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Amino acid as well as preparation method and application thereof

A technology of amino acids and carbamates, which is applied in the preparation of sulfonate esters, carboxylate esters, chemical instruments and methods, etc., and can solve the problems of cumbersome overall steps, low efficiency, and many overall steps

Active Publication Date: 2022-03-01
SHANDONG DYNE MARINE BIOTECHCAL PHARM HLDG CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Counting from raw material A, the total number of steps is 7, and the total yield is 24%. The overall steps are cumbersome and inefficient
Moreover, the raw material A used in this route is not supplied with commercial reagents and needs to be prepared by itself, with more overall steps and lower overall yield

Method used

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  • Amino acid as well as preparation method and application thereof
  • Amino acid as well as preparation method and application thereof
  • Amino acid as well as preparation method and application thereof

Examples

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preparation example Construction

[0030] The present invention provides a kind of preparation method of amino acid, comprises the following steps:

[0031] Mixing methyl cinnamate, AD-mix-alpha, methylsulfonamide and the first solvent, performing an asymmetric dihydroxylation reaction to obtain o-diol compounds;

[0032] Mixing the o-diol compound, p-toluenesulfonyl chloride, triethylamine and a second solvent for esterification to obtain p-toluenesulfonate ester compounds;

[0033] Mixing the p-toluenesulfonate ester compound, tert-butyldimethylsilyl chloride, 2,6-lutidine and a third solvent to carry out a silicon etherification reaction to obtain a first intermediate;

[0034] Mix the first intermediate, methyl-carbamate compound, sodium hydride and a fourth solvent to perform a substitution reaction to obtain a second intermediate; the methyl-carbamate compound is methyl-amino tert-butyl formate or benzyl methyl-carbamate;

[0035] mixing the second intermediate, the base and the fifth solvent, and perfo...

Embodiment 1

[0087] 1) Substitution reaction between methyl cinnamate C and AD-mix-alph to obtain o-diol compound D:

[0088]

[0089] Dissolve 3.65g (22.5mmol, 1eq) of methyl cinnamate in 110mL of tert-butanol and 110mL of water, then add 31g of AD-mix-alpha and 2.15g (22.5mmol, 1eq) of methylsulfonamide, under nitrogen protection, at 25°C The reaction was stirred for 24 hours; after the reaction was completed, sodium bisulfite solution was added to the resulting system to quench the reaction, extracted three times with ethyl acetate, the combined organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated, column After separation by chromatography (PE:EA=2:1), the product was obtained as a white solid with a yield of 77%. 1 H NMR (400MHz, CDCl 3)δ7.54-7.31(m,5H),5.04(m,1H),4.39(s,1H),3.83(s,3H),3.16(s,1H),2.80(s,1H); MS(API -ES):[M+H] + = 197.2.

[0090] 2) Reaction of o-diol compound D with p-toluenesulfonyl chloride (TsCl) to obta...

Embodiment 2

[0104] Step 1~3) with embodiment 1;

[0105] 4) Compound F reacts with methyl-benzyl carbamate to prepare methyl ester compounds:

[0106]

[0107] 4.96g (30mmol) methyl-benzyl carbamate (CH 3 NHCbz) was dissolved in 30ml of anhydrous tetrahydrofuran and cooled to 0°C, NaH 1.32g (60% content, equivalent to 33mmol) was added in batches, and after stirring was continued at 0°C for 30 minutes, the resulting mixed solution was added dropwise to a solution containing 4.65g ( 10mmol) in anhydrous tetrahydrofuran (30mL) solution of compound F, and continue to cool down with an ice-water bath to ensure that the temperature of the reaction solution is 5°C; Adjust the pH to neutral with 1M dilute hydrochloric acid, concentrate the resulting mixture, disperse it in 200mL ethyl acetate, wash with 1M dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine successively, concentrate the obtained organic phase, and distill the concentrated The residue was sep...

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Abstract

The invention provides amino acid as well as a preparation method and application thereof, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: taking methyl cinnamate as a raw material, carrying out Sharpless asymmetric dihydroxylation on the methyl cinnamate and AD-mix-alpha to obtain a vicinal diol compound, esterifying paratoluensulfonyl chloride, introducing a tert-butyl dimethyl silyl ether protecting group, reacting with methyl-carbamate, and removing C-terminal methyl ester to dissociate carboxyl to obtain amino acid. Compared with the prior art, the method has the advantages that the raw materials are cheap and easy to obtain, the steps are short, and the overall yield is high; the used primary raw material methyl cinnamate is a commercial reagent easy to obtain and low in price; from methyl cinnamate, the N-methyl-3-hydroxyphenylalanine can be obtained by only five steps in the method disclosed by the invention, and the technical route is shorter; the total yield is close to 60% and is more than two times that of the prior art.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to an amino acid and its preparation method and application. Background technique [0002] N-methyl-3-hydroxyphenylalanine is a kind of phenylalanine derivatives with special structure, appearing in such as Asperterrestide A (He Fei, Zhang Xiao-Yong, Tu Zheng-Chao, Shi Yi-Ming, Qi Shu-Hua. Asperterrestide A, a Cytotoxic Cyclic Tetrapeptide from the Marine-Derived Fungus Aspergillus terreus SCSGAF0162. Journal of Natural Products. 2013, 76, 1182-1186) among molecules with biological activities such as anti-tumor and anti-virus. This amino acid can be used to optimize the structure of the active compound to improve its pharmaceutical properties and improve its druggability; it can also be used to design and construct structural analogs to discover new drug molecules. How to efficiently synthesize N-methyl-3-hydroxyphenylalanine is the key to preparing compounds containing t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18C07C67/31C07C69/732C07C303/28C07C309/73A61P35/00A61P31/12A61K31/695
CPCC07F7/1804C07F7/188C07F7/1892C07C67/31C07C303/28A61P35/00A61P31/12C07C69/732C07C309/73Y02P20/55
Inventor 颜世强何淑旺张伟王文笙程中伟
Owner SHANDONG DYNE MARINE BIOTECHCAL PHARM HLDG CO LTD
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