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Preparation method for Palbociclib

A technology of pyridine and methyl, which is applied in the field of preparation of the anticancer drug palbociclib, which can solve the problems of difficult synthesis of organic phosphine ligands, increased difficulty of use, harsh reaction conditions, etc., and achieves low price and short production cycle , the effect of stable quality

Active Publication Date: 2016-09-07
河北泽运生物医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Among them, the first step of the Heck reaction uses transition metal palladium and organophosphine ligands as catalysts. The organophosphine ligands have problems such as difficult synthesis and high price, and are very sensitive to water and air, which makes the reaction conditions harsh and increases the use of difficulty
This series of reasons makes the whole reaction cost expensive, which is not conducive to its industrialization

Method used

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  • Preparation method for Palbociclib
  • Preparation method for Palbociclib
  • Preparation method for Palbociclib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Step 1: 4-{6-[6-(1-Butoxy-vinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2, Synthesis of 3-d]pyrimidin-2-ylamino)-pyridin-3-yl}-piperazine-1-carboxylate tert-butyl ester

[0047] 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (9.8g, 0.017mol), DMF (98ml), vinyl n-butyl ether (17g, 0.17mol), K 2 CO 3 (5.27g, 0.041mol), Pd 2 dba 3 (1.6g, 0.17mmol) and DABCO (0.23 g, 2.04mmol) were added to the reaction flask, heated to 80-85°C for 10h, TLC detected that the reaction was over, cooled to 30°C, filtered, added 98ml of purified water, and crystallized , suction filtration, and vacuum drying at 60°C for 5h to obtain 4-{6-[6-(1-butoxy-vinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8- Dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (9.5 g, yield 94%).

[0048] Step 2: 6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-y...

Embodiment 2

[0053] Step 1: 4-{6-[6-(1-Butoxy-vinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2, Synthesis of 3-d]pyrimidin-2-ylamino)-pyridin-3-yl}-piperazine-1-carboxylate tert-butyl ester

[0054] 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.8g, 0.010mol), DMF (58ml), vinyl n-butyl ether (10g, 0.10mol), K 2 CO 3 (3.3g, 0.024mol), Pd 2 dba 3 (0.091g, 0.10mmol) and DABCO (0.13 g, 112.17, 1.2mmol) were added to the reaction flask, heated to 80-85°C for 12h, TLC detected the end of the reaction, cooled to about 20°C, filtered, and added 58ml of purified water , crystallization, suction filtration, and vacuum drying at 60°C for about 5h to obtain 4-{6-[6-(1-butoxy-vinyl)-8-cyclopentyl-5-methyl-7-oxo- tert-butyl 7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl}-piperazine-1-carboxylate (5.6g, yield 93%) .

[0055] Step 2: 6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(pi...

Embodiment 3

[0060] Step 1: 4-{6-[6-(1-Butoxy-vinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2, Synthesis of 3-d]pyrimidin-2-ylamino)-pyridin-3-yl}-piperazine-1-carboxylate tert-butyl ester

[0061] 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino) -pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (9.8g, 0.017mol), DMF (98ml), vinyl n-butyl ether (17g, 0.17mol), K 2 CO 3 (5.27g, 0.041mol), Pd 2 dba 3 (1.6g, 0.17mmol) and DABCO (0.23 g, 2.04mmol) were added to the reaction flask, heated to 80-85°C for 10h, TLC detected the end of the reaction, cooled to 15°C, filtered, added 58ml of purified water, and crystallized , suction filtration, and vacuum drying at 60°C for 5h to obtain 4-{6-[6-(1-butoxy-vinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8- Dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (9.5 g, yield 94%).

[0062] Step 2: 6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)p...

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Abstract

The invention relates to a preparation method for Palbociclib. The method comprises the following steps: taking 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridino[2,3-d]pyridine-2-yl-amino)-pyridine-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a starting raw material; performing Heck reaction, rearrangement, deprotection and neutral reaction to obtain the Palbociclib, wherein the total yield is 70 to 80 percent. According to the preparation method disclosed by the invention, non-Pd-catalyzed heck reaction is investigated, such that a phosphorus-containing ligand which is high in cost and needs harsh reaction conditions is avoided, and the production cost and the technological operation risk are reduced; acetylchloride is used for rearrangement and deprotection reaction to obtain Palbociclib hydrochloride, and the Palbociclib hydrochloride is alkalized to obtain the high-purity Palbociclib.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of an anticancer drug palbociclib. Background technique [0002] Palbociclib (English name: Palbociclib) is a new anticancer drug for the treatment of breast cancer developed by Pfizer Products Company of the United States. Its structural formula is as follows: [0003] [0004] Palbociclib, an inhibitor of cyclin-dependent kinase (CDK) 4 and 6, is an inhibitor of Rb-positive tumor cell proliferation, which prevents cells from entering the S phase of the cell cycle and causes G1 phase arrest. In vivo pharmacology showed that PD-0332991 had antitumor effects against a variety of Rb-positive tumors, with tumor regression or tumor stasis. PD-0332991 and letrozole treatment resulted in reproducible therapeutic outcomes in in vitro findings. [0005] Pfizer's palbociclib capsules (brand name IBRANCE ® ) was granted Breakthrough Thera...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 胡永亮武倩倩范丽佳
Owner 河北泽运生物医药科技有限公司
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