3-Isopropylidenecarbazic acid tert-butyl ester

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: Alternatively, tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (0.51 g, 3.0 mmol) was dissolved in 20 mL of THF, treated with NaBH3CN (0.19 g, 3.0 mmol) and a few mg of bromocresol green, followed by a solution of p-toluenesulfonic acid (0.57 g, 3.0 mmol) in 1.5 mL of THF which was added dropwise over approximately 1 h to maintain the reaction pH between 3.5-5.0. After stirring at room temperature for an additional hour, the solvent was removed by rotary evaporation, and the residue was partitioned between EtOAc (30 mL) and brine. The organic phase was extracted with sat. NaHCO3, 20 mL and brine, evaporated to a residue and dissolved in 10 mL of ethanol. The ethanolic solution was treated with 3.6 mL of 1M NaOH solution (3.6 mmol) and left to stir at rt for 30 min. The solvent was removed by rotary evaporation and the residue was taken up into ethyl acetate and extracted with water. The organic layer was evaporated under reduced pressure and the residue was purified by column chromatography using 5% MeOH in DCM as eluent to collect tert-butyl 2-isopropylhydrazinecarboxylate 3 (0.4 g, 77% yield): mp=47-49° C.; Rf=0.44 (5% MeOH in DCM); 1H NMR 300 MHz (CDCl3) d 6.03 (s, N—H, 1H), 3.92 (s, N—H, 1H), 3.14 (m, 1H), 1.46 (s, 9H), 1.02 (d, 6H, J=6 Hz); 13C NMR 300 MHz (CDCl3) d 157.2, 80.8, 51.2, 28.7, 21.0. was added dropwise over approximately 1 h to maintain the reaction pH between 3.5-5.0 the solvent was removed by rotary evaporation the residue was partitioned between EtOAc (30 mL) and brine The organic phase was extracted with sat. NaHCO3, 20 mL and brine evaporated to a residue dissolved in 10 mL of ethanol left to stir at rt for 30 min The solvent was removed by rotary evaporation extracted with water The organic layer was evaporated under reduced pressure the residue was purified by column chromatography

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

Procedure: tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 was reduced with palladium catalyst on carbon with hydrogen gas in acetic acid and methanol to give tert-butyl 2-isopropylhydrazinecarboxylate 3 (CAS Reg. No. 16689-35-3).

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

Procedure: tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 was reduced with palladium catalyst on carbon with hydrogen gas in acetic acid and methanol to give tert-butyl 2-isopropylhydrazinecarboxylate 3 (CAS Reg. No. 16689-35-3).

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

Procedure: To a solution of tert-butyl hydrazinecarboxylate 1 (CAS Reg. No. 870-46-2) (25.1 g, 0.190 mol) in acetone (185 mL) was added the magnesium sulfate (6 g) and 12 drops acetic acid (Wu et al (2012) Jour. Med. Chem. 55(6):2724-2736; WO 2007/056170; Zawadzki et al (2003) Polish Jour. Chem. 77(3):315-319). The mixture was heated to reflux for 2.5 h and cooled to rt and filtered. The filtrate was concentrated to give tert-butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (CAS Reg. No. 16689-34-2) as an off-white solid (32 g, 98%) (used in the next step without further purification). LC-MS [M+H]+=172.9, RT=2.11 min. 1H NMR 300 MHz (CDCl3) d 7.35 (br s, 1H, NH), 2.04 (s, 3H), 1.82 (s, 3H), 1.54 (s, 9H); 13C NMR 300 MHz (CDCl3) d 152.9, 149.7, 80.7, 28.1, 25.3, 15.9. The mixture was heated to reflux for 2.5 h filtered The filtrate was concentrated

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

Procedure: Scheme 1 shows the synthesis of intermediate isopropylhydrazine hydrochloride 4 from Boc-hydrazine 1. Condensation of 1 with acetone and magnesium sulfate gave Boc-hydrazone, tert-butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (Example 1). Palladium-catalyzed hydrogenation of 2 in acetic acid and methanol gave Boc-isopropyl-hydrazine 3 (Example 2) which was treated in situ with hydrogen chloride gas to give 4 (Example 3).

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 mechanically stirred solution of tert-butylcarbazate (450 g, 3.4 mol) in acetone (2.5 L) was added magnesium sulfate (100 g, 0.83 mol) and 100 drops of acetic acid. The mixture was warmed to reflux and stirred for 3.5 h. After being cooled to rt, the mixture was filtered and partially concentrated, at which point the product crystallized from the supersaturated solvent. The crystals were filtered and dried in a vacuum oven overnight to provide the title compound as colorless needles (463 g, 79%): 1H NMR (300 MHz, d6-DMSO) δ 1.40 (s, 9H), 1.75 (s, 3H), 1.83 (s, 3H). The mixture was warmed to reflux the mixture was filtered partially concentrated, at which point the product crystallized from the supersaturated solvent The crystals were filtered dried in a vacuum oven overnight

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Powdered KOH (4.24 g, 75.48 mmol) and tetrabutylammonium hydrogen sulfate (1.97 g, 5.81 mmol) were added to a solution of tert-butyl 2-isopropylidenehydrazinecarboxylate (10 g, 58.05 mmol) in toluene (150 mL). The mixture was stirred vigorously and heated to 50° C. and 1-(bromomethyl)-2-fluorobenzene (13.17 g, 69.68 mmol) was added slowly. The temperature was increased to 80° C. and maintained for 3 h and cooled to room temperature. The mixture was washed with water until the pH of the aqueous wash was neutral. The organic layer was washed with brine and dried over MgSO4 and concentrated to give a yellow oil (17.11 g) used for the next step without further purification). LC-MS [M+H]+=280.9, RT=3.41 min. The temperature was increased to 80° C. maintained for 3 h cooled to room temperature The mixture was washed with water until the pH of the aqueous wash The organic layer was washed with brine dried over MgSO4 concentrated

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

Procedure: To a solution of tert-butyl hydrazinecarboxylate (25.1 g, 0.190 mol) in acetone (185 mL) was added the magnesium sulfate (6 g) and 12 drops acetic acid. The mixture was heated to reflux for 2.5 h and cooled to rt and filtered. The filtrate was concentrated to give an off-white solid (32 g, 98%) (used in the next step without further purification). LC-MS [M+H]+=172.9, RT=2.11 min. The mixture was heated to reflux for 2.5 h filtered The filtrate was concentrated