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Solid acid catalyst for preparing antitumor drug intermediate and preparation method of solid acid catalyst

A solid acid catalyst and catalyst technology, applied in the field of medicine, can solve the problems of cumbersome processing procedures, low efficiency, easy deactivation, etc., and achieve the effects of high conversion rate and selectivity of raw materials, wide application range, and convenient separation

Active Publication Date: 2018-01-19
广东君奇医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Zhao Hui et al. of Jiangnan University (Chinese Journal of Pharmaceutical Industry, 2017, 48(10): 1436-1441, process optimization of CDK inhibitor PHA-848125) further optimized this step reaction, although it improved to a certain extent Part of the yield has been achieved, but it is only maintained at about 60%. However, the reaction is also carried out under the condition of a large excess of acetic acid. The post-treatment is extracted and concentrated by ethyl acetate and water, and then crystallized. The processing procedure is cumbersome and the efficiency is not high.
[0008] Solid acid catalyzed dehydration is a research hotspot in the field of catalysis, such as heteropoly acids, metal oxides, zeolites and acidic clay minerals; although the catalyst supported by phosphotungstic acid has strong acidity, which is beneficial to the dehydration reaction, the reaction is easy to coke , and the catalyst has poor thermal stability and is easily deactivated; and the surface acidity and pore structure of the catalyst and support affect the catalytic performance

Method used

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  • Solid acid catalyst for preparing antitumor drug intermediate and preparation method of solid acid catalyst
  • Solid acid catalyst for preparing antitumor drug intermediate and preparation method of solid acid catalyst
  • Solid acid catalyst for preparing antitumor drug intermediate and preparation method of solid acid catalyst

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Preparation of solid acid catalyst:

[0035] 1) Modification of alumina with acetic acid: put 10g of acidic aluminum oxide in 100mL of 20V% acetic acid aqueous solution, stir at 60°C for 2 hours at high speed, then filter, wash the filter cake with purified water until the pH of the filtrate reaches 5-6, and then Dry the filter cake at 110°C to constant weight, and finally crush it until the particle size is less than 30 microns to obtain acid-modified alumina;

[0036]2) Alumina-supported silica: put 5.5g tetraethyl orthosilicate in 30ml 5V% acetic acid aqueous solution, stir at 40°C for 30min to obtain a gelatinous silica gel; add 2.1g step 1) Prepare the acid-modified alumina, heat up to 80°C and stir for 9 hours, then concentrate the solvent under reduced pressure at 60°C, dry under reduced pressure at 60°C to constant weight, and then pulverize to a particle size of less than 20 microns to obtain catalyst support precursor;

[0037] 3) Preparation of solid acid c...

Embodiment 2

[0039] Preparation of solid acid catalyst:

[0040] 1) Modification of alumina with acetic acid: put 10g of acidic aluminum oxide in 100mL of 20V% acetic acid aqueous solution, stir at 60°C for 2 hours at high speed, then filter, wash the filter cake with purified water until the pH of the filtrate reaches 5-6, and then Dry the filter cake at 110°C to constant weight, and finally crush it until the particle size is less than 30 microns to obtain acid-modified alumina;

[0041] 2) Alumina-supported silica: put 5.5g tetraethyl orthosilicate in 30ml 5V% acetic acid aqueous solution, stir at 40°C for 30min to obtain gelatinous silica gel; add 2.6g step 1) Prepare the acid-modified alumina, heat up to 80°C and stir for 9 hours, then concentrate the solvent under reduced pressure at 60°C, dry under reduced pressure at 60°C to constant weight, and then pulverize to a particle size of less than 20 microns to obtain catalyst support precursor;

[0042] 3) Preparation of solid acid ca...

Embodiment 3

[0044] Preparation of solid acid catalyst:

[0045] 1) Modification of alumina with acetic acid: put 10g of acidic aluminum oxide in 100mL of 20V% acetic acid aqueous solution, stir at 60°C for 2 hours at high speed, then filter, wash the filter cake with purified water until the pH of the filtrate reaches 5-6, and then Dry the filter cake at 110°C to constant weight, and finally crush it until the particle size is less than 30 microns to obtain acid-modified alumina;

[0046] 2) Alumina-supported silica: put 5.5g tetraethyl orthosilicate in 30ml 5V% acetic acid aqueous solution, stir at 40°C for 30min to obtain a gelatinous silica gel; add 2.4g step 1) Prepare the acid-modified alumina, heat up to 80°C and stir for 9 hours, then concentrate the solvent under reduced pressure at 60°C, dry under reduced pressure at 60°C to constant weight, and then pulverize to a particle size of less than 20 microns to obtain catalyst support precursor;

[0047] 3) Preparation of solid acid ...

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Abstract

The invention belongs to the technical field of drugs and particularly relates to a solid acid catalyst for preparing an antitumor drug intermediate and a preparation method of the solid acid catalyst. The preparation method comprises the steps of treating acid aluminum oxide by virtue of acetic acid, hybridizing acid aluminum oxide with silica sol so as to prepare an aluminum oxide-silicon dioxide composite carrier, and finally, loading ammonium phosphomolybdate, so as to obtain the novel solid acid catalyst. The prepared solid acid catalyst can be used for catalyzing dehydration cyclizationreaction between 2-(3-methoxy-6,6-dimethyl-2-oxocyclohexyl-3-ene-1-yl)- 2-oxo-ethyl acetate and methylhydrazine so as to produce an antitumor drug intermediate, so that compared with prior art, the yield and the quality of the product are substantially increased.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a solid acid catalyst for preparing antitumor drug intermediates and a preparation method thereof. Background technique [0002] PHA-848125 (milciclib, compound 1), chemical name 8-[4-(4-methylpiperazin-1-yl)anilino]-1,4,4-trimethyl-4,5-dihydro -1H-pyrazolo[4,3-h]quinazoline-3-carboxamide is a kind of oral cyclin dependent kinases (cyclin dependent kinases) inhibitor developed by Italy NervianoMedical Sciences company, the structural formula of compound 1 is as follows Shown: [0003] [0004] In 2012, the drug was granted orphan drug certification by the US FDA and the European EMA for the treatment of malignant thymoma and thymic epithelial tumors. A key intermediate in the synthesis of compound 1 is ethyl 1,4,4-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (defined as compound 3), which is composed of ethyl 2-(3-methoxy-6,6-dimethyl-2-oxocycl...

Claims

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Application Information

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IPC IPC(8): B01J27/19B01J37/03B01J37/08B01J38/52B01J38/62B01J38/02C07D231/56
CPCY02P20/584
Inventor 张法军李法成刘凤珍王健林陈伯达
Owner 广东君奇医药科技有限公司
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