Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/056—Triazole or tetrazole radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• 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.
• 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.
• 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
• 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.
• 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 (I) wherein
• the compound of formula I is obtained as a solid product, such as a crystalline or amorphous product.
• 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.
• the present invention relates to a process for preparing 5-
• 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
• the compound of formula I is obtained as a solid product, such as a crystalline or amorphous product.
• 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.
• 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.
• 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.
• a basic fluoride source agent such as TBAF or CsF.
• 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.
• reaction takes place under inert atmosphere, such as ar gon or nitrogen atmosphere.
• reaction takes place under atmospheric pressure.
• the organic solvent is selected from toluene or a polar aprotic solvent, such as acetonitrile or DMF, and mixtures thereof.
• the suitable temperature is between 15 and 25 °C, such as about room temperature.
• 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.
• 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.
• 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.
• the base is an organic base, such as triethylamine or DI PEA.
• the basic fluoride source agent is TBAF.
• 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.
• 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.
• 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.
• 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.
• 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.
• the ether is tert- Bu- tylmethyl ether (TBME).
• the suitable temperature is 15-25 °C, such as about room temperature.
• the organic solvent is selected from an alcohol, such as Ci- 6 alkohol, e.g. methanol.
• 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.
• the base is sodium methoxide in methanol, such as 25 wt% sodium methoxide solution in meth anol.
• the reaction with the base is for at least 1 hour, such as 2-24 hours.
• 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.
• an organic solvent such as a Ci- 6 alcohol, e.g. methanol or ethanol
• a base e.g. sodium methoxide
• the present process of the invention comprises a step di rectly preceding step a)
• 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.
• the compound of formula IX is obtained as a solid.
• the deprotonating agent is sodium bis(trimethylsilyl)amide.
• Rl, R2, R3 are all acetyl groups and R4 is as defined above.
• R4 is chlorine.
• reaction takes place under inert atmosphere.
• inert atmosphere typically, under an argon or nitrogen atmosphere.
• the organic solvent is selected from the group consist ing of ethyl acetate, THF, toluene, DMF and acetonitrile, and mixtures thereof.
• 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.
• 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.
• the suitable temperature is below 25 °C.
• reaction is continued for at least 2 hours, such as 16-72 hours, at the suitable temperature.
• the molar ratio between the compound of formula VIII and the base is 1:1 to 1:3, such as 5:7.
• the process of the present invention comprises a step directly preceding step ia)
• 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
• reaction takes place under an inert atmosphere, such as an ar gon or nitrogen atmosphere.
• the organic solvent is an aprotic solvent, preferably di- chloromethane, toluene or a,a,a-trifluorotoluene, and mixtures thereof.
• the reagent for activating the anomeric position for nucleo philic substitution is a halogenating agent.
• the halogenating agent is a metal hal ide, for example, AlCh, or SOCh, dichloromethyl methyl ether (DCMME) or a halide of phosphorus.
• DCMME dichloromethyl methyl ether
• the halogenating agent is PCb.
• the catalyst is an acid, such as a lewis acid, preferably BF3 OEt2.
• 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 1 ⁇ 2 hour, such as 12-96 hours, at the suitable temperature.
• 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.
• the molar ratio between the compound of formula VII and the catalyst is 10:1 to 200:1, typically 100:1.
• 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.
• 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
• 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.
• Rl, R2, 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,
• step a) are reacting 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.
• 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.
• 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.
• 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.
• 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.
• 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 ⁇ H.
• 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
• the compound of formula I is obtained as a solid product, such as a crystalline or amorphous product.
• the compound of formula I is iso- lated as a crystal, such as a polymorph.
• the compound of formula I is isolated as the polymorphic form 1.
• the compound of formula I is isolated as a salt, such as a HC1 salt. Typically, a crystalline HC1 salt.
• 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.
• 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.
• 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.
• 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.
• reaction takes place under inert atmosphere, such as an argon or nitrogen atmosphere.
• the organic solvent is selected from toluene or a polar aprotic solvent, such as acetonitrile or DMF, and mixtures thereof.
• the suitable temperature is between 15 and 25 °C, such as about room temperature.
• 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.
• reaction is continued for at least 2 hours, such as 3 hours, e.g. from 2.5 to 4 hours.
• 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.
• a metal catalyst such as a metal halide, e.g. Cu(I) or Cu(II), in particular Cu halide, such as Cu iodide.
