methyl 2-oxocycloheptane-1-carboxylate

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

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

Procedure: Methyl 2,2-di(tertiary-butylperoxy)-1-cycloheptanecarboxylate was prepared by the addition of 92.28% TBHP (tertiary butyl hydroperoxide) (12.21 g, 0.1250 mol) to 99% methyl 2-oxo-1-cycloheptanecarboxylate (8.600 g, 0.0500 mol) at room temperature in a three necked 125-mL round bottomed flask equipped with a thermometer and mechanical stirrer. The solution was then cooled via a dry ice-acetone bath to −5° C. and 78% sulfuric acid (7.540 g, 0.0600 mol) was added dropwise to the solution with temperature at −5° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for ninety minutes with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then washed with saturated NaCl solution until the aqueous washings had a pH of 4.5 or greater. The organic layer was then dried over MgSO4, filtered through a Buchner funnel and analyzed by gas chromatography. The purity was found to be 17%. This product was not purified due to low conversion of product. equipped with a thermometer and mechanical stirrer to reach 5° C. was maintained by an ice-water bath for ninety minutes with mechanical stirring The reaction was transferred to a separatory funnel the lower acidic aqueous layer separated The organic layer was then washed with saturated NaCl solution until the aqueous washings The organic layer was then dried over MgSO4 filtered through a Buchner funnel This product was not purified due to low conversion of product

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

Procedure: Methyl 2,2-di(tertiary-butylperoxy)-1-cycloheptanecarboxylate was prepared by the addition of 92.28% TBHP (tertiary butyl hydroperoxide) (12.21 g, 0.1250 mol) to 99% methyl 2-oxo-1-cycloheptanecarboxylate (8.600 g, 0.0500 mol) at room temperature in a three necked 125-mL round bottomed flask equipped with a thermometer and mechanical stirrer. The solution was then cooled via a dry ice-acetone bath to −5° C. and 78% sulfuric acid (7.540 g, 0.0600 mol) was added dropwise to the solution with temperature at −5° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for ninety minutes with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then washed with saturated NaCl solution until the aqueous washings had a pH of 4.5 or greater. The organic layer was then dried over MgSO4, filtered through a Buchner funnel and analyzed by gas chromatography. The purity was found to be 17%. This product was not purified due to low conversion of product. equipped with a thermometer and mechanical stirrer to reach 5° C. was maintained by an ice-water bath for ninety minutes with mechanical stirring The reaction was transferred to a separatory funnel the lower acidic aqueous layer separated The organic layer was then washed with saturated NaCl solution until the aqueous washings The organic layer was then dried over MgSO4 filtered through a Buchner funnel This product was not purified due to low conversion of product

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

Procedure: Using the method of Example 1 Part A, methyl 2-oxocycloheptanecarboxylate (50.5 g, 0.30 mole) was reacted with urethane to provide 59 g of methyl 2-[(ethoxycarbonyl)amino]-1-cycloheptene-1-carboxylate as an oil.

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

Procedure: Using the method of Example 1 Part A, methyl 2-oxocycloheptanecarboxylate (50.5 g, 0.30 mole) was reacted with urethane to provide 59 g of methyl 2-[(ethoxycarbonyl)amino]-1-cycloheptene-1-carboxylate as an oil.

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N′-Allyl-N′-cyclobutyl-hydrazine hydrochloride (2.01 g, 12.37 mmol) was dissolved in methanol (40 mL). 2-Oxo-cycloheptanecarboxylic acid methyl ester (1.93 mL, 12.37 mmol), sodium acetate (2.04 g, 24.74 mmol), sodium cyanoborohydride (1.55 g, 24.74 mmol) and 4 Å molecular sieves (2.80 g) were added sequentially. The reaction was stirred at 25° C. for 18 h before it was quenched via the addition of saturated aqueous sodium bicarbonate solution (30 mL). The mixture was extracted with ethyl acetate (3×40 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-(N′-allyl-N′-cyclobutyl-hydrazino)-cycloheptanecarboxylic acid methyl ester, as a yellow oil. The residue was used directly in the next step. LC-MS (ESI) calcd for C16H28N2O2 280.41, found 281.2 [M+H+]. was quenched via the addition of saturated aqueous sodium bicarbonate solution (30 mL) The mixture was extracted with ethyl acetate (3×40 mL) dried over magnesium sulfate filtered concentrated in vacuo

