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Preparation method of 4AA diastereoisomer

A technology of epimerization and compound, applied in the field of preparation of 4AA diastereoisomers, can solve the problems of difficult preparation and purification, poor selectivity, inability to synthesize 4AA diastereoisomers in a targeted manner, and achieve simple purification Effect

Pending Publication Date: 2022-07-01
WUHAN ZY PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The technical problem to be solved by the present invention is that the prior art cannot directionally synthesize specific 4AA diastereoisomers, the selectivity is poor and subsequent preparation and purification are difficult. Therefore, the present invention provides a preparation of 4AA diastereoisomers Method, the preparation method can efficiently synthesize 4AA diastereoisomers and the subsequent steps are simple to purify

Method used

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  • Preparation method of 4AA diastereoisomer
  • Preparation method of 4AA diastereoisomer
  • Preparation method of 4AA diastereoisomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Synthesis of Example 1 Compound A4

[0060]

[0061] 300 g of tetrahydrofuran, 28.7 g of 4AA and 15 g of triethylamine were added to a 500 mL three-necked flask at 20°C. The system was cooled to 0-10°C, 30 g of trimethylchlorosilane was added dropwise, the dropping was completed, the temperature of the system was raised to 40°C, and the reaction was continued for 2 hours. After TLC showed that the raw material 4AA was completely consumed, the system was cooled to 20° C. and concentrated to remove tetrahydrofuran to obtain crude A4, which was purified by column chromatography once to obtain 21.8 g of pure A4 with a yield of 60.5% and a purity of 97.9%.

Embodiment 2

[0062] Embodiment 2 is as the synthesis of compound shown in formula I

[0063]

[0064] 200 g of anhydrous tetrahydrofuran (water 0.01% or less) and 10 g of compound A4 were added to a 500 mL three-neck flask at 20°C. The system was cooled to -78 °C, and 50 mL of lithium hexamethyldisilazide (LiHMDS) (2M, n-hexane) was added dropwise. After the dropwise addition was completed, the system was heated to 20 °C within 2 hours and kept at the temperature for 1 hour. The mixed solution of the compound shown in II was detected by HPLC, and the reaction system was quenched into 100 g of ice water (containing 5.0 g of acetic acid). The system was concentrated under reduced pressure, and 100 g of ethyl acetate and 50 g of ice water were added to the concentrated residue to separate the layers; the lower aqueous phase was extracted once with 20 g of ethyl acetate, and the organic phases were combined and washed once with 50 g of saturated aqueous sodium bicarbonate solution. The org...

Embodiment 3

[0072] Embodiment 3 is as the synthesis of compound shown in formula I

[0073]

[0074] 200 g of anhydrous n-hexane (water content of 0.01% or less) and 11.2 g of compound A4 were added to a 500 mL three-necked flask at 20°C. The system was cooled to -78°C, and 50 mL of lithium diisopropylamide (LDA) (2M, n-hexane) was added dropwise. The dropwise addition was completed. The mixed solution of the indicated compounds was detected by HPLC. The reaction system was quenched into 100 g of ice water and stirred at 20° C. for 1 h (containing 5.0 g of acetic acid). The system was concentrated under reduced pressure, and 100 g of ethyl acetate and 50 g of ice water were added to the concentrated residue to separate the layers; the lower aqueous phase was extracted once with 20 g of ethyl acetate, and the organic phases were combined and washed once with 50 g of saturated aqueous sodium bicarbonate solution. The organic phase was concentrated and dried to obtain a crude product, wh...

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Abstract

The invention discloses a preparation method of a 4AA diastereoisomer. Comprising the following steps: in a solvent, carrying out epimerization reaction on a compound A4 under the action of organic alkali to obtain the compound as shown in the formula II, the compound as shown in the formula II can be further subjected to deprotection reaction in a mixed solution of ice water and acetic acid, and the 4AA diastereoisomer as shown in the formula I is obtained. According to the preparation method, the target product can be directionally synthesized, the subsequent step purification is simple, and the 4AA diastereoisomer can be obtained with better yield and purity.

Description

technical field [0001] The present invention relates to a preparation method of 4AA diastereomer. Background technique [0002] The chemical name of 4AA is (3R,4R)-4-acetoxy-3-[(R)-(tert-butyldimethylsilyl)oxy]-2-azetidinone, which is a synthetic penem and carbon The key starting material of penem antibiotic parent ring, mainly used for the synthesis of various penem antibiotics, such as imipenem, biapenem, meropenem and faropenem, etc. [0003] [0004] 4AA has three chiral centers and one β-lactam ring, which is difficult to synthesize, and a variety of diastereomers will be produced during the synthesis process. isomer. The analysis of 4AA diastereomers and the study of their preparation methods play an important role in improving the yield and purity of 4AA preparation, and play a vital role in the quality control of the synthesized 4AA products. SUMMARY OF THE INVENTION [0005] The technical problem to be solved by the present invention is that the prior art ca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
CPCC07F7/1804C07F7/1892C07B2200/07
Inventor 申理滔涂志波朱婷婷顾利民王朝东
Owner WUHAN ZY PHARM CO LTD
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