Synthesis method of oseltamivir

A synthesis method and technology of oseltamivir are applied in the field of preparation of drug oseltamivir, which can solve the problems of many reaction steps, high cost, low total yield and the like, and achieve the effects of easy recovery and short route.

Inactive Publication Date: 2017-10-31
HANGZHOU NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In order to solve the problems of many reaction steps, low total yield and high cost in the currently known synthetic method of oseltamivir, the present invention provides a synthetic method of oseltamivir, which has the advantages of short route, easy recovery of catalyst, etc. features

Method used

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  • Synthesis method of oseltamivir
  • Synthesis method of oseltamivir
  • Synthesis method of oseltamivir

Examples

Experimental program
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Effect test

Embodiment 1

[0040] (1) Synthesis of Intermediate C:

[0041]

[0042] Add dichloromethane (6ml) in reaction bottle, then add acetamido nitroalkene (260mg, 2 mmol), 3-pentyloxyacetaldehyde (520mg, 4mmol) and chloroacetic acid (76mg, 0.8mmol), finally N,N-Dimethylbenzylaminoprolinol trimethylsilyl ether catalyst (88mg, 0.2mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction system was cooled to 0°C, and 2-diethoxyethylphosphonoacrylate (0.95g, 4mmol) and cesium carbonate (1.60g, 5mmol) were added thereto, and the reaction was stirred at 0°C for 3 hours, and then decompressed Remove the solvent, then add absolute ethanol (8mL), stir at room temperature for 15 minutes, then add p-cresylthiophenol (1.0g, 8mmol) at -15°C, stir the reaction system at room temperature for 48 hours, then wash it with cold 2 equivalents of hydrochloric acid Quenched, the aqueous phase was extracted three times with dichloromethane (10mL), the combined organic phas...

Embodiment 2

[0049] (1) Synthesis of Intermediate C:

[0050] Add dichloromethane (6ml) in the reaction flask, then add acetamidonitroolefin (260mg, 2 mmol), 3-pentyloxyacetaldehyde (520mg, 4mmol) and o-nitrobenzoic acid (134mg, 0.8mmol ), and finally N, N-dimethylbenzylamine prolinol trimethylsilyl ether catalyst (88mg, 0.2mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours. The reaction system was cooled to 0°C, and 2-diethoxyethylphosphonoacrylate (0.95g, 4mmol) and cesium carbonate (1.60g, 5mmol) were added thereto, and the reaction was stirred at 0°C for 3 hours, and then decompressed Remove the solvent, then add absolute ethanol (8mL), stir at room temperature for 15 minutes, then add p-cresylthiophenol (1.0g, 8mmol) at -15°C, stir the reaction system at room temperature for 48 hours, then wash it with cold 2 equivalents of hydrochloric acid Quenching, the aqueous phase was extracted three times with dichloromethane (10mL), the combined organic pha...

Embodiment 3

[0054] (1) Synthesis of Intermediate C:

[0055] Add chloroform (6ml) in reaction bottle, then add acetamido nitroalkene (260mg, 2 mmol), 3-pentyloxyacetaldehyde (520mg, 4mmol) and benzoic acid (98mg, 0.8mmol), finally N,N-Dimethylbenzylaminoprolinol trimethylsilyl ether catalyst (88mg, 0.2mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction system was cooled to 0°C, and 2-diethoxyethyl phosphoacrylate (0.95g, 4mmol) and cesium carbonate (1.60g, 5mmol) were added thereto, and the reaction was stirred at 0°C for 3 hours, and then depressurized Remove the solvent, then add absolute ethanol (8mL), stir at room temperature for 15 minutes, then add p-cresylthiophenol (1.0g, 8mmol) at -15°C, stir the reaction system at room temperature for 48 hours, then wash it with cold 2 equivalents of hydrochloric acid Quenched, the aqueous phase was extracted three times with dichloromethane (10mL), the combined organic phase was washed with 15mL...

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Abstract

The invention belongs to the technical field of organic synthesis, aims at solving the problems that an existing synthesis method of oseltamivir is multiple in reaction steps, low in overall yield and high in cost. The invention provides a synthesis method of oseltamivir. The method comprises the following steps of (1) adopting 3-pentyloxy acetaldehyde and nitroolefin as substrates and reacting under catalysis of a catalyst in the presence of lewis acid to obtain an aldehyde intermediate A; (2) reacting the obtained aldehyde intermediate A with 2-diethoxy oxygen-phosphorus acrylic acid ethyl ester under the action of an alkali catalyst to obtain a cyclohexenyl intermediate B; (3) reacting the cyclohexenyl intermediate B with thiocresol to obtain a cyclohexane intermediate C; (4) preparing a compound D from the cyclohexane intermediate C under the action of zinc powder and trimethylchlorosilane; and (5) obtaining a final product oseltamivir from the intermediate D obtained in the step (4) under the action of an ammonia gas and potassium carbonate. The method has the characteristics that the route is short and the catalyst is easy to recover.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of oseltamivir, a medicine for treating influenza virus. Background technique [0002] Oseltamivir is a specific inhibitor of neuraminidase, which inhibits the action of neuraminidase and can inhibit the mature influenza virus from leaving the host cell, thereby inhibiting the spread of influenza virus in the human body To play a role in the treatment of influenza. The development of such specific drugs and their derivatives has become a global research hotspot. However, the currently known synthetic methods of oseltamivir all have the disadvantages of many reaction steps, low overall yield and high cost. Therefore, developing an efficient and low-cost synthetic method has become a challenge for the chemical community. [0003] In 2010, Ma Dawei's research group reported a Michael / Horner-Wadsworth-Emmons tandem reaction to synthesize ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C233/52
CPCC07B2200/07C07C231/12C07C319/18C07C319/20C07C233/52C07C323/61C07C233/31
Inventor 徐利文袁洋郑战江曹建崔玉明徐征杨科芳蒋剑雄胡炜锋
Owner HANGZHOU NORMAL UNIVERSITY
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