SI21850A - Salts of olanzapin and their transformation into free base of olanzapin - Google Patents
Salts of olanzapin and their transformation into free base of olanzapin Download PDFInfo
- Publication number
- SI21850A SI21850A SI200400219A SI200400219A SI21850A SI 21850 A SI21850 A SI 21850A SI 200400219 A SI200400219 A SI 200400219A SI 200400219 A SI200400219 A SI 200400219A SI 21850 A SI21850 A SI 21850A
- Authority
- SI
- Slovenia
- Prior art keywords
- olanzapine
- intermediates
- production
- methyl
- isopropanol
- Prior art date
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- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical class C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 title claims abstract description 122
- 150000003839 salts Chemical class 0.000 title abstract description 16
- 239000012458 free base Substances 0.000 title description 5
- 230000009466 transformation Effects 0.000 title description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- 239000000543 intermediate Substances 0.000 claims abstract description 9
- 229960005017 olanzapine Drugs 0.000 claims description 101
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 96
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 53
- 239000002904 solvent Substances 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- 239000012453 solvate Substances 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 13
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 13
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 10
- 150000001242 acetic acid derivatives Chemical group 0.000 claims description 8
- -1 dichloride Chemical compound 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 5
- 150000002170 ethers Chemical class 0.000 claims description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 5
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 229940077388 benzenesulfonate Drugs 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 abstract description 11
- 239000000243 solution Substances 0.000 description 30
- 238000001914 filtration Methods 0.000 description 28
- 229960004592 isopropanol Drugs 0.000 description 24
- 238000000605 extraction Methods 0.000 description 21
- 238000002329 infrared spectrum Methods 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- 238000001035 drying Methods 0.000 description 13
- 238000001704 evaporation Methods 0.000 description 13
- 230000008020 evaporation Effects 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 239000005711 Benzoic acid Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 235000010233 benzoic acid Nutrition 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000002955 isolation Methods 0.000 description 6
- 229940011051 isopropyl acetate Drugs 0.000 description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 150000002826 nitrites Chemical class 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N anhydrous trimethylamine Natural products CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- CQCVGXWYFQCZKX-UHFFFAOYSA-N benzoic acid 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine Chemical compound OC(=O)c1ccccc1.CN1CCN(CC1)C1=Nc2ccccc2Nc2sc(C)cc12 CQCVGXWYFQCZKX-UHFFFAOYSA-N 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000004682 monohydrates Chemical group 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- VMLRGLWEZFXINP-UHFFFAOYSA-N 1h-1,5-benzodiazepin-5-ium;chloride Chemical compound Cl.N1C=CC=NC2=CC=CC=C12 VMLRGLWEZFXINP-UHFFFAOYSA-N 0.000 description 1
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical compound N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 description 1
- FDWMAKNNNPSUTL-UHFFFAOYSA-N 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine hydrochloride Chemical compound Cl.N1C2=CC=CC=C2N=C(N)C2=C1SC(C)=C2 FDWMAKNNNPSUTL-UHFFFAOYSA-N 0.000 description 1
- MFURKUWVJOJUHP-UHFFFAOYSA-N 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride Chemical compound Cl.C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 MFURKUWVJOJUHP-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- MVIOINXPSFUJEN-UHFFFAOYSA-N benzenesulfonic acid;hydrate Chemical compound O.OS(=O)(=O)C1=CC=CC=C1 MVIOINXPSFUJEN-UHFFFAOYSA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical class [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000004683 dihydrates Chemical group 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000035784 germination Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Psychiatry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
SOLI OLANZAPINA IN NJIHOVA PRETVORBA V PROSTO BAZO OLANZAPINAOlanzapine salts and their conversion to Olanzapine free base
PODROČJE IZUMAFIELD OF THE INVENTION
Predloženi izum sodi v področje organske kemije in se nanaša na nove soli 2-metil-4(4-metil-l-piperazinil)-10/7-tieno[2,3-/)][1,5]benzodiazepina (v nadaljevanju naveden s svojim generičnim imenom olanzapin) s kislinami, izbranimi iz skupine ocetne, benzojske, klorovodikove, benzensulfonske in perklorove kisline, na postopke za njihovo proizvodnjo, na njihovo uporabo za čiščenje olanzapina in na postopek za njihovo pretvorbo v polimorfno obliko I olanzapina.The present invention falls within the field of organic chemistry and relates to novel salts of 2-methyl-4 (4-methyl-1-piperazinyl) -10 / 7-thieno [2,3 - /)] [1,5] benzodiazepine (hereinafter referred to by its generic name olanzapine) with acids selected from the group of acetic, benzoic, hydrochloric, benzenesulfonic and perchloric acids, to processes for their production, to their use for the purification of olanzapine, and to a process for converting them to polymorphic form I of olanzapine.
Pokazalo se je, da ima olanzapin visoko aktivnost na centralni živčni sistem in je tudi uporaben za zdravljenje shizofrenije, shizofreniformnih motenj, akutne manije, blagih anksioznih stanj in psihoz.Olanzapine has been shown to have high activity in the central nervous system and is also useful for the treatment of schizophrenia, schizophrenic disorders, acute mania, mild anxiety and psychosis.
TEHNIČNI PROBLEMITECHNICAL PROBLEMS
Po postopkih stanja tehnike so se za kristalizacijo olanzapa v obliki proste baze, za čiščenje olanzapina in za proizvodnjo polimorfne oblike I uporabljala topila kot je acetonitril. Vendar pa se po navodilih ICH ta topila ne priporočajo za uporabo v končnih stopnjah priprave farmacevtikov, saj so škodljiva. Poleg tega pogosto ne vodijo do zadovoljivih izkoristkov polimorfne oblike I olanzapina. Nadalje postopki po stanju tehnike pogosto ne vodijo do olanzapina s čistoto, ki je zadovoljiva za pripravo farmacevtskih formulacij, saj so prisotne nečistote, ki jih je težko odstraniti po postopkih stanja tehnike.According to the prior art, solvents such as acetonitrile were used to crystallize olanzapine as a free base, to purify olanzapine and to produce polymorphic Form I. However, according to the ICH, these solvents are not recommended for use in the final stages of pharmacist preparation as they are harmful. In addition, they often do not lead to satisfactory yields of olanzapine polymorphic Form I. Furthermore, prior art procedures often do not lead to olanzapine having a purity satisfactory for the preparation of pharmaceutical formulations since impurities that are difficult to remove by prior art are present.
Zatorej še vedno obstaja potreba po izboljšanem postopku za pripravo očiščene oblike I olanzapina, s katerim bi se izognili predhodno omenjenim pomanjkljivostim in ki bi imel za rezultat olanzapin s čistoto, primemo za pripravo farmacevtskih formulacij.Therefore, there is still a need for an improved process for the preparation of purified form I olanzapine, to avoid the aforementioned disadvantages and resulting in olanzapine with purity, suitable for the preparation of pharmaceutical formulations.
Nadalje obstaja potreba po prekurzoijih, ki omogočajo lahko pripravo polimorfnih oblik olanzapina ali pretvorbo v druge oblike olanzapina.Furthermore, there is a need for precursors that can easily prepare polymorphic forms of olanzapine or convert to other forms of olanzapine.
Ti problemi so rešeni s predloženim izumom.These problems are solved by the present invention.
OZADJE IZUMABACKGROUND OF THE INVENTION
Britanski patent GB 1 533 235 opisuje antipsihotično učinkovite tienobenzodiazepine s splošno formulo, ki pokriva tudi olanzapin.British Patent GB 1 533 235 describes antipsychotically effective thienobenzodiazepines of general formula, which also covers olanzapine.
EP 0 454 436 opisuje eksplicitno olanzapin. Opisan postopek za njegovo sintezo nadalje vključuje kristalizacijo iz acetonitrila in določeno je bilo, da je tališče kristalizirane spojine pri 195 °C.EP 0 454 436 explicitly describes olanzapine. The process described for its synthesis further involves crystallization from acetonitrile and the melting point of the crystallized compound was determined to be at 195 ° C.
V EP-B-733 635 je zahtevana zaščita za kristalinično obliko II olanzapina. Navedeno je, daje ta polimorfna oblika bolj stabilna od materiala, dobljenega po EP 0 454 436, ki je imenovan oblika I olanzapina. Tako oblika I, kot oblika II olanzapina sta okaraktezirani z npr. rentgenskimi podatki. Pripravo bolj stabilne oblike II olanzapina so izvedli z raztapljanjem olanzapina tehnične čistote v etil acetatu in s kristalizacijo iz nastale raztopine s kakršnimkoli konvencionalnim postopkom, kot je cepljenje s kalmi, ohlajanje, praskanje stekla reakcijske posode ali druge običajne tehnike.EP-B-733 635 requires protection for crystalline form II of olanzapine. It is stated that this polymorphic form is more stable than the material obtained according to EP 0 454 436, which is called form I olanzapine. Both Form I and Form II of olanzapine are characterized by e.g. X-ray data. The preparation of more stable Form II olanzapine was performed by dissolving olanzapine of technical purity in ethyl acetate and crystallizing from the resulting solution by any conventional method such as germination, cooling, glass scattering of reaction vessels or other conventional techniques.
WO 02/18390 opisuje monohidratno obliko I in dihidratno obliko I olanzapina, postopek za njuno proizvodnjo in postopek za proizvodnjo oblike I olanzapina, ki obsega stopnje mešanja monohidratne oblike I olanzapina ali surovega olanzapina ali oblike II olanzapina v merilen kloridu pri refluksu, ohlajanja, filtriranja in sušenja.WO 02/18390 describes monohydrate form I and dihydrate form I of olanzapine, a process for their production and a process for the production of form I of olanzapine, comprising the steps of mixing monohydrate form I of olanzapine or crude olanzapine or form II of olanzapine in reflux, cooling, filtering and drying.
Opisano je tudi, da ponavljanje postopka, opisanega v EP 0 454 436, primer 1, podprimer 4, ni vodilo do tvorbe oblike I olanzapina.It is also described that repeating the process described in EP 0 454 436, Example 1, Example 4, did not lead to the formation of Form I olanzapine.
WO 03/1011997 se nanaša na postopke za pripravo oblike I olanzapina z regulacijo pH vrednosti raztopine.WO 03/1011997 relates to processes for the preparation of form I olanzapine by regulating the pH of the solution.
WO 03/055438 opisuje kristalizacijo iz etanola in naknadno transformacijo etanolnega solvata v polimorfno obliko I olanzapina.WO 03/055438 describes crystallization from ethanol and subsequent transformation of ethanol solvate into polymorphic form I of olanzapine.
US patent US 5,637,584 opisuje (mono)metilensko solvatno obliko olanzapina in postopek za njeno pretvorbo v polimorfno obliko I olanzapina.US Patent 5,637,584 describes the (mono) methylene solvate form of olanzapine and the process for its conversion to polymorphic form I of olanzapine.
EP-B-733 634 se nanaša na tri specifične solvate olanzapina in sicer metanolni, etanolni in 1-propanolni sol vat in na postopek za proizvodnjo oblike II olanzapina s sušenjem ustreznih solvatov.EP-B-733 634 relates to three specific solvates of olanzapine, namely the methanolic, ethanol and 1-propanol solvates, and to a process for the production of form II of olanzapine by drying the corresponding solvates.
V WO 03/097650 sta opisani dve novi obliki mešanih solvatov, mešan voda/metilen kloridni in voda/DMSO solvat, postopki za njuno pripravo in njima transformacija v polimorfno obliko I.WO 03/097650 describes two new forms of mixed solvates, mixed water / methylene chloride and water / DMSO solvate, processes for their preparation and transformation into polymorph I.
WO 2004/006933 A2 opisuje pripravo oblike I, nekatere psevdopolimorfne oblike, namreč izopropanolni solvat, acetonitril/metilen klorid/vodni in acetonitril/vodni mešan solvat olanzapina, polimorfno obliko A in postopke za njihovo pripravo.WO 2004/006933 A2 describes the preparation of Form I, certain pseudopolymorphic forms, namely, isopropanol solvate, acetonitrile / methylene chloride / aqueous and acetonitrile / aqueous mixed solvate of olanzapine, polymorphic Form A, and processes for their preparation.
SI P-200400073 (patentna prijava, ki je v postopku) opisuje nov izopropanol-vodni mešan solvat olanzapina, primeren za proizvodnjo diklorometanskega solvata olanzapina in oblike I olanzapina.SI P-200400073 (patent application pending) describes a new isopropanol-aqueous mixed solvate of olanzapine suitable for the production of the dichloromethane solvate of olanzapine and form I of olanzapine.
Iz stanja tehnike so znani različni postopki za pripravo olanzapina, kot GB 1 533 235, EP 0 454 436, EP-B-733 635, PTC/EP04/00299 (patentna prijava, ki je v postopku) in WO2004/000847.Various processes for the preparation of olanzapine, such as GB 1 533 235, EP 0 454 436, EP-B-733 635, PTC / EP04 / 00299 (pending patent) and WO2004 / 000847, are known in the art.
POVZETEK IZUMASUMMARY OF THE INVENTION
Predloženi izum zagotavlja nove soli 2-metil-4-(4-metil-l-piperazinil)-1077-tieno[2,3-b][l,5]benzodiazepina ali olanzapina, uporabne kot intermediati v izolaciji olanzapina iz kompleksnih reakcijskih zmesi. Te soli lahko uporabimo za proizvodnjo olanzapinove baze, ki ima ustrezno čistoto za farmacevtsko uporabo in jo zlahka pretvorimo v brezvodno polimorfno obliko I olanzapina v visokih dobitkih.The present invention provides novel salts of 2-methyl-4- (4-methyl-1-piperazinyl) -1077-thieno [2,3-b] [1,5] benzodiazepine or olanzapine, useful as intermediates in the isolation of olanzapine from complex reaction mixtures . These salts can be used to produce olanzapine base, which has a suitable purity for pharmaceutical use and can be easily converted to anhydrous polymorphic form I olanzapine in high yields.
PODROBEN OPIS IZUMADETAILED DESCRIPTION OF THE INVENTION
Kot je omenjeno zgoraj, po postopkih stanja tehnike prosto bazo olanzapina izoliramo iz reakcijskih zmesi z uporabo kristalizacije iz topil, kot sta merilen klorid in acetonitril. Ti postopki se uporabljajo za čiščenje proste baze olanzapina in za proizvodnjo oblike I, toda pogosto ne vodijo do zadovoljivih celotnih dobitkov oblike I olanzapina. Nadalje ti postopki stanja tehnike pogosto ne vodijo do olanzapina s čistoto, ki je zadovoljiva za pripravo farmacevtskih formulacij, saj so prisotne nečistote, ki jih je po postopkih stanja tehnike težko odstraniti.As mentioned above, according to the prior art, the free olanzapine base is isolated from the reaction mixtures using crystallization from solvents such as measuring chloride and acetonitrile. These processes are used to purify the free base of olanzapine and to produce Form I, but often do not lead to satisfactory overall yields of Form I olanzapine. Furthermore, these prior art procedures often do not lead to olanzapine having a purity satisfactory for the preparation of pharmaceutical formulations, since impurities are present that are difficult to remove after the prior art.
Torej še vedno obstaja potreba po izboljšanem postopku za pripravo očiščenega olanzapina, ki bi odpravil zgoraj omenjene pomanjkljivosti in ki ima za rezultat olanzapin, ki ima čistoto, zaradi katere je zelo primeren za pripravo farmacevtskih formulacij.Therefore, there is still a need for an improved process for the preparation of purified olanzapine, which would eliminate the aforementioned disadvantages and which result in olanzapine having a purity that makes it very suitable for the preparation of pharmaceutical formulations.
Nadalje obstaja potreba po prekurzoijih, ki omogočajo lahko pripravo polimorfnih oblik olanzapina ali konverzijo v druge oblike olanzapina.Furthermore, there is a need for precursors that may facilitate the preparation of polymorphic forms of olanzapine or conversion to other forms of olanzapine.
Ti problemi so rešeni s predloženim izumom.These problems are solved by the present invention.
V proizvodnji olanzapina z uveljavljenimi sinteznimi postopki dajejo končne reakcije običajno kompleksne reakcijske zmesi, iz katerih je težko izolirati produkt s farmacevtsko sprejemljivo čistoto. Zaradi tega so potrebne dodatne stopnje čiščenja, kot je opisano v npr. EP 0 454 436, kjer je potrebno uporabiti prekristalizacijo iz toksičnega in potemtakem farmacevtsko nezaželenega acetonitrila ali drage in dolgotrajne kromatografske metode. Na ta način pripravljena substanca ni v farmacevtsko najbolj zaželeni polimorfni obbki, zato so potrebne dodatne kristalizacije.In the production of olanzapine by established synthesis methods, the final reactions give typically complex reaction mixtures from which it is difficult to isolate a product of pharmaceutically acceptable purity. This requires additional cleaning steps as described in e.g. EP 0 454 436 where recrystallization from toxic and therefore pharmaceutically undesirable acetonitrile or expensive and time-consuming chromatographic methods is to be used. In this way, the prepared substance is not in the pharmaceutically most desirable polymorphs, so further crystallizations are required.
Naši primeri so nas vodili k rešitvi teh problemov z izolacijo olanzapina s formulo I:Our examples have led us to solve these problems by isolating Formula I olanzapine:
v obliki soli s formulo II:in the form of a salt of formula II:
kjer X predstavlja acetatni, benzoatni, kloridni, dikloridni, benzensulfonatni ali perkloratni anion. Soli s formulo II lahko vsebujejo bodisi n = 1 ali n = 2 ekvivalenta dodane kisline. Soli s formulo II lahko pripravimo s splošno uporabljanimi kislinami, kot je ocetna, benzojska, klorovodikova, benzensulfonska in perklorova kislina, na presenetljivo enostaven in učinkovit način. Te soli lahko izoliramo po minimalnih dodatnih stopnjah po zaključku konverzije intermediatov v olanzapin in so dobro primerne za konverzijo v obliko I olanzapina z ustrezno čistoto preko diklorometanskega solvata olanzapina.wherein X represents an acetate, benzoate, chloride, dichloride, benzenesulfonate or perchlorate anion. Salts of formula II may contain either n = 1 or n = 2 equivalents of added acid. The salts of formula II can be prepared with commonly used acids such as acetic, benzoic, hydrochloric, benzenesulfonic and perchloric acid in a surprisingly simple and effective way. These salts can be isolated at minimal additional rates upon completion of the conversion of the intermediates to olanzapine and are well suited for conversion to form I of olanzapine with appropriate purity via the dichloromethane solvate of olanzapine.
