150058-27-8|Methyl 2-ethoxy-1H-benzo[d]imidazole-7-carboxylate| Ambeed

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Quality Control of [ 150058-27-8 ] Purity: 98% SDS Specification

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Product Details of [ 150058-27-8 ]

CAS No. :	150058-27-8
Formula :	C₁₁H₁₂N₂O₃
M.W :	220.23
SMILES Code :	O=C(C1=C2NC(OCC)=NC2=CC=C1)OC
MDL No. :	MFCD14636510
InChI Key :	MOPLKVMMSFGZIR-UHFFFAOYSA-N
Pubchem ID :	15654707

Safety of [ 150058-27-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 150058-27-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	9
Fraction Csp3	0.27
Num. rotatable bonds	4
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	58.67
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	64.21 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.27
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.01
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.75
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.34
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.19
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.91

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.62
Solubility	0.524 mg/ml ; 0.00238 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.99
Solubility	0.228 mg/ml ; 0.00103 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.53
Solubility	0.0654 mg/ml ; 0.000297 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.22 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.19

Application In Synthesis of [ 150058-27-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 150058-27-8 ]

[ 150058-27-8 ] Synthesis Path-Downstream 1~35

1
[ 78-09-1 ]
[ 107582-20-7 ]
[ 150058-27-8 ]

Yield	Reaction Conditions	Operation in experiment
83.1%	In acetic acid; at 25 - 35℃; for 2 - 3h;	Methyl 2-amino-3-nitrobenzoate (150.0 grams, 0.765 moles) was placed inan autoclave vessel and 1000 mlof ethyl acetate and 75 grams of Raney nickelwere added to the vessel and stirred under a 2-3 kg/cm2 hydrogen pressure for12-15 hours. The catalyst was removed by filtration, and the ethyl acetate wasevaporated under reduced pressure. Acetic acid (170 ml) was added to theresidue, and 180 grams of tetraethylorthocarbonate was slowly added at 25-35°C.The reaction mass was stirred for 2-3 hours, and water (750 ml) was added afterthe reaction mass was cooled to 10°C. The solid was filtered, washed with 150 mlof water, and dried at 50-60°C to get 140 grams (83.1 percent) of methyl 2-ethoxybenzimidazole-7-carboxylate.; 150 grams of 2-Amino-3-nitro-benzoic acid methylester, Raney nickel (75grams), ethyl acetate (1 litre) were charged in an autoclave vessel. 3.0kg/cm2 ofdry hydrogen gas was passed into the reaction suspension for about 20-25 hoursunder agitation. Reaction mass was filtered on celite, followed by washing thecelite with 150 ml of ethyl acetate. Solvent was removed completely from thefiltrate at about 45-50°C by distillation. 171 ml of acetic acid was charged andtetraethylorthocarbonate (180 grams) was added over about 30-45 minutes.Reaction mass was maintained for about 1-3 hours and was cooled to about 0-5°C. 750 ml of water was added over about 15-30 minutes and the separatedsolid was filtered and washed with 150 ml water, followed by 150 ml of ethylacetate. Solid obtained was dried at about 55-65°C for about 10-12 hours to yield140 grams of 2-Ethoxy-3H-benzoimidazole-4-carboxylic acid methylestercompound of Formula (IV).
	With acetic acid; at 25 - 30℃;	(1) Add 120 g of AM5 and 300 ml of glacial acetic acid to the reaction flask.The original tetraethyl carbonate 185g.(2) The reaction is warmed up to 25 to 30°C for 2 to 3 hours. The reaction conditions of the raw materials are observed by spotting until the basic reaction of the raw materials is complete.(3) After the reaction, the water is slowly cooled to 5-10 DEG C and stirred for 2 hours. The mixture is suction filtered, and the solid is washed with water twice and dried to obtain methyl 2-ethoxybenzimidazole-7-carboxylate as a product.

References: [1]Patent: WO2006/15134,2006,A1 .Location in patent: Page/Page column 15; 16.
[2]Patent: CN104876877,2018,B .Location in patent: Paragraph 0033; 0069-0072.

