ethylhydrazine

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

Procedure: 3.05 g of Ethylhydrazine and 6.54 g of Ethyl acetoacetate was dissolved in 10 mL of EtOH and the mixture was heated at 80° C. overnight. The mixture was cooled and partitioned between CHCl3 and water. The organic layer was drier over Na2SO4, concentrated to give 2.43 g of crude 2-ethyl-5-methyl-2,4-dihydro-3H-pyrazol-3-one. 2.35 g of the material was diluted with 4 mL of DMF and 6.2 mL of POCl3 was added dropwise thereto. The mixture was heated at 80° C. overnight, then cooled to room temperature. After addition of ice, the mixture was partitioned between CHCl3 and water. The organic layer was dried over Na2SO4 and concentrated to give 1.46 g of crude 5-chloro-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde. 516 mg of the material was diluted with 10 mL of EtOH and 440 mg of HSCH2COOEt and 930 mg of K2CO3 was added thereto. The mixture was stirred at 80° C. overnight. The reaction mixture was cooled and 5 mL of 1N NaOHaq and 5 mL of MeOH was added thereto successively. Then the mixture was heated at 85° C. for 3 hrs. After cooled, the mixture was acidified with 1N HCl (to pH 1.5), then diluted with water. The precipitate was filtered, washed with water and n-hexane, dried in vacuo to afford 214 mg of the targeted compound. The mixture was cooled partitioned between CHCl3 and water concentrated

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

Procedure: 27.9 g. of 4,6-Dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.2 mol.) are dissolved in about 100 ml. of methanol and 20 ml. of water. 15 g. of triethylamine are added and at 25°-30° 4.5 g. ethyl hydrazine are dropped in with stirring. After the addition is complete, stirring is continued for 1 additional hour. On cooling, 4-chloro-6-(1-ethyl)hydrazino-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester precipitates, yield 19.7 g. (65%) m.p. 117°-120°. After the addition stirring On cooling 4-chloro-6-(1-ethyl)hydrazino-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester precipitates

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

Procedure: 5-chloromethyl-1-ethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole was prepared in analogy to the prepaparation of 5-chloromethyl-1-ethyl-3-(3,4,5-trimethoxy-phenyl)-1H-pyrazole described by Kodama et al. (U.S. Pat. No. 6,472,386), but starting from 4-trifluoromethylacetophenone instead of 3′4′5′-trimethoxyacetophenone and using ethyl hydrazine instead of methylhydrazine.

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

Procedure: A 100 L cylindrical flask with a bottom valve was equipped with a mechanical stirrer, internal heating coil, 5 L dropping funnel, and thermocouple was charged with the acetonitrile (39 L) and 1-(1-(t-butoxycarbonyl)piperidin-4-yl)-4-phenylbutane-1,3-dione 4 (3.00 Kg, 8.68 mol). To the resulting clear light yellow solution was added water (18.6 l). The mixture was warmed to 19° C. and the mixture became clear. An ethyl hydrazine solution (35% in water, 1.66 Kg, 1.71 L, 9.55 mol) was added via a dropping funnel over 100 min. The batch temperature after the addition was 20° C. The reaction solution was aged for 1 h at 20 □ C then checked for completion by HPLC. If any 4 remained, additional ethyl hydrazine was added to complete the reaction. At the end of reaction the ratio of products 5:6:7 is 83.6:14.3:2.1 with complete consumption of 4. A 100 L cylindrical flask with a bottom valve was equipped with a mechanical stirrer The batch temperature after the addition was 20° C the reaction At the end of reaction the ratio of products 5:6:7 with complete consumption of 4

Conditions: temp:19.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 100 L cylindrical flask with a bottom valve was equipped with a mechanical stirrer, internal heating coil, 5 L dropping funnel, and thermocouple was charged with the acetonitrile (39 L) and 1-(1-(t-butoxycarbonyl)piperidin-4-yl)-4-phenylbutane-1,3-dione 4 (3.00 Kg, 8.68 mol). To the resulting clear light yellow solution was added water (18.6 l). The mixture was warmed to 19° C. and the mixture became clear. An ethyl hydrazine solution (35% in water, 1.66 Kg, 1.71 L, 9.55 mol) was added via a dropping funnel over 100 min. The batch temperature after the addition was 20° C. The reaction solution was aged for 1 h at 20 □ C then checked for completion by HPLC. If any 4 remained, additional ethyl hydrazine was added to complete the reaction. At the end of reaction the ratio of products 5:6:7 is 83.6:14.3:2.1 with complete consumption of 4. A 100 L cylindrical flask with a bottom valve was equipped with a mechanical stirrer The batch temperature after the addition was 20° C the reaction At the end of reaction the ratio of products 5:6:7 with complete consumption of 4

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

Procedure: The title compound was prepared from the semi-crude (1-benzylpiperidin-4-yl)-(cyclohexanon-2-yl)ketone from step A and 34% aqueous ethylhydrazine in 4:1 acetonitrile and water at room temperature. This provided 8:1 ratio of isomeric ethyl pyrazoles in favor of the title compound. (Note: Use of ethyl hydrazine oxalate in the presence of DIEA gave about 2:1 ratio of the same isomers.) The 1-benzylpiperidine-4-carboxylic acid ethyl ester present in the starting β-diketone was removed after saponification of the crude product with sodium hydroxide in water ethanol mixture followed by extractive work-up. The desired ethyl isomer is the higher Rf isomer. It was isolated on silica gel chromatography (60˜100% ethyl acetate in hexanes and 5˜20% methanol in ethyl acetate, both with 1% triethylamine).