cas 477600-69-4, (3S,4S)-1-Benzyl-N,4-dimethylpiperidin-3-amine

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Synthesis method of tofacitinib citrate diastereomer impurities
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.
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(2021/10/27)

Novel method for preparing 3-amino-piperidine
The present invention relates to a manufacturing method which is capable of mass production of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine on an industrial scale with high quality optical purity, which is a key intermediate necessary for synthesizing tofacitinib.
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Paragraph 0054-0058

(2020/10/10)

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.
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(2020/01/25)

Preparation methods of tofacitinib intermediate amine and dihydrochloride thereof
The invention discloses preparation methods of tofacitinib intermediate amine and dihydrochloride thereof. According to the preparation method of the tofacitinib intermediate amine, methyl acetoacetate and cyanoacetamide are taken as starting materials and subjected to condensation, olefinic bond reduction, cyano hydrolysis into amide, N benzylation and Hofmann degradation to prepare primary amine, monomethylation and chiral resolution of the primary amine are performed, and a carbonyl group is reduced with zinc borohydride, so a target product is obtained. The obtained (3R,4R)-1-benzyl-3-methylamino-4-methylpiperidine is subjected to salifying with hydrochloric acid to obtain the dihydrochloride. The methods have the advantages that the whole process avoids a high-pressure hydrogenation reaction under an acidic condition; all the reaction steps adopt conventional reaction reagents and solvents, so raw material sources are not limited, and cost is low; and the method avoids a lithium aluminum hydride reduction reagent with high risk, each step has high selectivity, the reaction product of each step can be easily refined, and the method has advantages in industrialization.
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Paragraph 0025; 0089-0090

(2020/11/12)

Preparation method and application of chiral amine B
The invention discloses a preparation method of chiral amine B. The preparation method comprises the following steps: (1) carrying out nucleophilic substitution reaction on N-tert-butoxycarbonyl-3-pyridine and halogenated benzyl to obtain an intermediate
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Paragraph 0115-0129

(2019/06/05)

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.
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(2019/01/15)

Preparation method for 1-benzyl-N,4-dimethylpiperidin-3-amine
The invention provides a preparation method for 1-benzyl-N,4-dimethylpiperidin-3-amine. The preparation method comprises the following steps: (1) reacting a compound N,4-dimethylpyridin-3-methylamineas shown in a formula (I) with dimethyl dicarbonate under basic conditions to obtain a compound as shown in a formula (II); (2) reacting the compound as shown in the formula (II) with benzyl chlorideto obtain a compound as shown in a formula (III); (3) reducing the compound as shown in the formula (III) to synthesize to a compound as shown in a formula (IV); and (4) subjecting the compound as shown in the formula (III) to a reaction under the action of lithium aluminum hydride to form the target product 1-benzyl-N,4-dimethylpiperidin-3-amine. The preparation method for 1-benzyl-N,4-dimethylpiperidin-3-amine in the invention has the advantages of easy availability of raw materials, environment-friendly reaction conditions in each step, simple operation and high yield.
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(2019/11/13)

Preparing method of N-methyl-N-(4-methylpiperidine)-3-yl-7H-pyrropyrimidine-4-amine
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.
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(2019/10/01)

Synthesis method of tofacitinib intermediate (3R, 4R)-1-benzyl-N,4-dimethylpiperidine-3-amine
The invention discloses a synthesis method of a tofacitinib intermediate (3R, 4R)-1-benzyl-N,4-dimethylpiperidine-3-amine. The synthesis method comprises the steps: making 3-chlorobutyraldehyde (II) serving as a raw material react with sodium cyanide, then, carrying out Leuckart-Wallach reaction and a Thorpe-Ziegler reaction, next, reacting with a 30% methylamine methanol solution to generate enamine, and carrying out asymmetric catalytic hydrogenation to obtain a final product (3R, 4R)-1-benzyl-N,4-dimethylpiperidine-3-amine (I). In the synthesis method, a compound VI is synthesized by a Thorpe-Ziegler reaction, and the yield is high; and due to the adoption of the asymmetric catalytic hydrogenation, the final product is not needed to be subjected to chiral resolution, the total yield andpurity are high, and few byproducts are generated.
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(2019/01/08)

