Chemical Name: | (R)-2-[2-[4-[1-(4-Chlorophenyl)-1-phenylmethyl]piperazin-1-yl]ethoxy]acetic acid | Generic Name: | 左西替利嗪;Levocetirizine | Other Names: | (-)-Cetirizine;Levocetirizine;Xusal;Xyzal | CAS: | 130018-77-8 | Formula: | C21H25ClN2O3 | Mole Weight: | 388.898 | structure: | | Company: | Sepracor (Originator), UCB (Licensee) | Usage: | Allergic Skin Disorders, Treatment for, Asthma Therapy, DERMATOLOGIC DRUGS, Drugs for Allergic Rhinitis, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, Urticaria, Treatment for, Histamine H1 Antagonists, IL8 Expression Inhibitors, TNF Expression Inhibitors | | | |
Route 1 The resolution of racemic 1-[(4-chlorophenyl)phenylmethyl]piperazine (I) with L-tartaric acid provided the required (R)-enantiomer (II), which was condensed with (2-chloroethoxy)acetonitrile (III) in the presence of Na2CO3 and KI in refluxing n-butanol to give the alkylated piperazine (IV). The nitrile group of (IV) was finally hydrolyzed by means of concentrated hydrochloric acid to yield the target carboxylic acid. | | Intermediates: | Serial No. | (4aS,6R,8aS)-6-hydroxy-11-methyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-3-yl pivalate | (I) | | (II) | | (III) | | (IV) | | Reference 1: Cossement, E.; Motte, G.; Gobert, J.; Bodson, G. (UCB SA); Process for preparation of a 1-piperazine-ethoxyacetic acid. GB 2225321 . | Route 2 In a further procedure, racemic (4-chlorophenyl)phenylmethyl amine (V) was resolved by means of L-tartaric acid. The undesired (S)-enantiomer (VII) could be recovered by racemization to (V) upon treatment with 2-hydroxybenzaldehyde and NaOMe. The required (R)-enantiomer (VI) was condensed with N,N-bis(chloroethyl)-p-toluenesulfonamide (VIII) in refluxing diisopropylethylamine to provide the N-tosyl piperazine (IX). Deprotection of the p-toluenesulfonamide of (IX) was achieved by treatment with HBr in the presence of 4-hydroxybenzoic acid. The resulting piperazine (X) was alkylated with either (2-chloroethoxy)acetamide (XI) or methyl (2-chloroethoxy)acetate (XIII), affording the N-alkylated piperazines (XII) and (XIV), respectively. The title carboxylic acid was then obtained by hydrolysis of amide (XII) with aqueous HCl or, alternatively, by hydrolysis of ester (XIV) with ethanolic KOH. | | Intermediates: | Serial No. | 3-[(carboxymethyl)(hydroxy)phosphoryl]alanine | (XI) | benzhydryl 4-(benzhydryloxy)-4,6-dioxo-1,4lambda(5)-azaphosphinane-2-carboxylate | (XIII) | | (X) | | (V) | | (VI) | | (VIII) | | (IX) | | (XII) | methyl (2S)-2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | (XIV) | methyl (2S)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[(4-formylbenzoyl)amino]pentanoate | (VII) | | Reference 1: Bodson, G.; Gobert, J.; Cossement, E. (UCB SA); Enantiomers of 1-[4-(chlorophenyl)phenylmethyl]-4-(methylphenyl)sulfonyl piperazine. EP 0617028 . | Route 3 The reaction of racemic cetiricine (I) with SOCl2 in toluene gives the acyl chloride (II), which is treated with ammonia to yield the corresponding racemic amide (III). The optical resolution of (III) by preparative chiral chromatography on a Chiralpak AD column affords the (R)-isomer (IV), which is treated with HCl in refluxing methanol to provide the chiral methyl ester (V). Finally, ester (V) is hydrolyzed with aqueous HCl to provide the chiral target compound. The hydrolysis of amide (IV) is not performed directly to the target acid owing to purification problems (separation of the ammonium chloride formed in the hydrolysis with HCl). | | Intermediates: | Serial No. | | (IV) | methyl (2S)-2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | (V) | (6aS,10aS)-9-(bromomethyl)-3-(1,1-dimethylheptyl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol | (I) | (1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4S,5S,6R)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylic acid | (II) | benzhydryl (1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4S,5S,6R)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate | (III) | | Reference 1: Pflum, D.A.; et al.; A large-scale synthesis of enantiomerically pure cetirizine dihydrochloride using preparative chiral HPLC. Org Process Res Dev 2001, 5, 2, 110. | | | |