WO2012101475A1 - Procédé de préparation amélioré d'antihistaminiques faisant appel à un nouvel intermédiaire carbamate - Google Patents

Procédé de préparation amélioré d'antihistaminiques faisant appel à un nouvel intermédiaire carbamate Download PDF

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Publication number
WO2012101475A1
WO2012101475A1 PCT/IB2011/003075 IB2011003075W WO2012101475A1 WO 2012101475 A1 WO2012101475 A1 WO 2012101475A1 IB 2011003075 W IB2011003075 W IB 2011003075W WO 2012101475 A1 WO2012101475 A1 WO 2012101475A1
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Prior art keywords
formula
compound
process according
optically active
base
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PCT/IB2011/003075
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English (en)
Inventor
Sujay Biswas
Shailendra Kumar Dubey
Amit MANGLA
Mukesh MASAND
Dharam Vir
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Jubilant Life Sciences Limited
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Publication of WO2012101475A1 publication Critical patent/WO2012101475A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • 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 (IVA) 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).
  • drugs having antihistaminic activity such as cetirizine (IA), meclizine (IB), chlorcyclizine (IC), clocinizine (ID), buclizine (IE) and enantiomers thereof such as levocetirizine (I).
  • Another aspect of the present invention is directed to an improved process for the preparation of levocetirizine of formula (I) and pharmaceutically acceptable salts thereof,
  • the present invention is also related to a novel process for the preparation of compound (II),
  • Cetirizine (IA), meclizine (IB), chlorcyclizine (IC), clocinizine (ID), buclizine (IE) and enantiomers thereof such as levocetirizine i.e. (-) cetirizine of formula (I) are known to possess antihistaminic activity. Furthermore, the administration of (-)- cetirizine is found to be pharmacologically advantageous over racemic cetirizine, as less side effects are experienced.
  • United Kingdom Patent No. GB2225321 discloses the preparation of 1- [(4-chlorophenyl)-phenylmethyl]piperazine of formula (III), which is a key intermediate in the process for the preparation of levocetirizine
  • WO 2007/066163 discloses a process for the preparation of benzyl protected (-)-l-[(4-chlorophenyl)phenylmethyl]piperazine, followed by replacement with 2,2,2- trichloroethyl chloroformate and finally isolated as its hydrochloride salt.
  • Optically pure (-)-l-[(4-chlorophenyl)phenylmethyl]piperazine is isolated in the form of its hydrochloride salt with poor over all yield of about -50% yield.
  • the racemization occurs during the alkaline hydrolysis of ethoxycarbonyl group when used as a protecting group in the preparation of piperazine ring.
  • WO 2009/065622 discloses the process for synthesizing optically active compounds of formula (III) by reacting compound of formula (V) with compound of formula (X);
  • Z is C 3 -C 2 o cycloalkyl group, C 7 -C 20 aralkyl group, C 6 -C 20 aryl/alkylaryl group, each of which groups can be substituted by one to four halogen, alkoxy, amino and/or nitro groups; followed by alkaline hydrolysis.
  • the leaving group X may be represented by halogen or sulphonyl group such as mesyloxy, besyloxy, anisylsulfonyloxy or tosyloxy group.
  • the yield obtained by following the said process is poor, which is only 53%.
  • the challenge remains to obtain highly optically pure levocetirizine of pharmaceutical grade purity in good yield.
  • levocetirizine of formula (I) which is cost effective, safe and environment friendly. It appears to be desirable to provide an improved route for preparing levocetirizine or salt thereof
  • the object of present invention is a novel racemic or optically active carbamate intermediate of formula (IV A).
  • this novel racemic or optically active carbamate intermediate of formula (IVA) 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).
  • drugs having antihistaminic activity such as cetirizine (IA), meclizine (IB), chlorcyclizine (IC), clocinizine (ID), buclizine (IE) and enantiomers thereof such as levocetirizine (I).
  • Compound of formula (III) can be optionally converted into acid addition salts thereof. It is then treated with 2-chloroethanol in the presence of a suitable base and compound of formula
  • the compound of formula (II) is converted into acid addition salts thereof.
  • the salt of compound (II), thus obtained is crystallized by heating in suitable solvent and then cooling to produce the salt in good yield with enhanced optical purity, which subsequently give levocetirizine or pharmaceutically acceptable salt thereof.
  • 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 (IVA) 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).
  • drugs having antihistaminic activity such as cetirizine (IA), meclizine (IB), chlorcyclizine (IC), clocinizine (ID), buclizine (IE) and enantiomers thereof such as levocetirizine (I).
  • the compounds and reactions involving the optically active compounds are also applicable to their racemic mixture.
  • the present invention is directed to an improved process for the preparation of levocetirizine of formula (I) and pharmaceutically acceptable salts thereof via a novel optically active carbamate intermediate of formula (IV).
  • the present invention discloses a process, which does not involve use of expensive and toxic reagents. Further, the removal of carbamate group is carried out under mild conditions with less racemization, thus making the process environment friendly.
  • X is a leaving group.
  • the said leaving group can be selected from the group comprising of halogen, or sulphonyloxy group such as mesyloxy, besyloxy, anisylsulfonyloxy, tosyloxy group, preferably X is chloro; in the presence of a suitable base to yield the optically active compound of formula (IV).
  • Suitable base is selected from the group comprising of N,N-diisopropyl ethylamine, triethylamine, pyridine and the like.
  • the preferred base is N,N- diisopropyl ethylamine.
  • the optically active l-(4-chlorophenyl)phenylmethylamine (V) is prepared by resolution of racemic l-(4-chlorophenyl)phenylmethylamine by means of optically active tartaric acid according to the method described by R. Clemo et. al. (J. Chem. Soc, 1939, p. 1958-1960).
  • Suitable base is selected from inorganic bases.
