Ethyl 3-(4-chlorophenyl)-3-oxopropanoate

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:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl 3-(4-chloro-phenyl)-3-oxo-propionate (18.1 g, 0.080 mol) and ethyl 5-amino-1H-pyrazole-4-carboxylate (13.7 g, 0.088 mol) was stirred at for 3 h 160° C. Ethyl acetate (40 mL) and hexane (40 mL) were successively added to the cooled mixture and stirring was continued at 0° C. for 0.5 h. The crystals were isolated by filtration and triturated for 1.2 h with 0.2 N HCl (80 mL). The solid was filtered off, washed with water and dried to give ethyl 5-(4-chloro-phenyl)-7-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate (13.3 g, 52%). White solid. MS (ISN) 316.3 [(M−H)−]; mp 190-192° C. stirring was continued at 0° C. for 0.5 h The crystals were isolated by filtration triturated for 1.2 h with 0.2 N HCl (80 mL) The solid was filtered off washed with water dried

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

Procedure: To a solution of 5.0 g of ethyl-4-chlorobenzoylacetate in 100 ml of methylene chloride cooled to -30° C., 77.3 ml of diisopropylaluminium hydride (1.0 mol/l toluene solution) was added, and the resulting mixture was stirred for 30 minutes and then brought back to room temperature over 3 hours, and 4.14 g of methanol and 24.3 g of water were added carefully, and the mixture was stirred for another 1.5 hours. The precipitate was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane/ethyl acetate=1/1), to obtain 2.45 g of the title compound as a pale yellow oily substance. brought back to room temperature over 3 hours the mixture was stirred for another 1.5 hours The precipitate was filtered off the filtrate was concentrated The resulting residue was purified by silica gel column chromatography (eluent; n-hexane/ethyl acetate=1/1)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl 3-(4-chloro-phenyl)-3-oxo-propionate (5.8 g, 26.0 mmol) and 2H-pyrazol-3-ylamine (2.1 g, 26.0 mmol) was stirred at 150° C. for 2 h. EtOAc (22 mL) was successively added to the cooled mixture and stirring was continued at 0° C. for 0.5 h. The crystals were isolated by filtration to give 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-7-ol (4.80 g, 75%) as a white solid. MS (ISP) 246.1 [(M+H)+]; mp 306-308° C. stirring was continued at 0° C. for 0.5 h The crystals were isolated by filtration

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl 3-(4-chloro-phenyl)-3-oxo-propionate (5.8 g, 26.0 mmol) and 2H-pyrazol-3-ylamine (2.1 g, 26.0 mmol) was stirred at 150° C. for 2 h. EtOAc (22 mL) was successively added to the cooled mixture and stirring was continued at 0° C. for 0.5 h. The crystals were isolated by filtration to give 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-7-ol (4.80 g, 75%) as a white solid. MS (ISP) 246.1 [(M+H)+]; mp 306-308° C. stirring was continued at 0° C. for 0.5 h The crystals were isolated by filtration

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

Procedure: 2.00 g (8.82 mmol) of ethyl 3-(4-chlorophenyl)-3-oxopropanoate and 1.25 g (9.71 mmol) of methyl 3-aminopent-2-enoate [Pena et al., J. Am. Chem. Soc. 124, 14552-14553 (2002)] were taken up in 12 ml of xylene, 3.50 g molecular sieve (4 Å) which had been dried by heating were added and the mixture was reacted at reflux temperature overnight. The molecular sieve was removed by filtration and washed with methanol/chloroform (1/1). The combined organic phases were concentrated on a rotary evaporator and the crude product was purified by preparative MPLC (Biotage 40M cartridge; mobile phase: isohexane/ethyl acetate 4/1). This gave 550 mg (21% of theory) of the target compound. 3.50 g molecular sieve (4 Å) which had been dried by heating were added the mixture was reacted at reflux temperature overnight The molecular sieve was removed by filtration washed with methanol/chloroform (1/1) The combined organic phases were concentrated on a rotary evaporator the crude product was purified by preparative MPLC (Biotage 40M cartridge; mobile phase: isohexane/ethyl acetate 4/1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 98.9 g of P2O5 is added to a mixture of 64 g of ethyl p-chlorobenzoylacetate and 90.4 g of pyrocatechol, heated at 80°C in portions over about 1/2 hour. After 15 minutes the heating is interrupted and 1000 cc of benzene are added. The organic phase is decanted. The latter is repeatedly washed first with NaHCO3 and subsequently with H2O until same is rendered neutral and finally dried with Na2SO4. The solvent is removed in vacuum and the residual oil fractionated, b.p. 150°-155°C (0.4 mm.Hg). The organic phase is decanted finally dried with Na2SO4 The solvent is removed in vacuum

