tert-butyl N-methyl-N-(3-oxopropyl)carbamate

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

Procedure: 11.1 g (1.3 eq.) tert-butyl methyl(3-oxopropyl)carbamate were added to a solution of 11 g (1 eq.) N,N-dimethyl-4-phenylpiperidin-4-amine dihydrochloride in 110 ml methanol at 0° C. and the reaction mixture was stirred for 15 min at 0° C. 6.2 g (3 eq.) sodium cyanoboron hydride were then added in portions and the mixture was stirred for 30 min at room temperature. The reaction mixture obtained was adjusted to a pH of 5-6 with acetic acid and stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). As the conversion was still not complete, 2.4 g sodium cyanoboron hydride were added and the reaction mixture obtained was adjusted to pH 5-6 with acetic acid and stirred for 60 min at room temperature. Once the conversion was complete, the methanol was distilled off, the mixture was made alkaline with saturated NaHCO3 solution, the mixture obtained was extracted with chloroform (3×100 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 5% MeOH/CHCl3). 9 g (60%) of product were obtained. the mixture was stirred for 30 min at room temperature The reaction mixture obtained stirred for 12 h at room temperature the reaction mixture obtained stirred for 60 min at room temperature the methanol was distilled off the mixture obtained was extracted with chloroform (3×100 ml) the combined organic phases were dried over Na2SO4 removal of the solvent under reduced pressure the residue was purified by column chromatography (silica gel; 5% MeOH/CHCl3)

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

Procedure: 11.1 g (1.3 eq.) tert-butyl methyl(3-oxopropyl)carbamate were added to a solution of 11 g (1 eq.) N,N-dimethyl-4-phenylpiperidin-4-amine dihydrochloride in 110 ml methanol at 0° C. and the reaction mixture was stirred for 15 min at 0° C. 6.2 g (3 eq.) sodium cyanoboron hydride were then added in portions and the mixture was stirred for 30 min at room temperature. The reaction mixture obtained was adjusted to a pH of 5-6 with acetic acid and stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). As the conversion was still not complete, 2.4 g sodium cyanoboron hydride were added and the reaction mixture obtained was adjusted to pH 5-6 with acetic acid and stirred for 60 min at room temperature. Once the conversion was complete, the methanol was distilled off, the mixture was made alkaline with saturated NaHCO3 solution, the mixture obtained was extracted with chloroform (3×100 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 5% MeOH/CHCl3). 9 g (60%) of product were obtained. the mixture was stirred for 30 min at room temperature The reaction mixture obtained stirred for 12 h at room temperature the reaction mixture obtained stirred for 60 min at room temperature the methanol was distilled off the mixture obtained was extracted with chloroform (3×100 ml) the combined organic phases were dried over Na2SO4 removal of the solvent under reduced pressure the residue was purified by column chromatography (silica gel; 5% MeOH/CHCl3)

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

Procedure: 6.4 g (1.3 eq.) tert-butyl methyl(3-oxopropyl)carbamate were added to a solution of 7.5 g (1 eq.) N,N-dimethyl-4-(thiophen-2-yl)piperidin-4-amine bis hydrochloride in 75 ml methanol at 0° C. and the reaction mixture was stirred for 15 min at 0° C. 4.9 g (3 eq.) sodium cyanoboron hydride were then added in portions and the mixture was stirred for 90 min at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). As the conversion was not yet complete, the pH of the reaction mixture was adjusted to 5-6 with acetic acid and the mixture was stirred for 12 h at room temperature. Once the conversion was complete, the methanol was distilled off, water was added, the mixture obtained was extracted with IPA/chloroform (2×100 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 5% MeOH/CHCl3). 8.5 g (84%) of product were obtained. the mixture was stirred for 90 min at room temperature the mixture was stirred for 12 h at room temperature the methanol was distilled off water was added the mixture obtained was extracted with IPA/chloroform (2×100 ml) the combined organic phases were dried over Na2SO4 removal of the solvent under reduced pressure the residue was purified by column chromatography (silica gel; 5% MeOH/CHCl3)

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

Procedure: A catalytic amount of TEMPO was added to a mixture of 20 g (1 eq.) tert-butyl 3-hydroxypropyl(methyl)carbamate in 200 ml dichloromethane and 17.7 g (2 eq.) sodium hydrogen carbonate in 100 ml water at 0° C. 140 ml (7 eq.) NaOCl were then added dropwise over a period of 30 min to the solution at a temperature of 0° C. and the reaction mixture obtained was stirred for a further 15 min at 0° C. The reaction course was monitored by thin-layer chromatography (40% EtOAc/hexane). Once the conversion was complete, the reaction mixture was mixed with 150 ml water and the phases were separated. The organic phase was dried over Na2SO4. Following removal of the solvent under reduced pressure, 16 g (85%) of product were obtained in the form of a yellowish oil. the reaction mixture obtained the phases were separated The organic phase was dried over Na2SO4 removal of the solvent under reduced pressure

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

Procedure: The compound (47 mg, 78.6 μmol) obtained in Example 63b and tert-butyl methyl(3-oxopropyl)carbamate (Bioorg. Med. Chem., 12, 19, 2004, 5147-5160) (18 mg, 94.3 μmol) were used to give the title compound (48 mg; yield, 79%) as a colorless oily substance according to the method described in Example 41a.

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

Procedure: The compound (47 mg, 78.6 μmol) obtained in Example 63b and tert-butyl methyl(3-oxopropyl)carbamate (Bioorg. Med. Chem., 12, 19, 2004, 5147-5160) (18 mg, 94.3 μmol) were used to give the title compound (48 mg; yield, 79%) as a colorless oily substance according to the method described in Example 41a.

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

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

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

Procedure: Methyl-(3-oxopropyl)carbamic acid, 1,1-dimethylethyl ester (320 mg, 1.71 mmol) and (trifluoromethyl)trimethylsilane (298 mg, 2.10 mmol) were dissolved in tetrahydrofuran (10 ml) under nitrogen and cooled to 0° C. with stirring. To the resulting solution was added tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran, 1.0 ml, 1.0 mmol) and the mixture was then allowed to warm to room temperature with stirring over 20 h. The mixture was then poured into saturated ammonium chloride solution and then extracted with diethyl ether three times. The combined organic fractions were then washed with brine and dried over magnesium sulphate. The solvent was evaporated and the residue eluted down a flash chromatography column using 50% diethyl ether/isohexane as eluent to give 290 mg (66%) of the title compound as an oil. to warm to room temperature with stirring over 20 h extracted with diethyl ether three times The combined organic fractions were then washed with brine dried over magnesium sulphate The solvent was evaporated the residue eluted down a flash chromatography column