- Synthesis and application of 1-benzyl-4-methyl-5-alkoxy-1, 2, 3, 6-tetrahydropyridine derivative
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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.
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- Preparation methods of tofacitinib citrate intermediate and tofacitinib citrate
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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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Paragraph 0094; 0096; 0102-0107
(2020/01/25)
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- 4-methylpiperidine-3-ketone and simple preparation method of 4-methylpiperidine-3-ketone derivative
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The invention relates to 4-methylpiperidine-3-ketone and a simple preparation method of a 4-methylpiperidine-3-ketone derivative. According to the 4-methylpiperidine-3-ketone and the simple preparation method of the 4-methylpiperidine-3-ketone derivative, 1-nitro-3-methyl-5-hydroxy n-amyl-2-ketone is prepared by using a reaction of alpha-methyl-gamma-butyrolactone and nitromethane, then 1-nitro-3-methyl-5-protection oxy-n-pentyl-2-ketone is obtained through sulfonyl chloride reagent protection hydroxide radical, then nitro is reduced to amino through hydrogenation, and meanwhile 4-methylpiperidine-3-ketone is obtained through cyclization. The invention further provides a method for preparing 2-chlorin-3-amino-4-methylpyridine and N-benzyl-4-methylpiperidine-3-ketone from 4-methylpiperidine-3-ketone. Raw materials used in the simple preparation method and the method are cheap and readily available, the condition is mild, operation is simple and convenient and safe, reaction selectivityis high, the product yield and purity are high, the cost is low, the amount of "three wastes" is low, and environmental protection is realized.
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- Preparing method of N-methyl-N-(4-methylpiperidine)-3-yl-7H-pyrropyrimidine-4-amine
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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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Paragraph 0026-0027
(2019/10/01)
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- Tofacitinib compound preparation method
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The invention discloses a tofacitinib compound preparation method. Under alkali and solvent existence condition, 4-methyl piperidine-3-ketamine hydrochloride (II) and benzyl chloride are subjected toa reaction to obtain a compound III, acid catalysis is carried out to obtain a compound V, and steps of asymmetric catalytic hydrogenation, deprotection, and condensation are carried out to obtain a final product tofacitinib (I), the preparation method has the advantages of short technical process, mild reaction condition, high overall yield and purity, and less by-product, and is suitable for industrial preparation.
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Paragraph 0016; 0032-0040
(2018/11/27)
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- Synthesis method of tofacitinib intermediate (3R, 4R)-1-benzyl-N,4-dimethylpiperidine-3-amine
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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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Paragraph 0051-0053; 0056; 0059
(2019/01/08)
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- A supporting france for cloth as the starting material of the preparation method (by machine translation)
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The invention discloses a method for supporting france for cloth starting material N - ((3 R, 4 R) - 4 - methyl - 1 - benzyl - 3 - piperidinyl) - N - methyl - 7 - paratoluene sulfonyl - 7 H - pyrrolo [2, 3 - D] pyrimidine - 4 - amine (I) synthetic method, specific steps are as follows: to 4 - methyl pyridine as the starting material, with the benzyl chloride undergo nucleophilic substitution by the 4 - methyl - 1 - phenylmethyl - pyridine hydrochloride, under the action of the sodium borohydride reduction reaction, borohydrite - oxidation reaction, hydroxy oxidation, the introduction of the reductive amination of the stereo selectivity of the two chiral center, through a readily available and inexpensive chiral acid (L - DTTA) splitting, to obtain optically pure intermediates (3 R, 4 R) - (1 - benzyl - 4 - methyl - piperidin - 3 - yl) - methylamine, and finally with the 4 - chloro pyrrolo pyrimidine condensation is obtained. The whole method raw materials are easy, simple operation, after treatment is easy, and the cost is low. (by machine translation)
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Paragraph 0007; 0026; 0032
(2017/12/06)
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- Preparation method of tofacitinib intermediate
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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.
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Paragraph 0033; 0034
(2017/08/29)
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- Preparation method of tofacitinib citrate
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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.
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Paragraph 0056; 0057
(2016/10/17)
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- The protection of the nitrogen of (3R, 4R) -3 - methylamino -4 - methyl piperidine asymmetric synthesis method, relevant intermediate and a method for preparing raw materials thereof
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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.
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Paragraph 0040; 0041; 0042
(2016/10/09)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF (3R,4R)-(1-BENZYL-4-METHYLPIPERIDIN-3-YL)-METHYLAMINE
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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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Page/Page column 18
(2015/06/25)
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- Iridium-catalyzed selective hydrogenation of 3-hydroxypyridinium salts: A facile synthesis of piperidin-3-ones
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The selective hydrogenation of 3-hydroxypyridinium salts has been achieved using a homogeneous iridium catalyst, providing a direct access to 2- and 4-substituted piperidin-3-one derivatives with high yields, which are important organic synthetic intermediates and the prevalent structural motifs in pharmaceutical agents. Mild reaction conditions, high chemoselectivity, and easy scalability make this reaction highly practical for the synthesis of piperidin-3-ones.
- Huang, Wen-Xue,Wu, Bo,Gao, Xiang,Chen, Mu-Wang,Wang, Baomin,Zhou, Yong-Gui
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supporting information
p. 1640 - 1643
(2015/04/14)
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- Development of a scaleable route for the production of cis-N-benzyl-3-methylamino-4-methylpiperidine
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The synthesis of cis-N-benzyl-3-methylamino-4-methylpiperidine (5) via hydroboration of tetrahydropyridine 3 followed by oxidation and reductive amination was optimized and scaled up to produce 10-kg quantities of product. Three routes to 3 were identified, and the reduction of pyridinium salt 7 was selected as the most preferable to run on-scale. The hydroboration and oxidative workup were carefully studied to optimize throughput on that transformation, as was the reductive amination.
- Brown Ripin, David H.,Abele, Stefan,Cai, Weiling,Blumenkopf, Todd,Casavant, Jeffrey M.,Doty, Jonathan L.,Flanagan, Mark,Koecher, Christian,Laue, Klaus W.,McCarthy, Keith,Meltz, Cliff,Munchhoff, Mike,Pouwer, Kees,Shah, Bharat,Sun, Jianmin,Teixeira, John,Vries, Ton,Whipple, David A.,Wilcox, Glenn
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p. 115 - 120
(2013/09/05)
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- Pyrrolo[2,3-d]pyrimidine compounds
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A compound of the formula wherein R1, R2 and R3 are as defined above, useful as inhibitors of protein kinases, such as the enzyme Janus Kinase 3.
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