CN101198599A - Process for preparing quetiapine fumarate - Google Patents
Process for preparing quetiapine fumarate Download PDFInfo
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- CN101198599A CN101198599A CNA200680021216XA CN200680021216A CN101198599A CN 101198599 A CN101198599 A CN 101198599A CN A200680021216X A CNA200680021216X A CN A200680021216XA CN 200680021216 A CN200680021216 A CN 200680021216A CN 101198599 A CN101198599 A CN 101198599A
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- Prior art keywords
- quetiapine
- solvent
- reaction
- aforementioned
- alkali
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 title claims description 18
- 229960005197 quetiapine fumarate Drugs 0.000 title claims description 18
- 238000004519 manufacturing process Methods 0.000 title 1
- 239000011541 reaction mixture Substances 0.000 claims abstract description 73
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 claims abstract description 52
- 229960004431 quetiapine Drugs 0.000 claims abstract description 51
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 229910001508 alkali metal halide Inorganic materials 0.000 claims abstract description 9
- 150000008045 alkali metal halides Chemical class 0.000 claims abstract description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 195
- 241000534944 Thia Species 0.000 claims description 59
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 59
- 238000000034 method Methods 0.000 claims description 51
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 46
- 238000010992 reflux Methods 0.000 claims description 45
- 238000002360 preparation method Methods 0.000 claims description 36
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 32
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 30
- 239000007810 chemical reaction solvent Substances 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 27
- -1 ethyl piperazidine Chemical compound 0.000 claims description 27
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 claims description 23
- 239000003513 alkali Substances 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 18
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 16
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 15
- 235000010755 mineral Nutrition 0.000 claims description 15
- 239000011707 mineral Substances 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000001530 fumaric acid Substances 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 11
- 235000015320 potassium carbonate Nutrition 0.000 claims description 11
- 235000007715 potassium iodide Nutrition 0.000 claims description 10
- 229960004839 potassium iodide Drugs 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 150000007530 organic bases Chemical class 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- LAXBNTIAOJWAOP-UHFFFAOYSA-N 2-chlorobiphenyl Chemical group ClC1=CC=CC=C1C1=CC=CC=C1 LAXBNTIAOJWAOP-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- 230000008034 disappearance Effects 0.000 claims description 2
- 238000001030 gas--liquid chromatography Methods 0.000 claims description 2
- 150000003512 tertiary amines Chemical group 0.000 claims description 2
- 238000004809 thin layer chromatography Methods 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims 2
- 229910001512 metal fluoride Inorganic materials 0.000 claims 1
- 229910001511 metal iodide Inorganic materials 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 150000004820 halides Chemical class 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000010410 layer Substances 0.000 description 82
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 44
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
- 238000003756 stirring Methods 0.000 description 41
- 239000000243 solution Substances 0.000 description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 36
- 239000000523 sample Substances 0.000 description 25
- 238000005406 washing Methods 0.000 description 23
- 239000012044 organic layer Substances 0.000 description 22
- 235000017550 sodium carbonate Nutrition 0.000 description 22
- 229910000029 sodium carbonate Inorganic materials 0.000 description 22
- 239000000284 extract Substances 0.000 description 20
- 239000002994 raw material Substances 0.000 description 19
- 238000004458 analytical method Methods 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 238000010790 dilution Methods 0.000 description 12
- 239000012895 dilution Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000012535 impurity Substances 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 9
- 238000013016 damping Methods 0.000 description 8
- 239000012530 fluid Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- FLNQAPQQAZVRDA-UHFFFAOYSA-N 1-(2-(2-Hydroxyethoxy)ethyl)piperazine Chemical compound OCCOCCN1CCNCC1 FLNQAPQQAZVRDA-UHFFFAOYSA-N 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 238000005660 chlorination reaction Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 150000002825 nitriles Chemical class 0.000 description 5
