114798-26-4

Basic information

• Product Name: Losartan
• Synonyms: 2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl]imidazole;DUP 89;1H-imidazole-5-methanol, 2-butyl-4-chloro-1-[[2-(2H-tetrazol-5-yl)[1,1-biphenyl]-4-yl]methyl]-;[2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol;2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5ylphenyl)benzyl]imidazole-5-methanol;2-Butyl-4-chloro-1-[[2-(1H-tetrazol-5-yl)[1,1-biphenyl]-4-yl]methyl-1H-imidazole-5-methanol;Losartan Base
• CAS NO: 114798-26-4
• Molecular Formula: C22H23ClN6O
• Molecular Weight: 422.9106
• EINECS: 601-329-8
• Product Categories: Isotopically Labeled Pharmaceutical Reference Standard
• Mol File: 114798-26-4.mol

Chemical Properties

• Melting Point: 183-184 C
• Boiling Point: 682 °C at 760mmHg
• Flash Point: 366.3 °C
• Appearance: pale yellow solid
• Density: 1.35 g/cm³
• Vapor Pressure: 8.63E-20mmHg at 25°C
• Refractive Index: 1.68
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 5-6(at 25℃)
• Water Solubility: 4.8mg/L at 20℃
• CAS DataBase Reference: Losartan(CAS DataBase Reference)
• NIST Chemistry Reference: Losartan(114798-26-4)
• EPA Substance Registry System: Losartan(114798-26-4)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36
• Hazardous Substances Data: 114798-26-4(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Losartan is used as an antihypertensive agent for the treatment of hypertension. It functions as an antagonist of angiotensin type 1, helping to lower blood pressure by blocking the effects of angiotensin II, a potent vasoconstrictor.
Used in Cardiovascular Applications:
Losartan is used as a medication for the treatment of heart failure and to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy. By blocking the AT1 receptor, it helps to prevent the negative effects of angiotensin II on the cardiovascular system, such as vasoconstriction and remodeling of the heart muscle.

Originator

Alsartan, Aristo Pharmaceutical Ltd., India

Manufacturing Process

2-Butyl-4-chloro-1-(2'-(tetrazol-5-yl)biphenyl-4-ylmethyl)-1H-imidazole-5- methanolpotassium was synthesized in 5 stages. 1. Methyl 4'-methylbiphenyl-2-carboxylate (44.2 mmol), 0.5 N KOH in methanol (133 mmol), and water (50 mL) were mixed and refluxed under nitrogen. After 5 hours, the solvent was removed in vacuo and water (200 mL) and ethyl acetate (200 mL) added. The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 3 and the layers were separated. The aqueous phase was extracted with ethyl acetate, the organic layers collected, dried (MgSO4) and the solvent removed in vacuo to yield 8.71 g of a 4'-methylbiphenyl-2-carboxylic acid, melting point 140.0-145.0°C. 2. 4'-Methylbiphenyl-2-carboxylic acid (41 mmol) and thionyl chloride (411 mmol) were mixed and refluxed for 2 hours. The excess thionyl chloride was removed in vacuo and the residue was taken up in toluene. The toluene was removed by rotary evaporation. The crude acid chloride was then added slowly to cold (0°C) concentrated NH4OH (50 mL) so that the temperature was kept below 15°C. After 15 minutes of stirring, water (100 mL) was added and solids precipitated. These were collected, washed with water and dried under high vacuum over P2O5 to yield 7.45 g of a white solid, melting point 126.0-128.5°C. The above product amide (35 mmol) and thionyl chloride (353 mmol) were mixed and refluxed for 3 hours. The thionyl chloride was removed using the same procedure as described above. The residue was washed with a little hexane to yield 6.64 g of 4'-methyl-2-cyanobiphenyl, melting point 44.0- 47.0°C. 3. 4'-Methyl-2-cyanobiphenyl (5.59 g) was brominated using benzoyl peroxide as an initiator. The product was recrystallized from ether to yield 4.7 g of 4'- bromomethyl-2-cyanobiphenyl, melting point 114.5-120.0°C.4. 4'-Bromomethyl-2-cyanobiphenyl (4.6 g) was alkylated onto 2-n-butyl-4- chloro-5-(hydroxymethyl)-imidazole. For separation of the product was used a flash chromatography in 1:1 hexane/ethyl acetate over silica gel. The regioisomeric products yielded 2.53 g of the faster eluting isomer. Recrystallization from acetonitrile yielded 1.57 g of analytically pure 2-n-butyl4-chloro-1-[2'-cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole, melting point 153.5 -155.5°C. 5. 2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]-5-(hydroxymethyl)- imidazole (10 mmole), sodium azide (10 mmol), and ammonium chloride (30 mmol) were mixed in DMF (150 mL) under N2 at 100°C for 2 days, after which the temperature was raised to 120°C for 6 days. The reaction was cooled and 3 more equivalents each of ammonium chloride and sodium azide were added. The reaction was again heated for 5 days at 120°C. The reaction was cooled, the inorganic salts filtered, and the filtrate solvent removed in vacuo. Water (200 mL) and ethyl acetate (200 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with ethyl acetate, the organic layers were collected, dried (MgSO4) and the solvent removed in vacuo, to yield a dark yellow oil. The product was purified by flash chromatography in 100% ethyl acetate to 100% ethanol over silica gel to yield 5.60 g of a light yellow 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1Htetrazol-5-yl)biphenyl-4-yl)methyl]imidazole. Recrystallization from acetonitrile yielded 4.36 g of light yellow crystals which still melted broadly. The crystals were taken up in 100 mL of hot acetonitrile. The solid that did not dissolve was filtered off to yield 1.04 g of product as a light yellow solid, melting point of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]imidazole 183.5-184.5°C. 2-n-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]imidazole may be converted to potassium salt.

