WO2017216661A1 - Process for the preparation of brexpiprazole from 7-(4-chlorobutoxy)quinolin-2(1h)-one and 1-(benzo[b]thiophen-4-yl)piperazine - Google Patents
Process for the preparation of brexpiprazole from 7-(4-chlorobutoxy)quinolin-2(1h)-one and 1-(benzo[b]thiophen-4-yl)piperazine Download PDFInfo
- Publication number
- WO2017216661A1 WO2017216661A1 PCT/IB2017/053018 IB2017053018W WO2017216661A1 WO 2017216661 A1 WO2017216661 A1 WO 2017216661A1 IB 2017053018 W IB2017053018 W IB 2017053018W WO 2017216661 A1 WO2017216661 A1 WO 2017216661A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- brexpiprazole
- quinolin
- solvent
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 52
- 229960001210 brexpiprazole Drugs 0.000 title claims abstract description 44
- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- DPQAKBJISUNJNK-UHFFFAOYSA-N 7-(4-chlorobutoxy)-1h-quinolin-2-one Chemical compound C1=CC(=O)NC2=CC(OCCCCCl)=CC=C21 DPQAKBJISUNJNK-UHFFFAOYSA-N 0.000 title abstract description 13
- VMIRJNDPLCQEHB-UHFFFAOYSA-N 1-(1-benzothiophen-4-yl)piperazine Chemical compound C1CNCCN1C1=CC=CC2=C1C=CS2 VMIRJNDPLCQEHB-UHFFFAOYSA-N 0.000 title abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 47
- 239000002904 solvent Substances 0.000 claims abstract description 29
- 239000000539 dimer Substances 0.000 claims abstract description 27
- 229920005989 resin Polymers 0.000 claims abstract description 8
- 239000011347 resin Substances 0.000 claims abstract description 8
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 50
- 239000012535 impurity Substances 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 24
- -1 Brexpiprazole compound Chemical class 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 15
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 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 description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 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 claims description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- 229940090181 propyl acetate Drugs 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- SVYKKECYCPFKGB-UHFFFAOYSA-N N,N-dimethylcyclohexylamine Chemical compound CN(C)C1CCCCC1 SVYKKECYCPFKGB-UHFFFAOYSA-N 0.000 claims description 3
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 3
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 150000004982 aromatic amines Chemical class 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 229910052792 caesium Inorganic materials 0.000 claims description 3
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- 150000008282 halocarbons Chemical class 0.000 claims description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 3
- 150000004678 hydrides Chemical class 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 3
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 239000004925 Acrylic resin Substances 0.000 claims description 2
- 229920000178 Acrylic resin Polymers 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 229920003053 polystyrene-divinylbenzene Polymers 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- NIDSRGCVYOEDFW-UHFFFAOYSA-N 1-bromo-4-chlorobutane Chemical compound ClCCCCBr NIDSRGCVYOEDFW-UHFFFAOYSA-N 0.000 abstract description 7
- DBSPUDKBNOZFMX-UHFFFAOYSA-N 7-hydroxyquinolin-2(1H)-one Chemical compound C1=CC(=O)NC2=CC(O)=CC=C21 DBSPUDKBNOZFMX-UHFFFAOYSA-N 0.000 abstract description 7
- 229920001429 chelating resin Polymers 0.000 abstract description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 abstract description 4
- 229960003638 dopamine Drugs 0.000 abstract description 4
- 208000024714 major depressive disease Diseases 0.000 abstract description 3
- 201000000980 schizophrenia Diseases 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 239000004031 partial agonist Substances 0.000 abstract description 2
- 239000000463 material Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 238000010992 reflux Methods 0.000 description 10
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000011097 chromatography purification Methods 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- YGYUMNQONHLLNC-UHFFFAOYSA-N 4-chloro-1-benzothiophene Chemical compound ClC1=CC=CC2=C1C=CS2 YGYUMNQONHLLNC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N thianaphthalene Natural products C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- CYPYTURSJDMMMP-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1.C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1.C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 CYPYTURSJDMMMP-UHFFFAOYSA-N 0.000 description 1
- AFBFXBNCAHKEMO-UHFFFAOYSA-N 1-butoxyquinolin-2-one dihydrochloride Chemical compound CCCCON1C(=O)C=CC2=CC=CC=C21.Cl.Cl AFBFXBNCAHKEMO-UHFFFAOYSA-N 0.000 description 1
- QOLJDCZXEUUSKM-UHFFFAOYSA-N C(C(c1cccc2c1cc[s]2)Sc1ccc2)c1c2N1CCNCC1 Chemical compound C(C(c1cccc2c1cc[s]2)Sc1ccc2)c1c2N1CCNCC1 QOLJDCZXEUUSKM-UHFFFAOYSA-N 0.000 description 1
- XPNZFZVNUDTXBN-UHFFFAOYSA-N C(CN(CC1)c2c(cc[s]3)c3ccc2)N1c1c(cc[s]2)c2ccc1 Chemical compound C(CN(CC1)c2c(cc[s]3)c3ccc2)N1c1c(cc[s]2)c2ccc1 XPNZFZVNUDTXBN-UHFFFAOYSA-N 0.000 description 1
- 238000012369 In process control Methods 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- HUZZJLWJYPLYOL-UHFFFAOYSA-N O=C1Nc(cc(cc2)OCCCCOc(cc3)cc(N4)c3C=CC4=O)c2C=C1 Chemical compound O=C1Nc(cc(cc2)OCCCCOc(cc3)cc(N4)c3C=CC4=O)c2C=C1 HUZZJLWJYPLYOL-UHFFFAOYSA-N 0.000 description 1
- SQGBMQLIANXDLQ-UHFFFAOYSA-N O=C1Nc2cc(ON(CC3)CCN3c3c(cc[s]4)c4ccc3)ccc2C=C1 Chemical compound O=C1Nc2cc(ON(CC3)CCN3c3c(cc[s]4)c4ccc3)ccc2C=C1 SQGBMQLIANXDLQ-UHFFFAOYSA-N 0.000 description 1
- 238000011360 adjunctive therapy Methods 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 238000010420 art technique Methods 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 description 1
- 238000010965 in-process control Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000002941 palladium compounds Chemical class 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229940011389 rexulti Drugs 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- 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
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
Definitions
- the present invention relates to process for the preparation of benzo[b]thiophene compound used for the treatment of schizophrenia and as an adjunct for major depressive disorder. More particularly, the present invention is directed to the process for the preparation of 7- ⁇ 4-[4-(l-benzothiophen-4-yl) piperazin-l-yl] butoxy ⁇ quinolin-2 (1H)- one (Brexpiprazole) and its intermediates thereof.
