4-methylpentanehydrazide

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

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

Procedure: Under nitrogen, a solution of 53.8 g (1.68 mol) of anhydrous hydrazine in 300 mL of methanol was cooled to 0° C. and treated with 186 g (1.4 mol) of methyl 4-methylvalerate. The reaction was allowed to warm to ambient temperature and stir overnight prior to stirring at reflux for 4 h. The reaction was concentrated in vacuo giving 166 g (93%) of 4-methylvaleric acid hydrazide as a colorless solid: 49–51° C.; NMR (CDCl3) δ 0.89 (d, J=7 Hz, 6H), 1.48–1.64 (m, 3H), 2.15 (t, J=7 Hz, 2H), 3.91 (br s, 2H), 6.94 (br s, 1H). A 7.86 g (60 mmol) sample of the hydrazide was dissolved in 50 mL of methanol and treated with 7.8 g (60 mmol) of ethyl iminovalerate under nitrogen. The reaction was stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (40:60) gave 9.6 g (82.%) of 3-butyl-5-isopentyl-1H-1,2,4-triazole as a colorless solid which melts close to ambient temperature: NMR (CDCl3) δ 0.81–0.90 (m, 9H), 1.25–1.40 (m, 2H), 1.47–1.74 (m, 5H), 2.70 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 196 (100); HRMS. Calcd for M+H: 196.1814. Found: 196.1832. to stirring at reflux for 4 h The reaction was concentrated in vacuo

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

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

Procedure: Under nitrogen, a sclution of 53.8 g (1.68 mol) of anhydrous hydrazine in 300 mL of methanol was cooled to 0° C. and treated with 186 g (1.4 mol) of methyl 4-methylvalerate. The reaction was allowed to warm to ambient temperature and stir overnight prior to stirring at reflux for 4 h. The reaction was concentrated in vacuo giving 166 g (93%) of 4-methylvaleric acid hydrazide as a colorless solid: 49°-51° C.; NMR (CDCl3) δ 0.89 (d, J=7 Hz, 6H), 1.48-1.64 (m, 3H), 2.15 (t, J=7 Hz, 2H), 3.91 (br s, 2H), 6.94 (br s, 1H). A 7.86 g (60 mmol) sample of the hydrazide was dissolved in 50 mL of methanol and treated with 7.8 g (60 mmol) of ethyl iminovalerate under nitrogen. The reaction was stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (40:60) gave 9.6 g (82%) of 3-butyl-5-isopentyl-1H-1,2,4-triazole as a colorless solid which melts close to ambient temperature: NMR (CDCl3) δ 0.81- 0.90 (m, 9H), 1.25-1.40 (m, 2H), 1.47-1.74 (m, 5H), 2.70 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 196 (100); HRMS. Calcd for M+H: 196.1814. Found: 196.1832. to stirring at reflux for 4 h The reaction was concentrated in vacuo

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

Procedure: A solution of 0.157 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-methylvalerohydrazide in 5 ml of dimethylformamide was treated at room temperature under nitrogen with 0.250 g of 2-[N-(9-fluorenylmethyloxycarbonyl)-4-piperidine]acetic acid and 0.132 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride. The mixture was stirred overnight at room temperature and evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous citric acid solution, 5% aqueous sodium hydrogen carbonate solution, saturated sodium chloride solution, and then dried over anhydrous magnesium sulphate and evaporated to give 0.500 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-2-(N-(9-fluorenylmethyloxycarbonyl)-4-piperidyl)acetyl]-4-methylvalerohydrazide in the form of a clear oil. evaporated The residue was dissolved in ethyl acetate washed with 5% aqueous citric acid solution, 5% aqueous sodium hydrogen carbonate solution, saturated sodium chloride solution dried over anhydrous magnesium sulphate evaporated

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

Procedure: In a manner analogous to that described in the first paragraph of Example 5, starting from 0.058 g of a mixture of (E)-2′-(D-alanyl)-2′-cyclopentyl-2(R)-[1(S)-[tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methylvalero-hydrazide and (E)-2′-(D-alanyl)-2′-cyclopentyl-2(S)-[1(R)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methylvalerohydrazide there was obtained 0.048 mg of a mixture of (E)-2′-(D-alanyl)-2′-cyclopentyl-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide p-toluene-sulphonate and (E)-2′-(D-alanyl)-2′-cyclopentyl-2(S)-[1(R)-(hydroxycarbonyl)-4-phenyl-3-butenyl]-methylvalerohydrazide p-toluenesulphonate in the form of a pale pink solid.

