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The preparation method of rivastigmine intermediate (r)-n-ethyl-n-methylcarbamate-3-(1-hydroxyethyl)phenyl ester

A technology of methyl carbamic acid and acetyl phenyl ester, which is applied in the field of preparation of rivastigmine intermediate-N-ethyl-N-methyl carbamic acid-3-phenyl ester, can solve the problem of unfavorable hydrogen source for environmental protection, Achieving high industrial application value, good selectivity, and cost-saving effects due to the problems of large catalyst consumption and high production costs

Active Publication Date: 2016-04-06
浙江瑞博制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In order to solve the above-mentioned prior art, the resolving agent needs to be used in the reaction process, and multiple recrystallizations are required, raw materials are wasted, the product loss is serious, the production cost is high, the catalyst consumption is large, the hydrogen source is not conducive to environmental protection and other technical problems, The invention provides a new method for preparing optically pure rivastigmine intermediate (R)-N-ethyl-N-methylcarbamate-3-(1-hydroxyethyl)phenyl ester, specific scheme as follows:

Method used

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  • The preparation method of rivastigmine intermediate (r)-n-ethyl-n-methylcarbamate-3-(1-hydroxyethyl)phenyl ester
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Embodiment 1

[0024] Embodiment 1: Preparation of (R)-N-ethyl-N-methylcarbamate-3-(1-hydroxyethyl)phenyl ester

[0025] Weigh (1.0mg, 0.001mmol) chiral catalyst (X is 3-methyl) and (224mg, 2.0mmol) potassium tert-butoxide into the reaction inner tube, put the reaction inner tube into the autoclave, and add to the reaction Add 30 mL of ethanol and (22.2 g, 100 mmol) N-ethyl-N-methylcarbamate-3-acetylphenyl ester into the inner tube, replace the gas in the kettle body with hydrogen, keep the hydrogen pressure at 0.2-10 MPa, and put the reaction The kettle was moved into an oil bath at 50°C to stir the reaction. After reacting for 9 hours, the hydrogen pressure no longer drops, and the heating and reaction are stopped. The reaction solution was concentrated. Add 100mL of water and 100mL of ethyl acetate to the system, and separate the layers. The aqueous phase was extracted twice with ethyl acetate (50 mL×2), the organic phases were combined, washed once with saturated brine, and dried over...

Embodiment 2

[0026] Embodiment 2: Preparation of (R)-N-ethyl-N-methylcarbamate-3-(1-hydroxyethyl)phenyl ester

[0027] Weigh (1.0mg, 0.001mmol) chiral catalyst (X is 6-ethyl) and (78mg, 2.0mmol) sodium amide into the reaction inner tube, put the reaction inner tube into the autoclave, and insert the reaction inner tube Add methanol 20mL and (11.1g, 50mmol) N-ethyl-N-methylcarbamate-3-acetylphenyl ester, replace the gas in the kettle body with hydrogen, keep the hydrogen pressure at 0.2-10MPa, and move the reaction kettle into The reaction was stirred in an oil bath at 50°C. After reacting for 8 hours, the hydrogen pressure no longer drops, and the heating and reaction are stopped. The reaction solution was concentrated. Add 80mL of water and 80mL of ethyl acetate to the system, and separate the layers. The aqueous phase was extracted twice with ethyl acetate (50 mL×2), the organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. Suction f...

Embodiment 3

[0028] Embodiment 3: Preparation of (R)-N-ethyl-N-methylcarbamate-3-(1-hydroxyethyl)phenyl ester

[0029] Weigh (1.9mg.0.002mmol) chiral catalyst (X is H) and (68mg, 1.0mmol) sodium ethoxide into the inner tube of the reaction, put the inner tube into the autoclave, and add tetrahydrofuran into the inner tube of the reaction 40mL and N-ethyl-N-methylcarbamate-3-acetylphenyl ester (44.3g, 200mmol), replace the gas in the kettle body with hydrogen, keep the hydrogen pressure at 0.2-10MPa, and move the reaction kettle into a 50°C The reaction was stirred in an oil bath. After 12 hours of reaction, the hydrogen pressure no longer drops, and the heating and reaction are stopped. The reaction solution was concentrated. Add 100mL of water and 100mL of ethyl acetate to the system, and separate the layers. The aqueous phase was extracted twice with ethyl acetate (100 mL×2), and the organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfat...

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Abstract

The invention relates to the field of pharmaceutical synthesis, and in particular relates to a preparation method of a rivastigmine intermediate (R)-N-ethyl-N-methyl carbamic acid-3-(1-hydroxyethyl) phenyl ester. The method employs N-ethyl-N-methyl carbamic acid-3-acetyl phenyl ester as a raw material to prepare a rivastigmine chiral intermediate compound (R)-N-ethyl-N-methyl carbamic acid-3-(1-hydroxyethyl) phenyl ester under the action of a chiral catalyst, alkali and hydrogen. The chiral catalyst is a compound with the following structure. The preparation method of the rivastigmine intermediate provided by the invention can obtain an (R) rivastigmine intermediate with high purity, and the intermediate has ee value greater than 98% through chiral HPLC analysis. The molar ratio of the catalyst only accounts for 1 / 100000-1 / 1000000 of reactant to achieve the required optical purity, and the reactant can be completely converted.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for preparing a rivastigmine intermediate (R)-N-ethyl-N-methylcarbamate-3-(1-hydroxyethyl)phenyl ester. Background technique [0002] Rivastigmine is an acetylcholinesterase inhibitor that can inhibit the activity of central acetylcholinesterase. The carbamate in its structure can bind to the active site of acetylcholinesterase, thereby inhibiting the activity of this enzyme and increasing central cholinergic activity. Nerve activity. It can improve the neuropsychiatric deficit of Alzheimer's disease and improve the symptoms. The trade name is Exelon, which is produced by Novartis Pharmaceuticals of the United States. Its chemical name is (S)-N-ethyl-N-methylcarbamate-3-(1-dimethylaminoethyl)phenyl ester. [0003] Rivastigmine and other phenyl carbamates were first described in European patent EP193926, which describes the synthesis of 3-(1-dimethylaminoethyl)h...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/44C07C269/06C07B53/00
Inventor 严普查章向东李原强车大庆
Owner 浙江瑞博制药有限公司
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