ethyl cyclopropanecarboxylate

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

Procedure: 2-(4-Chlorophenyl)acetonitrile (5.74 g) is dissolved in 120 mL of THF at 0° C. After adding 60% NaH (4.2 g, 2.7 eq), the reaction mixture is stirred for 10 minutes. Ethylcyclopropane carboxylate is added and the mixture is stirred overnight. The reaction is stopped by adding acetic acid (5 mL) and water. The aqueous layer is extracted with ethyl acetate (50 mL×3). The collected organic layer is washed with brine and dehydrated with MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield 7.74 g of the target compound. 1H NMR (CDCl3, 300 MHz): δ 7.42 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.7 Hz, 2H), 4.79 (s, 1H), 2.10 (m, 1H) 1.16 (m, 2H), 1.03 (m, 2H). the mixture is stirred overnight The aqueous layer is extracted with ethyl acetate (50 mL×3) The collected organic layer is washed with brine The dehydrated organic layer is concentrated by distillation under reduced pressure purified by column chromatography

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

Procedure: A solution of 2.59 g of 1-amino-3-cyclopropyl-3-p-trifluoromethylphenoxy-propane (obtainable by a condensation reaction of ethyl cyclopropanecarboxylate with ethyl acetate to give ethyl 3-cyclopropyl-propan-3-on-1-oate; reduction of the latter to ethyl 3-cyclopropyl-propan-3-ol-1-oate; reaction of the latter with p-trifluoromethylphenol analogously to Example 3, to give ethyl 3-cyclopropyl-3-p-trifluoromethylphenoxy-propanoate; reaction with NH3 to give the amide; and reduction of the latter with LiAlH4) and 1.5 g of benzaldehyde in 25 ml of toluene is boiled for one hour under a water separator. The solution of the resulting 1-benzylideneamino-3-cyclopropyl-3-p-trifluoromethylphenoxy-propane is heated with 5 g of methyl iodide for 12 hours at 150° in a tube and then evaporated. The resulting quaternary salt is boiled for 10 minutes in 90% ethanol. The mixture is again evaporated, the residue is taken up in dilute hydrochloric acid and the benzaldehyde which has been split off is removed by extraction with ether. The acid, aqueous solution is rendered alkaline with sodium hydroxide solution and worked up in the customary manner. 1-Methylamino-3-cyclopropyl-3-p-trifluoromethylphenoxypropane is obtained. Rf 0.22 (A).

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

Procedure: To a solution of acetonitrile (500 μL, 390 mg, 9.6 mmol) in THF (30 mL) at RT was added a solution of potassium 2-methylbutan-2-olate in toluene (1.7 M, 17.0 mL, 29.0 mmol) followed by the dropwise addition of ethyl cyclopropanecarboxylate (4.56 mL, 4.37 g, 38.0 mmol) and the reaction mixture maintained at RT for 16 hr. The resulting mixture was concentrated in vacuo to a volume of ˜15 mL and was then diluted with EtOH (20 mL) and p-tolylhydrazine hydrochloride (1.52 g, 9.57 mmol) was added. The mixture was acidified to pH 1 by the addition of conc hydrochloric acid and the resulting heterogeneous mixture was heated to 70° C. for 2 hr, then cooled to RT and concentrated in vacuo to a volume of ˜20 mL. The mixture was diluted with water (30 mL) and was adjusted to pH 12 by the addition of 2M aq NaOH and extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with brine (30 mL) and then dried and evaporated in vacuo. The residue was triturated with isohexane (20 mL) to afford the title compound, Intermediate A28, as a beige solid (1.60 g, 77%); Rt 3.35 min (Method 1 basic); m/z 214 (M+H)+, (ES+). The resulting mixture was concentrated in vacuo to a volume of ˜15 mL was added the resulting heterogeneous mixture was heated to 70° C. for 2 hr cooled to RT concentrated in vacuo to a volume of ˜20 mL The mixture was diluted with water (30 mL) was adjusted to pH 12 by the addition of 2M aq NaOH extracted with diethyl ether (2×20 mL) The combined organic extracts were washed with brine (30 mL) dried evaporated in vacuo The residue was triturated with isohexane (20 mL)

