1-(2-chloroethyl)imidazolidin-2-one

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

Procedure: A mixture of 1-(4-fluorophenyl)-5-(2-methyl-5-tetrazolyl)-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (21a) (4 g), 1-(2-chloroethyl)imidazolidin-2-one (1.8 g), potassium carbonate (2.1 g) and potassium iodide (0.5 g) in MIBK (80 mL) was boiled at reflux for 20 hours. After cooling, inorganic salts were filtered off and the solvent evaporated in vacuo. The title compound crystallised from ethyl acetate. Yield 3.0 g. Mp 201-203° C. 1H NMR (CDCl3): δ 2.60-2.70 (m, 4H), 2.80 (t, 2H), 3.30 (broad s, 2H), 3.35-3.45 (m, 4H), 3.55 (t, 2H), 4.40 (s, 3H), 4.65 (s, 1H), 6.35 (broad s, 1H), 7.20 (t, 2H), 7.25 (s, 1H), 7.40-7.50 (m, 3H), 7.95 (d, 1H), 8.25 (s, 1H); MS m/z (%): 487 (MH+, 12), 142 (49), 113 (100). at reflux for 20 hours After cooling inorganic salts were filtered off the solvent evaporated in vacuo The title compound crystallised from ethyl acetate

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

Procedure: To a solution of sodium (1.63 g, 0.071 mol) in methanol (60 mL) is added dropwise 3-hydroxy-2,4,6-trimethylbenzaldehyde (11.90 g, 0.073 mol) in anhydrous toluene (300 mL). The mixture is heated under reflux and then the methanol is distilled off (volume of azeotropic mixture collected 80-90 mL). After returning to 80-90° C., (2-chloroethyl)imidazolidin-2-one (10.45 g, 0.070 mol) is added all at once to the reaction medium. After heating for 7 hours under reflux, the solvents are evaporated under reduced pressure (Tbath 50° C., 25 mbar). Dichloromethane (150 mL) and water (30 mL) are added to the mixture obtained. The organic phase is then washed twice with water (20 mL). After drying over Na2SO4, the dichloromethane is evaporated under reduced pressure (Tbath 35° C., 33 mbar). Petroleum ether (3 times 50 mL) and water (50 mL) are added to the mixture obtained (24 g) and the precipitate obtained is filtered and washed on the filter with water (15 mL) and petroleum ether (twice 15 mL). The mixture is heated under reflux the methanol is distilled off (volume of azeotropic mixture collected 80-90 mL) After returning to 80-90° C. After heating for 7 hours under reflux the solvents are evaporated under reduced pressure (Tbath 50° C., 25 mbar) Dichloromethane (150 mL) and water (30 mL) are added to the mixture obtained The organic phase is then washed twice with water (20 mL) After drying over Na2SO4 the dichloromethane is evaporated under reduced pressure (Tbath 35° C., 33 mbar) Petroleum ether (3 times 50 mL) and water (50 mL) are added to the mixture obtained (24 g) the precipitate obtained is filtered washed on the filter with water (15 mL) and petroleum ether (twice 15 mL)

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

Procedure: To a solution of sodium (1.63 g, 0.071 mol) in methanol (60 mL) is added dropwise 3-hydroxy-2,4,6-trimethylbenzaldehyde (11.90 g, 0.073 mol) in anhydrous toluene (300 mL). The mixture is heated under reflux and then the methanol is distilled off (volume of azeotropic mixture collected 80-90 mL). After returning to 80-90° C., (2-chloroethyl)imidazolidin-2-one (10.45 g, 0.070 mol) is added all at once to the reaction medium. After heating for 7 hours under reflux, the solvents are evaporated under reduced pressure (Tbath 50° C., 25 mbar). Dichloromethane (150 mL) and water (30 mL) are added to the mixture obtained. The organic phase is then washed twice with water (20 mL). After drying over Na2SO4, the dichloromethane is evaporated under reduced pressure (Tbath 35° C., 33 mbar). Petroleum ether (3 times 50 mL) and water (50 mL) are added to the mixture obtained (24 g) and the precipitate obtained is filtered and washed on the filter with water (15 mL) and petroleum ether (twice 15 mL). The mixture is heated under reflux the methanol is distilled off (volume of azeotropic mixture collected 80-90 mL) After returning to 80-90° C. After heating for 7 hours under reflux the solvents are evaporated under reduced pressure (Tbath 50° C., 25 mbar) Dichloromethane (150 mL) and water (30 mL) are added to the mixture obtained The organic phase is then washed twice with water (20 mL) After drying over Na2SO4 the dichloromethane is evaporated under reduced pressure (Tbath 35° C., 33 mbar) Petroleum ether (3 times 50 mL) and water (50 mL) are added to the mixture obtained (24 g) the precipitate obtained is filtered washed on the filter with water (15 mL) and petroleum ether (twice 15 mL)

