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1. (WO2019004936) PROCESS FOR PREPARING LIFITEGRAST AND INTERMEDIATES THEREOF
ملاحظة: نص مبني على عمليات التَعرف الضوئي على الحروف. الرجاء إستخدام صيغ PDF لقيمتها القانونية

WHAT IS CLAIMED IS:

A process for preparing the compound of Formula I:


(I)

or a pharmaceutically acceptable salt thereof; the process comprising:

a) contacting the compound of Formula II


(II)

with a first activating reagent in a first activating solvent to provide an activated intermediate of Formula Ila


(Ila), and

contacting the activated intermediate of Fromula Ila with a compound of Formula III or ΙΙΓ


in a first coupling solvent to provide a compound of Formula IV


b) contacting the compound of Formula IV with a second activating reagent in a second activating solvent to provide an activated intermediate of Formula IVa


contacting the activated intermediate of Fromula IVa with a compound of


in a second coupling solvent to provide a compound of Formula I; wherein AG 1 and AG2 are each independently CI or an activated hydroxyl moiety and X _ is CI , Br", Γ, or CF3C(0)0~ .

2. The process according to claim 1, wherein the first activating solvent and the first coupling solvent are each a first solvent; and the second activating solvent and the second coupling solvent are each a second solvent,

the first solvent and the second solvent are each independently selected from the group consisting of C1-4 alkyl-alcohol, dioxane, N-methyl-2-pyrrolidone (NMP),

dimethylacetamide (DMAc), Ν,Ν-dimethylmethanamide (DMF), ethyl acetate, acetonitrile, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dichloromethane, toluene, water, and mixtures thereof.

3. The process according to claim 2, wherein the first solvent and/or the second solvent is independently selected from the group consisting of DMF, DCM, toluene, DMAc, acetonitrile, THF, and mixtures thereof.

4. The process according to claim 2 or claim 3, wherein the first solvent and/or the second solvent comprises tetrahydrofuran THF.

5. The process according to claim 1, wherein the first activating solvent and the first coupling solvent are each independently selected from the group consisting of C1-4 alkyl-alcohol, dioxane, N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAc), N,N-dimethylmethanamide (DMF), ethyl acetate, acetonitrile, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dichloromethane, toluene, water, and mixtures thereof.

6. The process according to claim 1 , wherein the second activating solvent and the second coupling solvent are each independently selected from the group consisting of Ci_ alkyl-alcohol, dioxane, N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAc), N,N-

dimethylmethanamide (DMF), ethyl acetate, acetonitrile, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dichloromethane, toluene, water, and mixtures thereof.

7. The process according to any one of claims 1 to 6, wherein the conversion of step a) and/or step b) further comprise a non-nucleophilic base.

8. The process according to claim 7, wherein the non-nucleophilic base is selected from the group consisting of triethylamine, Ν,Ν-diisopropylethylamine (DIPEA), and N-methylmorpholine.

9. The process according to claim 8, wherein the non-nucleophilic base is Ν,Ν-diisopropylethylamine (DIPEA).

10. The process according to any one of claims 1 to 9, wherein the first activating reagent is a first chlorinating reagent.

11. The process according to any one of claims 1 to 10, wherein the second activating reagent is a second chlorinating reagent.

12. The process according to claim 10 or claim 11, wherein the first chlorinating reagent and/or second chlorinating reagent is selected from the group consisting of (COCl)2 (oxalyl chloride), SOCl2 (thionyl chloride), POCl3 (Phosphoryl chloride), and PC15 (phosphorus pentachloride).

13. The process according to claim 12, wherein the first chlorinating reagent and/or second chlorinating reagent is (COCl)2 (oxalyl chloride).

14. The process according to claim 12, wherein the first chlorinating reagent and/or second chlorinating reagent is (SOCl)2 (thionyl chloride).

15. The process according to any one of claims 1 to 9 or claim 11, wherein the first activating reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), l -ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 0-(benzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate (HBTU), 0-(7-azabenzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate (HATU),

hydroxybenzotriazole (HOBt), 1 -hydroxy-7-azabenzotriazole (HO At), and mixtures thereof.

