Large scale process for preparation of 5-bromopyridin-3-yl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1h-1,2,3-triazol-1-yl]- 1-thio-alpha-d-galactopyranoside and crystalline form thereof

Abstract

To provide a compound useful as a galectin-3 inhibitor for the treatment of various disorders or diseases, and a crystalline form of a salt thereof.SOLUTION: Provided is a crystalline form of 5-bromopyridin-3-yl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside having the formula (I).SELECTED DRAWING: Figure 1A

Description

Technical Field

[0001] The present invention relates to a method for preparing 5-bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, and this method can be scaled up. The method parameters are stable and this method is suitable for GMP production.

Background Art

[0002] The compound of formula I is described in International Patent Application Publication No. WO2016120403 as a galectin 3 inhibitor useful for the treatment of various disorders or diseases. The compound of formula I was produced in a small-scale experimental method with a yield of 60%, but the parameters for scale-up are not disclosed.

Summary of the Invention

[0003] The present invention relates to a new method for preparing 5-bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, and this method can be scaled up to large-scale and / or industrial scale such as 30 kg or more. This method can also be used for small-scale such as 200 g to 3 kg or medium-scale such as 3 kg to 30 kg.

[0004] In a first aspect, the present invention relates to a method for preparing 5-bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside having formula (I),

Chemical formula

Chemical formula

Chemical formula

[0005] In a further embodiment, the appropriate conditions for step a) are that a compound of formula IX (wherein R1, R2, R3 are independently selected from a protecting group or hydrogen, provided that at least one of R1, R2, and R3 is a protecting group) is reacted with trimethyl((3,4,5-trifluorophenyl)ethynyl)silane in an organic solvent at an appropriate temperature, optionally under an inert atmosphere, a catalyst is added if necessary, a base is added to the organic solvent if necessary to form a reaction mixture, the reaction mixture is heated if necessary to raise the temperature by at least 15 °C above the appropriate temperature, a basic fluoride source is added, and the reaction is continued for at least 1 hour to obtain a compound of formula X (wherein R1, R2, R3 are as defined above).

[0006] In a typical embodiment, the present invention provides a compound of formula (I)

Chemical formula

Chemical formula

Chemical formula

[0007] In one embodiment, a basic fluoride source is added. In another embodiment, a basic fluoride source is not added.

[0008] In a further embodiment, the compound of formula I is isolated as a crystalline form such as a polymorph, e.g., polymorph 1.

[0009] In another embodiment, the compound of formula I is isolated as a salt such as a sulfate, bromide, or phosphate salt, preferably as an HCl salt. Typically, a crystalline HCl salt.

[0010] In a further embodiment, the appropriate conditions for step a) are to react a compound of formula IX (wherein R1, R2, and R3 are independently selected from a protecting group or hydrogen, provided that at least one of R1, R2, and R3 is a protecting group) with 5-ethynyl-1,2,3-trifluorobenzene in an organic solvent under an inert atmosphere at an appropriate temperature, add a catalyst, add a base to the organic solvent to form a reaction mixture, heat the reaction mixture to raise the temperature by at least 15 °C from the appropriate temperature, and continue the reaction for at least 1 hour to obtain a compound of formula X (wherein R1, R2, and R3 are as defined above). In particular, under these conditions, there is no need to add a basic fluoride source such as TBAF or CsF.

[0011] In yet another embodiment, R1, R2, and R3 are independently selected from ester protecting groups such as acetyl, benzoyl, and pivaloyl, and typically all of R1, R2, and R3 are acetyl.

[0012] Compound X may be further purified and isolated as a solid. Typically, compound X is isolated, but since most of the impurities are intermediates in the deacetylation to the compound of formula I, the purification is carried out in the latter half of the process.

[0013] In a further embodiment, the reaction is carried out under an inert atmosphere such as an atmosphere of argon or nitrogen.

[0014] In another embodiment, the reaction is carried out at atmospheric pressure.

[0015] In yet another embodiment, the organic solvent is selected from toluene or polar aprotic solvents such as acetonitrile or DMF, and mixtures thereof.

[0016] In a further embodiment, the appropriate temperature is 15 - 25 °C, for example, approximately room temperature.

[0017] In yet another embodiment, the temperature of the reaction mixture is raised by heating the mixture to 40 °C - 70 °C, for example 45 °C - 70 °C, for example about 60 °C.

[0018] In a further embodiment, the reaction is continued for 1 to 3 hours, for example about 2 hours. The reaction may continue for at least 2 hours, for example 3 hours, and in many cases, it is completed within 2 hours.

[0019] In yet another embodiment, the catalyst is a metal catalyst, for example a metal halide, such as Cu(I) or Cu(II), in particular, Cu halide, such as Cu iodide.

[0020] In a further embodiment, the base is an organic base such as triethylamine or DIPEA.

[0021] In yet another embodiment, the basic fluoride source is TBAF.

[0022] In a further embodiment, the molar ratio of the compound of formula IX to trimethyl((3,4,5-trifluorophenyl)ethynyl)silane is 5:4 to 1:3, for example 1:1 to 5:7, typically 5:6, and the organic solvent is in excess.

[0023] In yet another embodiment, the molar ratio of the compound of formula IX to 5-ethynyl-1,2,3-trifluorobenzene is 5:4 to 1:3, for example 1:1 to 5:7, typically 5:6, and the organic solvent is in excess.

[0024] In a further embodiment, the molar ratio of the compound of formula IX to the catalyst is 20:1 to 2:1, for example 20:1 to 5:1, typically 10:1, and the organic solvent is in excess.

[0025] In yet another embodiment, the molar ratio of the compound of formula IX to the base is 1:1 to 1:10, for example 2:3 to 1:3, typically 1:2, and the organic solvent is in excess.

[0026] In a further embodiment, the removal of the protecting group in step b) is carried out by mixing the compound of formula X with a base in an organic solvent, optionally under an inert atmosphere, reacting at a suitable temperature for at least 15 minutes, and then washing with ether to obtain the compound of formula I. Typically, the ether is tert-butyl methyl ether (TBME). Preferably, the suitable temperature is 15-25 °C, for example, approximately room temperature. Typically, the organic solvent is an alcohol, for example C 1~6 selected from alcohols such as methanol. Further, the base is preferably selected from bases at a concentration sufficient to provide a pH of 12 or more, such as organic bases. Typically, the base is sodium methoxide in methanol, for example, a methanol solution of 25 wt% sodium methoxide. In one embodiment, the reaction with the base is for at least 1 hour, for example, 2-24 hours.

[0027] In another embodiment, the removal of the protecting group in step b) is carried out by mixing the compound of formula X with a base (such as sodium methoxide) in an organic solvent (C 1~6 such as an alcohol, for example, methanol or ethanol) under an inert atmosphere, reacting at a suitable temperature (for example, room temperature) for at least 15 minutes (for example, 1 hour), then reacting with additional base at a suitable temperature for at least 15 minutes (for example, 1 hour), then cooling the reaction mixture (for example, to 5 °C), then washing with an alcohol (C 1~6 such as an alcohol, for example, methanol or ethanol), drying (for example, under vacuum at 60 °C), adding an alcohol (C 1~6 such as an alcohol, for example, methanol or ethanol, ethanol, etc.), heating until a solution is formed, then cooling (such as to 5 °C), filtering, washing (for example, with ethanol), precipitating, drying the crystallization product (such as at 60 °C), washing with ether (such as TBME) under cooling (such as at 5 °C) to obtain the compound of formula I in a continuous process.

[0028] In a further embodiment, the method of the present invention is a step immediately before step a), (ia) formula VIII

Chemical formula

[0029] In one embodiment, the compound of formula IX is obtained as a solid.

[0030] In a further embodiment, the deprotonating agent is sodium bis(trimethylsilyl)amide.

[0031] In yet another embodiment, R1, R2, R3 are all acetyl groups and R4 is as defined above. Preferably, R4 is chlorine.

[0032] In a further embodiment, the reaction is carried out under an inert atmosphere. Typically, it is under an argon or nitrogen atmosphere.

[0033] In yet another embodiment, the organic solvent is selected from the group consisting of ethyl acetate, THF, toluene, DMF, and acetonitrile, and mixtures thereof.

[0034] In a further embodiment, the suitable conditions for step (ia) are that the compound of formula VIII (wherein R1, R2, R3 and R4 are as defined above) Optionally, under an inert atmosphere, at an appropriate temperature, in an organic solvent, react 5-bromopyridine-3-thiol with a base, maintain the reaction mixture at the appropriate temperature, then continue the reaction for at least 15 minutes, and isolate and purify as necessary to obtain the compound of formula IX as a solid. Preferably, after cooling the base below room temperature, add 5-bromopyridine-3-thiol at an appropriate time and temperature, and then add the compound of formula VIII.

[0035] In yet another embodiment, the appropriate temperature is less than 25 °C.

[0036] In a further embodiment, the reaction is continued at an appropriate temperature for at least 2 hours, for example 16 to 72 hours.

