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The synthetic method of ruxolitinib intermediate (r)‑3‑(4‑bromo‑1h‑pyrazole‑1‑yl)‑3‑cyclopentylpropionitrile

A technology for the synthesis of cyclopentylpropionitrile, which is applied in the fields of medicinal chemistry and organic chemistry, can solve the problems of long routes, harsh conditions, and high catalyst costs, and achieve the effects of high yield, simple method, and low cost

Inactive Publication Date: 2017-12-19
滨州市帅博木业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The route is long, the preparation of asymmetric catalyst is difficult, the conditions are harsh, and the cost of catalyst is high

Method used

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  • The synthetic method of ruxolitinib intermediate (r)‑3‑(4‑bromo‑1h‑pyrazole‑1‑yl)‑3‑cyclopentylpropionitrile
  • The synthetic method of ruxolitinib intermediate (r)‑3‑(4‑bromo‑1h‑pyrazole‑1‑yl)‑3‑cyclopentylpropionitrile
  • The synthetic method of ruxolitinib intermediate (r)‑3‑(4‑bromo‑1h‑pyrazole‑1‑yl)‑3‑cyclopentylpropionitrile

Examples

Experimental program
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Effect test

Embodiment 1

[0036] The synthetic method of (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile is realized through the following steps:

[0037] 1) Preparation of ethyl (R)-3-(4-bromo-1H-pyrazol-1-yl)-2-cyano-3-cyclopentylpropionate

[0038] Add 1.93g (0.01mol) of ethyl 3-cyclopentyl-2-cyanoacrylate, 0.45g (0.001mol) of chiral square amide catalyst compound IIIa, and 1.59g of 4-bromo-1H-pyrazole into a 25ml single-necked bottle (0.0108mol), 15mL of dry toluene, react at -20°C for about 10 hours, follow the reaction by TLC, after the reaction is complete, concentrate under reduced pressure to remove the solvent, and the residue is directly used in the next reaction.

[0039] 2) Preparation of (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile

[0040]Add 2.1g (0.013molNaOH) of 25% sodium hydroxide solution to the residue of step 1), heat up to 65°C and reflux for about 8 hours until TLC follows the reaction until the hydrolysis is complete, then use 35% hydrochloric acid A...

Embodiment 2

[0046] The synthetic method of (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile is realized through the following steps:

[0047] 1) Preparation of (R)-3-(4-bromo-1H-pyrazol-1-yl)-2-cyano-3-cyclopentylpropionic acid methyl ester

[0048] Add 1.79g (0.01mol) of methyl 3-cyclopentyl-2-cyanoacrylate, 0.45g (0.001mol) of chiral square amide catalyst compound IIIa, and 1.61g of 4-bromo-1H-pyrazole into a 25ml single-necked bottle (0.011mol), 15mL of dry toluene, react at -50°C for about 10, follow the reaction by TLC, after the reaction is complete, concentrate under reduced pressure to remove the solvent, and the residue is directly used in the next reaction.

[0049] 2) Preparation of (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile

[0050] Add 2.4 g (0.015 mol NaOH) of sodium hydroxide solution with a mass fraction of 25% to the residue in step 1), heat up to 65°C and reflux for about 8 hours, follow the reaction by TLC until the hydrolysis is complete, and...

Embodiment 3

[0052] The synthetic method of (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile is realized through the following steps:

[0053] 1) Preparation of (R)-3-(4-bromo-1H-pyrazol-1-yl)-2-cyano-3-cyclopentyl propionate propyl ester

[0054] Add 1.93g (0.01mol) of ethyl 3-cyclopentyl-2-cyanoacrylate, 0.45g (0.001mol) of chiral square amide catalyst compound IIIa, and 1.64g of 4-bromo-1H-pyrazole into a 25ml single-necked bottle (0.011mol), 15mL of dry toluene, reacted at 0°C, followed the reaction by TLC until the reaction was complete, concentrated under reduced pressure to remove the solvent, and the residue was directly used in the next reaction.

[0055] 2) Preparation of (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile

[0056] Add 1.8 g (0.011 mol NaOH) of sodium hydroxide solution with a mass fraction of 25% to the residue, heat up to 65° C. and reflux for about 8 hours, and follow the reaction by TLC until the hydrolysis is complete, and adjust the pH to ...

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Abstract

The invention relates to a method for synthesizing a ruxolitinib intermediate (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentyl propionitrile. The method includes the steps that 3-cyclopentyl-2-cyanoacrylate (I) serves as a raw material, the 3-cyclopentyl-2-cyanoacrylate (I) and 4-bromo-1H-pyrazol (II) are subjected to Michael addition under the condition of a chiral squaric acid amide catalyst (III), and (R)-3-(4-bromo-1H-pyrazol-1-yl)-2-cyano-3-cyclopentyl propanoic acid alkyl ester (IV) is obtained; the (R)-3-(4-bromo-1H-pyrazol-1-yl)-2-cyano-3-cyclopentyl propanoic acid alkyl ester (IV) is hydrolyzed and decarboxylated to obtain the (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentyl propionitrile (V). The synthesis method is simple, the product yield can be 80% or above, the enantioselectivity of the product is 90% or above, conditions are moderate, operation is easy, production cost is low, and the method can be used for industrial production.

Description

technical field [0001] The invention relates to a synthetic method of ruxolitinib intermediate (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile, which belongs to the technical field of organic chemistry and also belongs to Medicinal chemistry technology field. Background technique [0002] (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile is an important intermediate in the synthesis of ruxolitinib. In 2011, the FDA approved ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis. In 2014, the FDA approved ruxolitinib for the treatment of polycythemia vera. It is currently reported abroad that this drug can also be used to treat alopecia areata, and the research work in this area is being further developed. Therefore, the study of this drug is of great significance. [0003] The preparation method of (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile, reported in the literature (Organic Syntheses, Coll.Vol.5, p.989 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/16
CPCC07D231/16
Inventor 陈甫雪夏定邹万智邹淑静邹颖
Owner 滨州市帅博木业有限公司
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