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

Procedure: A mixture of 1-(4-fluorophenyl)-5-(2-methyl-5-tetrazolyl)-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (21a) (4 g), 1-(2-chloroethyl)imidazolidin-2-one (1.8 g), potassium carbonate (2.1 g) and potassium iodide (0.5 g) in MIBK (80 mL) was boiled at reflux for 20 hours. After cooling, inorganic salts were filtered off and the solvent evaporated in vacuo. The title compound crystallised from ethyl acetate. Yield 3.0 g. Mp 201-203° C. 1H NMR (CDCl3): δ 2.60-2.70 (m, 4H), 2.80 (t, 2H), 3.30 (broad s, 2H), 3.35-3.45 (m, 4H), 3.55 (t, 2H), 4.40 (s, 3H), 4.65 (s, 1H), 6.35 (broad s, 1H), 7.20 (t, 2H), 7.25 (s, 1H), 7.40-7.50 (m, 3H), 7.95 (d, 1H), 8.25 (s, 1H); MS m/z (%): 487 (MH+, 12), 142 (49), 113 (100). at reflux for 20 hours After cooling inorganic salts were filtered off the solvent evaporated in vacuo The title compound crystallised from ethyl acetate

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

Procedure: A mixture of 1-(4-fluorophenyl)-5-(2-methyl-5-tetrazolyl)-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (21a) (4 g), 1-(2-chloroethyl)imidazolidin-2-one (1.8 g), potassium carbonate (2.1 g) and potassium iodide (0.5 g) in MIBK (80 mL) was boiled at reflux for 20 hours. After cooling, inorganic salts were filtered off and the solvent evaporated in vacuo. The title compound crystallised from ethyl acetate. Yield 3.0 g. Mp 201-203° C. 1H NMR (CDCl3): δ 2.60-2.70 (m, 4H), 2.80 (t, 2H), 3.30 (broad s, 2H), 3.35-3.45 (m, 4H), 3.55 (t, 2H), 4.40 (s, 3H), 4.65 (s, 1H), 6.35 (broad s, 1H), 7.20 (t, 2H), 7.25 (s, 1H), 7.40-7.50 (m, 3H), 7.95 (d, 1H), 8.25 (s, 1H); MS m/z (%): 487 (MH+, 12), 142 (49), 113 (100). at reflux for 20 hours After cooling inorganic salts were filtered off the solvent evaporated in vacuo The title compound crystallised from ethyl acetate

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

Procedure: 21.4 g (0.144 mol) of 1-(2-chloroethyl)imidazolidin-2-one, 23.6 g (0.107 mol) of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine, 92.9 g (0.67 mol) of potassium carbonate, 2.6 g of potassium iodide and 524 ml of methyl isobutyl ketone are placed in a three-necked flask. Refluxing is carried out for one night, and then the reaction mixture is concentrated and taken up in a mixture of water/ethyl acetate. Decanting is carried out, and the organic phase is washed several times with water and then extracted with a normal solution of hydrochloric acid. The acidic phase is then rendered basic with sodium hydroxide solution and extracted with methylene chloride. Drying is carried out over MgSO4. After evaporation, the residue is recrystallised from 80 ml of acetonitrile to yield 22 g of a solid that corresponds to the expected product. M.p.=137°-141° C. (Yield=46%). Refluxing is carried out for one night the reaction mixture is concentrated taken up in a mixture of water/ethyl acetate Decanting the organic phase is washed several times with water extracted with a normal solution of hydrochloric acid extracted with methylene chloride Drying After evaporation the residue is recrystallised from 80 ml of acetonitrile

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

Procedure: A mixture of piperazine (86 g, 1.0 mol), 1-(2-chloroethyl)-imidazolidin-2-one (74 g, 0.5 mol) and sodium carbonate (159 g, 1.5 mol) in ethanol (500 ml) was refluxed with stirring for 1.5 hours. A solution of 1-(2-chloroethyl)-imidazolidin-2-one (74 g, 0.5 mol) in methanol (75 ml) was then added in the course of 1.5 hours, at reflux temperature, whereupon the reaction mixture was refluxed for 18 hours. After cooling, the reaction mixture was filtered and evaporated in vacuo. The residue was dissolved in hot ethanol (100 ml), whereupon ethyl acetate (200 ml) was added. The crystals were filtered and dried to give 1-(2-(2-imidazolidinon-1-yl)ethyl)piperazine (60 g) mp. 136°-140° C. Additional 22 g could be obtained from the mother liquor. was refluxed at reflux temperature whereupon the reaction mixture was refluxed for 18 hours After cooling the reaction mixture was filtered evaporated in vacuo The residue was dissolved in hot ethanol (100 ml) whereupon ethyl acetate (200 ml) was added The crystals were filtered dried

