133909-99-6

Basic information

• Product Name: Trityl losartan
• Synonyms: 2-BUTYL-4-CHLORO-1-[[2'-[2-(TRIPHENYLMETHYL)-TETRAZOL-5-YL]-[1,1'-BIPHENYL]-4-YL]METHYL]-1H-IMIDAZOLE-5-METHANOL;2-BUTYL-4-CHLORO-1-[2'-(2-TRITYL-2H-TETRAZOLE-5-YL)BIPHENYL-4-YL-METHYL-1H-IMIDAZOLE-5-YL-METHANOL;(2-butyl-4-chloro-1-((2`-(1-trityl-1H-tetrazol-5-yl)biphenyl-1-4-yl)methyl)-1H-i;(2-Butyl-4-Chloro-1-((2'-(1-Trityl-1h-Tetrazole-5-Yl)Biphenyl-4-Yl)Methyl)-1h-Imidazol-5-Yl)Methanol;Trithyl Losartan;2-butyl-4-chloro-1-[2'(2-trityl-2h-tetrazol-5-yl)biphenyl-4-ylmethyl]-1h-imidazol-5-ylmethanol;TRIPHENYL LOSARTAN;2-butyl-4-chloro-4,5-dihydro-5-hydroxymethyl-1-[2'-(2-triphenylmethyl-1,2,3,4-2H-tetrazol-5-yl)-1,1'-biphenyl-4-methyl]-1H-imidazole
• CAS NO: 133909-99-6
• Molecular Formula: C₄₁H₃₇ClN₆O
• Molecular Weight: 665.23
• EINECS: 412-420-5
• Mol File: 133909-99-6.mol

Chemical Properties

• Boiling Point: 856.6 °C at 760 mmHg
• Flash Point: 471.9 °C
• Appearance: /
• Density: 1.22 g/cm³
• PKA: 13.66±0.10(Predicted)
• CAS DataBase Reference: Trityl losartan(CAS DataBase Reference)
• NIST Chemistry Reference: Trityl losartan(133909-99-6)
• EPA Substance Registry System: Trityl losartan(133909-99-6)

Safety Data

• Statements: 53
• Safety Statements: 61
• Hazardous Substances Data: 133909-99-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Trityl losartan is used as an intermediate in the preparation of Losartan impurities for the pharmaceutical industry. It plays a crucial role in the synthesis of Losartan, a medication used to treat high blood pressure and heart failure. The presence of Trityl losartan helps in the development and quality control of Losartan-based drugs, ensuring their safety and efficacy.
Used in Quality Control:
Trityl losartan is used as a reference standard in the quality control and analysis of Losartan-based pharmaceutical products. It helps in the identification, quantification, and assessment of impurities in the final drug formulation, ensuring that the medication meets the required standards for purity and potency.
Used in Research and Development:
Trityl losartan is also used in research and development for the discovery and development of new pharmaceutical compounds. Its unique chemical properties make it a valuable tool in the synthesis and study of novel drug candidates, potentially leading to the development of new treatments for various medical conditions.

Synthetic route

2-n-butyl-4-chloro-1H-imidazol-5-carboxaldehyde (83857-96-9) + N-(triphenylmethyl)-5-<4'-(bromomethyl)biphenyl-2-yl>tetrazole (133051-88-4) → 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)

Conditions	Yield
Stage #1: 2-n-butyl-4-chloro-1H-imidazol-5-carboxaldehyde; N-(triphenylmethyl)-5-<4'-(bromomethyl)biphenyl-2-yl>tetrazole With potassium carbonate In N,N-dimethyl-formamide at 20 - 22℃; for 3h; Stage #2: With sodium tetrahydroborate In water; N,N-dimethyl-formamide at 48 - 52℃; for 3.08333h;	99.2%
With potassium carbonate In N,N-dimethyl acetamide
With potassium carbonate In N,N-dimethyl acetamide

trityl chloride (76-83-5) + cozaar (124750-99-8) → 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)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃; for 18h;	91%

2-n-butyl-4-chloro-5-hydroxymethylimidazole (79047-41-9) + N-(triphenylmethyl)-5-<4'-(bromomethyl)biphenyl-2-yl>tetrazole (133051-88-4) → 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)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h;	80%

n-Butyl chloride (109-69-3) + 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) → 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)

Conditions	Yield
With sodium borohydrid In water; ethyl acetate	72%
With sodium borohydrid In water; ethyl acetate	72%

