Production Process of PRMT5 Inhibitor

Abstract

The present disclosure provides a process for preparing a compound of chemical formula (VIa-1) and pharmaceutically acceptable salts thereof. Intermediates useful for the preparation of the compound of chemical formula (VIa-1) are also provided. 【Chemical Formula 1】 JPEG2025519695000106.jpg4955

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the priority of U.S. Patent Application No. 63 / 366,335, filed on June 14, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] This disclosure relates to a method for producing a PRMT5 inhibitor.

Background Art

[0003] The compound of Chemical Formula (VIa - 1), or Compound (VIa - 1), (2S,3S,4R,5R)-2 - ((R)-6 - chloro - isochroman - 1 - yl)-5 - (4 - methyl - 7H - pyrrolo[2,3 - d]pyrimidin - 7 - yl)tetrahydrofuran - 3,4 - diol is a PRMT5 inhibitor described in U.S. Patent No. 10,711,007.

Chemical Formula

[0004] There is a need for a process capable of preparing Compound (VIa - 1) and its pharmaceutically acceptable salts in high yield and high stereochemical purity.

Summary of the Invention

[0005] This disclosure provides a method for preparing a compound of Chemical Formula (VIa - 1), its pharmaceutically acceptable salts, and mixtures thereof in high yield and high stereochemical purity.

Chemical Formula

Modes for Carrying Out the Invention

[0006] The present disclosure can be more fully understood by reference to the following description, which includes the following definitions and examples. Specific features of the disclosed processes are described herein in the context of separate aspects, but can also be provided in combination in a single aspect. Alternatively, for the sake of brevity, the various features of the disclosed processes described in the context of a single aspect can also be provided separately or in any sub-combination.

[0007] In the present disclosure, the singular forms “a,” “an,” and “the” include plural references, and a reference to a particular numerical value includes at least that particular value unless the context clearly indicates otherwise. Thus, for example, references to “an organic solvent,” “the organic solvent,” “a suitable organic solvent,” etc. are references to one organic solvent or a mixture of organic solvents. When a range of values is expressed, another embodiment includes from one particular value and / or to another particular value. All ranges are inclusive and combinable.

[0008] The modifier “about” should also be considered to disclose a range defined by the absolute values of the two endpoints. For example, the expression “about 2 to about 4” also discloses the range “2 to 4.” When used to modify a single numerical value, the term “about” refers to plus or minus 10% of the indicated value and includes the indicated value. For example, “about 10 °C” indicates a range of 9 °C to 11 °C, and “about 1” means 0.9 to 1.1.

[0009] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic acid addition salts or organic acid addition salts. Specifically, such salts are formed with inorganic acids such as (1) hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, laurylsulfonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc., including acid addition salts formed with such organic acids.

[0010] The term "heteroaryl", when used alone or as part of a substituent, refers to a monocyclic or bicyclic aromatic ring structure containing carbon atoms and up to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl ring can contain a total of 5, 6, 7, 8, 9, or 10 ring atoms. -C5-C 10The term "heteroaryl" refers to a heteroaryl group containing 5 to 10 ring atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, etc. The heteroaryl groups of the present disclosure may be unsubstituted or substituted. In those embodiments where the heteroaryl group is substituted, the heteroaryl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Additional substituents include -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -OC(O)NH(C1-C6 alkyl), -OC(O)N(C1-C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), and -S(O)2N(C1-C6 alkyl)2.

[0011] The term "aryl", when used alone or as part of a substituent, refers to a monocyclic or bicyclic aromatic carbocyclic structure. The aryl ring can contain a total of 5, 6, 7, 8, 9, or 10 ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, etc. The aryl groups of the present disclosure may be unsubstituted or substituted. In those embodiments where the aryl group is substituted, the aryl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Additional substituents include -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -OC(O)NH(C1-C6 alkyl), -OC(O)N(C1-C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), and -S(O)2N(C1-C6 alkyl)2.

[0012] The term "heterocycloalkyl", when used alone or as part of a substituent, refers to any 3- to 10-membered monocyclic or bicyclic saturated ring structure containing at least one heteroatom selected from the group consisting of O, N, and S. The heterocycloalkyl groups of the present disclosure include monocyclic groups, as well as polycyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one polycyclic heterocycloalkyl group, the cyclic groups can share one common atom (i.e., spiro ring). In other embodiments having at least one polycyclic heterocycloalkyl group, the cyclic groups share two common atoms. The term -C3-C6 heterocycloalkyl refers to a heterocycloalkyl group having 3 to 6 carbon ring atoms. -C3-C 10The term "heterocycloalkyl" refers to a heterocycloalkyl group having 3 to 10 ring atoms. The heterocycloalkyl group can be attached to any heteroatom or carbon atom of the ring such that a stable structure results. Examples of suitable heterocycloalkyl groups include azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, azepanyl, diazepanyl, oxepanyl, dioxepanyl, azocanyl, diazocanyl, oxocanyl, dioxocanyl, azaspiro[2.2]pentanyl, oxazaspiro[3.3]heptanyl, oxaspiro[3.3]heptanyl, dioxaspiro[3.3]heptanyl, and the like, but are not limited thereto. The heterocycloalkyl groups of the present disclosure may be unsubstituted or substituted. In those embodiments where the heterocycloalkyl group is substituted, the heterocycloalkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Additional optional substituents include -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -OC(O)NH(C1-C6 alkyl), -OC(O)N(C1-C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), and -S(O)2N(C1-C6 alkyl)2.

[0013] In some aspects, the present disclosure relates to a process for preparing a compound of formula (II), or a pharmaceutically acceptable salt thereof, by reacting a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the presence of a P(R 2 )3 reagent and an azodicarboxylic acid or azodicarboxamide, in the presence of an organic solvent,

Chemical Formula

[0014] In these embodiments, X 1 is OH or OPG 1 . For example, in some embodiments, X 1 is OH. In some embodiments, X 1 is OPG 1 and PG 1 is a hydroxyl protecting group. As used herein, the term "hydroxyl protecting group" refers to the moiety attached to the oxygen atom of a compound (e.g., -O-PG 2 ), and that moiety (e.g., -PG 2 ) can be removed under controlled conditions to produce a hydroxyl group (i.e., -OH). Hydroxyl protecting groups, methods for introducing protecting groups, and methods for removing protecting groups are known to those skilled in the art and are described, for example, in Wuts, P.G.M., Greene’s Protective Groups in Organic Synthesis, John Wiley & Sons, 5th ed. 2014. Preferred hydroxyl protecting groups include acid-labile protecting groups known in the art. Acid-labile protecting groups suitable for use in the methods of the present disclosure include C 1-6 alkyl. Also, in these embodiments, PG 2 , PG 3 and PG 4 are each independently H or a hydroxyl protecting group. In other embodiments, PG 2 and PG 3Together with the oxygen atoms to which they are attached, they form a 1,2-dihydroxyl protecting group.

[0015] In some embodiments, PG 1 PG 2 PG 3 and PG 4 are each independently a hydroxyl protecting group that is stable to nucleophiles (i.e., not removed during the reaction).

[0016] In some embodiments, PG 1 PG 2 PG 3 and PG 4 are each independently a hydroxyl protecting group that is stable during the reaction with other compounds. Examples of hydroxyl protecting groups that are stable to nucleophiles include alkyl ethers, benzyl ethers, substituted benzyl ethers (e.g., p-methoxybenzyl ether), and silyl ethers (e.g., t-butyldimethylsilyl ether, trimethylsilyl ether).

[0017] In some embodiments, PG 1 PG 2 PG 3 and PG 4 are each independently an alkyl ether such as, for example, methyl ether, methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, substituted benzyloxymethyl ether, t-butoxymethyl ether, siloxymethyl ether, methoxyethoxymethyl ether, tetrahydropyranyl ether, 1-ethoxyethyl ether, t-butyl ether, trimethylsilyl ether, t-butyldimethylsilyl ether, etc.

[0018] In some embodiments, PG 1 PG 2 PG 3 and PG 4 are each independently a methyl ether. In some embodiments, PG 2 or PG 3is a methyl ether. In some embodiments, PG 2 is a methyl ether. In some embodiments, PG 3 is a methyl ether.

[0019] In some embodiments, PG 2 and PG 3 together with the oxygen atom to which they are attached form a 1,2-dihydroxyl protecting group. In some embodiments, PG 2 and PG 3 are each independently a hydroxyl protecting group stable to nucleophiles. In some embodiments, PG 2 and PG 3 together with the oxygen atom to which they are attached form a 1,2-dihydroxyl protecting group stable during reaction with other compounds. Examples of 1,2-dihydroxyl protecting groups stable to nucleophiles include acetals (e.g., methylene acetal, ethylidene acetal, benzylidene acetal, p-methoxybenzylidene acetal, etc.) and ketals (e.g., acetonide, etc.).

[0020] In some embodiments, PG 2 and PG 3 together with the oxygen atom to which they are attached form an acetonide protecting group.