• the base is present.
• the base is an organic base, such as triethylamine or DIPEA.
• the basic fluoride source agent is TBAF.
• 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.
• 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.
• 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.
• 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.
• the ether is fe/V-Butylmethyl ether (TBME).
• the suitable temperature is 15-25 °C, such as about room temper ature.
• the organic solvent is selected from an alcohol, such as Ci- 6 alcohol, e.g. methanol.
• 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.
• a base such as an organic base
• the base is sodium methoxide in methanol, such as 25 wt% sodium methoxide solution in methanol.
• 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.
• reaction with a base is for at least 1 hour, such as 2-24 hours.
• the present process of the invention comprises a step di rectly preceding step a)
• the compound of formula IX is obtained as a solid.
• the deprotonating agent is sodium bis(trimethylsilyl)amide.
• Rl, R2, R3 are all acetyl groups and R4 is as defined above.
• R4 is chlorine.
• reaction takes place under inert atmosphere.
• organic solvent is selected from the group consist ing of ethyl acetate, THF, toluene, DMF and acetonitrile, and mixtures thereof.
• 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.
• 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
• the suitable temperature is below 25 °C.
• reaction is continued for at least 2 hours, such as 16-72 hours, at the suitable temperature.
• the molar ratio between the compound of formula VIII and the base is 1:1 to 1:3, such as 5:7.
• the process of the present invention comprises a step directly preceding step ia)
• 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
• R2, and R3 is an acetyl group and R4 is a Cl or Br.
• reaction takes place under an inert atmosphere, such as an ar gon or nitrogen atmosphere.
• R4 is a Cl or Br, such as Cl.
• the organic solvent is an aprotic solvent, preferably dichloro- methane, toluene or a,a,a-trifluorotoluene, and mixtures thereof.
• the reagent for activating the anomeric position for nu cleophilic substitution is a halogenating agent.
• 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.
• the halogenating agent is PCI 5 .
• the catalyst is an acid, such as a lewis acid, preferably BF3 OEt2.
• 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 1 ⁇ 2 hour, such as 1-96 hours, at the suitable temperature.
• 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.
• 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 basic bromide source agent such as TBAB
• 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.
• 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.
• treatment 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
• 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.
• 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”).
• 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.
• ad ministering a composition of the present invention such as an amorphous solid dispersion composition or a drug layered composition
• a therapeutically active compound different from the compound of formula (I) (interchangeable with “a different therapeuti cally active compound”.
• the present invention relates to a combination of a composition comprising a compound of formula (I) of the present invention,
• a therapeutically effective amount of at least one composition of the present invention is administered to a mammal in need thereof in combination with a different therapeutically active compound.
• said combination of a composition of the present invention 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; path
• 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, sebace
• 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.
• 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.
• 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.
• such anti-fibrotic compound may be se lected from the following non-limiting group of anti-fibrotic compounds: pirfenidone, nintedanib, pumpuzumab (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.
• 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.
• 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.
• 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, Mitox
• 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.
• the further conventional cancer treatment includes radiation therapy.
• radiation therapy includes lo calized radiation therapy delivered to the tumor.
• radiation therapy includes total body irradiation.
• the further cancer treatment is se lected from the group of immunostimulating substances e.g. cytokines and antibodies.
• 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.
• 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.
• the compound of formula (I) is ad ministered together with at least one additional therapeutic agent selected from a checkpoint inhibitor.
• 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.
• targets are known targets and some of these targets are described in Melero et ak, Nature Reviews Cancer (2015).
• 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).
• 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).
• 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.
• the inhibitor of the CTLA4 path way is selected from one or more antibodies against CTLA4.
• 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.
• 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.
• 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.
• 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.
• NMR Nuclear Magnetic Resonance
• 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.
• MP-TMT Macroporous polystyrene-bound trimercaptotriazine
• 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.
• 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.
• PC (1.00 kg, 4.8 mol) was charged to a jacketed vessel under argon.
• 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.
• 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).
• 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.
• 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.
• 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 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 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.
• 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.
• FIG 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.
• a genovac centrifugal evaporator was used to remove low boiling solvents over 20 minutes at controlled vacuum.
• 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.
• 3,3'-Dideoxy-3,3’-bis-[4-(3-fluorophenyl)-lH-l,2,3-triazol-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.

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