- 239000003444 phase transfer catalyst Substances 0.000 description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 4
- 239000005695 Ammonium acetate Substances 0.000 description 4
- 229940043376 ammonium acetate Drugs 0.000 description 4
- 235000019257 ammonium acetate Nutrition 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 4
- 229960000935 dehydrated alcohol Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LECMBPWEOVZHKN-UHFFFAOYSA-N 2-(2-chloroethoxy)ethanol Chemical compound OCCOCCCl LECMBPWEOVZHKN-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 230000003139 buffering effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000011003 system suitability test Methods 0.000 description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- SCLAUTQTMPTDII-LFIBNONCSA-N (5e)-2-(2-chloroanilino)-5-[[4-(dimethylamino)phenyl]methylidene]-1,3-thiazol-4-one Chemical compound C1=CC(N(C)C)=CC=C1\C=C\1C(=O)N=C(NC=2C(=CC=CC=2)Cl)S/1 SCLAUTQTMPTDII-LFIBNONCSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- UOGBMDMLDZZHGP-UHFFFAOYSA-N 2,2,2-triethoxyethanol Chemical compound CCOC(CO)(OCC)OCC UOGBMDMLDZZHGP-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- QJUAQWIXSIVLFO-UHFFFAOYSA-N 2-ethyl-n,n-di(propan-2-yl)aniline Chemical compound CCC1=CC=CC=C1N(C(C)C)C(C)C QJUAQWIXSIVLFO-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 1
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Natural products C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- QSRFYFHZPSGRQX-UHFFFAOYSA-N benzyl(tributyl)azanium Chemical compound CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 QSRFYFHZPSGRQX-UHFFFAOYSA-N 0.000 description 1
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical compound CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 0.000 description 1
- 239000012496 blank sample Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 229960000800 cetrimonium bromide Drugs 0.000 description 1
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 150000005826 halohydrocarbons Chemical group 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- ZTHJULTYCAQOIJ-WXXKFALUSA-N quetiapine fumarate Chemical group [H+].[H+].[O-]C(=O)\C=C\C([O-])=O.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 ZTHJULTYCAQOIJ-WXXKFALUSA-N 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 229940035004 seroquel Drugs 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 1
- UZPGPVQCDJXSNM-UHFFFAOYSA-M tetrabutylazanium;iodate Chemical compound [O-]I(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC UZPGPVQCDJXSNM-UHFFFAOYSA-M 0.000 description 1
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
- ADBMSVFHVFJBFR-UHFFFAOYSA-N triethyl(hexadecyl)azanium Chemical compound CCCCCCCCCCCCCCCC[N+](CC)(CC)CC ADBMSVFHVFJBFR-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
Provided is a novel synthesis of quetiapine, and pharmaceutically acceptable salts thereof, in which an alkali metal halide or siliyl halide is included in the reaction mixture.
Description
Present patent application requires U.S. Provisional Patent Application 60/672, April 14 2005 submission day of 175 Japan and the United States state temporary patent application 60/677, the rights and interests in the May 11 2005 submission day of May 2 2005 submission day of 091 and U.S. Provisional Patent Application 60/680,140.
Technical field
The present invention relates to the synthetic of Quetiapine and drug acceptable salt thereof.
Background of invention
Quetiapine, 2-(2-(4-dibenzo [b, f] [1,4] thia azepine -11-base-1-piperazinyl) oxyethyl group) ethanol has following chemical structure:
Quetiapine
Be a kind of effects on neural system organic compound,, it is reported to be used for the treatment of diseases such as schizophrenia, see the Merck index, 13th Ed., 8130 (2001) as major tranquilizer as the antagonist of various neurotransmitters acceptor in the brain.This medicine is for CAS number 111974-69-7, obtains the FDA approval in the U.S., can be obtained by developer AstraZeneca PLC, and trade(brand)name is Seroquel
For example can be according to U.S. Pat 4,879, the synthetic Quetiapine of instruction in 288, this patent integral body by reference is attached to herein.
As patent US4,879,288 instructions, Quetiapine can through type I compound hydrochloric acid 11-piperazinyl-dibenzo [b, f] [1,4] thia azepine and formula II compound 1-(2-hydroxyl ethoxy ethyl) the piperazine reaction of about 2 molar equivalents obtain,
Wherein the reaction times is about 30 hours, and yield is about 77%, through the rapid column chromatography purifying.
Therefore this area needs improved preparation method, promptly by 11-piperazinyl-dibenzo [b, f] [1,4] thia azepine and 2-(2-chloroethoxy) ethanol preparation Quetiapine and salt thereof, with respect to 11-piperazine-dibenzo [b, f] [1,4] thia azepine uses 2-(2-chloroethoxy) ethanol that is less than 2 molar equivalents, shorten the reaction times, obtain comprising the Quetiapine product of reduced levels of impurities (as unreacted starting raw material), so that the preparation method is simple, convenient, be applied to industrially scalable inexpensively.
