13349-82-1

Basic information

• Product Name: 1-Hydroxyethylethoxypiperazine
• Synonyms: 1-piperazidine;1-Hydroxyethylethoxypiperazine, 95% 5ML;Ethanol, 2-[2-(1-piperazinyl)ethoxy]-;Quetiapine IMpurity (1-[2-(2-Hydroxyethoxy)ethyl]piperazine);Quetiapine HEEP IMpurity;1-[2-(2-Hydroxyethoxy)ethyl]piperazine,95%;Anti-EPHB6, C-Terminal antibody produced in rabbit;EPB6
• CAS NO: 13349-82-1
• Molecular Formula: C₈H₁₈N₂O₂
• Molecular Weight: 174.24
• EINECS: 1533716-785-6
• Product Categories: Building Blocks;C4 to C8;Chemical Synthesis;Heterocyclic Building Blocks;Piperazines;PIPERIDINE;Piperidines, Piperidones, Piperazines;Piperazine derivates;API intermediates;(intermediate of quadipine);(intermediate of quetiapine fumarate);Miscellaneous Reagents;Intermediates of Quetiapine
• Mol File: 13349-82-1.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 112-114 °C0.25 mm Hg(lit.)
• Flash Point: >230 °F
• Appearance: Clear colorless to yellow-brownish/Liquid
• Density: 1.061 g/mL at 25 °C(lit.)
• Vapor Pressure: 7.57E-05mmHg at 25°C
• Refractive Index: n20/D 1.497(lit.)
• Storage Temp.: -20°C
• Solubility: Acetone (Slightly), Chloroform (Slightly), Methanol (Slightly)
• PKA: 14.41±0.10(Predicted)
• CAS DataBase Reference: 1-Hydroxyethylethoxypiperazine(CAS DataBase Reference)
• NIST Chemistry Reference: 1-Hydroxyethylethoxypiperazine(13349-82-1)
• EPA Substance Registry System: 1-Hydroxyethylethoxypiperazine(13349-82-1)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-37/39
• WGK Germany: 3
• HazardClass: IRRITANT
• Hazardous Substances Data: 13349-82-1(Hazardous Substances Data)

Usage

Description

1-Hydroxyethylethoxypiperazine is an organic compound that serves as an intermediate in the synthesis of various pharmaceuticals and chemicals. It is characterized by its yellow-brown oily appearance and is known for its potential applications in chemical synthesis and as a quetiapine intermediate.

Uses

Used in Chemical Synthesis:
1-Hydroxyethylethoxypiperazine is used as a chemical intermediate for the synthesis of various compounds, contributing to the development of new pharmaceuticals and chemicals.
Used in Pharmaceutical Industry:
1-Hydroxyethylethoxypiperazine is used as a quetiapine intermediate, playing a crucial role in the production of quetiapine, a medication used to treat various mental health disorders such as schizophrenia, bipolar disorder, and major depressive disorder.

InChI:InChI=1/C8H18N2O2/c11-6-8-12-7-5-10-3-1-9-2-4-10/h9,11H,1-8H2/p+2

Synthetic route

piperazine (110-85-0) + 2-(2-Chloroethoxy)ethanol (628-89-7) → 1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1)

Conditions	Yield
With piperazine dihydrochloride In ethanol for 10h; Reflux; Large scale;	95.1%
at 120 - 140℃; for 1h;	70%

tert-butyl 4-(2-(2-hydroxyethoxy)ethyl)piperazine-1-carboxylate (166388-52-9) → 1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1)

Conditions	Yield
With trifluoroacetic acid In dichloromethane at 20℃; for 2h;	95%
With trifluoroacetic acid In dichloromethane at 20℃; for 1h;	80%

C17H34N4O4S → 1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1)

Conditions	Yield
With dipotassium peroxodisulfate at 30 - 60℃; for 6h; Reagent/catalyst;	80.5%

4-ethoxycarbonylpiperazine (120-43-4) + 2-(2-Chloroethoxy)ethanol (628-89-7) → 1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1)

Conditions	Yield
With potassium hydroxide; ethanol

Quetiapine (111974-69-7) → 1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + 2-[2-(4,5-dihydro-1H-imidazol-1-yl)ethoxy]ethanol + 2-[2-(1-oxidopiperazin-1-yl)ethoxy]ethanol (1216996-50-7) + dibenzo[b,f]-1,4-thiazepine (257-15-8) + Quetiapine sulfoxide

Conditions	Yield
In methanol at 25℃; for 6h; Kinetics; UV-irradiation;

2,2'-iminobis[ethanol] (111-42-2) + 2-(2-Aminoethoxy)ethanol (929-06-6) → 1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1)

