In some embodiments, the period of time is at least 30 minutes. In some embodiments, the period of time is at least 60 minutes. In some embodiments, the period of time is at least 120 minutes. In some embodiments, the period of time is about 15 minutes. In some embodiments, the period of time is about 30 minutes. In some embodiments, the period of time is about 60 minutes. In some embodiments, crystallization comprises at a temperature T g The acid is added to the crystallization mixture at a temperature T g As described above and herein.

[0176] 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 its salt. 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 its salt. 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 its salt. 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 its salt. 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 its salt. 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 its salt. In some embodiments, the seed crystals are added in an amount of about 0.04% to about 0.10% w / w relative to compound 2 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.05% to about 0.10% w / w relative to Compound 2 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.06% to about 0.10% w / w relative to Compound 2 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.03% to about 0.08% w / w relative to Compound 2 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.05% to about 0.07% w / w relative to Compound 2 or its salt. 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 relative to Compound 2 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.04% w / w relative to Compound 2 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.05% w / w relative to Compound 2 or its salt. In some embodiments, the seed crystals are added in an amount of 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 0.07% w / w relative to Compound 2 or a salt thereof. In some embodiments, the seed crystals are added in an amount of about 0.08% w / w relative to Compound 2 or a salt thereof.

[0177] In some embodiments, the seed is provided in a seed solvent (e.g., a crystallization solvent as described above and herein). In some embodiments, the seed solvent is or includes an amount between about 0kg and about 0.41kg. In some embodiments, the seed solvent suspension is or includes an amount between about 0kg and about 0.31kg. In some embodiments, the seed solvent suspension is or includes an amount between about 0kg and about 0.21kg. In some embodiments, the seed solvent suspension is or includes an amount between about 0kg and about 0.16kg. In some embodiments, the seed solvent suspension is or includes an amount between about 0kg and about 0.11kg. In some embodiments, the seed solvent suspension is or includes an amount between about 0kg and about 0.60kg. In some embodiments, the seed solvent suspension is or includes an amount between about 0.10kg and about 0.21kg. In some embodiments, the seed solvent suspension is or includes an amount between about 0.16kg and about 0.21kg. In some embodiments, the seed 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 solvent suspension is or comprises an amount of about 0.10 kg. In some embodiments, the seed solvent suspension is or comprises an amount of about 0.15 kg. In some embodiments, the seed solvent suspension is or comprises an amount of about 0.20 kg. In some embodiments, the seed solvent suspension is or comprises an amount of about 0.25 kg.

[0178] In some embodiments, the crystallization mixture is at a temperature T g Aging for a period of time, where the temperature T g As described above and herein. In some embodiments, the time period is between about 5 to about 300 minutes. In some embodiments, the time period is between about 5 to about 240 minutes. In some embodiments, the time period is between about 10 to about 180 minutes. In some embodiments, the time period is between about 30 to about 120 minutes. In some embodiments, the time period is between about 60 to about 100 minutes. In some embodiments, the time period is about 30, 60, 90 or 120 minutes. In some embodiments, the time period is about 90 minutes. In some embodiments, the time period is at least 10 minutes. In some embodiments, the time period is at least 30 minutes. In some embodiments, the time period is at least 60 minutes. In some embodiments, the time period is at least 90 minutes. In some embodiments, the crystallization mixture is aged for a time period of at least 120 minutes.

[0179] In some embodiments, the crystallization mixture is cooled to a temperature T over a period of time. i. In some embodiments, the time period is between about 15 minutes and about 240 minutes. In some embodiments, the time period is between about 15 minutes and about 200 minutes. In some embodiments, the time period is between about 15 minutes and about 180 minutes. In some embodiments, the time period is between about 15 minutes and about 150 minutes. In some embodiments, the time period is between about 15 minutes and about 120 minutes. In some embodiments, the time period is between about 15 minutes and about 90 minutes. In some embodiments, the time period is between about 30 minutes and about 180 minutes. In some embodiments, the time period is between about 60 minutes and about 180 minutes. In some embodiments, the time period is between about 90 minutes and about 180 minutes. In some embodiments, the time period is between about 30 minutes and about 150 minutes. In some embodiments, the time period is between about 60 minutes and about 120 minutes. In some embodiments, the time period is between about 80 minutes and about 100 minutes. In some embodiments, the time period is about 90 minutes. In some embodiments, the time period is about 100 minutes. In some embodiments, the time period is about 120 minutes. In some embodiments, the time period is about 150 minutes. In some embodiments, the time period is at least 30 minutes. In some embodiments, the time period is at least 60 minutes. In some embodiments, the time period is at least 90 minutes. In some embodiments, the time period is at least 120 minutes.

[0180] In some embodiments, the temperature T i Between about -40°C and about 40°C. In some embodiments, the temperature T i Between about -40°C and about 30°C. In some embodiments, the temperature T i Between about -40°C and about 20°C. In some embodiments, the temperature T i Between about -40°C and about 10°C. In some embodiments, the temperature T i Between about -20°C and about 40°C. In some embodiments, the temperature T i Between about -10°C and about 40°C. In some embodiments, the temperature T i Between about 0°C and about 40°C. In some embodiments, the temperature T i Between about -30°C and about 30°C. In some embodiments, the temperature T i Between about -20°C and about 20°C. In some embodiments, the temperature T i Between about -10°C and about 10°C. In some embodiments, the temperature T i Between about -5°C and about 5°C. In some embodiments, the temperature Ti 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 about 4°C.

[0181] In some embodiments, the crystallization mixture is at a temperature T i Aging for a period of time. In some embodiments, the time period is between about 30 minutes and 7 days. In some embodiments, the time period is between about 30 minutes and 1 day. In some embodiments, the time period is between about 30 minutes and 12 hours. In some embodiments, the time period is between about 30 minutes and 6 hours. In some embodiments, the time period is between about 30 minutes and 3 hours. In some embodiments, the time period is between about 30 minutes and 2 hours. In some embodiments, the time period is about 30 minutes. In some embodiments, the time period is about 60 minutes. In some embodiments, the crystallization mixture is aged for a time period of about 90 minutes. In some embodiments, the crystallization mixture is aged for a time period of about 120 minutes. In some embodiments, the time period is at least 30 minutes. In some embodiments, the time period is at least 60 minutes. In some embodiments, the time period is at least 90 minutes. In some embodiments, the time period is at least 120 minutes. In some embodiments, the time period is at least 5 minutes. In some embodiments, the time period is less than 7 days.

[0182] In some embodiments, step 2 further comprises step (g) optionally filtering or washing the crystallization mixture to provide a filtered mixture. In some embodiments, step 2 further comprises filtering the crystallization mixture to provide a filtered mixture. In some embodiments, step 2 further comprises washing the crystallization mixture to provide a filtered mixture.

[0183] In some embodiments, filtration is performed at a temperature T i The temperature T i As described above and herein.

[0184] In some embodiments, the filtration is carried out in a period of time. In some embodiments, the period of time is between about 10 minutes to about 4 days. In some embodiments, the period of time is between about 10 minutes to about 1 day. In some embodiments, the period of time is between about 10 minutes to about 12 hours. In some embodiments, the period of time is between about 10 minutes to about 6 hours. In some embodiments, the period of time is between about 10 minutes to about 1 hour. In some embodiments, the period of time is between about 10 minutes to about 30 minutes. In some embodiments, the period of time is at least 10 minutes. In some embodiments, the period of time is at least 20 minutes. In some embodiments, the period of time is at least 30 minutes. In some embodiments, the period of time is at least 60 minutes.

[0185] In some embodiments, washing comprises washing A. In some embodiments, washing A comprises washing with washing solvent A. In some embodiments, washing solvent A is or comprises chloroform, ethyl 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 A is or comprises chloroform. In some embodiments, washing solvent A is or comprises ethyl ether. In some embodiments, washing solvent A is or comprises ethyl acetate. In some embodiments, washing solvent A is or comprises cyclopentyl methyl ether. In some embodiments, washing solvent A is or comprises toluene. In some embodiments, washing solvent A is or comprises benzene. In some embodiments, washing solvent A is or comprises α,α,α-trifluorotoluene. In some embodiments, washing solvent A is or comprises chlorobenzene. In some embodiments, washing solvent A is or comprises xylene. In some embodiments, washing solvent A is or comprises dichloromethane. In some embodiments, washing solvent A is or comprises isopropyl acetate.

[0186] In some embodiments, washing solvent A is present in an amount of about 0.30kg / kg to about 5.0kg / kg. In some embodiments, washing solvent A is present in an amount of about 0.30kg / kg to about 4.0kg / kg. In some embodiments, washing solvent A is present in an amount of about 0.30kg / kg to about 3.0kg / kg. In some embodiments, washing solvent A is present in an amount of about 0.30kg / kg to about 2.0kg / kg. In some embodiments, washing solvent A is present in an amount of about 0.50kg / kg to about 5.0kg / kg. In some embodiments, washing solvent A is present in an amount of about 1.00kg / kg to about 5.0kg / kg. In some embodiments, washing solvent A is present in an amount of about 1.25kg / kg to about 5.0kg / kg. In some embodiments, washing solvent A is present in an amount of about 0.25kg / kg to about 4.0kg / kg. In some embodiments, washing solvent A is present in an amount of about 0.50kg / kg to about 3.0kg / kg. In some embodiments, washing solvent A exists in an amount of about 0.69kg / kg to about 2.5kg / kg. In some embodiments, washing solvent A exists in an amount of about 0.95kg / kg to about 1.75kg / kg. In some embodiments, washing solvent A exists in an amount of about 1.25kg / kg to about 1.5kg / kg. In some embodiments, washing solvent A exists in an amount of about 1.15kg / kg, 1.25kg / kg, 1.35kg / kg, 1.55kg / kg or 1.75kg / kg. In some embodiments, washing solvent A exists in an amount of about 1.15kg / kg. In some embodiments, washing solvent A exists in an amount of about 1.35kg / kg. In some embodiments, washing solvent A exists in an amount of about 1.55kg / kg.

[0187] In some embodiments, the wash solvent A is at a temperature T i is present, wherein Ti is as described above and herein.

[0188] In some embodiments, after adding washing solvent A, the filtered mixture is stirred for a period of time. In some embodiments, the time period is between about 5 minutes to about 60 minutes. In some embodiments, the time period is between about 5 minutes to about 45 minutes. In some embodiments, the time period is between about 5 minutes to about 30 minutes. In some embodiments, the time period is about 5 minutes to about 15 minutes. In some embodiments, the time period is about 5 minutes or longer. In some embodiments, the time period is about 10 minutes or longer. In some embodiments, the time period is about 15 minutes or longer. In some embodiments, the time period is about 20 minutes or longer. In some embodiments, the time period is about 30 minutes or longer. In some embodiments, the time period is about 60 minutes or longer.

[0189] In some embodiments, washing comprises washing B. In some embodiments, washing B comprises washing with a washing solvent B. In some embodiments, washing solvent B is or comprises chloroform, ethyl 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 B is or comprises chloroform. In some embodiments, washing solvent B is or comprises ethyl ether. In some embodiments, washing solvent B is or comprises ethyl acetate. In some embodiments, washing solvent B is or comprises cyclopentyl methyl ether. In some embodiments, washing solvent B is or comprises toluene. In some embodiments, washing solvent B is or comprises benzene. In some embodiments, washing solvent B is or comprises α,α,α-trifluorotoluene. In some embodiments, washing solvent B is or comprises chlorobenzene. In some embodiments, washing solvent B is or comprises xylene. In some embodiments, washing solvent B is or comprises dichloromethane. In some embodiments, washing solvent B is or comprises isopropyl acetate. In some embodiments, wash solvent B is or comprises tert-butyl methyl ether.