[0021] In some aspects, PG 2 and PG 3 are H or a hydroxyl protecting group, or PG 2 and PG 3 together with the oxygen atom to which they are attached form a 1,2-dihydroxyl protecting group.

[0022] In some embodiments, PG 2 is H. In other embodiments, PG 2 is a hydroxyl protecting group. In some embodiments, PG 2 is a hydroxyl protecting group stable to nucleophiles. In some embodiments, PG2 include methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, substituted benzyloxymethyl ether, t-butoxymethyl ether, siloxymethyl ether, methoxyethoxymethyl ether, tetrahydropyranyl ether, 1-ethoxyethyl ether, t-butyl ether, trimethylsilyl ether, t-butyldimethylsilyl ether, and the like.

[0023] In some embodiments, PG 3 is H. In other embodiments, PG 3 is a hydroxyl protecting group. In some embodiments, PG 3 is a hydroxyl protecting group that is stable to nucleophiles. In some embodiments, PG 3 include methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, substituted benzyloxymethyl ether, t-butoxymethyl ether, siloxymethyl ether, methoxyethoxymethyl ether, tetrahydropyranyl ether, 1-ethoxyethyl ether, t-butyl ether, trimethylsilyl ether, t-butyldimethylsilyl ether, and the like.

[0024] In some embodiments, PG 2 and PG 3 together with the oxygen atom to which they are attached form a 1,2-dihydroxyl protecting group. 1,2-Dihydroxyl protecting groups are known in the art. See, for example, Wuts, P.G.M., Greene’s Protective Groups in Organic Synthesis, John Wiley & Sons, 5th ed. 2014. A suitable 1,2-dihydroxyl protecting group is acetonide.

[0025] In some embodiments, PG 2 and PG 3 together with the oxygen atom to which they are attached form a 1,2-dihydroxyl protecting group that is stable to nucleophiles. In some embodiments, PG 2 and PG3 Together with the oxygen atoms to which they are attached, they form an acetonide protecting group.

[0026] Also, in these embodiments, each R in the P(R 2 )3 reagent is independently C1-C6 alkyl or aryl. In some embodiments, each R in the P(R 2 )3 reagent is independently C1-C6 alkyl. In some embodiments, each R in the P(R 2 )3 reagent is independently aryl. Examples of P(R 2 )3 reagents suitable for use in the methods of the present disclosure include trimethylphosphine, triethylphosphine, tri-n-propyl-phosphine, tri-n-butyl-phosphine, triphenylphosphine, (p-dimethylaminophenyl)diphenylphosphine, and diphenyl-2-pyridylphosphine. In some embodiments, the P(R 2 )3 reagent is trimethylphosphine. In some embodiments, the P(R 2 )3 reagent is triethylphosphine. In some embodiments, the P(R 2 )3 reagent is tri-n-propyl-phosphine. In some embodiments, the P(R 2 )3 reagent is tri-n-butyl-phosphine. In some embodiments, the P(R 2 )3 reagent is triphenylphosphine. In some embodiments, the P(R 2 )3 reagent is (p-dimethylaminophenyl)diphenylphosphine. In some embodiments, the P(R 2 )3 reagent is diphenyl-2-pyridylphosphine.

[0027]

[0028]

[0027] The methods of the present disclosure use azodicarboxylic acid or azodicarboxamide to produce a compound of formula (II). The azodicarboxylic acid is R-C(O)-N=N-C(O)-O-R ’It contains a base, and suitable azodicarboxylic acids are known in the art. Examples of azodicarboxylic acids or azodicarboxamides suitable for use in the described method include diisopropyl azodicarboxylate (DIAD), tetramethyl azodicarboxylate (TMAD), and diethyl azodicarboxylate (DEAD). In some embodiments, the azodicarboxylic acid or azodicarboxamide is DIAD. In some embodiments, the azodicarboxylic acid or azodicarboxamide is TMAD. In some embodiments, the azodicarboxylic acid or azodicarboxamide is DEAD. Mixtures of azodicarboxylic acids and azodicarboxamides can also be used.

[0028] Organic solvents suitable for the preparation of the compound of formula (II) are known in the art. Suitable organic solvents include, for example, halogenated solvents such as dichloromethane, ether solvents such as diethyl ether, t-butyl methyl ether, tetrahydrofuran, and combinations thereof.

[0029] In some embodiments, the compound of formula (I) is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, and the compound of formula (II) is a compound of formula (IIa) or a pharmaceutically acceptable salt thereof:

Chem.

[0030] In some embodiments, the present disclosure relates to a process for preparing a compound of formula (IIa) or a pharmaceutically acceptable salt thereof, the process comprising reacting a compound of formula (Ia) or a pharmaceutically acceptable salt thereof with P(R 2 )3 reagent and an azodicarboxylic acid or azodicarboxamide in the presence of an organic solvent:

Chem.

[0031] In some embodiments, the compound of formula (I) is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, and the compound of formula (II) is a compound of formula (IIb) or a pharmaceutically acceptable salt thereof:

Chem.

[0032] In some aspects, the present disclosure relates to a process for preparing a compound of formula (IIb) or a pharmaceutically acceptable salt thereof, said process comprising reacting a compound of formula (Ib) or a pharmaceutically acceptable salt thereof with P(R 2 )3 reagent and an azodicarboxylic acid in the presence of an organic solvent:

Chem.

[0033] In some embodiments of the process of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia-1) or a pharmaceutically acceptable salt thereof:

Chem.

[0034] In some embodiments of the process of the present disclosure, the compound of formula (Ib) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-1):

Chem.

[0035] In the process of the present disclosure, the azodicarboxylic acid or azodicarboxamide used to react a compound of formula (Ia) (or formula (Ib)) to produce a compound of formula (IIa) (or formula (IIb)) is any azodicarboxylic acid or azodicarboxamide known in the art. Suitable azodicarboxylic acids or azodicarboxamides include those known to be generally useful in Mitsunobu reactions. In some embodiments, the azodicarboxylic acid or azodicarboxamide is DEAD, DIAD, or TMAD, or a mixture thereof. In some of these embodiments, the azodicarboxylic acid or azodicarboxamide is DIAD. In some of these embodiments, the azodicarboxylic acid or azodicarboxamide is TMAD. In some of these embodiments, the azodicarboxylic acid or azodicarboxamide is DEAD.

[0036] In the process of the present disclosure, the P(R 2 )3 reagent used to react a compound of formula (Ia) or formula (Ib) to produce a compound of formula (IIa) or formula (IIb), respectively, is any phosphine known to be useful in organic synthetic chemistry. Suitable phosphines include those known to be generally useful in Mitsunobu reactions. In some embodiments, the phosphine is (R 2 )3P, where R 2 is C1-C6 alkyl, such as trimethylphosphine, triethylphosphine, tri-n-propylphosphine, tri-n-butylphosphine, etc. Tri-n-butylphosphine, (n-Bu)3P, is an example of a phosphine reagent. In other embodiments, the phosphine is (R 2 )3P, where R 2 is, for example, triphenylphosphine, (p-dimethylaminophenyl)diphenylphosphine, diphenyl-2-pyridylphosphine, etc. Triphenylphosphine is an example of a phosphine reagent.

[0037] In the process of the present disclosure, the organic solvent used to react a compound of formula (Ia) or formula (Ib) to produce a compound of formula (IIa) or formula (IIb), respectively, is any organic solvent known to be generally suitable for use in Mitsunobu reactions. In some embodiments, the organic solvent is dichloromethane, chloroform, tetrahydrofuran, dioxane, diisopropyl ether, DMF, acetonitrile, or a mixture thereof. In some embodiments, the organic solvent is dichloromethane. In some embodiments, the organic solvent is tetrahydrofuran. In other embodiments, the organic solvent is a mixture of dichloromethane and tetrahydrofuran.

[0038] In some embodiments, the organic solvent used to react a compound of formula (Ia) or formula (Ib) to produce a compound of formula (IIa) or formula (IIb), respectively, is an aprotic organic solvent. Examples of aprotic organic solvents include perfluorohexane, α,α,α-trifluorotoluene, pentane (Pent), hexane (Hex), cyclohexane (Cy), methylcyclohexane, decalin [c+t], dioxane, carbon tetrachloride, Freon-11, benzene, toluene, triethylamine, carbon disulfide, diisopropyl ether, diethyl ether (ether), t-butyl methyl ether (MTBE), chloroform, ethyl acetate, 1,2-dimethoxyethane (glyme), 2-methoxyethyl ether (diglyme), tetrahydrofuran (THF), methylene chloride, pyridine (Py), 2-butanone (MEK), acetone, hexamethylphosphoramide (HMPA), N-methylpyrrolidone (NMP), nitromethane, dimethylformamide (DMF), acetonitrile, sulfolane, dimethyl sulfoxide (DMSO), propylene carbonate, and mixtures thereof.

