Preparation method of tofacitinib

A methyl, -4- technology, applied in the field of pharmaceutical preparation, can solve the problems of difficult control of enantiomeric impurity limit, expensive raw materials, long synthesis route, etc., and achieves easy operation and scale-up production, and the reaction route is simple and easy to operate and purify. The effect of the simple method

Inactive Publication Date: 2014-05-28
湖南华腾制药有限公司
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Problems solved by technology

[0014] Technical problem: the synthesis route announced by CN1409712 patent has expensive raw materials, the final product needs to be separated and purified, the limit of enantiomer impurities is difficult to control, and the production cost is high; the two routes announced by Pfizer company WO2007012953 have relatively expensive raw materials, and expensive The rhodium catalyst is used to reduce the pyridine ring, the synthetic route is long, the cycle is long, the cost is high, and it is not suitable for industrialized production

Method used

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  • Preparation method of tofacitinib

Examples

Experimental program
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Embodiment 1

[0033] Synthesis of 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine (Ⅳ)

[0034] Benzyl bromide (17.1g, 100mmol) and pyridine (7.9g, 100mmol) were reacted at 20°C for 24h, the viscous liquid was heated to 130°C for 1h, and the reaction liquid was cooled to room temperature. Ethanol (120 mL) was added to dissolve, and the resulting yellow solution was cooled to 0° C., and sodium borohydride (5.0 g, 130 mmol) was added in portions within 2 h. The reaction solution was continued to react at 20°C for 12h. Water (60 mL) was slowly added dropwise to control the temperature of the system at 5-10° C., and diatomaceous earth (4.0 g) was added. Continue to stir at 0°C for 5 h, filter, wash the filter cake with ethanol (3×15 mL), combine the organic phases, concentrate under reduced pressure to a volume of about 50-60 mL, add dropwise sodium hydroxide solution (0.25M, 50 mL), methyl Extracted with tert-butyl ether (3×40 mL), combined the organic layers, washed with saturated brine (2×30 m...

Embodiment 2

[0036] Synthesis of (3R,4R)-4-methyl-1-(phenylmethyl)-3-piperidinol (V)

[0037] 1-Benzyl-4-methyl-1,2,3,6-tetrahydropyridine (18.7g, 100mmol) was dissolved in tetrahydrofuran (150mL), and sodium borohydride (6.5g, 170mmol ). The temperature of the reaction solution was lowered to 0°C, and a mixed solution of boron trifluoride diethyl ether (16.8g, 118.3mmol) and tetrahydrofuran (25mL) was slowly added dropwise to control the system temperature to ≤0°C. Return to room temperature and stir for 1.5h. The reaction solution was cooled to 0°C again, and water (50 mL) was slowly added dropwise to the system to destroy excess borane. After the reaction solution was stirred at room temperature for 2 h, it was lowered to 0°C, and a mixed solution of potassium hydrogen persulfate (110 g, 342.8 mmol) and water (500 mL) was slowly added dropwise. After the addition was complete, the system was warmed to room temperature for 12 h. The excess oxidant was quenched with sodium bisulfite in t...

Embodiment 3

[0039] N-methyl-N-((3R,4R)-4-methyl-1-phenylmethylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine ( VII) Synthesis

[0040] N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (14.8g, 100mmol) and (3R,4R)-4-methyl-1-(phenylmethyl)-3- Piperidinol (20.5g, 100mmol) was dissolved in dioxane (200mL), triphenylphosphine (26.2g, 100mmol) was added under stirring, the reaction solution was cooled to 0°C, diisopropyl azodicarboxylate was added dropwise (20.2g, 100mmol), after the dropwise addition, return to room temperature and react for 2h, then raise the temperature to 100°C and react for 2h, cool to room temperature, concentrate under reduced pressure to obtain a tan solid, add dichloromethane (200mL) to dissolve, and successively wash with saturated carbonic acid Sodium hydrogen (2×50 mL), washed with saturated brine (2×50 mL), and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain 22.8 g of anhydrous oily liquid with a yield of 68%.

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Abstract

The invention discloses a preparation method of tofacitinib, namely 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d] pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile. According to the preparation method, an onium pyridine salt is formed by using benzyl bromide as a raw material; then reduction, selective oxidation, alkylation, deprotection and an acylation reaction are conducted to obtain a compound, namely 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d] pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile shown as the formula I.

Description

technical field [0001] The present invention relates to 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}- The preparation method of 3-oxopropionitrile (tofacitinib, Tofacitinib) belongs to the technical field of medicine preparation. Background technique [0002] 3-{(3R,4R)-4-Methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo Propionitrile citrate (Tofacitinib, trade name: Xeljanz), whose structural formula is shown in formula I, is a Janus kinase (JAKs) inhibitor developed by Pfizer (Pfizer). On November 6, 2012, the U.S. Food and Drug Administration (FDA) approved the marketing of tofacitinib citrate (Xeljanz) for moderately to severely active rheumatoid patients who have insufficient response or intolerance to methotrexate treatment. A novel oral JAK inhibitor for the treatment of adult patients with rheumatoid arthritis (RA). [0003] [0004] The preparation method of tofacitinib mainly contains followin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 邓泽平蒋江平陈芳军
Owner 湖南华腾制药有限公司
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