EP1718627A4 - Process for preparing optically active cetirizine or its salt - Google Patents

Process for preparing optically active cetirizine or its salt

Info

Publication number
EP1718627A4
EP1718627A4 EP05726293A EP05726293A EP1718627A4 EP 1718627 A4 EP1718627 A4 EP 1718627A4 EP 05726293 A EP05726293 A EP 05726293A EP 05726293 A EP05726293 A EP 05726293A EP 1718627 A4 EP1718627 A4 EP 1718627A4
Authority
EP
European Patent Office
Prior art keywords
formula
optically active
cetirizine
compound
chlorophenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05726293A
Other languages
German (de)
French (fr)
Other versions
EP1718627A1 (en
Inventor
Jae-Shin Kim
Y-K Park
Mun-Choun Ha
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hanlim Pharmaceutical Co Ltd
Original Assignee
Hanlim Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hanlim Pharmaceutical Co Ltd filed Critical Hanlim Pharmaceutical Co Ltd
Publication of EP1718627A1 publication Critical patent/EP1718627A1/en
Publication of EP1718627A4 publication Critical patent/EP1718627A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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 method for optical resolution of racemic cetirizine or its salt. More particularly, the present invention relates to a process for preparing optically active cetirizine or its salt from racemic cetirizine or its salt using glutamate of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]acetic ester, and the glutamate of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]acetic ester useful as an intermediate for the preparation of the optically active cetirizine or its salt.
  • Background Art
  • Cetirizine is a material known as an antihistamine represented by the following structural formula. Generally, cetirizine is used in its dihydrochloride form and its chemical name is 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]acetic acid.
  • U.K Patent No. 2,225,321 discloses a process for preparing an optical isomer of cetirizine, that is, a process for preparing optically active cetirizine or its salt using optically active ace- tonitrile derivative as an intermediate.
  • U.S. Patent No. 5,478,941 discloses a process for preparing optically active cetirizine or its salt using (4-mefhylphenyl)sulfonyl-piperazine derivative as an intermediate.
  • the present invention provides a process for preparing optically active cetirizine or its salt.
  • the present invention also provides a compound useful as an intermediate for preparation of optically active cetirizine or its salt.
  • a process for preparing optically active cetirizine or its salt including: (a) reacting an optically active compound represented by formula 1 below with a base to prepare an optically active compound represented by formula 2a below; and (b) hydrolyzing the compound of the formula 2a:
  • R 1 is alkyl of C -C and R 2 is an amino protecting group.
  • the amino protecting group may be a common amino protecting group, for example, phenylsulfonyl, unsubstituted or substituted by lower alkyl of C -C ; sulfonyl 1 4 substituted by lower alkyl of C -C ; acetyl; ethoxycarbonyl; t-butoxycarbonyl; benzy- 1 4 loxycarbonyl; benzoyl; nicotinoyl; phthaloyl; or the like.
  • the amino protecting group may be phenylsulfonyl or (4-methylphenyl)sulfonyl.
  • the base that can be used in operation (a) is a common organic or inorganic base.
  • the base include sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide.
  • Operation (a) may be performed in a mixed solvent of a non-polar organic solvent and water, preferably a mixed solvent of methylene chloride and water or a mixed solvent of ethyl acetate and water.
  • the mixture ratio of the non-polar organic solvent to water is about 1 to 1 (v/v).
  • the optically active compound of the formula 2a can be separated using a common method, for example, by extraction of an organic layer followed by washing (if necessary), drying, and concentration.
  • amino protecting group-containing glutamic acids can be reused after recovery. That is, amino protecting group-containing glutamic acids obtained in operation (a) are mobilized to a water layer. The water layer is adjusted to pH 3 or less by addition of hydrochloric acid (HC1) and extracted with an organic solvent such as ethyl acetate. A combined organic layer is dried, filtered, and washed by common methods. An organic phase is concentrated, crystallized in an organic solvent such as diisopropylether, and filtered, to recover the amino protecting group-containing glutamic acids (yield: about 82 %) for reuse.
  • HC1 hydrochloric acid
  • an organic solvent such as ethyl acetate
  • a combined organic layer is dried, filtered, and washed by common methods.
  • An organic phase is concentrated, crystallized in an organic solvent such as diisopropylether, and filtered, to recover the amino protecting group-containing glutamic acids (yield: about 82 %) for reuse.
  • the hydrolysis reaction of operation (b) may be performed in an acidic or basic condition.
  • a basic condition is preferable.
  • Hydrolysis reaction in a basic condition may be performed using 1-2 equivalents of sodium hydroxide or potassium hydroxide.
  • the hydrolysis reaction may be performed in alcohol such as methanol, ethanol, and isopropanol, or a mixed solvent of alcohol and water, preferably in a mixed solvent of methanol and water.
  • the ratio (v/v) of alcohol to water may be about 4 to 6.
  • the hydrolysis reaction may be performed at 0 °C to reflux temperature, preferably 20 to 40 °C .
  • a reaction solution may be purified by washing with ethyl acetate.
  • a washed aqueous solution may be adjusted to pH 4-5 by addition of HC1 and extracted with methylene chloride.
  • Organic phases are combined and dried by a common method.
  • a hydrolysate obtained in operation (b) may react with HC1 in the presence of an organic solvent such as acetone to prepare optically active cetirizine hydrochloride.
  • optically active compound of the formula 1 used as a starting material in the preparation process of the present invention may be prepared by reacting a racemic compound represented by formula 2b below with an optically active compound represented by formula 3 below:
  • the compound of the formula 2b may be easily prepared by a preparation process disclosed in European Patent No. EP 58146 or by esterification of cetirizine dihydrochloride in alcohol in the presence of acid catalyst.
  • the compound of the formula 3 is commercially available or may be prepared by reacting glutamic acid with a common amino protecting group.
  • the amino protecting group may be phenylsulfonyl, unsubstituted or substituted by lower alkyl of C -C ; sulfonyl substituted by lower alkyl of C -C ; acetyl; ethoxycarbonyl; t-butoxycarbonyl; benzyloxycarbonyl; benzoyl; nicotinoyl; phthaloyl; or the like.
  • the amino protecting group may be phenylsulfonyl or (4-methylphenyl)sulfonyl.
  • the compound of the formula 3 may be prepared by reacting glutamic acid with phenylsulfonyl chloride or (4-methylphenyl)sulfonyl chloride in a mixed solvent of a common organic solvent and water, for example a mixed solvent of tetrahydrofuran and water, in the presence of a base such as triethylamine.
  • the reaction between the compound of the formula 2b and the optically active compound of the formula 3 may be performed in alcohol selected from the group consisting of methanol, ethanol, and isopropanol, or a mixed solvent of alcohol and water, preferably in ethanol, isopropanol, or a mixed solvent of isopropanol and water (95:5, v/v).
  • the compound of the formula 3 may react with the compound of the formula 2b in a mole ratio of 0.4-2.2 to 1, preferably 0.4-1.1 to 1.