The invention summary
In one embodiment, the invention provides a kind of method for preparing Quetiapine, comprise: in the presence of at least a organic bases or mineral alkali and alkali metal halide or silyl halides, make also [b of 1 1-chlorodiphenyl, f] [1,4] thia azepine and 1-(2-hydroxyl ethoxy ethyl) piperazine reacts in reaction solvent, and solvent is selected from C
5-C
12Saturated or aromatic hydrocarbon, C
1-C
4Alcohol, C
1-C
4Alkyl ester, C
2-C
8Ketone, C
2-C
8Straight chain, side chain, ring-type or aliphatic ether, C
3-C
10Alkyl ester and C
1-C
4Alkyl nitrile, or their mixture obtains Quetiapine, and reclaims the Quetiapine that obtains.
On the other hand, the present invention relates to a kind of method for preparing the drug acceptable salt of Quetiapine, comprise making acid and, and reclaim the drug acceptable salt of the Quetiapine that obtains according to the Quetiapine combination of method for preparing.Preferred described drug acceptable salt is a quetiapine fumarate, and described acid is fumaric acid.
In another embodiment, the invention provides a kind of method for preparing Quetiapine, comprise: in the presence of at least a organic bases or mineral alkali and phase-transfer catalyst, make also [b of 11-chlorodiphenyl, f] [1,4] thia azepine and 1-(2-hydroxyl ethoxy ethyl) piperazine reacts in reaction solvent, and this solvent is selected from C
5-C
12Saturated or aromatic hydrocarbon, C
1-C
4Alcohol, C
1-C
4Alkyl ester, C
2-C
8Ketone, C
2-C
8Straight chain, side chain, ring-type or aliphatic ether, C
3-C
10Alkyl ester and C
1-C
4Alkyl nitrile, or their mixture obtains Quetiapine; And reclaim the Quetiapine obtain.
On the other hand, the present invention relates to a kind of method for preparing the drug acceptable salt of Quetiapine, comprise making acid and according to the Quetiapine combination of method for preparing; And reclaim the drug acceptable salt of the Quetiapine obtain.Preferred described drug acceptable salt is a quetiapine fumarate, and described acid is fumaric acid.
Detailed Description Of The Invention
In one embodiment, the invention provides a kind of method for preparing Quetiapine, may further comprise the steps: in the presence of at least a organic bases or the mineral alkali and specifically in the presence of alkali metal halide and silyl halides halid, make also [b of 11-chlorodiphenyl, f] [1,4] thia azepine (claiming " I " herein) reacts in reaction solvent with 1-(2-hydroxyl ethoxy ethyl) piperazine (claiming " II " herein), and this solvent is selected from C
5-C
12Stable hydrocarbon or C
6-C
12Aromatic hydrocarbon, C
1-C
4Alcohol, C
1-C
4Alkyl ester, C
2-C
8Ketone, C
2-C
8Straight chain, side chain, ring-type or aliphatic ether, C
3-C
10Alkyl ester and C
1-C
4Alkyl nitrile, or their mixture obtains Quetiapine; And the optional Quetiapine that obtains that reclaims.
Be used to implement alkali metal halide of the present invention and comprise alkali-metal fluorochemical, iodide or bromide.The preferred as alkali iodide.Silyl halides also can be used to implement the inventive method.Potassiumiodide (KI) is to be used to implement particularly preferred alkali metal halide of the present invention.With respect to the formula I compound mole number that uses, use molar ratio to be about 0.2 or higher alkali metal halide or silyl halides.
In another embodiment, the invention provides a kind of method for preparing Quetiapine, comprise: in the presence of at least a organic bases or mineral alkali and phase-transfer catalyst, make also [b of 11-chlorodiphenyl, f] [1,4] thia azepine and 1-(2-hydroxyl ethoxy ethyl) piperazine reacts in reaction solvent, and this solvent is selected from C
5-C
12Saturated or aromatic hydrocarbon, C
1-C
4Alcohol, C
1-C
4Alkyl ester, C
2-C
8Ketone, C
2-C
8Straight chain, side chain, ring-type or aliphatic ether and C
1-C
4Alkyl nitrile, or their mixture; And the optional Quetiapine that obtains that reclaims.
