Preparation method of palbociclib intermediate

A technology of intermediates and treatment methods, which is applied in the field of preparation of palbociclib intermediates, can solve problems such as high cost ratio, large amount of sewage, complex components, etc., and achieve reduction of solid waste discharge, reduction of three waste discharge, Emission reduction effect

Active Publication Date: 2021-04-16
SHANDONG BOYUAN PHARM CO LTD
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  • Abstract
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  • Claims
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AI Technical Summary

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

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1 Preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one

[0033] 110 grams (0.42mol) of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one, 1100 milliliters of acetonitrile were added successively to the 2000 milliliter reaction flask, 2.7 grams of oxalic acid, 55 grams of acetic anhydride and 89.7 grams (0.50 mol) of NBS, heated to 60 ° C for 12 hours, the reaction was completed, cooled to 0 ~ 10 ° C, kept warm for 4 hours, filtered, washed with 100 ml of acetonitrile, and dried to obtain 140 grams of white solid , yield 98.1%, HPLC purity 98.5%.

[0034] The reaction mother liquor is distilled to near dryness, 1150ml of purple liquid, 50g of sodium hydroxide solid is added, stirred at room temperature for 2h, filtered to obtain a colorless filtrate, distilled at normal pressure to obtain 1105ml of acetonitrile, the GC detection of this acetonitrile is 99.9%, moisture (cal method) 0.2%.

[0035] Add 200ml of water...

example 2

[0036] Example 2: Preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one

[0037] Add 110 grams (0.42mol) of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one successively to a 2000 ml reaction flask, and recover acetonitrile in 1100 ml , 2.7 g of oxalic acid, 55 g of acetic anhydride and 89.7 g (0.50 mol) of NBS, heated to 60 ° C for 12 hours, the reaction was completed, cooled to 0 ~ 10 ° C, kept warm for 4 h, filtered, washed with 100 ml of acetonitrile, dried to obtain a white solid 139 grams, yield 97.2%, HPLC purity 98.6%.

[0038] The reaction mother liquor was distilled to nearly dryness under atmospheric pressure, and 1130ml of purple liquid was added, 50g of sodium hydroxide solid was added, stirred at room temperature for 2h, and filtered to obtain a colorless filtrate, which was distilled under atmospheric pressure to obtain 1110ml of acetonitrile. 0.3%.

[0039]Add 200ml of water to dissolve the residue, adjust the p...

example 3

[0040] Example 3: Preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one

[0041] Add 870 kg of acetonitrile, 110 kg of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one, 2.7 kg of oxalic acid, 55g of acetic anhydride and 89.7kg of NBS were heated up to 60°C and reacted for 12 hours. After the reaction was completed, the temperature was lowered to 0-10°C, kept warm for 4h, centrifuged, washed with 80kg of acetonitrile, and dried to obtain 138.4kg of white solid with a yield of 96.9%. HPLC 98.4% purity.

[0042] Transfer the reaction mother liquor to the recovery kettle, and distill at normal pressure to obtain a total of 920 kg of purple-red liquid. Add 45 kg of sodium hydroxide to recovery acetonitrile, stir at room temperature for 4 hours, press filter, filter the hydraulic pressure to the secondary distillation kettle, wash the filter residue with water, and discharge into the sewage station. After secondary atmospheric distil...

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Abstract

The invention discloses a preparation method of a palbociclib intermediate, which comprises the following steps: by using 2-chlorine-8-cyclopentyl-5-methylpyrido [2, 3-D] pyrimidine -7 (8H) -ketone as a raw material, carrying out NBS bromination and cooling crystallization centrifugation under the catalysis of oxalic acid and acetic anhydride to obtain 6-bromine-2-chlorine-8-cyclopentyl-5-methylpyrido [2, 3-D] pyrimidine -7 (8H) -ketone; meanwhile, waste liquid generated in the preparation process is fully reutilized, three wastes are reduced, and the preparation method which is high in quality, low in cost, environmentally friendly and suitable for industrial production is provided.

Description

technical field [0001] The invention relates to a preparation method of a palbociclib intermediate, belonging to the field of drug synthesis. Background technique [0002] Since palbociclib was approved by the US FDA in 2015, it has been approved by the EU EMA and Japan's PDMA in 2016 and 2017. The sales of palbociclib capsules were 732 million US dollars in 2016. The sales volume was US$2.135 billion, and the sales in 2017 were US$3.126 billion. It is expected that the sales in 2020 will reach more than US$5 billion, marking that the drug has been recognized by patients and has become a blockbuster new drug. 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 acti...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 李太同张庆涛朱义胜
Owner SHANDONG BOYUAN PHARM CO LTD
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