Refining method of tofacitinib citrate

A technology of tofacitinib and purification method, applied in the field of medicine, can solve the problem of high content of maximum single impurity and total impurity, and achieve the effects of easy operation, few by-products and simple synthesis route

Active Publication Date: 2018-11-13
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] There are many types of impurities contained in the prior art preparation method and the method for refining tofacitinib citrate, and the maximum single impurity and total impurity content is relatively high, which is a technical problem that this field has been facing. Therefore, there is an urgent need for research in this field It is of great significance to develop a new preparation and refining method to overcome the existing technical defects and improve the quality of the product

Method used

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  • Refining method of tofacitinib citrate
  • Refining method of tofacitinib citrate
  • Refining method of tofacitinib citrate

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preparation example Construction

[0028] Preparation of compound Ⅳ

[0029] Add 74.08g (0.5mol) of N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 20g of sodium hydroxide, and 1000mL of acetonitrile into the reaction flask, stir at room temperature at 30°C, and then dropwise add 95.35 g (0.5 mol) of methanesulfonyl chloride was added after dropping, and the temperature was raised to 50° C. to react, and the reaction was monitored by TLC. After the reaction is complete, cool to room temperature, remove the solvent by rotary evaporation, add 1000mL of water and 1000mL of ethyl acetate, stir, let stand for liquid separation, extract the water layer with 800mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and dry under reduced pressure 146.57g of compound III was obtained, with a yield of 96.8% and a purity of 99.85%.

Embodiment 1

[0031] (1) Synthesis of Tofacitinib Citrate Crude Product

[0032] a. Under nitrogen protection, (0.194mmol) [Ir(COD)Cl]2 (1,5-cyclooctadiene iridium chloride dimer), R-(+)-1 ,1'-binaphthyl-2,2'-diphenylphosphine (0.192mmol), 150ml of toluene, stirred at room temperature for 20min, then added 20.59g of potassium iodide (0.0962mol) and 12.27g of 3-chloro-4-methylpyridine ( 0.0962mol), and put the reaction bottle into a stainless steel autoclave, replace it with hydrogen for three times, and finally rush into the required hydrogen pressure of 600psi. After reacting at room temperature for 12 hours, release the hydrogen slowly, and dilute the reaction system with 150mL of dichloromethane. Add 150mL saturated sodium carbonate solution, stir for 15min, separate the organic layer, then extract the aqueous layer with dichloromethane (3×150mL), combine the organic layers with Na 2 SO 4 After drying, the solvent was removed to obtain 17.89 g of compound III, with a yield of 99.2%, an...

Embodiment 2

[0039] (1) Synthesis of Tofacitinib Citrate Crude Product

[0040]a. Under nitrogen protection, add (0.966mmol) [Ir(COD)Cl] 2 (1,5-cyclooctadiene iridium chloride dimer), R-(+)-1 ,1'-binaphthyl-2,2'-diphenylphosphine (0.193mmol), 150ml of toluene, stirred at room temperature for 20min, then added 20.67g of potassium iodide (0.0966mol) and 12.32g of 3-chloro-4-methylpyridine ( 0.0966mol), and put the reaction bottle into a stainless steel autoclave, replace it with hydrogen for three times, finally rush into the required hydrogen pressure of 600psi, react at room temperature for 12 hours, release hydrogen slowly, and dilute the reaction system with 150mL dichloromethane, Add 150mL saturated sodium carbonate solution, stir for 15min, separate the organic layer, then extract the aqueous layer with dichloromethane (3×150mL), combine the organic layers with Na 2 SO 4 After drying, the solvent was removed to obtain 17.73 g of compound III, with a yield of 95.8%, an HPLC purity of ...

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Abstract

The invention discloses a refining method of tofacitinib citrate. The refining method comprises the following steps: (1) dissolving a tofacitinib citrate coarse product into a mixed solvent composed of methanol and butanone, and controlling the temperature at 45 to 50 DEG C till the tofacitinib citrate is completely dissolved; (2) adding active carbon for decoloration, filtering the solution, cooling filtrate at a certain cooling rate till the temperature is -10 to 0 DEG C, separating out crystals, and growing the crystals; (3) filtering the solution, washing filtered solids with methanol, anddrying the solids in vacuum to obtain the refined tofacitinib citrate. According to the refining method disclosed by the invention, the purity of the obtained tofacitinib citrate can be up to 99.9 percent or above, and the content of total impurities and the content of a single impurity are respectively controlled within 0.1 percent and 0.05 percent; the quality of a product is obviously improved; furthermore, the refining process is easy to operate and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a method for refining tofacitinib citrate. Background technique [0002] Tofacitinib citrate is a new type of Janus kinase inhibitor developed by Pfizer, the trade name is Xeljanz. This product can effectively inhibit the activity of JAK1 and JAK3, and block the signal transduction of various inflammatory cytokines. Existing studies have shown that tofacitinib citrate has a good therapeutic effect on rheumatoid arthritis, ulcerative colitis, psoriasis and other inflammation-related diseases. [0003] The chemical name of tofacitinib citrate is 3-[(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino ]piperidin-1-yl]-3-oxopropionitrile citrate has a chemical structure shown in formula I: [0004] [0005] There are many types of impurities contained in the prior art preparation method and the method for refining tofacitinib citrate, and the maximum single impuri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 李志滨秦丽丽李宣宣
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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