139481-59-7

Basic information

• Product Name: Candesartan
• Synonyms: 2-ethoxy-3-[[4-[2-(1h-tetrazol-5-yl)phenyl]phenyl]methyl]-3h-benzoimidazole-4-carboxylic acid;2-ETHOXY-1-[[2'-(1H-TETRAZOL-5-YL)(1,1'-BIPHENYL)-4-YL]METHYL]-1H-BENZIMIDAZOLE-7-CARBOXYLIC ACID;CANDESARTAN;CV-11974;CILEXITIL;Candesartan[CandesartanCilexetilIntermediates];Candesartan ( For Candesartan Cilexetil );2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylic Acid, CV-11974
• CAS NO: 139481-59-7
• Molecular Formula: C₂₄H₂₀N₆O₃
• Molecular Weight: 440.45
• EINECS: 1806241-263-5
• Product Categories: Active Pharmaceutical Ingredients;Candesartan Cilexetil;API intermediates;Bases & Related Reagents;Intermediates & Fine Chemicals;Nucleotides;Pharmaceuticals;Candesartan Cilexatil;Aromatics;Heterocycles;Pharmaceutical raw material;Isotope
• Mol File: 139481-59-7.mol
• Article Data: 19

Chemical Properties

• Melting Point: 183-185°C
• Boiling Point: 754.8 °C at 760 mmHg
• Flash Point: 410.3 °C
• Appearance: crystalline solid
• Density: 1.41 g/cm³
• Vapor Pressure: 4.39E-24mmHg at 25°C
• Refractive Index: 1.746
• Storage Temp.: -20°C Freezer
• Solubility: Soluble in DMSO (up to 40 mg/ml)
• PKA: 2.06±0.10(Predicted)
• Water Solubility: Soluble in ethyl acetate, methanol, water (<1 mg/ml at 25°C), DMSO (88 mg/ml at 25°C), and ethanol (1 mg/ml at 25°C).
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 2 months.
• CAS DataBase Reference: Candesartan(CAS DataBase Reference)
• NIST Chemistry Reference: Candesartan(139481-59-7)
• EPA Substance Registry System: Candesartan(139481-59-7)

Safety Data

• Hazard Codes: Xn
• Statements: 20/21/22-36/37/38
• Safety Statements: 26-36-60-36/37-9
• RTECS: DD6671000
• Hazardous Substances Data: 139481-59-7(Hazardous Substances Data)

Usage

Description

Candesartan (CAS 139481-59-7) is an angiotensin II receptor I (AT1) antagonist, IC50s=1.12 and 2.86 nM for bovine adrenal cortex and rabbit aorta respectively.1?Selectively inhibits angiotensin II-induced contraction of rabbit aortic strips with no effect on contraction induced by other agents such as norepinephrine, KCl, serotonin, PGF2αor endothelin. Prevents astrocyte and microglial activation and neuroinflammation and improves hippocampal neurogenesis.2?Attenuates angiogenesis in hepatocellular carcinoma.3?Clinically useful antihypertensive agent. Ameliorates brain inflammation associated with Alzheimer’s disease.4?Active?in vivo?and orally active.

Chemical Properties

Crystalline Solid

Uses

Different sources of media describe the Uses of 139481-59-7 differently. You can refer to the following data:
1. An angiotensin II type-1 receptor antagonist. Used in treatment of congestive heart failure. Antihypertensive
2. antihypertensive, angiotensin II inhibitor
3. Candesartan is a selective AT1 (angiotensin II receptor 1) antagonist. Antagonism of angiotensin receptors inhibits vasoconstriction and the production of aldosterone, leading to a decrease in water and sodium concentration in blood plasma. Exhibits antihypertensive effects in animal models. Used in treatment of congestive heart failure, as antihypertensive. Candesartan does not affect cell viability or proliferation but increases the expression of VEGF and interleukin-8 in the cultured medium of KU-19-19 cells. Candesartan (0.1 nM) could reduce the maximal contractile response to angiostensin II by approximately 50%.

Definition

ChEBI: A benzimidazolecarboxylic acid that is 1H-benzimidazole-7-carboxylic acid substituted by an ethoxy group at position 2 and a ({2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl}methyl) group at position 1. It is a angiotensin eceptor antagonist used for the treatment of hypertension.

Brand name

Atacand (AstraZeneca).

