130018-77-8

Basic information

• Product Name: Levocetirizine
• Synonyms: LEVOCETIRIZINE;alerlisin;LEVOCETRIZINE;(R)-2-[2-[4-(4-chlorophenyl)-phenylmethyl]-phenylmethyl-1-]-piperazinyl-]ethoxyl﹞acetic acid dihydrochloride;LevocetirizineHydrochloride;2-[2-[4-[(4-Chlorophenyl)-phenyl-methyl]piperazin-1-yl]ethoxy]acetic acid;Cetirizine-d4;Levocetirizine-d4
• CAS NO: 130018-77-8
• Molecular Formula: C₂₁H₂₅ClN₂O₃
• Molecular Weight: 388.89
• EINECS: 1312995-182-4
• Product Categories: Aromatics;Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;XYZAL
• Mol File: 130018-77-8.mol
• Article Data: 14

Chemical Properties

• Melting Point: 205-208°C (dec.)
• Boiling Point: 542.1 °C at 760 mmHg
• Flash Point: 281.6 °C
• Appearance: white powder
• Density: 1.237 g/cm³
• Vapor Pressure: 1.39E-12mmHg at 25°C
• Storage Temp.: -20°C Freezer
• PKA: 3.46±0.10(Predicted)
• CAS DataBase Reference: Levocetirizine(CAS DataBase Reference)
• NIST Chemistry Reference: Levocetirizine(130018-77-8)
• EPA Substance Registry System: Levocetirizine(130018-77-8)

Safety Data

• Hazardous Substances Data: 130018-77-8(Hazardous Substances Data)

Usage

Description

Levocetirizine, also known as the (R)-enantiomer of the second-generation antihistamine cetirizine, is a nonsedating type histamine H1-receptor antagonist. It was first introduced in Germany for the treatment of seasonal allergic rhinitis (including ocular symptoms), perennial allergic rhinitis, and chronic idiopathic urticaria. Levocetirizine is a 2-fold more potent H1 antagonist than cetirizine, while the other enantiomer (distomer) is 10-fold less potent compared to levocetirizine. It is an off-white solid and is marketed under the brand name Xusal.

Uses

Used in Pharmaceutical Industry:
Levocetirizine is used as an H1 antihistamine and antiallergic agent for the treatment of allergic conditions such as seasonal allergic rhinitis, perennial allergic rhinitis, and chronic idiopathic urticaria. It provides relief from symptoms such as sneezing, itching, and runny nose associated with these conditions.
Used in Research and Analysis:
Levocetirizine is also used as an internal standard for the quantification of cetirizine by gas chromatography (GC) or liquid chromatography (LC) mass spectrometry. This helps in the accurate measurement and analysis of cetirizine levels in various samples.
Levocetirizine's high metabolic stability and lack of effect on the activities of major CYP isoenzymes make it less likely to cause interactions with other administered drugs. Additionally, it has no clinically relevant effect on electrocardiograms of healthy volunteers, ensuring its safety in usage.

Originator

Sepracor (US)

Metabolism

The extent of metabolism of levocetirizine in humans is less than 14% of the dose. Metabolic pathways include aromatic oxidation, N- and O- dealkylation and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. The major route of excretion of levocetirizine and metabolites is via urine. Excretion via faeces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.

InChI:InChI=1/C21H25ClN2O3.2ClH/c22-19-8-6-18(7-9-19)21(17-4-2-1-3-5-17)24-12-10-23(11-13-24)14-15-27-16-20(25)26;;/h1-9,21H,10-16H2,(H,25,26);2*1H/t21-;;/m1../s1

Synthetic route

C23H29ClN2O3 → levocetirizine (130018-77-8)

Conditions	Yield
With lithium hydroxide In tetrahydrofuran; methanol; water at 65℃; for 2h;	90%

(2-chloroethoxy)-acetic acid (14869-41-1) + (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → levocetirizine (130018-77-8)

Conditions	Yield
With tetrabutylammomium bromide; sodium hydride In N,N-dimethyl-formamide at 95℃; for 5h; Inert atmosphere;	86.5%

(R)-(2-{4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl}ethoxy)acetic acid methyl ester → levocetirizine (130018-77-8)

