2-chloro-1-cyclopentylethanone

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

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

Procedure: Potassium carbonate (3.1 g, 22 mmol) was added to a solution of 2-(2-Fluoro-4-hydroxy-phenyl)-2-methyl-propionitrile (1.0 g, 6.0 mmol) and 2-Chloro-1-cyclopentyl-ethanone (3.3 g, 22 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with EtOAc (2×50 mL). The organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0–15% EtOAc in hexanes) to give the product (1.2 g, 75% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ: 1.57–1.93 (m, 14 H), 3.10 (m, 1 H), 4.64 (s, 2 H), 6.65 (d, J=9.6 Hz, 2 H), 7.37 (t, J=8.9 Hz, 1 H). extracted with EtOAc (2×50 mL) The organics were washed with brine (100 mL) dried over Na2SO4 filtered concentrated The residue was purified by flash column chromatography (0–15% EtOAc in hexanes)

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

Procedure: The intermediate 2-Chloro-1-cyclopentyl-ethanone from Step 1 (1 g, 6.81 mmol), was combined with 4-methoxy-benzenethiol (1.05 g, 7.50 mmol), in THF (20 mL) and treated with Triethylamine (1.05 mL, 7.50 mmol). The mixture was stirred for 1 hour at room temperature then poured into water (50 mL) and extracted with EtOAc (2×50 mL). The organics were then washed with 0.5N HCl (2×50 mL), 2N NaOH (2×50 mL), water (2×50 mL) and brine (1×50 mL) the organics were dried over Na2SO4, filtered and concentrated. The residue was used without further purification (1.65 g, 97%). extracted with EtOAc (2×50 mL) The organics were then washed with 0.5N HCl (2×50 mL), 2N NaOH (2×50 mL), water (2×50 mL) and brine (1×50 mL) the organics were dried over Na2SO4 filtered concentrated The residue was used without further purification (1.65 g, 97%)

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

Procedure: The intermediate 2-Chloro-1-cyclopentyl-ethanone from Step 1 (1 g, 6.81 mmol), was combined with 4-methoxy-benzenethiol (1.05 g, 7.50 mmol), in THF (20 mL) and treated with Triethylamine (1.05 mL, 7.50 mmol). The mixture was stirred for 1 hour at room temperature then poured into water (50 mL) and extracted with EtOAc (2×50 mL). The organics were then washed with 0.5N HCl (2×50 mL), 2N NaOH (2×50 mL), water (2×50 mL) and brine (1×50 mL) the organics were dried over Na2SO4, filtered and concentrated. The residue was used without further purification (1.65 g, 97%). extracted with EtOAc (2×50 mL) The organics were then washed with 0.5N HCl (2×50 mL), 2N NaOH (2×50 mL), water (2×50 mL) and brine (1×50 mL) the organics were dried over Na2SO4 filtered concentrated The residue was used without further purification (1.65 g, 97%)

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

Procedure: Cyclopentanecarbonyl chloride (5.0 g, 0.038 mol) was dissolved in THF (100 mL) and cooled to 0° C. The solution was treated with a 2M solution of TMS-Diazomethane in hexanes (56.56 mL, 0.113 mol) over 10 min. The resulting yellow solution was allowed to stand at room temperature for 12 hours. The solution was then concentrated and the residue was dissolved in THF (100 mL) and treated slowly with a 4N HCl in Dioxane solution (28.28 mL, 0.113 mol). The result was allowed to stir at 24° C. for 2 hours. The solution was concentrated to an oil which was chromatographed on silica gel eluting with 5% EtOAc in Hexanes to give the intermediate depicted below (4.9 g, 88%). The solution was then concentrated the residue was dissolved in THF (100 mL) The solution was concentrated to an oil which was chromatographed on silica gel eluting with 5% EtOAc in Hexanes to give the intermediate

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

Procedure: To a cold (˜0° C.) solution of K2CO3 (31.2 g, 225 mmol, ) in water (125 mL) was added N, O-dimethylhydroxylamine hydrochloride (10 g, 100 mmol) and toluene (125 mL). The reaction mixture was further cooled to −5° C. and chloroacetyl chloride (10 mL, 125 mmol, )was added slowly under vigorous agitation. The reaction mixture was then warmed to ambient temperature over 45 min and analyzed by GC for completion. The layers were separated and the aqueous layer was extracted with toluene (3×50 mL). The combined organic layers were concentrated to a solid residue. The residue was dissolved in anhydrous THF (200 mL) cooled to ˜0° C. To the reaction mixture was then added a solution of the cyclopentylmagnesium chloride (60 mL, 2M in diethyl ether), drop-wise, maintaining the temperature at less than about 5° C. The resulting solution was then warmed to ambient temperature over a period of ˜1 hr and then slowly quenched into a cold 3N HCl (100 mL, ). The resulting mixture was then aged for ˜30 min. The layers were separated and the aqueous layer extracted with MTBE (50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and concentrated to dryness to yield the title compound as a crude product, as a yellow liquid. The reaction mixture was then warmed to ambient temperature over 45 min The layers were separated the aqueous layer was extracted with toluene (3×50 mL) The combined organic layers were concentrated to a solid residue The residue was dissolved in anhydrous THF (200 mL) cooled to ˜0° C To the reaction mixture was then added a solution of the cyclopentylmagnesium chloride (60 mL, 2M in diethyl ether) maintaining the temperature at less than about 5° C The resulting solution was then warmed to ambient temperature over a period of ˜1 hr slowly quenched into a cold 3N HCl (100 mL, ) The layers were separated the aqueous layer extracted with MTBE (50 mL) The combined organic layers were washed with brine (50 mL) dried over MgSO4 concentrated to dryness