General Description

Candesartan, (+)-1-[[(cyclohexyloxy)carbonyl]-oxy]ethyl 2- ethoxy-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylate(Atacand), like losartan, possesses the acidic tetrazole system,which most likely plays a role in binding to the angiotensin IIreceptor similarly to the acidic groups of angiotensin II. Also,the imidazole system has been replaced with a benzimidazolepossessing an ester at position. This ester must be hydrolyzedto the free acid. Fortunately, this conversion takesplace fairly easily because of the carbonate in the ester sidechain. This facilitates hydrolysis of the ester so much thatconversion to the free acid takes place during absorption fromthe gastrointestinal tract.

References

1) Shibouta?et al.?(1993),?Pharmacological profile of a highly potent and long-acting angiotension II receptor antagonist, 2-ethoxy-1-[[2’-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazol-7-carboxylic acid (CV-11974), and its prodrug, (+/-)-1-(cyclohexyloxycarbonyloxy)-ethyl 2-ethoxy-1-[[2’-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (TCV-116); J. Pharmacol. Exp. Therap.,?266?114 2) Bhat?et al. (2017),?Angiotensin receptor Blockade by Inhibiting Glial Activation Promotes Hippocampal Neurogenesis Via Activation of Wnt/B-Catenin signaling in hypertension; Mol. Neurobiol.,?55 5282 3) Fan?et al.?(2016),?Candesartan attenuates angiogenesis in hepatocellular carcinoma via downregulating AT1R/VEGF pathway; Biomed. Pharmacother.,?83?704 4) Torika?et al.?(2018),?Candesartan ameliorates brain inflammation associated with Alzheimer’s disease; CNS Neurosci. Ther.?24?231

InChI:InChI:1S/C24H20N6O3/c1-2-33-24-25-20-9-5-8-19(23(31)32)21(20)30(24)14-15-10-12-16(13-11-15)17-6-3-4-7-18(17)22-26-28-29-27-22/h3-13H,2,14H2,1H3,(H,31,32)(H,26,27,28,29)

Synthetic route

methyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (139481-69-9) → candesartan (139481-59-7)

Conditions	Yield
Stage #1: methyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate With sodium hydroxide; water In methanol at 78 - 80℃; for 1h; Stage #2: With acetic acid In ethyl acetate at 10 - 15℃; pH=4 - 5;	95%
With methanol; sodium hydroxide; water at 10 - 70℃;	90%
With sodium hydroxide In methanol at 80 - 90℃; for 1h;	85%

ethyl 2-ethoxy-1-{[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-1,1'-biphenyl-4-yl]methyl}-benzimidazole-7-carboxylate (856414-35-2) → candesartan (139481-59-7)

Conditions	Yield
With lithium hydroxide In ethanol at 80℃; for 3h;	85%

ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate (139481-58-6) → candesartan (139481-59-7)

Conditions	Yield
Stage #1: ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate With sodium hydroxide; ethanol; water for 24h; Heating / reflux; Stage #2: With hydrogenchloride In ethanol; water pH=4 - 4.5;	80%
Stage #1: ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate With sodium hydroxide; water In o-xylene at 25 - 65℃; for 3h; Stage #2: With acetic acid In methanol pH=4.5 - 5.5;
With water; sodium hydroxide at 40 - 80℃; Reagent/catalyst;

candesartan cilexetil → methanol-methyl carbonate + candesartan (139481-59-7) + cyclohexanol (108-93-0)

Conditions	Yield
With sodium hydroxide In methanol; dichloromethane at 30℃; for 8h;	A n/a B 78.01% C n/a

methanol ethyl acetate (914771-42-9) + ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate (139481-58-6) → candesartan (139481-59-7)

