Process for preparing prmt5 inhibitors

Abstract

The present disclosure provides processes for the preparation of compounds of Formula (VIa-1) and pharmaceutically acceptable salts thereof. Intermediates useful in the preparation of the compounds of Formula (VIa-1) are also provided. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. patent application No. 63 / 366,335 filed on June 14, 2022, the disclosure of which is incorporated by reference in its entirety. Technical Field

[0003] The present disclosure relates to methods of preparing PRMT5 inhibitors. Background Art

[0004] The compound of formula (VIa-1) or compound (VIa-1) (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 is a PRMT5 inhibitor described in U.S. Patent No. 10,711,007.

[0005]

[0006] There is a need for a method for preparing compound (VIa-1) and a pharmaceutically acceptable salt thereof in high yield and high stereochemical purity. Summary of the invention

[0007] The present disclosure provides a method for preparing compounds of formula (VIa-1) and pharmaceutically acceptable salts thereof and mixtures thereof in high yield and high stereochemical purity.

[0008] DETAILED DESCRIPTION

[0009] By reference to the following description, including the following definitions and examples, the disclosure can be more fully understood. Some features of the disclosed method described in the context of the individual aspects herein can also be provided in combination in a single aspect. Alternatively, for the sake of brevity, the various features of the disclosed method described in the context of the individual aspects can also be provided separately or in any sub-combination.

[0010] In this disclosure, the singular forms "a", "an", and "the" include plural references, and references to a particular value include at least that particular value unless the context clearly indicates otherwise. Thus, for example, references to "an organic solvent", "an organic solvent", "a suitable organic solvent", etc. refer to an 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.

[0011] 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 a range of "2 to 4". When used to modify a single number, the term "about" refers to ±10% of the indicated number, and includes the indicated number. For example, "about 10°C" indicates a range of 9°C to 11°C, and "about 1" means 0.9-1.1.

[0012] "Pharmaceutically acceptable salt" refers to a salt of the compounds of the present disclosure that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and may be inorganic or organic acid addition salts. Specifically, such salts include: (1) acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or from 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, amygdaloid acid, Acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethylsulfonic 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, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.

[0013] The term "heteroaryl" when used alone or as part of a substituent group refers to a monocyclic or bicyclic aromatic ring structure comprising carbon atoms and up to five heteroatoms selected from nitrogen, oxygen and sulfur. The heteroaryl ring may include a total of 5, 6, 7, 8, 9 or 10 ring atoms. The term -C 5 -C 10Heteroaryl refers to a heteroaryl group containing five to ten ring atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl (thienyl), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridyl, 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 groups are substituted, the heteroaryl groups may be substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -CN, amino, halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 Other substituents include -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 、-OC(O)NH(C 1 -C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 、-S(O) 2 NH(C 1 -C 6 Alkyl) and -S(O) 2 N(C 1 -C 6 alkyl) 2 .

[0014] When used alone or as part of a substituent, the term "aryl" refers to a monocyclic or bicyclic aromatic carbocyclic structure. The aryl ring may include a total of 5, 6, 7, 8, 9, or 10 ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and the like. The aryl groups of the present disclosure may be unsubstituted or substituted. In those embodiments where the aryl group is substituted, the aryl group may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of: -OH, -CN, amino, halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 Other substituents include -C(O)NH(C 1-C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 、-OC(O)NH(C 1 -C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 、-S(O) 2 NH(C 1 -C 6 Alkyl) and -S(O) 2 N(C 1 -C 6 alkyl) 2 .

[0015] When used alone or as part of a substituent, the term "heterocycloalkyl" refers to any three to ten membered monocyclic or bicyclic saturated ring structure containing at least one heteroatom selected from the group consisting of O, N, and S. Heterocycloalkyl of the present disclosure includes monocyclic groups, as well as polycyclic groups, such as bicyclic groups and tricyclic groups. In those embodiments with at least one polycyclic heterocycloalkyl, the cyclic groups may share one common atom (i.e., spirocycle). In other embodiments with at least one polycyclic heterocycloalkyl, the cyclic groups share two common atoms. The term -C 3 -C 6 Heterocycloalkyl refers to a heterocycloalkyl group having between three and six carbon ring atoms. 3 -C 10Heterocycloalkyl refers to a heterocycloalkyl having three to 10 ring atoms. Heterocycloalkyl can be attached to any heteroatom or carbon atom of the ring so that the result is a stable structure. The example of suitable heterocycloalkyl includes but is not limited to azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, 1.3]heptanyl, 1.4-1.6-1.7-1.8-1.9-2.10-1.3-1.9-2.10-1.8 ... 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 Additional optional substituents include -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 、-OC(O)NH(C 1 -C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 、-S(O) 2 NH(C 1 -C 6 Alkyl) and -S(O) 2 N(C 1 -C 6 alkyl) 2 .

[0016] In some aspects, the present disclosure relates to a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound of formula (II) with a P(R 2 ) 3 In the case of azodicarbonyl ester or azodicarbonamide, a compound of formula (I) or a pharmaceutically acceptable salt thereof is reacted:

[0017]

[0018] Where X 1 Is OH or OPG 1 PG 1 is a hydroxyl protecting group; PG 2 PG 3 and PG 4 Each independently is H or a hydroxyl protecting group; or PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a 1,2-dihydroxy protecting group; and each R 2 Independently C 1 -C 6 Alkyl or aryl.

[0019] In these embodiments, X 1 Is OH or OPG 1 For example, in some aspects, X 1 is OH. In some aspects, X 1 OPG 1 , where PG 1 As used herein, the term "hydroxyl protecting group" refers to a portion that is bound to the oxygen atom of a compound (e.g., -O-PG 2 ), so that the portion (e.g., -PG 2 ) can be removed under controlled conditions to produce a hydroxyl group (i.e., -OH). Hydroxyl protecting groups, methods for installing protecting groups, and methods for removing protecting groups are well known to those skilled in the art and are described in, for example, Wuts, PGM, Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, 5th edition. 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 In addition, in these embodiments, PG 2 PG 3 and PG 4Each is independently H or a hydroxyl protecting group. In other embodiments, PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a 1,2-dihydroxy protecting group.

[0020] In some embodiments, PG 1 PG 2 PG 3 and PG 4 Each is independently a hydroxy protecting group that is stable to the nucleophile (ie, is not removed during the reaction).

[0021] In some embodiments, PG 1 PG 2 PG 3 and PG 4 Each independently is a hydroxyl protecting group, which is stable during reaction with other compounds. Exemplary nucleophilic stable hydroxyl protecting groups include alkyl ethers, benzyl ethers, substituted benzyl ethers (e.g., p-methoxybenzyl ether) and silyl ethers (e.g., tert-butyldimethylsilyl ether, trimethylsilyl ether).

[0022] In some embodiments, PG 1 PG 2 PG 3 and PG 4 Each is independently an alkyl ether such as methyl ether, methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, substituted benzyloxymethyl ether, tert-butoxymethyl ether, siloxymethyl ether, methoxyethoxymethyl ether, tetrahydropropyl ether, 1-ethoxyethyl ether, tert-butyl ether, trimethylsilyl ether, tert-butyldimethylsilyl ether and the like.

[0023] In some embodiments, PG 1 PG 2 PG 3 and PG 4 Each is independently a methyl ether. In some embodiments, PG 2 or PG 3 In some embodiments, PG 2 In some embodiments, PG 3 It is methyl ether.

[0024] In some embodiments, PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a 1,2-dihydroxy protecting group. 2 and PG 3 Each is independently a hydroxyl protecting group that is stable to nucleophiles.2 and PG 3 Together with the oxygen atom to which it is attached, a 1,2-dihydroxy protecting group is formed, which is stable during reactions with other compounds. Exemplary nucleophile-stable 1,2-dihydroxy protecting groups include acetals (e.g., methylene acetal, ethylidene acetal, benzylidene acetal, p-methoxybenzylidene acetal, etc.) and ketals (e.g., acetone acetal, etc.).

[0025] In some embodiments, PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms an acetonide protecting group.

[0026] In some respects, PG 2 and PG 3 is H or a hydroxyl protecting group; or PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a 1,2-dihydroxy protecting group.

[0027] 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 that is stable to nucleophiles. 2 Examples of the ether include methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, substituted benzyloxymethyl ether, tert-butoxymethyl ether, silyloxymethyl ether, methoxyethoxymethyl ether, tetrahydropropyl ether, 1-ethoxyethyl ether, tert-butyl ether, trimethylsilyl ether, and tert-butyldimethylsilyl ether.

