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Preparation method of tofacitinib impurity

A tofacitinib, preparation process technology, applied in the direction of organic chemistry, etc., can solve the problems of difficult to effectively obtain compound I and compound, easy to produce other impurities, etc., and achieve the effect of easy separation and purification, high product purity, and simple synthesis process

Active Publication Date: 2019-02-15
珠海优润医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The process of using tofacitinib to prepare compound I and compound II involves the hydrolysis reaction of the nitrile group of tofacitinib, but this reaction requires very strict reaction conditions, and other impurities are easily produced, and it is often difficult to effectively obtain compound I and compound II

Method used

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  • Preparation method of tofacitinib impurity
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  • Preparation method of tofacitinib impurity

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preparation example Construction

[0032] A preparation method of tofacitinib related substances, the structural formula of tofacitib related substances is shown in formula I, The synthetic route is as follows:

[0033]

[0034] Including the following steps:

[0035] 1) Dissolve tofacitib in an acid solution with a mass concentration of 50%-60%, the acid being one of sulfuric acid and methanesulfonic acid;

[0036] 2) Raise the temperature to 40~50℃ to react;

[0037] 3) End the reaction, neutralize, extract, and crystallize to obtain the tofacitib related substances represented by formula I.

[0038] As a further improvement of the above preparation method, the mass concentration of the acid used in the preparation process of the compound of formula I is 50%-60%.

[0039] As a further improvement of the above preparation method, the mass concentration of the acid used in the preparation process of the compound of formula I is 55%.

[0040] As a further improvement of the above preparation method, the reaction temperatur...

Embodiment 1

[0062] 1) Add 3.12g (10mmol) of tofacitib and sulfuric acid (55%, 75ml) into the reaction flask, heat to 50°C and stir for 7-8 hours;

[0063] 2) HPLC confirms that the reaction is complete, cool to 5-10°C, add sodium hydroxide solution (10%) to neutralize to pH 8-9;

[0064] 3) Extract three times with dichloromethane (50ml×3);

[0065] 4) After drying, filtering, and concentrating the extract, methyl tert-butyl ether (25 ml) was added, and an off-white solid (compound I, 1.34 g) was precipitated out with slow stirring. The yield was 40.5%.

[0066] After testing, the purity of the off-white solid is 99.0%; the mass spectrum and nuclear magnetic data are as follows:

[0067] ESI-MS: m / z(M+H + )=331.2;

[0068] 1 HNMR(500MHz, DMSO-d6), δ(ppm): 1.00~1.02(d,5H), 1.53~1.84(m,2H), 2.34~2.43(m,1H), 3.21~3.32(m,5H), 3.50~3.52(t,1H), 3.62~3.71(m,1H), 3.77~3.92(d,1H), 6.55(s,1H), 6.95~7.02(d,1H), 7.13~7.14(d,1H) ), 7.42~7.49(d,1H), 8.10~8.12(d,1H), 11.64~11.70(d,1H);

[0069] 13 CNMR (125MHz, D...

Embodiment 2

[0071] Add 3.12g (10mmol) of tofacitib and methanesulfonic acid (50%, 80ml) into the reaction flask, heat to 50°C and stir to react for 12 hours. After HPLC confirms that the reaction is complete, the temperature is reduced to 5-10°C, and sodium hydroxide is added The solution (10%) was neutralized to pH 8-9, and extracted three times with dichloromethane (50ml×3); the extract was dried, filtered and concentrated, then methyl tert-butyl ether (25ml) was added, and an off-white solid was precipitated out under slow stirring. (Compound I, 1.00 g, purity 98.2%), the yield is 30.2%.

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Abstract

The invention discloses a preparation method of tofacitinib impurity. A synthetic route is as shown in the specification. The preparation method provided by the invention has the advantages that the synthetic process is simple, the products are easy to separate and purify and the purity of the obtained products is as high as 98.0%. Therefore, the obtained compound I, II in the preparation method can be used for the quality research and process research of related products as impurity reference substances of tofacitinib raw medicinal materials and preparations.

Description

Technical field [0001] The present invention relates to a method for preparing chemicals for quality research of chemical raw materials, in particular to a tofacitib (chemical name: 3-{(3R,4R)-4-methyl-3-[methyl(7H- Pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropionitrile) preparation method. Background technique [0002] The structural formula of Tofacitinib (Tofacitinib, its citrate for medicinal use, trade name: Xeljanz) is It is a new oral JAK3 inhibitor developed by Pfizer Pharmaceuticals in the United States and was approved by the FDA in November 2012. The drug can be used for moderate to severe adult patients with active rheumatoid arthritis who have insufficient or intolerant response to methotrexate therapy. [0003] In the preparation of tofacitib, the N-nitrile acetylation reaction on the piperidine ring is an essential step. Considering the efficiency and cost control in actual production, the intermediate ((3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyr...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 付长安赵红升刘夷之左斌海柯兴斌黄丽萍符雪仁曾勇填李振宇
Owner 珠海优润医药科技有限公司
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