[0190] In some embodiments, washing solvent B is present in an amount of about 0.50kg / kg to 4.0kg / kg. In some embodiments, washing solvent B is present in an amount of about 0.50kg / kg to 3.0kg / kg. In some embodiments, washing solvent B is present in an amount of about 0.50kg / kg to 2.0kg / kg. In some embodiments, washing solvent B is present in an amount of about 1.0kg / kg to 4.0kg / kg. In some embodiments, washing solvent B is present in an amount of about 1.50kg / kg to 4.0kg / kg. In some embodiments, washing solvent B is present in an amount of about 1.75kg / kg to 4.0kg / kg. In some embodiments, washing solvent B is present in an amount of about 1.0kg / kg to 3.0kg / kg. In some embodiments, washing solvent B is present in an amount of about 1.25kg / kg to 2.55kg / kg. In some embodiments, washing solvent B is present in an amount of about 1.50kg / kg to 2.05kg / kg. In some embodiments, washing solvent B exists in an amount of about 1.75kg / kg to 1.85kg / kg. In some embodiments, washing solvent B exists in an amount of about 1.65kg / kg, 1.70kg / kg, 1.75kg / kg, 1.80kg / kg or 1.85kg / kg. In some embodiments, washing solvent B exists in an amount of about 1.65kg / kg. In some embodiments, washing solvent B exists in an amount of about 1.70kg / kg. In some embodiments, washing solvent B exists in an amount of about 1.75kg / kg. In some embodiments, washing solvent B exists in an amount of about 1.80kg / kg. In some embodiments, washing solvent B exists in an amount of about 1.85kg / kg.

[0191] In some embodiments, the wash solvent B is at a temperature T i exists, where T i As described above and herein.

[0192] In some embodiments, after adding wash solvent B, the filtered mixture is stirred for a period of time, eg, as described above and herein for wash A.

[0193] In some embodiments, washing comprises wash C. In some embodiments, wash C is the same as wash B, as described above and herein.

[0194] In some embodiments, step 2 further comprises the step (h) drying the filtered mixture.

[0195] In some embodiments, drying comprises heating the filtered mixture to a temperature T m In some embodiments, the temperature T mBetween about 0°C and about 60°C. In some embodiments, the temperature T m Between about 0°C and about 50°C. In some embodiments, the temperature T m Between about 0°C and about 40°C. In some embodiments, the temperature T m Between about 0°C and about 30°C. In some embodiments, the temperature T m Between about 10°C and about 40°C. In some embodiments, the temperature T m Between about 20°C and about 40°C. In some embodiments, the temperature T m Between about 30°C and about 40°C. In some embodiments, the temperature T m Less than or about 10° C. In some embodiments, the temperature T m Below or about 20° C. In some embodiments, the temperature T m Below or about 25° C. In some embodiments, the temperature T m Below or about 30° C. In some embodiments, the temperature T m Below or about 35° C. In some embodiments, the temperature T m Less than or about 40° C. In some embodiments, the temperature T m Less than or about 100° C. In some embodiments, the filtered mixture is stirred for a period of time.

[0196] In some embodiments, the filtered mixture is maintained at a temperature T m In some embodiments, the period of time is until little condensate is visible in the filter dryer.

[0197] In some embodiments, the filtered mixture is heated to a temperature T m (as described above and herein) with stirring.

[0198] In some embodiments, the filtered mixture is heated at a temperature between about 0°C and about 80°C. n In some embodiments, the filtered mixture is dried at a temperature between about 20°C and about 80°C. n In some embodiments, the filtered mixture is dried at a temperature between about 40°C and about 80°C. n In some embodiments, the filtered mixture is dried at a temperature between about 60°C and about 80°C. n In some embodiments, the filtered mixture is dried at a temperature between about 10°C and about 60°C. n In some embodiments, the filtered mixture is dried at a temperature between about 20°C and about 50°C. nIn some embodiments, the filtered mixture is dried at a temperature between about 40°C and about 50°C. n In some embodiments, the filtered mixture is dried at a temperature between about 25°C and about 60°C. n In some embodiments, the filtered mixture is dried at a T of less than or about 45°C. n In some embodiments, the filtered mixture is dried at a T of less than or about 50°C. n In some embodiments, the filtered mixture is dried at a T of less than or about 55°C. n In some embodiments, the filtered mixture is dried at a T of less than or about 60°C. n In some embodiments, the filtered mixture is dried at a T of less than or about 65°C. n In some embodiments, the filtered mixture is dried at a T of less than or about 70°C. n Dry.

[0199] In some embodiments, the filtered mixture is maintained at a temperature T n For a period of time. In some embodiments, the period of time is until the total solvent content is less than 1.5% w / w (e.g., as measured by GCHS). In some embodiments, the period of time is until the total solvent content is less than 1.3% w / w (e.g., as measured by GCHS). In some embodiments, the period of time is until the total solvent content is less than 1.1% w / w (e.g., as measured by GCHS). In some embodiments, the period of time is until the total solvent content is less than 0.8% w / w (e.g., as measured by GCHS). In some embodiments, the period of time is until the total solvent content is less than 0.5% w / w (e.g., as measured by GCHS). In some embodiments, the period of time is until the total solvent content is less than 0.2% w / w (e.g., as measured by GCHS). In some embodiments, the period of time is until the total solvent content is less than 0.1% w / w (e.g., as measured by GCHS).

[0200] In some embodiments, the filtered mixture is maintained at a temperature T nFor a period of time. In some embodiments, the period of time is until the water content is less than 1.5% w / w (e.g., as measured by the Karl Fischer method). In some embodiments, the period of time is until the water content is less than 1.3% w / w (e.g., as measured by the Karl Fischer method). In some embodiments, the period of time is until the water content is less than 1.1% w / w (e.g., as measured by the Karl Fischer method). In some embodiments, the period of time is until the water content is less than 0.8% w / w (e.g., as measured by the Karl Fischer method). In some embodiments, the period of time is until the water content is less than 0.5% w / w (e.g., as measured by the Karl Fischer method). In some embodiments, the period of time is until the water content is less than 0.2% w / w (e.g., as measured by the Karl Fischer method). In some embodiments, the period of time is until the water content is less than 0.1% w / w (e.g., as measured by the Karl Fischer method). Step 3

[0201] In some embodiments, the present invention provides an improved synthesis of Compound 1: or a pharmaceutically acceptable salt thereof, wherein each R 1 and R 2 As defined above and described herein.

[0202] In some embodiments, the present invention provides an improved synthesis of maribavir: or a pharmaceutically acceptable salt thereof.

[0203] As shown in Scheme 4, step 3 is the last of three steps for preparing maribavir as disclosed herein. Any byproducts (or derivatives thereof) formed in steps 1, 2, or 3 may be present in the provided compositions comprising maribavir and / or may reduce the overall yield or quality of maribavir. In some embodiments, the present invention provides methods for preparing maribavir or a pharmaceutically acceptable salt thereof having reduced and / or low levels of impurities (e.g., as described herein).

[0204] In some embodiments, the present invention provides a composition comprising maribavir or a pharmaceutically acceptable salt thereof and one or more of the following compounds: or a salt thereof.

[0205] In some embodiments, provided compositions comprising maribavir are as described herein.

[0206] In some embodiments, the present invention also provides the following recognition: certain reagents (and their amounts) and / or reaction conditions can provide improved quality of maribavir or its pharmaceutical salt (e.g., with higher purity and / or minimal by-products), and / or improve the yield of maribavir or its pharmaceutical salt. Without wishing to be bound by a particular theory, the present invention provides the following recognition: incorporating crystallization into step 3 can improve yield and / or reduce the formation of by-products (e.g., compounds 2, 3 or 4 or their salts). In some embodiments, the present invention provides the following recognition: the amount of maribavir or its salt and / or water in the crystallization mixture can affect the yield and / or quality (e.g., particle size distribution) of maribavir. Additionally or alternatively, the present invention provides the following recognition: incorporating phase separation and / or extraction into step 3 at a specific pH can improve yield and / or reduce the formation of by-products (e.g., compounds 2, 3 or 4 or their salts).

[0207] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is prepared as shown in step 3 of Scheme 4. In some embodiments, in step 3, Compound 1 or a pharmaceutically acceptable salt thereof is prepared by a method comprising the following steps: (a) Compound 3a: or a salt thereof, wherein R 1 , R 2 , X and PG 1 each as defined above and described herein; The reaction is carried out under suitable reaction conditions to provide maribavir or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, maribavir or a pharmaceutically acceptable salt thereof is prepared as shown in step 3 of Scheme 5. In some embodiments, in step 3, maribavir or a pharmaceutically acceptable salt thereof is prepared by a method comprising the steps of: (a) Compound 3: or a salt thereof, The reaction is carried out under suitable reaction conditions to provide maribavir or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, step 3 further provides one or more of the following compounds: or a salt thereof.

[0210] 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 less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 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 wherein compound 2 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0211] 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 less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 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 wherein compound 3 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0212] 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 less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 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 wherein compound 4 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0213] 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 less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 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% (a / a 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 wherein compound 2 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0214] 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 less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 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 wherein compound 3 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0215] 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 less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 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 wherein compound 4 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0216] In some embodiments, step 3 provides a composition as provided in any one of Tables 4-12 to 4-21 in Example 4.

[0217] In some embodiments, the reaction conditions include solvents. In some embodiments, the solvent is or includes methanol, ethanol, isopropanol, tert-butyl alcohol, 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-butyl alcohol. 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 includes methanol and tert-butyl methyl ether.

[0218] In some embodiments, the solvent is provided in an amount of about 1L / kg to about 12L / kg. In some embodiments, the solvent is provided in an amount of about 2L / kg to about 12L / kg. In some embodiments, the solvent is provided in an amount of about 4L / kg to about 12L / kg. In some embodiments, the solvent is provided in an amount of about 1L / kg to about 8L / kg. In some embodiments, the solvent is provided in an amount of about 1L / kg to about 6L / kg. In some embodiments, the solvent is provided in an amount of about 1L / kg to about 4L / kg. In some embodiments, the solvent is provided in an amount of about 3L / kg to about 9L / kg. In some embodiments, the solvent is provided in an amount of about 4L / kg to about 8L / kg. In some embodiments, the solvent is provided in an amount of about 5L / kg to about 7L / kg. In some embodiments, the solvent is provided in an amount of about 1L / kg, 2L / kg, 3L / kg, 4L / kg, 5L / kg, 6L / kg, 7L / kg, 8L / kg, 9L / kg, 10L / kg, 11L / kg or 12L / kg. In some embodiments, the solvent is provided in an amount of about 3L / kg. In some embodiments, the solvent is provided in an amount of about 4L / kg. In some embodiments, the solvent is provided in an amount of about 5L / kg. In some embodiments, the solvent is provided in an amount of about 6L / kg. In some embodiments, the solvent is provided in an amount of about 7L / kg.

