- A novel synthesis of the enantiomers of an antihistamine drug by piperazine formation from a primary amine
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An enantioselective synthesis of each enantiomer of the antihistamine drug 2-(2-{4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl}ethoxy)acetic acid dihydrochloride (1) is described, involving the preparation of the benzhydrylpiperazine portion of the molecule from reaction of each enantiomer of 4-chlorobenzhydrylamine with N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide. A modification of standard toluenesulfonamide deprotection with hydrogen bromide in acetic acid was introduced, substituting 4-hydroxybenzoic acid for phenol.
- Opalka,D'Ambra,Faccone,Bodson,Cossement
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Read Online
- A synthesis process of cetirizine hydrochloride
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A new technology for synthesizing cetirizine hydrochloride. The technology includes following steps: oxidizing hydroxyzine, which is used as a raw material, into a substance containing an aldehyde group; further oxidizing the substance containing the aldehyde group into cetirizine; and finally performing a salification and purification process to obtain the cetirizine hydrochloride. A total yield of the synthetic method is higher than 80%. Meanwhile, the method is simple in operation, is short in production period, is low in energy consumption and cost, is little in waste water, waste gas and residues and is suitable for large-scale industrial production.
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Paragraph 0074; 0075; 0076; 0077
(2017/03/08)
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- New manufacturing procedure of cetirizine
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A new procedure for the manufacture of cetirizine dihydrochloride via the new intermediate 2-(2-{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)- N,N-dimethylacetamide dihydrochloride, synthesized by O-alkylation of 2-{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethanol with 2-chloro-N,N-dimethylacetamide, is elaborated. Hydrolysis of the resulting amide and subsequent salification provided cetirizine dihydrochloride.
- Reiter, Jozsef,Trinka, Peter,Bartha, Ferenc L.,Pongo, Laszlo,Volk, Balazs,Simig, Gyula
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p. 1279 - 1282
(2012/09/08)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF ANTIHISTAMINIC DRUGS VIA A NOVEL CARBAMATE INTERMEDIATE
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The present invention relates to a novel racemic or optically active carbamate intermediate of formula (IV A). This novel racemic or optically active carbamate intermediate of formula (IV A) can be used to prepare drugs having antihistaminic activity such as cetirizine (IA), meclizine (IB), chlorcyclizine (IC), clocinizine (ID), buclizine (IE) and enantiomers thereof such as levocetirizine (I). Further, disclosed herein is an improved process for the preparation of levocetirizine via a novel optically active intermediate i.e. compound of formula (IV). Also, disclosed herein is a novel process for the preparation of compound (II) and for crystallization of its salt.
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- Processes for the Synthesis of Levocetirizine and Intermediates for Use Therein
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The present invention provides a compound of formula (IV) wherein R is Cl, Br, NO2, OH or OR′, and R′ is alkyl, and its use in the synthesis of levocetirizine, including its use in the synthesis of (?)-1-[(4-chlorophenyl)-phenylmethyl]piperazin
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Page/Page column 8
(2011/08/06)
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- NEW PROCESS FOR THE PREPARATION OF LEVOCETIRIZINE AND INTERMEDIATES THEREOF
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The present invention describes a novel process for the preparation of levocetirizine and pharmaceutically acceptable acid addition salts thereof via a ketocetirizine ester and new ketocetirizine ester intermediates used in that process. reaction of ketocetirizine of the formula (IIIb) to a ketocetirizine ester of the formula (IV) or a salt thereof.
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- PROCESS FOR PREPARATION OF SUBSTANTIALLY OPTICALLY PURE LEVOROTATORY AND DEXTROROTATORY ENANTIOMERS OF CETIRIZINE USING NOVEL INTERMEDIATES
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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.
