A kind of preparation method of 7h-pyrrolo[2,3-d]pyrimidine compound

A 3-d, compound technology, applied in the preparation of 7H-pyrrolo[2,3-d]pyrimidine compound, trans-N-methyl-4-cyclohexylmethanesulfonamide maleate field, can Solve the problems of low utilization rate of raw materials and excessive solid waste, and achieve the effects of simplifying operations, reducing raw material costs, and reducing usage

Active Publication Date: 2022-04-05
CHANGZHOU YABANG QH PHARMACHEM +2
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Problems solved by technology

[0020] Although this route has few steps, (4-(methylamino)phenyl)methanesulfonic acid is catalyzed by Pd / C to hydrogenate the benzene ring to generate a mixture of cis and trans products, about 30% after separation by recrystallization The cis product cannot be isomerized, the utilization rate of raw materials is low, and the solid waste generated is much

Method used

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  • A kind of preparation method of 7h-pyrrolo[2,3-d]pyrimidine compound
  • A kind of preparation method of 7h-pyrrolo[2,3-d]pyrimidine compound
  • A kind of preparation method of 7h-pyrrolo[2,3-d]pyrimidine compound

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Experimental program
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Embodiment 1

[0052] Preparation of trans-4-(benzoylmethylamino)cyclohexyl methylsulfonate:

[0053] Add 350 g of toluene and 48.7 g (0.2 mol) of trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid to a 1L four-necked flask, and add 65% dihydrobis(2-methoxyethane) dropwise. 217.8 g (0.7 mol) of oxy)sodium aluminate toluene solution was heated up to 110° C., and kept for reaction for 6 hours. Add 320 g (0.4 mol) of 5% sodium hydroxide solution to quench the reaction, separate the water layer, and concentrate the toluene layer to dryness. Add 150 g of dichloromethane and 36.4 g (0.36 mol) of triethylamine, start stirring, cool down to -5°C, add 30.9 g (0.22 mol) of benzoyl chloride dropwise, and the dropping time is 2 hours. -10°C heat preservation reaction for 5 hours. Add 300g of water, stir for 15 minutes and let stand to separate layers, separate the lower organic layer, dry with 20g of anhydrous sodium sulfate for 1 hour, filter, cool the filtrate to 5-10°C, add dropwise 34....

Embodiment 2

[0055] Preparation of sodium trans-4-(benzoylmethylamino)cyclohexylmethylsulfonate:

[0056] Add 290g of ethanol and 150g of water to a 1L four-neck flask, add 48.8g (0.15mol) of trans-4-(benzoylmethylamino)cyclohexyl methylsulfonate, and then add 56.7g (0.45mol) of sodium sulfite , heat up to 75-85°C, and keep warm for 24 hours. Cool down to 0-5°C, filter with suction, and dry the filter cake at 80-85°C to obtain 43.2 g of sodium trans-4-(benzoylmethylamino)cyclohexylmethylsulfonate; the yield is 86.4%. HPLC purity 97.5%.

Embodiment 3

[0058] Preparation of trans-N-methyl-N-(4-methylsulfamoylmethyl-cyclohexyl)-benzamide:

[0059] Add 165g of acetonitrile to a 1L four-neck flask, add 33.3g (0.1mol) of trans-4-(benzoylmethylamino)cyclohexylmethanesulfonate sodium and 2.4g (0.03mol) of pyridine, and cool down to 5°C , add 16.5g (0.13mol) of oxalyl chloride dropwise, keep stirring at 5-10°C for at least 3 hours, start dropping 78g (1mol) of 35% methylamine aqueous solution, control the temperature at 0-10°C, after the dropwise addition, keep warm at 0-10°C Stir for at least 0.5-1 hour, add 495g of drinking water, keep stirring for 1 hour, filter with suction, and dry the filter cake at 75-85°C to obtain trans-N-methyl-N-(4-methylsulfamoylmethyl- Cyclohexyl)-benzamide off-white solid 30.8g, yield 94.7%. The purity by HPLC was 98.5%.

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Abstract

The invention discloses a preparation method of a 7H-pyrrolo[2,3-d]pyrimidine compound. The full name of the 7H-pyrrolo[2,3-d]pyrimidine compound is: trans-N-methyl-4- (Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate. Using trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine as starting materials, after reduction, protection, esterification, Sulfonation, chlorination, methylation, deprotection, condensation, salt formation reaction to obtain trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino ) Cyclohexylmethanesulfonamide maleate. The preparation method first prepares trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid into N-methyl-1-[trans-4-(methylamino)cyclohexyl]methanesulfonamide salt salt, and then condensed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, which improves the utilization rate of high-priced raw material 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and reduces the Cost; relatively mild reaction conditions, easy to operate, green and environmentally friendly, suitable for domestic industrial production. The total yield reaches more than 62%, and the product purity reaches more than 99.5%.

Description

technical field [0001] The present invention belongs to the field of chemistry or medicinal chemistry, and specifically relates to a preparation method of a 7H-pyrrolo[2,3-d]pyrimidine compound. The full name of the 7H-pyrrolo[2,3-d]pyrimidine compound is: trans- N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate. Background technique [0002] The full name of 7H-pyrrolo[2,3-d]pyrimidine compound is: trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexyl Methylsulfonamide maleate (common name: oclatinib maleate) was approved by the US FDA in 2013 for the control of itching and atopic dermatitis caused by canine allergic dermatitis. in the US and Europe to Brand names are approved. It is a novel Janus kinase inhibitor (JAKi) with dual indications for the control of pruritus associated with atopic dermatitis and for the treatment of atopic dermatitis (AD) in dogs 12 months of age and older. The chemical structura...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 朱建民王学成苏文杰张建峰
Owner CHANGZHOU YABANG QH PHARMACHEM
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