Izolacijo soli lahko strokovnjak s področja izvede z izkoriščanjem postopkov, ki se široko uporabljajo v kemijski sintezi, na naslednje načine: po uparitvi hlapnih komponent ali topil iz reakcijske zmesi po zaključeni sintezi olanzapina, ekstrahiramo zmes z organskim topilom in vodo, da odstranimo v vodi topne nečistote, ločimo vodno plast od plasti organskega topila, odparimo ekstrakcijsko topilo, raztopimo ostanek v drugem ustreznem topilu ali zmesi topil in dodamo kislino kot tako ali raztopino te kisline. Potem, ko se sol obori, jo izoliramo s filtracijo.Salt isolation can be accomplished by one of ordinary skill in the art using methods widely used in chemical synthesis in the following ways: after evaporation of volatile components or solvents from the reaction mixture after completion of olanzapine synthesis, extract the mixture with an organic solvent and water to remove water soluble impurities, separate the aqueous layer from the organic solvent layer, evaporate the extraction solvent, dissolve the residue in another suitable solvent or solvent mixture, and add acid as such or a solution of this acid. After the salt has precipitated, it is isolated by filtration.
Kot ekstrakcijsko topilo lahko uporabimo topilo ali zmes topil, ki se slabo mešajo z vodo, npr. acetate (npr. metil, etil, n-propil, i-propil, butil acetat), klorirana topila (npr. diklorometan, kloroform) ali etre (npr. dietileter, diizopropileter, t-butil metil eter).As the extraction solvent, a solvent or mixture of solvents miscible with water, e.g. acetates (e.g. methyl, ethyl, n-propyl, i-propyl, butyl acetate), chlorinated solvents (e.g. dichloromethane, chloroform) or ethers (e.g. diethyl ether, diisopropylether, t-butyl methyl ether).
Kot topila za raztapljanje ostanka po uparitvi organske ekstrakcijske plasti lahko izberemo topilo iz skupine nižjih alkoholov (npr. metanol, etanol, izopropanol, n-propanol, n-, i- ali t-butanol), ketonov (npr. aceton, metil etil keton, dietil keton), nitritov (npr. acetonitril, propionitril), acetatov (npr. metil, etil, n-propil, i-propil, butil acetat) ali etrov (npr. dietil eter, diizopropil eter, t-butil metil eter) ali njihove zmesi ali celo njihove zmesi z vodo.Solvents from the lower alcohol group (eg methanol, ethanol, isopropanol, n-propanol, n-, i- or t-butanol), ketones (eg acetone, methyl ethyl ketone) can be selected as solvents for dissolving the residue after evaporation of the organic extraction layer. , diethyl ketone), nitrites (e.g. acetonitrile, propionitrile), acetates (e.g. methyl, ethyl, n-propyl, i-propyl, butyl acetate) or ethers (e.g. diethyl ether, diisopropyl ether, t-butyl methyl ether) or mixtures thereof or even mixtures thereof with water.
Kot kislino lahko izberemo organsko ali anorgansko kislino iz skupine, katero sestavljajo ocetna, benzojska, klorovodikova, benzensulfonska in perklorova kislina. Kislina je lahko v svoji čisti obliki ali v zmesi s topilom ali vodo.Organic or inorganic acid may be selected from the group consisting of acetic, benzoic, hydrochloric, benzenesulfonic and perchloric acids. The acid may be in its pure form or mixed with solvent or water.
Drug postopek izolacije soli lahko izvedemo na naslednje načine: po odparitvi hlapnih komponent ali topil iz reakcijske zmesi po zaključeni sintezi olanzapina sledi ekstrakcija zmesi z organskim topilom in nakisano vodo. S tem postopkom odstranimo nečistote, topne v organskem topilu, medtem ko olanzapin ostane v vodni plasti. Z ločitvijo topila od vodne plasti, dodajanjem nove količine organskega topila in naalkaljenjem vodne plasti, ponovno pridobimo olanzapin v organski plasti. Po ločitvi plasti sledi odparitev topila ah topil iz organske plasti, raztapljanje ostanka v še enem ustreznem topilu ali zmesi topil, dodajanje kisline kot takšne ah raztopine te kisline.Another procedure for the isolation of salts can be carried out in the following ways: after evaporation of volatile components or solvents from the reaction mixture, after the synthesis of olanzapine is completed, extraction of the mixture with an organic solvent and acidified water is followed. This process removes impurities soluble in the organic solvent, while olanzapine remains in the aqueous layer. By separating the solvent from the aqueous layer, adding a new amount of organic solvent and basifying the aqueous layer, olanzapine is recovered in the organic layer. Separation of the layers is followed by evaporation of the solvent ah solvents from the organic layer, dissolution of the residue in another suitable solvent or mixture of solvents, addition of acid as such ah solution of this acid.
Potem, ko se obori sol olanzapina, jo izoliramo s filtracijo. Kot ekstrakcijsko topilo lahko uporabimo običajna topila ali zmesi topil, ki se slabo mešajo z vodo, npr. acetate (npr. metil, etil, n-propil, i-propil, butil acetat), klorirana topila (npr. diklorometan, kloroform) ali etre (npr. dietil eter, diizopropil eter, t-butil metil eter).After olanzapine salt precipitates, it is isolated by filtration. As the extraction solvent, conventional solvents or mixtures of miscible miscible water can be used, e.g. acetates (e.g. methyl, ethyl, n-propyl, i-propyl, butyl acetate), chlorinated solvents (e.g. dichloromethane, chloroform) or ethers (e.g. diethyl ether, diisopropyl ether, t-butyl methyl ether).
Kot topila za raztapljanje ostanka po uparitvi organske ekstrakcijske plasti lahko izberemo topilo iz skupine nižjih alkoholov (npr. metanol, etanol, izopropanol, n-propanol, n-, i- ali t-butanol), ketonov (npr. aceton, metil etil keton, dietil keton), nitrilov (npr. acetonitril, propionitril), acetatov (npr. metil, etil, n-propil, i-propil ali butil acetat) ah etrov (npr. dietil eter, diizopropil eter, t-butil metil eter), njihove zmesi ali celo njihove zmesi z vodo.Solvents from the lower alcohol group (eg methanol, ethanol, isopropanol, n-propanol, n-, i- or t-butanol), ketones (eg acetone, methyl ethyl ketone) can be selected as solvents for dissolving the residue after evaporation of the organic extraction layer. , diethyl ketone), nitrile (e.g. acetonitrile, propionitrile), acetates (e.g. methyl, ethyl, n-propyl, i-propyl or butyl acetate) ah ethers (e.g. diethyl ether, diisopropyl ether, t-butyl methyl ether) , mixtures thereof or even mixtures thereof with water.
Kot kislino lahko izberemo organsko ali anorgansko kislino iz skupine ocetne, benzojske, klorovodikove, benzensulfonske in perklorove kisline. Kislino lahko uporabimo v čisti obliki ali v zmesi s topilom ali vodo.Organic or inorganic acid from the group of acetic, benzoic, hydrochloric, benzenesulfonic and perchloric acids may be selected as the acid. The acid can be used in pure form or in admixture with solvent or water.
Vodno plast lahko naalkalimo z uporabo običajnih baz, ki se uporabljajo v organski sintezi, npr. baz zemeljskoalkalijskih kovin ali organskih baz, kot so litijevi, natrijevi, kalijevi, kalcijevi hidroksidi, hidrogenkarbonati ali karbonati, amoniak, trimetil- ali trietilamin.The aqueous layer can be basified using conventional bases used in organic synthesis, e.g. alkaline earth metal bases or organic bases such as lithium, sodium, potassium, calcium hydroxides, hydrogen carbonates or carbonates, ammonia, trimethyl or triethylamine.
Postopek lahko poenastavimo tako, da ekstrakcijsko topilo ne odparimo, ampak da zgoraj navedeno kislino ali raztopino kisline dodamo po ločitvi vodne plasti neposredno v ekstrakcijsko raztopino.The process can be simplified so that the extraction solvent is not evaporated but that the above acid or acid solution is added after separation of the aqueous layer directly into the extraction solution.