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Page/Page column 3
(2009/12/04)
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- A PROCESS FOR THE SYNTHESIS OF 2-[2-[4-[(4-CHLOROPHENYL)PHENYL METHYL]-1-PIPERAZINYL] ETHOXY ACETIC ACID
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TAbstract A process for the preparation of 2-[2-[4-[(4-chloro phenyl) phenyl methyl]-1-piperazinyl] ethoxy acetic acid of formula (Ia) and pharmaceutically acceptable salts thereof, and compounds of formula (IIa) and (VIIIa), wherein R1 = H or C1-C4 alkyl; R2 = aryl or heteroaryl or R1 and R2 together with the carbon to which they are attached form a C3-C8 cycloalkyl group and X is a suitable leaving group for example, chlorine, bromine, iodine, 4-methylphenyl-sulfonyloxy, methylsulfonyloxy group or 4-bromophenyl-sulfonyloxy group are described.
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Page/Page column 6; 20
(2009/06/27)
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- Process for obtaining cetirizine dihydrochloride
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Process for the synthesis of cetirizine dihydrochloride, wherein (a) a solution of {2-[4-(α-phenyl-p-chlorobenzyl)piperazin-1-yl]}ethanol in 1-7 volumes, referred to the weight of {2-[4-(α-phenyl-p-chlorobenzyl)piperazin-1-yl]}ethanol, of an organic solvent having a boiling point higher than 90° C. and being chosen from the group consisting of aliphatic, cycloalifatic or aromatic solvents is provided, whereafter(b) per equivalent of {2-[4-(α-phenyl-p-chlorobenzyl)piperazin-1-yl]}ethanol employed, 1-2 equivalents of a metal haloacetate or of haloacetic acid, as well as 3-7 equivalents of an alkaly metal hydroxyde are added to the solution as per (a), providing a reaction mixture, where 0.05-0.3 volumes, referred to the weight of {2-[4-(α-phenyl-p-chlorobenzyl)piperazin-1-yl]}ethanol employed, of water and 0.1-1.2 volumes, referred to the weight of {2-[4-(α-phenyl-p-chlorobenzyl)piperazin-1-yl]}ethanol employed, of a polar aprotic, water miscible solvent are added, keeping the internal temperature of the reaction mixture below 60° C., whereafter(c) the cetirizine base formed within the reaction mixture is converted into its dihydrochloride salt and isolated as such.
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Page/Page column 3-4
(2009/02/11)
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- PROCESSES FOR THE SYNTHESIS OF LEVOCETIRIZINE AND INTERMEDIATES FOR USE THEREIN
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The present invention provides a compound of formula (IV) wherein R is Cl, Br, NO2, OH or OR', and R' is alkyl, and its use in the synthesis of levocetirizine, including its use in the synthesis of (-)-1-[(4-chlorophenyl)-phenyl methyl] piperaz
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- PROCESS FOR PREPARATION OF SUBSTANTIALLY OPTICALLY PURE LEVOROTATORY AND DEXTROROTATORY ENANTIOMERS OF CETIRIZINE USING NOVEL INTERMEDIATES
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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.
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Page/Page column 7
(2009/01/24)
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- NEW PROCESS FOR THE PREPARATION OF LEVOCETIRIZINE AND INTERMEDIATES THEREOF
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The present invention describes a novel process for the preparation of levocetirizine and pharmaceutically acceptable acid addition salts thereof using diglycolic acid or derivatives thereof and new intermediates used in that process.
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Page/Page column 24-25
(2008/12/07)
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- PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL INTERMEDIATE
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The present invention relates to a process for the preparation of {2-[4-(α-phenyl-p-chlorobenzyl)-piperazin-1-yl]-ethoxy}-acetic acid-N,N-dimethylamide of the Formula (I) and enantiomers thereof. The compound of the Formula (I) or enantiomers thereof are
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Page/Page column 16
(2008/06/13)
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- PROCESS FOR PREPARING OPTICALLY ACTIVE CETIRIZINE OR ITS SALT
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Provided are a process for preparing optically active cetirizine or its salt from racemic cetirizine or its salt using glutamate of 2-[2-[4-[(4-chlorphenyl)phenylmethyl]-1-piperazinyl] ethoxy]acetic ester and the glutamate of 2-[2-[4-[(4-chlorophenyl)phen
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Page/Page column 13
(2008/06/13)
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- Process for preparing (S) and (R)—2-[4-(4-chlorobenzhydryl)piperazin-1-yl]-ethoxyacetamide
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The present invention relates to a process for preparing (S)-2-[4-(4-chlorobenzhydryl)piperazin-1-yl]-ethoxyacetamide and (R)-2-[4-(4-chlorobenzhydryl)piperazin-1-yl]-ethoxyacetamide by separation of a racemic mixture using multiple column chromatography.
