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Preparation method for intermediate compound of iclaprim

A technology for intermediates and compounds, applied in the field of preparation of intermediate compounds, can solve problems such as expensive reagents

Active Publication Date: 2019-11-26
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is to overcome the deficiency of using expensive reagents in the existing method for preparing the key intermediate of Elaprime, and to provide a method that is different from the prior art and does not use heptahydrate chlorination The simple, economical and industrialized large-scale production of cerium and the preparation method of eraprine intermediate 2

Method used

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  • Preparation method for intermediate compound of iclaprim
  • Preparation method for intermediate compound of iclaprim
  • Preparation method for intermediate compound of iclaprim

Examples

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preparation example Construction

[0039] The present invention provides a kind of preparation method of the intermediate 2 of Elapulene as shown below, it comprises the following steps:

[0040]

[0041] In an organic solvent, in the presence of acetic acid and sodium borohydride, intermediate 3 (i.e. 1-cyclopropyl-3-(trimethylsilyl) propyl-2-yn-1-one) and sodium borohydride A reduction reaction affords intermediate 2 (ie, 1-cyclopropyl-3-(trimethylsilyl)propyl-2-yn-1-ol).

[0042] In another preferred example, the preparation method includes the steps of:

[0043] (1) After intermediate 3 and acetic acid are dissolved in the organic solvent, sodium borohydride is added to obtain a reaction mixture;

[0044] (2) The reaction mixture obtained in step (1) is reacted at 0-50° C., and the intermediate 2 is obtained after the reaction is completed.

[0045] In another preferred example, step (2) further includes a post-processing step for the reaction mixture after the reaction, and the post-processing step is...

Embodiment 1

[0069] Example 1 Preparation of 1-cyclopropyl-3-(trimethylsilyl)propyl-2-yn-1-ol (intermediate 2)

[0070] Add 50.0 g (0.30 mol) of intermediate 3, 36.0 g of acetic acid (0.60 mol), and 500 ml of tetrahydrofuran into a 1000 ml four-necked flask, and add 11.35 g of sodium borohydride (0.30 mol) in portions under stirring. After reacting at 20° C. for 4 h, TLC (petroleum ether:ethyl acetate=20:1) showed that no raw material remained. Pour the reaction solution into 180ml of 2mol / L hydrochloric acid and dilute with 400ml of ice water. Extracted three times with 1000ml petroleum ether, washed the organic phase twice with 200ml ice water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 47.8g of yellow oil, and after vacuum distillation, 41.6g of colorless liquid was obtained (boiling point: 76-79°C , 5mmHg), the yield is 82.3%, and the purity is higher than 98%.

Embodiment 2

[0071] Example 2 Preparation of 1-cyclopropyl-3-(trimethylsilyl)propyl-2-yn-1-ol (intermediate 2)

[0072] Add 50.0 g (0.30 mol) of intermediate 3, 36.0 g of acetic acid (0.60 mol), and 500 ml of methanol into a 1000 ml four-necked flask, and add 11.35 g of sodium borohydride (0.30 mol) in portions under stirring. After reacting at 20° C. for 4 h, TLC (petroleum ether:ethyl acetate=20:1) showed that no raw material remained. Pour the reaction solution into 180ml of 2mol / L hydrochloric acid and dilute with 400ml of ice water. Extracted three times with 1000ml of petroleum ether, washed the organic phase twice with 200ml of ice water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 47.1g of yellow oil, and after vacuum distillation, 35.7g of colorless liquid was obtained (boiling point: 76-79°C , 5mmHg), the yield is 70.6%, and the purity is higher than 98%.

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Abstract

The invention provides a preparation method for an intermediate compound of iclaprim. Specifically, the invention provides a method of reducing 1-cyclopropyl-3-(trimethylsilyl)propyl-2-yn-1-one into 1-cyclopropyl-3-(trimethylsilyl)propyl-2-yn-1-ol in the presence of acetic acid. The method provided by the invention uses the acetic acid which is less expensive, thereby significantly reducing costs.

Description

technical field [0001] The present invention relates to the field of medicine production, in particular to a preparation method of an intermediate compound of Elaprime. Background technique [0002] Ilaprim (English name: iclaprim), the chemical name is 5-[(2RS)-2-cyclopropyl-7,8-dimethoxy-2H-benzopyran-5-methyl]pyrimidine- 1,4-diamine, as shown in structural formula 1, is a dihydrofolate reductase inhibitor developed by MotifBio, and is expected to be submitted in the United States in the second quarter of 2018 for the treatment of acute bacterial skin and skin tissue infections (ABSSSI) New Drug Application. [0003] [0004] Intermediate 2 is an important intermediate in the preparation process of Elaprime. At present, the method for preparing intermediate 2 in the literature is as follows: [0005] Literature method: (Reference: WO / 1997020839) [0006] [0007] In this method, compound 3 (i.e. intermediate 3) uses cerium chloride heptahydrate as a Lewis acid, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/08
Inventor 和波周伟澄林快乐刘潍源
Owner SHANGHAI INST OF PHARMA IND CO LTD
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