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Novel intermediate of palbociclib, and crystal form and preparation method of novel intermediate

A crystal form, piperazine-based technology, applied in the field of medicinal chemistry, can solve the problems of high process cost, low yield, unsuitable for industrial production and the like

Inactive Publication Date: 2020-11-06
QILU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The post-treatment of this route produces a large amount of waste liquid, and the yield is not high (83%). The obtained compound III crude product needs to be further purified, and the process cost is relatively high, so it is not suitable for industrial production.

Method used

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  • Novel intermediate of palbociclib, and crystal form and preparation method of novel intermediate
  • Novel intermediate of palbociclib, and crystal form and preparation method of novel intermediate
  • Novel intermediate of palbociclib, and crystal form and preparation method of novel intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1, 4-(6-(8-cyclopentyl-5-methyl-7-oxo-6-(1-propoxyvinyl)-7,8-dihydropyridine Preparation of [2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-piperazinyl-1-carboxylic acid tert-butyl ester

[0038] Under nitrogen protection, 180ml of n-propanol was added into the reaction flask, and the stirring was started. 20.0 g of compound II and 10.6 g of diisopropylethylamine were added. 9.0 g of propyl vinyl ether, 0.3 g of palladium acetate and 0.9 g of bis(2-phenylphosphorylphenyl)ether were added. The temperature was raised to 85-95° C., and after 5 hours of incubation, the reaction was detected by TLC. Add 180 ml of n-heptane. Cool down to 5-15°C, keep warm and crystallize for 2.5h. Suction filter and wash with n-propanol-n-heptane mixed solution. After drying at 75°C for 5 h, 18.4 g of compound I was obtained, with a yield of 91.2% and a purity of 99.5%.

Embodiment 2

[0039] Example 2, 4-(6-(8-cyclopentyl-5-methyl-7-oxo-6-(1-propoxyvinyl)-7,8-dihydropyridine Preparation of [2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-piperazinyl-1-carboxylic acid tert-butyl ester

[0040] Under nitrogen protection, 160ml of ethanol was added into the reaction flask, and the stirring was started. 20.0 g of compound II and 10.6 g of diisopropylethylamine were added. 9.0 g of propyl vinyl ether, 0.3 g of palladium acetate and 0.9 g of bis(2-phenylphosphorylphenyl)ether were added. The temperature was raised to 75-78°C, and after 8 hours of incubation, the reaction was detected by TLC. 180 ml of isopropyl ether was added. Cool down to 5-15°C, keep warm and crystallize for 2.5h; filter with suction and wash with a mixed solution of isopropyl ether. After drying at 75°C for 5 h, 18.8 g of compound I was obtained, with a yield of 93.2% and a purity of 99.2%.

Embodiment 3

[0041] Example 3, 4-(6-(8-cyclopentyl-5-methyl-7-oxo-6-(1-propoxyvinyl)-7,8-dihydropyridine Preparation of [2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-piperazinyl-1-carboxylic acid tert-butyl ester

[0042]Under nitrogen protection, 160ml of n-butanol was added into the reaction flask, and the stirring was started. 20.0 g of compound II and 10.6 g of diisopropylethylamine were added. 9.0 g of propyl vinyl ether, 0.3 g of palladium acetate and 0.9 g of bis(2-phenylphosphorylphenyl)ether were added. The temperature was raised to 85-95° C., and after 4 hours of incubation, the reaction was detected by TLC. Add 200ml of n-heptane. Cool down to 5-15°C, keep warm and crystallize for 2.5h; filter with suction and wash with a mixed solution of n-butanol and n-heptane. After drying at 75°C for 5 h, 18.2 g of compound I was obtained, with a yield of 90.2% and a purity of 99.3%.

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel intermediate of palbociclib, namely 4-(6-(8-cyclopentyl-5-methyl-7-oxo-6-(1-propoxyvinyl)-7,8-dihydropyrido[2, 3-d]pyrimidin-2-ylamino)pyridin-3-yl)-piperazinyl-1-carboxylic acid tert-butyl ester, and a crystal form and a preparation method of the novel intermediate. The method is simple in technological operation and post-treatment, a crystallization solvent is easy to recycle, cost is low, and the obtained intermediate is easy to crystallize, good in stability, good in purity, high in yield and more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a new palbociclib intermediate 4-(6-(8-cyclopentyl-5-methyl-7-oxo-6-(1-propoxyvinyl) )-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-piperazinyl-1-carboxylic acid tert-butyl ester and its crystal form and preparation method. Background technique [0002] Palbociclib, English name is Palbociclib, chemical name: 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino} Pyrido[2,3-d]pyrimidin-7(8H)-one. Palbociclib is an inhibitor of cyclin-dependent kinases CDK4 and CDK6 developed by Pfizer. It is clinically suitable for the treatment of estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative in combination with letrozole. Postmenopausal women with advanced breast cancer, as an initial endocrine therapy-based regimen for metastatic disease. This product was approved for marketing by the US FDA on Februa...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07B2200/13C07D471/04
Inventor 张涛单茂华尹燕振初乐玲刘荣旺仉明范传文
Owner QILU PHARMA
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