Suitable phase-transfer catalyst is an ammonium salt, for example chlorination three capryloyl ammonium methyls (Aliquat.RTM.336); bromination tetra-n-butyl ammonium (" TBAB "); benzyltriethylammonium chloride (" TEBA "); cetrimonium bromide; brocide ; chlorination N-benzyl quinine ; chlorination tetra-n-butyl ammonium; hydroxide tetra-n-butyl ammonium; iodate tetra-n-butyl ammonium; etamon chloride; bromination benzyl tributyl ammonium; bromination benzyl triethyl ammonium; chlorination hexadecyl triethyl ammonium; Tetramethylammonium chloride; cetyltrimethylammonium chloride and chlorination octyl group trimethyl ammonium.Preferred phase-transfer catalyst is RTM.336, TBAB, TEBA and composition thereof, most preferably RTM.336.Be used to implement mineral alkali of the present invention and comprise alkaline carbonate or oxyhydroxide, for example salt of wormwood/saleratus, sodium carbonate/bicarbonate or sodium hydroxide, cesium carbonate/cesium hydroxide.Metal carbonate is to be used to implement preferred mineral alkali of the present invention.
When separating Quetiapine, the working temperature that reaction mixture is cooled to suit as room temperature, and is mixed with moisture non-oxidizing acid (example hydrochloric acid).Separate each layer, the optionally washing water merges organic layer.Concentrate the organic layer that merges and obtain Quetiapine.Available suitable solvent such as re-crystallizing in ethyl acetate Quetiapine.
In said process, temperature of reaction is that about room temperature (being generally 22-27 ℃) is to about reflux temperature, preferably at about reflux temperature.Preferably, reaction solvent is halohydrocarbon or alkyl ester.Toluene and dimethylbenzene are particularly preferred reaction solvent, but alkyl alcohol (as propyl carbinol) also is to implement fit closely reaction solvent of the present invention.
Preferably, the 11-chlorodiphenyl also amount of [b, f] [1,4] thia azepine (I) is about 1-1.5 molar equivalent of 1-(2-hydroxyl-oxethyl) ethyl piperazidine (II), preferably about 1-1.2 molar equivalent (based on the mole number of I).
Be used to implement mineral alkali of the present invention and known, comprise alkaline carbonate, alkali metal hydrocarbonate and alkali metal hydroxide by the technician.Be used to implement organic bases of the present invention and comprise monoamine, diamines or three (C
1-C
4Alkyl) amine, N for example, accelerine and N, N-diisopropylethylamine.Be used to implement organic bases of the present invention and be preferably tertiary amine.The organic bases that uses or the molar weight of mineral alkali are preferably about 1 to 3 times of molar weight of the I that uses in the reaction, more preferably from about 2 times.
Preferably, can separate the Quetiapine crude product that obtains in the aforesaid method then.Separate and preferably undertaken by reaction mixture being cooled to suitable temperature such as room temperature.Handle optional refrigerative reaction mixture with non-oxidizable mineral acid, preferred mineral acid example hydrochloric acid then.Mineral acid can and preferably use with its solution form.When using non-oxidizable aqueous acid,, then obtain two-phase mixture if use preferred reaction solvent.If there is two-phase, then separate each phase, water mineral alkali such as metal hydroxides or metal carbonate alkalization.Use organic solvent, in particular as the water of the organic solvent extraction of reaction solvent alkalization.For example after distillating the removal of solvents organic solvent, obtain Quetiapine alkali.Before the separation, isolating water can extract with reaction solvent, and described reaction solvent can be identical or different with the solvent that uses in the first step, and extract and isolating nonaqueous phase are merged, separated product from the reaction mixture that merges and extract then, if any.The 90 area % that the product purity that obtains is by this method measured greater than HPLC, the area of measuring more preferably greater than HPLC 95%, the area of measuring greater than HPLC 97% most preferably, and thick product needn't carry out for example purifying of flash chromatography.
In the preferred embodiment of the invention, reach 20 hours easily or the shorter reaction times, preferred about 10 to about 14 hours.The technician should know monitoring and adjusting reaction time, as detecting measured response reagent with suitable technique in preferred embodiments is the disappearance of Compound I, described detection technique such as thin-layer chromatography, gas liquid chromatography or high performance liquid chromatography or the like are only mentioned three kinds herein.
On the other hand, the present invention relates to prepare the method for the drug acceptable salt of Quetiapine, described method comprise with acid with according on the Quetiapine of institute's method preparation combine and the drug acceptable salt of the Quetiapine that obtains of recovery.Preferred described drug acceptable salt is a quetiapine fumarate, and described acid is fumaric acid.