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

Procedure: Oxalic acid (11.2 g, 0.124 mol) was dissolved in water (40 mL) and 144,4,6-trimethyl-[1,3]oxazinan-2-yl)-cyclopropanecarboxylic acid ethyl ester (15 g, 0.062 mol) was added. Steam distillation of this mixture was carried out until 500 mL of distillate had been collected. The distillate was saturated with NaCl and extracted with EtOAc (2×100 mL). The organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give 1-formyl-cyclopropanecarboxylic acid ethyl ester (4.5 g, 51%). 1H NMR (CDCl3 400 MHz): δ10.39 (s, 1H), 4.26 (q, J=7.2 Hz, 2H), 1.67-1.64 (m, 2H), 1.61-1.58 (m, 2H), 1.31 (t, J=7.2 Hz, 3H). Steam distillation of this mixture had been collected extracted with EtOAc (2×100 mL) The organic extracts were dried over Na2SO4 concentrated under reduced pressure

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

Procedure: Magnesium metal (98.2 g) was stirred with 100 ml of anhydrous ether under nitrogen for 1 hr. 4-Fluorobromobenzene (700 g) was dissolved in 1750 ml of anhydrous ether. A 20 ml aliquot of the solution was added to the magnesium metal to initiate reaction. Once reflux had begun, the 4-fluorobromobenzene solution was added at such a rate as to maintain a gentle reflux. After the addition was complete, the mixture was heated under reflux for 1 hr. Ethyl cylopropylcarboxylate (180.6 g) was dissolved in 500 ml of anhydrous ether. After the Grignard solution had been cooled to ambient temperature, the solution was added dropwise such that a gentle reflux was maintained. After complete addition of the ester, the mixture was heated under reflux for 45 mins and cooled to ambient temperature. The reaction mixture was quenched with 500 ml of saturated aqueous ammonium chloride and 2 l of ice water. The ether layer was separated and the aqueous layer was extracted twice with ether. The ether extracts were combined and washed with water and saturated brine. The ethereal mixture was dried over sodium sulfate, filtered and the solvent removed under vacuum to provide a quantitative yield or cyclopropyl-bis-(4-fluorophenyl)methanol. reaction Once reflux to maintain a gentle reflux After the addition the mixture was heated under reflux for 1 hr the solution was added dropwise such that a gentle reflux was maintained the mixture was heated under reflux for 45 mins cooled to ambient temperature The reaction mixture was quenched with 500 ml of saturated aqueous ammonium chloride and 2 l of ice water The ether layer was separated the aqueous layer was extracted twice with ether washed with water and saturated brine The ethereal mixture was dried over sodium sulfate filtered the solvent removed under vacuum

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

Procedure: Magnesium metal (98.2 g) was stirred with 100 ml of anhydrous ether under nitrogen for 1 hr. 4-Fluorobromobenzene (700 g) was dissolved in 1750 ml of anhydrous ether. A 20 ml aliquot of the solution was added to the magnesium metal to initiate reaction. Once reflux had begun, the 4-fluorobromobenzene solution was added at such a rate as to maintain a gentle reflux. After the addition was complete, the mixture was heated under reflux for 1 hr. Ethyl cylopropylcarboxylate (180.6 g) was dissolved in 500 ml of anhydrous ether. After the Grignard solution had been cooled to ambient temperature, the solution was added dropwise such that a gentle reflux was maintained. After complete addition of the ester, the mixture was heated under reflux for 45 mins and cooled to ambient temperature. The reaction mixture was quenched with 500 ml of saturated aqueous ammonium chloride and 2 l of ice water. The ether layer was separated and the aqueous layer was extracted twice with ether. The ether extracts were combined and washed with water and saturated brine. The ethereal mixture was dried over sodium sulfate, filtered and the solvent removed under vacuum to provide a quantitative yield or cyclopropyl-bis-(4-fluorophenyl)methanol. reaction Once reflux to maintain a gentle reflux After the addition the mixture was heated under reflux for 1 hr the solution was added dropwise such that a gentle reflux was maintained the mixture was heated under reflux for 45 mins cooled to ambient temperature The reaction mixture was quenched with 500 ml of saturated aqueous ammonium chloride and 2 l of ice water The ether layer was separated the aqueous layer was extracted twice with ether washed with water and saturated brine The ethereal mixture was dried over sodium sulfate filtered the solvent removed under vacuum