[0039] In some embodiments, the aprotic organic solvent is diethyl ether, t-butyl methyl ether, or tetrahydrofuran, or a mixture thereof.

[0040] In some embodiments, the aprotic organic solvent is diethyl ether.

[0041] In other embodiments, the aprotic organic solvent is t-butyl methyl ether.

[0042] In other embodiments, the aprotic organic solvent is tetrahydrofuran.

[0043] In some embodiments of the process of the present disclosure, the preparation of the compound of formula (II), such as the compound of formula (IIa) or (IIb), is carried out in the presence of an additive. As used herein, the term "additive" refers to a compound or mixture of compounds that enhance the yield, rate, or selectivity of the reaction. Additives suitable for use in the methods of the present disclosure are those that are generally known to be useful in Mitsunobu reactions.

[0044] In some embodiments, for the production of the compound of formula (IIa) or the compound of formula (IIb) respectively, the temperature of the reaction mixture in which the compound of formula (Ia) or the compound of formula (Ib) is reacted is between about 0 °C and about 50 °C. In some embodiments, the temperature is ambient temperature. In some embodiments, the temperature is about 25 °C. In other embodiments, the temperature is between about 10 °C and about 25 °C, or between about 20 °C and about 25 °C. In some aspects, the temperature is 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 °C.

[0045] In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt thereof, is the compound of formula (Ia-1), or a pharmaceutically acceptable salt thereof.

Chemical formula

[0046] In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt thereof, is the compound of formula (Ib-1), or a pharmaceutically acceptable salt thereof. [Chemistry]

[0047] In some embodiments, the compound of formula (IIa), or a pharmaceutically acceptable salt thereof, is the compound of formula (IIa-1), or a pharmaceutically acceptable salt thereof. [Chemistry]

[0048] In some embodiments, the compound of formula (IIb), or a pharmaceutically acceptable salt thereof, is the compound of formula (IIb-1), or a pharmaceutically acceptable salt thereof. [Chemistry]

[0049] It will be apparent to those skilled in the art that reacting a compound of formula (I) (e.g., formula (Ia), formula (Ia-1), formula (Ib), formula (Ib-1), or a mixture thereof), or a pharmaceutically acceptable salt thereof, to produce a compound of formula (II) (e.g., formula (IIa), formula (IIa-1), formula (IIb), formula (IIba-1)), or a pharmaceutically acceptable salt thereof, results in the formation of an asymmetric cyclopentyl carbon atom (*). [Chemistry]

[0050] In some embodiments, the enantiomeric excess at the cyclopentyl carbon atom (*) upon formation of the compound of formula (II), or a pharmaceutically acceptable salt thereof, is at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or at least 99.9%. As used herein, the term "enantiomeric excess" refers to the difference obtained by subtracting the amount of one enantiomer at the (*) carbon from the amount of the other enantiomer at the (*) carbon. The enantiomeric excess of a racemic mixture is 0%. The enantiomeric excess of a single enantiomer is 100%. For example, when 99% of enantiomer 1 and 1% of enantiomer 2 are produced by a reaction, the enantiomeric excess is 98%. Methods for determining the enantiomeric excess at the (*) carbon atom are known to those skilled in the art and include, for example, HPLC using a chiral stationary phase.

[0051] The compounds of the present disclosure containing two or more chiral stereocenters can be produced with a diastereomeric excess, i.e., one diastereomer can be produced in greater abundance than the other possible diastereomers. In some embodiments, the compound of formula (II) produced according to the methods disclosed herein is produced with a diastereomeric excess, i.e., a particular diastereomer is produced in greater abundance. In some embodiments, the diastereomeric excess is at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or at least 99.9%. Methods for determining the diastereomeric excess are known to those skilled in the art and include, for example, HPLC using a chiral or achiral stationary phase.

[0052] In some embodiments of the disclosed process, X of formula (I) 1 is OPG, as represented by the compound of formula (III), or a pharmaceutically acceptable salt thereof 1 :

Chemical formula

[0053] In some embodiments, the compound of formula (III) is a compound of formula (IIIa) or a compound of formula (IIIb), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0054] In some embodiments of the process of the present disclosure, the compound of formula (IIIa) or the compound of formula (IIIb), or a pharmaceutically acceptable salt thereof, is a compound of formula (IIIa-1) or a compound of formula (IIIb-1), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0055] In some embodiments of the process of the present disclosure, the compound of formula (IV), or a pharmaceutically acceptable salt thereof, is produced by reacting the compound of formula (III), or a pharmaceutically acceptable salt thereof, with an aqueous acid capable of hydrolyzing a hydroxyl protecting group. Such acids are known to those skilled in the art and depend on the nature of the hydroxyl protecting group (PG), for example, as described in Wuts, P.G.M., Greene’s Protective Groups in Organic Synthesis, John Wiley & Sons, 5th ed. 2014.

Chemical formula

[0056] The aqueous acid of the present disclosure comprises a mixture of water and an acid capable of hydrolyzing a hydroxyl protecting group. Examples of suitable acids include mineral acids such as HCl, H3PO4, H2SO4, and mixtures thereof. In some embodiments, the acid is HCl. In some embodiments, the acid is H3PO4. In some embodiments, the acid is H2SO4. In other embodiments, the acid is an acidic ion exchange resin. Non-limiting examples of such resins include those sold under the trade names Dowex (styrene divinylbenzene (gel) having a sulfonic acid functional group), Amberlite (styrene-divinylbenzene (DVB) gel or macroporous having a sulfonic acid functional group), and Amberlyst (styrene-divinylbenzene (macroporous) having a sulfonic acid functional group). In some embodiments, the aqueous acid is used in the presence of an organic solvent. Non-limiting examples of organic solvents that can be used in this regard include acetonitrile (ACN), THF, DMF, and alcohols such as methanol, ethanol, and isopropanol. In some embodiments, the aqueous acid is a mixture of H2SO4, water, and ACN. In other embodiments, the aqueous acid is a mixture of water, an acidic ion exchange resin, and an optional organic solvent.

[0057] In some embodiments, the compound of formula (IV) is the compound of formula (IVa) or the compound of formula (IVb), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0058] In some embodiments of the process of the present disclosure, the compound of formula (IVa), or a pharmaceutically acceptable salt thereof, is produced by reacting the compound of formula (IIIa), or a pharmaceutically acceptable salt thereof, with an aqueous acid:

Chemical formula

[0059] In some embodiments of the process of the present disclosure, a compound of Chemical Formula (IVa), or a pharmaceutically acceptable salt thereof, is produced by reacting a compound of Chemical Formula (IIIa-1), or a pharmaceutically acceptable salt thereof, with an aqueous acid:

Chemical formula

[0060] In some embodiments of the process of the present disclosure, a compound of Chemical Formula (IV), or a pharmaceutically acceptable salt thereof, is produced by reacting a compound of Chemical Formula (IIIa), or a pharmaceutically acceptable salt thereof, with an aqueous acid:

Chemical formula

[0061] In some embodiments of the method of the present disclosure, a compound of Chemical Formula (IV), or a pharmaceutically acceptable salt thereof, is produced by reacting a compound of Chemical Formula (IIIa-1), or a pharmaceutically acceptable salt thereof, with an aqueous acid:

Chemical formula

[0062] In some embodiments of the method of the present disclosure, a compound of Chemical Formula (IVb), or a pharmaceutically acceptable salt thereof, is produced by reacting a compound of Chemical Formula (IIIb), or a pharmaceutically acceptable salt thereof, with an aqueous acid:

Chemical formula

[0063] In some embodiments of the process of the present disclosure, a compound of Chemical Formula (IVb), or a pharmaceutically acceptable salt thereof, is produced by reacting a compound of Chemical Formula (IIIb-1), or a pharmaceutically acceptable salt thereof, with an aqueous acid:

Chemical formula

[0064] In some embodiments, the reaction to produce the compound of formula (IV) or a pharmaceutically acceptable salt thereof is carried out at a temperature between about 0 °C and about 20 °C, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 °C. In some aspects, the reaction is carried out at a temperature between 0 and 5 °C.

[0065] In some embodiments of the process of the present disclosure, the present disclosure relates to a process for preparing a compound of formula (VI) or a pharmaceutically acceptable salt thereof, said process comprising reacting a compound of formula (IV) or a pharmaceutically acceptable salt thereof with a compound of formula (V) or a pharmaceutically acceptable salt thereof in the presence of a P(R 2 )3 reagent and an azodicarboxylic acid or azodicarboxamide in the presence of an organic solvent,

Chemical formula

[0066] In some aspects, G is halogen, for example F, Cl, Br, or I. The preferred halogen is Cl. In some aspects, G is C1-C6 alkyl, for example methyl, ethyl, propyl, i-propyl, etc. The preferred C1-C6 alkyl is methyl.

[0067] In some aspects, Q is N-H. In some aspects, Q is N-K + is. In some aspects, Q is N-Li + is. In some aspects, Q is N-Na + is. In some aspects, Q is N-Cs + is.