16 The process according to any one of claims 1 to 10, wherein the second activating reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), l -ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 0-(benzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate (HBTU), 0-(7-azabenzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate (HATU), hydroxybenzotriazole (HOBt), 1 -hydroxy-7-azabenzotriazole (HO At), and mixtures thereof.

17. The process according to claim 15 or claim 16, wherein the first activating reagent and/or the second activating reagent is 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).

18. The process according to claim 15 or claim 16, wherein the first activating reagent and/or the second activating reagent is l -hydroxy-7-azabenzotriazole (HO At).

19. The process according to any one of claims 1 to 18, wherein the activated hydroxyl moiety is the reaction product of a carboxylic acid with dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), l -ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 0-(benzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate (HATU), hydroxybenzotriazole (HOBt), 1 -hydroxy-7-azabenzotriazole (HO At), or mixtures thereof.

20. A process for preparing the compound of Formula I:


or a pharmaceutically acceptable salt thereof; the process comprising:

contacting the compound of Formula TV


with a activating reagent in an activating solvent to provide an activated

intermediate of Formula rVa


contacting the activated intermediate of Fromula IVa with a compound of

Formula V or V


in a coupling solvent to provide a compound of Formula I,

wherein AG2 is CI or an activated hydroxyl moiety and X is CI , Br , I , or CF3C(0)0 .

21. The process according to claim 20, wherein the activating solvent and the coupling solvent are each a solvent selected from the group consisting of Ci-4 alkyl-alcohol, dioxane, N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAc), N,N-dimethylmethanamide (DMF), ethyl acetate, acetonitrile, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dichloromethane, toluene, water, and mixtures thereof.

22. The process according to claim 21, wherein the solvent is selected from the group consisting of DMF, DCM, DMAc, acetonitrile, THF, and mixtures thereof.

23. The process according to claim 20 , wherein the activating solvent and the coupling solvent are each independently selected from the group consisting of Ci-4 alkyl-alcohol, dioxane, N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAc), N,N-dimethylmethanamide (DMF), ethyl acetate, acetonitrile, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dichloromethane, toluene, water, and mixtures thereof.

24. The process according to any one of claims 20 to 23, further comprising a non-nucleophilic base.

25. The process according to claim 24, wherein the non-nucleophilic base is selected from the group consisting of triethylamine, Ν,Ν-diisopropylethylamine (DIPEA), and N-methylmorpholine.

26. The process according to claim 25, wherein the non-nucleophilic base is Ν,Ν-diisopropylethylamine (DIPEA).

27. The process according to any one of claims 20 to 26, wherein the activating reagent is a chlorinating reagent.

28. The process according to claim 27, wherein the chlorinating reagent is selected from the group consisting of (COCl)2 (oxalyl chloride), SOCl2 (thionyl chloride), POCI3 (Phosphoryl chloride), and PCI5 (phosphorus pentachloride).

29. The process according to claim 28, wherein the first chlorinating reagent and/or second chlorinating reagent is (COCl)2 (oxalyl chloride).

30. The process according to claim 28, wherein the first chlorinating reagent and/or second chlorinating reagent is (SOCl)2 (thionyl chloride).

31. The process according to any one of claims 20 to 26, wherein the activating reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),

0-(benzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate (HBTU), 0-(7-azabenzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate (HATU), hydroxybenzotriazole (HOBt), 1 -hydroxy-7-azabenzotriazole (HO At), and mixtures thereof.

32. The process according to claim 31, wherein the activating reagent is 0-(7-azabenzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate (HATU).

33. The process according to any one of claims 20 to 32, wherein the activated hydroxyl moiety is the reaction product of a carboxylic acid with dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 0-(benzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate (HATU), hydroxybenzotriazole (HOBt), 1 -hydroxy-7-azabenzotriazole (HO At), or mixtures thereof.