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The preparation method of ruxolitinib intermediate (3r)-3-(4-bromo-1h-pyrazol-1-yl)-cyclopentylpropionitrile

A technology of cyclopentyl propionitrile and cyclopentyl propionitrile is applied in the field of preparation of ruxolitinib intermediate-3--cyclopentyl propionitrile, and can solve the problem of high cost and many impurities in API isomers. , the ee value of the intermediate is not high enough, and the effect of mild reaction conditions, good stereoselectivity and high stereoselectivity is achieved.

Active Publication Date: 2019-12-06
海化生命(厦门)科技有限公司
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Problems solved by technology

[0005] The disadvantage of this route is: separation by chiral column chromatography, the cost is too high, and it is not suitable for industrial production
[0008] The disadvantage of patent WO201008328 is that the resolution reagents are relatively uncommon and the price is high; in addition, the ee value of one resolution is not high, and API with high chiral purity can only be obtained through multiple resolutions. The cost of the API produced is quite high, and there is no competitive advantage
[0010] The disadvantage of this route is that the ee value of the intermediate is not high enough, and there are more API isomer impurities in the further process, and the subsequent crystallization is not easy to remove
At the same time, the non-commercial raw materials of chiral inducing reagents are not easy to obtain, and must be obtained through 4-step chemical reactions, so the cost of chiral inducing reagents is too high

Method used

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  • The preparation method of ruxolitinib intermediate (3r)-3-(4-bromo-1h-pyrazol-1-yl)-cyclopentylpropionitrile

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preparation example Construction

[0029] A preparation method of ruxolitinib intermediate (3R)-3-(4-bromo-1H-pyrazol-1-yl)-cyclopentylpropionitrile, which comprises the following steps:

[0030] (1) Synthesis of 3-oxo-3-cyclopentylpropionitrile (II): Methyl cyclopentylformate reacts with CH under strongly basic conditions 3 CN reaction makes 3-oxo-3-cyclopentylpropionitrile (II);

[0031] (2) Synthesis of (S)-3-cyclopentyl-3-hydroxypropionitrile (III): the 3-oxo-3-cyclopentyl obtained in step (1) is synthesized with chiral borane reagent R-CBS Reduction of propionitrile into (S)-3-cyclopentyl-3-hydroxypropionitrile (III);

[0032] (3) Synthesis of (3R)-3-(4-nitro-1H-pyrazol-1-yl)-cyclopentyl propionitrile (IV): (S)-3- Cyclopentyl-3-hydroxypropionitrile (III) and 4-nitropyrazole were reacted by Mitsunobu to give (3R)-3-(4-nitro-1H-pyrazol-1-yl)-cyclopentylpropane Nitrile (IV);

[0033] (4) Synthesis of (3R)-3-(4-amino-1H-pyrazol-1-yl)-cyclopentylpropionitrile (V): (3R)-3-( Reduction of 4-nitro-1H-pyrazol-1...

Embodiment 1

[0055] 1.1 Synthesis of 3-oxo-3-cyclopentylpropionitrile (II)

[0056] Add NaH (2.75g, 68.7mmol, content 60%) and 20mlTHF in the there-necked flask of 200ml, heat up to 70-75 ℃, dropwise add cyclopentyl formate methyl ester (8.00g, 62.4mmol) under this condition Anhydrous acetonitrile (15ml) solution, control the temperature of the system at 70-75°C, react for 15h, then cool to room temperature, add 50ml of ethyl acetate and 1N HCl solution, control the system pH=2-3, extract and separate the water layer It was extracted three times with ethyl acetate, the organic layers were combined, dried and rotary evaporated to obtain 2.42 g of yellow oil (compound II), with a yield of 91.2%. NMR analysis:

[0057] 1 H-NMR (400MHz, DMSO-d6): 4.09 (2H, s), 3.01 (1H, m), 1.90 (8H, m).

[0058] 1.2 Synthesis of (S)-3-cyclopentyl-3-hydroxypropionitrile (III)

[0059] Under nitrogen protection, 150mlTHF, R-CBS (1.0M toluene solution, 4.35ml, 4.35mmol) and borane dimethyl sulfide (2.0M THF ...

Embodiment 2

[0075] 2.1 Synthesis of 3-oxo-3-cyclopentylpropionitrile (II)

[0076] Add NaH (2.75g, 68.7mmol, content 60%) and 20mlTHF in the there-necked flask of 200ml, heat up to 60-65 ℃, dropwise add cyclopentyl formate methyl ester (8.00g, 62.4mmol) under this condition Anhydrous acetonitrile (15ml) solution, control the temperature of the system at 60-65°C, react for 20h, then cool to room temperature, add 50ml of ethyl acetate and 1N HCl solution, control the system pH=4-5, extract and separate the water layer Then it was extracted three times with ethyl acetate, the organic layers were combined, dried and rotary evaporated to obtain 2.25 g of a yellow oil with a yield of 84.90%.

[0077] 2.2 Synthesis of (S)-3-cyclopentyl-3-hydroxypropionitrile (III)

[0078]Under nitrogen protection, 150mlTHF, R-CBS (1.0M toluene solution, 4.35ml, 4.35mmol) and borane dimethyl sulfide (2.0M THF solution, 33ml, 66mmol) were added to a 500ml three-necked flask, and the reaction temperature was cool...

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Abstract

The present invention relates to a preparation method of ruxolitinib intermediate (3R)-3-(4-Br-1H-pyrazole-1-yl)-cyclopentyl propanenitrile, and the method comprises the following steps: (1) synthesisof 3-oxo-3-cyclopentyl propionitrile (II); (2) synthesis of (S)-3-cyclopentyl-3-hydroxypropionitrile (III); (3) synthesis of (3R)-3-(4-nitro-1H-pyrazole-1-yl)-cyclopentyl propionitrile (IV); (4) synthesis of (3R)-3-(4-amino-1H-pyrazole-1-yl)-cyclopentyl propionitrile (V); and (5) (3R)-3-(4-Br-1H-pyrazole-1-yl)-cyclopentyl propanenitrile (VI). The method has the advantages of good stereoselectivity, low cost, mild reaction conditions, no requirement on harsh reaction such as high temperature, high pressure and ultra-low temperature.

Description

technical field [0001] The invention relates to a preparation method of ruxolitinib intermediate (3R)-3-(4-bromo-1H-pyrazol-1-yl)-cyclopentylpropionitrile. Background technique [0002] Ruxolitinib is a small molecule inhibitor of protein kinases JAK1 and JAK2. In 2011, the FDA approved the first drug for the treatment of myelofibrosis. In 2014, a new indication was added for the treatment of patients with polycythemia vera. The global market sales in 2015 were US$1.01 billion, and the global market sales in 2016 were US$1.434 billion. Therefore, ruxolitinib can be said to be a blockbuster drug, and research on this drug is of great significance. [0003] At present, the synthesis of ruxolitinib bulk drug has been reported in the literature. There are mainly the following options: [0004] 1. In patent WO2010083283, through Suzuki reaction, SM1 and SM2 are docked to obtain intermediate A, and NH is conjugated to alkenyl nitrile under alkaline conditions to obtain intermedi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/16
CPCC07D231/16
Inventor 邱炳林钟宝香陈华栋李金林黄志征
Owner 海化生命(厦门)科技有限公司
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