Novel synthesis method of CDK4 (cyclin-dependent kinase 4) inhibitor

A synthetic method and inhibitor technology, applied in the field of medicine, can solve problems such as harsh reaction conditions, difficulty in industrial production, and low yield of intermediate preparation

Active Publication Date: 2015-09-09
BEIJING KANG LISHENG PHARMA TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In summary, there are following defects in the process of preparing palbociclib; the yield of intermediate preparation is too low, and a lot of complex noble metal auxiliary reagents are used, and organometallic reagents with harsh reaction conditions are not easy to industrialize Production

Method used

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  • Novel synthesis method of CDK4 (cyclin-dependent kinase 4) inhibitor
  • Novel synthesis method of CDK4 (cyclin-dependent kinase 4) inhibitor
  • Novel synthesis method of CDK4 (cyclin-dependent kinase 4) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Embodiment 1: the synthesis of intermediate (1)

[0063] Add 13.2g of 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, 6.2g of acetyl chloride, and 65ml of chloroform into the reaction flask, stir to dissolve , the temperature was lowered to 0°C, 10g of anhydrous aluminum chloride was added to the system, the temperature was kept at 10°C for 1 hour, the temperature was raised to 60°C, and the reaction was continued for 4 hours. TLC monitoring (petroleum ether: ethyl acetate = 5: 1) until the reaction at the raw material point was basically complete. Lower the feed solution to room temperature, add 30ml of dilute hydrochloric acid, stir for 5 minutes, let stand, separate the liquid, wash the organic phase with water, wash the organic phase with an appropriate amount of 5% sodium hydroxide solution, wash the organic phase with water, dry over anhydrous sodium sulfate, and filter with suction , concentrated to dryness under reduced pressure at 40°C to obta...

Embodiment 2

[0064] Embodiment 2: the synthesis of intermediate (2)

[0065] Dissolve 10g of the above-mentioned oil intermediate (1) in 100ml of DMF, add 9g of potassium carbonate and 11.8g of tert-butyl 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylate, stir and heat up To 80°C, keep warm at 85°C and stir for 4 hours. TLC (petroleum ether: ethyl acetate = 1:2) monitors, after the starting point disappears, cool down to room temperature. Pour the feed liquid into water, a large amount of orange-yellow solid is precipitated, filter, wash the filter cake with a large amount of water until the mother liquor is neutral, dry at 50°C, and dry to obtain 14.2g of crude yellow solid, add 300ml of DMSO and heat until dissolved, cool down, and filter with suction. The filter cake was washed with a small amount of ethanol, and dried under reduced pressure at 50°C to obtain 12.5 g of bright yellow intermediate (2). Overall yield: 70%. 1 H NMR (500MHz, DMSO-d 6 ): δ8.15(s, 1H), 7.83(s, 1H), 7.03(d,...

Embodiment 3

[0066] Embodiment 3: the synthesis of compound I

[0067] Add 10 g of intermediate (2) into a mixed solution of 100 ml of acetone and 200 ml of water, stir until the material is uniformly dispersed, add 12 ml of 35% concentrated hydrochloric acid, and heat up to 50° C. for 10 hours. TLC (dichloromethane:methanol, 10:1) monitored until the starting point disappeared. Cool down to 10°C, slowly add 13g of triethylamine to the system until pH > 9, stir well until a large amount of solids are precipitated, continue stirring for 3 hours, filter with suction, wash the filter cake with water until neutral. Dry at 40°C until dry to obtain 7.28g yellow solid I crude product, dissolve the crude product in 150ml n-butanol and 150ml anisole mixture, heat to 100-110°C until dissolved, add 0.5g activated carbon, reflux for 30min and heat filter, The mother liquor was allowed to crystallize naturally at room temperature, filtered, and dried at 40°C to obtain 6.8 g of bright yellow solid comp...

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Abstract

The invention relates to a novel synthesis method of a CDK4 (cyclin-dependent kinase 4) inhibitor. A reaction of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one with acetylchloride is taken as an initial reaction, consequent reactions are performed, and the CDK4 inhibitor is prepared; the preparation method is simple and easy to implement, the yield is high, the quality is high, and industrial production is facilitated.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a method for synthesizing a novel CDK4 inhibitor. Background technique [0002] Palbociclib (Palbociclib), chemical name 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyridine And[2,3-d]pyrimidin-7-one, American Chemical Abstracts registration number CAS: 571190-30-2, structure: [0003] [0004] Palbociclib is an oral cyclin-dependent kinase (CDKs) 4 / 6 inhibitor. CDKs 4 / 6 are key regulators of the cell cycle, which can trigger cell cycle progression. The indication of IBRANCE in the United States is combined with letrozole for the treatment of estrogen receptor positive, human epidermal growth factor receptor 2 negative (ER+ / HER2-) postmenopausal patients with advanced breast cancer, as an initial endocrine therapy-based regimen Treatment of metastatic disease. [0005] The FDA reviewed and approved IBRANCE on the basis of the Breakthrough Therapy Des...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/519A61K9/22A61P35/00
CPCA61K9/0002A61K9/0053A61K9/2009A61K9/2013A61K9/2031A61K9/2054C07D471/04
Inventor 程刚
Owner BEIJING KANG LISHENG PHARMA TECH DEV
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