Postopek lahko poenostavimo nadalje tudi tako, da izpustimo ekstrakcijo in zgoraj navedeno kislino ali raztopino kisline dodamo v raztopino reakcijske zmesi po uparitvi hlapnih komponent. V tem primeru lahko izberemo topilo iz skupine nižjih alkoholov (npr. metanola, etanola, izopropanola, n-propanola, n-, i-, ali t-butanola), ketonov (npr. acetona, metil etil ketona, dietil ketona), nitritov (acetonitrila, propionitrila) ali acetatov (npr. metil, etil, n-propil, i-propil ali buril acetata) ali njihovih zmesi ali celo njihovih zmesi z vodo.The process can be further simplified by omitting the extraction and adding the above acid or acid solution to the solution of the reaction mixture after evaporation of the volatile components. In this case, a solvent can be selected from the group of lower alcohols (e.g. methanol, ethanol, isopropanol, n-propanol, n-, i-, or t-butanol), ketones (e.g. acetone, methyl ethyl ketone, diethyl ketone), nitrites (acetonitrile, propionitrile) or acetates (e.g. methyl, ethyl, n-propyl, i-propyl or buryl acetate) or mixtures thereof or even mixtures thereof with water.
Postopek lahko poenostavimo nadalje celo tako, da uparitev hlapnih komponent izpustimo in zgoraj navedeno kislino ali raztopino kisline dodamo v raztopino reakcijske zmesi, običajno z dodajanjem topila. V tem primeru lahko topilo izberemo iz skupine nižjih alkoholov (npr. metanola, etanola, izopropanola, n-propanola, n-, i-, ali t-butanola), ketonov (npr. acetona, metil etil ketona, dietil ketona), nitritov (acetonitrila, propionitrila) ali acetatov (npr. metil, etil, n-propil, i-propil, buril acetata), njihovih zmesi ali celo njihovih zmesi z vodo.The process can be further simplified even by evaporating the volatile components and adding the above acid or acid solution to the solution of the reaction mixture, usually by adding a solvent. In this case, the solvent can be selected from the group of lower alcohols (e.g. methanol, ethanol, isopropanol, n-propanol, n-, i-, or t-butanol), ketones (e.g. acetone, methyl ethyl ketone, diethyl ketone), nitrites (acetonitrile, propionitrile) or acetates (e.g. methyl, ethyl, n-propyl, i-propyl, buryl acetate), mixtures thereof or even mixtures thereof with water.
Strukture soli, pripravljenih z gornjimi postopki, smo potrdili z običajnimi analitskimi metodami, kot so NMR spektrometrija, IR spektrometrija, elementna analiza in določanje tališča. Z uporabo “H-NMR spektrometrije je postalo jasno, da čeprav olanzapin vsebuje tri potencialno sol tvoreče skupine, se izolirajo 1:1 spojine (molsko razmerje) v primerih soli z ocetno, benzojsko, benzensulfonsko in perklorovo kislino.The structures of the salts prepared by the above procedures were confirmed by conventional analytical methods such as NMR spectrometry, IR spectrometry, elemental analysis and melting point determination. Using H-NMR spectrometry, it has become clear that although olanzapine contains three potential salt forming groups, 1: 1 compounds (molar ratio) are isolated in cases of acetic, benzoic, benzenesulfonic and perchloric acid salts.
Izjema je klorovodikova kislina, kjer lahko z variiranjem reakcijskih pogojev presenetljivo izoliramo tako dihidrokloridno kot monohidrokloridno sol.An exception is hydrochloric acid, where by varying the reaction conditions it is surprising to isolate both the dihydrochloride and the monohydrochloride salt.
Na ta način pripravljene soli lahko nadalje, če je potrebno, očistimo s prekristalizacijo iz ustreznih topil.In this way, the prepared salts can be further purified, if necessary, by recrystallization from suitable solvents.
Soli olanzapina, pripravljene z gornjimi postopki, lahko pretvorimo v prosto bazo olanzapina z ekstakcijo ali kristalizacijo.Olanzapine salts prepared by the above procedures can be converted to the free olanzapine base by extraction or crystallization.
Ekstrakcijo lahko izvedemo z uporabo organskih topil ali alkalnih vodnih medijev. Kot alkalne medije lahko uporabimo vodne raztopine natrijevega karbonata, natrijevega hidrogenkarbonata ali hidroksida ali njihovih kalijevih ekvivalentov. Namesto njih lahko prav tako uporabimo raztopine amoniaka ali drugih organskih aminov.The extraction can be carried out using organic solvents or alkaline aqueous media. Aqueous solutions of sodium carbonate, sodium hydrogen carbonate or hydroxide or their potassium equivalents may be used as alkaline media. Solutions of ammonia or other organic amines may also be used instead.
Kot ekstrakcijsko topilo lahko uporabimo običajno ekstrakcijsko topilo kot je definirano zgoraj. Po ločitvi plasti organsko plast uparimo do oljnega ostanka, katerega raztopimo v ustreznem topilu in kristaliziramo. Kristalizacijo lahko izvedemo s suspendiranjem soli olanzapina v ustreznem topilu in pretvorbo le-te z dodajanjem baze.A conventional extraction solvent as defined above may be used as the extraction solvent. After separation of the layers, the organic layer was evaporated to an oily residue, which was dissolved in a suitable solvent and crystallized. Crystallization can be accomplished by suspending the olanzapine salt in a suitable solvent and converting it by adding a base.
V prednostni izvedbi obliko mešanega voda-izopropanolnega solvata pripravimo z običajno ekstrakcijo v organskih topilih in alkalnih vodnih medijih. Kot alkalne medije lahko uporabimo vodne raztopine natrijevega karbonata, natrijevega hidrogenkarbonata ali hidroksida ali njihovih kalijevih ekvivalentov. Namesto njih lahko prav tako uporabimo raztopine amoniaka ali drugih organskih aminov.In a preferred embodiment, the mixed water-isopropanol solvate form is prepared by conventional extraction in organic solvents and alkaline aqueous media. Aqueous solutions of sodium carbonate, sodium hydrogen carbonate or hydroxide or their potassium equivalents may be used as alkaline media. Solutions of ammonia or other organic amines may also be used instead.
Kot ekstrakcijsko topilo lahko uporabimo običajno ekstrakcijsko topilo, kot je definirano zgoraj. Po ločitvi plasti organsko plast uparimo do oljnega ostanka, katerega raztopimo v izopropanolu. Po dodatku ustrezne količine vode se obori mešan solvat. Postopek lahko poenostavimo tako, da izpustimo ekstrakcijo. V tem primeru se sol olanzapina suspendira v izopropanolu. Po dodatku ustrezne količine vodne raztopine baze se trdna snov transformira v voda-izopropanolni solvat olanzapina. Produkt izoliramo s filtracijo. Kot bazo lahko ponovno uporabimo vodne raztopine natrijevega karbonata, natrijevega hidrogenkarbonata ali hidroksida ali njihovih kalijevih ekvivalentov.As the extraction solvent, a conventional extraction solvent as defined above can be used. After separation of the layers, the organic layer was evaporated to an oily residue, which was dissolved in isopropanol. After addition of the appropriate amount of water, the mixed solvate precipitates. The process can be simplified by omitting extraction. In this case, the olanzapine salt is suspended in isopropanol. After the addition of an appropriate amount of aqueous base solution, the solid is transformed into an olanzapine water-isopropanol solvate. The product is isolated by filtration. Aqueous solutions of sodium carbonate, sodium hydrogen carbonate or hydroxide or their potassium equivalents may be reused.
Transformacijo voda-izopropanolnega solvata olanzapina v diklorometanski solvat dosežemo z raztapljanjem voda-izopropanolnega solvata olanzapina v diklorometanu, koncentriranjem raztopine z uparevanjem in zbiranjem trdnega dikorometanskega solvata olanzapina. Dobitek solvata je odvisen od razmaja med olanzapinom in diklorometanom.The transformation of the water-isopropanol solvate of olanzapine into a dichloromethane solvate is achieved by dissolving the water-isopropanol solvate of olanzapine in dichloromethane, concentrating the solution by evaporation and collecting a solid dichromethane solvate of olanzapine. The solvation yield depends on the gap between olanzapine and dichloromethane.
Transformacijo diklorometanskega solvata olanzapina v obliko I olanzapina lahko izvedemo s suspendiranjem trdnega diklorometanskega solvata olanzapina v izopropanolu in izoliramo trdne oblike I olanzapina s filtracijo.The transformation of the dichloromethane solvate of olanzapine into form I of olanzapine can be accomplished by suspending the solid dichloromethane solvate of olanzapine in isopropanol and isolating the solid forms of olanzapine by filtration.
Postopek za pripravo oblike I olanzapina lahko poenostavimo tako, da izpustimo izolacijo voda-izopropanolnega solvata olanzapina. V tem primeru lahko soli olanzapina, pripravljene z gornjimi postopki, pretvorimo v prosto bazo olanzapina v obliki dikorometanskih solvatov, kot je opisano v US 5,637,584, WO 2004/006933 in SI P-200400073, z običajno ekstrakcijo ob uporabi diklorometana in alkalnih vodnih medijev. Kot alkalne medije lahko uporabimo vodne raztopine natrijevega karbonata, natrijevega hidrogenkarbonata ali hidroksida ali njihovih kalijevih ekvivalentov. Namesto njih lahko uporabimo tudi raztopine amoniaka ali drugih organskih aminov. Po ločitvi plasti organsko plast delno koncentriramo in trden diklorometanski solvat olanzapina zberemo s filtracijo. Diklorometan kot ekstrakcijsko topilo lahko nadomestimo s katerimkoli drugim običajnim ekstrakcijskim topilom, kot je definirano zgoraj. Če je topilo drugačno od diklorometana, potem moramo najprej organsko plast upariti in ostanek raztopiti v diklorometanu.The process for the preparation of form I olanzapine can be simplified by omitting the isolation of the water-isopropanol solvate olanzapine. In this case, the olanzapine salts prepared by the above procedures can be converted to the free base of olanzapine in the form of dichromoethane solvates as described in US 5,637,584, WO 2004/006933 and SI P-200400073, by conventional extraction using dichloromethane and alkaline aqueous media. Aqueous solutions of sodium carbonate, sodium hydrogen carbonate or hydroxide or their potassium equivalents may be used as alkaline media. Solutions of ammonia or other organic amines may be used instead. After separation of the layers, the organic layer was partially concentrated and a solid dichloromethane solvate of olanzapine was collected by filtration. Dichloromethane as an extraction solvent can be replaced by any other conventional extraction solvent as defined above. If the solvent is different from dichloromethane, then the organic layer must first be evaporated and the residue dissolved in dichloromethane.
Na ta način tvorjen olanzapin diklorometan lahko pretvorimo v obliko I olanzapina z zgoraj definiranim postopkom.The olanzapine dichloromethane thus formed can be converted to form I olanzapine by the procedure defined above.
Predloženi izum je ponazoijen z naslednjimi primeri, ne da bi bil nanje omejen.The present invention is exemplified by, but not limited to, the following examples.
PRIMERIEXAMPLES
Olanzapin acetatOlanzapine acetate
Primer 1Example 1
Zmes 0,5 g 4-amino-2-metil-10//-tieno[2,3-b][l,5]benzodiazepin hidroklorida (okoli 92 % čistote), 0,67 ml dimetil sulfoksida, 2,25 ml toluena in 1,75 ml Λ-inetilpiperazina refluktiramo 4 ure. Topila odparimo v vakuumu, dodamo majhno količino vode in ekstrahiramo z diklorometanom. Organsko fazo posušimo s slanico in natrijevim sulfatom, filtriramo in topilo odstranimo z odparevanjem. Ostanek raztopimo v acetonu in dodamo 0,15 ml ocetne kisline. Zmes mešamo preko noči in produkt izoliramo s filtracijo izoliramo s filtracijo. Po sušenju je dobitek 0,30 g, tal. (nekorigirano) 190-193 °C. Struktura spojine je potijena z 'H-NMR (DMSO-D6): δ = l, 91 (3H, s, CH3COO), 2,21 (3H, s, 4'-CH3), 2,27 (3H, D, J=l,2 Hz, 2-CH3), 2,38 (4H, m, 3'-CH2), 3,33 (4H, m, 2’-CH2), 6,34 (IH, d, J=l,2 HZ, 3-CH), 6,66-6,88 (4H, m, 6, 7, 8, 9-H), 7,60 (delno zamenjan 2H, s, NH2 +).A mixture of 0.5 g of 4-amino-2-methyl-10 H -thieno [2,3-b] [1,5] benzodiazepine hydrochloride (about 92% purity), 0.67 ml of dimethyl sulfoxide, 2.25 ml toluene and 1.75 ml of in-inethylpiperazine were refluxed for 4 hours. The solvents were evaporated in vacuo, a small amount of water was added and extracted with dichloromethane. The organic phase was dried with brine and sodium sulfate, filtered and the solvent removed by evaporation. The residue was dissolved in acetone and 0.15 ml of acetic acid was added. The mixture was stirred overnight and the product was isolated by filtration and isolated by filtration. After drying, a yield of 0.30 g, m.p. (uncorrected) 190-193 ° C. The structure of the compound was quenched with 1 H-NMR (DMSO-D 6): δ = 1.91 (3H, s, CH 3 COO), 2.21 (3H, s, 4'-CH 3 ), 2.27 (3H , D, J = 1.2 Hz, 2-CH 3 ), 2.38 (4H, m, 3'-CH 2 ), 3.33 (4H, m, 2'-CH 2 ), 6.34 ( 1H, d, J = 1,2 HZ, 3-CH), 6.66-6.88 (4H, m, 6, 7, 8, 9-H), 7.60 (partially replaced by 2H, s, NH 2 + ).
Primer 2Example 2
K raztopini 1,0 g olanzapina v 50 ml izopropanola dodamo 2,5 ml ocetne kisline. Potem, ko odstranimo topilo v vakuumu, dodamo 2,5 ml izopropanola in zmes ohladimo. Oborino izoliramo s filtracijo in jo posušimo. Dobitek je 0,30 g. IR spekter je identičen spektru substance, pripravljene v primeru 1.To a solution of 1.0 g of olanzapine in 50 ml of isopropanol was added 2.5 ml of acetic acid. After removal of the solvent in vacuo, 2.5 ml of isopropanol is added and the mixture is cooled. The precipitate was isolated by filtration and dried. The yield is 0.30 g. The IR spectrum is identical to the spectrum of the substance prepared in Example 1.
Olanzapin benzoatOlanzapine benzoate
Primer 3Example 3
Zmes 0,5 g 4-amino-2-metil-/0//-tieno[2,3-b][l,5]benzodiazepin hidroklorida (okoli 92 % čistote), 0,67 ml dimetil sulfoksida, 2,25 ml toluena in 1,75 ml V-rnetilpiperazina refluktiramo 4 ure. Hlapne komponente uparimo v vakuumu, dodamo majhno količino vode in zmes ekstrahiramo z uporabo diklorometana.A mixture of 0.5 g of 4-amino-2-methyl-N-thieno [2,3-b] [1,5] benzodiazepine hydrochloride (about 92% purity), 0.67 ml of dimethyl sulfoxide, 2.25 ml of toluene and 1.75 ml of V-rnetylpiperazine are refluxed for 4 hours. The volatile components were evaporated in vacuo, a small amount of water was added and the mixture was extracted using dichloromethane.
Organsko fazo posušimo s slanico in brezvodnim natrijevim sulfatom, jo filtriramo in topilo odstranimo z uparevanjem. Ostanek raztopimo v acetonu in dodamo 0,318 g benzojske kisline. Zmes mešamo preko noči in produkt izoliramo s filtracijo. Po sušenju je dobitek 0,69 g, tališče (nekorigirano) 205 - 209 °C. Struktura spojine je potijena z ‘H-NMR (DMSO-d6): δ = 2,23 (3H, s, 4'-CH3), 2,27 (3H, d, J=l,2 Hz, 2CH3), 2,41 (4H, m, 3’-CH2), 3,34 (4H, m, 2’-CH2), 6,34 (IH, d, J=l,2 HZ, 3-CH), 6,66-6,88 (4H, m, 6, 7, 8, 9-H), 7,45-7,65 (4H, m, benzoat), 7,92 - 7,98 (delno izmenjano 2H, m, benzoat NH2 +).The organic phase was dried with brine and anhydrous sodium sulfate, filtered and the solvent removed by evaporation. The residue was dissolved in acetone and 0.318 g of benzoic acid was added. The mixture was stirred overnight and the product was isolated by filtration. After drying, the yield was 0.69 g, melting point (uncorrected) 205 - 209 ° C. The structure of the compound was impeded by 1 H-NMR (DMSO-d 6): δ = 2.23 (3H, s, 4'-CH 3 ), 2.27 (3H, d, J = 1.2 Hz, 2CH 3 ) , 2.41 (4H, m, 3'-CH 2 ), 3.34 (4H, m, 2'-CH 2 ), 6.34 (1H, d, J = 1.2 HZ, 3-CH) , 6.66-6.88 (4H, m, 6, 7, 8, 9-H), 7.45-7.65 (4H, m, benzoate), 7.92 - 7.98 (partially exchanged 2H , m, benzoate NH 2 + ).
Primer 4Example 4
Substanco pripravimo iz 4-amino-2-metil-/0//-tieno[2,3-b][l,5]benzodiazepin hidroklorida kot zgoraj. Po ekstrakciji, sušenju in odparitvi topila ostanek raztopimo v izopropanolu in dodamo 0,318 g benzojske kisline. Zmes mešamo preko noči in produkt izoliramo s filtracijo. Po sušenju je dobitek 0,64 g. IR spekter je identičen spektru substance, pripravljene s primerom 3.The substance is prepared from 4-amino-2-methyl- N -thieno [2,3-b] [1,5] benzodiazepine hydrochloride as above. After extraction, drying and evaporation of the solvent, the residue was dissolved in isopropanol and 0.318 g of benzoic acid was added. The mixture was stirred overnight and the product was isolated by filtration. After drying, the yield was 0.64 g. The IR spectrum is identical to the spectrum of the substance prepared in Example 3.
Primer 5Example 5
Zmes 0,20 g 4-amino-2-metil-70H-tieno[2,3-b][l,5]benzodiazepin hidroklorida (okoli 92 % čistote), 1,2 ml dimetil sulfoksida in 0,52 ml jV-metilpiperazina segrevamo pri 115 °C 16 ur. Ohlajeno reakcijsko zmes ekstrahiramo z izopropil acetatom in vodo. Organsko plast speremo s slanico, jo posušimo z natrijevim sulfatom in filtriramo. K raztopini dodamo 0,092 g benzojske kisline. Zmes mešamo preko noči in produkt izoliramo s filtracijo. Po sušenju je dobitek 0,144 g. IR spekter ustreza spektru primera 3.A mixture of 0.20 g of 4-amino-2-methyl-70H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride (about 92% purity), 1.2 ml of dimethyl sulfoxide and 0.52 ml of j- methylpiperazine is heated at 115 ° C for 16 hours. The cooled reaction mixture was extracted with isopropyl acetate and water. The organic layer was washed with brine, dried with sodium sulfate and filtered. 0.092 g of benzoic acid was added to the solution. The mixture was stirred overnight and the product was isolated by filtration. After drying, the yield is 0.144 g. The IR spectrum corresponds to the spectrum of Example 3.
Primer 6Example 6
Zmes 3,0 g 4-amino-2-metil-//?/7-tieno[2,3-b][l,5]benzodiazepin hidroklorida (okoli 92 % čistote), 4 ml dimetil sulfoksida, 13,5 ml toluena in 10,5 ml iV-metilpiperazina refluktiramo 4 ure. Topila odparimo v vakuumu. Ostanek raztopimo v acetonu in dodamo 1,477 g benzojske kisline. Zmes mešamo preko noči in produkt izoliramo s filtracijo. Po sušenju je dobitek 2,82 g. IR spekter ustreza spektrom primera 3.A mixture of 3.0 g of 4-amino-2-methyl-N- [7-thieno [2,3-b] [1,5] benzodiazepine hydrochloride (about 92% purity), 4 ml of dimethyl sulfoxide, 13.5 ml toluene and 10.5 ml of N-methylpiperazine were refluxed for 4 hours. The solvents were evaporated in vacuo. The residue was dissolved in acetone and 1,477 g of benzoic acid was added. The mixture was stirred overnight and the product was isolated by filtration. After drying, the yield was 2.82 g. The IR spectrum corresponds to the spectra of Example 3.
Primer 7Example 7
K raztopini 1,0 g olanzapina v 50 ml izopropanola dodamo 0,41 g benzojske kisline in raztopino mešamo. Oborino izoliramo s filtracijo in posušimo. Dobitek je 1,06 g. IR spekter je identičen spektru primera 3.To a solution of 1.0 g of olanzapine in 50 ml of isopropanol is added 0.41 g of benzoic acid and the solution is stirred. The precipitate was isolated by filtration and dried. The yield is 1.06 g. The IR spectrum is identical to the spectrum of Example 3.
Primer 8Example 8
Raztopino 2,4-bis(4-metil-1 -piperazinil)-3-propiliden-3/7-[ l,5]benzodiazepina (3,81 g, 10 mmol), piridinijevega p-toluensulfonata (5,29 g, 21 mmol) in žvepla (1,15 g, 35,8 mmol) v benzonitrilu (100 ml) mešamo pri 140 °C 8,5 h, ohladimo na 90 °C in koncentriramo, da se tvori oljnat ostanek. Ostanek razredčimo z diklorometanom in 2propanolom (60 ml, 1:1). Oborino odfiltriramo in speremo z diklorometanom in 2propanolom (15 ml, 1:1). Filtrat ekstrahiramo s HCI (50 ml, 0,5 M). Organsko fazo razredčimo z diklorometanom in 2-propanolom (100 ml, 1:1) in ekstrahiramo s HCI (50 ml, IM). Organsko fazo ponovno ekstrahiramo s HCI (50 ml, 2M). Združene vodne faze naalkalimo s 5 M NaOH na pH 10 in ekstrahiramo z diklorometanom (150 ml). K organski fazi dodamo benzojske kislino (1,832 g, 15 mmol). Raztopino koncentriramo, da se tvori oljnat ostanek in suspendiramo v izopropil acetatu. Trdno snov izoliramo s filtracijo in posušimo. IR spekter je identičen spektru substance, pripravljene v primeru 3.A solution of 2,4-bis (4-methyl-1-piperazinyl) -3-propylidene-3 / 7- [1,5] benzodiazepine (3.81 g, 10 mmol), pyridinium p-toluenesulfonate (5.29 g, 21 mmol) and sulfur (1.15 g, 35.8 mmol) in benzonitrile (100 ml) were stirred at 140 ° C for 8.5 h, cooled to 90 ° C and concentrated to form an oily residue. The residue was diluted with dichloromethane and 2propanol (60 ml, 1: 1). The precipitate was filtered off and washed with dichloromethane and 2propanol (15 ml, 1: 1). The filtrate was extracted with HCl (50 ml, 0.5 M). The organic phase was diluted with dichloromethane and 2-propanol (100 ml, 1: 1) and extracted with HCl (50 ml, IM). The organic phase was re-extracted with HCl (50 ml, 2M). The combined aqueous phases were basified with 5 M NaOH at pH 10 and extracted with dichloromethane (150 ml). Benzoic acid (1.832 g, 15 mmol) was added to the organic phase. The solution was concentrated to form an oily residue and suspended in isopropyl acetate. The solid was isolated by filtration and dried. The IR spectrum is identical to the spectrum of the substance prepared in Example 3.
Olanzapin dihidrokloridOlanzapine dihydrochloride
Primer 9Example 9
Zmes 3 g 4-amino-2-metil-107/-tieno[2,3-b][l,5]benzodiazepin hidroklorida (okoli 92 % čistote), 4 ml dimetil sulfoksida, 13,5 ml toluena in 10,5 ml /V-metilpiperazina refluktiramo 4 ure, ohladimo in dodamo vodo. Zmes ekstrahiramo s 30 ml izopropil acetata. Organsko plast speremo s slanico in dodamo 1 ml koncentrirane klorovodikove kisline. Po ločitvi oljnega produkta dodamo 10 ml izopropanola in zmes mešamo preko noči. Trdno snov izoliramo s filtracijo, speremo z majhnim volumnom izopropil acetata in posušimo do konstantne teže. Dobitek je 1,3 g tal. (nekorigirano) 225-223 °C (razpad). Struktura spojine je potrjena z *H-NMR (DMSOd6): δ = 2,31 (3H, d, J=l,2 Hz, 2-CH3), 2,81 (3H, s, 4'-CH3), 3,5 (m, 3'(ali 2’)-CH2), 3,89 (4H, m, 2’(ali 3’)-CH2), 6,69 (IH, d, J=l,2 Hz, 3-CH), 7,04-7,36 (4H, m, 6, 7, 8, 9-H), 9,51 (IH, s, 10H), 11,70 (IH, širok s, izmenljiv v D2O, NH+), 11,93 (IH širok s, izmenljiv v D2O, NH+).A mixture of 3 g of 4-amino-2-methyl-107 H -thieno [2,3-b] [1,5] benzodiazepine hydrochloride (about 92% purity), 4 ml of dimethyl sulfoxide, 13.5 ml of toluene and 10.5 ml / V-methylpiperazine was refluxed for 4 hours, cooled and water was added. The mixture was extracted with 30 ml of isopropyl acetate. The organic layer was washed with brine and 1 ml of concentrated hydrochloric acid was added. After separation of the oil product, 10 ml of isopropanol is added and the mixture is stirred overnight. The solid was isolated by filtration, washed with a small volume of isopropyl acetate and dried to constant weight. The yield is 1.3 g of soil. (uncorrected) 225-223 ° C (decomposition). The structure of the compound was confirmed by * H-NMR (DMSOd 6): δ = 2.31 (3H, d, J = 1.2 Hz, 2-CH 3 ), 2.81 (3H, s, 4'-CH 3 ) , 3.5 (m, 3 '(or 2') - CH 2 ), 3.89 (4H, m, 2 '(or 3') - CH 2 ), 6.69 (1H, d, J = l , 2 Hz, 3-CH), 7.04-7.36 (4H, m, 6, 7, 8, 9-H), 9.51 (1H, s, 10H), 11.70 (1H, broad s, exchangeable in D 2 O, NH + ), 11.93 (1H wide s, exchangeable in D 2 O, NH + ).
Primer 10Example 10
Po refluktiranju reakcijske zmesi kot v primeru 9 hlapne komponente odstranimo v vakuumu in ostanek raztopimo v acetonu. Po dodatku 0,95 ml koncentrirane klorovodikove kisline zmes mešamo preko noči. Hlapne komponente odstranimo in dodamo 10 ml izopropanola in novo količino 0,95 ml koncentrirane klorovodikove kisline. Zmes mešamo 1 uro. Trdno snov izoliramo s filtracijo, jo speremo z izopropanolom in posušimo do konstantne teže. Dobitek je 3,15 g. IR spekter ustreza spektru predhodnega primera.After refluxing the reaction mixture as in Example 9, the volatile component was removed in vacuo and the residue dissolved in acetone. After the addition of 0.95 ml of concentrated hydrochloric acid, the mixture was stirred overnight. Remove volatile components and add 10 ml of isopropanol and a new amount of 0.95 ml of concentrated hydrochloric acid. The mixture was stirred for 1 hour. The solid was isolated by filtration, washed with isopropanol and dried to constant weight. The yield is 3.15 g. The IR spectrum corresponds to the spectrum of the preceding example.
Primer 11Example 11
Potem, ko pripravimo acetonsko raztopino reakcijske zmesi kot v predhodnem primeru, dodamo 1,9 ml koncentrirane klorovodikove kisline. Zmes mešamo preko noči, topilo odstranimo z odparevanjem v vakuumu in dodamo 20 ml acetona. Nato dodamo 4 ml izopropanola, raztopino mešamo dodatni 2 uri, trdno snov izoliramo s filtracijo in jo posušimo do konstantne teže. Dobitek je 3,7 g. IR spekter ustreza spektru primera 9.After preparing the acetone solution of the reaction mixture as in the preceding example, 1.9 ml of concentrated hydrochloric acid was added. The mixture was stirred overnight, the solvent was removed by evaporation in vacuo and 20 ml of acetone was added. Then 4 ml of isopropanol is added, the solution is stirred for an additional 2 hours, the solid is isolated by filtration and dried to constant weight. Yield 3.7 g. The IR spectrum corresponds to the spectrum of Example 9.
Olanzapin hidrokloridOlanzapine hydrochloride
Primer 12Example 12
K raztopini 1,0 g (3,20 mmol) olanzapina v 50 ml izopropil acetata dodamo 0,30 ml (3,35 mmol) koncentrirane klorovodikove kisline in mešamo. Hlapne komponente odparimo v vakuumu in dodamo sveže topilo. Po mešanju nastalo oborino izoliramo s filtracijo in jo posušimo. Dobitek je 1,01 g, tal. (nekorigirano) 250-270 °C (razpad). IR spekter je drugačen v primeijavi s spektrom produkta primera 9. Struktura spojine je potijena z ‘H-NMR (DMSO-d6); δ = 2,29 (3H, d, J= 1,2 Hz, 2-CH3), 2,77 (3H, s, 4'CH3), 3,35 (m, 3’(ali 2’)-CH2), 3,98 (4H, m, 2’(ali 3’)-CH2), 6,50 (IH, m, 3-CH), 6,87,1 (4H, m, 6,7,8,9-H), 8,3 (IH, razširjen s, 10-H), 11,5 (IH, razširjen s, NH+).To a solution of 1.0 g (3.20 mmol) of olanzapine in 50 ml of isopropyl acetate was added 0.30 ml (3.35 mmol) of concentrated hydrochloric acid and stirred. Evaporate the volatile components in vacuo and add fresh solvent. After stirring, the resulting precipitate was isolated by filtration and dried. The yield is 1.01 g, m.p. (uncorrected) 250-270 ° C (decomposition). The IR spectrum is different in comparison with the product spectrum of Example 9. The structure of the compound is swept with 1 H-NMR (DMSO-d 6); δ = 2.29 (3H, d, J = 1.2 Hz, 2-CH 3 ), 2.77 (3H, s, 4'CH 3 ), 3.35 (m, 3 '(or 2') -CH 2 ), 3.98 (4H, m, 2 '(or 3') - CH 2 ), 6.50 (1H, m, 3-CH), 6.87.1 (4H, m, 6, 7,8,9-H), 8,3 (1H, broad s, 10-H), 11,5 (1H, broad s, NH + ).
Olanzapin benzensulfonatOlanzapine benzenesulfonate
Primer 13Example 13
K raztopini 1,0 g (3,20 mmol) olanzapina v 50 ml izopropil acetata dodamo 0,53 g (3,35 mmol) benzensulfonske kisline hidrata in mešamo. Nastalo oborino izoliramo s filtracijo in posušimo. Dobitek je 1,3 g, tal. (nekorigirano) 168-170 °C. Struktura spojine je potijena z Ίΐ-NMR (DMSO-d6): δ 2,28 (3H, d, J=l,2 Hz, 2-CH3), 2,81 (3H, s, 4’-CH3), 3,23 (m, 3’(ali 2’)-CH2), 3,35 (4H, m, 2’(ab 3’)-CH2), 6,43 (IH, m, 3CH), 6,7-7,0 (4H, m, 6,7,8,9-H), 7,25-7,35 (3H, m, PhSO3H), 7,55-7,65 (2H, m, PhSO3H), 7,9 (IH, razšiijen s, 10-H), 9,7 (IH, razšiijen s, NH).To a solution of 1.0 g (3.20 mmol) of olanzapine in 50 ml of isopropyl acetate was added 0.53 g (3.35 mmol) of benzenesulfonic acid hydrate and stirred. The resulting precipitate was isolated by filtration and dried. The yield is 1.3 g, m.p. (uncorrected) 168-170 ° C. The structure of the compound was impaired by Ίΐ-NMR (DMSO-d6): δ 2.28 (3H, d, J = 1.2 Hz, 2-CH 3 ), 2.81 (3H, s, 4'-CH 3 ) , 3.23 (m, 3 '(or 2') - CH 2 ), 3.35 (4H, m, 2 '(ab 3') - CH 2 ), 6.43 (1H, m, 3CH), 6.7-7.0 (4H, m, 6,7,8,9-H), 7,25-7,35 (3H, m, PhSO 3 H), 7,55-7,65 (2H, m, PhSO 3 H), 7.9 (1H, broad s, 10-H), 9.7 (1H, broad s, NH).
Olanzapin perkloratOlanzapine perchlorate
Primer 14Example 14
Zmes 0,5 g 4-amino-2-metil-10//-tieno[3,2-b][l,5]benzodiazepin hidroklorida, 0,67 ml dimetil sulfoksida, 2,25 toluena in 1,75 ml N-metilpiperazina refluktiramo 4 ure. Topila odparimo v vakuumu, dodamo majhno količino vode in zmes ekstrahiramo z diklorometanom. Organsko fazo posušimo s slanico in natrijevim sulfatom, jo filtriramo in topilo odstranimo z odparevanjem. Ostanek raztopimo v izopropanolu in dodamo 0,22 ml 70 % perklorove kisline. Zmes mešamo preko noči in produkt izoliramo s filtracijo. Po sušenju je dobitek 0,63 g, tal. (nekorigirano) 180183 °C. Struktura spojine je potrjena z ’Η-NMR (DMSO-d6): δ = 2,29 (3H, d, J=l,2 Hz, 2-CH3), 2,82 (3H, s, 4'-CH3), 3,25 (m, 3'(ali 2')-CH2), 3,35 (4H, m, 2’(ali 3')-CH2), 6,45 (IH, s, 3-CH), 6,65-7,05 (4H, m, 6,7,8,9-H), 7,87 (IH, razšiijen s, 10-H), 9,67 (IH, razšiijen s, NH+).A mixture of 0.5 g of 4-amino-2-methyl-10 H -thieno [3,2-b] [1,5] benzodiazepine hydrochloride, 0.67 ml of dimethyl sulfoxide, 2.25 toluene and 1.75 ml of N -methylpiperazine was refluxed for 4 hours. The solvents were evaporated in vacuo, a small amount of water was added and the mixture was extracted with dichloromethane. The organic phase is dried with brine and sodium sulfate, filtered and the solvent removed by evaporation. The residue was dissolved in isopropanol and 0.22 ml of 70% perchloric acid was added. The mixture was stirred overnight and the product was isolated by filtration. After drying, a yield of 0.63 g, m.p. (uncorrected) 180183 ° C. The structure of the compound was confirmed by 1 H-NMR (DMSO-d 6): δ = 2.29 (3H, d, J = 1.2 Hz, 2-CH 3 ), 2.82 (3H, s, 4'-CH 3 ), 3.25 (m, 3 '(or 2') - CH 2 ), 3.35 (4H, m, 2 '(or 3') - CH 2 ), 6.45 (1H, s, 3 -CH), 6.65-7.05 (4H, m, 6,7,8,9-H), 7,87 (1H, broad s, 10-H), 9,67 (1H, broad s, NH + ).
Primer 15Example 15
K raztopini 1,0 g olanzapina v 50 ml izopropanola dodamo 0,3 ml 70 % perklorove kisline in zmes mešamo. Oborino izoliramo s filtracijo in posušimo. Dobitek je 0,60 g. IR spekter je identičen spektru predhodnega primera.To a solution of 1.0 g of olanzapine in 50 ml of isopropanol is added 0.3 ml of 70% perchloric acid and the mixture is stirred. The precipitate was isolated by filtration and dried. The yield is 0.60 g. The IR spectrum is identical to that of the preceding example.
Voda-izopropilni solvat olanzapinaOlanzapine water-isopropyl solvate
Primer 16Example 16
Zmes 1,0 g olanzapin dihidroklorida, pripravljenega s postopkom kot v primeru 11, 6 ml izopropanola, 0,77 ml trietilamina in 1,5 ml vode mešamo okoli 1,5 ure. Potem, ko produkt izoliramo s filtracijo in posušimo v vakuumu pri sobni temperaturi do konstantne teže, je dobitek 0,64 g. Izguba pri sušenju pri (140 °C): 13,1 %. IR spekter in NMR spekter ustrezata strukturi.A mixture of 1.0 g olanzapine dihydrochloride prepared by the procedure as in Example 11, 6 ml isopropanol, 0.77 ml triethylamine and 1.5 ml water was stirred for about 1.5 hours. After the product was isolated by filtration and dried under vacuum at room temperature to constant weight, a yield of 0.64 g was obtained. Loss on drying at (140 ° C): 13.1%. The IR spectrum and the NMR spectrum correspond to the structure.
Diklorometanski solvat olanzapinaDichloromethane solvate of olanzapine
Primer 17Example 17
Zmes 5,0 g olanzapin benzoata, pripravljenega s postopkom kot v primeru 3, 100 ml diklorometana, 12 ml 1 M NaOH raztopine mešamo okoli 0,5 ure. Plasti se ločijo in organsko plast speremo s slanico in brezvodnim natrijevim sulfatom. Raztopino koncentriramo do okoli 1/10 začetnega volumna z destilacijo v vakuumu. Med destilacijo temperatura pade na okoli 10 °C in produkt (diklorometanski solvat) olanzapina) kristalizira. Po zbiranju produkta s filtracijo in sušenjem v vakuumu pri sobni temperaturi do konstantne teže je dobitek 1,8 g. Izguba pri sušenju pri (140 °C):A mixture of 5.0 g of olanzapine benzoate prepared by the procedure as in Example 3, 100 ml of dichloromethane, 12 ml of 1 M NaOH solution was stirred for about 0.5 hour. The layers were separated and the organic layer was washed with brine and anhydrous sodium sulfate. Concentrate the solution to about 1/10 of the initial volume by distillation in vacuo. During distillation, the temperature drops to about 10 ° C and the product (dichloromethane solvate of olanzapine) crystallizes. After collecting the product by filtration and vacuum drying at room temperature to constant weight, a yield of 1.8 g was obtained. Loss on drying at (140 ° C):
9,9 %. IR spekter in NMR spekter ustrezata strukturi.9.9%. The IR spectrum and the NMR spectrum correspond to the structure.
Primer 18Example 18
Zmes 1,0 g olanzapin dihidroklorida, pripravljenega s postopkom kot v primeru 10, 20 ml diklorometana, 0,77 ml trietilamina in 6 ml vode mešamo nekaj minut. Plasti se ločijo in organsko plast obdelamo s slanico in brezvodnim natrijevim sulfatom. Raztopino koncentriramo do okoli 1/5 začetnega volumna z destilacijo. Po izolaciji produkta s filtriranjem in sušenju v vakuumu pri sobni temperaturi do konstantne teže je dobitek 0,45 g. IR spekter ustreza spektrom predhodnega primera.A mixture of 1.0 g olanzapine dihydrochloride prepared by the procedure as in Example 10, 20 ml dichloromethane, 0.77 ml triethylamine and 6 ml water was stirred for several minutes. The layers were separated and the organic layer was treated with brine and anhydrous sodium sulfate. Concentrate the solution to about 1/5 of the initial volume by distillation. After isolation of the product by filtration and drying under vacuum at room temperature to constant weight, 0.45 g is obtained. The IR spectrum corresponds to the spectra of the preceding example.
Primer 19Example 19
Zmes 2,0 g voda-izopropanolnega mešanega solvata olanzapina, pripravljenega s postopkom kot je opisan v primeru 16, raztopimo v 24 ml diklorometana. Raztopino koncetriramo do okoli 1/5 začetnega volumna z destilacijo. Po izolaciji produkta s filtriranjem in sušenju v vakuumu pri sobni temperaturi do konstantne teže, je dobitekA mixture of 2.0 g of the water-isopropanol mixed solvate of olanzapine prepared by the procedure described in Example 16 was dissolved in 24 ml of dichloromethane. The solution was concentrated to about 1/5 of the initial volume by distillation. After isolation of the product by filtration and drying in vacuum at room temperature to constant weight, the yield is
1,6 g. IR spekter ustreza spektrom predhodnega primera.1.6 g. The IR spectrum corresponds to the spectra of the preceding example.
Oblika I olanzapinaForm I olanzapine
Primer 20Example 20
Zmes 1,0 g diklorometanskega solvata olanzapina, pripravljenega s postopkom kot v primeru 17, in 2,5 ml izopropanola mešamo okoli 0,5 ure. Trdno snov izoliramo s filtracijo in posušimo. Dobitek je 0,79 g. IR spekter ustreza obliki I olanzapina iz literatumih podatkov.A mixture of 1.0 g of olanzapine dichloromethane solvate prepared by the procedure as in Example 17 and 2.5 ml of isopropanol was stirred for about 0.5 hour. The solid was isolated by filtration and dried. The yield is 0.79 g. The IR spectrum corresponds to form I olanzapine from the literature data.
Primer 21Example 21
Zmes 0,24 g diklorometanskega solvata olanzapina, pripravljenega s postopkom kot v primeru 18, in 0,6 ml izopropanola mešamo okoli 0,5 ure. Trdno snov izoliramo s filtriranjem in posušimo. Dobitek je 0,19 g. IR spekter ustreza obliki I olanzapina iz literatumih podatkov.A mixture of 0.24 g of dichloromethane solvate of olanzapine prepared by the procedure as in Example 18 and 0.6 ml of isopropanol was stirred for about 0.5 hours. The solid was isolated by filtration and dried. The yield is 0.19 g. The IR spectrum corresponds to form I olanzapine from the literature data.
Claims (12)
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| Application Number | Priority Date | Filing Date | Title |
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| SI200400219A SI21850A (en) | 2004-07-28 | 2004-07-28 | Salts of olanzapin and their transformation into free base of olanzapin |
| PCT/EP2005/008218 WO2006010620A2 (en) | 2004-07-28 | 2005-07-28 | Olanzapine salts and their conversion to olanzapine free base |
| EP05779020A EP1781665A2 (en) | 2004-07-28 | 2005-07-28 | Olanzapine salts and their conversion to olanzapine free base |
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| US7323459B2 (en) | 2002-12-24 | 2008-01-29 | Teva Pharmaceutical Industries Ltd. | Crystal forms, methods for their preparation and method for preparation of olanzapine |
| PL377084A1 (en) * | 2005-09-15 | 2007-03-19 | Koźluk Tomasz Nobilus Ent | New olanzapine compounds and method for their manufacture |
| WO2007138376A1 (en) | 2006-06-01 | 2007-12-06 | Aurobindo Pharma Limited | An improved process for preparing olanzapine form i |
| KR20150081370A (en) * | 2006-07-10 | 2015-07-13 | 파이온 유케이 리미티드 | Short-acting benzodiazepine salts and their polymorphic forms |
| GB0613693D0 (en) * | 2006-07-10 | 2006-08-16 | Cenes Ltd | Benzodiazepine salts (3) |
| PL381564A1 (en) | 2007-01-22 | 2008-08-04 | Koźluk Tomasz Nobilus Ent | The manner of production of basically clean variety of polymorphic olanzapine |
| EP2450039A1 (en) | 2010-11-08 | 2012-05-09 | PAION UK Ltd. | Dosing regimen for sedation with CNS 7056 (Remimazolam) |
| AR094963A1 (en) | 2013-03-04 | 2015-09-09 | Ono Pharmaceutical Co | EXCELLENT OXIDATION REACTION IN THE CONVERSION INDEX |
| KR20230006896A (en) * | 2020-05-05 | 2023-01-11 | 신유알엑스 인터내셔널 (타이완) 코포레이션 | Salts of neurosuticals and uses thereof |
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| GB9009229D0 (en) * | 1990-04-25 | 1990-06-20 | Lilly Industries Ltd | Pharmaceutical compounds |
| US5637584A (en) * | 1995-03-24 | 1997-06-10 | Eli Lilly And Company | Solvate of olanzapine |
| CA2471341C (en) * | 2001-12-24 | 2012-01-24 | Sun Pharmaceutical Industries Limited | Crystalline form i of 2-methyl-4-(4-methyl-1-piperazinyl) 10h thieno [2,3-b][1,5]benzodiazepine |
| EP1513846B1 (en) * | 2002-05-31 | 2011-03-02 | Sandoz Ag | Process of preparation of olanzapine form i |
| HU226410B1 (en) * | 2003-04-22 | 2008-11-28 | Egis Gyogyszergyar Nyilvanosan | Novel polymorphous forms of olanzapine hydrochlorides, process for producing them, use thereof and pharmaceutical compositions containing them |
| WO2005070937A1 (en) * | 2004-01-27 | 2005-08-04 | Synthon B.V. | A process for making olanzapine in a polymorph form i |
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| WO2006010620A3 (en) | 2006-06-08 |
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