2
[ 150058-27-8 ]
[ 114772-54-2 ]
[ 139481-44-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In methanol; at 50 - 55℃; for 24h;	To 80.0 grams (0.363 moles) of methyl 2-ethoxybenzimidazole-7-carboxylate were added 400 ml of methanol, 99 grams of potassium carbonateand 94 grams of 4-bromomethyl-2'-cyanobiphenyl, and the resulting mixture wasstirred at ambient temperature for 24 hours. The reaction mass was quenchedwith chilled 2400 ml of water, filtered and washed with 160ml of water. The wetsolid was washed with 370 ml of hot ethyl acetate, and then dried at 50-60°C toget 105.0 grams of methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-benzimidazole-7-carboxylate, substantially free from methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-benzimidazole-4-carboxylate.;150 g of 2-ethoxy-3H-benzoimidazole-4-carboxylic acid methyl ester, 750 ml.of methanol, 231.8 g of 4'-Bromomethyl-biphenyl-2-carbonitrile and 235.2 g ofpotassium carbonate were charged in a four neck round bottom flask equippedwith a half moon shaped Teflon type blade. The reaction mixture was heated toabout 50-55°C and was maintained under stirring for about 3-4 hours. Cooled thereaction mixture to about 25-35°C. Charged 6 liters of water in a four neck roundflask followed by cooling to about 0-5°C.The reaction mass was added to thewater under stirring over about 10-30 minutes under stirring and was stirredfurther for about 1-2 hours. Separated solid was filtered and washed with 300 ml.of water. The wet compound was charged in a four neck round bottom flask followed by charging 2250 ml of ethyl acetate. Reaction suspension was heated toabout 70-75°C and was stirred for about 30-45 minutes. Reaction suspension wascooled to about 0-5°C and was stirred for about 1-2 hours. Separated solid wasfiltered and washed with 150 ml of ethyl acetate. Solid obtained was dried at about60-65°C for about 3-5 hours to yield 177 g of title compound of Formula (V);
	With potassium carbonate; In acetone;Reflux;	To a 500 mL flask was added 200 mL of acetone,Ethoxybenzimidazole-7-carboxylate (XIII, 22.0 g,0.10 mol),K2CO3 (17.9 g, 0.13 mol) and 4-bromomethyl-2'-cyanobiphenyl (28.6 g, 0.105 mol).The temperature was raised to reflux and reaction was complete until TLC disappeared (about 5 to 8 hours).

References: [1]Patent: WO2006/15134,2006,A1 .Location in patent: Page/Page column 16; 21-22.
[2]Patent: CN107089972,2017,A .Location in patent: Paragraph 0032; 0035; 0037.

3
[ 150058-27-8 ]
1-benzyl-5-[4'-(chloromethyl)biphenyl-2-yl]-1H-tetrazole [ No CAS ]
[ 1215298-35-3 ]
C₃₂H₂₉N₆O₃⁽¹⁺⁾ [ No CAS ]

References: [1]ACS Catalysis,2014,vol. 4,p. 4047 - 4050.

4
[ 150058-27-8 ]
1-benzyl-5-[4'-(chloromethyl)biphenyl-2-yl]-1H-tetrazole [ No CAS ]
[ 101-83-7 ]
C₃₁H₂₆N₆O₃*C₁₂H₂₃N [ No CAS ]

References: [1]ACS Catalysis,2014,vol. 4,p. 4047 - 4050.

5
[ 150058-27-8 ]
1-benzyl-5-[4'-(chloromethyl)biphenyl-2-yl]-1H-tetrazole [ No CAS ]
[ 1215298-35-3 ]
C₃₂H₂₈N₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		BIM (20 g, 1 eq) was dissolved in dimethylacetamide:methanol [(1:4), (100 mL, 5 vol)], potassium carbonate (18.8 g, 1.5 eq) was added thereto, and the mixture was stirred at 25°C - 30°C for 15 min. Furthermore, BCL (34.4 g, 1.05 eq) and tetrabutylammonium iodide (1.67 g, 0.05 eq) were added thereto, and the mixture was stirred at the same temperature for 26 hr. Using TLC (TLC: 40percent ethyl acetate/hexane, detection method: UV), complete consumption of BIM was confirmed. To the reaction mixture was added water (200 mL, 10 vol), the mixture was stirred for 2 hr, and the precipitated pink solid was filtered. The obtained solid was washed with water (40 mL, 2 vol), dried with suction for 15 min, and blast dried at 50°C - 55°C for 4 hr to give a mixture of crude CBME and compound 37 (49 g, CBME:compound 37=6:1 (molar ratio)). The crude product was directly used for the next step (4).