- Brexpiprazole is a D2 dopamine partial agonist called serotonin-dopamine activity modulator (SDAM). Brexpiprazole is chemically known as 7- ⁇ 4-[4-(l-benzothiophen-4- yl) piperazin-l-yl] butoxy ⁇ quinolin-2 (lH)-one. It is known from US 7,888,362 and is represented by Formula I.
- Brexpiprazole is sold in USA under the proprietary name of "REXULTI” and is indicated for the treatment of schizophrenia and also as an adjunctive therapy to antidepressants in adults having major depressive disorder.
- Another intermediate 1- benzo[b]thiophene-4-yl-piperazine hydrochloride compound of Formula V is prepared by reacting compound of Formula IV with anhydrous piperazine using (R) (+)-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl(BINAP), dipalladiumtris (dibenzylidene acetone) in presence of sodium i-butoxide by heating under reflux.
- Impurity D (Dimer impurity)
- the main drawback of the said process is the use of expensive palladium carbene complex on commercial scale, which makes the process costly and needs special handling equipment for industrial scale production.
- Another disadvantage of this process is the formation of impurity A and impurity B during the reaction of compound of Formula V with compound of Formula III which is difficult to separate from the final product and requires multiple purifications, thus in order to attain the purity of final compound, it leads to undue operational steps for removal of impurities, thus makes the process expensive and tedious on commercial scale.
- CN 105175401A discloses the synthesis of Brexpiprazole wherein 7-hydroxyl-lH- quinolin-2-one of Formula II reacts with 1 -chlorine-4-bromobutane to obtain 7-(4- chlorobutoxy)-lH-quinolin-2-one of Formula III, which then reacts with N-Boc piperazine to obtain 7-(l-piperazine) butoxy-lH-quinolin-2-one dihydrochloride of Formula VIII followed by reaction with compound of Formula IV and isopropyl magnesium chloride in THF to obtain brexpiprazole compound of Formula I according to Scheme-Ill.
- Scheme-Ill CN 105440026A discloses the synthesis of Brexpiprazole wherein 7-hydroxyl-lH- quinolin-2-one of Formula II reacts with l-chloro-4-bromobutane to obtain 7-(4- chlorobutoxy)-lH-quinolin-2-one of Formula III which reacts with piperazine monohydrochloride to obtain 7-(4-(piperazin-l-yl)butoxy)quinolin-2(lH)-one hydrochloride compound of formula VHP.
- the resulting compound of Formula VHP then reacts with 4-chlorobenzo [b] thiophene in presence of a base and palladium triphenyl complex to give Brexpiprazole compound of Formula I according to Scheme - IV.
- the principal object of the present invention is to provide a process for the preparation of Brexpiprazole of Formula I, which alleviates one or more drawbacks of prior art processes.
- a process for the preparation of Brexpiprazole of Formula I comprising the steps of: AA) reacting compound of Formula II with compound of Formula X in presence of a base and solvent at temperature below 45°C to obtain compound of Formula XIII;
- Impurity D (Dimer impurity) DETAIL DESCRIPTION OF THE INVENTION:
- the present invention is directed to a process of preparing brexpiprazole that is simple, convenient, environment friendly and economical for industrial application.
- the method utilizes a careful reaction condition and reagent for reducing the formation of known and unknown impurities while at the reaction stage itself, avoids the additional requirements of purifying intermediates at various stages and accordingly reduces the use of solvents and reagents. This in turn results in decrease in costs attributed to a more efficient use of reagents and solvents and at the same time becomes more environment friendly and cost effective.
- a process for the preparation of Brexpiprazole of Formula I comprising the steps of: AA) reacting compound of formula II with compound of formula X in the presence of a base and solvent at temperature below 45°C to obtain compound of formula XIII;
- reaction of compound of formula II with compound of formula X in step AA) is carried out in presence of a base and solvent wherein the base is selected from the group comprising of inorganic or organic base.
- the organic base is selected from the group comprising of triethylamine, diisopropylethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, N-methylpiperidine, N- methylpyrrolidine, N-methylmorpholine and the like; aromatic amines such as pyridine, lutidine, ⁇ , ⁇ -dimethylaniline and the like.
- the inorganic base is selected from the group comprising of alkali and alkaline earth metal hydroxide, carbonate, bicarbonate, hydride and the like, wherein the alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, cesium, calcium, magnesium and the like.
