289686-70-0

Basic information

• Product Name: 2-(3,5-bis(trifluoroMethyl)phenyl)-2-Methyl propanoic acid
• Synonyms: 2-(3,5-bis(trifluoroMethyl)phenyl)-2-Methyl propanoic acid;α,α-DiMethyl-3,5-bis(trifluoroMethyl)benzeneaceticAcid;Netupitant SM1
• CAS NO: 289686-70-0
• Molecular Formula: C₁₂H₁₀F₆O₂
• Molecular Weight: 300.1970192
• EINECS: -0
• Mol File: 289686-70-0.mol

Chemical Properties

• Melting Point: 105.5-107℃
• Boiling Point: 232.5±35.0 °C(Predicted)
• Appearance: /
• Density: 1.378±0.06 g/cm3(Predicted)
• Storage Temp.: Sealed in dry,Room Temperature
• PKA: 4.06±0.14(Predicted)
• CAS DataBase Reference: 2-(3,5-bis(trifluoroMethyl)phenyl)-2-Methyl propanoic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 2-(3,5-bis(trifluoroMethyl)phenyl)-2-Methyl propanoic acid(289686-70-0)
• EPA Substance Registry System: 2-(3,5-bis(trifluoroMethyl)phenyl)-2-Methyl propanoic acid(289686-70-0)

Safety Data

• Hazardous Substances Data: 289686-70-0(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
2-(3,5-bis(trifluoroMethyl)phenyl)-2-Methyl propanoic acid is used as a reagent for the synthesis of NK1/NK3 receptor antagonists, which are crucial in the treatment of depression. By modulating the activity of these receptors, this compound can help alleviate the symptoms of depression and improve the overall well-being of patients suffering from this mental health condition.

InChI:InChI=1S/C12H10F6O2/c1-10(2,9(19)20)6-3-7(11(13,14)15)5-8(4-6)12(16,17)18/h3-5H,1-2H3,(H,19,20)

Synthetic route

methyl 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoate (334477-48-4) → α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0)

Conditions	Yield
Stage #1: methyl 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoate With lithium hydroxide; water In tetrahydrofuran; methanol at 20℃; for 72h; Stage #2: With hydrogenchloride In water	100%
With lithium hydroxide; water In tetrahydrofuran; methanol at 20℃; for 72h;	100%
With water; sodium hydroxide In methanol at 100℃; for 7h; Time; Temperature; Inert atmosphere;	90%

carbon monoxide (201230-82-2) + α,α-dimethyl-3,5-bis(trifluoromethyl)benzenemethanol (67570-38-1) → α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0)

Conditions	Yield
With trifluorormethanesulfonic acid In dichloromethane; water at 20℃; under 22501.8 Torr; for 2h;	97%

3,5-bistrifluoromethylphenyl acetic acid (85068-33-3) + methyl iodide (74-88-4) → 2-methyl-2-(4-methyl-3,5-bis-trifluoromethyl-phenyl)-propionic acid + (RS)-α-Methyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-73-3) + α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0)

Conditions	Yield
Stage #1: 3,5-bistrifluoromethylphenyl acetic acid With n-butyllithium Stage #2: methyl iodide	A n/a B n/a C 91%

2-(3,5-bis-trifluoromethylphenyl)-2-methyl propionitrile → α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0)

Conditions	Yield
With sulfuric acid In water for 4h; Time; Reflux;	87%
With potassium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene; ethylene glycol at 135℃; for 12h; Autoclave; Large scale;	80%
Stage #1: 2-(3,5-bis-trifluoromethylphenyl)-2-methyl propionitrile With sodium hydroxide at 145℃; for 12h; Sealed tube; Large scale; Stage #2: With hydrogenchloride In water at 20℃; pH=1; Large scale;	2.43 kg

2-bromo-2-methylpropionic acid (2052-01-9) + 3,5-bis-trifluromethylphenylboronic acid (73852-19-4) → α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0)