Conditions	Yield
With hydrogenchloride In water Large scale; enantioselective reaction;	74%
Stage #1: (R)-(2-{4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl}ethoxy)acetic acid methyl ester With water; potassium hydroxide In methanol at 80℃; for 1h; Stage #2: With hydrogenchloride In dichloromethane; water pH=4 - 4.5; Product distribution / selectivity;

levocetirizine N-benzyl amide (1150310-68-1) → levocetirizine (130018-77-8)

Conditions	Yield
Stage #1: levocetirizine N-benzyl amide With sulfuric acid In methanol for 16h; Reflux; Stage #2: With sodium hydroxide In methanol for 2h; pH=10 - 12; Stage #3: With hydrogenchloride In methanol; water pH=4.5;	70%
Stage #1: levocetirizine N-benzyl amide With sulfuric acid; water at 80 - 85℃; for 8h; Stage #2: With sodium hydroxide In water pH=4.0 - 4.5;	n/a

(R)-2-(2-{4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl}ethoxy)acetamide (909779-33-5) → levocetirizine (130018-77-8)

Conditions	Yield
With hydrogenchloride In water at 65℃; for 4h;
Multi-step reaction with 2 steps 1.1: hydrogenchloride / methanol / 4 h / Reflux 1.2: 7 h 2.1: hydrogenchloride / water / Large scale View Scheme

(+)-[2-[4-[(4-chlorophenyl)-phenyl methyl]-1-piperazinyl]]ethanol (705289-61-8) + sodium monochloroacetic acid (3926-62-3) → levocetirizine (130018-77-8)

Conditions	Yield
Stage #1: (+)-[2-[4-[(4-chlorophenyl)-phenyl methyl]-1-piperazinyl]]ethanol With potassium hydroxide In N,N-dimethyl-formamide at 0 - 5℃; for 1.5h; Stage #2: sodium monochloroacetic acid at 0 - 5℃; for 1.5h; Stage #3: at 30 - 35℃;
Stage #1: (+)-[2-[4-[(4-chlorophenyl)-phenyl methyl]-1-piperazinyl]]ethanol With potassium hydroxide In DMF (N,N-dimethyl-formamide) at 0 - 5℃; for 1.5h; Stage #2: sodium monochloroacetic acid In DMF (N,N-dimethyl-formamide) at 0 - 35℃; Stage #3: With hydrogenchloride In DMF (N,N-dimethyl-formamide); water pH=4 - 4.5;

(R)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-1-(S)-[N-(1-phenyIethyl)]acetamide (1150310-67-0) → levocetirizine (130018-77-8)

Conditions	Yield
With water; hydrogen bromide at 90 - 95℃; for 24h; Product distribution / selectivity;
Stage #1: (R)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-1-(S)-[N-(1-phenyIethyl)]acetamide With sulfuric acid; water at 80 - 85℃; for 48h; Stage #2: With sodium hydroxide In water pH=4.5 - 5.0; Product distribution / selectivity;

cetirizine (83881-51-0) → (S)-cetirizine + levocetirizine (130018-77-8)

Conditions	Yield
Resolution of racemate;
With N,N-diethylaniline In hexane; isopropyl alcohol at 25℃; Reagent/catalyst; Resolution of racemate;
With maltodextrin In aq. buffer at 25℃; pH=3; Reagent/catalyst; pH-value; Temperature; Resolution of racemate;

C19H23ClN2O*ClH + sodium monochloroacetic acid (3926-62-3) → levocetirizine (130018-77-8)

Conditions	Yield
Stage #1: C19H23ClN2O*ClH With ammonia In water; toluene for 0.25h; pH=8.5 - 9; Stage #2: sodium monochloroacetic acid With potassium hydroxide In N,N-dimethyl-formamide at 0 - 10℃; Stage #3: With hydrogenchloride In dichloromethane; water pH=4.3 - 4.8;