Therapeutic Function

Antihypertensive

Flammability and Explosibility

Nonflammable

InChI:InChI=1/C22H23ClN6O/c1-2-3-9-20-24-21(23)19(14-30)29(20)13-15-10-11-17(16-7-5-4-6-8-16)18(12-15)22-25-27-28-26-22/h4-8,10-12,30H,2-3,9,13-14H2,1H3,(H,25,26,27,28)

Synthetic route

2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole (114772-55-3) → lorsartan (114798-26-4)

Conditions	Yield
With sodium azide In 1-methyl-pyrrolidin-2-one	99%
With sodium azide In toluene at 20℃;	95%
With sodium azide; zinc trifluoromethanesulfonate In water at 100℃; for 6h; Solvent; Temperature; Time; Green chemistry;	91%

methanol (67-56-1) + 2-Butyl-4-chloro-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol (124751-00-4) → methoxytriphenylmethane (596-31-6) + lorsartan (114798-26-4)

Conditions	Yield
for 7h; Heating / reflux;	A 90% B 98%

1-{[2′-(1-benzyl-1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-2-butyl-4-chloro-1H-imidazole-5-carbaldehyde → lorsartan (114798-26-4)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen at 20℃; under 760.051 Torr; for 24h;	97%
With palladium on carbon; hydrogen; acetic acid at 20℃; for 12h;	94%
Multi-step reaction with 2 steps 1: sodium tetrahydroborate / methanol; toluene / 0.5 h / 25 °C / Inert atmosphere 2: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 8 h / 25 - 60 °C View Scheme
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; methanol / toluene / 0.58 h / 0 - 25 °C 2: 5% palladium on barium sulphate; ammonium formate / water; isopropyl alcohol / 8 h / 60 °C View Scheme

2-Butyl-4-chloro-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol (124751-00-4) → methoxytriphenylmethane (596-31-6) + lorsartan (114798-26-4)

Conditions	Yield
Stage #1: 2-Butyl-4-chloro-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol With hydroxylamine hydrochloride In methanol; water; acetone at 20℃; for 2h; Stage #2: With sodium hydroxide In methanol; water; acetone at 20 - 25℃; pH=3.8 - 4.2;	A n/a B 95%
Stage #1: 2-Butyl-4-chloro-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol With hydrogenchloride In methanol; water; acetone at 20℃; for 2h; Stage #2: With sodium hydroxide In methanol; water; acetone at 20 - 25℃; pH=3.8 - 4.2;	A n/a B 93%
Stage #1: 2-Butyl-4-chloro-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol With sulfuric acid In methanol; water; acetone at 20℃; for 2h; Stage #2: With sodium hydroxide In methanol; water; acetone at 20 - 25℃; pH=3.8 - 4.2;	A n/a B 91.3%

ethyl acetate (141-78-6) → C24H25ClN6O2 + methoxytriphenylmethane (596-31-6) + lorsartan (114798-26-4)

Conditions	Yield
Stage #1: 2-Butyl-4-chloro-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol With hydroxylamine hydrochloride In methanol; water; acetone at 20℃; for 2h; Stage #2: With sodium hydroxide In methanol; water; acetone at 20 - 25℃; pH=3.8 - 4.2; Stage #3: ethyl acetate at 40℃; for 1h;	A n/a B n/a C 95%

2-Butyl-4-chloro-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol (124751-00-4) → lorsartan (114798-26-4)

