923036-25-3Relevant academic research and scientific papers
Synthesis method of tofacitinib citrate diastereomer impurities
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, (2021/10/27)
The invention discloses a synthesis method of tofacitinib citrate diastereomer impurities, relates to the technical field of drug organic synthesis, and relates to 3 - amino -4 - methylpyridine as a starting material and a quaternary ammonium salt. Raw materials of the whole synthetic route are easily available, the reaction conditions are mild, the post-treatment separation and purification operation is simple and feasible, and the preparation method is good in repeatability.
PROCESSES FOR PREPARING (3R,4R)-1-BENZYL-N,4-DIMETHYLPIPERIDIN-3-AMINE OR A SALT THEREOF AND PROCESSES FOR PREPARING TOFACITINIB USING THE SAME
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Paragraph 114-118, (2020/10/20)
The present invention provides a novel process for preparing (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine or a salt thereof, which is an intermediate useful for the preparation of tofacitinib. The present invention also provides a novel intermediate used in the process, i.e., isopropanol solvate of methyl ((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)carbamate dibenzoyl-L-tartrate. The present invention also provides a novel intermediate, having excellent stability, useful for the preparation of tofacitinib, i.e., (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine acetate. In addition, the present invention provides a process for preparing tofacitinib or a pharmaceutically acceptable salt thereof using the process.
Synthesis method of tofacitinib citrate
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, (2020/08/29)
The invention relates to the technical field of medicinal chemistry, and discloses a synthesis method of tofacitinib citrate. The method comprises 1) preparing 2,4-dihydroxy pyrrolopyrimidine: adding4-aminouracil and anhydrous sodium acetate into water (in a molar ratio of (1: 3)-(1: 5)), heating to 60-80 DEG C, slowly adding a 2-chloroacetaldehyde aqueous solution having a concentration of 40%,stirring to react for 4-6 hours, cooling to room temperature, filtering, washing a solid with water, and drying under reduced pressure to obtain 2,4-dihydroxy pyrrolopyrimidine. According to the synthesis method of tofacitinib citrate, through two times of impurity removal, the purity of the produced tofacitinib citrate finished product is higher, subsequent purification is not needed, the synthesis time is short, the process is simple, the method is suitable for factory production, the production time of the tofacitinib citrate finished product can be saved, the production efficiency of the tofacitinib citrate finished product is improved, and the tofacitinib citrate is more convenient to use.
Preparation method of tofacitinib citrate
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Page/Page column 8; 9; 10; 12; 13, (2020/02/14)
The invention relates to the field of medicine synthesis, and particularly discloses a preparation method of tofacitinib citrate. The preparation method comprises the following steps: S1, dissolving acompound SM1, a compound SM2 and an alkaline reagent in a solvent A, and performing a reaction to obtain a first compound; S2, taking and mixing a catalyst, a solvent B and the first compound, introducing hydrogen, and carrying out a catalytic hydrogenation reaction to obtain a second compound; S3, taking and mixing active anhydride, a solvent C and the second compound, and carrying out an acylation reaction to obtain a third compound, wherein R in the active anhydride comprises an alkyl group or an aryl group; and S4, taking and mixing citric acid, a solvent D and the third compound, and carrying out a salt-forming reaction to obtain a compound T that is the tofacitinib citrate. The preparation method has the advantages of easily available initial raw materials, no use of complex or toxic compounds, short synthesis process route, simple and convenient reaction operation of each step, high total yield and high productivity, and is suitable for large-scale industrial production.
Preparation method of tofacitinib key intermediate
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Paragraph 0019; 0020; 0023, (2018/11/03)
The invention discloses a preparation method of a tofacitinib key intermediate with a chemical name as (3R, 4R)-methyl-(4-methyl-piperidine-3-yl)-(7H-pyridine[2,3-d]pyridine-4-yl)amine and the CAS number of 477600-74-1. The preparation method is characterized in that ammonium formate or hydrazine hydrate is used as a hydrogen donator, phenyl and chlorine of the 2-chloro-4-{(methyl)[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine are removed under the catalysis of catalysts such as palladium/carbon hydroxide to generate the intermediate. By adopting the preparation method, no autoclave is used. The preparation method has the advantages of mild reaction conditions, higher safety, high reaction rate, fewer process byproducts, simple operation and higher productivity, can effectively solve the problem that more impurities exist in the preparation process, and facilitates the industrialized production.
Preparation method of tofacitinib citrate
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Paragraph 0038; 0039, (2018/07/30)
The invention discloses a preparation method of tofacitinib citrate. The preparation method comprises the following steps: stirring an organic solvent, a compound 3, 5 percent wet palladium on carbonand acetic acid until a mixture is suspended; conveying the mixture into a micro-reactor from a channel A; meanwhile, conveying alkylsilane into the micro-reactor from a channel B; controlling the temperature of the micro-reactor to 20 to 30 DEG C and carrying out reaction; carrying out post-treatment to obtain a compound 2; after uniformly mixing an alcohol type solvent, the compound 2, ethyl cyanoacetate and DBU (1,8-Diazabicyclo [5,4,0]undec-7-ene), conveying a mixture into the micro-reactor from the channel A; dissolving citric acid into a mixed solution of water and the alcohol type solvent, conveying a mixture into the micro-reactor from the channel B; controlling the temperature in the micro-reactor to 70 to 80 DEG C and carrying out reaction; cooling and crystallizing to obtain thetofacitinib citrate. The method provided by the invention has the advantages of controllable reaction condition and simplicity in operation; dangers caused by the fact that flammable and explosive gas is used are avoided and the safety is higher; reaction can be finished instantly and the reaction time is greatly shortened; debenzylation reaction and acylation reaction are complete and post-treatment is simple; the preparation method is suitable for industrial large-scale production. A formula is shown in the description.
A tofacitinib citrate purification method
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Paragraph 0025; 0026; 0027, (2019/01/08)
The invention belongs to the field of medicine synthesis and provides a tofacitinib citrate purification method which can effectively remove an impurity G. The method includes adding a tofacitinib citrate crude product to be purified into a mixed solvent, stirring and heating the mixture until the crude product is fully dissolved, cooling the mixture for crystallization, and performing filtrationand vacuum drying to obtain a purified tofacitinib citrate product. The method is simple to operate and suitable for industrial scale-up production, and has obvious impurity removing effects and a high yield.
PYRROLO[2,3-D]PYRIMIDINE DERIVATIVES; THEIR INTERMEDIATES AND SYNTHESIS
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Page/Page column 20, (2010/11/25)
This invention relates to methods and intermediates useful for the synthesis of pyrrolo [2,3-d] pyrimidine compounds. Specifically novel synthetic methods and intermediates for the synthesis of 3- {(3R, 4R)-4-methyl-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-amino}-piperidin-1-yl)-3-oxo-propionitrile and its corresponding citrate salt are disclosed.
