(3R,4R)-1-Benzyl-N,4-dimethylpiperidin-3-amine

Procedure: MeNHAdd 1-benzyl-3-methylamino-4-methyl-pyridine bromide 15 (10 g, 34.1 mmol) to a 250 ml reaction vial, add ethanol (100 g), and start stirring at a temperature below 30 °C. Add sodium borohydride (3.87 g, to the reaction solution, 102.3 mmol), after the addition was completed, the reaction solution was stirred for 16 hours, and the compound 15 was detected by HPLC to be less than 1percent.2M HCl was added dropwise to the reaction solution, no bubbles were formed in the reaction system, and the reaction solution was concentrated to a one-third volume under reduced pressure.It was extracted twice with dichloromethane and the organic phases were combined and concentrated under reduced pressure to basic solvent free.To the crude product, ethanol (40 g) was added, and 2M hydrochloric acid ethanol (20 ml) was added dropwise at a temperature below 30 °C, and a solid precipitated. After the addition, stirring was continued for 1 hour, suction filtration, and the filter cake was dried under reduced pressure.Obtained a white product (6.9 g, 23.8 mmol), The yield was 70percent.Preparation of enriched -(3R, 4R)-(1-benzyl-4-methyl-piperidine-3-yl)-methylamine via Asymmetric Hydrogenation.; Step A. Preparation of1-benzyl-3-methoxycarbonylamino-4-methyl-pyridinium bromide to a clean, dry, nitrogen purged 500 mL flask were added (4-methyl-pyridin-3-yl)-carbamic acid methyl ester (25.0 g, 150 mmol), toluene (250 ml) and benzyl bromide (28.3 g, 165 mmol). The reaction was heated to 110Preparation of enriched (3R, 4R)-(1-benzyl-4-methyl-piperidine-3-yl)-methylamine via Asymmetric Hydrogenation of 1-benzyl-4-methyl-1, 2, 5, 6-tetrahydro-pyridin-3-yl)-carbamic acid methyl ester; To the reaction vessel were added 1-benzyl-4-methyl-1 , 2, 5, 6-tetrahydro-pyridin-3-yl)-carbamic acid methyl ester (150 mg, 0.577 mmoles) , bis(1, 5-cyclooctadiene)rhodium (I) trifluoromethanesulfonate (13 mg, 0.0288 mmoles - available from Strem Chemical Co. Newburyport, Massachusetts) and (R)-(-)-1 - [(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine(32 mg, 0.033 mmoles - available from Solvias, Basel Switzerland). The solids were purged with nitrogen (5x at 90 psi) then degassed THF (2 ml) and degassed ethanol (1 ml) were added. The mixture was purged with nitrogen (5x at 90 psi) followed by hydrogen (1x at 210 psi). The reaction mixture was heated to 70 2-Chloro-7-toluenesulfonyl-7H-pyrrolo[2, 3-d]pyrimidine (7.5 g, 0.024 mol), Preparation of intermediate TF-3: Intermediate TF-2 (19.2 g, 0.09 mol), 400 mL of ethanol water was placed in a reaction flask.(50:50) solution, dissolved by stirring, and then added ((2R, 3R)-2, 3-bis[(4-methylbenzoyl)oxy]succinic acid (69.5 g, 0.18 mol, 2.0 q), stirred, and then heated to 40-45 C, a solid precipitated in the reaction mixture, and the reaction was monitored by TLC.reactionAfter completion, suction filtration and the filtrate is ready for use. The filter cake is placed in 400 mL of water, heated to 60-65 C, stirred and dissolved, and then 2 M hydroxide is added dropwise.The sodium solution (45 mL, 0.09 mol) was stirred and ethyl acetate was evaporated (200 mL×2). Combine the organic phase, Wash with saturated sodium chloride solution (150 mL × 1), Dry over anhydrous sodium sulfate and concentrate to dryness under reduced pressure.8.4 g of intermediate TF-3 product was obtained in a yield: 44%.In a 250 ml three-necked flask, 15.8 g of compound VII, 27.9 mg of Ru(OAc) 2 and 0.27 g of (R)-BINAP were sequentially added, and dissolved in 50 ml of N, N-dimethylformamide. Substituting nitrogen three times in sequence, three times of hydrogen, and introducing hydrogen gas to 3.5 MPa. The reaction was stirred at 20 to 25 C for 12 h, suction filtered, and the solvent was evaporated to give compound I 15.3 g. The yield was 96.1%, the HPLC purity was 98.89%, and the ee value was 98%.Preparation of (3R, 4R)-N, 4-dimethyl-1-(phenylmethyl)-3-piperidinamine dihydrochloride: Intermediate TF-3 (16.2 g, in a reaction flask) 0.07 mol) was placed in 80 mL of ethanol, stirred to dissolve, and then 10 M hydrochloric acid in ethanol (56 mL, 0.26 mol, 8.0 eq) was added.The pH of the reaction solution was controlled to be between 3-4, and the temperature was lowered to 0-5 C, stirred and crystallized, suction filtered, and dried under reduced pressure to obtain 16 g of crude product. The crude product was placed in 90 mL of isopropanol, heated to reflux to dissolve, stirred for 1 h, cooled to 0-5 C for crystallization, suction filtered, and dried under reduced pressure to give 15.2 g (3R, 4R)-N, 4- Dimethyl-1-(phenylmethyl)-3-piperidinamine dihydrochloride product, yield 94%, purity 99.5%.To a solution of

Tofacitinib intermediate

(3R,4R)-N,4-Dimethyl-1-benzyl-3-piperidinamine (D464895) is a reagent used in the preparation of Janus tyrosine kinase inhibitors for the treatment of autoimmune diseases.

Molecular Weight:218.34
XLogP3:2.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:218.178298710
Monoisotopic Mass:218.178298710
Topological Polar Surface Area:15.3
Heavy Atom Count:16
Complexity:199
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes