57061-71-9

Basic information

• Product Name: 1-(2-CHLOROETHYL)-4-[3-(TRIFLUOROMETHYL)PHENYL]PIPERAZINE DIHYDROCHLORIDE
• Synonyms: Piperazine,1-(2-chloroethyl)-4-[3-(trifluoromethyl)phenyl]- dihydrochloride;1-(2-CHLORO-ETHYL)-4-(3-TRIFLUOROMETHYL-PHENYL)-PIPERAZINE(WXG02663)
• CAS NO: 57061-71-9
• Molecular Formula: C₁₃H₁₆ClF₃N₂
• Molecular Weight: 292.73
• EINECS: 1533716-785-6
• Mol File: 57061-71-9.mol
• Article Data: 16

Chemical Properties

• Boiling Point: 352.6 °C at 760 mmHg
• Flash Point: 167.1 °C
• Appearance: /
• Density: 1.244 g/cm³
• CAS DataBase Reference: 1-(2-CHLOROETHYL)-4-[3-(TRIFLUOROMETHYL)PHENYL]PIPERAZINE DIHYDROCHLORIDE(CAS DataBase Reference)
• NIST Chemistry Reference: 1-(2-CHLOROETHYL)-4-[3-(TRIFLUOROMETHYL)PHENYL]PIPERAZINE DIHYDROCHLORIDE(57061-71-9)
• EPA Substance Registry System: 1-(2-CHLOROETHYL)-4-[3-(TRIFLUOROMETHYL)PHENYL]PIPERAZINE DIHYDROCHLORIDE(57061-71-9)

Safety Data

• Hazardous Substances Data: 57061-71-9(Hazardous Substances Data)

Usage

General Description

1-(2-chloroethyl)-4-[3-(trifluoromethyl)phenyl]piperazine dihydrochloride is a compound with the chemical formula C12H18Cl3F3N2. It is a dihydrochloride salt of a piperazine derivative that contains a chloroethyl group and a trifluoromethylphenyl group. 1-(2-CHLOROETHYL)-4-[3-(TRIFLUOROMETHYL)PHENYL]PIPERAZINE DIHYDROCHLORIDE has potential pharmaceutical applications and is used in the synthesis of potential anti-cancer and anti-tumor agents. It is also used as a research chemical in the study of neurotransmitters and related receptors. Additionally, it has been investigated for its potential use as an anti-inflammatory and analgesic agent.

Synthetic route

N-2-hydroxyethyl-N'-(3-trifluoromethylphenyl)-piperazine (40004-29-3) → 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9)

Conditions	Yield
With thionyl chloride In dichloromethane for 2h; Reagent/catalyst; Solvent; Cooling with ice; Reflux;	96%
With thionyl chloride In 1,2-dichloro-ethane at 20 - 80℃; for 4h; Temperature; Large scale;	88%

1-Bromo-2-chloroethane (107-04-0) + 1-(3-Trifluoromethylphenyl)piperazine (15532-75-9) → 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9)

Conditions	Yield
With sodium hydroxide In acetone at 20℃; for 48h;	79%
With sodium carbonate In N,N-dimethyl-formamide for 22h; Ambient temperature;
Stage #1: 1-(3-Trifluoromethylphenyl)piperazine With sodium hydroxide In dimethyl sulfoxide for 0.166667h; Stage #2: 1-Bromo-2-chloroethane In dimethyl sulfoxide for 24h;

2-chloro-1-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethanone → 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 40℃; for 0.5h;	60%

3-trifluoromethylaniline (98-16-8) + tris-(2-chloroethyl)amine hydrochloride (817-09-4) → 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9)

Conditions	Yield
With potassium carbonate In butan-1-ol at 115 - 120℃; for 22h; Time;	52.8%

tris-(2-chloro-ethyl)-amine (555-77-1) + 3-trifluoromethylaniline (98-16-8) → 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9)

Conditions	Yield
With potassium carbonate In butan-1-ol at 115 - 120℃; for 24h;	45.9%

1-Bromo-2-chloroethane (107-04-0) + 1-(3-Trifluoromethylphenyl)piperazine (15532-75-9) → 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) + 4,4'-bis-(3-trifluoromethyl-phenyl)-1,1'-ethane-1,2-diyl-bis-piperazine (51299-16-2)

Conditions	Yield
In toluene for 6h; Alkylation; Heating;

1-Bromo-2-chloroethane (107-04-0) + 1-[3-(trifluoromethyl)phenyl]piperazine hydrochloride → 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9)

Conditions	Yield
With triethylamine In hexane; dichloromethane
With triethylamine In hexane; dichloromethane
With triethylamine In dichloromethane for 9h; Heating / reflux;
With triethylamine In hexane; dichloromethane