[0037] In yet another embodiment, the molar ratio of the compound of formula VIII to the base is 1:1 to 1:3, for example 5:7.

[0038] In still a further embodiment, the method of the present invention is a step immediately before step ia), (ib) formula VII

Chemical formula

[0039] In an embodiment, the reaction is carried out under an inert atmosphere such as an atmosphere of argon or nitrogen.

[0040] In a further embodiment, the organic solvent is an aprotic solvent, preferably dichloromethane, toluene or α,α,α-trifluorotoluene, and mixtures thereof.

[0041] In a further embodiment, the reagent for activating the anomeric position for nucleophilic substitution is a halogenating agent. Typically, the halogenating agent is a metal halide, such as AlCl3, or SOCl2, dichloromethyl methyl ether (DCMME), or a phosphorus halide. Preferably, the halogenating agent is PCl5.

[0042] In a further embodiment, the catalyst is an acid such as a Lewis acid, preferably BF3·OEt2.

[0043] In yet another embodiment, the suitable conditions include a suitable temperature of 15 to 45 °C. In a further embodiment, the reaction is continued at the suitable temperature for at least 15 hours, at least 1 / 2 hour, for example 12 to 96 hours.

[0044] In yet another embodiment, the molar ratio of the compound of formula VII to the reagent for activating the anomeric position for nucleophilic substitution such as a halogenating agent is 5:1 to 1:5, typically 5:6.

[0045] In a further embodiment, the molar ratio of the compound of formula VII to the catalyst is from 10:1 to 200:1, typically 100:1.

[0046] In yet another aspect, the present invention relates to a method for preparing compounds of formula III and formula IV starting from a compound of formula II.

Chemical formula

[0047] In a further aspect, the present invention relates to preparing a compound of formula VI starting from a compound of formula V.

Chemical formula

[0048] <Further Embodiments of the Present Invention> Embodiment 1. Formula (I)

Chemical formula

Chemical formula

Chemical formula

[0049] 2. The method according to embodiment 1, wherein suitable conditions for step a) are such that a compound of formula IX (wherein R1, R2, and R3 are independently selected from a protecting group or hydrogen, provided that at least one of R1, R2, and R3 is a protecting group) is reacted with trimethyl((3,4,5-trifluorophenyl)ethynyl)silane in an organic solvent at a suitable temperature, optionally under an inert atmosphere, a catalyst and optionally a base are added to the organic solvent to form a reaction mixture, the reaction mixture is optionally heated to raise the temperature by at least 15 °C above the suitable temperature, a basic fluoride source is added, and the reaction is continued for at least 1 hour to obtain a compound of formula X (wherein R1, R2, and R3 are as defined above).

[0050] 3. The method according to any one of embodiments 1 to 2, wherein R1, R2, and R3 are independently selected from ester protecting groups.

[0051] 4. The method according to any one of embodiments 1 to 3, wherein the reaction is carried out under an inert atmosphere.

[0052] 5. The method according to any one of embodiments 1 to 4, wherein the organic solvent is selected from toluene or a polar aprotic solvent.

[0053] 6. The method according to any one of embodiments 1 to 5, wherein the suitable temperature is 15 to 25 °C.

[0054] 7. The method according to any one of embodiments 1 to 6, wherein the temperature of the reaction mixture is raised by heating the mixture to 45 °C to 70 °C.

[0055] 8. The method according to any one of Embodiments 1 to 7, wherein the reaction is continued for at least 2 hours.

[0056] 9. The method according to any one of Embodiments 1 to 8, wherein the catalyst is a metal catalyst.

[0057] 10. The method according to any one of Embodiments 1 to 9, wherein the base is an organic base.

[0058] 11. The method according to any one of Embodiments 1 to 10, wherein the basic fluoride source is TBAF.

[0059] 12. The method according to any one of Embodiments 1 to 11, wherein the removal of the protecting group in step b) is carried out by mixing a compound of formula X with a base in an organic solvent, optionally under an inert atmosphere, reacting at a suitable temperature for at least 15 minutes, and then washing with ether to obtain the compound of formula I.

[0060] 13. The method according to Embodiment 12, wherein the ether is TBME.

[0061] 14. The method according to any one of Embodiments 12 to 13, wherein the suitable temperature is 15 to 25 °C.

[0062] 15. The method according to any one of Embodiments 12 to 14, wherein the organic solvent is selected from alcohols.

[0063] 16. The method according to any one of Embodiments 12 to 15, wherein the base is selected from bases at a concentration sufficient to provide a pH of 12 or higher.

[0064] 17. The method according to any one of Embodiments 12 to 16, wherein the base is sodium methoxide in methanol.

[0065] 18. The method according to any one of Embodiments 12 to 17, wherein the reaction with the base is at least 1 hour.

[0066] 19. The method according to any one of Embodiments 1 to 18, wherein the molar ratio of the compound of Formula IX to trimethyl((3,4,5-trifluorophenyl)ethynyl)silane is from 5:4 to 1:3, and the organic solvent is in excess.

[0067] 20. The method according to Embodiment 19, wherein the molar ratio of the compound of Formula IX to the catalyst is from 20:1 to 2:1, and the organic solvent is in excess.

[0068] 21. The method according to Embodiment 19 or 20, wherein the molar ratio of the compound of Formula IX to the base is from 1:1 to 1:10, and the organic solvent is in excess.

[0069] 22. A step immediately before step a), (ia) A compound of Formula VIII

Chemical formula

[0070] 23. The method according to any one of Embodiments 21 to 22, wherein the deprotonating agent is sodium bis(trimethylsilyl)amide.

[0071] 24. The method according to any one of Embodiments 21 to 23, wherein R1, R2, and R3 are all acetyl groups, and R4 is as defined above.

[0072] 25. The method according to any one of Embodiments 21 to 24, wherein R4 is chlorine.

[0073] 26. The method according to any one of Embodiments 21 to 25, wherein the reaction is carried out under an inert atmosphere.

[0074] 27. The method according to any one of Embodiments 21 to 26, wherein the organic solvent is selected from the group consisting of ethyl acetate, THF, toluene, DMF, and acetonitrile, and mixtures thereof.

[0075] 28. Appropriate conditions for step (ia) are to react a compound of formula VIII (wherein R1, R2, R3, and R4 are as defined above) optionally under an inert atmosphere, at an appropriate temperature, in an organic solvent, with 5-bromopyridine-3-thiol and a base, maintaining the reaction mixture at the appropriate temperature, then continuing the reaction for at least 15 minutes, and optionally isolating and purifying to obtain the compound of formula IX as a solid, according to the method of any one of Embodiments 21 to 27.

[0076] 29. The method according to Embodiment 28, wherein the base is cooled below room temperature, then 5-bromopyridine-3-thiol is added at an appropriate time and temperature, followed by addition of the compound of formula VIII.

[0077] 30. The method according to Embodiment 28 or 29, wherein the appropriate temperature is less than 25°C.

[0078] 31. The method according to any one of Embodiments 28 to 30, wherein the reaction is continued at the appropriate temperature for at least 1 / 2 hour.

[0079] 32. The method according to any one of Embodiments 28 to 31, wherein the molar ratio of the compound of formula VIII to the base is 1:1 to 1:3.

[0080] 33. The step immediately preceding step ia), (ib) formula VII

Chemical formula

[0081] 34. A crystalline form of 5-bromo-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside having formula (I).

[0082] 35. The crystalline form according to Embodiment 34, which is Polymorph 1 identified by the XRPD diffractogram of FIG. 1A.

[0083] 36. The crystalline form according to Embodiment 34, which is a hydrochloride.

Brief Description of the Drawings

[0084]

Figure 1A

Figure 1B

Figure 1C

Figure 1D

Figure 1E

Figure 1F

Figure 1G

Figure 2

Figure 3

DETAILED DESCRIPTION OF THE INVENTION

[0085] The compound of formula (I) has the chemical name (IUPAC) of 5-bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside and can be prepared as described in International Publication No. WO 2016 / 120403. The yield is relatively low and it is impossible to directly scale up the method.

[0086] Furthermore, throughout this application, the terms "compound of formula I" or "compound having formula I" or "5-bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside having formula I" are used synonymously and mean the compound of formula I in any solid or liquid form, particularly in crystalline forms such as polymorphs or amorphous forms, and further including its free form, any solvate or any salt.

[0087] As used herein, the term "alcoholytic" refers to a transesterification reaction in which an ester R'COOR1' reacts with an alcohol R2'OH to form another ester R'COOR2' and liberate the alcohol R1'OH. Deacylation may be catalyzed by lipase in an organic solvent and constitutes a useful step in the synthesis of complex molecules having different groups. A suitable reference for explaining this is deacylation catalyzed by lipase by alcoholysis. A selective, useful transesterification reaction by Santaniello, Enzo; Casati, Silvana; Ciuffreda, Pierangela Current Organic Chemistry (2006), 10(10), 1095 - 1123 | Language: English, Database: CAplus.

