Tofacitinib citrate impurity as well as analysis method and application thereof

A technology of tofacitinib and analysis method, which is applied in the field of the treatment of rheumatoid arthritis drug tofacitinib citrate impurities and its analysis, can solve problems such as harm and hidden dangers of drug safety, and achieve the goal of ensuring safe drug use and yield. The effect of high efficiency and simple synthesis process

Inactive Publication Date: 2019-12-24
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, the research on tofacitinib citrate impurities is mostly focused on the process impurities, and the research on degradable impurities is still insufficient, especially for the degradable impurities with high biological activity and great harm, such as genotoxic impurities, etc. Low concentrations can cause harm to the human body, so there are still certain hidden dangers in the safety of drugs

Method used

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  • Tofacitinib citrate impurity as well as analysis method and application thereof
  • Tofacitinib citrate impurity as well as analysis method and application thereof
  • Tofacitinib citrate impurity as well as analysis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: Formula (I) compound 3-((3R,4R)-3-((7-hydroxyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)- Preparation of 4-methylpiperidin-1-yl)-3-oxopropionitrile

[0046] Weigh 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)- Put 11.2g (30.35mmol) of 3-oxopropionitrile citrate and 9.9g (0.13mol) of peracetic acid into 358mL of methanol and 538mL of water, stir at 60-65°C for 22h, filter with suction, and concentrate the filtrate to remove methanol. Extract three times with dichloromethane, combine the organic phases, and wash with anhydrous Na 2 SO 4Dry, evaporate the solvent under reduced pressure, and purify by silica gel column chromatography, eluting with methanol:dichloromethane=1:15 to obtain 0.2g 3-((3R,4R)-3-((7-hydroxyl -7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropionitrile, yield 7.1%, The purity is 97.2%.

[0047] Confirm the structure of the prepared compound (I), the results are ...

Embodiment 2

[0051] Example 2: Formula (I) compound 3-((3R,4R)-3-((7-hydroxyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)- Preparation of 4-methylpiperidin-1-yl)-3-oxopropionitrile

[0052] Weigh 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)- Add 11.2g (30.35mmol) of 3-oxopropionitrile citrate and 9.9g (0.13mol) of peracetic acid into 358mL of methanol and 538mL of water, stir at 50-55°C for 24h, filter with suction, and concentrate the filtrate to remove methanol. Extract three times with dichloromethane, combine the organic phases, and wash with anhydrous Na 2 SO 4 Dry, evaporate the solvent under reduced pressure, and purify by silica gel column chromatography, eluting with methanol:dichloromethane=1:15 to obtain 0.2g 3-((3R,4R)-3-((7-hydroxyl -7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropionitrile, yield 6.9%, The purity is 96.6%.

Embodiment 3

[0053] Example 3: 3-((3R,4R)-3-((7-hydroxyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl) in tofacitinib citrate Content determination of amino)-4-methylpiperidin-1-yl)-3-oxopropionitrile

[0054] Chromatographic conditions:

[0055] Column: CAPCELL PAK MGⅡC 18 Column, length 250mm, inner diameter 4.6mm, packing particle size 5μm;

[0056] Column temperature: 35°C;

[0057] Flow rate: 1.0ml / min;

[0058] Detection wavelength: 217nm;

[0059] Injection volume: 20μl;

[0060] Diluent: 50% acetonitrile;

[0061] The mobile phase A is 10mmol / L ammonium dihydrogen phosphate buffer (adjusted to pH 6.5 with ammonia water), the mobile phase B is methanol, and the elution gradient is as follows:

[0062] time (min) Mobile phase A(%) Mobile phase B(%) 0 90 10 25 60 40 35 50 50 40 50 50 41 90 10 45 90 10

[0063] Test operation:

[0064] Preparation of formula (I) compound control solution: take 10 mg of this product, put it in a 5...

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Abstract

The invention provides a novel impurity in tofacitinib citrate, namely, 3-((3R,4R)-3-((7-hydroxy-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile. The preparation method of the compound is simple to operate, the obtained product is high in yield and purity, the invention further provides an analysis method of the compound, the method is sensitive, rapid and good in specificity, and the compound can be used as a reference substance for researching impurities in tofacitinib citrate raw materials and preparations, so that the product quality is effectively controlled.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an impurity of tofacitinib citrate, a medicine for treating rheumatoid arthritis, and an analysis method and application thereof. Background technique [0002] Tofacitinib citrate is a JAK inhibitor drug developed by Pfizer, which can effectively inhibit the activity of JAK1 and JAK3, and block the signal transduction of various inflammatory cytokines. For the treatment of moderate to severe rheumatoid arthritis that is ineffective or intolerant to methotrexate, it can be used alone or in combination with methotrexate or other non-biologic disease-modifying antirheumatic drugs (DMARDs) , the drug should not be used in combination with biological DMARDs or strong immunosuppressants such as azathioprine and cyclosporine. It was approved for listing in the United States in November 2012, listed in Japan in March 2013, and listed in China in March 2017. [0003] Tofacitinib citra...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04G01N30/02G01N30/06
CPCC07D471/04G01N30/02G01N30/06
Inventor 王珍张钰张园园刘翠艳张亚静齐珊
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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