Preparation method of palbociclib intermediate

An intermediate and solid technology, which is applied in the field of preparation of palbociclib intermediates, can solve the problems of unfavorable final product palbociclib product popularization, unfavorable sewage treatment, unfavorable recycling, etc., to achieve the benefits of three wastes treatment, Ease of handling and reduction of environmental pollution

Active Publication Date: 2021-06-04
SHANDONG BOYUAN PHARM CO LTD
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  • Claims
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Problems solved by technology

[0007] The synthesis process uses 5-bromo-2,4-dichloropyrimidine as the starting material, which is cheap and easy to obtain, but the compound of formula (3) is prepared by using ethanol as a solvent, triethylamine as an acid-binding agent, and separating the product by adding water. Because of containing a large amount of triethylamine hydrochloride and ethanol in the waste water, the amount of sewage is large, and the composition is complicated, is unfavorable for the treatment of sewage, brings certain difficulty to the industrialization of product; Preparation formula (4) compound, adopts the acetic acid of 0.03 equivalent Palladium, because palladium acetate price is higher, and is unfavorable for recycling, therefore, accounts for formula (1) compound cost ratio is on the high side, accounts for 60~70% of total cost, is unfavorable for the product popularization of final product palbociclib
[0008] WO2016030439A1 reported that diisopropylethylamine was used as an acid-binding agent, bis(cyanophenyl)palladium dichloride was used as a catalyst, and tri(o-methylphenyl)phosphorus was used as a ligand to prepare the formula from formula (3) (4) Heck reaction route, but the amount of palladium catalyst still reaches 0.02 equivalent

Method used

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  • Preparation method of palbociclib intermediate
  • Preparation method of palbociclib intermediate
  • Preparation method of palbociclib intermediate

Examples

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Embodiment 1

[0035] Example 1 Synthesis of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one

[0036] (1) Preparation of 5-bromo-2-chloro-N-cyclopentamine-4 amine

[0037] Add 228 grams (1.0mol) of 5-bromo-2,4-dichloropyrimidine, 1500 milliliters of dichloromethane, 1000 milliliters of water and 127.2 grams (1.2mol) of sodium carbonate successively in the 5000ml reaction flask, cool to 0 ℃, keep 89.5 g (1.05 mol) of cyclopentylamine was added dropwise at a reaction temperature of 0-5°C, and the reaction was maintained at 0-5°C for 16 hours after addition. After the reaction is complete, remove the water layer, then add 1000 ml of water, adjust the pH value to 6-7 with hydrochloric acid, separate the water layer, and distill the dichloromethane layer under normal pressure to recover the dichloromethane, and the residue is decomposed with 1140 ml of n-hexane. After purification, the solid was collected by filtration and dried to obtain 261.0 g of 5-bromo-2-chloro-N-cyc...

example 2

[0043] Example 2: Synthesis of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one

[0044] (1) Preparation of 5-bromo-2-chloro-N-cyclopentamine-4 amine

[0045] Add 228 grams (1.0mol) of 5-bromo-2,4-dichloropyrimidine successively to a 5000ml reaction flask, recover dichloromethane at 1500, 1000 milliliters of water and 48 grams (1.2mol) of sodium hydroxide, cool to 0°C, Keeping the reaction temperature at 0-5°C, add 89.5 g (1.05mol) of cyclopentylamine dropwise, and keep at 0-5°C for 16 hours after the addition. After the reaction is complete, remove the water layer, add 1000 ml of water, adjust the pH value to 6-7 with hydrochloric acid, separate the water layer, and distill the dichloromethane layer under normal pressure, reclaim the dichloromethane, and use 1140ml of dichloromethane for the remainder. The n-hexane was refined, the solid was collected by filtration, and dried to obtain 262.5 g of 5-bromo-2-chloro-N-cyclopentaline-4amine as a white soli...

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Abstract

The invention discloses a preparation method of a palbociclib intermediate. The method comprises the following steps: preparing 5-bromine-2-chloro-N-cyclopentylamine pyrimidine-4 amine from 5-bromine-2,4-dichloropyrimidine and cyclopentylamine by taking solvents such as dichloromethane and water as solvents and taking inorganic base as an acid-binding agent; with DIEA as an acid-binding agent, DMF as a solvent and TBAB as a phase transfer catalyst, in the presence of water, catalyzing with a trace amount of palladium, and carrying out normal hexane reflux dehydration; further subjecting the acetic anhydride to dehydration cyclization, such that 2-chloro-8-cyclopentyl-5-methylpyridino[2,3-D]pyrimidine-7-(8H)-ketone is obtained; and reacting the obtained compound with NBS (N-bromosuccinimide) in acetonitrile to obtain the 6-bromo-2-chloro-8-cyclopentyl-5-methylpyridino[2, 3-D]pyrimidine-7(8H)-ketone. The method is mild in reaction, simple and convenient to operate, recyclable in solvent, less in environmental pollution, high in yield, low in cost, high in product quality and suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a palbociclib intermediate, belonging to the field of chemical synthesis. Background technique [0002] Palbociclib (Palbociclib), the chemical name is 2-[(4-piperidinyl)benzyl]-6-acetyl-8-cyclopentyl-5-methylpyrido[2,3-d] Pyrimidin-7(8H)-one, developed by Pfizer, was the first to be approved for marketing in the United States in February 2015. It is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6, mainly by regulating the cell cycle, inhibiting (CDK) 4 and 6 activities to prevent cells from G1 phase to S phase and then inhibit DNA synthesis; it is mainly used clinically to treat patients with advanced breast cancer. [0003] Formula (1) compound 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one is the key intermediate for the synthesis of palbociclib body, the English name is 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]py-rimidin-7(8H)-one, the CAS number is 1016636...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 李太同朱义胜周朋李斌高波
Owner SHANDONG BOYUAN PHARM CO LTD
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