Tofacitinib citrate intermediate as well as preparation method and application thereof

A technology of tofacitinib and citric acid, which is applied in the field of tofacitinib citrate intermediates and its preparation, can solve the problems of only 65% ​​total yield and cumbersome process, and reduce production cost and reactivity High, avoid the effect of incomplete reaction

Active Publication Date: 2020-11-27
山东金城昆仑药业有限公司
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  • Abstract
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Problems solved by technology

This patent mentions the use of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine to prepare the Tropol method For Tifatinib, about 4.0% of the raw materials remain in the reaction solution, and about 0.5% remains in Tofacitinib, and then it is salted with citric acid. The process is cumbersome, and the total yield is only about 65%.

Method used

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  • Tofacitinib citrate intermediate as well as preparation method and application thereof
  • Tofacitinib citrate intermediate as well as preparation method and application thereof
  • Tofacitinib citrate intermediate as well as preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0047] (1) N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine dihydrochloride Hydrate Synthesis

[0048] Add 33.5 g (0.10 mol) of N-methyl-N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7H-pyrrole to the autoclave And [2,3-d]pyrimidin-4-amine, add 20ml of water and 400ml of ethanol, add 10g (0.10mol) of hydrochloric acid, 1.5g of palladium hydroxide on carbon, stir, replace the air in the reactor with nitrogen, and heat up to 50°C , pass hydrogen gas to 0.3MPa to react for 8h, vent, filter out palladium hydroxide carbon, add 320ml of acetone dropwise to the reaction solution at room temperature, a large amount of solid precipitates, filter with suction, and dry at 45°C for 3h to obtain 32.7g of compound 1, yield 97.3%.

[0049] Compound 1 was analyzed: through DSC thermal analysis, compound 1 had a broad endothermic peak before 200°C, which was initially judged to be a desolvation endothermic peak; through TGA thermal analysis, compound 1 ha...

Embodiment 2

[0053] (1) N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine dihydrochloride Hydrate Synthesis

[0054] Add 33.5 g (0.10 mol) of N-methyl-N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7H-pyrrole to the autoclave And [2,3-d] pyrimidin-4-amine, add 30ml of water and 500ml of isopropanol, add 15g (0.15mol) of hydrochloric acid, 1.8g of palladium hydroxide carbon, stir, replace the air in the reactor with nitrogen, and heat up to At 60°C, pass hydrogen gas to 0.5MPa to react for 5h, vent, filter out palladium hydroxide carbon, add 280ml of tetrahydrofuran dropwise to the reaction solution at room temperature, a large amount of solid precipitates, filter with suction, and dry at 40°C for 5h to obtain 32.5g of compound 1. Yield 96.8%.

[0055] (2) Synthesis of Tofacitinib Citrate

[0056] The preparation method was the same as the synthesis of tofacitinib citrate in Example 1 to obtain 39.1 g of tofacitinib citrate with a purity of 99.93%, no c...

Embodiment 3

[0058] (1) N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine dihydrochloride Hydrate Synthesis

[0059] Add 33.5 g (0.10 mol) of N-methyl-N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7H-pyrrole to the autoclave And [2,3-d]pyrimidin-4-amine, add 25ml of water and 600ml of methanol, add 20g (0.20mol) of hydrochloric acid, 3.0g of palladium hydroxide on carbon, stir, replace the air in the reactor with nitrogen, and heat up to 60°C , pass hydrogen gas to 0.4MPa to react for 8h, vent, filter off palladium hydroxide carbon, add 200ml of acetonitrile dropwise to the reaction solution at room temperature, a large amount of solid precipitates, filter with suction, and dry at 50°C for 4h to obtain 32.6g of compound 1, yield 97.1%.

[0060] (2) Synthesis of Tofacitinib Citrate

[0061] The preparation method was the same as the synthesis of tofacitinib citrate in Example 1 to obtain 39.2 g of tofacitinib citrate with a purity of 99.93%, no compoun...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a tofacitinib citrate intermediate as well as a preparation method and an application thereof. Whereinthe tofacitinib citrate intermediate is N-methyl-N-((3R, 4R)-4-methylpiperidine-3-yl)-7H-pyrrolo [2, 3-D] pyrimidine-4-amine dihydrochloride monohydrate. The preparation method comprises the followingsteps: adding N-methyl-N-((3R, 4R)-1-benzyl-4-methylpiperidine-3-yl)-N-methyl-7H-pyrrolo [2, 3-d] pyrimidine-4-amine into water and an organic solvent, then adding hydrochloric acid and palladium hydroxide carbon, introducing hydrogen to react, and filtering out the palladium hydroxide carbon; cooling to room temperature, dropwise adding an organic solvent, crystallizing, carrying out suction filtration, and drying to obtain the tofacitinib citrate intermediate. The method greatly improves the utilization rate of raw materials, reduces the production cost, and improves the product quality.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a tofacitinib citrate intermediate and a preparation method and application thereof. Background technique [0002] Tofacitinib citrate, compound name: 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino] 1-yl}-3-oxopropionitrile monocitrate, which targets intracellular signal transduction pathways and acts on the core part of the cytokine network. The inhibitory strength of tofacitinib on JAK3 is 5-100 times that of JAK1 and JAK2, and it is the first drug for the treatment of rheumatoid arthritis. FDA approved the JAK inhibitor tofacitinib on November 6, 2012 for the treatment of Active adult patients with moderate to severe rheumatoid arthritis (RA) who do not respond well to methotrexate (MTX). [0003] N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine is tofacitidine citrate An important intermediate of cl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07C59/265C07C51/41C07C51/43
CPCC07C51/412C07C51/43C07C59/265C07D487/04
Inventor 周海洋王雷王云静胡高云孟宾杨鲁伟
Owner 山东金城昆仑药业有限公司
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