[0028] 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. 3 Examples of the ether include methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, substituted benzyloxymethyl ether, tert-butoxymethyl ether, silyloxymethyl ether, methoxyethoxymethyl ether, tetrahydropropyl ether, 1-ethoxyethyl ether, tert-butyl ether, trimethylsilyl ether, and tert-butyldimethylsilyl ether.

[0029] In some embodiments, PG 2 and PG 3Together with the oxygen atom to which it is attached, a 1,2-dihydroxy protecting group is formed. 1,2-dihydroxy protecting groups are known in the art. See, for example, Wuts, PGM, Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, 5th edition. 2014. A suitable 1,2-dihydroxy protecting group is acetone acetal.

[0030] In some embodiments, PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a nucleophile-stable 1,2-dihydroxy protecting group. 2 and PG 3 Together with the oxygen atom to which it is attached, it forms an acetonide protecting group.

[0031] Furthermore, in these embodiments, P(R 2 ) 3 Each R in the reagent 2 Independently C 1 -C 6 In some aspects, P(R 2 ) 3 Each R in the reagent 2 Independently C 1 -C 6 In some aspects, P(R 2 ) 3 Each R in the reagent 2 are independently alkyl. P(R) suitable for use in the methods of the present disclosure 2 ) 3 Examples of reagents include trimethylphosphine, triethylphosphine, tri-n-propylphosphine, tri-n-butylphosphine, triphenylphosphine, (p-dimethylaminophenyl)diphenylphosphine, and diphenyl-2-pyridylphosphine. 2 ) 3 The reagent is trimethylphosphine. In some aspects, P(R 2 ) 3 The reagent is triethylphosphine. In some aspects, P(R 2 ) 3 The reagent is tri-n-propylphosphine. In some aspects, P(R 2 ) 3 The reagent is tri-n-butylphosphine. In some aspects, P(R 2 ) 3 The reagent is triphenylphosphine. In some aspects, P(R 2 ) 3 The reagent is (p-dimethylaminophenyl)diphenylphosphine. In some aspects, P(R 2 ) 3 The reagent is diphenyl-2-pyridylphosphine.

[0032] The method of the present disclosure uses azodicarboxylic acid esters or azodicarbonamide to produce compounds of formula (II). Azodicarboxylic acid esters include RC (O) -N = NC (O) -O-R 'groups, and suitable azodicarboxylic acid esters are known in the art. Examples of azodicarboxylic acid esters or azodicarbonamides suitable for the described method include diisopropyl azodicarboxylate (DIAD), tetramethylazodicarboxamide (TMAD) and diethyl azodicarboxylate (DEAD). In some aspects, azodicarboxylic acid esters or azodicarbonamides are DIAD. In some aspects, azodicarboxylic acid esters or azodicarbonamides are TMAD. In some aspects, azodicarboxylic acid esters or azodicarbonamides are DEAD. A mixture of azodicarboxylic acid esters and azodicarbonamides can also be used.

[0033] Organic solvents suitable for producing compounds 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, tert-butyl methyl ether, tetrahydrofuran), and combinations thereof.

[0034] 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:

[0035]

[0036] In some aspects, the present disclosure relates to a method for preparing a compound of formula (IIa) or a pharmaceutically acceptable salt thereof, the method comprising reacting a mixture of: 2 ) 3 In the case of azodicarbonyl ester or azodicarbonamide, a compound of formula (Ia) or a pharmaceutically acceptable salt thereof is reacted:

[0037]

[0038] 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:

[0039]

[0040] In some aspects, the present disclosure relates to a method for preparing a compound of formula (IIb) or a pharmaceutically acceptable salt thereof, the method comprising reacting a mixture of: 2 ) 3In the case of azodicarboxylate reagent, a compound of formula (Ib) or a pharmaceutically acceptable salt thereof is reacted:

[0041]

[0042] In some embodiments of the methods 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:

[0043]

[0044] In some embodiments of the methods of the present disclosure, the compound of formula (Ib) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-1):

[0045]

[0046] In the methods of the present disclosure, the azodicarboxylic acid ester or azodicarboxamide used to react the compound of formula (Ia) (or formula (Ib)) to produce the compound of formula (IIa) (or the compound of formula (IIb)) is any azodicarboxylic acid ester or azodicarboxamide known in the art. Suitable azodicarboxylic acid esters or azodicarboxamides include those known to be generally useful in the Mitsunobu reaction. In some embodiments, the azodicarboxylic acid ester or azodicarboxamide is DEAD, DIAD or TMAD or a mixture thereof. In some of these embodiments, the azodicarboxylic acid ester or azodicarboxamide is DIAD. In some of these embodiments, the azodicarboxylic acid ester or azodicarboxamide is TMAD. In some of these embodiments, the azodicarboxylic acid ester or azodicarboxamide is DEAD.

[0047] In the methods of the present disclosure, P(R) is used to react a compound of formula (Ia) or formula (Ib) to produce a compound of formula (IIa) or formula (IIb), respectively. 2 ) 3 The reagent is any phosphine known to be useful in synthetic organic chemistry. Suitable phosphines include those known to be generally useful in Mitsunobu reactions. In some embodiments, the phosphine is (R 2 ) 3 P, where R 2 It is C 1 -C 6 Alkyl, such as trimethylphosphine, triethylphosphine, tri-n-propylphosphine, tri-n-butylphosphine, etc. Tri-n-butylphosphine (n-Bu) 3 P is an exemplary phosphine reagent. In other embodiments, the phosphine is (R 2 ) 3 P, where R 2is an aryl group, for example, triphenylphosphine, (p-dimethylaminophenyl)diphenylphosphine, diphenyl-2-pyridylphosphine, etc. Triphenylphosphine is an exemplary phosphine reagent.

[0048] In the method of the present disclosure, the organic solvent used to react the compound of formula (Ia) or formula (Ib) to produce the compound of formula (IIa) or formula (IIb) respectively is any known organic solvent generally suitable for use in Mitsunobu reaction. 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 propane dichloromethane. In some embodiments, the organic solvent is tetrahydrofuran. In other embodiments, the organic solvent is a mixture of dichloromethane and tetrahydrofuran.

[0049] In some embodiments, the organic solvent used to react the compound of Formula (Ia) or Formula (Ib) to produce the compound of Formula (IIa) or Formula (IIb), respectively, is an aprotic organic solvent. Exemplary 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), tert-butyl methyl ether (MTBE), chloroform, ethyl acetate, 1,2-dimethoxyethane (glyme), 2-methoxyethyl ether (diglyme), tetrahydrofuran (THF), dichloromethane, pyridine (Py), 2-butanone (MEK), acetone, hexamethylphosphoramide (HMPA), N-methyl-pyrrolidone (NMP), nitromethane, dimethylformamide (DMF), acetonitrile, sulfolane, dimethyl sulfoxide (DMSO), propylene carbonate, and mixtures thereof.

[0050] In some embodiments, the aprotic organic solvent is diethyl ether, tert-butyl methyl ether, or tetrahydrofuran, or a mixture thereof.

[0051] In some embodiments, the aprotic organic solvent is diethyl ether.

[0052] In other embodiments, the aprotic organic solvent is tert-butyl methyl ether.

[0053] In other embodiments, the aprotic organic solvent is tetrahydrofuran.

[0054] In some embodiments of the disclosed methods, the preparation of the compound of formula (II) (e.g., a 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 increases the yield, rate, or selectivity of a reaction. Additives suitable for use in the disclosed methods are those known to be generally useful additives in Mitsunobu reactions.

[0055] In some embodiments, the temperature of the reaction mixture for reacting a compound of formula (Ia) or formula (Ib) to produce a compound of formula (IIa) or formula (IIb) respectively 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 to about 25°C or between about 20°C to about 25°C. In some aspects, the temperature is 15°C, 16°C, 17°C, 28°C, 19°C, 20°C, 21°C, 2°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C or 30°C.

[0056] In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia-1) or a pharmaceutically acceptable salt thereof.

[0057]

[0058] In some embodiments, the compound of formula (Ib) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib-1) or a pharmaceutically acceptable salt thereof.

[0059]

[0060] In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof is a compound of formula (IIa-1) or a pharmaceutically acceptable salt thereof.