Conditions	Yield
With hydrogen at 180℃; under 150015 Torr; for 15h;
With hydrogen at 180℃; under 750.075 - 150015 Torr; Time;
With hydrogen at 180℃; under 150015 Torr; for 15h;

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + (2′Z-3′E)-6-bromoindirubin-3′-[O-(2-bromoethyl)oxime] (1067884-35-8) → (2'Z-3'E)-6-bromoindirubin-3'-[O-(2-{4-[2-(2-hydroxyethoxy)-ethyl]piperazin-1-yl}ethyl)oxime] (1067884-49-4)

Conditions	Yield
In N,N-dimethyl-formamide at 50℃;	100%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + acrylonitrile (107-13-1) → 3-{4-[2-(2-hydroxy-ethoxy)ethyl]-piperazin-1-yl}-propionitrile (1278584-73-8)

Conditions	Yield
at 20℃; for 72h; Michael addition;	100%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + 11-chloro-dibenzo[b,f][1,4]thiazepine (13745-86-3) → Quetiapine (111974-69-7)

Conditions	Yield
In toluene at 105 - 107℃;	99%
In toluene at 110 - 120℃; for 8h; Product distribution / selectivity;	98%
In toluene Reflux;	92%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + (S)-N-[(3-bromo-propyl)(oxido)phenyl-λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide (1027727-66-7) → (S)-N-[(3-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}propyl)(oxido)phenyl-λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide (1027727-68-9)

Conditions	Yield
In N,N-dimethyl-formamide at 80℃; for 0.5h;	96%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + 11-chlorodibenzo[b,f][1,4]thiazepin-11-one + (2E)-but-2-enedioic acid (110-17-8) → 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine hemifumarate salt

Conditions	Yield
Stage #1: 1-[2-(2-hydroxyethoxy)ethyl]piperazine; 11-chlorodibenzo[b,f][1,4]thiazepin-11-one With potassium carbonate In toluene for 5h; Reflux; Large scale; Stage #2: (2E)-but-2-enedioic acid In ethanol for 1.5h; Reflux; Large scale;	95.3%

2,2-dimethylthiirane (3772-13-2) + 1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) → 2-(2-{4-[2-Methyl-2-sulfanylpropyl]piperazinyl}ethoxy)ethan-1-ol

Conditions	Yield
at 80℃; for 4h;	93%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + di-tert-butyl dicarbonate (24424-99-5) → tert-butyl 4-(2-(2-hydroxyethoxy)ethyl)piperazine-1-carboxylate (166388-52-9)

Conditions	Yield
In dichloromethane at 0 - 20℃; for 12h;	92%
In dichloromethane at 0 - 20℃;	92%
With sodium hydrogencarbonate In dichloromethane at 0 - 20℃; for 12h;	92%
In dichloromethane at 20℃;
With triethylamine In dichloromethane at 20℃; for 12h;

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + 2-(4-chloro-3-nitrophenyl)-3-hydroxyquinoline-4(1H)-one (1011306-89-0) → 3-hydroxy-2-(4-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-3-nitrophenyl)quinolin-4(1H)-one

Conditions	Yield
With 1-methyl-pyrrolidin-2-one at 110℃; for 2h;	91%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (835616-61-0) → 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)isoindoline-1,3-dione

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; for 3h;	89.8%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + 2‑(2‑nitrophenylsulfanyl)benzoic acid (19806-43-0) → 2-nitro-2'-[4-[2-(2-hydroxyethoxy)ethyl]-piperazinylcarbonyl]diphenylsulfide (849790-30-3)

Conditions	Yield
Stage #1: 2‑(2‑nitrophenylsulfanyl)benzoic acid With thionyl chloride In dichloromethane at 40℃; Stage #2: 1-[2-(2-hydroxyethoxy)ethyl]piperazine With triethylamine In dichloromethane at 0 - 5℃;	89.7%
Stage #1: 2‑(2‑nitrophenylsulfanyl)benzoic acid With 4-methyl-morpholine; triethylamine In dichloromethane at 20℃; for 0.25h; Stage #2: 1-[2-(2-hydroxyethoxy)ethyl]piperazine With pivaloyl chloride In dichloromethane

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + carbon disulfide (75-15-0) + t-butyl bromide (507-19-7) → 4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazine-1-carbodithioic acid tert-butyl ester

Conditions	Yield
With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h;	89%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + (3E)-6-fluoro-3-[4-(2-fluoropyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one → (3E)-6-fluoro-3-[4-(2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}pyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one

Conditions	Yield
In dimethyl sulfoxide at 105℃; for 6h;	89%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + 6,7-difluoro-3-hydroxy-2-phenylquinolin-4(1H)-one → 7-fluoro-3-hydroxy-6-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)2-phenylquinolin-4(1H)-one

Conditions	Yield
In 1-methyl-pyrrolidin-2-one for 3h; Reflux;	89%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) → 2-(2-(4-(pyrazin-2-yl)piperazin-1-yl)ethoxy)ethan-1-ol

Conditions	Yield
With iodine; sodium acetate In acetonitrile at 70℃;	88%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + 13-cyclohexyl-10-[[((dimethylamino)sulfonyl)amino]carbonyl]-3-methoxy-7H-indolo[2,1a][2]benzazepine-6-carboxylic acid (902148-42-9) → 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxamide

Conditions	Yield
With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h;	87%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + C66H84Cl8N34 → C98H152Cl4N42O8

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; dichloromethane at -20 - 20℃;	85%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + N-hydroxyethyl-4-bromine-1,8-naphthalimide (52559-37-2) → N-(2-hydroxyethyl)-4-(4-[2-(2-hydroxyethoxy)ethyl]-piperazine-1-yl)-1,8-naphthalimide

Conditions	Yield
In 2-methoxy-ethanol at 130℃; for 1h; Microwave irradiation; Inert atmosphere;	85%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + 6-bromo-2-(2-methoxyethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (651768-37-5) → N-(2-methoxyethyl)-4-(4-[2-(2-Hydroxyethoxy)ethyl]-piperazine-1-yl)-1,8-naphthalimide

Conditions	Yield
In 2-methoxy-ethanol at 130℃; for 1h; Microwave irradiation; Inert atmosphere;	85%

2-iodopyridine (5029-67-4) + 1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) → C13H21O2N3 + 1-(2-(2-(pyridin-2-yloxy)ethoxy)ethyl)piperazine

Conditions	Yield
With 2-(2-methyl-1-oxopropyl)cyclohexanone; caesium carbonate; copper(l) iodide In N,N-dimethyl-formamide at 20℃; for 16h;	A 83% B n/a

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + dibenzo[b,f][1,4]thiazepin-11-ylamine hydrochloride (1176987-11-3) + (2E)-but-2-enedioic acid (110-17-8) → quetiapine fumarate (111974-72-2)

Conditions	Yield
Stage #1: 1-[2-(2-hydroxyethoxy)ethyl]piperazine; dibenzo[b,f][1,4]thiazepin-11-ylamine hydrochloride at 172 - 176℃; for 5h; Stage #2: In water at 20 - 65℃; Stage #3: (2E)-but-2-enedioic acid In isopropyl alcohol at 4 - 20℃; Product distribution / selectivity;	83%
Stage #1: 1-[2-(2-hydroxyethoxy)ethyl]piperazine; dibenzo[b,f][1,4]thiazepin-11-ylamine hydrochloride at 173 - 175℃; for 5h; Stage #2: With potassium carbonate In water at 20 - 75℃; Stage #3: (2E)-but-2-enedioic acid In isopropyl alcohol at 4 - 20℃; Product distribution / selectivity;	79%

2-iodopyridine (5029-67-4) + 1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) → 1-(2-(2-(pyridin-2-yloxy)ethoxy)ethyl)piperazine

Conditions	Yield
With 3,4,7,8-Tetramethyl-o-phenanthrolin; 3 A molecular sieve; caesium carbonate; copper(l) iodide at 90℃; for 20h;	82%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + 5-chloro-2-bromomethyl-9H-xanthen-9-one (76967-95-8) → 5-chloro-2-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)methyl)-9H-xanthen-9-one dihydrochloride

Conditions	Yield
Stage #1: 1-[2-(2-hydroxyethoxy)ethyl]piperazine; 5-chloro-2-bromomethyl-9H-xanthen-9-one With potassium carbonate In toluene at 110℃; for 72h; Stage #2: With hydrogenchloride In ethanol; water	82%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + benzyl(bromo)zinc (62673-31-8) + benzaldehyde (100-52-7) → 2-(2-(4-(1,2-diphenylethyl)piperazin-1-yl)ethoxy)ethanol

Conditions	Yield
In acetonitrile at 20℃; for 4h;	80%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + 1-(7-chloroquinolin-4-yl)-3-(3-nitrophenyl)thiourea → 1-(7-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)quinolin-4-yl)-3-(3-nitrophenyl)thiourea

Conditions	Yield
With copper In water at 100℃; Sealed tube;	79%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + N-[(3-bromopropyl)(methyl)oxido-λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide → N-[(3-{4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-yl}propyl)(methyl)oxido-λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

