METHOD OF PRODUCING BERAPROST

• US 20120323025A1
• Filed: 06/15/2012
• Published: 12/20/2012
• Est. Priority Date: 06/16/2011
• Status: Active Grant

• Current Assignee: Lung Biotechnology PBC (United Therapeutics Corporation)
• Original Assignee: Lung Biotechnology PBC (United Therapeutics Corporation)
• Inventors: Sharma, Vijay, Batra, Hitesh, Tuladhar, Sudersan
• Granted Patent: US 8,779,170 B2
• Time in Patent Office: Days
• US Class Current: 549/458
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07C 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07D 307/93 condensed with a ring other than six-membered
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07F 7/1892 by reactions not provided for in C07F7/1876 - C07F7/1888
• CPC Class Codes: C07F 9/28 with one or more P—C bonds
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

An improved method is described for making single isomers of synthetic benzoprostacyclin analogue compounds, in particular the pharmacologically active 314-d isomer of beraprost. In contrast to the prior art, the method is stereoselective and requires fewer steps than the known methods for making these compounds.

Claims

1. A process for preparing a compound of the following formula:

2. The process of claim 1, wherein the compound of formula (I) is produced as a substantially pure single isomer.

3. The process of claim 1, wherein R¹ is a cation or H, R² and R³ are H, R⁴ and R⁵ are CH₃.

4. The process of claim 1, wherein R², R³, R^2a and R⁶ each independently represent trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, phenyldimethylsilyl, or tetrahydropyranyl.

5. The process of claim 1, wherein the cycloaddition of step (1) is an inverse electron demand Diels Alder reaction followed by thermal decarboxylation.

6. The process of claim 1, wherein the aromatization step (2) is treatment of the compound of formula (IV) with palladium on carbon.

7. The process of for preparing the stereoselectively produced isomeric compound of the following formula:

8. The process of claim 7, wherein R^2a and R⁶ each independently represent trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, phenyldimethylsilyl, or tetrahydropyranyl.

9. The process of claim 7, wherein the cycloaddition of step (1) is an inverse electron demand Diels Alder reaction followed by thermal decarboxylation.

10. The process of claim 7, wherein the aromatization step (2) is treatment of the compound of formula (IV) with palladium on carbon.

11. A process for preparing a compound of the following formula:

12. The process of claim 11, wherein the compound of formula (VII) is produced as a substantially pure single isomer.

13. A compound represented by the formula:

14. The compound of claim 13, wherein R⁴ and R⁵ are each CH₃.

15. A process for preparing a substantially pure compound of the following formula:

16. The method of claim 15, wherein selective reduction of the carbonyl includes an asymmetric catalyst.

17. The method of claim 15, wherein step 3 is not optional, and Z′

is C_1-12 alkyl-COOR^12′

, and R^12′

is a C_1-6 alkyl.

18. The method of claim 15, wherein step 3 is not optional, and R⁴ and R⁵ are each CH₃, Z is (CH₂)₃COOR¹² and R¹² is a cation or H.

19. The method of claim 18, wherein R¹² is a cation and the cation is K.

20. The method of claim 19, wherein the resulting substantially pure compound comprises greater than 99% of the isomer represented by the following formula: