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A crystalline form of a cyclin-dependent protein kinase inhibitor and a preparation method thereof

A crystallization and solvent technology, which is applied in the direction of pharmaceutical formulations, organic active ingredients, and medical preparations containing active ingredients, etc., can solve problems such as easy agglomeration, poor product stability, and difficult filtration, and achieve repeatable and controllable production processes. Good crystal form stability and stable production process

Active Publication Date: 2018-12-28
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally speaking, amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, poor fluidity, etc.

Method used

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  • A crystalline form of a cyclin-dependent protein kinase inhibitor and a preparation method thereof
  • A crystalline form of a cyclin-dependent protein kinase inhibitor and a preparation method thereof
  • A crystalline form of a cyclin-dependent protein kinase inhibitor and a preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Take (1.0g, 2.24mmol) the compound shown in formula (I) (prepared according to the method provided by WO2014183520) and add it to a 250ml Erlenmeyer flask, add 40ml ethanol, stir at room temperature, then drop dilute hydrochloric acid (219mg, 6.01mmol) (dissolved in 4ml of water), heated to 60°C, dissolved, dropped into sodium hydroxide solution (576mg, 14.40mmol) (dissolved in 40ml of water), cooled to room temperature and stirred overnight. After drying, 0.88 g of solid was obtained, and the yield was 88.0%. The X-ray diffraction spectrum figure of this crystalline sample is shown in figure 1 . The crystallization at about 5.84 (15.12), 6.16 (14.35), 10.75 (8.22), 12.56 (7.04), 12.96 (6.82), 16.25 (5.45), 17.24 (5.14), 18.97 (4.67), 20.22 (4.39), 21.74 (4.08), 22.99(3.87), and 25.85(3.44) have characteristic peaks. See the DSC spectrum figure 2 , with a sharp melting endothermic peak at 294.42°C, this crystal form is defined as II crystal form.

Embodiment 2

[0036] Get (1.0g, 2.24mmol) compound shown in formula (I) (prepared by Example 1) and join in the 250ml Erlenmeyer flask, add 40ml methyl alcohol, stir at room temperature, drop dilute hydrochloric acid (219mg, 6.01mmol) then ( dissolved in 4ml of water), heated to 60°C, dissolved, dropped into sodium hydroxide solution (576g, 14.40mmol) (dissolved in 40ml of water), cooled to room temperature and stirred overnight. After drying, 0.86 g of solid was obtained, and the yield was 86.0%. Its X-diffraction and DSC patterns are researched and compared, and it is determined that the product is in the II crystal form.

Embodiment 3

[0038] Get (1.0g, 2.24mmol) the compound shown in formula (I) (prepared by Example 1) and join in the 250ml Erlenmeyer flask, add 40ml isopropanol, stir at room temperature, then drop dilute hydrochloric acid (219mg, 6.01mmol ) (dissolved in 4ml of water), heated to 60°C, dissolved, dropped into sodium hydroxide solution (576mg, 14.40mmol) (dissolved in 40ml of water), cooled to room temperature and stirred overnight. After drying, 0.90 g of solid was obtained, and the yield was 90.0%. Its X-diffraction and DSC patterns are researched and compared, and it is determined that the product is in the II crystal form.

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Abstract

Provided are a crystalline form of a cyclin-dependent protein kinase (CDK4&6) inhibitor and a preparation method thereof. Specifically, 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d ] type II crystal of pyrimidine-7(8H)-ketone (compound of formula (I)) and preparation method thereof, said crystal has X-ray powder diffraction pattern as shown in Figure 1, and it possesses good chemical stability and The crystal form is stable, and the crystallization solvent with low toxicity and low residue is used, which can be better used in clinical treatment.

Description

technical field [0001] The present invention relates to 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d] Pyrimidin-7(8H)-one and its crystalline form II. The compound of formula (I) prepared according to the method of the present invention can be used for the treatment of breast cancer. Background technique [0002] Breast cancer is one of the most common malignant tumors in women. It has a high incidence rate and is quite invasive, but the course of the disease progresses slowly. On February 1, 2010, the China Population Association released the "China Breast Disease Survey Report" in Beijing. The report shows that, The mortality rate of breast cancer in my country's urban areas has increased by 38.91%. Breast cancer has become the most threatening disease to women's health. Currently, there are at least 156 breast cancer drugs under research and on the market, of which 68% are targeted therapy drugs. A large number of studies It was fo...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/519A61K31/55A61P35/00
CPCA61K31/519A61K31/55C07D471/04
Inventor 武乖利高晓晖张全良卢韵吴玉霞
Owner JIANGSU HENGRUI MEDICINE CO LTD