[0068] In some embodiments, the compound of formula (VI) is a compound of formula (VIa) or a compound of formula (VIb), or a pharmaceutically acceptable salt thereof: [Chemical formula] .

[0069] In some embodiments of the process of the present disclosure, the present disclosure relates to a process for preparing a compound of formula (VIa), or a pharmaceutically acceptable salt thereof, the process comprising reacting a compound of formula (IV), or a pharmaceutically acceptable salt thereof, with a compound of formula (V), or a pharmaceutically acceptable salt thereof, in the presence of a P(R 2 )3 reagent, an azodicarboxylate or an azodicarboxamide, in the presence of an organic solvent: [Chemical formula] .

[0070] In some embodiments of the method of the present disclosure, the present disclosure relates to a process for preparing a compound of formula (VIa), or a pharmaceutically acceptable salt thereof, the process comprising reacting a compound of formula (IVa), or a pharmaceutically acceptable salt thereof, with a compound of formula (V), or a pharmaceutically acceptable salt thereof, in the presence of a P(R 2 )3 reagent and an azodicarboxylic acid or an azodicarboxamide, in the presence of an organic solvent: [Chemical formula] .

[0071] In some embodiments of the process of the present disclosure, the present disclosure relates to a process for preparing a compound of formula (VIb), or a pharmaceutically acceptable salt thereof, the process comprising reacting a compound of formula (IVb), or a pharmaceutically acceptable salt thereof, with a compound of formula (V), or a pharmaceutically acceptable salt thereof, in the presence of a P(R 2)Reacting in the presence of a reagent, an azodicarboxylate or an azodicarboxamide and in the presence of an organic solvent:

Chem.

[0072] In some embodiments, the reaction of the compound of formula (IV) and the compound of formula (V) proceeds via an epoxide intermediate having formula IVaa:

Chem.

[0073] In some embodiments, the compound of formula (IVaa) is isolated prior to reaction with the compound of formula (V).

[0074] In some aspects, the process of the present disclosure for preparing a compound of formula (VIa) further comprises converting a compound of formula (IV) to an epoxide of formula (IVaa) by reacting the compound of formula (IV) with a phosphine, an azodicarboxylic acid or an azodicarboxamide in the presence of a suitable organic solvent,

Chem.

[0075] In some embodiments, the organic solvent is an aprotic organic solvent.

[0076] In some embodiments, the process further comprises obtaining a compound of formula (VIa) by reacting a compound of formula (IVaa) with a compound of formula (V) or a basic salt thereof in an organic solvent,

Chem.

[0077] In embodiments where G is -Cl, the compound of formula (V), or a pharmaceutically acceptable salt thereof, is the compound of formula (Va), or a pharmaceutically acceptable salt thereof,

Chemical formula

[0078] In embodiments where Q is N-K + is, the compound (V) is prepared from the compound (V) where Q is N-H by mixing with a suitable base in an organic solvent. Suitable bases can be any base capable of forming an N-K + salt, such as potassium tert-butoxide or potassium hydroxide.

[0079] In embodiments where G is methyl, the compound of formula (V), or a pharmaceutically acceptable salt thereof, is the compound of formula (Vb), or a pharmaceutically acceptable salt thereof,

Chemical formula

[0080] In embodiments where G is -Cl, the compound of formula (VIa), or a pharmaceutically acceptable salt thereof, is the compound of formula (VIa-2), or a pharmaceutically acceptable salt thereof: [Chemistry] 。

[0081] In embodiments where G is methyl, the compound of formula (VIa), or a pharmaceutically acceptable salt thereof, is a compound of formula (VIa-1), or a pharmaceutically acceptable salt thereof: [Chemistry] 。

[0082] In embodiments where G is methyl, the compound of formula (VIa), or a pharmaceutically acceptable salt thereof, is a compound of formula (VIa-3), or a pharmaceutically acceptable salt thereof: [Chemistry] 。

[0083] In embodiments of the disclosed process in which the compound of formula (VIa-1) is isolated as a solid salt (e.g., HCl salt, phosphate, sulfate, oxalate, maleate, etc.), the salt can be converted to the free base of formula (VIa-1) by reacting it with a suitable base in the presence of a suitable solvent. In some embodiments, the free base of formula (VIa-1) is obtained by treating the HCl salt of formula (VIa-3) with an aqueous base, such as aqueous ammonium hydroxide: [Chemistry] 。

[0084] In some embodiments, this conversion is carried out at a temperature of about 10 °C to about 50 °C, such as about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 °C, preferably about 15 °C to about 35 °C.

[0085] In some embodiments, the process of the present disclosure involves reacting a compound of formula (VIa-2), or a pharmaceutically acceptable salt thereof, with a Grignard reagent in the presence of a catalyst to obtain a compound of formula (VIa-1), or a pharmaceutically acceptable salt thereof, as follows:

Chemical formula

[0086] Suitable catalysts are known in the art. In one embodiment, a suitable catalyst is M(acac)3, where M is Fe. Suitable Grignard reagents are known in the art and can include any suitable methyl nucleophile combined with a suitable catalyst. In some embodiments, the Grignard reagent is MeMgBr.

[0087] In embodiments where G is -Cl, the compound of formula (VIb), or a pharmaceutically acceptable salt thereof, is a compound of formula (VIb-2), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0088] In embodiments where G is methyl, the compound of formula (VIb), or a pharmaceutically acceptable salt thereof, is a compound of formula (VIb-1), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0089] In embodiments where G is methyl, the compound of formula (VIb), or a pharmaceutically acceptable salt thereof, is a compound of formula (VIb-3), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0090] In embodiments of the disclosed process in which the compound of formula (VIb-1) is isolated as a solid salt (e.g., HCl salt, phosphate, sulfate, oxalate, maleate, etc.), the salt can be converted to the free base of formula (VIb-1) by reacting it with a suitable base in the presence of a suitable solvent. In some embodiments, the free base of formula (VIb-1) is obtained by treating the HCl salt of formula (VIb-3) with an aqueous base, such as aqueous ammonium hydroxide: [Chemical formula] .

[0091] In some embodiments, the conversion is carried out at a temperature of about 10 °C to about 50 °C, such as about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 °C, preferably about 15 °C to about 35 °C.

[0092] In some embodiments, the process of the present disclosure involves reacting a compound of formula (VIb-2), or a pharmaceutically acceptable salt thereof, with a Grignard reagent in the presence of a metal acetylacetonate to obtain a compound of formula (VIb-1), or a pharmaceutically acceptable salt thereof: [Chemical formula]

[0093] In some embodiments, M is Fe. Suitable Grignard reagents are known in the art. In some embodiments, the Grignard reagent is MeMgBr.

[0094] In some embodiments, the process of the present disclosure further comprises contacting a compound of formula (VIa-1) with an acid to form a pharmaceutically acceptable salt of the compound of formula (VIa-1). In some embodiments, the pharmaceutically acceptable salt of the compound of formula (VIa-1) is a hydrochloride salt, a phosphate salt, a sulfate salt, an oxalate salt, a tartrate salt, or a maleate salt. The pharmaceutically acceptable salt can be prepared by treating the compound of formula (VIa-1) with an appropriate acid in the presence of an appropriate solvent.

[0095] In some embodiments, the process of the present disclosure further comprises reacting a compound of formula (VIa-1) with hydrochloric acid in a solvent to produce a pharmaceutically acceptable salt of the compound of formula (VIa-1) which is a compound of formula (VIa-3):

Chemical formula

[0096] In some embodiments, the process of the present disclosure further comprises reacting a compound of formula (VIb-1) with an acid to form a pharmaceutically acceptable salt of the compound of formula (VIb-1). In some embodiments, the pharmaceutically acceptable salt of the compound of formula (VIb-1) is a hydrochloride salt, a phosphate salt, a sulfate salt, an oxalate salt, a tartrate salt, or a maleate salt. The pharmaceutically acceptable salt can be prepared by treating the compound of formula (VIb-1) with an appropriate acid in the presence of an appropriate solvent.

[0097] In some embodiments, the process of the present disclosure further comprises contacting a compound of formula (VIb-1) with hydrochloric acid in a solvent to produce a pharmaceutically acceptable salt of the compound of formula (VIb-1) which is a compound of formula (VIb-3):

Chemical formula

[0098] In some embodiments, the solvent used to convert the compound of (VIa-1) or (VIb-1) into the compound of (VIa-3) or (VIb-3) respectively is an alcohol such as methanol, ethanol, isopropanol, and mixtures thereof. In some embodiments, the solvent is ethanol. In some embodiments, the conversion is carried out at a temperature of about 0 °C to about 75 °C, for example, 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 °C, preferably at a temperature between about 35 and 50 °C.

[0099] In some embodiments, the present disclosure relates to a process for preparing a compound of formula (VIa-1), formula (VIa-2), formula (VIa-3), formula (VIb-1), formula (VIb-2) or (VIb-3), or a pharmaceutically acceptable salt thereof, and this process includes any process disclosed herein.

