Large-scale method for preparing 5-bromopyridine-3-yl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-YL]-1-thio-alpha-D-galactopyranoside and its crystalline form.

Abstract

The present invention relates to a compound of formula (I) [Formula 1] JPEG2023506066000051.jpg3862(I) The present invention relates to a method for preparing a compound of formula (I), which method is suitable for large-scale synthesis.

Description

[Technical Field]

[0001] This invention relates to a method for preparing 5-bromopyridine-3-yl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-YL]-1-thio-α-D-galactopyranoside, and the method can be scaled up. The method parameters are stable, and the method is suitable for GMP production. [Background technology]

[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 60% yield using a small-scale experimental method, but parameters for scaling up are not disclosed. [Overview of the project]

[0003] The present invention relates to a novel method for preparing 5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside, the method of which can be extended to large and / or industrial scales such as 30 kg or more. The method can also be used on small scales such as 200 g to 3 kg or medium scales of 3 kg to 30 kg.

[0004] In the first aspect, the present invention relates to formula (I) [ka] Regarding a method for preparing 5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside, for example, a method suitable for large-scale synthesis, The method is, a) Formula IX [ka] A compound of formula X (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) and a catalyst, and a base is added to the organic solvent as needed, and a basic fluoride source such as TBAF is added as needed under appropriate conditions to obtain the compound of formula X [ka] The process of obtaining a compound (wherein R1, R2, and R3 are as defined above), b) A step of removing protecting groups R1, R2, and R3 from a compound of formula X to obtain a compound of formula I, This includes a series of steps. In one embodiment, the compound of formula I is obtained as a solid product such as a crystalline or amorphous product.

[0005] In further embodiments, suitable conditions for step a) are to react 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) with trimethyl((3,4,5-trifluorophenyl)ethynyl)silane in an organic solvent at a suitable temperature and optionally under an inert atmosphere, to produce a reaction mixture by adding a catalyst optionally and a base optionally to the organic solvent, to heat the reaction mixture to a temperature at least 15°C above the suitable temperature optionally, to add a basic fluoride source, and to continue the reaction for at least 1 hour to obtain a compound of formula X (wherein R1, R2, and R3 are as defined above).

[0006] In a typical embodiment, the present invention relates to formula (I) [ka] 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, The method comprises a) reacting a compound of formula IX [Chemical formula] (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 and a catalyst (e.g., CuI(I)), and adding a base (e.g., triethylamine) to an organic solvent (e.g., acetonitrile) under appropriate conditions to obtain a compound of formula X [Chemical formula] (wherein R1, R2, R3 are as defined above), b) removing the protecting group of the compound of formula X to obtain a compound of formula I, and including the above consecutive steps. In one embodiment, the compound of formula I is obtained as a solid product such as a crystalline or amorphous product.

[0007] In one embodiment, a basic fluoride source is added. In another embodiment, no basic fluoride source is 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 salt or phosphate salt, preferably as the HCl salt. Typically, the crystalline HCl salt.

[0010] In further embodiments, suitable conditions for step a) are to react 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) with 5-ethynyl-1,2,3-trifluorobenzene in an organic solvent, under an inert atmosphere, at a suitable temperature, add a catalyst, add a base to the organic solvent to produce a reaction mixture, heat the reaction mixture to a temperature 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). In particular, under these conditions, it is not necessary 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 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 performed later in the process.

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

[0014] In another embodiment, the reaction is carried out under 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 further embodiments, the optimal temperature is 15-25°C, for example, approximately room temperature.

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

[0018] In further embodiments, 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 is often completed within 2 hours.

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

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

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

[0022] In further embodiments, 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 further embodiments, 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 further embodiments, 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 The alcohol is selected from, for example, methanol. Furthermore, the base is preferably selected from a base, such as an organic base, at a concentration sufficient to provide a pH of 12 or higher. Typically, the base is sodium methoxide in methanol, for example, a methanol solution of 25% by weight sodium methoxide. In one embodiment, the reaction with the base lasts for at least 1 hour, for example, 2 to 24 hours.

[0027] In another embodiment, the removal of the protecting group in step b) involves using an organic solvent (C) to remove the compound of formula X. 1~6 Mix a base (e.g., sodium methoxide) with an alcohol (e.g., methanol or ethanol) under an inert atmosphere and react at a suitable temperature (e.g., room temperature) for at least 15 minutes (e.g., 1 hour), then add an additional base and react at a suitable temperature for at least 15 minutes (e.g., 1 hour), then cool the reaction mixture (e.g., 5°C), and then add an alcohol (C 1~6 Wash with alcohol (e.g., methanol or ethanol), dry (e.g., in a vacuum at 60°C), and then use alcohol (C 1~6 The process is carried out in a series of steps: adding an alcohol (e.g., methanol or ethanol), heating until a solution is formed, then cooling (e.g., 5°C), filtering, washing (e.g., with ethanol), precipitation, drying the crystallized product (e.g., 60°C), and washing it with ether (e.g., TBME) under cooling (e.g., 5°C) to obtain the compound of formula I.

[0028] In a further embodiment, the present invention relates to a step immediately preceding step a), (ia) Formula VIII [ka] The process includes reacting 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, and R4 is a halogen) with a 5-bromopyridine-3-thiol and a base in a suitable organic solvent, under suitable conditions, and optionally under an inert atmosphere, to obtain 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). The base may be selected from NaH, KOtBu, KOH, sodium bis(trimethylsilyl)amide, or a carbonate base, such as K2CO3 and / or Cs2CO3. In one embodiment, the base is selected from NaH, KOtBu, KOH, sodium bis(trimethylsilyl)amide, K2CO3 and / or Cs2CO3.

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

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

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

[0032] In further embodiments, the reaction is carried out under an inert atmosphere, typically 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, as well as mixtures thereof.

[0034] In a further embodiment, suitable conditions for step (ia) are to use a compound of formula VIII (wherein R1, R2, R3 and R4 are as defined above), The reaction is carried out in an organic solvent with 5-bromopyridine-3-thiol and a base, under an inert atmosphere and at a suitable temperature as needed, maintaining the reaction mixture at a suitable temperature, then continuing the reaction for at least 15 minutes, and is isolated and purified as needed to obtain the compound of formula IX as a solid. Preferably, the base is cooled to below room temperature, then 5-bromopyridine-3-thiol is added for an appropriate amount of time and at a suitable temperature, followed by the addition of the compound of formula VIII.

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

[0036] In further embodiments, the reaction is continued at a suitable 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 further embodiments, the method of the present invention is the step immediately preceding step ia), (ib) Formula VII [ka] (In the formula, R1, R2, and R3 are selected independently of protecting groups 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 Alkenil, Z''-C 3~6 Branched alkyl, Z''-C 3~6The process includes reacting a compound of formula VIII (wherein R1, R2, and R3 are independently selected from cycloalkyl Z''-heteroaryl and Z''-aryl, where Z'' is SO, SO2, C=O, or C=S) in a suitable organic solvent, using a suitable catalyst, and optionally under an inert atmosphere and under suitable conditions, with a reagent for activating the anomeric position for nucleophilic substitution, such as a halogenating agent, to obtain a compound of formula VIII (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, and R4 is a halogen).

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

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

[0041] In further embodiments, 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 further embodiments, the catalyst is an acid such as a Lewis acid, preferably BF3·OEt2.

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

[0044] In yet another embodiment, the molar ratio of the compound of formula VII to a 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 further embodiments, the molar ratio of the compound of formula VII to the catalyst is 10:1 to 200:1, typically 100:1.

