149506-35-4

Basic information

• Product Name: 2-(4-BROMOPHENYL)-PROPANEDIOIC ACID, 1,3-MDIETHYL ESTER
• Synonyms: 2-(4-BROMOPHENYL)-PROPANEDIOIC ACID, 1,3-MDIETHYL ESTER;diMethyl 2-(4-broMophenyl)Malonate;Propanedioic acid, 2-(4-broMophenyl)-, 1,3-diMethyl ester;DiMethyl (4-BroMophenyl)-Malonate;2-(4-Bromophenyl)malonic acid dimethyl ester;2-(4-Bromophenyl)-malonic acid 1,3-dimethyl ester;dimethyl 2-(4-bromophenyl)malonaAte;1,3-dimethyl 2-(4-bromophenyl)propanedioate
• CAS NO: 149506-35-4
• Molecular Formula: C₁₁H₁₁BrO₄
• Molecular Weight: 287.108
• Mol File: 149506-35-4.mol
• Article Data: 14

Chemical Properties

• Boiling Point: 330.0±27.0 °C(Predicted)
• Appearance: /
• Density: 1.467±0.06 g/cm3(Predicted)
• PKA: 11.03±0.46(Predicted)
• CAS DataBase Reference: 2-(4-BROMOPHENYL)-PROPANEDIOIC ACID, 1,3-MDIETHYL ESTER(CAS DataBase Reference)
• NIST Chemistry Reference: 2-(4-BROMOPHENYL)-PROPANEDIOIC ACID, 1,3-MDIETHYL ESTER(149506-35-4)
• EPA Substance Registry System: 2-(4-BROMOPHENYL)-PROPANEDIOIC ACID, 1,3-MDIETHYL ESTER(149506-35-4)

Safety Data

• Hazardous Substances Data: 149506-35-4(Hazardous Substances Data)

Usage

Uses

Dimethyl (4-Bromophenyl)malonate is a useful synthetic intermediate in the synthesis of Macitentan (M105005); an orally active, potent dual endothelin receptor antagonist used for pulmonary arterial hypertension.

Synthetic route

(4-bromo-phenyl)-acetic acid methyl ester (41841-16-1) + carbonic acid dimethyl ester (616-38-6) → 2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4)

Conditions	Yield
Stage #1: (4-bromo-phenyl)-acetic acid methyl ester With sodium hydride In tetrahydrofuran; mineral oil at 40 - 45℃; for 5h; Stage #2: carbonic acid dimethyl ester In tetrahydrofuran; mineral oil at 20 - 32℃; for 24h;	79%
Stage #1: (4-bromo-phenyl)-acetic acid methyl ester With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1h; Stage #2: carbonic acid dimethyl ester In tetrahydrofuran; mineral oil at 20℃; for 72h;	77%
In toluene; paraffin oil

dimethyl diazomalonate (6773-29-1) + 4-Bromophenylboronic acid (5467-74-3) → C11H10BrFO4 + 2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4)

Conditions	Yield
With (pentamethylcyclopentadienyl)*Rh(OAc)2; potassium carbonate; N-fluorobis(benzenesulfon)imide In N,N-dimethyl acetamide at 40℃; for 16h; Reagent/catalyst; Solvent; Temperature;	A 40% B 13%
With (pentamethylcyclopentadienyl)*Rh(OAc)2; potassium acetate; N-fluorobis(benzenesulfon)imide In N,N-dimethyl acetamide at 80℃; for 16h; Solvent; Temperature;	A 17% B 21%

(4-bromo-phenyl)-acetic acid methyl ester (41841-16-1) + methyl chloroformate (79-22-1) → 2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4)

Conditions	Yield
With lithium diisopropyl amide 1.) THF, hexane, -78 deg C, 15 min, 2.) THF, hexane, -78 deg C, 40 min; Yield given. Multistep reaction;

2-(4-bromophenyl)acetyl chloride (37859-24-8) → 2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 2 h / Ambient temperature 2: 1.) LDA / 1.) THF, hexane, -78 deg C, 15 min, 2.) THF, hexane, -78 deg C, 40 min View Scheme

