LARGE SCALE PROCESS FOR THE PREPARATION OF

5-BROMOPYRIDIN-3-YL-3-DEOXY-3-[4-(3,4,5-TRIFLUOROPHENYL)- 1 H-1 ,2,3-TRIAZOL-1 -YL]- 1 -THIO-ALPHA-D-GALACTOPYRANOSIDE AND A CRYSTALLINE FORM THEREOF

Technical field

The present invention relates to a process of preparing 5-Bromopyridin-3-yl 3-de- oxy-3 -[4-(3 ,4,5-trifluorophenyl)- 1 H- 1,2,3 -triazol- 1 -yl]- 1 -thio-a-D-galactopyranoside which process can be scaled up. The process parameters are stable, and the process is suitable for GMP manufacture.

Background Art

The compound of formula I has been described in international patent application publication number W02016120403 as a galectin 3 inhibitor useful for treating various dis orders or diseases, as described therein. The compound of formula I was made in a 60% yield in a small scale lab process, but no parameters for scaling up have been disclosed.

Summary of the invention

The present invention relates to a new process for preparing 5-Bromopyridin-3-yl 3- deoxy-3 -[4-(3 ,4,5-trifluorophenyl)- 1 H- 1 ,2,3 -triazol- 1 -yl]- 1 -thio-a-D-galactopyranoside which process can be scaled up to large scale and/or industrial scale such as 30 kg or higher. The process can also be used for smaller scale such as from 200 g to 3 kg, or medium scale from 3 kg to 30kg.

In a first aspect the present invention relates to a process, such as suitable for large scale synthesis, for preparing 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)- lH-l,2,3-triazol-l-yl]-l-thio-a-D-galactopyranoside having formula (I) wherein the process comprises the consecutive steps of a) reacting a compound of formula IX wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, R2, and R3 is a protecting group, with 5-ethynyl-l,2,3-tri- fluorobenzene (or a silane protected 5-ethynyl-l,2,3-trifluorobenzene), and a catalyst and optionally adding a base in an organic solvent, and optionally adding a basic fluoride source agent, such as TBAF, under suitable conditions to obtain a compound of formula X wherein Rl, R2, R3 are as defined above, and b) removing the protecting groups Rl, R2 and R3 from the compound of formula X to ob tain the compound of formula I. In an embodiment the compound of formula I is obtained as a solid product, such as a crystalline or amorphous product. In a further embodiment the suitable conditions in step a) are reacting a compound of formula IX wherein Rl, R2, R3 are independently selected from protecting groups or hy drogen, provided that at least one of Rl, R2, R3, is a protecting group, with trime- thyl((3,4,5-trifluorophenyl)ethynyl)silane in the organic solvent at a suitable temperature, optionally under inert atmosphere, and adding a catalyst and optionally adding a base in the organic solvent to create a reaction mixture and optionally heating the reaction mixture to raise the temperature at least 15 °C above the suitable temperature, and adding the basic flu oride source agent and continue the reaction for at least 1 hour to obtain the compound of formula X wherein Rl, R2, R3 are as defined above. In a typical embodiment the present invention relates to a process for preparing 5-

Brom opyri din-3 -yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-lH-l,2,3-triazol-l-yl]- l-thio-a-D- galactopyranoside having formula (I) wherein the process comprises the consecutive steps of a) reacting a compound of formula IX

wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, R2, and R3 is a protecting group, with 5-ethynyl-l,2,3-tri- fluorobenzene, and a catalyst (e.g. CuI(I)) and adding a base (e.g. triethylamine) in an or- ganic solvent (e.g. acetonitrile) under suitable conditions to obtain a compound of formula

X wherein Rl, R2, R3 are as defined above, and b) removing the protecting groups of the compound of formula X to obtain the compound of formula I. In an embodiment the compound of formula I is obtained as a solid product, such as a crystalline or amorphous product.

In an embodiment the basic fluoride source agent is added. In another embodiment no basic fluoride source agent is added. In a further embodiment the compound of formula I is isolated as a crystalline form, such as a polymorph, e.g. polymorphic form 1.

In another embodiment the compound of formula I is isolated as a salt, such as a sul fate, bromide or phosphate salt, preferably a HC1 salt. Typically, a crystalline HC1 salt.

In a further embodiment the suitable conditions in step a) are reacting a compound of formula IX wherein Rl, R2, R3 are independently selected from protecting groups or hy drogen, provided that at least one of Rl, R2, R3, is a protecting group, with 5-ethynyl-l,2,3- trifluorobenzene in the organic solvent at a suitable temperature under inert atmosphere, and adding a catalyst and adding a base in the organic solvent to create a reaction mixture and heating the reaction mixture to raise the temperature at least 15 °C above the suitable tem perature, and continue the reaction for at least 1 hour to obtain the compound of formula X wherein Rl, R2, R3 are as defined above. In particular under these conditions it is not nec essary to add a basic fluoride source agent, such as TBAF or CsF.

In a still further embodiment Rl, R2, R3 are independently selected from ester pro tecting groups, such as acetyl, benzoyl and pivaloyl, typically all Rl, R2, R3, are acetyl.

The compound X may be further purified and isolated as a solid. Typically, com pound X is isolated whereas purification takes place later in the process as majority of im purities are intermediates in the deacetylation to compound of formula I.

In a further embodiment the reaction takes place under inert atmosphere, such as ar gon or nitrogen atmosphere.

In another embodiment the reaction takes place under atmospheric pressure.

In a still further embodiment the organic solvent is selected from toluene or a polar aprotic solvent, such as acetonitrile or DMF, and mixtures thereof.

In a further embodiment the suitable temperature is between 15 and 25 °C, such as about room temperature.

In a still further embodiment the temperature is raised in the reaction mixture heating the mixture to 40 °C to 70 °C, such as 45 °C to 70 °C, such as about 60 °C.

In a further embodiment the reaction is continued for 1 to 3 hours, such as about 2 hours. The reaction may continue for at least 2 hours, such as 3 hours, in many instances it will be complete within 2 hours.

In a still further embodiment the catalyst is a metal catalyst, such as a metal halide, e.g. Cu(I) or Cu(II), in particular Cu halide, such as Cu iodide. In a further embodiment the base is an organic base, such as triethylamine or DI PEA.

In a still further embodiment the basic fluoride source agent is TBAF.

In a further embodiment the molar ratio between the compound of formula IX and trimethyl((3,4,5-trifluorophenyl)ethynyl)silane is 5:4 to 1:3, such as 1:1 to 5:7, typically 5:6, and the organic solvent is in surplus.

In a still further embodiment the molar ratio between the compound of formula IX and 5-ethynyl-l,2,3-trifluorobenzene is 5:4 to 1:3, such as 1:1 to 5:7, typically 5:6, and the organic solvent is in surplus.

In a further embodiment the molar ratio between the compound of formula IX and the catalyst is 20:1 to 2:1, such as 20:1 to 5:1, typically 10:1 and the organic solvent is in surplus.

In a still further embodiment the molar ratio between the compound of formula IX and the base is 1 : 1 to 1 : 10, such as 2:3 to 1 :3, typically 1 :2 and the organic solvent is in sur plus.

In a further embodiment the removing of protecting groups in step b) is done by mixing the compound of formula X in an organic solvent and with a base optionally under inert atmosphere and reacting for at least 15 minutes at a suitable temperature, followed by washing with an ether to obtain the compound of formula I. Typically, the ether is tert- Bu- tylmethyl ether (TBME). Preferably, the suitable temperature is 15-25 °C, such as about room temperature. Typically, the organic solvent is selected from an alcohol, such as Ci- ₆ alkohol, e.g. methanol. Furthermore, the base is preferably selected from a base, such as an organic base, in a concentration sufficient to provide a pH of 12 or higher. Typically, the base is sodium methoxide in methanol, such as 25 wt% sodium methoxide solution in meth anol. In an embodiment the reaction with the base is for at least 1 hour, such as 2-24 hours.

In another embodiment the removing of protecting groups in step b) is done by the consecutive steps of mixing the compound of formula X in an organic solvent (such as a Ci- ₆ alcohol, e.g. methanol or ethanol) with a base (e.g. sodium methoxide) under inert atmos phere and reacting for at least 15 minutes (such as 1 hour) at a suitable temperature (such as room temperature), followed by additional base and reacting for at least 15 minutes (such as 1 hour) at the suitable temperature, then cooling (e.g. 5 °C) the reaction mixture followed by washing with an alcohol (such as a Ci- ₆ alcohol, e.g. methanol or ethanol), drying (e.g. in vacuo at 60 °C), adding alcohol (such as a Ci- ₆ alcohol, e.g. methanol or ethanol, such as ethanol) and heating (such as reflux) until a solution was formed, then cooling (such as 5 °C), filtering, washing (e.g. ethanol) and precipitation, and the crystallized product dried (such as at 60 °C), and washing with an ether (such as TBME) under cooling (such as at 5 °C) to obtain the compound of formula I.

In a further embodiment the present process of the invention comprises a step di rectly preceding step a)

(ia) reacting a compound of formula VIII

VIII wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, 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, optionally under inert atmosphere, to obtain the compound of formula IX wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, R2, and R3 is a protecting group. The base may be selected from NaH, KOtBu, KOH or sodium bis(trimethylsilyl)amide or carbonate bases, e.g. K2CO3 and/or CS2CO3. In an embodiment the base is selected from NaH, KOtBu, KOH, sodium bis(trime- thylsilyl)amide, K2CO3 and/or CS2CO3.

In an embodiment the compound of formula IX is obtained as a solid.