Conditions	Yield
Stage #1: 2-Butyl-4-chloro-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol; hydroxylamine hydrochloride In methanol at 60℃; for 2.5h; pH=2.95; Stage #2: With triethylamine In methanol at 0 - 40℃; for 1h; pH=3.6; Product distribution / selectivity;	94.7%
Stage #1: 2-Butyl-4-chloro-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol; hydroxyammonium sulfate In isopropyl alcohol at 60 - 65℃; for 4h; pH=2.4; Stage #2: With triethylamine In isopropyl alcohol at 0 - 5℃; for 2h; pH=3.5; Product distribution / selectivity;	93.8%
With hydrogenchloride; water In tetrahydrofuran at 20℃; for 4h;	90%

2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]]-1H-imidazole sodium salt → lorsartan (114798-26-4)

Conditions	Yield
With sulfuric acid In water; ethyl acetate at 10 - 25℃; for 1h; pH=3.6 - 3.8; Purification / work up;	94%

cozaar (124750-99-8) → lorsartan (114798-26-4)

Conditions	Yield
With sulfuric acid In water; ethyl acetate at 10 - 25℃; for 1h; pH=3.6 - 3.8; Purification / work up;	93%
With hydrogenchloride In tetrahydrofuran; water; chlorobenzene	86.8%
With hydrogenchloride In tetrahydrofuran; water; chlorobenzene pH=3.5 - 3.6;	84%
With hydrogenchloride In tetrahydrofuran; water; chlorobenzene pH=3.5 - 3.6;	42.6 g

2-n-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol p-toluenesulfonate → lorsartan (114798-26-4)

Conditions	Yield
With potassium hydroxide In water; acetonitrile at 15 - 25℃; pH=3.5 - 3.6;	93%

2-n-butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-methanol (133909-99-6) → lorsartan (114798-26-4)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran at 25℃; for 4h;	89%

trityl losartan → lorsartan (114798-26-4)

Conditions	Yield
With methanol for 4 - 5h; Heating / reflux;	88%

(1-{[2′-(1-benzyl-1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-2-butyl-4-chloro-1H-imidazol-5-yl)methanol → lorsartan (114798-26-4)

Conditions	Yield
With 5% palladium on barium sulphate; ammonium formate In water; isopropyl alcohol at 25 - 60℃; for 8h;	71%
With 5% palladium on barium sulphate; ammonium formate In water; isopropyl alcohol at 60℃; for 8h; Temperature; Time;	70.7%

2-n-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde (114798-36-6) → lorsartan (114798-26-4)

Conditions	Yield
With sodium tetrahydroborate; sodium hydroxide In water at 5 - 20℃; for 4.41667h;	65%
With sodium tetrahydroborate; water; sodium hydroxide In acetonitrile at 5 - 25℃; for 4.41667h;	29.2%
Stage #1: 2-n-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde With sodium tetrahydroborate In water at 25 - 45℃; Stage #2: With hydrogenchloride In water at 15 - 20℃; pH=4.0;

C30H33ClN6O2 → lorsartan (114798-26-4)

Conditions	Yield
Stage #1: C30H33ClN6O2 With trifluoroacetic acid In methoxybenzene at 60℃; for 1.5h; Stage #2: With potassium hydroxide In water; methoxybenzene	49%

(2-butyl-5-chloro-3-{2'-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-biphenyl-4-ylmethyl}-3H-imidazol-4-yl)-methanol (852357-69-8) → lorsartan (114798-26-4)

Conditions	Yield
Stage #1: (2-butyl-5-chloro-3-{2'-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-biphenyl-4-ylmethyl}-3H-imidazol-4-yl)-methanol With water; hydrogen bromide at 15 - 20℃; for 4h; Stage #2: With sodium acetate In water Product distribution / selectivity;
Stage #1: (2-butyl-5-chloro-3-{2'-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-biphenyl-4-ylmethyl}-3H-imidazol-4-yl)-methanol With hydrogenchloride In dichloromethane; water at 0 - 10℃; for 2h; Stage #2: With sodium acetate In dichloromethane; water Product distribution / selectivity;

2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline (57598-33-1) → lorsartan (114798-26-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: tetrahydrofuran / 2 h / 20 °C 2: 96 percent / pyridine, phosphorus oxychloride / 3 h / 100 °C 3: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 4: 1.) sodium methoxide / 1.) DMF, 25 deg C, 0.25 h, 2.) DMF, 40 deg C, 4 h 6: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme
Multi-step reaction with 7 steps 1: tetrahydrofuran / 2 h / 20 °C 2: 96 percent / pyridine, phosphorus oxychloride / 3 h / 100 °C 3: 1.) tributyltin chloride, sodium azide, 2.) 10 N aq. sodium hydroxide / 1.) toluene, reflux, 70 h, 20 deg C, 3 h 4: 92 percent / N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 5: 49 percent / potassium carbonate / dimethylformamide / 24 h / 25 °C 6: sodium borohydride / CH2Cl2 / 24 h / 25 °C 7: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme

2-Cyano-4'-methylbiphenyl (114772-53-1) → lorsartan (114798-26-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 2: 1.) sodium methoxide / 1.) DMF, 25 deg C, 0.25 h, 2.) DMF, 40 deg C, 4 h 4: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme
Multi-step reaction with 5 steps 1: 1.) tributyltin chloride, sodium azide, 2.) 10 N aq. sodium hydroxide / 1.) toluene, reflux, 70 h, 20 deg C, 3 h 2: 92 percent / N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 3: 49 percent / potassium carbonate / dimethylformamide / 24 h / 25 °C 4: sodium borohydride / CH2Cl2 / 24 h / 25 °C 5: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme
Multi-step reaction with 4 steps 1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 3 h / 80 °C / Green chemistry 2: potassium carbonate / N,N-dimethyl-formamide / 6 h / 40 °C / Green chemistry 3: sodium tetrahydroborate / methanol / 1.17 h / 20 - 40 °C / Green chemistry 4: sodium azide; zinc trifluoromethanesulfonate / water / 6 h / 100 °C / Green chemistry View Scheme
Multi-step reaction with 3 steps 1: N-Bromosuccinimide / tetrachloromethane 2: sodium methylate / N-methyl-acetamide; hexane; ethyl acetate; N,N-dimethyl-formamide 3: ammonium chloride / ethanol; water; ethyl acetate; N,N-dimethyl-formamide; acetonitrile View Scheme

2-n-butyl-4-chloro-5-hydroxymethylimidazole (79047-41-9) → lorsartan (114798-26-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 77 percent / 1.0 N aq. ceric ammonium nitrate / acetic acid / 3 h / 25 °C 2: 49 percent / potassium carbonate / dimethylformamide / 24 h / 25 °C 3: sodium borohydride / CH2Cl2 / 24 h / 25 °C 4: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme
Multi-step reaction with 3 steps 1: NH4Ca(NO3)3; sodium hydroxide / acetic acid 2: sodium hydroxide; sodium tetrahydroborate / water; toluene 3: hydrogenchloride; sodium hydroxide; acetic acid / methanol; water; ethyl acetate; toluene View Scheme

2-n-butyl-4-chloro-1H-imidazol-5-carboxaldehyde (83857-96-9) → lorsartan (114798-26-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 49 percent / potassium carbonate / dimethylformamide / 24 h / 25 °C 2: sodium borohydride / CH2Cl2 / 24 h / 25 °C 3: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile / 20 h / 25 - 85 °C / Inert atmosphere 2: sodium tetrahydroborate / methanol; toluene / 0.5 h / 25 °C / Inert atmosphere 3: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 8 h / 25 - 60 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 6 h / 40 °C / Green chemistry 2: sodium tetrahydroborate / methanol / 1.17 h / 20 - 40 °C / Green chemistry 3: sodium azide; zinc trifluoromethanesulfonate / water / 6 h / 100 °C / Green chemistry View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl acetamide / 5 h / 20 °C 2.1: sodium tetrahydroborate / methanol; N,N-dimethyl acetamide / 1 h / 5 - 20 °C 3.1: sodium azide; triethylamine hydrochloride / N,N-dimethyl acetamide / 16 h / 120 °C 3.2: 80 °C / pH 4.0 View Scheme
Multi-step reaction with 3 steps 1: sodium carbonate; tetraethylammonium bromide / toluene / 90 - 95 °C 2: sodium tetrahydroborate; sodium hydroxide / water / 20 - 85 °C 3: sodium azide; triethylamine hydrochloride / toluene / 90 - 95 °C View Scheme