References: [1]Patent: EP2891650,2015,A1 .Location in patent: Paragraph 0323; 0324.

6
[ 150058-27-8 ]
1-benzyl-5-[4'-(chloromethyl)biphenyl-2-yl]-1H-tetrazole [ No CAS ]
1-({4-[2-(1-benzyl-1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-2-ethoxy-1H-1,3-benzodiazole-7-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%		To the crude CBME (20 g, 1 eq) obtained in the above-mentioned (3) were added methanol:water [(1:1) (160 mL)] and sodium hydroxide (4.4 g, 3 eq) at 25°C - 30°C, and the reaction mixture was stirred at 75°C - 80°C for 4 hr. Using TLC (TLC: 40percent ethyl acetate/hexane, detection method: UV), complete consumption of CBME was confirmed. The reaction mixture was cooled to 25°C - 30°C, and the organic solvent was evaporated under reduced pressure at 40°C - 45°C. To the concentrated residue was added water (200 mL, 10 vol), and the aqueous layer was washed with t-butyl methyl ether (100 mL, 2×5 vol). The aqueous layer was adjusted to pH 5.5 - 6.5 by adding acetic acid (6 mL, 0.3 vol), the obtained slurry was stirred at 25°C-30°C for 1 hr, and the precipitated solid was filtered. The solid was washed with water (40 mL, 2 vol), dried with suction for 15 min, and further dried at 50°C - 55°C for 4 hr to give crude CBCA (16 g). [0327] To the obtained crude CBCA (16 g) were added ethyl acetate (160 mL, 10 vol) and dicyclohexylamine (DCHA) (8.2 g, 1.5 eq), and the mixture was stirred at 25°C - 30°C for 2 hr. The precipitated solid was filtered, washed with ethyl acetate (80 mL, 5 vol), dried with suction for 15 min, and further blast dried at 50°C - 55°C for 4 hr to give a DCHA salt (16 g) of CBCA. To the salt was added isopropyl alcohol (192 mL, 12 vol) at 25°C - 30°C, and the salt was dissolved by heating to 75°C - 85°C, and the mixture was stirred for 15 min. Thereafter, the reaction mixture was cooled to 25°C - 30°C, and stirred at the same temperature for 2 hr. The precipitated solid was filtered, washed with isopropyl alcohol (32 mL, 2 vol), dried with suction for 15 min, and further blast dried at 50°C - 55°C for 4 hr to give a pure DCHA salt (13 g) of CBCA. To this salt was added 25percent aqueous sodium hydroxide solution (120 mL, 10 vol) at 25°C - 30°C, and the mixture was stirred for 15 min, adjusted to pH 5.5 - 6.5 by adding acetic acid (5.8 mL, 0.48 vol), and extracted with methylene chloride (120 mL, 2×5 vol). The extract was combined with the organic layer, and the mixture was washed with water (120 mL, 2×5 vol) and further with saturated brine (60 mL, 5 vol). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure at 40°C - 45°C to give CBCA (9 g, 47percent from BCL).

References: [1]Patent: EP2891650,2015,A1 .Location in patent: Paragraph 0325-0327.