[0061]

[0062] In some embodiments, the compound of formula (IIb) or a pharmaceutically acceptable salt thereof is a compound of formula (IIb-1) or a pharmaceutically acceptable salt thereof.

[0063]

[0064] It will be apparent to those skilled in the art that 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 is reacted 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, thereby forming an asymmetric cyclopentyl carbon atom (*).

[0065]

[0066] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof is produced to result in an enantiomeric excess of at least 80% at the cyclopentyl carbon atom (*); 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 amount of one enantiomer at the (*) carbon minus 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, if the reaction produces 99% enantiomer 1 and 1% enantiomer 2, the enantiomeric excess is 98%. Methods for determining the enantiomeric excess at the (*) carbon atom are well known to those skilled in the art and include, for example, HPLC using a chiral stationary phase.

[0067] Compounds of the present disclosure that include more than one chiral stereocenter may be produced in diastereomeric excess, i.e., enriched in one diastereomer relative to the other possible diastereomers. In some embodiments, compounds of formula (II) produced according to the methods disclosed herein are produced in diastereomeric excess, i.e., enriched in a specific diastereomer. 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 diastereomeric excess will be known to those skilled in the art and include, for example, HPLC using a chiral or achiral stationary phase.

[0068] In some embodiments of the disclosed methods, X of formula (I) 1 OPG is a compound of formula (III) 1 or a pharmaceutically acceptable salt thereof:

[0069]

[0070] 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:

[0071]

[0072] In some embodiments of the methods of the present disclosure, the compound of formula (IIIa) or (IIIb) or a pharmaceutically acceptable salt thereof is a compound of formula (IIIa-1) or (IIIb-1) or a pharmaceutically acceptable salt thereof:

[0073]

[0074] In some embodiments of the disclosed methods, the compound of formula (IV) or a pharmaceutically acceptable salt thereof is produced by reacting a compound of formula (III) or a pharmaceutically acceptable salt thereof with an aqueous acid capable of hydrolyzing the hydroxy protecting group. Such an acid will depend on the identity of the hydroxy protecting group (PG) and will be known to those skilled in the art, as described in, for example, Wuts, PGM, Protective Groups in Greene's Organic Synthesis, John Wiley & Sons, 5th ed. 2014.

[0075]

[0076] The aqueous acid of the present disclosure includes a mixture of water and an acid capable of hydrolyzing the hydroxyl protecting group. Examples of suitable acids include mineral acids such as HCl, H 3 PO 4 , H 2 SO 4 and mixtures thereof. In some aspects, the acid is HCl. In some aspects, the acid is H 3 PO 4 In some aspects, the acid is H 2 SO 4 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) with sulfonic acid functional groups); Amberlite (styrene-divinylbenzene (DVB) gel or macroreticular type with sulfonic acid functional groups); and Amberlyst (styrene-divinylbenzene (macroreticular type) with sulfonic acid functional groups). 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 H 2 SO 4In other embodiments, the aqueous acid is a mixture of water, an acidic ion exchange resin, and optionally an organic solvent.

[0077] In some embodiments, the compound of formula (IV) is a compound of formula (IVa) or a compound of formula (IVb) or a pharmaceutically acceptable salt thereof:

[0078]

[0079] In some embodiments of the methods of the present disclosure, the compound of formula (IVa) or a pharmaceutically acceptable salt thereof is produced by reacting a compound of formula (IIIa) or a pharmaceutically acceptable salt thereof with an aqueous acid:

[0080]

[0081] In some embodiments of the methods of the present disclosure, the compound of formula (IVa) or a pharmaceutically acceptable salt thereof is produced by reacting a compound of formula (IIIa-1) or a pharmaceutically acceptable salt thereof with an aqueous acid:

[0082]

[0083] In some embodiments of the methods of the present disclosure, the compound of formula (IV) or a pharmaceutically acceptable salt thereof is produced by reacting a compound of formula (IIIa) or a pharmaceutically acceptable salt thereof with an aqueous acid:

[0084]

[0085] In some embodiments of the methods of the present disclosure, the compound of formula (IV) or a pharmaceutically acceptable salt thereof is produced by reacting a compound of formula (IIIa-1) or a pharmaceutically acceptable salt thereof with an aqueous acid:

[0086]

[0087] In some embodiments of the methods of the present disclosure, the compound of formula (IVb) or a pharmaceutically acceptable salt thereof is produced by reacting a compound of formula (IIIb) or a pharmaceutically acceptable salt thereof with an aqueous acid:

[0088]

[0089] In some embodiments of the methods of the present disclosure, the compound of formula (IVb) or a pharmaceutically acceptable salt thereof is produced by reacting a compound of formula (IIIb-1) or a pharmaceutically acceptable salt thereof with an aqueous acid:

[0090]

[0091] In some embodiments, the reaction to produce a compound of formula (IV) or a pharmaceutically acceptable salt thereof is carried out at a temperature between about 0° C. and about 20° C. (e.g., 0° C., 1° C., 2° C., 3° ​​C., 4° C., 5° C., 6° C., 7° C., 8° C., 9° C., 10° C., 11° C., 12° C., 13° C., 14° C., 15° C., 16° C., 17° C., 18° C., 19° C., or 20° C.) In some aspects, the reaction is carried out at a temperature between 0-5° C.

[0092] In some embodiments of the methods of the present disclosure, the present disclosure relates to a method for preparing a compound of formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising: in the presence of an organic solvent, in the presence of P(R 2 ) 3 In the case of azodicarbonyl ester or azodicarbonamide, a compound of formula (IV) or a pharmaceutically acceptable salt thereof is reacted with a compound of formula (V) or a pharmaceutically acceptable salt thereof:

[0093]

[0094] Where G is halogen or C 1 -C 6 Alkyl; each R 2 Independently C 1 -C 6 alkyl or aryl; and Q is -NH or N - K + .

[0095] In some aspects, G is a halogen, such as F, Cl, Br or I. The preferred halogen is Cl. In some aspects, G is C 1 -C 6 Alkyl, such as methyl, ethyl, propyl, isopropyl, etc. Preferred C 1 -C 6 The alkyl group is methyl.

[0096] In some aspects, Q is NH. In some aspects, Q is NK + In some aspects, Q is N-Li + In some aspects, Q is N-Na + In some aspects, Q is N-Cs + .

[0097] 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:

[0098]

[0099] In some embodiments of the methods of the present disclosure, the present disclosure relates to a method for preparing a compound of formula (VIa) or a pharmaceutically acceptable salt thereof, the method comprising: in the presence of an organic solvent, in the presence of P(R 2 ) 3 In the case of azodicarbonamide, a compound of formula (IV) or a pharmaceutically acceptable salt thereof is reacted with a compound of formula (V) or a pharmaceutically acceptable salt thereof:

[0100]

[0101] In some embodiments of the methods of the present disclosure, the present disclosure relates to a method for preparing a compound of formula (VIa) or a pharmaceutically acceptable salt thereof, the method comprising: in the presence of an organic solvent, in the presence of P(R 2 ) 3 In the case of azodicarbonyl ester or azodicarbonamide, a compound of formula (IVa) or a pharmaceutically acceptable salt thereof is reacted with a compound of formula (V) or a pharmaceutically acceptable salt thereof:

[0102]

[0103] In some embodiments of the methods of the present disclosure, the present disclosure relates to a method for preparing a compound of formula (VIb) or a pharmaceutically acceptable salt thereof, the method comprising: in the presence of an organic solvent, in the presence of P(R 2 ) 3 In the case of azodicarbonyl ester or azodicarbonamide, the compound of formula (IVb) or a pharmaceutically acceptable salt thereof is reacted with the compound of formula (V) or a pharmaceutically acceptable salt thereof:

[0104]

[0105] In some embodiments, the reaction of a compound of formula (IV) with a compound of formula (V) proceeds via an epoxide intermediate having formula IVaa:

[0106]

[0107] In some embodiments, the compound of Formula (IVaa) is isolated prior to reacting with the compound of Formula (V).

[0108] In some aspects, the disclosed method for preparing a compound of formula (VIa) further comprises converting the compound of formula (IV) to an epoxide of formula (IVaa) by reacting the compound of formula (IV) with a phosphine, an azodicarboxylate, or an azodicarbonamide in the presence of a suitable organic solvent:

[0109]

[0110] Each R 2 Independently C 1 -C 6 Alkyl or aryl.