2-(4-bromophenyl)-acetic acid (1878-68-8) → 2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: SOCl2, DMF / CH2Cl2 / Ambient temperature 2: Et3N / CH2Cl2 / 2 h / Ambient temperature 3: 1.) LDA / 1.) THF, hexane, -78 deg C, 15 min, 2.) THF, hexane, -78 deg C, 40 min View Scheme
Multi-step reaction with 2 steps 1.1: thionyl chloride / 0 - 20 °C 2.1: sodium hydride / tetrahydrofuran / 1.83 h / 40 °C 2.2: 22 h / 20 - 31 °C 2.3: -10 °C / pH 6 - 7 View Scheme
Multi-step reaction with 2 steps 1.1: thionyl chloride / 3 h / 0 - 20 °C 2.1: sodium hydride / tetrahydrofuran; mineral oil / 5 h / 40 - 45 °C 2.2: 24 h / 20 - 32 °C View Scheme

carbonic acid dimethyl ester (616-38-6) → 2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4)

Conditions	Yield
Stage #1: (4-bromo-phenyl)-acetic acid methyl ester With sodium hydride In tetrahydrofuran at 27℃; for 1.83333h; Stage #2: carbonic acid dimethyl ester In tetrahydrofuran at 20 - 31℃; for 22h;

formamidine hydrochloride (6313-33-3) + 2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → 5-(4-bromophenyl)-4,6-dihydroxypyrimidine (706811-25-8)

Conditions	Yield
at 25℃; for 16h; Temperature;	92.6%
Stage #1: 2-(4-bromophenyl)-malonic acid dimethyl ester With sodium In methanol at 0 - 20℃; for 18h; Stage #2: formamidine hydrochloride In methanol at 20℃; for 4h;	91%
Stage #1: 2-(4-bromophenyl)-malonic acid dimethyl ester With sodium methylate In methanol at 0℃; for 18h; Stage #2: formamidine hydrochloride In methanol at 20℃; for 4h;
Stage #1: 2-(4-bromophenyl)-malonic acid dimethyl ester With sodium In methanol at 0 - 20℃; for 18h; Stage #2: formamidine hydrochloride In methanol at 20℃; for 4h; Stage #3: With citric acid In water
Stage #1: 2-(4-bromophenyl)-malonic acid dimethyl ester With sodium In methanol at 0 - 20℃; for 18h; Stage #2: formamidine hydrochloride In methanol at 20℃; for 4h; Stage #3: With citric acid In water for 0.166667h;

formamide (77287-34-4, 77287-35-5, 60100-09-6) + 2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → 5-(4-bromophenyl)-4,6-dihydroxypyrimidine (706811-25-8)

Conditions	Yield
With sodium methylate In methanol at 70℃;	75.25%

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) + methyl iodide (74-88-4) → dimethyl (4-bromophenyl)(methyl)malonate

Conditions	Yield
Stage #1: 2-(4-bromophenyl)-malonic acid dimethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Stage #2: methyl iodide In tetrahydrofuran; mineral oil at 20℃; for 2h;	67%

acrylic acid methyl ester (292638-85-8) + 2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → methyl 4-(4'-bromophenyl)-4,4-dimethoxycarbonylbutanoate (177845-96-4)

Conditions	Yield
With sodium methylate In methanol for 6h; Ambient temperature;	64%

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → 6-bromo-1,2-dihydronaphthalene-1-carboxylic acid (177846-05-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 64 percent / NaOMe / methanol / 6 h / Ambient temperature 2: 100 percent / aq. KOH / Heating 3: 100 percent / conc. H2SO4 / H2O / 2 h / Heating 4: 46 percent / PPA / 4 h / 90 °C 5: 77 percent / H3PO4 / tetrahydrofuran / 4 h / 100 °C View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → 7-bromo-4-hydroxycarbonyltetralone (177845-98-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 64 percent / NaOMe / methanol / 6 h / Ambient temperature 2: 100 percent / aq. KOH / Heating 3: 100 percent / conc. H2SO4 / H2O / 2 h / Heating 4: 46 percent / PPA / 4 h / 90 °C View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → 7-bromo-1,2,3,4-tetrahydro-1,4-(epoxymethano)-naphthalen-9-one

