Preparation method of palbociclib intermediate

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...

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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

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