(R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → levocetirizine (130018-77-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / toluene / 7 h / 110 - 115 °C 1.2: 12 h / 25 - 30 °C 2.1: ammonia / toluene; water / 0.25 h / pH 8.5 - 9 2.2: 0 - 10 °C 2.3: pH 4.3 - 4.8 View Scheme
Multi-step reaction with 5 steps 1.1: tetrabutylammomium bromide / dimethyl sulfoxide / 10 h 2.1: oxalyl dichloride / tetrahydrofuran / 0 - 5 °C 3.1: tetrahydrofuran 4.1: dimethylsulfide borane complex / tetrahydrofuran / Reflux 5.1: water; potassium hydroxide / methanol / 1 h / 80 °C 5.2: pH 4 - 4.5 View Scheme

(R)-(4-chlorophenyl)(phenyl)methylamine (163837-57-8) → levocetirizine (130018-77-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 128 - 130 °C 2.1: potassium hydroxide / isopropyl alcohol / 9 h / 80 - 85 °C 3.1: triethylamine / toluene / 7 h / 110 - 115 °C 3.2: 12 h / 25 - 30 °C 4.1: ammonia / toluene; water / 0.25 h / pH 8.5 - 9 4.2: 0 - 10 °C 4.3: pH 4.3 - 4.8 View Scheme
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / 3 h / Reflux 1.2: 60 °C / Reflux 2.1: tetrabutylammomium bromide / dimethyl sulfoxide / 10 h 3.1: oxalyl dichloride / tetrahydrofuran / 0 - 5 °C 4.1: tetrahydrofuran 5.1: dimethylsulfide borane complex / tetrahydrofuran / Reflux 6.1: water; potassium hydroxide / methanol / 1 h / 80 °C 6.2: pH 4 - 4.5 View Scheme
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 3 h / 120 °C 2: sodium hydride; sodium iodide / N,N-dimethyl-formamide; acetone / 3 h / 25 °C 3: lithium hydroxide / water; tetrahydrofuran; methanol / 2 h / 65 °C View Scheme

C2H2O4*C17H19ClN2 → levocetirizine (130018-77-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water / 0.5 h / 65 - 70 °C 2.1: triethylamine / toluene / 7 h / 110 - 115 °C 2.2: 12 h / 25 - 30 °C 3.1: ammonia / toluene; water / 0.25 h / pH 8.5 - 9 3.2: 0 - 10 °C 3.3: pH 4.3 - 4.8 View Scheme

C22H27ClN2O2 (1391851-21-0) → levocetirizine (130018-77-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium hydroxide / isopropyl alcohol / 9 h / 80 - 85 °C 2.1: triethylamine / toluene / 7 h / 110 - 115 °C 2.2: 12 h / 25 - 30 °C 3.1: ammonia / toluene; water / 0.25 h / pH 8.5 - 9 3.2: 0 - 10 °C 3.3: pH 4.3 - 4.8 View Scheme

N-benzyl-2-(2-(bis(2-chloroethyl)amino)ethoxy)acetamide (1150310-73-8) + (R)-(4-chlorophenyl)(phenyl)methylamine (163837-57-8) → levocetirizine (130018-77-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / 4 h / 130 °C / Inert atmosphere 2.1: sulfuric acid / methanol / 16 h / Reflux 2.2: 2 h / pH 10 - 12 2.3: pH 4.5 View Scheme

p-chlorobenzhydrylamine (28022-43-7) → levocetirizine (130018-77-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; borane-ammonia complex / aq. phosphate buffer / 37 °C / pH 7.8 2.1: N-ethyl-N,N-diisopropylamine / 4 h / 130 °C / Inert atmosphere 3.1: sulfuric acid / methanol / 16 h / Reflux 3.2: 2 h / pH 10 - 12 3.3: pH 4.5 View Scheme
Multi-step reaction with 4 steps 1: L-Tartaric acid / 30 - 90 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / 3 h / 120 °C 3: sodium hydride; sodium iodide / N,N-dimethyl-formamide; acetone / 3 h / 25 °C 4: lithium hydroxide / water; tetrahydrofuran; methanol / 2 h / 65 °C View Scheme