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Page/Page column 8
(2008/06/13)
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- Crystalline cetirizine monohydrochloride
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A novel crystalline form of cetirizine monohydrochloride and processes for making the crystalline form as well as compositions, pharmaceutical compositions, and methods utilizing the crystalline form are described.
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- POLYMORPHIC FORMS OF DIHYDROCHLORIDE SALTS OF CETIRIZINE AND PROCESSES FOR PREPARATION THEREOF
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The present invention relates to crystalline and amorphous forms of dextrorotatory dihydrochloride salt of cetirizine, the process for the preparation thereof and compositions containing the same. The invention also relates to the crystalline and amorphous forms of levorotatory dihydrochloride salt of cetirizine, the process for the preparation thereof and compositions containing the same. Both crystalline and amorphous salt forms of cetirizine dihydrochloride are suitable for pharmaceutical purposes in the treatment of allergies, including ailments such as chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria and the like.
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- NEW PIPERAZINE DERIVATIVES AND THEIR USE AS SYNTHESIS INTERMEDIATES
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The present invention relates to new enantiomerically pure piperazine derivatives of formula (I) wherein Y represents hydroxy or a leaving group and n is 1, 2, 3, 4 or 5, and to their use as synthesis intermediates, especially for the preparation of pharmaceutically active compounds.
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- Novel amorphous form of [2-[4-[(4-chlorophenyl)-phenyl methyl]-1-piperazinyl]ethoxy]acetic acid and process for the preparation thereof
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A novel amorphous form of cetirizine and processes for making the amorphous form as well as compositions, pharmaceutical compositions, and methods utilizing the crystalline form are described.
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Page/Page column 6
(2008/06/13)
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- 2-[2-[4-[(4-CHLOROPHENYL) PHENYLMETHYL]-1-PIPERAZINYL]ETHOXY]ACETIC ACID MONOHYDROCHLORIDE AS ANTI-ALLERGENIC COMPOUND AND PROCESS FOR ITS PRODUCTION
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An anti-allergenic compound having therapeutic value and a process for its manufacture. The disclosure is directed to 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1piperazinyl]ethoxy]acetic acid monohydrochloride, to compositions containing 2-[2-[4-[(4chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid monohydrochloride, and to a process for the preparation of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid monohydrochloride.
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- AMORPHOUS FORM OF(-)-}2-}4-}(4-CHLOROPHENYL)-PHENYL METHYL}-1-PIPERAZINYL] ETHOXY] ACETIC ACID DIHYDROCHLORIDE (LEVOCETRIRIZINE DIHYDROCHLORIDE)
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The present invention relates to the amorphous form of levocetirizine dihydrochloride (I). The present invention also relates to the process for the preparation of the amorphous form of levocetirizine dihydrochloride. The amorphous form of levocetirizine dihydrochloride is suitable for pharmaceutical purposes in the treatment of allergies, including ailments such as chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, uiticaria and the like.
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- Process for the preparation of {2-[4-(alpha-phenyl-p-chlorobenzyl)piperazin-1-yl]ethoxy} acetic acid and novel intermediates therefor
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The invention refers to a novel process for the preparation of cetirizine of formula (I) as well as to novel {2-[4-(α-phenyl-p-chloro-benzyl)piperazin-1-yl]ethoxy}acetamides of formula II, wherein R1 and R2 represent, independently, a C1-4 alkyl group optionally substituted by a phenyl group, a C2-4 alkenyl group or a cyclohexyl group, or R1 and R2 form together with the adjacent nitrogen atom a morpholino group. According to the novel process, an acetamide of formula (II) is hydrolized, if desired in the presence of a phase transfer catalyst, to obtain cetirizine.