Conditions	Yield
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane; water at 60℃; for 3h; Reagent/catalyst; Inert atmosphere;	85%

3,5-bistrifluoromethylphenyl acetic acid (85068-33-3) + methyl iodide (74-88-4) → α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0)

Conditions	Yield
With n-butyllithium In tetrahydrofuran; hexane at -50 - 20℃; for 5h; Inert atmosphere; Large scale;	77%

2-(3,5-bistrifluoromethylphenyl)propanenitrile + ethylene glycol (107-21-1) → α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0)

Conditions	Yield
With potassium hydroxide at 135℃; for 20h; Reagent/catalyst; Temperature; Reflux;	73%

carbon monoxide (201230-82-2) + α,α-dimethyl-3,5-bis(trifluoromethyl)benzenemethanol (67570-38-1) → C22H16F12 + 4-methyl-2,4-di[3,5-bis(trifluoromethyl)phenyl]pent-1-ene + α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0)

Conditions	Yield
With trifluorormethanesulfonic acid at 0℃;	A n/a B n/a C 56%

3,6-bis(trifluoromethyl)bromobenzene (328-70-1) → α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: magnesium / diethyl ether / 1 h / 30 °C 1.2: diethyl ether / 0.75 h / 16 - 22 °C 2.1: 97 percent / CF3SO3H / CH2Cl2; H2O / 2 h / 20 °C / 22501.8 Torr View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 10 h / 90 °C 2.1: sodium hydroxide / methanol / 5 h / Reflux 3.1: sodium hydride / N,N-dimethyl-formamide / 1 h / -5 °C 3.2: 10 h / 50 °C View Scheme
Multi-step reaction with 2 steps 1: bis(η3-allyl-μ-chloropalladium(II)); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; 1,3,5-trimethyl-benzene / 20 h / 140 °C / Schlenk technique; Inert atmosphere; Reflux 2: potassium hydroxide / 20 h / 135 °C / Reflux View Scheme

3,5-(bistrifluoromethyl)chlorobenzene (328-72-3) → α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0)

Conditions

Yield

Multi-step reaction with 3 steps 1.1: bis(η3-allyl-μ-chloropalladium(II)); dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / 1,3,5-trimethyl-benzene / 20.25 h / 0 - 145 °C / Inert atmosphere; Large scale 2.1: sodium hydride / mineral oil; 1,4-dioxane / 10.25 h / 15 - 45 °C / Inert atmosphere; Large scale 3.1: sodium hydroxide / 12 h / 145 °C / Sealed tube; Large scale 3.2: 20 °C / pH 1 / Large scale View Scheme

dimethyl sulfate (77-78-1) + 3,5-bistrifluoromethylphenyl acetic acid (85068-33-3) → α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0)

Conditions	Yield
Stage #1: 3,5-bistrifluoromethylphenyl acetic acid With sodium hydride In N,N-dimethyl-formamide at -5℃; for 1h; Stage #2: dimethyl sulfate In N,N-dimethyl-formamide at 50℃; for 10h;	325.1 g

2-(3,5-bistrifluoromethylphenyl)propanenitrile + glycerol (56-81-5) → α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0)

Conditions	Yield
With barium(II) hydroxide Reagent/catalyst; Concentration;

α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (289686-69-7)

Conditions	Yield
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide; toluene for 4.5h;	100%
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 17h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 24h;

oxalyl dichloride (79-37-8) + α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (289686-69-7)

Conditions	Yield
In dichloromethane; N,N-dimethyl-formamide for 4.5h;	100%
In dichloromethane; N,N-dimethyl-formamide; toluene

4-(3,5-dichlorophenoxy)-2-(piperazin-1-yl)pyrimidine + α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → 2-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(4-(3,5-dichlorophenoxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylpropan-1-one

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 10h;	83%

C18H21ClN2O2 + α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(o-tolyl)pyridin-3-yl)-N,2-dimethylpropanamide (401891-55-2)

Conditions	Yield
Stage #1: C18H21ClN2O2 With trifluoroacetic acid In dichloromethane at 20℃; for 2h; Stage #2: α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In N,N-dimethyl-formamide at 100℃; for 4h;	75%

2-Amino-5-chlorobenzophenone (719-59-5) + α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → N-(2-benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-isobutyramide (289686-54-0)

Conditions	Yield
Stage #1: 5-chloro-2-aminobenzophenone; α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid In 1,2-dichloro-ethane at 80℃; for 1h; Stage #2: With dicyclohexyl-carbodiimide In 1,2-dichloro-ethane at 80℃;	58%

α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → α,α-dimethyl-3,5-bis(trifluoromethyl)benzenemethanamine hydrochloride (374822-30-7)

Conditions	Yield
Stage #1: α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid With diphenyl phosphoryl azide; triethylamine In toluene at 90℃; for 18h; Stage #2: With hydrogenchloride; water for 18h; Heating / reflux; Stage #3: With hydrogenchloride In diethyl ether	20%

4-amino-4-phenylcyclohexan-1-one (95261-39-5) + α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → α,α-dimethyl-N-[4-oxo-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide (374791-63-6)

Conditions	Yield
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In N,N-dimethyl-formamide at 20℃;

α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → α,α-dimethyl-3,5-bis(trifluoromethyl)benzenemethanamine (488098-44-8)

Conditions	Yield
Stage #1: α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid With diphenyl phosphoryl azide; triethylamine In toluene at 90℃; Stage #2: With hydrogenchloride In diethyl ether at 20℃;

α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → C12H11F6NO

Conditions	Yield
With ammonium chloride; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; 4-methyl-morpholine

C17H25N3O3 + α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → C29H31F6N3O3

Conditions	Yield
Stage #1: C17H25N3O3; α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In toluene at 110℃; Stage #2: In toluene at 110℃; Further stages.;

C17H24FN3O3 + α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → C29H30F7N3O3

Conditions	Yield
Stage #1: C17H24FN3O3; α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide Stage #2: In toluene at 110℃; Further stages.;

α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide (290296-68-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: (COCl)2 / CH2Cl2; dimethylformamide / 17 h / 0 - 20 °C 2: 17.3 g / i-Pr2NEt / CH2Cl2 / 3 h / 0 °C View Scheme

α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → netupitant (290297-26-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: (COCl)2 / CH2Cl2; dimethylformamide / 17 h / 0 - 20 °C 2: 13.5 g / i-Pr2NEt / CH2Cl2 / 3 h / 0 °C View Scheme
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 4.5 h 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 35 - 40 °C View Scheme
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide; dichloromethane / 4.5 h 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 35 - 40 °C / Cooling with ice View Scheme
Multi-step reaction with 2 steps 1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide; toluene / 4.5 h 2: sodium hydrogencarbonate; N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 35 - 40 °C / Cooling with ice View Scheme

α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → 4-oxo-1-phenyl-cyclohexanecarboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-1-methyl-ethyl]-amide

Conditions	Yield
Multi-step reaction with 2 steps 1.1: (PhO)2PON3; Et3N / toluene / 90 °C 1.2: HCl / diethyl ether / 20 °C 2.1: Et3N; EDC; HOBt / dimethylformamide / 20 °C View Scheme

α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → 2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-1-phenyl-cyclohexyl}-isobutyramide

Conditions	Yield
Multi-step reaction with 2 steps 1: Et3N; EDC; HOBt / dimethylformamide / 20 °C View Scheme

α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → 2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-1-phenyl-cyclohexyl}-isobutyramide

Conditions	Yield
Multi-step reaction with 2 steps 1: Et3N; EDC; HOBt / dimethylformamide / 20 °C View Scheme

α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-1-phenyl-cyclohexanecarboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-1-methyl-ethyl]-amide