[0100] In some aspects, the process of the present disclosure provides a compound of formula (VIa-1), or a pharmaceutically acceptable salt thereof, such as a compound of (VIa-3), or a compound of (VIa-2), with high stereoisomeric purity. That is, the compound of formula (VIa-1), or a pharmaceutically acceptable salt thereof, such as a compound of (VIa-3), or a compound of (VIa-2), is obtained mainly as a stereoisomer having the absolute configuration shown below:

Chemical formula

[0101] In some embodiments, the diastereomeric excess of the compound of chemical formula (VIa-1) or a pharmaceutically acceptable salt thereof, such as the compound of (VIa-3), or the compound of (VIa-2) is at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or at least 99.9%. In some embodiments, the enantiomeric excess of the compound of chemical formula (VIa-1) or a pharmaceutically acceptable salt thereof, such as the compound of (VIa-3), or the compound of (VIa-2) is at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or at least 99.9%. Methods for determining diastereomeric excess and enantiomeric excess are known to those skilled in the art and include, for example, HPLC methods known in the art and described herein.

[0102] In some aspects, the process of the present disclosure provides a compound of chemical formula (VIb), or a pharmaceutically acceptable salt thereof, such as the compound of (VIb-1) or (VIb-3), or the compound of (VIb-2), with high stereoisomeric purity. That is, the compound of chemical formula (VIb-1), or a pharmaceutically acceptable salt thereof, such as the compound of (VIb-3), or the compound of (VIb-2), or a pharmaceutically acceptable salt thereof, is obtained mainly as a stereoisomer having the absolute configuration shown below:

Chemical formula

[0103] In some embodiments, the diastereomeric excess in a compound of Chemical Formula (VIb-1) or a pharmaceutically acceptable salt thereof, such as a compound of (VIb-3) or a compound of (VIb-2), is at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or at least 99.9%. In some embodiments, the enantiomeric excess in a compound of Chemical Formula (VIb-1) or a pharmaceutically acceptable salt thereof, such as a compound of (VIb-3) or a compound of (VIb-2), is at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or at least 99.9%. Methods for determining diastereomeric excess and enantiomeric excess are known to those skilled in the art and include, for example, HPLC methods as described in the art and herein.

[0104] In some embodiments, the process of the present disclosure includes the following steps for generating a compound of Chemical Formula (VIa), such as a compound of Chemical Formula (VIa-1), or a compound of Chemical Formula (VIa-2), or a compound of Chemical Formula (VIa-3).

[0105] Chemical Formula (XXI ’ ) or a pharmaceutically acceptable salt thereof is reacted with an appropriate Grignard reagent to produce a compound of Chemical Formula (XXI) or a pharmaceutically acceptable salt thereof,

Chemical Formula

[0106] In certain embodiments, PG ’ of the compounds of Chemical Formula (XXI) and Chemical Formula (XXI 4 is a hydroxyl protecting group. In certain embodiments, PG ’ of the compounds of Chemical Formula (XXI) and Chemical Formula (XXI 4is tetrahydropyran (THP). In certain embodiments, the "C 1-6 alkylMgCl" C 1-6 alkyl is methyl or ethyl.

[0107] In certain embodiments, the compound of formula (XXI) is compound 10 shown below:

Chem.

[0108] In certain embodiments, the compound of formula (XXI ’ ) is compound 10 shown below ’ :

Chem.

[0109] To produce a compound of formula (XXIII), or a pharmaceutically acceptable salt thereof, a compound of formula (XXI ’ ), or a pharmaceutically acceptable salt thereof, is reacted with a compound of formula (XXII) (or its corresponding aldehyde or its adduct), or a pharmaceutically acceptable salt thereof,

Chem.

[0110] In certain embodiments, PG ’ , PG 1 , PG 2 , and PG 3 of the compounds of formula (XXI) and formula (XXI 4 are each independently a hydroxyl protecting group, or PG 2 and PG 3Together with the oxygen atoms to which they are attached, they form a 1,2-dihydroxyl protecting group. In certain embodiments, the PG of the compounds of Formula (XXI) and Formula (XXIII) 4 is tetrahydropyran (THP).

[0111] In certain embodiments, the compound of Formula (XXIII) is represented by the compound of Formula (Ia) or the compound of Formula (Ia-1).

[0112] In certain embodiments, the compound of Formula (XXII) is Compound 20 shown below:

Chemical formula

[0113] In certain embodiments, the compound of Formula (XXIII) is Compound 30 shown below:

Chemical formula

[0114] To produce a compound of Formula (XXIII ’ ), or a pharmaceutically acceptable salt thereof, react a compound of Formula (XXIII), or a pharmaceutically acceptable salt thereof, with an alcohol,

Chemical formula

[0115] In certain embodiments, the PG of the compound of Formula (XXIII) 1 , PG 2 , PG 3 and PG 4 , and the PG of the compound of Formula (XXIII ’ ) 1 , PG 2 and PG3 is, independently of each other, a hydroxyl protecting group, or PG 2 and PG 3 together with the oxygen atom to which they are attached form a 1,2-dihydroxyl protecting group. In certain embodiments, PG of the compound of formula (XXIII) 4 is tetrahydropyran (THP).

[0116] In certain embodiments, the compound of formula (XXIII ’ ) is represented by the compound of formula (Ia) or the compound of formula (Ia-1).

[0117] In certain embodiments, the compound of formula (XXIII ’ ) is compound 40 shown below:

Chemical formula

[0118] To produce a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, a compound of formula (XXIII ’ ), or a pharmaceutically acceptable salt thereof, is reacted with P(R 2 )3 reagent and azodicarboxylic acid,

Chemical formula

[0119] In certain embodiments, PG of the compounds of formula (XXIII ’ ) and formula (XXV) 1 , PG 2 , and PG 3 are, independently of each other, a hydroxyl protecting group, or PG 2 and PG 3 together with the oxygen atom to which they are attached form a 1,2-dihydroxyl protecting group.

[0120] In certain embodiments, the compound of formula (XXV) is represented by the compound of formula (IIa) or the compound of formula (IIIa) or the compound of formula (IVa).

[0121] In certain embodiments, the compound of formula (XXV) is compound 50 shown below:

Chem.

[0122] The compound of formula (XXV ’ ) or a pharmaceutically acceptable salt thereof is reacted with an acid to produce the compound of formula (XXV) or a pharmaceutically acceptable salt thereof,

Chem.

[0123] In certain embodiments, PG 1 , PG 2 , and PG 3 of the compound of formula (XXV) are each independently a hydroxyl protecting group, or PG 2 and PG 3 together with the oxygen atom to which they are attached form a 1,2-dihydroxyl protecting group.

[0124] In certain embodiments, the compound of formula (XXV ’ ) is represented by the compound of formula (IVa) or the compound of formula (IVb). In certain embodiments, the compound of formula (XXV ’ ) is compound 60 shown below:

Chem.

[0125] To produce a compound of formula (VIa-1) or a pharmaceutically acceptable salt thereof, react a compound of formula (XXV ’ ) or a pharmaceutically acceptable salt thereof with compound (Vb),

Chem.

[0126] In certain embodiments, Q of the compound of formula (Vb) is N - K + is. In certain embodiments, the compound of formula (Vb) is Compound 70 shown below:

Chem.

[0127] To produce a compound of formula (VIa-3) or a pharmaceutically acceptable salt thereof, react a compound of formula (VIa-1) or a pharmaceutically acceptable salt thereof with hydrochloric acid:

Chem.

[0128] The following examples are provided to illustrate, but not limit, aspects of the present invention.

Example

[0129] Example 1 - Synthesis of Compounds (VIa-1) and (VIa-3) A Synthesis Scheme

Chem.

[0130] (1H-Benzotriazol-1-yl)((3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (Compound 20) synthesis.

[0131] To a solution of crude (3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde (1.3 g, 6.4 mmol, 1 equiv) in MTBE (3 mL, 2.3 mL / g) was added benzotriazole (0.75 g, 6.3 mmol, 0.95 equiv), and the resulting solution was stirred overnight at ambient temperature to obtain a dilute white suspension. Heptane (9 mL, 3 v / v) was added dropwise, and the suspension was stirred for 1 h at ambient temperature to precipitate additional material, after which the solid was isolated by filtration. The filter cake was washed with heptane (3 × 1 CV), and the solid was dried at 50 °C under atmospheric pressure to obtain (1H-Benzotriazol-1-yl)((3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (Compound 20, 1.4 g, 70%) as a white solid.

[0132] (4-Chloro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)magnesium bromide (Compound 10 ’ ) synthesis.

