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Preparation method of lisinopril

A technology for preparing steps and proline, which is applied in the field of medicine and can solve the problems of poor impurity removal effect and the like

Pending Publication Date: 2019-06-07
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The applicant found in the previous research (CN108948136A) that an unknown impurity is easily produced under normal process conditions in the lisinopril DCC synthesis process, and its content can even reach about 0.20% in some abnormal batches of finished products, and The impurity removal effect in the crystallization process of the crude product and the finished product is very poor, resulting in the content of the impurity in the final lisinopril product will exceed the 0.10% impurity limit

Method used

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  • Preparation method of lisinopril
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  • Preparation method of lisinopril

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054]Add 5.2g of L-proline and 16.5mL of 25% tetramethylammonium hydroxide aqueous solution to the reaction flask, stir for 10 minutes, heat up to 50-60°C and distill to dryness under reduced pressure, then add 100mL of tetrahydrofuran, and stir for 10 minutes Afterwards, it is used as an L-proline ammonium salt solution for subsequent use; 16g of lisinopril hydride is added to the reaction flask, followed by 100mL of tetrahydrofuran, and then 4.8g of N-hydroxysuccinimide is added, stirred until the solid is completely dissolved; cooled to 0~5°C, slowly add 8.5g of DCC (dicyclohexylcarbodiimide) under stirring, then slowly add the above-mentioned L-proline ammonium salt solution dropwise at 0~5°C, and then slowly raise the temperature to 25~ Stir and react at 35°C for 7 hours, then cool to 0-5°C, filter, heat the filtrate to 25-40°C and distill to dryness under reduced pressure, after cooling to room temperature, adjust the pH value of the solution to 4-5 with 6mol / L hydrochlo...

Embodiment 2

[0056] Add 5.2g of L-proline and 16.5mL of 25% tetramethylammonium hydroxide aqueous solution to the reaction flask, stir for 10 minutes, heat up to 50-60°C and distill to dryness under reduced pressure, then add 100mL of tetrahydrofuran, and stir for 10 minutes Afterwards, it is used as an L-proline ammonium salt solution for subsequent use; 16g of lisinopril hydride is added to the reaction flask, followed by 100mL of tetrahydrofuran, and then 4.8g of N-hydroxysuccinimide is added, stirred until the solid is completely dissolved; cooled to 0~5°C, slowly add 8.5g of DCC (dicyclohexylcarbodiimide) under stirring, then slowly add the above-mentioned L-proline ammonium salt solution dropwise at 0~5°C, and then slowly raise the temperature to 25~ Stir and react at 35°C for 7 hours, then cool to 0-5°C, filter, dilute the filtrate with 50mL water, then heat up to 25-40°C to distill THF under reduced pressure, cool to room temperature, and adjust the solution with 6mol / L hydrochloric...

Embodiment 3

[0062] Add 26g of L-proline and 82.5mL of 25% tetramethylammonium hydroxide aqueous solution to the reaction flask, stir for 10 minutes, heat up to 50-60°C and distill to dryness under reduced pressure, then add 600mL of tetrahydrofuran, and stir for 10 minutes Use as L-proline ammonium salt solution for later use; add 80g lisinopril hydride to the reaction flask, then add 500mL tetrahydrofuran, then add 25g N-hydroxysuccinimide, stir until the solid is completely dissolved; cool to 0~ 5°C, slowly add 43g of DCC (dicyclohexylcarbodiimide) under stirring, then slowly add the above-mentioned L-proline ammonium salt solution dropwise at a temperature of 0-5°C, and then slowly raise the temperature to 25-35°C, Stir and react for 8 hours, then cool to 0-5°C, filter, heat the filtrate to 25-40°C to distill tetrahydrofuran under reduced pressure, cool to room temperature, adjust the pH value of the solution to 4-5 with 6mol / L sulfuric acid solution, and use 900mL Dichloromethane extr...

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Abstract

The invention provides a preparation method of lisinopril. pH is regulated to an appropriate range, and a lisinopril product and impurities are effectively separated, so that the content of the lisinopril impurities N<6>-(3-carboxyl propionyl) in the prepared lisinopril can be equal to lower than 0.02%.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of lisinopril. Background technique [0002] Lisinopril (Lisinopril), is the third-generation angiotensinase inhibitor (ACEI) developed by Merck, its chemical name is N-[N-[(S)-1-carboxy-3-phenylpropanol Base]-L-lysyl]-L-proline, its structural formula is as follows: [0003] [0004] The lisinopril synthetic technique that CN 95111698 reports is to use DCC and succinimide (NHS) as activator, the carboxyl of lisinopril hydride is formed activated ester, then with tetramethyl ammonium hydroxide L- Condensation of proline compound salt, the obtained condensate is added to NaOH solution to remove trifluoroacetyl and ethyl carboxyl protecting groups to obtain crude lisinopril, which has mild reaction conditions, simple operation, and chirality of products and intermediates The center is not easy to deflect, and the impurities are less and relatively removed...

Claims

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Application Information

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IPC IPC(8): C07K5/068C07K1/30
Inventor 林金生郑扬王安宇王吉超胡佳兴方玉玲朱文泉陈文斌李敏
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD