300543-56-0

Basic information

• Product Name: (-)-1-[(4-CHLOROPHENYL)PHENYLMETHYL]PIPERAZINE
• Synonyms: (-)-1-[(4-CHLOROPHENYL)PHENYLMETHYL]PIPERAZINE;(R)-(-)-1-[(4-Chlorophenyl)phenylmethyl]piperazine;(R)-1-(p-Chlorobenzhydryl)piperazine;Piperazine,1-[(R)-(4-chlorophenyl)phenylMethyl]-;(R)-1-[^a-(4-Chlorophenyl)benzyl]piperazine, 97%;(R)-1-[alpha-(4-Chlorophenyl)benzyl]piperazine;Levocetirizine Impurity A;Levocetirizine Impurity 2
• CAS NO: 300543-56-0
• Molecular Formula: C₁₇H₁₉ClN₂
• Molecular Weight: 286.8
• EINECS: 1312995-182-4
• Product Categories: Pharmaceutical Intermediates;Aromatics;Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 300543-56-0.mol
• Article Data: 10

Chemical Properties

• Boiling Point: 409.1°C at 760 mmHg
• Flash Point: 193.3°C
• Appearance: White/Solid
• Density: 1.158
• Vapor Pressure: 6.66E-07mmHg at 25°C
• Refractive Index: 1.592
• Storage Temp.: Keep in dark place,Inert atmosphere,Room temperature
• Solubility: Chloroform (Slightly), Dichloromethane (Slightly), Methanol (Slightly)
• PKA: 8.99±0.10(Predicted)
• Water Solubility: Soluble in chloroform, methanol, and dichloromethane. Slightly soluble in water.
• CAS DataBase Reference: (-)-1-[(4-CHLOROPHENYL)PHENYLMETHYL]PIPERAZINE(CAS DataBase Reference)
• NIST Chemistry Reference: (-)-1-[(4-CHLOROPHENYL)PHENYLMETHYL]PIPERAZINE(300543-56-0)
• EPA Substance Registry System: (-)-1-[(4-CHLOROPHENYL)PHENYLMETHYL]PIPERAZINE(300543-56-0)

Safety Data

• Hazardous Substances Data: 300543-56-0(Hazardous Substances Data)

Usage

Uses

Different sources of media describe the Uses of 300543-56-0 differently. You can refer to the following data:
1. Intermediate in the production of (R)-Cetirizine (C281106).
2. (R)-1-[alpha-(4-Chlorophenyl)benzyl]piperazine intermediate in the production of (R)-Cetirizine.

InChI:InChI=1/C17H19ClN2/c18-16-8-6-15(7-9-16)17(14-4-2-1-3-5-14)20-12-10-19-11-13-20/h1-9,17,19H,10-13H2/t17-/m1/s1

Synthetic route

(R)-(-)-1-[(4-chlorophenyl)phenylmethyl]piperazine N-acetyl-L-phenylalanine salt (1161573-31-4) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
With sodium hydroxide; water at 20℃; for 12.5h; Product distribution / selectivity;	99%
With sodium hydroxide; water In ethyl acetate Product distribution / selectivity;	90%

(-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methoxyphenyl)sulfonyl]piperazine (943987-59-5) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
Stage #1: (-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methoxyphenyl)sulfonyl]piperazine With hydrogen bromide; acetic acid at 70 - 75℃; for 3h; Industry scale; Stage #2: With sodium hydroxide In water at 0 - 35℃; pH=~ 12 - ~ 14; Product distribution / selectivity; Industry scale;	92.7%

(-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine (942283-97-8) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
Stage #1: (-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine With hydrogen bromide; acetic acid; 4-hydroxy-benzoic acid at 25℃; for 17h; Stage #2: With sodium hydroxide In water Product distribution / selectivity;	84.8%

bis-(2-chloroethyl)amine hydrochloride (821-48-7) + (R)-(4-chlorophenyl)(phenyl)methylamine (163837-57-8) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
Stage #1: bis-(2-chloroethyl)amine hydrochloride; (R)-(4-chlorophenyl)(phenyl)methylamine With N-ethyl-N,N-diisopropylamine for 3h; Heating / reflux; Stage #2: With diethylamine at 60℃; for 5h; Heating / reflux; Stage #3: With sodium hydroxide; water pH=10 - 11;
Stage #1: bis-(2-chloroethyl)amine hydrochloride; (R)-(4-chlorophenyl)(phenyl)methylamine With N-ethyl-N,N-diisopropylamine for 3h; Reflux; Stage #2: With diethylamine at 60℃; Reflux;

(R)-(+)-4-(4-chlorophenyl)-phenylmethyl-piperazine-1-carboxylic acid-2,2,2-trichloroethylester (941576-99-4) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
With sodium hydroxide; water In isopropyl alcohol at 20 - 100℃; Product distribution / selectivity;

C24H23ClN2O2 (1136010-90-6) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
With sodium hydroxide; water In isopropyl alcohol for 3 - 3.5h; Product distribution / selectivity; Heating / reflux;	n/a

C25H25ClN2O2 (1155402-57-5) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
With sodium hydroxide; water In isopropyl alcohol for 1.5h; Product distribution / selectivity; Heating / reflux;

C25H25ClN2O3 (1155402-66-6) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
With sodium hydroxide; water In isopropyl alcohol for 2.75h; Product distribution / selectivity; Heating / reflux;

C24H22ClN3O4 (1155402-68-8) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
With sodium hydroxide; water In isopropyl alcohol at 50℃; for 3.5h; Product distribution / selectivity;

C25H25ClN2O2 (1136010-92-8) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
With sodium hydroxide; water In isopropyl alcohol at 100℃; for 5h; Product distribution / selectivity;

(-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(phenyl)sulfonyl]piperazine (1092460-01-9) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
Stage #1: (-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(phenyl)sulfonyl]piperazine With hydrogen bromide; acetic acid at 25 - 60℃; for 5h; Stage #2: With water; sodium hydroxide In toluene

C28H37ClN2O2*H2O4S (1228582-98-6) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
Stage #1: C28H37ClN2O2*H2O4S With sulfuric acid In isopropyl alcohol at 20 - 90℃; Stage #2: With sodium hydroxide In di-isopropyl ether; water; isopropyl alcohol

C28H37ClN2O2*(x)H2O4S → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
Stage #1: C28H37ClN2O2*(x)H2O4S With sulfuric acid; isopropyl alcohol at 20 - 90℃; Stage #2: With sodium hydroxide In water pH=8;

(R)-(4-chlorophenyl)(phenyl)methylamine (163837-57-8) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 128 - 130 °C 2: potassium hydroxide / isopropyl alcohol / 9 h / 80 - 85 °C View Scheme

C2H2O4*C17H19ClN2 → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
With sodium hydroxide In water at 65 - 70℃; for 0.5h;

C22H27ClN2O2 (1391851-21-0) → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
With potassium hydroxide In isopropyl alcohol at 80 - 85℃; for 9h;

1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine → (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0)

Conditions	Yield
With hydrogen bromide; acetic acid In dichloromethane at 10℃; for 3h; Inert atmosphere;

2-chloroethyl cyanomethyl ether (31250-08-5) + (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinil]ethoxy]-acetonitrile dihydrochloride

Conditions	Yield
Stage #1: 2-chloroethyl cyanomethyl ether; (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine With sodium carbonate; potassium iodide In acetonitrile at 110 - 115℃; for 20h; Stage #2: With hydrogenchloride In acetonitrile for 0.333333h; pH=0.5 - 1;	95%

2-chloro-ethanol (107-07-3) + (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → (+)-[2-[4-[(4-chlorophenyl)-phenyl methyl]-1-piperazinyl]]ethanol (705289-61-8)

Conditions	Yield
With triethylamine at 80 - 105℃; for 5.5 - 6h; Industry scale;	90.49%
With sodium carbonate; potassium iodide In toluene for 24h; Reflux;

(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%

1,3-chlorobromopropane (109-70-6) + (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → C20H24Cl2N2 (942132-43-6)

Conditions	Yield
With triethylamine In toluene at 55℃;	70%

tert-butyl-[4-(5-chloromethyl-tetrahydro-furan-2-yl)-but-3-ynyloxy]-dimethyl-silane + (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → 1-{(2S,5S)-5-[4-(tert-Butyl-dimethyl-silanyloxy)-but-1-ynyl]-tetrahydro-furan-2-ylmethyl}-4-[(R)-(4-chloro-phenyl)-phenyl-methyl]-piperazine + 1-{(2S,5R)-5-[4-(tert-Butyl-dimethyl-silanyloxy)-but-1-ynyl]-tetrahydro-furan-2-ylmethyl}-4-[(R)-(4-chloro-phenyl)-phenyl-methyl]-piperazine

Conditions	Yield
With potassium carbonate; sodium iodide In N,N-dimethyl-formamide; toluene Heating;	A 36% B n/a

oxalic acid (144-62-7) + (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → C2H2O4*C17H19ClN2

Conditions	Yield
In ethanol at 5 - 20℃; Product distribution / selectivity;	16.2%
In ethanol; ethyl acetate at 5 - 20℃; Product distribution / selectivity;	n/a
In ethanol; ethyl acetate at 5 - 20℃; Product distribution / selectivity;	n/a
In isopropyl alcohol at 80 - 85℃; for 0.5h;

C7H8N2O4 + (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → C24H27ClN4O3

Conditions	Yield
With sodium cyanoborohydride; acetic acid In methanol

C10H10N2O4 + (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → C27H29ClN4O3

Conditions	Yield
With sodium cyanoborohydride; acetic acid In methanol

C10H10N2O4 (708263-47-2) + (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → C27H29ClN4O3

Conditions	Yield
With sodium cyanoborohydride; acetic acid In methanol

tert-butyl-[4-(5-chloromethyl-tetrahydro-furan-2-yl)-but-3-ynyloxy]-dimethyl-silane + (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → 1-{(2R,5S)-5-[4-(tert-Butyl-dimethyl-silanyloxy)-but-1-ynyl]-tetrahydro-furan-2-ylmethyl}-4-[(R)-(4-chloro-phenyl)-phenyl-methyl]-piperazine + 1-{(2R,5R)-5-[4-(tert-Butyl-dimethyl-silanyloxy)-but-1-ynyl]-tetrahydro-furan-2-ylmethyl}-4-[(R)-(4-chloro-phenyl)-phenyl-methyl]-piperazine

Conditions	Yield
With potassium carbonate; sodium iodide In N,N-dimethyl-formamide; toluene Heating;

(R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) + 4-[4-(2-Bromoethoxy)phenyl]but-3-yn-1-ol (299461-25-9) → 4-[4-(2-{4-[(R)-(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethoxy)-phenyl]-but-3-yn-1-ol (299461-26-0)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide

(R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) + 4-[4-(3-bromo-propoxy)-phenyl]-but-3-yn-1-ol (802982-14-5) → 4-[4-(3-{4-[(R)-(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-propoxy)-phenyl]-but-3-yn-1-ol (299461-37-3)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide

(R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) + 4-[4-(4-bromo-butoxy)-phenyl]-but-3-yn-1-ol (299461-39-5) → 4-[4-(4-{4-[(R)-(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-butoxy)-phenyl]-but-3-yn-1-ol

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide

1,4-dioxane-2,6-dione (4480-83-5) + (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → R-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-oxoethoxy)acetic acid (1058165-14-2)

