Synthesis of intermediate for treprostinil production

Patent metadata

Field	Value
Publication number	US-10077225-B2
Application number	US-201715440441-A
Country	US
Kind code	B2
Filing date	Feb 23, 2017
Priority date	Mar 2, 2011
Publication date	Sep 18, 2018
Grant date	Sep 18, 2018

Abstract

The compound according to Formula I is an intermediate in the synthesis of prostacylin analogs. The present invention provides an efficient method for synthesizing a Formula I compound.

First claim

What is claimed is:

1. In a process of preparing a pharmaceutical product comprising a prostacyclin, wherein the prostacyclin is synthesized from a starting material of Formula I:

the improvement comprising:
(I) synthesizing a compound of Formula A

by:
(i) contacting a compound of Formula B

with an organolithium;
(ii) contacting the lithiated product from step (i) with copper cyanide to form a cuprate; and
(iii) contacting the cuprate from step (ii) with an allyl halide selected from the group consisting of allyl chloride, allyl bromide and allyl iodide; and

(II) hydrolyzing the compound of Formula A to form the compound of Formula I, wherein,
x is an integer between 2 and 4 inclusive;
R is selected from the group consisting of straight or branched (C 1 -C 6 )alkyl, (C 6 -C 14 )aryl, and (C 6 -C 14 )aryl(C 1 -C 6 )alkylene-; and
R a , R b and R c are each independently selected from the group consisting of straight or branched (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 14 ) aryl, (C 6 -C 14 )aryl(C 1 -C 6 )alkylene, and (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkylene-.

2. The improvement of claim 1 , wherein R a , R b and R c are each independently (C 1 -C 6 )alkyl.

3. The improvement of claim 2 , wherein R a , R b and R c are each methyl.

4. The improvement of claim 1 , wherein R a is (C 1 -C 6 )alkyl and R b and R c are each independently (C 3 -C 6 )cycloalkyl.

5. The improvement of claim 1 , wherein integer x is 2.

6. The improvement of claim 1 , wherein R is straight or branched (C 1 -C 6 )alkyl.

7. The improvement of claim 1 , wherein R is methyl.

8. The improvement of claim 1 , wherein R is (C 6 -C 14 )aryl(C 1 -C 6 )alkylene-.

9. The improvement of claim 1 , wherein R is benzyl.

10. The improvement of claim 1 , wherein the organolithium is phenyllithium, or butyllithium.

11. The improvement of claim 1 , wherein said hydrolyzing comprises contacting the compound of Formula A with an agent selected from the group consisting of water, aqueous mineral acid, and an aqueous solution of sodium sulfite.

12. The improvement of claim 1 , wherein said hydrolyzing comprises contacting the compound of Formula A with an aqueous solution of sodium sulfite.

13. The improvement of claim 1 , wherein the prostacyclin is treprostinil.

14. In a process of preparing a pharmaceutical product comprising a prostacyclin, wherein the prostacyclin is synthesized from a starting material of Formula I:

the improvement comprising:
(a) contacting an aldehyde of Formula C

with a compound of formula R c R b N—(CHR′) x —NHR a in the presence of an organolithium;
wherein
x is an integer between 0 and 4 inclusive;
R′ is H,
R is an alcohol protecting group or is selected from the group consisting of straight or branched (C 1 -C 6 )alkyl, (C 6 -C 14 )aryl, and (C 6 -C 14 )aryl(C 1 -C 6 )alkylene-; and
R a , R b and R c are each independently selected from the group consisting of straight or branched (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 14 )aryl, (C 6 -C 14 )aryl(C 1 -C 6 )alkylene, and (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkylene-;

(b) contacting the product from step (a) with an organolithium to form an ortho-lithiated product, and then contacting the ortho-lithiated product with copper cyanide to form a cuprate;
(c) contacting the cuprate from step (b) with an allyl halide selected from the group consisting of allyl chloride, allyl bromide and allyl iodide; and
(d) hydrolyzing the product of step (c) to form the compound of Formula I.

15. The improvement of claim 14 , wherein said organolithium is phenyllithium.

16. The improvement of claim 14 , wherein integer x is 1 and R a , R b and R c are methyl and wherein the allyl halide is allyl iodide.

17. The improvement of claim 14 , wherein the prostacyclin is treprostinil.

Assignees

• United Therapeutics Corp

Inventors

• Sharma Vijay

Classifications

• C07C47/575

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07C45/42 Primary

  by hydrolysis · CPC title

• C07C213/08

  by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups · CPC title

• C07C51/00

  Preparation of carboxylic acids or their salts, halides or anhydrides (of acids by hydrolysis of oils, fats or waxes C11C) · CPC title

• C07C45/68

  by increase in the number of carbon atoms · CPC title