Conditions	Yield
Multi-step reaction with 3 steps 1.1: (PhO)2PON3; Et3N / toluene / 90 °C 1.2: HCl / diethyl ether / 20 °C 2.1: Et3N; EDC; HOBt / dimethylformamide / 20 °C View Scheme

α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-1-phenyl-cyclohexanecarboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-1-methyl-ethyl]-amide

Conditions	Yield
Multi-step reaction with 3 steps 1.1: (PhO)2PON3; Et3N / toluene / 90 °C 1.2: HCl / diethyl ether / 20 °C 2.1: Et3N; EDC; HOBt / dimethylformamide / 20 °C View Scheme

5-(2-methylphenyl)-2-morpholin-4-ylquinolin-6-amine (889650-17-3) + α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → 2-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-N-[5-(2-methylphenyl)-2-morpholin-4-ylquinolin-6-yl]propanamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h;

α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid (289686-70-0) → 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(o-tolyl)pyridin-3-yl)-N,2-dimethylpropanamide (401891-55-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 4.5 h 2: dmap / toluene / 23 h / 120 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 1 h / 20 °C 2.1: potassium hexamethylsilazane / tetrahydrofuran; toluene / 0.5 h / 20 °C / Inert atmosphere; Cooling with ice 2.2: 1 h / 20 °C / Inert atmosphere; Cooling with ice View Scheme
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide; dichloromethane / 4.5 h 2: dmap / toluene / 23 h / 120 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide; toluene / 4.5 h 2: dmap / toluene / 23 h / 120 °C / Inert atmosphere View Scheme

Upstream product

• 334477-48-4 methyl 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoate 
• 85068-33-3 3,5-bistrifluoromethylphenyl acetic acid 
• 74-88-4 methyl iodide 
• 328-70-1 3,6-bis(trifluoromethyl)bromobenzene 
• 328-72-3 3,5-(bistrifluoromethyl)chlorobenzene 
• 77-78-1 dimethyl sulfate 
• 107-21-1 ethylene glycol 
• 56-81-5 glycerol 
• 2052-01-9 2-bromo-2-methylpropionic acid 
• 73852-19-4 3,5-bis-trifluromethylphenylboronic acid 
• 201230-82-2 carbon monoxide 
• 67570-38-1 α,α-dimethyl-3,5-bis(trifluoromethyl)benzenemethanol 

Downstream Products

• 374791-63-6 α,α-dimethyl-N-[4-oxo-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide 
• 488098-44-8 α,α-dimethyl-3,5-bis(trifluoromethyl)benzenemethanamine 
• 289686-69-7 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride 
• 290296-68-3 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide 
• 290297-26-6 netupitant 
• 289686-54-0 N-(2-benzoyl-4-chloro-phenyl)-2-(3,5-bis-trifluoromethyl-phenyl)-isobutyramide 
• 374822-30-7 α,α-dimethyl-3,5-bis(trifluoromethyl)benzenemethanamine hydrochloride 
• 401891-55-2 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(o-tolyl)pyridin-3-yl)-N,2-dimethylpropanamide 
• 1431216-67-9 5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-2-chloro-4-(o-tolyl)pyridine 1-oxide 
• 1431216-62-4 5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-2-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridine-1-oxide 
• 1431216-60-2 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-1-oxido-4-(o-tolyl)pyridin-2-yl)-1-methylpiperazine-1-oxide 

Relevant articles and documents

A 2 - (3, 5 - double - trifluoromethyl - phenyl) -2 - methyl - propionic acid preparation method

The invention provides a 2 - (3, 5 - double - trifluoromethyl - phenyl) - 2 - methyl - propionic acid preparation method. In particular, the use of 3, 5 - trifluoro - methyl-bromobenzene as raw materials, through Grignard - sediment reaction, Suzuki coupling reaction, to obtain 2 - (3, 5 - double - trifluoromethyl - phenyl) - 2 - methyl - propionic acid. The method of short synthetic route, raw materials are easy and the cost is low, mild reaction conditions, easy purification of products, and have high yield, is suitable for industrial mass production.