The general reaction process of preparation quetiapine fumarate is as follows:
In another embodiment of the invention, a kind of method for preparing Quetiapine and drug acceptable salt thereof, preferred hemifumarate is provided, described method is included under the existence of at least a organic bases or mineral alkali and phase-transfer catalyst, make also [b of 11-chlorodiphenyl, f] [1,4] thia azepine (I) reacts in reaction solvent with 1-(2-hydroxyl ethoxy ethyl) piperazine, and this reaction solvent is selected from C
5-C
12Saturated or aromatic hydrocarbon, C
1-C
4Alcohol, C
1-C
4Alkyl ester, C
2-C
8Ketone, C
2-C
8Straight chain, side chain, ring-type or aliphatic ether, C
3-C
10Alkyl ester and C
1-C
4Alkyl nitrile.Preferably, the Quetiapine of gained can be by acidifying and extracting and separating, the area 90% that the purity that obtains detects greater than HPLC, the 95 area % that detect more preferably greater than HPLC, the most preferably 97 area % that detect greater than HPLC.
By liquid chromatogram measuring, by the purity of the crude product of Reaction Separation, generally as the detection 〉=97 area % of high pressure liquid chromatography, be enough to be used in for example being converted into drug acceptable salt, particularly hemifumarate in the process subsequently, and need not to make crude product to carry out purifying, for example pass through rapid column chromatography.
Preferably, with the synthetic preparation of one kettle way quetiapine fumarate, be about to fumaric acid and directly need not at first to separate Quetiapine with the Quetiapine mixing of the inventive method preparation.
The present invention in some embodiments will illustrate in the non-limiting examples below.In an embodiment, " HPLC area % " is meant the purity based on area percent, determined by area under the peak in the HPLC color atlas.
Analyze
Quetiapine can be with following HPLC methods analyst:
1: acetonitrile (HPLC level)
2: water (HPLC level)
3: ammonium acetate (AR level)
4: ammoniacal liquor (AR level)
5: acetate (AR level)
The preparation of damping fluid
Accurately the about 3.08g of weighing (0.04M) ammonium acetate is soluble in water, adds 2.0ml 25% solution of ammonium hydroxide and mixing in every 1000ml damping fluid.The pH value of damping fluid is not less than 9.2, exchange buffering every day liquid.
Elutriant A: damping fluid
Elutriant B: acetonitrile
Diluent
Acetonitrile
Chromatographic condition
Chromatographic column: Xterra RP8,3.5 μ, 150 * 4.6mm, Waters
Flow velocity: 1.5ml/min
Sampling volume: 20 μ l
Column temperature: 45 ℃
Detector: UV 250nm
Automatic sampling actuator temperature: 10 ℃
The gradient elution program
Time elutriant A% elutriant B%
0 75 25
25 75 25
60 22 78
61 75 25
70 75 25
Before analyzing beginning, with following elutriant flushing post 30min:20% elutriant A and 80% elutriant B.
The preparation of system flexibility solution
The mixture of about 1.0mg/ml quetiapine fumarate of preparation and 0.002mg/ml DBTP in diluent.
The evaluation of system suitability test
Sample introduction 20 μ l system flexibility solution.
The peak-to-peak resolution of DBTP and Quetiapine should reach and be not less than 7.
General retention time is about 17.5 minutes to DBTP, is about 25 minutes to Quetiapine.
The preparation of sample solution
The Quetiapine alkali sample solution of the about 1mg/ml of preparation
Program
Advance diluent as blank sample.
Sample introduction product solution is gone into chromatographic instrument, continues color atlas to complete gradient curve.Determine the area at all peaks with suitable integrator.
Any peak and the solvent peak of ignoring wash-out before 2 minutes.
Ignore any peak less than 0.05%.
Calculate
Area sum * 100 at all peaks in impurity area/color atlas in the impurity %=sample
Note:
DBT: dibenzo [b, f] [1,4] thia azepine -11 (10H)-ketone
CDBT: chlorodiphenyl is [b, f] [1,4] thia azepine -11 (10H)-ketone also
Half quetiapine fumarate
Reagent
1: acetonitrile (HPLC level)
2: ammonium acetate (AR level)
3: ammonium hydroxide (AR level)
4: acetate (AR level)
The preparation of damping fluid
Preparation 0.04M ammonium acetate aqueous solution adds 2.0ml 25% solution of ammonium hydroxide in every 1000ml damping fluid.The pH value of damping fluid should be not less than 9.2, exchange buffering every day liquid.