7
[ 150058-27-8 ]
1-benzyl-5-[4'-(bromomethyl)biphenyl-2-yl]-1H-tetrazole [ No CAS ]
[ 1215298-35-3 ]
C₃₂H₂₈N₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44.5%	With potassium carbonate; In methanol; N,N-dimethyl acetamide; at 25 - 30℃; for 24h;	Example 7-3 (0446) (0447) Dimethylacetamide (1 mL, 1 vol), methanol (4 mL, 4 vol), BIM (1 g, 1 equivalent) and potassium carbonate (1.56 g, 2.5 equivalents) were charged in a two-neck flask at 25° C.-30° C. The reaction mixture was stirred at 25° C.-30° C. for 15 min, and BBR (1.93 g, 1.05 equivalents) was gradually added. The reaction mixture was stirred at 25° C.-30° C. for 24 hr. The degree of progression of the reaction was checked by TLC (TLC eluent: 40percent ethyl acetate/hexane, detection method: UV). After BBR was completely consumed, water (10 mL, 10 vol) was added to the reaction mixture, and the mixture was stirred for 1 hr. The precipitated solid was filtered, washed with water (3 mL, 3 vol), and dried with suction for 15 min. The obtained solid was blast-dried at 50° C.-55° C. for 4 hr to give crude CBME (2.3 g, yield 93.1percent, HPLC purity: 74.80 area percent) as a pink solid. (0448) To the above-mentioned pink solid was added MTBE (8.0 mL, 8 vol), and the mixture was stirred at 25° C.-30° C. for 1 hr. The precipitated solid was filtered, washed with t-butyl methyl ether (4.0 mL, 4 vol), and dried with suction for 15 min. The obtained solid was blast-dried at 50° C.-55° C. for 4 hr to give CBME as a pink solid (1.7 g, yield 68.8percent, HPLC purity: 88.47 area percent). (0449) To this pink solid was added acetone (10 mL, 10 vol), and the obtained solution was heated to 50° C.-55° C. Water (5.0 mL, 5 vol) was added, and the mixture was stirred at 50° C.-55° C. for 30 min and at 0° C.-5° C. for 45 min. The precipitated solid was collected by filtration and washed with water (2.0 mL, 2 vol). The obtained solid was dried with suction and blast-dried at 50° C.-55° C. for 4 hr to give CBME (1.5 g, yield 60.7percent, HPLC purity: 95.66 area percent). (0450) The steps after acetone addition were performed once again to obtain CBME (1.1 g, yield 44.5percent, HPLC purity: 97.64 area percent).

References: [1]Patent: US2015/239854,2015,A1 .Location in patent: Page/Page column 52.

8
[ 150058-27-8 ]
[ 1234834-29-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	With methanol; sodium hydroxide;Reflux;	The 44g intermediate 2-ethoxy -1H-benzimidazole-7-carboxylic acid methyl ester and 300 ml of methanol are added to a reaction flask, opening stirring, add 120g10percent sodium hydroxide solution, to return thermal insulation reaction, with used in HPLC. After the reaction is complete, cooling to 15-25°C, dropwise 10percent dilute hydrochloric acid, to pH adjusting 1-2, stirring the accent finishes 1h, filtering, used 30 ml purified water washing, filtering to dry, for 55-65 °C reduced-pressure drying to the stem, be 2-ethoxy -3H-benzimidazole-7-carboxylic acid 37.9g, yield 92.0percent, purity 98.3percent

References: [1]Patent: CN105622595,2016,A .Location in patent: Paragraph 0029.

9
[ 150058-27-8 ]
[ 863031-21-4 ]

References: [1]Patent: CN105622595,2016,A .

10
[ 150058-27-8 ]
azilsartan medoxomil monopotassium salt [ No CAS ]

References: [1]Patent: CN105622595,2016,A .

11
[ 150058-27-8 ]
[ 91526-18-0 ]
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2-ethoxy-1H-benzo[d]imidazol-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.6%		The 45g2-ethoxy -1H-benzimidazole-7-carboxylic acid and 500 ml by adding dichloromethane for added to a reaction flask, stirring cooling to 20 °C the following, to-drop 50.7g triethylamine, the drop finishes, drop by adding 54.0g to toluene sulfonyl chloride and 100 ml dichloromethane mixed solution, drop Bi Yu 10-20 °C stirring reaction 3h, for 10-20 °C adding 39.7g4-hydroxymethyl-5-methyl -1,3-dioxol-2-one, the temperature rising to adding 30-40 °C stirring reaction, with used in HPLC. After the reaction is complete, cooling to 15-25°C, by adding 400 ml purified water stirring, layered, with 30g drying by anhydrous sodium sulfate. Decompression jeung dry dichloromethane, by adding 300 ml methyl tert-butyl ether refined, cooling to 0-5 °C stirring crystallization 3h, filtering, with 20 ml cool to 0-5 °C methyl tert-butyl ether washing, for 40-50 °C reduced-pressure drying to the job (5-methyl-2-oxo -1,3-dioxol-4-yl) methyl 2-ethoxy -1H-benzo[d] imidazol-7-carboxylic acid ester 63.6 g. The yield of 91.6percent, purity 98.1percent

References: [1]Patent: CN105622595,2016,A .Location in patent: Paragraph 0031.

