(1R,2S)-2-氨基环己醇盐酸盐

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2-chloro-4-fluoro-3-methyl-benzonitrile (500 mg, 2.95 mmol), (1R,2S)-2-aminocyclohexanol hydrochloride (671 mg, 4.42 mmol, Small Molecules, Inc.) and sodium bicarbonate (991 mg, 11.8 mmol) in DMSO (14.7 mL), and water (2.1 mL) is heated at 130° C. for 48 h. After cooling to room temperature, the mixture is diluted with 1 N HCl and extracted twice with EtOAc. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with 2% methanol/dichloromethane to furnish the title compound as an off-white solid (527 mg, 68%). LC-ES/MS m/z 265.2 (M+1). extracted twice with EtOAc dried over sodium sulfate filtered concentrated in vacuo The resulting residue is purified eluting with 2% methanol/dichloromethane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2-chloro-4-fluoro-3-methyl-benzonitrile (500 mg, 2.95 mmol), (1R,2S)-2-aminocyclohexanol hydrochloride (671 mg, 4.42 mmol, Small Molecules, Inc.) and sodium bicarbonate (991 mg, 11.8 mmol) in DMSO (14.7 mL), and water (2.1 mL) is heated at 130° C. for 48 h. After cooling to room temperature, the mixture is diluted with 1 N HCl and extracted twice with EtOAc. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with 2% methanol/dichloromethane to furnish the title compound as an off-white solid (527 mg, 68%). LC-ES/MS m/z 265.2 (M+1). extracted twice with EtOAc dried over sodium sulfate filtered concentrated in vacuo The resulting residue is purified eluting with 2% methanol/dichloromethane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid (94.0 g, 0.255 mol) in DMF (900 mL) was added with stirring TBTU (90.2 g, 0.28 mol), N,N-diisopropyl ethylamine (219 mL) and cis-2-aminocyclohexanol hydrochloride (42.6 g, 0.28 mol). The temperature rose to 35° C. After stirring was for 3 h the mixture was concentrated in high vacuo at 45° C. The residue was extracted with cold 1N—NaOH (2 L) and ethylacetate (1×2.5 L, 1×1.5 L). Organic phases were washed with water (2×1.5 L). The organic phases were combined, dried with MgSO4 and concentrated in vacuo to ˜800-900ml volume. The product precipitated and the mixture was stirred at 0° C. for about 30 min. Filtration, washing with ethyl acetate/n-heptane 1:1 (4×50 mL) and drying in vacuo at 40° C. for 18 h yielded the title compound (75.8 g as a white solid); MS (ISP) 465.0, 467.0 (M+H)+. rose to 35° C the mixture was concentrated in high vacuo at 45° C The residue was extracted with cold 1N—NaOH (2 L) and ethylacetate (1×2.5 L, 1×1.5 L) Organic phases were washed with water (2×1.5 L) dried with MgSO4 concentrated in vacuo to ˜800-900ml volume The product precipitated the mixture was stirred at 0° C. for about 30 min Filtration washing with ethyl acetate/n-heptane 1:1 (4×50 mL) drying in vacuo at 40° C. for 18 h

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid (94.0 g, 0.255 mol) in DMF (900 mL) was added with stirring TBTU (90.2 g, 0.28 mol), N,N-diisopropyl ethylamine (219 mL) and cis-2-aminocyclohexanol hydrochloride (42.6 g, 0.28 mol). The temperature rose to 35° C. After stirring was for 3 h the mixture was concentrated in high vacuo at 45° C. The residue was extracted with cold 1N—NaOH (2 L) and ethylacetate (1×2.5 L, 1×1.5 L). Organic phases were washed with water (2×1.5 L). The organic phases were combined, dried with MgSO4 and concentrated in vacuo to ˜800-900ml volume. The product precipitated and the mixture was stirred at 0° C. for about 30 min. Filtration, washing with ethyl acetate/n-heptane 1:1 (4×50 mL) and drying in vacuo at 40° C. for 18 h yielded the title compound (75.8 g as a white solid); MS (ISP) 465.0, 467.0 (M+H)+. rose to 35° C the mixture was concentrated in high vacuo at 45° C The residue was extracted with cold 1N—NaOH (2 L) and ethylacetate (1×2.5 L, 1×1.5 L) Organic phases were washed with water (2×1.5 L) dried with MgSO4 concentrated in vacuo to ˜800-900ml volume The product precipitated the mixture was stirred at 0° C. for about 30 min Filtration washing with ethyl acetate/n-heptane 1:1 (4×50 mL) drying in vacuo at 40° C. for 18 h

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2-chloro-4-fluoro-3-methyl-benzonitrile (500 mg, 2.95 mmol), (1R,2S)-2-aminocyclohexanol hydrochloride (671 mg, 4.42 mmol, Small Molecules, Inc.) and sodium bicarbonate (991 mg, 11.8 mmol) in DMSO (14.7 mL), and water (2.1 mL) is heated at 130° C. for 48 h. After cooling to room temperature, the mixture is diluted with 1 N HCl and extracted twice with EtOAc. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with 2% methanol/dichloromethane to furnish the title compound as an off-white solid (527 mg, 68%). LC-ES/MS m/z 265.2 (M+1). extracted twice with EtOAc dried over sodium sulfate filtered concentrated in vacuo The resulting residue is purified eluting with 2% methanol/dichloromethane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of cis-2-aminocyclohexanol hydrochloride (4.88 g; 32 mmol) (William S. Johnson and Elliot N. Schubert, J.A.C.S., Vol. 72, pp. 2187-2190 (1950), triphenylmethylchloride (10.7 g; 38.4 mmol) and triethylamine (16 ml; 115 mmol) in 250 ml methylene chloride are refluxed for 3 hrs. then stirred at room temperature overnight. The mixture is poured into H2O and extracted with CH2Cl2 (200 ml), dried (Na2SO4) concentrated in vacuo and flash chromatographed using 9:1 7:1; hexane:EtOAc to obtain cis-2-triphenylmethylaminocyclohexanol which is used directly in the next step. extracted with CH2Cl2 (200 ml) dried (Na2SO4) concentrated in vacuo and flash chromatographed

