A kind of preparation method of oclatinib maleate

A technology of formula and cyclohexane carboxylic acid, which is applied in the field of chemistry or medicinal chemistry, can solve the problems of low utilization rate of raw materials and excessive solid waste, and achieve the effect of reducing post-processing times, increasing conversion rate, and avoiding processing

Active Publication Date: 2022-04-05
CHANGZHOU YABANG QH PHARMACHEM +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] 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 oclatinib maleate
  • A kind of preparation method of oclatinib maleate
  • A kind of preparation method of oclatinib maleate

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0051] trans-4-(Methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclohexyl]methylsulfinate Preparation of:

[0052] 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 70% dihydrobis(2-methoxyethyl) dropwise. 202.2 g (0.7 mol) of oxy)sodium aluminate toluene solution was heated up to 110° C. and kept for 6 hours for reaction. 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 200g of acetonitrile, 58.5g (0.19mol) of 4-chloro-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine, 54.3g (0.42mol) of N,N-diisopropylethylamine and Potassium iodide 3.7g (0.022mol), start stirring and raise the temperature to 65°C, and keep the reaction for 28 hours. The temperature was lowered to 5-10°C, and 34.4 g (0.3 mol) of methanesulfonyl chloride was added dropwise. After the additio...

Embodiment 2

[0055] Preparation of trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonic acid:

[0056] Add 440g of ethanol and 296g of water to a 1L four-neck flask, add trans-4-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine-4 -yl}amino)cyclohexyl]methylsulfinate 73.9g (0.15mol), then add 52.3g (0.45mol) of ammonium sulfite, heat up to 75-85°C, and keep warm for 24-30 hours. Cool down to 20-25°C, add 47.1g (0.18mol) of tetrabutylammonium fluoride, keep the reaction at 25°C for 16 hours, adjust the pH value to 7-8 with phosphoric acid, cool down to 0-5°C, suction filter, filter The cake was dried at 80-85°C to obtain 42.1 g of trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonic acid; yield 86.5% . HPLC purity 98.2%.

[0057] [M-1]=323.1 (see figure 2 )

Embodiment 3

[0059] Preparation of N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide:

[0060] Add acetonitrile 130g to 1L four-neck flask, add trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonic acid 32.4g (0.1mol ) and 3.5g (0.03mol) of tetramethylethylenediamine, lower the temperature to 5°C, add 15.3g (0.12mol) of oxalyl chloride dropwise, keep stirring at 5-10°C for at least 3 hours, and drop 35-40% methylamine aqueous solution 70g (0.9mol), control the temperature at 0-10°C, after the dropwise addition, keep stirring at 0-10°C for at least 0.5-1 hour, add 400g of drinking water, keep stirring for 1 hour, filter with suction, and dry the filter cake at 75-85°C Obtain 30.5 g of N-methyl-1-{trans-4-[methyl(7H-pyrrolo[23-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide, yield 90.5%.HPLC 99.1% purity.

[0061] WNMR-I-500MHz nuclear magnetic resonance instrument nuclear magnetic hydrogen spectrum detection, th...

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Abstract

The invention discloses a preparation method of oclatinib maleate. Starting from trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid and 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, reduction , condensation, esterification, sulfonation, deprotection, chlorination, methylamination, and salt-forming reactions to obtain oclatinib maleate. The synthesis route is optimized through processes such as mesylate, sulfonation, methylamination, and salt formation, which reduces the number of post-treatments and improves production efficiency and yield; the operation is more convenient and suitable for domestic industrial production. The total yield reaches more than 65%, and the product purity reaches more than 99%.

Description

technical field [0001] The invention belongs to the field of chemistry or medicinal chemistry, and in particular relates to a preparation method of oclatinib maleate. Background technique [0002] Oclatinib was approved by the US FDA in 2013 for the control of pruritus and atopic dermatitis caused by canine allergic dermatitis. Oclatinib is a very effective JAK1 inhibitor, and also inhibits the function of JAK1-dependent cytokines in some anti-allergic, inflammatory and pruritus responses. It has little effect on cytokines that do not participate in the activation of JAK1. At the beginning of 2019, the oclatinib maleate tablet produced by the US company Zoetis was approved for registration in my country, and the "Imported Veterinary Drug Registration Certificate" was issued. Since 2013, Zoetis Since the launch of Aibok in 2010, it has benefited tens of millions of dogs suffering from itching diseases. Aibok ( Generic name: Oclatinib Maleate Tablets) has become the largest ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07C51/41C07C57/145
CPCC07D487/04C07C51/412C07C57/145
Inventor 朱建民苏文杰王学成张建峰黄金占
Owner CHANGZHOU YABANG QH PHARMACHEM
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