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

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

[0048] <Further Embodiments of the Invention> Embodiment 1. Formula (I) [ka] A method suitable for large-scale synthesis of 5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside having, a) Formula IX [ka] A compound of formula X (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 as needed, and a basic fluoride source such as TBAF is added as needed under appropriate conditions to obtain a compound of formula X [ka] The process of obtaining a compound (wherein R1, R2, and R3 are as defined above), b) A step of removing the protecting group from the compound of formula X to obtain the compound of formula I, A method comprising a series of steps.

[0049] 2. The method according to Embodiment 1, wherein the appropriate conditions for step a) are to react 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) with trimethyl((3,4,5-trifluorophenyl)ethynyl)silane in an organic solvent at a suitable temperature and optionally under an inert atmosphere, to add a catalyst and optionally a base to the organic solvent to produce a reaction mixture, to optionally heat the reaction mixture to a temperature at least 15°C above the suitable temperature, to add a basic fluoride source, and to continue the reaction 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 the ester protecting group.

[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 aproton solvent.

[0053] 6. The method according to any one of Embodiments 1 to 5, wherein the optimal 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 increases 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 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.

[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 optimal 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 in 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 lasts for 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 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 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 1:1 to 1:10, and the organic solvent is in excess.

[0069] 22. The process immediately preceding process a), (ia) Formula VIII [ka] The method according to any one of Embodiments 1 to 21, comprising the step of reacting 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, and R4 is a halogen) with 5-bromopyridine-3-thiol and a base in a suitable organic solvent, under suitable conditions, and optionally under an inert atmosphere, to obtain 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).

[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 such that the compound of formula VIII (wherein R1, R2, R3 and R4 are as defined above) The method according to any one of Embodiments 21 to 27, wherein the reaction is carried out in an organic solvent with 5-bromopyridine-3-thiol and a base at a suitable temperature, under an inert atmosphere if necessary, the reaction is maintained at a suitable temperature, the reaction is then continued for at least 15 minutes, and the compound of formula IX is isolated and purified as necessary to obtain the compound of formula IX as a solid.

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

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

[0078] 31. The method according to any one of embodiments 28 to 30, wherein the reaction is carried out at a suitable 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 process immediately preceding process ia), (ib) Formula VII [ka] (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, SO2, C=O or C=S), the compound is reacted in a suitable organic solvent under suitable conditions with a reagent for activating the anomeric position for nucleophilic substitution such as a halogenating agent or 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 a halogen). The method according to any one of Embodiments 1 to 32, comprising the step of

[0081] 34. The 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).

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

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

Brief Description of the Drawings

[0084]

Modes for Carrying Out the Invention

[0085] The compound of formula (I) has the chemical name (IUPAC) 5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside and can be prepared as described in International Publication No. 2016120403. The yield is relatively low, and it is not possible to scale up the method directly.

[0086] Furthermore, throughout this application, the terms “compound of formula I” or “compound having formula I” or “5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside having formula I” are used synonymously and mean any solid or liquid form of the compound of formula I, such as crystalline form, especially polymorphs or amorphous forms, and are intended to further include its free form, any solvate or any salt.

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

[0088] As a result, equation (I) [ka] A new method has been developed for preparing 5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside, for example, a method suitable for large-scale synthesis. The method is, a) Formula IX [ka] A compound of formula X (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 as needed, and a basic fluoride source such as TBAF is added under appropriate conditions as needed to obtain formula X [ka] The process of obtaining a compound (wherein R1, R2, and R3 are as defined above), b) A step of removing the protecting group from the compound of formula X to obtain the compound of formula I, This includes a series of steps.

[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 further embodiments, 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 silane-protected 5-ethynyl-1,2,3-trifluorobenzene in toluene or a polar aprotic solvent or a mixture thereof at a suitable temperature of 15 to 25°C, optionally under an inert atmosphere; to add a catalyst and optionally a base to the organic solvent to produce 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).

[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 or a mixture thereof at a suitable temperature of 15 to 25°C, optionally under an inert atmosphere, to add a catalyst, optionally add a base to the organic solvent to produce a reaction mixture, optionally heat the reaction mixture to a temperature 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 further embodiments, 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 or a mixture thereof at a suitable temperature of 15 to 25°C, optionally under an inert atmosphere, to add a catalyst, optionally add a base to the organic solvent to produce 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 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, the purification is performed later in the process.

[0095] In further embodiments, 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 further embodiments, the optimal 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 to 70°C, for example, 45°C to 70°C, for example, about 60°C.

[0099] In further embodiments, the reaction is continued for at least 2 hours, for example 3 hours, or for example 2.5 to 4 hours.

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

[0101] In further embodiments, 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 to 1:3, for example 1:1 to 5:7, typically 5:6, and the organic solvent is in excess.

[0104] In further embodiments, 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.

[0105] 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.

[0106] In further embodiments, 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 higher, reacting at a suitable temperature of 15–25°C for at least 15 minutes, and then 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 15–25°C, for example, approximately room temperature. Typically, the organic solvent is an alcohol, for example, C 1~6The alcohol is selected from, for example, methanol. Furthermore, the base is preferably selected from a base, for example, an organic base, at a concentration sufficient to provide a pH of 12 or higher. Typically, the base is sodium methoxide in methanol, for example, a methanol solution of 25% by weight sodium methoxide.

[0107] Typically, deprotection is carried out by hydrolysis (catalyzed acidic or basic) or by using a nucleophile to directly remove the acetyl protecting group, with basic conditions for alcohol decomposition being particularly preferred.

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

[0109] In a further embodiment, the present invention relates to a step immediately preceding step a), (ia) Formula VIII [ka] The process includes reacting 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, and R4 is a halogen) with a 5-bromopyridine-3-thiol and a base in a suitable organic solvent, under suitable conditions, and optionally under an inert atmosphere, to obtain 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). The base may be selected from NaH, KOtBu, KOH, or sodium bis(trimethylsilyl)amide or a carbonate base, such as K2CO3 and / or Cs2CO3.

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

[0111] In further embodiments, 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 further embodiments, the reaction is carried out under an inert atmosphere, typically 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, as well as mixtures thereof.

[0115] In further embodiments, suitable conditions for step (ia) are to react the compound of formula VIII (wherein R1, R2, and R3 are all acetyl groups and R4 is a halogen) with a 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, in an organic solvent selected from ethyl acetate, THF, toluene, DMF, and acetonitrile, and / or a carbonate base, such as K2CO3 and / or Cs2CO3, in an organic solvent selected from NaH, KOtBu, KOH, and 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, in an organic solvent selected from an organic solvent selected from NaH, KOtBu, KOH, and sodium bis(trimethylsilyl)amide, and / or a carbonate base, such as K2CO3 and / or Cs2CO3 ethyl acetate, THF, toluene, DMF, and acetonitrile, and mixtures thereof, in an organic solvent selected from ethyl acetate, THF, and toluene, and / or Cs2CO3, in an organic solvent selected from

[0116] In yet another embodiment, the optimal temperature is less than 25°C.

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

[0118] 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.

[0119] In further embodiments, the method of the present invention is the step immediately preceding step ia), (ib) Formula VII [ka] (In the formula, R1, R2, and R3 are selected independently of protecting groups 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 Alkenil, Z''-C 3~6 Branched alkyl, Z''-C 3~6 The process includes reacting a compound of cycloalkyl Z''-heteroaryl and Z''-aryl (where Z'' is SO, SO2, C=O, or C=S) with a reagent for activating the anomeric position for nucleophilic substitution, such as a halogenating agent, in a suitable organic solvent, using a suitable catalyst, and optionally under an inert atmosphere and under suitable conditions, to obtain a compound of formula VIII (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, and R4 is a halogen).