[0219] In some embodiments, methanol is provided in an amount of about 0.10L / kg to about 2.0L / kg. In some embodiments, methanol is provided in an amount of about 0.25L / kg to about 2.0L / kg. In some embodiments, methanol is provided in an amount of about 0.50L / kg to about 2.0L / kg. In some embodiments, methanol is provided in an amount of about 0.10L / kg to about 1.5L / kg. In some embodiments, methanol is provided in an amount of about 0.10L / kg to about 1.0L / kg. In some embodiments, methanol is provided in an amount of about 0.10L / kg to about 0.5L / kg. In some embodiments, methanol is provided in an amount of about 0.20L / kg to about 1.0L / kg. In some embodiments, methanol is provided in an amount of about 0.3L / kg to about 0.7L / kg. In some embodiments, methanol is provided in an amount of about 0.4L / kg to about 0.6L / kg. In some embodiments, methanol is provided in an amount of about 0.2L / kg, 0.3L / kg, 0.4L / kg, 0.5L / kg, 0.6L / kg, 0.7L / kg or about 0.8L / kg. In some embodiments, methanol is provided in an amount of about 0.3L / kg. In some embodiments, methanol is provided in an amount of about 0.4L / kg. In some embodiments, methanol is provided in an amount of about 0.5L / kg. In some embodiments, methanol is provided in an amount of about 0.6L / kg. In some embodiments, methanol is provided in an amount of about 0.7L / kg.

[0220] In some embodiments, tert-butyl methyl ether is provided in an amount of about 2L / kg to about 12L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 4L / kg to about 12L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 6L / kg to about 12L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 2L / kg to about 8L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 2L / kg to about 6L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 3L / kg to about 7L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 4L / kg to about 6L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 3L / kg, 4L / kg, 5L / kg, 6L / kg or about 7L / kg. In some embodiments, tert-butyl methyl ether is provided in an amount of about 3L / 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.

[0221] In some embodiments, methanol is provided in an amount of about 0.10L / kg to about 2.0L / kg, and tert-butyl methyl ether is provided in an amount of about 2L / kg to about 12L / kg. In some embodiments, methanol is provided in an amount of about 0.4L / kg to about 0.6L / kg, and tert-butyl methyl ether is provided in an amount of about 4L / kg to about 6L / kg. In some embodiments, methanol is provided in an amount of about 0.34L / kg to about 0.56L / kg, and tert-butyl methyl ether is provided in an amount of about 3.65L / kg to about 6.35L / kg. In some embodiments, methanol is provided in an amount of about 0.48L / kg, and tert-butyl methyl ether is provided in an amount of about 5.3L / kg.

[0222] In some embodiments, the reaction conditions include a base. In some embodiments, the base is or comprises 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 a LiOH aqueous solution. In some embodiments, the base is a NaOH aqueous solution. In some embodiments, the base is a KOH aqueous solution. In some embodiments, the aqueous base (aqueous base) is about 5% to about 50%. In some embodiments, the aqueous base (aqueous base) is about 10% to about 50%. In some embodiments, the aqueous base (aqueous base) is about 15% to about 50%. In some embodiments, the aqueous base (aqueous base) is about 20% to about 50%. In some embodiments, the aqueous base (aqueous base) is about 25% to about 50%. In some embodiments, the aqueous base (aqueous base) is about 30% to about 50%. In some embodiments, the aqueous base (aqueous base) is about 5% to about 45%. In some embodiments, the aqueous base (aqueous base) is about 5% to about 40%. In some embodiments, the aqueous alkali (alkaline aqueous solution) is about 5% to about 35%. In some embodiments, the aqueous alkali (alkaline aqueous solution) is about 5% to about 30%. In some embodiments, the aqueous alkali (alkaline aqueous solution) is about 20% to about 45%. In some embodiments, the aqueous alkali (alkaline aqueous solution) is about 25% to about 40%. In some embodiments, the aqueous alkali (alkaline aqueous solution) is about 28% to about 34%. In some embodiments, the aqueous alkali (alkaline aqueous solution) is about 5%, 10%, 15%, 20%, 25%, 30%, 35% or 40% w / w. In some embodiments, the aqueous alkali (alkaline aqueous solution) is about 5% w / w. In some embodiments, the aqueous alkali (alkaline aqueous solution) is about 10% w / w. In some embodiments, the aqueous alkali (alkaline aqueous solution) is about 10% w / w. In some embodiments, the aqueous alkali (alkaline aqueous solution) is about 15% w / w. In some embodiments, the aqueous alkali (alkaline aqueous solution) is about 25% w / w. In some embodiments, the aqueous base (alkaline water solution) is about 30% w / w. In some embodiments, the aqueous base (alkaline water solution) is about 35% w / w. In some embodiments, the aqueous base (alkaline water solution) is about 40% w / w. In some embodiments, the base is LiOR, NaOR, or KOR, wherein R is an optionally substituted C 1-6 In some embodiments, the base is an alkoxide such as LiOR, NaOR or KOR, wherein R is an optionally substituted C 1-6Aliphatic. In some embodiments, the base is an alkoxide, such as LiOR, NaOR or KOR, wherein R is methyl. In some embodiments, the base is an alkoxide, such as LiOR, NaOR or KOR, wherein R is ethyl. In some embodiments, the base is an alkoxide, such as LiOR, NaOR or KOR, wherein R is propyl. In some embodiments, the base is an alkoxide, such as LiOR, NaOR or KOR, wherein R is butyl. In some embodiments, the base is an alkoxide, such as LiOR, NaOR or KOR, wherein R is pentyl. In some embodiments, the base is an alkoxide, such as LiOR, NaOR or KOR, wherein 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 some embodiments, the base is NaOEt. In some embodiments, the base is KOEt. In some embodiments, the base is LiOtBu. In some embodiments, the base is NaOtBu. In some embodiments, the base is KOtBu.

[0223] In some embodiments, the reaction conditions include reacting at temperature T1 (e.g., heating to temperature T1). In some embodiments, temperature T1 is between about 0°C and 60°C. In some embodiments, temperature T1 is between about 20°C and 60°C. In some embodiments, temperature T1 is between about 24°C and 45°C. In some embodiments, temperature T1 is between about 24°C and 40°C. In some embodiments, temperature T1 is between about 24°C and 35°C. In some embodiments, temperature T1 is between about 24°C and 30°C. In some embodiments, 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, temperature T1 is about 30°C.

[0224] In some embodiments, the reaction is allowed to proceed for a period of time. In some embodiments, the reaction is stirred for a period of time. In some embodiments, the period of time is greater than 1 hour. In some embodiments, the period of time is greater than 4 hours. In some embodiments, the period of time is greater than 8 hours. In some embodiments, the period of time is about 2 hours to about 8 hours. In some embodiments, the period of time is between about 1 to about 12 hours. In some embodiments, the period of time is between about 2.5 to about 4 hours. In some embodiments, the period of time is less than 4 hours. In some embodiments, the period of time is less than 2 hours. In some embodiments, the period of time is less than 1 hour.

[0225] In some embodiments, the reaction conditions include cooling the reaction mixture to a temperature T2. In some embodiments, the temperature T2 is between about 0°C and about 60°C. In some embodiments, the temperature T2 is between about 0°C and about 50°C. In some embodiments, the temperature T2 is between about 0°C and about 40°C. In some embodiments, the temperature T2 is between about 0°C and about 30°C. In some embodiments, the temperature T2 is between about 10°C and about 60°C. In some embodiments, the temperature T2 is between about 20°C and about 60°C. In some embodiments, the temperature T2 is between about 20°C and about 30°C. In some embodiments, the temperature T2 is between about 15°C and about 25°C. In some embodiments, the temperature T2 is between about 20°C and 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, temperature T2 is about 23°C.

[0226] In some embodiments, the completion of the reaction is monitored (e.g., the presence of maribavir or compound 3). In some embodiments, the presence of maribavir or compound 3 in the reaction is monitored (e.g., by HPLC). In some embodiments, the presence of maribavir in an amount greater than 95.0% a / a is monitored in the reaction (e.g., by HPLC). In some embodiments, the presence of maribavir in an amount greater than 96.0% a / a is monitored in the reaction (e.g., by HPLC). In some embodiments, the presence of maribavir in an amount greater than 97.0% a / a is monitored in the reaction (e.g., by HPLC). In some embodiments, the presence of maribavir in an amount greater than 97.5% a / a is monitored in the reaction (e.g., by HPLC). In some embodiments, the presence of maribavir in an amount greater than 98.0% a / a is monitored in the reaction (e.g., by HPLC). In some embodiments, the presence of maribavir in an amount greater than 98.1% a / a is monitored in the reaction (e.g., by HPLC). In some embodiments, the presence of maribavir in an amount greater than 98.2% a / a is monitored in the reaction (e.g., by HPLC). In some embodiments, the reaction is monitored for an amount of greater than 98.3% a / a of maribavir (e.g., by HPLC). In some embodiments, the reaction is monitored for an amount of greater than 98.4% a / a of maribavir (e.g., by HPLC). In some embodiments, the reaction is monitored for an amount of greater than 98.5% a / a of maribavir (e.g., by HPLC). In some embodiments, the reaction is monitored for an amount of greater than 99.0% a / a of maribavir (e.g., by HPLC).

[0227] In some embodiments, step 3 further comprises the step (b) of phase separation and / or extraction of maribavir or a pharmaceutically acceptable salt thereof from the reaction mixture to provide a first resulting mixture.

[0228] In some embodiments, the 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, ethyl 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 ethyl 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.

[0229] In some embodiments, the phase separation and / or extraction of maribavir or its pharmaceutically acceptable salt includes adding a second phase separation solvent. In some embodiments, the second phase separation solvent is a sodium chloride aqueous solution, a lithium chloride aqueous solution, a calcium chloride aqueous solution or a potassium chloride aqueous solution. In some embodiments, the second phase separation solvent is a sodium chloride aqueous solution. In some embodiments, the second phase separation solvent is a lithium chloride aqueous solution. In some embodiments, the second phase separation solvent is a calcium chloride aqueous solution. In some embodiments, the second phase separation solvent is a potassium chloride aqueous solution.

[0230] In some embodiments, the phase separation and / or extraction of maribasvir 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, the phase separation and / or extraction of maribasvir 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, the phase separation and / or extraction of maribasvir 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, the phase separation and / or extraction of maribasvir 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, the phase separation and / or extraction of maribasvir 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, the phase separation and / or extraction of maribasvir 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, the phase separation and / or extraction of maribasvir 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, the phase separation and / or extraction of maribasvir 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, the phase separation and / or extraction of maribasvir 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, the phase separation and / or extraction of maribasvir 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, the phase separation and / or extraction of maribasvir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 6.8. In some embodiments, the phase separation and / or extraction of maribasvir or a pharmaceutically acceptable salt thereof comprises adjusting the pH of the reaction mixture to about 7.0. In some embodiments, the 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, the 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, the 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.

[0231] In some embodiments, step 3 further comprises the step (c) of distilling the reaction mixture or the first resulting mixture and / or exchanging the solvent of 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.

[0232] In some embodiments, the reaction mixture or the first resulting mixture comprises a first solvent. In some embodiments, the first solvent is or comprises chloroform, 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 ether. In some embodiments, the first solvent is or comprises 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 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.

[0233] In some embodiments, the second solvent is added to the reaction mixture or the first resulting mixture. In some embodiments, the second solvent is or comprises isopropanol, methanol, ethanol, n-propanol, n-butanol, sec-butanol, tert-butanol, chloroform, 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 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.

[0234] In some embodiments, the second resulting mixture comprises less than 1.0% w / w water (e.g., by 1 HNMR or Karl Fischer method). In some embodiments, the second resulting mixture comprises less than 0.75% w / w water (e.g., by 1 H NMR or Karl Fischer method). In some embodiments, the second resulting mixture comprises less than 0.50% w / w water (e.g., by 1 H NMR or Karl Fischer method). In some embodiments, the second resulting mixture comprises less than 0.25% w / w water (e.g., by 1 H NMR or Karl Fischer method). In some embodiments, the second resulting mixture comprises less than 1.0% w / w water (e.g., by 1 H NMR or Karl Fischer method). In some embodiments, the second resulting mixture comprises less than 0.2% w / w water (e.g., by 1 H NMR or Karl Fischer method). In some embodiments, the second resulting mixture comprises less than 0.09% w / w water (e.g., by 1 H NMR or Karl Fischer method). In some embodiments, the second resulting mixture comprises less than 0.05% w / w water (e.g., by 1 H NMR or Karl Fischer method). In some embodiments, the second resulting mixture comprises an undetectable amount of water (e.g., 1 H NMR or Karl Fischer method). In some embodiments, the amount of water in the second resulting mixture is determined by 1 H NMR Measurement. In some embodiments, the amount of water within the second resulting mixture is measured by the Karl Fischer method.