  • the reaction between the compound of the formula 2b and the optically active compound of the formula 3 may be performed at 0 °C to reflux temperature, preferably at about 60 to 82 °C (or reflux temperature of a solvent).
  • optically active compound of the formula 1 obtained after the reaction between the compound of the formula 2b and the optically active compound of the formula 3 is recrystallized in alcohol selected from the group consisting of methanol, ethanol, and isopropanol, or a mixed solvent of alcohol and water, to obtain a purer product.
  • the re- crystallization may be performed as follows: a solid obtained by gradual cooling after reflux is filtered at 20 to 40 °C , preferably at 25-30 °C , to obtain a purer product.
  • the thus obtained compound of the formula 1 is an optically active compound. Therefore, the compound of the formula 1 can be used for preparation of optically active cetirizine or its salt. That is, an optically pure compound of the formula 1 may be separated using a common filtration process.
  • the compound of the formula 2b reacts with an L-isomer of the compound of the formula 3 to obtain a dextrorotatory compound of the formula 1 which then reacts with a base followed by hydrolysis and reaction with HC1 to obtain levorotatory cetirizine • dihydrochloride. Also, the compound of the formula 2b reacts with a D-isomer of the compound of the formula 3 to obtain a levorotatory compound of the formula 1 which then reacts with a base followed by hydrolysis and reaction with HC1 to obtain dextrorotatory cetirizine • dihydrochloride.
  • optical purity was measured by high-performance liquid chromatography (HPLC) (CHIRALCELL OD-R column, 250 x 4.6 mm, water (0.5 M NaClO , pH 2 buffer)-acetonitrile, 60:40 (v/v) mixed solvent, flow rate 0.5 ml/min) on a chiral stationary phase.
  • HPLC high-performance liquid chromatography
  • polarity was measured using JASCO P-1030
  • nuclear magnetic resonance (NMR) spectrum was measured using 300 MHz FT-NMR Spectrometer (JEOL JNM-LA300), and a melting point was measured using Buchi B- 545.
  • Example 1 preparation of racemic methyl 2-r2-r4-r(4-chloropheny phenylmethyll - 1-piperazinyllethoxyl acetate
  • the resultant solution was adjusted to pH 3 or less by addition of 33.3 ml (0.2 mole) of a 6 N hydrochloric acid solution and extracted with 150 ml of ethyl acetate continuously three times.
  • a combined organic phase was washed with 100 ml of an aqueous saturated sodium chloride solution.
  • the washed organic phase was dried over anhydrous magnesium sulfate, filtered, washed with ethyl acetate, and concentrated.
  • the concentrate was crystallized by addition of 150 ml of diisopropylether.
  • the resultant solid was filtered and washed with a small quantity of diisopropylether to give 21.79 g of (+)-N-(phenylsulfonyl)-D-glutamic acid as a desired product.
  • Example 3 preparation of (-VN-r(4-methylphenyl)sulfonyll -D-glutamic acid
  • Example 4 preparation of dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- (phenylsulfonyl)-L- glutamate
  • the reaction solution was cooled to room temperature, and the precipitated solid was filtered, washed with a small quantity of a mixed solvent of isopropanol and water, and dried.
  • the dried solid was recrystallized in a mixed solvent (95:5, v/v) of isopropanol and water to give 7.68 g of dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy ] acetate • N- (phenylsulfonyl)-L-glutamate.
  • Example 5 preparation of levorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- (phenylsulfonylVD- lutamate [65] 15.19 g (0.038 mole) of the racemic methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl ]-l-piperazinyl]efhoxy]acetate prepared in Example 1 was dissolved in 150 ml of a mixed solvent (95:5, v/v) of isopropanol and water, heated to 60 °C , and then stirred for one hour after addition of 11.00 g (0.038 mole) of (+)-N- (phenylsulfonyl) -D-glutamic acid prepared in Example 2.
  • reaction solution was cooled to room temperature, and the precipitated solid was filtered, washed with a small quantity of a mixed solvent of isopropanol and water, and dried.
  • the dried solid was recrystallized in a mixed solvent (95:5, v/v) of isopropanol and water to give 8.47 g of levorotatory methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy ] acetate • N-(phenylsulfonyl)-D-glutamate.
  • Example 6 preparation of dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- [(4-methylphenyl)sulfonyll-L-glutamate
  • Example 7 preparation of dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- r(4-methylphenyl)sulfonyll-L-glutamate
  • Example 8 preparation of levorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- [(4-methylphenyl)sulfonyll -D-glutamate
  • the reaction solution was cooled to room temperature, and the precipitated solid was filtered, washed with a small quantity of a mixed solvent of isopropanol and water, and dried.
  • the dried solid was recrystallized in a mixed solvent (95:5, v/v) of isopropanol and water to give 10.10 g of levorotatory methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy ] acetate • N- [(4-methylphenyl)sulfonyl] -D-glutamate.
  • Example 10 preparation of levorotatory 2-r2-r4-r(4-chloropheny phenylmethyll - 1-piperazinyllethoxyl acetic acid • dihydrochloride (cetirizine • dihydrochloride)
  • Example 11 preparation of levorotatory 2-r2-r4-r(4-chloropheny phenylmethyll - 1-piperazinyllethoxyl acetic acid • dihydrochloride (cetirizine • dihydrochloride [ 104] 1.84 g of levorotatory 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetic acid • dihydrochloride was prepared in the same manner as in Example 10 using 3.25 g (4.62 mmole) of the dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetate • N- [(4-methylphenyl)sulfonyl]-L-glutamate prepared in Example 7.
  • Example 12 preparation of dextrorotatory 2-[2-[4-[(4-chlorophenyl)phenylmethyll -1 -piperazinyll ethoxyl acetic acid • dihydrochloride (cetirizine • dihydrochloride)
  • the concentrate was dissolved in 9.1 ml of methanol and 13.6 ml of a IN aqueous sodium hydroxide solution was gradually added thereto.
  • the reaction mixture was stirred at room temperature for 3 hours and then washed with 91 ml of ethyl acetate after addition of 77.4 ml of water.
  • the aqueous solution phase was adjusted to pH 4-5 by addition of a IN hydrochloric acid solution and extracted with 91 ml of methylene chloride continuously three times.
  • a combined organic phase was dried over anhydrous magnesium sulfate, filtered, washed with methylene chloride, and concentrated.
  • Example 13 preparation of dextrorotatory 2-r2-r4-r(4-chlorophenyl)phenylmethyll -1 -piperazinyll ethoxyl acetic acid • dihydrochloride (cetirizine • dihydrochloride)
  • Example 12 After 91 ml of ethyl acetate was added to 9.10 g (0.013 mole) of the levorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetate • N-[(4-methylphenyl)sulfonyl]-D-glutamate prepared in Example 8, 91 ml of a 0.5 M aqueous sodium hydrogen carbonate solution was gradually added and stirred for one hour, and then an organic phase was extracted, a residual aqueous solution of 0.5 M sodium hydrogen carbonate was adjusted to pH 3 or less by addition of 47 ml of IN hydrochloric acid solution and extracted with 50 ml of ethyl acetate continuously three times.
  • optical resolution of racemic cetirizine or its salt using glutamate of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy] acetic ester can produce optically active cetirizine or its salt with high yield and purity.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

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)phenylmethyl]-1-piperazinyl] ethoxy]acetic ester useful as an intermediate for the preparation of the optically active cetirizine or its salt.

