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Preparation methods of JAK inhibitor and salt thereof

A solvent and methoxyethylene technology, which is applied in the field of preparation of JAK inhibitor ruxolitinib, can solve problems such as low chiral purity, unsuitable for scale-up production, and difficult purification of intermediates

Active Publication Date: 2018-03-06
SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] This route uses cyclopentyl allene as a raw material to add 4-bromopyrazole under metal rhodium and chiral ligand catalytic conditions to obtain a chiral intermediate with an ee value of 91%. The raw material for this route is not easy to obtain, and the chiral purity is not high. , the purification of intermediates is difficult, the cost is high, and it is not suitable for scale-up production

Method used

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  • Preparation methods of JAK inhibitor and salt thereof
  • Preparation methods of JAK inhibitor and salt thereof
  • Preparation methods of JAK inhibitor and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Embodiment 1: the preparation of cyclopentylcarbaldehyde (compound 2)

[0076] Weigh some bromocyclopentane, dissolve a small amount in 5 times the volume of anhydrous THF, add magnesium chips (1eq), catalytic amount of iodine element, nitrogen protection, raise the temperature to about 40°C to initiate the reaction, control the temperature at 30-40°C and drop Add bromocyclopentane, drop it, keep stirring for 1-2 hours, add DMF (1.05eq) dropwise under temperature control below 10°C, after dropping, stir at room temperature 30°C for 1 hour, add 3 times the volume of MTBE to the feed solution, Add 3N dilute hydrochloric acid dropwise below 0°C to adjust the pH to 3-4, separate the liquids, extract the aqueous layer twice with MTBE (3 times the volume each time), until the product is basically extracted, combine the organic phases, wash twice with saturated brine, and anhydrous Na 2 SO 4 Dry, filter, and concentrate to dryness under reduced pressure to obtain crude cyclo...

Embodiment 2

[0077] Embodiment 2: the preparation of methyl 3-cyclopentyl acrylate (compound 3)

[0078] Weigh potassium tert-butoxide (1.05eq), dissolve it in 10 times the volume of anhydrous THF, protect it under nitrogen, and add trimethyl phosphoacetate (1.1eq) dropwise to the feed solution at about 0°C. Stir at around 0°C for 2 to 3 hours, weigh some cyclopentyl formaldehyde, and make 2 times the volume of anhydrous THF solution, add it dropwise to the above feed solution at around 0°C, after the drop is completed, warm it up to room temperature at about 30°C and stir After 12-15 hours of reaction, the reaction is complete. Add 5 times the volume of MTBE to the feed solution for dilution, 10 times the volume of water, and separate the liquids. The water layer is back-extracted twice with 3 times the volume of MTBE, washed twice with saturated brine, and anhydrous Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain crude methyl 3-cyclopentyl acrylate with a yield ...

Embodiment 3

[0079] Example 3: Preparation of methyl 3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentapropionate (compound 4)

[0080] Weigh some methyl 3-cyclopentyl acrylate, dissolve in 5 times the volume of acetonitrile, add 4-bromopyrazole (1.1eq) and DBU (1.5eq) to the feed solution, and stir the feed solution at room temperature at 30°C to react About 12 to 16 hours, the reaction of raw materials is complete. Concentrate under reduced pressure to a small volume, add 5 times the volume of MTBE to the feed liquid to dilute, wash with water, adjust the pH to 3-4 with 1N dilute hydrochloric acid, wash with water, wash with saturated brine, and wash with anhydrous Na 2 SO 4Dry, filter, and concentrate under reduced pressure to obtain crude methyl 3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentapropionate with a yield of 90-95%, which is directly used for the next step of hydrolysis.

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Abstract

The present invention relates to preparation methods of a JAK inhibitor and a salt thereof. The preparation method comprises: (1) carrying out a Suzuki coupling reaction on (R)-3-(4-boronic acid-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile and 6-halogen-5-(2-methoxyvinyl)pyrimidin-4-ylamine to generate (3R)-cyclopentyl-3-[4-(5-(2-methoxyvinyl)pyrimidin-4-ylamine)pyrazol-1-yl]propionitrile; and (2)carrying out a protection group removing and ring-closure reaction on the (3R)-cyclopentyl-3-[4-(5-(2-methoxyvinyl)pyrimidin-4-ylamine)pyrazol-1-yl]propionitrile to generate a JAK inhibitor ruxolitinib. According to the present invention, the new ruxolitinib preparation route is provided, wherein each reaction of the route has the high yield, the total yield of the route is high, the purity of theobtained product is good, the post-treatment of the reaction is simple, and column chromatography is not required; by adopting the route, the required raw materials or catalysts and other materials are relatively easy to obtain; and compared to the method in the prior art, the method of the present invention is economical and is suitable for industrial production.

Description

Technical field [0001] The present invention relates to the technical field of preparation of JAK inhibitor ruxolitinib, and specifically relates to a novel ruxolitinib intermediate, its preparation method and a preparation method of ruxolitinib. Background technique [0002] Ruxolitinib is an orally administrable selective JAK1 / JAK2 kinase inhibitor. It is the first drug approved by the US FDA for the treatment of intermediate or high-risk myelofibrosis (2011, trade name: Jakafi) , including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis (2014). At present, ruxolitinib Jakavi has been approved by more than 50 countries around the world, including the European Union, Canada and some Asian, Latin American and South American countries. At the same time, there have been recent foreign reports that this drug can also be used to treat bald spots. Research in this area is being further carried out. Therefore, the rese...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D239/42C07D231/16C07F5/02C07C67/44C07C45/43C07C69/608C07C47/30
CPCC07C45/43C07C67/44C07D231/16C07D239/42C07D487/04C07F5/025C07C69/608C07C47/30Y02P20/55
Inventor 曹标朱杭杭吴建忠田广辉
Owner SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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