112 results about "Tofacitinib" patented technology

The invention discloses a preparation method of tofacitinib, namely 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d] pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile. According to the preparation method, an onium pyridine salt is formed by using benzyl bromide as a raw material; then reduction, selective oxidation, alkylation, deprotection and an acylation reaction are conducted to obtain a compound, namely 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d] pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile shown as the formula I.

The invention relates to an industrial production method applicable to citric acid tofacitinib. The invention relates to a novel industrial production method of a high-purity orally taken JAK inhibitor and a medicine for treating rheumatoid arthritis. Raw materials are subjected to substitution, protecting group removal, reduction debenzylation, condensation and salifying to obtain a compound shown in a formula I, and the defects of a synthetic route reported in existing literatures that the impurity content in the prepared finished product is high, cost is high and yield is low are overcome. The novel industrial production method provided by the invention has the advantages that cost of a used reagent is low, environmental pollution is hardly caused, operation is easy, and short time is consumed, so that the novel industrial production method is applicable to industrial production; meanwhile, product quality is good, total impurity content is low, content of each individual impurity is controlled to be 0.1% or below, the finished product is controlled to be in a single stable crystal form, and medicinal-grade raw material requirements can be met.

The invention discloses an efficient and safe method for synthesizing citric acid tofacitinib. N-[(3R,4R)-1-benzyl-4-methylpiperidine-3-base]-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine is used as the raw material, Pd / C and HCOOH reduction debenzylation is conducted, condensation is conducted under the catalysis of an EDCI or EDCI, HOBT and triethylamine compound system with cyanoacetic acid, and salifying is conducted with citric acid in acetone to obtain citric acid tofacitinib. By the adoption of the synthesis method, potential safety hazards caused by hydrogen and ammonium formate are avoided, debenzylation reaction and amidation are thorough, no side reaction is caused basically, reaction time is shortened greatly, yield is high, aftertreatment is easy, and citric acid tofacitinib can be prepared efficiently and safely.

The present invention discloses novel crystalline and non-crystalline forms of 3-((3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)-3-oxopropionitrile, pharmaceutical composition containing the same, preparations thereof and the uses thereof.

The invention relates to a novel preparation method of a tofacitinib intermediate and in particular to a preparation method of the tofacitinib intermediate (3R,4R)-1-benzyl-N-4-dimethyl piperidine-3-amine dihydrochloride. The preparation method comprises the following steps of: by taking 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine as an initial raw material, oxidizing olefin to form a ketone II by means of a one-step process; forming imine III with amine; applying asymmetric reduction imine to form amine; removing a trans isomer by recrystallization to obtain a cis-form structure IV; and finally, applying chiral resolution to obtain a final product (3R,4R)-1-benzyl-N-4-dimethyl piperidine-3-amine dihydrochloride I. The preparation method is creative in process, the process steps are shortened, and the synthetic yield of an asymmetric compound is greatly increased, thereby laying a solid foundation for industrial production.

The present invention relates to a novel preparation method of a tofacitinib intermediate bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate. According to the preparation method, 3-amino-4-methyl piperidine is adopted as a starting raw material, is subjected to a N-methoxycarbonylation reaction under the sodium hydride effect, and is subjected to a catalytic hydrogenation reaction, a nucleophilic substitution reaction, an amide reduction reaction under the red aluminum effect, and L-di-p-toluyl tartaric acid (L-DTTA) chiral splitting so as to finally prepare the target compound bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate. The process of the present invention has characteristics of further existing process improving, simple operation, easy post-treatment, high yield, and low cost.

The present invention relates to oral sustained release formulations of tofacitinib and pharmaceutical acceptable salts thereof. The formulations described herein have desirable pharmacokinetic characteristics.