2-methylcyclohexan-1-ol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methanesulfonic acid (99%, 100 g, 1.0 mole) was added slowly to a stirred mixture of 5-amino-2-chlorobenzoic acid (85%, 100 g, 0.5 mole) in 2-methylcyclohexanol (200 g, 1.85 mole). The mixture was heated under reflux with stirring for 6 hours, then the excess 2-methylcyclohexanol was evaporated under reduced pressure. The residue was then dissolved in methylene chloride (800 ml), washed with water (300 ml), 5% sodium bicarbonate solution (300 ml), water (300 ml), dried (magnesium sulfate), and filtered. The solvent was then evaporated to give 109 g of 2-methylcyclohexyl 5-amino-2-chlorobenzoate as a light brown oil. The mixture was heated under reflux the excess 2-methylcyclohexanol was evaporated under reduced pressure The residue was then dissolved in methylene chloride (800 ml) washed with water (300 ml), 5% sodium bicarbonate solution (300 ml), water (300 ml) dried (magnesium sulfate) filtered The solvent was then evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 25.5 g (150 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of 2-methylcyclohexanol was added 2.5 g (purity: 99%; 15.0 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 100 g of pure water and 120 g of toluene were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 3.15 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 76.0%) and 9.0 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.2%) were obtained. a reaction for 3 hours After completion of the reaction added in an excess amount was separated Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 940 g (about 12.0 mole) of benzene was charged into a 3 L 4-necked flask and cooled to below 5° C. in an ice bath, followed by the addition of 1080 g (about 10.5 moles) of 95 concentrated sulfuric acid. The mixture was further cooled until the interior of the reaction vessel was cooled to below 5° C., followed by the addition of a mixture of 550 g (about 4.8 moles) of 2-methylcyclohexanol and 400 g (about 3.8 moles) of benzene in droplets over 5 hours. Thereafter, the reaction was continued for 2 hours. The reaction solution was transferred into a 5 L separatory funnel to separate the sulfuric acid phase. 1 L of pure water was then added to the solution 5 times so as to dissolve and remove the by-products and other impurities. The resulting solution was made alkali with 1% aqueous solution of sodium hydroxide, followed by the addition of 1 L of water until the aqueous phase was made neutral. After the separation of the aqueous phase, the remaining was dehydrated with sodium sulfate anhydride, followed by removal of the light fractions and the excess benzene under at a temperature of 100° C. and pressure of 0.4 kPa (3 mmHg) thereby obtaining about 900 g of crude 1-phenyl-1-methylcyclohexane. This was subjected to vacuum distillation thereby obtaining 800 g of a fraction having a boiling point of 119.7 to 120.5° C. at a pressure of 0.4 kPa (3 mmHg). The fraction was charged into a 2 L autoclave, followed by the addition of 8 g of a nickel-based hydrogenating catalyst. The reaction was carried out at a temperature of 150° C. and at a maximum pressure of 6.86×106 Pa (70 kg/cm2) until the absorption of hydrogen did not occurred. Thereafter, the catalyst was removed thereby obtaining about 820 g of the targeted product represented by the formula cooled to below 5° C. in an ice bath The mixture was further cooled until the interior of the reaction vessel was cooled to below 5° C. The reaction solution was transferred into a 5 L separatory funnel to separate the sulfuric acid phase 1 L of pure water was then added to the solution 5 times so as to dissolve remove the by-products and other impurities followed by the addition of 1 L of water until the aqueous phase After the separation of the aqueous phase followed by removal of the light fractions

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-methylcyclohexanol (0.20 g) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-[(2-methylcyclohexyl)oxy]-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.55 g, 86%) as a yellow oil. was added the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere the resulting product was extracted with ethyl acetate The organic layer was washed with water and saturated brine dried the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 6.7 ml of tetrahydrofuran was suspended 0.18 g of sodium hydride (60% in oil), to which 1 ml of a tetrahydrofuran solution containing 0.42 g of 2-methylcyclohexanol (cis:trans=3:7) was slowly added dropwise with stirring at 0° C. The mixture was stirred at 0° C. for 10 minutes, to which 1 ml of a tetrahydrofuran solution containing 0.5 g of 4,6-dichloropyrimidine was added at 0° C., followed by further stirring at room temperature for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.55 g of 4-chloro-6-(2-methylcyclohexyloxy)pyrimidine as a mixture of cis and trans forms. was slowly added dropwise was added at 0° C. by further stirring at room temperature for 2 hours extracted three times with t-butyl methyl ether washed with water dried over anhydrous magnesium sulfate concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 6.7 ml of tetrahydrofuran was suspended 0.18 g of sodium hydride (60% in oil), to which 1 ml of a tetrahydrofuran solution containing 0.42 g of 2-methylcyclohexanol(cis:trans=3:7) was slowly added dropwise with stirring at 0° C. The mixture was stirred at 0° C. for 10 minutes, to which 1 ml of a tetrahydrofuran solution containing 0.5 g of 4,6-dichloropyrimidine was added at 0° C., followed by further stirring at room temperature for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.55 g of 4-chloro-6-(2-methylcyclohexyloxy)pyrimidine as a mixture of cis and trans forms. was slowly added dropwise was added at 0° C. by further stirring at room temperature for 2 hours extracted three times with t-butyl methyl ether washed with water dried over anhydrous magnesium sulfate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methanesulfonic acid (99%, 100 g, 1.0 mole) was added slowly to a stirred mixture of 5-amino-2-chlorobenzoic acid (85%, 100 g, 0.5 mole) in 2-methylcyclohexanol (200 g, 1.85 mole). The mixture was heated under reflux with stirring for 6 hours, then the excess 2-methylcyclohexanol was evaporated under reduced pressure. The residue was then dissolved in methylene chloride (800 ml), washed with water (300 ml), 5% sodium bicarbonate solution (300 ml), water (300 ml), dried (magnesium sulfate), and filtered. The solvent was then evaporated to give 109 g of 2-methylcyclohexyl 5-amino-2-chlorobenzoate as a light brown oil. The mixture was heated under reflux the excess 2-methylcyclohexanol was evaporated under reduced pressure The residue was then dissolved in methylene chloride (800 ml) washed with water (300 ml), 5% sodium bicarbonate solution (300 ml), water (300 ml) dried (magnesium sulfate) filtered The solvent was then evaporated