4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile (114772-54-2) → lorsartan (114798-26-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) sodium methoxide / 1.) DMF, 25 deg C, 0.25 h, 2.) DMF, 40 deg C, 4 h 3: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 6 h / 40 °C / Green chemistry 2: sodium tetrahydroborate / methanol / 1.17 h / 20 - 40 °C / Green chemistry 3: sodium azide; zinc trifluoromethanesulfonate / water / 6 h / 100 °C / Green chemistry View Scheme
Multi-step reaction with 2 steps 1: sodium methylate / N-methyl-acetamide; hexane; ethyl acetate; N,N-dimethyl-formamide 2: ammonium chloride / ethanol; water; ethyl acetate; N,N-dimethyl-formamide; acetonitrile View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl acetamide / 5 h / 20 °C 2.1: sodium tetrahydroborate / methanol; N,N-dimethyl acetamide / 1 h / 5 - 20 °C 3.1: sodium azide; triethylamine hydrochloride / N,N-dimethyl acetamide / 16 h / 120 °C 3.2: 80 °C / pH 4.0 View Scheme
Multi-step reaction with 3 steps 1: sodium carbonate; tetraethylammonium bromide / toluene / 90 - 95 °C 2: sodium tetrahydroborate; sodium hydroxide / water / 20 - 85 °C 3: sodium azide; triethylamine hydrochloride / toluene / 90 - 95 °C View Scheme

N-(2-hydroxy-1,1-dimethyl)-2-methoxybenzamide (74201-13-1) → lorsartan (114798-26-4)

Conditions	Yield
Multi-step reaction with 7 steps 1: thionyl chloride / 1 h / 25 °C 2: tetrahydrofuran / 2 h / 20 °C 3: 96 percent / pyridine, phosphorus oxychloride / 3 h / 100 °C 4: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 5: 1.) sodium methoxide / 1.) DMF, 25 deg C, 0.25 h, 2.) DMF, 40 deg C, 4 h 7: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme
Multi-step reaction with 8 steps 1: thionyl chloride / 1 h / 25 °C 2: tetrahydrofuran / 2 h / 20 °C 3: 96 percent / pyridine, phosphorus oxychloride / 3 h / 100 °C 4: 1.) tributyltin chloride, sodium azide, 2.) 10 N aq. sodium hydroxide / 1.) toluene, reflux, 70 h, 20 deg C, 3 h 5: 92 percent / N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 6: 49 percent / potassium carbonate / dimethylformamide / 24 h / 25 °C 7: sodium borohydride / CH2Cl2 / 24 h / 25 °C 8: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme

4,4-dimethyl-2-(4'-methyl-biphenyl-2-yl)-4,5-dihydrooxazole (84392-32-5) → lorsartan (114798-26-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: 96 percent / pyridine, phosphorus oxychloride / 3 h / 100 °C 2: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 3: 1.) sodium methoxide / 1.) DMF, 25 deg C, 0.25 h, 2.) DMF, 40 deg C, 4 h 5: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme
Multi-step reaction with 6 steps 1: 96 percent / pyridine, phosphorus oxychloride / 3 h / 100 °C 2: 1.) tributyltin chloride, sodium azide, 2.) 10 N aq. sodium hydroxide / 1.) toluene, reflux, 70 h, 20 deg C, 3 h 3: 92 percent / N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 4: 49 percent / potassium carbonate / dimethylformamide / 24 h / 25 °C 5: sodium borohydride / CH2Cl2 / 24 h / 25 °C 6: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme

N-(trityl)-5-[4΄-(methyl)biphenyl-2-yl]-2H-tetrazole (133909-97-4) → lorsartan (114798-26-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 92 percent / N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 2: 49 percent / potassium carbonate / dimethylformamide / 24 h / 25 °C 3: sodium borohydride / CH2Cl2 / 24 h / 25 °C 4: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme

N-(triphenylmethyl)-5-<4'-(bromomethyl)biphenyl-2-yl>tetrazole (133051-88-4) → lorsartan (114798-26-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 49 percent / potassium carbonate / dimethylformamide / 24 h / 25 °C 2: sodium borohydride / CH2Cl2 / 24 h / 25 °C 3: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme

2-n-Butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-carboxaldehyde (133910-00-6) → lorsartan (114798-26-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium borohydride / CH2Cl2 / 24 h / 25 °C 2: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme

2-Methoxybenzoic acid (579-75-9) → lorsartan (114798-26-4)

Conditions	Yield
Multi-step reaction with 9 steps 1: 95 percent / thionyl chloride / 18 h / 20 °C 2: CH2Cl2 / 2 h / 20 °C 3: thionyl chloride / 1 h / 25 °C 4: tetrahydrofuran / 2 h / 20 °C 5: 96 percent / pyridine, phosphorus oxychloride / 3 h / 100 °C 6: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 7: 1.) sodium methoxide / 1.) DMF, 25 deg C, 0.25 h, 2.) DMF, 40 deg C, 4 h 9: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme
Multi-step reaction with 10 steps 1: 95 percent / thionyl chloride / 18 h / 20 °C 2: CH2Cl2 / 2 h / 20 °C 3: thionyl chloride / 1 h / 25 °C 4: tetrahydrofuran / 2 h / 20 °C 5: 96 percent / pyridine, phosphorus oxychloride / 3 h / 100 °C 6: 1.) tributyltin chloride, sodium azide, 2.) 10 N aq. sodium hydroxide / 1.) toluene, reflux, 70 h, 20 deg C, 3 h 7: 92 percent / N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 8: 49 percent / potassium carbonate / dimethylformamide / 24 h / 25 °C 9: sodium borohydride / CH2Cl2 / 24 h / 25 °C 10: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme

2-Methoxybenzoyl chloride (21615-34-9) → lorsartan (114798-26-4)

Conditions	Yield
Multi-step reaction with 8 steps 1: CH2Cl2 / 2 h / 20 °C 2: thionyl chloride / 1 h / 25 °C 3: tetrahydrofuran / 2 h / 20 °C 4: 96 percent / pyridine, phosphorus oxychloride / 3 h / 100 °C 5: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 6: 1.) sodium methoxide / 1.) DMF, 25 deg C, 0.25 h, 2.) DMF, 40 deg C, 4 h 8: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme
Multi-step reaction with 9 steps 1: CH2Cl2 / 2 h / 20 °C 2: thionyl chloride / 1 h / 25 °C 3: tetrahydrofuran / 2 h / 20 °C 4: 96 percent / pyridine, phosphorus oxychloride / 3 h / 100 °C 5: 1.) tributyltin chloride, sodium azide, 2.) 10 N aq. sodium hydroxide / 1.) toluene, reflux, 70 h, 20 deg C, 3 h 6: 92 percent / N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating 7: 49 percent / potassium carbonate / dimethylformamide / 24 h / 25 °C 8: sodium borohydride / CH2Cl2 / 24 h / 25 °C 9: 89 percent / 10percent HCl / tetrahydrofuran / 4 h / 25 °C View Scheme

2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]]-1H-imidazole magnesium salt → lorsartan (114798-26-4)

Conditions	Yield
With sulfuric acid In water; ethyl acetate at 10 - 25℃; for 1h; pH=3.6 - 3.8; Purification / work up;

2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]]-1H-imidazole calcium salt → lorsartan (114798-26-4)

Conditions	Yield
With sulfuric acid In water; ethyl acetate at 10 - 25℃; for 1h; pH=3.6 - 3.8; Purification / work up;

lorsartan (114798-26-4) + chloroacetic acid (79-11-8) → chloroacetyl losartan

Conditions	Yield
With dmap; diisopropyl-carbodiimide In tetrahydrofuran at 0 - 20℃;	100%

trityl chloride (76-83-5) + lorsartan (114798-26-4) → 2-Butyl-4-chloro-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol (124751-00-4)

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere;	98.5%
With triethylamine In N,N-dimethyl-formamide at 0 - 20℃;	96%
With triethylamine In N,N-dimethyl-formamide at 20℃;

lorsartan (114798-26-4) → cozaar (124750-99-8)

Conditions	Yield
With potassium tert-butylate In isopropyl alcohol at 10 - 25℃; Product distribution / selectivity;	94%
Stage #1: lorsartan With potassium hydroxide In isopropyl alcohol Stage #2: In cyclohexane at 20 - 50℃; for 3h;	93.7%
With potassium hydroxide In water; acetonitrile for 0.25 - 0.333333h; Product distribution / selectivity;	92%

lorsartan (114798-26-4) → 2-n-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde (114798-36-6)

Conditions	Yield
With dipyridinium dichromate In N,N-dimethyl-formamide at 20 - 50℃; for 6h; Alkaline conditions;	94%
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In dimethyl sulfoxide at 20℃; for 6h;	53%
With ruthenium trichloride; potassium metaperiodate; diperiodatocuprate(III) dihydrate; potassium nitrate; potassium hydroxide In water at 25℃; for 2h; Kinetics; Temperature; Sealed tube; Inert atmosphere;

lorsartan (114798-26-4) → losartan hydrochloride

Conditions	Yield
With hydrogenchloride In tetrahydrofuran	93.7%

lorsartan (114798-26-4) → losartan potassium (124750-99-8)

Conditions	Yield
With potassium hydroxide In methanol; isopropyl alcohol at 20℃; for 0.5h;	90%
With potassium hydroxide In methanol for 4h; Heating / reflux;	33%
With potassium hydroxide In methanol for 1h; pH=9; Reflux;

lorsartan (114798-26-4) → 2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]]-1H-imidazole sodium salt

