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Preparation VI; 6-Cyano-2-methyl-3-aminopyridine; A mixture of 3.5 g (18.6 mmol) of 6-bromo-2-methyl-3-aminopyridine, 352 mg (0.37 mmol) of tris(benzylideneacetone)dipalladium(0), 532 mg (0.92 mmol) of 1,1'-bis(diphenylphosphino)ferrocene, 146 mg (2.2 mmol) of zinc powder and 1.4 g (12 mmol) of zinc cyanide in 70 ml of N,N-dimethylacetamide is prepared and the reaction mixture is then stirred at 20° C. for 22 hours. It is diluted with 200 ml of ethyl acetate and washed with 2 N ammonium chloride solution. (Decantation is obtained only after filtration of the mixture on a filter aid of the Celite type.) The organic phase obtained is washed with sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a dichloromethane/ethyl acetate mixture (9/1; v/v) as the eluent to give 1.6 g of the expected compound in the form of a yellow powder (yield=65percent). M.p.=192-196° C.
With zinc;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tris-(dibenzylideneacetone)dipalladium(0); In ISOPROPYLAMIDE; at 20℃; for 22h;
Preparation VI; 6-Cyano-2-methyl-3-aminopyridine; A mixture of 3.5 g (18.6 mmol) of 6-bromo-2-methyl-3-aminopyridine, 352 mg (0.37 mmol) of tris(benzylideneacetone)dipalladium(0), 532 mg (0.92 mmol) of 1,1'-bis(diphenylphosphino)ferrocene, 146 mg (2.2 mmol) of zinc powder and 1.4 g (12 mmol) of zinc cyanide in 70 ml of N,N-dimethylacetamide is prepared and the reaction mixture is then stirred at 20 C. for 22 hours. It is diluted with 200 ml of ethyl acetate and washed with 2 N ammonium chloride solution. (Decantation is obtained only after filtration of the mixture on a filter aid of the Celite type.) The organic phase obtained is washed with sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a dichloromethane/ethyl acetate mixture (9/1; v/v) as the eluent to give 1.6 g of the expected compound in the form of a yellow powder (yield=65%). M.p.=192-196 C.
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 110℃; for 1h;Microwave irradiation;
To a solution of6-bromo-2-methylpyridin-3-amine (compound 1, 500 mg, 2.69 mmol) in DMF(10 mL) was added Zn(CN)2 (943 mg, 8.06 mmol) and Pd(PPh3)4 (288 mg, 0.3 mmol) at roomtemperature. The reaction was stirred at 110 C in microwave reactor for lh. After it was cooledto room temperature, the mixture was filtered and purified by reverse phase chromatography (Xbridge Prep C180BD, 40-60% MeOH in water with 10 mmol NH4HC03 modifier) to afford the10 compound as an oil.
With tert.-butylnitrite; copper(l) chloride; In acetonitrile; at 20 - 60℃; for 4.0h;Inert atmosphere;
A solution of <strong>[1079054-78-6]5-amino-6-methylpicolinonitrile</strong> (2) (260 mg, 1.95 mmol), CuCl (290 mg,2.93 mmol) and t-BuONO ( 456 mg, 3.9 mmol) in CH3CN (10 mL) was stirred at roomtemperature under N2 for 2 h, and then warmed to 60C. After 2h, 10 mL 6N HCl was added and15 extracted with EA (3x10 mL). The organic phase was dried with anhydrous Na2S04, filtered andconcentrated. The residue was purified by Prep-TLC using PE/ EtOAc =Ill to give titlecompound as oil.
With tert.-butylnitrite; copper(l) chloride; In acetonitrile; at 20 - 60℃; for 4.0h;Inert atmosphere;
Step B: 5-chloro-6-methylpicolinonitrile (3)A solution of <strong>[1079054-78-6]5-amino-6-methylpicolinonitrile</strong> (2) (260 mg, 1.95 mmol), CuCl (290 mg, 2.93 mmol) and t-BuONO ( 456 mg, 3.9 mmol) in CH3CN (10 mL) was stirred at room temperature under 2 for 2 h, and then warmed to 60C. After 2h, 10 mL 6N HCl was added and extracted with EA (3x10 mL). The organic phase was dried with anhydrous Na2S04, filtered and concentrated. The residue was purified by Prep-TLC using PE/ EtOAc = 1/1 to give title compound as oil.
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 110℃; for 1h;Microwave irradiation;
Step A: 5-amino-6-methylpicolinonitrile (2)To a solution of 6-bromo-2-methylpyridin-3-amine (compound 1, 500 mg, 2.69 mmol) in DMF (10 mL) was added Zn(CN)2(943 mg, 8.06 mmol) and Pd(PPh3)4(288 mg, 0.3 mmol) at room temperature. The reaction was stirred at 110 C in microwave reactor for lh. After it was cooled to room temperature, the mixture was filtered and purified by reverse phase chromatography (X bridge Prep C180BD, 40-60% MeOH in water with 10 mmol NH4HC03modifier) to afford the compound as an oil.
5-isothiocyanato-6-methylpyridine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20℃; for 24.5h;
l,l'-Thiocarbonyldiimidazole (368 mg, 1.96 mmol, 95 mass%) and then hydrochloric acid in dioxane (0.89 mL, 3.6 mmol, 4 mol/L) were added to a solution of <strong>[1079054-78-6]5-amino-6-methylpicolinonitrile</strong> (250 mg, 1.78 mmol, 95 mass%) in DCM (8.9 mL) under air. The reaction was stirred at r.t. for 24.5 hours before being concentrated in vacuo and purified by flash column chromatography on silica (gradient elution with 0% to 100% EtOAc in isohexanes) to give the title compound (176 mg, 56 % Yield). LCMS [M+H]+ 176, RT 0.93 minutes (Method 7).
(5S)-5-[3-[(6-cyano-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ No CAS ]
(5S)-5-[(6-cyano-2-methyl-3-pyridyl)carbamothioylamino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ No CAS ]
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