Conditions	Yield
Multi-step reaction with 6 steps 1: 64 percent / NaOMe / methanol / 6 h / Ambient temperature 2: 100 percent / aq. KOH / Heating 3: 100 percent / conc. H2SO4 / H2O / 2 h / Heating 4: 46 percent / PPA / 4 h / 90 °C 5: 0.62 g / NaBH4 / propan-2-ol 6: 74 percent / p-TSA / CH2Cl2 / 3 h / Ambient temperature View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → 4-(4'-bromophenyl)-4-hydroxycarbonylbutanoic acid (177845-97-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 64 percent / NaOMe / methanol / 6 h / Ambient temperature 2: 100 percent / aq. KOH / Heating 3: 100 percent / conc. H2SO4 / H2O / 2 h / Heating View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → 6-Bromo-4-hydroxy-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (177846-03-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: 64 percent / NaOMe / methanol / 6 h / Ambient temperature 2: 100 percent / aq. KOH / Heating 3: 100 percent / conc. H2SO4 / H2O / 2 h / Heating 4: 46 percent / PPA / 4 h / 90 °C 5: 0.62 g / NaBH4 / propan-2-ol View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → 2-(4-Bromo-phenyl)-2-carboxy-pentanedioic acid

Conditions	Yield
Multi-step reaction with 2 steps 1: 64 percent / NaOMe / methanol / 6 h / Ambient temperature 2: 100 percent / aq. KOH / Heating View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → C18H23(3)H3N2

Conditions

Yield

Multi-step reaction with 8 steps 1: 64 percent / NaOMe / methanol / 6 h / Ambient temperature 2: 100 percent / aq. KOH / Heating 3: 100 percent / conc. H2SO4 / H2O / 2 h / Heating 4: 46 percent / PPA / 4 h / 90 °C 5: 77 percent / H3PO4 / tetrahydrofuran / 4 h / 100 °C 6: 1.) DCC, HOBT*H2O / 1.) CH3CN, RT, 0.5 h, 2.) CH3CN, 48 h 7: 3H2, Et3N / 10percent Pd/C / ethyl acetate / 24 h 8: BH3*SMe2 / tetrahydrofuran / 8 h / Heating View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → C18H21(3)H3N2O

Conditions	Yield
Multi-step reaction with 7 steps 1: 64 percent / NaOMe / methanol / 6 h / Ambient temperature 2: 100 percent / aq. KOH / Heating 3: 100 percent / conc. H2SO4 / H2O / 2 h / Heating 4: 46 percent / PPA / 4 h / 90 °C 5: 77 percent / H3PO4 / tetrahydrofuran / 4 h / 100 °C 6: 1.) DCC, HOBT*H2O / 1.) CH3CN, RT, 0.5 h, 2.) CH3CN, 48 h 7: 3H2, Et3N / 10percent Pd/C / ethyl acetate / 24 h View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → C18H21BrN2O (177845-99-7)

Conditions	Yield
Multi-step reaction with 6 steps 1: 64 percent / NaOMe / methanol / 6 h / Ambient temperature 2: 100 percent / aq. KOH / Heating 3: 100 percent / conc. H2SO4 / H2O / 2 h / Heating 4: 46 percent / PPA / 4 h / 90 °C 5: 77 percent / H3PO4 / tetrahydrofuran / 4 h / 100 °C 6: 1.) DCC, HOBT*H2O / 1.) CH3CN, RT, 0.5 h, 2.) CH3CN, 48 h View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → C18H21BrN2O

Conditions	Yield
Multi-step reaction with 6 steps 1: 64 percent / NaOMe / methanol / 6 h / Ambient temperature 2: 100 percent / aq. KOH / Heating 3: 100 percent / conc. H2SO4 / H2O / 2 h / Heating 4: 46 percent / PPA / 4 h / 90 °C 5: 77 percent / H3PO4 / tetrahydrofuran / 4 h / 100 °C 6: 1.) DCC, HOBT*H2O / 1.) CH3CN, RT, 0.5 h, 2.) CH3CN, 48 h View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → 2-(4-bromophenyl)-1,3-propanediol (149506-34-3)