1-[3-(trifluoromethyl)phenyl]piperazine hydrochloride → 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / acetone / 4 h / 20 - 60 °C / Large scale 2: thionyl chloride / 1,2-dichloro-ethane / 4 h / 20 - 80 °C / Large scale View Scheme

4H-pyrido[3,2-b][1,4]oxazin-3-one (20348-09-8) + 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → 4-{2-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one

Conditions	Yield
With sodium ethanolate In N,N-dimethyl-formamide for 2h; Heating;	92%

1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one (52099-72-6) + 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → BIMT 17 hydrochloride (147359-76-0)

Conditions	Yield
Stage #1: 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one; 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane With potassium carbonate In dimethyl sulfoxide at 58℃; for 8h; Large scale; Stage #2: With hydrogenchloride In ethanol; water at 65℃; for 2h; Temperature; Large scale;	77%

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) + C9H6NO3(1-)*Na(1+) → 6-Acetyl-3-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-3H-benzooxazol-2-one (81522-22-7)

Conditions	Yield
In N,N-dimethyl-formamide for 1h; Heating;	70%

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → 1-(2-azidoethyl)-4-(3-trifluoromethylphenyl)piperazine (670234-48-7)

Conditions	Yield
With sodium azide In N,N-dimethyl-formamide at 60℃; for 16h;	67.3%
With sodium azide In N,N-dimethyl-formamide at 50℃; for 10h;

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) + C10H8NO3(1-)*Na(1+) → 6-Propionyl-3-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-3H-benzooxazol-2-one (81514-00-3)

Conditions	Yield
In N,N-dimethyl-formamide for 1h; Heating;	62%

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) + C14H7ClNO3(1-)*Na(1+) → 6-(2-Chloro-benzoyl)-3-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-3H-benzooxazol-2-one (81533-87-1)

Conditions	Yield
In N,N-dimethyl-formamide for 1h; Heating;	61%

2-ethoxy-1H-benzo[d]imidazole (22219-23-4) + 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → flibanserin

Conditions	Yield
Stage #1: 2-ethoxy-1H-benzo[d]imidazole; 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane With sodium hydroxide In water; isopropyl alcohol at 75℃; for 2h; Stage #2: With hydrogenchloride; isopropyl chloride at 4 - 70℃; for 2h; Temperature;	56.2%

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) + 3-hydroxy-3,4-dihydrobenzotriazine-4-one (28230-32-2) → 3-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethoxy}-3H-benzo[d][1,2,3]triazin-4-one

Conditions	Yield
With sodium hydroxide In ethanol for 24h; Substitution; Heating;	40%

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → 3-<2-<4-<3-(trifluoromethyl)phenyl>-1-piperazinyl>ethyl>oxazolo<4,5-b>pyridin-2(3H)-one

Conditions	Yield
	40%

3H-benzooxazol-2-one; sodium salt (42142-71-2) + 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → 3-{2-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-3H-benzooxazol-2-one (81513-96-4)

Conditions	Yield
In N,N-dimethyl-formamide for 1h; Heating;	38%

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) + C14H8NO3(1-)*Na(1+) → 6-Benzoyl-3-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-3H-benzooxazol-2-one (81513-99-7)

Conditions	Yield
In N,N-dimethyl-formamide for 1h; Heating;	37%

2,3-dihydro[1,3]oxazolo[4,5-b]pyridin-2-one (60832-72-6) + 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → 3-<2-<4-<3-(trifluoromethyl)phenyl>-1-piperazinyl>ethyl>oxazolo<4,5-b>pyridin-2(3H)-one

Conditions	Yield
With sodium ethanolate 1.) EtOH, RT, 1 h, 2.) DMF, reflux, 1.5 h; Yield given. Multistep reaction;

(E)-5-Benzylidene-6-methyl-(4H)-pyridazin-3-on (26717-37-3) + 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → 6-Methyl-5-[1-phenyl-meth-(E)-ylidene]-2-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-4,5-dihydro-2H-pyridazin-3-one

Conditions	Yield
With sodium ethanolate 1.) ethanol, reflux, 1 h, 2.) DMF, reflux, 10 h; Yield given. Multistep reaction;

5-(4-Methylbenzylidene)-6-methyl-(4H)-pyridazin-3-on (132372-50-0) + 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → 6-Methyl-5-[1-p-tolyl-meth-(E)-ylidene]-2-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-4,5-dihydro-2H-pyridazin-3-one

Conditions	Yield
With sodium ethanolate 1.) ethanol, reflux, 1 h, 2.) DMF, reflux, 10 h; Yield given. Multistep reaction;

5-(4-Fluorobenzylidene)-6-methyl-(4H)-pyridazin-3-on (132372-49-7) + 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → 5-[1-(4-Fluoro-phenyl)-meth-(E)-ylidene]-6-methyl-2-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-4,5-dihydro-2H-pyridazin-3-one

