A kind of synthetic method of continuous flow preparation olmesartan medoxomil intermediate

A technology for olmesartan medoxomil and a synthesis method, which is applied in the field of drug synthesis, can solve the problems of long reaction time, limited production capacity, and no controlled impurities, and achieves the effects of short reaction time, high purity and good quality.

Active Publication Date: 2022-04-22
拓信达(启东)医药生物科技有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] However, the control level of impurity A and impurity B in the examples is still 1.5%, and the synthesized olmesartan medoxomil cannot meet the requirements of raw materials, and there is no control of impurity C
And the amount of solvent used is large, the reaction time is long, generally 30 minutes to 48 hours, the production capacity is limited, and it is difficult to meet the demand for olmesartan medoxomil intermediates

Method used

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  • A kind of synthetic method of continuous flow preparation olmesartan medoxomil intermediate
  • A kind of synthetic method of continuous flow preparation olmesartan medoxomil intermediate
  • A kind of synthetic method of continuous flow preparation olmesartan medoxomil intermediate

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Embodiment 1

[0037] Step 1, the preparation of formula II compound 4-(1-hydroxyl-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester, 190g2-propyl-imidazole-4,5-dicarboxylate Acid diethyl ester (compound of formula I) was dissolved in a mixed solution of 338.2 g of tetrahydrofuran and 1316.3 g of toluene, stirred and dissolved into phase A, and the relative concentration was 0.1 g / mL. The commercially available methylmagnesium chloride tetrahydrofuran solution (3M) was used as phase B with a density of 1.04g / mL; the temperature of the reactor was set at 15°C, the flow rate of phase A was set at 10mL / min, and the flow rate of phase B was set at 1.13mL / min. Pump phase A and phase B into the mixer and then enter the reactor, retention time T Res =1.3min; set 10% hydrochloric acid aqueous solution as item C, and pump it into the quenching module at a feed rate of 5.52mL / min. The reaction liquid directly enters the continuous oil-water separator for continuous liquid separation, and...

Embodiment 2

[0042] Step 1, the preparation of formula II compound 4-(1-hydroxyl-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester, 950g2-propyl-imidazole-4,5-dicarboxylate Acid diethyl ester (compound of formula I) was dissolved in 1.69kg of 2-methyltetrahydrofuran and 6.58kg of toluene mixed solution, stirred and dissolved into phase A, and the relative concentration was 0.1g / mL. The commercially available methylmagnesium chloride tetrahydrofuran solution (3M) was used as phase B with a density of 1.04g / mL; the temperature of the reactor was set at 15°C, the flow rate of phase A was set at 50mL / min, and the flow rate of phase B was set at 5.65mL / min. Pump phase A and phase B into the mixer and then enter the reactor, retention time T Res =1.3min; set 10% hydrochloric acid aqueous solution as item C, and pump it into the quenching module at a feed rate of 27.6mL / min. The reaction liquid directly entered the continuous oil-water separator for continuous liquid separation, and...

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Abstract

The invention discloses a continuous flow method for preparing an intermediate of olmesartan medoxomil, which belongs to the technical field of pharmaceutical synthesis and comprises the following steps: step (1), compounding formula I compound 2-propyl-4,5-imidazole dicarboxylic acid Ethyl ester I is dissolved in organic solvent to form reaction phase A, step (2), the methylmagnesium chloride solution of commercialization purchase is used as reaction phase B, step (3), reaction phase A and reaction phase B are used plunger pump to Pump it into the mixer at a certain flow rate, then enter the reactor, keep it for a certain period of time, quench it with the acidic water phase C, and enter the oil-water continuous separator for liquid separation, that is, the organic solution of the compound formula II is obtained. The compound of formula II can be obtained by recrystallization, which solves the technical problems of low purity and high cost in the existing production process. The product of the present invention has high purity and few impurities, and the content of key impurity A, key impurity B and key impurity C can be controlled at 0.1 % or less, and the raw materials are cheap and easy to obtain, the reaction conditions are mild, the operation is simple, the synthesis efficiency is high, and it is suitable for industrial production. It provides a new continuous flow route for the preparation of olmesartan medoxomil and intermediates.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, in particular to the synthesis of olmesartan medoxomil intermediate 4-(1-hydroxyl-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester prepared by continuous flow method. Background technique [0002] Olmesartan medoxomil (formula III) is a novel angiotensin B receptor (AT1) inhibitor (ARB) jointly developed by Japan's Sankyo (Daiichi Sankyo) and U.S. Forest Laboratories. The English name is: Olmesartan Medoxomil , in May 2002, was approved by the US FDA for marketing, and the trade name was Benicar. In August 2002, it was approved to go on the market in Germany. It was approved for registration in China in 2013, and the product name is Aotan. In 2020, it will enter the second batch of national centralized procurement catalogues. [0003] [0004] Olmesartan medoxomil has unique pharmacokinetic and pharmacodynamic properties compared with other ARBs. Olmesartan m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/90
CPCC07D233/90
Inventor 皮红军姚彤吴江周威毛联岗吴晓发沈南星朱文涛
Owner 拓信达(启东)医药生物科技有限公司
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