Conditions	Yield
Stage #1: 1,4-dioxane-2,6-dione; (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine In acetonitrile for 12h; Heating / reflux; Stage #2: With sodium hydroxide; water In dichloromethane for 0.333333h; Stage #3: In dichloromethane; water pH=4 - 4.5; Product distribution / selectivity; Acidic conditions;
Stage #1: 1,4-dioxane-2,6-dione; (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine With tetrabutylammomium bromide In dimethyl sulfoxide for 10h; Stage #2: With sodium hydroxide; water In Isopropyl acetate pH=10; Stage #3: In Isopropyl acetate; water pH=4 - 4.5; Product distribution / selectivity; Acidic conditions;
With tetrabutylammomium bromide In dimethyl sulfoxide for 10h; Product distribution / selectivity;

1-Bromo-2-chloroethane (107-04-0) + (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → C19H22Cl2N2

Conditions	Yield
With triethylamine In toluene at 55℃;

(R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → C28H30ClN5O2S2 (1159975-50-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / toluene / 55 °C 2: potassium carbonate; triethylamine / acetone / Reflux View Scheme

(R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine (300543-56-0) → C31H35ClN6O2S (1159975-51-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / toluene / 55 °C 2: potassium carbonate; triethylamine / acetone / Reflux View Scheme

Upstream product

• 163837-57-8 (R)-(4-chlorophenyl)(phenyl)methylamine 
• 1391851-21-0 C₂₂H₂₇ClN₂O₂ 
• 163837-56-7 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine 
• 1228582-98-6 C₂₈H₃₇ClN₂O₂*H₂O₄S 
• 1092460-01-9 (-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(phenyl)sulfonyl]piperazine 
• 1161573-31-4 (R)-(-)-1-[(4-chlorophenyl)phenylmethyl]piperazine N-acetyl-L-phenylalanine salt 
• 1136010-92-8 C₂₅H₂₅ClN₂O₂ 
• 1155402-68-8 C₂₄H₂₂ClN₃O₄ 
• 1155402-66-6 C₂₅H₂₅ClN₂O₃ 
• 1155402-57-5 C₂₅H₂₅ClN₂O₂ 
• 1136010-90-6 C₂₄H₂₃ClN₂O₂ 
• 941576-99-4 (R)-(+)-4-(4-chlorophenyl)-phenylmethyl-piperazine-1-carboxylic acid-2,2,2-trichloroethylester 
• 943987-59-5 (-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methoxyphenyl)sulfonyl]piperazine 
• 942283-97-8 (-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine 

Downstream Products

• 299461-26-0 4-[4-(2-{4-[(R)-(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-ethoxy)-phenyl]-but-3-yn-1-ol 
• 299461-37-3 4-[4-(3-{4-[(R)-(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-propoxy)-phenyl]-but-3-yn-1-ol 
• 1058165-14-2 R-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-oxoethoxy)acetic acid 
• 705289-61-8 (+)-[2-[4-[(4-chlorophenyl)-phenyl methyl]-1-piperazinyl]]ethanol 
• 1177093-13-8 C₁₉H₂₃ClN₂O*ClH 
• 130018-87-0 levocetirizine dihydrochloride 
• 130018-77-8 levocetirizine 
• 1201648-49-8 trimethylsilyl R-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-oxoethoxy)acetate 
• 1201648-48-7 propyl R-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-oxoethoxy)acetate 
• 1201648-47-6 R-methyl 2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-oxoethoxy)acetate 

Relevant articles and documents

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.

LEVOCETIRIZINE BY MENTHYL INTERMEDIATE

The invention relates to a process for making levocetirizine, to a process for converting the racemic compound (4) into enantiomers, and to compounds used thereby.

PROCESS FOR PREPARATION OF SUBSTANTIALLY OPTICALLY PURE LEVOROTATORY AND DEXTROROTATORY ENANTIOMERS OF CETIRIZINE USING NOVEL INTERMEDIATES

The present invention relates to a novel and commercially viable process for substantially optically pure levorotatory and dextrorotatory enantiomers of cetirizine intermediate, 1-[(4-chlorophenyl)phenylmethyl]piperazine, thereby producing substantially optically pure levorotatory and dextrorotatory enantiomers of cetirizine and their pharmaceutical acceptable acid addition salts thereof in high purity and in high yield using novel intermediates.