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Example 8; 2-[4-(2-Carboxyethy1)phenyl]-4-(3-heptyl-1- methylureido)pyridini\\3m acetate; a. tert-Butyl (2-chlox:opyrlcL-4-yl)carbamate; 1.69 g (7.78 mmol, 1 eq) of tert-butyl dicarbonate dissolved in 50 ml of dichloromethane, in the presence of 95 mg of dimethylaminopyridine, are added to a solution of 1 g (7.78 mmol, 1 eq) of 4-amino-2-chloropyridine in 30 mL of dichloromethane in EPO <DP n="51"/>the presence of 1.19 mL (1.19 mmol, 1.1 eq) of triethylamine. The reaction mixture is stirred overnight at room temperature. The reaction is stopped by adding 100 ml of water and is then extracted with dichloromethane. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 to 50/50 heptane/ethyl acetate) . The oil obtained is crystallized from pentane. 1.40 g of tert- butyl (2-chloropyrid~4-yl) carbamate are obtained. Yield = 80percent.
77%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 20℃; for 0.5 h;
StepA; ci 1) NaHMDS N T) HGF0C20 l l l 9\\NH2 NHBoc the c : 2 [0073] To A solution containing 4-amino-2-chloropyridine (3. 05 g, 23. 72 mmol) in THF (24 ML) was added sodium bis (TRIMETHYLYSILYL) amide (47. 45 mmol) and stirred at room temperature for 30 minutes. To this solution was added BOC20 (23. 72 mmol) and the gelatinous mixture was stirred overnight. The reaction was diluted with water and extracted with ETOAC. The combined organic phase was washed with water and brine and dried over NA2S04 and concentrated to yield 4. 17 G (77percent). M+H+ (230).
73%
at 20℃; for 18 h;
A mixture of 4-amino-2-chloropyridine (193 mg, 1.50 mmol), di-tert-butyl-di- carbonate (393 mg, 1.80 mmol) and 4-dimethylaminopyridine (1.8 mg, 0.02 mmol) in acetonitrile (5 mL) was stirred at room temperature for 18 hours. This mixture was concentrated under reduced pressure. The residue was purified by column chroma- tography on silica-gel (hexane/ethyl acetate, 20: 1) to give tert-butyl (2-chloropyridin- 4-YL) carbamate (250 mg, 73percent).
A solution of 4-amino-2-chloropyridine (1.28 gm, 10 mmol) and di-tert-butyl dicarbonate (2.21 gm, 10.1 mmol) in THF (20 mL) was cooled to 00C and a solution of IM lithium bis(trimethylsilyl)amide in THF ( 20 mL, 20 mmol) was added slowly maintaining the temperature below 00C. The reaction was allowed to warm to room temperature over one hour and then quenched by the addition of 1.5 N aqueous ammonium chloride (15 mL). After stirring for several hours the reaction was extracted into ethyl acetate, washed with brine, the organic layer dried (Na2SO4), filtered and evaporated. The residue was triturated with diethyl ether give pure tert-butyl (2-chloropyridin-4- yl)carbamate. The mother liquors were chromatographed on silica gel eluting with 25 - 45% ethyl acetate/ hexane to afford more product. EPO <DP n="81"/>A solution of tert-butyl (2-chloropyridin-4-yl)carbamate (1.14 gm, 5 mmol) in dry THF (20 mL) was cooled to -700C under an inert atmosphere and 1.7 M t-butyl lithium/pentane (8 mL, 13.5 mmol) was slowly added. The reaction was stirred for two hours and then dry DMF (1.2 mL, 15.5 mmol) was added. The reaction was allowed to slowly warm to room temperature over a three hour period. The reaction mixture was quenched with 3 N HCl (12 mL) and diluted with diethyl ether. The ether layer was washed with aqueous NaHCtheta3, dried (over Na2SO4), filtered and evaporated. The residue was triturated with cold diethyl ether to give pure t-butyl (2-chloro-3-formylrhoyridin-4- yl)carbamate. The mother liquors were chromatographed on silica gel eluting with 15-20% ethyl acetate/hexane to give additional product. 1H-NMR(5OO MHz, CDCI3): deltall.O (IH, br s), 10.52 (IH, s), 8.38 (IH, d, J= 6 Hz), 8.31 (IH, d, J= 6 Hz), 1.54 (9H, s); m/e (m+1): 257.2.