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

Procedure: Other β-diketones can be prepared from esters and ketones containing R3 and R5 as previously defined. Thus, 1-cyclopropyl-3-phenyl-1,3-propanedione has been reported by G. W. Cannon et al., Journal of Organic Chemistry 17, 685 (1952) to be prepared as a solid, melting point 36°C to 37°C, from ethyl benzoate and cyclopropyl methylketone in the presence of sodium amide. Alternatively, it has been found that the same compound, melting point 38°C to 40°C, could be prepared from ethyl cyclopropanecarboxylate, acetophenone and sodium hydride. J. T. Adams and C. R. Hauser in Journal of the American Chemical Society 66, 1220 (1944) have prepared a series of 1-alkyl-3-phenyl-1,3-propanediones from carboxylic acid ethyl esters and acetophenone in the presence of sodium amide. Illustrative examples are tabulated employing the following equation: ##EQU2## where R3 and R5 are set forth in the Table I below.

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-methoxy-5-morpholino-imidazo[1,5-a]quinazoline-3-carboxamide oxime (0.9 g), ethyl cyclopropylcarboxylate (1.7 g), molecular sieves (3 g), and 80% sodium hydride (0.1 g) in 20 ml of dry DMF was heated for 11/2 hours at 120° C. The mixture was cooled to room temperature, diluted with acetic acid (0.5 ml) and methylene chloride (20 ml) and filtered. The filtered mixture was evaporated and the residue was purified by column chromatography (HPLC) (eluent: methylene chloride:acetone (2:1)) to give yellow crystals of the title compound, m.p. 227°-228° C. Yield 0.38 g. The mixture was cooled to room temperature filtered The filtered mixture was evaporated the residue was purified by column chromatography (HPLC) (eluent: methylene chloride:acetone (2:1))

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

Procedure: To a solution of acetonitrile (500 μL, 390 mg, 9.6 mmol) in THF (30 mL) at RT was added a solution of potassium 2-methylbutan-2-olate in toluene (1.7 M, 17.0 mL, 29.0 mmol) followed by the dropwise addition of ethyl cyclopropanecarboxylate (4.56 mL, 4.37 g, 38.0 mmol) and the reaction mixture maintained at RT for 16 hr. The resulting mixture was concentrated in vacuo to a volume of 15 mL and was then diluted with EtOH (20 mL) and p-tolylhydrazine hydrochloride (1.52 g, 9.57 mmol) was added. The mixture was acidified to pH 1 by the addition of conc hydrochloric acid and the resulting heterogeneous mixture was heated to 70° C. for 2 hr, then cooled to RT and concentrated in vacuo to a volume of 20 mL. The mixture was diluted with water (30 mL) and was adjusted to pH 12 by the addition of 2M aq NaOH and extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with brine (30 mL) and then dried and evaporated in vacuo. The residue was triturated with isohexane (20 mL) to afford the title compound, Intermediate A15, as a beige solid (1.60 g, 77%); Rt 3.35 min (Method 1 basic); m/z 214 (M+H)+, (ES+). The resulting mixture was concentrated in vacuo to a volume of 15 mL was added the resulting heterogeneous mixture was heated to 70° C. for 2 hr cooled to RT concentrated in vacuo to a volume of 20 mL The mixture was diluted with water (30 mL) was adjusted to pH 12 by the addition of 2M aq NaOH extracted with diethyl ether (2×20 mL) The combined organic extracts were washed with brine (30 mL) dried evaporated in vacuo The residue was triturated with isohexane (20 mL)