[0235] In some embodiments, the second resulting mixture comprises about 10-30% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as described by 1 H NMR measurement). In some embodiments, the second resulting mixture comprises about 13-25% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as determined by 1 H NMR measurement). In some embodiments, the second resulting mixture comprises about 15-22% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1HNMR measurement). In some embodiments, the second resulting mixture comprises about 16-20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as determined by 1 H NMR measurement). In some embodiments, the second resulting mixture comprises about 17-20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as determined by 1 H NMR measurement). In some embodiments, the second resulting mixture comprises about 17-19% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 HNMR measurement). In some embodiments, the second resulting mixture comprises about 15%, 16%, 17%, 18%, 19%, 20%, 21%, or 22% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as determined by 1 H NMR measurement). In some embodiments, the second resulting mixture comprises about 15% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as determined by 1 H NMR measurement). In some embodiments, the second resulting mixture comprises about 16% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as determined by 1 H NMR measurement). In some embodiments, the second resulting mixture comprises about 17% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as determined by 1 H NMR measurement). In some embodiments, the second resulting mixture comprises about 18% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as determined by 1 H NMR measurement). In some embodiments, the second resulting mixture comprises about 19% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as determined by 1 H NMR measurement). In some embodiments, the second resulting mixture comprises about 20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as determined by 1 H NMR measurement). In some embodiments, the second resulting mixture comprises about 21% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as determined by 1 H NMR). In some embodiments, the second resulting mixture comprises about 22% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as determined by 1 H NMR measurement).

[0236] In some embodiments, step 3 further comprises the step (d) of crystallizing maribavir or a pharmaceutically acceptable salt thereof (eg, from the reaction mixture, the first resulting mixture, or the second resulting mixture).

[0237] In some embodiments, crystallization comprises providing a crystallization mixture comprising maribavir or a pharmaceutically acceptable salt thereof and a primary solvent. In some embodiments, the primary solvent is or comprises chloroform, 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 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. In some embodiments, the primary solvent is or comprises isopropyl acetate.

[0238] In some embodiments, the crystallization mixture comprises less than 0.2% w / w water (e.g., by 1 H NMR measurement). In some embodiments, the crystallization mixture comprises less than 0.09% w / w water (e.g., by 1 H NMR measurement). In some embodiments, the crystallization mixture comprises less than 1.0% w / w water (e.g., by 1 H NMR or Karl Fischer method). In some embodiments, the crystallization mixture comprises less than 0.75% w / w water (e.g., by 1 HNMR or Karl Fischer method). In some embodiments, the crystallization mixture contains less than 0.50% w / w water (e.g., by 1 HNMR or Karl Fischer method). In some embodiments, the crystallization mixture contains less than 0.25% w / w water (e.g., by 1 H NMR or Karl Fischer method). In some embodiments, the crystallization mixture comprises less than 1.0% w / w water (e.g., by 1 H NMR or Karl Fischer method). In some embodiments, the crystallization mixture contains less than 0.2% w / w water (e.g., by 1 H NMR or Karl Fischer method). In some embodiments, the crystallization mixture contains less than 0.09% w / w water (e.g., by 1H NMR or Karl Fischer method). In some embodiments, the crystallization mixture contains less than 0.05% w / w water (e.g., by 1 HNMR or Karl Fischer method). In some embodiments, the second resulting mixture comprises an undetectable amount of water (e.g., 1 H NMR or Karl Fischer method). In some embodiments, the amount of water in the crystallization mixture is determined by 1 H NMR Measurement. In some embodiments, the amount of water within the crystallization mixture is measured by the Karl Fischer method.

[0239] Without wishing to be bound by a particular theory, it is believed that too low a concentration of maribavir or a pharmaceutically acceptable salt thereof may result in possible dissolution of the seed crystals and potentially affect the yield and / or particle size of maribavir. It is also believed that too high a concentration of maribavir or a pharmaceutically acceptable salt thereof may result in spontaneous crystallization and / or may affect the particle size of maribavir. In some embodiments, the crystallization mixture comprises about 10-30% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 HNMR measurement). In some embodiments, the crystalline mixture comprises about 13-25% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 H NMR measurement). In some embodiments, the crystalline mixture comprises about 15-22% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., as determined by 1 H NMR measurement). In some embodiments, the crystalline mixture comprises about 16-20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 HNMR measurement). In some embodiments, the crystalline mixture comprises about 17-20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 H NMR measurement). In some embodiments, the crystalline mixture comprises about 17-19% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 H NMR measurement). In some embodiments, the crystalline mixture comprises about 15%, 16%, 17%, 18%, 19%, 20%, 21%, or 22% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 H NMR measurement). In some embodiments, the crystalline mixture comprises about 15% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 H NMR measurement). In some embodiments, the crystalline mixture comprises about 16% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1H NMR measurement). In some embodiments, the crystalline mixture comprises about 17% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 H NMR measurement). In some embodiments, the crystalline mixture comprises about 18% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 H NMR measurement). In some embodiments, the crystalline mixture comprises about 19% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 H NMR measurement). In some embodiments, the crystalline mixture comprises about 20% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 HNMR measurement). In some embodiments, the crystalline mixture comprises about 21% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 H NMR measurement). In some embodiments, the crystalline mixture comprises about 22% w / w of maribavir or a pharmaceutically acceptable salt thereof (e.g., by 1 H NMR measurement).

[0240] In some embodiments, 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 between about 74°C and about 90°C. In some embodiments, the temperature T3 is between about 77°C and about 88°C. In some embodiments, the temperature T3 is between about 82°C and about 86°C. In some embodiments, the temperature T3 is between about 83°C and 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, 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.

[0241] In some embodiments, a secondary solvent is added to the crystallization mixture. In some embodiments, the secondary solvent is or comprises chloroform, 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 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 cyclopentyl methyl ether. 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. In some embodiments, the secondary solvent is or comprises toluene.

[0242] In some embodiments, after adding the secondary solvent, the crystallization mixture is aged for an amount of time between 10 minutes and 2 hours. In some embodiments, after adding the secondary solvent, the crystallization mixture is aged for an amount of time between 10 minutes and 1.5 hours. In some embodiments, after adding the secondary solvent, the crystallization mixture is aged for an amount of time between 10 minutes and 1 hour. In some embodiments, after adding the secondary solvent, the crystallization mixture is aged for an amount of time between 10 minutes and 45 minutes. In some embodiments, after adding the secondary solvent, the crystallization mixture is aged for an amount of time between 10 minutes and 30 minutes. In some embodiments, after adding the secondary solvent, the crystallization mixture is aged for less than about two hours. In some embodiments, after adding the secondary solvent, the crystallization mixture is aged for less than about 60 minutes. In some embodiments, after adding the secondary solvent, the crystallization mixture is aged for less than about 30 minutes. In some embodiments, after adding the secondary solvent, the crystallization mixture is aged for less than about 10 minutes. In some embodiments, after adding the secondary solvent, the crystallization mixture is aged for less than about 5 minutes. In some embodiments, the crystallization mixture is aged for at least about 30 minutes after adding the secondary solvent.

[0243] In some embodiments, seeds are added to the crystallization mixture. Without wishing to be bound by a particular theory, it is believed that too low an amount of seeds may allow spontaneous / uncontrolled crystallization, which may affect particle size. In addition, it is believed that higher amounts of seeds may adversely affect particle size.

[0244] In some embodiments, the seed is maribavir or a pharmaceutically acceptable salt thereof. In some embodiments, the seed is added in an amount of about 0.01% to 0.50% w / w relative to compound 3 or its salt. In some embodiments, the seed is added in an amount of about 0.01% to 0.15% w / w relative to compound 3 or its salt. In some embodiments, the seed is added in an amount of about 0.15% to 0.30% w / w relative to compound 3 or its salt. In some embodiments, the seed is added in an amount of about 0.05% to 0.30% w / w relative to compound 3 or its salt. In some embodiments, the seed is added in an amount of about 0.10% to 0.20% w / w relative to compound 3 or its salt. In some embodiments, the seed is added in an amount of about 0.12% to 0.18% w / w relative to compound 3 or its salt. In some embodiments, the seed is added in an amount of about 0.14% to 0.16% w / w relative to compound 3 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.13% w / w relative to Compound 3 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.14% w / w relative to Compound 3 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.15% w / w relative to Compound 3 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.16% w / w relative to Compound 3 or its salt. In some embodiments, the seed crystals are added in an amount of about 0.17% w / w relative to Compound 3 or its salt.

[0245] Without wishing to be bound by a particular theory, it is believed that the size of the seed crystals may affect the particle size of maribavir (e.g., seed crystals that are too small may result in a smaller particle size of maribavir, while seed crystals that are too large may result in a larger particle size of 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 should be understood that the "d(50) value" refers to the median particle size of the sample (e.g., 50% of the particles are less than the d(50) value and 50% of the particles are greater than the d(50) value). In some embodiments, the seed crystals comprise a d(50) value between about 1.00 μm and about 10.00 μm. In some embodiments, the seed crystals comprise a d(50) value between about 1.00 μm and about 9.00 μm. In some embodiments, the seed crystals comprise a d(50) value between about 1.00 μm and about 8.00 μm. In some embodiments, the seed comprises a d(50) value between about 1.00 μm and about 7.00 μm. In some embodiments, the seed comprises a d(50) value between about 1.00 μm and about 6.00 μm. In some embodiments, the seed comprises a d(50) value between about 1.00 μm and about 5.00 μm. In some embodiments, the seed comprises a d(50) value between about 1.00 μm and about 4.00 μm. In some embodiments, the seed comprises a d(50) value between about 1.00 μm and about 3.00 μm. In some embodiments, the seed comprises a d(50) value between about 2.00 μm and about 10.00 μm. In some embodiments, the seed comprises a d(50) value between about 3.00 μm and about 10.00 μm. In some embodiments, the seed comprises a d(50) value between about 4.00 μm and about 10.00 μm. In some embodiments, the seed comprises a d(50) value between about 5.00 μm and about 10.00 μm. In some embodiments, the seed comprises a d(50) value between about 6.00 μm and about 10.00 μm. In some embodiments, the seed comprises a d(50) value between about 7.00 μm and about 10.00 μm. In some embodiments, the seed comprises a d(50) value between about 1.25 μm and 9.00 μm. In some embodiments, the seed comprises a d(50) value between about 1.75 μm and about 8.00 μm. In some embodiments, the seed comprises a d(50) value between about 2.25 μm and about 7.00 μm. In some embodiments, the seed comprises a d(50) value between about 2.75 μm and about 6.25 μm. In some embodiments, the seed comprises a d(50) value between about 3.00 μm and 6.00 μm.In some embodiments, the seed 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, about 7.00 μm, about 8.00 μm, about 9.00 μm, or about 10.00 μm. In some embodiments, the seed comprises a d(50) value of about 1.25 μm. In some embodiments, the seed comprises a d(50) value of about 1.75 μm. In some embodiments, the seed comprises a d(50) value of about 2.25 μm. In some embodiments, the seed comprises a d(50) value of about 2.75 μm. In some embodiments, the seed comprises a d(50) value of about 3.00 μm. In some embodiments, the seed crystals comprise a d(50) value of about 4.00 μm. In some embodiments, the seed crystals comprise a d(50) value of about 5.00 μm. In some embodiments, the seed crystals comprise a d(50) value of about 6.00 μm. In some embodiments, the seed crystals comprise a d(50) value of about 6.25 μm. In some embodiments, the seed crystals comprise a d(50) value of about 7.00 μm. In some embodiments, the seed crystals comprise a d(50) value of about 8.00 μm. In some embodiments, the seed crystals comprise a d(50) value of about 9.00 μm. In some embodiments, the seed crystals comprise a d(50) value of about 10.00 μm.