[0133] In a 2 L four-necked flask dried in an oven equipped with an overhead stirrer, a thermocouple, and an addition funnel, Mg turnings (9.98 g, 411 mmol, 1.05 equiv) were suspended in dry 2-MeTHF (190 mL, 1.5 mL / g) under N2, and the suspension was warmed to 50 °C. iPrMgCl (9.8 mL, 19.6 mmol, 0.05 equiv, 2 M in THF) was added via syringe, followed by 40 mL (ca. 10 vol%) of a solution of 2-(2-bromo-5-chlorophenethoxy)tetrahydro-2H-pyran (Compound 10, 125 g, 391 mmol, 1 equiv) in dry 2-MeTHF (200 mL, 1.6 mL / g, total ca. 400 mL) to initiate Grignard formation. After stirring for 10 min, exotherm (e.g., 50 - 56 °C) was observed, indicating the start of the reaction. The remaining Compound 10 was added dropwise at a rate sufficient to keep the internal temperature below 75 °C. (Note: External heating was stopped as soon as the batch temperature reached 65 °C.) After the addition was complete, the batch was stirred at 50 °C for 1 h. HPLC assay of an aliquot quenched with MeOH demonstrated that all of Compound 10 had been consumed.

[0134] Synthesis of (1R)-(4-chloro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (Compound 30).

[0135] 1 ’ (1H-Benzotriazol-1-yl)((3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (Compound 20, 50 g, 156 mmol, 1 equiv) in 2-MeTHF (500 mL, 10 mL / g) containing (391 mmol, 2.5 equiv, usually 0.83 - 0.86 M) was added dropwise at ambient temperature under N2 to a four-necked flask. (Note: During the addition, it is recommended to use a water bath at ambient temperature as a heat sink.) The product diastereomers and quenched 1 ’The reaction was monitored by HPLC assay of an aliquot quenched with MeOH until a constant ratio of was observed (approximately 2.5 hours, showing a dr of approximately 4:1). The batch was quenched with 10 wt% aqueous citric acid (1×500 mL, 0.5 v / v) and the layers were separated. The organic phase was washed with 4 M aqueous NaOH (1×500 mL, 0.5 v / v) and then concentrated under reduced pressure to give a clear orange-yellow oil that was used directly without further purification.

[0136] Synthesis of 2-(5-chloro-2-((R)-hydroxy((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3)dioxol-4-yl)methyl)phenyl)ethan-1-ol (Compound 40).

[0137] The residue containing crude compound 30 (approximately 150 g) was dissolved in MeOH (375 mL, 2.5 mL / g) and pTsOH HO (3.86 g, 20.3 mmol, 1 ’ The mixture was diluted with 1M aqueous NaOH (375 mL, 1 v / v) and extracted with MTBE (3×250 mL, 0.67 v / v). The combined organic layers were concentrated under reduced pressure followed by azeotropic drying with 2-MeTHF (3× vol) to give crude compound 40 as a clear orange-yellow syrup which was used directly without further purification.

[0138] Synthesis of (R)-6-chloro-1-((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)isochroman (compound 50).

[0139] To a solution of crude compound 40 (ca. 130 g, 156 mmol, 1 equiv) in 2-MeTHF (910 mL, 7 mL / g) in a 2 L three-necked flask equipped with an overhead stirrer and a thermocouple, pyridine (12.6 mL, 12.33 g, 156 mmol, 1.0 equiv), TMAD (67.2 g, 390 mmol, 2.5 equiv), and Bu3P (63.1 g, 312 mmol, 2.0 equiv) were added under N2. The resulting dilute slurry was stirred at ambient temperature for 16 h, at which point HPLC assay demonstrated that the reaction was complete. The batch was quenched with 1 M aqueous HCl (900 mL, 1 v / v) and stirred for 1 h. The layers were separated and the aqueous phase was extracted with 2-MeTHF (1×500 mL, 0.5 v / v). The combined organic layers were concentrated under reduced pressure to afford 207 g of an orange oil. The crude product was filtered through a silica gel pad (621 g, 3 g / g) and eluted with heptane (1×1 CV), 5% MTBE in heptane (1×1 CV), and then 10% MTBE in heptane (1×1 CV), and the filtrate was concentrated under reduced pressure to afford 73 g of a pale yellow oil. This residue was diluted with 9:1 MeOH / H2O (146 mL, 2 mL / g) at ambient temperature for 2 h and then cooled in an ice bath for 4 h. The solid was isolated by filtration, washed with 3:2 MeOH / H2O (2x150 mL), and dried at 50 °C under atmospheric pressure to give compound 50 (34.16 g, 64% yield, 92% purity, 21:1 dr) as a white crystalline solid.

[0140] Synthesis of (3R,4S,5S)-5-((R)-6-chloroisochroman-1-yl)tetrahydrofuran-2,3,4-triol (Compound 60).

[0141] A solution of compound 50 (3.4 g, 10 mmol, 1 equiv) and 1 M aqueous H2SO4 (10 mL, 10 mmol, 1.0 equiv) in THF (40 mL, 4 v / v) was stirred at 70 °C for 20 h. The reaction was monitored by HPLC assay and LC-MS assay and when it was deemed complete, it was basified to pH 8 with solid NaHCO3 (1.7 g, 20 mmol) and the layers were separated. The aqueous phase was extracted with 2-MeTHF (2 × 20 mL, 2 v / v). The combined organic layers were concentrated under reduced pressure and subsequently co-evaporated with MeCN (3 × volume) to afford crude compound 60 as a clear syrup. This residue was diluted with 9:1 heptane / EA (40 mL) at ambient temperature and stirred overnight. The solid was isolated by filtration, washed with 9:1 heptane / EA (2 × 20 mL) and dried at 50 °C under atmospheric pressure to give compound 60 (2.1 g, 75%, purity 92%) as a white solid. LC-MS C 13 H 15 ClO5[M-H] - Calculated: m / z = 285.06 / 287.06, Found: 285.06 / 287.10.

[0142] Synthesis of potassium 4-methylpyrrolo[2,3-d]pyrimidin-7-ide (Compound 70).

[0143] To a dried-in-oven 100 mL round-bottom flask was added 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.33 g, 10 mmol, 1 equiv) and THF (20 mL, 15 mL / g), and KOtBu (1.12 g, 10 mmol, 1.0 equiv) was added portionwise under N2. The reaction mixture was stirred at ambient temperature for 2 h and then the volatiles were removed under reduced pressure. The residue was slurried with MTBE (20 mL, 15 mL / g) overnight and then the solid was isolated by filtration, washed with MTBE (2 × 10 mL) and the solid was dried at 50 °C under atmospheric pressure to give compound 70 (1.6 g, 94%) as an off-white solid.

[0144] (2S,3S,4R,5R)-2-((R)-6-Chloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (Compound VIa-1) synthesis.

[0145] Into an oven-dried 100 mL round-bottom flask, a solution of Compound 60 (715 mg, 2.5 mmol, 1 equiv) in MeCN (25 ml, 35 mL / g) was placed, and TMAD (646 mg, 3.75 mmol, 1.5 equiv) and Bu3P (1.2 mL, 5 mmol, 2.0 equiv) were sequentially added at ambient temperature under N2. After stirring for 0.5 h, a solution of 7 (855 mg, 5.0 mmol, 2.0 equiv) in anhydrous DMF (3 mL, 3.5 mL / g) was added dropwise, and the resulting dilute slurry was stirred at ambient temperature overnight. The reaction was monitored by HPLC assay, and when it was deemed complete, water (30 ml, 1 v / v) was slowly added to quench, diluted with EtOAc (30 mL, 0.5 v / v), and the layers were separated. The organic phase was washed with brine (1 × 20 mL, 0.67 v / v) and dried over Na2SO4. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a brown oil containing crude Compound VIa-1, which was used directly without further purification. LC-MS C 20 H 20 ClN3O4[M+H] + Calculated: m / z = 402.11 / 404.11, Found: 401.96 / 403.88.

[0146] (2S,3S,4R,5R)-2-((R)-6-Chloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol hydrochloride (Compound VIa-3) synthesis.

[0147] To an oven-dried 100 mL round-bottom flask containing a solution of crude compound VIa-1 (3 g) in MeOH (10 mL, 3.3 mL / g), 37 wt% aqueous HCl solution (1 mL, 0.1 v / v) was added dropwise. After stirring at ambient temperature for 20 minutes, MTBE (40 mL, 3.6 v / v) was added to precipitate the salt. The resulting slurry was cooled with stirring in an ice bath for 1 hour. The solid was isolated by filtration, and the wet cake was washed with MTBE (3×1 CV) and dried in vacuo at 35 °C to obtain compound VIa-3 as a white solid.

[0148] Example 2 - Synthesis B of Compound (VIa-3) Synthesis Scheme

Chemical Structure

[0149] In the step of converting compound 60 to compound VIa-3, NMP may be used as a solvent instead of MTBE.