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

Procedure: 2-(4-Chlorophenyl)acetonitrile (5.74 g) is dissolved in 120 mL of THF at 0° C. After adding 60% NaH (4.2 g, 2.7 eq), the reaction mixture is stirred for 10 minutes. Ethylcyclopropane carboxylate is added and the mixture is stirred overnight. The reaction is stopped by adding acetic acid (5 mL) and water. The aqueous layer is extracted with ethyl acetate (50 mL×3). The collected organic layer is washed with brine and dehydrated with MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield 7.74 g of the target compound. 1H NMR (CDCl3, 300 MHz): δ 7.42 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.7 Hz, 2H), 4.79 (s, 1H), 2.10 (m, 1H) 1.16 (m, 2H), 1.03 (m, 2H). the mixture is stirred overnight The aqueous layer is extracted with ethyl acetate (50 mL×3) The collected organic layer is washed with brine The dehydrated organic layer is concentrated by distillation under reduced pressure purified by column chromatography

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

Procedure: A solution of 2.59 g of 1-amino-3-cyclopropyl-3-p-trifluoromethylphenoxy-propane (obtainable by a condensation reaction of ethyl cyclopropanecarboxylate with ethyl acetate to give ethyl 3-cyclopropyl-propan-3-on-1-oate; reduction of the latter to ethyl 3-cyclopropyl-propan-3-ol-1-oate; reaction of the latter with p-trifluoromethylphenol analogously to Example 3, to give ethyl 3-cyclopropyl-3-p-trifluoromethylphenoxy-propanoate; reaction with NH3 to give the amide; and reduction of the latter with LiAlH4) and 1.5 g of benzaldehyde in 25 ml of toluene is boiled for one hour under a water separator. The solution of the resulting 1-benzylideneamino-3-cyclopropyl-3-p-trifluoromethylphenoxy-propane is heated with 5 g of methyl iodide for 12 hours at 150° in a tube and then evaporated. The resulting quaternary salt is boiled for 10 minutes in 90% ethanol. The mixture is again evaporated, the residue is taken up in dilute hydrochloric acid and the benzaldehyde which has been split off is removed by extraction with ether. The acid, aqueous solution is rendered alkaline with sodium hydroxide solution and worked up in the customary manner. 1-Methylamino-3-cyclopropyl-3-p-trifluoromethylphenoxypropane is obtained. Rf 0.22 (A).

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

Procedure: To a solution of acetonitrile (500 μL, 390 mg, 9.6 mmol) in THF (30 mL) at RT was added a solution of potassium 2-methylbutan-2-olate in toluene (1.7 M, 17.0 mL, 29.0 mmol) followed by the dropwise addition of ethyl cyclopropanecarboxylate (4.56 mL, 4.37 g, 38.0 mmol) and the reaction mixture maintained at RT for 16 hr. The resulting mixture was concentrated in vacuo to a volume of ˜15 mL and was then diluted with EtOH (20 mL) and p-tolylhydrazine hydrochloride (1.52 g, 9.57 mmol) was added. The mixture was acidified to pH 1 by the addition of conc hydrochloric acid and the resulting heterogeneous mixture was heated to 70° C. for 2 hr, then cooled to RT and concentrated in vacuo to a volume of ˜20 mL. The mixture was diluted with water (30 mL) and was adjusted to pH 12 by the addition of 2M aq NaOH and extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with brine (30 mL) and then dried and evaporated in vacuo. The residue was triturated with isohexane (20 mL) to afford the title compound, Intermediate A28, as a beige solid (1.60 g, 77%); Rt 3.35 min (Method 1 basic); m/z 214 (M+H)+, (ES+). The resulting mixture was concentrated in vacuo to a volume of ˜15 mL was added the resulting heterogeneous mixture was heated to 70° C. for 2 hr cooled to RT concentrated in vacuo to a volume of ˜20 mL The mixture was diluted with water (30 mL) was adjusted to pH 12 by the addition of 2M aq NaOH extracted with diethyl ether (2×20 mL) The combined organic extracts were washed with brine (30 mL) dried evaporated in vacuo The residue was triturated with isohexane (20 mL)