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Preparation method of ubenimex

A technology of ubimethoxine and phenylbutyryl, applied in the field of preparation of ubimethoxine, can solve the problems of large processing burden, easy residue, organic solvent residue and the like, and achieves the effects of cost saving and solubility improvement

Inactive Publication Date: 2017-09-08
SINOPHARM CHUANKANG PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In the prior art, tetrahydrofuran and triethylamine are mostly used as solvents or catalysts in the synthesis process of Ubenimex. These reagents are not environmentally friendly, and the burden of follow-up treatment is relatively large, which will generate a large amount of waste water and waste gas. This kind of organic base is easy to remain in the product, causing the problem of organic solvent residue

Method used

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  • Preparation method of ubenimex
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  • Preparation method of ubenimex

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The preparation method of Ubenimex is as follows:

[0038] 1) Add L-leucine benzyl ester p-toluenesulfonate, HOBt, and 10 times (V / m) ethyl acetate into the reaction kettle in sequence, after the feeding is completed, keep stirring and cooling down, and slowly add the ethyl acetate solution of DCC, Adding process system temperature between 0-5 ℃. After feeding, the system was reacted at 15-20°C for 4 hours, followed by TLC at the end of the reaction (ethyl acetate: petroleum ether = 2:1, UV 254nm), and the activated ester solution of L-leucine benzyl ester p-toluenesulfonate was obtained ;

[0039] 2) Add (2S,3R)-3-benzyloxycarboxamido-2-hydroxy-4-phenylbutyric acid, 10 times (V / m) 10% sodium bicarbonate solution into the reaction kettle in sequence, and stir Until it is completely dissolved, cool down to 10-15°C, add the activated ester solution of L-leucine benzyl p-toluenesulfonate dropwise under rapid stirring, and react at 15-20°C for about 4 hours after the drop...

Embodiment 2

[0045] The preparation method of Ubenimex is as follows:

[0046] 1) Add L-leucine benzyl ester p-toluenesulfonate, HOBt, and 10 times (V / m) ethyl acetate into the reaction kettle in sequence, after the feeding is completed, keep stirring and cooling down, and slowly add the ethyl acetate solution of DCC, Adding process system temperature between 0-5 ℃. After feeding, the system was reacted at 15-20°C for 5 hours, followed by TLC at the end of the reaction (ethyl acetate: petroleum ether = 2:1, UV 254nm), and the activated ester solution of L-leucine benzyl ester p-toluenesulfonate was obtained ;

[0047] 2) Add (2S,3R)-3-benzyloxycarboxamido-2-hydroxy-4-phenylbutyric acid, 10 times (V / m) 20% sodium bicarbonate solution into the reaction kettle in sequence, and stir Until it is completely dissolved, cool down to 10-15°C, add dropwise the activated ester solution of L-leucine benzyl p-toluenesulfonate under rapid stirring, and react at 15-20°C for about 5 hours after the addi...

Embodiment 3

[0053] The preparation method of Ubenimex is as follows:

[0054] 1) Add L-leucine benzyl ester p-toluenesulfonate, HOBt, and 10 times (V / m) ethyl acetate into the reaction kettle in sequence, after the feeding is completed, keep stirring and cooling down, and slowly add the ethyl acetate solution of DCC, Adding process system temperature between 0-5 ℃. After feeding, the system was reacted at 15-20°C for 4 hours, followed by TLC at the end of the reaction (ethyl acetate: petroleum ether = 2:1, UV 254nm), and the activated ester solution of L-leucine benzyl ester p-toluenesulfonate was obtained ;

[0055] 2) Add (2S,3R)-3-benzyloxycarboxamido-2-hydroxy-4-phenylbutyric acid, 10 times (V / m) 20% sodium bicarbonate solution into the reaction kettle in sequence, and stir Until it is completely dissolved, cool down to 10-15°C, add the activated ester solution of L-leucine benzyl p-toluenesulfonate dropwise under rapid stirring, and react at 15-20°C for about 4 hours after the drop...

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Abstract

The invention provides a preparation method of ubenimex. The preparation method comprises that L-leucine benzyl ester p-toluenesulfonate and HOBt undergo a condensation reaction to produce an activated ester solution, (2S, 3R)-3-benzyloxyformamido-2-hydroxy-4- phenylbutyric acid and a weak acid strong alkali inorganic salt are mixed, the activated ester solution is added into the mixture drop by drop and undergoes a reaction to produce N-[(2S, 3R)-3-benzoylformamido-2-hydroxy-4-phenylbutyryl]-L-leucine, and N-[(2S, 3R)-3-benzoylformamido-2-hydroxy-4-phenylbutyryl]-L-leucine is reduced into ubenimex through hydrogen gas. The preparation method utilizes ethyl acetate as an organic solvent, saves tetrahydrofuran-caused potential safety hazard, utilizes the weak acid strong alkali inorganic salt as a base catalyst, saves a cost, is free of an organic solvent and is easy to operate.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a preparation method of ubenimex. Background technique [0002] Ubenimex (I Ubenimex; NN), also known as bestatin, has the chemical formula N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine, is A competitive, reversible protease inhibitor. It is active against arginyl aminopeptidase (aminopeptidase B), leukotriene A4 hydrolase (zinc metalloprotease exhibiting epoxide hydrolase and aminopeptidase activity), alanyl aminopeptidase (aminopeptidase M / N), leucyl / cystyl aminopeptidase (oxytocin / vasopressinase) (leukotriene D4 hydrolase) is inhibited. It is being studied for the treatment of acute myelogenous leukemia. It is derived from Streptomyces olivoreticuli. Ubenimex has been found to inhibit the enzymatic degradation of oxytocin, vasopressin, enkephalins and various other peptides and compounds. [0003] Ubenimex can enhance immune function, and is used as an adjuvant therapy ...

Claims

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Application Information

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IPC IPC(8): C07C237/20C07C231/12C07C231/24C07C269/06C07C271/16
CPCC07C231/12C07C231/24C07C269/06C07C271/16C07C237/20
Inventor 蒲桂海许波文张宏王家勇邓丽文娅娅
Owner SINOPHARM CHUANKANG PHARMACEUTICAL CO LTD
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