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A kind of environment-friendly preparation method of low-cost prasugrel

An environmentally friendly, cyclopropylmagnesium bromide technology, applied in the field of pharmaceutical biochemical industry, can solve the problems of high cost, large safety hazards, high raw material prices, etc., and achieve the effect of low product cost

Active Publication Date: 2016-05-11
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The above route 1 and route 3 all need to use 1-cyclopropyl-2-o-fluorophenyl-2-bromoethanone as a starting material or intermediate, which has poor stability and low reaction selectivity, although the raw material of route 2 1-Cyclopropyl-2-o-fluorophenyl-2-hydroxyethanone has good stability, but the price of raw materials is high and it is not easy to obtain
In addition, the above routes all use 2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrochloride or 4,5,6,7-tetrahydrothiophene[ 3,2-c]pyridine, the raw material price is high, which is not conducive to reducing the cost of prasugrel
The Grignard reaction and butyllithium metal lithiation reaction used have high operational requirements, great safety hazards, and are not conducive to industrial production; in addition, the existing routes have the disadvantages of long routes, high costs, large amounts of waste water, and poor environmental protection, making it difficult to adapt to green Industrial Production Requirements

Method used

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  • A kind of environment-friendly preparation method of low-cost prasugrel
  • A kind of environment-friendly preparation method of low-cost prasugrel
  • A kind of environment-friendly preparation method of low-cost prasugrel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Ⅵ) preparation

[0047] a. Using 2-o-fluorophenylaminoacetonitrile as the starting material to prepare 2-o-fluorophenyl-N,N-di-tert-butoxycarbonylethylaminoacetonitrile (Ⅱ)

[0048] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, add 120 gram tetrahydrofuran, 15.0 gram (0.1 mol) 2-o-fluorophenyl amino acetonitrile, 0.1 gram piperidine, 26.3 gram (0.205 mol) tert-butyl acrylate, The reaction was stirred at 10 to 15°C for 4 hours to obtain a tetrahydrofuran solution of 2-o-fluorophenyl-N,N-di-tert-butoxycarbonylethylaminoacetonitrile (II), which was transferred to a constant pressure dropping funnel for later use.

[0049] b. Prepare cyclopropylmagnesium bromide tetrahydrofuran solution for subsequent use:

[0050] Into a 250ml four-necked flask connected with a stirring, thermometer, and reflux condenser, add 40g of tetrahydrofura...

Embodiment 2

[0053] Example 2: 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Ⅵ) preparation

[0054] According to the steps a-c described in Example 1, a THF solution of 1-cyclopropyl-2-o-fluorophenyl-N,N-di-tert-butoxycarbonylethylaminoethanone (III) was prepared; the difference was:

[0055] d. Add a solution of 1-cyclopropyl-2-o-fluorophenyl-N,N-di-tert-butoxycarbonylethylaminoethanone (Ⅲ) dropwise to 12.0 grams of potassium tert-butoxide and 50 grams of dry In a 500 ml four-necked flask of tetrahydrofuran (the flask is connected with stirring, a thermometer and a dropping funnel), the dropwise addition process is kept between -10 and -5°C, and the drop is completed in about 4 hours. After that, stir at 0°C for 3 hours to obtain Ⅳ; Thereafter, 14.5 grams (0.12 moles) of ethyl 2-chloroacetate was added dropwise between 5 and 10°C for about 1 hour, after which, after stirring at 25°C for 6 hours, 20 grams of 20% ammonium chloride aqueous solu...

Embodiment 3

[0056] Embodiment 3: the preparation of prasugrel (Ⅰ)

[0057] In the 250 milliliter four-neck flasks that are connected with stirring, thermometer and airway tube, add 80 grams of acetone, 18.6 grams (0.05 moles) of 2-acetoxy group-5-(alpha-cyclopropylcarbonyl-2- Fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Ⅵ), cooled, 4.5 g of dry hydrogen chloride gas was introduced between -5 and 0°C, and then stirred at 0°C React for 2 hours, filter, wash the filter cake with 10 g of cold acetone, and dry to obtain 18.9 g of white solid prasugrel (I), with a melting point of 194-196° C., a yield of 92.2%, and an HPLC purity of 99.8%.

[0058] The product analysis data is as follows:

[0059] LC-MS liquid mass spectrum (positive ion) m / z: 410 (M+1).

[0060] 1 HNMR (frequency 400MHz, solvent deuterated dimethyl sulfoxide): 0.84-0.88 (multiplet, 2H), 1.1 (multiplet, 2H), 2.23 (singlet, 3H), 2.72-2.75 (multiplet, 1H), 2.87-2.9 (multiplet, 1H), 2.96-3.0 (multiplet, 2H), 3.1-3.15...

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Abstract

The invention relates to a low-cost environment-friendly preparation method of prasugrel. The method comprises the following steps: carrying out N,N-disubstitution reaction on the initial raw material 2-o-fluorophenylaminoacetonitrile and tert-butyl acrylate, carrying out Grignard reaction to obtain 1-cyclopropyl-2-o-fluorophenyl-N,N-2-(di-tert-butoxycarbonyl)ethylaminoethyl ketone (III), carrying out intramolecular condensation to obtain N-alpha-cyclopropylcarbonyl-1-o-fluorobenzyl-3-tert-butoxycarbonylpiperidyl-4-one (IV), carrying out SN2 substitution to obtain N-alpha-cyclopropylcarbonyl-1-o-fluorobenzyl-3-(2-alkoxycarbonyl)ethylpiperidyl-4-one (V), reacting with zinc sulfide-acetic acid and acetic anhydride-triethylamine to obtain 2-acetoxy-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-thiophano[3,2-c]pyridine (VI), and salifying (VI) to obtain the prasugrel. The method has the advantages of cheap and accessible raw materials, safe technique and environmental protection, and is simple to operate.

Description

technical field [0001] The invention relates to an environment-friendly preparation method of low-cost prasugrel, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Prasugrel (Ⅰ, Prasugrel), the chemical name is 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2 -c] Pyridine hydrochloride, CAS number: [150322-43-3], is an oral antithrombotic drug jointly developed by Japan's Daiichi Sankyo and Eli Lilly and Company, used to prevent Atherosclerotic thrombosis in patients with acute coronary syndrome after delayed percutaneous coronary intervention, approved by the US FDA in July 2009, for the treatment of atherosclerosis and acute coronary syndrome. Prasugrel is an inactive prodrug that can irreversibly inhibit the P2Y12 adenosine diphosphate receptor on platelets after being metabolized by the cytochrome P450 enzyme system into an active metabolite. Compared with clopidogrel, prasugrel has a higher ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 戚聿新朱成臣李艳平鞠立柱李新发
Owner XINFA PHARMA