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Method for synthesizing ubenimex

A synthetic method, the technology of Ubenimex, is applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc. It can solve the problems of cumbersome synthesis steps, long recrystallization time, and many intermediate products, so as to simplify steps, The effect of less intermediate products and low cost

Active Publication Date: 2015-04-08
山东益康药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The present invention has the following defects: the synthesis steps of ubenimex in the present invention are cumbersome, the reaction time is long, the intermediate products are many, the cost is high, and thus the efficiency is low; L-lysine, L-arginine or L-histidine As a resolution reagent, the post-stirring and recrystallization time is long, resulting in low reaction efficiency

Method used

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  • Method for synthesizing ubenimex
  • Method for synthesizing ubenimex

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Preparation of (2RS, 3R)-3-tert-butoxyamido-2-hydroxyl-4-phenylbutyronitrile (1):

[0026]Dissolve 36g (0.143mol) D-Boc-phenylalaninaldehyde in 100mL ethyl acetate, add 400mL distilled water, 17.6g (0.171mol) sodium bisulfite, monitor the reaction process by thin layer chromatography (TLC), and react after 10h Finish, separate and take water phase, wash 2 times with 300mL ethyl acetate, add 7.7g (0.157mol) sodium cyanide to water phase, react overnight at room temperature, after extracting 3 times with 300mL ethyl acetate, wash 3 times with 300mL water, organic The phase was dried over anhydrous sodium sulfate for 24 h, and evaporated to dryness to obtain 27 g of (2RS, 3R)-3-tert-butoxyamido-2-hydroxy-4-phenylbutyronitrile (1), with a yield of 68.5%.

[0027] Preparation of (2RS, 3R)-3-tert-butoxyamido-2-hydroxyl-4-phenylbutanoic acid (2):

[0028] Dissolve 25g (0.09mol) (2RS, 3R)-3-tert-butoxyamido-2-hydroxy-4-phenylbutyronitrile (1) in 100mL 1,4-dioxane, drop into 1...

Embodiment 2

[0036] Preparation of (2RS, 3R)-3-tert-butoxyamido-2-hydroxyl-4-phenylbutyronitrile (1):

[0037] Dissolve 21.6g (0.0858mol) D-Boc-phenylalaninaldehyde in 43mL ethyl acetate, add 173mL distilled water, 6.5g (0.103mol) sodium bisulfite, monitor the reaction process by thin layer chromatography (TLC), after 10h After the reaction was completed, the aqueous phase was separated, washed twice with 300 mL of ethyl acetate, added 2.16 g (0.094 mol) of sodium cyanide to the aqueous phase, reacted overnight at room temperature, extracted three times with 300 mL of ethyl acetate, washed three times with 300 mL of water, The organic phase was dried over anhydrous sodium sulfate for 24 h, and evaporated to dryness to obtain 15 g of (2RS, 3R)-3-tert-butoxyamido-2-hydroxy-4-phenylbutyronitrile (1), with a yield of 63.4%.

[0038] Preparation of (2RS, 3R)-3-tert-butoxyamido-2-hydroxyl-4-phenylbutanoic acid (2):

[0039] Dissolve 10g (0.036mol) of (2RS, 3R)-3-tert-butoxyamido-2-hydroxy-4-phe...

Embodiment 3

[0047] Preparation of (2RS, 3R)-3-tert-butoxyamido-2-hydroxyl-4-phenylbutyronitrile (1):

[0048] Dissolve 11g (0.043mol) of D-Boc-phenylalaninaldehyde in 33mL of ethyl acetate, add 132mL of distilled water, 8.8g (0.052mol) of sodium bisulfite, and monitor the reaction process by thin-layer chromatography (TLC). After 10 hours, the reaction End, separate the water phase, wash it twice with 300mL ethyl acetate, add 4.4g (0.048mol) sodium cyanide to the water phase, react overnight at room temperature, extract three times with 100mL ethyl acetate, wash three times with 100mL water, organic The phase was dried over anhydrous sodium sulfate for 24 h and evaporated to dryness to obtain 8 g of (2RS, 3R)-3-tert-butoxyamido-2-hydroxy-4-phenylbutyronitrile (1), with a yield of 66%.

[0049] Preparation of (2RS, 3R)-3-tert-butoxyamido-2-hydroxyl-4-phenylbutanoic acid (2):

[0050]Dissolve 17g (0.06mol) of (2RS, 3R)-3-tert-butoxyamido-2-hydroxy-4-phenylbutyronitrile (1) in 68mL of 1,4-d...

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Abstract

The invention discloses a method for synthesizing ubenimex. The method comprises the following steps: by taking D-Boc-phenyl alaninal as a raw material, sequentially preparing hydroxynitrile, carrying out a nitrile hydrolysis reaction, performing amino protection, performing chiral resolution on (2RS,3R)-3-tert-butoxyacylamino-2-hydroxy-4-phenylbutyric acid, and synthesizing (S)-phenyl-2-((2S,3R)-3-(tert-butoxyacylamino)-2-hydroxy-4-phenylbutyramide)-4-mevalonate, thereby synthesizing the ubenimex. According to the synthetic method disclosed by the invention, the defect that the resolving agent used in the conventional synthetic method is high in toxicity (such as strychnine) or high in price (such as alpha-phenylethylamine) is overcome, the synthetic method is simple in steps and low in cost, and use of reagents such as strychnine is avoided; and moreover, a dextro-amino compound is taken as the chiral resolution agent, the price is low, the operation is simple, the stirring and recrystallization time is shortened, and the synthetic efficiency is greatly improved.

Description

technical field [0001] The invention belongs to the field of synthesis of chemical medicines, and relates to a synthesis method of antitumor drugs, in particular to a synthesis method of ubenimex. Background technique [0002] Ubenimex, its drug name is bestatin; alias: Ubenimex; trade name: Baishixin; chemical name: N-[(2S,3R)-3-amino-2-hydroxy-4- phenylbutyryl]-L-leucine. Ubenimex is a small molecule dipeptide compound isolated from the culture fluid of Streptomyces olivine by the Japanese scholar Umezawa Hamao in 1976, which can inhibit the activities of various aminopeptidases, such as APN, APB, APP, LAP and MetAP. In addition, ubenimex can also enhance host immune function, inhibit tumor tissue angiogenesis, thereby inhibiting tumor invasion and metastasis. In 1987, Ubenimex was officially launched in Japan as an anticancer drug. [0003] Clinical studies have shown that Ubenimex achieves its curative effect in cancer treatment by enhancing the cytotoxic activity of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/20C07C231/12
Inventor 高肇林王彦厚史永强张兴柱魏正风
Owner 山东益康药业股份有限公司
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