114772-40-6

Basic information

• Product Name: tert-Butyl 4'-(bromomethyl)biphenyl-2-carboxylate
• Synonyms: 4'-BROMOMETHYL-BIPHENYL-2-CARBOXYLIC ACID TERT-BUTYL ESTER;TERT-BUTYL 4'-(BROMOMETHYL)BIPHENYL-2-CARBOXYLATE;4-BROMOMETHYL BIPHENYL-2-CARBOXYLATE-t-BUTYL ESTER;Tert-Butyl-4'-Bromometilbiphenil-2-Carboxilate;tert-Butyl 4'-bromomethyl-2-biphenylcarboxylate;alpha-Bromo-2-(p-tolyl)benzoicacidtert-butylester;Tert-Buthyl;4'-BROMOMETHYLBIPHENYL-2-CARBOXYLIC
• CAS NO: 114772-40-6
• Molecular Formula: C₁₈H₁₉BrO₂
• Molecular Weight: 347.25
• EINECS: 1312995-182-4
• Product Categories: Biphenyl & Diphenyl ether;Pharmaceutical intermediate
• Mol File: 114772-40-6.mol
• Article Data: 28

Chemical Properties

• Boiling Point: 436.992 °C at 760 mmHg
• Flash Point: 218.085 °C
• Appearance: /
• Density: 1.278 g/cm³
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: Soluble in chloroform, ethyl acetate, and DMSO.
• CAS DataBase Reference: tert-Butyl 4'-(bromomethyl)biphenyl-2-carboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: tert-Butyl 4'-(bromomethyl)biphenyl-2-carboxylate(114772-40-6)
• EPA Substance Registry System: tert-Butyl 4'-(bromomethyl)biphenyl-2-carboxylate(114772-40-6)

Safety Data

• Statements: 43-53
• Safety Statements: 22-24-37-61
• Hazardous Substances Data: 114772-40-6(Hazardous Substances Data)

Usage

Chemical Properties

Solid

Uses

Different sources of media describe the Uses of 114772-40-6 differently. You can refer to the following data:
1. tert-Butyl 4'-(bromomethyl)biphenyl-2-carboxylate is a biphenyl derivative used in the preparation of angiotensin II receptor antagonists. T017000
2. 1,1-Dimethylethyl Esterbiphenyl is used in the preparation of angiotensin II receptor antagonists.

Synthetic route

tert-butyl 4'-methyl-2-biphenylcarboxylate (114772-36-0) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
With azobisisobutyronitrile; sodium acetate In acetic acid methyl ester; water; isopropyl alcohol; acetone	85%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 4.5h; Heating;	82%
With N-Bromosuccinimide; azobisisobutyronitrile; sodium acetate In acetic acid methyl ester; water; isopropyl alcohol	80%

biphenyl-2-carboxylic acid tert-butyl ester + formaldehyd (50-00-0) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Stage #1: biphenyl-2-carboxylic acid tert-butyl ester; formaldehyd With zinc dibromide In dichloromethane at 30 - 35℃; for 0.333333h; Stage #2: With phosphorus pentabromide In tetrachloromethane; dichloromethane	81.9%

tert-butyl 2-bromobenzoate (55666-42-7) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / tetrakis(triphenylphosphine)palladium, 2M aq. sodium carbonate / toluene; ethanol / 4 h / Heating 2: 82 percent / NBS, AIBN / CCl4 / 4.5 h / Heating View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.67 h / 100 °C / Sealed vial 2: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / tetrachloromethane / 2 h / 100 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium carbonate / isopropyl alcohol / 0.5 h / Inert atmosphere 1.2: 40 h / 90 °C / Inert atmosphere 2.1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / tetrachloromethane / Reflux View Scheme
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 1,4-dioxane; water / 0.75 h / 100 °C / Sealed tube 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 2 h / 100 °C View Scheme

4-methylphenylboronic acid (5720-05-8) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / tetrakis(triphenylphosphine)palladium, 2M aq. sodium carbonate / toluene; ethanol / 4 h / Heating 2: 82 percent / NBS, AIBN / CCl4 / 4.5 h / Heating View Scheme

2-bromobenzoic-acid (88-65-3) + copper powder → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) N,N'-carbonyldiimidazole, 2.) DBU / 1.) DMF, 40 deg C, 1 h, 2.) DMF, a) 40 deg C, 24 h, b) 50 deg C, 16 h 2: 95 percent / tetrakis(triphenylphosphine)palladium, 2M aq. sodium carbonate / toluene; ethanol / 4 h / Heating 3: 82 percent / NBS, AIBN / CCl4 / 4.5 h / Heating View Scheme

o-tolylbenzoic acid (7148-03-0) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 94 percent / sulfuric acid / diethyl ether / 25 °C 2: NBS, AIBN / CCl4 / Heating View Scheme
Multi-step reaction with 3 steps 1: oxalyl chloride / CH2Cl2 / 3 h / 25 °C 2: tetrahydrofuran / 1 h / 25 °C 3: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride / 5.5 h / 20 °C / Inert atmosphere 2: tetrahydrofuran / 1.5 h / 0 °C / Inert atmosphere 3: N-Bromosuccinimide; dibenzoyl peroxide / benzene / 6 h / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / dichloromethane / 3 h / 0 - 20 °C 1.2: 1 h / 10 - 20 °C 2.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 8 h / Reflux View Scheme

methyl 4'-methylbiphenyl-2-carboxylate (114772-34-8) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 99 percent / NaOH / H2O; methanol / Heating 2: 94 percent / sulfuric acid / diethyl ether / 25 °C 3: NBS, AIBN / CCl4 / Heating View Scheme

2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline (57598-33-1) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: tetrahydrofuran / 2 h / 20 °C 2: 88 percent / 4.5 N aq. HCl / 12 h / Heating 3: oxalyl chloride / CH2Cl2 / 3 h / 25 °C 4: tetrahydrofuran / 1 h / 25 °C 5: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating View Scheme

4'-methylbiphenyl-2-carboxylic acid chloride (114772-35-9) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 1 h / 25 °C 2: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating View Scheme
Multi-step reaction with 2 steps 1: tetrahydrofuran / 1.5 h / 0 °C / Inert atmosphere 2: N-Bromosuccinimide; dibenzoyl peroxide / benzene / 6 h / Inert atmosphere; Reflux View Scheme

N-(2-hydroxy-1,1-dimethyl)-2-methoxybenzamide (74201-13-1) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 6 steps 1: thionyl chloride / 1 h / 25 °C 2: tetrahydrofuran / 2 h / 20 °C 3: 88 percent / 4.5 N aq. HCl / 12 h / Heating 4: oxalyl chloride / CH2Cl2 / 3 h / 25 °C 5: tetrahydrofuran / 1 h / 25 °C 6: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating View Scheme

4,4-dimethyl-2-(4'-methyl-biphenyl-2-yl)-4,5-dihydrooxazole (84392-32-5) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 88 percent / 4.5 N aq. HCl / 12 h / Heating 2: oxalyl chloride / CH2Cl2 / 3 h / 25 °C 3: tetrahydrofuran / 1 h / 25 °C 4: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating View Scheme

2-Methoxybenzoic acid (579-75-9) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

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: 88 percent / 4.5 N aq. HCl / 12 h / Heating 6: oxalyl chloride / CH2Cl2 / 3 h / 25 °C 7: tetrahydrofuran / 1 h / 25 °C 8: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating View Scheme

2-Methoxybenzoyl chloride (21615-34-9) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

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: 88 percent / 4.5 N aq. HCl / 12 h / Heating 5: oxalyl chloride / CH2Cl2 / 3 h / 25 °C 6: tetrahydrofuran / 1 h / 25 °C 7: N-bromosuccinimide, dibenzoyl peroxide / CCl4 / 3 h / Heating View Scheme

C18H20O3 (145319-09-1) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -78 - 20℃;

tert-butyl 4'-methyl-2-biphenylcarboxylate (114772-36-0) → 4'-dibromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (901768-33-0) + 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 5h; Reflux; Inert atmosphere;

benzonitrile (100-47-0) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: n-butyllithium; 2,2,6,6-tetramethylpiperidinyl-lithium / tetrahydrofuran; hexane / 0.08 h / -78 - -10 °C / Inert atmosphere 1.2: 5 h / -78 - 20 °C / Inert atmosphere 2.1: toluene / 20 °C 3.1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / ethanol; toluene / 4 h / 100 °C / Inert atmosphere 4.1: hydrogenchloride; water / 12 h / Reflux 5.1: oxalyl dichloride / dichloromethane / 3 h / 0 - 20 °C 5.2: 1 h / 10 - 20 °C 6.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 8 h / Reflux View Scheme