Synthesis method of netupitant intermediate (2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propionic acid)

The invention discloses a synthesis method of a netupitant intermediate (2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propionic acid). The method includes the following steps of adding a compound III and trimethylcyanosilane to an organic solvent, cooling the organic solvent to 0 DEG C, dropwise adding an acid catalyst, heating reaction liquid to the room temperature after dropwise adding is completed, conducting quenching, extracting, organic phase drying, filtering, filtrate concentrating, recrystallizing, filtering and drying on reaction liquid after reaction ends to obtain a compound II, adding water to the compound II, dropwise adding concentrated sulfuric acid for reflux reaction, and conducting quenching, extracting, organic phase drying, filtering, concentrating, filtering and drying on the reaction liquid after reaction ends. The method has the advantages that the adopted synthesis method is simple in step, a highly-toxic product (methyl iodide) or a metal palladium catalyst is avoided, the reaction route is short, the raw materials are low in price and easy to obtain, the reaction conditions are mild, the production process is simple in operation, the product yield is high, and thus the method is suitable for large-scale production.

Preparation method of synthetic 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propioric acid

The invention discloses a preparation method of synthetic 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propioric acid. S1: 3,5-bis(trifluoromethyl)bromobenzene is dissolved in an organic solvent, the solution is added dropwisely into isopropylmagnesium chloride, and a Grignard reagent is obtained; mafosfamide is dissolved in an organic solvent, the solution is added dropwisely into the Grignard reagent, in order to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propyl-1-ketone; S2: 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propyl-1-ketone obtained in the step S1 is dissolved in an organicsolvent, and 2-(3,5-bis(trifluoromethyl)phenyl)-2-bromo-methyl propyl-1-ketone is obtained; S3: 2-(3,5-bis(trifluoromethyl)phenyl)-2-bromo-2-methyl propyl-1-ketone obtained in the step S2 is dissolved in an organic solvent, zinc bromide is added, in order to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl methacrylate; S4: 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl methacrylate obtained in the step S3 is dissolved in an organic solvent, the solution is added into an aqueous solution of alkali, and 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propioric acid is obtained.

Method for synthetizing Netupitant midbody impurity 2-(3,5-Bis-trifluoromethyl-phenyl) propionic acid

The invention discloses a method for synthetizing a Netupitant midbody impurity 2-(3,5-bis-trifluoromethyl-phenyl) propionic acid, comprising the following steps: dissolving 2-cyano propionate and 3,5-bis-trifluoromethyl halogeno benzene into a first solvent, and performing a decarboxylation cyanomethylation reaction under the effects of a palladium catalyst and phosphorus ligands to obtain 2-(3,5-bis-trifluoromethyl-phenyl) propionitrile; adding the 2-(3,5-bis-trifluoromethyl-phenyl) propionitrile and alkali into a second solvent to generate 2-(3,5-bis-trifluoromethyl-phenyl) propionate, and then acidizing to obtain the 2-(3,5-bis-trifluoromethyl-phenyl) propionic acid. According to the method for synthetizing the Netupitant midbody impurity 2-(3,5-bis-trifluoromethyl-phenyl) propionic acid, the raw materials are cheap and easy to get, the operation is simple, the synthesis is easy, a side reaction cannot occur, and higher yield is achieved.

Synthetic method for netupitant intermediate 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionate

The invention discloses a synthetic method for a netupitant intermediate 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionate. According to the synthetic method, 2-cyano-2-methyl propionate and 3,5-bistrifluoromethyl halogeno benzene are dissolved in a solvent for a decarboxylation cyanomethylation reaction under the action of a palladium catalyst and an organophosphorus ligand to obtain 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionitrile, and then the cyano group is converted into the carboxy group through alkali to obtain a target product. Through the synthetic method for the intermediate, operation is easy, raw materials are cheap and easy to get, synthesis is easy, a side reaction will not happen, and a high yield is achieved.