  • Inorganic base is selected from the group comprising of hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals. Examples include potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate and like.
  • the preferred base is potassium hydroxide.
  • Solvent is selected from group comprising of organic solvents.
  • the organic solvent is selected from group comprising of alcohols, dimethyl sulphoxide, dimethylformamide, acetonitrile and like.
  • isopropyl alcohol is used for the reaction. This deprotection step is carried out at a temperature ranging from 60-90°C, preferably at 80-85°C.
  • the compound of formula (III) can be converted into acid addition salts thereof in a suitable solvent.
  • the acid addition salts can be prepared using the acids selected from the group comprising of organic or inorganic acids.
  • Inorganic acids include hydrochloric acid, hydrobromic acid and hydroiodic acid and the like.
  • the organic acids include oxalic acid, succinic acid and like. Preferably, it is isolated as oxalate salt.
  • the oxalate salt of compound (III) is obtained in high yield with high purity and can be easily handled and stored.
  • Solvent used for salt formation is selected from alcohols. Alcohol is selected from the group comprising of methanol, ethanol, isopropyl alcohol and the like. Free compound (III) is made available for further reaction by neutralizing its salt using suitable base such as sodium hydroxide, potassium hydroxide, or their carbonates and bicarbonates, preferrably sodium hydroxide.
  • the base is selected from organic base.
  • the organic base is selected from the group comprising of potassium tert-butoxide, dimethylamine, triethylamine, diisopropyl ethylamine, pyridine and like.
  • the preferred organic base is triethylamine.
  • Suitable solvent is selected from the group comprising of aliphatic or aromatic hydrocarbon and the like.
  • Aliphatic hydrocarbon is selected from group comprising of hexane, heptane, octane etc.
  • Aromatic hydrocarbon is selected from group comprising of toluene, xylene, chlorobenzene etc.
  • the preferred solvent is toluene.
  • the acid addition salts can be prepared using the acids selected from the group comprising of inorganic acids and organic acids such as hydrochloric acid, hydrobromic acid, oxalic acid and like.
  • the preferred acid is hydrochloric acid.
  • Solvent is selected from ketones.
  • Ketone is selected from group comprising of acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone and like.
  • the preferred solvent used is acetone. Selection of solvent is critical. It has been observed that the use of isopropyl alcohol leads to the salt which is difficult to handle as it is sticky in nature and results in salt having comparatively low purity. While acetone gives the salt which is free flowing. Due to better physical characteristics, the activities such as filtration etc are convenient on large scale.
  • Ketone is selected from group comprising of acetone, diethyl ketone, methyl isobutyl ketone, methyl ethyl ketone and the like.
  • the preferred solvent is aqueous acetone.
  • the temperature for carrying out crystallization is 40-70°C.
  • the crystallization is carried out at temperature of 50-55°C.
  • the salt gets dissolved, and on further cooling provides the salt of compound of formula (II) with enhanced optical purity of more than 99.5%.
  • hydrochloride salt of compound of formula (II) is obtained with optical purity 99.8%.
  • Compound (II) can be obtained as free base by neutralizing its salt with base such as aqueous ammonia in toluene.
  • Y is halogen and Z represents hydrogen or alkali metal such as sodium; in the presence of organic solvent and base.
  • the base is selected from the group comprising of hydrides, hydroxides, alkoxide of alkali metal or alkaline earth metal to yield levocetirizine.
  • the preferred base is alkali metal hydroxide such as potassium hydroxide.
  • Organic solvent is selected from the group comprising of ethers, amides, nitriles and dimethyl sulphoxide.
  • Amide is selected from the group comprising of dimethyl formamide, dimethyl acetamide and the like.
  • the preferred solvent is amide such as dimethylformamide.
  • isobutyloxy carbonyl derivative provides the superior results as compared with ethoxycarbonyl derivative. Quantitative yield of the reaction was obtained along with 90% purity of the reaction product, which makes the synthetic sequence commercially viable. Surprisingly, with isobutyloxycarbonyl derivative, racemization occurs comparatively to lesser extent.
  • the pH of the reaction mixture was adjusted to 5.0-5.5 by adding cone. HC1 (-30 ml) and then allowed to stir for 15 min. After separating the organic layer, 2% NaHC0 3 solution (dissolving 5 g NaHC0 3 in 250 ml water) was added with stirring. The organic layer was then separated and washed with water (250 ml). Finally, it was distilled out to obtain the residual mass as oil in quantitative yield.
  • the pH of the reaction mixture was adjusted to 0-1.0 by adding cone. HC1 (68 ml) at 25-30°C and allowed to stir for 15 min. After separating the aqueous layer, 380 ml of dichloromethane was added to acidic aqueous layer. The pH of the reaction mixture was adjusted to 1 1-12 by adding 30% NaOH solution at 25-30°C and stirred for 15 min. The aqueous layer was separated and extracted with dichloromethane (75 ml). The combined organic layer was washed with water (250 ml). The reaction mixture was concentrated under vacuum to give the title compound with 75% yield.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention concerne un nouvel intermédiaire carbamate de type racémique ou optiquement actif de formule (IV A). Ce nouvel intermédiaire carbamate de type racémique ou optiquement actif de formule (IV A) peut être utilisé pour préparer des médicaments ayant une activité antihistaminique tels que la cétirizine (IA), la méclizine (IB), la chlorcyclizine (IC), la clocinizine (ID), la buclizine (IE) et leurs énantiomères tels que la lévocétirizine (I). Cette invention concerne, en outre, un procédé de préparation amélioré de lévocétirizine faisant appel à un nouvel intermédiaire optiquement actif, à savoir, un composé de formule (IV). Un nouveau procédé de préparation d'un composé (II) et de cristallisation de son sel est également décrit.
PCT/IB2011/003075 2011-01-27 2011-12-19 Procédé de préparation amélioré d'antihistaminiques faisant appel à un nouvel intermédiaire carbamate WO2012101475A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN197/DEL/2011 2011-01-27
IN197DE2011 2011-01-27

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WO2012101475A1 true WO2012101475A1 (fr) 2012-08-02

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2819269A (en) * 1956-07-09 1958-01-07 Abbott Lab Carbalkoxy piperazine compounds
GB2225321A (en) 1988-11-23 1990-05-30 Ucb Sa Process for preparation of a 1-piperazine-ethoxyacetic acid
US5478941A (en) 1993-03-15 1995-12-26 U C B, S.A. Enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl) sulfonyl]piperazine
EP1236722A1 (fr) * 2001-02-22 2002-09-04 Sumitomo Chemical Company, Limited Dérivés optiquement actifs de 4-(tert-butoxycarbonyl)piperazine et leur procédé de fabrication
WO2007066163A2 (fr) 2005-12-08 2007-06-14 Egis Gyógyszergyár Nyilvanosan Mukodo Reszvenytarsasag Carbamates optiquement actifs, leur procede de preparation et leur utilisation en tant qu'intermediaires pharmaceutiques
WO2009065622A1 (fr) 2007-11-21 2009-05-28 Synthon B.V. Procédé de fabrication de n-(diphénylméthyl)pipérazines
WO2010057515A1 (fr) * 2008-11-21 2010-05-27 Synthon B.V. Lévocétirizine obtenue par des intermédiaires de menthyl

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2819269A (en) * 1956-07-09 1958-01-07 Abbott Lab Carbalkoxy piperazine compounds
GB2225321A (en) 1988-11-23 1990-05-30 Ucb Sa Process for preparation of a 1-piperazine-ethoxyacetic acid
US5478941A (en) 1993-03-15 1995-12-26 U C B, S.A. Enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl) sulfonyl]piperazine
EP1236722A1 (fr) * 2001-02-22 2002-09-04 Sumitomo Chemical Company, Limited Dérivés optiquement actifs de 4-(tert-butoxycarbonyl)piperazine et leur procédé de fabrication
US6803465B2 (en) 2001-02-22 2004-10-12 Sumitomo Chemical Company, Limited Optically active 4-(tert-butoxycarbonyl)piperazine compound, and method for producing the same
WO2007066163A2 (fr) 2005-12-08 2007-06-14 Egis Gyógyszergyár Nyilvanosan Mukodo Reszvenytarsasag Carbamates optiquement actifs, leur procede de preparation et leur utilisation en tant qu'intermediaires pharmaceutiques
WO2009065622A1 (fr) 2007-11-21 2009-05-28 Synthon B.V. Procédé de fabrication de n-(diphénylméthyl)pipérazines
WO2010057515A1 (fr) * 2008-11-21 2010-05-27 Synthon B.V. Lévocétirizine obtenue par des intermédiaires de menthyl

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
R. CLEMO, J CHEM. SOC., 1939, pages 1958 - 1960

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