[0111] In some embodiments, the organic solvent is an aprotic organic solvent.

[0112] In some embodiments, the method further comprises reacting a compound of formula (IVaa) with a compound of formula (V) or a basic salt thereof in an organic solvent to obtain a compound of formula (VIa):

[0113]

[0114] Where G is halogen or C 1 -C 6 Alkyl; each R 2 Independently C 1 -C 6 alkyl or aryl; and Q is -NH or N - K + .

[0115] In the embodiment where G is -Cl, the compound of formula (V) or a pharmaceutically acceptable salt thereof is a compound of formula (Va) or a pharmaceutically acceptable salt thereof:

[0116]

[0117] Where Q is -NH or N - K + In some embodiments of compounds of formula (Va), Q is NH. In some embodiments of compounds of formula (Va), Q is NK + .

[0118] In Q is NK + In the embodiment of the present invention, compound (V) is prepared by mixing compound (V) wherein Q is NH with a suitable base in an organic solvent. The suitable base can be any base capable of generating NK. + A base salt such as potassium tert-butoxide or potassium hydroxide.

[0119] In embodiments where G is methyl, the compound of formula (V) or a pharmaceutically acceptable salt thereof is a compound of formula (Vb) or a pharmaceutically acceptable salt thereof:

[0120]

[0121] Where Q is -NH or N - K +In some embodiments of compounds of Formula (Vb), Q is NH. In some embodiments of compounds of Formula (Vb), Q is NK + .

[0122] In the embodiment where G is -Cl, the compound of formula (VIa) or a pharmaceutically acceptable salt thereof is a compound of formula (VIa-2) or a pharmaceutically acceptable salt thereof:

[0123]

[0124] In the embodiment 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:

[0125]

[0126] In the embodiment 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:

[0127]

[0128] In embodiments of the disclosed methods where the compound of formula (VIa-1) is isolated as a solid salt (e.g., HCl salt, phosphate, sulfate, oxalate, oxalate, maleate), the salt can be converted to a free base of formula (VIa-1) by reaction with a suitable base in the presence of an appropriate solvent. In some embodiments, the free base of formula (VIa-1) is obtained by treating an HCl salt of formula (VIa-3) with an aqueous base (e.g., aqueous ammonium hydroxide):

[0129]

[0130] In some embodiments, the conversion is carried out at a temperature of about 10°C to about 50°C, e.g., about 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C or 50°C, preferably about 15°C to about 35°C.

[0131] In some embodiments, the method of the present disclosure comprises 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:

[0132]

[0133] Suitable catalysts are known in the art. In one embodiment, a suitable catalyst is M(acac) 3, wherein M is Fe. Suitable Grignard reagents are known in the art and may include any suitable methyl nucleophile combined with a suitable catalyst. In some embodiments, the Grignard reagent is MeMgBr.

[0134] In the embodiment 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:

[0135]

[0136] In the embodiment 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:

[0137]

[0138] In the embodiment 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:

[0139]

[0140] In embodiments of the disclosed methods where the compound of formula (VIb-1) is isolated as a solid salt (e.g., HCl salt, phosphate, sulfate, oxalate, oxalate, maleate), the salt can be converted to the free base of formula (VIb-1) by reaction with a suitable base in the presence of an appropriate 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 (e.g., aqueous ammonium hydroxide):

[0141]

[0142] In some embodiments, the conversion is carried out at a temperature of about 10°C to about 50°C, e.g., about 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C or 50°C, preferably about 15°C to about 35°C.

[0143] In some embodiments, the method of the present disclosure comprises 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:

[0144]

[0145] In some embodiments, M is Fe. Suitable Grignard reagents are known in the art. In some embodiments, the Grignard reagent is MeMgBr.

[0146] In some aspects, the method of the present disclosure further comprises contacting the 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 an HCl salt, a phosphate, a sulfate, an oxalate, an oxalate or a maleate. A pharmaceutically acceptable salt can be prepared by treating the compound of formula (VIa-1) with a suitable acid in the presence of a suitable solvent.

[0147] In some embodiments, the method of the present disclosure further comprises reacting a compound of formula (VIa-1) and 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):

[0148]

[0149] In some aspects, the method of the present disclosure further comprises reacting the 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 an HCl salt, a phosphate, a sulfate, an oxalate, an oxalate or a maleate. A pharmaceutically acceptable salt can be prepared by treating the compound of formula (VIb-1) with a suitable acid in the presence of a suitable solvent.

[0150] In some embodiments, the method 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):

[0151]

[0152] In some embodiments, the solvent used to convert the compound of (VIa-1) or (VIb-1) to the compound of (VIa-3) or (VIb-3), respectively, is an alcohol, such as methanol, ethanol, isopropanol, etc., 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, such as 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C or 75°C, preferably between about 35-50°C.

[0153] In some embodiments, the present disclosure relates to a method 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, wherein the method comprises any method disclosed herein.

[0154] In some aspects, the method 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 in the form of a stereoisomer having an absolute configuration as shown below:

[0155]

[0156] In some embodiments, the diastereomeric excess of a compound of formula (VIa-1) or a pharmaceutically acceptable salt thereof (e.g., a compound of (VIa-3) or a 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 a compound of formula (VIa-1) or a pharmaceutically acceptable salt thereof (e.g., a compound of (VIa-3) or a 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, those HPLC methods known in the art and described herein.

[0157] In some aspects, the methods of the present disclosure provide compounds of formula (VIb) or pharmaceutically acceptable salts thereof, such as compounds of (VIb-1) or compounds of (VIb-3) or compounds of (VIb-2) with high stereoisomeric purity. That is, the compound of formula (VIb-1) or pharmaceutically acceptable salts thereof (such as compounds of (VIb-3) or compounds of (VIb-2) or pharmaceutically acceptable salts thereof) are mainly obtained in the form of stereoisomers having the absolute configuration shown below:

[0158]

[0159] In some embodiments, the diastereomeric excess of a compound of formula (VIb-1) or a pharmaceutically acceptable salt thereof (e.g., 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 of a compound of formula (VIb-1) or a pharmaceutically acceptable salt thereof (e.g., 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 well known to those skilled in the art and include, for example, those HPLC methods described in the art and herein.

[0160] In some embodiments, the methods of the present disclosure comprise the following steps to produce a compound of formula (VIa), such as formula (VIa-1) or formula (VIa-2) or formula (VIa-3).

[0161] The compound of formula (XXI) or a pharmaceutically acceptable salt thereof is reacted with a suitable Grignard reagent to produce a compound of formula (XXI') or a pharmaceutically acceptable salt thereof:

[0162]

[0163] Among them PG 4 In compounds of formula (XXI), Br may be replaced by I as defined for formula (I).

[0164] In certain embodiments, the PG of the compounds of Formula (XXI) and Formula (XXI') 4 is a hydroxy protecting group. In certain embodiments, PG of the compounds of formula (XXI) and formula (XXI') 4 is tetrahydropyran (THP). In certain embodiments, "C 1-6 AlkylMgCl"C 1-6 The alkyl group is methyl or ethyl.

[0165] In certain embodiments, the compound of formula (XXI) is compound 10 shown below:

[0166]

[0167] In certain embodiments, the compound of formula (XXI') is compound 10' shown below:

[0168]

[0169] The compound of formula (XXI') or a pharmaceutically acceptable salt thereof is reacted with the compound of formula (XXII) (or its corresponding aldehyde or adduct thereof) or a pharmaceutically acceptable salt thereof to produce a compound of formula (XXIII) or a pharmaceutically acceptable salt thereof:

[0170]

[0171] Among them PG 1 PG 2 PG 3 and PG 4 As defined in formula (I).

[0172] In certain embodiments, the PG of the compounds of Formula (XXI) and Formula (XXI') 1 PG 2 PG 3 and PG 4 are each independently a hydroxyl protecting group; or PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a 1,2-dihydroxy protecting group. In certain embodiments, the PG of the compounds of formula (XXI) and formula (XXIII) 4 It is tetrahydropyran (THP).

[0173] In certain embodiments, the compound of formula (XXIII) is represented by a compound of formula (Ia) or a compound of formula (Ia-1).

[0174] In certain embodiments, the compound of formula (XXII) is compound 20 shown below:

[0175]

[0176] In certain embodiments, the compound of formula (XXIII) is compound 30 shown below:

[0177]

[0178] The compound of formula (XXIII) or a pharmaceutically acceptable salt thereof is reacted with an alcohol to produce a compound of formula (XXIII') or a pharmaceutically acceptable salt thereof:

[0179]

[0180] Among them PG 1 PG 2 PG 3 and PG 4 As defined in formula (I).