In a further embodiment the deprotonating agent is sodium bis(trimethylsilyl)amide.

In a still further embodiment Rl, R2, R3 are all acetyl groups and R4 is as defined above. Preferably, R4 is chlorine.

In a further embodiment the reaction takes place under inert atmosphere. Typically, under an argon or nitrogen atmosphere.

In a still further embodiment the organic solvent is selected from the group consist ing of ethyl acetate, THF, toluene, DMF and acetonitrile, and mixtures thereof. In a further embodiment the suitable conditions in step (ia) are reacting a compound of formula VIII wherein Rl, R2, R3 and R4, are as defined above, optionally under inert at mosphere and at a suitable temperature with 5-bromopyridine-3-thiol and the base in an or ganic solvent, and maintaining the reaction mixture at the suitable temperature, then con tinue the reaction for at least 15 minutes, and optionally isolating and purifying to obtain the compound of formula IX as a solid. Preferably, the base is cooled to below room tempera ture before adding 5-bromopyridine-3-thiol over a suitable time and at a suitable tempera ture and followed by addition of the compound of formula VIII.

In a still further embodiment the suitable temperature is below 25 °C.

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

In a still further embodiment the molar ratio between the compound of formula VIII and the base is 1:1 to 1:3, such as 5:7.

In a still further embodiment the process of the present invention comprises a step directly preceding step ia)

(ib) reacting a compound of formula VII

VII wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, R2 and R3 is a protecting group, and R4’ is a SR5 or OR5 wherein R5 is selected from H, Z”-Ci- ₆ alkyl, Z”-Ci- ₆ alkenyl, Z”-C3-6 branched alkyl, Z”- C3-6 cyclo alkyl Z”-heteroaryl and Z”-aryl wherein Z” is SO, SO2, C=0 or C=S, with a re agent for activating the anomeric position for nucleophilic substitution, such as a halogenat- ing agent, in a suitable organic solvent, with a suitable catalyst, optionally under inert at mosphere, under suitable conditions to obtain the compound of formula VIII wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, R2, and R3 is a protecting group and R4 is a halogen.

In an embodiment the reaction takes place under an inert atmosphere, such as an ar gon or nitrogen atmosphere.

In a further embodiment the organic solvent is an aprotic solvent, preferably di- chloromethane, toluene or a,a,a-trifluorotoluene, and mixtures thereof.

In a further embodiment the reagent for activating the anomeric position for nucleo philic substitution is a halogenating agent. Typically, the halogenating agent is a metal hal ide, for example, AlCh, or SOCh, dichloromethyl methyl ether (DCMME) or a halide of phosphorus. Preferably the halogenating agent is PCb.

In a further embodiment the catalyst is an acid, such as a lewis acid, preferably BF3 OEt2.

In a still further embodiment the suitable conditions involve a suitable temperature of between 15 and 45 °C. In a further embodiment the reaction is continued for at least 15 minutes, at least ½ hour, such as 12-96 hours, at the suitable temperature.

In a still further embodiment the molar ratio between the compound of formula VII and the reagent for activating the anomeric position for nucleophilic substitution such as the halogenating agent, is 5:1 to 1:5, typically 5:6.

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

In a still further aspect the present invention relates to a process of preparing a com pound of formula III as well as formula IV starting from compound of formula II.

In a further aspect the present invention relates to preparing a compound of formula VI starting from compound of formula V. Further embodiments of the present invention

Embodiment 1. A process suitable for large scale synthesis for preparing 5-Bro- mopyri din-3 -yl 3 -deoxy-3 -[4-(3 ,4, 5-trifluorophenyl)- 1H- 1 ,2,3 -triazol- 1 -yl] - 1 -thio-a-D-ga- lactopyranoside having formula (I) wherein the process comprises the consecutive steps of a) reacting a compound of formula IX

wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, R2, and R3 is a protecting group, with 5-ethynyl-l,2,3-tri- fluorobenzene or a silane protected 5-ethynyl-l,2,3-trifluorobenzene, such as trime- thyl((3,4,5-trifluorophenyl)ethynyl)silane, and a catalyst and optionally adding a base in an organic solvent, and optionally adding a basic fluoride source agent, such as TBAF, under suitable conditions to obtain a compound of formula X wherein Rl, R2, R3 are as defined above, and b) removing the protecting groups of the compound of formula X to obtain the compound of formula I.

2. The process of embodiment 1 wherein the suitable conditions in step a) are react ing a compound of formula IX wherein Rl, R2, R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, R2, R3, is a protecting group, with trimethyl((3,4,5-trifluorophenyl)ethynyl)silane in the organic solvent at a suita ble temperature, optionally under inert atmosphere, and adding a catalyst and optionally a base in the organic solvent to create a reaction mixture and optionally heating the reaction mixture to raise the temperature at least 15 °C above the suitable temperature, and adding the basic fluoride source agent and continue the reaction for at least 1 hour to obtain the compound of formula X wherein Rl, R2, R3 are as defined above.

3. The process of any one of embodiments 1-2 wherein Rl, R2, R3 are independently selected from ester protecting groups.

4. The process of any one of embodiments 1-3 wherein the reaction takes place un der inert atmosphere.

5. The process of any one of embodiments 1-4 wherein the organic solvent is se lected from toluene or a polar aprotic solvent.

6. The process of any one of embodiments 1-5 wherein the suitable temperature is between 15 and 25 °C.

7. The process of any one of embodiments 1-6 wherein the temperature is raised in the reaction mixture heating the mixture to 45 °C to 70 °C.

8. The process of any one of embodiments 1-7 wherein the reaction is continued for at least 2 hours.

9. The process of any one of embodiments 1-8 wherein the catalyst is a metal cata lyst.

10. The process of any one of embodiments 1-9 wherein the base is an organic base.

11. The process of any one of embodiments 1-10 wherein the basic fluoride source agent is TBAF.

12. The process of any one of embodiments 1-11 wherein the removing of protecting groups in step b) is done by mixing the compound of formula X in an organic solvent and with a base optionally under inert atmosphere and reacting for at least 15 minutes at a suita ble temperature, followed by washing with an ether to obtain the compound of formula I.

13. The process of embodiment 12 wherein the ether is TBME.

14. The process of any one of embodiments 12-13 wherein the suitable temperature is 15-25 °C. 15. The process of any one of embodiments 12-14 wherein the organic solvent is se lected from an alcohol.

16. The process of any one of embodiments 12-15 wherein the base is selected from a base in a concentration sufficient to provide a pH of 12 or higher.

17. The process of any one of embodiments 12-16 wherein the base is sodium meth- oxide in methanol.

18. The process of any one of embodiments 12-17 wherein the reaction with a base is for at least 1 hour.

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

20. The process of embodiment 19 wherein the molar ratio between the compound of formula IX and the catalyst is 20: 1 to 2: 1 and the organic solvent is in surplus.

21. The process of embodiment 19 or 20 wherein the molar ratio between the com pound of formula IX and the base is 1 : 1 to 1 : 10 and the organic solvent is in surplus.

22. The process of any one of embodiments 1-21 comprising a step directly preced ing step a)

(ia) reacting a compound of formula VIII wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, 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, optionally under inert atmosphere, to obtain the compound of formula IX wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, R2, and R3 is a protecting group.

23. The process of any one of embodiments 21-22 the deprotonating agent is sodium bi s(trimethyl silyl)amide . 24. The process of any one of embodiments 21-23 wherein Rl, R2, R3 are all acetyl groups and R4 is as defined above.

25. The process of any one of embodiments 21-24 wherein R4 is chlorine.

26. The process of any one of embodiments 21-25 wherein the reaction takes place under inert atmosphere.

27. The process of any one of embodiments 21-26 wherein the organic solvent is se lected from the group consisting of ethyl acetate, THF, toluene, DMF and acetonitrile, and mixtures thereof.

28. The process of any one of embodiments 21-27 wherein the suitable conditions in step (ia) are reacting a compound of formula VIII wherein Rl, R2, R3 and R4, are as de fined above, optionally under inert atmosphere and at a suitable temperature with 5-bro- mopyridine-3 -thiol and the base in an organic solvent, and maintaining the reaction mixture at the suitable temperature, then continue the reaction for at least 15 minutes, and optionally isolating and purifying to obtain the compound of formula IX as a solid.

29. The process of embodiment 28 wherein the base is cooled to below room temper ature before adding 5-bromopyridine-3-thiol over a suitable time and at a suitable tempera ture and followed by addition of the compound of formula VIII.

30. The process of embodiment 28 or 29 wherein the suitable temperature is below

25 °C.

31. The process of any one of embodiments 28-30 wherein the reaction is continued for at least ½ hours, at the suitable temperature.

32. The process of any one of embodiments 28-31 wherein the molar ratio between the compound of formula VIII and the base is 1:1 to 1:3.

33. The process of any one of embodiments 1-32 comprising a step directly preced ing step ia)

(ib) reacting a compound of formula VII VII wherein Rl, R2, and R3 are independently selected from protecting groups or hydro gen, provided that at least one of Rl, R2 and R3 is a protecting group, and R4’ is a SR5 or OR5 wherein R5 is selected from H, Z”-Ci- ₆ alkyl, Z”-Ci- ₆ alkenyl, Z”-C3-6 branched alkyl, Z”-C3-6 cyclo alkyl Z”-heteroaryl and Z”-aryl wherein Z” is SO, SO2, C=0 or C=S, with a reagent for activating the anomeric position for nucleophilic substitution, such as a halogen- ating agent or triflate, in a suitable organic solvent under suitable conditions to obtain the compound of formula VIII wherein Rl, R2, and R3 are independently selected from pro tecting groups or hydrogen, provided that at least one of Rl, R2, and R3 is a protecting group and R4 is a halogen.