[0246] In some embodiments, after adding the seed crystals, the crystallization mixture is aged for about 15 minutes to about 120 minutes. In some embodiments, after adding the seed crystals, the crystallization mixture is aged for about 30 minutes to about 90 minutes. In some embodiments, after adding the seed crystals, the crystallization mixture is aged for about 30 minutes to about 60 minutes. In some embodiments, after adding the seed crystals, the crystallization mixture is aged for about 60 minutes to about 90 minutes. In some embodiments, after adding the seed crystals, the crystallization mixture is aged for about 90 minutes to about 120 minutes. In some embodiments, after adding the seed crystals, the crystallization mixture is aged for at least about 5 minutes. In some embodiments, after adding the seed crystals, the crystallization mixture is aged for at least about 15 minutes. In some embodiments, after adding the seed crystals, the crystallization mixture is aged for at least about 30 minutes. In some embodiments, after adding the seed crystals, the crystallization mixture is aged for at least about 60 minutes. In some embodiments, after adding the seed crystals, the crystallization mixture is aged for at least about 90 minutes. In some embodiments, after adding the seed crystals, the crystallization mixture is aged for at least about 120 minutes. In some embodiments, the crystallization mixture is aged for about 30 minutes after the seed crystals are added. In some embodiments, the crystallization mixture is aged for about 60 minutes after the seed crystals are added. In some embodiments, the crystallization mixture is aged for about 90 minutes after the seed crystals are added. In some embodiments, the crystallization mixture is aged for about 120 minutes after the seed crystals are added.

[0247] In some embodiments, additional secondary solvent is added to the crystallization mixture. In some embodiments, additional secondary solvent is added with an amount (kg / kg) of about 5 / 1 to about 1 / 5 of the total primary solvent. In some embodiments, additional secondary solvent is added with an amount (kg / kg) of about 2 / 1 to about 1 / 2 of the total primary solvent. In some embodiments, additional secondary solvent is added with an amount (kg / kg) of about 24 / 7 to about 2 / 7 of the total primary solvent. In some embodiments, additional secondary solvent is added with an amount (kg / kg) of about 16 / 7 to about 4 / 7 of the total primary solvent. In some embodiments, additional secondary solvent is added with an amount (kg / kg) of about 8 / 7 of the total primary solvent. In some embodiments, additional secondary solvent is added with an amount (kg / kg) of about 9 / 7 of the total primary solvent. In some embodiments, additional secondary solvent is added with an amount (kg / kg) of about 10 / 7 of the total primary solvent. In some embodiments, the additional secondary solvent is added in an amount of about 11 / 7 of the total primary solvent (kg / kg). In some embodiments, the additional secondary solvent is added in an amount of about 12 / 7 of the total primary solvent (kg / kg). In some embodiments, the additional secondary solvent is added in an amount of about 13 / 7 of the total primary solvent (kg / kg). In some embodiments, the additional secondary solvent is added in an amount of about 15 / 7 of the total primary solvent (kg / kg).

[0248] In some embodiments, after adding the additional secondary solvent, the crystallization mixture is stirred for a period of time. In some embodiments, the period of time is at least 30 minutes. In some embodiments, the period of time is at least 60 minutes. In some embodiments, the period of time is between about 15 minutes and 120 minutes. In some embodiments, the period of time is between about 15 minutes and 90 minutes. In some embodiments, the period of time is between about 15 minutes and 60 minutes. In some embodiments, the period of time is between about 30 minutes and 90 minutes. In some embodiments, the period of time is between about 45 minutes and 90 minutes. In some embodiments, the period of time is between about 60 minutes and 90 minutes. In some embodiments, the period of time is about 15 minutes. In some embodiments, the period of time is about 30 minutes. In some embodiments, the period of time is about 45 minutes. In some embodiments, the period of time is about 60 minutes. In some embodiments, the period of time is about 90 minutes.

[0249] In some embodiments, after adding additional secondary solvent, the crystallization mixture is stirred at temperature T3. In some embodiments, temperature T3 is between about 50°C and about 150°C. In some embodiments, temperature T3 is between about 50°C and about 100°C. In some embodiments, temperature T3 is between about 50°C and about 90°C. In some embodiments, temperature T3 is between about 50°C and about 80°C. In some embodiments, temperature T3 is between about 70°C and about 115°C. In some embodiments, temperature T3 is between about 80°C and about 115°C. In some embodiments, temperature T3 is between about 60°C and about 105°C. In some embodiments, temperature T3 is between about 70°C and about 95°C. In some embodiments, temperature T3 is between about 75°C and about 90°C. In some embodiments, temperature T3 is between about 77°C and about 88°C. In some embodiments, temperature T3 is between about 81°C and about 87°C. In some embodiments, temperature T3 is between about 81°C and about 86°C. In some embodiments, 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, temperature T3 is about 83° C. In some embodiments, temperature T3 is about 84° C. In some embodiments, temperature T3 is about 85° C.

[0250] In some embodiments, the crystallization mixture is cooled to a temperature T4. In some embodiments, the temperature T4 is between about -20°C and about 25°C. In some embodiments, the temperature T4 is between about -15°C and about 20°C. In some embodiments, the temperature T4 is between about -15°C and about 15°C. In some embodiments, the temperature T4 is between about -15°C and about 10°C. In some embodiments, the temperature T4 is between about -15°C and about 5°C. In some embodiments, the temperature T4 is between about -15°C and about 0°C. In some embodiments, the temperature T4 is between about -5°C and about 25°C. In some embodiments, the temperature T4 is between about 0°C and about 25°C. In some embodiments, the temperature T4 is between about 5°C and about 25°C. In some embodiments, the temperature T4 is between about 10°C and about 25°C. In some embodiments, the temperature T4 is between about -10°C and about 20°C. In some embodiments, the temperature T4 is between about -5°C and about 15°C. In some embodiments, the temperature T4 is between about 0°C and about 10°C. In some embodiments, the temperature T4 is between about 3°C ​​and about 7°C. In some embodiments, the 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, the temperature T4 is about 4°C. In some embodiments, the temperature T4 is about 5°C. In some embodiments, the temperature T4 is about 6°C.

[0251] In some embodiments, the crystallization mixture is cooled to temperature T4 over about 0.5 hours to about 8 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over about 1 hour to about 5 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over about 2 hours to about 4 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over at least 1 hour. In some embodiments, the crystallization mixture is cooled to temperature T4 over at least 3 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over 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 about 2 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over about 3 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over about 4 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over about 6 hours. In some embodiments, the crystallization mixture is cooled to temperature T4 over about 8 hours.

[0252] In some embodiments, the crystallization mixture is stirred at temperature T4 for a period of time. In some embodiments, the time period is between about 3 hours to about 30 hours. In some embodiments, the time period is between about 3 hours to about 18 hours. In some embodiments, the time period is between about 3 hours to about 15 hours. In some embodiments, the time period is between about 3 hours to about 12 hours. In some embodiments, the time period is between about 3 hours to about 8 hours. In some embodiments, the time period is between about 3 hours to about 5 hours. In some embodiments, the time period is less than about 18 hours. In some embodiments, the time period is less than about 12 hours. In some embodiments, the time period is less than about 6 hours. In some embodiments, the time period is less than about 3 hours.

[0253] In some embodiments, step 3 further includes step (e) optionally filtering or washing the crystallization mixture to provide a filtered mixture. In some embodiments, step 3 further includes filtering the crystallization mixture to provide a filtered mixture. In some embodiments, step 3 further includes washing the crystallization mixture to provide a filtered mixture. In some embodiments, the crystallization mixture is washed with chloroform, 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 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.

[0254] In some embodiments, the crystallization washing solvent is provided in an amount of about 0.30L / kg to about 2.00L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.30L / kg to about 1.50L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.30L / kg to about 1.25g / g. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.30L / kg to about 1.00L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.30L / kg to about 0.9L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.50L / kg to about 2.00L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.75L / kg to about 2.00L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.85L / kg to about 2.00L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.30L / kg to about 2.00L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.40L / kg to about 1.75L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.50L / kg to about 1.50L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.60L / kg to about 1.25L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.67L / kg to about 1.00L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.75L / kg to about 0.90L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.80L / kg to about 0.85L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.60L / kg, 0.65L / kg, 0.70L / kg, 0.75L / kg, 0.80L / kg, 0.84L / kg, 0.90L / kg or 0.95L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.75L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.80L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.84L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.90L / kg. In some embodiments, the crystallization washing solvent is provided in an amount of about 0.95L / kg.

[0255] In some embodiments, the crystallization washing solvent is provided at a temperature between about -20°C and about 60°C. In some embodiments, the crystallization washing solvent is provided at a temperature between about -10°C and about 30°C. In some embodiments, the crystallization washing solvent is provided at a temperature between about -10°C and about 20°C. In some embodiments, the crystallization washing solvent is provided at a temperature between about -10°C and about 10°C. In some embodiments, the crystallization washing solvent is provided at a temperature between about -5°C and about 40°C. In some embodiments, the crystallization washing solvent is provided at a temperature between about 0°C and about 40°C. In some embodiments, the crystallization washing solvent is provided at a temperature between about 5°C and about 40°C. In some embodiments, the crystallization washing solvent is provided at a temperature between about -5°C and about 30°C. In some embodiments, the crystallization washing solvent is provided at a temperature between about -5°C and about 20°C. In some embodiments, the crystallization washing solvent is provided at a temperature between about 0°C and about 20°C. In some embodiments, the crystallization washing solvent is provided at a temperature between about 0°C and about 15°C. In some embodiments, the crystallization washing solvent is provided at a temperature between about 0°C and about 10°C. In some embodiments, the crystallization wash solvent is provided at a temperature between about 2°C and about 8°C. In some embodiments, the crystallization wash solvent is provided at a temperature between about 4°C and 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.

[0256] In some embodiments, a crystallization washing solvent is provided for a period of time, the period of time being less than 5 days. In some embodiments, a crystallization washing solvent is provided for a period of time, the period of time being between about 1 minute and about 5 days. In some embodiments, a crystallization washing solvent is provided for a period of time, the period of time being between about 1 minute and about 24 hours. In some embodiments, a crystallization washing solvent is provided for a period of time, the period of time being between about 1 minute and about 12 hours. In some embodiments, a crystallization washing solvent is provided for a period of time, the period of time being between about 1 minute and about 8 hours. In some embodiments, a crystallization washing solvent is provided for a period of time, the period of time being between about 1 minute and about 6 hours. In some embodiments, a crystallization washing solvent is provided for a period of time, the period of time being between about 1 minute and about 4 hours. In some embodiments, a crystallization washing solvent is provided for a period of time, the period of time being between about 1 minute and about 2 hours. In some embodiments, a crystallization washing solvent is provided for a period of time, the period of time being between about 1 minute and about 1 hour. In some embodiments, a crystallization washing solvent is provided for a period of time, the period of time being between about 1 minute and about 45 minutes. In some embodiments, a crystallization washing solvent is provided for a period of time, and the period of time is between about 1 minute and about 30 minutes. In some embodiments, a crystallization washing solvent is provided for a period of time, and the period of time is between about 1 minute and about 30 minutes. In some embodiments, a crystallization washing solvent is provided for a period of time, and the period of time is about 15 minutes. In some embodiments, a crystallization washing solvent is provided for a period of time, and the period of time is at least 15 minutes. In some embodiments, a crystallization washing solvent is provided for a period of time, and the period of time is at least 30 minutes. In some embodiments, a crystallization washing solvent is provided for a period of time, and the period of time is at least 60 minutes. In some embodiments, a crystallization washing solvent is provided for a period of time, and the period of time is at least 90 minutes. In some embodiments, a crystallization washing solvent is provided for a period of time, and the period of time is at least 1 day.