Conditions	Yield
With sodium hydroxide In water; isopropyl alcohol at 38 - 40℃; for 0.5h; pH=10 - 12; Product distribution / selectivity;	87%
With sodium t-butanolate In isopropyl alcohol Product distribution / selectivity;
With sodium hydroxide In water at 20℃; pH=9.62; Product distribution / selectivity;

L-N-Boc-Ala (15761-38-3) + lorsartan (114798-26-4) → (S)-(1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1H-imidazol-5-yl)methyl 2-(tert-butoxycarbonyl)aminopropanoate (1174760-85-0)

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 24.5h;	79%

lorsartan (114798-26-4) → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
With pyridine; potassium permanganate; tetrabutyl-ammonium chloride In water; acetone at 40 - 50℃; for 1h; Product distribution / selectivity;	78%
With sodium periodate; ruthenium(III) trichloride hydrate; potassium hydroxide In water at 0℃;
Stage #1: lorsartan With sodium periodate; ruthenium (III) chloride monohydrate; potassium hydroxide In water at 0℃; Stage #2: In water; isopropyl alcohol at 25℃; for 2.5h; Stage #3: With phosphoric acid In water; isopropyl alcohol at 30℃; for 0.5h;
With cytochrome P450 2C9 Enzymatic reaction;
With cytochrome b5; NADPH In aq. phosphate buffer at 37℃; for 0.75h; Kinetics; Reagent/catalyst; Enzymatic reaction;

lorsartan (114798-26-4) → 2-n-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol hydrobromide

Conditions	Yield
With hydrogen bromide In tetrahydrofuran	78%

lorsartan (114798-26-4) + 3‐[(nitrooxy)methyl]benzoic acid (646511-09-3) → 3-nitrooxymethyl-benzoic acid 2-butyl-5-chloro-3-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl ester

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 2h;	72%

toluene-4-sulfonic acid (104-15-4) + lorsartan (114798-26-4) → 2-n-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol p-toluenesulfonate

Conditions	Yield
In tetrahydrofuran; chlorobenzene	71.5%

pentafluorophenol 4-nitroxybutyrate (838878-70-9) + lorsartan (114798-26-4) → 2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5-[(3-nitrooxypropyl)carbonyloxy]methyl-1H-imidazole (838876-22-5)

Conditions	Yield
With dmap; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 4h;	53%

Upstream product

• 133910-00-6 2-n-Butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-carboxaldehyde 
• 124751-00-4 2-Butyl-4-chloro-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol 
• 67-56-1 methanol 
• 114798-36-6 2-n-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde 
• 21388-92-1 4-bromobenzyl acetate 
• 873-75-6 4-bromobenzenemethanol 
• 28386-90-5 5-benzyl-1-phenyl-1H-tetrazole 
• 624-31-7 4-tolyl iodide 
• 110-59-8 pentanonitrile 
• 193140-43-1 (pentanimidoylamino)acetic acid 
• 124750-67-0 2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde 
• 57246-71-6 methyl pentanimidate 
• 873-32-5 2-Chlorobenzonitrile 
• 696-61-7 4-tolylmagnesium chloride 

Downstream Products

• 124750-99-8 cozaar 
• 138584-34-6 losartan N₁-glucuronide 
• 138613-25-9 losartan O-glucuronide 
• 138584-35-7 losartan N₂-glucuronide 
• 727718-93-6 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4yl)methyl]-1H-imidazole 
• 1174760-85-0 (S)-(1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1H-imidazol-5-yl)methyl 2-(tert-butoxycarbonyl)aminopropanoate 
• 124750-92-1 2-n-butyl-5-chloro-3-[2'-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylic acid 
• 114798-36-6 EXP 3179 

Relevant articles and documents

Novel and efficient debenzylation of N-benzyltetrazole derivatives with the rosenmund catalyst

The Rosenmund catalyst (Pd/BaSO4) was found to efficiently catalyze debenzylation of N-benzyltetrazole derivatives with ammonium formate by catalytic transfer hydrogenation under mild conditions. The protocol has been applied to functionalized substrates to provide various angiotensin II receptor blockers in excellent yields.

Efficient synthesis of losartan, a nonpeptide angiotensin II receptor antagonist

A highly efficient, convergent approach to the synthesis of the angiotensin II receptor antagonist losartan (1) is described. Directed ortho-metalation of 2-trityl-5-phenyltetrazole provides the key boronic acid intermediate 10 for palladium-catalyzed biaryl coupling with bromide 5 obtained from the regioselective alkylation of the chloroimidazole 2. This methodology overcomes many of the drawbacks associated with previously reported syntheses.

Unusual detritylation of tritylated tetrazole in Sartan molecules

Tritylated tetrazole of 2a underwent unusual detritylation under basic reaction condition during the synthesis of methyl ether of olmesartan medoxomil 1. The unusual detritylation was found to be a common feature in the case of all tetrazole containing Sartan molecules (3-7).