- the solvent is selected from the group comprising of ethers such as dioxane, tetrahydrofuran, 2- methyltetrahydrofuran, methyl tert-buty ⁇ ether, and the like; esters such as ethyl acetate, propyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; aromatic hydrocarbons such as toluene, xylene chloroxylene, and the like; polar solvents such as DMF, DMSO, DMA, sulfolane, hexamethylphosphoric triamide, or mixture thereof.
- ethers such as dioxane, tetrahydrofuran, 2- methyltetrahydrofuran, methyl tert-buty ⁇ ether, and the
- reaction of compound of formula II with compound of formula X in step AA) is carried out at a temperature of about 20 to 45°C, preferably 35 to 45°C for about 2 to 8 hours, more preferably 6-8 hours.
- step AA crude compound of formula XIII obtained in step AA) contains high amount of dimer impurity.
- the inventors of present invention observed the presence of dimer impurity of formula D in an amount higher than regulatory recommendations, in brexpiprazole obtained by prior art process. Also, the inventors of present invention observed that removal of dimer impurity of formula D is not possible by general purification techniques and is difficult to remove once formed. Accordingly, the present invention provides a simple and efficient process for removal of dimer impurity of formula D at the intermediate stage by treating the 7-(4-halobutoxy) quinolin- 2(lH)-one compound of formula XIII using resin in suitable solvent.
- the resin is selected from the group comprising of polystyrene-divinylbenzene, acrylic resins, crosslinked organic monomer preferably AMBER LITE IR 120 H brand of resins, silica and the like.
- the solvent is selected from alcohols such as methanol, ethanol, propanol, butanol and the like.
- the reaction of compound of formula XIII with compound of formula V or its salt in step BB) is carried out in presence of a base and solvent, wherein the base is selected from the organic or inorganic base.
- the organic base is selected from triethylamine, diisopropylethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, N-methylpiperidine, N-methylpyrrolidine, N- methylmorpholine and the like; aromatic amines such as pyridine, lutidine, N,N- dimethylaniline and the like.
- the inorganic base is selected from the group comprising of alkali and alkaline earth metal hydroxide, carbonate, bicarbonate, hydride and the like, wherein the alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, cesium, calcium, magnesium and the like.
- the solvent used for the reaction of compound of formula XIII with compound of formula V or its salt in step BB) is selected from the group comprising of ethers such as dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-buty ⁇ ether, diethylene glycol, ethylene glycol and the like; esters such as ethyl acetate, propyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; aromatic hydrocarbons such as toluene, xylene chloroxylene, and the like; polar solvents such as DMF, DMSO, DMA, sulfolane, hexamethylphosphoric triamide, water or mixture thereof.
- ethers such as dioxane,
- reaction of compound of formula XIII with compound of formula V or its salt is optionally carried out in presence of reaction accelerator selected from sodium iodide, potassium iodide and the like at a suitable temperature selected from 80 to 120°C, preferably 90-100°C to obtain Brexpiprazole compound of Formula I.
- reaction accelerator selected from sodium iodide, potassium iodide and the like at a suitable temperature selected from 80 to 120°C, preferably 90-100°C to obtain Brexpiprazole compound of Formula I.
- Brexpiprazole obtained from above process is optionally further purified by techniques already known in prior art technique such as crystallization, solvent anti-solvent method etc.
- the solvent used for purification is selected from the group comprising of alcohol such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol and the like; chlorinated solvent such as dichloromethane and the like; esters such as ethyl acetate, propyl acetate and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; water or mixture thereof.
- Brexpiprazole obtained by the process of the present invention is in fact substantially pure, and in particular substantially free from the dimer impurity of Formula D, wherein the dimer impurity is less than 0.1%.
- the expression "substantially pure” means having a purity degree equal to or higher than 99%.
- Table no. 1 Comparative data for dimer impurity of Formula D of prior art vis-avis present invention:
- reaction conditions are very simple and do not involve stringent critical operating parameters.
- the resulting wet material was taken in methanol (1000 ml) at 25-30°C and heated to reflux till complete dissolution. Cooled the solution to 10-15°C. Filtered the resulting solid, wash with methanol (100 ml) and dried at 60-65 °C for 12-15 hours under vacuum to obtain title compound.
- wet material 40g.
- the resulting wet material was taken in a mixture of ethanol (400 ml) and acetic acid (50 ml) at 30-35°C and heated to reflux at 80°C. Cooled the resulting solution to 30- 35°C and filter, washed the wet material with ethanol. Charged the wet material to a mixture of ethanol (400 ml) and water (100 ml) at 30-35°C, heated to 75-80°C for complete dissolution. Added activated charcoal (1 g), stirred the resulting mixture for 30- 40 minutes filter at 75-80 °C.
- the resulting wet material was taken in a mixture of ethanol (3200 ml) and acetic acid (240 ml) and heated to reflux at 75-80°C. Cone HC1 (36 ml) was added and stirred for 30-40 minutes. Cooled the resulting solution and then heated to 75-80°C under stirring for 1-2 hours. Cooled, filtered and the resulting wet material was washed with ethanol. The resulting wet material was taken in ethanol (3200 ml) and water (100 ml) and heated to 75-80°C for complete dissolution. Added activated charcoal (16 g), stirred the resulting mixture for 1-2 hours, filtered through hyflow.
- the resulting filtrate was heated to 75-80°, and to this added aqueous solution of sodium bicarbonate (40 g in 800 ml water) under stirring. Added water (480 ml) at 75-80°C. Cooled the resulting mass to 35-40°C, filtered, washed with water. The resulting wet material was taken in ethanol (348 ml) and stirred for 1-2 hours. Filtered the material, washed the wet cake with ethanol and dried at 60-70°C for 12-16 hours to obtain title compound.