Conditions	Yield
With sodium hydroxide In ethanol	67%

methyl 2-carboxy-3-nitrobenzoate (21606-04-2) → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 9 steps 1: SOCl2, DMF / toluene / 0.5 h / Heating 2: NaN3 / acetone; H2O / 1 h 3: 1.5 h / Heating 4: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 5: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 6: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 7: 91 percent / acetic acid / 0.67 h / 80 - 90 °C 8: 100 percent / trimethyltin azide / toluene / 29 h / Heating 9: 85 percent / 1 N aq. NaOH / methanol / 1 h / 80 - 90 °C View Scheme
Multi-step reaction with 7 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / toluene / 2.5 h / 75 °C 2.1: sodium azide; tetrabutylammomium bromide / toluene / 4 h / -10 - -5 °C 2.2: 1 h / 80 - 85 °C 3.1: potassium carbonate; tetrabutylammomium bromide / toluene / 12 h / 80 - 85 °C 3.2: 3 h / Reflux 4.1: tin(ll) chloride / ethyl acetate / 1.5 h / Reflux 4.2: 4.5 h / -10 - 0 °C 4.3: 0.5 h / Reflux 5.1: acetic acid / toluene / 6 h / Reflux 6.1: sodium azide; tributyltin chloride / toluene / 100 h / Reflux 6.2: 0 - 20 °C 7.1: sodium hydroxide; water / ethanol / 3.5 h / Reflux 7.2: 3 h / 0 °C / pH 4 View Scheme

acid chloride of 1-methylhydrogen-3-nitrophthalate (73833-13-3) → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 8 steps 1: NaN3 / acetone; H2O / 1 h 2: 1.5 h / Heating 3: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 4: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 5: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 6: 91 percent / acetic acid / 0.67 h / 80 - 90 °C 7: 100 percent / trimethyltin azide / toluene / 29 h / Heating 8: 85 percent / 1 N aq. NaOH / methanol / 1 h / 80 - 90 °C View Scheme
Multi-step reaction with 6 steps 1.1: sodium azide; tetrabutylammomium bromide / toluene / 4 h / -10 - -5 °C 1.2: 1 h / 80 - 85 °C 2.1: potassium carbonate; tetrabutylammomium bromide / toluene / 12 h / 80 - 85 °C 2.2: 3 h / Reflux 3.1: tin(ll) chloride / ethyl acetate / 1.5 h / Reflux 3.2: 4.5 h / -10 - 0 °C 3.3: 0.5 h / Reflux 4.1: acetic acid / toluene / 6 h / Reflux 5.1: sodium azide; tributyltin chloride / toluene / 100 h / Reflux 5.2: 0 - 20 °C 6.1: sodium hydroxide; water / ethanol / 3.5 h / Reflux 6.2: 3 h / 0 °C / pH 4 View Scheme

3-nitrophthalic acid (603-11-2) → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 10 steps 1: concd. H2SO4 / methanol 2: SOCl2, DMF / toluene / 0.5 h / Heating 3: NaN3 / acetone; H2O / 1 h 4: 1.5 h / Heating 5: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 6: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 7: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 8: 91 percent / acetic acid / 0.67 h / 80 - 90 °C 9: 100 percent / trimethyltin azide / toluene / 29 h / Heating 10: 85 percent / 1 N aq. NaOH / methanol / 1 h / 80 - 90 °C View Scheme
Multi-step reaction with 8 steps 1.1: sulfuric acid / 24.75 h / 20 - 65 °C 2.1: N,N-dimethyl-formamide; thionyl chloride / toluene / 2.5 h / 75 °C 3.1: sodium azide; tetrabutylammomium bromide / toluene / 4 h / -10 - -5 °C 3.2: 1 h / 80 - 85 °C 4.1: potassium carbonate; tetrabutylammomium bromide / toluene / 12 h / 80 - 85 °C 4.2: 3 h / Reflux 5.1: tin(ll) chloride / ethyl acetate / 1.5 h / Reflux 5.2: 4.5 h / -10 - 0 °C 5.3: 0.5 h / Reflux 6.1: acetic acid / toluene / 6 h / Reflux 7.1: sodium azide; tributyltin chloride / toluene / 100 h / Reflux 7.2: 0 - 20 °C 8.1: sodium hydroxide; water / ethanol / 3.5 h / Reflux 8.2: 3 h / 0 °C / pH 4 View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 6 steps 1: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 2: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 3: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 4: 91 percent / acetic acid / 0.67 h / 80 - 90 °C 5: 100 percent / trimethyltin azide / toluene / 29 h / Heating 6: 85 percent / 1 N aq. NaOH / methanol / 1 h / 80 - 90 °C View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate; tetrabutylammomium bromide / toluene / 12 h / 80 - 85 °C 1.2: 3 h / Reflux 2.1: tin(ll) chloride / ethyl acetate / 1.5 h / Reflux 2.2: 4.5 h / -10 - 0 °C 2.3: 0.5 h / Reflux 3.1: acetic acid / toluene / 6 h / Reflux 4.1: sodium azide; tributyltin chloride / toluene / 100 h / Reflux 4.2: 0 - 20 °C 5.1: sodium hydroxide; water / ethanol / 3.5 h / Reflux 5.2: 3 h / 0 °C / pH 4 View Scheme

