Tofacitinib intermediate and preparation method thereof

A solid and compound technology, which is applied in the preparation of carboxylate, organic chemistry methods, organic chemistry, etc., can solve the problems of poor stability, easy to be oxidized, and increase the difficulty of quality control of the compound of formula I, and achieve high yield and easy operation. Simple, Gentle Effects

Inactive Publication Date: 2015-02-11
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The compound of formula Ⅲ contains a secondary amine and a tertiary amine group, which has the characteristics of easy moisture absorption and oxidation, poor stability, and difficult quality control, especially in the quality control of storage and transportation, thereby increasing the number of compounds of formula Ⅰ. Difficulty in quality control

Method used

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  • Tofacitinib intermediate and preparation method thereof
  • Tofacitinib intermediate and preparation method thereof
  • Tofacitinib intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Preparation of methyl-((3R,4R)-4-methyl-piperidin-3-yl)-(7H-pyrido[2,3-d]pyrimidin-4-yl)-amine (formula Ⅲ)

[0088] Method 1: the method for preparing formula III from formula IV

[0089] (3R,4R)-(1-Benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrido[2,3-d]pyrimidin-4-yl)-amine (formula Ⅳ) For the preparation method, refer to CN1729192. At room temperature, 8 g of (3R,4R)-(1-benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrido[2,3-d]pyrimidin-4-yl )-amine was added to a 200ml hydrogenation reactor, and 32ml of ethanol and 8ml of water were added to the reactor. Weigh 1.43g of acetic acid into the solution, stir, and the solids are completely dissolved. Weigh 1.6g of 20% palladium hydroxide on carbon and add it. The gas in the hydrogenation tank was replaced by nitrogen and hydrogen successively, then hydrogen was added to 0.7MPa, and then heated to an internal temperature of 50°C with stirring. After reacting for 5 hours, deflate and dismantle the device. After the reac...

Embodiment 2

[0093] Methyl-((3R,4R)-4-methyl-piperidin-3-yl)-(7H-pyrido[2,3-d]pyrimidin-4-yl)-amine.dihydrochloride (formula Ⅵ) Preparation

[0094] Method A:

[0095]5.0g of methyl-((3R,4R)-4-methyl-piperidin-3-yl)-(7H-pyrido[2,3-d]pyrimidin-4-yl)-amine was dissolved in 20ml of methanol , stir. At room temperature, a solution of 6ml of concentrated hydrochloric acid dissolved in 40ml of ethanol was added dropwise to the above solution, and crystals were precipitated. After dropping, stirred for 5 hours, filtered with suction, the filter cake was washed with 10ml of ethanol, and dried under reduced pressure at 50°C to constant weight to obtain off-white Solid title product (5.8 g, 85% yield, 99.2% purity by HPLC).

[0096] Determine the X-ray powder diffraction pattern (XRPD) of the obtained solid, the results are shown in figure 1 , which is Form A. The measured X-ray powder diffraction pattern, its 2θ angle, d value and relative intensity I value are shown in Table 3 below, and the ...

Embodiment 3

[0103] Preparation of Tofitinib Citrate

[0104] 5g methyl-((3R,4R)-4-methyl-piperidin-3-yl)-(7H-pyrido[2,3-d]pyrimidin-4-yl)-amine. dihydrochloride Suspend in 25ml of dichloromethane, adjust the pH of the solution to about 8.0 with 2mol / L sodium hydroxide aqueous solution, extract and separate the system, extract the water phase twice with 50ml of dichloromethane, combine the dichloromethane phase, and use 30ml of saturated saline After washing, dry the dichloromethane phase with 1.0 g of anhydrous sodium sulfate for 2 h. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain a foamy solid. The solid was added into a 100ml three-neck flask, 15ml of n-butanol, 3.3g of ethyl cyanoacetate, and 2.2g of DBU were added in sequence, stirred, protected by nitrogen, heated to an internal temperature of 40°C, and the reaction solution was stirred. Weigh 5.6g of citric acid and dissolve it in 30ml of acetone to prepare a solution. Thin chromatogra...

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Abstract

The invention discloses a tofacitinib intermediate, a crystal form and a preparation method thereof, the tofacitinib intermediate is a compound shown as a formula VI. The positions of characteristic diffraction peaks of the intermediate in an X-ray powder diffraction pattern when the reflection angle 2theta is about 7.4 DEG, 10.0 DEG, 11.8 DEG, 14.6 DEG, 16.3 DEG, 19.0 DEG, 19.3 DEG, 20.5 DEG, 23.8 DEG, 24.2 DEG, 25.2 DEG, 25.8 DEG, 26.0 DEG, 27.0 DEG, 28.0 DEG, 28.3 DEG, 28.9 DEG, 29.3 DEG, 31.2 DEG, 31.7 DEG, 32.1 DEG, 34.4 DEG and 38.2 DEG. The formula VI compound is stable and easy to store and transport.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to an intermediate compound and a crystal form of tofitinib and a preparation method thereof. technical background [0002] Tofitinib, the generic name is tofacitinib, and its chemical name is: 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrole[2,3-d]pyrimidin-4-yl) ) amino] piperidin-1-yl]-3-oxopropionitrile, whose chemical structural formula is the compound of formula II, [0003] . [0004] Tofitinib and its monocitrate are compounds of the following formula I, which are selective Janus kinase (JAK) 1 / 3 tyrosine protein kinase inhibitors developed by Pfizer. At present, the United States, Japan, Switzerland, Argentina, Kuwait and other countries have approved the marketing of tofitinib citrate (trade name: Xeljanz) for the treatment of adult rheumatic joints. At the same time, it can be used as an immunosuppressant and can also be used for the treatment of oth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07C59/265C07C51/41
CPCC07D487/04C07B2200/13
Inventor 但春燕左小勇蔡鹏飞郑德平段玉娟雷皇书叶文润
Owner CHONGQING PHARMA RES INST
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