40 results about "4-methylpiperidine" patented technology

The invention relates to a method for preparing tofacitinib citrate. The method comprises the following steps: by taking N-methyl-N-((3R, 4R)-1-benzyl-4-methylpiperidine-3-yl)-7H-pyrrolo (2, 3-d) pyrimidin-4-amine as a raw material, performing hydrogenation to remove an amino protecting group, performing amidation reaction and salt-forming reaction and finally drying to obtain tofacitinib citrate. In the preparation process, after-treatment is not required, the separation of a target intermediate is not required, and only reactants need to be added sequentially. The preparation method of tofacitinib citrate provided by the invention has the advantages of simplicity in operation, high yield, mild conditions and the like, and is suitable for industrial production.

The invention relates to a preparation method of tofacitinib citrate, in particular to high-yield synthesis of tofacitinib citrate. The tofacitinib citrate is synthesized from raw materials including4-chloro-7-pyrrolo[2,3-d]pyrimidine, (BOC)2O, (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyl tartrate, Pd/C, cyanoacetic acid and citric acid through six steps including an aminoprotection reaction, an amination reaction, a debenzylation reaction, a condensation reaction, a deprotection reaction and a salt forming reaction. The synthesis route provides the preparation methodof tofacitinib citrate, and the preparation method is high in yield, low in cost, easy to operate and suitable for industrialization.

The invention relates to a synthesis method for tofacitinib serving as a JAK inhibitor. According to the method, the tofacitinib is prepared by taking (4-picoline-3-yl)methyl carbamate as a raw material, and performing catalytic hydrogenation, benzyl protection, reduction, salification, separation, deprotection and amidation salification. The method specifically comprises the following steps: (1) performing catalytic hydrogenation and reduction on (4-picoline-3-yl)methyl carbamate in sulfuric acid and Pd/C; (2) reacting cis-(4-picoline-3-yl)methyl carbamate and benzyl chloride to obtain cis-(1-benzyl-4-methylpiperidine-3-yl)methyl carbamate; (3) performing HOBT catalytic condensation on N-[(3R,4R)-4-methylpiperidine-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine and cyanoacetic acid to obtain tofacitinib free alkali. The preparation method provided by the invention has easily obtained raw materials, mild reaction conditions, easiness and convenience in operation and high yield, and is suitable for industrial production.

The invention relates to a method for preparing 4-methylpiperidine-2-carboxylate hydrochloride which is an intermediate of argatroban active precursor (2R, 4R)-4-methylpiperidine-2-carboxylic acid ethyl ester. 4-methylpiperidine-2-carboxylic acid ethyl ester is adopted as a raw material, phosphomolybdic acid is used as a catalyst, oxidizing is performed to obtain 4-methylpiperidine-2-carboxylic acid ethyl ester nitrogen oxide, methanol or ethanol is taken as a solvent, and 4-methylpiperidine-2-carboxylate hydrochloride is produced through reduction reaction. The method is simple to operate and has moderate conditions; phosphomolybdic acid is adopted to increase the activity of an oxidizing agent of hydrogen peroxide, the usage of the oxidizing agent is reduced, and the reaction yield is increased; the purification is convenient, the product quality is excellent, and good safety is obtained; and pollution is reduced, and industrial production is benefited.

The invention relates to a preparation method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine (I). The method comprises the following steps: carrying out a reductive amination reaction on a compound of formula (III) and (R)-1-phenylethylamine to obtain a compound of formula (II), removing chiral prosthetic groups from the compound of formula (II), and adding a methyl group to the amino group of the compound of formula (II) in order to obtain nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine (I), wherein R in each of the formula (I), the formula (II) and the formula (III) is an amino protection group or hydrogen, and the amino protection group can be C1-4 alkoxycarbonyl, benzyloxycarbonyl or benzyl groups which can be removed through hydrolysis or hydrogenation. The asymmetric synthesis method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine (I) has the advantages of reasonable technology, concise route, obtaining of the required product in a high ee value manner by constructing two chiral centers through chiral induced one-step reductive amination, cheap raw materials, and no waste isomer emission, and is suitable for large-scale industrialized production.