Conditions	Yield
In N,N-dimethyl-formamide at 60℃; for 0.666667h;	78%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + 5-bromo-2-furancarboxaldehyde (1899-24-7) + N-phenyl-maleimide (941-69-5) → C18H25N3O4 (355003-04-2) + C23H25N3O5 (1017832-31-3)

Conditions	Yield
Stage #1: 1-[2-(2-hydroxyethoxy)ethyl]piperazine; 5-bromo-2-furancarboxaldehyde With triethylamine In 1,4-dioxane; water for 4h; Heating; Stage #2: N-phenyl-maleimide With magnesium sulfate In 1,4-dioxane; water for 18h; Diels-Alder reaction; Heating; Further stages.;	A n/a B 77%

1-[2-(2-hydroxyethoxy)ethyl]piperazine (13349-82-1) + bromoacetic acid tert-butyl ester (5292-43-3) → tert-butyl 2-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)acetate

Conditions	Yield
With triethanolamine In tetrahydrofuran; N,N-dimethyl-formamide at 50℃; for 16h;	77%

Upstream product

• 120-43-4 4-ethoxycarbonylpiperazine 
• 628-89-7 2-(2-Chloroethoxy)ethanol 
• 111974-69-7 Quetiapine 
• 111-42-2 2,2'-iminobis[ethanol] 
• 929-06-6 2-(2-Aminoethoxy)ethanol 
• 110-85-0 piperazine 
• 166388-52-9 tert-butyl 4-(2-(2-hydroxyethoxy)ethyl)piperazine-1-carboxylate 

Downstream Products

• 103858-30-6 2-{2-[4-(4-methoxy-benzhydryl)-piperazino]-ethoxy}-ethanol 
• 111974-69-7 Quetiapine 
• 329217-58-5 2-{2-[4-(7-benzyloxy-dibenzo[b,f][1,4]thiazepin-11-yl)-piperazin-1-yl]-ethoxy}-ethanol 
• 329217-60-9 2-{2-[4-(8-benzyloxy-dibenzo[b,f][1,4]thiazepin-11-yl)-piperazin-1-yl]-ethoxy}-ethanol 
• 848814-26-6 {4-[2-(2-hydroxy-ethoxy)ethyl]-piperazin-1-yl}-(2-iodophenyl)-methanone 
• 848786-52-7 4-[2-(2-hydroxyethoxy)-ethyl]-piperazine-carboxylic acid (2-phenylsulfanyl-phenyl)-amide 
• 549510-48-7 4-(2-(2-Hydroxyethoxy)ethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester 
• 549510-71-6 4-[2-(2-Hydroxyethoxy)ethyl]piperazine-1-carboxylic acid 4-(4-trifluoromethylphenoxy)phenyl ester 
• 67-63-0 isopropyl alcohol 
• 111974-72-2 quetiapine fumarate 
• 917021-52-4 C₃₉H₆₄N₈O₆ 

Relevant articles and documents

Base-Mediated 1,6-Aza-Michael Addition of Heterocyclic Amines and Amides to para-Quinone Methides Leading to Meclizine-, Hydroxyzine-and Cetirizine-like Architectures

An expeditious, cost-effective synthetic methodology for a wide range of nitrogen-containing unsymmetrical trisubstituted methanes (TRSMs) is reported. The synthesis involves base-mediated 1,6-conjugate addition of heterocyclic amines and amides to substituted para-quinone methides, giving the unsymmetrical TRSMs in moderate to very good yields (up to 83percent) in one pot. The low cost, mild temperature, high atom economy and yields, easy scale-up and broad substrate scope are some of the salient features of this protocol. Further, the methodology could be extended for the synthesis of meclizine-, -hydroxyzine-and cetirizine-like molecules. The structure of one such compound, 2,6-di-tert-butyl-4-((4-chlorophenyl)(4-methylpiperazin-1-yl)methyl)phenol, was determined by single crystal X-ray analysis.

New method for preparing quetiapine

The invention provides an efficient and concise method for preparing highly-pure 1-[2-(2-hydroxyethoxy)ethyl]piperazine hydrochloride, and a method for preparing quetiapine through directly reacting 11-chloro-dibenzo[b,f][(1,4)]thiazepine with 1-[2-(2-hydroxyethoxy)ethyl]piperazine hydrochloride which substitutes the free alkali form. A low-temperature recrystallization technology adopted to purify the 1-[2-(2-hydroxyethoxy)ethyl]piperazine hydrochloride avoids the residual of unknown tiny piperazine impurities in the product during high-temperature purification, so the highly-pure quetiapineis obtained in subsequent reactions.