尼达尼布杂质66

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

实验步骤: A solution of 2.11 g. (0.01 mole) 1,3,3-trimethyl-2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone in 10 ml. trimethylorthobenzoate is refluxed under nitrogen for 18 hours at a bath temperature of 140° C. during which time all distillate is removed. The resulting mixture is cooled and evaporated to dryness in vacuo. After filtering the residue dissolved in 2% methanol-chloroform through silica gel, and evaporation of the filtrate the resulting solid is triturated with ether, giving 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano [4,3-e]-as-triazine-4-oxide; m.p. 186.5° to 189° C. is removed The resulting mixture is cooled evaporated to dryness in vacuo After filtering the residue dissolved in 2% methanol-chloroform through silica gel, and evaporation of the filtrate the resulting solid is triturated with ether

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 1.00 mL (5.82 mmol) of trimethyl orthobenzoate was added 204 mg (0.70 mmol) of 5-(4-amino-3-hydroxy-5-methoxyphenyl)-4-t-butyl-3,3-dimethyl-2,3-dihydrofuran (Compound [61]), and the mixture was refluxed for 1.5 hours at 150° C. To this reaction mixture, 2.0 ml of ethyl acetate, and 0.2 ml of H2O, and 10.1 mg (0.05 mmol) of TsOH H2O was added and the mixture was refluxed for 1 hours at 97° C. The resulting mixture was poured in saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried with magnesium sulfate anhydride, and concentrated. The residue was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ethyl acetate=10:1) to obtain 207 mg of 4-t-butyl-5-(4-methoxy-2-phenylbenzo[d]oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [62]). Yield 78.4%. the mixture was refluxed for 1 hours at 97° C extracted with ethyl acetate The organic layer was washed with saturated aqueous solution of sodium chloride dried with magnesium sulfate anhydride concentrated the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ethyl acetate=10:1)

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

实验步骤: A solution of (±)-benzyl[2-amino-2-(aminocarbonyl)-2,3-dihydro-1H-inden-5-yl]carbamate (described in Intermediate 1, 35.0 mg, 0.108 mmol) and (trimethoxymethyl)benzene (0.022 mL, 0.129 mmol) in toluene (5 mL) was heated at reflux for 7.5 h. The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in DMSO (1 mL) and purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=412 (M+1). at reflux for 7.5 h The reaction mixture was concentrated under reduced pressure The crude product was dissolved in DMSO (1 mL) purified by HPLC eluting with a gradient of H2O The pure, product-containing fractions concentrated

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

实验步骤: Neat 23 (1.48 g, 12.65 mmol) was dissolved in CH2Cl2 (127 mL) and treated with a catalytic amount of p-toluene sulfonic acid monohydrate (0.048 g, 20 μmol) and (trimethoxymethyl)benzene (3.26 mL, 18.98 mmol) in CH2Cl2 at room temperature for 1 hr. After the formation of the orthoester was complete, a stoichiometric amount of water (340 μL, 18.98 mmol) was added to the mixture. The mixture was then stirred for 40 min and concentrated in vacuo. Purification of the residue by silica gel flash chromatography using 25% EtOAc/hexanes gave 2.6 g of monoacylated product 27 (93% yield) as a clear, colorless oil. 1H NMR (CDCl3, 400 MHz) δ: 8.03-8.06 (m, 2H), 7.58 (tt, J=1.6, 2.0, 1.6 1H), 7.43-7.47 (m, 2H), 4.54 (dd, J=4.4, 12.0 Hz, 1H), 4.46 (dd, J=6.8, 12.0 Hz, 1H), 3.85-3.91 (m, 1H), 3.80 (dd, J=4.8, 11.6 Hz, 1H), 3.73 (dd, J=6.0, 11.6 Hz, 1H). concentrated in vacuo Purification of the residue by silica gel flash chromatography

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

实验步骤: Neat 23 (1.48 g, 12.65 mmol) was dissolved in CH2Cl2 (127 mL) and treated with a catalytic amount of p-toluene sulfonic acid monohydrate (0.048 g, 20 μmol) and (trimethoxymethyl)benzene (3.26 mL, 18.98 mmol) in CH2Cl2 at room temperature for 1 hr. After the formation of the orthoester was complete, a stoichiometric amount of water (340 μL, 18.98 mmol) was added to the mixture. The mixture was then stirred for 40 min and concentrated in vacuo. Purification of the residue by silica gel flash chromatography using 25% EtOAc/hexanes gave 2.6 g of monoacylated product 27 (93% yield) as a clear, colorless oil. 1H NMR (CDCl3, 400 MHz) δ: 8.03-8.06 (m, 2H), 7.58 (tt, J=1.6, 2.0, 1.6 1H), 7.43-7.47 (m, 2H), 4.54 (dd, J=4.4, 12.0 Hz, 1H), 4.46 (dd, J=6.8, 12.0 Hz, 1H), 3.85-3.91 (m, 1H), 3.80 (dd, J=4.8, 11.6 Hz, 1H), 3.73 (dd, J=6.0, 11.6 Hz, 1H). concentrated in vacuo Purification of the residue by silica gel flash chromatography

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 25-mL, round bottomed flask equipped with a magnetic stirrer was charged with 2-amino-5-chloro-3-hydroxybenzoic acid (0.931 g, 4.96 mmol), trimethyl orthobenzoate (7.23 g, 39.7 mmol), and pyridinium p-toluenesulfonate (0.062 g, 0.248 mmol). After stirring at 90° C. for 1 h, the reaction was diluted with hexanes (30 mL) filtered, and the filter cake dried in a vacuum oven at 40° C. to afford 0.455 g (33% yield) of 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 8.24 (m, 3H), 7.84 (s, 1H), 7.65 (m, 3H); MS (ESI) m/z 272 (M−H). A 25-mL, round bottomed flask equipped with a magnetic stirrer filtered the filter cake dried in a vacuum oven at 40° C.

