ethyl 6-hydroxyhexanoate

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:0.00; pressure:0.00; stir:

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

Procedure: To an oven-dried 3-necked 10 mL round-bottom flask under nitrogen was added 1-cyclopentyl-3-(2-(4-hydroxyphenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)urea, prepared as described in Procedure 11, 6, 2 and 59, (50 mg, 0.1 mmol), triphenylphosphine (34 mg, 0.1 mmol), ethyl 6-hydroxyhexanoate (17 mg, 0.1 mmol) and dry THF (0.5 mL). The reaction mixture was cooled in an ice-methanol bath and diethylazodicarboxylate (23 mg, 0.13 mmol) was added via syringe. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated in vacuo and purified by ISCO silica gel chromatography using a gradient of 5-25% EtOAc/hexanes as eluent to yield ethyl 6-(4-(2-(3-cyclopentylureido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenoxy)hexanoate (Example 313) was isolated as a white solid (43 mg, 61% yield). HPLC: RT=4.69 minutes (Phenomenex Luna C18 5μ column 4.6×50 mm eluting with 10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minute gradient monitoring at 220 nm). LC/MS [M+H] 711.3 (Phenomenex Luna C18 5μ column 4.6×30 mm eluting with 10-90% aqueous methanol containing 0.1% TFA over a 4 minute gradient monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.33 (t, J=7.9 Hz, 2H), 7.20 (d, J=7.9 Hz, 2H), 7.12 (d, J=7.9 Hz, 2H), 7.07 (s, 2H), 6.62 (d, J=8.8 Hz, 2H), 6.56 (d, J=8.8 Hz, 2H), 4.10 (q, J=7.1 Hz, 2H), 3.86t, J=6.1 Hz, 2H), 3.68 (s, 1H), 3.62 (t, J=6.6 Hz, 1H), 2.30-2.27 (m, 2H), 1.82-1.14 (m, 17H), 1.23 (t, J=7.1 Hz, 3H). prepared The reaction mixture was cooled in an ice-methanol bath The reaction mixture was concentrated in vacuo purified by ISCO silica gel chromatography

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

Procedure: To the suspension of poly(4-methylpyridine) (2.24 g, 2 eq) in newly dried dichloromethane (25 mL ) at 0° C. was added trifluoromethanesulfonic anhydride (5 g, 1 eq) drop wise over 30 mins. Ethyl 6-hydroxyhexanoate (2.76 g, 0.95 eq) was then added in drop wise via a syringe. The mixture was stirred at 0° C. for 4 hrs and the polymer was filtered off by a frit. The solvent was evaporated under reduced pressure (without heating) and the crude product was subjected to a short silica gel pad with 1:4 (v/v) diethyl ether/hexane as the eluent solvent. The solvent was evaporated (without heating) and the product was used directly in the following step. (3.9 g, 75% yield based on ethyl 6-hydroxyhexanoate.) See FIG. 10. the polymer was filtered off by a frit The solvent was evaporated under reduced pressure (without heating) The solvent was evaporated (without heating)

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

Procedure: To the suspension of poly(4-methylpyridine) (2.24 g, 2 eq) in newly dried dichloromethane (25 mL ) at 0° C. was added trifluoromethanesulfonic anhydride (5 g, 1 eq) drop wise over 30 mins. Ethyl 6-hydroxyhexanoate (2.76 g, 0.95 eq) was then added in drop wise via a syringe. The mixture was stirred at 0° C. for 4 hrs and the polymer was filtered off by a frit. The solvent was evaporated under reduced pressure (without heating) and the crude product was subjected to a short silica gel pad with 1:4 (v/v) diethyl ether/hexane as the eluent solvent. The solvent was evaporated (without heating) and the product was used directly in the following step. (3.9 g, 75% yield based on ethyl 6-hydroxyhexanoate.) See FIG. 10. the polymer was filtered off by a frit The solvent was evaporated under reduced pressure (without heating) The solvent was evaporated (without heating)

