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Preparation methods of tofacitinib citrate intermediate and tofacitinib citrate
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A technology of tofacitinib and citric acid, which is applied in the preparation of tofacitinib citrate and the field of tofacitinib citrate intermediates, which can solve the problems of high catalyst consumption and catalyst poisoning
Inactive Publication Date: 2020-01-10
江苏海悦康医药科技有限公司
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The synthesis process of this compound has been improving, and the early process has great disadvantages
[0008] The synthetic route of the document Org.Process Res.Dev., 09, 2005, 51-56 has the following disadvantages: the total yield of the route is about 55%
The reason for the high amount of catalyst is catalyst poisoning caused by the residual sulfide in the previous step of removing Ts
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Embodiment 1
[0072] A preparation method of tofacitinib citrate, comprising the following steps:
[0073] One, the preparation of tofacitinib citrate intermediate; The described tofacitinib citrate intermediate is (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine double hydrochloride;
[0074] 2. N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7-p-toluenesulfonyl-pyrrolo[2,3-d]pyrimidine -The preparation of 4-amine; Concretely comprise the following steps:
[0076] B. Add 1.8kg of 4-chloro-7-p-toluenesulfonyl-pyrrolo[2,3-d]pyrimidin-4-amine to the result of the previous step in several times, and raise the temperature to 75-85°C for 10 hours to carry out HPLC detection;
[0077] C. Cool down to 20-30°C and keep stirring for 2 hours, filter with suction, wash the filter cake with 3kg of purified water, and set...
Embodiment 2
[0095] On the basis of Example 1, the preparation method of the tofacitinib citrate intermediate (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine dihydrochloride Specifically:
[0096]
[0097] (1) Preparation of N-(1-benzyl-4-methyl-1,2,5,6-tetrahydropiperidin-3-yl)acetamide; specifically comprising the following steps:
[0098] A. Add 2.2kg of 3-amino-4-methyl-pyridine into 15kg of dichloromethane and 22kg of toluene, cool down to 0-10°C, add 1.7kg of acetyl chloride dropwise, and react at 20-25°C for 10 hours; Below ℃, add aqueous sodium hydroxide solution dropwise, adjust the pH to 8-9, separate the lower aqueous phase; concentrate the organic phase under reduced pressure to a volume of 23-25L;
[0099] B. Add 1.9 kg of benzyl chloride to the resultant of the previous step, heat up to 70-80°C for reaction, and separate the dichloromethane distilled during the heating process; cool down to 0-10°C after the reaction;
[0100] C. Control the temperature below 10°C, and add...
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Abstract
The invention discloses preparation methods of a tofacitinib citrate intermediate and tofacitinib citrate. The preparation method of the tofacitinib citrate intermediate comprises: preparing N-(1-benzyl-4-methyl-1,2,5,6-tetrahydropiperidine-3-yl)acetamide by using 3-amino-4-methyl-pyridine, acetyl chloride, benzyl chloride and sodiumborohydride as raw materials; preparing 1-benzyl-N,4-dimethylpiperidine-3-amine by using the N-(1-benzyl-4-methyl-1,2,5,6-tetrahydropiperidine-3-yl)acetamide, hydrochloric acid, methylamine and sodiumborohydride as raw materials; and carrying out resolution and dissociation on the 1-benzyl-N,4-dimethylpiperidine-3-amine, and carrying out salt forming with hydrochloric acid to obtain the product. The invention provides the new tofacitinib citrate intermediatepreparation method, wherein the use amount of the catalytic hydrogenation catalyst is reduced in the preparation process of tofacitinib citrate so as to reduce the cost, and the generation of N-alkylated impurities can be well controlled by adopting the isopropanol / water mixed solvent.
Description
technical field [0001] The invention relates to the field of pharmacy, in particular to a tofacitinib citrate intermediate and a preparation method of tofacitinib citrate. Background technique [0002] 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-oxo-propionitrile, 2-hydroxypropane-1,2,3-tricarboxylate (1:1), the structural formula is as follows: [0003] [0004] Tofacitinib citrate is a Janus kinase (JAK) inhibitor, which can effectively inhibit the activity of JAK1 and JAK3, and block the signal transduction of various inflammatory cytokines. Tofacitinib citrate was developed by Pfizer, and in 2012, it was recognized by the FDA as a breakthrough therapy, and it was marketed for the treatment of rheumatoid arthritis that is intolerant to methotrexate treatment. [0005] The difficulty in the synthesis process of tofacitinib citrate is the dual-chiral center-substituted piperidine ...
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