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-oxocycloheptanecarboxylate (0.34 g, 2 mmol), methyl 3-amino-5-fluorobenzoate (0.33 g, 2 mmol), polyphosphoric acid (4.0 g) and dioxane (5 mL) was heated at 130° C. for 5 hours. After cooling to room temperature, the solution was diluted with water (100 mL), and NaOAc.3H2O (7.3 g) was added. Then the resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (20 mL) and SOCl2 (10 mL) was added, the mixture was stirred at reflux for 5 hours, concentrated and treated with water (50 mL), extracted with ethyl acetate (3×50 mL). The organic layer was separated, concentrated and the residue was chromatographed to give the crude product (0.62 g). MS (ESI) m/e [M+1]+290.0. After cooling to room temperature was added Then the resulting precipitate was collected by filtration dried SOCl2 (10 mL) was added at reflux for 5 hours concentrated treated with water (50 mL) extracted with ethyl acetate (3×50 mL) The organic layer was separated concentrated the residue was chromatographed

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

Procedure: Methyl 2-oxo-1-cycloheptanecarboxylate (50 g, 294 mmole) was dissolved in carbon tetrachloride (200 mL) and chilled to 0° C. Bromine (46.8 g, 294 mmole) was added via addition funnel over ˜30 minutes. The cooling bath was then removed and the reaction was allowed to warm to rt. The reaction was stirred under nitrogen at room temperature for 4 days. After 4 days the solution was poured into a separatory funnel containing water (1 L). The organic was washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave (72.4 g, 291 mmole, 99% crude yield). The material was carried on without further purification. The cooling bath was then removed to warm to rt After 4 days the solution was poured into a separatory funnel containing water (1 L) The organic was washed with water dried over sodium sulfate Removal of the solvent in vacuo gave (72.4 g, 291 mmole, 99% crude yield) The material was carried on without further purification

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

Procedure: Methyl 2-oxo-1-cycloheptanecarboxylate (50 g, 294 mmole) was dissolved in carbon tetrachloride (200 mL) and chilled to 0° C. Bromine (46.8 g, 294 mmole) was added via addition funnel over ˜30 minutes. The cooling bath was then removed and the reaction was allowed to warm to rt. The reaction was stirred under nitrogen at room temperature for 4 days. After 4 days the solution was poured into a separatory funnel containing water (1 L). The organic was washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave (72.4 g, 291 mmole, 99% crude yield). The material was carried on without further purification. The cooling bath was then removed to warm to rt After 4 days the solution was poured into a separatory funnel containing water (1 L) The organic was washed with water dried over sodium sulfate Removal of the solvent in vacuo gave (72.4 g, 291 mmole, 99% crude yield) The material was carried on without further purification

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

Procedure: Methyl 2,2-di(tertiary-butylperoxy)-1-cycloheptanecarboxylate was prepared by the addition of 92.28% TBHP (tertiary butyl hydroperoxide) (12.21 g, 0.1250 mol) to 99% methyl 2-oxo-1-cycloheptanecarboxylate (8.600 g, 0.0500 mol) at room temperature in a three necked 125-mL round bottomed flask equipped with a thermometer and mechanical stirrer. The solution was then cooled via a dry ice-acetone bath to −5° C. and 78% sulfuric acid (7.540 g, 0.0600 mol) was added dropwise to the solution with temperature at −5° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for ninety minutes with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then washed with saturated NaCl solution until the aqueous washings had a pH of 4.5 or greater. The organic layer was then dried over MgSO4, filtered through a Buchner funnel and analyzed by gas chromatography. The purity was found to be 17%. This product was not purified due to low conversion of product. equipped with a thermometer and mechanical stirrer to reach 5° C. was maintained by an ice-water bath for ninety minutes with mechanical stirring The reaction was transferred to a separatory funnel the lower acidic aqueous layer separated The organic layer was then washed with saturated NaCl solution until the aqueous washings The organic layer was then dried over MgSO4 filtered through a Buchner funnel This product was not purified due to low conversion of product

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

Procedure: Using the method of Example 1 Part A, methyl 2-oxocycloheptanecarboxylate (50.5 g, 0.30 mole) was reacted with urethane to provide 59 g of methyl 2-[(ethoxycarbonyl)amino]-1-cycloheptene-1-carboxylate as an oil.

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