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

实验步骤: A solution of 2.11 g. (0.01 mole) 1,3,3-trimethyl-2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone in 10 ml. trimethylorthobenzoate is refluxed under nitrogen for 18 hours at a bath temperature of 140° C. during which time all distillate is removed. The resulting mixture is cooled and evaporated to dryness in vacuo. After filtering the residue dissolved in 2% methanol-chloroform through silica gel, and evaporation of the filtrate the resulting solid is triturated with ether, giving 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano [4,3-e]-as-triazine-4-oxide; m.p. 186.5° to 189° C. is removed The resulting mixture is cooled evaporated to dryness in vacuo After filtering the residue dissolved in 2% methanol-chloroform through silica gel, and evaporation of the filtrate the resulting solid is triturated with ether

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

实验步骤: A solution of 2.11 g. (0.01 mole) 1,3,3-trimethyl-2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone in 10 ml. trimethylorthobenzoate is refluxed under nitrogen for 18 hours at a bath temperature of 140° C. during which time all distillate is removed. The resulting mixture is cooled and evaporated to dryness in vacuo. After filtering the residue dissolved in 2% methanol-chloroform through silica gel, and evaporation of the filtrate the resulting solid is triturated with ether, giving 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano [4,3-e]-as-triazine-4-oxide; m.p. 186.5° to 189° C. is removed The resulting mixture is cooled evaporated to dryness in vacuo After filtering the residue dissolved in 2% methanol-chloroform through silica gel, and evaporation of the filtrate the resulting solid is triturated with ether

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

实验步骤: 9.3 g (54.3 mmol) of 3,6-difluoro-2-methylbenzoic acid and 9.88 g (54.3 mmol) of 3,4,5-trimethoxytoluene were introduced into 250 ml of absolute dichloromethane, and 54 g (380 mmol) of pulverulent phosphorus pentoxide were then added. The mixture was stirred for 16 hours at room temperature. According to HPLC check, the trimethoxytoluene had not been reacted completely. A further 13.5 g of phosphorus pentoxide were added. After a further four hours, the reaction mixture was poured into water and extracted with dichloromethane. The combined organic phases were then dried and concentrated. The crude product was purified by reversed-phase MPLC (eluent acetonitrile/water 7:3). This gave 12.2 g of the compound I.5-02 (36 mmol, 67% yield). were then added After a further four hours extracted with dichloromethane The combined organic phases were then dried concentrated The crude product was purified by reversed-phase MPLC (eluent acetonitrile/water 7:3)

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

实验步骤: 9.3 g (54.3 mmol) of 3,6-difluoro-2-methylbenzoic acid and 9.88 g (54.3 mmol) of 3,4,5-trimethoxytoluene were introduced into 250 ml of absolute dichloromethane, and 54 g (380 mmol) of pulverulent phosphorus pentoxide were then added. The mixture was stirred for 16 hours at room temperature. According to HPLC check, the trimethoxytoluene had not been reacted completely. A further 13.5 g of phosphorus pentoxide were added. After a further four hours, the reaction mixture was poured into water and extracted with dichloromethane. The combined organic phases were then dried and concentrated. The crude product was purified by reversed-phase MPLC (eluent acetonitrile/water 7:3). This gave 12.2 g of the compound I.5-02 (36 mmol, 67% yield). were then added After a further four hours extracted with dichloromethane The combined organic phases were then dried concentrated The crude product was purified by reversed-phase MPLC (eluent acetonitrile/water 7:3)

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

实验步骤: A solution of 1.97 g. (0.01 mole) 1,3-dimethyl-2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone in 10 ml. trimethylorthobenzoate is refluxed under nitrogen for 18 hours at a bath temperature of 140° C. during which time all distillate is removed. The resulting mixture is cooled and evaporated to dryness in vacuo. After filtering the residue dissolved in 2% methanol-chloroform through silica gel, and evaporation of the filtrate gives 3-phenyl-5,8-dihydro-6,8-dimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-oxide. is removed The resulting mixture is cooled evaporated to dryness in vacuo After filtering the residue dissolved in 2% methanol-chloroform through silica gel, and evaporation of the filtrate

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

实验步骤: A 2.6 gm. portion of 2-imidazolecarboxylic acid hydrazide is added to 200 ml. of ethanol. To this is added 20 ml. of trimethylorthobenzoate. The mixture is refluxed for 31 hours, then the solvents are evaporated giving a white solid which is washed twice with diethyl ether giving 3.0 gm. of white solid. This solid is combined with 50 ml. of diphenyl ether and heated with stirring in an oil bath at 265°-275° C. for 10 minutes. The mixture is cooled, petroleum ether is added and the mixture is filtered. The solid is washed twice with hot petroleum ether, giving 1.4 gm. of the desired product as a light tan solid, m.p. 292°-295° C. To this is added 20 ml The mixture is refluxed for 31 hours the solvents are evaporated giving a white solid which is washed twice with diethyl ether giving 3.0 gm of diphenyl ether and heated The mixture is cooled petroleum ether is added the mixture is filtered The solid is washed twice with hot petroleum ether giving 1.4 gm