Conditions	Yield
With sulfuric acid In tetrahydrofuran; diethyl ether; water

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → 5-(4-bromophenyl)-4,6-dichloropyrimidine (146533-41-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium / methanol / 18 h / 0 - 20 °C 1.2: 4 h / 20 °C 1.3: 0.17 h 2.1: trichlorophosphate; N,N-dimethyl-aniline / 2 h / 130 °C 2.2: 0.33 h / Cooling with ice View Scheme
Multi-step reaction with 2 steps 1.1: sodium / methanol / 18 h / 0 - 20 °C 1.2: 4 h / 20 °C 2.1: trichlorophosphate / N,N-dimethyl-aniline / 2 h / 130 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium methylate; methanol / 1.25 h / 0 - 5 °C / Inert atmosphere 1.2: 6 h / 0 - 30 °C 1.3: 1.5 h / 25 - 30 °C 2.1: triethylamine; trichlorophosphate / acetonitrile / 5 h / 25 - 85 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: sodium methylate / methanol / 70 °C 2: trichlorophosphate / 90 °C View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → N-[5-(4-bromophenyl)-6-chloro-4-pyrimidinyl]-N'-benzyl-sulfamide (441797-42-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium / methanol / 18 h / 0 - 20 °C 1.2: 4 h / 20 °C 1.3: 0.17 h 2.1: trichlorophosphate; N,N-dimethyl-aniline / 2 h / 130 °C 2.2: 0.33 h / Cooling with ice 3.1: dimethyl sulfoxide / 24 h / 20 °C View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → N-[5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-N'-benzyl-sulfamide (441796-08-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium / methanol / 18 h / 0 - 20 °C 1.2: 4 h / 20 °C 1.3: 0.17 h 2.1: trichlorophosphate; N,N-dimethyl-aniline / 2 h / 130 °C 2.2: 0.33 h / Cooling with ice 3.1: dimethyl sulfoxide / 24 h / 20 °C 4.1: potassium tert-butylate / 1,2-dimethoxyethane / 24 h / 95 °C View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → benzylsulfamic acid {5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yloxy)-ethoxy]-pyrimidine-4-yl}-amide (441796-09-4)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: sodium / methanol / 18 h / 0 - 20 °C 1.2: 4 h / 20 °C 1.3: 0.17 h 2.1: trichlorophosphate; N,N-dimethyl-aniline / 2 h / 130 °C 2.2: 0.33 h / Cooling with ice 3.1: dimethyl sulfoxide / 24 h / 20 °C 4.1: potassium tert-butylate / 1,2-dimethoxyethane / 24 h / 95 °C 5.1: sodium hydride / tetrahydrofuran; mineral oil / 0.17 h 5.2: 3.33 h / 20 - 60 °C 5.3: 20 °C View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → ACT-132577 (1103522-45-7)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: sodium / methanol / 18 h / 0 - 20 °C 1.2: 4 h / 20 °C 1.3: 0.17 h 2.1: trichlorophosphate; N,N-dimethyl-aniline / 2 h / 130 °C 2.2: 0.33 h / Cooling with ice 3.1: dimethyl sulfoxide / 24 h / 20 °C 4.1: potassium tert-butylate / 1,2-dimethoxyethane / 24 h / 95 °C 5.1: sodium hydride / tetrahydrofuran; mineral oil / 0.17 h 5.2: 3.33 h / 20 - 60 °C 5.3: 20 °C 6.1: boron tribromide / dichloromethane; chloroform / 35 h / 20 °C 6.2: 20 °C View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl-N‘-propylsulfamide (1393813-42-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium / methanol / 18 h / 0 - 20 °C 1.2: 4 h / 20 °C 2.1: trichlorophosphate / N,N-dimethyl-aniline / 2 h / 130 °C 3.1: dimethyl sulfoxide / 48 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium methylate; methanol / 1.25 h / 0 - 5 °C / Inert atmosphere 1.2: 6 h / 0 - 30 °C 1.3: 1.5 h / 25 - 30 °C 2.1: triethylamine; trichlorophosphate / acetonitrile / 5 h / 25 - 85 °C / Inert atmosphere 3.1: sodium amide / dimethyl sulfoxide / 10 h / 25 - 30 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: sodium methylate / methanol / 70 °C 2: trichlorophosphate / 90 °C 3: lithium amide / dimethyl sulfoxide / 2 h / 20 - 25 °C View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → N‐[5‐(4‐bromophenyl)‐6‐[2‐hydroxyethoxy]‐4‐pyrimidinyl]‐N‐propylsulfamide (1393813-43-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium / methanol / 18 h / 0 - 20 °C 1.2: 4 h / 20 °C 2.1: trichlorophosphate / N,N-dimethyl-aniline / 2 h / 130 °C 3.1: dimethyl sulfoxide / 48 h / 20 °C 4.1: potassium tert-butylate / 1,2-dimethoxyethane / 0.17 h / 40 °C 4.2: 70 h / 100 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium methylate; methanol / 1.25 h / 0 - 5 °C / Inert atmosphere 1.2: 6 h / 0 - 30 °C 1.3: 1.5 h / 25 - 30 °C 2.1: triethylamine; trichlorophosphate / acetonitrile / 5 h / 25 - 85 °C / Inert atmosphere 3.1: sodium amide / dimethyl sulfoxide / 10 h / 25 - 30 °C / Inert atmosphere 4.1: potassium tert-butylate / 10 h / 25 - 90 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: sodium methylate / methanol / 70 °C 2: trichlorophosphate / 90 °C 3: lithium amide / dimethyl sulfoxide / 2 h / 20 - 25 °C 4: lithium amide / 18 h / 100 - 105 °C / Green chemistry View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → C11H10BrClN4O2S