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

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

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

[0123] In further embodiments, the organic solvent is an aprotic solvent, preferably dichloromethane, toluene, or α,α,α-trifluorotoluene, or a mixture 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 further embodiments, 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 15–45°C. In yet another embodiment, the reaction is continued at the suitable temperature for at least 15 hours, at least 1 / 2 hour, for example, 1–96 hours.

[0127] In yet another embodiment, the molar ratio of the compound of formula VII to a 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 further embodiments, 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 embodiment, the present invention relates to a method for preparing compounds of formula III and formula IV starting from a compound of formula II. [ka]

[0130] A further embodiment 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 and, if necessary, under an inert atmosphere; and b) adding benzyl mercaptan to obtain a compound of formula III.

[0131] A further embodiment relates to a method for preparing a compound of formula IV, comprising a) treating 5-bromo-3-mercaptobenzylpyridine(III) in an organic solvent at a suitable temperature with a reducing agent such as AlCl3 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, [ka] The present invention relates to a method comprising: a) treating 5-bromo-1,2,3-trifluorobenzene(V) with a base such as triethylamine and, optionally, a catalyst such as a metal catalyst such as CuI at a suitable temperature and, if necessary, under an inert atmosphere; and b) preparing a compound of formula VI by adding bis(triphenylphosphine)palladium(II) dichloride and ethynyltrimethylsilane to an organic solvent at a suitable temperature.

[0133] Another aspect relates to the crystalline form of the compound of formula I. In one embodiment, the crystalline form is polymorph 1, identified in the XRPD diffractograms of Figures 1A and 2.

[0134] In further embodiments, the crystalline form of the compound of formula I includes the following 17 characteristic XRPD peaks. [Table 1]

[0135] Further embodiments relate to salts of the compound of formula I, preferably HCl salts of the compound of formula I, as identified by the XRPD diffractogram in Figure 3.

[0136] Alpha and beta anomers can be separated by various methods, such as crystallization. However, in this method, the starting point can be the mixture and one of the anomers.

[0137] As used herein, the terms “treatment” and “to treat” mean the management and care of a patient aimed at combating a disease or disorder or other condition. The term is intended to encompass the entire range of treatments for a given condition in which a patient is suffering, including, for example, the administration of an active compound to alleviate symptoms or complications, to slow the progression of a disease, disorder or condition, to alleviate or reduce symptoms and complications, and / or to cure or eliminate a disease, disorder or condition, and to prevent a condition. Prevention should be understood as the management and care of a patient aimed at combating a disease, condition or disorder, and includes the administration of an active compound to prevent the onset of symptoms or complications. The diseases or disorders treated are preferably inflammation; fibrosis, e.g., pulmonary fibrosis, hepatic fibrosis, renal fibrosis, ophthalmic fibrosis, and cutaneous 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, aortic stenosis, aortic stenosis Selected from the group consisting of loamyne arteriosclerosis, pathological neovascularization, such as ocular neovascularization, or diseases or conditions associated with ocular neovascularization, such as cancer-related neovascularization; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases such as diabetes mellitus; type 2 diabetes mellitus; insulin resistance; obesity; diastolic HF; asthma and other interstitial lung diseases, such as Hermanski-Pudlak syndrome, pulmonary arterial hypertension, RA-ILD, SSc-ILD, COPD, and lung diseases with fibrosis such as asthma. Otosclerosis, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease; cirrhosis of various origins, such as alcoholic and non-alcoholic autoimmune cirrhosis, such as primary biliary cirrhosis and sclerosing cholangitis; virus-induced cirrhosis; and cirrhosis induced by genetic disorders.Liver cancer, bile duct cancer, and biliary tract cancer in mammals such as humans; neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, and cognitive impairment; cerebrovascular diseases, such as stroke, traumatic brain injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and peripheral nephropathy; and the present invention involves administering a therapeutically effective amount of a composition containing a compound of formula I, such as an amorphous solid dispersion composition or a drug layer composition.

[0138] Another aspect of the present invention relates to 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 different therapeutically active compound (synonymous with "different therapeutically active compound") than the compound of formula (I). In one embodiment, the present invention relates to a combination of a composition comprising the 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 treating disorders of galectin-3 binding to a ligand in mammals. 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 layer 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 layer composition, and a different therapeutically active compound is used to treat: inflammation; fibrosis, e.g., pulmonary fibrosis, hepatic fibrosis, renal fibrosis, ophthalmic fibrosis, and cutaneous and cardiac fibrosis; scarring; keloid formation; abnormal scarring; surgical adhesions; 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, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart It is administered to mammals suffering from disorders selected from the group consisting of diseases; heart failure; pathological angiogenesis, such as ocular angiogenesis or diseases or conditions related to ocular angiogenesis, such as cancer-related neovascularization; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases such as diabetes mellitus; type 2 diabetes mellitus; insulin resistance; obesity; diastolic HF; asthma and other interstitial lung diseases, such as Hermanskie-Pudlak syndrome and mesothelioma; and liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.

[0140] Examples of cancers that can be treated, managed and / or prevented by administering a composition containing the compound of formula (I) of the present invention, for example, an amorphous solid dispersion composition or a drug layer composition, in combination with different therapeutically active compounds, include, but are not limited to, colorectal cancer, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endosarcoma, and lymphoma. Tubosarcoma, intralymphatic sarcoma, synoviomas, 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, bronchogenic lung cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminomas, embryonic carcinoma, Wilms' tumor, cervical cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioblastoma, schwannoma, craniopharyngioma, Schwann cell tumor, glioblastoma Tumors, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal glandoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia and lymphoma, acute lymphoblastic leukemia and acute myeloid polycythemia vera, multiple myeloma, Waldenström macroglobulinemia and heavy chain disease, acute nonlymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's disease, non-Hodgkin lymphoma, rectum The following are selected from cancers, urinary tract cancers, uterine cancers, oral cancers, skin cancers, stomach cancers, brain tumors, liver cancers, laryngeal cancers, esophageal cancers, mammary gland tumors, 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 leukemias, small cell and large non-small cell lung cancers, acute granulocytic leukemia, germ cell tumors, endometrial cancers, stomach cancers, head and neck cancers, chronic lymphocytic leukemias, hairy cell leukemias, and thyroid cancers.

[0141] In some aspects 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 aspects of the method of the present invention, the measured 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 the additional therapeutic agent is improved compared to the same measured 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] Further embodiments of the present invention relate to combination therapy, which includes administering a composition containing a compound of formula (I) of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, together with an antifibrotic compound different from the compound of formula (I) to a mammal in need of combination therapy. In further embodiments, such antifibrotic compounds may be selected from the following non-limiting group of antifibrotic 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] A further aspect of the present invention relates to a combination therapy comprising administering a composition containing a compound of formula (I) of the present invention, such as an amorphous solid dispersion composition or a drug layer composition, to a mammal in need of treatment in combination with further conventional cancer treatments, such as chemotherapy or radiotherapy, or immunostimulant therapy, gene therapy, antibody therapy and dendritic cell therapy.

[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 layer composition, is administered together with at least one additional therapeutic agent selected from antitumor chemotherapeutic agents. In further embodiments, the antitumor chemotherapeutic agent is selected from all-trans retinoic acid, actimide, azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, irinotecan, lenalidomide, leucovorin, mechloretamine, melphalan, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, levlimide, temozolomide, teniposide, thioguanine, barrubicin, vinblastine, vincristine, vindesine, and vinorelbine. In one embodiment, the chemotherapeutic agents used in combination with this drug may themselves be combinations of different chemotherapeutic agents. Suitable combinations include FOLFOX and IFL. FOLFOX is a combination containing 5-fluorouracil (5-FU), leucovorin, and oxaliplatin. IFL treatment includes irinotecan, 5-FU, and leucovorin.