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Abstract
The present invention relates to a process for the preparation of 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy} quinolin-2(1H)-one (brexpiprazole) from 7-(4-chlorobutoxy)quinolin-2(1H)-one and 1-(benzo[b]thiophen-4-yl)piperazine. The intermediate 7-(4-chlorobutoxy)quinolin-2(1H)-one is prepared from 7-hydroxy-quinolin-2(1H)-one and 1-bromo-4-chloro-butane at a temperature below 45°C. The crude intermediate 7-(4-chlorobutoxy)quinolin-2(1H)-one is then treated with a resin (e.g. AMBER LITE IR 120 h) in an alcohol solvent (e.g. methanol) whereby the dimer impurity D is removed. The brexpiprazole obtained by this process is substantially free from dimer impurity D. Brexpiprazole is a D2 dopamine partial agonist called serotonin-dopamine activity modulator (SDAM) used for the treatment of schizophrenia and as an adjunct for major depressive disorder.
Description
PROCESS FOR THE PREPARATION OF BREXPIPRAZOLE FROM
7-(4-CHLOROBUTOXY)QUINOLIN-2(1 H)-ONE AND 1 -(BENZO[B]THIOPHEN-4-YL)PIPERAZINE
FIELD OF THE INVENTION:
The present invention relates to process for the preparation of benzo[b]thiophene compound used for the treatment of schizophrenia and as an adjunct for major depressive disorder. More particularly, the present invention is directed to the process for the preparation of 7-{4-[4-(l-benzothiophen-4-yl) piperazin-l-yl] butoxy} quinolin-2 (1H)- one (Brexpiprazole) and its intermediates thereof.
BACKGROUND OF THE INVENTION:
Brexpiprazole is a D2 dopamine partial agonist called serotonin-dopamine activity modulator (SDAM). Brexpiprazole is chemically known as 7-{4-[4-(l-benzothiophen-4- yl) piperazin-l-yl] butoxy} quinolin-2 (lH)-one. It is known from US 7,888,362 and is represented by Formula I.
Formula I
Brexpiprazole is sold in USA under the proprietary name of "REXULTI" and is indicated for the treatment of schizophrenia and also as an adjunctive therapy to antidepressants in adults having major depressive disorder.
US 7,888,362 describes a process for the preparation of Brexpiprazole compound of Formula I wherein compound of Formula II reacts with l-bromo-4-chlorobutane using potassium hydroxide as base in methanol at 50°C to obtain compound of Formula III which was purified by silica gel column chromatography (dichlorome thane: methanol=100:3) to obtain pure compound of Formula III. Another intermediate 1- benzo[b]thiophene-4-yl-piperazine hydrochloride compound of Formula V is prepared by
reacting compound of Formula IV with anhydrous piperazine using (R) (+)-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl(BINAP), dipalladiumtris (dibenzylidene acetone) in presence of sodium i-butoxide by heating under reflux. The resulting 1- benzo[b]thiophene-4-yl-piperazine hydrochloride compound of Formula V then reacts with compound of Formula III to obtain brexpiprazole compound of Formula I as residue which was purified by silica gel column chromatography (dichlorome thane: methanol=100:3) followed by recrystalhzation with ethanol to obtain pure compound of Formula I as shown in Scheme-I.
Formula II Formula III
HCI
Scheme-I
The main drawback of this process is the use of expensive and laborious column chromatographic purification at various stages, which not only require handling of large volume of solvent at commercial scale but also makes the process expensive and time consuming. Another drawback of the process is the formation of by-product mainly Impurity D (dimer impurity) during the reaction of compound of Formula II with 1-
bromo-4-chlorobutane, which is difficult to separate, thus require multiple purification which in turn decreases the yield and increases the cost of the final product.
Impurity D (Dimer impurity)
US 9,206,169 describes an improved process for the preparation of 4-(l- piperazinyl)benzo[b]thiophene compound of Formula V which involves reaction of compound of Formula VII with piperazine in presence of (a) a palladium compound and a tertiary phosphine or (b) a palladium carbene complex, in an inert solvent or without a solvent to obtain compound of Formula V which further reacts with compound of Formula III to obtain Brexpiprazole of Formula I as shown in (Scheme II)
Scheme-II
The main drawback of the said process is the use of expensive palladium carbene complex on commercial scale, which makes the process costly and needs special handling equipment for industrial scale production. Another disadvantage of this process is the formation of impurity A and impurity B during the reaction of compound of Formula V with compound of Formula III which is difficult to separate from the final
product and requires multiple purifications, thus in order to attain the purity of final compound, it leads to undue operational steps for removal of impurities, thus makes the process expensive and tedious on commercial scale.
Impurity -A Impurity - B
CN 105175401A discloses the synthesis of Brexpiprazole wherein 7-hydroxyl-lH- quinolin-2-one of Formula II reacts with 1 -chlorine-4-bromobutane to obtain 7-(4- chlorobutoxy)-lH-quinolin-2-one of Formula III, which then reacts with N-Boc piperazine to obtain 7-(l-piperazine) butoxy-lH-quinolin-2-one dihydrochloride of Formula VIII followed by reaction with compound of Formula IV and isopropyl magnesium chloride in THF to obtain brexpiprazole compound of Formula I according to Scheme-Ill.
Formula I
Scheme-Ill
CN 105440026A discloses the synthesis of Brexpiprazole wherein 7-hydroxyl-lH- quinolin-2-one of Formula II reacts with l-chloro-4-bromobutane to obtain 7-(4- chlorobutoxy)-lH-quinolin-2-one of Formula III which reacts with piperazine monohydrochloride to obtain 7-(4-(piperazin-l-yl)butoxy)quinolin-2(lH)-one hydrochloride compound of formula VHP. The resulting compound of Formula VHP then reacts with 4-chlorobenzo [b] thiophene in presence of a base and palladium triphenyl complex to give Brexpiprazole compound of Formula I according to Scheme - IV.
1- HN NH .HCI
Formula I
Scheme-IV
The main drawback of the processes disclosed in Scheme-Ill & IV is the formation of di- benzo[b] thiophene impurity (Impurity C) during the reaction of compound of Formula VIII or VHP with compound of Formula IV or VII using isopropyl magnesium chloride or palladium triphenylphosphine complex used as a catalyst which once formed, is difficult to remove and gets carried forward to the final step and affects the yield and purity of the final product.
Thus the processes disclosed in the prior arts suffer from one or more disadvantages like use of expensive chemicals, purification via column chromatography, formation of byproducts/impurities at various stages, which makes the process unsuitable for commercial scale production.
Thus, there is a need in the art for an efficient and economical process for the preparation of Brexpiprazole of Formula I which not only overcomes one or more problems of the prior art processes as mentioned above, but also is simple, cost effective, environment friendly, industrially feasible, capable of restricting undesired by-products and avoids the use of column chromatographic purification at various stages.
OBJECT AND SUMMARY OF THE INVENTION
The principal object of the present invention is to provide a process for the preparation of Brexpiprazole of Formula I, which alleviates one or more drawbacks of prior art processes.
According to one aspect of the present invention, there is provided a commercially viable, safe and cost effective process for the preparation of Brexpiprazole of Formula I.
According to another aspect of the present invention there is provided a process that avoids the use of column chromatography for purification of Brexpiprazole and its intermediates and provides a pure product substantially free of impurities preferably dimer impurity of Formula D.
According to another aspect of the present invention, there is provided a process for the preparation of Brexpiprazole of Formula I, comprising the steps of:
AA) reacting compound of Formula II with compound of Formula X in presence of a base and solvent at temperature below 45°C to obtain compound of Formula XIII;
Formula II Formula XIII wherein X and X' are independently selected from halogen;
BB) reacting compound of Formula XIII with compound of Formula V or its salt in presence of base and solvent to obtain Brexpiprazole compound of Formula I.
According to another aspect of the present invention, there is provided a process for the removal of dimer Impurity of formula D from compound of Formula XIII, comprising treating compound of Formula XIII with resin in suitable solvent.
Impurity D (Dimer impurity)
DETAIL DESCRIPTION OF THE INVENTION:
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
During the laboratory optimization of brexpiprazole, many process related impurities were identified. The formation of impurities and in-turn the control of formation of impurities is dependent upon the reagents, solvents and conditions used for carrying out various reactions, therefore it is a challenge to reach at such reaction conditions, selection of solvents and reagents in such a way that they provide brexpiprazole with desired purity standards, wherein the process should not involve working difficulties, high costs, expensive techniques/reagents etc, rather the process should be simple, convenient, easy to operate, environment friendly and economical on industrial scale. Further as per the guidelines recommended by ICH state that the acceptable levels for a known and unknown compound (impurity) in the drug should be less than 0.15 and 0.10%, respectively.
In view of above requirements, the present invention is directed to a process of preparing brexpiprazole that is simple, convenient, environment friendly and economical for industrial application. The method utilizes a careful reaction condition and reagent for reducing the formation of known and unknown impurities while at the reaction stage itself, avoids the additional requirements of purifying intermediates at various stages and accordingly reduces the use of solvents and reagents. This in turn results in decrease in costs attributed to a more efficient use of reagents and solvents and at the same time becomes more environment friendly and cost effective.
According to one embodiment of the present invention, there is provided a process for the preparation of Brexpiprazole of Formula I, comprising the steps of:
AA) reacting compound of formula II with compound of formula X in the presence of a base and solvent at temperature below 45°C to obtain compound of formula XIII;
Formula II Formula XIII wherein X and X' are independently selected from halogen;
BB) reacting compound of formula XIII with compound of formula V or its salt in presence of base and solvent to obtain Brexpiprazole compound of Formula I.
wherein X is defined as above.
According to the present invention, reaction of compound of formula II with compound of formula X in step AA) is carried out in presence of a base and solvent wherein the base is selected from the group comprising of inorganic or organic base. The organic base is selected from the group comprising of triethylamine, diisopropylethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, N-methylpiperidine, N- methylpyrrolidine, N-methylmorpholine and the like; aromatic amines such as pyridine, lutidine, Ν,Ν-dimethylaniline and the like. The inorganic base is selected from the group comprising of alkali and alkaline earth metal hydroxide, carbonate, bicarbonate, hydride and the like, wherein the alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, cesium, calcium, magnesium and the like. The solvent
is selected from the group comprising of ethers such as dioxane, tetrahydrofuran, 2- methyltetrahydrofuran, methyl tert-buty\ ether, and the like; esters such as ethyl acetate, propyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; aromatic hydrocarbons such as toluene, xylene chloroxylene, and the like; polar solvents such as DMF, DMSO, DMA, sulfolane, hexamethylphosphoric triamide, or mixture thereof.
The reaction of compound of formula II with compound of formula X in step AA) is carried out at a temperature of about 20 to 45°C, preferably 35 to 45°C for about 2 to 8 hours, more preferably 6-8 hours.
The applicant observed that crude compound of formula XIII obtained in step AA) contains high amount of dimer impurity. The inventors of present invention observed the presence of dimer impurity of formula D in an amount higher than regulatory recommendations, in brexpiprazole obtained by prior art process. Also, the inventors of present invention observed that removal of dimer impurity of formula D is not possible by general purification techniques and is difficult to remove once formed. Accordingly, the present invention provides a simple and efficient process for removal of dimer impurity of formula D at the intermediate stage by treating the 7-(4-halobutoxy) quinolin- 2(lH)-one compound of formula XIII using resin in suitable solvent. The resin is selected from the group comprising of polystyrene-divinylbenzene, acrylic resins, crosslinked organic monomer preferably AMBER LITE IR 120 H brand of resins, silica and the like. The solvent is selected from alcohols such as methanol, ethanol, propanol, butanol and the like.
According to the present invention, the reaction of compound of formula XIII with compound of formula V or its salt in step BB) is carried out in presence of a base and solvent, wherein the base is selected from the organic or inorganic base. The organic base is selected from triethylamine, diisopropylethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, N-methylpiperidine, N-methylpyrrolidine, N- methylmorpholine and the like; aromatic amines such as pyridine, lutidine, N,N-
dimethylaniline and the like. The inorganic base is selected from the group comprising of alkali and alkaline earth metal hydroxide, carbonate, bicarbonate, hydride and the like, wherein the alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, cesium, calcium, magnesium and the like.
The solvent used for the reaction of compound of formula XIII with compound of formula V or its salt in step BB) is selected from the group comprising of ethers such as dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-buty\ ether, diethylene glycol, ethylene glycol and the like; esters such as ethyl acetate, propyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; aromatic hydrocarbons such as toluene, xylene chloroxylene, and the like; polar solvents such as DMF, DMSO, DMA, sulfolane, hexamethylphosphoric triamide, water or mixture thereof.
The reaction of compound of formula XIII with compound of formula V or its salt is optionally carried out in presence of reaction accelerator selected from sodium iodide, potassium iodide and the like at a suitable temperature selected from 80 to 120°C, preferably 90-100°C to obtain Brexpiprazole compound of Formula I.
Brexpiprazole obtained from above process is optionally further purified by techniques already known in prior art technique such as crystallization, solvent anti-solvent method etc. The solvent used for purification is selected from the group comprising of alcohol such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol and the like; chlorinated solvent such as dichloromethane and the like; esters such as ethyl acetate, propyl acetate and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; water or mixture thereof.
Brexpiprazole obtained by the process of the present invention is in fact substantially pure, and in particular substantially free from the dimer impurity of Formula D, wherein the dimer impurity is less than 0.1%. The expression "substantially pure" means having a purity degree equal to or higher than 99%.
Table no. 1: Comparative data for dimer impurity of Formula D of prior art vis-avis present invention:
The process of present invention has following advantages:
(a) The reaction conditions are very simple and do not involve stringent critical operating parameters.
(b) The process provides brexpiprazole with purity of pharmacopoeial standard without involving any crystallization or cumbersome chromatographic purifications of intermediates or final brexpiprazole.
(c) The process is carried out in precisely selected solvents, which is integrated with in-process control of impurity formation or removal of impurities to provide intermediates and final brexpiprazole with high purity.
The process for the preparation of Brexpiprazole described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLE:
Example 1: Synthesis of 7-(4-chlorobutoxy) quinolin-2(lH)-one
Add 7-Hydroxy quinolin-2(lH)-one (20g) in DMF (100ml) in round bottom flask at 25- 30°C. To this, added aqueous solution of potassium carbonate (17.2 g) at 25-30°C and heated the mixture to 35-40°C. To this added l-Bromo-4-chloro butane (28.6 ml) at 35- 40°C and stirred the reaction mass for 6-8 hours. Water (200ml) was added over a period of 30-40 minutes. The resulting mass was stirred for 30-40 minutes at 35-40°C and cooled to 10°C and filter. The resulting wet material was taken in methanol (200 ml) at 25-30°C and heated to reflux till complete dissolution. Cooled the solution to 5-10 °C and stirred for 30 minutes. Filtered the resulting solid, washed with methanol (20 ml) and dried at 60-65 °C for 6-8 hours to obtain title compound.
Yield 24.5 g.
Example 2: Synthesis of 7-(4-chlorobutoxy) quinolin-2(lH)-one
Add potassium carbonate (9.42 g) in water (10ml) in round bottom flask and stirred for 10-15 min at 30-35°C. To this add DMF (50ml) and 7-Hydroxy quinolin-2(lH)-one (lOg), heated the resulting mixture to 35-40°C and stirred for 10-15 min. To this added 1- Bromo-4-chloro butane (21.29 g) and stirred the reaction mass for 6-8 hours at 35-40°C, added water (20ml) drop wise over a period of 30-40 minutes and stirred the reaction mass for 30-40 min at 35-40°C. Cooled the reaction mass to 10°C, filtered and washed with methanol (20 ml) and DM water (20 ml) at 25-30°C to obtain wet material.
Yield: 11.0 g, HPLC purity- 95.8%; Dimer Impurity: 1.49%
To the resulting wet material (11.0 g), methanol (200ml) was added at 25-30°C and heated to reflux till complete dissolution. To this added AMBER LITE IR 120 H (lOg) at 65-70°C and stirred for 1-1.5 hours at reflux temperature. Filtered the resulting mixture through hyflo at 60-65°C and cooled the filtrate to 5-10°C and stirred for 30 minutes. Filtered the material, washed with methanol (10 ml) and dried at 60-65°C for 5-8 hours. Yield: 8.0 g, HPLC purity: 97.3%; Dimer impurity: 0.027%.
Example 3: Synthesis of 7-(4-chlorobutoxy) quinolin-2(lH)-one
Add 7-Hydroxy quinolin-2(lH)-one (lOg) in DMF (50ml) in round bottom flask at 25- 30°C. To this, added aqueous solution of potassium carbonate (9.87 g) and heated the mixture to 35-40°C under stirring. To this added 1 -Bromo-4-chloro butane (21.3 ml) at 35-40°C and stirred the reaction mass for 5-6 hours. Water (15 ml) was added over a period of 30-40 minutes in 45-60 minutes. The resulting mass was stirred for 30-40 minutes at 35-40°C and cooled to 10-15°C and filter. The resulting wet material was washed with water, and suck dried.
Yield: 10.9 g, HPLC purity: 95.4%; Dimer Impurity: 1.48%;
To the resulting wet material (11.0 g), methanol (200ml) was added at 25-30°C and heated to reflux till complete dissolution. To this added AMBER LITE IR 120 H (lOg) at 65-70°C and stirred for 1-1.5 hours at reflux temperature. Filtered the resulting mixture through hyflo at 60-65°C and cooled the filtrate to 5-10°C and stirred for 30 minutes. Filtered the material, washed with methanol (10 ml) and dried at 60-65°C for 5-8 hours. Yield: 7.9 g, HPLC purity: 97.3% Dimer impurity: 0.014%.
Example 4: Synthesis of 7-(4-chlorobutoxy) quinolin-2(lH)-one
Add 7-Hydroxy quinolin-2(lH)-one (lOOg) in DMF (500ml) in round bottom flask at 25- 30°C. To this, added aqueous solution of potassium carbonate (98.62 g) ) at 25-30°C and heated the mixture to 35-40°C. To this added 1 -Bromo-4-chloro butane (212 g) at 35- 40°C and stirred the reaction mass for 6-8 hours. Water (150ml) was added over a period of 30-40 minutes. The resulting mass was stirred for 30-40 minutes at 35-40°C and cooled to 10°C and filter. The resulting wet material was taken in methanol (1000 ml) at 25-30°C and heated to reflux till complete dissolution. Cooled the solution to 10-15°C. Filtered the resulting solid, wash with methanol (100 ml) and dried at 60-65 °C for 12-15 hours under vacuum to obtain title compound.
Yield 120 g (76%); HPLC purity: <96%
Example 5: Synthesis of crude Brexpiprazole
Add l-(benzo[b]thiophen-4-yl) piperazine (21.20 g) and potassium carbonate (11.60g) in DMF (5ml) in round bottom flask at 25-30°C, heated the reaction mixture to 40-45 °C
under stirring for 30 minutes. To this added 7-(4-chlorobutoxy) quinolin-2(lH)-one (20.0 g) and potassium iodide (13.8 g) at 40-45°C and heated the reaction mixture to 85-90°C followed by stirring for 2-3 hours. Cooled the reaction mixture to 45-50°C, water (300 ml) was added at a temperature of 45-50 °C over a period of 30-40 minutes. Stirred the resulting mass for 30-40 minutes. Filtered the mixture at 30-35°C to obtain wet material (40g). The resulting wet material was taken in a mixture of ethanol (400 ml) and acetic acid (50 ml) at 30-35°C and heated to reflux at 80°C. Cooled the resulting solution to 30- 35°C and filter, washed the wet material with ethanol. Charged the wet material to a mixture of ethanol (400 ml) and water (100 ml) at 30-35°C, heated to 75-80°C for complete dissolution. Added activated charcoal (1 g), stirred the resulting mixture for 30- 40 minutes filter at 75-80 °C. The resulting filtrate was heated to 75-80°, and to this add aqueous solution of sodium bicarbonate (100 ml) at 75-80°C under stirring for 1 hours. Cooled the resulting mass to 35-40°C, filtered, wash with water and dried at 60-70°C for 8-10 hours to obtain title compound. Yield 23 g.
Example 6: Synthesis of pure Brexpiprazole
Crude Brexpiprazole (20 g) was taken in ethanol (300 ml) in round bottom flask at 30- 35°C and heated to reflux at 75-80°C followed by stirring for 30-40 minutes. Cooled the reaction mass to 30-35°C and filter. Washed the wet cake with ethanol and dried under vacuum at 60-65°C for 8-10 hours to obtain title compound. Yield 17.7 g.
Example 7: Synthesis of pure 7-{4-[4-(l-benzothiophen-4-yl) piperazin-l-yl] butoxy} quinolin-2 (lH)-one:
Add l-(benzo[b]thiophen-4-yl) piperazine (106 g) and potassium carbonate (60g) in DMF (500ml) in round bottom flask at 25-30°C, heated the reaction mixture to 45-50°C under stirring for 30 minutes. To this added 7-(4-chlorobutoxy) quinolin-2(lH)-one (100 g) and potassium iodide (69.25 g) and heated the reaction mixture to 90-95°C for 2-3 hours. Cooled the reaction mixture, water (1500 ml) was added. Stirred the resulting mass for 30-40 minutes. Cooled to 10-15°C, filtered and the resulting wet material was washed with water and ethanol. The resulting wet material was taken in a mixture of ethanol (3200 ml) and acetic acid (240 ml) and heated to reflux at 75-80°C. Cone HC1 (36 ml)
was added and stirred for 30-40 minutes. Cooled the resulting solution and then heated to 75-80°C under stirring for 1-2 hours. Cooled, filtered and the resulting wet material was washed with ethanol. The resulting wet material was taken in ethanol (3200 ml) and water (100 ml) and heated to 75-80°C for complete dissolution. Added activated charcoal (16 g), stirred the resulting mixture for 1-2 hours, filtered through hyflow. The resulting filtrate was heated to 75-80°, and to this added aqueous solution of sodium bicarbonate (40 g in 800 ml water) under stirring. Added water (480 ml) at 75-80°C. Cooled the resulting mass to 35-40°C, filtered, washed with water. The resulting wet material was taken in ethanol (348 ml) and stirred for 1-2 hours. Filtered the material, washed the wet cake with ethanol and dried at 60-70°C for 12-16 hours to obtain title compound.
Yield HOg (63.98%); HPLC purity: <99%; Dimer impurity: Not detected.
Claims
1. A process for the preparation of Brexpiprazole of Formula I, substantially free of dimer impurity of Formula D, comprising the steps of:
AA) reacting compound of Formula II with compound of Formula X in the presence of a base and solvent at temperature below 45°C to obtain compound of Formula XIII;
Formula II Formula XII wherein X and X' are independently selected from halogen;
BB) reacting compound of Formula XIII with compound of Formula V or its salt in presence of base and solvent to obtain Brexpiprazole compound of Formula I
wherein X is defined as above.
2. The process according to claim 1, wherein the base used in step (AA) and step (BB) are selected from inorganic and organic.
3. The process according to claim 2, wherein organic base is selected from the group comprising of triethylamine, diisopropylethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, N-methylpiperidine, N-methyl pyrrolidine, N-methylmorpholine; aromatic amines such as pyridine, lutidine and N,N-dimethylaniline.
4. The process according to claim 2, wherein the inorganic base is selected from the group comprising of alkali and alkaline earth metal hydroxide, carbonate, bicarbonate, hydride wherein the alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, cesium, calcium and magnesium.
5. The process according to claim 1, wherein the solvent used in step (AA) and step (BB) is independently selected from the group comprising of ethers such as dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-buty\ ether; esters such as ethyl acetate, propyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform; ketones such as acetone, methyl ethyl ketone; nitriles such as acetonitrile, propionitrile; aromatic hydrocarbons such as toluene, xylene chloroxylene,; polar solvents such as DMF, DMSO, DMA, sulfolane, hexamethylphosphoric triamide, or mixture thereof.
6. A process for the removal of dimer impurity of Formula D from compound of 7- (4-halobutoxy) quinolin-2(lH)-one compound of Formula XIII, comprising treating 7-(4-halobutoxy) quinolin-2(lH)-one compound of Formula XIII with resin in suitable solvent selected from the group of alcohols such as methanol, ethanol, propanol and butanol.
Impurity D (Dimer impurity)
7. The process according to claim 6, where in the resin is selected from the group comprising of polystyrene-divinylbenzene, acrylic resins, crosslinked organic monomer and silica.
8. Brexpiprazole, substantially free from dimer impurity of Formula D obtained according to the claim 1 , wherein the dimer impurity of Formula D is less than
0.15%.
9. A pharmaceutical composition comprising brexpiprazole substantially free from dimer impurity of Formula D obtained according to the claim 1.
10. A process for the preparation of Brexpiprazole of Formula I, substantially free of dimer impurity of Formula D, comprising the steps of:
AA) reacting compound of Formula II with compound of Formula X in the presence of a base and solvent at temperature below 45°C to obtain compound of Formula XIII;
Formula II Formula XIII wherein X and X' are independently selected from halogen;
BB) reacting the resulting compound of Formula XIII with resin in alcohol solvent to obtain compound of Formula XIII, substantially free from dimer impurity of Formula D, followed by reaction with compound of Formula V or its salt in presence of base and solvent to obtain Brexpiprazole compound of Formula I.
wherein X is defined as above.
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US7888362B2 (en) | 2005-04-14 | 2011-02-15 | Otsuka Pharmaceutical Co., Ltd. | Piperazine-substituted benzothiophenes for treatment of mental disorders |
US9206169B2 (en) | 2011-07-28 | 2015-12-08 | Otsuka Pharmaceutical Co., Ltd. | Method for producing benzo[b]thiophene compound |
CN105175401A (en) | 2015-10-16 | 2015-12-23 | 北京康立生医药技术开发有限公司 | Preparation method of brexpiprazole |
CN105440026A (en) | 2015-12-04 | 2016-03-30 | 上海勋和医药科技有限公司 | Elopiprazole preparation method |
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- 2017-05-23 WO PCT/IB2017/053018 patent/WO2017216661A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US7888362B2 (en) | 2005-04-14 | 2011-02-15 | Otsuka Pharmaceutical Co., Ltd. | Piperazine-substituted benzothiophenes for treatment of mental disorders |
US9206169B2 (en) | 2011-07-28 | 2015-12-08 | Otsuka Pharmaceutical Co., Ltd. | Method for producing benzo[b]thiophene compound |
CN105175401A (en) | 2015-10-16 | 2015-12-23 | 北京康立生医药技术开发有限公司 | Preparation method of brexpiprazole |
CN105440026A (en) | 2015-12-04 | 2016-03-30 | 上海勋和医药科技有限公司 | Elopiprazole preparation method |
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CN111909159A (en) * | 2019-05-08 | 2020-11-10 | 成都弘达药业有限公司 | Epipiprazole related substance and preparation method thereof |
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