2-Azidocarbonyl-3-nitro-benzoic acid methyl ester (856414-36-3) → candesartan (139481-59-7)

Conditions

Yield

Multi-step reaction with 7 steps 1: 1.5 h / Heating 2: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 3: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 4: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 5: 91 percent / acetic acid / 0.67 h / 80 - 90 °C 6: 100 percent / trimethyltin azide / toluene / 29 h / Heating 7: 85 percent / 1 N aq. NaOH / methanol / 1 h / 80 - 90 °C View Scheme

methyl 3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate (136304-78-4) → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 91 percent / acetic acid / 0.67 h / 80 - 90 °C 2: 100 percent / trimethyltin azide / toluene / 29 h / Heating 3: 85 percent / 1 N aq. NaOH / methanol / 1 h / 80 - 90 °C View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid / toluene / 6 h / Reflux 2.1: sodium azide; tributyltin chloride / toluene / 100 h / Reflux 2.2: 0 - 20 °C 3.1: sodium hydroxide; water / ethanol / 3.5 h / Reflux 3.2: 3 h / 0 °C / pH 4 View Scheme

methyl 2-<<2'-cyanobiphenyl-4-yl)methyl>amino>-3-nitrobenzoate (139481-28-0) → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 2: 91 percent / acetic acid / 0.67 h / 80 - 90 °C 3: 100 percent / trimethyltin azide / toluene / 29 h / Heating 4: 85 percent / 1 N aq. NaOH / methanol / 1 h / 80 - 90 °C View Scheme
Multi-step reaction with 4 steps 1.1: tin(ll) chloride / ethyl acetate / 1.5 h / Reflux 1.2: 4.5 h / -10 - 0 °C 1.3: 0.5 h / Reflux 2.1: acetic acid / toluene / 6 h / Reflux 3.1: sodium azide; tributyltin chloride / toluene / 100 h / Reflux 3.2: 0 - 20 °C 4.1: sodium hydroxide; water / ethanol / 3.5 h / Reflux 4.2: 3 h / 0 °C / pH 4 View Scheme

methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-benzimidazole-7-carboxylate (139481-44-0) → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 100 percent / trimethyltin azide / toluene / 29 h / Heating 2: 85 percent / 1 N aq. NaOH / methanol / 1 h / 80 - 90 °C View Scheme
Multi-step reaction with 2 steps 1: azido tributyltin (IV) / N,N-dimethyl-formamide / 20 h / 140 - 150 °C 2: sodium hydroxide; water / 20 h / 70 - 80 °C View Scheme

methyl 2-amino>-3-nitrobenzoate (139481-38-2) → candesartan (139481-59-7)

Conditions

Yield

Multi-step reaction with 5 steps 1: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 2: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 3: 91 percent / acetic acid / 0.67 h / 80 - 90 °C 4: 100 percent / trimethyltin azide / toluene / 29 h / Heating 5: 85 percent / 1 N aq. NaOH / methanol / 1 h / 80 - 90 °C View Scheme

methyl 1-[(2-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium azide; tributyltin chloride / toluene / 100 h / Reflux 1.2: 0 - 20 °C 2.1: sodium hydroxide; water / ethanol / 3.5 h / Reflux 2.2: 3 h / 0 °C / pH 4 View Scheme

candesartan cilexetil (145040-37-5) → candesartan (139481-59-7)

Conditions	Yield
With Bis(p-nitrophenyl) phosphate In dimethyl sulfoxide; acetonitrile at 37℃; for 0.0333333h; pH=7.5; Reagent/catalyst; Enzymatic reaction;

methyl 2-ethoxy-1-<<2'-biphenyl-4-yl>methyl>-1H-benzimidazole-7-carboxylate → candesartan (139481-59-7)