Description

Description PROCESS FOR PREPARING OPTICALLY ACTIVE CETIRIZINE OR ITS SALT Technical Field
[1] The present invention relates to a method for optical resolution of racemic cetirizine or its salt. More particularly, the present invention relates to a process for preparing optically active cetirizine or its salt from racemic cetirizine or its salt using glutamate of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]acetic ester, and the glutamate of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]acetic ester useful as an intermediate for the preparation of the optically active cetirizine or its salt. Background Art
[2] Cetirizine is a material known as an antihistamine represented by the following structural formula. Generally, cetirizine is used in its dihydrochloride form and its chemical name is 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]acetic acid.
[3]
[4] Optically active cetirizine compounds including levorotatory (-) or dextrorotatory (+) forms of cetirizine dihydrochloride are known to have various additional pharmacological effects. For example, U.S. Patent No. 5,627,183 discloses therapeutic effects of (+) -cetirizine in urticaria and U.S. Patent No. 5,698,558 discloses therapeutic effects of (-)-cetirizine in allergic rhinitis.
[5] Meanwhile, U.K Patent No. 2,225,321 (Korean Patent Laid-Open Publication No. 1990-7825) discloses a process for preparing an optical isomer of cetirizine, that is, a process for preparing optically active cetirizine or its salt using optically active ace- tonitrile derivative as an intermediate. U.S. Patent No. 5,478,941 (Korean Patent Laid- Open Publication No. 1994-21541, European Patent No. EP955295) discloses a process for preparing optically active cetirizine or its salt using (4-mefhylphenyl)sulfonyl-piperazine derivative as an intermediate. [6] The above-described conventional processes are based on preparation of cetirizine or its salt as a final product using an optically active intermediate. However, multi-step preparation of the final product is required and yield is also unsatisfactory. That is, according to U.K. Patent No. 2,225,321, the optical resolution yield of l-[(4-chlorophenyl)phenylmethyl]piperazine used as a starting material is about 12.7%. According to U.S. Patent No. 5,478,941, the yield of dextrorotatory
[7] 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]acetic acid • dihydrochloride prepared from an intermediate which is an ester compound from optically resolved (-)-(4-chlorophenyl)phenylmethylamine is only about 29.3 %. Disclosure of Invention Technical Problem
[8] While searching for an improved preparation process for optically pure cetirizine or its salt, the present inventors found that when racemic cetirizine or its salt is switched to its glutamate intermediate, high yield and purity optical resolution of racemic cetirizine or its salt can be achieved. The present inventors thus completed the present invention.
[9] Therefore, the present invention provides a process for preparing optically active cetirizine or its salt.
[10] The present invention also provides a compound useful as an intermediate for preparation of optically active cetirizine or its salt. Technical Solution
[11] According to an aspect of the present invention, there is provided a process for preparing optically active cetirizine or its salt, including: (a) reacting an optically active compound represented by formula 1 below with a base to prepare an optically active compound represented by formula 2a below; and (b) hydrolyzing the compound of the formula 2a:
[12] <Formula 1>
[13] <Formula 2a>
[14] wherein R 1 is alkyl of C -C and R 2 is an amino protecting group. 1 6
[15] The amino protecting group may be a common amino protecting group, for example, phenylsulfonyl, unsubstituted or substituted by lower alkyl of C -C ; sulfonyl 1 4 substituted by lower alkyl of C -C ; acetyl; ethoxycarbonyl; t-butoxycarbonyl; benzy- 1 4 loxycarbonyl; benzoyl; nicotinoyl; phthaloyl; or the like. Preferably, the amino protecting group may be phenylsulfonyl or (4-methylphenyl)sulfonyl.
[16] In the preparation process of the present invention, the base that can be used in operation (a) is a common organic or inorganic base. Examples of the base include sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Operation (a) may be performed in a mixed solvent of a non-polar organic solvent and water, preferably a mixed solvent of methylene chloride and water or a mixed solvent of ethyl acetate and water. Preferably, the mixture ratio of the non-polar organic solvent to water is about 1 to 1 (v/v). The optically active compound of the formula 2a can be separated using a common method, for example, by extraction of an organic layer followed by washing (if necessary), drying, and concentration.
[17] Meanwhile, amino protecting group-containing glutamic acids can be reused after recovery. That is, amino protecting group-containing glutamic acids obtained in operation (a) are mobilized to a water layer. The water layer is adjusted to pH 3 or less by addition of hydrochloric acid (HC1) and extracted with an organic solvent such as ethyl acetate. A combined organic layer is dried, filtered, and washed by common methods. An organic phase is concentrated, crystallized in an organic solvent such as diisopropylether, and filtered, to recover the amino protecting group-containing glutamic acids (yield: about 82 %) for reuse. In particular, considering that D-glutamic acid is a 25 times more expensive reagent than L-glutamic acid, the preparation process of the present invention guaranteeing the recovery and reuse of D-glutamic acid is economically very advantageous.
[18] The hydrolysis reaction of operation (b) may be performed in an acidic or basic condition. A basic condition is preferable. Hydrolysis reaction in a basic condition may be performed using 1-2 equivalents of sodium hydroxide or potassium hydroxide. Also, the hydrolysis reaction may be performed in alcohol such as methanol, ethanol, and isopropanol, or a mixed solvent of alcohol and water, preferably in a mixed solvent of methanol and water. When the hydrolysis reaction is performed in a mixed solvent, the ratio (v/v) of alcohol to water may be about 4 to 6. The hydrolysis reaction may be performed at 0 °C to reflux temperature, preferably 20 to 40 °C . When needed, a reaction solution may be purified by washing with ethyl acetate. A washed aqueous solution may be adjusted to pH 4-5 by addition of HC1 and extracted with methylene chloride. Organic phases are combined and dried by a common method.
[19] According to the preparation process of the present invention, a hydrolysate obtained in operation (b) may react with HC1 in the presence of an organic solvent such as acetone to prepare optically active cetirizine hydrochloride.
[20] The optically active compound of the formula 1 used as a starting material in the preparation process of the present invention may be prepared by reacting a racemic compound represented by formula 2b below with an optically active compound represented by formula 3 below:
[21] <Formula 2b>
1 2
[23] wherein R and R are as defined in the above. [24] The compound of the formula 2b may be easily prepared by a preparation process disclosed in European Patent No. EP 58146 or by esterification of cetirizine dihydrochloride in alcohol in the presence of acid catalyst. [25] The compound of the formula 3 is commercially available or may be prepared by reacting glutamic acid with a common amino protecting group. The amino protecting group may be phenylsulfonyl, unsubstituted or substituted by lower alkyl of C -C ; sulfonyl substituted by lower alkyl of C -C ; acetyl; ethoxycarbonyl; t-butoxycarbonyl; benzyloxycarbonyl; benzoyl; nicotinoyl; phthaloyl; or the like. Preferably, the amino protecting group may be phenylsulfonyl or (4-methylphenyl)sulfonyl. For example, when phenylsulfonyl or (4-mefhylphenyl)sulfonyl is used as the amino protecting group, the compound of the formula 3 may be prepared by reacting glutamic acid with phenylsulfonyl chloride or (4-methylphenyl)sulfonyl chloride in a mixed solvent of a common organic solvent and water, for example a mixed solvent of tetrahydrofuran and water, in the presence of a base such as triethylamine.
[26] The reaction between the compound of the formula 2b and the optically active compound of the formula 3 may be performed in alcohol selected from the group consisting of methanol, ethanol, and isopropanol, or a mixed solvent of alcohol and water, preferably in ethanol, isopropanol, or a mixed solvent of isopropanol and water (95:5, v/v). The compound of the formula 3 may react with the compound of the formula 2b in a mole ratio of 0.4-2.2 to 1, preferably 0.4-1.1 to 1. Also, the reaction between the compound of the formula 2b and the optically active compound of the formula 3 may be performed at 0 °C to reflux temperature, preferably at about 60 to 82 °C (or reflux temperature of a solvent).
[27] The optically active compound of the formula 1 obtained after the reaction between the compound of the formula 2b and the optically active compound of the formula 3 is recrystallized in alcohol selected from the group consisting of methanol, ethanol, and isopropanol, or a mixed solvent of alcohol and water, to obtain a purer product. The re- crystallization may be performed as follows: a solid obtained by gradual cooling after reflux is filtered at 20 to 40 °C , preferably at 25-30 °C , to obtain a purer product.
[28] The thus obtained compound of the formula 1 is an optically active compound. Therefore, the compound of the formula 1 can be used for preparation of optically active cetirizine or its salt. That is, an optically pure compound of the formula 1 may be separated using a common filtration process.
[29] For example, in a case where a solid obtained by the filtration process is used in a next process, the compound of the formula 2b reacts with an L-isomer of the compound of the formula 3 to obtain a dextrorotatory compound of the formula 1 which then reacts with a base followed by hydrolysis and reaction with HC1 to obtain levorotatory cetirizine • dihydrochloride. Also, the compound of the formula 2b reacts with a D-isomer of the compound of the formula 3 to obtain a levorotatory compound of the formula 1 which then reacts with a base followed by hydrolysis and reaction with HC1 to obtain dextrorotatory cetirizine • dihydrochloride. [30] In a case where a filtrate obtained by the filtration process is used in a next process, the compound of the formula 2b reacts with a D-isomer of the compound of the formula 3 to obtain the compound of the formula 1 in the filtrate, which then reacts with a base followed by hydrolysis and reaction with HC1 to obtain levorotatory cetirizine • dihydrochloride. Also, the compound of the formula 2b reacts with a L- isomer of the compound of the formula 3 to obtain the compound of the formula 1 { [ ] 25 : +84.50 (c = 1, methanol)} in the filtrate, which then reacts with a base followed 365 by hydrolysis and reaction with HC1 to obtain dextrorotatory cetirizine • dihy- 25 drochloride { [ ] : + 10.91 (c = 1, water): optical purity 87 % ee}. 365
[31] Meanwhile, considering that D-glutamic acid is a 25 times more expensive reagent than L-glutamic acid (based on prices of Aldrich), to prepare levorotatory cetirizine • dihydrochloride, it is preferable to use a dextrorotatory compound of the formula 1 obtained as a solid by filtration after reaction between the compound of the formula 2b and an L-isomer of the compound of the formula 3. To prepare dextrorotatory cetirizine • dihydrochloride, it is preferable to use the compound of the formula 1 obtained as a filtrate by filtration after reaction between the compound of the formula 2b and an L-isomer of the compound of the formula 3.
[32] According to another aspect of the present invention, there is provided a compound of formula 1 below useful as an intermediate for preparation of optically active cetirizine or its hy drochloride:
[33] <Formula 1>
1 2
[34] wherein R and R are as defined in the above. [35] Even though an illustrative structural form of the compound of the formula 1 is unknown, it is inferred that 1 mole of the compound of the formula 2a and 1 mole of the compound of the formula 3 are present in the form of a salt.
[36] The overall scheme of the preparation process of the present invention is shown in Scheme 1 below:
[37] <Scheme 1>
1 2
[38] wherein R and R are as defined in the above. Best Mode
[39] Best mode for carrying out the Invention
[40] Hereinafter, the present invention will be described more specifically by Examples. However, the following Examples are provided only for illustrations and thus the present invention is not limited to or by them.
[41] In the following Examples, optical purity was measured by high-performance liquid chromatography (HPLC) (CHIRALCELL OD-R column, 250 x 4.6 mm, water (0.5 M NaClO , pH 2 buffer)-acetonitrile, 60:40 (v/v) mixed solvent, flow rate 0.5 ml/min) on a chiral stationary phase. In addition, polarity was measured using JASCO P-1030, nuclear magnetic resonance (NMR) spectrum was measured using 300 MHz FT-NMR Spectrometer (JEOL JNM-LA300), and a melting point was measured using Buchi B- 545.
[42] Example 1: preparation of racemic methyl 2-r2-r4-r(4-chloropheny phenylmethyll - 1-piperazinyllethoxyl acetate
[43] 100 g (0.217 mole) of racemic cetirizine dihydrochloride was dissolved in 400 ml of methanol and 2 ml of concentrated sulfuric acid was gradually added thereto. A reaction mixture was refluxed for 10 hours and concentrated. 300 ml of methylene chloride was added to an obtained concentrate and neutralized with 300 ml of an aqueous saturated sodium hydrogen carbonate solution to extract an organic phase. 300 ml of methylene chloride was added to an aqueous phase to re-extract an organic phase. Combined organic phases were washed with an aqueous saturated sodium chloride solution (2 x 200 ml). A washed organic phase was dried over anhydrous sodium sulfate, filtered, washed with methylene chloride, and concentrated, to give 82.88 g of racemic methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl] ethoxy] acetate as oil form.
[44] Yield: 95.0 %
[45] 1 H-NMR (CDC1 ) ppm : 2.43(br s, 4H), 2.55(br s, 4H), 2.64(t, 2H), 3.66(t, 2H), 3.72(s, 3H), 4.10(s, 2H), 4.20(s, 1H), 7.15-7.30(m, 5H), 7.33-7.37(m, 4H)
[46] Example 2: preparation of (+VN-(phenylsulfonylVD-glutamic acid
[47] 42 ml (0.3 mole) of triethylamine was gradually added to a solution of 14.71 g (0.1 mole) of D-glutamic acid in 150 ml of water with stirring. 150 ml of tetrahydrofuran was added to the reaction mixture and cooled to 5 °C . 12.8 ml (0.1 mole) of ben- zenesulfonyl chloride was gradually added to the reaction mixture and stirred for 3 hours. After the reaction terminated, the reaction solution was concentrated at 30 °C to remove tetrahydrofuran and washed with 150 ml of methylene chloride. The resultant solution was adjusted to pH 3 or less by addition of 33.3 ml (0.2 mole) of a 6 N hydrochloric acid solution and extracted with 150 ml of ethyl acetate continuously three times. A combined organic phase was washed with 100 ml of an aqueous saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate, filtered, washed with ethyl acetate, and concentrated. The concentrate was crystallized by addition of 150 ml of diisopropylether. The resultant solid was filtered and washed with a small quantity of diisopropylether to give 21.79 g of (+)-N-(phenylsulfonyl)-D-glutamic acid as a desired product.
[48] m.p.: 133.1 °C
[49] Yield: 75.9 %
[50] 1 H-NMR (DMSO-d ) ppm : 1.59-1.69(m, 1H), 1.80-1.86(m, 1H), 2.17(t, 2H), 3.76(m, 1H), 7.51-7.63(m, 3H), 7.73-7.76(m, 2H), 8.15(d, 1H), 12.40(br s, 2H) [51] [ ]24 : + 14.09 (c = 5, water) 589
[52] Example 3: preparation of (-VN-r(4-methylphenyl)sulfonyll -D-glutamic acid
[53] 23.53 g of (-)-N-[(4-methylphenyl)sulfonyl] -D-glutamic acid was prepared in the same manner as in Example 2 except that 19.07 g (0.1 mole) of p-toluenesulfonyl chloride was used instead of benzenesulfonyl chloride. [54] m.p. : 127.3 °C
[55] Yield: 78.1%
[56] 1 H-NMR (DMSO-d ) ppm: 1.58-1.68(m, 1H), 1.76-1.88(m, 1H), 2.18(t, 2H), 2.35(s, 3H), 3.73(m, 1H), 7.34(d, 2H), 7.62(d, 2H), 8.08(d, 1H), 12.40(br s, 2H) [57] [ ]20 : -12.90 (c = 5, acetone) 589
[58] Example 4: preparation of dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- (phenylsulfonyl)-L- glutamate
[59] 12.75 g (0.032 mole) of the racemic methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl ]-l-piperazinyl]efhoxy]acetate prepared in Example 1 was dissolved in 130 ml of a mixed solvent (95:5, v/v) of isopropanol and water, heated to 60 °C , and then stirred for one hour after addition of 9.3 g (0.032 mole) of (-)-N-(phenylsulfonyl)-L-glutamic acid. The reaction solution was cooled to room temperature, and the precipitated solid was filtered, washed with a small quantity of a mixed solvent of isopropanol and water, and dried. The dried solid was recrystallized in a mixed solvent (95:5, v/v) of isopropanol and water to give 7.68 g of dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy ] acetate • N- (phenylsulfonyl)-L-glutamate.
[60] m.p. : 124.3 °C
[61] Yield: 70.3 %
[62] 1 H-NMR (TFA-d ) ppm : 2.11-2.23(m, 1H), 2.40-2.52(m, 1H), 2.8 l(t, 2H), 3.76(br s, 2H), 3.93-4.17(m, 11H), 4.32-4.41(m, 5H), 5.54(br s, 1H), 7.58-7.83(m, 12H), 8.03(d, 2H)
[63] [ ]25 : +94.90 (c = 1, methanol) 365
[64] Example 5: preparation of levorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- (phenylsulfonylVD- lutamate [65] 15.19 g (0.038 mole) of the racemic methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl ]-l-piperazinyl]efhoxy]acetate prepared in Example 1 was dissolved in 150 ml of a mixed solvent (95:5, v/v) of isopropanol and water, heated to 60 °C , and then stirred for one hour after addition of 11.00 g (0.038 mole) of (+)-N- (phenylsulfonyl) -D-glutamic acid prepared in Example 2. The reaction solution was cooled to room temperature, and the precipitated solid was filtered, washed with a small quantity of a mixed solvent of isopropanol and water, and dried. The dried solid was recrystallized in a mixed solvent (95:5, v/v) of isopropanol and water to give 8.47 g of levorotatory methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy ] acetate • N-(phenylsulfonyl)-D-glutamate.
[66] m.p. : 125.4 °C
[67] Yield: 65.1 %
[68] 1 H-NMR (TFA-d ) ppm : 2.11-2.23(m, 1H), 2.40-2.52(m, 1H), 2.8 l(t, 2H), 3.76(br s, 2H), 3.93-4.17(m, 11H), 4.36-4.41(m, 5H), 5.54(br s, 1H), 7.58-7.83(m, 12H), 8.03(d, 2H)
[69] [ ]25 : - 92.23 (c = l, methanol) 365
[70] Example 6: preparation of dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- [(4-methylphenyl)sulfonyll-L-glutamate
[71] 13.07 g (0.032 mole) of the racemic methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl ]-l-piperazinyl]efhoxy]acetate prepared in Example 1 was dissolved in 130 ml of a mixed solvent (95:5, v/v) of isopropanol and water, heated to 60 °C , and then stirred for one hour after addition of 10.00 g (0.033 mole) of (+)-N-(p-toluenesulfonyl)-L-glutamic acid. The reaction solution was cooled to room temperature, and the precipitated solid was filtered, washed with a small quantity of a mixed solvent of isopropanol and water, and dried. The dried solid was recrystallized in a mixed solvent (95:5, v/v) of isopropanol and water to give 10.36 g of dextrorotatory methyl 2- [2- [4- [(4-chloropheny l)pheny lmethy 1] - 1 -piperaziny 1] ethoxy ] acetate • N-[(4-methylphenyl)sulfonyl]-L-glutamate.
[72] m.p. : 149.5 °C
[73] Yield: 90.7 %
[74] 1 H-NMR (TFA-d ) ppm : 2.23(m, 1H), 2.49(m, 1H), 2.61(s, 3H), 2.85(br s, 2H), 3.82(br s, 2H), 4.03-4.22(m, 11H), 4.44(m, 5H), 5.59(br s, 1H), 7.57(d, 2H), 7.66-7.73(m, 9H), 7.96(d, 2H)
[75] [ ]25 : + 110.73 (c = 1, methanol) 365
[76] Example 7: preparation of dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- r(4-methylphenyl)sulfonyll-L-glutamate
[77] A solid was obtained in the same manner as in Example 6 using 10.00 g (0.025 mole) of the racemic methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl] ethoxy] acetate prepared in Example 1 and 7.85 g (0.026 mole) of (+)-N-(p-toluenesulfonyl)-L-glutamic acid. The solid was twice recrystallized in ethanol to give 5.58 g of optically purer dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetate • N- [(4-methylphenyl)sulfonyl]-L-glutamate. [78] m.p. : 150.2 °C
[79] Yield: 63.9 %
[80] 1 H-NMR (TFA-d ) ppm : 2.17-2.25(m, IH), 2.46-2.52(m, IH), 2.60(s, 3H), 2.84(t, 2H), 3.80(br s, 2H), 4.01-4.21(m, 11H), 4.38-4.42(m, 5H), 5.58(br s, IH), 7.55(d, 2H), 7.62-7.73(m, 9H), 7.94(d, 2H) [81] [ ]25 : + 111.00 (c = 1, methanol) 365
[82] Example 8: preparation of levorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- [(4-methylphenyl)sulfonyll -D-glutamate
[83] 13.74 g (0.034 mole) of the racemic methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl ]-l-piperazinyl]efhoxy]acetate prepared in Example 1 was dissolved in 140 ml of a mixed solvent (95:5, v/v) of isopropanol and water, heated to 60 °C , and then stirred for one hour after addition of 10.50 g (0.035 mole) of the (-)-N-[(4-methylphenyl)sulfonyl]-D-glutamic acid prepared in Example 3. The reaction solution was cooled to room temperature, and the precipitated solid was filtered, washed with a small quantity of a mixed solvent of isopropanol and water, and dried. The dried solid was recrystallized in a mixed solvent (95:5, v/v) of isopropanol and water to give 10.10 g of levorotatory methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy ] acetate • N- [(4-methylphenyl)sulfonyl] -D-glutamate.
[84] m.p. : 150.2 °C
[85] Yield: 84.1%
[86] 1 H-NMR (TFA-d ) ppm : 2.20(m, IH), 2.47(m, IH), 2.58(s, 3H), 2.83(t, 2H), 3.79(br s, 2H), 4.00-4.19(m, 11H), 4.37-4.41(m, 5H), 5.57(br s, IH), 7.54(d, 2H), 7.61-7.72(m, 9H), 7.93(d, 2H)
[87] [ ]25 : - 104.62 (c = 1, methanol) 365
[88] Example 9: preparation of levorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- [(4-methylphenyl)sulfonyll -D-glutamate