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium / methanol / 18 h / 0 - 20 °C 1.2: 4 h / 20 °C 2.1: trichlorophosphate / N,N-dimethyl-aniline / 2 h / 130 °C 3.1: dimethyl sulfoxide / 48 h / 20 °C View Scheme

2-(4-bromophenyl)-malonic acid dimethyl ester (149506-35-4) → C12H12BrClN4O2S (441797-83-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium / methanol / 18 h / 0 - 20 °C 1.2: 4 h / 20 °C 2.1: trichlorophosphate / N,N-dimethyl-aniline / 2 h / 130 °C 3.1: dimethyl sulfoxide / 48 h / 20 °C View Scheme

Upstream product

• 37859-24-8 2-(4-bromophenyl)acetyl chloride 
• 6773-29-1 dimethyl diazomalonate 
• 5467-74-3 4-Bromophenylboronic acid 
• 41841-16-1 (4-bromo-phenyl)-acetic acid methyl ester 
• 616-38-6 carbonic acid dimethyl ester 
• 1878-68-8 2-(4-bromophenyl)-acetic acid 
• 79-22-1 methyl chloroformate 

Downstream Products

• 177845-96-4 methyl 4-(4'-bromophenyl)-4,4-dimethoxycarbonylbutanoate 
• 177845-97-5 4-(4'-bromophenyl)-4-hydroxycarbonylbutanoic acid 
• 149506-34-3 2-(4-bromophenyl)propane-1,3-diol 
• 706811-25-8 5-(4-bromophenyl)-4,6-dihydroxypyrimidine 
• 146533-41-7 5-(4-bromophenyl)-4,6-dichloropyrimidine 
• 441797-42-8 N-[5-(4-bromophenyl)-6-chloro-4-pyrimidinyl]-N'-benzyl-sulfamide 
• 441796-08-3 N-[5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-N'-benzyl-sulfamide 
• 1103522-45-7 ACT-132577 
• 1393813-42-7 N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl-N‘-propylsulfamide 
• 1393813-43-8 N‐[5‐(4‐bromophenyl)‐6‐[2‐hydroxyethoxy]‐4‐pyrimidinyl]‐N‐propylsulfamide 
• 441797-83-7 C₁₂H₁₂BrClN₄O₂S 
• 441797-82-6 C₁₃H₁₂BrClN₄O₂S 
• 441796-12-9 C₁₄H₁₇BrN₄O₄S 
• 441797-01-9 C₁₅H₁₇BrN₄O₄S 

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