4AA intermediate refining method

A refining method and intermediate technology, applied in the field of chemical drug refining process, can solve the problems of increasing the amount of post-treatment reagents, increasing the consumption of raw materials, reducing the conversion rate, etc., and achieve the effects of avoiding side reactions, reducing the amount, and increasing the yield

Inactive Publication Date: 2019-07-05
JIANGXI FUSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when compound III is prepared by the method reported in the literature, there are many impurities in the crude compound III obtained. If this part of impurities is not removed, it will have a negative impact on the quality of the final product 4AA, and it will compete with the main reaction. Side reactions will increase the consumption of raw materials and reduce the conversion rate; in the prior art, it is necessary to destroy these impurities through the last step of ozonation reaction, which will greatly increase the amount of post-treatment reagents, and it needs to be purified by refining means. Make 4AA product quality qualified

Method used

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Examples

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Effect test

Embodiment 1

[0045] Add (52.7g, 0.20mol) (2R,3R)-N-(4-methoxyphenyl)-N-(2-oxopropyl)-2,3-epoxybutanamide to a 500ml four-necked bottle , 250g of dichloromethane and (89g, 0.88mol) of diisopropylamine, cooled to -30°C, slowly added dropwise (41.6g, 0.22mol) of titanium tetrachloride, the dropwise addition was completed, and kept for 0.5h. The reaction solution was dropped into dilute hydrochloric acid, stirred and allowed to stand for liquid separation, and the aqueous layer was extracted with 400 g of dichloromethane. The organic layers were combined, and the organic layer was washed with saturated sodium bicarbonate until neutral, and dichloromethane was evaporated from the organic phase under reduced pressure. Add 100 mL of diethyl ether and 100 mL of petroleum ether to 60 g of the concentrate (purity is about 80%), raise the temperature to 40° C., and stand to separate layers. This operation was repeated three times, the supernatants were combined, and crystallized at 0°C for 1 h, filt...

Embodiment 2

[0050] Add (52.7g, 0.20mol) (2R,3R)-N-(4-methoxyphenyl)-N-(2-oxopropyl)-2,3-epoxybutanamide to a 500ml four-necked bottle , 250g of dichloromethane and (89g, 0.88mol) of diisopropylamine, cooled to -30°C, slowly added dropwise (41.6g, 0.22mol) of titanium tetrachloride, the dropwise addition was completed, and kept for 0.5h. The reaction solution was dropped into dilute hydrochloric acid, stirred and allowed to stand for liquid separation, and the aqueous layer was extracted with 400 g of dichloromethane. The organic layers were combined, and the organic layer was washed with saturated sodium bicarbonate until neutral, and dichloromethane was evaporated from the organic phase under reduced pressure. Add 100 mL of diethyl ether and 100 mL of petroleum ether to 60 g of the concentrate (purity is about 80%), raise the temperature to 40° C., and stand to separate layers. This operation was repeated three times, the supernatants were combined, and crystallized at 5°C for 1 h, filt...

Embodiment 3

[0052] Add (52.7g, 0.20mol) (2R,3R)-N-(4-methoxyphenyl)-N-(2-oxopropyl)-2,3-epoxybutanamide to a 500ml four-necked bottle , 250g of dichloromethane and (89g, 0.88mol) of diisopropylamine, cooled to -30°C, slowly added dropwise (41.6g, 0.22mol) of titanium tetrachloride, the dropwise addition was completed, and kept for 0.5h. The reaction solution was dropped into dilute hydrochloric acid, stirred and allowed to stand for liquid separation, and the aqueous layer was extracted with 400 g of dichloromethane. The organic layers were combined, and the organic layer was washed with saturated sodium bicarbonate until neutral, and dichloromethane was evaporated from the organic phase under reduced pressure. Add 100 mL of diethyl ether and 100 mL of petroleum ether to 60 g of the concentrate (purity is about 80%), raise the temperature to 40° C., and stand to separate layers. This operation was repeated three times, the supernatants were combined, and crystallized at 10°C for 1 h, fil...

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Abstract

The invention discloses a 4AA intermediate refining method. According to the refining method, a 4AA intermediate (III) to be refined is added into a mixed solvent system composed of a solvent A and asolvent , after the 4AA intermediate is dissolved, the solution is extracted, layering is performed, the phase containing the 4AA intermediate (III) is crystallized to obtain the refined 4AA intermediate (III). The provided refining method can remove organic impurities in the 4AA intermediate (III) namely (3S,4S)-1-(4-methoxylphenyl)-3-[((R)-1-hydroxylethyl)]-4-acetyl-2-azetidinone; the refining yield is high, the purity is high, the influence of impurities on subsequent reactions is eliminated, the using amount of organic reagents in subsequent reactions is reduced, and the 4AA product quality is improved.

Description

technical field [0001] The invention belongs to the field of chemical drug refining technology, and specifically provides a method for refining a 4AA intermediate. Background technique [0002] Penem antibiotics are currently a highly effective antibiotic product. Compared with macrocyclic drugs such as cephalosporins, it has the advantages of safer medication and wider application, and has relatively large advantages in process technology and cost control. 4AA (that is, 4-acetoxyazetidinone) is a key intermediate in the synthesis of new high-efficiency antibacterial drugs carbapenems and penems, and can be used to synthesize imipenem, meropenem, and ertapenem , doripenem and faropenem, etc. At present, industrial production generally adopts a production method using L-threonine as a starting material, which has the characteristics of mild reaction conditions, readily available raw materials, and high stereoselectivity. [0003] 4-Acetoxyazetidinone (4-acetoxyazetidin-2-o...

Claims

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Application Information

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IPC IPC(8): C07D205/08
CPCC07D205/08C07B2200/07
Inventor 谢永居刘文中周强周芳张惠芝
Owner JIANGXI FUSHINE PHARMA CO LTD
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