Preparation method of losartan

The invention provides a preparation method of losartan, wherein the preparation method comprises the steps: reacting a nitrile intermediate shown in the specification with an azide reagent in a solvent, adding an inorganic alkali aqueous solution selected from carbonate or bicarbonate, washing, and separating out an intermediate material layer; and further separating the intermediate material layer to obtain losartan. The azide ions after the reaction can be basically and completely removed by using the conventional inorganic alkali solution, the removal effect is good, the preparation process is simple and convenient, the operation conditions are mild and easy to control, and the method is suitable for large-scale industrial production.

Method for preparing high-purity losartan

The invention relates to a method for preparing high-purity losartan. The method comprises steps as follows: (1), a losartan crude product is added to an organic solvent or a mixed solvent of an organic solvent and water, and the mixture is heated to reach 20-80 DEG C and stirred; (2), the system is cooled directly or cooled after water is added or cooled to 0-5 DEG C after a part of solvent is evaporated, a material is precipitated, filtered and dried, and losartan is obtained, wherein the organic solvent used in the step (1) is any one of tetrahydrofuran, butanone, acetone and methyl alcohol or is a mixed solvent of any one of the four solvents and water. The losartan obtained with the method has high purity, any individual impurity can be reduced to 0.2% or even under 0.1%, the purity of the losartan can reach 99.5%, the cost of the method is lower, the refining yield is high, and the method is very simple in operation, environment-friendly and suitable for industrial production.

Preparation method of losartan

The invention provides a preparation method of losartan. The losartan is prepared by reacting a cyano-containing intermediate as shown in a formula (I), which is described in the specification, with an azide reagent in toluene in the presence of a catalyst. After the reaction is finished, azide ions are removed through the following procedures: adding water to divide a reaction system into three layers, separating out a middle layer, adding n-butyl alcohol into the middle layer for dilution, and adding triphenylphosphine into the obtained diluted solution to remove the residual azide ions in the diluted solution. According to the preparation method, sodium nitrite is not needed, so formation of the genotoxic impurity nitrosamine is fundamentally eradicated; the obtained target losartan isgood in purity and high in yield; and the method is simple and convenient in preparation process, mild and easily controllable in operation conditions, good in safety, and suitable for large-scale industrial production.

Nickel-Catalyzed Denitrogenative ortho-Arylation of Benzotriazinones with Organic Boronic Acids: an Efficient Route to Losartan and Irbesartan Drug Molecules

Denitrogenative ortho-arylation, vinylation and methylation of 1,2,3-benzotriazin-4-(3H)-ones with organic boronic acids catalyzed by nickel complexes to give a wide range of o-substituted benzamides were demonstrated. Further, the catalytic reaction is successfully applied to the synthesis of the popular hypertensive drugs losartan and irbesartan in high yields. (Figure presented.).

A trityl protecting group by removing method of preparing losartan medicine

The invention discloses a method for preparation of a Sartan drug by removal of a triphenylmethyl protective group. The method includes: under the catalysis of an insoluble weak acid, subjecting a Sartan prodrug and methanol to deprotection reaction, and after complete reaction, conducting aftertreatment to obtain the Sartan drug. The method has the characteristics of low cost, few side product, high quality product, and simple aftertreatment. At the same time, montmorillonite can be taken as insoluble weak acid, and the cost is low, thus being convenient for industrial production.

Sartan compound discoloration method

The invention relates to a sartan compound discoloration method. The method comprises the following steps: adding irbesartan or losartan crude products containing pigment impurities into solvent, and dissolving; and adding hydroboration reagent, stirring for discoloration, and crystallizing through dissociation, cooling, distillation and other means to obtain white losartan or irbesartan. The method has the advantages of mild reaction conditions, short operating cycle, high discoloration efficiency and environment friendliness, and is suitable for industrial production.

High-purity Losartan preparation method

The invention provides a high-purity Losartan preparation method. The method comprises the following steps: adding a catalyst having a structural formula as shown in Formula A into organic solvent, dropwisely adding acid, and stirring to perform salification; and adding a compound 1, sodium azide and tetrabutylammonium bromide into the system, heating, reacting with stirring, and performing posttreatment to obtain high-purity Losartan. The Losartan obtained by the invention is high in purity and favorable in appearance; the purity can be up to 98.4%; and the content of a single impurity can be reduced to 0.2%. The method is low in cost and high in yield; and meanwhile, the method provided by the invention is simple to operate and environment-friendly, thereby being suitable for industrial production.