氯沙坦杂质20

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 750 ml flask is charged with 54.4 g (0.2 mol) of 4′-bromomethyl-biphenyl-2-carbonitrile and 250 ml of toluene. To this suspension is added a solution of 30 g (0.3 mol) of potassium acetate in 15 ml of water. The heterogeneous mixture is heated up to an internal temperature of 90° C. to become a clear biphasic solution. After 12 hours at an internal temperature of 90° C. the conversion to the OAc derivative is complete. The biphasic mixture is cooled down to internal temperature of about 50° C. followed by addition of 150 ml NaOH (2N). The mixture is heated up to an internal temperature of ca. 70° C. (extern. temp. 80° C.). After 5 hours at this temperature the PTC saponification is complete (100% conversion, HPLC). Additional 150 ml toluene is added and the warm reaction solution (ca. 50° C.) is washed three times with 50 ml of hot water until the pH is around 7. The toluene phase is evaporated under reduced pressure and the resulting crystalline residue is dried at 50° C. over 24 hours in vacuum to give the white crystalline product with 98% purity (HPLC) and a water content of 0.23%. The biphasic mixture is cooled down to internal temperature of about 50° C. The mixture is heated up to an internal temperature of ca. 70° C. (extern. temp. 80° C.) the warm reaction solution (ca. 50° C.) is washed three times with 50 ml of hot water until the pH is around 7 The toluene phase is evaporated under reduced pressure the resulting crystalline residue is dried at 50° C. over 24 hours in vacuum to give the white crystalline product with 98% purity (HPLC)

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2.1 g of 4′-hydroxymethyl-biphenyl-2-carbonitrile (10 mmol), are treated, in a drop wise manner at 0° C. with 5.52 ml of triethyl aluminium (10 mmol, 1.8M in toluene). The reaction mixture is stirred for 5 minutes. After that, the clear colourless reaction mixture is added to the solution of diisobutyl aluminium azide (19 mmol), gradually warmed to an internal temperature of about 100° C. and stirred over the night (conversion 95.7%). For the work up the reaction mixture is cooled to 0° C. and added dropwise to a solution of 30 ml of HCl (2 N) containing 1.38 g of NaNO2 (20 mmol) (cooled to 0° C.). 40 ml of iso-propyl acetate are added and the mixture is extracted once with 15 ml of HCl 2N, once with 20 ml of water. The combining aqueous layers are extracted twice with 10 ml of isopropyl acetate. The organic phase is extracted three times with 15 ml portions of an aqueous solution of K2CO3 (10%). The aqueous phase is washed once with 15 ml of isopropyl acetate. HCl (2 N) is added to the aqueous phase to adjust the pH to 2, and the solution is extracted three times with 20 ml portion of isopropyl acetate. The combining organic phase is washed once with 20 ml of water and the solvent is removed to give the crude product. The crude product is crystallized from ethyl acetate and isopropyl ether to give the pure product. stirred over the night (conversion 95.7%) For the work up the reaction mixture is cooled to 0° C. the mixture is extracted once with 15 ml of HCl 2N, once with 20 ml of water The combining aqueous layers are extracted twice with 10 ml of isopropyl acetate The organic phase is extracted three times with 15 ml portions of an aqueous solution of K2CO3 (10%) The aqueous phase is washed once with 15 ml of isopropyl acetate. HCl (2 N) is added to the aqueous phase the solution is extracted three times with 20 ml portion of isopropyl acetate The combining organic phase is washed once with 20 ml of water the solvent is removed