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

[0146] In other embodiments of the present invention, further cancer treatments are selected from a group of immunostimulants, such as cytokines and antibodies. Such cytokines may be selected from the group consisting of GM-CSF, type I IFN, interleukin 21, interleukin 2, interleukin 12, and interleukin 15, but are not limited to these. Antibodies are preferably immunostimulant antibodies, such as anti-CD40 antibodies or anti-CTLA-4 antibodies. Immunostimulants may also be substances that can deplete immunosuppressive cells (e.g., regulatory T cells) or factors, such as E3 ubiquitin ligases. E3 ubiquitin ligases (HECT, RING, and U-box proteins) have emerged as important molecular regulators of immune cell function and may be involved in regulating the immune response during infection by targeting specific inhibitory molecules for proteolytic disruption, respectively. Several HECT and RING E3 proteins are now also involved in the induction and maintenance of immune self-tolerance, while 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 together 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, some of which are described in Melero et al., Nature Reviews Cancer (2015). Examples of checkpoint inhibitors administered together with the compound of formula (1) are anti-PD-1: nivolumab, pembrolizumab, and semiprimab. Anti-PD-L1: atezolizumab, avelumab, durvalumab, and one anti-CTLA-4: ipilimumab. Each of these checkpoint inhibitors can be targeted in combination with any one of the compounds of formula (1) in the embodiments.

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

[0149] 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 CTLA4 pathway. In some embodiments, the inhibitors of the CTLA4 pathway are 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 from other methods that can induce an anti-PD1 antibody, such as mRNA transduction of genetic material that exhibits in vivo production of an anti-PD1 or anti-PDL1 antibody or a fragment of said antibody.

[0151] As used herein, “pharmaceutically acceptable additives” includes, but is not limited to, carriers, excipients, diluents, adjuvants, colorants, fragrances, preservatives, etc., that a person skilled in the art might consider using when formulating the compounds of the present invention for the manufacture of a pharmaceutical composition.

[0152] 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 the recipient. Preferably, the composition does not contain substances that may cause adverse reactions such as allergic reactions. 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 this method are described in the experimental section of this specification, and each method and each starting material constitutes an embodiment that may form part of the embodiment.

[0154] Unless otherwise specified that the embodiments relate to a particular or multiple aspect of the Invention, the embodiments described herein (such as “method of treatment,” “pharmaceutical composition,” “compound for use as a pharmaceutical product,” or “compound for use in a method”) and any one of the embodiments described herein should be considered to refer to any one of the aspects described herein (such as “method of treatment,” “pharmaceutical composition,” “compound for use as a pharmaceutical product,” or “compound for use in a method”).

[0155] All references cited herein, including publications, patent applications, and patents, are incorporated herein by reference to the same extent as if they were included herein in their entirety, provided that each reference is individually and specifically indicated as being incorporated herein by reference.

[0156] All titles and subtitles used herein are 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 thereof is incorporated into the present invention unless otherwise indicated herein or unless it is clearly inconsistent with the context.

[0158] As used in the context describing this invention, the terms "a," "an," "the," and similar references should be interpreted as referring to both singular and plural forms, unless otherwise indicated herein or unless it is clearly inconsistent with the context.

[0159] The enumeration of value ranges in this specification is merely intended to serve as a convenient way to refer to each individual value within the range individually, unless otherwise indicated herein, and each individual value is incorporated herein as if it were individually enumerated herein. Unless otherwise specified, all exact values ​​provided herein represent the corresponding approximations (for example, all exact exemplary values ​​provided with respect to a particular factor or measure can be considered to also provide the corresponding approximate measure, modified by “approximately” where necessary).

[0160] All methods described herein may be carried out in any suitable order, unless otherwise indicated herein or unless it is clearly inconsistent with the context.

[0161] All examples or illustrative language provided herein (e.g., "etc.") are intended solely to facilitate understanding of the invention and, unless otherwise indicated, do not limit the scope of the invention. Nothing in this specification should be construed as indicating an essential element for carrying out the invention unless expressly stated.

[0162] The references and incorporations of patent documents in this specification are for convenience only and do not reflect any views regarding the validity, patentability, and / or enforceability of such patent documents.

[0163] Any description herein of any aspect or embodiment of the Invention that uses terms such as “comprising,” “having,” “including,” or “containing” with respect to one or more elements is intended to provide support for similar aspects or embodiments of the Invention that “consist of,” “essentially consist of,” or “substantially contain” that particular element or more elements (for example, a composition described herein as containing a particular element should also be understood, unless otherwise stated, or unless otherwise stated, or unless otherwise stated).

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

[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 may, individually or in any combination thereof, be materials for realizing the present invention in its various forms. [Examples]

[0166] <Experiment> [ka] The current method for producing 5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside having formula I involves several step steps, as described in detail below.

[0167] <General Procedure> Nuclear magnetic resonance (NMR) spectra were recorded at 25°C using a 400 MHz Bruker Avance AV400 spectrometer. Chemical shifts are reported in ppm(δ) using the residual solvent as an internal standard. Peak multiplicity is expressed as follows: s, single line; d, double line; t, triple line; q, quadruple line; m, multiple line; br s, broad single line.

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

[0169] Sample preparation: Samples performed under ambient conditions were prepared as flat specimens by placing isolated solids in a high-throughput sample holder.

[0170] The following abbreviations are used. Ac: Acetyl aq.: water-based DCM: Dichloromethane DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide MP-TMT: Macroporous polystyrene-bound trimercaptotriazine Sat.: Saturation TBAB: Tetra-n-butylammonium bromide TBAF: Tetra-n-butylammonium fluoride TBME: tert-butylmethyl ether TLC: Thin-layer chromatography XRPD: X-ray Powder Diffraction

[0171] <5-bromopyridine-3-thiol> [ka] In a jacketed container fitted with an aqueous NaOCl-filled scrubber, 3,5-dibromopyridine (5 kg, 21.1 mol), TBAB (308 g, 0.95 mol), and toluene (11.9 L) were added, and the mixture was stirred under argon. 50% aqueous NaOH (11.9 L) was added, and the mixture was heated to 30°C. While maintaining the temperature at 30°C ± 3°C, benzyl mercaptan (2.25 L, 19.1 mol) was added over 2 hours. The mixture was stirred for a further 30 minutes, and then cooled to 20°C. The aqueous phase was removed, and the organic phase was washed with a 10% NaCl solution (3 × 11.9 L). The organic phase was dried over MgSO4 and filtered to obtain a solution of 5-bromo-3-mercaptobenzylpyridine, which was used directly in the next step. [ka]

[0172] AlCl3 (4.35 kg, 32.6 mol) and toluene (16.1 L) were added to a jacketed container, 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% NaOH aqueous solution (2 × 2.68 L). The combined aqueous phase was washed with toluene (2 × 5.37 L), and then concentrated HCl was added to the aqueous phase under argon sparging at 5°C until the pH reached 2.5. The mixture was extracted with ethyl acetate (3 × 5.37 L), then the combined organic phase was washed with a 10% NaCl aqueous solution (2 × 5.37 L), dried over MgSO4, and concentrated under vacuum 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 In a container fitted with an aqueous NaOCl-filled scrubber, water (150 mL) and NaOH (150 g, 3.75 mol) were added, 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 a further 1-3 hours, and then cooled to 15-25°C. The aqueous phase was removed, and the organic phase was washed with a 10% NaCl solution (3 × 200 mL). The organic phase was dried over MgSO4 and filtered to obtain a solution of 5-bromo-3-mercaptobenzylpyridine, which was used directly in the next step. [ka]

[0174] AlCl3 (73 g, 0.23 mol) and toluene (271 mL) were added to an inert container, and the mixture was cooled to -5 to -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 to 3 hours, and the mixture was then stirred at 0 to 5°C for 2 to 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 to 10°C for 15 minutes. The phases were separated, and the organic phase was washed with water (2 × 271 mL) and then extracted with 5% NaOH aqueous 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 (approximately 108 mL) was added at 0°C until the pH reached 1.0-2.0. The phases were separated, the aqueous phase was extracted with DCM (271 mL), and the combined organic phase was dried over MgSO4. The dried solution was subjected to solvent exchange distillation to n-heptane under vacuum at 5-15°C to obtain approximately 90 ml. The product was recovered by filtration to obtain 37.4 g (61%) of 5-bromopyridine-3-thiol as a pale yellow solid.