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

Procedure: In a manner analogous to that described in Example 2, parts (iii)-(v), starting from 4-tert-butyl hydrogen 3(S)-[(tetrahydro-2H-pyran-4-ylidene)ethyl]-2(R)-isobutylsuccinate and isobutylhydrazine and using trimethylsilyl trifluoromethanesulphonate in 1,4-dioxane instead of trifluoroacetic acid to deprotect the tertiary butyl ester there was obtained 2(R)-[3-(tetrahydro-2H-pyran-4-ylidene)-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-propyl]-2′-isobutyl-2′-methanesulphonyl)-4-methylvalerohydrazide in the form of an off-white solid.

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

Procedure: Under nitrogen, a solution of 53.8 g (1.68 mol) of anhydrous hydrazine in 300 mL of methanol was cooled to 0° C. and treated with 186 g (1.4 mol) of methyl 4-methylvalerate. The reaction was allowed to warm to ambient temperature and stir overnight prior to stirring at reflux for 4 h. The reaction was concentrated in vacuo giving 166 g (93%) of 4-methylvaleric acid hydrazide as a colorless solid: 49°-51° C.; NMR (CDCl3) δ0.89 (d, J=7 Hz, 6H), 1.48-1.64 (m, 3H), 2.15 (t, J=7 Hz, 2H), 3.91 (br s, 2H), 6.94 (br s, 1H). A 7.86 g (60 mmol) sample of the hydrazide was dissolved in 50 mL of methanol and treated with 7.8 g (60 mmol) of ethyl iminovalerate under nitrogen. The reaction was stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (40:60) gave 9.6 g (82%) of 3-butyl-5-isopentyl-1H-1,2,4-triazole as a colorless solid which melts close to ambient temperature: NMR (CDCl3) δ0.81-0.90 (m, 9H), 1.25-1.40 (m, 2H), 1.47-1.74 (m, 5H), 2.70 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 196 (100); HRMS. Calcd for M+H: 196.1814. Found: 196.1832. to stirring at reflux for 4 h The reaction was concentrated in vacuo

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

Procedure: Under nitrogen, a solution of 53.8 g (1.68 mol) of anhydrous hydrazine in 300 mL of methanol was cooled to 0° C. and treated with 186 g (1.4 mol) of methyl 4-methylvalerate. The reaction was allowed to warm to ambient temperature and stir overnight prior to stirring at reflux for 4 h. The reaction was concentrated in vacuo giving 166 g (93%) of 4-methylvaleric acid hydrazide as a colorless solid: 49–51° C.; NMR (CDCl3) δ 0.89 (d, J=7 Hz, 6H), 1.48–1.64 (m, 3H), 2.15 (t, J=7 Hz, 2H), 3.91 (br s, 2H), 6.94 (br s, 1H). A 7.86 g (60 mmol) sample of the hydrazide was dissolved in 50 mL of methanol and treated with 7.8 g (60 mmol) of ethyl iminovalerate under nitrogen. The reaction was stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (40:60) gave 9.6 g (82.%) of 3-butyl-5-isopentyl-1H-1,2,4-triazole as a colorless solid which melts close to ambient temperature: NMR (CDCl3) δ 0.81–0.90 (m, 9H), 1.25–1.40 (m, 2H), 1.47–1.74 (m, 5H), 2.70 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 196 (100); HRMS. Calcd for M+H: 196.1814. Found: 196.1832. to stirring at reflux for 4 h The reaction was concentrated in vacuo