N-benzyl-2-(2-(bis(2-hydroxyethyl)amino)ethoxy)acetamide (1150310-72-7) → levocetirizine (130018-77-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / dichloromethane / 0 - 20 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / 4 h / 130 °C / Inert atmosphere 3.1: sulfuric acid / methanol / 16 h / Reflux 3.2: 2 h / pH 10 - 12 3.3: pH 4.5 View Scheme

cetirizine dihydrochloride (83881-52-1) → (S)-cetirizine + levocetirizine (130018-77-8)

Conditions	Yield
With CHIRALPAK human serum albumin (HSA) column In aq. phosphate buffer; isopropyl alcohol at 25℃; pH=7; Solvent; Concentration; Temperature; Resolution of racemate;

R-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-oxoethoxy)acetyl chloride → levocetirizine (130018-77-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: tetrahydrofuran 2.1: dimethylsulfide borane complex / tetrahydrofuran / Reflux 3.1: water; potassium hydroxide / methanol / 1 h / 80 °C 3.2: pH 4 - 4.5 View Scheme

R-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-oxoethoxy)acetic acid (1058165-14-2) → levocetirizine (130018-77-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: oxalyl dichloride / tetrahydrofuran / 0 - 5 °C 2.1: tetrahydrofuran 3.1: dimethylsulfide borane complex / tetrahydrofuran / Reflux 4.1: water; potassium hydroxide / methanol / 1 h / 80 °C 4.2: pH 4 - 4.5 View Scheme

R-methyl 2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-oxoethoxy)acetate (1201648-47-6) → levocetirizine (130018-77-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dimethylsulfide borane complex / tetrahydrofuran / Reflux 2.1: water; potassium hydroxide / methanol / 1 h / 80 °C 2.2: pH 4 - 4.5 View Scheme

triethanolamine (102-71-6) → levocetirizine (130018-77-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: thionyl chloride / dichloromethane / 3 h / 38 - 42 °C 2: N-ethyl-N,N-diisopropylamine / 3 h / 120 °C 3: sodium hydride; sodium iodide / N,N-dimethyl-formamide; acetone / 3 h / 25 °C 4: lithium hydroxide / water; tetrahydrofuran; methanol / 2 h / 65 °C View Scheme

tris-(2-chloro-ethyl)-amine (555-77-1) → levocetirizine (130018-77-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 3 h / 120 °C 2: sodium hydride; sodium iodide / N,N-dimethyl-formamide; acetone / 3 h / 25 °C 3: lithium hydroxide / water; tetrahydrofuran; methanol / 2 h / 65 °C View Scheme

4-chlorobenzophenone (134-85-0) → levocetirizine (130018-77-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: formamide / 170 - 175 °C / Inert atmosphere 2: L-Tartaric acid / 30 - 90 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / 3 h / 120 °C 4: sodium hydride; sodium iodide / N,N-dimethyl-formamide; acetone / 3 h / 25 °C 5: lithium hydroxide / water; tetrahydrofuran; methanol / 2 h / 65 °C View Scheme

triphenyltin(IV) hydroxide (76-87-9) + levocetirizine (130018-77-8) → (R)-triphenylstannyl 2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy) acetate

Conditions	Yield
With sulfuric acid In ethanol; acetone Reflux;	71%

hydrogenchloride (7647-01-0) + levocetirizine (130018-77-8) → (+)-Cetirizine dihydrochloride

Conditions	Yield
In acetone at 40 - 50℃;
In water; acetone at 20 - 35℃; for 0.166667 - 0.5h;

levocetirizine (130018-77-8) → levocetirizine dihydrochloride

Conditions	Yield
With hydrogenchloride In acetone at 55℃;
With hydrogenchloride In acetone at 0 - 30℃; for 4h; pH=1.0 - 2.0;
Stage #1: levocetirizine With hydrogenchloride In water; acetone at 20℃; for 0.166667 - 0.5h; Stage #2: In cyclohexane at 30 - 35℃; for 0.5h;
Stage #1: levocetirizine In ethyl acetate at 25 - 35℃; for 0.166667 - 0.25h; Stage #2: With hydrogenchloride In isopropyl alcohol pH=2; Stage #3: for 1 - 2h;
With hydrogenchloride In water; acetone at 25 - 30℃; for 12h;

levocetirizine (130018-77-8) → C21H23ClN2O3

Conditions	Yield
In methanol; water at 130℃; for 30.3333h; Temperature;	2.3 g

curcumin (458-37-7) + levocetirizine (130018-77-8) → C21H25ClN2O3*C21H20O6

Conditions	Yield
In methanol at 25℃;

