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Asymmetric synthesis method for preparing (2S, 3R)-p-methylsulfonyl phenyl serine ethyl ester

A technology of methylsulfonyl phenylserine ethyl ester and synthesis method, which is applied in the field of asymmetric synthesis of preparation-p-methylsulfonyl phenylserine ethyl ester, can solve the problems of complex process, low yield, many steps and the like, and achieves the process route The effect of brief, high product yield, and high optical purity

Active Publication Date: 2022-02-08
SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Some of these asymmetric synthesis processes have relatively expensive raw material costs, some have complex processes, many steps, low yields, and some have low d.r. values ​​or e.e. values.

Method used

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  • Asymmetric synthesis method for preparing (2S, 3R)-p-methylsulfonyl phenyl serine ethyl ester
  • Asymmetric synthesis method for preparing (2S, 3R)-p-methylsulfonyl phenyl serine ethyl ester
  • Asymmetric synthesis method for preparing (2S, 3R)-p-methylsulfonyl phenyl serine ethyl ester

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preparation example Construction

[0030] Such as figure 2 As shown, during specific implementation, the asymmetric synthesis method for preparing (2S, 3R)-p-thymphenylphenylserine ethyl ester of the present invention comprises the following steps:

[0031] The first step is to asymmetrically reduce the ketone carbonyl of the latent chiral ketone carbonyl compound with a chiral reagent, and the obtained reaction product is (3R)-p-thymphenylphenylserine ethyl ester; the chiral reagent is (-)-diiso Pine camphenyl boron chloride, the latent chiral ketone carbonyl compound is ethyl 2-amino-3-[4-(methylsulfonyl)phenyl]-3-oxopropionate; wherein, (-)- The molar ratio of diisopine camphenyl boron chloride to ethyl 2-amino-3-[4-(thymphenyl)phenyl]-3-oxopropionate is 1.1~3:1. Note: The structural formula of (-)-diisopine camphenyl boron chloride is as follows:

[0032]

[0033] The specific process is: under the protection of an inert gas, dissolve (-)-diisopine camphenyl boron chloride in an appropriate amount of ...

Embodiment 1

[0039] A. Synthesis of (3R)-p-thymphenylphenylserine ethyl ester

[0040] Under nitrogen protection, the (Ipc) 2 Add 6.4g (20mmol) of BCl and 20ml of anhydrous THF into the reaction flask, and cool to 0°C. Dissolve 3.8g (13.3mmol) of ethyl 2-amino-3-[4-(methylsulfonyl)phenyl]-3-oxopropanoate in 10ml of anhydrous THF, slowly drop into the reaction flask, and control the temperature At 0°C~5°C. Stir for 24 hours. Slowly add ice water, stir for half an hour and then rise to room temperature, and continue stirring for 1 hour. Dichloromethane was added for extraction, and the organic phase was spin-dried to obtain a light yellow solid, namely (3R)-ethyl p-thymphenylphenylserine, with a yield of 82%.

[0041] B. Synthesis of (2S,3R)-p-thymphenylphenylserine ethyl ester

[0042] Add 5.75g (20mmol) of compound (3R)-p-thymphenylphenylserine ethyl ester and 20g of ethanol into the reaction flask, add 0.17g (1mmol) of 5-nitrosalicylaldehyde as a catalyst, and heat to 60°C for 30 Mi...

Embodiment 2

[0044] A. Synthesis of (3R)-p-thymphenylphenylserine ethyl ester

[0045] Under nitrogen protection, the (Ipc) 2 Add 9.6g (30mmol) of BCl and 20ml of anhydrous THF into the reaction flask, and cool to 0°C. Dissolve 3.8g (13.3mmol) of ethyl 2-amino-3-[4-(methylsulfonyl)phenyl]-3-oxopropanoate in 10ml of anhydrous THF, slowly drop into the reaction flask, and control the temperature At 0°C~5°C. Stir for 24 hours. Slowly add ice water, stir for half an hour and then rise to room temperature, and continue stirring for 2 hours. Dichloromethane was added for extraction, and the organic phase was spin-dried to obtain a light yellow solid, namely (3R)-ethyl p-thymphenylphenylserine, with a yield of 84%.

[0046] B. Synthesis of (2S,3R)-p-thymphenylphenylserine ethyl ester

[0047] Add 5.75g (20mmol) of compound (3R)-p-thymphenylphenylserine ethyl ester and 30g of ethanol to the reaction flask, add 0.12g (0.72mmol) of 5-nitrosalicylaldehyde as a catalyst, and heat to reflux Reacti...

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Abstract

The invention relates to an asymmetric synthesis method for preparing (2S, 3R)-p-methylsulfonyl phenyl serine ethyl ester. (-)-diisocamphene boron chloride (namely (Ipc) 2BCl) as a chiral reagent and 2-amino-3-[4-(methylsulfonyl) phenyl]-3-oxo-ethyl propionate as a prochiral ketone carbonyl compound react to realize asymmetric reduction of keto-carbonyl groups of the 2-amino-3-[4-(methylsulfonyl) phenyl]-3-oxo-ethyl propionate, preparing (3R)-p-methylsulfonyl phenyl serine ethyl ester, and carrying out kinetic resolution to obtain the (2S, 3R)-p-methylsulfonyl phenyl serine ethyl ester. The process route is short, the optical purity of the product is high (e.e. Value is greater than 98%), and the product yield is high.

Description

technical field [0001] The invention relates to an asymmetric synthesis method for preparing (2S,3R)-p-thymphenylphenylserine ethyl ester, which belongs to the technical field of medicinal chemistry. Background technique [0002] As far as the applicant knows, (2S,3R)-p-thymphenylphenylserine ethyl ester is an important intermediate for the synthesis of thiamphenicol and florfenicol; its structural formula is shown in (I): [0003] [0004] At present, the relatively mature domestic production process uses p-thiamphenicol benzaldehyde as the starting material, reacts with copper sulfate and glycine to prepare copper salt, and then undergoes esterification reaction and tartaric acid resolution to obtain the intermediate (2S,3R)-p Thiamyl phenylserine ethyl ester; Its reaction scheme is as follows figure 1 shown. However, this process involves the resolution of the racemate, and the L configuration, which accounts for 50% of the content, needs to be recycled and reused, s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C315/04C07C317/48C07B53/00
CPCC07C315/04C07B53/00C07B2200/07C07C317/48
Inventor 黄忠林赵飞孙思朱家可雍成松
Owner SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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