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2.1 g of 4′-hydroxymethyl-biphenyl-2-carbonitrile (10 mmol), are treated, in a drop wise manner at 0° C. with 5.52 ml of triethyl aluminium (10 mmol, 1.8M in toluene). The reaction mixture is stirred for 5 minutes. After that, the clear colourless reaction mixture is added to the solution of diisobutyl aluminium azide (19 mmol), gradually warmed to an internal temperature of about 100° C. and stirred over the night (conversion 95.7%). For the work up the reaction mixture is cooled to 0° C. and added dropwise to a solution of 30 ml of HCl (2 N) containing 1.38 g of NaNO2 (20 mmol) (cooled to 0° C.). 40 ml of iso-propyl acetate are added and the mixture is extracted once with 15 ml of HCl 2N, once with 20 ml of water. The combining aqueous layers are extracted twice with 10 ml of isopropyl acetate. The organic phase is extracted three times with 15 ml portions of an aqueous solution of K2CO3 (10%). The aqueous phase is washed once with 15 ml of isopropyl acetate. HCl (2 N) is added to the aqueous phase to adjust the pH to 2, and the solution is extracted three times with 20 ml portion of isopropyl acetate. The combining organic phase is washed once with 20 ml of water and the solvent is removed to give the crude product. The crude product is crystallized from ethyl acetate and isopropyl ether to give the pure product. stirred over the night (conversion 95.7%) For the work up the reaction mixture is cooled to 0° C. the mixture is extracted once with 15 ml of HCl 2N, once with 20 ml of water The combining aqueous layers are extracted twice with 10 ml of isopropyl acetate The organic phase is extracted three times with 15 ml portions of an aqueous solution of K2CO3 (10%) The aqueous phase is washed once with 15 ml of isopropyl acetate. HCl (2 N) is added to the aqueous phase the solution is extracted three times with 20 ml portion of isopropyl acetate The combining organic phase is washed once with 20 ml of water the solvent is removed

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

实验步骤: According to U.S. Pat. No. 5,399,578, the process for the preparation of Valsartan (I) involves the reaction of 4′-bromomethyl-2-cyanobiphenyl (II) with sodium acetate and glacial acetic acid to produce 2′-cyano-4-hydroxymethylbiphenyl (III), which is reacted with oxalyl chloride in dichloromethane and dimethyl sulfoxide to produce 2′-cyano-4-formylbiphenyl (IV), which is further reacted with (L)-valine methyl ester hydrochloride (V) and sodium cyanoborohydride to produce N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VI), followed by treatment with valeryl chloride to produce N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII), which is treated with tri-n-butyltin azide followed by flash chromatography to produce Valsartan of formula (I).

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 750 ml flask is charged with 54.4 g (0.2 mol) of 4′-bromomethyl-biphenyl-2-carbonitrile and 250 ml of toluene. To this suspension is added a solution of 30 g (0.3 mol) of potassium acetate in 15 ml of water. The heterogeneous mixture is heated up to an internal temperature of 90° C. to become a clear biphasic solution. After 12 hours at an internal temperature of 90° C. the conversion to the OAc derivative is complete. The biphasic mixture is cooled down to internal temperature of about 50° C. followed by addition of 150 ml NaOH (2N). The mixture is heated up to an internal temperature of ca. 70° C. (extern. temp. 80° C.). After 5 hours at this temperature the PTC saponification is complete (100% conversion, HPLC). Additional 150 ml toluene is added and the warm reaction solution (ca. 50° C.) is washed three times with 50 ml of hot water until the pH is around 7. The toluene phase is evaporated under reduced pressure and the resulting crystalline residue is dried at 50° C. over 24 hours in vacuum to give the white crystalline product with 98% purity (HPLC) and a water content of 0.23%. The biphasic mixture is cooled down to internal temperature of about 50° C. The mixture is heated up to an internal temperature of ca. 70° C. (extern. temp. 80° C.) the warm reaction solution (ca. 50° C.) is washed three times with 50 ml of hot water until the pH is around 7 The toluene phase is evaporated under reduced pressure the resulting crystalline residue is dried at 50° C. over 24 hours in vacuum to give the white crystalline product with 98% purity (HPLC)

