WO2009022327A2 - Novel process for preparing highly pure levocetirizine and salts thereof - Google Patents
Novel process for preparing highly pure levocetirizine and salts thereof Download PDFInfo
- Publication number
- WO2009022327A2 WO2009022327A2 PCT/IL2008/001065 IL2008001065W WO2009022327A2 WO 2009022327 A2 WO2009022327 A2 WO 2009022327A2 IL 2008001065 W IL2008001065 W IL 2008001065W WO 2009022327 A2 WO2009022327 A2 WO 2009022327A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- levocetirizine
- organic solvent
- crystals
- levocetirizine dihydrochloride
- dihydrochloride
- Prior art date
Links
- 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 title claims abstract description 32
- 229960001508 levocetirizine Drugs 0.000 title claims abstract description 32
- 150000003839 salts Chemical class 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title abstract description 6
- PGLIUCLTXOYQMV-GHVWMZMZSA-N 2-[2-[4-[(r)-(4-chlorophenyl)-phenylmethyl]piperazine-1,4-diium-1-yl]ethoxy]acetic acid;dichloride Chemical compound Cl.Cl.C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PGLIUCLTXOYQMV-GHVWMZMZSA-N 0.000 claims abstract description 33
- 229960003308 levocetirizine dihydrochloride Drugs 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 239000003960 organic solvent Substances 0.000 claims description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000008346 aqueous phase Substances 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000012074 organic phase Substances 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 239000013078 crystal Substances 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 5
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- 230000005587 bubbling Effects 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 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 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 2
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 2
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 19
- 229960001803 cetirizine Drugs 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- 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 description 7
- JSFGZPUFCTXDJY-UHFFFAOYSA-N [2-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]phenyl]methanol Chemical compound OCC1=CC=CC=C1N1CCN(C(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 JSFGZPUFCTXDJY-UHFFFAOYSA-N 0.000 description 7
- RLZPNIGECDMAJH-QGZVFWFLSA-N 1-[(r)-(2-chlorophenyl)-phenylmethyl]piperazine Chemical compound ClC1=CC=CC=C1[C@@H](C=1C=CC=CC=1)N1CCNCC1 RLZPNIGECDMAJH-QGZVFWFLSA-N 0.000 description 6
- 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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- PGLIUCLTXOYQMV-UHFFFAOYSA-N Cetirizine hydrochloride Chemical compound Cl.Cl.C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PGLIUCLTXOYQMV-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 4
- HLVJBBWMBPQZAE-UHFFFAOYSA-M potassium;2-[2-[4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]acetate Chemical class [K+].C1CN(CCOCC(=O)[O-])CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 HLVJBBWMBPQZAE-UHFFFAOYSA-M 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UZKBSZSTDQSMDR-QGZVFWFLSA-N 1-[(r)-(4-chlorophenyl)-phenylmethyl]piperazine Chemical compound C1=CC(Cl)=CC=C1[C@@H](C=1C=CC=CC=1)N1CCNCC1 UZKBSZSTDQSMDR-QGZVFWFLSA-N 0.000 description 3
- CVYKQPLWSDHSSV-UHFFFAOYSA-N ethyl 2-(2-chloroethoxy)acetate Chemical compound CCOC(=O)COCCCl CVYKQPLWSDHSSV-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- ASHQTVRYHSZGQY-HSZRJFAPSA-N ethyl 2-[2-[4-[(r)-(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]acetate Chemical compound C1CN(CCOCC(=O)OCC)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ASHQTVRYHSZGQY-HSZRJFAPSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- KQHRCXCLILUNBX-UHFFFAOYSA-N 2-(2-chloroethoxy)acetamide Chemical compound NC(=O)COCCCl KQHRCXCLILUNBX-UHFFFAOYSA-N 0.000 description 1
- GQFCLJZQECVTDO-UHFFFAOYSA-N 2-(2-chloroethoxy)acetonitrile Chemical compound ClCCOCC#N GQFCLJZQECVTDO-UHFFFAOYSA-N 0.000 description 1
- PGLIUCLTXOYQMV-FGJQBABTSA-N 2-[2-[4-[(s)-(4-chlorophenyl)-phenylmethyl]piperazine-1,4-diium-1-yl]ethoxy]acetic acid;dichloride Chemical compound Cl.Cl.C1CN(CCOCC(=O)O)CCN1[C@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PGLIUCLTXOYQMV-FGJQBABTSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010039094 Rhinitis perennial Diseases 0.000 description 1
- 208000036284 Rhinitis seasonal Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000030949 chronic idiopathic urticaria Diseases 0.000 description 1
- 206010072757 chronic spontaneous urticaria Diseases 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 208000022719 perennial allergic rhinitis Diseases 0.000 description 1
- 208000017022 seasonal allergic rhinitis Diseases 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229940023159 xyzal Drugs 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- the field of the invention relates to methods of purifying levocetirizine from a crude sample of levocetirizine via extraction.