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

Procedure: Triethylamine (17 ml) and magnesium chloride (5.5 g) were added to a suspension of potassium ethyl malonate (8.2 g) in ethyl acetate (100 ml) under ice cooling, and the mixture was stirred for 18 hours while the temperature of the system was gradually raised to room temperature. On the other hand, a suspension composed of 4-chlorobenzoic acid (5.0 g), thionyl chloride (12 ml), N,N-dimethylformamide (one drop) and toluene (100 ml) was heated under reflux for 1 hour, and the reaction mixture was then concentrated. The resultant residue was dissolved in ethyl acetate, and the solution was added dropwise to the reaction mixture previously prepared under ice cooling. The resultant mixture was stirred for 18 hours while the temperature of the system was gradually raised to room temperature. A 10% aqueous solution of citric acid was added to the reaction mixture, and the mixture was stirred for 30 minutes to separate the resultant organic layer. The organic layer was washed with saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was isolated and purified by column chromatography on silica gel (chloroform) to obtain the title compound (6.4 g). was heated under reflux for 1 hour the reaction mixture was then concentrated The resultant residue was dissolved in ethyl acetate the solution was added dropwise to the reaction mixture previously prepared under ice cooling was gradually raised to room temperature the mixture was stirred for 30 minutes to separate the resultant organic layer The organic layer was washed with saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure

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

Procedure: Triethylamine (17 ml) and magnesium chloride (5.5 g) were added to a suspension of potassium ethyl malonate (8.2 g) in ethyl acetate (100 ml) under ice cooling, and the mixture was stirred for 18 hours while the temperature of the system was gradually raised to room temperature. On the other hand, a suspension composed of 4-chlorobenzoic acid (5.0 g), thionyl chloride (12 ml), N,N-dimethylformamide (one drop) and toluene (100 ml) was heated under reflux for 1 hour, and the reaction mixture was then concentrated. The resultant residue was dissolved in ethyl acetate, and the solution was added dropwise to the reaction mixture previously prepared under ice cooling. The resultant mixture was stirred for 18 hours while the temperature of the system was gradually raised to room temperature. A 10% aqueous solution of citric acid was added to the reaction mixture, and the mixture was stirred for 30 minutes to separate the resultant organic layer. The organic layer was washed with saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was isolated and purified by column chromatography on silica gel (chloroform) to obtain the title compound (6.4 g). was heated under reflux for 1 hour the reaction mixture was then concentrated The resultant residue was dissolved in ethyl acetate the solution was added dropwise to the reaction mixture previously prepared under ice cooling was gradually raised to room temperature the mixture was stirred for 30 minutes to separate the resultant organic layer The organic layer was washed with saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl 3-(4-chloro-phenyl)-3-oxo-propionate (18.1 g, 0.080 mol) and ethyl 5-amino-1H-pyrazole-4-carboxylate (13.7 g, 0.088 mol) was stirred at 160° C. for 3 h. AcOEt (40 mL) and hexane (40 mL) were successively added to the cooled mixture and stirring was continued at 0° C. for 0.5 h. The crystals were isolated by filtration and the solid was triturated for 1.2 h with 0.2 N HCl (80 mL). The solid was filtered off, washed with water and dried to give ethyl 5-(4-chloro-phenyl)-7-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate (13.3 g, 52%). White solid. MS (ISN) 316.3 [(M−H)−]; mp 190-192° C. stirring was continued at 0° C. for 0.5 h The crystals were isolated by filtration the solid was triturated for 1.2 h with 0.2 N HCl (80 mL) The solid was filtered off washed with water dried