2-chloroethoxybenzene

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

Procedure: To a flask was added 7.2 g. (0.150 mole) of a 50% oil dispersion of sodium hydride. After washing the sodium hydride several times with hexane to remove the mineral oil, 18.9 g. (0.125 mole) of 4-chlorobenzyl cyanide in 50 ml of dry DMF was added dropwise at 0° C. Upon completion of the addition, the reaction was stirred for one hour while warming to room temperature, then 20.0 g. (0.128 mole) of 1-chloro-2-phenoxyethane was added dropwise at 15° C. over a 30 minute period. The stirred reaction was allowed to warm to room temperature and was complete in two hours. The reaction mixture was diluted with 300 ml. of water and extracted three times with 100 ml. portions of methylene chloride. The combined extracts were washed with dilute hydrochloric acid and water followed by drying using sodium sulfate. Upon removal of the solvent, 33 g. of the crude 2-(4-chlorophenyl)-4-phenoxybutanenitrile was obtained (96% yield). To a flask was added 7.2 g After washing the sodium hydride several times with hexane to remove the mineral oil, 18.9 g Upon completion of the addition The stirred reaction to warm to room temperature was complete in two hours The reaction mixture was diluted with 300 ml of water and extracted three times with 100 ml The combined extracts were washed with dilute hydrochloric acid and water by drying Upon removal of the solvent, 33 g

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

Procedure: To a flask was added 7.2 g. (0.150 mole) of a 50% oil dispersion of sodium hydride. After washing the sodium hydride several times with hexane to remove the mineral oil, 18.9 g. (0.125 mole) of 4-chlorobenzyl cyanide in 50 ml of dry DMF was added dropwise at 0° C. Upon completion of the addition, the reaction was stirred for one hour while warming to room temperature, then 20.0 g. (0.128 mole) of 1-chloro-2-phenoxyethane was added dropwise at 15° C. over a 30 minute period. The stirred reaction was allowed to warm to room temperature and was complete in two hours. The reaction mixture was diluted with 300 ml. of water and extracted three times with 100 ml. portions of methylene chloride. The combined extracts were washed with dilute hydrochloric acid and water followed by drying using sodium sulfate. Upon removal of the solvent, 33 g. of the crude 2-(4-chlorophenyl)-4-phenoxybutanenitrile was obtained (96% yield). To a flask was added 7.2 g After washing the sodium hydride several times with hexane to remove the mineral oil, 18.9 g Upon completion of the addition The stirred reaction to warm to room temperature was complete in two hours The reaction mixture was diluted with 300 ml of water and extracted three times with 100 ml The combined extracts were washed with dilute hydrochloric acid and water by drying Upon removal of the solvent, 33 g

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

Procedure: To a flask was added 41.5 grams (g.) (0.3 mole) of 2-phenoxyethanol, 50 ml of toluene and 3.93 g. of pyridine, then 39.3 g. (0.33 mole) of thionyl chloride dropwise while stirring at room temperature. The exothermic reaction was heated at 50°-60° C. for two hours. After cooling to room temperature, the resulting salt was filtered and washed with methylene chloride. The filtrate was washed several times with aqueous sodium bicarbonate, dried using sodium sulfate, and then concentrated to obtain 39 g. of the 1-chloro-2-phenoxyethane as a yellow oil (83% yield). The exothermic reaction was heated at 50°-60° C. for two hours the resulting salt was filtered washed with methylene chloride The filtrate was washed several times with aqueous sodium bicarbonate dried concentrated to obtain 39 g

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

Procedure: To a flask was added 41.5 grams (g.) (0.3 mole) of 2-phenoxyethanol, 50 ml of toluene and 3.93 g. of pyridine, then 39.3 g. (0.33 mole) of thionyl chloride dropwise while stirring at room temperature. The exothermic reaction was heated at 50°-60° C. for two hours. After cooling to room temperature, the resulting salt was filtered and washed with methylene chloride. The filtrate was washed several times with aqueous sodium bicarbonate, dried using sodium sulfate, and then concentrated to obtain 39 g. of the 1-chloro-2-phenoxyethane as a yellow oil (83% yield). The exothermic reaction was heated at 50°-60° C. for two hours the resulting salt was filtered washed with methylene chloride The filtrate was washed several times with aqueous sodium bicarbonate dried concentrated to obtain 39 g

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

Procedure: 15.7 g (0.1 mol) of p-chloroethoxybenzene was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 100 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 100 ml diethyl ether solution of 0.5 g of [1,3-bis(diphenylphosphino)propane]nickel (II) chloride and 31.5 g (0.1 mol) of 4-(trans-4-(2-(trans-4-(3-methoxypropyl)-4-silacyclohexyl)ethyl)cyclohexyl)phenyl chloride. After a conventional after treatment, purification was conducted by means of chromatography to obtain 32.2 g (yield 67.5%) of 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-ethoxybiphenyl was obtained. to obtain a Grignard's reagent After a conventional after treatment, purification

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

Procedure: 15.7 g (0.1 mol) of p-chloroethoxybenzene was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 100 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 100 ml diethyl ether solution of 0.5 g of [1,3-bis(diphenylphosphino)propane]nickel (II) chloride and 31.5 g (0.1 mol) of 4-(trans-4-(2-(trans-4-(3-methoxypropyl)-4-silacyclohexyl)ethyl)cyclohexyl)phenyl chloride. After a conventional after treatment, purification was conducted by means of chromatography to obtain 32.2 g (yield 67.5%) of 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-ethoxybiphenyl was obtained. to obtain a Grignard's reagent After a conventional after treatment, purification

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

Procedure: Nefazodone and two processes for its preparation have) been described in Canadian Patent 1,198,436 and in PCT/EP93/03119 published May 26, 1994. The '436 patent relates to the preparation of 2-phenoxyalkyl-1,2,4 triazol-3-one derivatives Scheme 1 below depicts the two different methods described in the '436 patent. ##STR1## 5-Ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3-one, compound 1.3 is alkylated with 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine, compound 1.5 in the presence of base to give nefazodone. Alternatively, 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl-5-ethyl-4H-1,2,4-triazol-3-one, compound 1.4, is alkylated with 2-phenoxyethyl chloride in the presence of base to give nefazodone.

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

Procedure: 1-(2-Phenoxyethyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-2-phenoxyethane essentially as described above in Example 38, Scheme C, step a.