The invention relates to a preparing method of a (2R,4R)-4-methylpiperidine-2-ethyl formate compound. The method comprises the following steps of 1, regarding 4-methyl-2-cyanopiperidine as an initialraw material to be subjected to a hydrolysis reaction through hydrochloric acid to obtain 4-methyl-2-piperidinecarboxylicacid hydrochloride; 2, using ethyl alcohol to esterify 4-methyl-2-piperidinecarboxylicacid hydrochloride to obtain 4-methyl-2-ethyl nipecotate hydrochloride; 3, adding a mixed solvent of methyl tertiary butyl ether and ethyl alcohol, reacting the mixed liquid for pulping, filtering to remove cis-form 4-methyl-2-ethyl nipecotate hydrochloride solid, and collecting mother liquor to obtain anti-form 4-methyl-2-ethyl nipecotate hydrochloride; 4, using L-tartaric acid to split anti-form 4-methyl-2-ethyl nipecotate to obtain the target product (2R,4R)-4-methylpiperidine-2-ethyl formate.

The invention relates to a preparing method of a 1-triazole-2-butanol derivative. The preparing method comprises the steps of making 4-methylpiperidine addition salt react with (2R,3S)-2-(2,4-di-fluorophenyl)-3-methyl-2-[(1H-1,2,4-traizole-1-radical)methyl]oxirane in a solvent in the presence of lithium halide and/or magnesium halide and alkaline to generate the 1-triazole-2-butanol derivative. The reaction is complete, the selectivity is high, and the product of the 1-triazole-2-butanol derivative of which the purity is larger than 99% can be obtained through simple aftertreatment. Besides, the yield is high no matter which form of 4-methylpiperidine addition salt is adopted as raw materials.

The invention discloses four polymorphic substances B, E, H and D of (4-((R)-((2S, 5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazine-1-base)(3-hydroxyphenyl)methyl)phenyl)(4-methylpiperidine-1-base)ketone di-hydrochloride, a preparation method thereof, and application in preparing a drug.

The invention relates to a preparation method of argatroban intermediate (2R,4R)-ethyl-1-((S)-2-(tert-butoxy amido)-5-(3-nitroguanidine)valery)-4-methylpiperidine-2-ethyl carboxylate. The method comprises the following steps: enabling NG-nitro-N2-t-Boc-L-arginine and (2R,4R)-4-methyl-2-ethyl nipecotate to perform condensation reaction in the presence of a condensing agent selected from 1-ethyl-3-(3-dimethylamine propyl)carbodiimide hydrochloride, N,N-diisopropyl carbodiimide and N,N'-carbonyl diimidazole and an aprotic solvent to generate the argatroban intermediate. The raw material for the method is wide in source, cheap and easily-available; the method is mild in reaction condition, short in step, simple in operation, easy to purify the product, low in production cost and environment-friendly, not only suitable for laboratory synthesis, but also suitable for large-scale industrial production.

The invention relates to a synthesis method of (3R, 4R)-N-PG-4-methyl-3-methylaminopiperidine, the structural formula of which is as the following, wherein PG is an amino protecting group. The synthesis steps comprise: 1) cyclization: putting 2-butenal, N-PG-2-nitroethylamine, a catalyst and an organic acid into a reaction medium to react at a temperature ranging from -10 to 50DEG C for 0.5-8h; at the end of the reaction, adding an acid into the system to undergo dehydration, and letting the substances further react for 1-5h at 10-50DEG C so as to obtain (3R, 4R)-N-PG-4-methyl-3-nitro-3, 4-dihydropyridine, with the structure of the catalyst shown as the following; 2) subjecting (3R, 4R)-N-PG-4-methyl-3-nitro-3, 4-dihydropyridine to catalytic hydrogenation reduction so as to obtain (3R, 4R)-N-PG-3-amino-4-methylpiperidine; and 3) subjecting the (3R, 4R)-N-PG-3-amino-4-methylpiperidine to a methylation reaction so as to generate the target product.

