methyl 3-(4-chlorophenyl)-3-oxopropanoate

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

Procedure: Into a 1000 ml three necked flask equipped with an addition funnel, and condenser was added 15.4 g of 60% sodium hydride (0.63 mole). The sodium hydride was washed twice with hexane and then suspended in 300 ml of tetrahydrofuran and 29 g of dimethyl carbonate (0.32 mole). The reaction mixture was brought to reflux and a solution of 50 g (0.32 mole) of 4-chloroacetophenone in 50 ml of tetrahydrofuran was added over 30 minutes. After hydrogen evolution had ceased the reaction was cooled and poured onto ice. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl ether. The organic layer was dried, concentrated, and distilled at 15 torr bp 180°-205° C. to give 40 g of methyl 3-(4-chlorophenyl)-3-keto-propanoate. The sodium hydride was washed twice with hexane to reflux was cooled poured onto ice extracted with ethyl ether The organic layer was dried concentrated distilled at 15 torr bp 180°-205° C.

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

Procedure: Hydrazine monohydrate (0.80 g, 20 mmol) was added to a solution of methyl 4-chlorobenzoylacetate (3.19 g, 15.0 mmol) in ethanol (40 ml) at 0° C., and the mixture was stirred at room temperature for 2 days. After completion of the reaction, a precipitated solid was filtered and washed with diethyl ether, to give a white solid of 5-(4-chlorophenyl)-3-hydroxypyrazole (2.02 g, yield: 55.1%). mp: 240-241° C.; 1H-NMR (DMSO-d6, DMSO, ppm): δ 5.92 (s, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 9.30-10.60 (br s, 1H), 11.60-12.70 (br s, 1H). After completion of the reaction a precipitated solid was filtered washed with diethyl ether

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a chloroform (20 mL) solution of methyl 3-(4-chlorophenyl)-3-oxopropanoate (1.0 g), bromine (0.12 mL) was added, and the resultant was stirred at 70° C. for 1 hour under sealed conditions. Then, bromine (0.12 mL) was further added thereto, and the resultant was further stirred at 70° C. for 1 hour under sealed conditions. The reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=100/0→75/25) to obtain the title compound (0.44 g) as a pale yellow oil. the resultant was further stirred at 70° C. for 1 hour under sealed conditions The reaction solution was concentrated under reduced pressure The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=100/0→75/25)

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

Procedure: To 20.0 g of methyl 3-(4-chlorophenyl)-3-keto-propanoate in 100 ml of methanol was added a mixture of 4.7 g of hydrazine monohydrate and 7.6 g of 37% formalin in 50 ml of methanol. The reaction was stirred at room temperature for 18 hrs. The methanol was then removed in vacuo and the product was dissolved in 40 ml of methylene chloride and washed 5 times with 100 ml portions of water. The methylene chloride layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 22 g of 3-(4-chlorophenyl)-4-carbomethoxy-4,5-dihydro-1H-pyrazole which was used without further purification in the next reaction. The methanol was then removed in vacuo the product was dissolved in 40 ml of methylene chloride washed 5 times with 100 ml portions of water The methylene chloride layer was dried over anhydrous magnesium sulfate evaporated in vacuo

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

Procedure: Alternatively, MDBA may be prepared by the carbomethoxylation of a ketone. For example, 4-chloracetophenone reacts with excess dimethylcarbonate using sodium methoxide as a catalyst to produce methyl 4-chlorobenzoylacetate as described in U.S. Pat. No. 3,950,381. NMR data was consistent with the structure.

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

Procedure: Into a 1000 ml three necked flask equipped with an additional funnel, and condenser was added 15.4 g of 60% sodium hydride (0.63 mole). The sodium hydride was washed twice with hexane and then suspended in 300 ml of tetrahydrofuran and 29 g of dimethyl carbonate (0.32 mole). The reaction mixture was brought to reflux and a solution of 50 g (0.32 mole) of 4-chloroacetophenone in 50 ml of tetrahydrofuran was added over 30 minutes. After hydrogen evolution had ceased the reaction was cooled and poured onto ice. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl ether. The organic layer was dried, concentrated, and distilled at 15 torr bp 180°-205° C. to give 40 g of methyl 3-(4-chlorophenyl)-3-keto-propanoate. NMR data was consistent with the structure. The sodium hydride was washed twice with hexane to reflux was cooled poured onto ice extracted with ethyl ether The organic layer was dried concentrated distilled at 15 torr bp 180°-205° C.

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

Procedure: The procedure is as described in Example 1, except that 54 g of sodium methylate in 600 ml dimethylcarbonate are used and 154.5 g of p-chloro-acetophenone are added dropwise over a period of 2.5 hours at 60°C. Working up in accordance with Example 1 gives at 60°C 187 g (87% of the theoretical amount) of p-chloro-benzoylacetic acid methyl ester with a boiling point of 113°C/0.3 torr.

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 3-(4-chlorophenyl)-3-oxopropionic acid methyl ester (1.0 g, 0.0047 mol), N,N-dimethylacetamide (1 mL) and triethylamine hydrochloride (0.97 g, 0.0047×1.5 mol) were added and stirred at 140° C. for 3 hours under an argon atmosphere. In the reaction liquid, ethyl acetate and saturated sodium bicarbonate water were added, and the mixture was partitioned. After extracting the aqueous layer using ethyl acetate, the organic layer was dried using anhydrous sodium sulfate and concentrated. Thereafter, the dried and concentrated product was purified using a silica gel column, and a target product was obtained. were added the mixture was partitioned After extracting the aqueous layer the organic layer was dried concentrated Thereafter, the dried concentrated product was purified a target product was obtained

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

Procedure: Into a 1000 ml three necked flask equipped with an addition funnel, and condenser was added 15.4 g of 60% sodium hydride (0.63 mole). The sodium hydride was washed twice with hexane and then suspended in 300 ml of tetrahydrofuran and 29 g of dimethyl carbonate (0.32 mole). The reaction mixture was brought to reflux and a solution of 50 g (0.32 mole) of 4-chloroacetophenone in 50 ml of tetrahydrofuran was added over 30 minutes. After hydrogen evolution had ceased the reaction was cooled and poured onto ice. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl ether. The organic layer was dried, concentrated, and distilled at 15 torr bp 180°-205° C. to give 40 g of methyl 3-(4-chlorophenyl)-3-keto-propanoate. The sodium hydride was washed twice with hexane to reflux was cooled poured onto ice extracted with ethyl ether The organic layer was dried concentrated distilled at 15 torr bp 180°-205° C.

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

Procedure: Hydrazine monohydrate (0.80 g, 20 mmol) was added to a solution of methyl 4-chlorobenzoylacetate (3.19 g, 15.0 mmol) in ethanol (40 ml) at 0° C., and the mixture was stirred at room temperature for 2 days. After completion of the reaction, a precipitated solid was filtered and washed with diethyl ether, to give a white solid of 5-(4-chlorophenyl)-3-hydroxypyrazole (2.02 g, yield: 55.1%). mp: 240-241° C.; 1H-NMR (DMSO-d6, DMSO, ppm): δ 5.92 (s, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 9.30-10.60 (br s, 1H), 11.60-12.70 (br s, 1H). After completion of the reaction a precipitated solid was filtered washed with diethyl ether