[0181] In certain embodiments, the PG of the compound of formula (XXIII)1 PG 2 PG 3 and PG 4 and PG of the compound of formula (XXIII') 1 PG 2 and PG 3 are each independently a hydroxyl protecting group; or PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a 1,2-dihydroxy protecting group. In certain embodiments, the PG of the compound of formula (XXIII) 4 It is tetrahydropyran (THP).

[0182] In certain embodiments, the compound of formula (XXIII') is represented by a compound of formula (Ia) or a compound of formula (Ia-1).

[0183] In certain embodiments, the compound of formula (XXIII') is compound 40 shown below:

[0184]

[0185] The compound of formula (XXIII') or a pharmaceutically acceptable salt thereof and P(R 2 ) 3 The reagent is reacted with an azodicarboxylate to produce a compound of formula (XXV) or a pharmaceutically acceptable salt thereof:

[0186]

[0187] Among them PG 1 PG 2 and PG 3 As defined in formula (I).

[0188] In certain embodiments, the PG of the compounds of Formula (XXIII') and Formula (XXV) 1 PG 2 and PG 3 are each independently a hydroxyl protecting group; or PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a 1,2-dihydroxy protecting group.

[0189] In certain embodiments, the compound of formula (XXV) is represented by a compound of formula (IIa) or a compound of formula (IIIa) or a compound of formula (IVa).

[0190] In certain embodiments, the compound of formula (XXV) is compound 50 shown below:

[0191]

[0192] The compound of formula (XXV) or a pharmaceutically acceptable salt thereof is reacted with an acid to produce a compound of formula (XXV') or a pharmaceutically acceptable salt thereof:

[0193]

[0194] Among them PG 1 PG 2 and PG 3 As defined in formula (I).

[0195] In certain embodiments, the PG of the compound of formula (XXV) 1 PG 2 and PG 3 are each independently a hydroxyl protecting group; or PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a 1,2-dihydroxy protecting group.

[0196] In certain embodiments, the compound of formula (XXV') is represented by a compound of formula (IVa) or a compound of formula (IVb). In certain embodiments, the compound of formula (XXV') is compound 60 shown below:

[0197]

[0198] The compound of formula (XXV') or a pharmaceutically acceptable salt thereof is reacted with compound (Vb) to produce a compound of formula (VIa-1) or a pharmaceutically acceptable salt thereof:

[0199]

[0200] Where Q is NH or N - K + .

[0201] In certain embodiments, Q of the compound of formula (Vb) is N - K + In certain embodiments, the compound of formula (Vb) is compound 70 shown below:

[0202]

[0203] The compound of formula (VIa-1) or a pharmaceutically acceptable salt thereof is reacted with hydrochloric acid to produce a compound of formula (VIa-3) or a pharmaceutically acceptable salt thereof:

[0204]

[0205] The following examples are provided to illustrate various aspects of the invention and are not intended to be limiting.

[0206] Examples

[0207] Example 1 - Synthesis of Compound (VIa-1) and Compound (VIa-3)

[0208] Synthesis scheme

[0209]

[0210] Synthesis of (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).

[0211] To a solution of crude (3aR, 4S, 6R, 6aR) -6-methoxy-2,2-dimethyltetrahydrofurano [3,4-d] [1,3] dioxole-4-carbaldehyde (1.3 g, 6.4 mmol, 1 eq) in MTBE (3 mL, 2.3 mL / g) was added benzotriazole (0.75 g, 6.3 mmol, 0.95 eq) and the resulting solution was stirred overnight at ambient temperature to give a dilute white suspension. Heptane (9 mL, 3 v / v) was added dropwise and the suspension was stirred at ambient temperature for 1 hour to separate out additional material before 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 give (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, 1.4 g, 70%) as a white solid.

[0212] Synthesis of (4-chloro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)magnesium bromide (Compound 10').

[0213] Into an oven-dried 2 L four-necked flask equipped with an overhead stirrer, a thermocouple, and an addition funnel, Mg chips (9.98 g, 411 mmol, 1.05 eq.) were added under N 2The mixture was suspended in dry 2-MeTHF (190 mL, 1.5 mL / g) and the suspension was warmed to 50°C. iPrMgCl (9.8 mL, 19.6 mmol, 0.05 eq; 2M in THF) was added by syringe, followed by 40 mL (about 10 vol%) of 2-(2-bromo-5-chlorophenethoxy)tetrahydro-2H-pyran (compound 10, 125 g, 391 mmol, 1 eq) in dry 2-MeTHF (200 mL, 1.6 mL / g; about 400 mL in total) to initiate Grignard formation. After stirring for 10 minutes, an exotherm (e.g., 50°C to 56°C) was observed, indicating that the reaction had begun. The remaining compound 10 was charged dropwise at a rate sufficient to maintain an internal temperature of <75°C. (Please note: external heating was stopped once the batch temperature reached 65°C). After the addition was complete, the batch was stirred at 50°C for 1 hour. HPLC assay of an aliquot quenched with MeOH indicated that all of compound 10 had been consumed.

[0214] 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).

[0215] In N 2 To a four-necked flask containing 1' (391 mmol, 2.5 eq; typically 0.83-0.86 M) was added dropwise (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, 50 g, 156 mmol, 1 eq) in 2-MeTHF (500 mL, 10 mL / g) at ambient temperature. (Please note: During addition, it is recommended to use an ambient temperature water bath as a heat sink.) The reaction was monitored by HPLC assay of an aliquot quenched with MeOH until a constant ratio of product diastereomer to quenched 1' was observed (approximately 2.5 hours, demonstrating approximately 4:1 dr). The batch was quenched with 10 wt % aqueous citric acid (1 x 500 mL, 0.5 v / v) and the layers were separated. The organic phase was washed with 4 M aqueous NaOH (1 x 500 mL, 0.5 v / v) and then concentrated under reduced pressure to give a clear orange-yellow oil which was used directly without further purification.

[0216] 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).

[0217] The residue containing crude compound 30 (about 150 g) was diluted with MeOH (375 mL, 2.5 mL / g) and pTsOH·H 2 The mixture was stirred at ambient temperature for 1.5 hours, at which time HPLC determination indicated that the reaction was complete. The reaction was quenched with 1M NaOH aqueous solution (375mL, 1v / v) and extracted with MTBE (3×250mL, 0.67v / v). The combined organic layers were concentrated under reduced pressure and then azeotropically dried with 2-MeTHF (3×volumes) to give a crude compound 40 as a clear orange-yellow slurry, which was used directly without further purification.

[0218] 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).

[0219] In N 2 To a solution of crude compound 40 (about 130 g, 156 mmol, 1 eq.) in 2-MeTHF (910 mL, 7 mL / g) in a 2L three-necked flask equipped with an overhead stirrer and a thermocouple were charged pyridine (12.6 mL, 12.33 g, 156 mmol, 1.0 eq.), TMAD (67.2 g, 390 mmol, 2.5 eq.) and Bu 3 P (63.1g, 312mmol, 2.0 equivalents). The resulting slurry was stirred at ambient temperature for 16 hours, when HPLC determination showed that the reaction was complete. The batch was quenched with 1MHCl aqueous solution (900mL, 1v / v) and stirred for 1 hour. Each layer was separated, and the aqueous phase was extracted with 2-MeTHF (1×500mL, 0.5v / v). The combined organic layer was concentrated under reduced pressure to obtain 207g of orange oil. The crude product was filtered through a silica gel pad (621g, 3g / g), eluted with heptane (1×1CV), 5%MTBE / heptane (1×1CV), then 10%MTBE / heptane (1×1CV), and the filtrate was concentrated under reduced pressure to obtain 73g of light yellow oil. The residue was purified by 9:1MeOH / H at ambient temperature. 2O (146 mL, 2 mL / g) for 2 hours, then cooled in an ice bath for 4 hours. The solid was isolated by filtration and washed with 3:2 MeOH / H 2 O (2 x 150 mL), and dried at 50 °C under atmospheric pressure to afford compound 50 (34.16 g, 64% yield, 92% purity, 21:1 dr) as a white crystalline solid.

[0220] Synthesis of (3R,4S,5S)-5-((R)-6-chloroisochroman-1-yl)tetrahydrofuran-2,3,4-triol (Compound 60).

