Methods for producing beraprost and its derivatives

• US 10,005,753 B2
• Filed: 05/19/2015
• Issued: 06/26/2018
• Est. Priority Date: 05/20/2014
• Status: Active Grant

• Current Assignee: Lung Biotechnology PBC (United Therapeutics Corporation)
• Original Assignee: Lung Biotechnology PBC (United Therapeutics Corporation)
• Inventors: Batra, Hitesh, Tuladhar, Sudersan M., Tummala, Sri Harsha, Penmasta, Raju, Walsh, David A.
• Primary Examiner(s): Rahmani, Niloofar
• Application Number:
  US15/312,295
• Publication Number:
  US 20170166545A1
• Time in Patent Office: 1,134 Days
• Field of Search: 549458, 549214
• CPC Class Codes: C07C 233/20 having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
• CPC Class Codes: C07C 2601/10 the ring being unsaturated
• CPC Class Codes: C07C 67/00 Preparation of carboxylic acid esters
• CPC Class Codes: C07C 67/307 by introduction of halogen; by substitution of halogen atoms by other halogen atoms
• CPC Class Codes: C07C 69/65 of unsaturated acids
• CPC Class Codes: C07D 307/93 condensed with a ring other than six-membered
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention is directed to methods for preparing Beraprost and novel synthetic intermediates for Beraprost. In one aspect, a process is provided to produce a pharmaceutical compound represented by the general Formula (I) via a radical cyclization route. The process is completed in fewer steps than the known synthetic methods and may be conducted to prepare commercially useful quantities. In another aspect, synthetic methods are provided for producing Beraprost and its derivatives, which are stereoselective, efficient, scalable and economical. In another aspect, substantially isomerically pure compounds and intermediates are produced by the above processes.

Claims

1. A method of preparing a beraprost ester diol compound represented by the structural Formula (IX):

2. The method of claim 1, further comprising converting the beraprost ester diol compound of Formula (IX) to a compound represented by the structural Formula (I):

3. The method of claim 1, wherein R¹is methyl or ethyl.

4. The method of claim 1, wherein the palladium catalyst is PdCl₂(PPh₃)₂.

5. The method of claim 1, wherein the terminal olefin isomerization reaction is carried out in the presence of a transition metal catalyst.

6. The method of claim 1, wherein the palladium catalyst is PdCl₂(PPh₃)₂, Pd(Ph₃)₄, and PdCl₂(dppf)₂ , Pd(OAc)₂, Pd₂(dba)₃.

7. The method of claim 1 wherein the allylating reagent is allyltributyltin (allyl-BusSn), allylmagnesium bromide (allyl-MgBr);

allyl halide;

allyltrihalosilane;

allyl carboxylate;

allyl carbonate;

diallyl carboxylate;

diallyl sulfate;

metalallyl reagent or a combination thereof.

8. The method of claim 1, wherein the allylating reagent is allyltributyltin.

9. The method of claim 1, wherein the allylating is Keck radical allylation.

10. The method of claim 1, wherein the radical initiator is azobis-iso-butyronitrile, di-tert-butyl, dilauroyl, or dibenzoyl peroxide.

11. The method of claim 1, wherein the allylating reagent is allyltributyltin and the radical initiator is azobis iso butyronitrile.

12. The method of claim 1, wherein X is Br or I, R¹ is C₁-C₄ alkyl and R² is H.

13. The method of claim 1, wherein X is Br, R¹ is methyl and R² is H.