34. A crystalline form of 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)- lH-l,2,3-triazol-l-yl]-l-thio-a-D-galactopyranoside having formula (I).

35. The crystalline form of embodiment 34 which is a polymorphic form 1 as identi fied in the XRPD diffractogram in Figure 1 A.

36. The crystalline form of embodiment 34 which is a hydrochloride salt.

Detailed Description

The compound of formula (I) has the chemical name (IUPAC) 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3, 4, 5-tri fluorophenyl)- liT-1, 2, 3-triazol-l-yl]-l-thio-a-D-galactopyranoside and may be prepared as described in W02016120403. The yield is relatively low and the process in not directly possible to scale up.

Moreover, throughout the application the terms “the compound of formula I” or “the compound having formula I” or “5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluoro- phenyl )- 1 //- 1 ,2,3-triazol- 1 -yl]- l -thio-a-D-galactopyranoside having formula I” are used in terchangeable and means the compound of formula I in any solid form or liquid form, such as a crystalline form, in particular a polymorphic form, or amorphous form, and furthermore is intended to comprise the free form, any solvate or any salt thereof.

The term “alcoholytic” as used herein is a transesterification reaction, according to which an ester R’COORl’ reacts with an alcohol R2OH with formation of another ester R’COOR2’ and liberation of the alcohol R1 ΌH. The deacylation may be catalyzed by a li pase in organic solvents and constitutes a useful step in the synthesis of complex molecules where different groups are present. A suitable reference describing this is Lipase-catalyzed deacylation by alcoholysis. A selective, useful transesterification reaction By: Santaniello, Enzo; Casati, Silvana; Ciuffreda, Pierangela Current Organic Chemistry (2006), 10(10), 1095-1123 | Language: English, Database: CAplus.

Consequently, a new process has been developed concerning a process, such as suit able for large scale synthesis, for preparing 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-tri- fluorophenyl)-lH-l,2,3-triazol-l-yl]-l-thio-a-D-galactopyran oside having formula (I) wherein the process comprises the consecutive steps of a) reacting a compound of formula IX wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, R2, and R3 is a protecting group, with 5-ethynyl-l,2,3-tri- fluorobenzene (or a silane protected 5-ethynyl-l,2,3-trifluorobenzene), such as trime- thyl((3,4,5-trifluorophenyl)ethynyl)silane, and a catalyst and optionally adding a base in an organic solvent, and optionally adding a basic fluoride source agent, such as TBAF, under suitable conditions to obtain a compound of formula X wherein Rl, R2, R3 are as defined above, and b) removing the protecting groups of the compound of formula X to obtain the compound of formula I.

In an embodiment the compound of formula I is obtained as a solid product, such as a crystalline or amorphous product. In an embodiment the compound of formula I is iso- lated as a crystal, such as a polymorph. Preferably, the compound of formula I is isolated as the polymorphic form 1. In another embodiment the compound of formula I is isolated as a salt, such as a HC1 salt. Typically, a crystalline HC1 salt.

In a further embodiment the suitable conditions in step a) are reacting a compound of formula IX wherein Rl, R2, R3 are acetyl groups or hydrogen, provided that at least one of Rl, R2, R3, is an acetyl group, with a silane protected 5-ethynyl-l,2,3-trifluorobenzene in toluene or a polar aprotic solvent, and mixtures thereof, at a suitable temperature between 15 and 25 °C, optionally under inert atmosphere, and adding a catalyst and optionally a base in the organic solvent to create a reaction mixture and optionally heating the reaction mix ture to raise the temperature at least 15 °C above the suitable temperature, and adding the basic fluoride source agent and continue the reaction for at least 1 hour to obtain the com pound of formula X wherein Rl, R2, R3 are as defined above.

In a still further embodiment the suitable conditions in step a) are reacting a com pound of formula IX wherein Rl, R2, R3 are acetyl groups or hydrogen, provided that at least one of Rl, R2, R3, is an acetyl group, with 5-ethynyl-l,2,3-trifluorobenzene in toluene or a polar aprotic solvent, and mixtures thereof, at a suitable temperature between 15 and 25 °C, optionally under inert atmosphere, and adding a catalyst and optionally a base in the organic solvent to create a reaction mixture and optionally heating the reaction mixture to raise the temperature at least 15 °C above the suitable temperature, and continue the reac tion for at least 1 hour to obtain the compound of formula X wherein Rl, R2, R3 are as de fined above.

In a further embodiment the suitable conditions in step a) are reacting a compound of formula IX wherein Rl, R2, R3 are acetyl groups or hydrogen, provided that at least one of Rl, R2, R3, is an acetyl group, with trimethyl((3,4,5-trifluorophenyl)ethynyl)silane in toluene or a polar aprotic solvent, and mixtures thereof, at a suitable temperature between 15 and 25 °C, optionally under inert atmosphere, and adding a catalyst and optionally a base in the organic solvent to create a reaction mixture and optionally heating the reaction mix ture to raise the temperature at least 15 °C above the suitable temperature, and adding the basic fluoride source agent and continue the reaction for at least 1 hour to obtain the com pound of formula X wherein Rl, R2, R3 are as defined above.

In a still further embodiment Rl, R2, R3 are independently selected form ester pro tecting groups, such as acetyl, benzoyl and pivaloyl, typically all Rl, R2, R3, are acetyl. The compound X may be further purified and isolated as a solid. Typically, com pound X is isolated whereas purification takes place later in the process as majority of im purities are intermediates in the deacetylation to compound of formula I.

In a further embodiment the reaction takes place under inert atmosphere, such as an argon or nitrogen atmosphere.

In a still further embodiment the organic solvent is selected from toluene or a polar aprotic solvent, such as acetonitrile or DMF, and mixtures thereof.

In a further embodiment the suitable temperature is between 15 and 25 °C, such as about room temperature.

In a still further embodiment the temperature is raised in the reaction mixture heating the mixture to 40 °C to 70 °C, such as 45 °C to 70 °C, such as about 60 °C.

In a further embodiment the reaction is continued for at least 2 hours, such as 3 hours, e.g. from 2.5 to 4 hours.

In a still further embodiment the catalyst is a metal catalyst, such as a metal halide, e.g. Cu(I) or Cu(II), in particular Cu halide, such as Cu iodide.

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

In a still further embodiment the basic fluoride source agent is TBAF.

In a still further embodiment the molar ratio between the compound of formula IX and trimethyl((3,4,5-trifluorophenyl)ethynyl)silane is 5:4 to 1:3, such as 1:1 to 5:7, typically 5:6, and the organic solvent is in surplus.

In a further embodiment the molar ratio between the compound of formula IX and the catalyst is 20: 1 to 2:1, such as 20: 1 to 5: 1, typically 10: 1 and the organic solvent is in surplus.

In a still further embodiment the molar ratio between the compound of formula IX and the base is 1 : 1 to 1 : 10, such as 2:3 to 1 :3, typically 1 :2 and the organic solvent is in sur plus.

In a further embodiment the removing of protecting groups in step b) is done by mixing the compound of formula X in an alcohol and with a base in a concentration suffi cient to provide a pH of 12 or higher, optionally under inert atmosphere and reacting for at least 15 minutes at a suitable temperature between 15-25 °C, followed by washing with an alkyl ether to obtain the compound of formula I. Typically, the ether is fe/V-Butylmethyl ether (TBME). Preferably, the suitable temperature is 15-25 °C, such as about room temper ature. Typically, the organic solvent is selected from an alcohol, such as Ci- ₆ alcohol, e.g. methanol. Furthermore, the base is preferably selected from a base, such as an organic base, in a concentration sufficient to provide a pH of 12 or higher. Typically, the base is sodium methoxide in methanol, such as 25 wt% sodium methoxide solution in methanol.

Typically, deprotection is performed under hydrolytic (catalytic acidic or basic) con ditions or with nucleophilic reagents to directly remove the acetyl protecting groups, in par ticular alcoholytic basic conditions are preferred.

In an embodiment the reaction with a base is for at least 1 hour, such as 2-24 hours.

In a further embodiment the present process of the invention comprises a step di rectly preceding step a)

(ia) reacting a compound of formula VIII wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, 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, optionally under inert atmosphere, to obtain the compound of formula IX wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, R2, and R3 is a protecting group. The base may be selected from NaH, KOtBu, KOH or sodium bis(trimethylsilyl)amide or carbonate bases, e.g. K2CO3 and/or CS2CO3.

In an embodiment the compound of formula IX is obtained as a solid.

In a further embodiment the deprotonating agent is sodium bis(trimethylsilyl)amide.

In a still further embodiment Rl, R2, R3 are all acetyl groups and R4 is as defined above. Preferably, R4 is chlorine.

In a further embodiment the reaction takes place under inert atmosphere. Typically, under an argon or nitrogen atmosphere. In a still further embodiment the organic solvent is selected from the group consist ing of ethyl acetate, THF, toluene, DMF and acetonitrile, and mixtures thereof.

In a further embodiment the suitable conditions in step (ia) are reacting a compound of formula VIII wherein Rl, R2, R3 are all acetyl groups and R4 is a halogen, optionally under inert atmosphere and at a suitable temperature below 25 °C with 5-bromopyridine-3- thiol and a base, such as a base selected form NaH, KOtBu, KOH, sodium bis(trimethylsi- lyl)amide, and/or carbonate bases, e.g. K2CO3 and/or CS2CO3, in an organic solvent selected from ethyl acetate, THF, toluene, DMF and acetonitrile, and mixtures thereof, and maintain ing the reaction mixture at the suitable temperature, then continue the reaction for at least 15 minutes, and optionally isolating and purifying to obtain the compound of formula IX as a solid. Preferably, the base is cooled to below room temperature before adding 5-bro- mopyridine-3 -thiol over a suitable time and at a suitable temperature and followed by addi tion of the compound of formula VIIF

In a still further embodiment the suitable temperature is below 25 °C.

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

In a still further embodiment the molar ratio between the compound of formula VIII and the base is 1:1 to 1:3, such as 5:7.

In a still further embodiment the process of the present invention comprises a step directly preceding step ia)

(ib) reacting a compound of formula VII

VII wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, R2 and R3 is a protecting group, and R4’ is a SR5 or OR5 wherein R5 is selected from H, Z”-Ci- ₆ alkyl, Z”-Ci- ₆ alkenyl, Z”-C3-6 branched alkyl, Z”- C3-6 cyclo alkyl Z”-heteroaryl and Z”-aryl wherein Z” is SO, SO2, C=0 or C=S, with a re agent for activating the anomeric position for nucleophilic substitution, such as a halogenat- ing agent, in a suitable organic solvent, with a suitable catalyst, optionally under inert at mosphere, under suitable conditions to obtain the compound of formula VIII wherein Rl, R2, and R3 are independently selected from protecting groups or hydrogen, provided that at least one of Rl, R2, and R3 is a protecting group and R4 is a halogen.

In an embodiment Rl, R2, and R3 are acetyl groups or hydrogen, provided that at least one of Rl, R2 and R3 is an acetyl group, and R4’ is OR5 wherein R5 is selected from Z”-Ci- ₆ alkyl wherein Z” is C=0, with a halogenating agent, in an aprotic solvent, with an acid catalyst, optionally under inert atmosphere, at a temperature of between 15 and 45 °C for at least 15 minutes to obtain the compound of formula VIII wherein Rl, R2, and R3 are independently selected from acetyl groups or hydrogen, provided that at least one of Rl,

R2, and R3 is an acetyl group and R4 is a Cl or Br.

In an embodiment the reaction takes place under an inert atmosphere, such as an ar gon or nitrogen atmosphere.

In a further embodiment R4 is a Cl or Br, such as Cl.

In a further embodiment the organic solvent is an aprotic solvent, preferably dichloro- methane, toluene or a,a,a-trifluorotoluene, and mixtures thereof.

In a still further embodiment the reagent for activating the anomeric position for nu cleophilic substitution is a halogenating agent. Typically, the halogenating agent is a metal halide, for example, AICI ₃ , or a halogenating agent such as SOCb, dichloromethyl methyl ether (DCMME) or a halide of phosphorus. Preferably the halogenating agent is PCI ₅ .

In a further embodiment the catalyst is an acid, such as a lewis acid, preferably BF3 OEt2.

In a still further embodiment the suitable conditions involve a suitable temperature of between 15 and 45 °C. In a further embodiment the reaction is continued for at least 15 minutes, at least ½ hour, such as 1-96 hours, at the suitable temperature.

In a still further embodiment the molar ratio between the compound of formula VII and the reagent for activating the anomeric position for nucleophilic substitution such as the halogenating agent, is 5:1 to 1:5, typically 5:6. In a further embodiment the molar ratio between the compound of formula VII and the catalyst is 10:1 to 200:1, typically 100:1.

In a further aspect the present invention relates to a process of preparing a compound of formula III as well as formula IV starting from compound of formula II.

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

A further aspect concerns a process for preparing a compound of formula IV comprising a) treating a 5-bromo-3-mercaptobenzylpyridine (III) in an organic solvent with a reducing agent such as AlCh at a suitable temperature to obtain the compound of formula IV.

A still further concerns a process of preparing a compound of formula VI starting from compound of formula V comprising a) treating 5-bromo-l,2,3-trifluorobenzene (V) with a base, such as triethylamine, at a suitable temperature, and optionally a catalyst, such as a metal catalyst, e.g. Cul, and optionally under an inert atmosphere, and b) adding bis(triphenylphosphine) palladium (II) dichloride and ethynyltrimethylsilane in an organic solvent at a suitable temperature to prepare the compound of formula VI. A still further aspect concerns a crystal form of the compound of formula I. In one embodiment the crystalline form is polymorphic form 1 as identified in XRPD diffractogram in figure 1 A and in Figure 2.

In a further embodiment the crystal form of the compound of formula I comprises the 17 characteristic XRPD peaks:

A further aspect concerns a salt of the compound of formula I, preferably the HC1 salt of the compound of formula I as identified by the XRPD diffractogram in Figure 3.

The alpha and beta anomers may be separated by various methods such as via crys- tallization. However, for the present process the starting point can be the mixture as well as one of the anomers.

The term “treatment” and “treating” as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symp toms or complications, to delay the progression of the disease, disorder or condition, to alle viate or relief the symptoms and complications, and/or to cure or eliminate the disease, dis order or condition as well as to prevent the condition, wherein prevention is to be under stood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. The disease or disorder to be treated is preferably selected from the group consisting of inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; scarring; keloid formation; aberrant scar formation; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancer, such as carcinomas, sarcomas, leukemias and lym phomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, intestinal fibrosis, anky losing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; aortic stenosis, atherosclerosis, pathological angiogenesis, such as ocular angiogene sis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization re lated to cancer; and eye diseases, such as age-related macular degeneration and corneal neo vascularization; atherosclerosis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistance; obesity; Diastolic HF; asthma and other interstitial lung diseases, including Her- mansky-Pudlak syndrome, pulmonary arterial hypertension, RA-ILD, SSc-ILD, Lung dis ease with fibrosis such as COPD and asthma. Otosclerosis, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease, Liver cirrhosis of various origins, such as alcoholic and non-alcoholic, autoimmune cirrhosis such as primary biliary cirrhosis and sclerosing cholangitis, virally induced cirrhosis, cirrhosis induced by genetic disease. Liver cancer, cholangiocarcinoma, biliary tract cancer; neurodegenerative disorders such as Parkinsons disease, Alzheimers disease, cognitive impairment, cerebro vascular diseases such as stroke, traumatic brain injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, peripheral nephropathy, in a mammal, such as a human, comprising administering a therapeutically effective amount 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.

Another aspect of the present invention concerns combination therapy involving ad ministering a composition of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, together with a therapeutically active compound different from the compound of formula (I) (interchangeable with “a different therapeuti cally active compound”). In one embodiment the present invention relates to a combination of a composition comprising a compound of formula (I) of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, and a different therapeutically active compound for use in treatment of a disorder relating to the binding of a galectin-3 to a ligand in a mammal. Such disorders are disclosed below.

In an embodiment of the present invention, a therapeutically effective amount of at least one composition of the present invention, such as an amorphous solid dispersion com position or a drug layered composition, is administered to a mammal in need thereof in combination with a different therapeutically active compound. In a further embodiment, said combination of a composition of the present invention, such as an amorphous solid dis persion composition or a drug layered composition, together with a different therapeutically active compound is administered to a mammal suffering from a disorder selected from the group consisting of inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; scarring; keloid for mation; aberrant scar formation; surgical adhesions; septic shock; cancer, such as carcino mas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising can cers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn’s disease, ulcera tive colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; pathological angiogenesis, such as ocular angiogenesis or a dis ease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and corneal neovascular ization; atherosclerosis; metabolic diseases such as diabetes; type 2 diabetes; insulin resis- tens; obesity; Diastolic HF; asthma and other interstitial lung diseases, including Herman- sky-Pudlak syndrome, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.

A non-limiting group of cancers given as examples of cancers that may be treated, managed and/or prevented by administration of a composition comprising a compound of formula (I) of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, in combination with a different therapeutically active compound is selected from: colon carcinoma, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangeosarcoma, lymphangeoendothelia sarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosar coma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystandeocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioblastomas, neuronomas, craniopharingiomas, schwan nomas, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pine- aloma, hemangioblastoma, acoustic neuroama, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemias and lymphomas, acute lymphocytic leukemia and acute myelocytic polycythemia vera, multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's Disease, non-Hodgkin's lymphomas, rectum can cer, urinary cancers, uterine cancers, oral cancers, skin cancers, stomach cancer, brain tu mors, liver cancer, laryngeal cancer, esophageal cancer, mammary tumors, childhood-null acute lymphoid leukemia (ALL), thymic ALL, B-cell ALL, acute myeloid leukemia, myelo- monocytoid leukemia, acute megakaryocytoid leukemia, Burkitt's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and T cell leukemia, small and large non-small cell lung carcinoma, acute granulocytic leukemia, germ cell tumors, endometrial cancer, gastric cancer, cancer of the head and neck, chronic lymphoid leukemia, hairy cell leukemia and thyroid cancer.

In some aspects of the present invention, the administration of at least one composi tion of the present invention, such as an amorphous solid dispersion composition or a drug layered composition, and at least one additional therapeutic agent demonstrates therapeutic synergy. In some aspects of the methods of the present invention, a measurement of re sponse to treatment observed after administering both at least one composition of the pre sent invention, such as an amorphous solid dispersion composition or a drug layered com position, and the additional therapeutic agent is improved over the same measurement of re sponse to treatment observed after administering either the at least one compound of for mula (I) of the present invention or the additional therapeutic agent alone.

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

A still further aspect of the present invention concerns combination therapy involv ing administering a composition comprising a compound of formula (I) of the present in vention, such as an amorphous solid dispersion composition or a drug layered composition in combination with a further conventional cancer treatment such as chemotherapy or radio therapy, or treatment with immunostimulating substances, gene therapy, treatment with an tibodies and treatment using dendritic cells, to a mammal in need thereof.

In an embodiment the composition comprising a compound of formula (I) of the pre sent invention, such as an amorphous solid dispersion composition or a drug layered com position is administered together with at least one additional therapeutic agent selected from an antineoplastic chemotherapy agent. In a further embodiment, the antineoplastic chemo therapeutic agent is selected from: all-trans retinoic acid, Actimide, Azacitidine, Azathio- prine, Bleomycin, Carboplatin, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Irinotecan, Lenalido- mide, Leucovorin, Mechlorethamine, Melphalan, Mercaptopurine, Methotrexate, Mitoxan- trone, Oxaliplatin, Paclitaxel, Pemetrexed, Revlimid, Temozolomide, Teniposide, Thiogua- nine, Valrubicin, Vinblastine, Vincristine, Vindesine and Vinorelbine. In one embodiment, a chemotherapeutic agent for use in the combination of the present agent may, itself, be a combination of different chemotherapeutic agents. Suitable combinations include FOLFOX and IFL. FOLFOX is a combination which includes 5 -fluorouracil (5-FU), leucovorin, and oxaliplatin. IFL treatment includes irinotecan, 5-FU, and leucovorin.

In a further embodiment of the present invention, the further conventional cancer treatment includes radiation therapy. In some embodiments, radiation therapy includes lo calized radiation therapy delivered to the tumor. In some embodiments, radiation therapy includes total body irradiation. In other embodiments of the present invention the further cancer treatment is se lected from the group of immunostimulating substances e.g. cytokines and antibodies. Such cytokines may be selected from the group consisting of, but not limited to: GM-CSF, type I IFN, interleukin 21, interleukin 2, interleukin 12 and interleukin 15. The antibody is prefer ably an immunostimulating antibody such as anti-CD40 or anti-CTLA-4 antibodies. The immunostimulatory substance may also be a substance capable of depletion of immune in hibitory cells (e.g. regulatory T-cells) or factors, said substance may for example be E3 ubiquitin ligases. E3 ubiquitin ligases (the HECT, RING and U-box proteins) have emerged as key molecular regulators of immune cell function, and each may be involved in the regu lation of immune responses during infection by targeting specific inhibitory molecules for proteolytic destruction. Several HECT and RING E3 proteins have now also been linked to the induction and maintenance of immune self-tolerance: c-Cbl, Cbl-b, GRAIL, Itch and Nedd4 each negatively regulate T cell growth factor production and proliferation.

In some embodiments of the present invention the compound of formula (I) is ad ministered together with at least one additional therapeutic agent selected from a checkpoint inhibitor. In some embodiments of the invention, the checkpoint inhibitor is acting on one or more of the following, non-limiting group of targets: CEACAM1, galectin-9, TIM3, CD80, CTLA4, PD-1, PD-L1, HVEM, BTLA, CD160, VISTA, B7-H4, B7-2, CD155, CD226, TIGIT, CD96, LAG3, GITF, 0X40, CD 137, CD40, IDO, and TDO. These are known targets and some of these targets are described in Melero et ak, Nature Reviews Cancer (2015). Examples of check point inhibitors administered together with the com pound of formula (1) are Anti-PD-1: Nivolumab, Pembrolizumab, Cemiplimab. Anti-PD- Ll: Atezolizumab, Avelumab, Durvalumab and one Anti-CTLA-4: Ipilimumab. Each one of these check point inhibitors can be made the subject of an embodiment in combination with any one of the compounds of formula (1).

In some embodiments of the present invention the compound of formula (I) is ad ministered together with at least one additional therapeutic agent selected from an inhibitor of indoleamine-2, 3 -di oxygenase (IDO).

In some embodiments of the present invention the compound of formula (I) is ad ministered together with at least one additional therapeutic agent selected from one or more inhibitors of the CTLA4 pathway. In some embodiments, the inhibitor of the CTLA4 path way is selected from one or more antibodies against CTLA4. In some embodiments of the present invention the compound of formula (I) is ad ministered together with at least one additional therapeutic agent selected from one or more inhibitors of the PD-l/PD-L pathway. In some embodiments, the one or more inhibitors of the PD-l/PD-L pathway are selected from one or more antibodies or antibody fragments against PD-1, PD-L1, and/or PD-L2, or other ways by which an anti -PD 1 antibodies can be induced such as mRNA based introduction of genetic material which sets forth in-body pro duction of anti -PD 1 or anti-PDLl antibodies or fragments of such antibodies.

As used herein “pharmaceutically acceptable additive” is intended without limitation to include carriers, excipients, diluents, adjuvant, colorings, aroma, preservatives etc. that the skilled person would consider using when formulating a compound of the present inven tion in order to make a pharmaceutical composition.

The adjuvants, diluents, excipients and/or carriers that may be used in the composi tion of the invention must be pharmaceutically acceptable in the sense of being compatible with the compound of formula (I) and the other ingredients of the pharmaceutical composi tion, and not deleterious to the recipient thereof. It is preferred that the compositions shall not contain any material that may cause an adverse reaction, such as an allergic reaction.

The adjuvants, diluents, excipients and carriers that may be used in the pharmaceutical com position of the invention are well known to a person within the art.

Further embodiments of the process are described in the experimental section herein, and each individual process as well as each starting material constitutes embodiments that may form part of embodiments.

The above embodiments should be seen as referring to any one of the aspects (such as ‘method for treatment’, ‘pharmaceutical composition’, ‘compound for use as a medicament’, or ‘compound for use in a method’) described herein as well as any one of the embodiments described herein unless it is specified that an embodiment relates to a certain aspect or aspects of the present invention.

All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference to the same extent as if each reference was individu ally and specifically indicated to be incorporated by reference and was set forth in its en tirety herein.

All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way. Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly con tradicted by context.

The terms “a” and “an” and “the” and similar referents as used in the context of de scribing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless oth erwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise stated, all exact values provided herein are representative of corresponding approximate values ( e.g ., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also pro vide a corresponding approximate measurement, modified by "about," where appropriate).

All methods described herein can be performed in any suitable order unless other wise indicated herein or otherwise clearly contradicted by context.

The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise indicated. No language in the specification should be construed as indicating any element is essential to the practice of the invention unless as much is explicitly stated.

The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability and/or enforceability of such patent documents.

The description herein of any aspect or embodiment of the invention using terms such as “comprising”, “having”, “including” or “containing” with reference to an element or elements is intended to provide support for a similar aspect or embodiment of the invention that “consists of’, “consists essentially of’, or “substantially comprises” that particular ele ment or elements, unless otherwise stated or clearly contradicted by context (e.g, a compo sition described herein as comprising a particular element should be understood as also de scribing a composition consisting of that element, unless otherwise stated or clearly contra dicted by context). This invention includes all modifications and equivalents of the subject matter re cited in the aspects or claims presented herein to the maximum extent permitted by applica ble law.

The present invention is further illustrated by the following examples that, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combi nation thereof, be material for realizing the invention in diverse forms thereof.

Experimental The current process to manufacture 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluoro- phenyl )-]//-] ,2,3-triazol- 1 -yl]-l -thio-a-D-galactopyranoside having formula I involves sev eral process steps as described in detail hereunder.

General Procedures

Nuclear Magnetic Resonance (NMR) spectra were recorded on a 400 MHz Bruker Avance AV400 spectrometer at 25 °C. Chemical shifts are reported in ppm (d) using the residual solvent as the internal standard. Peak multiplicities are expressed as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet.

X-Ray Powder Diffraction patterns were collected in reflection mode on a Scintag XI dif fractometer using Cu Ka radiation (45 kV, 40 mA) in continuous coupled Two-Theta/Theta mode from 7 to 37°, 0.05 degrees per sample point, 15 minute collection time, custom colli mator with divergence slit of ~lmm, anti-scatter slit 0.5mm.

Sample preparation: Samples run under ambient condition were prepared as flat specimens by placing isolated solids on a high-throughput sample holder.

The following abbreviations are used:

Ac: Acetyl aq. : aqueous

DCM: Dichloromethane

DMF: A ^f ,A ^f -Di methyl form amide

DMSO: Dimethylsulfoxide

MP-TMT : Macroporous polystyrene-bound trimercaptotriazine

Sat.: Saturated

TBAB: Tetra-n-butylammonium bromide

TBAF: Tetra-n-butylammonium fluoride

TBME: /ert-Butylmethyl ether

TLC: thin layer chromatography

XRPD: X-ray powder diffraction

5-Bromopyridine-3-thiol To a jacketed vessel fitted with an aq. NaOCl filled scrubber was charged 3,5- dibromopyridine (5 kg, 21.1 mol), TBAB (308 g, 0.95 mol) and toluene (11.9 L) and the mixture was stirred under argon. 50% aq. NaOH (11.9 L) was added and the mixture heated to 30 °C. Benzyl mercaptan (2.25 L, 19.1 mol) was added over 2 h maintaining the temperature 30 °C ± 3 °C. The mixture was stirred for an additional 30 minutes then cooled to 20 °C. The aqueous phase was removed and the organic phase was washed with 10% NaCl solution (3 x 11.9 L). The organic phase was dried over MgS0 ₄ , filtered to give a solution of 5-bromo-3-mercaptobenzylpyridine which was used directly in the next step.

