2-hydroxyacetohydrazide

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 6-(4-(5-(Hydroxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. Ethyl 4-(2-oxo-3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (See Example 195.B) (0.250 g, 0.63 mmol) in ethanol (20 mL) was treated with 2-hydroxyacetohydrazide (0.17 g, 1.9 mmol) and triethylamine (0.26 mL, 1.9 mmol), and the resulting reaction mixture was stirred in a sealed tube at 110° C. for 16 h. The cooled reaction solvent removed under reduced pressure. The resulting material was purified using reverse-phase semi-preparatory HPLC (15-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing clean product were passed through a Phenomenex Strata-X-C ion exchange column to remove TFA. The column was washed successively with water, methanol, and then 5% ammonium hydroxide in methanol. The product came off with the 5% ammonium hydroxide in methanol eluent and was concentrated on a rotary evaporator. The residue was triturated with ethyl ether in hexane to make a fine powder and dried under vacuum at 50° C. to give the desired product (0.130 g, 49%) as a white solid. MS (ESI) m/z 422.3[M+1]+. the resulting reaction mixture The cooled reaction solvent removed under reduced pressure The resulting material was purified reverse-phase semi-preparatory HPLC (15-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) Fractions containing clean product to remove TFA The column was washed successively with water, methanol was concentrated on a rotary evaporator The residue was triturated with ethyl ether in hexane dried under vacuum at 50° C.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.1 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione are refluxed for 8 hours with 1.5 g of glycolic acid hydrazide in absolute butanol. The solvent is then distilled off and the residue recrystallized from ethyl acetate containing active carbon to yield 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-methanol, melting point 219°-221° C. The solvent is then distilled off the residue recrystallized from ethyl acetate containing active carbon

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.1 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione are refluxed for 8 hours with 1.5 g of glycolic acid hydrazide in absolute butanol. The solvent is then distilled off and the residue recrystallized from ethyl acetate containing active carbon to yield 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-methanol, melting point 219°-221° C. The solvent is then distilled off the residue recrystallized from ethyl acetate containing active carbon

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 9 g of glycolic acid hydrazide, 7.3 g of methyl isothiocyanate 50 ml of methanol and 50 ml of ethanol was heated under reflux for 5 hours. Following the addition of 2.3 g of sodium metal, the mixture was further refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 150 ml of water and adjusted to pH 2.5 with phosphoric acid. The resultant crystals were collected by filtration and recrystallized from ethanol. By the above procedure there were obtained 5.2 g of the captioned compound. m.p. 199°-201° C. was heated under reflux for 5 hours the mixture was further refluxed for 24 hours The reaction mixture was concentrated under reduced pressure the residue was dissolved in 150 ml of water The resultant crystals were collected by filtration recrystallized from ethanol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 9 g of glycolic acid hydrazide, 7.3 g of methyl isothiocyanate 50 ml of methanol and 50 ml of ethanol was heated under reflux for 5 hours. Following the addition of 2.3 g of sodium metal, the mixture was further refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 150 ml of water and adjusted to pH 2.5 with phosphoric acid. The resultant crystals were collected by filtration and recrystallized from ethanol. By the above procedure there were obtained 5.2 g of the captioned compound. m.p. 199°-201° C. was heated under reflux for 5 hours the mixture was further refluxed for 24 hours The reaction mixture was concentrated under reduced pressure the residue was dissolved in 150 ml of water The resultant crystals were collected by filtration recrystallized from ethanol

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 6-(4-(5-(Hydroxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. Ethyl 4-(2-oxo-3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (See Example 195. B) (0.250 g, 0.63 mmol) in ethanol (20 mL) was treated with 2-hydroxyacetohydrazide (0.17 g, 1.9 mmol) and triethylamine (0.26 mL, 1.9 mmol), and the resulting reaction mixture was stirred in a sealed tube at 110° C. for 16 h. The cooled reaction solvent removed under reduced pressure. The resulting material was purified using reverse-phase semi-preparatory HPLC (15-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing clean product were passed through a Phenomenex Strata-X-C ion exchange column to remove TFA. The column was washed successively with water, methanol, and then 5% ammonium hydroxide in methanol. The product came off with the 5% ammonium hydroxide in methanol eluent and was concentrated on a rotary evaporator. The residue was triturated with ethyl ether in hexane to make a fine powder and dried under vacuum at 50° C. to give the desired product (0.130 g, 49%) as a white solid. MS (ESI) m/z 422.3 [M+1]+ the resulting reaction mixture The cooled reaction solvent removed under reduced pressure The resulting material was purified reverse-phase semi-preparatory HPLC (15-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) Fractions containing clean product to remove TFA The column was washed successively with water, methanol was concentrated on a rotary evaporator The residue was triturated with ethyl ether in hexane dried under vacuum at 50° C.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In the manner given in Preparation 1, a solution of 1,3-dihydro-7-fluoro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butyl alcohol is refluxed to give 8-fluoro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 7 8-Chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner given in Preparation 1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In the manner given in Preparation 1, a solution of 1,3-dihydro-7-fluoro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butyl alcohol is refluxed to give 8-fluoro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 7 8-Chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner given in Preparation 1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In the manner given in Preparation 1, a solution of 1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butyl alcohol is refluxed to give 1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 6 8-Fluoro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner given in Preparation 1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In the manner given in Example 1, a solution of 1,3-dihydro-7-trifluoromethyl-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butyl alcohol is refluxed to give 8-trifluoromethyl-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 5 1-(Hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In the manner given in Example 1, a solution of 1,3-dihydro-7-trifluoromethyl-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butyl alcohol is refluxed to give 8-trifluoromethyl-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 5 1-(Hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In the manner given in Preparation 1, a solution of 1,3-dihydro-7-nitro-5-(o-fluorophenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol is heated to reflux with hydroxyacetic acid hydrazide to give 8-nitro-1-(hydroxymethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 4 8-(Trifluoromethyl)-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner given in Preparation 1