1-bromo-4-isocyanatobutane

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:

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromobutylisocyanate (15.1 g) in methylene chloride (50 ml) is added to a stirred solution of ethyl 3-amino-3-methylbutanoate (12.3 g), dissolved in methylene chloride (50 ml) at -20° C. The mixture is stirred for 30 minutes at -20° C. and then for an additional 2 hours at room temperature. Evaporation of the solvent yields a residue of ethyl 3-[(4-bromobutyl)aminocarbonylamino]-3-methylbutanoate (26 g). for an additional 2 hours at room temperature Evaporation of the solvent

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromobutylisocyanate (15.1 g) in methylene chloride (50 ml) is added to a stirred solution of ethyl 3-amino-3-methylbutanoate (12.3 g), dissolved in methylene chloride (50 ml) at -20° C. The mixture is stirred for 30 minutes at -20° C. and then for an additional 2 hours at room temperature. Evaporation of the solvent yields a residue of ethyl 3-[(4-bromobutyl)aminocarbonylamino]-3-methylbutanoate (26 g). for an additional 2 hours at room temperature Evaporation of the solvent

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromobutylisocyanate (15.1 g) in methylene chloride (50 ml) is added to a stirred solution of ethyl 3-amino-3-methylbutanoate (12.3 g), dissolved in methylene chloride (50 ml) at -20° C. The mixture is stirred for 30 minutes at -20° C. and then for an additional 2 hours at room temperature. Evaporation of the solvent yields a residue of ethyl 3-[(4-bromobutyl)aminocarbonylamino]-3-methylbutanoate (26 g). for an additional 2 hours at room temperature Evaporation of the solvent

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Hexadecyloxy-2-methylenepropane-1-ol (from Preparation 1) (2.0 g) was dissolved in ether (40 ml). 4-Dimethylaminopyridine (0.16 g) and 4-bromobutyl isocyanate (1.6 g) were added, and the mixture was stirred for 22 hours at 22° C. Chloroform (40 ml) was added, and the mixture was purified through a column of silica gel 60 (70-230 mesh, 20 g) eluting with ether/chloroform 1:1. Further purification was achieved by chromatography on a Waters PrepLC®/System 500A using a prepPAK®-500/SILICA cartridge with ether/chloroform 1:1 as eluent. the mixture was purified through a column of silica gel 60 (70-230 mesh, 20 g) eluting with ether/chloroform 1:1 Further purification

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Octadecylaminocarbonyloxy-2-methylenepropan-1-ol (from Preparation 3) (2.0 g) was dissolved in methylene chloride (40 ml). 4-Dimethylaminopyridine (0.13 g) and 4-bromobutyl isocyanate (1.30 g) were added, and the mixture was stirred for 22 hours at 22° C. Ether (40 ml) was added, and the mixture was purified through a column of silica gel 60 (70-230 mesh, 20 g) eluting with ether/chloroform 1:1. Further purification was achieved by chromatography on a Waters PrepLC®/System 500A using a PrepPAK®-500/SILICA cartridge with ether/chloroform/pentane 1:1:2 as eluent. the mixture was purified through a column of silica gel 60 (70-230 mesh, 20 g) eluting with ether/chloroform 1:1 Further purification

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

Procedure: The title compound was prepared by dissolving N-(4-bromobutyl)-N'-(4-carbomethoxythien-3-yl)urea (6.92g, 21 mmol) in isopropanol (100 ml) and then successively treating the solution with 4-(4-fluorobenzoyl)piperidine hydrochloride (10.16 g, 42 mmol), sodium bicarbonate (3.7 g, 44 mmol) and sodium iodide (1.90 g, 12 mmol) to form a mixture. The urea was prepared by reacting methyl 4-aminothiophene-3-carboxylate with 4-bromobutylisocyanate in toluene at room temperature for 12 hours to produce the urea as a tan solid, mp 85°-86° C. The mixture was then heated to reflux under a nitrogen atmosphere for 12 hours. The reaction mixture was reduced to half volume, diluted with water, and concentrated to remove the remainder of the alcohol solvent. The residue was extracted with methylene chloride and the combined organic extracts were dried with saturated brine and magnesium sulfate. After concentration of the extracts, the residue was purified on silica gel using methylene chloride/ethanol/ammonium hydroxide (96:3.5:0.5) as eluant. There was obtained 3.62 g (40.8% yield) of the title compound as a brown solid. This material was recrystallized from CH2Cl2 /ether, mp 190°-192° C. The title compound was prepared to form a mixture The urea was prepared at room temperature for 12 hours

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

Procedure: Methyl 4-aminothiophene-3-carboxylate was reacted with one equivalent of 4-bromobutylisocyanate in toluene at room temperature for 12 hours to produce N-(4-bromobutyl)-N'-(4-carbomethoxythien-3-yl] urea as a tan solid, mp 85°-86° C.

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

Procedure: The title compound was prepared by the procedure of Example 10 using N-(4-bromobutyl)-N'-(4-carbomethoxythien-3-yl)urea (6.92 g, 21 mmol) and 4-(4-fluorobenzoyl)piperidine hydrochloride (10.16 g, 42 mmol). The urea was prepared by reacting methyl 4-aminothiophene-3-carboxylate with 4-bromobutylisocyanate in toluene at room temperature for 12 hours to produce the urea as a tan solid, mp 85°-86° C. There was obtained 3.62 g (40.8% yield) of the title compound as a brown solid. This material was recrystallized from CH2Cl2 /ether, mp 190°-192° C. The urea was prepared at room temperature for 12 hours