To a jacketed vessel was charged AlCh (4.35 kg, 32.6 mol) and toluene (16.1 L) and the mixture was stirred and cooled to -5 °C. The solution of 5-bromo-3- mercaptobenzylpyridine (19.1 mol) was added over 2-3 h maintaining the temperature below 5 °C. The resulting mixture was then quenched by the addition of water (16.1 L) over 3 h maintaining the temperature below 20 °C. The phases were separated and the organic phase was washed with water (2 x 16.1 L) then extracted with 10% aq. NaOH solution (2 x 2.68 L). The combined aqueous phases were washed with toluene (2 x 5.37 L), then to the aqueous phase at 5 °C under argon sparging was added concentrated HC1 until pH 2.5 was attained. The mixture was extracted with ethyl acetate (3 x 5.37 L) and the combined organic phases were subsequently washed with 10% aq. NaCl solution (2 x 5.37 L), dried over MgSCri and concentrated in vacuo to give 2.99 kg (82%) of 5-bromopyridine-3-thiol as an orange solid. ¾NMR (400 MHz, CDCh) d 8.45 (d, J= 2.0 Hz, 1H), 8.41 (d, J= 2.0 Hz, 1H), 7.77 (t, 7=2.0 Hz, 1H).

Alternative procedure

To a vessel fitted with an aq. NaOCl filled scrubber was charged water (150 mL), NaOH (150 g, 3.75 mol) and the mixture adjusted to 28 to 33 °C whilst stirred under nitrogen. 3,5- dibromopyridine (84g, 0.35 mol), TBAB (5.2 g, 16 mmol) and toluene (200 mL) were added then benzyl mercaptan (40 g, 0.32 mol) was added over 2 h, maintaining the temperature at 28 to 33 °C. The mixture was stirred for an additional 1 to 3 hours then cooled to 15 to 25 °C. The aqueous phase was removed and the organic phase was washed with 10% NaCl solution (3 x 200 mL). The organic phase was dried over MgSCL, filtered to give a solution of 5-bromo-3-mercaptobenzylpyridine which was used directly in the next step.

To an inerted vessel were charged AlCh (73 g, 0.23 mol), toluene (271 mL) and the mixture cooled to -5 to -15 °C. The solution of 5-bromo-3-mercaptobenzylpyridine (90.2g 0.32 mol) was added over 2 to 3 h, maintaining the temperature below 5 °C and the mixture then stirred at 0 to 5 °C for 2 to 4 h. The reaction mixture was quenched by addition to ice water (271 mL) maintaining the temperature below 5 °C and the biphasic mixture stirred for 15 minutes at 5 to 10 °C. The phases were separated and the organic phase washed with water (2 x 271 mL) then extracted with 5% aq. NaOH solution (271 mL). The layers were separated and the organic layer extracted with 10% NaOH (90 mL). The combined aqueous phases were washed with toluene (2 x 271 mL). To the aqueous phase at 5 °C was added dichloromethane (DCM, 271 mL) and butylated hydroxytoluene (BHT, 0.9 g, 4 mmol). Concentrated HC1 (ca. 108 mL) was added at 0 °C until pH 1.0 to 2.0 was attained. The phases were separated, the aqueous phase extracted with DCM (271 mL) and the combined organic phases dried over MgS0 ₄ The dried solution was subjected to solvent exchange distillation to n-heptane in vacuo at 5 to 15 °C to ca. 90 ml. The product was collected by filtration to deliver 37.4g, (61%) of 5-bromopyridine-3-thiol as a pale yellow solid

Trimethyl((3,4,5-trifluorophenyl)ethynyl)silane

To a jacketed vessel was charged triethylamine (5.45 L, 39.1 mol), 5-bromo-l,2,3- trifluorobenzene (2.75 kg, 13.0 mol) and Cul (191 g, 0.65 mol) and the mixture was heated to reflux under argon. A solution of bis(triphenylphosphine) palladium (II) dichloride (91.5 g, 0.13 mol) and ethynyltrimethylsilane (2.40 L, 17.3 mol) in DMF (27.5 L) was charged to the vessel over 2 h. The mixture was stirred for 3 h then cooled to 20 °C and filtered. The filtrate was re-charged to the vessel and diluted with TBME (13.75 L) and 2M aq. HC1 solution (13.75 L) was added maintaining the temperature less than 30 °C. The aqueous phase was drained and the organic phase was subsequently washed with 6 % aq. NH ₄ OH solution (3 x 13.75 L) and 10% aq. NaCl solution (13.75 L). The organic phase was concentrated in vacuo at 40 °C and the filtrate was slurried in heptane (13.75 L) for 1 h at 20 °C and filtered through a bed of celite. The filtrate was concentrated in vacuo at 40 °C to give 2.11 kg (71%) of trimethyl((3,4,5-trifluorophenyl)ethynyl)silane as a brown oil. 'H NMR (400 MHz, CDCh) d 7.11-7.01 (m, 2H), 0.24 (s, 9H). ¹⁹ F NMR (376 MHz, CDCh) d -134.3 (d, J= 20.5 Hz, 2F), -158.6 (t, J= 20.5 Hz, IF).

Alternative procedure:

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

Alternative procedure

To a jacketed vessel were charged Cul (1.06 kg, 5.57 mol), bis(triphenylphosphine) palladium (II) dichloride (1.96 kg, 2.79 mol), acetonitrile (223 L), 5-bromo-l,2,3- trifluorobenzene (23.5 kg, 111 mol) and triethylamine (46.6 L, 334 mol) followed by an acetonitrile line rinse (11.8 L). The mixture was heated to 72 °C and ethynyltrimethylsilane (14.55 kg) added over ca. 2 hours followed by an acetonitrile (2.5 L) line rinse. The mixture was stirred at reflux for 4 hours until reaction was complete, then cooled to 22 °C and filtered through a bed of celite. The filter cake was washed with further acetonitrile (58.8 L) and the combined filtrates were subjected to solvent exchange distillation in vacuo to n- heptane at up to 50 °C. Ethyl acetate (23.5 L) was added to the solution and SEM26 resin (2-mercaptoethyl ethyl sulfide silica, 5.9 kg) charged. The mixture was heated to 25-29 °C, stirred for 8 hours then cooled to 5 °C and filtered through a charcoal pad. The filter cake was washed with a mixture of heptane: ethyl acetate (82.3 : 11.8 L) and the combined filtrates subjected to solvent exchange distillation to acetonitrile at up to 50 °C, to give 19.3 kg (76%) of trimethyl((3,4,5-trifluorophenyl)ethynyl)silane contained in a 24% w/w acetonitrile solution (80.5 kg).

2,4,6-Tri-0-acetyl-3-azido-3-deoxy-P-D-galactopyranosyl chloride

To a solution of PCb (335 g, 1.61 mol) in DCM (1.5 L) under argon was added BF3 OEt2 (1.65 mL, 0.013 mol) followed by a solution of l,2,4,6-Tetra-0-acetyl-3-azido-3-deoxy-P- D-galactopyranoside (500 g, 1.34 mol) in DCM (1 L), maintaining the temperature less than 25 °C. The reaction mixture was stirred in the range 20 °C ± 5 °C for 1 hour when complete consumption of starting material was observed by TLC. The mixture was cooled to 5 °C and a solution of 20% aq. KHCO3 (2 L) was added over 20 minutes maintaining the temperature less than 20 °C. The mixture was stirred for 15 minutes and then the layers were separated. To the stirred organic phase was added a further charge of 20% aq. KHCO3 solution (2 L) was added over 10 minutes maintaining the temperature less than 20 °C. The mixture was stirred for 15 minutes and then the layers were separated. The organic phase was dried over MgSCE (250 g), filtered and concentrated in vacuo at 40 °C to give an off-white solid. The crude material was slurried on a rotary evaporator with TBME (1 L) for 1 h at 40 °C at atmospheric pressure then cooled to 5 °C and held for 16 h. The material was collected by filtration, the filter cake washed with TBME (80 mL) and the material dried by pulling air through the filter to yield 330 g (70%) of 2,4,6-Tri-0-acetyl-3-azido-3-deoxy-P-D- galactopyranosyl chloride as an off-white solid. 'H NMR (400 MHz, CDCI3) d 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, 7= 11.6, 6.6 Hz, 1H), 3.91 (td, 7= 6.6, 1.2 Hz.lH), 3.54 (dd, J = 10.2, 3.3 Hz, 1H), 2.13 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H).

Alternative procedure:

PC (1.00 kg, 4.8 mol) was charged to a jacketed vessel under argon. A solution of BF ₃ OEt ₂ (5 mL, 0.04 mol) in a,a,a-trifluorotoluene (3 L) was charged and the mixture was heated to 40 °C. A solution of l,2,4,6-Tetra-0-acetyl-3-azido-3-deoxy-P-D- galactopyranoside (1.50 kg, 4.02 mol) in a,a,a-trifluorotoluene (6.75 L) was dosed to the reaction mixture, maintaining the temperature 35 °C ± 5 °C. A line rinse was conducted with a,a,a-trifluorotoluene (0.75 L). The reaction mixture was stirred in the range of 35 °C ± 5 °C for 1 hour. The mixture was cooled to -5 °C, cyclohexane (4.5 L) was charged over 30 minutes, and the resulting suspension was stirred for 16 h. The reaction mixture was filtered under argon. The filter cake was dried in a vacuum oven at 20 °C for 3 hours to yield 942 g (67 %) of 2,4,6-Tri-0-acetyl-3-azido-3-deoxy-P-D-galactopyranosyl chloride as an off-white solid.

