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Synthesis method of henatinib intermediate and obtained henatinib intermediate

A synthetic method and intermediate technology, applied in the field of pharmaceutical intermediate synthesis, can solve the problems of environmental protection, high cost, and high price

Active Publication Date: 2021-05-11
烟台舜康生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The object of the present invention is to provide a kind of synthetic method of Henatinib intermediate and the gained Henatinib intermediate, aim to solve the synthetic method of Heinatinib intermediate in the prior art because of long working route, in the process of synthesis. The production of a large amount of acid water also requires an expensive reducing agent, which leads to the problems of complicated post-treatment, environmental protection, high cost and low yield

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  • Synthesis method of henatinib intermediate and obtained henatinib intermediate
  • Synthesis method of henatinib intermediate and obtained henatinib intermediate

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preparation example Construction

[0027] A kind of synthetic method of henatinib intermediate of the present invention, comprises the following steps:

[0028] 1) Take 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid-2-tert-butyl-4-ethyl ester as a starting material, add it to an organic solvent, stir at room temperature, and make it Dissolve, then add cerium ammonium nitrate, the ratio of the amount of cerium ammonium nitrate to the starting material is 3:1-4:1, stir at room temperature, fully react until the end of the reaction, purify, and obtain intermediate 1;

[0029] 2) Under the protection of an inert gas, add intermediate 1 to an organic solvent, stir at room temperature to dissolve it, and then add (benzyloxyethyl)phenylphosphine, (benzyloxyethyl)phenylphosphine The ratio of the amount of substances to the intermediate 1 is 1.2:1-1.5:1, stirred at room temperature, fully reacted, and purified to the end of the reaction to obtain intermediate 2;

[0030] 3) Add intermediate 2 to the alcohol solvent, sti...

Embodiment 1

[0041] A kind of synthetic method of henatinib intermediate of the present invention, comprises the following steps:

[0042] 1) Preparation of formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (intermediate 1)

[0043] In a 2L reaction flask, add 590g of tetrahydrofuran and 720g of acetic acid, under stirring at room temperature, add 60g of 2-tert-butyl 4-ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate (0.22mol ) as the starting material, stirred and dissolved, then added cerium ammonium nitrate 437g (0.8mol) to obtain the mixture; the mixture was stirred at room temperature for 0.5h, and TLC was monitored until the reaction was complete. The TLC detection conditions were: silica gel GF254 thin-layer plate, developer It is a mixture of n-hexane and ethyl acetate with a volume ratio of 8:1, the main spot Rf is 0.5, the raw material Rf is 0.4, and the color is developed by ultraviolet light;

[0044] Under the condition of stirring, the reaction...

Embodiment 2

[0057] A kind of synthetic method of henatinib intermediate of the present invention, comprises the following steps:

[0058] 1) Preparation of formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (intermediate 1)

[0059] In a 2L reaction flask, add 590g of tetrahydrofuran and 720g of acetic acid, and add 2-tert-butyl 4-ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate under stirring at room temperature (23°C) 60g (0.22mol) was used as the starting material, stirred and dissolved, and then 361g (0.66mol) of ammonium cerium nitrate was added to obtain a mixture; the mixture was stirred at room temperature for 1.0h, and TLC was monitored until the reaction was complete. The TLC detection conditions were: silica gel GF254 thin For laminates, the developer is a mixture of n-hexane and ethyl acetate with a volume ratio of 8:1, the main spot Rf is 0.5, the raw material Rf is 0.4, and the ultraviolet color is developed;

[0060] Under the condition of sti...

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Abstract

The invention discloses a synthesis method of a henatinib intermediate and the obtained henatinib intermediate. The preparation method comprises the following steps of: (1) adding 3, 5-dimethyl-1H-pyrrole-2, 4-dicarboxylic acid-2-tert-butyl-4-ethyl ester into an organic solvent, then adding ceric ammonium nitrate, and reacting at room temperature to obtain an intermediate 1; (2) under the protection of inert gas, adding the intermediate 1 into an organic solvent, then adding (benzyloxyethyl) phenylphosphine, and reacting at room temperature to obtain an intermediate 2; and (3) adding the intermediate 2 into methanol, then adding a palladium-carbon catalyst, introducing hydrogen, and fully reacting at 30-35 DEG C to obtain the henatinib intermediate. The method has few reaction steps, only comprises three steps of oxidation, Wittig reaction and hydrogenation, does not have a hydrolysis process, avoids the phenomenon of environmental unfriendliness caused by a large amount of acid water, does not have a reduction reaction process of an expensive reducing agent, and is simple to operate, high in yield, few in impurities and high in purity.

Description

technical field [0001] The invention belongs to the technical field of synthesizing pharmaceutical intermediates, in particular to a method for synthesizing a henatinib intermediate and the resulting henatinib intermediate. Background technique [0002] Hinatinib, the chemical name is (R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indole-3-methine)-5-(2-hydroxy- 3-Morpholin-4-yl-propyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one, Jiangsu Hansoh Medical Research Institute independently developed a multi-target tyrosine kinase inhibitor. The structure of Henatinib is similar to that of Sunitinib (Pfizer). Compared with Sunitinib, Henatinib has better in vivo and in vitro activities and oral availability. [0003] The chemical name of the intermediate of Henatinib is 5-(3-hydroxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylate-2-tert-butyl-4-ethyl ester. In the prior art, the intermediate of Henatinib is synthesized as follows: 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid...

Claims

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Application Information

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IPC IPC(8): C07D207/34
CPCC07D207/34
Inventor 陈化群史汝金申川生
Owner 烟台舜康生物科技有限公司
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