[0257] In some embodiments, step 3 further comprises the step (f) drying the filtered mixture.

[0258] In some embodiments, drying comprises heating the filtered mixture without stirring to a temperature T5 for a period of time. In some embodiments, the temperature T5 is between about 20°C and about 100°C. In some embodiments, the temperature T5 is between about 20°C and about 70°C. In some embodiments, the temperature T5 is between about 20°C and about 50°C. In some embodiments, the temperature T5 is between about 30°C and about 80°C. In some embodiments, the temperature T5 is between about 40°C and about 80°C. In some embodiments, the temperature T5 is between about 50°C and about 80°C. In some embodiments, the temperature T5 is between about 35°C and about 60°C. In some embodiments, the temperature T5 is between about 40°C and about 50°C. In some embodiments, the temperature T5 is less than or equal to 20°C. In some embodiments, the temperature T5 is less than or equal to about 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C. In some embodiments, the temperature T5 is less than or equal to 40°C. In some embodiments, temperature T5 is less than or equal to 50° C. In some embodiments, temperature T5 is less than or equal to 60° C.

[0259] In some embodiments, the filtered mixture is maintained at temperature T5 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 2 hours. In some embodiments, the period of time is at least 3 hours. In some embodiments, the period of time is at least 4 hours. In some embodiments, the period of time is at least 5 hours. In some embodiments, the period of time is at least 6 hours. In some embodiments, the period of time is at least 7 hours. In some embodiments, the period of time is at least 8 hours. In some embodiments, the period of time is at least 9 hours. In some embodiments, the period of time is at least 10 hours.

[0260] In some embodiments, drying further comprises heating the filtered mixture without stirring to a temperature T6 for a period of time. In some embodiments, the temperature T6 is between about 20°C and about 100°C. In some embodiments, the temperature T6 is between about 40°C and about 100°C. In some embodiments, the temperature T6 is between about 20°C and about 80°C. In some embodiments, the temperature T6 is between about 20°C and about 70°C. In some embodiments, the temperature T6 is between about 20°C and about 60°C. In some embodiments, the temperature T6 is between about 30°C and about 60°C. In some embodiments, the temperature T6 is between about 40°C and about 60°C. In some embodiments, the temperature T6 is between about 45°C and about 55°C. In some embodiments, the temperature T6 is between about 45°C and about 50°C. In some embodiments, the temperature T6 is less than or equal to 25°C, 30°C, 40°C, 45°C, 50°C, 55°C, 60°C. In some embodiments, the temperature T6 is less than or equal to 90°C. In some embodiments, temperature T6 is less than or equal to 70°C. In some embodiments, temperature T6 is less than or equal to 60°C. In some embodiments, temperature T6 is less than or equal to 55°C. In some embodiments, temperature T6 is less than or equal to 50°C. In some embodiments, temperature T6 is less than or equal to 45°C. In some embodiments, temperature T6 is less than or equal to 40°C.

[0261] In some embodiments, the filtered mixture is maintained at temperature T6 for a period of time. In some embodiments, the time period is about 1 hour to 5 days. In some embodiments, the time period is about 1 hour to 2 days. In some embodiments, the time period is about 1 hour to 1 day. In some embodiments, the time period is between about 1 hour and 12 hours. In some embodiments, the time period is between about 1 hour and 6 hours. In some embodiments, the time period is at least 1 hour. In some embodiments, the time period is at least 2 hours. In some embodiments, the time period is at least 3 hours. In some embodiments, the time period is at least 4 hours. In some embodiments, the time period is at least 5 hours. In some embodiments, the time period is at least 6 hours. In some embodiments, the time period is until the filtered mixture looks dry.

[0262] In some embodiments, the time period is until there is toluene between about 100ppm to about 1600ppm (e.g., as measured by GCHS). In some embodiments, the time period is until there is toluene between about 100ppm to about 1400ppm (e.g., as measured by GCHS). In some embodiments, the time period is until there is toluene between about 100ppm to about 1200ppm (e.g., as measured by GCHS). In some embodiments, the time period is until there is toluene between about 100ppm to about 1000ppm (e.g., as measured by GCHS). In some embodiments, the time period is until there is toluene between about 100ppm to about 800ppm (e.g., as measured by GCHS). In some embodiments, the time period is until there is toluene between about 100ppm to about 700ppm (e.g., as measured by GCHS). In some embodiments, the time period is until there is toluene between about 300ppm to about 1400ppm (e.g., as measured by GCHS). In some embodiments, the time period is until there is toluene between about 500ppm to about 1400ppm (e.g., as measured by GCHS). In some embodiments, the time period is until there is toluene between about 700ppm to about 1400ppm (e.g., as measured by GCHS). In some embodiments, the time period is until there is toluene between about 300ppm to about 1200ppm (e.g., as measured by GCHS). In some embodiments, the time period is until there is toluene between about 500ppm to about 1000ppm (e.g., as measured by GCHS). In some embodiments, the time period is until there is toluene between about 600ppm to about 800ppm (e.g., as measured by GCHS). In some embodiments, the time period is until there is toluene between about 650ppm to about 750ppm (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 1500ppm of toluene (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 1200ppm of toluene (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 1000ppm of toluene (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 800 ppm of toluene (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 700 ppm of toluene (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 600 ppm of toluene (e.g., as measured by GCHS).In some embodiments, the time period is until there is less than 500 ppm of toluene (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 400 ppm of toluene (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 300 ppm of toluene (e.g., as measured by GCHS).

[0263] In some embodiments, the time period is until there is about 1,000 ppm to about 10,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is about 1,000 ppm to about 8,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is about 1,000 ppm to about 6,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is about 1,000 ppm to about 5,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is about 1,000 ppm to about 4,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is about 1,000 ppm to about 3,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is about 3,000 ppm to about 10,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is about 4,000 ppm to about 10,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is about 5,000 ppm to about 10,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is about 2,000 ppm to about 8,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is about 3,000 ppm to about 6,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is about 4,000 ppm to about 5,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 10,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 8,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 6,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 5,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 4,000 ppm of isopropyl acetate (e.g., as measured by GCHS).In some embodiments, the time period is until there is less than 3,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 2,000 ppm of isopropyl acetate (e.g., as measured by GCHS). In some embodiments, the time period is until there is less than 1,000 ppm of isopropyl acetate (e.g., as measured by GCHS).

[0264] In some embodiments, step 3 provides unmilled maribavir or a pharmaceutically acceptable salt thereof. In some embodiments, step 3 further comprises the following steps: (g) milling unmilled maribavir or a pharmaceutically acceptable salt thereof to provide milled maribavir or a pharmaceutically acceptable salt thereof. In some embodiments, milling comprises formulating into tablets (e.g., 200 mg tablets). Formulations and compositions

[0265] In some embodiments, the compositions provided comprise at least 90% by weight of maribavir. In some embodiments, the compositions provided comprise at least 95% by weight of maribavir. In some embodiments, the compositions provided comprise at least 99% by weight of maribavir. In some embodiments, the compositions provided comprise at least 99% by weight of maribavir. In some embodiments, the compositions provided comprise at least 99.5% by weight of maribavir. In some embodiments, the compositions provided comprise at least 99.6% by weight of maribavir. In some embodiments, the compositions provided comprise at least 99.7% by weight of maribavir. In some embodiments, the compositions provided comprise at least 99.8% by weight of maribavir. In some embodiments, the compositions provided comprise at least 99.9% by weight of maribavir.

[0266] In some embodiments, provided compositions include maribavir substantially free of impurities. As used herein, the term "substantially free of impurities" means that the composition or compound does not contain a significant amount of foreign matter. Such foreign matter may include starting materials, residual solvents, or other impurities that may be produced by the preparation and / or separation of maribavir.

[0267] In some embodiments, the present invention provides a composition comprising maribavir and one or more compounds selected from compound 2, compound 3, and compound 4. In some embodiments, such compositions comprise 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 compositions comprise 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 present invention provides a composition comprising maribavir and 0.01-0.5% enantiomer-maribavir (ie, D-maribavir):

[0268] In some embodiments, the present invention provides a composition as described in any one of Tables 4-12 to 4-20 in Example 4.

[0269] In some embodiments, steps 1-3 provide a specific polymorphic form of maribavir. In some embodiments, steps 1-3 provide maribavir form VI as described in US6,482,939 (e.g., at least 90% by weight, 95% by weight, or 99% by weight of maribavir form VI). 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.

[0270] In some embodiments, the compositions provided include Maribavir Form VI as described in US6,482,939 (e.g., at least 90%, 95%, or 99% by weight of Maribavir Form VI). In some embodiments, the compositions provided include Maribavir Form VI as described in US6,482,939 (e.g., at least 90%, 95%, or 99% by weight of Maribavir Form VI) and another polymorphic form of Maribavir as described in US6,482,939, US8,546,344, or US11,130,777. In some embodiments, the compositions provided include Maribavir Form VI as described in US6,482,939 and an isopropyl acetate solvate of Maribavir (e.g., as described in US6,482,939, US8,546,344, or US11,130,777). In some embodiments, the compositions provided include Form VI of maribavir and less than 10%, 5%, 1%, or 0.5% by weight of another polymorphic form of maribavir, for example, as described in US6,482,939, US8,546,344, or US11,130,777. In some embodiments, the compositions provided include Form VI of maribavir and less than 10%, 5%, 1%, or 0.5% by weight of another polymorphic form of maribavir, for example, as described in US6,482,939, US8,546,344, or US11,130,777. In some embodiments, the compositions provided include Form VI of maribavir, which is substantially free of other polymorphic forms, for example, as described in US6,482,939, US8,546,344, or US11,130,777.

[0271] In some embodiments, maribavir (eg, Form VI) is milled (eg, hammer mill) and formulated into tablets (eg, 200 mg tablets).

[0272] Particle size distribution ("PSD") is a measurement of the number of particles present according to their size definition. It should be understood that PSD is a valuable indicator of quality and performance and is necessary to ensure consistency in the manufacturability of a drug product. For example, when formulated (e.g., made into tablets), PSD may affect the ease of handling of the compound and excipients. Consistent formulations are important for ensuring that the active drug is delivered to the correct location in the body at the correct concentration and the correct rate. In some embodiments, the present invention provides compositions of maribavir, and methods for preparing maribavir and compositions comprising maribavir, which have a PSD that results in a consistent tablet formulation. In some embodiments, steps 1, 2, 3 and / or grinding (e.g., hammer grinding) provide a PSD for maribavir that allows for the manufacture of tablets with uniformity. In some embodiments, step 3 provides maribavir form VI particles with a desired PSD. In some embodiments, the present invention provides a composition comprising maribavir form VI particles having a PSD of d(50) between about 100 and about 400 μm. In some embodiments, the present invention provides a composition comprising maribavir form VI particles having a PSD of d(50) between about 100 and about 400 μm, wherein such maribavir form VI is manufactured by using maribavir seed crystals having a PSD of d(50) between about 1 and about 10 μm. In some embodiments, the present invention provides a method of manufacturing maribavir form VI particles by using maribavir form VI seed crystals having a PSD of d(50) between about 1 and about 10 μm.

