3-cyclohexylpropanoyl chloride

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

Procedure: Stage 1 of the preparation was carried out under an argon atmosphere. To a stirred solution of t butyl alcohol (4.92 g) in tetrahydrofuran (20 ml) at -30° C. was added dropwise n-butyl lithium (41.8 ml of 1.6 molar solution). The resultant lithium t-butoxide solution was allowed to warm to 0° C. and was added to a stirred solution of cuprous iodide (12.65 g) in tetrahydrofuran (50 ml). After about 15 minutes, the grey cuprous iodide was replaced by a beige solid, and the reaction mixture turned brown. The reaction mixture was then cooled to -70° C. and t-butyl lithium (34.0 ml of 1.9 molar solution) was added dropwise. A cooled (-40° C.) solution of 3-cyclohexyl propionic acid chloride (10 .0 g) in tetrahydrofuran (20 ml) was added rapidly. After 11/2 hours, the reaction was quenched by the addition of methanol (30 ml) and the reaction mixture was allowed to stand overnight at room temperature. The mixture was then poured into saturated ammonium chloride (200 ml) and insolubles were filtered off. The aqueous layer was extracted with ether (300 ml) and the extract was washed with 1% sodium thiosulphate solution (200 ml) and then dried over magnesium sulphate in the presence of charcoal. Concentration yielded an amber oil which was distilled to give a colourless liquid (5.56 g) which turned yellow on standing. The reaction mixture was then cooled to -70° C. was added rapidly After 11/2 hours, the reaction was quenched by the addition of methanol (30 ml) to stand overnight at room temperature The mixture was then poured into saturated ammonium chloride (200 ml) and insolubles were filtered off The aqueous layer was extracted with ether (300 ml) the extract was washed with 1% sodium thiosulphate solution (200 ml) dried over magnesium sulphate in the presence of charcoal Concentration yielded an amber oil which was distilled

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

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

Procedure: The title compound was synthesized analogous to Example 27, using 3-cyclohexylpropanoyl chloride and intermediate 2. Yield: 49%; 1H NMR (DMSO-d6, 300 MHz): δ 10.09 (s, 1H), 8.74 (d, 1H), 8.35 (s, 1H), 7.71 (s, 4H), 4.32 (t, 1H), 3.69 (s, 3H), 2.36 (t, 2H), 2.30 (m, 1H), 1.73 (m, 5H), 1.51 (q, 2H), 1.17 (m, 4H), 0.96 (t, 6H), 0.92 (m, 2H); MS (ESI) m/z 472.0 [M+H]+.

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

Procedure: The title compound was synthesized analogous to Example 27, using 3-cyclohexylpropanoyl chloride and intermediate 2. Yield: 49%; 1H NMR (DMSO-d6, 300 MHz): δ 10.09 (s, 1H), 8.74 (d, 1H), 8.35 (s, 1H), 7.71 (s, 4H), 4.32 (t, 1H), 3.69 (s, 3H), 2.36 (t, 2H), 2.30 (m, 1H), 1.73 (m, 5H), 1.51 (q, 2H), 1.17 (m, 4H), 0.96 (t, 6H), 0.92 (m, 2H); MS (ESI) m/z 472.0 [M+H]+.

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

Procedure: A suspension of 7-chloro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (100 mg, Reference Example 1) in dry dichloromethane (10 mL) was treated with dry triethylamine (0.11 mL), then with a solution of 3-cyclohexylpropionyl chloride (45 mg) in dry dichloromethane (5 mL). After stirring at room temperature overnight the reaction mixture was washed with water, then the organic phase was dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of methanol and dichloromethane (1:19, v/v) to give 7-chloro-2-(3-cyclohexylpropionyl)-6-phenyl-1,2,3,4-tetrahydropyrrolo [1,2-a]pyrazine-8-carboxylic acid amide (80 mg) as a white solid, m.p. 181–182° C. MS: 416 [MH]+, 414 [MH]+. was washed with water the organic phase was dried over magnesium sulfate evaporated The residue was subjected to column chromatography on silica eluting with a mixture of methanol and dichloromethane (1:19