Conditions	Yield
With methanol; sodium hydroxide at 50℃; for 3h;	44.5 g

2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester (150058-27-8) → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium tert-butylate / N,N-dimethyl acetamide / 60 °C / Inert atmosphere 2: sodium hydroxide; methanol / 3 h / 50 °C View Scheme

ethyl 1-[(2'-cyano-[1,1']-biphenyl-4-yl)methyl]-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate (139481-41-7) → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: azido tributyltin (IV) / 5,5-dimethyl-1,3-cyclohexadiene / 20 h / 140 - 150 °C 2: sodium hydroxide; water / 40 - 80 °C View Scheme

ethyl 1-(4-bromobenzyl)-2-ethoxy-benzimidazole-7-carboxylate (854538-88-8) → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium carbonate / palladium diacetate; triphenylphosphine / water; toluene / 16 h / 60 - 70 °C 2.1: sodium hydroxide; ethanol; water / 24 h / Heating / reflux 2.2: pH 4 - 4.5 View Scheme

ethyl 3-amino-2-(4-bromobenzylamine)-benzoate (916891-90-2) → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: acetic acid / 1 h / 80 °C 2.1: potassium carbonate / palladium diacetate; triphenylphosphine / water; toluene / 16 h / 60 - 70 °C 3.1: sodium hydroxide; ethanol; water / 24 h / Heating / reflux 3.2: pH 4 - 4.5 View Scheme

ethyl 2-(4-bromobenzylamine)-3-nitrobenzoate (854538-89-9) → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: tin(ll) chloride / ethanol / 2 h / Heating / reflux 1.2: 0 °C 2.1: sodium hydroxide; water 3.1: acetic acid / 1 h / 80 °C 4.1: potassium carbonate / palladium diacetate; triphenylphosphine / water; toluene / 16 h / 60 - 70 °C 5.1: sodium hydroxide; ethanol; water / 24 h / Heating / reflux 5.2: pH 4 - 4.5 View Scheme

ethyl 3-amino-2-(4-bromobenzylamine)-benzoate hydrochloride → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydroxide; water 2.1: acetic acid / 1 h / 80 °C 3.1: potassium carbonate / palladium diacetate; triphenylphosphine / water; toluene / 16 h / 60 - 70 °C 4.1: sodium hydroxide; ethanol; water / 24 h / Heating / reflux 4.2: pH 4 - 4.5 View Scheme

ethyl 2-ethoxy-1-[[2'-[(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-[1,1']biphenyl-4-yl]methyl]-1H-benzoimidazole-7-carboxylate (916891-91-3) → candesartan (139481-59-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium formate / palladium 10% on activated carbon / ethanol / 72 h / Heating / reflux 2.1: sodium hydroxide; ethanol; water / 24 h / Heating / reflux 2.2: pH 4 - 4.5 View Scheme

ethyl 2-chloro-3-nitrobenzoate (3979-45-1) → candesartan (139481-59-7)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: triethylamine / toluene / 12 h / Heating / reflux 2.1: tin(ll) chloride / ethanol / 2 h / Heating / reflux 2.2: 0 °C 3.1: sodium hydroxide; water 4.1: acetic acid / 1 h / 80 °C 5.1: potassium carbonate / palladium diacetate; triphenylphosphine / water; toluene / 16 h / 60 - 70 °C 6.1: sodium hydroxide; ethanol; water / 24 h / Heating / reflux 6.2: pH 4 - 4.5 View Scheme

2-chloro-3-nitrobezoic acid (3970-35-2) → candesartan (139481-59-7)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: sulfuric acid / 24 h / 15 - 30 °C / Heating / reflux 2.1: triethylamine / toluene / 12 h / Heating / reflux 3.1: tin(ll) chloride / ethanol / 2 h / Heating / reflux 3.2: 0 °C 4.1: sodium hydroxide; water 5.1: acetic acid / 1 h / 80 °C 6.1: potassium carbonate / palladium diacetate; triphenylphosphine / water; toluene / 16 h / 60 - 70 °C 7.1: sodium hydroxide; ethanol; water / 24 h / Heating / reflux 7.2: pH 4 - 4.5 View Scheme

candesartan (139481-59-7) → (1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazol-7-yl)methanol (924654-25-1)

Conditions	Yield
Stage #1: candesartan With lithium aluminium tetrahydride In tetrahydrofuran at -78 - 50℃; for 6.5h; Stage #2: With hydrogenchloride In tetrahydrofuran; water	96.5%
With lithium aluminium tetrahydride In tetrahydrofuran at -78℃;	90%
Stage #1: candesartan With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; Stage #2: With water In tetrahydrofuran at 0℃; for 0.5h;	77%
With lithium aluminium tetrahydride In tetrahydrofuran at 20℃;	77%

trityl chloride (76-83-5) + candesartan (139481-59-7) → 2-Ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (139481-72-4)