[0273] In some embodiments, maribasvir or a pharmaceutically acceptable salt thereof has a PSD of d(50) between about 50 and about 500 μm. In some embodiments, maribasvir or a pharmaceutically acceptable salt thereof has a PSD of d(50) between about 100 and about 400 μm. In some embodiments, maribasvir or a pharmaceutically acceptable salt thereof has a PSD of d(50) between about 170 and about 350 μm. In some embodiments, maribasvir or a pharmaceutically acceptable salt thereof has a PSD of d(50) between about 170 and about 226 μm. In some embodiments, maribasvir or a pharmaceutically acceptable salt thereof has a PSD of d(50) between about 227 and about 280 μm. In some embodiments, maribasvir or a pharmaceutically acceptable salt thereof has a PSD of d(50) between about 281 and about 336 μm.

[0274] In some aspects, the present invention provides a composition comprising maribavir or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a composition prepared by the method disclosed herein (e.g., steps 1-3). In some embodiments, the present invention provides a composition comprising maribavir or a pharmaceutically acceptable salt thereof and one or more compounds selected from the following: or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the present invention provides a composition comprising 0.01-0.10% (w / w HPLC) of Compound 2 relative to Maribavir. In some embodiments, the present invention provides a composition comprising 0.01-0.05% w / w (e.g., as measured by HPLC) of Compound 2 relative to Maribavir. In some embodiments, the present invention provides a composition comprising 0.02-0.05% w / w (e.g., as measured by HPLC) of Compound 2 relative to Maribavir. In some embodiments, the present invention 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 invention provides a composition comprising 0.01-0.10% a / a (e.g., as measured by HPLC) of Compound 2 relative to Maribavir. In some embodiments, the present invention provides a composition comprising 0.01-0.05% a / a (e.g., as measured by HPLC) of Compound 2 relative to maribavir. In some embodiments, the present invention provides a composition comprising 0.02-0.05% a / a (e.g., as measured by HPLC) of Compound 2 relative to maribavir. In some embodiments, the present invention provides a composition comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% a / a (e.g., as measured by HPLC) of Compound 2 relative to maribavir. In some embodiments, the present invention provides a composition wherein Compound 2 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0276] In some embodiments, the present invention provides a composition comprising 0.01-0.10% (w / w HPLC) of compound 3 relative to maribavir. In some embodiments, the present invention provides a composition comprising 0.01-0.05% w / w (e.g., as measured by HPLC) of compound 3 relative to maribavir. In some embodiments, the present invention provides a composition comprising 0.02-0.05% w / w (e.g., as measured by HPLC) of compound 3 relative to maribavir. In some embodiments, the present invention 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 invention provides a composition comprising 0.01-0.10% a / a (e.g., as measured by HPLC) of compound 3 relative to maribavir. In some embodiments, the present invention provides a composition comprising 0.01-0.05% a / a (e.g., as measured by HPLC) of Compound 3 relative to maribavir. In some embodiments, the present invention provides a composition comprising 0.02-0.05% a / a (e.g., as measured by HPLC) of Compound 3 relative to maribavir. In some embodiments, the present invention provides a composition comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% a / a (e.g., as measured by HPLC) of Compound 3 relative to maribavir. In some embodiments, the present invention provides a composition wherein Compound 3 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement).

[0277] In some embodiments, the present invention provides a composition comprising 0.01-0.10% (w / w HPLC) of Compound 4 relative to Maribavir. In some embodiments, the present invention provides a composition comprising 0.01-0.05% w / w (e.g., as measured by HPLC) of Compound 4 relative to Maribavir. In some embodiments, the present invention provides a composition comprising 0.02-0.05% w / w (e.g., as measured by HPLC) of Compound 4 relative to Maribavir. In some embodiments, the present invention 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 4 relative to Maribavir. In some embodiments, the present invention provides a composition comprising 0.01-0.10% a / a (e.g., as measured by HPLC) of Compound 4 relative to Maribavir. In some embodiments, the present invention provides a composition comprising 0.01-0.05% a / a (e.g., as measured by HPLC) of Compound 4 relative to maribavir. In some embodiments, the present invention provides a composition comprising 0.02-0.05% a / a (e.g., as measured by HPLC) of Compound 4 relative to maribavir. In some embodiments, the present invention provides a composition comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% a / a (e.g., as measured by HPLC) of Compound 4 relative to maribavir. In some embodiments, the present invention provides a composition wherein Compound 4 or a salt thereof is undetectable (e.g., by HPLC or 1 H NMR measurement). Dosage regimen

[0278] Provided herein are methods for treating patients with CMV, comprising administering maribavir to the patient (e.g., by administering a composition comprising and / or delivering maribavir as described herein). In some embodiments, the methods provided include orally administering about 400 mg of maribavir to the patient twice a day. In some embodiments, the methods provided include orally administering about 200 mg of maribavir to the patient twice a day.

[0279] 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.

[0280] In some embodiments, the present invention provides a method for treating a patient suffering from post-transplant CMV infection or a disease that is inadequately responsive to treatment with ganciclovir, valganciclovir, cidofovir or foscarnet, the method comprising orally administering to the patient 400 mg of maribavir or a salt thereof twice daily, wherein maribavir is administered as an oral solid composition, wherein the composition comprises (i) maribavir Form VI having a PSD of d(50) 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 present invention provides a method for treating a patient suffering from post-transplant CMV infection or a disease that is intolerant to treatment with ganciclovir, valganciclovir, cidofovir or sodium foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice a day, wherein maribavir is administered as an oral solid composition, wherein the composition comprises (i) maribavir Form VI having a PSD of d(50) 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 present invention provides a method for treating a patient suffering from post-transplant CMV infection or a disease that is inadequately responsive to treatment with ganciclovir, valganciclovir, cidofovir or sodium foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily, wherein maribavir is administered as an oral solid composition, wherein the composition comprises (i) maribavir Form VI having a PSD of d(50) 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, (v) less than 0.05% of D-maribavir or a salt thereof, and (v) a pharmaceutically acceptable excipient.In some embodiments, the present invention provides a method for treating a patient suffering from post-transplant CMV infection or a disease that is inadequately responsive to treatment with ganciclovir, valganciclovir, cidofovir or sodium foscarnet, the method comprising orally administering to the patient 400 mg twice daily of maribavir or a salt thereof, wherein maribavir is administered as an oral solid composition, wherein the composition comprises (i) maribavir Form VI having a PSD of d(50) 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, wherein the patient is administered an immunosuppressant drug that is a substrate for CYP3A4 and / or P-gp, including tacrolimus, cyclosporine, sirolimus and everolimus. In some embodiments, the present invention provides a method for controlling the drug concentration of maribavir and an immunosuppressant in a patient suffering from post-transplant CMV infection or disease, the method comprising orally administering maribavir or a salt thereof to the patient in an amount of 400 mg twice a day, wherein maribavir is administered as an oral solid composition, wherein the composition comprises (i) maribavir Form VI having a PSD of d(50) 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, wherein the immunosuppressant drug is administered to the patient. In some embodiments, the present invention provides a method for controlling the drug concentration of maribavir and an immunosuppressant in a patient suffering from post-transplant CMV infection or a disease that is inadequately responsive to treatment with ganciclovir, valganciclovir, cidofovir or sodium foscarnet, the method comprising orally administering maribavir or a salt thereof to the patient in an amount of 400 mg twice daily, wherein maribavir is administered as an oral solid composition, wherein the composition comprises (i) maribavir Form VI having a PSD of d(50) 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, wherein the patient is administered an immunosuppressant drug that is a substrate for CYP3A4 and / or P-gp, including tacrolimus, cyclosporine, sirolimus and everolimus.In some embodiments, the present invention provides a method for treating a patient suffering from post-transplant CMV infection or a disease that is inadequately responsive to treatment with ganciclovir, valganciclovir, cidofovir or sodium foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily, wherein maribavir is administered as an oral solid composition, wherein the composition comprises (i) maribavir Form VI having a PSD of d(50) 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, wherein the patient is administered an immunosuppressant drug that is a substrate for CYP3A4 and / or P-gp, including tacrolimus, cyclosporine, sirolimus and everolimus, wherein the immunosuppressant drug level in the patient is monitored after administration of maribavir. In some embodiments, the present invention provides a method for treating a patient suffering from post-transplant CMV infection or a disease that is inadequately responsive to treatment with ganciclovir, valganciclovir, cidofovir or sodium foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 800 mg twice daily, wherein maribavir is administered as an oral solid composition, wherein the composition comprises (i) maribavir form VI particles having a PSD of d(50) 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, wherein the patient has received carbamazepine prior to administration of maribavir. In some embodiments, the present invention provides a method for treating a patient suffering from post-transplant CMV infection or a disease that is inadequately responsive to treatment with ganciclovir, valganciclovir, cidofovir or sodium foscarnet, the method comprising orally administering to the patient 1200 mg of maribavir or a salt thereof twice daily, wherein maribavir is administered as an oral solid composition, wherein the composition comprises (i) maribavir Form VI having a PSD of d(50) 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, wherein the patient has received phenytoin or phenobarbital prior to administration of maribavir.In some embodiments, the present invention provides a method for treating a patient suffering from post-transplant CMV infection or a disease that is inadequately responsive to treatment with ganciclovir, valganciclovir, cidofovir or sodium foscarnet, the method comprising orally administering to the patient 400 mg of maribavir or a salt thereof twice daily for more than 6 months, wherein maribavir is administered as an oral solid composition, wherein the composition comprises (i) maribavir Form VI having a PSD of d(50) 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 present invention provides a method for treating a patient suffering from post-transplant CMV infection or a disease that is inadequately responsive to treatment with ganciclovir, valganciclovir, cidofovir or sodium foscarnet, the method comprising orally administering to the patient maribavir or a salt thereof in an amount of 400 mg twice daily for more than 12 months, wherein maribavir is administered as an oral solid composition, wherein the composition comprises (i) maribavir Form VI having a PSD of d(50) 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 present invention provides a method for treating a patient suffering from post-transplant CMV infection or a disease that is inadequately responsive to treatment with ganciclovir, valganciclovir, cidofovir or sodium foscarnet, the method comprising orally administering to the patient 400 mg of maribavir or a salt thereof twice daily, wherein maribavir is administered as an oral solid composition, wherein the composition comprises (i) maribavir Form VI having a PSD of d(50) between about 50 and 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 present invention provides a method for treating a patient suffering from post-transplant CMV infection or a disease that is inadequately responsive to treatment with ganciclovir, valganciclovir, cidofovir or sodium foscarnet, the method comprising orally administering to the patient 400 mg of maribavir or a salt thereof twice daily, wherein maribavir is administered as an oral solid composition, wherein the composition comprises (i) maribavir Form VI having a PSD of d(50) between about 50 and 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. List of implementation plans

[0281] 1. A composition comprising (i) maribavir: or a pharmaceutically acceptable salt thereof; and (ii) and one or more of the following: Compound 2, or a pharmaceutically acceptable salt thereof; Compound 3, or a pharmaceutically acceptable salt thereof; or Compound 4: or a pharmaceutically acceptable salt thereof.

