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Preparation method of palbociclib intermediate

An intermediate and reaction time technology, which is applied in the field of preparation of Palbociclib intermediates, can solve the problems of many three wastes, many reaction steps, difficult process amplification, etc., and achieves the advantages of simple reaction system, short reaction time and shortened reaction time. Effect

Pending Publication Date: 2022-02-01
CHANGZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This process route has many reaction steps, produces more three wastes, and uses hazardous chemicals, so it is not easy to scale up the process

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

example 1

[0030] Preparation of 5-bromo-2-chloro-4-cyclopentylaminopyrimidine (Ⅱ)

[0031] The molar ratio of 5-bromo-2,4-dichloropyrimidine to cyclopentylamine is 1:1.2, and the mass ratio of 5-bromo-2,4-dichloropyrimidine to triethylamine is 1:3.1.

[0032] Take 5-bromo-2,4-dichloropyrimidine (7g, 0.03072mol) in a 100ml flask, add triethylamine (21.84g, 0.21583mol), and slowly add cyclopentylamine (3.14g, 0.03686mol), after the dropwise addition, react for 0.5h, TLC detects that the raw material has reacted completely, stop the reaction, remove triethylamine by rotary evaporation, add 30ml of water, stir for 1h and then filter with suction, wash the filter cake with 14ml of n-heptane, 50°C Dry under reduced pressure to obtain 7.66 g of white crystals, yield: 90.2%.

[0033] Preparation of 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Ⅳ)

[0034] The molar ratio of 5-bromo-2-chloro-4-cyclopentylaminopyrimidine to crotonic acid, diisopropylethylamine, palladium acet...

example 2

[0037] Preparation of 5-bromo-2-chloro-4-cyclopentylaminopyrimidine (Ⅱ)

[0038] The molar ratio of 5-bromo-2,4-dichloropyrimidine to cyclopentylamine is 1:1.15, and the mass ratio of 5-bromo-2,4-dichloropyrimidine to diisopropylethylamine is 1:3.1.

[0039] Take 5-bromo-2,4-dichloropyrimidine (5g, 0.0219mol) in a 100ml flask, add diisopropylethylamine (15.64g, 0.1210mol), and slowly add cyclopentylamine ( 2.15g, 0.0252mol), after the dropwise addition, react for 0.5h, TLC detects that the reaction of the raw materials is complete, stop the reaction, rotary evaporate most of the diisopropylethylamine, add 20ml of water, stir for 1h and then filter with suction, use 10ml of diisopropylethylamine for the filter cake Washed with n-heptane, dried under reduced pressure at 50°C to obtain 5.43 g of white crystals, yield: 89.5%.

[0040] Preparation of 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Ⅳ)

[0041] The molar ratio of 5-bromo-2-chloro-4-cyclopentylamino...

example 3

[0044] Preparation of 5-bromo-2-chloro-4-cyclopentylaminopyrimidine (Ⅱ)

[0045] The molar ratio of 5-bromo-2,4-dichloropyrimidine to cyclopentylamine is 1:1.2, and the mass ratio of 5-bromo-2,4-dichloropyrimidine to tripropylamine is 1:3.0.

[0046] Take 5-bromo-2,4-dichloropyrimidine (5g, 0.0219mol) in a 100ml flask, add tripropylamine (15.06g, 0.1051mol), and slowly add cyclopentylamine (2.24g, 0.02628 mol), after the dropwise addition, react for 0.5h, TLC detects that the reaction of the raw materials is complete, stop the reaction, distill off part of tripropylamine, add 30ml of water, stir for 1h and then filter with suction, wash the filter cake with 10ml of n-heptane, and dry under reduced pressure at 50°C , to obtain 5.29 g of white crystals, yield: 87.2%.

[0047] Preparation of 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Ⅳ)

[0048] The molar ratio of 5-bromo-2-chloro-4-cyclopentylaminopyrimidine to crotonic acid, diisopropylethylamine, pallad...

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Abstract

The invention discloses a preparation method of a palbociclib intermediate, and belongs to the field of chemical synthesis. The method specifically comprises the following steps: a) carrying out a substitution reaction on 5-bromine-2, 4-dichloropyrimidine and cyclopentylamine under the condition of taking organic alkali as a solvent to obtain 5-bromine-2-chloro-4-cyclopentylaminopyrimidine; and b) under the condition of an organic solvent, adding a palladium catalyst, polyethylene glycol, organic alkali, 5-bromine-2-chloro-4-cyclopentyl aminopyrimidine and butenoic acid to carry out a heck reaction, and after the reaction is completed, adding acetic anhydride to carry out dehydration and ring closing to obtain the intermediate 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2, 3-d] pyrimidine-7-ketone. The organic alkali is used as the solvent in the step a), the reaction system is simpler, the reaction time is short, and the yield is higher. In the step b), polyethylene glycol is used as a palladium catalyst ligand to replace a traditional expensive phosphine ligand, so that the reaction time is shortened, the reaction effect is better, and acetic anhydride can be directly added for dehydration and ring closure without treatment.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a preparation method of a palbociclib intermediate. Background technique [0002] The commodity palbociclib (trade name Ibrance) is the world's first CDK4 / 6 inhibitor developed by Pfizer. In 2015, the US Food and Drug Administration approved and approved palbociclib for the treatment of postmenopausal patients. Women's ER + , HER2 - patients with advanced breast cancer. Palbociclib Chinese chemical name: 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)pyridin-2-yl]amino]-8H-pyridine And[2,3-d]pyrimidin-7-one, molecular formula: C 24 h 29 N 7 o 2 , CAS No.: 571190-30-2. The structural formula is as follows: [0003] [0004] 2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (compound IV) is a key intermediate for the synthesis of palbociclib, and its structural formula is as follows: [0005] [0006] The synthetic routes reported i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 邱滔周云港吕新宇孙益群
Owner CHANGZHOU UNIV
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