[0088] As a result, for formula (I)

Chemical formula

Chemical formula

[0089] In one embodiment, the compound of formula I is obtained as a solid product, such as a crystalline or amorphous product. In one embodiment, the compound of formula I is isolated as a crystal, such as a polymorph. Preferably, the compound of formula I is isolated as polymorph 1. In another embodiment, the compound of formula I is isolated as a salt, such as an HCl salt. Typically, a crystalline HCl salt

[0090] In a further embodiment, the appropriate conditions for step a) are that a compound of formula IX (wherein, R1, R2, and R3 are an acetyl group or hydrogen, provided that at least one of R1, R2, and R3 is an acetyl group) is reacted with silane-protected 5-ethynyl-1,2,3-trifluorobenzene at a suitable temperature of 15-25 °C in toluene or a polar aprotic solvent, and mixtures thereof, and if necessary, under an inert atmosphere, a catalyst is added, and if necessary, a base is added to the organic solvent to form a reaction mixture, and if necessary, the reaction mixture is heated to raise the temperature by at least 15 °C from the suitable temperature, a basic fluoride source agent is added, and the reaction is continued for at least 1 hour to obtain a compound of formula X (wherein, R1, R2, and R3 are as defined above)

[0091] In yet another embodiment, suitable conditions for step a) are to react a compound of formula IX (wherein R1, R2, and R3 are acetyl groups or hydrogen, provided that at least one of R1, R2, and R3 is an acetyl group) with 5-ethynyl-1,2,3-trifluorobenzene in toluene or a polar aprotic solvent, and mixtures thereof, at a suitable temperature of 15 to 25 °C, optionally under an inert atmosphere, add a catalyst, optionally add a base to the organic solvent to form a reaction mixture, optionally heat the reaction mixture to raise the temperature by at least 15 °C above the suitable temperature, and continue the reaction for at least 1 hour to obtain a compound of formula X (wherein R1, R2, and R3 are as defined above).

[0092] In a further embodiment, suitable conditions for step a) are to react a compound of formula IX (wherein R1, R2, and R3 are acetyl groups or hydrogen, provided that at least one of R1, R2, and R3 is an acetyl group) with trimethyl((3,4,5-trifluorophenyl)ethynyl)silane in toluene or a polar aprotic solvent, and mixtures thereof, at a suitable temperature of 15 to 25 °C, optionally under an inert atmosphere, add a catalyst, optionally add a base to the organic solvent to form a reaction mixture, optionally heat the reaction mixture to raise the temperature by at least 15 °C above the suitable temperature, add a basic fluoride source, and continue the reaction for at least 1 hour to obtain a compound of formula X (wherein R1, R2, and R3 are as defined above).

[0093] In yet another embodiment, R1, R2, and R3 are independently selected from ester protecting groups such as acetyl, benzoyl, and pivaloyl, and typically all of R1, R2, and R3 are acetyl.

[0094] Compound X may be further purified and isolated as a solid. Typically, compound X is isolated, but since most of the impurities are intermediates in the deacetylation to the compound of formula I, purification is carried out later in the process.

[0095] In a further embodiment, the reaction is carried out under an inert atmosphere such as an argon or nitrogen atmosphere.

[0096] In yet another embodiment, the organic solvent is selected from toluene or polar aprotic solvents such as acetonitrile or DMF, and mixtures thereof.

[0097] In a further embodiment, the appropriate temperature is 15 - 25 °C, for example, approximately room temperature.

[0098] In yet another embodiment, the temperature of the reaction mixture is increased by heating the mixture to 40 °C - 70 °C, for example 45 °C - 70 °C, for example about 60 °C.

[0099] In a further embodiment, the reaction is continued for at least 2 hours, for example 3 hours, for example 2.5 - 4 hours.

[0100] In yet another embodiment, the catalyst is a metal catalyst, for example a metal halide, such as Cu(I) or Cu(II), in particular, copper halide, such as copper iodide.

[0101] In a further embodiment, a base is present. Typically, the base is an organic base such as triethylamine or DIPEA.

[0102] In yet another embodiment, the basic fluoride source is TBAF.

[0103] In yet another embodiment, the molar ratio of the compound of formula IX to trimethyl((3,4,5 - trifluorophenyl)ethynyl)silane is 5:4 - 1:3, for example 1:1 - 5:7, typically 5:6, and the organic solvent is in excess.

[0104] In a further embodiment, the molar ratio of the compound of formula IX to the catalyst is 20:1 - 2:1, for example 20:1 - 5:1, typically 10:1, and the organic solvent is in excess.

[0105] In yet another embodiment, the molar ratio of the compound of formula IX to the base is from 1:1 to 1:10, for example 2:3 to 1:3, typically 1:2, and the organic solvent is in excess.

[0106] In a further embodiment, the removal of the protecting group in step b) is carried out by mixing the compound of formula X with a base in an alcohol, optionally under an inert atmosphere, at a concentration sufficient to provide a pH of 12 or more, reacting at a suitable temperature of 15 to 25 °C for at least 15 minutes, and subsequently washing with an alkyl ether to obtain the compound of formula I. Typically, the ether is tert-butyl methyl ether (TBME). Preferably, the suitable temperature is 15 to 25 °C, for example, approximately room temperature. Typically, the organic solvent is an alcohol, for example C 1~6 selected from alcohols such as methanol. Further, the base is preferably selected from bases at a concentration sufficient to provide a pH of 12 or more, such as organic bases. Typically, the base is sodium methoxide in methanol, for example, a methanol solution of 25 wt% sodium methoxide.

[0107] Typically, for the direct removal of the acetyl protecting group, deprotection is carried out under hydrolysis (catalytic acidic or basic) conditions or using a nucleophile, and in particular, alcoholysis basic conditions are preferred.

[0108] In one embodiment, the reaction with the base is for at least 1 hour, for example 2 to 24 hours.

[0109] In a further embodiment, the method of the present invention is a step immediately before step a), (ia) formula VIII

Chemical formula

[0110] In one embodiment, the compound of formula IX is obtained as a solid.

[0111] In a further embodiment, the deprotonating agent is sodium bis(trimethylsilyl)amide.

[0112] In yet another embodiment, R1, R2, and R3 are all acetyl groups, and R4 is as defined above. Preferably, R4 is chlorine.

[0113] In a further embodiment, the reaction is carried out under an inert atmosphere. Typically, it is under an argon or nitrogen atmosphere.

[0114] In yet another embodiment, the organic solvent is selected from the group consisting of ethyl acetate, THF, toluene, DMF, and acetonitrile, and mixtures thereof.

[0115] In a further embodiment, suitable conditions for step (ia) are to react a compound of formula VIII (wherein R1, R2, and R3 are all acetyl groups and R4 is a halogen) with 5-bromopyridine-3-thiol and a base, such as a base selected from NaH, KOtBu, KOH, sodium bis(trimethylsilyl)amide, and / or a carbonate base, such as K2CO3 and / or Cs2CO3, in an organic solvent selected from ethyl acetate, THF, toluene, DMF, and acetonitrile, and mixtures thereof, at a suitable temperature below 25 °C, optionally under an inert atmosphere, maintain the reaction mixture at the suitable temperature, then continue the reaction for at least 15 minutes, and optionally isolate and purify to obtain the compound of formula IX as a solid. Preferably, after cooling the base below room temperature, 5-bromopyridine-3-thiol is added at a suitable time and temperature, followed by addition of the compound of formula VIII.

[0116] In yet another embodiment, the suitable temperature is below 25 °C.

[0117] In a further embodiment, the reaction is continued at a suitable temperature for at least 2 hours, such as 16 to 72 hours.

[0118] In yet another embodiment, the molar ratio of the compound of formula VIII to the base is from 1:1 to 1:3, such as 5:7.

[0119] In still a further embodiment, the method of the present invention is a step immediately preceding step ia), (ib) formula VII

Chemical formula

[0120] In one embodiment, R1, R2, and R3 are acetyl groups or hydrogen, provided that at least one of R1, R2, and R3 is an acetyl group, and R4' is OR5 (where R5 is selected from Z'''-C alkyl where Z''' is C=O), using a halogenating agent, in an aprotic solvent, using an acid catalyst, optionally under an inert atmosphere, at a temperature of 15-45 °C for at least 15 minutes, to obtain a compound of formula VIII (wherein R1, R2, and R3 are independently selected from acetyl groups or hydrogen, provided that at least one of R1, R2, and R3 is an acetyl group and R4 is Cl or Br). 1~6 A compound of formula VIII (wherein R1, R2, and R3 are independently selected from acetyl groups or hydrogen, provided that at least one of R1, R2, and R3 is an acetyl group and R4 is Cl or Br) is obtained using a halogenating agent, in an aprotic solvent, using an acid catalyst, optionally under an inert atmosphere, at a temperature of 15-45 °C for at least 15 minutes.

[0121] In an embodiment, the reaction is carried out under an inert atmosphere such as an argon or nitrogen atmosphere.

[0122] In a further embodiment, R4 is Cl or Br, for example Cl.

[0123] In a further embodiment, the organic solvent is an aprotic solvent, preferably dichloromethane, toluene or α,α,α-trifluorotoluene, and mixtures thereof.

