Preparation method of fmoc-O-tert-butyl-L-serine

A technology of fluorenylmethoxycarbonyl and tert-butyl, applied in the field of preparation of N--O-tert-butyl-L-serine, can solve the problems of difficult drying of water, low purity, long preparation time, etc., and achieve reduction Requirements for production equipment, a wide range of applications, and the effect of simple preparation methods

Inactive Publication Date: 2019-01-25
四川什邡市三高生化实业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] The current preparation method of N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-serine has many steps in the preparation process, which will lead to N-(9-fluorenylmethoxycarbonyl)-O- The preparation cost of tert-butyl-L-serine is relatively high, and the preparation time is also long at the same time. The traditional synthesis preparation route will lead to very easy racemization in the original synthesis process, the optical purity is not high, and the process parameters are not easy to control; Due to the presence of multiple steps in the preparation process, it is easy to cause more impurities in the preparation process, which increases the burden on the subsequent purification and impurity removal work, resulting in increased preparation costs; the traditional preparation of N-(9-fluorenylmethoxycarbonyl )-O-tert-butyl-L-serine The final product generated by the method still has the problem of low purity, the single impurity is about 0.3%, the product is difficult to dry, and the moisture content is difficult to dry to below 1%.

Method used

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  • Preparation method of fmoc-O-tert-butyl-L-serine
  • Preparation method of fmoc-O-tert-butyl-L-serine

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Add 20g of L-serine and 600g of methanol into the reaction flask, and add 28g of SOCl dropwise to the reaction flask under stirring 2 , use reflux reaction, and use TLC to detect the reaction solution in the reaction bottle. If there is no L-serine in the reaction bottle, the reaction is complete; The solution obtained L-serine methyl ester hydrochloride solid 29g, wherein the yield of L-serine methyl ester hydrochloride was 98%;

[0027] Get a new reaction flask, add 410g tert-butyl acetate, 50g perchloric acid (analytical pure), 29g L-serine methyl ester hydrochloride successively in this reaction flask, then add 10g H 2 SO 4 (analytically pure), at room temperature, stirred and reacted for 3 days, when TLC detection (thin-layer chromatography) detected that there was substantially no L-serine methyl ester hydrochloride in the reaction system, 50g of water was added to the reaction bottle, and the reaction was adjusted with NaOH solution The PH in the bottle is 8, l...

Embodiment 2

[0032] Add 20 g of L-serine and 600 g of methanol into the reaction flask, and add 30 g of SOCl dropwise to the reaction flask under stirring 2 , use reflux reaction, and use TLC to detect the reaction solution in the reaction bottle. If there is no L-serine in the reaction bottle, the reaction is complete; The solution obtained L-serine methyl ester hydrochloride solid 29g, wherein the yield of L-serine methyl ester hydrochloride was 98%;

[0033] Get a new reaction flask, add 410g tert-butyl acetate, 52g perchloric acid (analytical pure), 29g L-serine methyl ester hydrochloride successively in this reaction flask, then add 12g H 2 SO 4 (analytical pure), at room temperature, stirred and reacted for 4 days, when TLC detection (thin layer chromatography) detects that there is substantially no L-serine methyl ester hydrochloride in the reaction system, add 60g water in the reaction flask, adjust the reaction with NaOH solution The pH in the bottle is 9, let stand to separate th...

Embodiment 3

[0037] Add 10 g of L-serine and 300 g of methanol into the reaction flask, and add 14 g of SOCl dropwise to the reaction flask under stirring 2 , use reflux reaction, and use TLC to detect the reaction solution in the reaction bottle. If there is no L-serine in the reaction bottle, the reaction is complete; The solution obtained L-serine methyl ester hydrochloride solid 15g, wherein the yield of L-serine methyl ester hydrochloride was 98.6%;

[0038] Get a new reaction flask, add about 210g tert-butyl acetate, 25g perchloric acid (analytical pure), 15g L-serine methyl ester hydrochloride successively in this reaction flask, then add 5g H 2 SO 4 (analytically pure), at room temperature, stirred and reacted for 4 days, when TLC detection (thin layer chromatography) detects that there is substantially no L-serine methyl ester hydrochloride in the reaction system, add 30g water in the reaction bottle, adjust the reaction with NaOH solution The pH in the bottle is 9, let stand to...

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Abstract

The invention discloses a preparation method of fmoc-O-tert-butyl-L-serine. The method comprises the steps that 1, L-serine and a methanol solution are added into a reaction container, and under stirring, SOCl2 is added dropwise for reflux reaction to obtain L-serine methyl ester hydrochloride; 2, the L-serine methyl ester hydrochloride is added into tert-butyl acetate, and a catalyst is added forreaction to obtain O-tert-butyl-L-serine methyl ester; 3, the O-tert-butyl-L-serine methyl ester is added into alkaline liquid for saponification reaction to obtain an O-tert-butyl-L-serine aqueous solution; 4, an organic solvent and NaCO3 are added into O-tert-butyl-L-serine, then fmoc n-hydroxysuccinimide este is added to adjust a pH value to be 8-10, and extraction separation is conducted to obtain the fmoc-O-tert-butyl-L-serine. In the preparation method, the L-serine, methanol and SOCl2 are adopted as raw materials, and through the reflux reaction, the L-serine methyl ester hydrochlorideis prepared; the reaction is carried out in liquid phases respectively, and is safe and pollution-free.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a preparation method of N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-serine. Background technique [0002] The current preparation method of N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-serine has many steps in the preparation process, which will lead to N-(9-fluorenylmethoxycarbonyl)-O- The preparation cost of tert-butyl-L-serine is relatively high, and the preparation time is also long at the same time. The traditional synthesis preparation route will lead to very easy racemization in the original synthesis process, the optical purity is not high, and the process parameters are not easy to control; Due to the presence of multiple steps in the preparation process, it is easy to cause more impurities in the preparation process, which increases the burden on the subsequent purification and impurity removal work, resulting in increased preparation costs; th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/04C07C271/22
CPCC07C227/16C07C227/18C07C269/06C07C269/08C07C2603/18C07C229/22C07C271/22
Inventor 李万昌冯旭斌王俊田明成文浪梁松王佰国
Owner 四川什邡市三高生化实业有限公司
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