Preparation method of Palbociclib intermediate

A technology for pabociclib and intermediates, which is applied in the field of preparation of pabociclib intermediates, can solve the problems of unavailable raw materials and low operability of process routes, and achieve stable process, strong operability, The effect of less by-products

Active Publication Date: 2018-07-20
HANGZHOU FST PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, the raw materials of this route are not easy to obtain, and the operability of the process route is not high.

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

[0041] 1) Preparation of Intermediate II:

[0042] The ratio of the amount of feed material is 5-bromo-2,4-dichloropyrimidine I: cyclopentylamine: triethylamine=1.0: 1.3: 1.3.

[0043] 5-Bromo-2,4-dichloropyrimidine I (227.9g, 1mol), ethanol (276g, 6mol) were successively added to a 2L three-necked flask, triethylamine (131.5g, 1.3mol) was added at -15°C, and cyclohexanol was added dropwise Amylamine (106.2g, 1.3mol) in ethanol (92g, 2mol), react for 2-3 hours, filter the solid, take the filter cake in a 2L reaction flask, add petroleum ether (600g), stir for 1 hour, and filter again , the filter cake was washed with petroleum ether (100 g). The filter cake was collected and vacuum-dried at 40°C to obtain 243.4g of intermediate II, a white solid, with a yield of 88%, a melting point of 442-443.5°C, and a HPLC purity of 99.8%.

[0044] Hydrogen spectrum and mass spectrometry characterization of intermediate II:

[0045] 1 H NMR (600MHz, CDCl 3 ): δ8.09(s, 1H), 5.54(d, J=4....

Embodiment 2

[0062] 1) Preparation of Intermediate II:

[0063] The ratio of the amount of feed material is 5-bromo-2,4-dichloropyrimidine:cyclopentylamine:triethylamine=1.0:1.3:1.3.

[0064] Add 5-bromo-2,4-dichloropyrimidine (227.9g, 1mol) and isopropanol (360g, 6mol) successively into a 2L three-necked flask, add triethylamine (131.5g, 1.3mol) at -15°C, dropwise Cyclopentylamine (106.2g, 1.3mol) in isopropanol (120g, 2mol) solution, reacted for 2 to 3 hours, filtered the solid, took the filter cake in a 2L reaction flask, added petroleum ether (600g), stirred for 1 hour, Suction filtration was performed again, and the filter cake was washed with petroleum ether (100 g). The filter cake was collected and vacuum-dried at 40°C to obtain 262.8g of intermediate II, a white solid, with a yield of 95%, a melting point of 442-443.5°C, and an HPLC purity of 99.7%.

[0065] 2) Preparation of Intermediate III:

[0066] The ratio of the amount of the feed material is intermediate II: crotonic ac...

Embodiment 3

[0075] 1) Preparation of Intermediate II:

[0076] The ratio of the amount of feed material is 5-bromo-2,4-dichloropyrimidine:cyclopentylamine:diisopropylethylamine=1.0:1.3:1.3.

[0077] Add 5-bromo-2,4-dichloropyrimidine (227.9g, 1mol) and isopropanol (360g, 6mol) in sequence to a 2L three-necked flask, and add diisopropylethylamine (167.7g, 1.3mol) at -15°C , drop cyclopentylamine (106.2g, 1.3mol) in isopropanol (120g, 2mol) solution, react for 2 to 3 hours, filter the solid, take the filter cake in a 2L reaction flask, add petroleum ether (600g), stir After 1 hour, suction filtered again, and the filter cake was washed with petroleum ether (100 g). The filter cake was collected and vacuum-dried at 40°C to obtain 260.0 g of intermediate II, a white solid, with a yield of 94%, a melting point of 442-443.5°C, and a HPLC purity of 99.9%.

[0078] 2) Preparation of Intermediate III:

[0079] The ratio of the amount of the feed material is intermediate II: crotonic acid: triet...

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Abstract

The invention relates to the field of medicine synthesis, and discloses a preparation method of a Palbociclib intermediate. In the preparation process, 5-bromine-2,4-dichloropyrimidine is used as a starting raw material; through ammoniation substitution reaction, green solvent PEG (polyethylene glycol) promotion palladium catalysis coupled reaction, BTC (triphosgene) promotion cyclization reactionand NBS (N-bromosuccinimide) bromination reaction, a target compound V is finally obtained; through aftertreatment improvement, the HPLC purity of the final product can reach 99 percent or higher. Compared with a traditional process, the preparation method has the main beneficial effects that the reaction conditions are mild; the operation is simple and convenient; the palladium catalyst consumption is low; the yield is high; the cost is low; the three-waste quantity is small; the industrialization is easy; high implementation values and socioeconomic benefits are realized.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of a palbociclib intermediate. Background technique [0002] Palbociclib is a cyclin-dependent kinase (CDK4 / 6) inhibitor developed by Pfizer for the treatment of advanced breast cancer in postmenopausal women. Pabociclib can act on the key nodes of cell mitosis and decisively inhibit the crazy proliferation of cancer cells. Relevant agencies predict that the sales of palbociclib will reach US$4.722 billion in 2020, which can be said to have broad market prospects. [0003] The chemical name of palbociclib is 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]pyrido[2 , 3-d]pyrimidin-7(8H)-one, the structure is as follows: [0004] [0005] In the current synthetic method of palbociclib reported in the literature, the key lies in how to efficiently construct the key intermediate parent ring molecule 6-bromo-2-chloro-8-cyclopentyl-5-methyl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 许伟凌飞古大军司体明钟为慧方璐
Owner HANGZHOU FST PHARMA
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