[0221] Compound 50 (3.4 g, 10 mmol, 1 eq.) was dissolved in THF (40 mL, 4 v / v) and 1 M H 2 SO 4 The solution in aqueous solution (10 mL, 10 mmol, 1.0 equiv) was stirred at 70 °C for 20 h. The reaction was monitored by HPLC and LC-MS assays and was washed with solid NaHCO when deemed complete. 3 To the mixture of 4-nitro-1-yl pyridine-2 ... 13 H 15 C1O 5 [MH] - LC-MS calculated value: m / z=285.06 / 287.06; found value: 285.06 / 287.10.

[0222] Synthesis of potassium 4-methylpyrrolo[2,3-d]pyrimidine-7-ol (Compound 70).

[0223] In N 2KOtBu (1.12 g, 10 mmol, 1.0 equiv) was added to a 100 mL round-bottom flask containing 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.33 g, 10 mmol, 1 equiv) and THF (20 mL, 15 mL / g) in batches. The reaction mixture was stirred at ambient temperature for 2 hours, and then the volatiles were removed under reduced pressure. The residue was slurried in MTBE (20 mL, 15 mL / g) overnight, and the solid was separated by filtration, washed with MTBE (2 × 10 mL), and the solid was dried at 50 ° C at atmospheric pressure to obtain compound 70 (1.6 g, 94%) as an off-white solid.

[0224] Synthesis of (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).

[0225] In N 2 To a dried 100 mL round-bottom flask containing a solution of compound 60 (715 mg, 2.5 mmol, 1 eq.) in MeCN (25 ml, 35 mL / g) were sequentially charged TMAD (646 mg, 3.75 mmol, 1.5 eq.) and Bu 3 4-(4-(4-(4-(4-oxo-1-yl)-2-nitropropene)-1-yl)-4-nitropropene ... 2 SO 4 The insoluble material was 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. 20 H 20 C1N 3 O 4 [M+H] + LC-MS calculated value: m / z=402.11 / 404.11; found value: 401.96 / 403.88.

[0226] Synthesis of (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).

[0227] A 100 mL round-bottom flask containing a solution of crude compound VIa-1 (3 g) in MeOH (10 ml, 3.3 mL / g) was dried and charged dropwise with 37 wt% aqueous HCl solution (1 mL, 0.1 v / v). After stirring at ambient temperature for 20 minutes, MTBE (40 ml, 3.6 v / v) was added to precipitate salt. The resulting slurry was cooled in an ice bath under stirring for 1 hour. The solid was separated 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.

[0228] Example 2-Synthesis of Compound (VIa-3) B

[0229] Synthesis scheme

[0230]

[0231] In the step of converting compound 60 to compound VIa-3, NMP may be used as a solvent instead of MTBE.

[0232]

[0233] Preparation of Grignard reagent

[0234] To a clean 100 L reactor charged with Mg turnings (576.8 g, 23.80 mol) was added 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) at 15-25° C. under nitrogen. Iodine (4.58 g, 0.036 mol) was charged to the reactor. The resulting mixture was stirred at 30-60° C. [Please note: after the addition of iodine, the internal temperature increased to 42° C. The onset of the formation of compound 10′ was confirmed by observing the color change from light yellow to green. HPLC also indicated initiation. 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 not less than 2 hours before being cooled to 0-10° C.

[0235] Grignard Addition of Aldehyde Adducts

[0236] 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 to a 100 L reactor with the formed Grignard reagent at a rate that maintained the batch temperature at 0-20°C. The resulting mixture was then warmed to 20-30°C and agitated at that temperature for not less than 4 hours. After 12 hours, the reaction mixture was cooled to 0-10°C. Ammonium chloride (NH 4 Cl, 2896g, 54.14mol) in water (16.5L) 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 (11.6L). The combined organic phases were first washed with a 75wt% solution of sodium hydroxide (NaOH, 776g, 19.40mol) in water (18.6L), followed by a second wash with the remaining aqueous NaOH solution. The resulting organic phase was then washed with a solution of sodium chloride (NaCl, 580g, 9.92mol) in water (5.2L). The organic phase was collected and distilled to a minimum stirring volume to give 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, 162% yield; theoretical yield, 3997 g) as a brown liquid, which was directly used in the next reaction without further purification. A small amount of crude compound 30 was purified to a colorless oil by column chromatography.

[0237] 1 H NMR (400 Hz, DMSO-d 6): δ7.41(d,J=8.4Hz,1H),7.31(d,J=2.4Hz,1H),7.29(dd,J=8.4,2.4Hz,1H),5.48(d,J=6.0Hz,1H),4.98(d,J=6.1Hz,1 H),4.80(s,1H),4.64(d,J=6.0Hz,1H),4.64-4.54(m,2H),4.35(d,J=9.3Hz,1H),3.88–3.74(m,1H),3.68(ddd,J=11.2,8 .3,5.6Hz,1H),3.58(tdd,J=10.0,7.9,6.3Hz,1H),3.40(dt,J=10.0,4.4Hz,1H),3.32(s,3H),3.00(dt,J=14.1,7.0Hz, 1H),2.93–2.85(m,1H),1.79–1.66(m,1H),1.61(tq,J=8.6,2.7Hz,1H),1.54–1.42(m,4H),1.40(s,3H),1.29(s,3H)ppm; 13 C NMR (100 Hz, DMSO-d 6 ): δ140.39,140.36,139.45,131.95,129.84,126.35,118.83,109.68,98.49,88.63,85 .06,82.40,69.02,67.31,61.83,55.32,32.10,30.68,26.77,25.49,25.17,19.62ppm.

[0238]

[0239] At 15-25°C, methanol (MeOH, 16.0 L) and acetone (26.0 L) containing crude compound 30 (6438 g, 14.54 mol; the theoretical yield of step 1 is 3997 g of compound 3, 9.02 mol) were placed in a clean 100 L reactor under nitrogen. At 15-30°C, 2,2-dimethoxypropane (1409.7 g, 13.53 mol) and p-toluenesulfonic acid monohydrate (p-TSA·H 2 O, 512 g, 2.69 mol). The reaction mixture was stirred at 15-30°C for not less than 1 hour. After HPLC (standard: ≤3% of compound 30 to compound 40) indicated the reaction was complete, sodium bicarbonate (NaHCO 3, 600g, 7.14mol) in water (11.2L) solution was added to the reaction mixture while maintaining the internal temperature below 30°C. The mixture was distilled to about 24L (about 6 volumes) at ≤50°C under vacuum. Dichloromethane (DCM, 12.0L) was added to the resulting mixture. The organic phase was separated, washed with water (12.0L) and distilled to a minimum stirring volume to obtain a crude 2-(5-chloro-2-((R)-hydroxy((3aR, 4R, 6R, 6aR)-6-methoxy-2,2-dimethyltetrahydrofuran [3,4-d][1,3]dioxol-4-yl)methyl)phenyl)ethan-1-ol (crude compound 40) (5576g, 15.54mol, 172% yield; theoretical yield 3237.9g, 9.02mol), which can be directly used in the next reaction without further purification. A small amount of crude compound 40 was purified by column chromatography to give compound 40 as a colorless oil.

[0240] 1 H NMR (400 Hz, DMSO-d 6 ): δ7.44(d,J=8.8Hz,1H),7.29–7.22(m,2H),5.44(d,J=6.0Hz,1H),4.98(dd,J=6.0 ,0.9Hz,1H),4.80(s,1H),4.77(t,J=5.0Hz,1H),4.63(d,J=6.0Hz,1H),4.57(dd,J= 9.6,6.0Hz,1H),4.35(dd,J=9.5,0.9Hz,1H),3.61(dt,J=11.7,7.0Hz,2H),3.32(s, 3H),2.93-2.86(m,1H),2.77(dt,J=13.9,7.1Hz,1H),1.40(s,3H),1.29(s,3H)ppm; 13 C NMR (100 Hz, DMSO-d 6 ): δ141.02,139.45,131.91,129.88,129.68,126.19,111.83,109.61,88.52,85.08,82.46,68.69,61.87,35.40,26.78,25.18ppm.