In tetrahydrofuran; N,N-dimethyl-formamide; pentane; at -70 - 20℃; for 5h;Product distribution / selectivity;
A solution of 4-amino-2-chloropyridine (1.28 g, 10 mmol) and di-tert-butyl dicarbonate (2.21 g, 10.1 mmol) in TEtaF (20 mL) was cooled to O0C and a solution of IM lithium bis(trimethylsilyl)amide in TEtaF ( 20 mL, 20 mmol) was added slowly maintaining the temperature below O0C. The reaction was allowed to warm to room temperature over one hour and then quenched by the addition of 1.5 N aqueous ammonium chloride (15 mL). The mixture was extracted into ethyl acetate, washed with brine and the organic layer was dried (Na2SO4), filtered and evaporated. The residue was triturated with diethyl ether give pure tert-butyl (2-chloropyridin-4-yl)carbamate. The mother liquors were chromatographed on silica gel eluting with 25 - 45% ethyl acetate/ hexane to afford more product.A solution of tert-butyl (2-chloropyridin-4-yl)carbamate (1.14 g, 5 mmol) in dry TBDF (20 rriL) was cooled to -700C under an inert atmosphere and 1.7 M t-butyl lithium/pentane (8 mL, 13.5 mmol) was slowly added. The reaction was stirred for two hours and then dry DMF (1.2 mL, 15.5 mmol) was added. The reaction was allowed to slowly warm to room temperature over a three hour period. The reaction mixture was quenched with 3 N HCl (12 mL) and diluted with diethyl ether. The ether layer was washed with aqueous NaHCtheta3, dried (over Na2SO4), filtered and evaporated. The residue was triturated with cold diethyl ether to give pure t-butyl (2-chloro-3-formylpyridm-4-yl)carbamate. The mother liquors were chromatographed on silica gel eluting with 15-20% ethyl acetate/hexane to give additional product. lH-NMR(500 MHz, CDCI3): delta 11.0 (IH, br s), 10.52 (IH, s), 8.38 (IH, d, J= 6 Hz),8.31 (IH, d, J= 6 Hz), 1.54 (9H, s); m/e (m+1): 257.2.
With C45H65FeNO3P2PdS; caesium carbonate; In toluene; at 100℃; for 24h;Inert atmosphere; Sealed tube;
General procedure: A vial with a septum was charged with 4-hydroxybenzonitrile (78 mg, 0.656mmol), tert-butyl (2-chloropyridin-4-yl)carbamate(100 mg, 0.437 mmol), J009-PreCat (8.08 mg, 8.75 mumol), Cs2CO3 (285 mg, 0.875mmol) and a stir bar. The vessel was then evacuated under vacuum and refilledwith nitrogen three times. Toluene (1 mL) was injected under N2 andthe vial was sealed and heated at 100 oC for 24 h. The reactionmixture was then cooled to room temperature and diluted with EtOAc (5 mL). Themixture was then filtered through a pad of silica which was washed with EtOAc(2 x 5 mL). The filtrate was concentrated and purified on ISCO CombiFlash (4 gsilica gel column, 0-20% EtOAc in hexanes gradient)
With C45H65FeNO3P2PdS; caesium carbonate; In toluene; at 100℃; for 24h;Inert atmosphere; Sealed tube;
General procedure: A vial with a septum was charged with 4-hydroxybenzonitrile (78 mg, 0.656mmol), tert-butyl (2-chloropyridin-4-yl)carbamate(100 mg, 0.437 mmol), J009-PreCat (8.08 mg, 8.75 mumol), Cs2CO3 (285 mg, 0.875mmol) and a stir bar. The vessel was then evacuated under vacuum and refilledwith nitrogen three times. Toluene (1 mL) was injected under N2 andthe vial was sealed and heated at 100 oC for 24 h. The reactionmixture was then cooled to room temperature and diluted with EtOAc (5 mL). Themixture was then filtered through a pad of silica which was washed with EtOAc(2 x 5 mL). The filtrate was concentrated and purified on ISCO CombiFlash (4 gsilica gel column, 0-20% EtOAc in hexanes gradient)
Multi-step reaction with 2 steps
1.1: lithium tert-butyl / tetrahydrofuran / 0.5 h / -78 °C
1.2: 2 h / -78 - 20 °C
2.1: trifluoroacetic acid / dichloromethane / 6 h / 20 °C
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