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Preparation method of 2-chlorophenylglycine

A technology of o-chlorophenylglycine and o-chlorobenzaldehyde, which is applied in the field of preparation of clopidogrel drug intermediate o-chlorophenylglycine, can solve the problems of dark color and low product yield, optimize process parameters and avoid side reactions , Improve the effect of atom economy

Pending Publication Date: 2022-07-01
抚顺顺能化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Therefore, there is an urgent need to find a new preparation method of o-chlorophenylglycine, reduce or avoid the occurrence of such side reactions in the process, and fundamentally solve the problem of low product yield and dark color. How to develop a simple The preparation method of o-chlorophenylglycine which is feasible, high in yield, low in cost and suitable for large-scale industrial production is a problem urgently needed by those skilled in the art

Method used

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  • Preparation method of 2-chlorophenylglycine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 1) 35g o-chlorobenzaldehyde, 49.21g ammonium bicarbonate and 13.42g sodium cyanide are added in the there-necked flask of 1000mL, then 185g water and 95g methanol are added, stirring and dissolving, the insulation reaction temperature is 25-30 ℃, the insulation reaction The time is 24h, after the reaction is completed, the pH of the reaction solution is adjusted to 5.5 with 30% dilute sulfuric acid, then the methanol is removed by distillation under reduced pressure, suction filtration, and the filter cake is washed with deionized water, added to 300 g of methanol, and heated to dissolve , the insoluble impurities were filtered out by hot filtration, and then the solvent was distilled off under reduced pressure to obtain an off-white crystalline solid, which was o-chlorodihydantoin, and the HPLC content was 99.59%;

[0037] 2) 200 g of o-chlorodihydantoin was added to the sodium hydroxide solution with a mass percentage of 40%, transferred to an autoclave, stirred and he...

Embodiment 2

[0039] 1) 35g o-chlorobenzaldehyde, 59.05g ammonium bicarbonate and 14.64g sodium cyanide are added in the there-necked flask of 1000mL, then 210g water and 105g ethanol are added, stirring and dissolving, the insulation reaction temperature is 30-35 ℃, insulation reaction The time is 24h, after the reaction is completed, the pH of the reaction solution is adjusted to 6 with 30% dilute sulfuric acid, then the ethanol is removed by distillation under reduced pressure, suction filtration, the filter cake is washed with deionized water, added to ethanol, heated to dissolve, The insoluble impurities are filtered out by hot filtration, and then the solvent is distilled off under reduced pressure to obtain an off-white crystalline solid, which is o-chlorodihydantoin, and the HPLC content is 99.71%.

[0040] 2) 200 g of o-chlorodihydantoin was added to the potassium hydroxide solution with a mass percentage of 40%, transferred into the autoclave, stirred and heated to 135° C. After the ...

Embodiment 3

[0042] 1) 35g o-chlorobenzaldehyde, 68.89g ammonium bicarbonate and 15.86g sodium cyanide are added in the there-necked flask of 1000mL, then 210g water and 140g methanol are added, stirring and dissolving, the insulation reaction temperature is 30-35 ℃, insulation reaction The time is 18h, after the reaction is completed, the pH of the reaction solution is adjusted to 6.5 with 20% hydrochloric acid, then the methanol is removed by distillation under reduced pressure, suction filtration, and the filter cake is washed with deionized water, added to methanol, heated to dissolve, and heated. The insoluble impurities were filtered out, and then the solvent was distilled off under reduced pressure to obtain an off-white crystalline solid, which was o-chlorodihydantoin, and the HPLC content was 99.79%.

[0043] 2) o-chlorodihydantoin was added to 300 g of sodium hydroxide solution with a mass percentage of 30%, transferred to an autoclave, stirred and heated to 140° C. After the hydr...

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Abstract

The invention discloses a preparation method of 2-chlorophenylglycine, which comprises the following steps: mixing o-chlorobenzaldehyde, ammonium bicarbonate and a sodium cyanide aqueous solution, then adding a mixed solvent of water and an alcohol reagent, stirring and dissolving, then carrying out a heat preservation reaction, after the reaction is finished, firstly acidifying, and then carrying out reduced pressure distillation to remove the alcohol solvent, thereby obtaining the 2-chlorophenylglycine. And filtering, washing and recrystallizing to obtain the o-chlorophenylhydantoin. Mixing the obtained o-chlorophenylhydantoin with an alkaline reagent, stirring and heating to perform hydrolysis reaction, cooling to room temperature after the reaction is finished, acidifying, filtering, washing and drying to obtain the o-chlorophenylglycine. On the basis of an original process route, process parameters are optimized, side reactions are reduced, and the overall reaction efficiency is improved. The preparation method is simple and feasible, the yield and chemical purity of the product are relatively high, the whole technological process is green and environment-friendly, the atom economy is high, and large-scale industrial production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and more particularly relates to a preparation method of o-chlorophenylglycine, a medicine intermediate of clopidogrel. Background technique [0002] Clopidogrel was developed by the French company Sanofi in the 1980s. Its chemical structure has a thiophene pyridine ring. This type of compound has a high activity of inhibiting the aggregation of platelets and is an inhibitor of platelet aggregation. It is clinically used to treat and prevent arteriovenous thrombosis such as atherosclerosis, cerebral infarction, myocardial infarction, and acute coronary syndrome. o-Chlorophenylglycine is an important intermediate in the synthesis of clopidogrel, and its quality and production cost directly affect the quality and competitiveness of downstream drugs. [0003] Patent CN101058547A introduces a preparation method of o-chlorophenylglycine, an intermediate of clopidogrel, which takes o-chlor...

Claims

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Application Information

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IPC IPC(8): C07C229/36C07C227/24C07D233/76
CPCC07C227/24C07D233/76C07C229/36
Inventor 周怡胡成楠李昊
Owner 抚顺顺能化工有限公司
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