WO2005073207A1 - Process for preparing optically active cetirizine or its salt - Google Patents
Process for preparing optically active cetirizine or its salt Download PDFInfo
- Publication number
- WO2005073207A1 WO2005073207A1 PCT/KR2005/000231 KR2005000231W WO2005073207A1 WO 2005073207 A1 WO2005073207 A1 WO 2005073207A1 KR 2005000231 W KR2005000231 W KR 2005000231W WO 2005073207 A1 WO2005073207 A1 WO 2005073207A1
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- WO
- WIPO (PCT)
- Prior art keywords
- formula
- optically active
- cetirizine
- compound
- chlorophenyl
- Prior art date
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- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 229960001803 cetirizine Drugs 0.000 title claims abstract description 39
- 150000003839 salts Chemical class 0.000 title claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- 239000012046 mixed solvent Substances 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000006239 protecting group Chemical group 0.000 claims description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 9
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000000413 hydrolysate Substances 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 57
- 238000002360 preparation method Methods 0.000 abstract description 27
- 235000019439 ethyl acetate Nutrition 0.000 abstract description 19
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 abstract description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 13
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 abstract description 12
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 abstract description 9
- -1 4-chlorphenyl Chemical group 0.000 abstract description 8
- 229930195712 glutamate Natural products 0.000 abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000003287 optical effect Effects 0.000 description 11
- KKOZKXBAPIYWAT-SNVBAGLBSA-N (2r)-2-[(4-methylphenyl)sulfonylamino]pentanedioic acid Chemical compound CC1=CC=C(S(=O)(=O)N[C@H](CCC(O)=O)C(O)=O)C=C1 KKOZKXBAPIYWAT-SNVBAGLBSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- BYCHNMFDSQCCDD-UHFFFAOYSA-N methyl 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]acetate Chemical compound C1CN(CCOCC(=O)OC)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 BYCHNMFDSQCCDD-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- KNFXXAGQEUUZAZ-UHFFFAOYSA-N ethyl ethaneperoxoate Chemical compound CCOOC(C)=O KNFXXAGQEUUZAZ-UHFFFAOYSA-N 0.000 description 6
- 229960002989 glutamic acid Drugs 0.000 description 6
- 239000004220 glutamic acid Substances 0.000 description 6
- DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229940049906 glutamate Drugs 0.000 description 5
- 235000013922 glutamic acid Nutrition 0.000 description 5
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 4
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 4
- 229930182847 D-glutamic acid Natural products 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- PJLOGZZDKDUMFU-SECBINFHSA-N (2r)-2-(benzenesulfonamido)pentanedioic acid Chemical compound OC(=O)CC[C@H](C(O)=O)NS(=O)(=O)C1=CC=CC=C1 PJLOGZZDKDUMFU-SECBINFHSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
- 150000002307 glutamic acids Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- YZGQDNOIGFBYKF-UHFFFAOYSA-N Ethoxyacetic acid Chemical compound CCOCC(O)=O YZGQDNOIGFBYKF-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 0 *OC(COCCN1CCN(CSC(c2ccccc2)c(cc2)ccc2Cl)CC1)=O Chemical compound *OC(COCCN1CCN(CSC(c2ccccc2)c(cc2)ccc2Cl)CC1)=O 0.000 description 1
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 description 1
- ZKLPARSLTMPFCP-NRFANRHFSA-N 2-[2-[4-[(s)-(4-chlorophenyl)-phenylmethyl]piperazin-1-ium-1-yl]ethoxy]acetate Chemical compound C1CN(CCOCC(=O)O)CCN1[C@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-NRFANRHFSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 150000007960 acetonitrile Chemical class 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229960004342 cetirizine hydrochloride Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- MMEIYVXPSXIGET-UHFFFAOYSA-N n-benzyl-4-chloroaniline Chemical compound C1=CC(Cl)=CC=C1NCC1=CC=CC=C1 MMEIYVXPSXIGET-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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.
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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>
[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>
[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
[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:
[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:
[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:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05726293A EP1718627A4 (en) | 2004-02-02 | 2005-01-27 | Process for preparing optically active cetirizine or its salt |
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|---|---|---|---|
| KR10-2004-0006608 | 2004-02-02 | ||
| KR1020040006608A KR100503443B1 (en) | 2004-02-02 | 2004-02-02 | Processes for preparing an optically active cetirizine or its salt |
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| PCT/KR2005/000231 WO2005073207A1 (en) | 2004-02-02 | 2005-01-27 | Process for preparing optically active cetirizine or its salt |
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| EP (1) | EP1718627A4 (en) |
| KR (1) | KR100503443B1 (en) |
| WO (1) | WO2005073207A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101128446B (en) * | 2005-03-03 | 2010-12-08 | Ucb法奇姆股份有限公司 | Pyroglutamate salts and their use in the optical resolution of intermediates for the synthesis of dextrocetirizine and levocetirizine |
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| 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 (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO1997037982A1 (en) * | 1996-04-10 | 1997-10-16 | Ucb S.A. | Novel substituted [2-(1-piperazinyl)ethoxy]methyl |
| EP0952153A2 (en) * | 1998-04-23 | 1999-10-27 | Chemagis Ltd. | A process for the preparation of esters of [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]acetic acid |
| WO2001012584A2 (en) * | 1999-08-12 | 2001-02-22 | Nicox S.A. | Pharmaceutical compounds |
| WO2001032641A1 (en) * | 1999-10-29 | 2001-05-10 | Salsbury Chemicals, Inc. | Process for preparing piperazine-substituted aliphatic carboxylates |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO155805C (en) * | 1981-02-06 | 1987-06-10 | Ucb Sa | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITY 2- (4- (DIPHENYLMETHYL) -1-PIPERAZINYL) -ACDIC ACIDS AND THEIR AMIDS AND NON-TOXIC SALTS. |
-
2004
- 2004-02-02 KR KR1020040006608A patent/KR100503443B1/en not_active IP Right Cessation
-
2005
- 2005-01-27 WO PCT/KR2005/000231 patent/WO2005073207A1/en active Application Filing
- 2005-01-27 EP EP05726293A patent/EP1718627A4/en not_active Withdrawn
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO1997037982A1 (en) * | 1996-04-10 | 1997-10-16 | Ucb S.A. | Novel substituted [2-(1-piperazinyl)ethoxy]methyl |
| EP0952153A2 (en) * | 1998-04-23 | 1999-10-27 | Chemagis Ltd. | A process for the preparation of esters of [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]acetic acid |
| WO2001012584A2 (en) * | 1999-08-12 | 2001-02-22 | Nicox S.A. | Pharmaceutical compounds |
| WO2001032641A1 (en) * | 1999-10-29 | 2001-05-10 | Salsbury Chemicals, Inc. | Process for preparing piperazine-substituted aliphatic carboxylates |
Non-Patent Citations (3)
| Title |
|---|
| COREY ET AL: "Catalytic enantioselective synthesis of the second generation histamine antagonist cetirizine hydrochloride", TETRAHEDRON LETTERS, vol. 37, no. 28, 8 July 1996 (1996-07-08), pages 4837 - 4840, XP004029527 * |
| PFLUM, D.A. ET AL., ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 5, no. 2, March 2001 (2001-03-01), pages 110 - 115 |
| See also references of EP1718627A4 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101128446B (en) * | 2005-03-03 | 2010-12-08 | Ucb法奇姆股份有限公司 | Pyroglutamate salts and their use in the optical resolution of intermediates for the synthesis of dextrocetirizine and levocetirizine |
Also Published As
| Publication number | Publication date |
|---|---|
| KR100503443B1 (en) | 2005-07-22 |
| EP1718627A4 (en) | 2007-04-18 |
| EP1718627A1 (en) | 2006-11-08 |
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