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Preparation method of palbociclib parent nucleus structure compound

A technology of compound and mother nucleus, which is applied in the field of preparation of palbociclib mother nucleus structure compound, can solve the problems of many side reactions, unguaranteed purity and difficulty in obtaining

Active Publication Date: 2020-07-03
SHANDONG MAYOHUAWEI TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The original research patents WO2003062236, WO2012018540, etc. all reported the synthesis method of palbociclib. There are two main synthetic routes, both of which use the 2-position side chain reaction of the palbociclib mother nucleus, and then modify the 6-position to obtain palbociclib. Cicrib; patent WO2014128588 reported the preparation method of the palbociclib core (reaction scheme is as follows), but the inventors found that due to the main starting material 2,4,5-trisubstituted pyrimidine raw material (such as in the report patent What adopt is 5-bromo-2,4-dichloropyrimidine) is difficult to obtain, and the halogen of similar activity causes selectivity poorer, and side reaction is more and causes purification difficulty, causes purity to not be guaranteed, and overall this parent nucleus Increased difficulty of industrial production

Method used

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  • Preparation method of palbociclib parent nucleus structure compound
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  • Preparation method of palbociclib parent nucleus structure compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1 Preparation of 2-chloro-4-aminopyrimidine (intermediate 1)

[0061] Under the condition of mechanical stirring, add cytosine (57.05g, 0.5mol), phosphorus pentachloride (312.36g, 1.5mol) and 570mL of toluene into the reaction flask, stir well, heat up to 110°C for reflux reaction, TLC monitoring The reaction of the raw materials was completed; concentrated under reduced pressure to remove most of the solvent, lowered to room temperature, added 500 mL of water, extracted several times with dichloromethane, combined the organic phases, dried with anhydrous sodium sulfate to remove water, concentrated under reduced pressure to remove dichloromethane, and obtained Light yellow transparent liquid intermediate 1 (62.84g, yield 97%, purity 97.7%), directly used in the next step without purification; or further, add 250ml of n-hexane in an ice-water bath, stir and crystallize for 2h, suction filter, and a small amount of n-hexane Rinse and dry in vacuo to obtain ligh...

Embodiment 2

[0063] Example 2 Preparation of 5-bromo-2-chloro-4 aminopyrimidine (intermediate 2)

[0064] Add 500 mL of glacial acetic acid to the light yellow transparent liquid of Intermediate 1 and stir to dissolve, add KBr (6.2 g, 10%), slowly add bromine (81.4 g, 0.51 mol) in 80 mL of glacial acetic acid solution dropwise at room temperature, and the addition is complete , the reaction system turns vermilion, slowly warming up to 55°C for 1h, the reaction solution turns from vermilion to white, and a solid precipitates; continue to react for 1h, cool down to room temperature, add 10ml of saturated aqueous sodium bisulfite solution, and continue stirring for 0.5h , filtered with suction, rinsed with purified water, and dried under vacuum at 45°C to obtain white solid powder intermediate 2 (97.06g, yield 96%, purity 98.73%); 1 H NMR (400MHz, CDCl 3 )δ: 8.71(s,1H), 5.77(s,2H).

[0065] When changing the amount of intermediate 1 and brominating reagent so that the molar ratio is in t...

Embodiment 3

[0066] Example 3 Preparation of 5-bromo-2-chloro-4-N-cyclopentylpyrimidine (intermediate 3)

[0067] Intermediate 2 (83.4g, 0.4mol), triethylamine (40.5g, 0.4mol) and methanol 300ml were added to the reaction flask and stirred to dissolve, and chloropentane (50.2g, 0.48mol) was added dropwise at room temperature, and After the addition is completed, the temperature is controlled and stirred for reaction 2, and TLC is monitored until the reaction is completed. Add 350ml of ice water, stir and crystallize at a temperature of 0-10°C for 1 hour, filter with suction, rinse with ice water, drain, and vacuum dry at 45°C to obtain a white solid powder Intermediate 3 (102.57g, yield 92.74%, purity 99.18%), 1 H NMR (400MHz, CDC1 3 )δ: 8.10 (s, 1H), 5.47 (d, J = 4.5Hz, 1H), 4.42 (dd, J = 14.0, 7.0Hz, 1H), 1.44 ~ 2.17 (m, 8H).

[0068] When changing the amount of intermediate 2 and halocyclopentane so that the molar ratio is in the range of 1:1.18-1:1.25, the yield of intermediate 3 ...

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Abstract

The invention provides a preparation method of a palbociclib mother nucleus structure compound. The preparation method comprises the following step: preparing the palbociclib parent nucleus structurecompound as shown in a formula (I) which is described in the specification by taking cytosine or an intermediate 1 or an intermediate 2 as a starting raw material, wherein the intermediate 1 and the intermediate 2 are as described in the specification, and X is selected from halogen. The method is wide in the source of the starting material, simple in operation process, less in side reaction and high in purity, and accords with the concept of modern green industrial production.

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to a preparation method of a palbociclib core structure compound. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] Palbociclib (trade name Ibrance) is a cyclin-dependent kinase CDK4 / 6 inhibitor developed by Pfizer of the United States. It restores cell cycle control by selectively inhibiting cyclin-dependent kinase (CDK4 / 6), preventing Block tumor cell proliferation; combined with letrozole for estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) women with advanced breast cancer, is the first approved cycl...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 刘思源孙运明王法平
Owner SHANDONG MAYOHUAWEI TECH CO LTD
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