[0175] <Trimethyl((3,4,5-trifluorophenyl)ethynyl)silane> [ka] Triethylamine (5.45 L, 39.1 mol), 5-bromo-1,2,3-trifluorobenzene (2.75 kg, 13.0 mol), and CuI (191 g, 0.65 mol) were placed in a jacketed container, and the mixture was heated under argon reflux. A solution of DMF (27.5 L) containing bis(triphenylphosphine)palladium(II) dichloride (91.5 g, 0.13 mol) and ethynyltrimethylsilane (2.40 L, 17.3 mol) was added to the container over 2 hours. The mixture was stirred for 3 hours, then cooled to 20°C and filtered. The filtrate was refilled into the container, diluted with TBME (13.75 L), and 2M aqueous HCl (13.75 L) was added while maintaining the temperature below 30°C. The aqueous phase was drained, and the organic phase was subsequently washed with a 6% NH4OH aqueous solution (3 × 13.75 L) and a 10% NaCl aqueous solution (13.75 L). The organic phase was vacuum concentrated at 40°C, and the filtrate was slurryed in heptane (13.75 L) at 20°C for 1 hour and filtered through a celite bed. The filtrate was vacuum concentrated at 40°C to obtain 2.11 kg (71%) of trimethyl((3,4,5-trifluorophenyl)ethynyl)silane as brown oil. 1 H NMR(400 MHz,CDCl3)δ 7.11-7.01(m,2H),0.24(s,9H). 19 F NMR(376 MHz,CDCl3)δ-134.3(d,J=20.5 Hz,2F),-158.6(t,J=20.5 Hz,1F).

[0176] Alternative procedure: 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) were added to a jacketed container. The mixture was heated under argon reflux. A solution of acetonitrile (4.9 L) containing ethynyltrimethylsilane (611 mL, 4.41 mol) was added to the container over 2 hours. The mixture was stirred under reflux for 2 hours, then cooled to 25°C and filtered through a celite bed. The filtrate was concentrated under vacuum at 40°C. MP-TMT resin (145.5 g) was added to the crude product. The mixture was slurryed with 9:1 heptane:ethyl acetate (7L) at 30°C for 2 hours and filtered through a Celite bed. The filtered cake was washed with 9:1 heptane:ethyl acetate (7L), and the filtrate was concentrated under vacuum at 40°C to obtain 698 g (93%) of trimethyl((3,4,5-trifluorophenyl)ethynyl)silane as brown oil.

[0177] Alternative procedure In a jacketed vessel, 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) were added, followed by acetonitrile line washing solution (11.8 L). The mixture was heated to 72°C, and ethynyltrimethylsilane (14.55 kg) was added over approximately 2 hours, after which acetonitrile (2.5 L) line washing solution was added. The mixture was stirred under reflux for 4 hours until the reaction was complete, then cooled to 22°C and filtered through a celite bed. The filtrate cake was washed with additional acetonitrile (58.8 L), and the combined filtrate was subjected to solvent exchange distillation to n-heptane under vacuum at a maximum temperature of 50°C. Ethyl acetate (23.5 L) was added to the solution, and SEM26 resin (2-mercaptoethyl ethyl sulfide silica, 5.9 kg) was added. The mixture was heated to 25-29°C, stirred for 8 hours, then cooled to 5°C, and filtered through a charcoal pad. The filtered cake was washed with a mixture of heptane:ethyl acetate (82.3:11.8 L), and the combined filtrate was subjected to solvent exchange distillation to acetonitrile at a maximum of 50°C to obtain 19.3 kg (76%) of trimethyl((3,4,5-trifluorophenyl)ethynyl)silane in a 24% wt / wt acetonitrile solution (80.5 kg).

[0178] <2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosilloride> [ka] To a 1.5 L solution of PCl5 (335 g, 1.61 mol) in DCM, BF3·OEt2 (1.65 mL, 0.013 mol) was added under argon, followed by the addition of a 1 L solution of 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside (500 g, 1.34 mol) in DCM, while maintaining the temperature below 25°C. When complete consumption of the starting material was observed by TLC, the reaction mixture was stirred for 1 hour at a temperature of 20°C ± 5°C. The mixture was cooled to 5°C, and a 2 L solution of 20% KHCO3 aqueous solution was added over 20 minutes while maintaining the temperature below 20°C. The mixture was stirred for 15 minutes, and then the layers were separated. To the stirred organic phase, a 2 L solution of 20% KHCO3 aqueous solution was added over a further 10 minutes while maintaining the temperature below 20°C. The mixture was stirred for 15 minutes, and then the layers were separated. The organic phase was dried with MgSO4 (250 g), filtered, and concentrated under vacuum at 40°C to obtain an off-white solid. The crude substance was slurryed in a rotary evaporator containing TBME (1 L) at 40°C and atmospheric pressure for 1 hour, then cooled to 5°C and held for 16 hours. The substance was recovered by filtration, the filtration cake was washed with TBME (80 mL), and the substance was dried by drawing air through a filter to obtain 330 g (70%) of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosilloride 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 added to 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 α,α,α-trifluorotoluene (6.75 L) containing 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside (1.50 kg, 4.02 mol) was added to the reaction mixture. A line rinse was performed with α,α,α-trifluorotoluene (0.75 L). The reaction mixture was stirred for 1 hour in the range of 35°C ± 5°C. 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 filtered 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-galactopyranosilloride as an off-white solid.

[0180] <5-bromopyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside> [ka] A solution of sodium bis(trimethylsilyl)amide (4.2 L, 2 M solution in THF, 8.37 mol) was added to a jacketed container, and the solution was stirred under argon at 5°C. While maintaining the temperature below 20°C, a solution of THF (2.1 L) containing 5-bromopyridine-3-thiol (1.6 kg, 8.37 mol) was added over 1 hour and 15 minutes. Then, a solution of THF (2.1 L) containing 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosilloride (2.1 kg, 5.98 mol) was added over 15 minutes. A line rinse was performed with an additional THF (1 L). The resulting mixture was stirred for 18 hours, then TBME (6.3 L) was added, 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 phase was washed with 10% NaCl aqueous solution (3 × 6.3 L) and then concentrated under vacuum at 40°C. The crude substance was co-evaporated with methanol (4.2 L) under vacuum and then slurryed in methanol (4.2 L) at 50°C for 2 hours. The mixture was cooled to 20°C and then filtered, and the filtered cake was washed with methanol (1 L). The solid substance was further dried under vacuum at 40°C until constant weight was obtained, yielding 2.09 kg (69%) of 5-bromopyridine-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: A solution of sodium bis(trimethylsilyl)amide (2.4 L, 2 M solution in THF, 4.80 mol) was added to a jacketed container, and the solution was stirred under argon at 5°C. While maintaining the temperature below 20°C, a solution of THF (1.2 L) containing 5-bromopyridine-3-thiol (913 g, 4.80 mol) was added over 1 hour and 15 minutes. A line rinse was performed with an additional 0.6 L of THF. Then, a solution of THF (1.2 L) containing 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosilloride (1.2 kg, 3.43 mol) was added to the mixture over 15 minutes. A line rinse was performed with an additional 0.6 L of THF. 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% NaCl aqueous solution (3 × 3.6 L) and then concentrated under vacuum at 40°C. The crude substance was co-evaporated with methanol (2.4 L) under vacuum and then slurryed in methanol (2.4 L) at 50°C for 2 hours. The mixture was cooled to 20°C, then filtered, and the filtered cake was washed with methanol (0.5 L). The solid substance was dried under vacuum at 40°C until constant weight was obtained, yielding 1.21 kg (70%) of 5-bromopyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside.