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

Procedure: The intermediate may be worked up in a conventional manner. The further process leading to sertindole comprises cyclization of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine to the corresponding 3-acetoxy-indole using eg. acetic anhydride in the presence of alkalimetal acetate such as sodium acetate. 5-chloro-1-(4-fluoro)indole is then obtained from the 3-acetoxy-indole by reduction and subsequent elimination of H2O. The resulting 5-chloro-1-(4-fluorophenyl)indole is reacted with 4-piperidone according to the above procedure, the resulting 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole is reduced in order to obtain 5-chloro-1-(4-fluorophenyl)-3-(piperidin-4-yl)indole which in turn is reacted with 1-(2-chloroethyl)-2-imidazolidinon to obtain sertindole. Alternatively, the 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole may first be reacted with 1-(2-chloroethyl)-2-imidazolidinon followed by reduction, thereby obtaining sertindole, which may be isolated as an acid addition salt, e.g. the tartrate, or as the free base.

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

Procedure: A solution of 5.00 g (38.42 mmol) of 1-(2-hydroxyethyl)imidazolidin-2-one 44-1 and 3.82 mL (52.39 mmol) of thionyl chloride in 75 mL of chloroform was stirred at reflux for 4 hours. The reaction was concentrated in vacuo to an orange oil, which was redissolved in chloroform and washed twice with water. The organic layer was dried and reconcentrated to give the crude desired product as an orange solid. The solid was used as obtained from the reaction without further purification. at reflux for 4 hours The reaction was concentrated in vacuo to an orange oil, which was redissolved in chloroform washed twice with water The organic layer was dried

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

Procedure: To a solution of sodium (1.63 g, 0.071 mol) in methanol (60 mL) is added dropwise 3-hydroxy-2,4,6-trimethylbenzaldehyde (11.90 g, 0.073 mol) in anhydrous toluene (300 mL). The mixture is heated under reflux and then the methanol is distilled off (volume of azeotropic mixture collected 80-90 mL). After returning to 80-90° C., (2-chloroethyl)imidazolidin-2-one (10.45 g, 0.070 mol) is added all at once to the reaction medium. After heating for 7 hours under reflux, the solvents are evaporated under reduced pressure (Tbath 50° C., 25 mbar). Dichloromethane (150 mL) and water (30 mL) are added to the mixture obtained. The organic phase is then washed twice with water (20 mL). After drying over Na2SO4, the dichloromethane is evaporated under reduced pressure (Tbath 35° C., 33 mbar). Petroleum ether (3 times 50 mL) and water (50 mL) are added to the mixture obtained (24 g) and the precipitate obtained is filtered and washed on the filter with water (15 mL) and petroleum ether (twice 15 mL). The mixture is heated under reflux the methanol is distilled off (volume of azeotropic mixture collected 80-90 mL) After returning to 80-90° C. After heating for 7 hours under reflux the solvents are evaporated under reduced pressure (Tbath 50° C., 25 mbar) Dichloromethane (150 mL) and water (30 mL) are added to the mixture obtained The organic phase is then washed twice with water (20 mL) After drying over Na2SO4 the dichloromethane is evaporated under reduced pressure (Tbath 35° C., 33 mbar) Petroleum ether (3 times 50 mL) and water (50 mL) are added to the mixture obtained (24 g) the precipitate obtained is filtered washed on the filter with water (15 mL) and petroleum ether (twice 15 mL)

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

Procedure: A mixture of 1-(4-fluorophenyl)-5-(2-methyl-5-tetrazolyl)-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (21a) (4 g), 1-(2-chloroethyl)imidazolidin-2-one (1.8 g), potassium carbonate (2.1 g) and potassium iodide (0.5 g) in MIBK (80 mL) was boiled at reflux for 20 hours. After cooling, inorganic salts were filtered off and the solvent evaporated in vacuo. The title compound crystallised from ethyl acetate. Yield 3.0 g. Mp 201-203° C. 1H NMR (CDCl3): δ 2.60-2.70 (m, 4H), 2.80 (t, 2H), 3.30 (broad s, 2H), 3.35-3.45 (m, 4H), 3.55 (t, 2H), 4.40 (s, 3H), 4.65 (s, 1H), 6.35 (broad s, 1H), 7.20 (t, 2H), 7.25 (s, 1H), 7.40-7.50 (m, 3H), 7.95 (d, 1H), 8.25 (s, 1H); MS m/z (%): 487 (MH+, 12), 142 (49), 113 (100). at reflux for 20 hours After cooling inorganic salts were filtered off the solvent evaporated in vacuo The title compound crystallised from ethyl acetate