Conditions	Yield
With triethylamine In dichloromethane at 15 - 23℃; for 3.5h; Temperature; Flow reactor; Large scale;	94%
With triethylamine In acetone at 55 - 60℃; for 4 - 8h; Product distribution / selectivity;	90%
With triethylamine In acetone at 55 - 60℃; Product distribution / selectivity;	90%

candesartan (139481-59-7) → C24H20N6O3*H3N

Conditions	Yield
With ammonium hydroxide In water for 2h;	89%

ethylenediamine (107-15-3) + candesartan (139481-59-7) → C24H20N6O3*C2H8N2

Conditions	Yield
In water for 2h;	85%

Trimethylenediamine (109-76-2) + candesartan (139481-59-7) → C24H20N6O3*C3H10N2

Conditions	Yield
In water for 2h;	80%

trityl chloride (76-83-5) + candesartan (139481-59-7) → 2-ethoxy-1-<<2'-biphenyl-4-yl>methyl>-1H-benzimidazole-7-carboxylic acid (894806-43-0)

Conditions	Yield
With triethylamine In dichloromethane for 1h; Ambient temperature;	76%

zinc(II) acetate dihydrate (5970-45-6) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) + candesartan (139481-59-7) → C24H18N6O3(2-)*2C3H7NO*Zn(2+)

Conditions	Yield
In methanol	68%

ethyl acetate-benzene + trityl chloride (76-83-5) + candesartan (139481-59-7) → 2-Ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (139481-72-4)

Conditions	Yield
With triethylamine In dichloromethane	66%

pyridine (110-86-1) + water (7732-18-5) + candesartan (139481-59-7) + cadmium(II) iodide → C24H18N6O3(2-)*Cd(2+)*C5H5N*H2O

Conditions	Yield
In methanol at 150℃; for 72h; Autoclave;	56%

4,4'-bipyridine (553-26-4) + zinc(II) sulfate heptahydrate + candesartan (139481-59-7) → 2C24H18N6O3(2-)*2Zn(2+)*C10H8N2

Conditions	Yield
In methanol; water at 135℃; for 72h; Autoclave;	45%

1-chloromethyl-3-methylbutylamine hydrochloride (1160386-36-6) + candesartan (139481-59-7) → 2-Ethoxy-3-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-4-carboxylic acid (1-chloromethyl-3-methylbutyl)amide (1160386-25-3)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In DCM at 20℃;	15%

candesartan (139481-59-7) + uridine-5'-diphospho-α-D-glucuronic acid trisodium salt (63700-19-6) → candesartan-O-glucuronide

Conditions	Yield
With saccharic acid-1,4-lactone; recombinant human UDP-glucuronyltransferase 1A8 at 37℃; for 48h;	7.4%

candesartan (139481-59-7) + uridine-5'-diphospho-α-D-glucuronic acid trisodium salt (63700-19-6) → candesartan-N2-glucuronide

Conditions	Yield
With saccharic acid-1,4-lactone; recombinant human UDP-glucuronyltransferase 1A3 at 37℃; for 48h;	4%

candesartan (139481-59-7) → 2-Ethoxy-3-[2'-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-4-carboxylic acid acetoxymethyl ester

Conditions	Yield
Multi-step reaction with 3 steps 1: 76 percent / triethylamine / CH2Cl2 / 1 h / Ambient temperature 2: potassium iodide, potassium carbonate / dimethylformamide / 2 h / 60 °C 3: 1N aq. HCl / methanol / 1.5 h / Ambient temperature View Scheme

candesartan (139481-59-7) → 2-Ethoxy-3-[2'-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-4-carboxylic acid 1-acetoxy-ethyl ester

Conditions	Yield
Multi-step reaction with 3 steps 1: 76 percent / triethylamine / CH2Cl2 / 1 h / Ambient temperature 2: potassium iodide, potassium carbonate / dimethylformamide / 2 h / 60 °C 3: 1N aq. HCl / methanol / 1.5 h / Ambient temperature View Scheme

