Methods of making lubiprostone and intermediates thereof

• US 9,382,272 B2
• Filed: 01/22/2010
• Issued: 07/05/2016
• Est. Priority Date: 01/22/2009
• Status: Active Grant

• Current Assignee: Apotex Pharmachem India PVT Limited (Apotex Holdings Incorporated)
• Original Assignee: Apotex Pharmachem India PVT Limited (Apotex Holdings Incorporated)
• Inventors: Kothakonda, Kiran Kumar, Wang, Fan, Guntoori, Bhaskar Reddy, Nguyen, Minh T. N., Ceccarelli, Alfredo Paul, Zhao, Yajun, Kotipalli, Uma, Duncan, Sammy Chris, Milnes, Kaarina K., Kells, Kevin Wade, Montemayor, Laura Kaye
• Primary Examiner(s): Oh, T. Victor
• Application Number:
  US13/145,999
• Publication Number:
  US 20120065409A1
• Time in Patent Office: 2,356 Days
• Field of Search: 549/214, 549/396, 549/421, 549/465, 562/503, 560/121
• US Class Current: 1/1
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 405/00 Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
• CPC Class Codes: C07C 69/734 Ethers
• CPC Class Codes: C07C 69/738 Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• CPC Class Codes: C07D 307/935 Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
• CPC Class Codes: C07F 7/1892 by reactions not provided for in C07F7/1876 - C07F7/1888

Abstract

There is provided processes for preparing Lubiprostone and intermediates thereof. Also provided are compounds, including intermediates for preparing Lubiprostone as well compositions comprising Lubiprostone and other compounds, including intermediates for preparing Lubiprostone and other compounds. (I)

Claims

1. A process for preparation of Lubiprostone comprising hydrogenation, in the presence of a suitable hydrogenation catalyst, of a compound of Formula 10:

2. The process of claim 1 wherein the hydrogenation is performed using hydrogen gas.

3. The process of claim 1 wherein the suitable hydrogenation catalyst is selected from the group consisting of palladium, platinum, rhodium, ruthenium, and Raney-nickel.

4. The process of claim 1 wherein the suitable hydrogenation catalyst is palladium on carbon.

5. The process of claim 4 wherein the suitable hydrogenation catalyst is 10 wt % palladium on carbon (dry basis), 50 wt % (wet support).

6. The process of claim 1 wherein the S/D is a double bond.

7. The process of claim 1 wherein the compound of Formula 10 is a compound of Formula 18:

8. The process of claim 7 wherein the compound of Formula 18 is a compound of Formula 18a:

9. The process of claim 8 wherein the compound of Formula 18a is prepared by reacting, in the presence of a seventh base selected from the group consisting of:

alkali hydroxides, Zn(OH)₂, mixtures of ammonia and alkali hydroxides, and mixtures thereof, a compound of Formula 17a;

10. The process of claim 9 wherein the compound of Formula 17a is prepared by oxidizing a compound of Formula 16a:

11. The process of claim 10 wherein the compound of Formula 16a is prepared by deprotection of a compound of Formula 15:

12. The process of claim 8 wherein the compound of Formula 18a is prepared by oxidizing a compound of Formula 23:

13. The process of claim 12 wherein oxidizing comprises using an oxidizing agent selected from the group consisting of:

Dess-Martin periodinane, CrO₃, MnO₂, 2,2,6,6-tetramethyl-piperidinyloxy free radical/sodium hypochlorite, SO₃/pyridine and oxalyl chloride/dimethylsulfoxide/triethylamine.

14. The process of claim 13 wherein the oxidizing agent is Dess-Martin periodinane.

15. The process of claim 12 wherein oxidizing comprises using a eighth solvent selected from the group consisting of:

dichloromethane, dimethylsulfoxide, and mixtures thereof.

16. The process of claim 11 wherein the compound of Formula 15 is prepared by reacting, in the presence of a ninth base selected from the group consisting of triethylamine, diisopropylamine, diisopropylethylamine, pyridine and 1,8-Diazabicyclo[5.4.0]undec-7-ene, a compound of having a structure of R⁷-G, wherein G is a leaving group and R⁷ is C(R^1′

)(R^2′

)(R^3′

), with a compound of Formula 14;

17. The process of claim 16 wherein G is selected from the group consisting of:

chlorine, bromine, iodine, methansulfonyloxy, trifluoromethansulfonyloxy and p-toluenesulfonyloxy.

18. The process of claim 16 wherein R⁷-G is a benzyl halide.

19. The process of claim 16 wherein the ninth base is selected from the group consisting of:

triethylamine, diisopropylamine, pyridine and 1,8-Diazabicyclo[5.4.0]undec-7-ene.

20. The process of claim 1 wherein the compound of Formula 10 is prepared by oxidation of a compound of Formula 9:

21. The process of claim 20 wherein oxidation is performed using an oxidizing agent selected from the group consisting of Dess-Martin periodinane, o-iodoxybenzoic acid, CrO₃, MnO₂, 2,2,6,6-tetramethyl-piperidinyloxy free radical/sodium hypochlorite and SO₃/pyridine.

