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Method for preparing erivedge by adopting microchannel reaction device

A technology of microchannel reaction and microstructure reactor, which is applied in the direction of organic chemistry, can solve the problems of high cost, complex reaction conditions, and long reaction time, and achieve the effects of high continuity, simple operation, and shortened reaction time

Active Publication Date: 2018-05-08
南京天越星生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Purpose of the invention: the technical problem to be solved by this invention is to provide a method for preparing Vimodeji using a microchannel reaction device to solve the existing cost of the prior art by means of a new microchannel reaction device. Higher, complex reaction conditions, long reaction time and other problems, and improve the reaction efficiency to achieve industrial production

Method used

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  • Method for preparing erivedge by adopting microchannel reaction device
  • Method for preparing erivedge by adopting microchannel reaction device
  • Method for preparing erivedge by adopting microchannel reaction device

Examples

Experimental program
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Effect test

Embodiment 1

[0033] (1) Preparation of N-(phenylsulfonyl)-N-)3-(pyridin-2-yl)phenyl)benzenesulfonamide (compound Ⅱ):

[0034]

[0035] Add 10mmol 2-phenylpyridine, 15mmol diphenylsulfonimide, 0.5mmol triruthenium dodecacarbonyl, 20mmol iodobenzene diacetate, 40mL dichloroethane to a 100mL reaction flask, that is, compound Ⅰ, diphenylsulfonyl The molar ratio of imine, metal catalyst (triruthenium dodecacarbonyl) and oxidant (iodobenzene diacetate) is: 1:1.5:0.05:2, reflux in an oil bath at 100°C for 24 hours, cool down to room temperature, filter, and recover Triruthenium dodecacarbonyl, then add 100 mL of water to the filtrate, then add dichloromethane to extract three times (100 mL×3), combine the organic phases, wash with saturated brine, add anhydrous sodium sulfate to dry, and distill off the solvent under reduced pressure, Column chromatography (mobile phase V / V: ethyl acetate / petroleum ether=1 / 4) gave a white solid with a yield of 80%; HRMS (ESI-TOF-MS) m / z: 451.0776 ([M+H] + ); ...

Embodiment 2

[0045] The preparation method is the same as in Example 1, but the reaction temperature of step (1) is 125° C. to obtain white N-(phenylsulfonyl)-N-(3-(pyridin-2-yl)phenyl)benzenesulfonamide (compound Ⅱ), yield 75%;

[0046] Step (2) The reaction temperature is 120°C, and white N-(4-chloro-3-(pyridin-2-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (compound III) is obtained in a yield of 82%;

[0047] Step (3) The reaction temperature was 50°C, and 4-chloro-3-(pyridin-2-yl)aniline (compound IV) was obtained as a colorless oil with a yield of 94%;

[0048] Step (4) The reaction temperature of the first microstructure reactor is 100° C., and the reaction temperature is 100° C., and the residence time is 5 minutes. The reaction temperature of the second microstructure reactor is 120° C., and the residence time is 10 minutes to obtain white Vimodergib with a yield of 85%.

Embodiment 3

[0050] The preparation method is the same as in Example 1, but the reaction temperature of step (1) is 25° C. to obtain white N-(phenylsulfonyl)-N-(3-(pyridin-2-yl)phenyl)benzenesulfonamide (compound Ⅱ), yield 65%;

[0051] Step (2) The reaction temperature is 80°C, and white N-(4-chloro-3-(pyridin-2-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (compound III) is obtained. The yield is 83%;

[0052] Step (3) The reaction temperature was 0°C, and 4-chloro-3-(pyridin-2-yl)aniline (compound IV) was obtained as a colorless oil with a yield of 90%;

[0053] Step (4) The reaction temperature of the first microstructure reactor is 25° C., and the residence time is 20 minutes. The reaction temperature of the second microstructure reactor is 50° C., and the residence time is 50 minutes to obtain white Vimodeji with a yield of 80%.

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Abstract

The invention discloses a method for preparing erivedge by adopting a microchannel reaction device. The method comprises the following steps: by using 2-phenylpyridine as a starting material, preparing an important intermediate 4-chloro-3-(pyridine-2-yl) aniline by metal catalysis amination, oxidation and reduction reaction in sequence, finally carrying out oxidation and amidation reaction with 2-chloro-1-methyl-4-(methylsulfonyl)benzene by two-step continuous flow in the novel microchannel reaction device, and preparing the erivedge. The microchannel reaction device has the characteristics ofcheap price, convenience in transportation and cleaning, higher heat and mass transfer efficiency and easier industrial amplification and the like. Compared with the prior art, the synthesis method has the advantages that the starting material is simple and cheap and is easy to obtain, the process is concise, the production cost can be effectively reduced, and the adaptability to industrial production is achieved.

Description

technical field [0001] The invention relates to a method for preparing Vimodeji by adopting a microchannel reaction device, and belongs to the field of medicinal chemistry. Background technique [0002] Vismodegib is the first oral, highly selective small molecule inhibitor of the Hedgehog signaling pathway developed by the Swiss pharmaceutical company Roche in the United States. Vimodeji binds to the Smoothened receptor and inhibits its signaling. In vivo and in vitro studies have shown that Vimodegib can act as a potential inhibitor of the Hedgehog-glioma-associated oncogene (GLI) signaling pathway by antagonizing the Smoothened (SMO) receptor. Vimodeji was approved for marketing by the US Food and Drug Administration (FDA) on January 30, 2012, under the trade name Erivedge. The drug is suitable for patients with locally advanced skin basal cell carcinoma who cannot undergo surgery or radiotherapy and patients whose tumors have metastasized. Therefore, the research and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/40
CPCC07D213/40
Inventor 吴学平邢继刚严东洋储贻结
Owner 南京天越星生物技术有限公司
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