[0182] Alternative procedure: [ka] PCl5 (38.8 kg, 186 mol) was placed in a jacketed container, followed by α,α,α-trifluorotoluene (406 L). A solution of 1 M BF3·OEt2 (1.55 L, 1.55 mol) was added, and the mixture was heated to 33°C. While maintaining a temperature of 35°C ± 5°C, 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside (58 kg, 155 mol) was added to the reaction mixture in 4 equivalents over 2 hours. The reaction mixture was stirred at 39°C for 1 hour. The mixture was cooled to -23°C, cyclohexane (348 L) was added over 1 hour, and the resulting suspension was stirred at -20 to -26°C for 2 hours. The reaction mixture was filtered, the filter cake was washed with TBME (116 L) at -22°C, and dried by blowing nitrogen over the filter. 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosilloride was dissolved in THF (130 L) at 41°C on a filter.

[0183] In the second container, 5-bromopyridine-3-thiol (33.1 kg, 174 mol) and THF (217 L) were added. THF containing 2 M NaHMDS (87 L, 174 mol) was added at 25-22°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-galactopyranosilloride was added to a suspension of sodium 5-bromopyridine-3-thiolate at 21°C, followed by the addition of THF line washing solution (22 L). The resulting mixture was stirred at 22°C for 21 hours. Water (130 L) and ethyl acetate (130 L) were added at 18-20°C, and the mixture was stirred for 15 minutes to separate the phases. The aqueous phase was extracted with ethyl acetate (130 L) at 20°C. The combined organic phases were washed with 10% NaCl aqueous solution (3 × 130 L), and then solvent-exchange distillation to methanol at a maximum of 40°C under vacuum to obtain a slurry in methanol (approximately 435 L). The mixture was heated under reflux and then cooled to 5°C over 1.5 hours, and held at this temperature for 2 hours. The mixture was filtered, and the filter cake was washed with methanol (87 L) at 5°C. When the solid material was dried in a vacuum at 40°C, 41.7 kg (53%) of 5-bromopyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside was obtained.

[0185] <5-bromopyridine-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside> [ka] Trimethyl((3,4,5-trifluorophenyl)ethynyl)silane (1.11 kg, 4.88 mol), CuI (81.68 g, 0.41 mol), and acetonitrile (20 L) were added to a jacketed container, and the mixture was stirred under argon. 5-bromopyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (2.02 kg, 3.98 mol) and triethylamine (1.2 L, 8.15 mol) were added, and the mixture was heated to 60°C. THF solution containing 1 M TBAF (3 × 200 mL, 0.20 mol) was added three times at 30-minute intervals, and the mixture was stirred for another 30 minutes after the final addition of the reactants. Ethyl acetate (20 L) was added, and the mixture was cooled to 20°C. The mixture was washed with 10% NH4OH solution (4 × 6 L) until the aqueous phase no longer turned blue. Subsequently, the organic phase was washed with 2 M HCl aqueous solution (2 × 6 L) and 5% NaHCO3 aqueous solution (6 L), and then concentrated at 50°C under vacuum. Without further purification, 5-bromopyridine-3-yl2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside was used in the next step. 1 H NMR(400 MHz,CDCl3)δ 8.61(dd,J=6.3,2.0 Hz,2H),8.00(t,J=2.0 Hz,1H),7.79(s,1H),7.48-7.39(m,2H).6.14(d,J=5.7 Hz,1H),6.09(dd,J=11.5,5.5 Hz,1H),5.62(dd,J=3.0,1.1 Hz,1H),5.22(dd,J=11.4,3.1 Hz,1H),4.89-4.81(m,1H),4.16(dd,J=11.7,4.9 Hz,1H),4.08(dd,J=11.7,7.6 Evidence of the formation of 5-bromopyridine-3-yl 4,6-di-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside is also present. 1 Observed by 1H NMR spectroscopy.1 H NMR(400 MHz,CDCl3)δ 8.60(dd,J=14.0,2.0,2H),8.07(t,J=2.0,1H),7.90(s,1H),7.42-7.32(m,2H),5.93(d,J=5.3 Hz,1H),5.64(dd,J=3.0,1.1,1H),5.27(dt,J=10.9,5.6,1H),4.93(dd,J=10.9,3.0 Hz,1H),4.87-4.79(m,1H),4.43(d,J=5.8 Hz,1H),4.21-4.05(m,2H),2.04(s,3H),2.01(s,3H).

[0186] Alternative procedure: [ka] Acetonitrile / heptane (28 kg) as a solution containing trimethyl((3,4,5-trifluorophenyl)ethynyl)silane (10.5 kg, 45.9 mol) was distilled into acetonitrile using solvent exchange distillation to obtain a volume of approximately 52 L. Further acetonitrile (21.0 L), ethanol (6.4 L), and potassium carbonate (3.17 kg, 23.0 mol) were added to the container and stirred at 20°C for 5.5 hours, after which further potassium carbonate (3.17 kg, 23.0 mol) was added. The mixture was stirred at 20°C for a further 16.5 hours, then filtered, and the filter was washed with acetonitrile (21.0 L) to produce a solution of 5-ethynyl-1,2,3-trifluorobenzene, which was used without further isolation.

[0187] In a separate container, a solution of 5-bromopyridine-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 added. The mixture was heated to 44°C and stirred at this temperature for 3.25 hours. The mixture was cooled to 18°C, and 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 at 22°C with 10% ammonium hydroxide aqueous solution (2 × 134 L), 2 M hydrochloric acid (134 L), and 5% sodium bicarbonate aqueous solution (134 L). The phases were separated, and the organic phases were subjected to solvent exchange distillation to methanol under vacuum at ≤50°C to obtain approximately 89 L of slurry. The slurry was cooled to 2°C, held at this temperature for 16 hours, and filtered. The filtration cake was washed with methanol (53.5 L) at 5°C, and the product was dried at a maximum of 60°C to obtain 20.0 kg (66%) of 5-bromopyridine-3-yl2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside.

[0188] <5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside, I> [ka] Crude 5-bromopyridine-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside (5.36 kg, 8.13 mol) was dissolved in methanol (13.4 L) and stirred under argon. 25 wt% sodium methoxide solution (185 mL, 0.81 mol) was added, and the mixture was stirred at 20°C for 16 hours. An additional 25 wt% sodium methoxide solution (90 mL, 0.41 mol) was added, and the mixture was stirred at 20°C for 24 hours. TBME (8.5 L) was added, and the mixture was stirred at 20°C for 2 hours. The mixture was filtered, and the filtered cake was washed with TBME (5.3 L). When the solid material was dried in a vacuum at 30°C until a constant weight was achieved, 2.79 kg of 5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside was obtained as an off-white solid (65% in two steps). 1 H NMR(400 MHz,DMSO-d6)δ 8.81(s,1H),8.68(d,J=1.9 Hz,1H),8.61(d,J=2.1 Hz,1H),8.30(t,J=2.1 Hz,1H),7.90-7.80(m,2H),5.99(d,J=5.2 Hz,1H),5.96(br s,1H),5.54(d,J=5.6 Hz,1H),4.85(dd,J=11.3,2.8 Hz,1H),4.81-4.69(m,2H),4.27(t,J=6.2 Hz,1H),4.08-4.00(m,1H),3.59-3.49(m,1H),3.46-3.36(m,1H).

[0189] Alternative procedure: 5-bromopyridine-3-yl2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-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 adding 30 wt% sodium methoxide solution (0.54 kg, 3.01 mol), methanol line washing solution (2.5 L) was added, and the mixture was stirred at 20°C for 1 hour and 43 minutes. An additional 30 wt% sodium methoxide solution (0.52 kg, 2.89 mol) was added, 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 filtered cake was washed with methanol (30 L) at 5°C. The crude material was vacuum-dried at 55°C to obtain 14.19 kg. The crude product was then returned to the reactor and ethanol (525 L) was added. The mixture was heated under reflux until a solution was formed, then cooled to 2°C and aged at this temperature for 6 hours and 14 minutes, after which it was filtered. The filtered 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 slurred in TBME (142 L) at 19°C for 27 hours. The mixture was cooled to 2°C, stirred at this temperature for 3 hours and 2 minutes, then filtered, and the filtered cake was washed with TBME (21 L) at 2°C. When the product was vacuum-dried at a maximum temperature of 60°C, 12.44 kg of 5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside was obtained as a light brown solid (77.4% throughout the reaction and purification steps).

[0190] [Preparation of polymorphs and salt forms] 5-Bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside is a crystalline solid that can potentially exist as seven crystalline polymorphs as well as amorphous forms. 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 (pseudoisostructure) solvates. Table 1 lists the polymorphs and the key solvents in which they are produced. Figures 1A–G provide XRPD diffractograms of the identified polymorphs 1–7, respectively. [Table 2]

[0191] Figures 1A to 1G allow for the identification of the XRPD patterns of polymorphs of the compound of formula I: 1A is morphology 1, 1B is morphology 2, 1C is morphology 3, 1D is morphology 4, 1E is morphology 5, 1F is morphology 6, and 1G is morphology 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 contains the following characteristic XRPD peaks. [Table 7]

[0197] Form 6 contains the following characteristic XRPD peaks. [Table 8]

[0198] Form 7 contains 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 the steps of suspending or dissolving 3,3'-dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazole-1-yl]-1,1'-sulfandiyl-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, precipitation from the solvent by adding a poor solvent, or a combination thereof. Samples were prepared by fast and slow evaporation by mixing 7 mg of 3,3'-dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazole-1-yl]-1,1'-sulfandiyl-di-β-D-galactopyranoside with a solvent (see Table 2 below) and sonicating to ensure complete dissolution. For high-speed evaporation, the low-boiling point solvent was removed over 20 minutes under controlled vacuum using a Genovac centrifugal evaporator. For low-speed evaporation, the solvent was evaporated 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-triazole-1-yl]-1,1'-sulfandiyl-di-β-D-galactopyranoside with the solvent (see Table 2 below). The resulting slurry was sonicated in a bath and then stirred for 48 hours. The solid was isolated by filtration onto a sintered filter. The sample subjected to precipitation with a poor solvent was prepared by mixing 7 mg of 3,3'-dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazole-1-yl]-1,1'-sulfandiyl-di-β-D-galactopyranoside with a solvent (see Table 2 below) and mixing until dissolved. The poor solvent (see Table 2 below) was added to rapidly precipitate the solid, which was isolated on a sintered metal filter by vacuum filtration. Table 2 lists the forms produced by these methods. Form 1 was also prepared as an off-white solid by the method described in the large-scale method above. [Table 10]

[0201] 3,3'-dideoxy-3,3'-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazole-1-yl]-1,1'-sulfandiyl-di-β-D-galactopyranoside can exist in various salt forms, including hydrochloride, hydrobromide, sulfate, phosphate, ethanesulfonate, and methanesulfonate. Salt forms of the compound of formula I can be prepared by rapidly evaporating or slurrying a 1:1 mixture of the compound of formula I with an acid such as sulfuric acid, hydrochloric acid, hydrobromide, phosphoric acid, ethanesulfate, and methanesulfate 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 a salt form of the compound of formula I is the hydrochloride (HCl salt), which is a crystalline salt with a melting point of 221°C. The HCl salt is identified by the XRPD diffractogram in 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-triazole-1-yl]-1,1'-sulfandiyl-di-β-D-galactopyranoside in a vial with equimolar amounts of hydrochloric acid and a 1:1 ethyl acetate:heptane mixture 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. The invention described in the original claims of this application is as follows: [Section 1] Equation (I) [C1] JPEG0007839730000044.jpg3862 A method suitable for large-scale synthesis of 5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside having, a) Formula IX [Case 2] JPEG0007839730000045.jpg4761 A compound of formula X (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 as needed, and a basic fluoride source such as TBAF is added as needed under appropriate conditions to obtain a compound of formula X [C3] JPEG0007839730000046.jpg71102 The process of obtaining the compound (wherein R1, R2, and R3 are as defined above), b) A step of removing the protecting group from the compound of formula X to obtain the compound of formula I. A method comprising a series of steps. [Section 2] The method according to claim 1, wherein the appropriate conditions for step a) are to react a compound of formula IX (wherein R1, R2, and R3 are independently selected from protecting groups and 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 at a suitable temperature and optionally under an inert atmosphere, to add a catalyst and a base to the organic solvent to produce a reaction mixture, to heat the reaction mixture to a temperature at least 15°C above the suitable temperature, and to continue the reaction for at least 1 hour to obtain a compound of formula X (wherein R1, R2, and R3 are as defined above). [Section 3] The method according to claim 1 or 2, wherein R1, R2, and R3 are independently selected from ester protecting groups. [Section 4] The method according to any one of claims 1 to 3, wherein the reaction is carried out under an inert atmosphere. [Section 5] The method according to any one of claims 1 to 4, wherein the organic solvent is selected from toluene or a polar aproton solvent. [Section 6] The method according to any one of items 1 to 5, wherein the optimal temperature is 15 to 25°C. [Section 7] The method according to any one of claims 1 to 6, wherein the temperature of the reaction mixture increases by heating the mixture to 40°C to 70°C. [Section 8] The method according to any one of claims 1 to 7, wherein the reaction is continued for at least 2 hours. [Section 9] The method according to any one of claims 1 to 8, wherein the catalyst is a metal catalyst. [Section 10] The method according to any one of items 1 to 9, wherein the base is an organic base. [Section 11] The method according to claim 10, wherein the organic base is selected from tertiary amine bases such as triethylamine, diisopropylethylamine, and tributylamine, or from strong non-nucleophilic bases such as DBU (1,8-diazabicyclo(5.4.0)undeca-7-ene). [Section 12] The method according to any one of claims 1 to 11, wherein the removal of the protecting group in step b) is carried out by a series of steps: 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, then reacting with an additional base, reacting at the same suitable temperature for at least 15 minutes, then cooling the reaction mixture, then washing with alcohol, and drying as necessary to obtain the compound of formula I. [Section 13] The method according to paragraph 12, wherein the ether is TBME. [Section 14] The method according to item 12 or 13, wherein the appropriate temperature is 15 to 25°C. [Section 15] The aforementioned organic solvent is an alcohol, for example, C 1~6 The method according to any one of claims 12 to 14, selected from alcohols, preferably methanol. [Section 16] The method according to any one of claims 12 to 15, wherein the basic conditions are alcoholic basic conditions. [Section 17] The method according to any one of claims 12 to 16, wherein the base is sodium methoxide in methanol. [Section 18] The method according to any one of claims 12 to 17, wherein the reaction with the base lasts for at least one hour. [Section 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. [Section 20] The method according to item 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. [Section 21] The method according to item 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. [Section 22] The process immediately preceding process a), (ia) Formula VIII [C4] JPEG0007839730000047.jpg3044 The method according to any one of claims 1 to 21, comprising the step of reacting 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, and R4 is a halogen) with 5-bromopyridine-3-thiol and a base in a suitable organic solvent, under suitable conditions, and optionally under an inert atmosphere, to obtain 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). [Section 23] The method according to item 21 or 22, wherein the deprotonating agent is sodium bis(trimethylsilyl)amide. [Section 24] The method according to any one of items 21 to 23, wherein R1, R2, and R3 are all acetyl groups and R4 is as defined above. [Section 25] The method according to any one of items 21 to 24, wherein R4 is chlorine. [Section 26] The method according to any one of items 21 to 25, wherein the reaction is carried out under an inert atmosphere. [Section 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, acetonitrile, and mixtures thereof. [Section 28] The method according to any one of claims 21 to 27, wherein the suitable conditions for step (ia) are to react a compound of formula VIII (wherein R1, R2, R3 and R4 are as defined above) with a 5-bromopyridine-3-thiol and a base in an organic solvent at a suitable temperature, preferably under an inert atmosphere, to maintain the reaction at the suitable temperature, then to continue the reaction for at least 15 minutes, and to isolate and purify as necessary to obtain a compound of formula IX as a solid. [Section 29] The method according to claim 28, wherein the base is cooled to below room temperature, 5-bromopyridine-3-thiol is added at a suitable temperature and for a suitable amount of time, and then the compound of formula VIII is added. [Section 30] The method according to item 28 or 29, wherein the appropriate temperature is less than 25°C. [Section 31] The method according to any one of claims 28 to 30, wherein the reaction is carried out at the appropriate temperature for at least 1 / 2 hour. [Section 32] The method according to any one of items 28 to 31, wherein the molar ratio of the compound of formula VIII to the base is 1:1 to 1:3. [Section 33] The process immediately preceding process ia), (ib) Formula VII [5] JPEG0007839730000048.jpg4858 (In the formula, R1, R2, and R3 are selected independently of protecting groups 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 Alkenil, Z''-C 3~6 Branched alkyl, Z''-C 3~6 Selected from cycloalkyl Z''-heteroaryl and Z''-aryl, where Z'' is SO, SO 2 The method according to any one of claims 1 to 32, comprising the step of reacting a compound of formula VIII (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, and R4 is a halogen) in a suitable organic solvent under suitable conditions to obtain a compound of formula VIII (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, and R4 is a halogen). [Section 34] The crystalline form of 5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside having formula (I). [Section 35] The crystalline form described in section 34 is polymorph 1, which contains the following 17 characteristic XRPD peaks. [Table 1] JPEG0007839730000049.jpg90168 [Section 36] The crystalline form described in item 34, which is a hydrochloride salt.