- Levocetirizine dihydrochloride is a third generation non-sedative antihistamine, developed from cetirizine, which is a second generation antihistamine.
- Levocetirizine is the active enantiomer of cetirizine, is more effective than cetirizine itself, and has fewer side effects.
- Levocetirizine dihydrochloride blocks histamine receptors and is used for treating seasonal and perennial allergic rhinitis, chronic idiopathic urticaria, and for preventing and treating symptoms of allergic asthma.
- Levocetirizine dihydrochloride was first launched in 2001 by UCB, available as 5 mg tablets and marketed under the brand names XYZAL® in the United States, United Kingdom and France, and XUSAL® elsewhere in Europe.
- levocetirizine which is the R enantiomer of cetirizine, is (-)-2-[2-[4-[(4-chloropheyl)phenymethyl]-l-piperazinyl]-ethoxy]acetic acid, and it is represented by the following structural formula (I):
- cetirizine dihydrochloride [0007] The preparation of cetirizine also is described in US Patent No. 6, 100,400, comprising reacting Compound II with ethyl 2-chloroethoxyacetate IIIA in a tertiary amine, such as triethylamine or triisopropylamine, to obtain ethyl 2-[2-[4-[(4-chloropheyl)- phenymethyl]-l-piperazinyl]-ethoxy]acetate IVA, which is further purified and hydrolyzed to afford cetirizine via cetirizine potassium salt (V), as depicted in Scheme 2 below.
- a tertiary amine such as triethylamine or triisopropylamine
- the dextrorotatory 2-[2-[4- [(4-chloropheyl)phenymethyl]-l-piperazinyl]-ethoxy]acetonitrile is heated in 37% hydrochloric acid, followed by addition of NaOH to afford free levocetirizine by extraction with several successive fractions of dichloromethane. Then, a solution of hydrochloric acid in acetone is added, and levocetirizine dihydrochloride is obtained.
- the disadvantages of this process are that it is very lengthy and provides the desired product in a relatively low enantiomeric purity of 95% by weight.
- the present invention provides a process for purifying levocetirizine or a salt thereof from a crude sample comprising levocetirizine, which comprises the steps of: a) admixing a crude sample comprising levocetirizine potassium salt with a first organic solvent and water to form a first organic phase and a first aqueous phase; b) separating the first aqueous phase from the first organic phase; c) adding an acid and a second organic solvent to the first aqueous phase to form a second organic phase and a second aqueous phase; d) separating the second organic phase from the second aqueous phase; e) distilling the second organic solvent from the second organic phase to form a residue; f) dissolving the residue of step (e) in a third organic solvent; g) bubbling hydrogen chloride gas through the solution of step (f) to precipitate crystals of levocetirizine dihydrochloride; and h) optionally isolating
- the crystals of levocetirizine dihydrochloride obtained using the methods as described herein have a chemical purity of at least 98% by weight, preferably have a purity of at least 99.5% by weight.
