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With 18-crown-6 ether; sodium hydride In N,N-dimethyl-formamide at 25℃; for 4 h;
Synthesis of Amine Building Block A-064-[4-(3-Pyrrolidin-1-yl-propyl)-piperidin-4-yl]-pyridine trihydrochloride (A-06) Step-1: To a THF solution (72 ml) of 4-pyridyl acetate (4 g) was added bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (3 eqv), NaH (3 eqv), 18-crown-6 (0.4 eqv) and DMF (10 ml) at 25° C. and the resulting reaction mixture was allowed to stir at same temperature for 4 hrs (monitored by TLC). Reaction was cooled to 0° C., quenched with crushed ice and diluted with ethyl acetate. Organic layer was washed successively with water and brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product which was purified by column chromatography. Yield: 67percent
Stage #1: With sodium hydride In dimethyl sulfoxide for 5 h; Stage #2: at 0 - 20℃;
A: 1,1 -Dimethylethyl 4-cyano-4-(2-fluoro-4-methylphenyl)- 1 -piperidinecarboxylate(2-Fluoro-4-methylphenyl)acetonitrile (11.49 g, 77 mmol) was gradually added to a suspension of sodium hydride (11.70 g, 293 mmol) and DMSO (200 mL) in a 1-L round-bottomed flask fitted with a mechanical overhead stirrer. The reaction was stirred for about 5 hours, after which time the mixture was cooled in an ice bath. A mixture of 1,1 -dimethylethyl bis(2-chloroethyl)carbamate (20.38 g, 84 mmol) in 30 mL of DMSO was then added, and the resulting solution was allowed to warm to ambient temperature and stir overnight. Water was added slowly, and the organics were extracted with DCM (3 x 300 mL). The combined DCM extracts were washed with water (2 x 400 mL) then dried over sodium sulfate and concentrated. The product was purified on a 330 g silica gel column, eluting with 70-100percent hexanes in DCM. The product was obtained as a yellow oil (8.2g, 33percent). MS (ES) m/e 219.1[M+H]+.
33%
Stage #1: With sodium hydride In dimethyl sulfoxide for 5 h; Cooling with ice Stage #2: at 20℃;
(2-Fluoro-4-methylphenyl)acetonitrile (11.49 g, 77 mmol) was gradually added to a suspension of sodium hydride (11.70 g, 293 mmol) and DMSO (200 mL) in a 1-L round- bottomed flask fitted with a mechanical overhead stirrer. The reaction was stirred for about 5 h, after which time the mixture was cooled in an ice bath. A mixture of 1,1- dimethylethyl bis(2-chloroethyl)carbamate (20.38 g, 84 mmol) in DMSO (30 mL) was then added, and the resulting solution was allowed to warm to room temperature and stir overnight. Water was added slowly, and the organics were extracted with DCM (3 x 300 mL). The combined DCM extracts were washed with water (2 x 400 mL) then dried over sodium sulfate and concentrated. The product was purified on a 330 g silica gel column, eluting with 70-100percent hexanes in DCM. The product was obtained as a yellow oil (8.2g, 33percent). MS (ES) m/e 219.1 [M+H]+.
4-Cyano-4-(2,4-difluorophenyl)-piperidine-1-carboxylic acid tert-butyl ester. To bis(2-chloroethyl)-carbamic acid tert-butyl ester (1.0 g, 3.8 mmol) and 2,4-difluorophenyl acetonitrile (0.581 g, 3.8 mmol) in DMF (35 ml), NaH (95%) (0.258 g, 9.68 mmol) was added in one batch at 0 C. The solution was stirred for 10 minutes at room temperature. When foaming subsided, the solution was heated at 60 C. for 24 hours. It was then quenched with water at 0 C. and concentrated. The residue was extracted with ethyl acetate (25 mL) and washed three times with water (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (hexane:ethyl acetate 4:1) yielded 0.720 g (62%) of the product as a syrup.
Step B: Tertbutyl 4-amino-1-piperazine carboxylate Under an inert atmosphere at ambient temperature, 15.3 g of the product of Step A and 80 ml of hydrazine hydrate were mixed together and then 150 ml of a saturated aqueous solution of ammonium chloride were added. Extraction was done with methylene chloride and the organic phase was washed with an aqueous solution of ammonium chloride, dried, and the solvent was eliminated under reduced pressure. After chromatography on silica (eluent:methylene chloride - methanol, 100/7) 5 g of the expected product were obtained.
Preparation of Intermediate A A 12-L-three-neck flask equipped with an overhead stir, nitrogen inlet, a 2 -L addition funnel, and an internal temperature probe was charged with <strong>[5654-97-7]7-azaoxindole</strong> (72 g, 537 mmol) and anhydrous DME (2.5L). The solution was cooled to -60C and LiHMDS (296 g, 1771 mmol) was added as solution in DME (IL) via addition funnel over 30 minutes while the temperature was maintained at -60 to -54C. The reaction was allowed to warm up -20C and stirred for 40 <n="21"/>minutes. The mixture was cooled to -60C and a solution of N-BOC-bis(2-chloroethyl)amine (149 g, 617 mmol) in DME (0.5L) was added within 2 minutes. The resulting reaction mixture was allowed to reach room temperature over 10h, and stirred for 3 days. The reaction mixture was heated to 50C for 60h, cooled to room temperature and poured onto 10L of ice, combined with 4L of AcOEt, separated, aqueous layer washed with additional 2L of AcOEt, combined organic layers washed with brine and concentrated. Column chromatography afforded pure intermediate A as a solid. The slurry was filtered and the cake washed with hexanes affording the title compound as a white solid.
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