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2.1 g of 4′-hydroxymethyl-biphenyl-2-carbonitrile (10 mmol), are treated, in a drop wise manner at 0° C. with 5.52 ml of triethyl aluminium (10 mmol, 1.8M in toluene). The reaction mixture is stirred for 5 minutes. After that, the clear colourless reaction mixture is added to the solution of diisobutyl aluminium azide (19 mmol), gradually warmed to an internal temperature of about 100° C. and stirred over the night (conversion 95.7%). For the work up the reaction mixture is cooled to 0° C. and added dropwise to a solution of 30 ml of HCl (2 N) containing 1.38 g of NaNO2 (20 mmol) (cooled to 0° C.). 40 ml of iso-propyl acetate are added and the mixture is extracted once with 15 ml of HCl 2N, once with 20 ml of water. The combining aqueous layers are extracted twice with 10 ml of isopropyl acetate. The organic phase is extracted three times with 15 ml portions of an aqueous solution of K2CO3 (10%). The aqueous phase is washed once with 15 ml of isopropyl acetate. HCl (2 N) is added to the aqueous phase to adjust the pH to 2, and the solution is extracted three times with 20 ml portion of isopropyl acetate. The combining organic phase is washed once with 20 ml of water and the solvent is removed to give the crude product. The crude product is crystallized from ethyl acetate and isopropyl ether to give the pure product. stirred over the night (conversion 95.7%) For the work up the reaction mixture is cooled to 0° C. the mixture is extracted once with 15 ml of HCl 2N, once with 20 ml of water The combining aqueous layers are extracted twice with 10 ml of isopropyl acetate The organic phase is extracted three times with 15 ml portions of an aqueous solution of K2CO3 (10%) The aqueous phase is washed once with 15 ml of isopropyl acetate. HCl (2 N) is added to the aqueous phase the solution is extracted three times with 20 ml portion of isopropyl acetate The combining organic phase is washed once with 20 ml of water the solvent is removed

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2.1 g of 4′-hydroxymethyl-biphenyl-2-carbonitrile (10 mmol), are treated, in a drop wise manner at 0° C. with 5.52 ml of triethyl aluminium (10 mmol, 1.8M in toluene). The reaction mixture is stirred for 5 minutes. After that, the clear colourless reaction mixture is added to the solution of diisobutyl aluminium azide (19 mmol), gradually warmed to an internal temperature of about 100° C. and stirred over the night (conversion 95.7%). For the work up the reaction mixture is cooled to 0° C. and added dropwise to a solution of 30 ml of HCl (2 N) containing 1.38 g of NaNO2 (20 mmol) (cooled to 0° C.). 40 ml of iso-propyl acetate are added and the mixture is extracted once with 15 ml of HCl 2N, once with 20 ml of water. The combining aqueous layers are extracted twice with 10 ml of isopropyl acetate. The organic phase is extracted three times with 15 ml portions of an aqueous solution of K2CO3 (10%). The aqueous phase is washed once with 15 ml of isopropyl acetate. HCl (2 N) is added to the aqueous phase to adjust the pH to 2, and the solution is extracted three times with 20 ml portion of isopropyl acetate. The combining organic phase is washed once with 20 ml of water and the solvent is removed to give the crude product. The crude product is crystallized from ethyl acetate and isopropyl ether to give the pure product. stirred over the night (conversion 95.7%) For the work up the reaction mixture is cooled to 0° C. the mixture is extracted once with 15 ml of HCl 2N, once with 20 ml of water The combining aqueous layers are extracted twice with 10 ml of isopropyl acetate The organic phase is extracted three times with 15 ml portions of an aqueous solution of K2CO3 (10%) The aqueous phase is washed once with 15 ml of isopropyl acetate. HCl (2 N) is added to the aqueous phase the solution is extracted three times with 20 ml portion of isopropyl acetate The combining organic phase is washed once with 20 ml of water the solvent is removed

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: 53 ml of oxalyl chloride in 2 litres of methylene chloride are cooled to -60°. A solution of 88 ml of dimethyl sulfoxide in 150 ml of methylene chloride is added dropwise at this temperature and the mixture is then stirred for 2 minutes. After this, 117 g of 4-hydroxymethyl-2'-cyanobiphenyl in 1 litre of methylene chloride are added dropwise at -60°. After addition has ended (about 5 minutes), the mixture is subsequently stirred for 15 minutes. After this, 390 ml of triethylamine are added dropwise. The mixture is then stirred at -60° for 2 minutes and allowed to wann to room temperature. The reaction mixture is poured into water, extracted with methylene chloride, and the organic phase is washed with dilute hydrochloric acid and brine, dried and concentrated. The product is stirred in hexane, filtered off with suction, washed and dried at 600 in a high vacuum. Elemental analysis: C 80.7%, H 4.5%, N 6.7%, O 7.7%. After addition (about 5 minutes) the mixture is subsequently stirred for 15 minutes The mixture is then stirred at -60° for 2 minutes to wann to room temperature extracted with methylene chloride the organic phase is washed with dilute hydrochloric acid and brine dried concentrated The product is stirred in hexane filtered off with suction washed dried at 600 in a high vacuum