Upstream product

• 914771-42-9 methanol ethyl acetate 
• 139481-58-6 ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate 
• 3970-35-2 2-chloro-3-nitrobezoic acid 
• 3979-45-1 ethyl 2-chloro-3-nitrobenzoate 
• 916891-91-3 ethyl 2-ethoxy-1-[[2'-[(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-[1,1']biphenyl-4-yl]methyl]-1H-benzoimidazole-7-carboxylate 
• 854538-89-9 ethyl 2-(4-bromobenzylamine)-3-nitrobenzoate 
• 916891-90-2 ethyl 3-amino-2-(4-bromobenzylamine)-benzoate 
• 854538-88-8 ethyl 1-(4-bromobenzyl)-2-ethoxy-benzimidazole-7-carboxylate 
• 139481-41-7 ethyl 1-[(2'-cyano-[1,1']-biphenyl-4-yl)methyl]-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate 
• 150058-27-8 2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester 
• 145040-37-5 candesartan cilexetil 
• 856414-35-2 ethyl 2-ethoxy-1-{[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-1,1'-biphenyl-4-yl}methyl]-benzimidazole-7-carboxylate 
• 139481-38-2 methyl 2-amino>-3-nitrobenzoate 
• 139481-44-0 methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-benzimidazole-7-carboxylate 

Downstream Products

• 139481-72-4 2-Ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid 
• 924654-29-5 C₄₃H₃₅BrN₆O 
• 924654-27-3 C₄₃H₃₆N₆O₂ 
• 170791-09-0 cilexetil trityl candesartan 
• 1376615-11-0 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carbaldehyde O-methyl oxime 
• 1376615-09-6 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carbaldehyde oxime 
• 1225044-10-9 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carbaldehyde 
• 145040-37-5 candesartan cilexetil 
• 1160386-25-3 2-Ethoxy-3-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-4-carboxylic acid (1-chloromethyl-3-methylbutyl)amide 

Relevant articles and documents

Host-Guest Interactions between Candesartan and Its Prodrug Candesartan Cilexetil in Complex with 2-Hydroxypropyl-β-cyclodextrin: On the Biological Potency for Angiotensin II Antagonism

Renin-angiotensin aldosterone system inhibitors are for a long time extensively used for the treatment of cardiovascular and renal diseases. AT1 receptor blockers (ARBs or sartans) act as antihypertensive drugs by blocking the octapeptide hormone Angiotensin II to stimulate AT1 receptors. The antihypertensive drug candesartan (CAN) is the active metabolite of candesartan cilexetil (Atacand, CC). Complexes of candesartan and candesartan cilexetil with 2-hydroxylpropyl-β-cyclodextrin (2-HP-β-CD) were characterized using high-resolution electrospray ionization mass spectrometry and solid state 13C cross-polarization/magic angle spinning nuclear magnetic resonance (CP/MAS NMR) spectroscopy. The 13C CP/MAS results showed broad peaks especially in the aromatic region, thus confirming the strong interactions between cyclodextrin and drugs. This experimental evidence was in accordance with molecular dynamics simulations and quantum mechanical calculations. The synthesized and characterized complexes were evaluated biologically in vitro. It was shown that as a result of CAN's complexation, CAN exerts higher antagonistic activity than CC. Therefore, a formulation of CC with 2-HP-β-CD is not indicated, while the formulation with CAN is promising and needs further investigation. This intriguing result is justified by the binding free energy calculations, which predicted efficient CC binding to 2-HP-β-CD, and thus, the molecule's availability for release and action on the target is diminished. In contrast, CAN binding was not favored, and this may allow easy release for the drug to exert its bioactivity.

METHOD FOR PREPARING TRITYL CANDESARTAN

The present invention uses a candesartan cyclic compound as a starting material and performs thereon a three-step reaction of forming tetrazole, hydrolysis and adding a protecting group to directly obtain trityl candesartan without separating an intermediate product via crystallization. The operating process is simple and thus is more applicable to industrial production.

Preparation method of candesartan

The invention relates to a preparation method of candesartan. The preparation method comprises the steps of carrying out N-alkylation reaction, deprotection reaction and ester hydrolysis reaction on raw materials including 2-ethoxybenzimidazole-7-carboxylate and a tetrazole compound, so as to obtain the candesartan. According to the preparation method, compounds with high toxicity and large environmental protection pressure such as sodium azide, tributyl tin chloride or tributyl tin azide are not used; and compared with processes in the prior art, the preparation method is simple and convenient in operation and is beneficial to industrial large-scale production.