139481-59-7

Hazards Identification

Pictogram(s):

Signal:

Warning

GHS Hazard Statements:

H361: Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]
H400: Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]
H410: Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes:

P203, P273, P280, P318, P391, P405, and P501

Usage

Uses

Used in Pharmaceutical Industry:
Candesartan is used as an antihypertensive agent for the treatment of hypertension. It acts as an angiotensin II type-1 receptor antagonist, inhibiting vasoconstriction and the production of aldosterone, leading to a decrease in water and sodium concentration in blood plasma.
Used in Cardiology:
Candesartan is used in the treatment of congestive heart failure. It prevents astrocyte and microglial activation and neuroinflammation, improving hippocampal neurogenesis and attenuating angiogenesis in hepatocellular carcinoma.
Used in Neurology:
Candesartan is used to ameliorate brain inflammation associated with Alzheimer's disease. It exhibits neuroprotective effects by inhibiting angiotensin II-induced contractions and reducing the maximal contractile response to angiostensin II.
Used in Oncology:
Candesartan has been shown to attenuate angiogenesis in hepatocellular carcinoma, potentially offering therapeutic benefits in cancer treatment.
Chemical Properties:
Candesartan is a crystalline solid with the CAS number 139481-59-7. It possesses an acidic tetrazole system, which likely plays a role in binding to the angiotensin II receptor, similar to the acidic groups of angiotensin II. The ester sidechain of candesartan facilitates hydrolysis, allowing for conversion to the free acid during absorption from the gastrointestinal tract.
Brand Name:
Atacand (AstraZeneca) is the brand name for candesartan, which is available in the pharmaceutical market for the treatment of hypertension and congestive heart failure.

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

• 139481-58-6 ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate 
• 139481-41-7 ethyl 1-[(2'-cyano-[1,1']-biphenyl-4-yl)methyl]-2-ethoxy-1H-benzo[d]imidazole-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 
• 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 
• 914771-42-9 methanol ethyl acetate 
• 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

• 894806-43-0 2-ethoxy-1-<<2'-biphenyl-4-yl>methyl>-1H-benzimidazole-7-carboxylic acid 
• 139481-72-4 2-Ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid 
• 180603-77-4 candesartan acyl-β-D-glucuronide 
• 1160386-25-3 2-Ethoxy-3-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-4-carboxylic acid (1-chloromethyl-3-methylbutyl)amide 
• 886999-34-4 2-Ethoxy-3-[2'-(2-trityl-2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-4-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester 

Relevant academic research and scientific papers

Method for treating azide ions, non-genotoxic impurity Sartan raw material medicine and immediate thereof

The invention discloses a method for treating azide ions in a system and application thereof to the preparation of a compound with a tetrazolium group and without genotoxic impurities. The method is that the azide ions contained in the hydrogen peroxide treatment system are used. The method is used for preparing the compound with the tetrazolium group and comprises the following preparation steps:enabling a compound containing a cyano group to react with an azide, adding hydrogen peroxide after the reaction to quench and remove excessive sodium azide and further obtaining the compound with the tetrazolium group. The compound prepared by the method does not contain the genotoxic impurities. The method is simple in operation, mild in reaction conditions and suitable for industrial production.

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.

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.

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.

Different hydrolases involved in bioactivation of prodrug-type angiotensin receptor blockers: Carboxymethylenebutenolidase and carboxylesterase 1

Olmesartan medoxomil (OM) is a prodrug-type angiotensin II type 1 receptor blocker (ARB). We recently identified carboxymethylenebutenolidase homolog (CMBL) as the responsible enzyme for OM bioactivation in humans. In the present study, we compared the bioactivating properties of OM with those of other prodrug-type ARBs, candesartan cilexetil (CC) and azilsartan medoxomil (AM), by focusing on interspecies differences and tissue specificity. In invitro experiments with pooled tissue subcellular fractions of mice, rats, monkeys, dogs, and humans, substantial OM-hydrolase activities were observed in cytosols of the liver, intestine, and kidney in all the species tested except for dog intestine, which showed negligible activity, whereas lung cytosols showed relatively low activities compared with the other tissues. AM-hydrolase activities were well correlated with the OM-hydrolase activities. In contrast, liver microsomes exhibited the highest CC-hydrolase activity among various tissue subcellular fractions in all the species tested. As a result of Western blot analysis with the tissue subcellular fractions, the band intensities stained with anti-human CMBL and carboxylesterase 1 (CES1) antibodies well reflected OM- and AM-hydrolase activities and CC-hydrolase activity, respectively, in animals and humans. Recombinant human CMBL and CES1 showed significant AM- and CC-hydrolase activities, respectively, whereas CC hydrolysis was hardly catalyzed with recombinant carboxylesterase 2 (CES2). In conclusion, OM is bioactivated mainly via intestinal and additionally hepatic CMBL not only in humans but also in mice, rats, and monkeys, while CC is bioactivated via hepatic CES1 rather than intestinal enzymes, including CES2. AM is a substrate for CMBL. Copyright

PROCESS FOR PREPARATION OF CANDESART AN CILEXETIL SUBSTANTIALLY FREE OF DES-CANDESARTAN CILEXETIL IMPURITY

The present invention provides a process for preparation of candeartan cilexetil substantially free of 2,3-dihydro-2-oxo-3-[[2'-(2H-tetrazol-5-yl)[l,l-biphenyl]-4- yl]methyl]-l-[[(cyclohexyloxy)carbonyl]oxy]ethylester-lH-benzimidazole-7- carboxylate (des-candesartan cilexetil) impurity.

METHOD FOR ISOLATING 5-SUBSTITUTED TETRAZOLES

The invention relates to a method for isolating 5-substituted tetrazoles of general formula (I) in which R represents a substituted biphenyl radical during which the ring closure, starting from a corresponding nitrile, is carried out in organic solvents while using alkali, alkaline-earth or organotin azides. The organic phases containing the nitrile and the tetrazol are firstly mixed with water while firstly forming three liquid phases, after which the aqueous phase containing the azide and the phase containing the nitrile are separated out, and the middle organic phase containing the tetrazol is subsequently processed. In the case of ester groups to be saponified, this phase is mixed with alkali lye, after which the organic phase is separated out and the aqueous phase is acidified or otherwise, this phase is immediately acidified and purified.

PROCESS FOR PREPARATION OF CANDESARTAN CILEXETIL

There was provided a process for preparing candesartan cilexetil, the said process comprises hydrogenating a solution of trityl candesartan cilexetil in an alcohol with hydrogen in the presence of a palladium catalyst. Mixture of toluene and methanol was added to 1-(Cyclohexyloxy carbonyloxy)ethyl-2-ethoxy-1-[[2'-(N-triphenylmethyltetrazole-5-yl)biphenyl-4-yl] methyl]benzimidazole-7-carboxylate and hydrogenated at room temperature with hydrogen at atmospheric pressure in the presence of palladium on carbon until the hydrogen uptake was ceased. Filtered over celite bed, washed the bed with a mixture of toluene and methanol, filtrate was collected and concentrated. Co- distilled with acetonitrile, acetonitrile was added, stirred at room temperature, cooled to 0°C. stirred, filtered, washed with chilled acetonitrile and dried to get candesartan cilexetil.