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1. WO2020161362 - PROCÉDÉ DE FABRICATION D'ACIDE 3-(4'-AMINOPHÉNYL)-2-MÉTHOXYPROPIONIQUE, ET ANALOGUES ET INTERMÉDIAIRES DE CELUI-CI

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]
CLAIMS

What is claimed is:

1. A process for preparing a substantially optically pure compound of Formula (VII):


the process comprising:

reacting a compound of Formula (I):

with an activating agent, in the optional presence of a base,

to form an intermediate of Formula (I-A):

wherein LG is a leaving group;


treating the intermediate of Formula (I-A) with a base solution in the presence of an alcohol solvent, to eliminate the leaving group and thereby forming an intermediate of Formula (I-B):

hydrolyzing the intermediate of Formula (I-B) to form a compound of Formula (IV):


hydrogenating the compound of Formula (IV) to form a compound of Formula (V):


resolving the compound of Formula (V) to form a substantially optically pure compound of Formula (VI):

and


acylating the compound of Formula (VI) to form the compound of Formula (VII).

2. The process of claim 1, wherein reacting a compound of Formula (I) with an activating agent comprises reacting in the presence of a base and a solvent.

3. The process of claim 2, wherein the solvent is selected from the group consisting of toluene, dichloromethane, tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, and acetonitrile.

4. The process of claim 2 or 3, wherein the solvent is toluene.

5. The process of any one of claims 1-4, wherein the base is an amine base.

6. The process of claim 5, wherein the amine base is selected from the group consisting of triethylamine, N,N -diisopropylethylamine, and pyridine.

7. The process of any one of claims 5-6, wherein the amine base is triethylamine.

8. The process of any one of claims 1-7, wherein the activating agent is a sulfonylating agent, or a halogenating agent.

9. The process of any one of claims 1-8 wherein the activating agent is selected from the group consisting of a methanesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, phenyl triflimide, triflic anhydride, and nonafluorobutanesulfonic anhydride.

10. The process of any one of claims 1-9, wherein the activating agent is methanesulfonyl chloride.

11. The process of any one of claims 1-7, wherein the leaving group is selected from the group consisting of -OSO2-aryl, -OSO2-C1-4alkyl, chloro, bromo, and iodo; wherein C1- 4alkyl and aryl may be optionally substituted with one or more substituents each independently selected, for each occurrence, from the group consisting of fluoro, bromo, and -CH3.

12. The process of any one of claims 11, wherein the leaving group is -OSO2-phenyl or -OSO2-C1-4alkyl.

13. The process of any one of claims 11 or 12, wherein the leaving group is independently

selected from the group consisting of: -OSO2Me,
-OSO2CF3

, and -NSO2CF2CF2CF2CF3.


14. The process of any one of claims 1-13, wherein the leaving group is -OSO2Me.

15. The process of any one of claims 1-14 wherein the alcohol solvent comprises at least one of methanol, ethanol, isopropanol, and butanol.

16. The process of claim 15, wherein the alcohol solvent comprises methanol.

17. The process of any one of claims 1-16, wherein the base solution, comprises at least one of: sodium hydroxide, lithium hydroxide, and potassium hydroxide.

18. The process of claim 17, wherein the base solution comprises sodium hydroxide.

19. The process of any one of claims 1-18, wherein the base solution comprises about 30% sodium hydroxide.

20. The process of any one of claims 1-19 wherein hydrolyzing the intermediate of Formula (I-B) to form a compound of Formula (IV) comprises:

(i) contacting the intermediate of Formula (I-B) with an alkali hydroxide and water;

and

(ii) neutralizing to form the compound of Formula (IV).

21. The process of claim 20, wherein the alkali hydroxide is sodium hydroxide.

22. The process of claim 20 or 21, wherein neutralizing comprises acidifying to a pH of less than or equal to 3 by adding an acid.

23. The process of claim 22, wherein the acid is phosphoric acid or hydrochloric acid, or a mixture thereof.

24. The process of any one of claims 1-23 wherein, hydrogenating the compound of Formula (IV) to form a compound of Formula (V) comprises contacting the compound of Formula (IV) with hydrogen and a catalyst.

25. The process of claim 24, wherein the catalyst is about 5% Pd/C.

26. The process of any one of claims 1-25, wherein hydrogenating is performed at a reaction temperature which is maintained between about 60-80 °C and at a pressure between about 3 to 5 atm.

27. The process of any one of claims 1-26, wherein resolving the compound of Formula (V) to form a substantially optically pure compound of Formula (VI) comprises:

(a) resolving a compound of Formula (V) in the presence of a chiral acid thereby forming a chiral salt of the compound of Formula (VI); and

(b) neutralizing the chiral salt of the compound of Formula (VI) thereby forming the compound of Formula (VI).

28. The process of claim 27, wherein the chiral acid is selected from the group consisting of (S)-(+)-camphor-10-sulfonic acid, (2R ,3R )-(+)-tartaric acid, (S)-(-)-malic acid, and (R )-(-)-mandelic acid or an enantiomer thereof.

29. The process of claim 27 or 28, wherein the chiral acid is (S)-(+)-camphor-10-sulfonic acid.

30. The process of any one of claims 27-29, wherein the chiral salt of the compound of Formula (VI) is:


•( S)-(+)-camphor-10-sulfonic acid

31. The process of any one of claims 1-30, wherein resolving further comprises maintaining a temperature between 55-60 °C while stirring.

32. The process of any one of claims 27-31, wherein neutralizing comprises contacting the chiral salt of the compound of Formula (VI), with (i) an aqueous base; and then (ii) acidifying the solution by adding an acid.

33. The process of claim 32, wherein the aqueous base comprises aqueous ammonium hydroxide.

34. The process of any one of claims 1-33, wherein acylating comprises contacting the compound of Formula (VI) with an acylating agent in the presence of an organic solvent selected from the group consisting of ethyl acetate, tetrahydrofuran, diethyl ether, dichloromethane, and toluene.

35. The process of claim 34, wherein the acylating agent is acetic anhydride.

36. The process of claim 34 or 35, wherein the organic solvent is ethyl acetate.

37. The process of any one of claims 1-36, wherein acylating occurs at a temperature between 60-70 °C.

38. The process of any one of claims 1-37, wherein the compound of Formula (VII) is produced on a multi-kilogram scale.

39. The process of claim 38, wherein at least about 130 kg of the compound of Formula (VII) is obtained.

40. The process of any one of claims 1-39, wherein the substantially optically pure compound of Formula (VII) is at least 98% of the enantiomer:


(expressed as a percentage of both enantiomers).

41. The purified compound of Formula (VII) of claim 40, wherein the content of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid is not more than 0.15% by HPLC.

42. A process for preparing a compound of Formula (I):


the process comprising, providing a mixture of a compound of Formula (II):


and a compound of Formula (III):


and contacting the mixture with a base; thereby forming a compound of Formula (I).

43. The process of claim 42, wherein contacting occurs in a solvent.

44. The process of claim 42 or 43, wherein the solvent is tetrahydrofuran.

45. The process of any one of claims 42-44, wherein contacting is performed at a temperature less than or equal to 0 °C.

46. The process of any one of claims 42-45, wherein contacting comprises stirring for about 5 minutes and/or is performed at a reaction temperature which is maintained between -5 to 0 °C.

47. The process of any one of claims 42-46, wherein the base is an alkali metal alkoxide.

48. The process of claim 47, wherein the alkali metal alkoxide is selected from the group consisting of sodium methoxide, lithium methoxide, and potassium methoxide.

49. The process of claims 47 or 48, wherein the alkali metal alkoxide is sodium methoxide.

50. A compound represented by:


or a pharmaceutically acceptable salt thereof.

51. A purified compound of Formula (VII):


obtainable by a process according to any one of claims 1 to 40, having a content of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid not more than 0.15% by HPLC.