C13H18BNO2 → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: toluene / 20 °C 2.1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / ethanol; toluene / 4 h / 100 °C / Inert atmosphere 3.1: hydrogenchloride; water / 12 h / Reflux 4.1: oxalyl dichloride / dichloromethane / 3 h / 0 - 20 °C 4.2: 1 h / 10 - 20 °C 5.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 8 h / Reflux View Scheme

2-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-benzonitrile (214360-47-1) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / ethanol; toluene / 4 h / 100 °C / Inert atmosphere 2.1: hydrogenchloride; water / 12 h / Reflux 3.1: oxalyl dichloride / dichloromethane / 3 h / 0 - 20 °C 3.2: 1 h / 10 - 20 °C 4.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 8 h / Reflux View Scheme

2-Cyano-4'-methylbiphenyl (114772-53-1) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; water / 12 h / Reflux 2.1: oxalyl dichloride / dichloromethane / 3 h / 0 - 20 °C 2.2: 1 h / 10 - 20 °C 3.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 8 h / Reflux View Scheme

2-bromobenzoic-acid (88-65-3) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: dicyclohexyl-carbodiimide / dmap / dichloromethane / 20 h / 20 °C / Inert atmosphere 2: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.67 h / 100 °C / Sealed vial 3: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / tetrachloromethane / 2 h / 100 °C View Scheme
Multi-step reaction with 3 steps 1.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 6 h / 0 - 20 °C 2.1: sodium carbonate / isopropyl alcohol / 0.5 h / Inert atmosphere 2.2: 40 h / 90 °C / Inert atmosphere 3.1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / tetrachloromethane / Reflux View Scheme
Multi-step reaction with 3 steps 1: dmap; dicyclohexyl-carbodiimide / dichloromethane / 20 h / 20 °C / Inert atmosphere 2: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 1,4-dioxane; water / 0.75 h / 100 °C / Sealed tube 3: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 2 h / 100 °C View Scheme

2-Biphenylcarboxylic acid (947-84-2) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sulfuric acid / 6 h / Reflux 2: zinc dibromide / dichloromethane / 0.33 h / 30 - 35 °C View Scheme

para-bromotoluene (106-38-7) + tert-butyl 2-iodobenzoate (110349-26-3) → 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride; tert.-butyl lithium / zinc(II) chloride / tetrahydrofuran; hexane; ethyl acetate; pentane View Scheme

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → 4'-(Azidomethyl)[1,1'-biphenyl]-2-carboxylic acid,1,1-dimethylethyl ester (139476-12-3)

Conditions	Yield
With sodium azide In N,N-dimethyl-formamide for 24h; Ambient temperature;	100%
With sodium azide In N,N-dimethyl-formamide at 100℃; for 1.5h; Inert atmosphere;	100%
In N-methyl-acetamide; water

N-BOC-1,2-diaminoethane (57260-73-8) + 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → 4'-[(2-t-butoxycarbonylaminoethylamino)methyl]biphenyl-2-carboxylic acid t-butyl ester (1043607-99-3)

Conditions	Yield
With potassium carbonate In tetrahydrofuran at 20℃;	98.4%

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) + 3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (145486-47-1) → t-Butyl 4'-[[3(R)-[[3-[2(R)-benzyloxypropyl]amino-3-methyl-1-oxobutyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-carboxylate (170277-86-8)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide for 1.5h; Ambient temperature;	92%

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) + 6-butyl-4-chloro-1,2-dihydro-2,2-dimethyl-5-pyrimidinecarboxylic acid, ethyl ester (142385-38-4) → 2-butyl-1-<2'-<(1,1-dimethylethoxy)carbonyl><1,1'-biphenyl>-4-yl>-6-chloro-1,4-dihydro-4,4-dimethyl-5-pyrimidinecarboxylic acid, ethyl ester (142385-39-5)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide for 5h; Ambient temperature;	91.1%

allyl 2,3-dimethyl-1H-indole-5-carboxylate (1266458-65-4) + 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → allyl 1-((2'-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylate

Conditions	Yield
Stage #1: allyl 2,3-dimethyl-1H-indole-5-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; Stage #2: 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester In N,N-dimethyl-formamide; mineral oil at 20℃; Inert atmosphere;	90%

2-n-butyl-4-chloro-1H-imidazol-5-carboxaldehyde (83857-96-9) + 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → 4’-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)biphenyl-2-carboxylic acid t-butyl ester (133694-34-5)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	89%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;

2-methylthioquinazolin-4(3H)-one (54855-81-1) + 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → 4'-(2-methylsulfanyl-4-oxo-4H-quinazolin-3-ylmethyl)biphenyl-2-carboxylic acid tert-butyl ester

Conditions	Yield
Stage #1: 2-methylthioquinazolin-4(3H)-one With potassium tert-butylate In dimethyl sulfoxide at 20℃; for 0.5h; Stage #2: 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester In dimethyl sulfoxide at 20℃; for 19h;	88%

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) + 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one hydrochloride → tert-butyl-4'-<(2-n-butyl-4-oxo-1,3-diazaspiro<4.4>non-1-en-3-yl)methyl>biphenyl-2-carboxylate (138401-20-4)

Conditions	Yield
In N,N-dimethyl-formamide for 0.0180556h; microwave irradiation;	88%

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) + 3-butyl-1,2,4-oxadiazol-5(4H)-one (150694-23-8) → 4'-<<3-butyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl>methyl><1,1'-biphenyl>-2-carboxylic acid t-butyl ester (150694-24-9)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 25℃; for 17h;	87%

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) + 4-butyl-1-<<2-(trimethylsilyl)ethoxy>methyl>imidazole → 5-butyl-1-[[2'-(tert-butoxycarbonyl)biphenyl-4-yl]methyl]-3-[(2-(trimethylsilyl)ethoxy)methyl]-1H-imidazolium bromide (1400934-15-7)

Conditions	Yield
In acetonitrile for 3h; Reflux; Inert atmosphere;	87%

2-butyl-1H-imidazole (50790-93-7) + 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → 1-<<2'-(tert-butoxycarbonyl)biphenyl-4-yl>methyl>-2-butylimidazole

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide 1.) RT, 30 min, 2.) RT, overnight;	86%
With sodium hydride In N,N-dimethyl-formamide	86%

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) + 2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole (152628-02-9) → tert-butyl 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate (144702-26-1)

Conditions	Yield
With potassium tert-butylate In 1-methyl-pyrrolidin-2-one at 10℃; for 4h;	86%
With sodium In methanol at 70℃; Reagent/catalyst; Temperature; Solvent;	71%
With potassium tert-butylate In N,N-dimethyl acetamide at 75 - 80℃; for 3h; Inert atmosphere;	70%
With potassium tert-butylate 1.) DMSO, RT, 30 min, 2.) DMSO, 14 h; Multistep reaction;
With potassium tert-butylate In dimethyl sulfoxide at 25 - 30℃; for 3.5h; Product distribution / selectivity;

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) + methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (177478-49-8) → methyl 1-((2'-(tert-butoxycarbonyl)-[1,1'-biphenyl]-4-yl)methyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 12h;	85%

2-butyl-1H-imidazole (50790-93-7) + 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → 2-butyl-N,N'-bis{[2'-(tert-butoxycarbonyl)biphenyl-4-yl]methyl}imidazolium bromide (1431152-75-8)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h; Inert atmosphere;	84%

potassium phtalimide (1074-82-4) + 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → N-[[2'-(t-Butoxycarbonyl)biphenyl-4-yl]-methyl]phthalimide (133690-72-9)

Conditions	Yield
In N,N-dimethyl-formamide for 7h; Ambient temperature;	82%

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) + 4-n-Butyl-imidazole (146953-86-8) → 4-butyl-N,N'-bis{[2'-(tert-butoxycarbonyl)biphenyl-4-yl]methyl}imidazolium bromide (1431152-06-5)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h; Inert atmosphere;	82%