[0124] In yet another embodiment, the reagent for activating the anomeric position for nucleophilic substitution is a halogenating agent. Typically, the halogenating agent is a metal halide such as AlCl3, or a halogenating agent such as SOCl2, dichloromethyl methyl ether (DCMME), or a phosphorus halide. Preferably, the halogenating agent is PCl5.

[0125] In a further embodiment, the catalyst is an acid such as a Lewis acid, preferably BF3·OEt2.

[0126] In yet another embodiment, suitable conditions include a suitable temperature of 15 to 45 °C. In a further embodiment, the reaction is continued at the suitable temperature for at least 15 hours, at least 1 / 2 hour, for example 1 to 96 hours.

[0127] In yet another embodiment, the molar ratio of the compound of formula VII to the reagent for activating the anomeric position for nucleophilic substitution such as a halogenating agent is 5:1 to 1:5, typically 5:6.

[0128] In a further embodiment, the molar ratio of the compound of formula VII to the catalyst is 10:1 to 200:1, typically 100:1.

[0129] In a further aspect, the present invention relates to a method for preparing the compounds of formula III and formula IV starting from the compound of formula II.

Chemical formula

[0130] A further aspect relates to a method for preparing a compound of formula III, comprising: a) treating 3,5-dibromopyridine (II) in an organic solvent in the presence of a basic bromide source such as TBAB at a suitable temperature, optionally under an inert atmosphere; and b) adding benzyl mercaptan to obtain the compound of formula III.

[0131] A further aspect relates to a method for preparing a compound of formula IV, comprising a) treating 5-bromo-3-mercaptobenzylpyridine (III) with a reducing agent such as AlCl3 in an organic solvent at a suitable temperature to obtain a compound of formula IV.

[0132] Furthermore, a method for preparing a compound of formula VI starting from a compound of formula V,

Chemical Formula

[0133] Yet another aspect relates to a crystalline form of the compound of formula I. In one embodiment, the crystalline form is polymorph 1 identified by the XRPD diffractograms of FIGS. 1A and 2.

[0134] In a further embodiment, the crystalline form of the compound of formula I comprises the following 17 characteristic XRPD peaks.

Table 1

[0135] A further aspect relates to a salt of the compound of formula I, preferably the HCl salt of the compound of formula I, identified by the XRPD diffractogram of FIG. 3.

[0136] The alpha and beta anomers can be separated by various methods, for example via crystallization. However, in the case of the present method, the starting point can be the mixture as well as one of the anomers.

[0137] As used herein, the terms "treatment" and "treating" mean the management and care of a patient for the purpose of combating a condition such as a disease or disorder. This term is intended to encompass the full range of treatment for a given condition from which a patient suffers, e.g., to alleviate symptoms or complications, to slow the progression of a disease, disorder or condition, to relieve or reduce symptoms and complications, and / or to cure or eliminate a disease, disorder or condition, and also to prevent a condition, where prevention should be understood as the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of an active compound to prevent the onset of symptoms or complications. The disease or disorder to be treated is preferably selected from the group consisting of: inflammation; fibrosis, e.g., pulmonary fibrosis, hepatic fibrosis, renal fibrosis, ophthalmic fibrosis as well as skin and cardiac fibrosis; scarring; keloid formation; abnormal scarring; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancer, e.g., carcinoma, sarcoma, leukemia and lymphoma, e.g., T cell lymphoma; metastatic cancer; autoimmune diseases, e.g., psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, intestinal fibrosis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; aortic stenosis, atherosclerosis, pathological angiogenesis, e.g., ocular angiogenesis, or diseases or conditions associated with ocular angiogenesis, e.g., angiogenesis associated with cancer; and eye diseases, e.g., age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistance; obesity; diastolic HF; asthma and other interstitial lung diseases, e.g., Hermansky-Pudlak syndrome, pulmonary arterial hypertension, RA-ILD, SSc-ILD, COPD and asthma, such as fibrotic lung diseases. Otosclerosis, mesothelioma; liver disorders, e.g., non-alcoholic steatohepatitis or non-alcoholic fatty liver disease, cirrhosis of various origins, e.g., alcoholic and non-alcoholic autoimmune cirrhosis, e.g., primary biliary cirrhosis and sclerosing cholangitis, virus-induced cirrhosis, cirrhosis induced by genetic diseases.Liver cancer, bile duct cancer, biliary tract cancer in mammals such as humans; neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, cognitive impairment, cerebrovascular diseases such as stroke, traumatic brain injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, peripheral nephropathy, and administering a therapeutically effective amount of a composition comprising a compound of formula I of the present invention, such as an amorphous solid dispersion composition or a drug layered composition.

[0138] Another aspect of the present invention relates to a combination therapy comprising administering a composition of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, together with a therapeutically active compound different from the compound of formula (I) (synonymous with "different therapeutically active compound"). In one embodiment, the present invention relates to a combination of a composition comprising a compound of formula (I) of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, and a different therapeutically active compound for use in the treatment of disorders related to the binding of galectin-3 to mammalian ligands. Such disorders are disclosed below.

[0139] In one embodiment of the present invention, a therapeutically effective amount of at least one composition of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, is administered to a mammal in need of treatment in combination with a different therapeutically active compound. In a further embodiment, the combination of a composition of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, and a different therapeutically active compound is used for treating inflammation; fibrosis, such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, ophthalmic fibrosis, and dermal and cardiac fibrosis; scarring; keloid formation; abnormal scar formation; surgical adhesions; septic shock; cancer, such as carcinoma, sarcoma, leukemia, and lymphoma, such as T cell lymphoma; metastatic cancer; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; pathological angiogenesis, such as ocular angiogenesis or diseases or conditions associated with ocular angiogenesis, such as angiogenesis associated with cancer; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistance; obesity; dilated HF; asthma and other interstitial lung diseases, such as Hermansky-Pudlak syndrome, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease in a mammal suffering from a disorder selected from the group consisting of.

[0140] Compositions comprising a compound of formula (I) of the present invention, such as amorphous solid dispersion compositions or drug-layered compositions, can be used for the treatment, management, and / or prevention of cancer by administering them in combination with different therapeutically active compounds. A non-limiting group of cancers that can be treated includes colon cancer, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchiogenic lung cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioblastoma, schwannoma, craniopharyngioma, schwannocytoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, epithelioma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia and lymphoma, acute lymphoblastic leukemia and acute myeloid true erythrocytosis, multiple myeloma, Waldenström macroglobulinemia and heavy chain disease, acute non-lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, rectal cancer, urinary tract cancer, uterine cancer, oral cancer, skin cancer, gastric cancer, brain tumor, liver cancer, laryngeal cancer, esophageal cancer, breast tumor, childhood-null acute lymphoblastic leukemia (ALL), thymic ALL, B-cell ALL, acute myeloid leukemia, myelomonocytic leukemia, acute megakaryocytic leukemia, Burkitt lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and T-cell leukemia, small cell and large non-small cell lung cancer, acute granulocytic leukemia, germ cell tumor, endometrial cancer, gastric cancer, head and neck cancer, chronic lymphocytic leukemia, hairy cell leukemia, and thyroid cancer.

[0141] In some embodiments of the present invention, administration of at least one composition of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, and at least one additional therapeutic agent exhibits a therapeutic synergistic effect. In some embodiments of the methods of the present invention, the measured value of the response to treatment observed after administration of both at least one composition of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, and an additional therapeutic agent is improved compared to the same measured value of the response to treatment observed after administration of either at least one compound of formula (I) of the present invention or the additional therapeutic agent alone.

[0142] A further aspect of the present invention relates to a combination therapy, which comprises administering to a mammal in need of combination therapy a composition comprising a compound of formula (I) of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, together with an anti-fibrotic compound different from the compound of formula (I). In a further embodiment, such anti-fibrotic compounds can be selected from the following non-limiting group of anti-fibrotic compounds: pirfenidone, nintedanib, simtuzumab (GS-6624, AB0024), BG00011 (STX100), PRM-151, PRM-167, PEG-FGF21, BMS-986020, FG-3019, MN-001, IW001, SAR156597, GSK2126458, PAT-1251 and PBI-4050.

[0143] Yet another aspect of the present invention relates to a combination therapy comprising administering to a mammal in need of treatment a composition comprising a compound of formula (I) of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, in combination with a further conventional cancer treatment, such as chemotherapy or radiotherapy, or treatment with an immunostimulant, gene therapy, treatment with an antibody and treatment using dendritic cells.

[0144] In one embodiment, a composition comprising a compound of formula (I) of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, is administered together with at least one additional therapeutic agent selected from anti-tumor chemotherapeutic agents. In a further embodiment, the anti-tumor chemotherapeutic agent is all-trans retinoic acid, actinomycin D, azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, irinotecan, lenalidomide, leucovorin, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, revlimid, temozolomide, teniposide, thioguanine, valrubicin, vinblastine, vincristine, vindesine and vinorelbine. In one embodiment, the chemotherapeutic agent for use in combination with the present agent may itself be a combination of different chemotherapeutic agents. Suitable combinations include FOLFOX and IFL. FOLFOX is a combination comprising 5-fluorouracil (5-FU), leucovorin and oxaliplatin. IFL treatment includes irinotecan, 5-FU and leucovorin.