Asymmetric Synthesis of a Key Intermediate for Tofacitinib via a Dynamic Kinetic Resolution-Reductive Amination Protocol
We report the first example of a catalytic asymmetric reductive amination under dynamic kinetic resolution (DKR) conditions for the preparation of a chiral amine as a key intermediate toward Tofacitinib, an active pharmaceutical ingredient developed by Pfizer. Such a protocol allows the preferential formation of a single product out of four possible diastereomers of the chiral amine starting from the corresponding racemic ketone. The chiral iridium catalyst able to perform such a feast was discovered through a mix of high-throughput screening, racemization study, and reaction optimization.
Verzijl, Gerard K. M.,Schuster, Christian,Dax, Thomas,De Vries, André H. M.,Lefort, Laurent
supporting information
p. 1817 - 1822
(2019/01/04)

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.
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Page/Page column 11-14

(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.
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Paragraph 0012; 0013; 0017; 0018; 0022; 0023

(2019/01/08)

Novel method for synthesizing cis-1-benzyl-3-methylamino-4-methyl-piperidine
The invention provides a novel method for synthesizing cis-1-benzyl-3-methylamino-4-methyl-piperidine. The method has the advantages that aminopyridine is used as the raw material, the original two-step arylamine methylation becomes one-step reaction, unfriendly lithium aluminum hydrogen reduction is avoided, toxic controlled product methyl chloroformate is avoided, the used raw materials are simple and easy to obtain, the method is suitable for industrial production, the generation of a large amount of aluminum-containing wastewater is reduced, production cycle is shortened evidently, and productivity is increased.
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(2018/10/19)

Synthesis method for preparing intermediates of tofacitinib
The invention provides a novel method for synthesizing primary ring cis-4-methyl-3-methylamino-1-benzylpiperidine bis-hydrochloride of tofacitinib. The primary ring cis-4-methyl-3-methylamino-1-benzylpiperidine bis-hydrochloride is made from 3-halogenation-picoline. The novel method includes steps of catalytic Ullman coupling, 3-halogenation-picoline and benzyl halide salifying, hydroboration reagent reduction, salifying and the like to obtain target compounds. The method has the advantages of simple conditions, easily available reagents and operational safety.
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(2018/11/04)

Formal asymmetric synthesis of (+)-tofacitinib
Tofacitinib is an efficient and selective Janus kinase 3 (JAK3) inhibitor, and is used as an immunosuppressant drug for the treatment of rheumatoid arthritis and transplant patients. Herein we report a concise formal asymmetric synthesis of tofacitinib from homochiral 1,3-dioxolanone 10b, which was elaborated through a highly stereoselective Michael addition followed by solvent-free removal of the chiral auxiliary and ring cyclization to furnish chiral imide 8. The preparation of tofacitinib's precursor 16 could be obtained after reduction of 8 followed by sequential oxidation, reductive amination and SNAr reactions.
Liao, Hao-Chun,Uang, Biing-Jiun
p. 105 - 109
(2017/01/12)

An Efficient Method for Synthesis of Tofacitinib Citrate
An efficient and mild synthetic method was developed for tofacitinib citrate from 3-amino-4-methylpyridine and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. The related reactions were systematically optimized. Sodium hydride instead of potassium tert-butoxide employed in the methoxycarbonylation reaction of compound 9 made the reaction proceed effectively to present compound 8 in a better yield. The replacement of benzaldehyde with benzyl bromide simplified the protection process of amino group. Red-Al provided a cost-effective method for the reduction of amides. The introduction of tosyl group into compound 10 enhanced the nucleophilic substitution of 10 with compound 4 dramatically. Thus, under the optimized conditions, tofacitinib citrate was obtained in 13.3% yield (based on compound 9) with a purity of 99.9%, much better than the reported yield 8.6%. This cost-effective and environmental friendly process is more suitable for scale-up production.
Zhi, Shuang,Liu, Dengke,Liu, Ying,Liu, Bingni,Wang, Donghua,Chen, Ligong
p. 1259 - 1263
(2016/07/29)

AN IMPROVED PROCESS FOR THE PREPARATION OF (3R,4R)-(1-BENZYL-4-METHYLPIPERIDIN-3-YL)-METHYLAMINE
The present invention is related to an improved and efficient process for preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine which comprises: (a) N-acylation of 3-Amino-4-methyl pyridine; (b) Quarternization of 3-Acetylamino-4- methyl pyridine using benzyl halide; (c) Partial reduction of quarternized 3-Acetylamino- 4-methyl pyridine by Sodium borohydride in Methanol or water; (d) Hydrolysis of partially reduced product to 1-Benzyl-4-methylpiperidin-3-one in presence of acid; (e) Reductive animation of 1-Benzyl-4-methylpiperidin-3-one using Methanolic methylamine in presence of Titanium(IV) isopropoxide in Methanol; (f) Resolution of 1-Benzyl-4- methylpiperidin-3-yl)-methylamine using Ditoluoyl (L) tartaric acid to get (3R,4R)-(1- benzyl-4-methylpiperidin-3-yl)-methylamine. The invention is also related to novel intermediates.
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(2015/06/25)