5-Bromopyridin-3-yl 2,4,6-tri-0-acetyl-3-azido-3-deoxy-l-thio-a-D-galactopyranos ide

A jacketed vessel was charged with sodium bis(trimethylsilyl)amide solution (4.2 L, 2 M solution in THF, 8.37 mol) and the solution was stirred at 5 °C under argon. A solution of 5- bromopyridine-3 -thiol (1.6 kg, 8.37 mol) in THF (2.1 L) was added over 1 h 15 min maintaining the temperature less than 20 °C. To the mixture was subsequently added a solution of 2,4,6-Tri-0-acetyl-3-azido-3-deoxy-P-D-galactopyranosyl chloride (2.1 kg, 5.98 mol) in THF (2.1 L) over 15 minutes. A line rinse was conducted with additional THF (1 L). The resulting mixture was stirred for 18 h then TBME (6.3 L) was charged and the temperature of the mixture reduced to 10 °C. Water (6.3 L) was added over 20 minutes and the resulting mixture was stirred for 30 minutes. The phases were separated, and the aqueous phase was extracted with TBME (6.3 L). The combined organic phases were washed with 10% aq. NaCl solution (3 x 6.3 L) then concentrated in vacuo at 40 °C. The crude material was co-evaporated in vacuo with methanol (4.2 L) then slurried in methanol (4.2 L) at 50 °C for 2 h. The mixture was cooled to 20 °C then filtered and the filter cake washed with methanol (1 L). The solid material was further dried to a constant mass in vacuo at 40 °C to give 2.09 kg (69%) of 5-Bromopyridin-3-yl 2,4,6-tri-0-acetyl-3-azido-3- deoxy-l-thio-a-D-galactopyranoside. ¹ HNMR (400 MHz, CDCh) d 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, 7= 7.8, 4.6, 0.8 Hz, 1H), 4.13 (dd, 11.7, 4.3 Hz, 1H), 4.02 (dd, 711.7, 7.8 Hz, 1H), 3.96 (dd, 711.0, 3.3 Hz, 1H), 2.20 (s, 3H), 2.17 (s, 3H). 2.03 (s, 3H).

Alternative procedure:

A jacketed vessel was charged with sodium bis(trimethylsilyl)amide solution (2.4 L, 2 M solution in THF, 4.80 mol) and the solution was stirred at 5 °C under argon. A solution of 5- bromopyridine-3 -thiol (913 g, 4.80 mol) in THF (1.2 L) was added over 1 h 15 min maintaining the temperature less than 20 °C. A line rinse was conducted with additional THF (0.6 L). To the mixture was subsequently added a solution of 2,4,6-Tri-0-acetyl-3- azido-3-deoxy-P-D-galactopyranosyl chloride (1.2 kg, 3.43 mol) in THF (1.2 L) over 15 minutes. A line rinse was conducted with additional THF (0.6 L). The resulting mixture was stirred for 72 hours at 20 °C. The temperature of the mixture was reduced to 5 °C and water (3.6 L) was added over 45 minutes followed by ethyl acetate (3.6 L). The resulting mixture was stirred for 1 hour at 20 °C. The phases were separated and the aqueous phase was extracted with ethyl acetate (3.6 L). The combined organic phases were washed with 10% aq. NaCl solution (3 x 3.6 L) then concentrated in vacuo at 40 °C. The crude material was co-evaporated in vacuo with methanol (2.4 L) then slurried in methanol (2.4 L) at 50 °C for 2 hours. The mixture was cooled to 20 °C then filtered and the filter cake washed with methanol (0.5 L). The solid material was dried to a constant mass in vacuo at 40 °C to give 1.21 kg (70%) of 5-Bromopyridin-3-yl 2,4,6-tri-0-acetyl-3-azido-3-deoxy-l-thio-a-D- gal actopy ranosi de .

Alternative procedure: PC (38.8 kg, 186 mol) was charged to a jacketed vessel followed by a,a,a-trifluorotoluene (406 L). A solution of 1M BF3 OEt2 (1.55 L, 1.55 mol) was charged and the mixture was heated to 33 °C. l,2,4,6-Tetra-0-acetyl-3-azido-3-deoxy-P-D-galactopyranoside (58 kg, 155 mol) was charged to the reaction mixture in 4 equal portions, maintaining the temperature 35 °C ± 5 °C, 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 charged 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 washed with TBME (116 L) at -22 °C and blown dry with nitrogen on the filter. The 2,4,6-Tri-0-acetyl-3-azido-3-deoxy-P-D-galactopyranosyl chloride was dissolved, on the filter, in THF (130 L) at 41 °C.

To a second vessel was charged 5-bromopyridine-3-thiol (33.1 kg, 174 mol) and THF (217 L). 2M NaHMDS in THF (87 L, 174 mol) was charged at 25 to 22 °C and the mixture stirred for 30 minutes at 20 °C.

The THF solution of 2,4,6-Tri-0-acetyl-3-azido-3-deoxy-P-D-galactopyranosyl chloride was charged to the suspension of sodium 5-bromopyridine-3-thiolate at 21 °C followed by a THF line rinse (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 to 20 °C, the mixture stirred for 15 minutes and the phases separated. The aqueous phase was extracted with ethyl acetate (130 L) at 20°C. The combined organic phases were washed with 10% aq. NaCl solution (3 x 130 L) then subjected to solvent exchange distillation to methanol, in vacuo, at up to 40 °C resulting in a slurry in methanol (ca. 435 L). The mixture was heated to reflux then cooled over 1.5 hours to 5 °C and held at this temperature for 2 hours. The mixture was filtered and the filter cake washed with methanol (87 L) at 5 °C. The solid material was dried in vacuo at 40 °C to give 41.7 kg (53%) of 5-Bromopyridin-3-yl 2,4,6-tri-0-acetyl-3-azido-3- deoxy- 1 -thio-a-D-galactopyranoside. 5-Bromopyridin-3-yl 2,4,6-tri-0-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-l//- l,2,3- triazol-l-yl]-l-thio-a-D-galactopyranoside

A jacketed vessel was charged with trimethyl((3,4,5-trifluorophenyl)ethynyl)silane (1.11 kg, 4.88 mol), Cul (81.68 g, 0.41 mol) and acetonitrile (20 L) and the mixture was stirred under argon. 5-Bromopyridin-3-yl 2,4, 6-tri -(7-acetyl -3 -azido-3-deoxy- l -thio-a-D- galactopyranoside (2.02 kg, 3.98 mol) and triethylamine (1.2 L, 8.15 mol) were charged and the mixture was heated to 60 °C. Three portions of 1M TBAF solution in THF (3 x 200 mL, 0.20 mol) were added every 30 minutes and the reaction was stirred for a further 30 minutes after the final addition. Ethyl acetate (20 L) was charged and the mixture was cooled to 20 °C. The mixture was washed with 10% NH ₄ OH solution (4 x 6 L) until the aqueous phase no longer turns blue. The organic phase was subsequently washed with 2M aq. HC1 solution (2 x 6 L), 5% aq. NaHCCh solution (6 L) and then concentrated in vacuo at 50 °C. The 5- B romopyri din-3 -yl 2,4,6-tri-(7-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-li7 -l,2,3-triazol- l-yl]-l-thio-a-D-galactopyranoside was used in the next step without further purification.

¾ NMR (400 MHz, CDCh) d 8.61 (dd, 7 = 6.3, 2.0 Hz, 2H), 8.00 (t, 7 = 2.0 Hz, 1H), 7.79 (s, 1H), 7.48-7.39 (m, 2H). 6.14 (d, 7 = 5.7 Hz, 1H), 6.09 (dd, 7=11.5, 5.5 Hz, 1H), 5.62 (dd, 7= 3.0, 1.1 Hz, 1H), 5.22 (dd, 7= 11.4, 3.1 Hz, 1H), 4.89-4.81 (m, 1H), 4.16 (dd, 7 = 11.7, 4.9 Hz, 1H), 4.08 (dd, 7= 11.7, 7.6 Hz, 1H), 2.06 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H). Evidence of the formation of 5-B romopyri din-3 -yl 4,6-di-(7-acetyl-3-deoxy-3-[4-(3,4,5- trifluorophenyl )- ]//- ] ,2,3-triazol- 1 -yl ]- 1 -thio-a-D-galactopyranoside was also observed by ¾ NMR spectroscopy. ¾ NMR (400 MHz, CDCh) d 8.60 (dd, 7= 14.0, 2.0, 2H), 8.07 (t, 7 = 2.0, 1H), 7.90 (s, 1H), 7.42-7.32 (m, 2H), 5.93 (d, 7= 5.3 Hz, 1H), 5.64 (dd, 7= 3.0, 1.1, 1H), 5.27 (dt, 7= 10.9, 5.6, 1H), 4.93 (dd, 7= 10.9, 3.0 Hz, 1H), 4.87-4.79 (m, 1H), 4.43 (d, 7= 5.8 Hz, 1H), 4.21-4.05 (m, 2H), 2.04 (s, 3H), 2.01 (s, 3H). Alternative procedure:

Trimethyl((3,4,5-trifluorophenyl)ethynyl)silane (10.5 kg, 45.9 mol) as solution in acetonitrile/heptane (28 kg) was subjected to solvent exchange distillation to acetonitrile resulting in an approximate volume of 52 L. Further acetonitrile (21.0 L), ethanol (6.4 L) and potassium carbonate (3.17 kg, 23.0 mol) were charged to the vessel and stirred at 20°C for 5.5 h prior to addition of further potassium carbonate (3.17 kg, 23.0 mol). The mixture was stirred for a further 16.5 h at 20 °C then filtered and the filter washed with acetonitrile (21.0 L) to generate a solution of 5-ethynyl-l,2,3-trifluorobenzene, which was used without further isolation.

