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Treprostinil production

A technology of cyclic compounds and structural formulas, applied in the field of intermediate compounds, can solve the problems of lengthy chromatographic purification technology, expensive reagents, and no description of a feasible preparation method of treprostinil

Active Publication Date: 2013-08-21
UNITED THERAPEUTICS CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the methods described in these patent documents do not describe a feasible preparation method for the preparation of stereochemically pure treprostinil, for example, because these methods require the use of expensive reagents and lengthy chromatographic purification technology

Method used

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preparation example Construction

[0043] The present application is directed to the preparation method of Treprostinil and the preparation method of the synthetic intermediate used for the synthesis of Treprostinil and the synthetic intermediate itself. The present application is also directed to a method of preparing treprostinil or a pharmaceutically acceptable salt thereof comprising the alkyne addition reaction described herein. Preferred treprostinil salts may include sodium and diethanolamine salts (see, eg, US Patent No. 7,417,070).

[0044] In some embodiments, the present application is directed to a method for preparing treprostinil synthetic intermediate (A) through stereoselective alkyne addition reaction.

Embodiment approach

[0045] One embodiment is directed to a novel process (reaction 1) for the preparation of compounds of formula (A) comprising the step of reacting an aldehyde of formula (I) with an alkyne of formula (a):

[0046]

[0047] in:

[0048] P 1 is an alcohol protecting group;

[0049] R is -(CH 2 ) n X;

[0050] X is H, phenyl, -CN, -OR 1 or COOR 1 ;

[0051] R 1 is alkyl, THP, TBDMS, or substituted or unsubstituted benzyl; and

[0052] n is 1, 2 or 3.

[0053]As used herein, an "alcohol protecting group" is a functional group that protects an alcohol group from reactions occurring with other parts of the molecule. Suitable alcohol protecting groups are known to those skilled in the art and include those known from the following document and the entire teaching of which document is incorporated herein by reference: T.W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981. Exemplary alcohol protecting groups include, but are not limited to, ace...

Embodiment 1

[0125] Example 1. Preparation of Chiral Benzyl Alcohol (A-1)

[0126]

[0127] Zinc triflate (2.16 g, 0.0059 mol) and (+)-N-methylephedrine (0.814 g, 0.0045 mol) in toluene (10 mL) were charged to a 50 mL bismuth equipped with a mechanical stirrer. necked round bottom flask. Triethylamine (0.459 g, 0.0045 mol) was added to the mixture and the gel-like mixture was stirred at ambient temperature for 30-60 minutes. The mixture was then treated with a solution of the alkyne (1.08 g, 0.0045 mol) in toluene (1 mL), stirred at ambient temperature for 15 minutes, followed by a solution of acetaldehyde (0.250 g, 0.0014 mol). The progress of the reaction was monitored by TLC (completion of the reaction was monitored by TLC using a thin-layer silica gel plate; eluent: 20% ethyl acetate in hexane). After stirring the mixture for 3 hours, TLC indicated the reaction was complete. At this stage, the reaction mixture was quenched by the slow addition of saturated ammonium chloride (10 m...

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Abstract

A method is disclosed for preparing a synthetic intermediate for treprostinil via a stereoselective alkyne addition reaction using a chiral inducing agent. Also described are methods of preparing treprostinil or a pharmaceutically acceptable salt thereof comprising the alkyne addition reaction as well as novel intermediates useful for synthesis prostacyclin derivatives. A functional alcohol protecting group protects the alcohol group from participating in reactions that are occurring in other parts of the molecule. The intermediate is later deprotected prior to conversion and hydrolyzing to obtain the final treprostinil product.

Description

[0001] This application claims the benefit of US Provisional Application No. 61 / 351,115, filed June 3, 2010, which is hereby incorporated by reference in its entirety. technical field [0002] The present application relates to a process for the preparation of cycloprostaglandin derivatives such as treprostinil and novel intermediate compounds for use in the process. Background technique [0003] (+)-Treprostinil (also known as UT-15) is active ingredient in It is an FDA-approved commercial drug for the treatment of pulmonary arterial hypertension (PAH). Treprostinil was first described in US Patent No. 4,306,075. Treprostinil is cycloprostaglandin (PGI 2 ), a stable analogue of the cycloprostaglandin (PGI 2 ) belongs to the class of compounds known as benzindene cycloprostaglandins, which are useful pharmaceutical compounds having activities such as inhibition of platelet aggregation, reduction of gastric secretion, injury inhibition and bronchodilation. [0004] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C62/00
CPCC07B2200/07C07C51/09C07C51/367C07C67/343C07C253/30C07F7/1892Y02P20/55C07C59/72C07C69/736C07C255/13C07C51/16C07C62/12C07C29/143C07C29/42C07C45/00C07C45/29C07C45/61C07C45/64C07C51/00
Inventor 海特史·巴特拉拉杜·潘马斯塔维贾伊·沙玛苏德瑞撒恩·M·图拉达尔大卫·A·沃尔什
Owner UNITED THERAPEUTICS CORP
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