Chemical Structure

[0150] Preparation of Grignard Reagent Under nitrogen, a solution of 2-(2-bromo-5-chlorophenethoxy)tetrahydro-2H-pyran (Compound 10, 360.5 g, 1.13 mol) in tetrahydrofuran (THF, 3.6 L) was added to a clean 100 L reactor charged with Mg turnings (576.8 g, 23.80 mol) at 15 - 25 °C. Iodine (4.58 g, 0.036 mol) was added to the reactor. The resulting mixture was stirred at 30 - 60 °C [Note: The internal temperature rose to 42 °C upon addition of iodine. Compound 10 ’The start of the formation was confirmed by observing the color change from pale yellow to green. The start was also indicated by HPLC. A solution of 2-(2-bromo-5-chlorophenethoxy)tetrahydro-2H-pyran (Compound 10, 6343 g, 19.84 mol) in 2-methyl-tetrahydrofuran (2-MeTHF, 11.6 L) was charged into a 100 L reactor while maintaining the internal temperature at 20 - 40 °C. The mixture was stirred at 20 - 40 °C for 2 hours or more and then cooled to 0 - 10 °C.

[0151] Grignard addition to the aldehyde adduct A solution of (S)-(1H-benzo[d][1,2,3]triazol-1-yl)((3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (Compound 20, 2900 g, 9.02 mol) in 2-MeTHF (11.6 L) was charged into a 100 L reactor with the generated Grignard reagent at a rate that maintained the batch temperature at 0 - 20 °C. Subsequently, the resulting mixture was warmed to 20 - 30 °C and stirred at that temperature for at least 4 hours. After 12 hours, the reaction mixture was cooled to 0 - 10 °C. A solution of ammonium chloride (NH4Cl, 2896 g, 54.14 mol) in water (16.5 L) was added to the reaction mixture while maintaining the internal temperature below 30 °C. After phase separation, the aqueous phase was extracted with 2-MeTHF (11.6 L). The combined organic phases were first washed with a solution of 75 wt% sodium hydroxide (NaOH, 776 g, 19.40 mol) in water (18.6 L), followed by a second wash with the remaining aqueous NaOH solution. Subsequently, the resulting organic phase was washed with a solution of sodium chloride (NaCl, 580 g, 9.92 mol) in water (5.2 L). The organic phase was recovered and distilled to a minimum stirring volume to obtain crude (1R)-(4-chloro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)-((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (crude Compound 30) (6438 g, 14.54 mol, yield 162%, theoretical yield 3997 g) as a brown liquid, which was used directly in the next reaction without further purification. A small amount of crude Compound 30 was purified by column chromatography as a colorless oil.

[0152] 11H NMR (400 Hz, DMSO-d6): δ 7.41 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 8.4, 2.4 Hz, 1H), 5.48 (d, J = 6.0 Hz, 1H), 4.98 (d, J = 6.1 Hz, 1H), 4.80 (s, 1H), 4.64 (d, J = 6.0 Hz, 1H), 4.64 - 4.54 (m, 2H), 4.35 (d, J = 9.3 Hz, 1H), 3.88 - 3.74 (m, 1H), 3.68 (ddd, J = 11.2, 8.3, 5.6 Hz, 1H), 3.58 (tdd, J = 10.0, 7.9, 6.3 Hz, 1H), 3.40 (dt, J = 10.0, 4.4 Hz, 1H), 3.32 (s, 3H), 3.00 (dt, J = 14.1, 7.0 Hz, 1H), 2.93 - 2.85 (m, 1H), 1.79 - 1.66 (m, 1H), 1.61 (tq, J = 8.6, 2.7 Hz, 1H), 1.54 - 1.42 (m, 4H), 1.40 (s, 3H), 1.29 (s, 3H) ppm; 13 13C NMR (100 Hz, DMSO-d6): δ 140.39, 140.36, 139.45, 131.95, 129.84, 126.35, 118.83, 109.68, 98.49, 88.63, 85.06, 82.40, 69.02, 67.31, 61.83, 55.32, 32.10, 30.68, 26.77, 25.49, 25.17, 19.62 ppm. [Chemical formula]

[0153] Into a clean 100 L reactor under nitrogen, crude compound 30 (6438 g, 14.54 mol, the theoretical yield in Step 1 is 3997 g, 9.02 mol in compound 3) was added to methanol (MeOH, 16.0 L) and acetone (26.0 L) at 15 - 25 °C. To this solution, 2,2 - dimethoxypropane (1409.7 g, 13.53 mol) and p - toluenesulfonic acid monohydrate (p - TSA·H2O, 512 g, 2.69 mol) were sequentially added at 15 - 30 °C. The reaction mixture was stirred at 15 - 30 °C for 1 hour or more. After the completion of the reaction was indicated by HPLC (criterion: 3% or less of compound 30 vs compound 40), while maintaining the internal temperature at 30 °C or below, a solution of sodium bicarbonate (NaHCO3, 600 g, 7.14 mol) in water (11.2 L) was added to the reaction mixture. The mixture was distilled under vacuum to about 24 L (about 6 vol) at 50 °C or below. Dichloromethane (DCM, 12.0 L) was added to the resulting mixture. The organic phase was separated, washed with water (12.0 L), and distilled to a minimum stirring volume to obtain crude 2 - (5 - chloro - 2 - ((R) - hydroxy((3aR,4R,6R,6aR) - 6 - methoxy - 2,2 - dimethyltetrahydrofuro[3,4 - d][1,3]dioxol - 4 - yl)methyl)phenyl)ethan - 1 - ol (crude compound 40) (5576 g, 15.54 mol, yield 172%, theoretical yield 3237.9 g, 9.02 mol) as a brown liquid, which was used directly in the next reaction without further purification. A small amount of crude compound 40 was purified by column chromatography to obtain compound 40 as a colorless oil.

[0154] 11H NMR (400 Hz, DMSO-d6): δ 7.44 (d, J = 8.8 Hz, 1H), 7.29 - 7.22 (m, 2H), 5.44 (d, J = 6.0 Hz, 1H), 4.98 (dd, J = 6.0, 0.9 Hz, 1H), 4.80 (s, 1H), 4.77 (t, J = 5.0 Hz, 1H), 4.63 (d, J = 6.0 Hz, 1H), 4.57 (dd, J = 9.6, 6.0 Hz, 1H), 4.35 (dd, J = 9.5, 0.9 Hz, 1H), 3.61 (dt, J = 11.7, 7.0 Hz, 2H), 3.32 (s, 3H), 2.93 - 2.86 (m, 1H), 2.77 (dt, J = 13.9, 7.1 Hz, 1H), 1.40 (s, 3H), 1.29 (s, 3H) ppm; 13 13C NMR (100 Hz, DMSO-d6): δ 141.02, 139.45, 131.91, 129.88, 129.68, 126.19, 111.83, 109.61, 88.52, 85.08, 82.46, 68.69, 61.87, 35.40, 26.78, 25.18 ppm。

Chem.

[0155] Into a clean 100 L reactor under nitrogen, crude compound 40 (5576 g, 15.54 mol, theoretical yield 3237.9 g, 9.02 mol) was placed in methyl tert-butyl ether (MTBE, 32.4 L) at 15 - 30 °C. To this solution, tetramethylazodicarboxamide (TMAD, 1927 g, 11.19 mol) was added at 15 - 30 °C. The mixture was stirred at that temperature for 1 hour and then cooled to 0 - 10 °C. While maintaining the internal temperature below 15 °C, tri-n-butylphosphine (P(n-Bu)3, 2614.7 g, 12.92 mol) was added to the solution. The resulting reaction mixture was warmed to 15 - 30 °C and stirred in that temperature range for over 1 hour. After completion of the reaction was indicated by HPLC (criterion: 3% or less of compound 40 vs compound 50), while maintaining the batch temperature below 30 °C, a solution of NaCl (2590 g, 44.32 mol) in water (23.3 L) was added. The organic phase was separated and distilled under reduced pressure to 50 °C or below to a minimum stirring volume. To the resulting residue, MeOH (12.6 L) was added, followed by slow addition of water (7.1 L). The mixture was stirred at 15 - 30 °C for 12 hours and then cooled to 0 - 10 °C. After stirring at 0 - 10 °C for 2 hours, the solid was recovered by filtration and subsequently washed with a mixed solvent of MeOH (3.2 L) and water (3.2 L). The wet cake was dried on the filter for 22 hours to obtain (R)-6-chloro-1-((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)isochroman (compound 50, 1826 g, 5.36 mol, 59.4% yield over 3 steps) as a white solid.

[0156] 11H NMR (400 Hz, DMSO-d6): δ 7.63 - 7.51 (m, 1H), 7.28 - 7.25 (m, 2H), 5.06 (s, 1H), 4.94 (dd, J = 6.1, 1.5 Hz, 1H), 4.61 (d, J = 6.0 Hz, 1H), 4.56 - 4.46 (m, 1H), 4.17 (dd, J = 8.3, 1.6 Hz, 1H), 4.07 (ddd, J = 11.2, 5.6, 3.6 Hz, 1H), 3.68 (ddd, J = 11.2, 9.5, 4.0 Hz, 1H), 3.36 (s, 3H), 2.90 (ddd, J = 15.7, 9.4, 5.7 Hz, 1H), 2.72 (dt, J = 16.7, 3.9 Hz, 1H), 1.38 (s, 3H), 1.26 (s, 3H) ppm; 13 13C NMR (100 Hz, DMSO-d6): δ 137.18, 135.18, 128.81, 128.28, 126.33, 112.11, 109.99, 89.48, 84.58, 81.31, 74.78, 63.05, 55.66, 28.68, 26.98, 25.35 ppm。

Chem.

