Synthesis of intermediate for treprostinil production

Patent metadata

Field	Value
Publication number	US-9611206-B2
Application number	US-201514689244-A
Country	US
Kind code	B2
Filing date	Apr 17, 2015
Priority date	Mar 2, 2011
Publication date	Apr 4, 2017
Grant date	Apr 4, 2017

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. A method for synthesizing a compound of Formula I, comprising:

hydrolyzing a compound of Formula A

the method further comprising synthesizing the 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;
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 method of claim 1 , wherein R a , R b and R c are each independently (C 1 -C 6 )alkyl.

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

4. The method 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 method of claim 1 , wherein integer x is 2.

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

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

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

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

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

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

13. A method for synthesizing a compound of Formula I, 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 give the Formula I compound.

14. The method of claim 13 , wherein said organolithium is phenyllithium.

15. The method of claim 13 , wherein integer x is 1 and R a , R b and R c are methyl and wherein the allyl halide is allyl iodide.

Assignees

• United Therapeutics Corp

Inventors

• Sharma Vijay

Classifications

• C07C51/00 Primary

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

• C07C45/42 Primary

  by hydrolysis · CPC title

• C07C45/68

  by increase in the number of carbon atoms · CPC title

• C07F1/08

  Copper compounds · CPC title

• C07C213/08

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