[0241]

[0242] At 15-30°C, methyl tert-butyl ether (MTBE, 32.4 L) containing crude compound 40 (5576 g, 15.54 mol, theoretical yield 3237.9 g, 9.02 mol) was placed in a clean 100 L reactor under nitrogen. Tetramethylazodicarbonamide (TMAD, 1927 g, 11.19 mol) was charged to the solution at 15-30°C. The mixture was stirred at the temperature for 1 hour before cooling to 0-10°C. Tri-n-butylphosphine (P(n-Bu) 3 , 2614.7g, 12.92mol) was added to the solution while maintaining the internal temperature below 15°C. The resulting reaction mixture was warmed to 15-30°C and stirred within the temperature range for no less than one hour. After HPLC (standard: ≤3% of compound 40 to compound 50) indicated that the reaction was complete, a solution of NaCl (2590g, 44.32mol) in water (23.3L) was added while maintaining the batch temperature below 30°C. The organic phase was separated and distilled to a minimum stirring volume at ≤50°C under vacuum. MeOH (12.6L) was added to the resulting residue, followed by slow addition of water (7.1L). 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 collected by filtration and then washed with a mixed solvent of MeOH (3.2L) and water (3.2L). The wet cake was dried on the filter for 22 hours to give (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.

[0243] 1 H NMR (400 Hz, DMSO-d 6 ): δ7.63–7.51(m,1H),7.28–7.25(m,2H),5.06(s,1H),4.94(dd,J=6.1,1.5Hz,1H), 4.61(d,J=6.0Hz,1H),4.56–4.46(m,1H),4.17(dd,J=8.3,1.6Hz,1H),4.07(ddd,J= 11.2,5.6,3.6Hz,1H),3.68(ddd,J=11.2,9.5,4.0Hz,1H),3.36(s,3H),2.90(ddd,J =15.7,9.4,5.7Hz,1H),2.72(dt,J=16.7,3.9Hz,1H),1.38(s,3H),1.26(s,3H)ppm; 13C NMR (100 Hz, DMSO-d 6 ): δ137.18,135.18,128.81,128.28,126.33,112.11,109.99,89.48,84.58,81.31,74.78,63.05,55.66,28.68,26.98,25.35ppm.

[0244]

[0245] Compound 50 (3037 g, 8.91 mol) in 1,4-dioxane (9.1 L) was placed in a clean reactor under nitrogen at 15-25°C. Sulfuric acid (H 2 SO 4 , 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 not less than 14 hours. After HPLC indicated that the reaction was complete, the batch was cooled to 20-40 ° C. Ethyl acetate (EtOAc, 36.4 L) was charged to the reaction mixture, followed by solid NaHCO 3 The mixture was stirred for 2 hours at 15-30°C. The mixture was stirred for 2 hours at 15-30°C. The n-heptane (6.4L) was added, and the mixture was stirred for another 2 hours at 15-30°C. The obtained solid was collected by filtration, and the wet cake was washed with a mixed solvent of toluene (3.0L) and n-heptane (6.1L). The filter cake was transferred to a tray and dried in an oven at ≤35°C under vacuum to afford (3R,4S,5S)-5-((R)-6-chloroisochroman-1-yl)tetrahydrofuran-2,3,4-triol (Compound 60, 2302 g, 8.03 mol; yield 90.1%) as an off-white solid. Compound 60 was isolated from a mixture of isomers (approximately 1:1).

[0246] 1 H NMR (400 Hz, DMSO-d 6): 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 C NMR (100 Hz, DMSO-d 6 ): δ (Group 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; (Group 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 ClO 5 (Molecular weight: 286.71), LCMS (EI) m / e 285.06 [M-H] - 。

[0247]

[0248] At 15-25°C, N,N-dimethylacetamide (DMAc, 17.7 L) containing 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 a clean reactor under nitrogen. Anhydrous potassium phosphate (K 3 PO 4 , 852 g, 4.01 mol). After 30 minutes, TMAD (2022 g, 11.74 mol) was added to the reactor at 15-25 °C, followed by the addition of P(n-Bu) 3 (2381g, 11.77mol), while maintaining the internal temperature at 20-35°C. The reaction mixture was stirred at 20-35°C for no less than 16 hours. After HPLC (standard: ≤3% of compound 60 to compound VIa-3) indicated that the reaction was complete, the batch was filtered and the filtrate was collected. The reactor was rinsed with EtOAc (26.6L), and the rinse mixture was used to wash the resulting filter cake. The filtrates were combined and cooled to 0-10°C. A solution of NaCl (436g) in water (43.6L) was added to the solution 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 (2×26.6L). All organic phases were combined and washed twice with a solution of NaCl (145g) in water (14.5L). The separated organic phase was distilled to a minimum stirring volume at ≤55°C under vacuum. To the distillation residue was added MeOH (10.3 L) and subsequently a solution of concentrated hydrochloric acid (HCl, 12 M, 1.71 L, 20.5 mol) in MeOH (6.8 L) while maintaining the batch temperature below 30° C. After stirring at 15-30° C. for 30 minutes, MTBE (68.2 L) was charged. The mixture was heated to 35-45° C. for 1 hour before cooling to 0-10° C. After stirring at 0-10° C. for 1 hour, the solid was collected by filtration.

[0249] The wet cake was washed with a mixed solvent of MeOH (4.5 L) and MTBE (18.2 L). The resulting cake was dried on a filter under vacuum for 16 hours and then transferred to a clean reactor. Isopropyl alcohol (IPA, 11.8 L) and dichloromethane (DCM, 2.0 L) were loaded into the reactor. The suspension was heated to 35-45 ° C and stirred for 1 hour in the temperature range. The hot slurry was then cooled to 10-20 ° C. After stirring for 1 hour at 10-20 ° C, the solid was collected by filtration and washed with a mixed solvent of IPA (3.4 L) and DCM (0.56 L). The resulting cake was dried on the filter under vacuum for 16 hours to give (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%) as a white to off-white solid.

[0250]

[0251] At 15-25 ℃, MeOH (7.8L) containing crude compound VIa-3 (1742g, 3.97mol) is placed in a clean container. The solution is filtered into a clean reactor under nitrogen through a series filter. The container is rinsed with MeOH (0.9L), and the rinse solution is subsequently filtered into the reactor through the same series filter. The solution is distilled at atmospheric pressure, while adding polished filtered 2-propanol (IPA, 12.2L) in batches. Distillation is continued until solid precipitation is observed. The mixture is then cooled to 15-25 ℃ and stirred at the temperature for 2 hours. The solid is collected by filtration and washed with a mixed solvent of polished filtered DCM (0.57L) and IPA (3.5L). After washing with polished filtered n-heptane (5.2L), the cake is dried on the filter for 3 hours, and further dried in a drying tray under vacuum at ≤60 ℃. The dried solid is ground and passed through a 100 mesh sieve. The resulting solid was dried under vacuum at ≤60 °C in a drying tray to give (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

1. A method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound of formula (I) or a pharmaceutically acceptable salt thereof with P(R 2 ) 3 Reagents and azodicarbonate esters or azodicarbonamides combined: in X 1 Is OH or OPG 1 ; PG 1 is a hydroxyl protecting group; PG 2 PG 3 and PG 4 Each independently is H or a hydroxyl protecting group; or PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a 1,2-dihydroxy protecting group; and Each R 2 Independently C 1 -C 6 Alkyl or aryl.

2. The method according to claim 1, wherein 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:

3. The method according to claim 1 or claim 2, wherein PG 2 and PG 3 Together with the atom to which it is attached, it forms a 1,2-dihydroxy protecting group. The method of claim 3 , wherein the 1,2-dihydroxy protecting group is an acetonide moiety.

5. The method according to claim 4, wherein the compound of formula (Ia) is formula (Ia-1) or a pharmaceutically acceptable salt thereof:

6. The method according to claim 4, wherein the compound of formula (IIa) is a compound of formula (IIa-1) or a pharmaceutically acceptable salt thereof:

7. A method according to any one of the preceding claims, wherein X 1 It's OH.

8. The method according to any one of claims 1 to 6, wherein X 1 OPG 1 .

9. The method according to any one of the preceding claims, wherein the compound of formula (I) is combined with the P(R 2 ) 3 reagent, where R 2 is C 1 -C 6 alkyl, and the phosphine is trimethylphosphine, triethylphosphine, tri-n-propylphosphine or tri-n-butylphosphine.

10. The process according to claim 9, wherein the phosphine is tri-n-butylphosphine.

11. The method according to any one of claims 1 to 8, wherein the compound of formula (I) is reacted with the P(R 2 ) 3 The reagents are combined, and R 2 is an aryl group, and the phosphine is triphenylphosphine, (p-dimethylaminophenyl)diphenylphosphine or diphenyl-2-pyridylphosphine.

