2-methylpropylhydrazine

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: To a solution of 2-fluoro-5-nitrobenzoic acid (1.5 g) in DMF (50 mL) was added EDCI.HCl (1.71 g) followed by N-ethyldiisopropylamine (5.51 mL). After 10 minutes isobutylhydrazine.p-toluenesulfonicacid salt (2.32 g) was added. The reaction mixture was stirred at ambient temperature for 22 hours and the reaction was poured onto aqueous 1N HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. Purification via ISCO combiflash chromatography afforded pure desired 1-isobutyl-5-nitro-1,2-dihydro-indazol-3-one (0.9 g) as a yellow solid. MS (ESI−):234.1 ([M−H]−). extracted with EtOAc The organic layer was washed with brine dried over sodium sulfate filtered evaporated in vacuo Purification via ISCO combiflash chromatography

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

Procedure: To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (300 mg, 0.85 mmol) in 20 mL of methanol, 2-methylpropylhydrazine (300 mg, 3.39 mmol) was added, the resulting mixture was refluxed for 4 hours, then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (48 mg, 15% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3): δ 0.83 (6H, d, J=6.8 Hz), 2.17-2.25 (1H, m), 3.25-3.27 (4H, m), 3.89-3.92 (4H, m), 4.34 (2H, d, J=7.6 Hz), 6.72 (1H, d, J=8.0 Hz), 7.00-7.04 (2H, m), 7.33 (1H, d, J=2.4 Hz), 7.45-7.49 (2H, m), 7.59 (1H, d, J=2.0 Hz), 8.15 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=3.396 min; MS Calcd.: 379, MS Found: 380 [M+H]+. the resulting mixture was refluxed for 4 hours concentrated The residue was dissolved in dichloromethane (20 mL) washed with 1 M acetic acid aqueous solution and brine dried over anhydrous Na2SO4 concentrated under reduced pressure The residue was purified by prep-HPLC

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

Procedure: A solution of 0.78 g of 2(R)-[3-benzamido-1(S)-(tert-butoxycarbonyl)propyl]-4-methylvaleric acid in 10 ml of dichloromethane was cooled to 0° C. under nitrogen and treated sequentially with 0.80 ml of N-ethylmorpholine, 0.437 g of hydroxybenzotriazole hydrate, and 0.50 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred for 5 minutes at 0° C. and then 1.1 g of isobutyl hydrazine was added. Stirring was continued overnight at room temperature and then the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate, water, 2M aqueous hydrogen chloride, and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulfate, filtration and evaporation of the solvent gave 0.763 g of 2(R)-[3-benzamido-1(S)-(tert-butoxycarbonyl)propyl]-2′-isobutyl-4-methylvalerohydrazide in the form of an off-white foam. Stirring was continued overnight at room temperature the solvent was evaporated The residue was dissolved in ethyl acetate washed with 5% aqueous sodium hydrogen carbonate, water, 2M aqueous hydrogen chloride, and saturated aqueous sodium chloride Drying over anhydrous magnesium sulfate, filtration and evaporation of the solvent

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: To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (300 mg, 0.85 mmol) in 20 mL of methanol, 2-methylpropylhydrazine (300 mg, 3.39 mmol) was added, the resulting mixture was refluxed for 4 hours, then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (48 mg, 15% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3): δ 0.83 (6H, d, J=6.8 Hz), 2.17-2.25 (1H, m), 3.25-3.27 (4H, m), 3.89-3.92 (4H, m), 4.34 (2H, d, J=7.6 Hz), 6.72 (1H, d, J=8.0 Hz), 7.00-7.04 (2H, m), 7.33 (1H, d, J=2.4 Hz), 7.45-7.49 (2H, m), 7.59 (1H, d, J=2.0 Hz), 8.15 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=3.396 min; MS Calcd.: 379, MS Found: 380 [M+H]+. the resulting mixture was refluxed for 4 hours concentrated The residue was dissolved in dichloromethane (20 mL) washed with 1 M acetic acid aqueous solution and brine dried over anhydrous Na2SO4 concentrated under reduced pressure The residue was purified by prep-HPLC

