Methods for producing Beraprost and its derivatives

• US 10,246,430 B2
• Filed: 05/04/2018
• Issued: 04/02/2019
• 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:
  US15/971,132
• Publication Number:
  US 20180265490A1
• Time in Patent Office: 333 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.

Claims

1. A method of preparing a compound represented by the structural Formula (I):

2. The method of claim 1, wherein R¹ is methyl or ethyl.

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

4. The method of claim 1, wherein the allylation reaction is carried out in the presence of an allylating reagent.

5. The method of claim 1, wherein the allylic acetoxylation reaction is carried out in the presence of acetic acid and PdCl₂ catalyst.

6. The method of claim 1, wherein the catalytic dihydroxylation is carried out in the presence of N-methylmorpholine N-oxide (NMO) oxidant and a catalytic amount of OsO₄.

7. The method of claim 1, wherein the dihydroxy compound (VII) is oxidized in the presence of a periodate compound.

8. The method of claim 1, wherein the transition metal catalyst is a hydride of ruthenium, iridium, cobalt, rhodium, osmium, platinum, nickel, iron, or combinations thereof or a carbonyl hydride complex of ruthenium, iridium, cobalt, rhodium, osmium, platinum, nickel, iron, or combinations thereof.

9. The method of claim 1, wherein the transition metal catalyst is a ruthenium hydride complex.

10. The method of claim 1, wherein the transition metal catalyst carbonylchlorohydridotris(triphenylphosphine)ruthenium(II).