Claims

1. Equation (I) 【Chemistry 1】 A method suitable for large-scale synthesis of 5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-yl]-1-thio-α-D-galactopyranoside having, a) Formula IX 【Chemistry 2】 A compound of formula X (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 and a catalyst, a base is added to the organic solvent, a reaction mixture is produced at a suitable temperature of 15-25°C, and the reaction mixture is heated to a temperature at least 15°C above the suitable temperature to obtain a compound of formula X 【Transformation 3】 The process of obtaining a compound (wherein R1, R2, and R3 are as defined above), b) A step of removing the protecting group from the compound of formula X to obtain the compound of formula I. A method comprising a series of steps.

2. The appropriate conditions for step a) are to react 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) with 5-ethynyl-1,2,3-trifluorobenzene in an organic solvent at a suitable temperature under an inert atmosphere, add a catalyst and a base to the organic solvent to produce a reaction mixture, heat the reaction mixture to a temperature 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), The method according to claim 1, wherein the appropriate temperature is 15 to 25°C.

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 claim 2 or 3, wherein the temperature of the reaction mixture increases by heating the mixture to 40°C to 70°C.

5. The method according to any one of claims 1 to 4, wherein the reaction is continued for at least two hours, the catalyst is a metal catalyst, and the base is an organic base selected from triethylamine, diisopropylethylamine, tributylamine, a tertiary amine base, or DBU (1,8-diazabicyclo(5.4.0)undec-7-ene), a strong non-nucleophilic base.

6. The molar ratio of the compound of formula IX to trimethyl((3,4,5-trifluorophenyl)ethynyl)silane is 5:4 to 1:

3. The molar ratio of the compound of formula IX to the catalyst is 20:1 to 2:

1. The method according to any one of claims 1 to 5, wherein the molar ratio of the compound of formula IX to the base is 1:1 to 1:

10.

7. The removal of the protecting group in step b) is carried out by a series of steps: mixing the compound of formula X in an inert atmosphere, in an organic solvent, under basic conditions; reacting at a suitable temperature for at least 15 minutes; subsequently reacting with an additional base; reacting at the same suitable temperature for at least 15 minutes; then cooling the reaction mixture; subsequently washing with alcohol and drying to obtain the compound of formula I. The method according to any one of claims 1 to 6, wherein the appropriate temperature is 15 to 25°C.

8. The organic solvent contains alcohol and methanol. １～６ The method according to claim 7, wherein alcohol is selected from among alcohols.

9. The method according to claim 7 or 8, wherein the basic conditions are alcoholic basic conditions.

10. The method according to any one of claims 7 to 9, wherein the base is sodium methoxide in methanol.

11. The process immediately preceding process a), (ia) Formula VIII 【Chemistry 4】 The process includes a step of reacting 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, and R4 is chlorine) with 5-bromopyridine-3-thiol and a base in a suitable organic solvent under an inert atmosphere to obtain 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), The method according to any one of claims 1 to 10, wherein the appropriate organic solvent is selected from the group consisting of ethyl acetate, THF, toluene, DMF, and acetonitrile, and mixtures thereof.

12. The bases used in process (ia) are NaH, KOTBu, KOH, sodium bis(trimethylsilyl)amide, and K ２ CO ３ and / or Cs ２ CO ３ The method according to claim 11, selected from the following.

13. The process immediately preceding process (ia), (ib) Formula VII 【Transformation 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), reacting the compound in a suitable organic solvent under suitable conditions with a halogenating agent or triflate or a reagent for activating the anomeric position for nucleophilic substitution 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 chlorine), The aforementioned suitable organic solvent is an aprotic solvent, The method according to claim 11 or 12, wherein the appropriate conditions include an appropriate temperature of 15 to 45°C.

14. The method according to claim 13, wherein the aprotic solvent is selected from dichloromethane, toluene, or α,α,α-trifluorotoluene, and mixtures thereof.

15. The method according to any one of claims 1 to 14, wherein the silane-protected 5-ethynyl-1,2,3-trifluorobenzene is trimethyl((3,4,5-trifluorophenyl)ethynyl)silane.

16. The method according to any one of claims 1 to 15, wherein step a) further includes adding a basic fluoride source to obtain the compound of formula X.

17. The method according to claim 16, wherein the basic fluoride source is TBAF.

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