12
[ 150058-27-8 ]
3-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1,2,4-oxadiazol-5(4H)-one [ No CAS ]
[ 147403-52-9 ]

Yield	Reaction Conditions	Operation in experiment
78%	With tetrabutylammomium bromide; potassium carbonate; In ethanol; at 20℃; for 10h;Reflux;	60 g of 2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester and 500 ml of ethanol were added to the clean reaction flask, Stirred at room temperature for 10 minutes, 75.5 g of potassium carbonate was added, 60.3g 3-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1,2,4-oxadiazol-5(4H)-one , and 4.8 g of tetrabutylammonium bromide, heated to reflux 10h, the ethanol was evaporated to dryness under reduced pressure, and the mixture was stirred for half an hour in 1800 ml of water, 120ml water washing, filter to dry, solid with 400ml ethanol temperature reflux solution dissolved, cooling to 0-5 , 2 hours of crystallization temperature.Filtered, washed with 20 ml of ethanol, suction filtered to dryness, in 50 to 60 vacuum drying, 2-ethoxy-1-((2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)benzimidazole-7-carboxylic acid methyl ester was obtained 66.8 g, yield: 78.0percent, purity: 98.9percent)

References: [1]Patent: CN105669495,2016,A .Location in patent: Paragraph 0016; 0033.

13
[ 150058-27-8 ]
[ 139481-69-9 ]

References: [1]Patent: CN107056757,2017,A .

14
[ 150058-27-8 ]
[ 139481-59-7 ]

References: [1]Patent: CN107056757,2017,A .

15
[ 150058-27-8 ]
[ 124750-51-2 ]
methyl 2-ethoxy-1-<<2'-<N-(triphenylmethyl)tetrazol-5-yl>biphenyl-4-yl>methyl>-1H-benzimidazole-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43.6 g	With potassium tert-butylate; In N,N-dimethyl acetamide; at 60℃;Inert atmosphere;	In the reaction vessel by adding lOOOmlDMAC,Add with stirring2-ethoxybenzimidazole-7- Carboxylic acid methyl ester50 g (Compound 1),N- (3-phenylmethyl) -5- (4'-bromomethylbiphenyl-2-yl) tetrazole(Compound 2), to be dissolved, under nitrogen protection,25.5 g of potassium tert-butoxide was slowly added,The reaction temperature is controlled at 60 ± 5 ° C and the reaction is carried out for 3 to 4 hours. After the reaction of the compound 1 is completed, the reaction solution is slowly added dropwise to 10 ml of ice water, and after the dropwise addition, the mixture is stirred at 0 to 10 ° C 1 hour. Filtration, crude product 146g. The purity was 85.6percent and the isomer was 10.2percent by HPLC.Purification program II: 50 g of the crude product was charged into a mixed solvent of 200 ml of THF / isopropanol in a volume ratio of 1: 1, Heating and stirring to dissolve, Back for half an hour, Cooling to 0 ~ 10 ° c crystallization 1 hour, Filter, After drying the product 43.6g HPLC detection purity of 99.28percent Isomer 0.24percent.

References: [1]Patent: CN107056757,2017,A .Location in patent: Paragraph 0028-0029; 0033.

16
[ 150058-27-8 ]
[ 632322-62-4 ]

References: [1]Patent: CN107089972,2017,A .

17
[ 150058-27-8 ]
(+/-)-1-<<(cyclohexyloxy)caarbonyl>oxy>ethyl 2-ethoxy-1-<<2'-(1H-tetrazol-5-yl)biphenyl-4-yl>methyl>-1H-benzimidazole-7-carboxylate [ No CAS ]

References: [1]Patent: CN107089972,2017,A .

18
[ 150058-27-8 ]
[ 632322-61-3 ]

References: [1]Patent: CN107089972,2017,A .

19
[ 150058-27-8 ]
methyl 1-((2'-cyano-5'-(4-methylpyridin-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate [ No CAS ]