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Prasugrel intermediate and preparation method thereof

A technology of intermediates and reaction time, applied in the fields of pharmaceutical intermediates and their preparation, prasugrel intermediates and their preparations, can solve problems such as unfavorable industrialized production, high product purification difficulty, high environmental protection pressure, etc., and achieve production costs. Low, low environmental pressure, less effect of three wastes

Active Publication Date: 2011-01-19
ZHEJIANG APELOA JIAYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Using the above method to prepare prasugrel, the product yield of this key step is low, and the product purification is difficult, which is not conducive to industrial production
[0016] In view of the defects such as low yield, high cost, and high environmental protection pressure in the current synthesis of prasugrel, further research on high yield, low cost, and green and environmentally friendly prasugrel synthesis methods has broad market prospects, which requires the development of new The prasugrel intermediate provides a guarantee for improving the synthesis method of prasugrel

Method used

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  • Prasugrel intermediate and preparation method thereof
  • Prasugrel intermediate and preparation method thereof
  • Prasugrel intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1: Alkylation reaction

[0059] 4,5,6,7-Tetrahydrothiophene[3,2-c]pyridine hydrochloride (140.4g, 0.80mol) was dissolved in dichloromethane (500mL), added triethylamine 233.6mL (1.68mol) and stirred After 15 min, a solution of triphenylchloromethane (234.0 g, 0.84 mol) in dichloromethane (400 mL) was added dropwise at room temperature, and the drop was completed within 2 h. Stir at the same temperature for 8 hours, pour the reaction solution into 500 mL of water, separate the organic phase, wash 3 times with saturated brine, dry the organic phase with anhydrous magnesium sulfate, rotary evaporate under reduced pressure, and wash the residue with cold ethanol (100 mL) to obtain white dry 298.1 g of solid, yield 98%.

[0060] white solid: 1H NMR (δ, CDCl 3 ): 7.57~7.59(m, 6H), 7.25~7.35(m, 6H), 7.17~7.20(m, 3H), 7.06, (s, 1H), 6.68(d, 1H), 3.45(s, 2H) , 3.01(s, 2H), 2.63(s, 2H). According to the data analysis of nuclear magnetic resonance, it can be confir...

Embodiment 2

[0061] Embodiment 2: Alkylation reaction

[0062] 140.4g (0.8mol) of 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride was dissolved in dichloromethane (500mL), and 231.8g (1.68mol) of solid potassium carbonate was added, and stirred After 15 minutes, a solution of 234.0 g (0.84 mol) of triphenylchloromethane in dichloromethane (400 mL) was added dropwise at room temperature, and the drop was completed within 2 hours. Raise the temperature to 60°C and stir for 8 hours. After the reaction is complete, cool the reaction solution to room temperature and pour it into 500 mL of water. Separate the organic phase and wash it with saturated brine for 3 times. Dry the organic phase with anhydrous magnesium sulfate. After washing with cold ethanol (100 mL), 282.7 g of a white dry solid was obtained, with a yield of 93%.

Embodiment 3

[0063] Embodiment 3: borylation reaction

[0064] Take 19.0 g (0.05 mol) of the product (N-trityl-4,5,6,7-tetrahydrothiophene [3,2-c] pyridine) obtained in Example 1, dissolve it in 50 mL tetrahydrofuran (THF) 30 mL (0.075 mol) of n-butyllithium was added dropwise for 1 h at 0°C, under nitrogen protection, and stirred at the same temperature for 2 h. After cooling to -30°C, a mixture of 19 mL (0.075 mol) of trimethyl borate and THF (50 mL) was added dropwise, the addition was completed dropwise in half an hour, and the reaction was carried out at the same temperature for 1 h. Add 100 mL of ethyl acetate, wash three times with 100 mL of saturated sodium bicarbonate solution, wash and separate with 100 mL of saturated brine × 3, dry the organic phase with anhydrous magnesium sulfate, and concentrate by rotary evaporation at 40°C to obtain 20.2 g of the product, with a yield of 95% .

[0065] 1 H NMR (δ, CDCl 3 ): 7.55~7.57(m, 6H), 7.29~7.34(m, 7H), 7.09~7.20(m, 3H), 3.25~3.4...

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PUM

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Abstract

The invention discloses a prasugrel intermediate with a structural formula shown in the formula (I). The preparation method which uses the intermediate to prepare prasugrel is characterized in that the yield is high, the cost is low, the operation is simple, the method is suitable for mass production, etc. The invention also discloses a preparation method of the intermediate. The method comprises the steps of alkylation reaction, hydroboration reaction, deprotection reaction and coupling reaction. Compared with the prior art, the raw material for the preparation of the prasugrel intermediate is cheap and accessible; the process operation is simple, three wastes generated in the production process are less, the environmental protection pressure is low; and the yield is high, and the prasugrel intermediate is suitable for the industrial production.

Description

technical field [0001] The invention relates to a pharmaceutical intermediate and a preparation method thereof, in particular to a prasugrel intermediate and a preparation method thereof, belonging to the field of pharmaceutical chemical industry. Background technique [0002] Prasugrel is an oral antiplatelet drug jointly developed by Eli Lilly and its partner Daiichi Sankyo Pharmaceutical Co., Ltd. It was approved for marketing in the European Union on February 27, 2009. Its structural formula is as follows: [0003] [0004] Prasugrel is used to treat cardiovascular and cerebrovascular diseases such as heart failure, stroke, unstable angina, and patients with acute coronary syndrome requiring percutaneous coronary intervention. It is a prodrug, which forms an active molecule after metabolism in the body, and binds to the platelet P2Y receptor to exert anti-platelet aggregation activity. Clinical studies have proved that prasugrel has a better anticoagulant effect than...

Claims

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Application Information

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IPC IPC(8): C07F5/02C07D495/04
Inventor 何昆仑潘仙华彭锡江卢鑫陈庆鲍毅陈书花郑毓余珍艳
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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