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

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

Used in Pharmaceutical Industry:
2-(4-BROMOPHENYL)-PROPANEDIOIC ACID, 1,3-MDIETHYL ESTER is used as a synthetic intermediate for the development of Macitentan (M105005), an orally active and potent dual endothelin receptor antagonist. Macitentan is specifically utilized for the treatment of pulmonary arterial hypertension, a severe lung disease characterized by high blood pressure in the arteries of the lungs.
Application Reason:
The use of 2-(4-BROMOPHENYL)-PROPANEDIOIC ACID, 1,3-MDIETHYL ESTER in the synthesis of Macitentan is due to its structural properties that allow for the formation of the desired drug molecule. Its presence in the synthesis process contributes to the overall effectiveness of Macitentan in treating pulmonary arterial hypertension by blocking the action of endothelin, a potent vasoconstrictor that can cause the narrowing of blood vessels and increased blood pressure in the lungs.

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

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

Downstream Products

• 177845-96-4 methyl 4-(4'-bromophenyl)-4,4-dimethoxycarbonylbutanoate 
• 149506-34-3 2-(4-bromophenyl)propane-1,3-diol 
• 706811-25-8 5-(4-bromophenyl)-4,6-dihydroxypyrimidine 
• 1433875-21-8 ACT-080803 
• 2211059-05-9 2‐((6‐amino‐5‐(4‐bromophenyl)pyrimidin‐4‐yl)oxy)ethan‐1‐ol 
• 556797-16-1 C₂₀H₂₁Br₂N₅O₄S 
• 441796-13-0 C₁₈H₁₈Br₂N₆O₄S 
• 441798-25-0 C₁₇H₁₆Br₂N₆O₄S 
• 441797-01-9 C₁₅H₁₇BrN₄O₄S 
• 441796-12-9 C₁₄H₁₇BrN₄O₄S 

Relevant articles and documents

-catalyzed arylfluorination of α-diazoketoesters for facile synthesis of α-aryl-α-fluoroketoesters

Here we describe the Cp?Rh(iii)-catalyzed cascade arylfluorination reactions of α-diazoketoesters with arylboronic acids and N-fluorobenzenesulfonimide for one-pot C(sp3)-C(aryl) and C(sp3)-F bond formation. The arylfluorination reaction can be accomplished with remarkable chemo- and regioselectivity. Our mechanistic investigation showed that the Rh-catalyzed arylfluorination of diazoacetates occurred by (1) transmetalation of arylboronic acids to form an arylrhodium(iii) complex, (2) coupling of diazomalonates with the arylrhodium(iii) complex to form carbene-rhodium, (3) migratory carbene insertion to form a diketonato-rhodium(iii) complex-probably via rearrangement of the putative σ-alkylrhodium(iii) complex, and (4) electrophilic fluorination of the diketonato-rhodium to form the α-aryl-α-fluoromalonates.

Improved and single-pot process for the synthesis of macitentan, an endothelin receptor antagonist, via lithium amide-mediated nucleophilic substitution

Abstract: An improved, simple, efficient, and telescoped synthesis of macitentan, an endothelin receptor antagonist, starting from 5-(4-bromophenyl)-4,6-dichloropyrimidine in an overall yield of around 62% is described. Graphical abstract: [Figure not available: see fulltext.].

Palladium-Catalyzed Asymmetric Allylic Alkylation of 4-Substituted Isoxazolidin-5-ones: Straightforward Access to β2,2-Amino Acids

We report here an unprecedented and highly enantioselective palladium-catalyzed allylic alkylation applied to 4-substituted isoxazolidin-5-ones. Ultimately, the process provides a straightforward access to β2,2-amino acids bearing an all-carbon quaternary stereogenic center in great yields and a high degree of enantioselectivity.

Preparation method of 5-(4-bromophenyl)-4,6-dichloropyrimidine

The invention belongs to the technical field of pharmaceutical chemistry synthesis, and relates to a preparation method of 5-(4-bromophenyl)-4,6-dichloropyrimidine. The preparation method comprises the following steps: carrying out catalytic esterification on bromophenylacetic acid to prepare methyl p-bromophenylacetate, then carrying out a reaction with dimethyl carbonate to synthesize 2-(4-bromophenyl)-malonic acid-1,3-diethyl ester, carrying out cyclization by using formamidine hydrochloride to obtain 5-(4-bromophenyl)-4,6-dihydroxy pyrimidine, and then carrying out chlorination to obtain the product 5-(4-bromophenyl)-4,6-dichloropyrimidine. In the preparation process of the intermediate 1, a solid acid is adopted as a catalyst, so that the synthesis process and a post-treatment step are simplified. The solid acid is easy to separate and can be repeatedly used, so that resources are saved, and production cost is reduced. In a process of preparing the intermediate 2, sodium methoxideis adopted as an alkali to replace sodium hydride or amino sodium used in the prior art, so that production safety is improved, and production cost is reduced. Meanwhile, the intermediate 3 is prepared by adopting a one-pot method, so that operation steps are reduced.

AN IMPROVED PROCESS FOR THE PREPARATION OF MACITENTAN

The present invention relates to an improved process for the preparation of macitentan and pharmaceutical acceptable salts thereof. Further present invention also relates to methylene chloride solvate of macitentan and their use in the preparation of pure macitentan.

SUBSTITUTED BIPIPERIDINYL DERIVATIVES

The invention relates to novel substituted bipiperidinyl derivatives, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of diabetic microangiopathies, diabetic ulcers on the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disorders, peripheral and cardiac vascular disorders, thromboembolic disorders and ischaemias, peripheral circulatory disturbances, Raynaud's phenomenon, CREST syndrome, microcirculatory disturbances, intermittent claudication, and peripheral and autonomous neuropathies.

Gold(I)-Catalyzed Enantioselective Desymmetrization of 1,3-Diols through Intramolecular Hydroalkoxylation of Allenes

A gold(I)-catalyzed enantioselective desymmetrization of 1,3-diols was achieved by intramolecular hydroalkoxylation of allenes. The catalyst system 3-F-dppe(AuCl)2 /(R)-C8-TRIPAg proved to be specifically efficient to promote the desymmetrizing cyclization of 2-aryl-1,3-diols, which have proven challenging substrates in previous reports. Multisubstituted tetrahydrofurans were prepared in good yield with good enantioselectivity and diastereoselectivity by this method.

The discovery of N -[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] ethoxy]-4-pyrimidinyl]- N ′-propylsulfamide (macitentan), an orally active, potent dual endothelin receptor antagonist

Starting from the structure of bosentan (1), we embarked on a medicinal chemistry program aiming at the identification of novel potent dual endothelin receptor antagonists with high oral efficacy. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ETA with significant affinity for the ET B receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension.

4-PYRIMIDINESULFAMIDE DERIVATIVE

The invention relates to the compound of structural formula (I) and the salts thereof. Said compound is useful as endothelin receptor antagonist. The invention further relates to a process for preparing said compound.

4-PYRIMIDINESULFAMIDE DERIVATIVE

The invention relates to the compound of structural formula (I) and the salts thereof. Said compound is useful as endothelin receptor antagonist. The invention further relates to a process for preparing said compound.