Spinning polyamide 6 comprises the following raw materials, by mass part, 96-98 parts of caprolactam, 2-4 parts of desalted water, 0.28-0.3 part of a molecular weight control agent, and 0.05-0.15 part of a heat stabilizer, wherein the molecular weight control agent is any two of adipic acid, terephthalic acid and acetic acid, and the heat stabilizer is any one of 4-amino-2,2,6,6-4-methyl piperidine and N,N'-di(2,2,6,6-tetramethyl-4-piperidyl)-1,3-benzenedicarboxamide.

The application discloses five polymorphic substances: B, C, A, M and I of (4-((R)-((2S,5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazine-1-yl)(3-hydroxyphenyl)methyl)phenyl)(4-methylpiperidine-1-yl)methyl ketone dihydrochloride, a preparation method thereof, and applications thereof in preparation for medicines.

The invention relates to a novel synthesis route of N-methyl-N-(4-methylpiperidine)-3-yl-7H-pyrropyrimidine-4-amine. According to the synthesis route, 4-methyl-3-piperidone and 4-hydroxyl-6,7-dihydro-5H-pyrrolo[2,3-D]pyrimidine are taken as raw materials separately, and a key tofacitinib intermediate, namely N-methyl-N-((3R,4R)-4-methylpiperidine-3-yl)-7H-pyrrolo[2,3D]pyrimidine-4-amine with highyield is synthesized through six-step reactions. The preparing method of the key tofacitinib intermediate, namely the N-methyl-N-((3R,4R)-4-methylpiperidine-3-yl)-7H-pyrrolo[2,3D]pyrimidine-4-amine has the advantages of being high in yield, high in chiral purity, low in cost, environmentally friendly, easy to operate and suitable for industrialization.

The invention discloses a preparation method for a Xeljanz related substance. The preparation method is characterized by comprising the following steps: with N-methyl-N-((3R,4R)-4-methylpiperidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine hydrochloride and acetaldehyde as starting materials, preparing N-((3R,4R)-1-ethyl-4-methylpiperidine-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine under the action of a reducing agent, and carrying out salification so as to obtain the Xeljanz related substance namely N-((3R,4R)-1-ethyl-4-methylpiperidine-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine hydrochloride as shown in a formula (I) which is described in the specification.

The invention discloses a synthesis method of N-benzyl-4-methylpiperidine-3-one hydrochloride. The synthesis method includes the steps of: a) with N-benzyl glycine ethyl ester as a raw material, performing a condensation reaction to the raw material with 2-methyl-4-halogenated ethyl acetate; and b) after the reaction is finished, performing an intramolecular cyclization reaction and finally performing hydrolytic decarboxylation to prepare the product. Compared with methods reported in references, the method establishes a novel synthesis route which is short in process, is novel in technology, employs low-cost raw materials and simple process operations, has good product quality and high total yield, and is suitable for industrial production.

The invention provides a novel impurity in tofacitinib citrate, namely, 3-((3R,4R)-3-((7-hydroxy-7H-pyrrolo[2,3-d]pyrimidine-4-yl)(methyl)amino)-4-methylpiperidine-1-yl)-3-oxopropionitrile. The preparation method of the compound is simple to operate, the obtained product is high in yield and purity, the invention further provides an analysis method of the compound, the method is sensitive, rapid and good in specificity, and the compound can be used as a reference substance for researching impurities in tofacitinib citrate raw materials and preparations, so that the product quality is effectively controlled.

The invention discloses a preparation method of (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyltartaric acid salt prepared from the following reaction steps shown in the description. The preparation method of (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyltartaric acid salt has the following advantages that the process is novel in design, extremely dangerous chemicals (such as lithium aluminum hydride) are not required to be used, a folding condensation process is adopted, and the total yield is high; more importantly, the starting materials are cheap and easy to obtain, and the cost is low; and the maneuverability is high, and industrialization is easy.

The application discloses five polymorph forms B, P, F, J, O of (4-((R)-((2S,5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazine-1-yl)(3-hydroxyphenyl)methyl)phenyl)(4-methylpiperidine-1-yl)methanone dihydrochloride, preparation methods thereof and application thereof in the manufacture of a medicament for preventing or treating a mood disorder or a disease related to a δ opioid receptor.