N-(3-氯丙基)四氢吡咯烷盐酸盐

反应条件: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 1-bromo-3-chloropropane (99.5 kg) in toluene (237 kg) was heated to 40-45° C. To this solution was added pyrrolidine (94.5 kg) over 1.5 hours, maintaining the temperature at 40-45° C. A line wash of toluene (37 kg) was applied and the reaction maintained at 40-45° C. for a further four hours. The reaction mixture was cooled to 20-25° C. and washed with water (211 kg). Further water (138 kg) was added and the pH adjusted to 8.8-9.0 by the addition of 34% w/w hydrochloric acid (4.7 kg). The aqueous phase was separated and discarded. To the organic phase was added 34% w/w hydrochloric acid (61 kg) until the pH was 0.5-1.0. The aqueous was separated and concentrated under vacuum, maintaining the temperature <50° C. until the toluene content was <0.1%, giving an aqueous solution of 1-(3-chloropropyl)pyrrolidine hydrochloride 129.1 kg at 71.5% w/w, 79.9% A line wash of toluene (37 kg) the reaction maintained at 40-45° C. for a further four hours The reaction mixture was cooled to 20-25° C. washed with water (211 kg) Further water (138 kg) was added the pH adjusted to 8.8-9.0 by the addition of 34% w/w hydrochloric acid (4.7 kg) The aqueous phase was separated To the organic phase was added 34% w/w hydrochloric acid (61 kg) until the pH was 0.5-1.0 The aqueous was separated concentrated under vacuum maintaining the temperature <50° C. until the toluene content

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 71.5% w/w aqueous solution of 1-(3-chloropropyl)pyrrolidine hydrochloride (25 kg) was diluted with water (14 l) and methyl tert-butyl ether (12 l) added. The stirred mixture was basified to pH>11 by addition of 46% w/w aqueous sodium hydroxide solution (6.5 l). The layers were separated and he lower aqueous phase was further extracted with methyl tert-butyl ether (12 l). The combined organic layers were washed with 20% w/w aqueous sodium chloride solution (12.5 kg) to give a solution of 1-(3-chloropropyl)pyrrolidine in methyl tert-butyl ether. added The layers were separated he lower aqueous phase was further extracted with methyl tert-butyl ether (12 l) The combined organic layers were washed with 20% w/w aqueous sodium chloride solution (12.5 kg)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: After adding the N-[2,3-dimethyl-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl]-N′-cyclopropylurea (100 mg) synthesized in Example 721, 1-(3-chloropropyl)pyrrolidine hydrochloride (95 mg) and potassium carbonate (150 mg) to dimethylformamide (2 ml), the mixture was heated at 60° C. for 7 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was washed with ethyl acetate to obtain the title compound (49 mg) as light yellow crystals. the organic layer was washed with water and saturated saline in that order dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure The obtained crude product was washed with ethyl acetate

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were dissolved in dry dimethylformamide (100 ml) at 100° , 1-(3-chloropropyl)pyrrolidine hydrochloride (3.6 g, 20 mmol) added, and stirring continued for 1 hour. The mixture was diluted with water and extracted with ether, and the ether extracts dried and evaporated. Chromatography (silica gel, 0-3% methanolic ammonia in chloroform) and recrystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-(1-pyrrolidinyl)propoxy)quinoline (0.35 g, 8.5 %), m.p. 101°-103°. extracted with ether the ether extracts dried evaporated Chromatography (silica gel, 0-3% methanolic ammonia in chloroform) and recrystallisation from ether

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: After adding the N-[2,3-dimethyl-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl]-N′-cyclopropylurea (100 mg) synthesized in Example 721, 1-(3-chloropropyl)pyrrolidine hydrochloride (95 mg) and potassium carbonate (150 mg) to dimethylformamide (2 ml), the mixture was heated at 60° C. for 7 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was washed with ethyl acetate to obtain the title compound (49 mg) as light yellow crystals. the organic layer was washed with water and saturated brine in that order dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure The obtained crude product was washed with ethyl acetate

