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Intermediates for synthesizing treprostinil and preparation method thereof as well as the preparation method of treprostinil thereby

A compound and alkyl technology, applied in the field of intermediates for the preparation of Treprostinil, can solve the problems of excess and high synthesis cost

Active Publication Date: 2014-06-25
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This chiral synthesis route has good chiral control, but it needs to use an excessive amount of expensive chiral CBS reagent and dicobalt octacarbonyl, and the synthesis cost is high

Method used

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  • Intermediates for synthesizing treprostinil and preparation method thereof as well as the preparation method of treprostinil thereby
  • Intermediates for synthesizing treprostinil and preparation method thereof as well as the preparation method of treprostinil thereby
  • Intermediates for synthesizing treprostinil and preparation method thereof as well as the preparation method of treprostinil thereby

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Embodiment 1: Preparation of compound Xa

[0081] Under nitrogen protection, 1-(trimethylsilyl) propyne (XVIa, purchased from Shanghai Ruiyi Pharmaceutical Technology Co., Ltd.) (74 g) in anhydrous tetrahydrofuran (200 ml) was added dropwise at 0°C. Lithium (250 mL, 2.5M in hexane). After stirring at 0°C for 3 hours, a solution of compound XIIa (65.8 g, synthesized with reference to literature: Tetrahedron2010, 66, 2351) in anhydrous tetrahydrofuran (100 ml) was added dropwise, and the reaction mixture was slowly warmed to 20°C and stirred at 20°C 12 hours. The reaction was quenched with saturated aqueous ammonium chloride, ethyl acetate and water were added to separate the layers, and the organic phase was collected. The organic phase was concentrated to obtain the crude product XIa as a yellow oil, which was directly used in the next reaction without purification.

[0082] To a solution of the crude product XIa in ethanol was slowly added sodium hydroxide (39.2 g) ...

Embodiment 2

[0084] Embodiment 2: preparation compound VIIIa

[0085] Under the protection of nitrogen, add a toluene solution of dimethyl zinc (200 ml, 1.0M) to a solution of compound Xa (47.3 g) in toluene (200 ml) at 20°C, and then add compound XIIIa (3.80 g, synthesized by referring to literature: Tetrahedron: Asymmetry2005, 16, 1953) in toluene solution. The mixture was cooled to -10°C, and a toluene solution of compound IXa (12.6 g, synthesized by reference to J. Am. Chem. Soc. 1985, 107, 1421) was added dropwise. After stirring at -10°C for 6 hours, the reaction was quenched with saturated aqueous ammonium chloride, ethyl acetate was added and water was separated, and the organic phase was collected. The organic phase was concentrated and separated by column chromatography to obtain compound VIIIa (23.2 g, yield 95%).

[0086] VIIIa: 1 HNMR (400MHz, CDCl 3 )δ7.46-7.16(m,7H),6.91(d,J=8.2Hz,1H),6.05-5.95(m,1H),5.87-5.71(m,1H),5.64(s,1H),5.08 (s, 2H), 5.05-4.89 (m, 4H), 4.70-4.60 ...

Embodiment 3

[0087] Embodiment 3: preparation compound VIIIa

[0088] step one:

[0089] To a solution of compound Xa (39 g) in anhydrous tetrahydrofuran (150 ml) was added dropwise n-butyllithium (61 ml, 2.5M hexane solution) at -78°C under nitrogen. After stirring at -78°C for 1 hour, a solution of compound IXa (30 g, synthesized by referring to literature: J. Am. Chem. Soc. 1985, 107, 1421.) in anhydrous tetrahydrofuran (100 ml) was added dropwise. After stirring at -78°C for 1 hour, it was quenched with water, ethyl acetate and water were added and the organic phase was collected. The organic phase was concentrated and separated by column chromatography to obtain compound XIVa (53.0 g, yield 91%).

[0090] XIVa: 1 H NMR (400MHz, CDCl 3 )δ7.46-7.16(m,7H),6.91(d,J=8.2Hz,1H),6.05-5.95(m,1H),5.87-5.71(m,1H),5.64(s,1H),5.08 (s, 2H), 5.05-4.89 (m, 4H), 4.70-4.60 (m, 1H), 3.90-3.42 (m, 5H), 2.50-1.27 (m, 16H).

[0091] Step two:

[0092] To a solution of compound XIVa (45.4 g) in anhy...

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Abstract

The present invention relates to intermediates for preparing treprostinil, a preparation method for same, and a preparation of treprostinil thereby. Specifically, the invention relates to a compound of formula (VI), the preparation thereof and the application of said compound for the synthesis of treprostinil (as represented by formula (I)). The method for the preparation of treprostinil comprises: obtaining the compound of formula (III) by means of reducing the compound of formula (VI) and deprotecting the hydroxy group thereof; reacting said compound of formula (III) with chloroacetonitrile followed by hydrolysis to obtain the treprostinil of formula (I). The present method has simple operation and high synthesis yields, and is suitable for large-scale production.

Description

technical field [0001] The invention relates to an intermediate for preparing treprostinil, a preparation method thereof and a method for preparing treprostinil through the intermediate. Background technique [0002] Pulmonary hypertension is a group of clinical pathophysiological syndromes in which the mean pulmonary artery pressure measured by right heart catheterization is greater than or equal to 25 mmHg in a resting state caused by various reasons. As a common clinical cardiovascular disease, pulmonary arterial hypertension leads to increased pulmonary vascular resistance through vasospasm, intimal hyperplasia and remodeling of pulmonary arterioles, which can eventually lead to right heart failure and even death. [0003] As a targeted drug for the treatment of pulmonary arterial hypertension, prostacyclin (PGI2) can promote pulmonary vasodilation, inhibit platelet aggregation and thrombus formation, stimulate thrombus dissolution, and inhibit pulmonary vascular remodel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/12C07F7/08C07F7/18C07C51/08C07C59/72
CPCC07C51/08C07F7/08C07C59/72C07D309/12C07F7/18C07C37/055C07C253/30C07C2603/14C07F7/0812C07F7/083C07F7/1804C07F7/1892C07C39/17C07C255/13Y02P20/55
Inventor 张富尧郭鹏飞季维
Owner JIANGSU HENGRUI MEDICINE CO LTD
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