[89] A solid was obtained in the same manner as in Example 8 using 12.17 g (0.030 mole) of the racemic methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl]-l -piperazinyl] ethoxy] acetate prepared in Example 1 and 9.29 g (0.031 mole) of the (-)-N-[(4-methylphenyl)sulfonyl]-D-glutamic acid prepared in Example 3. The solid was twice recrystallized in ethanol to give 6.47 g of optically purer levorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetate • N- [(4-methylphenyl)sulfonyl]-D-glutamate.
[90] m.p. : 151.0 °C
[91] Yield: 60.8 % [92] 1 H-NMR (TFA-d ) ppm : 2.19-2.24(m, IH), 2.45-2.49(m, IH), 2.59(s, 3H), 2.84(t, 2H), 3.79(br s, 2H), 4.01-4.20(m, 11H), 4.37-4.41(m, 5H), 5.58(br s, IH), 7.55(d, 2H), 7.61-7.72(m, 9H), 7.94(d, 2H)
[93] [ ]25 365 : - 107.08 (c = 1, methanol)
[94] Example 10: preparation of levorotatory 2-r2-r4-r(4-chloropheny phenylmethyll - 1-piperazinyllethoxyl acetic acid • dihydrochloride (cetirizine • dihydrochloride)
[95] 94 ml of ethyl acetate was added to 9.36 g (0.013mole) of the dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetate • N- [(4-methylphenyl)sulfonyl]-L-glutamate prepared in Example 6 and 94 ml of a 0.5 M aqueous sodium hydrogen carbonate solution was gradually added thereto. The reaction mixture was stirred for one hour, and an organic phase was extracted and washed with a 0.5 M aqueous sodium chloride solution (2 x 94 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and washed with ethyl acetate, and concentrated.
[96] The concentrate was dissolved in 9.4 ml of methanol and 14 ml of a IN aqueous sodium hydroxide solution was gradually added thereto. The reaction mixture was stirred at room temperature for 3 hours and then washed with 94 ml of ethyl acetate after addition of 80 ml of water. The resultant aqueous solution was adjusted to pH 4-5 by addition of 14 ml of a IN hydrochloric acid solution and extracted with 94 ml of methylene chloride continuously three times. A combined organic phase was dried over anhydrous magnesium sulfate, filtered, washed with methylene chloride, and concentrated.
[97] The concentrate was dissolved in 94 ml of acetone at room temperature and 2.50 ml of concentrated hydrochloric acid was added thereto. The precipitated solid was filtered, washed with a small quantity of acetone, and dried, to give 5.11 g of levorotatory 2- [2- [4- [(4-chlorophenyl)phenylmethyl]-l -piperazinyl] ethoxy] acetic acid • dihydrochloride.
[98] m.p. : 216.7 °C
[99] Yield: 83.3 %
[100] 1 H-NMR (CD OD) ppm : 3.59(br s, 6H), 3.93(br s, 6H), 4.20 (d, 2H), 5.74(br s, IH), 7.39-7.50(m, 5H), 7.86-7.90(m, 4H)
[101] [ ]25 : - 12.49 (c = 1, water) 365
[ 102] Optical purity : 95 % ee
[103] Example 11: preparation of levorotatory 2-r2-r4-r(4-chloropheny phenylmethyll - 1-piperazinyllethoxyl acetic acid • dihydrochloride (cetirizine • dihydrochloride [ 104] 1.84 g of levorotatory 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetic acid • dihydrochloride was prepared in the same manner as in Example 10 using 3.25 g (4.62 mmole) of the dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetate • N- [(4-methylphenyl)sulfonyl]-L-glutamate prepared in Example 7.
[105] m.p. : 215.7 °C
[106] Yield: 86.3%
[107] 1 H-NMR (CD OD) ppm : 3.57(br s, 6H), 3.93(br s, 6H), 4.20 (d, 2H), 5.74(br s, IH), 7.38-7.50(m, 5H), 7.86-7.90(m, 4H)
[108] [ ]25 : - 12.79 (c = 1, water) 365
[109] Optical purity: 99.6 % ee
[110] Example 12: preparation of dextrorotatory 2-[2-[4-[(4-chlorophenyl)phenylmethyll -1 -piperazinyll ethoxyl acetic acid • dihydrochloride (cetirizine • dihydrochloride)
[111] 91 ml of ethyl acetate was added to 9.10 g (0.013mole) of the levorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetate • N- [(4-methylphenyl)sulfonyl] -D-glutamate prepared in Example 8 and 91 ml of a 0.5 M aqueous sodium hydrogen carbonate solution was gradually added thereto. The reaction mixture was stirred for one hour, and an organic phase was extracted and washed with a 0.5 M aqueous sodium chloride solution (2 x 91 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, washed with ethyl acetate, and concentrated.
[112] The concentrate was dissolved in 9.1 ml of methanol and 13.6 ml of a IN aqueous sodium hydroxide solution was gradually added thereto. The reaction mixture was stirred at room temperature for 3 hours and then washed with 91 ml of ethyl acetate after addition of 77.4 ml of water. The aqueous solution phase was adjusted to pH 4-5 by addition of a IN hydrochloric acid solution and extracted with 91 ml of methylene chloride continuously three times. A combined organic phase was dried over anhydrous magnesium sulfate, filtered, washed with methylene chloride, and concentrated.
[113] The concentrate was dissolved in 91 ml of acetone at room temperature and 2.44 ml of concentrated hydrochloric acid was added thereto. The precipitated solid was filtered, washed with a small quantity of acetone, and dried, to give 5.27 g of dextrorotatory 2- [2- [4- [(4-chlorophenyl)phenylmethyl]-l -piperazinyl] ethoxy] acetic acid • dihydrochloride.
[114] m.p. : 217.3 °C
[115] Yield: 88.3%
[116] 1 H-NMR (CD OD) ppm : 3.57(br s, 6H), 3.92(br s, 6H), 4.21(d, 2H), 5.71(br s, IH), 7.38-7.49(m, 5H), 7.85-7.89(m, 4H)
[117] [ ]25 : + 12.25 (c = 1, water) 365
[118] Optical purity: 95 % ee
[119] Example 13: preparation of dextrorotatory 2-r2-r4-r(4-chlorophenyl)phenylmethyll -1 -piperazinyll ethoxyl acetic acid • dihydrochloride (cetirizine • dihydrochloride)
[ 120] 2.23 g of dextrorotatory 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetic acid • dihydrochloride was prepared in the same manner as in Example 12 using 4.00 g (5.68 mmole) of the levorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetate • N- [(4-methylphenyl)sulfonyl] -D-glutamate prepared in Example 9.
[121] m.p. : 215.6 °C
[122] Yield: 85.0%
[123] 1 H-NMR (CD OD) ppm : 3.58(br s, 6H), 3.93(br s, 6H), 4.20 (d, 2H), 5.74(br s, IH), 7.38-7.50(m, 5H), 7.86-7.90(m, 4H)
[124] [ ]25 : + 12.81 (c = 1, water) 365
[125] Optical purity: 99.2 % ee
[126] Example 14: recovery of (-)-N-[(4-methylphenyl)sulfonyll-D-glutamic acid
[127] In Example 12, after 91 ml of ethyl acetate was added to 9.10 g (0.013 mole) of the levorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetate • N-[(4-methylphenyl)sulfonyl]-D-glutamate prepared in Example 8, 91 ml of a 0.5 M aqueous sodium hydrogen carbonate solution was gradually added and stirred for one hour, and then an organic phase was extracted, a residual aqueous solution of 0.5 M sodium hydrogen carbonate was adjusted to pH 3 or less by addition of 47 ml of IN hydrochloric acid solution and extracted with 50 ml of ethyl acetate continuously three times. A combined organic phase was washed with 50 ml of an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, washed with ethyl acetate, and concentrated. The concentrate was crystallized in 50 ml of diisopropylether. An obtained solid was filtered and washed with a small quantity of diisopropylether to give 3.19 g of (-)-N-[(4-methylphenyl)sulfonyl]-D-glutamic acid.
[128] m.p. : 127.2 °C
[129] Yield (recovery rate): 81.9%
[130] 1 H-NMR (DMSO-d ) ppm : 1.56-1.68(m, IH), 1.76-1.87(m, IH), 2.18(t, 2H), 2.35(s, 3H), 3.72(br s, IH), 7.34(d, 2H), 7.62 (d, 2H), 8.06(d, IH), 12.40(br s, 2H)
[131] [ ]20 : - 12.91 (c = 5, acetone) 589 Industrial Applicability
[132] According to the present invention, optical resolution of racemic cetirizine or its salt using glutamate of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy] acetic ester can produce optically active cetirizine or its salt with high yield and purity.

