Method for preparingtofacitinib citrate

A technology of tofacitinib and citric acid, which is applied in the field of pharmaceutical preparations, can solve problems such as undisclosed process parameter information, and achieve the effects of reducing the pressure of process quality control, complete reaction, and easy access

Active Publication Date: 2019-10-18
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This process is a relatively common reaction route, which can successfully prepare tofacitinib citrate, but the detailed process parameter information is not disclosed. With the improvement of the quality of pharmaceutical products in the pharmaceutical industry, the cognition of impurities is getting deeper and deeper. A more optimized preparation process plan is required to improve product purity and reduce impurity content, especially to remove genotoxic impurities to the greatest extent

Method used

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  • Method for preparingtofacitinib citrate
  • Method for preparingtofacitinib citrate
  • Method for preparingtofacitinib citrate

Examples

Experimental program
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Effect test

Embodiment 1

[0037] Step 1: 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)- Preparation of 3-oxopropionitrile

[0038]87g N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 161g ethyl cyanoacetate and 0.26L of methanol into the reaction vessel, control the temperature at 5-15°C and slowly add 54g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and then adjust the temperature to 15-15°C Stir the reaction at 20°C for 10 hours, TLC detection (methanol: dichloromethane 1:6) the reaction is almost complete, filter, wash the filter cake with a mixed solvent made of 0.12L water and 0.06L methanol, and dry to obtain a white solid 3-(( 3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropionitrile 100.6 g. Based on N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, the molar yield is 90.8 %. The reaction formula is as follows:

[0039]

[0040] Step 2: 3-((3R,4R)-...

Embodiment 2

[0044] In this embodiment, the solvent ratio in step 2 of embodiment 1 is adjusted.

[0045] Step 1: 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)- Preparation of 3-oxopropionitrile

[0046] 87g N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 161g ethyl cyanoacetate and Put 0.26L of methanol into the reactor, control the temperature at 5-15°C and slowly add 54g of DBU, after the completion, adjust the temperature to 20-25°C for 10 hours, TLC detection (methanol:dichloromethane 1:6) The reaction is basically complete, filter, and use The filter cake was washed with a mixed solvent made of 0.12L purified water and 0.06L methanol, and dried to obtain a white solid 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3 -d] pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropionitrile 101 g. Based on N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, the molar yield is 91.2 %.

[0047] Step 2: 3...

Embodiment 3

[0050] In this embodiment, the solvent ratio in step 2 of embodiment 1 is adjusted.

[0051] Step 1: 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)- Preparation of 3-oxopropionitrile

[0052] 87g N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 161g ethyl cyanoacetate and Put 0.26L of methanol into the reactor, control the temperature at 5-15°C and slowly add 54g of DBU, after the completion, adjust the temperature to 15-20°C for 8 hours, TLC detection (methanol: dichloromethane 1:6) The reaction is basically complete, filter, and use The filter cake was washed with a mixed solution of 0.12L water and 0.06L methanol, and dried to obtain a white solid 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3- d] pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropionitrile 100.8 g. Based on N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, the molar yield is 91.0 %.

[0053] Step 2: 3-((3R,4R)-4...

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Abstract

The invention provides a method for preparing tofacitinib citrate. The method for preparing tofacitinib citratecomprises the following steps that1, N-methyl-N-((3R,4R)-4-methylpiperidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and ethyl cyanoacetate are added into methyl alcohol for condensation reaction to prepare and obtain 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile;and 2,3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileis added to a mixed solvent and subjected to 80+ / -5 DEG reflux, additionally, citric acid is dissolved in the mixed solvent and then added slowly to a reflux system forsalt forming reaction, cooling, filtration, washing, and drying to obtain 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile citrate. According to the method for preparing tofacitinib citrate, operation isconvenient, time consumption isless, the yield rate is high, product impurity is low,and purity is good.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a preparation method of tofacitinib citrate. Background technique [0002] Tofacitinib Citrate (Tofacitinib Citrate) was developed by Pfizer of the United States and was approved by the FDA for marketing in the United States in November 2012. The product name is The preparation is a tablet with a specification of 5 mg (calculated as tofacitinib). Indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It can be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is the first drug developed for the treatment of rheumatoid arthritis, and has a broad market prospect. [0003] Chemical name of tofacitinib citrate: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07C51/41C07C59/265
CPCC07C51/412C07C59/265C07D487/04
Inventor 王珍张园园刘翠艳张鈺魏旭郭小丰
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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