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

Procedure: A solution of monodispersed ethyl 6-hydroxyhexanoate (50.76 ml, 50.41 g, 227 mmol) in dry dichloromethane (75 ml) was chilled in an ice bath and placed under a nitrogen atmosphere. Triethylamine (34.43 ml, 24.99 g, 247 mmol) was added. A solution of methanesulfonyl chloride (19.15 ml, 28.3 g, 247 mmol) in dry dichloromethane (75 ml) was added dropwise from an addition funnel. The mixture was stirred for three and one half hours, slowly being allowed to come to room temperature as the ice bath melted. The mixture was filtered through silica gel, and the filtrate was washed successively with water, saturated NaHCO3, water and brine. The organics were dried over Na2SO4, filtered and concentrated in vacuo to a pale yellow oil. Final purification of the crude product was achieved by flash chromatography (silica gel, 1/1 hexanes/ethyl acetate) to give the monodispersed compound 2 (46.13 g, 85%) as a clear, colorless oil. FAB MS: m/e 239 (M+H), 193 (M-C2H5O). The mixture was filtered through silica gel the filtrate was washed successively with water, saturated NaHCO3, water and brine The organics were dried over Na2SO4 filtered concentrated in vacuo to a pale yellow oil Final purification of the crude product

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

Procedure: 160 g of ethyl 6-hydroxy-hexanoate, 145.4 g of N,N-dimethylaniline and 200 ml of anhydrous toluene are placed in a round flask which is provided with a dropping funnel, a thermometer and a stirrer. 119.4 g of ethyl chloroformate are added dropwise at 25° C. within a half hour while stirring. The reaction mixture is held under reflux for 3 hours. After cooling the reaction mixture is poured on to ice-water, the organic phase is washed twice with water, with 100 ml of a 5% hydrochloric acid solution and then neutral with water. After drying over sodium sulphate the solvent is distilled off. 173 g of crude product are obtained. Fractional distillation gives 112 g (yield 48.3% of theory) of chemically pure ethyl 6-ethoxycarbonyloxy-hexanoate; 75 g thereof can be used as an olfactorily pure product without further treatment. which is provided with a dropping funnel under reflux for 3 hours After cooling the reaction mixture the organic phase is washed twice with water, with 100 ml of a 5% hydrochloric acid solution After drying over sodium sulphate the solvent is distilled off 173 g of crude product are obtained Fractional distillation

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

Procedure: 240 g of ethyl 6-hydroxy-hexanoate are placed in a round flask which is provided with a dropping funnel, a thermometer and a stirrer. A mixture of 180 g of acetic anhydride and 3 g of 85% phosphoric acid is added dropwise thereto within a half hour while stirring. During the addition the temperature is held at 25° C. by cooling. Thereafter, the reaction mixture is heated slowly to 50° C. and held at this temperature for 3 hours. After cooling the mixture is treated with ice-water and taken up in 500 ml of hexane. The hexane solution is washed with water, with 100 ml of a 10% sodium carbonate solution and thereupon neutral with water. After drying over sodium sulphate the solvent is distilled off. 282 g of crude product are obtained. Fractional distillation gives 223 g (yield 73.7% of theory) of chemically pure ethyl 6-acetoxy-hexanoate; 190 g thereof can be used as an olfactorily pure product without further treatment. which is provided with a dropping funnel is added dropwise During the addition the temperature is held at 25° C. by cooling After cooling the mixture The hexane solution is washed with water, with 100 ml of a 10% sodium carbonate solution After drying over sodium sulphate the solvent is distilled off 282 g of crude product are obtained Fractional distillation

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

Procedure: 240 g of ethyl 6-hydroxy-hexanoate are placed in a round flask which is provided with a dropping funnel, a thermometer and a stirrer. A mixture of 180 g of acetic anhydride and 3 g of 85% phosphoric acid is added dropwise thereto within a half hour while stirring. During the addition the temperature is held at 25° C. by cooling. Thereafter, the reaction mixture is heated slowly to 50° C. and held at this temperature for 3 hours. After cooling the mixture is treated with ice-water and taken up in 500 ml of hexane. The hexane solution is washed with water, with 100 ml of a 10% sodium carbonate solution and thereupon neutral with water. After drying over sodium sulphate the solvent is distilled off. 282 g of crude product are obtained. Fractional distillation gives 223 g (yield 73.7% of theory) of chemically pure ethyl 6-acetoxy-hexanoate; 190 g thereof can be used as an olfactorily pure product without further treatment. which is provided with a dropping funnel is added dropwise During the addition the temperature is held at 25° C. by cooling After cooling the mixture The hexane solution is washed with water, with 100 ml of a 10% sodium carbonate solution After drying over sodium sulphate the solvent is distilled off 282 g of crude product are obtained Fractional distillation