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (1.28 g), 3-(pyrrolidin-1-yl)propyl chloride hydrochloride (Chem. Abs., 82, 57736; 1.5 g), potassium carbonate (2.8 g) and DMF (20 ml) was stirred and heated to 80° C. for 5 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 20:3 mixture of methylene chloride and methanol as eluent. The material so obtained (1.1 g) was triturated under ethyl acetate to give 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-pyrrolidin-1-ylpropoxy)quinazoline (0.094 g). The organic solution was evaporated and the residual solid was recrystallised from acetonitrile. There was thus obtained a second crop (0.85 g) of the same product. The material gave the following characterising data: The mixture was cooled to ambient temperature partitioned between ethyl acetate and water The organic phase was washed with water dried (MgSO4) evaporated The residue was purified by column chromatography a 20:3 mixture of methylene chloride and methanol as eluent The material so obtained (1.1 g) was triturated under ethyl acetate

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (1.28 g), 3-(pyrrolidin-1-yl)propyl chloride hydrochloride (Chem. Abs., 82, 57736; 1.5 g), potassium carbonate (2.8 g) and DMF (20 ml) was stirred and heated to 80° C. for 5 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 20:3 mixture of methylene chloride and methanol as eluent. The material so obtained (1.1 g) was triturated under ethyl acetate to give 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-pyrrolidin-1-ylpropoxy)quinazoline (0.094 g). The organic solution was evaporated and the residual solid was recrystallised from acetonitrile. There was thus obtained a second crop (0.85 g) of the same product. The material gave the following characterising data: The mixture was cooled to ambient temperature partitioned between ethyl acetate and water The organic phase was washed with water dried (MgSO4) evaporated The residue was purified by column chromatography a 20:3 mixture of methylene chloride and methanol as eluent The material so obtained (1.1 g) was triturated under ethyl acetate

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Following the procedure described in example 2, but starting from trans-5-(3-hydroxyprop-1-en-1-yl)benzodioxolane (400 mg), potassium hydroxide (283 mg, 85% wt) and 1-(3-chloropropyl)pyrrolidine, hydrochloride (376 mg) in dimethylsufoxide (5 mL) affords 90 mg of trans-1-{3-[3-(benzodioxol-5-yl)allyloxy]-propyl}pyrrolidine, oxalate as a white solid melting at 109-111° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A Following the procedure described in example 2, but starting from trans-3-(benzofuran-5-yl)prop-2-en-1-ol (600 mg), potassium hydroxide (477 mg 85% wt) and 1-(3-chloropropyl)pyrrolidine, hydrochloride (647 mg) in dimethylsufoxide (5 mL) affords 120 mg of trans-1-{3-[3-(benzofuran-5-yl)allyloxy]propyl}pyrrolidine, oxalate as a white solid.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Following the procedure described in example 2, but starting from trans-3-(4-fluoro-3-methylphenyl)prop-2-en-1-ol (710 mg), potassium hydroxide (592 mg, 85% wt) and 1-(3-chloropropyl)pyrrolidine, hydrochloride (802 mg) in dimethylsufoxide (6 mL) affords 280 mg of trans-1-{3-[3-(4-fluoro-3-methylphenyl)allyloxy]propyl}-pyrrolidine.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Following the procedure described in example 2, but starting from 3-(4-fluoro-3-methoxyphenyl)prop-2-en-1-ol (600 mg), potassium hydroxide (456 mg, 85% wt) and 1-(3-chloropropyl)pyrrolidine, hydrochloride (618 mg) in dimethylsufoxide (5 mL) affords 40 mg of trans-1-{3-[3-(4-fluoro-3-methoxyphenyl)allyloxy]-propyl}pyrrolidine, oxalate as a solid melting at 143-144° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Following the procedure described in example 2, but starting from 3-(4-fluoro-3-methoxyphenyl)prop-2-en-1-ol (600 mg), potassium hydroxide (456 mg, 85% wt) and 1-(3-chloropropyl)pyrrolidine, hydrochloride (618 mg) in dimethylsufoxide (5 mL) affords 40 mg of trans-1-{3-[3-(4-fluoro-3-methoxyphenyl)allyloxy]-propyl}pyrrolidine, oxalate as a solid melting at 143-144° C.