Claims

Claims
[1] A process for preparing optically active cetirizine or its salt, comprising (a) reacting an optically active compound represented by formula 1 below with a base to obtain an optically active compound represented by formula 2a below; and (b) hydrolyzing the compound of the formula 2a:
(2a) wherein R 1 is alkyl of C -C and R 2 is an amino protecting group. 1 6
[2] The process of claim 1, wherein the amino protecting group is phenylsulfonyl or (4-methylphenyl)sulfonyl. [3] The process of claim 1, wherein the base is sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, or potassium carbonate. [4] The process of claim 1, further comprising reacting a hydrolysate of the compound of the formula 2a with hydrochloric acid in an organic solvent. [5] The process of any one of claims 1-4, wherein the optically active compound of the formula 1 is prepared by reacting a racemic compound represented by formula 2b below with an optically active compound represented by formula 3 below:
(2b)
(3) 1 2 wherein R and R are as defined in claim 1.
[6] The process of claim 5, wherein the reaction between the racemic compound of the formula 2b and the optically active compound of the formula 3 is performed in alcohol selected from the group consisting of methanol, ethanol, and isopropanol, or a mixed solvent of the alcohol and water.
[7] The process of claim 5, further comprising recrystallizing the optically active compound of the formula 1 in alcohol selected from the group consisting of methanol, ethanol, and isopropanol, or a mixed solvent of the alcohol and water.
[8] An optically active compound represented by formula 1 below:
(1) wherein R 1 and R 2 are as defined in claim 1. [9] The optically active compound of claim 8, wherein the amino protecting group is phenylsulfonyl or (4-methylphenyl)sulfonyl.
EP05726293A 2004-02-02 2005-01-27 Process for preparing optically active cetirizine or its salt Withdrawn EP1718627A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020040006608A KR100503443B1 (en) 2004-02-02 2004-02-02 Processes for preparing an optically active cetirizine or its salt
PCT/KR2005/000231 WO2005073207A1 (en) 2004-02-02 2005-01-27 Process for preparing optically active cetirizine or its salt

