Process for preparing synthetic prostacyclins

• US 9,388,154 B2
• Filed: 09/12/2012
• Issued: 07/12/2016
• Est. Priority Date: 09/12/2011
• Status: Active Grant

• Current Assignee: Lung Biotechnology PBC (United Therapeutics Corporation)
• Original Assignee: Lung Biotechnology PBC (United Therapeutics Corporation)
• Inventors: Yiannikouros, George Petros, Kalaritis, Panos, Gamage, Chaminda Priyapushpa, Arefyev, Denis Viktorovich
• Primary Examiner(s): Leeser, Erich A
• Application Number:
  US14/343,550
• Publication Number:
  US 20150025255A1
• Time in Patent Office: 1,399 Days
• Field of Search: 549/458, 549/214
• US Class Current: 1/1
• CPC Class Codes: A61K 31/557 Eicosanoids, e.g. leukotrienes or prostaglandins
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 31/5578 having a pentalene ring system, e.g. carbacyclin, iloprost
• CPC Class Codes: A61K 31/5585 having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
• CPC Class Codes: C07C 2601/10 the ring being unsaturated
• 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 67/31 by introduction of functional groups containing oxygen only in singly bound form
• CPC Class Codes: C07C 67/313 by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
• CPC Class Codes: C07C 69/738 Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• CPC Class Codes: C07D 307/93 condensed with a ring other than six-membered

Abstract

The presently disclosed subject matter provides methods of preparing synthetic prostacyclin analogs, including Beraprost, either as racemic mixtures or as single stereoisomers. Also provided are novel synthetic intermediates for use in these methods.

Claims

1. A method for preparing a synthetic prostacyclin or a synthetic intermediate thereof, wherein the method comprises contacting an aldehyde with an enantiomerically pure phosphonate in a Horner-Emmons reaction to provide an alkene,

wherein the enantiomerically pure phosphonate has a structure:

2. The method of claim 1, wherein the aldehyde is a product of the ozonolysis of a compound of formula (V), (V′

) or (V″

);

3. The method of claim 2, wherein R is —

CO₂R′

, —

(CH₂)_n—

CO₂R′

, —

O—

(CH₂)_n—

CO₂R′

, or —

CH₂═

CH₂—

(CH₂)_n—

CO₂R′

, wherein n is an integer between 1 and 8 and R′

is H, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl.

4. The method of claim 2, wherein Y and Z are each —

C(═

O)CH₃.

5. The method of claim 2, wherein the aldehyde is the product of the ozonolysis of a compound of formula (V):

6. The method of claim 5, wherein the compound of formula (V) is the compound:

7. The method of claim 1, further comprising stereoselectively reducing a ketone in the alkene compound formed during the Horner-Emmons reaction.

8. The method of claim 7, wherein the stereoselective reduction is performed using a Corey-Bakshi-Shibata (CBS) catalyst.

9. The method of claim 1, further comprising deprotecting protected hydroxyl groups.

10. The method of claim 1, wherein the synthetic prostacyclin is Beraprost.

11. A synthetic prostacyclin or synthetic intermediate thereof, prepared according to the method of claim 1.

12. A synthetic prostacyclin prepared according to the method of claim 1, wherein the synthetic prostacyclin is a single isomer of Beraprost.

13. A method for preparing a synthetic prostacyclin or synthetic intermediate thereof, wherein the method comprises:

(a) providing a compound of formula (V), (V′

) or (V″

);

14. A method for producing a compound of formula (V), wherein the method comprises:

(a) coupling compound A;

15. A method for preparing a synthetic prostacyclin or synthetic intermediate thereof, wherein the method comprises the use of a synthetic intermediate of formula (V), (V′

), or (V″

) or a hydroxyl group deprotected derivative thereof, wherein formulas (V), (V′

), and (V″

) are;

16. A compound of formula (V), (V′

), or (V″

) or a hydroxyl group deprotected derivative thereof, wherein formulas (V), (V′

), and (V″

) are;

17. A method for preparing an intermediate for a synthetic prostacyclin, wherein the method comprises contacting compound A:

18. A compound of formula (XIV), (XIV′

), or (XIV″

);

19. A method of preparing a synthetic prostacyclin, wherein the method comprises alkylating a compound of formula (XIV), (XIV′

), or (XIV″

).