Process for the preparation of 17-phenyl-18,19,20-thinor-pgf 2a and its derivatives

• US 7,157,590 B2
• Filed: 05/03/2002
• Issued: 01/02/2007
• Est. Priority Date: 05/31/2001
• Status: Expired due to Term

• Current Assignee: FineTech Pharmaceutical Ltd. (RxElite, Inc.)
• Original Assignee: FineTech Laboratories Ltd. (RxElite, Inc.)
• Inventors: Pertsikov, Boris, Gutman, Arie, Nisnevich, Gennady, Etinger, Marina, Zaltzman, Igor, Yudovitch, Lev
• Primary Examiner(s): Carr; Deborah D.
• Application Number:
  US10/478,849
• Publication Number:
  US 20040171873A1
• Time in Patent Office: 1,705 Days
• Field of Search: 554/141, 554/142, 554/159, 554/221, 554/222, 549/465, 549/466, 549/312
• US Class Current: 554/142
• 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

Abstract

The present invention provides a new and effective process for the synthesis of 17-phenyl-18,19,20-trinor-PGF_2α and its derivatives, including the anti-glaucoma drugs Bimatoprost and Latanoprost. The benefit of the present invention rises inter alia from the fact that a major intermediate involved in the synthesis of the above compounds may be isolated from a mixture containing also an undesired isomer, by crystallization. In addition, the undesired isomer may be oxidized to give the starting compound, which is then recycled.

Claims

1. A process for the preparation of compound of Formula (1b)

2. A process according to claim 1 wherein one of R¹ and R² is arylcarbonyl and the second one is selected from the group consisting of unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-yl groups and arylcarbonyl group.

3. A process according to claim 1 wherein one of R¹ and R² is arylcarbonyl and the second one is selected from the group consisting of benzoyl, p-toluoyl, p-phenylbenzoyl (PPB) and tetrahydro-2H-pyran-2-yl (THP) groups and R⁶ is a hydroxy, methoxy, isopropoxy or ethylamino group.

4. A process according to claim 1 wherein R¹ is p-phenylbenzoyl group and R² is tetrahydro-2H-pyran-2-yl (THP) group.

5. A process according to claim 1 wherein said stereoselective reduction of the carbonyl group of the compound (4) in step (a) is carried out by (−

)-B-chlorodiisopinocampheylborane.

6. A process according to claim 1, which further comprises purifying the compound of formula (5) obtained in step (a) by re-crystallization.

7. A process for the preparation of compound of the formula [5] (5a)

8. The process according to claim 7, wherein said process is maintained at a reaction mixture temperature in the range of from −

50°

C. to 20°

C.

9. The process according to claim 7, further comprising the step of quenching said reduction with a boron complexing agent.

10. The process according to claim 8, wherein said boron complexing agent is methanol.

11. A process for the preparation of compound of the formula (5a):

12. The process according to claim 11, wherein said reduction is maintained at a reaction mixture temperature in the range of from about −

50°

C. to 20°

C.

13. A process for the preparation of compound of the formula (5a):

14. The process according to claim 13, wherein said boron complexing agent is methanol.