[0145] In a further embodiment of the present invention, further conventional cancer treatments include radiotherapy. In some embodiments, radiotherapy includes local radiotherapy delivered to the tumor. In some embodiments, radiotherapy includes whole body irradiation.

[0146] In other embodiments of the present invention, additional cancer treatments are selected from the group of immune activating substances such as cytokines and antibodies. Such cytokines can be selected from, but are not limited to, the group consisting of GM-CSF, type I IFN, interleukin 21, interleukin 2, interleukin 12, and interleukin 15. The antibody is preferably an immune activating antibody such as an anti-CD40 antibody or an anti-CTLA-4 antibody. The immune activating substance may also be a substance capable of depleting immunosuppressive cells (such as regulatory T cells) or factors, and the substance may be, for example, an E3 ubiquitin ligase. E3 ubiquitin ligases (HECT, RING, and U box proteins) have emerged as important molecular regulators of immune cell function and can be involved in the regulation of the immune response during infection by targeting specific inhibitory molecules for proteolytic destruction. Some HECT and RING E3 proteins are also currently associated with the induction and maintenance of immune self-tolerance, and c-Cbl, Cbl-b, GRAIL, Itch, and Nedd4 negatively regulate the production and proliferation of T cell growth factors, respectively.

[0147] In some embodiments of the present invention, the compound of formula (I) is administered with at least one additional therapeutic agent selected from checkpoint inhibitors. In some embodiments of the present invention, the checkpoint inhibitor acts on one or more of the following non-limiting target groups: CEACAM1, galectin-9, TIM3, CD80, CTLA4, PD-1, PD-L1, HVEM, BTLA, CD160, VISTA, B7-H4, B7-2, CD155, CD226, TIGIT, CD96, LAG3, GITF, OX40, CD137, CD40, IDO and TDO. These are known targets, and some of these targets are described in Melero et al., Nature Reviews Cancer (2015). Examples of checkpoint inhibitors administered with the compound of formula (1) are anti-PD-1: nivolumab, pembrolizumab, cemiplimab. Anti-PD-L1: atezolizumab, avelumab, durvalumab and one anti-CTLA-4: ipilimumab. Each of these checkpoint inhibitors can be the subject of embodiments in combination with any one of the compounds of formula (1).

[0148] In some embodiments of the present invention, the compound of formula (I) is administered with at least one additional therapeutic agent selected from inhibitors of indoleamine-2,3-dioxygenase (IDO).

[0149] In some embodiments of the present invention, the compound of formula (I) is administered with at least one additional therapeutic agent selected from one or more inhibitors of the CTLA4 pathway. In some embodiments, the inhibitor of the CTLA4 pathway is selected from one or more antibodies against CTLA4.

[0150] In some embodiments of the present invention, the compound of formula (I) is administered together with at least one additional therapeutic agent selected from one or more inhibitors of the PD-1 / PD-L pathway. In some embodiments, one or more inhibitors of the PD-1 / PD-L pathway are selected from one or more antibodies or antibody fragments against PD-1, PD-L1, and / or PD-L2, or other methods capable of inducing anti-PD1 antibodies, such as mRNA-based introduction of genetic material that exhibits in vivo production of anti-PD1 or anti-PDL1 antibodies or fragments of such antibodies.

[0151] As used herein, "pharmaceutically acceptable additives" are intended to include, but are not limited to, carriers, excipients, diluents, adjuvants, colorants, fragrances, preservatives, etc. that those skilled in the art would consider for use in formulating the compounds of the present invention for the manufacture of pharmaceutical compositions.

[0152] The adjuvants, diluents, excipients, and / or carriers that can be used in the compositions of the present invention must be pharmaceutically acceptable in the sense that they are compatible with the compound of formula (I) and the other components of the pharmaceutical composition and are not harmful to its recipient. The composition preferably does not contain substances that may cause adverse reactions such as allergic reactions. The adjuvants, diluents, excipients, and carriers that can be used in the pharmaceutical compositions of the present invention are well known to those skilled in the art.

[0153] Further embodiments of the method are described in the experimental section herein, and the individual methods as well as each starting material constitute embodiments that can form part of the embodiments.

[0154] The above embodiments should be regarded as referring to any one of the aspects described herein (such as "treatment method", "pharmaceutical composition", "compound for use as a medicament", or "compound for use in a method") and any one of the embodiments described herein, unless it is specified that the embodiment relates to a particular aspect or aspects of the present invention.

[0155] All references, including publications, patent applications, and patents, cited in this specification are hereby incorporated by reference in their entirety to the same extent as if each reference had been individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0156] All headings and subheadings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0157] Any combination of the above elements in all possible variations is included in the invention unless otherwise indicated herein or clearly inconsistent with the context.

[0158] The terms "a," "an," "the," and similar referents used in the context of describing the invention are to be construed to cover both the singular and the plural forms unless otherwise indicated herein or clearly inconsistent with the context.

[0159] The recitation of a range of values herein is merely intended to serve as a shorthand method of referring individually to each separate value within the range, and each separate value is incorporated herein as if it were individually recited herein. Unless otherwise indicated, all exact values provided herein represent corresponding approximate values (e.g., all exact exemplary values provided for a particular factor or measurement value can be considered to also provide the corresponding approximate measurement value modified by "about" as necessary).

[0160] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly inconsistent with the context.

[0161] All examples provided in this specification, or the use of exemplary language (e.g., "such as"), are merely intended to make the understanding of the present invention easier and, unless otherwise indicated, do not limit the scope of the present invention. No language in the specification should be construed as indicating an essential element for the implementation of the present invention unless explicitly stated.

[0162] The citation and incorporation of patent documents in this specification are for convenience only and do not reflect any opinion on the validity, patentability, and / or enforceability of such patent documents.

[0163] The description in this specification of any aspect or embodiment of the present invention using terms such as "comprising", "having", "including", or "containing" with respect to one or more elements is, unless otherwise stated or clearly inconsistent with the context, intended to provide support for similar aspects or embodiments of the invention that "consist of", "consist essentially of", or "substantially comprise" the specific element or elements (e.g., a composition described herein as including a specific element should be understood, unless otherwise stated or clearly inconsistent with the context, as also describing a composition consisting of that element).

[0164] This invention includes, to the maximum extent permitted by applicable law, all modifications and equivalents of the subject matter recited in the aspects or claims presented herein.

[0165] The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of protection. The features disclosed in the foregoing description and the following examples can be materials for implementing the present invention in its various forms, separately and in any combination thereof.

Examples

[0166] <Experiment>

Chemical Formula

[0167] <General Procedure> Nuclear magnetic resonance (NMR) spectra were recorded at 25 °C on a 400 MHz Bruker Avance AV400 spectrometer. Chemical shifts are reported in ppm (δ) using the residual solvent as an internal standard. Peak multiplicities are represented as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet.

[0168] Powder X-ray diffraction patterns were collected in reflection mode on a Scintag X1 diffractometer using Cu Kα irradiation (45 kV, 40 mA) in continuous coupled 2-theta / theta mode from 7 to 37°, with a collection time of 15 minutes per 0.05 degree per sample point, a custom collimator with a divergence slit of approximately 1 mm, and a scatter guard slit of 0.5 mm.

[0169] Sample Preparation: Samples run under ambient conditions were prepared as flat specimens by placing the isolated solid in a high-throughput sample holder.

[0170] The following abbreviations are used. Ac: acetyl aq.: aqueous DCM: dichloromethane DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide MP-TMT: macro-porous polystyrene-bound trimercaptotriazine Sat.: saturated TBAB: tetra-n-butylammonium bromide TBAF: tetra-n-butylammonium fluoride TBME: tert-Butyl Methyl Ether TLC: Thin Layer Chromatography XRPD: X-Ray Powder Diffraction

[0171] <5-Bromopyridine-3-thiol>

Chem.

Chem.

[0172] Into a jacketed vessel, AlCl3 (4.35 kg, 32.6 mol) and toluene (16.1 L) were charged, the mixture was stirred and cooled to -5 °C. While maintaining the temperature below 5 °C, a solution of 5-bromo-3-mercaptobenzylpyridine (19.1 mol) was added over 2 - 3 hours. Then, while maintaining the temperature below 20 °C, the resulting mixture was quenched by adding water (16.1 L) over 3 hours. The phases were separated, the organic phase was washed with water (2 × 16.1 L), and then extracted with 10% aqueous NaOH solution (2 × 2.68 L). The combined aqueous phases were washed with toluene (2 × 5.37 L), and then concentrated HCl was added to the aqueous phase under argon sparging at 5 °C until a pH of 2.5 was reached. The mixture was extracted with ethyl acetate (3 × 5.37 L), and then the combined organic phases were washed with 10% aqueous NaCl solution (2 × 5.37 L), dried over MgSO4, and concentrated in vacuo to obtain 2.99 kg (82%) of 5-bromopyridine-3-thiol as an orange solid. 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.77 (t, J = 2.0 Hz, 1H).

[0173] Alternative procedure Into a vessel equipped with an aqueous NaOCl scrubber, water (150 mL), NaOH (150 g, 3.75 mol) were charged, and the mixture was adjusted to 28 - 33 °C while stirring under nitrogen. 3,5-Dibromopyridine (84 g, 0.35 mol), TBAB (5.2 g, 16 mmol) and toluene (200 mL) were added, and then benzyl mercaptan (40 g, 0.32 mol) was added over 2 hours while maintaining the temperature at 28 - 33 °C. The mixture was stirred for an additional 1 - 3 hours and then cooled to 15 - 25 °C. The aqueous phase was removed, and the organic phase was washed with 10% NaCl solution (3 × 200 mL). The organic phase was dried over MgSO4, filtered to obtain a solution of 5-bromo-3-mercaptobenzylpyridine, which was used directly in the next step.

Chemical formula

[0174] Into an inert container, AlCl3 (73 g, 0.23 mol) and toluene (271 mL) were charged, and the mixture was cooled to -5~-15 °C. While maintaining the temperature below 5 °C, a solution of 5-bromo-3-mercaptobenzylpyridine (90.2 g, 0.32 mol) was added over 2~3 hours, and then the mixture was stirred at 0~5 °C for 2~4 hours. While maintaining the temperature below 5 °C, the reaction mixture was quenched by adding it to ice water (271 mL), and the two-phase mixture was stirred at 5~10 °C for 15 minutes. The phases were separated, the organic phase was washed with water (2×271 mL), and then extracted with 5% aqueous NaOH solution (271 mL). The layers were separated, and the organic layer was extracted with 10% NaOH (90 mL). The combined aqueous phase was washed with toluene (2×271 mL). Dichloromethane (DCM, 271 mL) and butylated hydroxytoluene (BHT, 0.9 g, 4 mmol) were added to the aqueous phase at 5 °C. Concentrated HCl (about 108 mL) was added at 0 °C until pH 1.0~2.0 was reached. The phases were separated, the aqueous phase was extracted with DCM (271 mL), and the combined organic phases were dried over MgSO4. The dried solution was solvent-exchanged and distilled with n-heptane at 5~15 °C in vacuo to obtain about 90 mL. The product was recovered by filtration to give 37.4 g (61%) of 5-bromopyridine-3-thiol as a pale yellow solid.

[0175] <Trimethyl((3,4,5-trifluorophenyl)ethynyl)silane>

Chemical formula

[0176] Alternative procedure: Into a jacketed vessel were charged triethylamine (1.39 L, 9.95 mol), 5-bromo-1,2,3-trifluorobenzene (700 g, 3.32 mol), CuI (31.6 g, 0.17 mol), bis(triphenylphosphine)palladium(II) dichloride (58.2 g, 0.08 mol), and acetonitrile (2.1 L). The mixture was heated to reflux under argon. A solution of ethynyltrimethylsilane (611 mL, 4.41 mol) in acetonitrile (4.9 L) was added to the vessel over 2 hours. The mixture was stirred at reflux for 2 hours, then cooled to 25 °C and filtered through a celite bed. The filtrate was concentrated in vacuo at 40 °C. MP-TMT resin (145.5 g) was added to the crude product. The mixture was slurried at 30 °C for 2 hours in 9:1 heptane:ethyl acetate (7 L) and filtered through a celite bed. The filter cake was washed with 9:1 heptane:ethyl acetate (7 L) and the filtrate was concentrated in vacuo at 40 °C to give 698 g (93%) of trimethyl((3,4,5-trifluorophenyl)ethynyl)silane as a brown oil.

[0177] Alternative procedure Into a jacketed vessel were charged CuI (1.06 kg, 5.57 mol), bis(triphenylphosphine)palladium(II) dichloride (1.96 kg, 2.79 mol), acetonitrile (223 L), 5-bromo-1,2,3-trifluorobenzene (23.5 kg, 111 mol) and triethylamine (46.6 L, 334 mol), followed by the acetonitrile line wash (11.8 L). The mixture was heated to 72 °C and ethynyltrimethylsilane (14.55 kg) was added over about 2 hours, followed by the acetonitrile (2.5 L) line wash. The mixture was stirred at reflux for 4 hours until the reaction was complete, then cooled to 22 °C and filtered through a celite bed. The filter cake was washed with additional acetonitrile (58.8 L) and the combined filtrate was solvent-exchanged by distillation into n-heptane at up to 50 °C under vacuum. Ethyl acetate (23.5 L) was added to the solution and SEM26 resin (2-mercaptoethyl ethyl sulfide silica, 5.9 kg) was charged. The mixture was heated to 25 - 29 °C, stirred for 8 hours, then cooled to 5 °C and filtered through a charcoal pad. The filter cake was washed with a mixture of heptane:ethyl acetate (82.3:11.8 L) and the combined filtrate was solvent-exchanged by distillation into acetonitrile at up to 50 °C to give 19.3 kg (76%) of trimethyl((3,4,5-trifluorophenyl)ethynyl)silane in a 24% weight / weight acetonitrile solution (80.5 kg).

[0178] <2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride> [Chemical formula] To a solution of PCl5 (335 g, 1.61 mol) in DCM (1.5 L) was added BF3·OEt2 (1.65 mL, 0.013 mol) under argon, and then a solution of 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside (500 g, 1.34 mol) in DCM (1 L) was added while maintaining the temperature below 25 °C. When complete consumption of the starting material was observed by TLC, the reaction mixture was stirred at 20 °C ± 5 °C for 1 h. The mixture was cooled to 5 °C, and 20% aqueous KHCO3 solution (2 L) was added over 20 min while maintaining the temperature below 20 °C. The mixture was stirred for 15 min and then the layers were separated. To the stirred organic phase, 20% aqueous KHCO3 solution (2 L) was further added over 10 min while maintaining the temperature below 20 °C. The mixture was stirred for 15 min and then the layers were separated. The organic phase was dried over MgSO4 (250 g), filtered, and concentrated in vacuo at 40 °C to give an off-white solid. The crude material was slurried in a rotary evaporator containing TBME (1 L) at 40 °C and atmospheric pressure for 1 h, then cooled to 5 °C and held for 16 h. The material was recovered by filtration, the filter cake was washed with TBME (80 mL), and the material was dried by pulling air through the filter to give 330 g (70%) of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.41 (dd, J = 3.1, 1.1 Hz, 1H), 5.27 (dd, J = 10.2, 8.8 Hz, 1H), 5.17 (d, J = 8.8 Hz, 1H), 4.11 (dd, J = 11.6, 6.1 Hz, 1H), 4.03 (dd, J = 11.6, 6.6 Hz, 1H), 3.91 (td, J = 6.6, 1.2 Hz, 1H), 3.54 (dd, J = 10.2, 3.3 Hz, 1H), 2.13 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H).

[0179] Alternative procedure: PCl5 (1.00 kg, 4.8 mol) was charged into a jacketed vessel under argon. A solution of α,α,α-trifluorotoluene (3 L) containing BF3·OEt2 (5 mL, 0.04 mol) was added, and the mixture was heated to 40 °C. While maintaining the temperature at 35 °C ± 5 °C, a solution of 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside (1.50 kg, 4.02 mol) in α,α,α-trifluorotoluene (6.75 L) was added to the reaction mixture. The line was rinsed with α,α,α-trifluorotoluene (0.75 L). The reaction mixture was stirred at 35 °C ± 5 °C for 1 hour. The mixture was cooled to -5 °C, cyclohexane (4.5 L) was added over 30 minutes, and the resulting suspension was stirred for 16 hours. The reaction mixture was filtered under argon. The filter cake was dried in a vacuum oven at 20 °C for 3 hours to obtain 942 g (67%) of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride as an off-white solid.

[0180] <5-Bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside> [Chemical formula] To a jacketed vessel was charged sodium bis(trimethylsilyl)amide solution (4.2 L, 2 M solution in THF, 8.37 mol), and the solution was stirred at 5 °C under argon. While maintaining the temperature below 20 °C, a solution of 5-bromopyridine-3-thiol (1.6 kg, 8.37 mol) in THF (2.1 L) was added over 1 hour 15 minutes. Thereafter, a solution of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (2.1 kg, 5.98 mol) in THF (2.1 L) was added to the mixture over 15 minutes. The line was rinsed with additional THF (1 L). The resulting mixture was stirred for 18 hours and then TBME (6.3 L) was charged and the temperature of the mixture was lowered to 10 °C. Water (6.3 L) was added over 20 minutes and the resulting mixture was stirred for 30 minutes. The phases were separated and the aqueous phase was extracted with TBME (6.3 L). The combined organic phases were washed with 10% aqueous NaCl solution (3 × 6.3 L) and then concentrated in vacuo at 40 °C. The crude material was co-evaporated with methanol (4.2 L) in vacuo and then slurried in methanol (4.2 L) at 50 °C for 2 hours. The mixture was cooled to 20 °C and then filtered, and the filter cake was washed with methanol (1 L). The solid material was further dried in vacuo at 40 °C until constant weight to give 2.09 kg (69%) of 5-bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside. 1 H NMR (400 MHz, CDCl3) δ 8.57 (dd, J = 10.5, 2.2 Hz, 2H), 7.96 (t, J = 2.1 Hz, 1H), 5.98 (d, J = 5.5 Hz, 1H), 5.52 - 5.45 (m, 1H), 5.27 (dd, J = 11.0, 5.5 Hz, 1H), 4.63 (ddd, J = 7.8, 4.6, 0.8 Hz, 1H), 4.13 (dd, J 11.7, 4.3 Hz, 1H), 4.02 (dd, J 11.7, 7.8 Hz, 1H), 3.96 (dd, J 11.0, 3.3 Hz, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 2.03 (s, 3H).

