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A kind of synthetic method of ruxolitinib intermediate

A ruxolitinib and synthetic method technology, applied in the direction of organic chemistry, etc., can solve the problems of unsuitability for industrialized large-scale production, poor stereoselectivity, long synthesis route, etc., and achieve stable and controllable reaction, mild conditions, and reaction. The effect of fewer steps

Active Publication Date: 2017-01-11
BIOCOMPOUNDS PHARMACEUTICAL INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In 2012, Anderson, Kevin et al. reported in the patent US20120184542 (19Jul 2012) that methyl cyclopentanecarboxylate was used as a starting material to react with propionitrile and sodium hydride to generate racemic 1-hydroxyl-1 cyclopentylpropionitrile, The yield is very low, only 14%
This route uses a noble metal complex as a catalyst, which is expensive and has poor stereoselectivity. It also tries to obtain a single-configuration product by chemical resolution, but the result is not ideal, and the synthetic route is very long and cumbersome.
[0013] In addition, the patent US20120184542 (19Jul 2012) reported another route using protected 4-chloropyrrolopyrimidine as a raw material. When introducing chiral cyclopentapropylnitrile side chains, it adopted a direct addition reaction with cyclopentapropenal. However, a preparative column is required to separate chiral products, which is not suitable for large-scale industrial production

Method used

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  • A kind of synthetic method of ruxolitinib intermediate
  • A kind of synthetic method of ruxolitinib intermediate
  • A kind of synthetic method of ruxolitinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] 1) Preparation of 3-cyclopentyl-3-oxopropionitrile (Ⅱ)

[0060] 8.95 g (78.07 mmol) of 35 wt% potassium hydride was added to 40 mL of tetrahydrofuran, and heated to 60°C. 10 g (78.07 mmol) of methyl cyclopentacarboxylate was dissolved in 3.2 g (78.07 mmol) of acetonitrile, and slowly added dropwise to the reaction solution of potassium hydride. After completion of the dropwise addition, react at 60°C for 6 hours, cool, concentrate to remove part of the solvent, add 60 mL of water, extract three times with ethyl acetate, and discard the organic phase. The aqueous phase was acidified with 1M hydrochloric acid to pH = 1, extracted three times with ethyl acetate, dried, filtered, and the filtrate was rotary evaporated to obtain 9.63 g of bright yellow oil 3-cyclopentyl-3-oxopropionitrile (II). The yield was 90%.

[0061] 1 H-NMR (400MHz, DMSO-d 6 ): 4.10(2H,s), 3.00(1H,m), 1.90(8H,m).

[0062] 2) Preparation of (S)-3-cyclopentyl-3-hydroxypropionitrile (Ⅲ)

[0063] Add...

Embodiment 2

[0069] 1) Preparation of 3-cyclopentyl-3-oxopropionitrile (Ⅱ)

[0070] 14.4 g (0.36 mol) of 60% sodium hydride was added to 175 mL of tetrahydrofuran, and heated to 80°C. 23.1 g (0.18 mol) of methyl cyclopentacarboxylate was dissolved in 14.8 g (0.36 mol) of acetonitrile, and slowly added dropwise to the reaction solution of sodium hydride. After the dropwise addition, react at 80°C for 20 hours, cool, concentrate to remove part of the solvent, add 160 mL of water, extract three times with ethyl acetate, and discard the organic phase. The aqueous phase was acidified with 6M sulfuric acid to pH=5, extracted three times with ethyl acetate, dried, and rotary evaporated to obtain 22.45 g of bright yellow 3-cyclopentyl-3-oxopropionitrile (II), with a yield of 91%.

[0071] NMR data is the same as in Example 1.

[0072] 2) Preparation of (S)-3-cyclopentyl-3-hydroxypropionitrile (Ⅲ)

[0073] Add D-glucose (7g), D-glucose dehydrogenase (0.28g), NADPH (reduced coenzyme II) (0.42g) a...

Embodiment 3

[0079] 1) Preparation of 3-cyclopentyl-3-oxopropionitrile (Ⅱ)

[0080] Add 24.4 g (0.61 mol) of 60% sodium hydride into 335 mL of tetrahydrofuran, and heat to 75°C. 50 g (0.39 mol) of methyl cyclopentacarboxylate was dissolved in 25 g (0.61 mol) of acetonitrile, and slowly added dropwise to the reaction solution of sodium hydride. After the dropwise addition, react at 70°C for 15 hours, cool, concentrate to remove part of the solvent, add 180 mL of water, extract three times with ethyl acetate, and discard the organic phase. The aqueous phase was acidified with 4M hydrochloric acid to pH = 2, extracted three times with ethyl acetate, dried, and rotary evaporated to obtain 49.75 g of bright yellow 3-cyclopentyl-3-oxopropionitrile (II), with a yield of 93%.

[0081] Nuclear magnetic data is with embodiment 1.

[0082] 2) Preparation of (S)-3-cyclopentyl-3-hydroxypropionitrile (Ⅲ)

[0083] Add D-glucose (22.7g), D-glucose dehydrogenase (750mg), NADPH (reduced coenzyme II) (750...

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Abstract

The invention relates to a synthesis method of a ruxolitinib intermediate. The method comprises the following steps: firstly, carrying out catalytic reaction on cyclopentane methyl formate and acetonitrile to prepare 3-cyclopentyl-3-oxypropionitrile; carrying out enzymatic asymmetric reduction on 3-cyclopentyl-3-oxypropionitrile to generate chiral alcohol (S)-3-cyclopentyl-3-oxypropionitrile; and carrying out Mitsunobu reaction and 4-bromopyrazole coupling on (S)-3-cyclopentyl-3-oxypropionitrile to obtain ruxolitinib intermediate (3R)-3-(4-bromo-1H-pyrazole-1-yl)-3-cyclopentane propionitrile. The synthesis method has the advantages of short route, low cost, mild condition and good stereoselectivity, and is suitable for industrialized mass production.

Description

technical field [0001] The present invention relates to a synthetic method of ruxolitinib intermediate, in particular to a key intermediate (3R)-3-(4 -Bromo-1H-pyrazol-1-yl)-3-cyclopentanepropanecyanide (I) preparation method. Background technique [0002] Ruxolitinib, an orally administrable selective JAK1 / JAK2 kinase inhibitor developed by Incyte of the United States, is the first drug approved by the FDA for the treatment of myelofibrosis in November 2011. The drug (trade name Jakafi) was granted rare disease drug qualification, and was approved for marketing by the European Union (trade name Jakavi) by Novartis in August 2012. [0003] Myelofibrosis (myelofibrosis, MF) is a common clinical complex and refractory disease. It is a rare myeloproliferative neoplasm. The bone marrow in the body is replaced by scar tissue, which leads to the production of blood cells in organs such as the liver and spleen. For splenomegaly, anemia, leukopenia and thrombocytopenia, and varyin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/16
CPCC07D231/16
Inventor 王永刘利刚项杰杨世琼李倩康立涛
Owner BIOCOMPOUNDS PHARMACEUTICAL INC
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