- Investigation of practical routes for the kilogram-scale production of cis-3-methylamino-4-methylpiperidines
-
Two routes for the synthesis of cis-N-protected-3-methylamino-4- methylpiperidine (3) were examined: a route hinging on the electrochemical oxidation of carbamate 1 to install a ketone at the 3 position of the piperidine followed by reductive animation (disconnection A), and a route involving the hydrogenation of an appropriately functionalized pyridine (disconnection B). While both routes to the desired compound were ultimately successful, the pyridine hydrogenation approach proved to be more amenable to kilogram-scale preparations due to the crystallinity and purity of intermediates in that route.
- Cai, Weiling,Colony, James L.,Frost, Heather,Hudspeth, James P.,Kendall, Peter M.,Krishnan, Ashwin M.,Makowski, Teresa,Mazur, Duane J.,Phillips, James,Brown Ripin, David H.,Ruggeri, Sally Gut,Stearns, Jay F.,White, Timothy D.
-
-
Read Online
- Preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride
-
The invention discloses a preparation method of a tofacitinib intermediate cis-1benzyl-N, 4-dimethyl piperidine-3-amine dihydrochloride. The synthetic method comprises the following steps: taking 3-bromo-4-methylpyridine as an initial raw material, performing substitution reaction with amine to obtain a compound III, and performing acetyl or tert-butyloxycarbonyl protection and catalytic hydrogenation on the compound III to obtain a piperidine compound V. The compound V and benzaldehyde are subjected to reductive amination or react with benzyl halide to obtain a compound VI. A protecting groupis removed from the compound VI, and a hydrochloride compound I. 2HCl is formed at the same time. The synthesis method is simple to operate, high in total yield, high in product purity, stable in quality and suitable for industrial production.
- -
-
-
- Synthesis and application of 1-benzyl-4-methyl-5-alkoxy-1, 2, 3, 6-tetrahydropyridine derivative
-
The invention relates to the field of synthesis of drug intermediates, in particular to the field of synthesis of key intermediates for preparing anti-rheumatoid arthritis drug tofacitinib, and specifically relates to a 1-benzyl-4-methyl-5-alkoxy-1, 2, 3, 6-tetrahydropyridine compound, a synthetic method thereof, and an application of the 1-benzyl-4-methyl-5-alkoxy 1, 2, 3, 6-tetrahydropyridine compound in preparation of a key intermediate cis-1-benzyl-3-methylamino-4-methyl piperidine of tofacitinib.
- -
-
-
- Preparation methods of tofacitinib citrate intermediate and tofacitinib citrate
-
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 sodium borohydride 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 sodium borohydride 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.
- -
-
-
- Tropsch process for cloth intermediate (3 R, 4 R) - N, 4 - dimethyl -1 - benzyl -3 - amino piperdine and its oxalate salt hydrate of new synthetic method
-
The invention relates to a supporting france for cloth intermediate (3 R, 4 R) - N, 4 - dimethyl - 1 - benzyl - 3 - amino piperdine and its oxalate salt hydrate of new synthetic method. In order to 3 - amino - 4 - methyl pyridine as the starting material, its amino with orthoformate [...] is generated by the reaction, after after simple concentration, for the metal borohydride reduction to obtain N - methyl derivatives; Boc protection after the, re-covering and into a quaternary ammonium salt, the metal borohydride reduction, then the Rh catalyst for selective hydrogenation, form an enriched (3 R, 4 R - rel -) configuration of compounds, hydrochloric acid/alcohol system deprotected and into salt splitting removing (3 R, 4 S - rel -) isomer to, the resulting (3 R, 4 R - rel -) configuration product for free after L - DTTA obtained through splitting 3 R, 4 R - configuration product; splitting the resulting salts are free after through, into the oxalate purification, to further remove the residual small amount of 3 S, 4 S - isomer so as to obtain a corresponding high-purity and high optical purity (3 R, 4 R) - N, 4 - dimethyl - 1 - benzyl - 3 - amino piperdine. The method of the invention more beneficial for safe, simple and convenient of industrialized scale preparation Tropsch process for cloth intermediate (3 R, 4 R) - N, 4 - dimethyl - 1 - benzyl - 3 - amino piperdine oxalic acid salt hydrate.
- -
-
-
- PROCESS FOR THE PREPARATION OF CHIRAL 3-AMINO-PIPERIDINS, USEFUL INTERMEDIATES FOR THE PREPARATION OF TOFACITINIB
-
Object of the present invention is an improved process for the preparation of (3R,4R)-1-benzyl-4-methylpiperidin-3-amine by means of chiral Rhodium catalysts.
- -
-
-
- PROCESS FOR PREPARING CHIRAL AMINES
-
The invention pertains to a process for the preparation of an amine having at least two chiral centers from a ketone having a chiral center at the a position and an amine comprising the steps of: (a) contacting a ketone having a chiral center at the a position and a primary amine thereby forming an imine; (b) contacting the imine with a reducing agent in the presence of an enantioselective catalyst to form an amine having at least two chiral centers, wherein step (a) and/or step (b) are conducted under racemization-enhancing conditions, wherein the racemization-enhancing conditions are achieved by addition of an acid and/or by addition of a salt of a primary amine and an acid, which salt is added in addition to or instead of the primary amine, and wherein the reducing agent is hydrogen.
- -
-
Page/Page column 16; 17
(2018/04/17)
-
- Preparation method for chiral piperylhydrazine compound and recycling method for chiral resolving agent
-
The invention discloses a preparation method for a chiral piperylhydrazine compound and a recycling method for a chiral resolving agent. In the invention, 1-benzyl-4-methyl-3-pipradrol is taken as aninitial raw material and is subjected to reactions of halogenation, methylamination, chiral resolution, and the like, so as to prepare a (3R, 4R)-N,4-dimethyl-1-(phenyl methyl)-3-piperylhydrazine dihydrochloride product, and meanwhile, a resolving mother solution is subjected to alkalization, refined, purified and recycled, so as to acquire a (2R,3R)-2,3-bi[(4-methyl benzoyl) oxo] succinic acid product meeting the reaction requirement. The invention has the beneficial effects of 1) short synthetic route, easily controlled intermediate purity and benefit to the control on impurity content, and2) simple and convenient technological operation in each step reaction, capability of recycling the high-dosage chiral resolving agent, capability of reducing production cost while reducing yield of solid wastes and suitability for large-scale industrial production.
- -
-
Paragraph 0012; 0015; 0017; 0020; 0022; 0025
(2019/01/08)
-
- A synthetic cis - 1 - benzyl - 3 - methylamino - 4 - methyl - piperidine
-
The invention relates to a method for synthesizing cis-1-benzyl-3-methylamino-4-methyl-piperidine, in particular to a method for synthesizing cis-1-benzyl-3-methylamino-4-methyl-piperidine by taking 1-benzyl-3-methylamino-4-methyl-piperidine bromide as an
- -
-
Paragraph 0031; 0035
(2017/08/25)
-
- Preparation method of tofacitinib intermediate
-
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.
- -
-
Paragraph 0033; 0036
(2017/08/29)
-
- Preparation method of tofacitinib intermediate
-
The invention discloses a preparation method of a tofacitinib intermediate compound-1-benzyl-3-methyl amino-4-methyl piperidine dihydrochloride. The method comprises the following steps: (1) carrying out selective deprotection on a compound as shown in a structural formula (V) to synthesize a compound-1-benzyl-3-amino-4-methyl piperidine as shown in a structural formula (VI); (2) enabling the compound as shown in the structural formula (VI) to have a primary amine monomethylation reaction to generate the target compound-1-benzyl-3-methyl amino-4-methyl piperidine dihydrochloride as shown in a structural formula (I). The method has the characteristics of being easy in obtaining of raw materials, novel in route, less in by-products, simple and convenient to operate, high in yield, and the like.
- -
-
-
- Preparation method of tofacitinib citrate
-
The invention belongs to the field of medicine and chemical engineering and particularly relates to a preparation method of tofacitinib citrate. The method comprises steps as follows: 1-benzyl-4-methyl-2,6-dihydro-3-piperidone taken as a starting material is subjected to an asymmetric reduction reaction, 1-benzyl-4-methyl-3-piperidone is obtained, and (3R,4R)-cis-1-benzyl-4-methyl-3-methylamino-piperidine dihydrochloride is produced under the action of a chiral catalyst; (3R,4R)-cis-1-benzyl-4-methyl-3-methylamino-piperidine dihydrochlorid and a paratoluensulfonyl chloride protection product 4-chloro-7-(methyl-4-benzenesulfonyl) pyrrolo[2,3-d]pyrimidine of 4-chloropyrrolo[2,3-d]pyrimidine are subjected to a condensation reaction, [(3R,4R)]-1-benzyl-4-methyl-piperidine-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine is obtained through deprotection, and tofacitinib citrate is obtained through debenzylation protection, an acylation reaction and citric acid salifying. The process route is short, the process cycle is short, chiral synthesis is performed by means of a catalyst, the product purity is improved, the cost is reduced, the yield is high, and the operation is simple and convenient.
- -
-
Paragraph 0055
(2016/10/17)
-
- THERAPEUTIC AGENTS
-
The invention provides a compound of formula (I): wherein R1, and W have any of the values defined in the application; or a salt thereof. The compounds and salts thereof have beneficial therapeutic properties (e.g. immunosuppressant properties).
- -
-
Page/Page column 28; 32
(2010/04/03)
-
- COMBINATION THERAPIES FOR RHEUMATOID ARTHRITIS
-
This disclosure relates to pharmaceutical combination therapies for the treatment or prevention of arthritis, such as rheumatoid arthritis, in a human comprising a Janus Kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof. This disclosure also relates to certain methods for treating or preventing arthritis, such as rheumatoid arthritis, in a human comprising co-administering to a human a Janus Kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof.
- -
-
Page/Page column 50
(2010/11/30)
-
- 3-Amino-piperadine derivatives and methods of manufacture
-
This invention relates to 3-amino piperadine derivatives, their intermediates and methods of manufacture. As such, the present invention includes methods of making a compound of the formulas (Ia) and (Ib) wherein R1, R2, R3/sub
- -
-
-