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

Procedure: To a cold (˜0° C.) solution of K2CO3 (31.2 g, 225 mmol, ) in water (125 mL) was added N, O-dimethylhydroxylamine hydrochloride (10 g, 100 mmol) and toluene (125 mL). The reaction mixture was further cooled to −5° C. and chloroacetyl chloride (10 mL, 125 mmol, )was added slowly under vigorous agitation. The reaction mixture was then warmed to ambient temperature over 45 min and analyzed by GC for completion. The layers were separated and the aqueous layer was extracted with toluene (3×50 mL). The combined organic layers were concentrated to a solid residue. The residue was dissolved in anhydrous THF (200 mL) cooled to ˜0° C. To the reaction mixture was then added a solution of the cyclopentylmagnesium chloride (60 mL, 2M in diethyl ether), drop-wise, maintaining the temperature at less than about 5° C. The resulting solution was then warmed to ambient temperature over a period of ˜1 hr and then slowly quenched into a cold 3N HCl (100 mL, ). The resulting mixture was then aged for ˜30 min. The layers were separated and the aqueous layer extracted with MTBE (50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and concentrated to dryness to yield the title compound as a crude product, as a yellow liquid. The reaction mixture was then warmed to ambient temperature over 45 min The layers were separated the aqueous layer was extracted with toluene (3×50 mL) The combined organic layers were concentrated to a solid residue The residue was dissolved in anhydrous THF (200 mL) cooled to ˜0° C To the reaction mixture was then added a solution of the cyclopentylmagnesium chloride (60 mL, 2M in diethyl ether) maintaining the temperature at less than about 5° C The resulting solution was then warmed to ambient temperature over a period of ˜1 hr slowly quenched into a cold 3N HCl (100 mL, ) The layers were separated the aqueous layer extracted with MTBE (50 mL) The combined organic layers were washed with brine (50 mL) dried over MgSO4 concentrated to dryness

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

Procedure: To a solution of (5-cyclohexyl-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl)-acetic acid ethyl ester (50 g, 151.7 mmol) in DMF (250 mL) was added potassium carbonate (325 mesh, 102 g, 738 mmol) and tetrabutylammonium iodide (46.0 g, 124.5 mmol). The resulting mixture was heated to about 50-55° C. and while at this temperature, 2-chloro-1-cyclopentylethanone (57.0 g, 373.5 mmol) was added drop-wise over a period of about 1 hr. The reaction mixture was then aged for 1 hr, cooled to ambient temperature and diluted with MTBE (50 mL). The inorganic solids were removed by filtration and rinsed with additional MTBE (50 mL). To the combined filtrates was added DMF (50 mL) and the resulting mixture was treated with 3N NaOH (150 mL), then stirred at −30° C. for about 1 hr. The reaction mixture was then again diluted with MTBE (100 mL) and the layers were separated. The aqueous layer was poured slowly under vigorous agitation, into another flask containing cold 2N HCl solution (400 mL) which was maintained at ˜5° C. Isopropyl acetate (300 mL) was added to the reaction mixture and the layers were separated. The organic layer was rinsed with water (300 mL) and then diluted with n-heptane (300 mL), at which point a solid was observed to precipitate. The precipitate was filtered and dried under vacuum to constant weight to yield the title compound as an off-white solid. was added drop-wise over a period of about 1 hr The inorganic solids were removed by filtration rinsed with additional MTBE (50 mL) To the combined filtrates was added DMF (50 mL) the resulting mixture was treated with 3N NaOH (150 mL) The reaction mixture was then again diluted with MTBE (100 mL) the layers were separated The aqueous layer was poured slowly under vigorous agitation, into another flask containing cold 2N HCl solution (400 mL) which was maintained at ˜5° C Isopropyl acetate (300 mL) was added to the reaction mixture the layers were separated The organic layer was rinsed with water (300 mL) diluted with n-heptane (300 mL), at which point a solid to precipitate The precipitate was filtered dried under vacuum to constant weight

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

Procedure: reacting the (5-cyclohexyl-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl)-acetic acid ethyl ester with 2-chloro-1-cyclopentyl-ethanone; in the presence of an organic or inorganic base; in an organic solvent; in the presence of a source of iodide; to yield [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid ethyl ester;

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

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

Procedure: In a manner similar to that described above, 2-(chloroacethyl)furan, 2-(chloroacethyl)thiophene, 4-(chloroacetyl)-1,2-dimethoxybenzene, chloroacetyl-cyclopropane, and o-methylphenacyl chloride were prepared. were prepared

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

Procedure: Potassium carbonate (3.1 g, 22 mmol) was added to a solution of 2-(2-Fluoro-4-hydroxy-phenyl)-2-methyl-propionitrile (1.0 g, 6.0 mmol) and 2-Chloro-1-cyclopentyl-ethanone (3.3 g, 22 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with EtOAc (2×50 mL). The organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0-15% EtOAc in hexanes) to give the product (1.2 g, 75% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ: 1.57-1.93 (m, 14H), 3.10 (m, 1H), 4.64 (s, 2H), 6.65 (d, J=9.6 Hz, 2H), 7.37 (t, J=8.9 Hz, 1H). extracted with EtOAc (2×50 mL) The organics were washed with brine (100 mL) dried over Na2SO4 filtered concentrated The residue was purified by flash column chromatography (0-15% EtOAc in hexanes)