Upstream product

• 909779-33-5 (R)-2-(2-{4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl}ethoxy)acetamide 
• 705289-61-8 (+)-[2-[4-[(4-chlorophenyl)-phenyl methyl]-1-piperazinyl]]ethanol 
• 3926-62-3 sodium monochloroacetic acid 
• 1150310-67-0 (R)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-1-(S)-[N-(1-phenyIethyl)]acetamide 
• 1150310-68-1 levocetirizine N-benzyl amide 
• 83881-51-0 cetirizine 
• 1177093-13-8 C₁₉H₂₃ClN₂O*ClH 
• 300543-56-0 (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine 
• 163837-57-8 (R)-(4-chlorophenyl)(phenyl)methylamine 
• 1391851-21-0 C₂₂H₂₇ClN₂O₂ 
• 1150310-73-8 N-benzyl-2-(2-(bis(2-chloroethyl)amino)ethoxy)acetamide 
• 28022-43-7 p-chlorobenzhydrylamine 
• 1150310-72-7 N-benzyl-2-(2-(bis(2-hydroxyethyl)amino)ethoxy)acetamide 
• 83881-52-1 cetirizine dihydrochloride 

Downstream Products

• 130018-87-0 (+)-Cetirizine dihydrochloride 
• 130018-87-0 levocetirizine dihydrochloride 

Relevant articles and documents

Investigation of maltodextrin-based synergistic system with amino acid chiral ionic liquid as additive for enantioseparation in capillary electrophoresis

The combined use of chiral ionic liquids (ILs) and chiral selectors in capillary electrophoresis (CE) to establish a synergistic system has proven to be an effective approach for enantioseparation. In this article, tetramethylammonium-L-arginine, a kind of amino acid chiral IL, was applied to investigate its potential synergistic effect with maltodextrin in CE enantioseparation. The established maltodextrin-based synergistic system showed markedly improved enantioseparations compared with the single maltodextrin system. Parameters such as the chiral IL concentration, maltodextrin concentration, buffer pH, applied voltage, and capillary temperature were optimized. Satisfactory enantioseparation of the five studied drugs, including nefopam, duloxetine, ketoconazole, cetirizine, and citalopram was achieved in 50 mM Tris-H3PO4 buffer solution (pH 3.0) containing 7.0% (m/v) maltodextrin and 60 mM tetramethylammonium-L-arginine. In addition, the chiral configuration of tetramethylammonium-L-arginine was also investigated to demonstrate the existence of a synergistic effect between chiral ILs and maltodextrin.

Preparation method of levocetirizine

The invention provides a preparation method of levocetirizine. The preparation method comprises following steps: carrying out a reaction on a compound represented by a formula (I) under the action ofa reduction system and L-tartaric acid to obtain a compound represented by a formula (II); and reacting the compound shown in a formula (II) with a compound shown in a formula (III) under the action of NaH, N,N-dimethyl formamide and tetrabutyl ammonium bromide to obtain levocetirizine. The levocetirizine is prepared by taking the compound shown by the formula (I) and the compound shown by the formula (III) as raw materials, at first, the compound shown by the formula (I) is de-protected and then racemized to obtain the compound shown by the formula (II); and the compound shown by the formula(II) and the compound shown by the formula (III) carry out reactions to obtain levocetirizine. The provided method is short in reaction route, the yield can reach 54% or above, and the purity can reach 99.65% at most.

Enantiomeric separation and simulation studies of pheniramine, oxybutynin, cetirizine, and brinzolamide chiral drugs on amylose-based columns

Solid phase extraction (SPE)-chiral separation of the important drugs pheniramine, oxybutynin, cetirizine, and brinzolamide was achieved on the C 18 cartridge and AmyCoat (150 x 46 mm) and Chiralpak AD (25 cm x 0.46 cm id) chiral columns in hum