[0181] Alternative procedure: To a jacketed vessel was charged sodium bis(trimethylsilyl)amide solution (2.4 L, 2 M solution in THF, 4.80 mol), and the solution was stirred at 5 °C under argon. While maintaining the temperature below 20 °C, a solution of 5-bromopyridine-3-thiol (913 g, 4.80 mol) in THF (1.2 L) was added over 1 hour 15 minutes. The line was rinsed with additional THF (0.6 L). Then, a solution of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (1.2 kg, 3.43 mol) in THF (1.2 L) was added to the mixture over 15 minutes. The line was rinsed with additional THF (0.6 L). The resulting mixture was stirred at 20 °C for 72 hours. The temperature of the mixture was lowered to 5 °C, water (3.6 L) was added over 45 minutes, and then ethyl acetate (3.6 L) was added. The resulting mixture was stirred at 20 °C for 1 hour. The phases were separated, and the aqueous phase was extracted with ethyl acetate (3.6 L). The combined organic phases were washed with 10% aqueous NaCl solution (3 × 3.6 L) and then concentrated in vacuo at 40 °C. The crude material was co-evaporated with methanol (2.4 L) in vacuo and then slurried in methanol (2.4 L) at 50 °C for 2 hours. The mixture was cooled to 20 °C and then filtered, and the filter cake was washed with methanol (0.5 L). The solid material was dried in vacuo at 40 °C to constant weight to give 1.21 kg (70%) of 5-bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside.

[0182] Alternative procedure:

Chemical formula

[0183] 5-Bromopyridine-3-thiol (33.1 kg, 174 mol) and THF (217 L) were charged into a second vessel. THF containing 2 M NaHMDS (87 L, 174 mol) was added at 25 to 22 °C, and the mixture was stirred at 20 °C for 30 minutes.

[0184] A THF solution of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride was added to a suspension of sodium 5-bromopyridine-3-thiolate at 21 °C, followed by the addition of a THF line wash solution (22 L). The resulting mixture was stirred at 22 °C for 21 h. Water (130 L) and ethyl acetate (130 L) were added at 18–20 °C, the mixture was stirred for 15 min, and the phases were separated. The aqueous phase was extracted with ethyl acetate (130 L) at 20 °C. The combined organic phases were washed with 10% aqueous NaCl solution (3 × 130 L) and then solvent-exchanged and distilled into methanol in vacuo at a maximum of 40 °C to give a slurry in methanol (ca. 435 L). The mixture was heated to reflux and then cooled to 5 °C over 1.5 h and held at this temperature for 2 h. The mixture was filtered and the filter cake was washed with methanol (87 L) at 5 °C. Drying the solid material in vacuo at 40 °C gave 41.7 kg (53%) of 5-bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside.

[0185] <5-Bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside>

Chemical formula

[0186] Alternative procedure:

Chem.

[0187] In another container, a solution of 5-bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (17.84 kg, 35.4 mol), 3,4,5-trifluorophenylacetylene, acetonitrile (48.5 L), triethylamine (9.9 L, 70.9 mol) and copper(I) iodide (0.68 kg, 3.54 mol) was charged. The mixture was heated to 44 °C and stirred at this temperature for 3.25 hours. The mixture was cooled to 18 °C, dichloromethane (134 L) and 10% aqueous ammonium hydroxide solution (134 L) were added, and the mixture was stirred for 30 minutes. The phases were separated and the aqueous phase was extracted with DCM (89 L). The combined organic phases were washed with 10% aqueous ammonium hydroxide solution (2×134 L), 2 M hydrochloric acid (134 L) and 5% aqueous sodium hydrogen carbonate solution (134 L) at 22 °C. The phases were separated and the organic phase was subjected to solvent exchange distillation into methanol in vacuo at ≤50 °C to obtain about 89 L of a slurry. The slurry was cooled to 2 °C, held at this temperature for 16 hours and filtered. The filter cake was washed with methanol (53.5 L) at 5 °C and the product was dried at a maximum of 60 °C to give 20.0 kg (66%) of 5-bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside.

[0188] <5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, I>

Chemical formula

[0189] Alternative procedure: 5-Bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (19.88 kg, 30.15 mol) was suspended in methanol (199 L) at 15 °C under an inert atmosphere. After charging 30 wt% sodium methoxide solution (0.54 kg, 3.01 mol), methanol line washings (2.5 L) were charged and the mixture was stirred at 20 °C for 1 hour 43 minutes. Additional 30 wt% sodium methoxide solution (0.52 kg, 2.89 mol) was charged and the mixture was stirred at 20 °C for 2.5 hours. The mixture was cooled to 1 °C and stirred at this temperature for 12 hours, then filtered and the filter cake was washed with methanol (30 L) at 5 °C. The crude was dried in vacuo at 55 °C to give 14.19 kg. The crude product was then recharged to the reactor and ethanol (525 L) was added. The mixture was heated to reflux until a solution was formed, then cooled to 2 °C and aged at this temperature for 6 hours 14 minutes, then filtered. The filter cake was washed with ethanol (21 L) at 3 °C and the crystallized product was dried at 55 °C. The crystallized material was returned to the reactor and slurried in TBME (142 L) at 19 °C for 27 hours. The mixture was cooled to 2 °C and stirred at this temperature for 3 hours 2 minutes, then filtered and the filter cake was washed with TBME (21 L) at 2 °C. Drying the product in vacuo at up to 60 °C gave 12.44 kg of 5-bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside as a light brown solid (77.4% over the reaction and purification steps).

[0190] [Preparation of Polymorphs and Salt Forms] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside is a crystalline solid that can potentially exist as seven crystalline polymorphs as well as an amorphous form. Five of the seven solid forms are solvated forms (Forms 2, 4, 5, 6, and 7), which crystallize from alcoholic solvents and appear to be unique but structurally related (pseudo-isostructural) solvates. Table 1 lists the polymorphs and the important solvents from which they are produced. Figures 1A - G provide the XRPD diffractograms of the identified polymorphs 1 - 7, respectively. [Table 2]

[0191] In Figures 1A - 1G, the XRPD patterns of the polymorphs of the compound of Formula I can be identified: 1A is Form 1, 1B is Form 2, 1C is Form 3, 1D is Form 4, 1E is Form 5, 1F is Form 6, and 1G is Form 7.

[0192] Form 1 includes the following characteristic XRPD peaks. [Table 3]

[0193] Form 2 includes the following characteristic XRPD peaks. [Table 4]

[0194] Form 3 includes the following characteristic XRPD peaks. [Table 5]

[0195] Form 4 includes the following characteristic XRPD peaks. [Table 6]

[0196] Form 5 includes the following characteristic XRPD peaks.

Table 7

[0197] Form 6 includes the following characteristic XRPD peaks.

Table 8

[0198] Form 7 includes the following characteristic XRPD peaks.

Table 9

[0199] The compound of formula (I) is called polymorph 1, which is identified by the XRPD diffractogram of Figure 1A or Figure 2. Polymorph 1 of the compound of formula (I) is a high crystalline form with a melting point of 233.7 °C. Form 1 is not hygroscopic and does not show any indication of the formation of hydrates or solvates.

[0200] Polymorphs of the compound of formula I can be prepared by a method comprising suspending or dissolving 3,3'-dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sulfanediyl-di-β-D-galactopyranoside in an organic solvent or solvent mixture (see Table 2 below), and then preparing the polymorph using fast evaporation, slow evaporation, equilibrium slurry, and precipitation from the solvent by addition of a poor solvent, or combinations thereof. Samples for fast and slow evaporation were generated by mixing 7 mg of 3,3'-dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sulfanediyl-di-β-D-galactopyranoside with a solvent (see Table 2 below) and sonicating to ensure complete dissolution. For fast evaporation, a Genovac centrifugal evaporator was used to remove the low-boiling solvent under controlled vacuum over 20 minutes. For slow evaporation, the solvent was allowed to evaporate over 24 hours. Samples subjected to equilibrium slurry conditions were prepared by mixing 7 mg of 3,3'-dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sulfanediyl-di-β-D-galactopyranoside with a solvent (see Table 2 below). The resulting slurry was sonicated in a bath and subsequently stirred for 48 hours. The solid was isolated by filtration onto a sintered filter. Samples subjected to precipitation with a poor solvent were prepared by mixing 7 mg of 3,3'-dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sulfanediyl-di-β-D-galactopyranoside with a solvent (see Table 2 below) and mixing until dissolved. A poor solvent (see Table 2 below) was added to rapidly precipitate the solid, which was isolated onto a sintered metal filter by vacuum filtration. Table 2 lists each of the forms produced by these methods. Form 1 was also made as an off-white solid by the method described in the above large-scale method.