22. The process of claim 20 wherein oxidation is conducted in a fourth solvent, the fourth solvent comprising dichloromethane.

23. The process of any one of claims 1 or 20 wherein the compound of Formula 10 that is hydrogenated to Lubiprostone is a compound of Formula 10a:

24. The process of any one of claims 1, 7, 8, 9, 10, 11, 12, and 20 wherein hydrogenation comprises using ethyl acetate.

25. The process of any one of claims 1 and 20 wherein the S/D bond between carbon 9b1 and carbon 9b2 of the compound of Formula 10 is a single bond.

26. The process of any one of claims 1 and 20 wherein the S/D bond between carbon 9b1 and carbon 9b2 of the compound of Formula 10 is a double bond.

27. The process of any one of claims 1 and 20 wherein the reaction comprises a mixture of compounds of Formula 10 wherein the mixture comprises compounds in which the S/D bond between carbon 9b1 and carbon 9b2 is a single bond and compounds in which the S/D bond between carbon 9b1 and carbon 9b2 is a double bond.

28. A compound of Formula 15:

29. A compound of Formula 16a:

30. A compound of Formula 17a:

31. A compound of Formula 18a:

32. A compound selected from the group consisting of:

(3aR,4S,5R,6aS)-5-(phenylmethoxy)-4-(triisopropylsilyloxymethyl)hexahydrocyclopenta[b]furan-2-ol;

(5Z)-7-[(1R,2S,3R,5S)-3-Benzyloxy-5-hydroxy-2-[(triisopropylsilyloxy)methyl]cyclopentyl]hept-5-enoic acid;

Benzyl (Z)-7-[(1R,2S,3R,5S)-5-hydroxy-3-(2-phenylmethoxy)-2-(triisopropylsilyloxymethyl)cyclopentyl]-5-heptanoate;

(5Z)-Benzyl 7-[(1R,2S,3R,5S)-3-benzyloxy-5-hydroxy-2-(hydroxymethyl)cyclopentyl]hept-5-enoate;

(5Z)-Benzyl 7-[(1R,2R,3R)-3-benzyloxy-2-formyl 5-oxocyclopentyl]hept-5-enoate;

Benzyl (Z)-7-[(1R,2S,3R,5S)-2-(triisopropylsilyloxymethyl)-3-(2-phenylmethoxy)-5-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptanoate;

Benzyl (Z)-7-[(1R,2S,3R,5S)-2-hydroxymethyl-3-(2-phenylmethoxy)-5-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptanoate;

Benzyl (Z)-7-[(1R,2S,3R,5S)-2-formyl-3-(2-phenylmethoxy)-5-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptanoate;

Benzyl (Z)-7-[(1R,2R,3R,5S)-5-(2-tetrahydropyranyloxy)-2-((E)-3-oxo-1-octenyl)-3-(phenylmethoxy)cyclopentyl]heptanoate; and

Benzyl (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-((E)-3-oxo-1-octenyl)-3-(phenylmethoxy)cyclopentyl]heptanoate.

33. A compound of Formula 10:

34. A compound selected from the group consisting of:

(3aR,4R,5R,6aS)-hexahydro-2-oxo-5-(phenylmethoxy)-2H-cyclopenta[b]furan-4-carboxaldehyde;

(3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan;

(3aR,4R,5R,6aS)-4-(4,4-difluoro-3-oxo-1-octyl)-2-oxo-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan;

(3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-hydroxy-1-octenyl)-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan-2-ol;

(3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan-2-ol;

(3aR,4R,5R,6aS)-4-(4,4-difluoro-3-hydroxy-1-octyl)-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan-2-ol;

(3aR,4R,5R,6aS)-4-(4,4-difluoro-3-oxo-1-octyl)-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan-2-ol;

(Z)-7-[(1R,2R,3R,5S)-2-((E)-4,4-difluoro-3-hydroxy-1-octenyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoic acid;

(Z)-7-[(1R,2R,3R,5S)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoic acid;

(Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxy-1-octyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoic acid;

(Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-oxo-1-octyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoic acid;

Benzyl (Z)-7-[(1R,2R,3R,5S)-2-((E)-4,4-difluoro-3-hydroxy-1-octenyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoate;

Benzyl (Z)-7-[(1R,2R,3R,5S)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoate;

Benzyl (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxy-1-octyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoate;

Benzyl (Z)-7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-oxo-1-octyl)-3-(phenylmethoxy)-5-hydroxycyclopentyl]-5-heptenoate;

(Z)-7-[(1R,2R,3R)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5-oxocyclopentyl]-5-heptenoic acid;

(Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxo-1-octyl)-3-(phenylmethoxy)-5-oxocyclopentyl]-5-heptenoic acid;

Benzyl (Z)-7-[(1R,2R,3R)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5-oxocyclopentyl]-5-heptenoate; and

Benzyl (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxo-1-octyl)-3-(phenylmethoxy)-5-oxocyclopentyl]-5-heptenoate.