Method for synthesizing drug intermediate

The invention discloses a method for synthesizing a drug intermediate. Cyano-acetate and 3,5-bis(trifluoromethyl) halogenobenzene are dissolved in a solvent and have a decarboxylation cyanomethylation reaction under the action of a palladium catalyst and an organic phosphorus ligand to obtain 2-(3,5-bis(trifluoromethyl phenyl) acetonitrile, then 2-(3,5-bis(trifluoromethyl phenyl) acetonitrile reacts with a methylation reagent to obtain 2-(3,5-bis(trifluoromethyl phenyl)-2-methyl propanenitrile, and finally cyano groups are converted into carboxyl groups with alkali to obtain the target product. The method for synthesizing the drug intermediate is easy to operate, raw materials are cheap and easy to obtain, synthesis is easy, side reactions do not happen, and the yield is high.

A intermediate [...] 2 - (3,5-bis-trifluoromethyl-phenyl) - 2-methyl-propionic acid synthetic method (by machine translation)

The invention discloses a intermediate [...] 2 - (3,5-bis-trifluoromethyl-phenyl) - 2-methyl-propionic acid synthetic method, comprising the following steps: in order to compound 3.5-bis (trifluoromethyl) bromobenzene as raw materials, the presence of the alkali reagent 1st the 1st diethyl malonate in a solvent in the reaction, a generating compound, then the compound in the solvent 2nd, through the 2nd alkali reagent to carry out saponification, decarboxylation reaction, and the second generating compound, the final compound II in the presence of the alkali reagent 3rd the 3rd with methylation reagent in the reaction in the solvent to obtain 2 - (3,5-bis-trifluoromethyl-phenyl) - 2-methyl-propionic acid. The invention uses the one-pot synthesis preparation [...] intermediate, not only the easily obtained raw material used, the cost is low, and the reaction flow is short, the operation is simple, the production cost is low, is convenient for industrial production and application. (by machine translation)

Synthesis method of netupitant intermediates

The invention discloses a synthesis method of netupitant intermediates. The method includes the steps of dissolving cyano-acetate and 3,5-bis(trifluoromethylphenyl halide) in solvent, conducting decarboxylation and cyanomethylation reaction under the effect of a palladium catalyst and organophosphorus ligand to obtain 2-(3,5-bistrifluoromethylphenyl)acetonitrile, converting a cyano group into a carboxy group through alkali to obtain 2-(3,5-bistrifluoromethylphenyl)acetic acid, and making 2-(3,5-bistrifluoromethylphenyl)acetic acid react with a methylating agent to obtain a target product. The method is easy to operate, free of side reaction and high in yield, and raw materials are low in price, easy to obtain and easy to synthesize.

Pyrrolidine-carboxamides and oxadiazoles as potent hNK1 antagonists

The preparation and structure-activity-relationships of novel pyrrolidine-carboxamides and oxadiazoles are described. Compounds in this series were found to be potent hNK1 antagonists in vitro and efficacious in vivo with minimal interactions with P450 liver enzymes. Oxadiazole analog 22 was determined to have excellent hNK1 binding affinity, functional activity, and a good PD response in vivo.

Efficient synthesis of novel NK1 receptor antagonists: Selective 1,4-addition of Grignard reagents to 6-chloronicotinic acid derivatives

A new efficient synthesis of two novel classes of NK1 receptor antagonists, among them befetupitant and netupitant, starting from 6-chloronicotinic acid is described. The introduction of the o-tolyl substituent at C(4) of the pyridine ring was achieved by a one-pot selective 1,4-Grignard addition/oxidation sequence to 6-chloronicotinic acid or a derivative of it. The scope of this addition/oxidation sequence was examined. It was also shown that the carboxylic function can be converted to a methyl amino group by a Hofmann rearrangement followed by reduction. Furthermore, a new high-yielding synthesis of 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionic acid based on the carbonylation of the tertiary alcohol obtained by Grignard addition of 3,5-bis(trifluoromethyl)bromobenzene to acetone was established.