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Preparation method of (2R, 3R)-3-methyl-3-phenylalanine

A technology of phenylalanine and diethyl acetamidomalonate, which is applied in the field of preparation of 3-methyl-3-phenylalanine, can solve the difficulty of industrial production and isomer resolution , the selection of expensive reagents and other issues, to achieve quality advantages, cost advantages, and avoid the effects of dangerous reagents

Active Publication Date: 2021-06-22
KANGHUA SHANGHAI DRUG RES DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] The object of the present invention is to provide a kind of (2R,3R)-3-methyl-3-phenylalanine preparation method, mainly solves the existing synthetic method Existing technical problems such as expensive and dangerous reagents, difficult separation of isomers, and impossibility of industrial production

Method used

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  • Preparation method of (2R, 3R)-3-methyl-3-phenylalanine
  • Preparation method of (2R, 3R)-3-methyl-3-phenylalanine

Examples

Experimental program
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Effect test

Embodiment 1

[0043] (1): Add 1085 g (5 mol) diethyl N-acetylaminomalonate and N,N-dimethylformamide (5 L) sequentially into a 10L three-necked flask, stir to dissolve and cool to -10~0 ℃, potassium tert-butoxide (672 g, 6 mol) was added in batches, the temperature was controlled < 0 ℃, and the reaction was stirred for 0.5 hours. Then 1-bromoethylbenzene (925 g, 5 mol) was added dropwise, the temperature was controlled <10°C, and the addition was completed in about 1 hour. The cooling bath was removed, and the reaction was continued to stir at room temperature for 5 hours. The reaction solution was poured into 20L of water, stirred, and a large amount of solids were precipitated. Filter, wash the solid with 10L of water, and dry to obtain intermediate 1 [2-acetamido-2-(1-phenylethyl)diethyl malonate, 1.36 kg, yield 85%].

[0044] (2): Add intermediate 1 [2-acetamido-2-(1-phenylethyl)diethyl malonate, 1.3683 kg, 4.23 mol], 12N concentrated hydrochloric acid (5 L ) and glacial acetic acid (...

Embodiment 2

[0049] (1): Add 108 g (0.5 mol) N-acetylaminomalonate diethyl ester and absolute ethanol (500 mL) in sequence in a 10L three-necked flask, stir to dissolve, then add ethanol solution of sodium ethoxide (20%, w / w, 200 mL, 0.6 mol ), stirred at room temperature for 0.5 hours. Then 1-bromoethylbenzene (92.5 g, 0.5 mol) was added dropwise. After the addition was complete, it was heated to 60°C and stirred for 5 hours. After cooling, the reaction solution was poured into 2L of water, stirred, and a large amount of solids were precipitated. Filter, wash the solid with water, and dry to obtain intermediate 1 [diethyl 2-acetamido-2-(1-phenylethyl)malonate, 105 g, yield 65%].

[0050] All the other steps are the same as in Example 1, and the combined yield of steps (2), (3), (4) and (5) is 20%.

Embodiment 3

[0052] Step (1) is the same as in Example 1; (2) Add intermediate 1 [2-acetamido-2-(1-phenylethyl)diethyl malonate, 100 g, 0.31mol in sequence in a 10L three-necked flask ], 8N concentrated hydrochloric acid (500 L) and 1,4-dioxane (100 mL), stirred and heated to reflux for 12 hours. After cooling, the reaction solution was concentrated to about 150 mL, and crystallized by cooling. Filter, wash the solid with a small amount of ice water, and dry to obtain intermediate 2 (erythro-3-methyl-3-phenylalanine hydrochloride, 21.7 g, yield 32%). All the other steps are the same as in Example 1, and the combined yield of steps (3), (4) and (5) is 25%.

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Abstract

The invention relates to a preparation method of (2R, 3R)-3-methyl-3-phenylalanine. The technical problems that an existing preparation method is long in route, expensive in used reagent, incapable of achieving large-scale production and the like are mainly solved. According to the technical scheme, the preparation method of the (2R, 3R)-3-methyl-3-phenylalanine comprises the following steps: condensing 2-acetamidomalonic acid diethyl ester and 1-bromoethyl benzene under the action of alkali to obtain 2-acetamido-2-(1-phenylethyl) malonic acid diethyl ester; heating and hydrolyzing in concentrated hydrochloric acid, concentrating and crystallizing to obtain erythro 3-methyl-3-phenylalanine; then performing acylation to obtain the erythro 2-acetamido-3-methyl 3-phenylalanine; splitting under the action of acetamido transferase, and obtaining (2R, 3R)-2-acetamido-3-methyl 3-phenylalanine; and finally, heating and hydrolyzing by using hydrochloric acid to obtain the product (2R, 3R)-3-methyl-3-phenylalanine (hydrochloride).

Description

technical field [0001] The invention relates to a preparation method of (2R,3R)-3-methyl-3-phenylalanine. Background technique [0002] 3-methyl-3-phenylalanine (β-methyl-phenylalanine) is an important intermediate in drug synthesis, it has two chiral carbon four isomers, respectively (2S,3S)-, ( 2S,3R)-, (2R,3S)- and (2R,3R)-3-methyl-3-phenylalanine, which are widely found in natural products such as Mannopeptimycins molecules with potent antibacterial activity Existence of (2S,3R)-3-methyl-3-phenylalanine, from Streptomyces griseoflavus The hormaomycin molecule isolated from the strain also contained (2S,3R)-3-methyl-3-phenylalanine. [0003] [0004] 3-methyl-3-phenylalanine with two chiral carbons and four isomers can be divided into two groups, one group is the threo structure [(2S,3R)-3-methyl- 3-phenylalanine and (2R,3S)-3-methyl-3-phenylalanine], another group is the red structure [(2R,3R)-3-methyl-3-benzene phenylalanine and (2S,3S)-3-methyl-3-phenylalanine],...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/04C07C229/36
CPCC07C227/04C07C231/12C07C227/12C07C231/02C07B2200/07C07C229/36C07C233/47Y02P20/55
Inventor 徐红岩袁伟芳徐欣
Owner KANGHUA SHANGHAI DRUG RES DEV CO LTD
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