Publications (2)

Publication Number Publication Date
EP1718627A1 EP1718627A1 (en) 2006-11-08
EP1718627A4 true EP1718627A4 (en) 2007-04-18

Family

ID=34825062

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05726293A Withdrawn EP1718627A4 (en) 2004-02-02 2005-01-27 Process for preparing optically active cetirizine or its salt

Country Status (3)

Country Link
EP (1) EP1718627A4 (en)
KR (1) KR100503443B1 (en)
WO (1) WO2005073207A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101239795B1 (en) * 2005-03-03 2013-03-06 유씨비 파쉼 소시에떼아노님 Pyroglutamate salts and their use in the optical resolution of intermediates for the synthesis of dextrocetirizine and levocetirizine
KR100954755B1 (en) * 2007-12-17 2010-04-27 한미약품 주식회사 Method for preparing r---1-[4-chloro-phenylphenyl-methyl]piperazine
KR100998067B1 (en) 2008-09-08 2010-12-03 주식회사 삼오제약 A novel Bis1-[4-chlorophenylphenylmethyl]piperazine-2,3-Dibenzoyl tartarate intermediate salt and the method for isolating optically active 1-[4-chlorophenylphenylmethyl]piperazine using thereby
KR102491445B1 (en) * 2021-01-05 2023-01-25 (주)분자와물질 Method of manufacturing levocetirizine by optical resolution

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0058146A1 (en) * 1981-02-06 1982-08-18 U C B, S.A. 2-(4-(Diphenylmethyl)-1-piperazinyl)-acetic acids and their amides, process for their preparation and pharmaceutical compositions

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8827391D0 (en) 1988-11-23 1988-12-29 Ucb Sa Process for preparation of 2-(2-(4-((4-chlorophenyl)phenylmethyl)-1-pipera-zinyl)ethoxy)-acetic acid & its dihydrochloride
GB9305282D0 (en) 1993-03-15 1993-05-05 Ucb Sa Enantiomers of 1-(4-chlorophenyl)phenylmethyl)-4-(4-methylphenyl)sulphonyl)piperazine
BE1010094A3 (en) * 1996-04-10 1997-12-02 Ucb Sa NEW [2- (1-piperazinyl) ethoxy] SUBSTITUTED.
IL124195A (en) * 1998-04-23 2000-08-31 Chemagis Ltd Process for the preparation of esters of 2-¬4-¬4-chlorophenyl¾phenylmethyl¾-1-piperazinyl¬ethoxy¾acetic acid
IT1314184B1 (en) * 1999-08-12 2002-12-06 Nicox Sa PHARMACEUTICAL COMPOSITIONS FOR THE THERAPY OF STRESS-OXIDATIVE CONDITIONS
US6265579B1 (en) * 1999-10-29 2001-07-24 Salsbury Chemicals, Inc. Process for preparing piperazine-substituted aliphatic carboxylates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0058146A1 (en) * 1981-02-06 1982-08-18 U C B, S.A. 2-(4-(Diphenylmethyl)-1-piperazinyl)-acetic acids and their amides, process for their preparation and pharmaceutical compositions

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PFLUM, D. A. ET AL: "A Large-Scale Synthesis of Enantiomerically Pure Cetirizine Dihydrochloride Using Preparative Chiral HPLC", ORGANIC PROCESS RESEARCH & DEVELOPMENT , 5(2), 110-115 CODEN: OPRDFK; ISSN: 1083-6160, March 2001 (2001-03-01), XP002255197 *
See also references of WO2005073207A1 *

Also Published As

Publication number Publication date
WO2005073207A1 (en) 2005-08-11
KR100503443B1 (en) 2005-07-22
EP1718627A1 (en) 2006-11-08

Similar Documents

Publication Publication Date Title
US20040242875A1 (en) Novel processes
US11897843B2 (en) Process for the preparation of enantiomerically enriched 3-aminopiperidine
JP6568221B2 (en) Method for producing benzoxazole oxazine ketone compound, intermediate and crystal form thereof
CA2961984C (en) Novel chiral synthesis of n-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines
WO2005073207A1 (en) Process for preparing optically active cetirizine or its salt
TWI491607B (en) A new method for preparing 4,4&#39;-(1-methyl-1,2-ethandiyl)-bis-(2,6-piperazinedione)
JP2010111684A (en) Stereoselective alkylation of chiral 2-methyl-4-protected piperazine
EP2062881B1 (en) Process for making N-(diphenylmethyl)piperazines
US7989623B2 (en) Process for making n-(diphenylmethyl)piperazines
RU2248974C2 (en) Method for preparing {2-[4-(alpha-phenyl-para-chlorobenzyl)piperazine-1-yl]ethoxy}-acetic acid and new intermediate compounds
US20060183903A1 (en) Piperazine derivatives and their use as synthesis intermediates
US5252747A (en) Chiral quinolone intermediates
KR100928776B1 (en) (R) -1-[(4-chlorophenyl) phenylmethyl] piperazine or a salt thereof
US5623087A (en) Method for preparation of optically active diarylalanines
JP4524841B2 (en) Optically active amino acid ester tartaric acid amide and process for producing the same
WO2009078627A2 (en) Method for preparing (r)-(-)-1-[(4-chlorophenyl)phenylmethyl]piperazine
US5710321A (en) Process for preparing the cyclohexylamine salt of (+) - threo-2-hydroxy-3-(2&#39;-aminophenylthio) -3-(4&#34;-methoxyphenyl) -propionic acid and of its (-) -antipode&#34;
US8383833B2 (en) Method for producing optically active amino acid derivative
KR101427100B1 (en) Method for Preparing an Optically Active 1-[(4-chlorophenyl)phenylmethyl] -piperazine
CN115594613A (en) Edoxaban intermediate and preparation method thereof
JP3656002B2 (en) Process for producing and purifying optically active amide carboxylic acid
CN117015542A (en) Process for preparing pyrrolopyridine derivatives
JP3287258B2 (en) Method for producing 1,5-benzothiazepine derivative
JP2002179634A (en) Method for manufacturing n-methyleneglycinate
JP2001278865A (en) Method for producing 4-aminoquinolines

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20060901

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR

A4 Supplementary search report drawn up and despatched

Effective date: 20070320

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20110519

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20120801