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) + 3-butyl-6-(phenylethyl)-4H-1,2,4-oxadiazin-5(6H)-one (150694-39-6) → 4'-<<3-butyl-5,6-dihydro-5-oxo-6-(phenylethyl)-4H-1,2,4-oxadiazin-4-yl>methyl><1,1'-biphenyl>-2-carboxylic acid t-butyl ester (150694-40-9)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 25℃; for 19h;	81%

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → 4-<2'-<(1,1-dimethylethoxy)carbonyl>phenyl>benzaldehyde (145319-08-0)

Conditions	Yield
With hexamethylenetetramine; water; sodium dodecyl-sulfate; lanthanum(lll) triflate at 100℃; for 4.5h; Sommelet Aldehyde Synthesis; Green chemistry;	80%
With silver tetrafluoroborate; chromium chlorochromate; sodium hydrogencarbonate 1.) dimethyl sulfoxide, RT, 6 h 2.) dichloromethane, RT, 1 h; Yield given. Multistep reaction;

3-(2-butyl-1H-imidazol-4-yl)propan-1-ol + 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → 4'-[2-butyl-4-(3-hydroxypropyl)imidazol-1-ylmethyl]biphenyl-2-carboxylic acid tert-butyl ester + 4'-[2-butyl-5-(3-hydroxypropyl)imidazol-1-ylmethyl]biphenyl-2-carboxylic acid tert-butyl ester

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 18h; Inert atmosphere;	A 80% B 6%

8-Butyl-1,3-dimethyl-1,2,3,6-tetrahydro-2,6-dioxopurine (35873-40-6) + 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → 7-(2'-t-butoxycarbonylbiphenyl-4-yl)methyl-8-n-butyl-1,3-dimethylxanthine

Conditions	Yield
In N,N-dimethyl-formamide; mineral oil	78.7%

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) + 3-butyl-6-methyl-4H-1,2,4-oxadiazin-5(6H)-one (150694-19-2) → 4'-<(3-butyl-5,6-dihydro-6-methyl-5-oxo-4H-1,2,4-oxadiazin-4-yl)methyl><1,1'-biphenyl>-2-carboxylic acid t-butyl ester (150694-20-5)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 25℃; for 19h;	78%

sodium cyanide (143-33-9) + 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → 4-<2'-(tert-butoxycarbonyl)phenyl>benzyl cyanide (150871-50-4)

Conditions	Yield
In dimethyl sulfoxide 1.) 45-50 deg C, 30 min, 2.) RT, 2.5 h;	76%

2-hydroxymethyl-2,5,7,8-tetramethyl-chroman-6-ol (79907-49-6) + 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → 4'-(2-hydroxymethyl-2,5,7,8-tetramethylchroman-6-yloxymethyl)biphenyl-2-carboxylic acid tert-butyl ester

Conditions	Yield
With potassium carbonate In acetone for 48h; Inert atmosphere;	76%

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) + 3-butyl-6-phenyl-4H-1,2,4-oxadiazin-5(6H)-one (150758-58-0) → 4'-<<(oxophenylacetyl)amino>methyl><1,1'-biphenyl>-2-carboxylic acid t-butyl ester

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 25℃; for 1h;	75%

6-hydroxymethyl-4-methyl-2-propyl-1H-benzimidazole (1092951-05-7) + 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) → 4'-(6-hydroxymethyl-4-methyl-2-propyl-1H-benzimidazol-1-ylmethyl)biphenyl-2-carboxylic acid t-butyl ester (1190092-28-4)

Conditions	Yield
With potassium carbonate; tetra(n-butyl)ammonium hydrogensulfate In acetonitrile at 55℃; for 5h; Inert atmosphere;	73.5%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;	10.61g

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) + 2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole (152628-02-9) → tert butyl 4'-[4-methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl-1H-benzimidazol-1-ylmethyl]biphenyl-2-carboxylate hydrochloride (921208-39-1)

Conditions	Yield
Stage #1: 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester; 2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole With potassium hydroxide In water; acetone at 0 - 30℃; for 6.5h; Stage #2: With hydrogenchloride In dichloromethane; water at 20 - 25℃; pH=1.8;	73%

