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New preparation method of intermediate product of barnidipine hydrochloride

A technology of barnidipine hydrochloride and an intermediate, which is applied in the field of preparation of a barnidipine hydrochloride intermediate-N-benzyl-3-acetoethoxy pyrrolidine ester, can solve the problem that diketene has a low boiling point, is not suitable for industrial production, and is not suitable for industrial production. Dangerous issues, etc.

Active Publication Date: 2009-10-14
大道隆达(北京)医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The diketene used in this synthetic route has a low boiling point, is flammable, explosive, and dangerous, and is not suitable for industrial production.

Method used

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  • New preparation method of intermediate product of barnidipine hydrochloride
  • New preparation method of intermediate product of barnidipine hydrochloride
  • New preparation method of intermediate product of barnidipine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] In a 1000ml three-necked flask, add 1 mol of methyl acetoacetate, 1 mol of (S)-N-benzyl-3-hydroxypyrrolidine, add 0.1 mol of catalyst p-toluenesulfonic acid, heat and reflux for 12 hours, stop the reaction, and remove by distillation under reduced pressure. Solvent, add appropriate amount of water and ethyl acetate for extraction, separate and dry to obtain (S)-N-benzyl-3-acetoethoxypyrrolidinate. The product was determined to be 262.1 (M+H) by electrospray ionization mass spectrometry (ESI-MS). + ) (theoretical molecular weight is 261.14), b.p. is 130-135°C / 0.1mmHg (literature is 130-135°C / 0.1mmHg).

Embodiment 2

[0015] In a 1000ml three-neck flask, add 1 mol of methyl acetoacetate, 5 mol of (S)-N-benzyl-3-hydroxypyrrolidine, add 0.1 mol of benzenesulfonic acid as a catalyst, heat to reflux for 24 hours, stop the reaction, and distill off the solvent under reduced pressure , adding an appropriate amount of water and ethyl acetate for extraction, separation, and drying to obtain (S)-N-benzyl-3-acetoethoxypyrrolidinyl ester. The product was measured by electrospray ionization mass spectrometry (ESI-MS) at 262.1 (M+H + ) (theoretical molecular weight is 261.14), b.p. is 130-135°C / 0.1mmHg (literature is 130-135°C / 0.1mmHg).

Embodiment 3

[0017] In a 1000ml three-neck flask, add 3 mol of ethyl acetoacetate, 1 mol of (S)-N-benzyl-3-hydroxypyrrolidine, add 0.1 mol of catalyst p-toluenesulfonic acid, heat and reflux for 6 hours, stop the reaction, and remove by distillation under reduced pressure. Solvent, add appropriate amount of water and ethyl acetate for extraction, separate and dry to obtain (S)-N-benzyl-3-acetoethoxypyrrolidinate. The product was measured by electrospray ionization mass spectrometry (ESI-MS) at 262.1 (M+H + ) (theoretical molecular weight is 261.14), b.p. is 130-135°C / 0.1mmHg (literature is 130-135°C / 0.1mmHg).

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Abstract

The invention relates to a new preparation method of intermediate of (S)-N- benzyl-3-acetyloxethyl pyrrole ester of calcium channel blocker barnidipine hydrochloride. In the preparation method of intermediate of barnidipine hydrochloride, methyl acetoacetate or acetacetic ester is adopted as the substitute of the traditional diacetyl. The reaction is safe, convenient and economical, thus being more suitable for industrial production.

Description

technical field [0001] The invention relates to a pharmaceutical intermediate, especially a preparation method of a barnidipine hydrochloride intermediate (S)-N-benzyl-3-acetoethoxypyrrolidinate. Background technique [0002] (S)-N-Benzyl-3-acetoethoxypyrrolidinate is an important intermediate in the synthesis of barnidipine hydrochloride. The following synthetic route using diketene is disclosed in the document J.Med.Chem., 1986, 29(12), 2504-2511. The diketene used in this synthetic route has a low boiling point, is inflammable and explosive, and is dangerous, so it is not suitable for industrial production. [0003] Contents of the invention [0004] Aiming at the above deficiencies in the background technology, the present invention provides a safe and convenient method for synthesizing the intermediate (S)-N-benzyl-3-acetoethoxypyrrolidinate of barnidipine hydrochloride. [0005] The present invention is synthesized by adopting the following synthetic route: [...

Claims

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Application Information

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IPC IPC(8): C07D207/12
Inventor 周英郭勇王家强郑艳萍
Owner 大道隆达(北京)医药科技发展有限公司
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