PREPARATION OF 3-AMINO-PIPERIDINE COMPOUNDS VIA NITRO-TETRAHYDROPYRIDINE PRECURSORS
The present invention relates to the preparation of 3-amino-piperidine compounds via nitro-tetrahydropyridine precursors and salts thereof. These compounds can be used as intermediates in the synthesis of pharmaceutically active agents such as tofacitinib or derivatives thereof.
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Page/Page column 30

(2014/06/23)

NEW SYNTHETIC ROUTE FOR THE PREPARATION OF 3-AMINO-PIPERIDINE COMPOUNDS
The present invention relates in general to the field of organic chemistry and in particular to the preparation of 3-amino-piperidine compounds. These compounds can be used as intermediates in the synthesis of pharmaceutically active agents such as preferably tofacitinib or derivatives thereof, or further pharmaceutically active agents comprising as a structure a 3-aminopiperidine moiety.
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(2014/02/16)

PROCESS FOR THE PREPARATION OF TOFACITINIB AND INTERMEDIATES THEREOF
The present invention provides compounds of Formula III and Formula VI, and processes for their preparation. The present invention further provides use of the compounds of Formula III and Formula VI for the preparation of tofacitinib or isomers or a mixture of isomers or salts thereof.
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Page/Page column 24

(2014/07/08)

PHARMACEUTICAL COMPOSITIONS AND METHODS OF TREATING DRY EYE DISORDERS
Ophthalmic compositions comprising Inhibitors of Janus kinase-3 (“Jak3”) are useful for treating dry eye disorders and other disorders requiring the wetting of the eye.
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Paragraph 0092

(2013/11/19)

HETEROCYCLIC COMPOUNDS AS JANUS KINASE INHIBITORS
The invention provides compounds of formula (I) or a salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of formula (I), processes for preparing compounds of formula (I), intermediates useful for preparing compounds of formula I and therapeutic methods for suppressing an immune response or treating cancer or a hematologic malignancy using compounds of formula (I).
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Page/Page column 195

(2011/04/18)

PIPERIDINE INHIBITORS OF JANUS KINASE 3
The present invention relates to a new piperidine inhibitors of Janus Kinase 3 activity, pharmaceutical compositions thereof, and methods of use there-of.
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Page/Page column 51

(2010/11/05)

Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile (CP-690,550)
Here, we examine the significance that stereochemistry plays within the clinically relevant Janus kinase 3 (Jak3) inhibitor 1 (CP-690,550). A synthesis of all four enantiopure stereoisomers of the drug was carried out and an examination of each compound revealed that only the enantiopure 3R,4R isomer was capable of blocking Stat5 phosphorylation (Jak3 dependent). Each compound was profiled across a panel of over 350 kinases, which revealed a high level of selectivity for the Jak family kinases for these related compounds. Each stereoisomer retained a degree of binding to Jak3 and Jak2 and the 3R,4S and 3S,4R stereoisomers were further revealed to have binding affinity for selected members of the STE7 and STE20 subfamily of kinases. Finally, an appraisal of the minimum energy conformation of each stereoisomer and molecular docking at Jak3 was performed in an effort to better understand each compounds selectivity and potency profiles.
Jiang, Jian-Kang,Ghoreschi, Kamran,Deflorian, Francesca,Chen, Zhi,Perreira, Melissa,Pesu, Marko,Smith, Jeremy,Nguyen, Dac-Trung,Liu, Eric H.,Leister, William,Costanzi, Stefano,O'Shea, John J.,Thomas, Craig J.
supporting information; experimental part
p. 8012 - 8018
(2009/12/07)

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.
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Page/Page column 50

(2010/11/30)

PYRROLO[2,3-D]PYRIMIDINE DERIVATIVES; THEIR INTERMEDIATES AND SYNTHESIS
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.
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Page/Page column 18-19

(2010/11/25)

METHOD OF TREATMENT OF TRANSPLANT REJECTION
A method of treating or preventing chronic organ transplant rejection comprising administering a compound of the formula (I) wherein R1, R2 and R3 are as defined above.
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Page/Page column 37

(2008/06/13)

Method of treatment of atherosclerosis
A method of treating or preventing atherosclerosis comprising administering a compound of the formula wherein R1, R2 and R3 are as defined above.
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Page/Page column 11

(2008/06/13)

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.
p. 51 - 56
(2012/12/24)

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
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Page 10

(2008/06/13)