piperazine;dihydrochloride

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10 g), sodium azide (7.7 g) and piperazine dihydrochloride (7.5 g) in xylene (30 ml) was refluxed for 7 hours under stirring. The reaction was cooled to room temperature and extracted with 5% NaOH solution. The pooled alkaline solution was washed with toluene or xylene (15 ml) and the aqueous phase neutralized to pH 6.5 using concentrated HCL. The resulting suspension was stirred for 3 hours at room temperature and filtered obtain irbesartan (3.6 g, 96% purity by HPLC). was refluxed for 7 hours extracted with 5% NaOH solution The pooled alkaline solution was washed with toluene or xylene (15 ml) using concentrated HCL The resulting suspension was stirred for 3 hours at room temperature filtered

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10g), sodium azide (7.7 g) and piperazine dihydrochloride (7.5 g) in N,N-dimethylformamide (30 ml) was refluxed for 7 hours under stirring. The reaction was cooled to room temperature and 20 ml water was added. The reaction mixture was adjusted to pH of about 12 using 10% NaOH solution. The alkaline solution was washed with toluene (15 ml) and the aqueous phase was neutralized to pH of 6.0 using concentrated HCl. The resulting suspension was stirred for 3 hours at room temperature and filtered to obtain irbesartan (6.0 g, 92.7% purity by HPLC) and content of the impurity 2-n-butyl-3-[(2′-carboxamidobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-1-one 0.07%. When the pH was adjusted to 5.6, the yield remained same but the purity was further reduced to 90.2% and content of the impurity 2-n-butyl-3-[(2′-carboxamidobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-ene-4-one; 0.09%. was refluxed for 7 hours The alkaline solution was washed with toluene (15 ml) The resulting suspension was stirred for 3 hours at room temperature filtered

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10 g), sodium azide (7.7 g) and piperazine dihydrochloride (7.5 g) in N,N-dimethylformamide (30 ml) was refluxed for 7 hours under stirring. The reaction was cooled to room temperature and 20 ml water was added. The reaction mixture was adjusted to pH of about 12 using 10% NaOH solution. The alkaline solution was washed with toluene (15 ml) and the aqueous phase was neutralized to pH of 6.5 using concentrated HCl. The resulting suspension was stirred for 3 hours at room temperature and filtered to obtain irbesartan (5.8 g, 98% purity by HPLC). Recrystallization of the Product using ethanol results in 5.2 g of irbesartan with 99.94% purity and content of the impurity 2-n-butyl-3-[(2′-carboxamidobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one: 0.07%. was refluxed for 7 hours The alkaline solution was washed with toluene (15 ml) The resulting suspension was stirred for 3 hours at room temperature filtered

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10 g), sodium azide (7.7 g) and piperazine dihydrochloride (7.5 g) in N,N-dimethylformamide (30 ml) was refluxed for 7 hours under stirring. The reaction was cooled to room temperature and 20 ml water was added. The reaction mixture was adjusted to pH of about 12 using 10% NaOH solution. The alkaline solution was washed with toluene (15 ml) and the aqueous phase was neutralized to pH of 6.5 using concentrated HCl. The resulting suspension was stirred for 3 hours at room temperature and filtered to obtain irbesartan (5.8 g, 98% purity by HPLC). Recrystallization of the Product using ethanol results in 5.2 g of irbesartan with 99.94% purity and content of the impurity 2-n-butyl-3-[(2′-carboxamidobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one: 0.07%. was refluxed for 7 hours The alkaline solution was washed with toluene (15 ml) The resulting suspension was stirred for 3 hours at room temperature filtered

反応条件: temp:190.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add 3-bromo-2-chloro-pyridine (10.08 g, 52.4 mmol) to piperazine (45 g) and piperazine dihydrochloride (83.4 g). Heat the mixture to 190° C. with stirring for one hr. Allow the mixture to cool to about 80° C. then pour the material into water and extract 5 times with DCM. Dry the solution (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 15:85 methanol (with 2 M ammonia): DCM to give 1-(3-bromo-pyridin-2-yl)-piperazine as a white solid (8.98 g, 71%). Allow the mixture to cool to about 80° C. extract 5 times with DCM Dry the solution (sodium sulfate) filter concentrate Purify eluting with 15:85 methanol (with 2 M ammonia)

反応条件: temp:190.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add 3-bromo-2-chloro-pyridine (10.08 g, 52.4 mmol) to piperazine (45 g) and piperazine dihydrochloride (83.4 g). Heat the mixture to 190° C. with stirring for one hr. Allow the mixture to cool to about 80° C. then pour the material into water and extract 5 times with DCM. Dry the solution (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 15:85 methanol (with 2 M ammonia): DCM to give 1-(3-bromo-pyridin-2-yl)-piperazine as a white solid (8.98 g, 71%). Allow the mixture to cool to about 80° C. extract 5 times with DCM Dry the solution (sodium sulfate) filter concentrate Purify eluting with 15:85 methanol (with 2 M ammonia)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixtue of 38 g. (0.2 mole) piperazine hexahydrate, 28 g. (0.2 mole) piperazine dihydrochloride and 150 ml. methanol is mixed, while stirring at ambient temperature, with 45 g. (0.2 mole) methyl 4-bromomethylbenzoate. The reaction mixture is left to stand for 2 days and suction filtered from the precipitate. The clear solution is evaporated and the residue is recrystallised from ethanol to give 39 g. (64%) of the desired compound as a monohydrochloride; m.p. 226°-227° C. The reaction mixture is left suction filtered from the precipitate The clear solution is evaporated the residue is recrystallised from ethanol to give 39 g

