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Preparation method of faropenem sodium

A technology of faropenem sodium and ethyl, applied in the field of medicinal chemistry, can solve the problems of low yield, many preparation steps, influence on the yield of faropenem sodium, etc., and achieve the effects of high yield and high purity

Pending Publication Date: 2022-04-12
赤峰万泽药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the many reaction substances involved and the complex structure, there will be by-products in the reaction, and the conditions for each step of the reaction are not the same. One-step reaction, intermediates need to be extracted after each step of reaction, and there are many preparation steps. If the generation of by-products and the loss of intermediates cannot be effectively reduced, the final yield of faropenem sodium will be greatly affected.
[0004] The existing method for preparing faropenem sodium has a low product yield, and there is a lot of room for improvement

Method used

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  • Preparation method of faropenem sodium
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  • Preparation method of faropenem sodium

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preparation example Construction

[0027] The invention provides a preparation method of faropenem sodium, comprising the following steps:

[0028] S1. Potassium carbonate, R-(+)-thiotetrahydrofuran-2-carboxylic acid, (3R,4R)-4-acetoxy-3-[(R)-(tert-butyldimethylsilyloxy) Ethyl]azetidin-2-one is mixed, and after the reaction, (3S,4R)-3-[(1R)-(tert-butyldimethylsilyloxy)ethyl]-4-[(2R) -tetrahydrofuroylthio]azetidin-2-one. Among them, the potassium carbonate, R-(+)-thiotetrahydrofuran-2-carboxylic acid, (3R,4R)-4-acetoxy-3-[(R)-(tert-butyldimethylsilyloxy ) ethyl] azetidin-2-one in a molar ratio of 1:1:1.

[0029] For ease of writing and reading, (3R,4R)-4-acetoxy-3-[(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one is denoted as FPS-SS1, R-(+)-thiotetrahydrofuran-2-carboxylic acid is recorded as FPS-SS2, and (3S,4R)-3-[(1R)-(tert-butyldimethylsilyloxy)ethyl Base]-4-[(2R)-tetrahydrofuroylthio]azetidin-2-one is designated as FPS-1.

[0030] specifically,

[0031] Dissolve potassium carbonate in water, add ...

Embodiment 1

[0057] This embodiment provides a preparation method of faropenem sodium, comprising the following steps:

[0058] Synthesis of S1, FPS-1

[0059] Dissolve 1.2 mol of anhydrous potassium carbonate in 287.43 g of purified water, add 1.2 mol of FPS-SS2 dropwise at 10-20°C, after the addition is complete, stir and react for 30-60 minutes to obtain a solution;

[0060] Dissolve 287.43g (1mol) FPS-SS1 in 287.43g acetone to obtain a second solution;

[0061] Slowly add the B solution to the A solution, rinse the container holding the B solution and the instrument for transferring the B solution with 287.43 g of acetone, add it to the above reaction solution, and react at 30-35°C for 4-6 hours;

[0062] After the TLC detection reaction was completed, 287.43g of toluene was added for extraction, and the organic phase was collected;

[0063] The organic phase is backwashed twice with purified water (the purified water used for backwashing is 287.43g each time here), after washing, th...

Embodiment 2

[0089] This embodiment provides a preparation method of faropenem sodium, comprising the following steps:

[0090] Synthesis of S1, FPS-1

[0091] Dissolve 1.2 mol of anhydrous potassium carbonate in 287.43 g of purified water, add 1.2 mol of FPS-SS2 dropwise at 15°C, after the addition is complete, stir and react for 45 minutes to obtain a solution;

[0092] Dissolve 287.43g (1mol) FPS-SS1 in 287.43g acetone to obtain a second solution;

[0093] Slowly add the B solution to the A solution, rinse the container holding the B solution and the instrument for transferring the B solution with 287.43 g of acetone, add it to the above reaction solution, and react at 33°C for 5 hours;

[0094] After the TLC detection reaction was completed, 287.43g of toluene was added for extraction, and the organic phase was collected;

[0095] The organic phase is backwashed twice with purified water (the purified water used for backwashing is 287.43g each time here), after washing, the organic p...

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Abstract

The invention discloses a preparation method of faropenem sodium, which comprises the following steps: mixing potassium carbonate, R-(+)-thiotetrahydrofuran-2-formic acid and (3R, 4R)-4-acetoxyl-3-[(R)-(tert-butyldimethylsiloxy) ethyl] azetidin-2-ketone, and reacting to obtain FPS-1; mixing the FPS-1, triethylamine and oxalyl chloride monoallyl ester, and carrying out a reaction so as to obtain FPS-2; mixing the FPS-2 with triethyl phosphite, and carrying out a reaction so as to obtain FPS-3; mixing the FPS-3 with tetrabutylammonium fluoride, and carrying out a reaction so as to obtain FPS-4; and mixing the FPS-4, triphenylphosphine, sodium isooctoate and tetrakis (triphenylphosphine) palladium, and reacting to obtain the faropenem sodium. According to the preparation method disclosed by the invention, high-purity and high-yield faropenem sodium can be obtained.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of faropenem sodium. Background technique [0002] Faropenem Sodium (Faropenem Sodium), chemical name (5R,6S)-6-[(1R)-hydroxyethyl]-2-[(2R)-tetrahydrofuran-2-yl]-penem-3-carboxylic acid Monosodium salt two times hemihydrate. Faropenem sodium has a stable chemical structure, broad-spectrum antibacterial activity, less drug resistance and less adverse reactions. [0003] When preparing faropenem sodium, generally use (3R,4R)-4-acetoxy-3-[(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2- Ketone (4AA) is used as the starting material, and faropenem sodium is prepared through 5 or more steps. Due to the large number of reaction substances involved and the complex structure, there will be by-products in the reaction, and the conditions for each step of the reaction are not the same. One-step reaction, intermediates need to be extracted after each ...

Claims

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Application Information

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IPC IPC(8): C07D499/893A61P31/00
Inventor 张海立张赞波郭振军
Owner 赤峰万泽药业股份有限公司
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