12. The method according to any one of claims 1 to 8, wherein the azodicarboxylic acid ester or azodicarboxamide is diisopropyl azodicarboxylate (DIAD).

13. The process according to any one of claims 1 to 8, wherein the azodicarboxylic acid ester or azodicarbonamide or a derivative thereof is tetramethylazodicarbonamide (TMAD).

14. The process according to any one of claims 1 to 8, wherein the azodicarboxylic acid ester or azodicarbonamide or a derivative thereof is diethyl azodicarboxylate (DEAD).

15. The process according to any one of the preceding claims, wherein the organic solvent is diethyl ether, tert-butyl methyl ether, dichloromethane or tetrahydrofuran or a combination thereof.

16. The method according to any one of the preceding claims, wherein the compound of formula (II) is a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein PG 1 is an acid-labile hydroxy protecting group, and wherein the compound of formula (III) or a pharmaceutically acceptable salt thereof is treated with an acid for a time and under conditions sufficient to provide a compound of formula (IV) or a pharmaceutically acceptable salt thereof:

17. The method according to claim 16, wherein the compound of formula (III) is a compound of formula (IIIa) or a pharmaceutically acceptable salt thereof:

18. The method according to claim 17, wherein the compound of formula (IIIa) is a compound of formula (IIIa-1) or a pharmaceutically acceptable salt thereof:

19. The method of claim 16, wherein the acid is an aqueous acid comprising a mixture of water and an acid capable of hydrolyzing a hydroxy protecting group.

20. The method of claim 19, wherein the acid is HCl, H 3 PO 4 or H 2 SO 4 .

21. The method of claim 19, wherein the acid is HCl.

22. The method of claim 19, wherein the acid is H 3 PO 4 .

23. The method of claim 19, wherein the acid is H 2 SO 4 .

24. The method according to any one of claims 16 to 23, further comprising: in the presence of an organic solvent, in the presence of P(R 2 ) 3 In the case of a reagent and an azodicarbonate or azodicarbonamide, the compound of formula (IV) or a pharmaceutically acceptable salt thereof is reacted with a compound of formula (V) to produce a compound of formula (VI) or a pharmaceutically acceptable salt thereof: Where G is halogen or C 1 -C 6 Alkyl; Q is NH or N - K + , and each R 2 Independently C 1 -C 6 Alkyl or aryl.

25. The method of claim 24, wherein the compound of formula (VI) is a compound of formula (VIa) or a pharmaceutically acceptable salt thereof:

26. The method of claim 24, wherein Q is N - K + .

27. The method of claim 24, wherein Q is NH.

28. A method according to claim 24 or claim 25, wherein G is halogen.

29. The method of claim 28, wherein the halogen is -Cl, -Br or -I.

30. The method of claim 28, wherein the halogen is -Cl.

31. The method of claim 24 or claim 25, wherein G is C 1 -C 6 alkyl.

32. The method of claim 31 , wherein G is methyl.

33. The method of claim 24 or claim 25, wherein R 2 It is C 1 -C 6 The phosphine reagent is trimethylphosphine, triethylphosphine, tri-n-propylphosphine or tri-n-butylphosphine.

34. The method of claim 33, wherein the phosphine reagent is tri-n-butylphosphine.

35. The method of claim 24 or claim 25, wherein R 2 is an aryl group, and the phosphine is triphenylphosphine, (p-dimethylaminophenyl)diphenylphosphine or diphenyl-2-pyridylphosphine.

36. The method of claim 35, wherein the azodicarboxylic acid ester or azodicarbonamide or a derivative thereof is diisopropyl azodicarboxylate (DIAD).

37. The method of claim 35, wherein the azodicarboxylate or azodicarbonamide or a derivative thereof is tetramethylazodicarbonamide (TMAD).

38. The method of claim 35, wherein the azodicarboxylic acid ester or azodicarbonamide or a derivative thereof is diethyl azodicarboxylate (DEAD).

39. The method according to any one of claims 24 to 38, wherein the organic solvent is diethyl ether, tert-butyl methyl ether, dichloromethane or tetrahydrofuran or a combination thereof.

40. The method according to any one of claims 24 to 39, wherein the compound of formula (V) is a compound of formula (Va):

41. The method according to any one of claims 24 to 39, wherein the compound of formula (V) is a compound of formula (Vb):

42. The method of claim 41, wherein the compound of formula (V) is compound 70:

43. The method according to any one of claims 24 to 40, wherein the compound of formula (VI) is a compound of formula (VIa-2):

44. The method according to any one of claims 24 to 39, 41 or 42, wherein the compound of formula (VI) is a compound of formula (VIa-1):

45. The method of claim 44, further comprising reacting the compound of formula (VIa-1) with an acid to form a pharmaceutically acceptable salt of the compound of formula (VIa-1).

46. ​​The method of claim 45, wherein the acid is hydrochloric acid and the compound of formula (VIa-1) is a compound of formula (VIa-3):

47. The method according to any one of the preceding claims, wherein the compound of formula (I) is a compound of formula (XXIII) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (XXIII) is prepared by reacting a compound of formula (XXI') with a compound of formula (XXII):

48. The method of claim 47, wherein PG 4 It is the THP part.

49. The method according to claim 47 or 48, wherein PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a 1,2-dihydroxy protecting group.

50. The method according to any one of claims 47 to 49, wherein the compound of formula (XXII) is compound 20:

51. The method according to any one of claims 47 to 50, wherein the compound of formula (XXIII) is compound 30:

52. The method according to any one of claims 47 to 51, further comprising reacting the compound of formula (XXIII) or a pharmaceutically acceptable salt thereof with an alcohol to produce a compound of formula (XXIII') or a pharmaceutically acceptable salt thereof:

53. The method according to claim 52, wherein PG 4 is a THP moiety.

54. The method of claim 52 or claim 53, wherein PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a 1,2-dihydroxy protecting group.

55. The method according to any one of claims 52 to 54, wherein the compound of formula (XXIII') is compound 40:

56. The method according to any one of claims 52 to 55, further comprising reacting the compound of formula (XXIII') or a pharmaceutically acceptable salt thereof with P(R 2 ) 3 The reagents are reacted to produce a compound of formula (XXV) or a pharmaceutically acceptable salt thereof:

57. The method of claim 56, wherein PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a 1,2-dihydroxy protecting group.

58. The method of claim 56 or claim 57, wherein the compound of formula (XXV) is compound 50:

59. The method according to any one of claims 55 to 58, further comprising reacting the compound of formula (XXV) or a pharmaceutically acceptable salt thereof with an acid to produce a compound of formula (XXV') or a pharmaceutically acceptable salt thereof:

60. The method of claim 59, wherein PG 2 and PG 3 Together with the oxygen atom to which it is attached, it forms a 1,2-dihydroxy protecting group.

61. A method according to claim 59 or claim 60, wherein the acid is sulfuric acid.

62. The method according to any one of claims 59 to 61, wherein the compound of formula (XXV') is compound 60:

63. The method according to claim 62, wherein the compound of formula (XXV') is a compound of formula (IVa-1) or a compound of formula (IVb-1) 64. The method according to any one of claims 24 to 46, further comprising converting the compound of formula (IV) into an epoxide of formula (IVaa) by reacting the compound of formula (IV) with P(R 2 ) 3 Reagent, azodicarbonate or azodicarbonamide to produce a compound of formula (IVaa): Each R 2 Independently C 1 -C 6 Alkyl or aryl.

65. The method of claim 64, further comprising reacting the compound of formula (IVaa) with a compound of formula (V) or a basic salt thereof, P(R 2 ) 3 Reagent, azodicarbonate or azodicarbonamide to produce a compound of formula (VIa): Where G is halogen or C 1 -C 6 Alkyl; each R 2 Independently C 1 -C 6 alkyl or aryl; and Q is -NH or N - K + .

66. The method of claim 64 or claim 65, wherein the P(R 2 ) 3 The reagent is triphenylphosphine or tributylphosphine, and the azodicarboxylate or azodicarboxamide is diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), or tetramethylazodicarboxamide (TMAD).

67. A compound which is compound 50 or a pharmaceutically acceptable salt thereof.

68. A compound which is compound 60 or a pharmaceutically acceptable salt thereof.

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