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixtue of 38 g. (0.2 mole) piperazine hexahydrate, 28 g. (0.2 mole) piperazine dihydrochloride and 150 ml. methanol is mixed, while stirring at ambient temperature, with 45 g. (0.2 mole) methyl 4-bromomethylbenzoate. The reaction mixture is left to stand for 2 days and suction filtered from the precipitate. The clear solution is evaporated and the residue is recrystallised from ethanol to give 39 g. (64%) of the desired compound as a monohydrochloride; m.p. 226°-227° C. The reaction mixture is left suction filtered from the precipitate The clear solution is evaporated the residue is recrystallised from ethanol to give 39 g

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the piperazine dihydrochloride (20 g, 119 mmol) in MeOH (96 mL) at 0° C. (ice bath) was added triethylamine (48.7 mL, 357 mmol). tert-Butyl dicarbonate (61 g, 280 mmol) in MeOH (145 mL) was added over 30 min. The reaction temperature was maintained at <10° C. for 1 h, warmed to ambient temperature over 1 h and then heated to 50° C. for 18 h. The reaction was concentrated and the residue dissolved in ethanol (397 mL). A solution of NaOH (23.8 g, 595 mmol) in water (397 mL) was added and the reaction heated to 100° C. for 18 h, then cooled to ambient temperature. Mixture was neutralised with 1M HCl (−300 mL) to pH 9 (using a pH meter), then extracted with chloroform (3×700 mL), dried over sodium sulfate, filtered and concentrated. The residue was redissolved in MeOH and concentrated, then dried in vacuo at 40° C., to give the title compound (21 g, 75%) as a colourless solid. 1H NMR (Me-d3-OD): 4.20-4.07 (1H, m), 3.79 (1H, dd), 3.71-3.58 (2H, m), 3.54 (1H, dd), 3.24 (1H, dd), 3.18-3.01 (1H, m), 3.01-2.89 (1H, m), 2.55 (1H, dd), 1.48 (9H, s), 1.25 (3H, s). The reaction temperature was maintained at <10° C. for 1 h heated to 50° C. for 18 h The reaction was concentrated the residue dissolved in ethanol (397 mL) the reaction heated to 100° C. for 18 h cooled to ambient temperature then extracted with chloroform (3×700 mL) dried over sodium sulfate filtered concentrated The residue was redissolved in MeOH concentrated dried in vacuo at 40° C.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10 g), sodium azide (7.7 g) and piperazine dihydrochloride (7.5 g) in xylene (30 ml) was refluxed for 7 hours under stirring. The reaction was cooled to room temperature and extracted with 5% NaOH solution. The pooled alkaline solution was washed with toluene or xylene (15 ml) and the aqueous phase neutralized to pH 6.5 using concentrated HCL. The resulting suspension was stirred for 3 hours at room temperature and filtered obtain irbesartan (3.6 g, 96% purity by HPLC). was refluxed for 7 hours extracted with 5% NaOH solution The pooled alkaline solution was washed with toluene or xylene (15 ml) using concentrated HCL The resulting suspension was stirred for 3 hours at room temperature filtered

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10g), sodium azide (7.7 g) and piperazine dihydrochloride (7.5 g) in N,N-dimethylformamide (30 ml) was refluxed for 7 hours under stirring. The reaction was cooled to room temperature and 20 ml water was added. The reaction mixture was adjusted to pH of about 12 using 10% NaOH solution. The alkaline solution was washed with toluene (15 ml) and the aqueous phase was neutralized to pH of 6.0 using concentrated HCl. The resulting suspension was stirred for 3 hours at room temperature and filtered to obtain irbesartan (6.0 g, 92.7% purity by HPLC) and content of the impurity 2-n-butyl-3-[(2′-carboxamidobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-1-one 0.07%. When the pH was adjusted to 5.6, the yield remained same but the purity was further reduced to 90.2% and content of the impurity 2-n-butyl-3-[(2′-carboxamidobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-ene-4-one; 0.09%. was refluxed for 7 hours The alkaline solution was washed with toluene (15 ml) The resulting suspension was stirred for 3 hours at room temperature filtered

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10 g), sodium azide (7.7 g) and piperazine dihydrochloride (7.5 g) in N,N-dimethylformamide (30 ml) was refluxed for 7 hours under stirring. The reaction was cooled to room temperature and 20 ml water was added. The reaction mixture was adjusted to pH of about 12 using 10% NaOH solution. The alkaline solution was washed with toluene (15 ml) and the aqueous phase was neutralized to pH of 6.5 using concentrated HCl. The resulting suspension was stirred for 3 hours at room temperature and filtered to obtain irbesartan (5.8 g, 98% purity by HPLC). Recrystallization of the Product using ethanol results in 5.2 g of irbesartan with 99.94% purity and content of the impurity 2-n-butyl-3-[(2′-carboxamidobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one: 0.07%. was refluxed for 7 hours The alkaline solution was washed with toluene (15 ml) The resulting suspension was stirred for 3 hours at room temperature filtered