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- A PROCESS FOR THE PREPARATION OF 2- 2- 4-(DIPHENYLMETHYL)-1-PIPERAZINYL]ETHOXY ACETIC ACID COMPOUNDS OR SALTS THEREOF
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2-{2-[4-(diphenylmethyl)-1-piperazinyl]ethoxy}acetic acid compounds of general formula (I) wherein R and R independently represent hydrogen, halogen, lower alkoxy or trifluoromethyl, or salts thereof are prepared by reacting a corresponding 2-[4-(diphenylmethyl)-1-piperazinyl]ethanol with a 2-substituted acetaldehyde dialkylacetal in the presence of a proton acceptor in an inert solvent to form a corresponding diphenylmethylpiperazinoethoxyacetaldehyde dialkylacetal, and thereafter hydrolysing the acetal to the corresponding aldehyde, catalysed by a proton donor, and then oxidising the aldehyde to the acid (I) by means of a suitable oxidation agent. If desired, the acid (I) is converted into a salt thereof. The process is cheap, easy to perform and gives a high yield. The most interesting compound is 2-{2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy}acetic acid in the form of its dihydrochloride known by the generic name of cetirizine. The 2-{2-[4-(diphenylmethyl)-1-piperazinyl]ethoxy}acetaldehyde compounds and their dialkylacetals are novel compounds.
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Page/Page column 5
(2008/06/13)
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- CRYSTALLINE [2-[4-[(4-CHLOROPHENYL)-PHENYL METHYL]-1-PIPERAZINYL] ETHOXY] ACETIC ACID DIHYDROCHLORIDE
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A crystalline form of cetirizine dihydrochloride is provided. A Form I of cetirizine dihydrochloride having a defined X-ray diffraction pattern is also provided, as well as pharmaceutical compositions containing the same.
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- Asymmetric synthesis of cetirizine dihydrochloride
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Practical route technology for the preparation of (S)-cetirizine·2HCl via diastereoselective organometallic addition to N-tert-butanesulfinyl aldimines is disclosed.
- Pflum, Derek A,Krishnamurthy, Dhileepkumar,Han, Zhengxu,Wald, Stephen A,Senanayake, Chris H
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p. 923 - 926
(2007/10/03)
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- PHARMACEUTICAL COMPOSITIONS FOR ORAL ADMINISTRATION, COMPRISING AN ACTIVE SUBSTANCE AND A CYCLODEXTRIN
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The invention concerns pharmaceutical compositions for oral administration, comprising an active substance belonging to the family of substituted benzhydrylpiperazines and at least a cyclodextrin.
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- Process for preparing piperazine-substituted aliphatic carboxylates
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A process is disclosed for the preparation of a piperazine-substituted aliphatic carboxylate having the formula where m and n are individually an integer of from 1 to 6, R and R′ are the same or different and are hydrogen, C1to C6alkyl or aryl or heteroaryl that is unsubstituted or is substituted with at least one substituent that is halo, C1to C6alkyl or C1to C6alkoxy and R″ is C3to C12branched alkyl or an organic or inorganic cation. The process comprises treating a solution comprising a compound of the formula wherein m, R and R′ are as defined above and an aliphatic ester of the formula X—(CH2)n—O—CH2—CO(O)R″ where X is a leaving group and n and R″ are as defined above, with an effective amount of a base for a time and at a temperature sufficient to form a piperazine-substituted aliphatic carboxylate. Hydrolysis of the carboxylate with acid produces a piperazine-substituted aliphatic carboxylic acid or the acid salt thereof.
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- Catalytic enantioselective synthesis of the second generation histamine antagonist cetirizine hydrochloride
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The first enantioselective synthesis of cetirizine hydrochloride (1) has been developed using the highly stereospecific chiral oxazaborolidine (CBS) reduction of 4-[η6-chromium tricarbonylbenzoyl]chlorobenzene to establish the benzhydryl stereocenter. The chromium tricarbonyl unit also served as stereocontroller to allow the stereospecific displacement of hydroxyl by amino at the benzylic stereocenter, as outlined in Scheme 1.
- Corey,Helal, Christopher J.
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p. 4837 - 4840
(2007/10/03)
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