Conditions	Yield
With sodium ethanolate 1.) ethanol, reflux, 1 h, 2.) DMF, reflux, 10 h; Yield given. Multistep reaction;

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → 2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethan-1-amine (27144-85-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 67.3 percent / NaN3 / dimethylformamide / 16 h / 60 °C 2: 83.6 percent / PPh3 / tetrahydrofuran; H2O / 2 h / 20 °C View Scheme

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → 2-nitro-3-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethylamino}phenol (670234-43-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 67.3 percent / NaN3 / dimethylformamide / 16 h / 60 °C 2.1: 83.6 percent / PPh3 / tetrahydrofuran; H2O / 2 h / 20 °C 3.1: K2CO3 / dimethylformamide / 2 h / 50 °C 3.2: 79 percent / 2-(methylsulfonyl)ethanol; NaH / dimethylformamide / 0.5 h / 20 °C View Scheme

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → 3,4,5-trihydroxy-6-(2-oxo-1-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-2,3-dihydro-1H-benzoimidazol-4-yloxy)-tetrahydropyran-2-carboxylic acid

Conditions

Yield

Multi-step reaction with 7 steps 1.1: 67.3 percent / NaN3 / dimethylformamide / 16 h / 60 °C 2.1: 83.6 percent / PPh3 / tetrahydrofuran; H2O / 2 h / 20 °C 3.1: K2CO3 / dimethylformamide / 2 h / 50 °C 3.2: 79 percent / 2-(methylsulfonyl)ethanol; NaH / dimethylformamide / 0.5 h / 20 °C 4.1: 80 percent / 1,1,4,7,10,10-Hexamethyltriethylenetetramine; Ag2CO3 / acetonitrile / 0.5 h / 20 °C 5.1: H2 / Pd/C / tetrahydrofuran / 30 h / 20 °C / 3375.27 Torr 6.1: 5.1 g / tetrahydrofuran / 48 h 7.1: 42 percent / aq. LiOH / tetrahydrofuran / 168 h / 20 °C View Scheme

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → (2S,3S,4S,5R,6S)-6-(2-Amino-3-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethylamino}-phenoxy)-3,4,5-tris-(2,2-dimethyl-propionyloxy)-tetrahydro-pyran-2-carboxylic acid methyl ester

Conditions

Yield

Multi-step reaction with 5 steps 1.1: 67.3 percent / NaN3 / dimethylformamide / 16 h / 60 °C 2.1: 83.6 percent / PPh3 / tetrahydrofuran; H2O / 2 h / 20 °C 3.1: K2CO3 / dimethylformamide / 2 h / 50 °C 3.2: 79 percent / 2-(methylsulfonyl)ethanol; NaH / dimethylformamide / 0.5 h / 20 °C 4.1: 80 percent / 1,1,4,7,10,10-Hexamethyltriethylenetetramine; Ag2CO3 / acetonitrile / 0.5 h / 20 °C 5.1: H2 / Pd/C / tetrahydrofuran / 30 h / 20 °C / 3375.27 Torr View Scheme

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → methyl 3-[[2-[4-(3-methylphenyl)piperazin-1-yl]ethyl]amino]-2-nitrophenyl-2,3,4-tris-O-(2,2-dimethylpropanoyl)-β-D-glucopyranosiduronate (670234-44-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 67.3 percent / NaN3 / dimethylformamide / 16 h / 60 °C 2.1: 83.6 percent / PPh3 / tetrahydrofuran; H2O / 2 h / 20 °C 3.1: K2CO3 / dimethylformamide / 2 h / 50 °C 3.2: 79 percent / 2-(methylsulfonyl)ethanol; NaH / dimethylformamide / 0.5 h / 20 °C 4.1: 80 percent / 1,1,4,7,10,10-Hexamethyltriethylenetetramine; Ag2CO3 / acetonitrile / 0.5 h / 20 °C View Scheme

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → (2S,3S,4S,5R,6S)-3,4,5-Tris-(2,2-dimethyl-propionyloxy)-6-(2-oxo-1-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-2,3-dihydro-1H-benzoimidazol-4-yloxy)-tetrahydro-pyran-2-carboxylic acid methyl ester (670234-49-8)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: 67.3 percent / NaN3 / dimethylformamide / 16 h / 60 °C 2.1: 83.6 percent / PPh3 / tetrahydrofuran; H2O / 2 h / 20 °C 3.1: K2CO3 / dimethylformamide / 2 h / 50 °C 3.2: 79 percent / 2-(methylsulfonyl)ethanol; NaH / dimethylformamide / 0.5 h / 20 °C 4.1: 80 percent / 1,1,4,7,10,10-Hexamethyltriethylenetetramine; Ag2CO3 / acetonitrile / 0.5 h / 20 °C 5.1: H2 / Pd/C / tetrahydrofuran / 30 h / 20 °C / 3375.27 Torr 6.1: 5.1 g / tetrahydrofuran / 48 h View Scheme