[0157] Compound 50 (3037 g, 8.91 mol) was placed in 1,4-dioxane (9.1 L) at 15 - 25 °C in a clean reactor under nitrogen. To this solution was added a solution of sulfuric acid (H2SO4, 305.5 g, 3.12 mol) in water (30.4 L). The reaction mixture was heated to 60 - 70 °C and stirred at that temperature for at least 14 hours. After completion of the reaction was indicated by HPLC, the batch was cooled to 20 - 40 °C. Ethyl acetate (EtOAc, 36.4 L) was charged to the reaction mixture, followed by solid NaHCO3 (916.9 g, 10.92 mol) added portionwise while adjusting the pH to 8 - 9 while keeping the internal temperature below 40 °C. NaCl (4560 g, 77.95 mol) was added to the mixture, and the resulting organic phase was separated and concentrated to a minimum stirring volume. Subsequently, toluene (20.0 L) and MTBE (9.1 L) were added to the distillation residue. The resulting mixture was stirred at 15 - 30 °C for 1 hour, after which n-heptane (2.7 L) was added. The suspension was stirred at 15 - 30 °C for 2 hours. An additional amount of n-heptane (6.4 L) was added and the mixture was stirred at 15 - 30 °C for a further 2 hours. The resulting solid was collected by filtration and the wet cake was washed with a mixed solvent of toluene (3.0 L) and n-heptane (6.1 L). The filter cake was transferred to a tray and dried in an oven under vacuum at 35 °C or below to obtain (3R,4S,5S)-5-((R)-6-chloroisochroman-1-yl)tetrahydrofuran-2,3,4-triol (Compound 60, 2302 g, 8.03 mol, 90.1% yield) as an off-white solid. Compound 60 was isolated from a mixture of isomers (approx. 1:1).

[0158] 11H NMR (400 Hz, DMSO-d6): δ 7.46 (d, J = 8.2 Hz, 0.5H), 7.33 (d, J = 8.2 Hz, 0.5H), 7.25 - 7.19 (m, 2H), 6.33 (d, J = 5.6 Hz, 0.5H), 5.80 (d, J = 7.0 Hz, 0.5H), 5.12 (dd, J = 7.0, 4.3 Hz, 0.5H), 5.01 (dd, J = 5.6, 2.9 Hz, 0.5H), 4.83 (d, J = 5.3 Hz, 0.5H), 4.69 (d, J = 4.0 Hz, 0.5H), 4.61 (d, J = 6.2 Hz, 0.5H), 4.60 (d, J = 5.6 Hz, 0.5H), 4.57 (d, J = 5.8 Hz, 0.5H), 4.44 (d, J = 8.1 Hz, 0.5H), 4.32 (d, J = 2.8 Hz, 0.5H), 4.31 (d, J = 2.8 Hz, 0.5H), 4.13 - 4.00 (m, 1.5H), 3.94 (dd, J = 6.5, 4.4 Hz, 0.5H), 3.85 (ddd, J = 8.1, 6.0, 4.3 Hz, 0.5H), 3.76 (td, J = 5.9, 2.8 Hz, 0.5H), 3.72 - 3.66 (m, 0.5H), 3.60 (td, J = 10.8, 3.5 Hz, 0.5H), 2.92 - 2.80 (m, 1H), 2.78 - 2.61 (m, 1H) ppm; 13 13C NMR (100 Hz, DMSO-d6): δ (set 1) 137.00, 135.14, 131.40, 128.98, 128.55, 125.91, 102.11, 84.99, 76.37, 76.00, 72.04, 62.46, 28.85; (set 2) 137.44, 134.13, 131.43, 128.78, 128.21, 126.28, 96.94, 86.68, 75.79, 71.68, 70.18, 63.12, 28.85 ppm; C 13 H 15 ClO5 (Molecular weight: 286.71), LCMS (EI) m / e 285.06 [M - H] - 。

Chem.

[0159] Into a clean reactor under nitrogen, compound 60 (1772 g, 6.18 mol) and 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 70’ , 1070 g, 8.04 mol) was placed in N,N-dimethylacetamide (DMAc, 17.7 L) at 15 - 25 °C. Potassium phosphate anhydrous (K3PO4, 852 g, 4.01 mol) was added to the resulting solution. After 30 minutes, TMAD (2022 g, 11.74 mol) was added to the reactor at 15 - 25 °C, and then P(n-Bu)3 (2381 g, 11.77 mol) was added over 5 hours while maintaining the internal temperature at 20 - 35 °C. The reaction mixture was stirred at 20 - 35 °C for 16 hours or more. After the completion of the reaction was indicated by HPLC (criterion: 3% or less of compound 60 to compound VIa-3), the batch was filtered and the filtrate was collected. The reactor was rinsed with EtOAc (26.6 L), and the filter cake obtained was washed with the rinse mixture. The filtrates were combined and cooled to 0 - 10 °C. To this solution, a solution of NaCl (436 g) in water (43.6 L) was added while maintaining the batch temperature below 30 °C. The mixture was stirred for 30 minutes and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 26.6 L). All the organic phases were combined and washed twice with a solution of NaCl (145 g) in water (14.5 L). The separated organic phase was distilled under reduced pressure at 55 °C or less to a minimum stirring volume. To the distillation residue, MeOH (10.3 L) was added while maintaining the batch temperature below 30 °C, and then a solution of concentrated hydrochloric acid (HCl, 12 M, 1.71 L, 20.5 mol) in MeOH (6.8 L) was added. After stirring at 15 - 30 °C for 30 minutes, MTBE (68.2 L) was added. The mixture was heated to 35 - 45 °C for 1 hour and then cooled to 0 - 10 °C. After stirring at 0 - 10 °C for 1 hour, the solid was collected by filtration.

[0160] The wet cake was washed with a mixed solvent of MeOH (4.5 L) and MTBE (18.2 L). The obtained cake was dried under vacuum on a filter for 16 hours and then transferred to a clean reactor. Isopropanol (IPA, 11.8 L) and dichloromethane (DCM, 2.0 L) were added to the reactor. The suspension was heated to 35 - 45 °C and stirred at that temperature range for 1 hour. Subsequently, the hot slurry was cooled to 10 - 20 °C. After stirring at 10 - 20 °C for 1 hour, the solid was recovered by filtration and washed with a mixed solvent of IPA (3.4 L) and DCM (0.56 L). The obtained cake was dried under vacuum on a filter for 16 hours, and (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol hydrochloride (crude compound VIa-3, 1355 g, 3.09 mol, yield 50%) was obtained as a white to off-white solid.

Chem.

[0161] The crude compound VIa-3 (1742 g, 3.97 mol) in MeOH (7.8 L) was placed in a clean container at 15 - 25 °C. The solution was filtered through an in-line filter into a clean reactor under nitrogen. The container was rinsed with MeOH (0.9 L), and subsequently the rinse solution was filtered through the same in-line filter and added to the reactor. The solution was distilled at atmospheric pressure while adding polished 2-propanol (IPA, 12.2 L) little by little. Distillation was continued until the precipitation of solids was observed. The mixture was then cooled to 15 - 25 °C and stirred at that temperature for 2 hours. The solid was collected by filtration and washed with a mixed solvent of polished DCM (0.57 L) and IPA (3.5 L). After washing with polished n-heptane (5.2 L), the cake was dried on the filter for 3 hours and further dried in a drying tray under vacuum at 60 °C or below. The dried solid was pulverized and passed through a 100-mesh sieve. The obtained solid was dried under vacuum in a drying tray at 60 °C or below to obtain (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol hydrochloride (Compound VIa-3, 1498 g, 86%) as a white to off-white solid.

Claims

【Request Item 1】 A process for preparing a compound of chemical formula (II) or a pharmaceutically acceptable salt thereof, wherein the compound of chemical formula (I) or a pharmaceutically acceptable salt thereof is P(R ２ ) ３ This includes combining a reagent with an azodicarboxylic acid or azodicarboxamide in the presence of an organic solvent. 【Chemistry 1】 In the formula, X １ OH or OPG １ And, PG １ It is a hydroxyl protecting group, PG ２ PG ３ and PG ４ Each of these is independently an H or a hydroxyl protecting group, Alternatively, PG ２ and PG ３ together with the oxygen atom to which they are attached form a 1,2-dihydroxyl protecting group and Each R ２ C is independent １ -C ６ A process that is alkyl or aryl.

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