[0282] 2. The composition of embodiment 1, comprising compound 2: or a pharmaceutically acceptable salt thereof.

[0283] 3. The composition of embodiment 2, comprising 0.01-0.10% w / w of Compound 2 relative to maribavir (eg, as measured by HPLC).

[0284] 4. The composition of embodiment 2 or 3, comprising 0.01-0.05% w / w of Compound 2 relative to maribavir (eg, as measured by HPLC).

[0285] 5. The composition of any one of embodiments 2-4, comprising 0.02-0.05% w / w of Compound 2 relative to maribavir (eg, as measured by HPLC).

[0286] 6. The composition of embodiment 2, comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% w / w of Compound 2 relative to maribavir (eg, as measured by HPLC).

[0287] 7. The composition of embodiment 2, comprising 0.01-0.10% a / a of Compound 2 relative to maribavir (eg, as measured by HPLC).

[0288] 8. The composition of embodiment 2 or 7, comprising 0.01-0.5% a / a of Compound 2 relative to maribavir (eg, as measured by HPLC).

[0289] 9. The composition of any one of embodiments 2 or 7-8, comprising 0.02-0.05% a / a of Compound 2 relative to maribavir (eg, as measured by HPLC).

[0290] 10. The composition of embodiment 2, comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% a / a of Compound 2 relative to maribavir (eg, as measured by HPLC).

[0291] 11. The composition of any one of embodiments 1-10, comprising compound 3: or a pharmaceutically acceptable salt thereof.

[0292] 12. The composition of embodiment 11, comprising 0.01-0.10% w / w of Compound 3 relative to maribavir (eg, as measured by HPLC).

[0293] 13. The composition of embodiment 11 or 12, comprising 0.01-0.5% w / w of Compound 3 relative to maribavir (eg, as measured by HPLC).

[0294] 14. The composition of any one of embodiments 11-13, comprising 0.02-0.05% w / w of Compound 3 relative to maribavir (eg, as measured by HPLC).

[0295] 14. The composition of embodiment 11, comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% w / w of Compound 3 relative to maribavir (eg, as measured by HPLC).

[0296] 15. The composition of embodiment 11, comprising 0.01-0.10% a / a of Compound 3 relative to maribavir (eg, as measured by HPLC).

[0297] 16. The composition of embodiment 11 or 15, comprising 0.01-0.5% a / a of Compound 3 relative to maribavir (eg, as measured by HPLC).

[0298] 17. The composition of any one of embodiments 11 or 15-16, comprising 0.02-0.05% a / a of Compound 3 relative to maribavir (eg, as measured by HPLC).

[0299] 18. The composition of embodiment 11, comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% a / a of Compound 3 relative to maribavir (e.g., as measured by HPLC).

[0300] 19. The composition of any one of embodiments 1-18, comprising compound 4: or a pharmaceutically acceptable salt thereof.

[0301] 20. The composition of embodiment 19, comprising 0.01-0.10% w / w of Compound 4 relative to maribavir (eg, as measured by HPLC).

[0302] 21. The composition of embodiment 19 or 20, comprising 0.01-0.5% w / w of Compound 4 relative to maribavir (eg, as measured by HPLC).

[0303] 22. The composition of any one of embodiments 19-21, comprising 0.02-0.05% w / w of Compound 4 relative to maribavir (eg, as measured by HPLC).

[0304] 23. The composition of embodiment 19, comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% w / w of Compound 4 relative to maribavir (eg, as measured by HPLC).

[0305] 24. The composition of embodiment 19, comprising 0.01-0.10% a / a of Compound 4 relative to maribavir (eg, as measured by HPLC).

[0306] 25. The composition of embodiment 19 or 24, comprising 0.01-0.5% a / a of Compound 4 relative to maribavir (eg, as measured by HPLC).

[0307] 26. The composition of any one of embodiments 19 or 24-25, comprising 0.02-0.05% a / a of Compound 4 relative to maribavir (eg, as measured by HPLC).

[0308] 27. The composition of embodiment 19, comprising less than 1%, 0.5%, 0.1%, 0.05%, 0.02% or 0.01% a / a of Compound 3 relative to maribavir (eg, as measured by HPLC).

[0309] 28. The composition of any one of embodiments 1-27, comprising maribavir having a particle size distribution (PSD) between 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).

[0310] 29. The composition of any one of embodiments 1-28, further comprising a pharmaceutically acceptable excipient.

[0311] 30. An oral solid formulation of maribavir, comprising the composition of any one of embodiments 1-29.

[0312] 31. The oral solid dosage form of embodiment 31, wherein the dosage form is a tablet.

[0313] 32. The oral solid dosage form of embodiment 30 or 31, comprising about 200 mg of maribavir.

[0314] 33. The composition of any one of embodiments 1-29 or the oral solid dosage form of any one of embodiments 30-32, wherein maribavir is prepared by the method of any one of embodiments 37-186.

[0315] 34. A method of treating a patient suffering from cytomegalovirus (CMV) infection, comprising administering to the patient the pharmaceutical composition of any one of embodiments 1-29 or the oral solid dosage form of any one of embodiments 30-33.

[0316] 35. The method of embodiment 34, wherein the patient is a transplant recipient.

[0317] 36. The method of embodiment 34 or 35, wherein the patient is refractory to treatment with ganciclovir, valganciclovir, cidofovir or foscarnet.

[0318] 37. A method for preparing maribavir or a pharmaceutically acceptable salt thereof: The method comprises the following steps: (a) Compound 3: or a salt thereof, The reaction is carried out under suitable reaction conditions to provide maribavir or a pharmaceutically acceptable salt thereof.

[0319] 38. A method for preparing the composition of any one of embodiments 1-32, comprising the steps of: (a) Compound 3: or a salt thereof, The reaction is carried out under suitable reaction conditions to provide maribavir or a pharmaceutically acceptable salt thereof.

[0320] 39. The method of embodiment 37 or 38, wherein the reaction conditions include a solvent.

[0321] 40. The method of embodiment 39, wherein the solvent is or comprises methanol.

[0322] 41. The method of embodiment 39, wherein the solvent is or comprises MTBE.

[0323] 42. The method of any one of embodiments 39-41, wherein the solvent comprises methanol and MTBE.

[0324] 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.

[0325] 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.

[0326] 45. The method of any one of embodiments 37-43, wherein the reaction conditions include a base.

[0327] 46. ​​The method of embodiment 45, wherein the base is NaOH.

[0328] 47. The method of embodiment 45 or 46, wherein the base is aqueous NaOH.

[0329] 48. The method of any one of embodiments 37-47, wherein the reaction conditions comprise heating to temperature T1.

[0330] 49. The method of embodiment 48, wherein the temperature T1 is between about 24°C and 45°C.

[0331] 50. The process according to embodiment 48 or 49, wherein the temperature T1 is about 30°C.

[0333] 51. The method of any one of embodiments 37-50, wherein the reaction is allowed to proceed for a period of time.

[0334] 52. The method of embodiment 51, wherein the reaction is stirred for a period of time.

[0335] 53. The method of embodiment 51 or 52, wherein the time period is between about 2.5 and about 4 hours.

[0336] 54. The method of any one of embodiments 37-53, wherein the reaction conditions comprise cooling the reaction mixture to temperature T2.

[0337] 55. The method of embodiment 54, wherein the temperature T2 is about 22°C.

[0338] 56. The method of any one of embodiments 37-55, wherein the reaction is monitored by HPLC for the presence of maribavir in an amount greater than 98.3% a / a.

[0339] 57. The method of any one of embodiments 37-56, further comprising the step (b) phase separating and / or extracting maribavir or a pharmaceutically acceptable salt thereof from the reaction mixture to provide a first resulting mixture.

[0340] 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.

[0341] 59. The method of embodiment 58, wherein the first phase separation solvent is MBTE.

[0342] 60. The method according to any one of embodiments 57 to 59, wherein phase separation and / or extraction comprises adding a second phase separation solvent.

[0343] 61. The method of embodiment 60, wherein the second phase separation solvent is an aqueous sodium chloride solution.

[0344] 62. The method of any one of embodiments 57-61, wherein phase separation and / or extraction comprises adjusting the pH of the reaction mixture to between about 6.0 and about 10.0.

[0345] 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 between about 6.8 and about 7.5.

[0346] 64. The method of any one of embodiments 37-63, further comprising step (c) distilling the reaction mixture or the first resulting mixture and / or exchanging the solvent of the reaction mixture or the first resulting mixture to provide a second resulting mixture comprising maribavir or a pharmaceutically acceptable salt thereof.

[0347] 65. The method of embodiment 64, wherein the reaction mixture or the first resulting mixture comprises a first solvent.

[0348] 66. The method of embodiment 65, wherein the first solvent is TBME.

[0349] 67. The method of any of embodiments 65-67, wherein the first solvent is removed from the reaction mixture or the first resulting mixture.

[0350] 68. The method of embodiment 67, wherein the first solvent is removed by distillation. [0351...

Claims

1. A method for preparing maribavir polymorph Form VI, wherein the method comprises crystallizing maribavir Form VI from a crystallization mixture comprising maribavir or a pharmaceutically acceptable salt thereof and isopropyl acetate.

2. The process according to claim 1, wherein the crystallization mixture comprises less than 0.2% w / w water.

3. The process of claim 2, wherein the crystallization mixture comprises less than 0.09% w / w water.

4. The method of claim 1, wherein the crystalline mixture comprises about 17-20% w / w of maribavir or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein the crystalline mixture comprises about 17-19% w / w of maribavir or a pharmaceutically acceptable salt thereof. The method of claim 1 , wherein seed crystals are added to the crystallization mixture.

7. The method according to claim 6, wherein the seed crystal is maribavir or a pharmaceutically acceptable salt thereof.

8. The method according to any one of claims 1 to 7, comprising: or a salt thereof to provide maribavir or a pharmaceutically acceptable salt thereof, wherein the maribavir seed crystals are added in an amount of about 0.05% to 0.30% w / w relative to Compound 3 or a salt thereof.

9. The method according to claim 8, wherein the seed crystals are added in an amount of about 0.15% w / w relative to Compound 3 or a salt thereof.

10. The method of claim 8, wherein the seed crystals have a size (d(50)) between about 2.25-7.00 μm.

11. The method of claim 8, wherein the seed crystals have a size (d(50)) between about 2.75-6.25 μm.

12. The method of claim 1, wherein crystallizing further comprises heating the crystallization mixture to a temperature T3, wherein the temperature T3 is between about 77°C and about 88°C.

13. The process of claim 1, wherein a secondary solvent is added to the crystallization mixture, wherein the secondary solvent is toluene.

14. The method of claim 8, wherein after adding the seed crystals, the crystallization mixture is aged for about 30 minutes.

15. The method of claim 14, wherein after aging of the crystallization mixture, additional secondary solvent is added to the crystallization mixture at about 11 / 7 (kg / kg) of the total primary solvent.

16. The method of claim 15, wherein after adding the additional secondary solvent, the crystallization mixture is stirred at temperature T3 for about 1 hour, wherein temperature T3 is between about 77°C and about 88°C.

17. The method of claim 16, wherein after stirring at temperature T3, the crystallization mixture is cooled to temperature T4, wherein temperature T4 is between about 3°C ​​and about 7°C, wherein the crystallization mixture cools to temperature T4 over about 3 hours, and wherein the crystallization mixture is stirred at temperature T4 for about 3 hours to about 18 hours.

18. The method of claim 8, further comprising filtering or washing the crystallization mixture to provide a filtered mixture.

19. The process according to claim 18, wherein the crystallization mixture is washed with toluene.

20. The method of claim 18, further comprising drying the filtered mixture.

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