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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  • Description
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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 procedur

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

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[0033] Example 1

[0034] Preparation of solid acid catalyst:

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

[0036] 2) Alumina supported silica: Put 5.5g of tetraethylorthosilicate in 30ml of 5V% acetic acid aqueous solution and stir at 40°C for 30min to obtain a gel-like silicone gel; add 2.1g to the silicone gel 1) The prepared acid-modified alumina is heated to 80°C and stirred for 9 hours, then the solvent is concentrated under reduced pressure at 60°C, dried under reduced pressure at 60°C to constant weight, and then crushed to a particle size of less than 20 microns to obtain a catalyst support Precursor

[0...

Example Embodiment

[0038] Example 2

[0039] Preparation of solid acid catalyst:

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

[0041] 2) Alumina supported silica: Put 5.5g of tetraethylorthosilicate in 30ml of 5V% acetic acid aqueous solution and stir at 40°C for 30min to obtain a gel-like silicone gel; add 2.6g to the silicone gel 1) The prepared acid-modified alumina is heated to 80°C and stirred for 9 hours, then the solvent is concentrated under reduced pressure at 60°C, dried under reduced pressure at 60°C to constant weight, and then crushed to a particle size less than 20 microns to obtain a catalyst support Precursor

[0042...

Example Embodiment

[0043] Example 3

[0044] Preparation of solid acid catalyst:

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

[0046] 2) Alumina supported silica: Put 5.5g of tetraethylorthosilicate in 30ml of 5V% acetic acid aqueous solution and stir at 40°C for 30min to obtain a gel-like silicone gel; add 2.4g to the silicone gel 1) The prepared acid-modified alumina is heated to 80°C and stirred for 9 hours, then the solvent is concentrated under reduced pressure at 60°C, dried under reduced pressure at 60°C to constant weight, and then crushed to a particle size less than 20 microns to obtain a catalyst support Precursor

[0047...

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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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