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Synthesis method for tofacitinib

A methyl and pyrrole technology, applied in the field of synthesis of the JAK inhibitor tofacitinib, can solve the problems of large improvement space, short overall route, cumbersome operation, etc., and achieve the effect of simple operation, less impurities and simple process

Inactive Publication Date: 2016-11-23
济南扬诺生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The raw material price of this route is relatively high, but the overall route is short and the yield is high, which is worthy of industrial development. The disadvantage is that more expensive reagents are used, and the operation is cumbersome, so there is a lot of room for improvement.

Method used

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  • Synthesis method for tofacitinib
  • Synthesis method for tofacitinib
  • Synthesis method for tofacitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: the synthesis of cis-(4-methylpiperidin-3-yl) methyl carbamate

[0026]

[0027] Ethanol (150ml), (4-methylpyridin-3-yl) methyl carbamate (16.6g, 0.1mol), ethanol (150ml), concentrated sulfuric acid (10.9g, 0.11mol) and 5% Pd / C ( 3.5 g) were sequentially added to the hydrogenation kettle, replaced with nitrogen three times, replaced with 5MPa hydrogen three times, and reacted under 5MPa hydrogen pressure for 24h. Cool to room temperature, filter with suction, and concentrate the filtrate under reduced pressure to obtain a colorless oily liquid product (16.4 g, 95%). MS(m / z): 173[M+H] + ; 1 H NMR (300MHz, DMSO-d 6 ): 6.80 (d, J=8.7Hz, 1H, OCONH), 3.53 (s, 3H, CH 3 O), 3.47 ~ 3.49 (m, 1H, CHCH 2 NH), 2.70~2.81(m, 2H, CHCH 2 NH), 2.50~2.58(m, 2H, CHCH 2 CH 2 ), 2.40~2.42 (m, 1H, CHCH 2 NH), 1.68~1.73(m, 1H, CH 3 CH), 1.25~1.27(m, 2H, CHCH 2 CH 2 ), 0.78 (d, J=6.6Hz, 3H, CH 3 CH).

Embodiment 2

[0028] Example 2: Synthesis of cis-(1-benzyl-4-methylpiperidin-3-yl) methyl carbamate

[0029]

[0030] Add cis-(4-methylpiperidin-3-yl) methyl carbamate (85g, 0.49mol), DIPEA (95g, 0.74mol) and acetonitrile (400ml) into the reactor, keep the temperature below 10 degrees and drop Add benzyl chloride (60 g, 0.5 mol) in acetonitrile solution (200 ml) and let it rise to room temperature for 2 h. Evaporate the solvent under reduced pressure, add ice water (1L) to the residue, add dropwise 2mol / L hydrochloric acid (about 100ml) to adjust the pH to 3~4, extract with ethyl acetate, separate the layers, and use concentrated ammonia water (about 10ml) for the aqueous layer Adjust to pH 7-8, and then extract three times with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and suction-filtered, and the filtrate was concentrated under reduced pressure to obtain a pale yellow oily product (110.3 g, 84%). MS(m / z): 263[M+H] + ; 1 H NMR (300MHz, ...

Embodiment 3

[0031] Embodiment 3, the synthesis of tofacitinib citrate

[0032]

[0033]N-[(3R,4R)-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (30g, 0.12mol), HOBT (23g, 0.17mol), cyanoacetic acid (13.6g, 0.16mol) and dichloromethane (300ml) were added to the reactor and reacted at room temperature for 12h. After the reaction was completed, add water (300ml) to quench, extract with dichloromethane, extract the aqueous layer with dichloromethane again, combine the organic layers, dry over anhydrous sodium sulfate and filter with suction, concentrate the filtrate under reduced pressure, add citrate monohydrate to the remaining light yellow solid A solution of citric acid (2.3g, 11mmol) in acetone (500ml) was stirred at 40°C for 2h. After cooling, stir overnight in an ice-water bath, filter with suction, wash the filter cake with acetone, and dry to obtain an off-white solid product (43 g, 70%). MS(m / z): 313[M+H] + ; 1 H NMR (500MHz, CD 3 OD): 11.62 (s, 1H, NH)...

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Abstract

The invention relates to a synthesis method for tofacitinib serving as a JAK inhibitor. According to the method, the tofacitinib is prepared by taking (4-picoline-3-yl)methyl carbamate as a raw material, and performing catalytic hydrogenation, benzyl protection, reduction, salification, separation, deprotection and amidation salification. The method specifically comprises the following steps: (1) performing catalytic hydrogenation and reduction on (4-picoline-3-yl)methyl carbamate in sulfuric acid and Pd / C; (2) reacting cis-(4-picoline-3-yl)methyl carbamate and benzyl chloride to obtain cis-(1-benzyl-4-methylpiperidine-3-yl)methyl carbamate; (3) performing HOBT catalytic condensation on N-[(3R,4R)-4-methylpiperidine-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine and cyanoacetic acid to obtain tofacitinib free alkali. The preparation method provided by the invention has easily obtained raw materials, mild reaction conditions, easiness and convenience in operation and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic and pharmaceutical synthesis, and in particular relates to a synthesis method of a JAK inhibitor tofacitinib. Background technique [0002] The chemical name of Tofacitinib is 3-[(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino] Piperidin-1-yl]-3-oxopropionitrile is a new type of JAK inhibitor developed by Pfizer of the United States. It was approved by the FDA in November 2012, and its trade name is Xeljanz. Unlike most other current RA therapeutic drugs that mainly act on extracellular targets, tofacitinib targets intracellular signaling pathways, acts on the core part of cytokines, and is used for patients with inadequate or inadequate response to methotrexate treatment. A Novel Oral JAK Inhibitor for the Treatment of Tolerated Adult Patients with Moderately to Severely Active Rheumatoid Arthritis (RA). At present, there are nearly 30 million patients with rheumatoid arthriti...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 许柏岩王杨杨小英
Owner 济南扬诺生物科技有限公司
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