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

Procedure: To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (300 mg, 0.85 mmol) in 20 mL of methanol, 2-methylpropylhydrazine (300 mg, 3.39 mmol) was added, the resulting mixture was refluxed for 4 hours, then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (48 mg, 15% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3): δ 0.83 (6H, d, J=6.8 Hz), 2.17-2.25 (1H, m), 3.25-3.27 (4H, m), 3.89-3.92 (4H, m), 4.34 (2H, d, J=7.6 Hz), 6.72 (1H, d, J=8.0 Hz), 7.00-7.04 (2H, m), 7.33 (1H, d, J=2.4 Hz), 7.45-7.49 (2H, m), 7.59 (1H, d, J=2.0 Hz), 8.15 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=3.396 min; MS Calcd.: 379. MS Found: 380 [M+H]+. the resulting mixture was refluxed for 4 hours concentrated The residue was dissolved in dichloromethane (20 mL) washed with 1 M acetic acid aqueous solution and brine dried over anhydrous Na2SO4 concentrated under reduced pressure The residue was purified by prep-HPLC

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

Procedure: To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (300 mg, 0.85 mmol) in 20 mL of methanol, 2-methylpropylhydrazine (300 mg, 3.39 mmol) was added, the resulting mixture was refluxed for 4 hours, then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (48 mg, 15% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3): δ 0.83 (6H, d, J=6.8 Hz), 2.17-2.25 (1H, m), 3.25-3.27 (4H, m), 3.89-3.92 (4H, m), 4.34 (2H, d, J=7.6 Hz), 6.72 (1H, d, J=8.0 Hz), 7.00-7.04 (2H, m), 7.33 (1H, d, J=2.4 Hz), 7.45-7.49 (2H, m), 7.59 (1H, d, J=2.0 Hz), 8.15 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=3.396 min; MS Calcd.:379, MS Found: 380 [M+H]+. the resulting mixture was refluxed for 4 hours concentrated The residue was dissolved in dichloromethane (20 mL) washed with 1 M acetic acid aqueous solution and brine dried over anhydrous Na2SO4 concentrated under reduced pressure The residue was purified by prep-HPLC

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

Procedure: To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (300 mg, 0.85 mmol) in 20 mL of methanol, 2-methylpropylhydrazine (300 mg, 3.39 mmol) was added, the resulting mixture was refluxed for 4 hours, then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (48 mg, 15% yield) as a yellow solid: NMR (400 MHz, CDCl3): δ 0.83 (6H, d, J=6.8 Hz), 2.17-2.25 (1H, m), 3.25-3.27 (4H, m), 3.89-3.92 (4H, m), 4.34 (2H, d, J=7.6 Hz), 6.72 (1H, d, J=8.0 Hz), 7.00-7.04 (2H, m), 7.33 (1H, d, J=2.4 Hz), 7.45-7.49 (2H, m), 7.59 (1H, d, J=2.0 Hz), 8.15 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=3.396 min; MS Calcd.: 379, MS Found: 380 [M+H]+. the resulting mixture was refluxed for 4 hours concentrated The residue was dissolved in dichloromethane (20 mL) washed with 1 M acetic acid aqueous solution and brine dried over anhydrous Na2SO4 concentrated under reduced pressure The residue was purified by prep-HPLC

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

Procedure: (step 1) To a solution of 4.4 g (9.6 mmol) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid in 200 ml CH2Cl2 were added 1.2 g (10.8 mmol,1.1 eq) N-hydroxy-2-pyridone, followed by 2.2 g (10.7 mmol, 1.1 eq) N, N-dicyclohexylcarbodiimide in 25 ml CH2Cl2 at 0° C. over a period of 30 min. The suspension was stirred for additional 4 h at that temperature before 4.2 ml (33.0 mmol, 3.4 eq) NEM and 1.9 g (mmol, 1.05 eq) isobutylhydrazine.sulfate were added. The reaction mixture was stirred at RT over night. The suspension was treated with 0.55 ml (9.6 mmol, 1.0 eq) glacial acetic acid in 10 ml water and stirred for 1.5 h, diluted with aq. NaHCO3 (5%) and extracted with CH2Cl2. The combined organic phases were washed with 1M KHSO4 solution, water and brine, dried over Na2SO4 and evaporated. Tituration with hexane yields 5.02 g (quant) (2S,4R)-4-(4-Methoxy -benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid N′-isobutyl-hydrazide, which was directly subjected to the following reaction. stirred for 1.5 h extracted with CH2Cl2 The combined organic phases were washed with 1M KHSO4 solution, water and brine dried over Na2SO4 evaporated