Table 10

[0201] 3,3'-Dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sulfanediyl-di-β-D-galactopyranoside can exist in various salt forms including hydrochloride, hydrobromide, sulfate, phosphate, ethanesulfonate and methanesulfonate. The salt forms of the compound of formula I can be prepared by fast evaporation or slurry conversion of a 1:1 mixture of the compound of formula I and an acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, ethanesulfuric acid and methanesulfuric acid in a suitable solvent such as methyl ethyl ketone, acetonitrile, acetone, ethanol, heptane, ethyl acetate, water or a mixture of the listed solvents. A typical example of the salt form of the compound of formula I is the hydrochloride (HCl salt), a crystalline salt having a melting point of 221 °C. The HCl salt is identified by the XRPD diffractogram of Figure 3. The HCl salt of the compound of formula I was prepared by mixing 7 mg of 3,3'-dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1'-sulfanediyl-di-β-D-galactopyranoside with an equimolar amount of hydrochloric acid and a 1:1 mixture of ethyl acetate:heptane in a vial at a concentration of 10 mg / mL. The vial was sealed and the mixture was stirred for 36 hours. The resulting solid was isolated by filtration onto a sintered metal filter.

Claims

1. 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside having the formula (I) 【Chemical 1】 A method suitable for large-scale synthesis for preparing, a) A compound of formula IX [Chemical 2] (wherein R1, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of R1, R2, and R3 is a protecting group) is reacted with 5-ethynyl-1,2,3-trifluorobenzene or silane-protected 5-ethynyl-1,2,3-trifluorobenzene, such as trimethyl((3,4,5-trifluorophenyl)ethynyl)silane, and a catalyst, and a base is added to the organic solvent if necessary, and a basic fluoride source such as TBAF is added under appropriate conditions to obtain a compound of formula X [Chemical 3] (wherein R1, R2, and R3 are as defined above), b) Removing the protecting group of the compound of formula X to obtain the compound of formula I A method comprising the consecutive steps of.

2. The appropriate conditions for step a) are that a compound of formula IX (wherein R1, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of R1, R2, and R3 is a protecting group) is reacted with 5-ethynyl-1,2,3-trifluorobenzene in an organic solvent at a suitable temperature, optionally under an inert atmosphere, a catalyst and a base are added to the organic solvent to form a reaction mixture, the reaction mixture is heated to raise the temperature by at least 15 °C from the suitable temperature, and the reaction is continued for at least 1 hour to obtain a compound of formula X (wherein R1, R2, and R3 are as defined above). The method according to claim 1.

3. The method according to claim 1 or 2, wherein R1, R2, and R3 are independently selected from ester protecting groups.

4. The method according to any one of claims 1 to 3, wherein the reaction is carried out under an inert atmosphere.

5. The method according to any one of claims 1 to 4, wherein the organic solvent is selected from toluene or polar aprotic solvents.

6. The method according to any one of claims 1 to 5, wherein the suitable temperature is 15 to 25 °C.

7. The method according to any one of claims 1 to 6, wherein the temperature of the reaction mixture is raised by heating the mixture to 40 °C to 70 °C.

8. The method according to any one of claims 1 to 7, wherein the reaction is continued for at least 2 hours.

9. The method according to any one of claims 1 to 8, wherein the catalyst is a metal catalyst.

10. The method according to any one of claims 1 to 9, wherein the base is an organic base.

11. The method according to claim 10, wherein the organic base is selected from tertiary amine bases such as triethylamine, diisopropylethylamine, tributylamine or strong non-nucleophilic bases such as DBU (1,8-diazabicyclo(5.4.0)undec-7-ene).

12. The removal of the protecting group in step b) is carried out by a continuous process of mixing the compound of formula X in an organic solvent under basic conditions in an inert atmosphere, reacting at a suitable temperature for at least 15 minutes, subsequently reacting with an additional base, reacting at the suitable temperature for at least 15 minutes, then cooling the reaction mixture, subsequently washing with alcohol and drying if necessary to obtain the compound of formula I. The method according to any one of claims 1 to 11.

13. The method according to claim 12, wherein the ether is TBME.

14. The method according to claim 12 or 13, wherein the suitable temperature is 15 to 25 °C.

15. The organic solvent is alcohol, such as C １～６ The method according to any one of claims 12 to 14, wherein the alcohol is preferably selected from methanol.

16. The method according to any one of claims 12 to 15, wherein the basic conditions are alcoholytic basic conditions.

17. The method according to any one of claims 12 to 16, wherein the base is sodium methoxide in methanol.

18. The method according to any one of claims 12 to 17, wherein the reaction with the base is at least 1 hour.

19. The method according to any one of claims 1 to 18, wherein the molar ratio of the compound of formula IX to trimethyl((3,4,5-trifluorophenyl)ethynyl)silane is 5:4 to 1:3 and the organic solvent is in excess.

20. The method according to claim 19, wherein the molar ratio of the compound of formula IX to the catalyst is 20:1 to 2:1 and the organic solvent is in excess.

21. The method according to claim 19 or 20, wherein the molar ratio of the compound of formula IX to the base is 1:1 to 1:10 and the organic solvent is in excess.

22. The step immediately before step a), (ia)Formula VIII 【Chemical Formula 4】 A compound of (wherein R1, R2, and R3 are independently selected from a protecting group or hydrogen, provided that at least one of R1, R2, and R3 is a protecting group, and R4 is a halogen) is reacted with 5-bromopyridine-3-thiol and a base in a suitable organic solvent under suitable conditions, optionally under an inert atmosphere, to obtain a compound of the formula IX (wherein R1, R2, and R3 are independently selected from a protecting group or hydrogen, provided that at least one of R1, R2, and R3 is a protecting group). The method according to any one of claims 1 to 21, comprising the step of

23. The method according to claim 21 or 22, wherein the deprotonating agent is sodium bis(trimethylsilyl)amide.

24. The method according to any one of claims 21 to 23, wherein R1, R2, and R3 are all acetyl groups and R4 is as defined above.

25. The method according to any one of claims 21 to 24, wherein R4 is chlorine.

26. The method according to any one of claims 21 to 25, wherein the reaction is carried out under an inert atmosphere.

27. The method according to any one of claims 21 to 26, wherein the organic solvent is selected from the group consisting of ethyl acetate, THF, toluene, DMF, and acetonitrile, and mixtures thereof.

28. The suitable conditions in step (ia) are to react a compound of formula VIII (wherein R1, R2, R3, and R4 are as defined above) with 5-bromopyridine-3-thiol and a base in an organic solvent at a suitable temperature, optionally under an inert atmosphere, maintain the reaction mixture at the suitable temperature, then continue the reaction for at least 15 minutes, and optionally isolate and purify to obtain the compound of formula IX as a solid. The method according to any one of claims 21 to 27.

29. The method according to claim 28, wherein the base is cooled to below room temperature, then 5-bromopyridine-3-thiol is added at a suitable temperature over a suitable time, and subsequently the compound of formula VIII is added.

30. The method according to claim 28 or 29, wherein the suitable temperature is below 25 °C.

31. The method according to any one of claims 28 to 30, wherein the reaction is continued at the suitable temperature for at least 1 / 2 hour.

32. The method according to any one of claims 28 to 31, wherein the molar ratio of the compound of formula VIII to the base is from 1:1 to 1:

3.

33. The step immediately preceding step ia), (ib) Formula VII [Chemical Formula 5] (wherein R1, R2, and R3 are independently selected from a protecting group or hydrogen, provided that at least one of R1, R2, and R3 is a protecting group, R4' is SR5 or OR5, and R5 is H, Z''-C １～６ alkyl, Z''-C １～６ alkenyl, Z''-C ３～６ branched alkyl, Z''-C ３～６ cycloalkyl Z''-heteroaryl, and Z''-aryl, and Z'' is SO, SO ２ , C=O or C=S), the compound is reacted in a suitable organic solvent under suitable conditions with a halogenating agent or a reagent for activating the anomeric position for nucleophilic substitution such as triflate to obtain a compound of formula VIII (wherein R1, R2, and R3 are independently selected from a protecting group or hydrogen, provided that at least one of R1, R2, and R3 is a protecting group, and R4 is halogen), the method according to any one of claims 1 to 32, comprising the step of.

34. A crystalline form of 5-bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside having formula (I).

35. The crystalline form according to claim 34, which is polymorph 1 comprising the following 17 characteristic XRPD peaks. 【Table 1】

36. The crystalline form according to claim 34, which is a hydrochloride.

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