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of cis-2-aminocyclohexanol hydrochloride (4.88 g; 32 mmol) (William S. Johnson and Elliot N. Schubert, J.A.C.S., Vol. 72, pp. 2187-2190 (1950), triphenylmethylchloride (10.7 g; 38.4 mmol) and triethylamine (16 ml; 115 mmol) in 250 ml methylene chloride are refluxed for 3 hrs. then stirred at room temperature overnight. The mixture is poured into H2O and extracted with CH2Cl2 (200 ml), dried (Na2SO4) concentrated in vacuo and flash chromatographed using 9:1 7:1; hexane:EtOAc to obtain cis-2-triphenylmethylaminocyclohexanol which is used directly in the next step. extracted with CH2Cl2 (200 ml) dried (Na2SO4) concentrated in vacuo and flash chromatographed

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-thioxo-1,3-thiazolidin-2-one (870 mg) in ethanol (30 mL) were added cis-2-aminocyclohexanol hydrochloride (1.00 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (2.32 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (504 mg). the mixture was heated under reflux overnight The reaction mixture was concentrated under reduced pressure the residue was purified by silica gel column chromatography (methanol/ethyl acetate) the obtained powder was washed with ethyl acetate

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under a nitrogen atmosphere, a solution of monomethyl phthalate (1.31 g, 7.31 mmol) and N,N-diisopropylamine (1.72 ml, 7.31 mmol) in tetrahydrofuran (10 ml) was added dropwise to a solution of benzotriazol-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate (3.77 g, 7.31 mmol) in tetrahydrofuran (10 ml) over a period of 15 minutes at room temperature. After 40 minutes, the solution thus prepared was slowly dropped into a solution of cis-2-aminocyclohexanol hydrochloride (1.0 g, 6.65 mmol) and triethylamine (1.01 ml, 7.31 mmol) in tetrahydrofuran (10 ml). After 3 hours, p-toluenesulfonic acid (35 mg) was added thereto, and the resulting mixture was refluxed. After 5 hours, water was added thereto and the resulting mixture was poured into a saturated aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) and purified again by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain cis-2-(2-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (1.5746 g, 97%). the solution thus prepared After 3 hours the resulting mixture was refluxed After 5 hours extracted with ethyl acetate The organic layer was dried over anhydrous magnesium sulfate The organic layer dried was concentrated under reduced pressure the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) purified again by a silica gel column chromatography (eluent: chloroform/ethyl acetate)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid (94.0 g, 0.255 mol) in DMF (900 mL) was added with stirring TBTU (90.2 g, 0.28 mol), N,N-diisopropyl ethylamine (219 mL) and cis-2-aminocyclohexanol hydrochloride (42.6 g, 0.28 mol). The temperature rose to 35° C. After stirring was for 3 h the mixture was concentrated in high vacuo at 45° C. The residue was extracted with cold 1N—NaOH (2 L) and ethylacetate (1×2.5 L, 1×1.5 L). Organic phases were washed with water (2×1.5 L). The organic phases were combined, dried with MgSO4 and concentrated in vacuo to ˜800-900ml volume. The product precipitated and the mixture was stirred at 0° C. for about 30 min. Filtration, washing with ethyl acetate/n-heptane 1:1 (4×50 mL) and drying in vacuo at 40° C. for 18 h yielded the title compound (75.8 g as a white solid); MS (ISP) 465.0, 467.0 (M+H)+. rose to 35° C the mixture was concentrated in high vacuo at 45° C The residue was extracted with cold 1N—NaOH (2 L) and ethylacetate (1×2.5 L, 1×1.5 L) Organic phases were washed with water (2×1.5 L) dried with MgSO4 concentrated in vacuo to ˜800-900ml volume The product precipitated the mixture was stirred at 0° C. for about 30 min Filtration washing with ethyl acetate/n-heptane 1:1 (4×50 mL) drying in vacuo at 40° C. for 18 h

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2-chloro-4-fluoro-3-methyl-benzonitrile (500 mg, 2.95 mmol), (1R,2S)-2-aminocyclohexanol hydrochloride (671 mg, 4.42 mmol, Small Molecules, Inc.) and sodium bicarbonate (991 mg, 11.8 mmol) in DMSO (14.7 mL), and water (2.1 mL) is heated at 130° C. for 48 h. After cooling to room temperature, the mixture is diluted with 1 N HCl and extracted twice with EtOAc. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with 2% methanol/dichloromethane to furnish the title compound as an off-white solid (527 mg, 68%). LC-ES/MS m/z 265.2 (M+1). extracted twice with EtOAc dried over sodium sulfate filtered concentrated in vacuo The resulting residue is purified eluting with 2% methanol/dichloromethane