- the crystals of levocetirizine dihydrochloride obtained as described herein have an enantiomeric excess (ee) of at least 99%, and preferably have an ee value of at least 99.8%.
- the term "chemical purity,” as defined herein, refers to the liquid chromatography area percent of the peak corresponding to the levocetirizine dihydrochloride isomer relative to the area percent of the levocetirizine dihydrochloride isomer and all the other detected impurities.
- Crude levocetirizine or a crude sample comprising levocetirizine refers to a sample having up to 88% by weight of levocetirizine.
- the crude sample also can contain the enantiomer of levocetirizine (i.e., dextrocetirizine).
- impurities that can be present in the crude sample include levocetirizine ethyl ester (Compound IVB), 2-[2-[4-dipheylphenymethyl-l- piperazinyl]-ethoxy]acetic acid (Compound VII), and Compound VIII.
- the present invention provides a process for preparing chemically and enantiomerically pure levocetirizine or a salt thereof, and, in particular, the dihydrochloride salt, which comprises the steps of: a) admixing a crude sample comprising levocetirizine potassium salt with a first organic solvent and water to form a first organic phase and a first aqueous phase; b) separating the first aqueous phase from the first organic phase; c) adding an acid and a second organic solvent to the first aqueous phase to form a second organic phase and a second aqueous phase; d) separating the second organic phase from the second aqueous phase; e) distilling the second organic solvent from the second organic phase to form a residue; f) dissolving the residue of step (e) in a third organic solvent; g) bubbling hydrogen chloride gas through the solution of step (f) to precipitate crystals of levocetirizine dihydrochloride; and
- the first organic solvent is selected from the group consisting of methyl acetate, ethyl acetate, isobutyl acetate, chloroform, and mixtures thereof. More preferably, the first organic solvent comprises ethyl acetate.
- the second organic solvent is selected from the group consisting of dichloromethane, chloroform, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), and mixtures thereof. More preferably, the second organic solvent comprises dichloromethane.
- the acid is typically an inorganic acid.
- the inorganic acid comprises hydrochloric acid, and more preferably, the source of hydrochloric acid is hydrogen chloride gas.
- the third organic solvent is selected from the group consisting of acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), acetonitrile, tetrahydrofuran (THF), chloroform, methyl tert-butyl ether (MTBE), and mixtures thereof. More preferably, the third organic solvent comprises acetone.
- purified levocetirizine dihydrochloride is obtained containing less than 0.1% of the dextrotatory isomer, preferably containing about 0.05% of the dextrotatory isomer, that is, having an ee of 99.9%.
- the purified levocetirizine dihydrochloride is obtained as described herein having a chemical purity of at least 98%, preferably having a purity equal to or greater than 99.5%.
- the purified crystalline levocetirizine dihydrochloride, produced as described herein contains residual solvents of less than 500 parts per million (ppm) acetone, less than 100 ppm ethanol, and less than 50 ppm dichloromethane.
- the levocetirizine dihydrochloride produced in accordance with the present invention can be used in a pharmaceutical composition, which can include levocetirizine dihydrochloride produced as described herein (e.g., in a therapeutically effective amount) and one or more pharmaceutically acceptable additives and/or excipients.
- a pharmaceutical composition which can include levocetirizine dihydrochloride produced as described herein (e.g., in a therapeutically effective amount) and one or more pharmaceutically acceptable additives and/or excipients.
- the main impurities identified were levocetirizine ethyl ester (Compound VB)-8.45% by weight, (R)-l-[(2-chlorophenyl)-phenylmethyl]-piperazine (Compound IX)-2.33% by weight, and (R)-l-[(4-chlorophenyl)-phenylmethyl]-piperazine (Compound 1IB)- 0.82% by weight.
- a reaction vessel was charged with a solution of (R)-2-[2-[4-[(4- chloropheyl)phenymethyl]-l-piperazinyl]-ethoxy]acetic acid potassium salt (87.7% purity by HPLC) in ethanol (165 ml) under mixing. The ethanol was distilled off under vacuum to afford an oily residue. Distilled water (210 ml) and ethyl acetate (250 ml) then were added and stirring was maintained for half an hour. The organic and aqueous layers were separated, and the aqueous layer, containing the potassium salt, was washed twice with ethyl acetate.
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Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08789741A EP2175856A4 (en) | 2007-08-15 | 2008-08-04 | Novel process for preparing highly pure levocetirizine and salts thereof |
US12/671,664 US20110230496A1 (en) | 2007-08-15 | 2008-08-04 | Novel process for preparing highly pure levocetirizine and salts thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US96489407P | 2007-08-15 | 2007-08-15 | |
US60/964,894 | 2007-08-15 |
Publications (2)
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WO2009022327A2 true WO2009022327A2 (en) | 2009-02-19 |
WO2009022327A3 WO2009022327A3 (en) | 2010-03-04 |
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PCT/IL2008/001065 WO2009022327A2 (en) | 2007-08-15 | 2008-08-04 | Novel process for preparing highly pure levocetirizine and salts thereof |
Country Status (4)
Country | Link |
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US (1) | US20110230496A1 (en) |
EP (1) | EP2175856A4 (en) |
KR (1) | KR20100059836A (en) |
WO (1) | WO2009022327A2 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103044355A (en) * | 2011-10-13 | 2013-04-17 | 湖南九典制药有限公司 | Key intermediate for synthesizing levocetirizine and preparation method thereof |
US9044479B2 (en) | 2010-06-16 | 2015-06-02 | Bruce Chandler May | Use of levocetirizine and montelukast in the treatment of influenza, common cold and inflammation |
CN105924409A (en) * | 2016-05-12 | 2016-09-07 | 浙江永宁药业股份有限公司 | Resolution method of (R)-1-((2-chlorphenyl)-(phenyl)-methyl)-piperazine |
US9522148B2 (en) | 2013-03-13 | 2016-12-20 | Inflammatory Response Research, Inc. | Use of levocetirizine and montelukast in the treatment of traumatic injury |
US9669025B2 (en) | 2013-03-13 | 2017-06-06 | Inflammatory Response Research, Inc. | Use of levocetirizine and montelukast in the treatment of vasculitis |
US9669026B2 (en) | 2013-03-13 | 2017-06-06 | Inflammatory Response Research, Inc. | Use of levocetirizine and montelukast in the treatment of autoimmune disorders |
US9925183B2 (en) | 2014-09-15 | 2018-03-27 | Inflammatory Response Research, Inc. | Levocetirizine and montelukast in the treatment of inflammation mediated conditions |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090247750A1 (en) * | 2008-03-28 | 2009-10-01 | Biocryst Pharmaceuticals, Inc. | Process for preparing nucleoside analogs |
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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 |
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WO2007066162A1 (en) | 2005-12-08 | 2007-06-14 | Egis Gyógyszergyár Nyilvanosan Mukodo Reszvenytarsasag | Process for the preparation of a pharmaceutical intermediate |
Family Cites Families (1)
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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 |
-
2008
- 2008-08-04 KR KR1020107004786A patent/KR20100059836A/en not_active Application Discontinuation
- 2008-08-04 US US12/671,664 patent/US20110230496A1/en not_active Abandoned
- 2008-08-04 WO PCT/IL2008/001065 patent/WO2009022327A2/en active Application Filing
- 2008-08-04 EP EP08789741A patent/EP2175856A4/en not_active Withdrawn
Patent Citations (4)
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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 |
US20040132743A1 (en) | 2002-06-21 | 2004-07-08 | Dr. Reddy's Laboratories Limited Dr. Reddy's Laboratories, Inc. | Amorphous form of (-)-[2-[4-[(4-Chlorophenyl)-phenyl methyl]-1- piperazinyl] ethoxy] acetic acid dihydrochloride (levocetirizine dihydrochloride) |
US20060183903A1 (en) | 2003-01-23 | 2006-08-17 | Ucb, S.A. | Piperazine derivatives and their use as synthesis intermediates |
WO2007066162A1 (en) | 2005-12-08 | 2007-06-14 | Egis Gyógyszergyár Nyilvanosan Mukodo Reszvenytarsasag | Process for the preparation of a pharmaceutical intermediate |
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Cited By (16)
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US10537568B2 (en) | 2010-06-16 | 2020-01-21 | IRR, Inc. | Use of levocetirizine and montelukast to ameliorate inflammation following radiation exposure |
US9044479B2 (en) | 2010-06-16 | 2015-06-02 | Bruce Chandler May | Use of levocetirizine and montelukast in the treatment of influenza, common cold and inflammation |
CN103044355A (en) * | 2011-10-13 | 2013-04-17 | 湖南九典制药有限公司 | Key intermediate for synthesizing levocetirizine and preparation method thereof |
US11344545B2 (en) | 2013-03-13 | 2022-05-31 | IRR, Inc. | Use of levocetirizine and montelukast in the treatment of autoimmune disorders |
US9522148B2 (en) | 2013-03-13 | 2016-12-20 | Inflammatory Response Research, Inc. | Use of levocetirizine and montelukast in the treatment of traumatic injury |
US9669025B2 (en) | 2013-03-13 | 2017-06-06 | Inflammatory Response Research, Inc. | Use of levocetirizine and montelukast in the treatment of vasculitis |
US9669026B2 (en) | 2013-03-13 | 2017-06-06 | Inflammatory Response Research, Inc. | Use of levocetirizine and montelukast in the treatment of autoimmune disorders |
US11103500B2 (en) | 2013-03-13 | 2021-08-31 | IRR, Inc. | Use of levocetirizine and montelukast in the treatment of traumatic injury |
US9937166B2 (en) | 2013-03-13 | 2018-04-10 | Inflammatory Response Research, Inc. | Use of levocetirizine and montelukast in the treatment of traumatic injury |
US10201537B2 (en) | 2013-03-13 | 2019-02-12 | IRR, Inc. | Use of levocetirizine and montelukast in the treatment of autoimmune disorders |
US10206919B2 (en) | 2013-03-13 | 2019-02-19 | IRR, Inc. | Use of levocetirizine and montelukast in the treatment of vasculitis |
US10195193B2 (en) | 2014-09-15 | 2019-02-05 | IRR, Inc. | Levocetirizine and montelukast in the treatment of inflammation mediated conditions |
US10792281B2 (en) | 2014-09-15 | 2020-10-06 | IRR, Inc. | Levocetirizine and montelukast in the treatment of inflammation mediated conditions |
US9925183B2 (en) | 2014-09-15 | 2018-03-27 | Inflammatory Response Research, Inc. | Levocetirizine and montelukast in the treatment of inflammation mediated conditions |
US11590125B2 (en) | 2014-09-15 | 2023-02-28 | IRR, Inc. | Levocetirizine and montelukast in the treatment of inflammation mediated conditions |
CN105924409A (en) * | 2016-05-12 | 2016-09-07 | 浙江永宁药业股份有限公司 | Resolution method of (R)-1-((2-chlorphenyl)-(phenyl)-methyl)-piperazine |
Also Published As
Publication number | Publication date |
---|---|
KR20100059836A (en) | 2010-06-04 |
EP2175856A4 (en) | 2011-08-24 |
US20110230496A1 (en) | 2011-09-22 |
EP2175856A2 (en) | 2010-04-21 |
WO2009022327A3 (en) | 2010-03-04 |
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