methyl 4-chlorobutanoate

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: Sodium (3.5 g, 0.15 mol) was added to methanol (150 mL) carefully. After cooling to room temperature, methyl 2-mercaptoacetate (15.6 g, 0.13 mol) was added. The mixture was stirred for 30 mins at room temperature and a little of NaI and methyl 4-chlorobutanoate 20.0 g, 0.15 mol) were added. The reaction mixture was refluxed over night. After cooling to room temperature, the solvent was removed under reduced pressure, then the residue was dissolved in CH2Cl2 (100 mL). The solution was washed with H2O (30 mL), brine (30 mL), and dried with Na2SO4. After removing the solvent, 28.3 g of the crude product was obtained (Yield: 94%). The reaction mixture was refluxed over night After cooling to room temperature the solvent was removed under reduced pressure the residue was dissolved in CH2Cl2 (100 mL) The solution was washed with H2O (30 mL), brine (30 mL) dried with Na2SO4 After removing the solvent

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

Procedure: To a solution of tetrahydofurfurylamine (2 mL) in EtOH (20 mL) were added 5 N NaOH (3.9 mL) and carbon disulfide (1.17 mL), and the mixture was stirred for 1.5 h. Methyl 4-chlorobutyrate (2.4 mL) was then added, and the mixture was stirred overnight. Upon quenching with saturated NaCl solution the mixture was extracted with ether. Chromatography on silica gel gave the desired 4-(tetrahydrofuran-2-ylmethylthiocarbamoylsulfanyl)-butyric acid methyl ester product (1.1 g). the mixture was stirred overnight Upon quenching with saturated NaCl solution the mixture was extracted with ether

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

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

Procedure: To a solution of 65 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((methylamino)methyl)cyclopentane from Example 18, Step B in 1 mL of acetonitrile was added 0.019 mL of methyl 4-chlorobutyrate and 0.037 mL of DIPEA. The reaction was heated at 50° C. for 48 hours, then an additional 0.038 mL of methyl 4-chlorobutyrate, 0.074 mL of DIPEA and 3 mg of tetrabutylammonium iodide were added and heating continued at 70° C. for 48 hours. The reaction was evaporated under a stream of nitrogen and the residue purified by prep TLC (10% methanol in ethyl acetate) to give 41 mg of title compound and 17 mg of recovered starting material. Mass spec (ESI): 564 (M+1). heating The reaction was evaporated under a stream of nitrogen the residue purified by prep TLC (10% methanol in ethyl acetate)

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

Procedure: To a solution of 65 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((methylamino)methyl)cyclopentane from Example 18, Step B in 1 mL of acetonitrile was added 0.019 mL of methyl 4-chlorobutyrate and 0.037 mL of DIPEA. The reaction was heated at 50° C. for 48 hours, then an additional 0.038 mL of methyl 4-chlorobutyrate, 0.074 mL of DIPEA and 3 mg of tetrabutylammonium iodide were added and heating continued at 70° C. for 48 hours. The reaction was evaporated under a stream of nitrogen and the residue purified by prep TLC (10% methanol in ethyl acetate) to give 41 mg of title compound and 17 mg of recovered starting material. Mass spec (ESI): 564 (M+1). heating The reaction was evaporated under a stream of nitrogen the residue purified by prep TLC (10% methanol in ethyl acetate)

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

Procedure: To a solution of 40 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(methylamino)cyclopentane from Example 15 in 1 mL of acetonitrile was added 0.011 mL of methyl 4-chlorobutyrate and 0.046 mL of DIPEA. The reaction was heated at 50° C. for 24 hours, then an additional 0.022 mL of methyl 4-chlorobutyrate, 0.030 mL of DIPEA and 3 mg of tetrabutylammonium iodide were added and heating continued at 80° C. for 60 hours. The reaction was evaporated under a stream of nitrogen and the residue purified by prep TLC (5% methanol in methylene chloride) to give 27 mg of title compound. Mass spec (ESI): 550 (M+1). heating The reaction was evaporated under a stream of nitrogen the residue purified by prep TLC (5% methanol in methylene chloride)

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

Procedure: 40.4 g (0.2 mol) of the dipotassium salt of 6-methyluracil and 57.4 g (0.42 mol) of methyl 4-chlorobutyrate are stirred in 350 ml of dimethylformamide for 10 hours at 125° C. The mixture is filtered and the clear solution is concentrated to dryness, 48.2 g of the desired crude product being obtained as a yellowish semi-solid mass (73.8% of theory). The mixture is filtered the clear solution is concentrated to dryness, 48.2 g of the desired crude product being obtained as a yellowish semi-solid mass (73.8% of theory)

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

Procedure: 45.48 g (0.1 mol) of 4,5,6,7-tetrabromobenzimidazolone are suspended in 250 ml of dimethylformamide and 75 ml of toluene and 27.4 g (0.2 mol) of finely powdered, dry potassium carbonate are added. 30.07 g (0.22 mol) of methyl γ-chlorobutyrate are added to this suspension and the mixture is heated up to the reflux temperature (internal temperature 108°-120° C.), whilst stirring. The toluene serves to remove water azeotropically. After 25 hours, the mixture is cooled to 80°-85° C. and filtered whilst still hot. The solution is concentrated to dryness and the desired product is isolated in the form of colourless crystals. Yield: 58.35 g (89.1% of theory). the mixture is heated up to the reflux temperature (internal temperature 108°-120° C.) to remove water azeotropically the mixture is cooled to 80°-85° C. filtered whilst still hot The solution is concentrated to dryness

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

Procedure: 45.48 g (0.1 mol) of 4,5,6,7-tetrabromobenzimidazolone are suspended in 250 ml of dimethylformamide and 75 ml of toluene and 27.4 g (0.2 mol) of finely powdered, dry potassium carbonate are added. 30.07 g (0.22 mol) of methyl γ-chlorobutyrate are added to this suspension and the mixture is heated up to the reflux temperature (internal temperature 108°-120° C.), whilst stirring. The toluene serves to remove water azeotropically. After 25 hours, the mixture is cooled to 80°-85° C. and filtered whilst still hot. The solution is concentrated to dryness and the desired product is isolated in the form of colourless crystals. Yield: 58.35 g (89.1% of theory). the mixture is heated up to the reflux temperature (internal temperature 108°-120° C.) to remove water azeotropically the mixture is cooled to 80°-85° C. filtered whilst still hot The solution is concentrated to dryness