Losartan

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

General Description

Losartan is an angiotensin II receptor antagonist, originally developed as DuP 753, that serves as a therapeutic agent for conditions such as hypertension by blocking the effects of angiotensin II. The study explored novel derivatives, including triazole, sulfur-containing diazole, and N-phenylthiatriazole biphenyltetrazoles, to identify compounds with comparable or improved efficacy, with one derivative showing promising in vitro activity. However, losartan remains a well-established reference in this class of medications. **Final paragraph (conclusion):** Losartan is a clinically effective angiotensin II receptor antagonist used primarily for hypertension management, with its structure serving as a basis for developing newer derivatives aimed at enhancing therapeutic potential.

Definition

ChEBI: A biphenylyltetrazole where a 1,1'-biphenyl group is attached at the 5-position and has an additional trisubstituted imidazol-1-ylmethyl group at the 4'-position

Brand name

Cozaar (Merck).