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 250 ml three-necked flask were added 5.00 g (28.74 mmol) in theoretical amount of 3-cyclohexylpropionyl chloride prepared in the step 1, 3.11 g (28.74 mmol) methylphenyl ether and 150 ml dichloromethane. The resulting mixture was cooled in ice salt bath to −5° C., added portionwise 3.83 g (28.74 mmol) anhydrous AlCl3 under stirring, upon the completion of addition. The mixture was stirred at room temperature for 2 hours, poured into a mixture (150 g ice+5 ml concentrated hydrochloric acid), the organic layer was separated, concentrated under a reduced pressure to about 10 ml, the aqueous layer was extracted with ethyl acetate 2×50 ml, the organic phase was combined, washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous magnesium sulfate, filtrated and concentrated to obtain a pale brown solid, which was recrystallized with petroleum ether to obtain a 5.6 g product as a white solid in a yield of 79.1%, mp: 64-65 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.85˜1.00 (2H, m, CH2), 1.10˜1.40 (4H, m, 2×CH2), 1.61˜1.1.82 (7H, m), 2.92 (2H, t, J=7.56 Hz, COCH2), 3.87 (3H, s, OCH3), 6.23 (2H, d, J=8.68 Hz, ArH), 7.94 (2H, d, J=8.68 Hz, ArH); ESI-MS m/e (%): 269.2 (M+Na, 100), 247.2 (M+1, 71). The mixture was stirred at room temperature for 2 hours the organic layer was separated concentrated under a reduced pressure to about 10 ml the aqueous layer was extracted with ethyl acetate 2×50 ml washed with saturated aqueous sodium bicarbonate solution with saturated brine, dried over anhydrous magnesium sulfate filtrated concentrated to obtain a pale brown solid, which was recrystallized with petroleum ether

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 250 ml three-necked flask were added 5.00 g (28.74 mmol) in theoretical amount of 3-cyclohexylpropionyl chloride prepared in the step 1, 3.11 g (28.74 mmol) methylphenyl ether and 150 ml dichloromethane. The resulting mixture was cooled in ice salt bath to −5° C., added portionwise 3.83 g (28.74 mmol) anhydrous AlCl3 under stirring, upon the completion of addition. The mixture was stirred at room temperature for 2 hours, poured into a mixture (150 g ice+5 ml concentrated hydrochloric acid), the organic layer was separated, concentrated under a reduced pressure to about 10 ml, the aqueous layer was extracted with ethyl acetate 2×50 ml, the organic phase was combined, washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous magnesium sulfate, filtrated and concentrated to obtain a pale brown solid, which was recrystallized with petroleum ether to obtain a 5.6 g product as a white solid in a yield of 79.1%, mp: 64-65 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.85˜1.00 (2H, m, CH2), 1.10˜1.40 (4H, m, 2×CH2), 1.61˜1.1.82 (7H, m), 2.92 (2H, t, J=7.56 Hz, COCH2), 3.87 (3H, s, OCH3), 6.23 (2H, d, J=8.68 Hz, ArH), 7.94 (2H, d, J=8.68 Hz, ArH); ESI-MS m/e (%): 269.2 (M+Na, 100), 247.2 (M+1, 71). The mixture was stirred at room temperature for 2 hours the organic layer was separated concentrated under a reduced pressure to about 10 ml the aqueous layer was extracted with ethyl acetate 2×50 ml washed with saturated aqueous sodium bicarbonate solution with saturated brine, dried over anhydrous magnesium sulfate filtrated concentrated to obtain a pale brown solid, which was recrystallized with petroleum ether

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

Procedure: Stage 1 of the preparation was carried out under an argon atmosphere. To a stirred solution of t butyl alcohol (4.92 g) in tetrahydrofuran (20 ml) at -30° C. was added dropwise n-butyl lithium (41.8 ml of 1.6 molar solution). The resultant lithium t-butoxide solution was allowed to warm to 0° C. and was added to a stirred solution of cuprous iodide (12.65 g) in tetrahydrofuran (50 ml). After about 15 minutes, the grey cuprous iodide was replaced by a beige solid, and the reaction mixture turned brown. The reaction mixture was then cooled to -70° C. and t-butyl lithium (34.0 ml of 1.9 molar solution) was added dropwise. A cooled (-40° C.) solution of 3-cyclohexyl propionic acid chloride (10 .0 g) in tetrahydrofuran (20 ml) was added rapidly. After 11/2 hours, the reaction was quenched by the addition of methanol (30 ml) and the reaction mixture was allowed to stand overnight at room temperature. The mixture was then poured into saturated ammonium chloride (200 ml) and insolubles were filtered off. The aqueous layer was extracted with ether (300 ml) and the extract was washed with 1% sodium thiosulphate solution (200 ml) and then dried over magnesium sulphate in the presence of charcoal. Concentration yielded an amber oil which was distilled to give a colourless liquid (5.56 g) which turned yellow on standing. The reaction mixture was then cooled to -70° C. was added rapidly After 11/2 hours, the reaction was quenched by the addition of methanol (30 ml) to stand overnight at room temperature The mixture was then poured into saturated ammonium chloride (200 ml) and insolubles were filtered off The aqueous layer was extracted with ether (300 ml) the extract was washed with 1% sodium thiosulphate solution (200 ml) dried over magnesium sulphate in the presence of charcoal Concentration yielded an amber oil which was distilled