4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (114772-40-6) + 2-butyl-1,6-dihydro-4,6-dimethyl-5-pyrimidinecarboxylic acid, ethyl ester (142385-35-1) → 2-butyl-1-<2'-<(1,1'-dimethylethoxy)carbonyl><1,1'-biphenyl>-4-yl>-1,6-dihydro-4,6-dimethyl-5-pyrimidinecarboxylic acid (142385-36-2)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide Ambient temperature;	72.5%

Upstream product

• 114772-36-0 tert-butyl 4'-methyl-2-biphenylcarboxylate 
• 106-38-7 para-bromotoluene 
• 110349-26-3 tert-butyl 2-iodobenzoate 
• 947-84-2 2-Biphenylcarboxylic acid 
• 50-00-0 formaldehyd 
• 88-65-3 2-bromobenzoic-acid 
• 114772-53-1 2-Cyano-4'-methylbiphenyl 
• 214360-47-1 2-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-benzonitrile 
• 100-47-0 benzonitrile 
• 145319-09-1 C₁₈H₂₀O₃ 
• 21615-34-9 2-Methoxybenzoyl chloride 
• 579-75-9 2-Methoxybenzoic acid 
• 84392-32-5 4,4-dimethyl-2-(4'-methyl-biphenyl-2-yl)-4,5-dihydrooxazole 
• 74201-13-1 N-(2-hydroxy-1,1-dimethyl)-2-methoxybenzamide 

Downstream Products

• 124750-36-3 1-<<2'-(tert-butoxycarbonyl)biphenyl-4-yl>methyl>-2-butyl-5-(hydroxymethyl)-4-nitroimidazole 
• 133690-73-0 4'-(Aminomethyl)[1,1'-biphenyl]-2-carboxylic acid,1,1-dimethylethyl ester 
• 139476-15-6 4'-(1,3-Dibutyl-5-oxo-1,5-dihydro-[1,2,4]triazol-4-ylmethyl)-biphenyl-2-carboxylic acid tert-butyl ester 
• 138401-34-0 tert-butyl-4'-<(2-n-butyl-4-thioxo-1,3-diazaspiro<4.4>non-1-en-3-yl)methyl>biphenyl-2-carboxylate 
• 151257-08-8 tert-butyl-4'-<(2-n-butyl-4-oxo-1,3-diazaspiro<4.4>nonan-3-yl)methyl>biphenyl-2-carboxylate 
• 133140-17-7 tert-butyl 4'-[(6-acetamino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate 
• 133139-73-8 tert.butyl 4'-[(2-n-butyl-5-acetamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate 
• 1026652-23-2 4'-(4-Acetylamino-2-butyl-benzoimidazol-1-ylmethyl)-biphenyl-2-carboxylic acid tert-butyl ester 
• 1026310-19-9 4'-(7-Acetylamino-2-butyl-benzoimidazol-1-ylmethyl)-biphenyl-2-carboxylic acid tert-butyl ester 
• 141864-82-6 tert.-butyl 4'-[[2-n-butyl-6-(piperidin-1-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate 

Relevant articles and documents

Discovery of TD-0212, an Orally Active Dual Pharmacology AT1 Antagonist and Neprilysin Inhibitor (ARNI)

Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy relative to ACE inhibitors but is associated with a higher risk of life-threatening angioedema due to bradykinin elevations. We hypothesized that dual AT1 (angiotensin II type 1 receptor) blockade and NEP inhibition with a single molecule would produce similar antihypertensive efficacy to omapatrilat without the risk of angioedema since ACE (the rate limiting enzyme in bradykinin metabolism) would remain uninhibited. Merging the structures of losartan (an AT1 antagonist) and thiorphan (a NEP inhibitor) led to the discovery of a novel series of orally active, dual AT1 antagonist/NEP inhibitors (ARNIs) exemplified by compound 35 (TD-0212). In models of renin-dependent and -independent hypertension, 35 produced blood pressure reductions similar to omapatrilat and combinations of AT1 receptor antagonists and NEP inhibitors. Upper airway angioedema risk was assessed in a rat tracheal plasma extravasation (TPE) model. Unlike omapatrilat, 35 did not increase TPE at antihypertensive doses. Compound 35 therefore provides the enhanced activity of dual AT1/NEP inhibition with a potentially lower risk of angioedema relative to dual ACE/NEP inhibition.

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