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) + 3-<3,4-bis(benzyloxy)phenyl>-1-aminopropane (99281-96-6) → [3-(3,4-bis-benzyloxy-phenyl)propyl](2-n-butyl-5-chloro-3-[2'-(2-trityl-2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl)amine (1370339-88-0) + 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)

Conditions	Yield
Stage #1: 2-n-Butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-carboxaldehyde; 3-<3,4-bis(benzyloxy)phenyl>-1-aminopropane With magnesium sulfate In dichloromethane at 20℃; for 17h; Inert atmosphere; Stage #2: With sodium tetrahydroborate In methanol; dichloromethane at 20℃; for 4h; Inert atmosphere;	A 34% B 40%

n-Butyl chloride (109-69-3) + 2-n-butyl-4-chloro-1H-imidazol-5-carboxaldehyde (83857-96-9) + 5-(4'-Methanesulfonyloxymethyl-1,1'-biphenyl-2-yl)-2-triphenylmethyl-2H-tetrazole (143722-28-5) → 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)

Conditions	Yield
With sodium borohydrid In water; ethyl acetate; acetone	28%
With sodium borohydrid In water; ethyl acetate; acetone	28%

2-n-butyl-4-chloro-5-hydroxymethylimidazole (79047-41-9) + N-(triphenylmethyl)-5-<4'-(bromomethyl)biphenyl-2-yl>tetrazole (133051-88-4) → 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) + {2-Butyl-5-chloro-1-[2'-(2-trityl-2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1H-imidazol-4-yl}-methanol

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide Product distribution; Ambient temperature; various ratios of reagents;
With potassium carbonate In N,N-dimethyl-formamide Ambient temperature;

trityl chloride (76-83-5) + 2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole (114772-55-3) → 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)

Conditions	Yield
Yield given. Multistep reaction;

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) → 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)

Conditions	Yield
With sodium tetrahydroborate In dichloromethane at 25℃; for 24h; Yield given;

2-trityl-5-phenyl-2H-tetrazole (87268-78-8) + 2-n-Butyl-4-chloro-1-(4-bromobenzyl)-1H-imidazole-5-methanol (151012-31-6) → 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)

Conditions	Yield
Yield given. Multistep reaction;

2-(2'-Triphenylmethyl-2'H-tetrazol-5'-yl)-phenylboronic acid (143722-25-2) + 2-n-Butyl-4-chloro-1-(4-bromobenzyl)-1H-imidazole-5-methanol (151012-31-6) → 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)

Conditions	Yield
With potassium carbonate; tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran; water at 75℃;
With potassium carbonate; tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 75℃; Mechanism; coupling rate effects of changing the initial composition; coupling rate effect of isomeric impurity of the aryl bromide;

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

Conditions	Yield
Multi-step reaction with 2 steps 1: K2CO3 / N,N-dimethyl-acetamide View Scheme
Multi-step reaction with 3 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 View Scheme

trityl chloride (76-83-5) + diphenylchloromethane (?) → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1: Et3N / tetrahydrofuran / 0.5 h View Scheme

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

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) K2CO3, 2.) NaBH4 / 1.) dimethylacetamide, -10 deg C, 2 h; room temp., 2 h, 2.) MeOH, room temp., 1 h View Scheme
Multi-step reaction with 2 steps 1: 49 percent / potassium carbonate / dimethylformamide / 24 h / 25 °C 2: sodium borohydride / CH2Cl2 / 24 h / 25 °C View Scheme

1-bromomethyl-4-bromobenzene (589-15-1) + sodium-<4-nitro benzoate> → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1: K2CO3 / N,N-dimethyl-acetamide View Scheme
Multi-step reaction with 2 steps 1: 1.) K2CO3, 2.) NaBH4 / 1.) dimethylacetamide, -10 deg C, 2 h; room temp., 2 h, 2.) MeOH, room temp., 1 h View Scheme

5-phenyl-2H-1,2,3,4-tetrazole (18039-42-4) → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1: Et3N / tetrahydrofuran / 0.5 h View Scheme

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

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 6 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 View Scheme

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

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 4 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 View Scheme

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

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) sodium methoxide / 1.) DMF, 25 deg C, 0.25 h, 2.) DMF, 40 deg C, 4 h View Scheme

N-(2-hydroxy-1,1-dimethyl)-2-methoxybenzamide (74201-13-1) → 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)

Conditions	Yield
Multi-step reaction with 6 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 View Scheme
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: 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 View Scheme

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

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 5 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 View Scheme

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

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

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

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

2-Methoxybenzoic acid (579-75-9) → 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)

Conditions	Yield
Multi-step reaction with 8 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 View Scheme
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: 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 View Scheme

2-Methoxybenzoyl chloride (21615-34-9) → 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)

Conditions	Yield
Multi-step reaction with 7 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 View Scheme
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: 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 View Scheme

1H-imidazole (288-32-4) + 2-(2'-Triphenylmethyl-2'H-tetrazol-5'-yl)-phenylboronic acid (143722-25-2) → 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)

Conditions	Yield
With potassium carbonate In tetrahydrofuran; formaldehyde diethyl acetal; water	15.5 g (93%)
With tributylphosphine; potassium carbonate In tetrahydrofuran; formaldehyde diethyl acetal; water	15.5 g (93%)
With potassium carbonate In tetrahydrofuran; formaldehyde diethyl acetal; water

2-methylpropyl acetate (110-19-0) + pyrographite (7440-44-0) + 2-(2'-Triphenylmethyl-2'H-tetrazol-5'-yl)-phenylboronic acid (143722-25-2) + 2-n-Butyl-4-chloro-1-p-bromobenzyl-1H-imidazole-5-carboxaldehyde (143722-29-6) → 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)

Conditions	Yield
With sodium borohydrid; nitrogen; tetrabutylammomium bromide; magnesium sulfate; potassium carbonate; thiourea; triphenylphosphine; tris-(dibenzylideneacetone)dipalladium(0) In water; toluene
With sodium borohydrid; nitrogen; tetrabutylammomium bromide; magnesium sulfate; potassium carbonate; thiourea; triphenylphosphine; tris-(dibenzylideneacetone)dipalladium(0) In water; toluene

4-bromobenzenemethanol (873-75-6) → 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)

Conditions	Yield
Multi-step reaction with 3 steps 1: nitrogen / tetrakis(triphenylphosphine)palladium (0) / toluene 2: potassium carbonate / N,N-dimethyl acetamide 3: sodium borohydrid / water; ethyl acetate; acetone View Scheme

2-n-butyl-4-chloro-1H-imidazol-5-carboxaldehyde (83857-96-9) + 1-bromomethyl-4-bromobenzene (589-15-1) → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl acetamide; water; toluene 2: sodium borohydrid; nitrogen; tetrabutylammomium bromide; magnesium sulfate; potassium carbonate; thiourea; triphenylphosphine / tris-(dibenzylideneacetone)dipalladium(0) / water; toluene View Scheme

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

Conditions	Yield
With sulfuric acid In water; acetonitrile for 0.583333h; Ambient temperature;	95%
Stage #1: 2-n-butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-methanol With hydrogenchloride In water; acetonitrile at 18 - 20℃; for 5h; Stage #2: With sodium hydroxide In water pH=12.3 - 12.7;	90.5%
With hydrogenchloride In dichloromethane; water at 25 - 35℃; for 1 - 1.5h; Product distribution / selectivity;

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%

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) → cozaar (124750-99-8)

Conditions	Yield
With potassium carbonate In methanol for 12h; Product distribution / selectivity; Heating / reflux;	82%
With potassium tert-butylate In methanol; isopropyl alcohol for 9h; Product distribution / selectivity; Heating / reflux;	81%
With potassium tert-butylate In methanol for 8h; Heating / reflux;	78%
With potassium tert-butylate In methanol for 8h; Heating / reflux;	78%
With potassium tert-butylate In methanol; tert-butyl alcohol for 9h; Product distribution / selectivity; Heating / reflux;	78%

3,5-di-tert-butyl-4-hydroxyphenyl acetic acid (1611-03-6) + 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) → (3,5-di-tert-butyl-4-hydroxyphenyl)-acetic acid 2-butyl-5-chloro-3-[2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-yl methyl ester (1195777-21-9)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In diethyl ether at 20℃; for 12h; Mitsunobu reaction; Inert atmosphere;	63%

3-(3,4-bis(benzyloxy)phenyl)propanoic acid (93559-04-7) + 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) → C64H57ClN6O4 (1195777-19-5)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In diethyl ether at 20℃; for 12h; Mitsunobu reaction; Inert atmosphere;	63%

4-(benzyloxy)-3,5-dimethoxybenzoic acid (14588-60-4) + 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) → 4-benzyloxy-3,5-dimethoxybenzoic acid 5-chloro-2-butyl-3-[2'-(2-trityl-2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-yl methyl ester (1195777-18-4)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In diethyl ether at 20℃; for 12h; Mitsunobu reaction; Inert atmosphere;	62%

dodecyl mesylate (51323-71-8) + 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) → 5-[4'-(2-butyl-4-chloro-5-dodecyloxymethylimidazol-1-ylmethyl)biphenyl-2-yl]-2-trityl-2H-tetrazole