To a separate vessel 5-Bromopyridin-3-yl 2,4,6-tri -(9-acetyl -3 -azi do-3 -deoxy- 1 -thio-a-D- galactopyranoside (17.84 kg, 35.4 mol), the solution of 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) were charged. The mixture was heated to 44 °C and stirred at this temperature for 3.25 hours. The mixture was cooled to 18 °C, dichloromethane (134 L) and 10% aqueous ammonium hydroxide (134 L) charged and the mixture stirred for 30 minutes. The phases were separated and the aqueous phase extracted with DCM (89 L). The combined organic phases were washed with 10% aqueous ammonium hydroxide (2 x 134 L), 2M hydrochloric acid (134 L) and 5% aqueous sodium hydrogen carbonate (134 L) at 22°C. The phases were separated and the organic phase subjected to solvent exchange distillation, in vacuo, at <50 °C to methanol resulting in a slurry of ca. 89 L. The slurry was cooled to 2 °C, held at this temperature for 16 hours and filtered. The filter cake was washed with methanol (53.5 L) at 5 °C and the product dried at up to 60 °C to give 5-B romopyri din-3 -yl 2,4,6-tri-(9-acetyl-3- deoxy-3 -[4-(3 ,4,5-trifluorophenyl)- 1 H- 1 ,2,3 -triazol- 1 -yl]- 1 -thio-a-D-galactopyranoside 20.0 kg, (66%).

5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-l//-l,2,3-triazol-l-yl] -l-thio- a-D-galactopyranoside, I

The crude 5-Bromopyridin-3-yl 2,4,6-tri-0-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-li7- l,2,3-triazol-l-yl]-l-thio-a-D-galactopyranoside (5.36 kg, 8.13 mol) was dissolved in meth anol (13.4 L) and stirred under argon. 25 wt% sodium methoxide solution (185 mL, 0.81 mol) was charged and the mixture was stirred at 20 °C for 16 h. Additional 25 wt% sodium methoxide solution (90 mL, 0.41 mol) was charged and the mixture was stirred at 20 °C for 24 h. TBME (8.5 L) was charged and the mixture stirred for 2 h at 20 °C. The mixture was filtered and the filter cake was washed with TBME (5.3 L). The solid material was dried to a constant mass in vacuo at 30 °C to give 2.79 kg of 5-Bromopyridin-3-yl 3-deoxy-3-[4- (3, 4, 5-tri fluorophenyl)-! H-\ ,2,3-triazol-l -yl]- l -thio-a-D-galactopyranoside as an off-white solid (65% over 2 steps).

¾ NMR (400 MHz, DMSO-de) d 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, 7= 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).

Alternative procedure:

5-Bromopyri din-3 -yl 2,4, 6-tri-0-acetyl-3 -deoxy-3 - [4-(3 ,4, 5 -trifluorophenyl)- 177-1,2,3- triazol-l-yl]-l-thio-a-D-galactopyranoside (19.88 kg, 30.15 mol) was suspended in methanol (199 L) under an inert atmosphere at 15°C. 30 wt% Sodium methoxide solution (0.54 kg, 3.01 mol) was charged followed by a methanol line rinse (2.5 L) and the mixture was stirred at 20 °C for 1 h 43 min. Additional 30 wt% sodium methoxide solution (0.52 kg, 2.89 mol) was charged and the mixture was stirred at 20 °C for 2.5 h. The mixture was cooled to 1°C and stirred at this temperature for 12 h then filtered and the filter cake was washed with methanol (30 L) at 5 °C. The crude material was dried in vacuo at 55 °C to deliver 14.19 kg. The crude product was then re-charged to the reactor and ethanol (525 L) added. The mixture was heated to reflux until a solution was formed then cooled to 2 °C and aged at this temperature for 6 h 14 min prior to filtration. The filter cake was washed with ethanol (21 L) at 3 °C and the crystallised product dried at 55 °C. The crystallised material was returned to the reactor and slurried in TBME (142 L) at 19 °C for 27 h. The mixture was cooled to 2 °C, stirred at this temperature for 3 h 2 min then filtered and the filter cake washed with TBME (21 L) at 2 °C. The product was dried in vacuo at max. 60 °C to give 12.44 kg of 5-Bromopyridin-3- yl 3 -deoxy-3-[4-(3, 4, 5 -tri fluorophenyl )-]//-] ,2,3-triazol- l -yl ]- 1 -thio-a-D-galactopyranoside as a light brown solid (77.4% over reaction and purification steps).

Polymorphs and Salt form preparation:

5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-lH-l,2,3-triazol-l-yl]- l-thio-a- D-galactopyranoside is a crystalline solid that can potentially exist as 7 crystalline poly morphs as well as an amorphous form. Five of the seven solid forms are solvated forms (Forms 2, 4, 5, 6, and 7), crystallize from an alcohol solvent, and appear to be unique but structurally related (pseudo-isostructural) solvates. Table 1 lists the polymorphic forms and the key solvents they are generated from. Figure 1 A-G provides the XRPD diffractograms for the polymorphic forms 1-7 identified, respectively.

Table 1: Polymorph Screen of Compound I

In figure 1 A-1G the XRPD patterns for polymorphic forms of the Compound of formula I can be identified: 1A is Form 1, IB is Form 2, 1C is Form 3, ID is Form 4, IE is Form 5, IF is Form 6, and 1G is Form 7.

Form 1 comprises the following characteristic XRPD peaks:

Form 2 comprises the following characteristic XRPD peaks:

Form 3 comprises the following characteristic XRPD peaks:

Form 4 comprises the following characteristic XRPD peaks:

Form 5 comprises the following characteristic XRPD peaks:

Form 6 comprises the following characteristic XRPD peaks:

Form 7 comprises the following characteristic XRPD peaks: The compound of formula (I) is designated polymorphic Form 1 as identified in XRPD dif- fractogram in Figure 1 A or Figure 2. The polymorphic Form 1 of the compound of formula (I) is a highly crystalline form with a melting point of 233.7°C. Form 1 is not hygroscopic and shows no indication of hydrate or solvate formation.

The polymorphic forms of the Compound of formula I can be prepared by the process com prising the steps of suspending or dissolving 3,3'-Dideoxy-3,3’-bis-[4-(3-fluorophenyl)-lH- 1 ,2,3-triazol- l -yl]- 1 , 1 '-sulfanediyl-di-P-D-galactopyranoside in an organic solvent or mix ture of solvents (see table 2 below) and then using fast evaporation, slow evaporation, equil ibrated slurry and precipitation from solvent by adding anti-solvent, or a combination thereof to prepare the polymorphs. Samples by fast and slow evaporation were generated by mixing 7 mg of 3,3'-Dideoxy-3,3’-bis-[4-(3-fluorophenyl)-lH-l,2,3-triazol -l-yl]-l,r-sul- fanediyl-di-P-D-galactopyranoside with a solvent (see Table 2 below) and sonicating to en sure complete dissolution. For fast evaporation, a genovac centrifugal evaporator was used to remove low boiling solvents over 20 minutes at controlled vacuum. For slow evapora tion, the solvents were allowed to evaporate over 24 hours. Samples subjected to equilib rium slurry conditions were prepared by mixing 7 mg of 3,3'-Dideoxy-3,3’-bis-[4-(3-fluoro- phenyl )- 1 H- l ,2,3-triazol- l -yl]- 1 , 1 '-sulfanediyl-di-P-D-galactopyranoside with a solvent (see Table 2 below). The resulting slurries were sonicated in a bath followed by stirring for 48 hours. Solids were isolated by filtration onto sintered filters. Samples subjected to precipita tion with anti-solvent were prepared by mixing 7 mg of 3,3'-Dideoxy-3,3’-bis-[4-(3-fluoro- phenyl )- 1 H- l ,2,3-triazol- l -yl]- 1 , 1 '-sulfanediyl-di-P-D-galactopyranoside with a solvent (see Table 2 below) and mixed until dissolution achieved. Anti-solvent (see Table 2 below) was added to rapidly precipitate a solid which was isolated by vacuum filtration onto sintered metal filters. Table 2 lists each form generated by these methods. Form 1 was also made by the process described in the large scale method described above as on off-white solid.

Table 2: List of Solvents in Polymorph Generation Experiments

3,3'-Dideoxy-3,3’-bis-[4-(3-fluorophenyl)-lH-l,2,3-tria zol-l-yl]-l, -sulfanediyl-di-P-D- galactopyranoside can exist in a variety of salt forms including hydrochloride, hydrobro mide, sulfate, phosphate, ethane sulfonate and methane sulfonate. Salt forms of the Com pound of formula I can be prepared via fast evaporation or slurry conversion of a 1 : 1 mix- ture of Compound of formula I and an acid such as sulfuric, hydrochloric, hydrobromic, phosphoric, ethane sulfuric and methane sulfuric acids in an appropriate solvent, such as methyl ethyl ketone, acetonitrile, acetone, ethanol, heptane, ethyl acetate, water or mixtures of the listed solvents. A typical example of a salt form of Compound of formula I is the hy drochloride salt (HC1 salt) which is a crystalline salt with a melting point of 221°C. The HC1 salt is identified by the XRPD diffractogram in Figure 3. The HC1 salt of the compound of formula I was made by mixing 7 mg of 3,3'-Dideoxy-3,3’-bis-[4-(3-fluorophenyl)-lH- 1 ,2,3-triazol- 1 -yl]- l , 1 '-sulfanediyl-di-P-D-galactopyranoside with an equimolar amount of hydrochloric acid and a mixture of 1 : 1 ethyl acetate: heptane at a concentration of 10 mg/mL in a vial. The vial was sealed, and the mixture stirred for 36 hours. The resulting solids were isolated by filtration onto sintered metal filters.