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Impurity in ubenimex synthesis and production method thereof

A technology of Ubenimex and impurities, which is applied in the field of drug synthesis, and can solve problems such as difficult quality control and difficult structure confirmation of Ubenimex raw materials

Inactive Publication Date: 2019-05-07
深圳万乐药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the extremely small amount, it is difficult to collect and confirm the structure, which brings difficulties to the quality control of Ubenimex API

Method used

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  • Impurity in ubenimex synthesis and production method thereof
  • Impurity in ubenimex synthesis and production method thereof
  • Impurity in ubenimex synthesis and production method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Synthesis of Example 1 Ubenimex, Collection of Compounds of Formula II

[0029] i Preparation of Ubenimex Crude Product

[0030] Add 1000 mL of tetrahydrofuran into the three-necked flask, start stirring, add 100 g of Z-AHPA, 131.5 g of L-leucine benzyl ester p-toluenesulfonate and 48.5 g of 1-hydroxybenzotriazole (HOBt) in sequence, and then cool down to 0 ±2°C. Add 33.6g of triethylamine and 74.5g of dicyclohexylcarbodiimide (DCC), control the temperature at 12±2°C after the addition, stir and react for 20-24 hours, and filter the reaction solution after the reaction is complete. The filtrate was concentrated under reduced pressure until no distillate was evaporated to obtain an oily substance, and then ethyl acetate was added and stirred until the oily substance was completely dissolved. Wash the above ethyl acetate solution with 650 mL of 0.5 mol / L hydrochloric acid, 650 mL of purified water, 650 mL of saturated sodium bicarbonate solution, and 650 mL of saturated...

Embodiment 2

[0036] The synthesis of embodiment 2 formula II compound

[0037] Preparation of i intermediate formula V compound

[0038] Add 226mL of tetrahydrofuran into a three-neck flask, add 20g of Z-AHPA, 26.3g of L-isoleucine benzyl ester p-toluenesulfonate and 9.7g of 1-hydroxybenzotriazole (HOBt) successively while stirring, and then cool down to 0± 2°C, add 6.72g of triethylamine and 14.9g of dicyclohexylcarbodiimide (DCC), after the addition, control the temperature at 12±2°C, stir and react for 20-24 hours, monitor by HPLC until the reaction is complete, filter the reaction solution , and the filter cake was washed with 25 mL of tetrahydrofuran. The filtrate and washing liquid were combined and then concentrated under reduced pressure until no fraction was distilled off to obtain an oily substance. Add 260 mL of ethyl acetate to dissolve the oily substance, and successively add 133.3 mL of 0.5 mol / L hydrochloric acid, 133.3 mL of purified water, and 133.3 mL of saturated sodium...

Embodiment 3

[0043] The synthesis of embodiment 3 formula II compound

[0044] Preparation of i intermediate formula V compound

[0045] Add 226mL of tetrahydrofuran into the three-necked flask, add Z-AHPA20g, L-isoleucine benzyl p-toluenesulfonate 26.3g and 1-hydroxybenzotriazole (HOBt)9.7g, PyBOP37.3g successively while stirring, and then Cool down to 0±2°C, add DIPEA8.58g, control the temperature at 12±2°C after the addition, stir and react for 20-24 hours, monitor by HPLC until the reaction is complete, filter the reaction solution, and wash the filter cake with 25mL of tetrahydrofuran. The filtrate and washing liquid were combined and then concentrated under reduced pressure until no fraction was distilled off to obtain an oily substance. Add 260 mL of ethyl acetate to dissolve the oily substance, and successively add 133.3 mL of 0.5 mol / L hydrochloric acid, 133.3 mL of purified water, and 133.3 mL of saturated sodium bicarbonate solution. mL, 133.3 mL of saturated sodium chloride so...

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Abstract

The invention provides an impurity in a ubenimex crude drug. Identification of a structure of the impurity benefits quality control of ubenimex so that the high-quality ubenimex crude drug can be obtained. The invention furthermore provides a production method of the impurity; and a product obtained through the method is high in purity, and can be used as an impurity reference substance of a ubenimex crude drug quality studying process.

Description

technical field [0001] The present invention relates to the field of pharmaceutical synthesis methods, in particular to an impurity N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]- L-isoleucine and its preparation method. Background technique [0002] Ubenimex (Ubenimex; Bestatin) is a low-molecular-weight dipeptide compound isolated from the culture medium of Streptomyces olivine reticulum, which has the ability to inhibit tumor cell surface aminopeptidase B, N and leucine aminopeptide Enzyme action, inducing tumor cell apoptosis, promoting host cell immune function, and enhancing anti-cancer effect. It was launched in Japan in 1987. Ubenimex is often used in combination with other chemotherapy drugs in the treatment of acute myeloid leukemia, chronic myelogenous leukemia, lung squamous cell carcinoma, malignant melanoma, gastric tumor, etc.; combined with radiotherapy, it is used for nasopharyngeal carcinoma It is also used for the treatment of tumor diseases such as tumor...

Claims

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Application Information

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IPC IPC(8): C07C237/20C07C231/12G01N30/02
Inventor 刘东华苏云淡吴子强于玉根李瑞远
Owner 深圳万乐药业有限公司
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