Conditions	Yield
Stage #1: 2-n-butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-methanol With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: dodecyl mesylate In tetrahydrofuran for 24h; Inert atmosphere; Reflux;	45%

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) + 6-tert-butyl(dimethyl)silyloxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (716320-66-0) → 6-(tert-butyl-dimethyl-silanyloxy)-2,5,7,8-tetramethylchroman-2-carboxylic acid 2-butyl-5-chloro-3-[2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-midazol-4-yl methyl ester (1195777-20-8)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In diethyl ether at 20℃; for 12h; Mitsunobu reaction; Inert atmosphere;	42%

4-hydroxy-benzaldehyde (123-08-0) + 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) → 4-{2-butyl-5-chloro-3-[2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethoxy}benzaldehyde

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 18h; Mitsunobu Displacement; Cooling with ice;	35%

Upstream product

• 79047-41-9 2-n-butyl-4-chloro-5-hydroxymethylimidazole 
• 133051-88-4 N-(triphenylmethyl)-5-<4'-(bromomethyl)biphenyl-2-yl>tetrazole 
• 76-83-5 trityl chloride 
• 114772-55-3 2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole 
• 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 
• 87268-78-8 2-trityl-5-phenyl-2H-tetrazole 
• 151012-31-6 2-n-Butyl-4-chloro-1-(4-bromobenzyl)-1H-imidazole-5-methanol 
• 143722-25-2 2-(2'-Triphenylmethyl-2'H-tetrazol-5'-yl)-phenylboronic acid 
• 83857-96-9 2-n-butyl-4-chloro-1H-imidazol-5-carboxaldehyde 
• 589-15-1 1-bromomethyl-4-bromobenzene 
• 18039-42-4 5-phenyl-2H-1,2,3,4-tetrazole 
• 57598-33-1 2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline 
• 114772-53-1 2-Cyano-4'-methylbiphenyl 
• 74201-13-1 N-(2-hydroxy-1,1-dimethyl)-2-methoxybenzamide 

Downstream Products

• 114798-26-4 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole 
• 124750-99-8 cozaar 
• 76-84-6 triphenylmethyl alcohol 
• 1195777-20-8 6-(tert-butyl-dimethyl-silanyloxy)-2,5,7,8-tetramethylchroman-2-carboxylic acid 2-butyl-5-chloro-3-[2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-midazol-4-yl methyl ester 
• 1195777-19-5 C₆₄H₅₇ClN₆O₄ 
• 1195777-18-4 4-benzyloxy-3,5-dimethoxybenzoic acid 5-chloro-2-butyl-3-[2'-(2-trityl-2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-yl methyl ester 
• 1195777-21-9 (3,5-di-tert-butyl-4-hydroxyphenyl)-acetic acid 2-butyl-5-chloro-3-[2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-yl methyl ester 
• 114798-26-4 lorsartan 

Relevant articles and documents

Trityl losartan

The title compound (systematic name: (2-butyl-4-chloro-1-[2-(2-trityl-2H- tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazol-5-yl}methanol), C 41H37ClN6O, crystallizes in the centrosym-metric space group P1 with two independent molecules in the asymmetric unit. These molecules differ significantly only in the relative orientations of the rings in the biphenylyltetrazole moieties. One of the molecules shows disorder for three C atoms in the n-butyl group. Hydrogen bonds link the molecules in an infinite chain along the a axis.

Mechanistic Studies of the Suzuki Cross-Coupling Reaction

The key step in the synthesis of the drug substance losartan is a palladium-catalyzed cross-coupling reaction of an aryl bromide and a boronic acid.The reaction scheme was defined in kinetic studies using HPLC, and computer simulation served to depict the

Continuous Synthesis and Separation ofp-Bromobenzyl Bromide Using Atom-Efficient Bromination ofp-Bromotoluene without Any Organic Effluent: Potential for Green Industrial Practice