1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) + 4-hydroxy-2-mercaptopyrimidine (141-90-2) → C17H19F3N4OS

N,N-dimethylformamide(DMF) + 1,5,6,7-tetrahydro-indol-4-one (13754-86-4) + 1-chloro-2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethane (57061-71-9) → 1-{2-[4-(3-trifluoromethylphenyl)piperazine-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one (496921-68-7)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane; methanol; hexane; dichloromethane; N,N-dimethyl-formamide
With hydrogenchloride In 1,4-dioxane; methanol; hexane; dichloromethane; N,N-dimethyl-formamide

Upstream product

• 40004-29-3 N-2-hydroxyethyl-N'-(3-trifluoromethylphenyl)-piperazine 
• 98-16-8 3-trifluoromethylaniline 
• 817-09-4 tris-(2-chloroethyl)amine hydrochloride 
• 76835-14-8 1-[3-(trifluoromethyl)phenyl]piperazine hydrochloride 
• 555-77-1 tris-(2-chloro-ethyl)-amine 
• 107-04-0 1-Bromo-2-chloroethane 
• 15532-75-9 1-(3-Trifluoromethylphenyl)piperazine 

Downstream Products

• 115762-37-3 1-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethylmercapto]-4-methyl-s-triazolo(4,3-a)quinoline 
• 115762-31-7 1-[2-(4-(3-Trifluoromethylphenyl)piperazin-1-yl)ethylmercapto]-s-triazolo(4,3-a)quinoline 
• 1092766-52-3 2-{2-[2-(3-methoxyphenyl)ethyl]phenoxy}ethyl-4-(3'-trifluoromethylphenyl)piperazine 
• 167933-07-5 flibanserin 
• 147359-76-0 BIMT 17 hydrochloride 
• 1334582-08-9 C₂₁H₂₂F₃N₅ 
• 1334582-18-1 C₂₁H₂₂F₃N₅ 
• 1372157-41-9 1-[2-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-ylsulfanyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine 
• 1372157-40-8 1-{2-[(1-methyl-1H-imidazol-2-yl)thio]ethyl}-4-[3-(trifluoromethyl)phenyl]piperazine 
• 496921-68-7 1-{2-[4-(3-trifluoromethylphenyl)piperazine-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one 
• 670234-49-8 (2S,3S,4S,5R,6S)-3,4,5-Tris-(2,2-dimethyl-propionyloxy)-6-(2-oxo-1-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-2,3-dihydro-1H-benzoimidazol-4-yloxy)-tetrahydro-pyran-2-carboxylic acid methyl ester 
• 670234-44-3 methyl 3-[[2-[4-(3-methylphenyl)piperazin-1-yl]ethyl]amino]-2-nitrophenyl-2,3,4-tris-O-(2,2-dimethylpropanoyl)-β-D-glucopyranosiduronate 

Relevant articles and documents

Preparation method of flibaserin hydrochloride

The invention relates to the technical field of synthesis of medical intermediates, particularly to a preparation method of flibaserin hydrochloride. According to the preparation method, o-phenylenediamine and 3-trifluoromethylphenylpyrazine are used as raw materials; o-phenylenediamine reacts with ethyl acetoacetate to obtain a compound 10-1-G; the 3-trifluoromethylphenylpyrazine compound I is subjected to a two-step substitution reaction to obtain a compound 10-1-B; and the compound 10-1-B and the compound 10-1-G are subjected to a substitution reaction to obtain a final product compound flibaserin hydrochloride. The invention aims to reduce the cost, optimize the process and facilitate industrial production. The method is simple and convenient to operate, reasonable in reaction process,low in production cost, good in product quality, free of environmental pollution and suitable for industrial production, wherein the content of the product is higher than 99.5%.

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Preparation method of flibaserin intermediate

The invention discloses a method belonging to the field of heterocyclic compounds, and concretely relates to a preparation method of a flibaserin intermediate. The preparation method comprises the following steps of (1) dissolving 1-(3-trifluoromethylphenyl) piperazine hydrochloride in a solvent a, and reacting with 2-halogenated ethanol or ethylene oxide in the presence of alkali to obtain 2-(4-(3-trifluoromethylphenyl) piperazine-1-ethanol; (2) reacting the 2-(4-(3-trifluoromethylphenyl) piperazine-1-ethanol with a chloride agent compound to obtain a compound as shown in a formula I. According to the preparation method, the reaction selectivity is improved, the generation of impurities is reduced, the product purity is improved, and the preparation method is simple and convenient to operate, environmentally-friendly, and beneficial for industrialized mass production.