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Method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity

A methylsulfonyl phenylserine ethyl ester and stereoselectivity technology, which is applied in the field of organic chemistry of small molecule catalysis, can solve the problems of low product yield, low yield, increased cost and the like, and achieves good stereoselectivity and reaction conditions. Gentle, recycling effect

Active Publication Date: 2021-03-12
APELOA PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these two methods all need to use a large amount of resolution reagents after synthesis, and the use of strong acids such as hydrochloric acid, sulfuric acid, etc. will also increase part of the cost, which limits their industrial production and application, and the recycling effect of solvents is also poor.
[0008] Using lipase to chirally resolve DL-threo-p-thiamphenyl phenylserine ethyl ester is also a method to obtain D-p-thiamphenyl phenylserine ethyl ester (Zhejiang Agricultural Science, 2012, 1203, 1197-1200) , although the stereoselectivity of the product is improved, but the yield is still low
At the same time, in order to obtain a good resolution effect, the enzyme needs to be screened, and the most suitable conditions for the enzyme need to be explored, which also increases the difficulty of the enzyme resolution in the synthesis of D-thymphenylphenylserine ethyl ester.
[0009] In summary, there are various deficiencies in the existing synthesis and resolution methods, such as: high requirements for reaction equipment, difficult recovery of chiral resolution reagents, low product yields, etc.

Method used

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  • Method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity
  • Method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity
  • Method for preparing D-p-methylsulfonylphenylserine ethyl ester with high stereoselectivity

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 1000g p-thymphenyl benzaldehyde is added to the reactor containing 10L dichloromethane, and PS-L-proline is added (L-proline load is 0.9mmol / g, 5mol%, in terms of proline) , 1100g N-Boc-glycine ethyl ester and di-n-butyl boron trifluoromethanesulfonate (2978g), after reacting at 25°C for 30 hours, realize the separation of the catalyst and the reaction system by means of suction filtration, and then to the reaction 1L of trifluoroacetic acid was added to the system for 1.5 hours, and then the reaction solvent was removed in vacuo. The obtained crude product was purified by recrystallization. The recrystallization solvent was a mixed solvent of dichloromethane and n-hexane (volume ratio: 1:1), The recrystallization temperature is room temperature, and D(-)-p-MPSE can be obtained with a yield of 45%.

[0036] Purity detection: the optical purity of the product of the present invention is detected by high performance liquid chromatography, and the results are as follows: ...

Embodiment 2

[0039] 1000g p-thymphenicyl benzaldehyde is added in the reactor that fills 10L methylene dichloride, the added PS-L-proline (L-proline load is 0.9mmol / g, 10mol%, calculated as proline ), 1100g N-Boc-glycine ethyl ester and di-n-butyl boron trifluoromethanesulfonate (2978g), after reacting for 30 hours at 25°C, the catalyst was separated from the reaction system by means of suction filtration. 1L trifluoroacetic acid was added to the system for 1.5 hours, and then the reaction solvent was removed in vacuo. The obtained crude product was purified by recrystallization. The recrystallization solvent was a mixed solvent of dichloromethane and n-hexane (volume ratio: 1:1). D(-)-p-MPSE can be obtained with a yield of 56%.

[0040] Purity detection: the optical purity of the product of the present invention is detected by high performance liquid chromatography, and the results are as follows: figure 2 Shown, show that the ee value of obtained product is 59.94%, and the retention ti...

Embodiment 3

[0043]1000g p-thymphenicyl benzaldehyde is added in the reactor that fills 10L methylene dichloride, the added PS-L-proline (L-proline load is 0.9mmol / g, 20mol%, calculated as proline ), 1100g N-Boc-glycine ethyl ester and di-n-butyl boron trifluoromethanesulfonate (2978g), after reacting for 30 hours at 25°C, the catalyst was separated from the reaction system by means of suction filtration. 1L trifluoroacetic acid was added to the system for 1.5 hours, and then the reaction solvent was removed in vacuo. The obtained crude product was purified by recrystallization. The recrystallization solvent was a mixed solvent of dichloromethane and n-hexane (volume ratio: 1:1). D(-)-p-MPSE can be obtained with a yield of 73%.

[0044] Purity detection: the optical purity of the product of the present invention is detected by high performance liquid chromatography, and the results are as follows: image 3 Shown, show that the ee value of obtained product is 71.24%, and the retention time...

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Abstract

The invention discloses a method for preparing D-p-methylsulfonylphenyl serine ethyl ester with high stereoselectivity, which has the advantages of mild reaction conditions, high stereoselectivity andlow corrosivity to production equipment, and belongs to the field of organic reaction catalyzed by small molecules. According to the preparation method provided by the invention, p-methylsulfonylbenzaldehyde and N-Boc glycine ethyl ester are used as basic raw materials, and trifluoromethanesulfonic acid di-n-butyl boron ester is used as an additive, so that optically pure D-type p-methylsulfonylphenylserine ethyl ester is obtained with high stereoselectivity under the condition that Lproline is used as a catalyst. Compared with the existing chemical synthesis method, the method disclosed by the invention has the advantages that the highest total yield of the D-methylsulfonylphenyl serine ethyl ester can reach 75%, and the ee value of the obtained product reaches 73%. The method is low incost and has better yield and optical purity.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry of small molecule catalysis, and specifically relates to a catalytic system using L-proline as a catalyst and dialkyl boron trifluoromethanesulfonate as an additive to prepare D- p-Thysylphenylserine ethyl ester. The method has mild reaction conditions, high stereoselectivity and low corrosion to production equipment. Background technique [0002] Chiral control is a very important part in the process of modern drug synthesis research and development. For biological organisms, different stereo configurations of drugs will lead to different effects. If the stereo configuration is incorrect, the drugs originally used to treat diseases It may become a "poison", so chiral control is particularly important in terms of the efficacy and safety of the drug. Therefore, how to make the produced drugs or drug intermediates exhibit good optically pure properties has attracted more and more attenti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C315/04C07C317/38C07C317/50C07B53/00B01J31/06
CPCC07C315/04C07B53/00B01J31/061C07B2200/07C07C317/38C07C317/50Y02P20/55
Inventor 王丽丽胡佳鹏徐健蔡祖强
Owner APELOA PHARM CO LTD
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