This work focuses on the bromination ofp-bromotoluene (PBT) using different brominating agents such as liquid Br2, NaBr-NaBrO3, NaBr-NaBrO3-NaCl, NaBr-H2O2, and HBr-H2O2. NaBr-NaBrO3-NaCl is an eco-friendly brominating agent obtained from a bromine recovery plant. Both NaBr-NaBrO3and NaBr-NaBrO3-NaCl were found to be nonhazardous and efficient brominating agents. Pure NaBr-NaBrO3resulted in the best PBT conversion with 79.7% Br atom efficiency in water and 98.2% average Br atom efficiency using dichloroethane as a solvent. Dichloroethane is de facto no longer used in the US and Europe and is not eco-friendly; the process with water as a solvent is the best. The substrate to active bromine molar ratio of 3:1 was found to be sufficient to get the maximum selectivity ofp-bromobenzyl bromide (PBBB). The low-temperature crystallization method was used for separation cum purification of the product. Unreacted PBT was recycled along with the dibromo byproduct obtained. The dibromo product, which was built up gradually in the reaction mixture over 10 successive batches, was converted back into PBBB/PBT through NaBH4treatment of the mother liquor. This continuous process is highly sustainable and produces zero organic waste, making it potentially attractive toward green industrial implementation.

Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor

Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands. We followed such a strategy in order to treat metabolic syndrome, by setting up molecules directed towards both type 1 angiotensin II (AT1) receptor and peroxisome proliferator-activated receptor-γ (PPAR-γ). For this purpose, many molecules were prepared by merging both pharmacophores following three different strategies. Their ability to activate PPAR-γ and to block AT1 receptors were evaluated in vitro. This strategy led to the preparation of many new PPAR-γ activating and AT1 blocking molecules. Among them, some exhibited both activities, highlighting the convenience of this approach.

New losartan-hydrocaffeic acid hybrids as antihypertensive-antioxidant dual drugs: Ester, amide and amine linkers

We report new examples of a series of losartan-hydrocaffeic hybrids that bear novel ester, amide and amine linkers. These compounds were made by linking hydrocaffeic acid to the side chain of losartan at the C-5 position of the imidazole ring through different strategies. Experiments performed in cultured cells demonstrate that these new hybrids retain the ability to block the angiotensin II effect and have increased antioxidant ability. Most of them reduced arterial pressure in rats better or as much as losartan.

A process for the preparation of losartan derivatives by chlorination and reduction of the respective 1H-imidazole-5-carbaldehydes

The invention provides a process for the preparation of a sartan derivative of formula (I): wherein R = C2-C7 straight or branched alkyl or C3-C9 cycloalkyl, or a pharmaceutically acceptable salt thereof, comprising the steps of chlorinating and reducing, in any order, a compound of formula (III): wherein R is defined as above to form a compound of formula (VI), wherein R is defined as above and then deprotecting said compound of formula (VI) to obtain the sartan derivative of formula (I), and optionally converting said sartan derivative into one of its pharmaceutically acceptable salts. A preferred embodiment of this invention is a process for the preparation of losartan and, particularly, its potassium salt.

PROCESS FOR THE PREPARATION OF LOSARTAN AND ITS SALTS

The invention relates to the preparation of losartan and its salts (e.g., losartan potassium). More particularly, the invention relates to the preparation of losartan and its salts (e.g., losartan potassium) in a simplified process that provides higher purity losartan potassium and losartan potassium having larger crystal sizes. The invention further includes formulating losartan, its salts (e.g., losartan potassium ) and/or in vivo cleavable prodrugs thereof (collectively "the compounds of the invention") into readily usable dosage units for the therapeutic treatment (including prophylactic treatment) of mammals, including humans.

Use of an angiotensin II receptor antagonist for the preparation of drugs to increase the survival rate of renal transplant patients

The present invention relates to the use, for the preparation of drugs to increase the survival rate of transplant patients, including renal and heart transplant patients, of a therapeutically effective amount of an angiotension II receptor antagonist compound, such as the class of substituted imidazoles represented by formula (I) and in particular by losartan potassium, 2-butyl-4-chloro-[(2′-tetrazol-5-yl)biphenyl-4-il]methyl]-5-(hydroxymethyl)imidazole potassium salt.

INSULIN SENSITIVITY WITH ANGIOTENSIN II RECEPTOR BLOCKING IMIDAZOLES

This invention relates to a novel method of using an Angiotensin II antagonist for the improvement of insulin sensitivity alone or in conjunction with the treatment of hypertension. Angiotensin II antagonists such as the class of substituted imidazoles represented by formula I: STR1 and specifically by Losartan, 2-butyl-4-chloro-1-[(2'-tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(hydroxymethyl)imidazole potassium salt.

Polymorphs of losartan and the process for the preparation of form II of losartan

Polymorphic forms of Losartan (Formula I) STR1 and a process for the preparation of Form II of Losartan. Losartan is known to be useful in the treatment of hypertension.