Elutriant A: damping fluid
Elutriant B: acetonitrile (gradient)
Chromatographic condition
Column type: XTerra RP
8, 3.5 μ, 150 * 4.6mm, Waters
Flow velocity: 1.5ml/min
Sampling volume: 20 μ l
Detector: 250nm
Column temperature: 45 ℃
The gradient elution program
Time | Elutriant A% | Elutriant B% |
0 | 75 | 25 |
25 | 75 | 25 |
60 | 22 | 78 |
Starting time: 8min
Before beginning to analyze, with following elutriant flushing post 30min:20% elutriant A and 80% elutriant B.For obtaining essential system flexibility, can change the composition and the flow velocity of moving phase.
The preparation of system flexibility solution
The mixture of about 1.0mg/ml quetiapine fumarate standard substance of preparation and 0.002mg/mlDBTP standard substance in diluent.
System suitability test
Sampling system adaptability solution.
The peak-to-peak resolution of DBTP and Quetiapine should reach and be not less than 7.
General retention time is about 17.5 minutes to DBTP, is about 25 minutes to Quetiapine.For the Quetiapine peak, should reach and be not less than 10000 post and imitate.
The preparation of sample solution
In diluent, accurately prepare the quetiapine fumarate sample solution of 1mg/ml.
Program
The sample introduction product are gone into chromatographic instrument, continue color atlas to complete gradient curve.
Adopt suitable integrator to determine the area at all peaks.
Ignore any peak of wash-out before 2 minutes and from any peak of diluent sample introduction.
Ignore peak less than 0.02% area.
Calculate
A.), calculate the QTP-triether, the QTP-desethanol that determine by RRT, DBTP-ethyl and the content of the DBTP that determines by SST according to separately relative response factor (F):
The response factor of the response factor/QTP of F=known impurities
For QTP-triether (RRT 0.32), F=0.62
For DBTP (RRT 0.72), F=1.2
For QTP-desethanol (RRT 0.84), F=1.0
For DBTP-ethyl (RRT 1.5), F=1.1
The following calculating of known impurities:
Known impurities %=(peak area of impurity in the sample/F)/(QTP area+other peak area+known peak/F)
B.) the following calculating of any other impurity:
The area of impurity in the impurity %=sample/(QTP area+other peak area+known peak/F)
RL is 0.05%
DL is 0.02%
Abbreviation
DBTP: dibenzo [b, f] [1,4] thia azepine , 11-(1-piperazine)
QTP: quetiapine fumarate
QTP-desethanol:2-[4-(dibenzo [b, f] [1,4] thia azepine -11-yl) piperazine-1-yl] ethanol
QTP-triether:2-(2-[4-(dibenzo [b, f] [1,4] thia azepine -11-yl) piperazine-1-yl)] triethoxy ethanol
DBTP-ethyl:4-ethyl (dibenzo [b, f] [1,4] thia azepine -11-yl) piperazine-1-base
Embodiment
Embodiment 1:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine
Add 50g (0.2mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine (I) and 500ml toluene in the 2L round-bottomed flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.Gained solution is mixed with 39g (0.22mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine (II), 56.2g (0.40mol) salt of wormwood and 16.89g (0.10mol) potassiumiodide.Reaction mixture heated 12 hours under gentle reflux, with HPLC analyze reaction mixture sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture is mixed with 1000ml 1N hydrochloric acid soln to room temperature, obtains the solution of pH 1-2.Separate each layer, water layer adds the 500ml dilution with toluene, and adding yellow soda ash accent pH is 8-9.Separate each layer (water and non-aqueous reaction solvent toluene), water layer extracts with 500ml toluene.Merge organic (toluene) layer, with 2 * 500ml water washing.Heat up in a steamer dereaction solvent (toluene) in 70-80 ℃ of following vacuum, get 60g oily matter, HPLC area %:99.5%.
Embodiment 2:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine
Add 50g (0.2mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine (I) and 500ml dimethylbenzene in the 2L round-bottomed flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.Gained solution is mixed with 39g (0.22mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine (II), 56.2g (0.40mol) salt of wormwood and 16.89g (0.10mol) potassiumiodide.Reaction mixture heated 12 hours under gentle reflux, with HPLC analyze reaction mixture sample.Analysis revealed starting raw material I residue is less than 1%.Reaction mixture is handled with 1000ml 1N hydrochloric acid soln to room temperature, obtains the solution of pH 1-2.Separate each layer, water layer extracts with 500ml dimethylbenzene, and adding yellow soda ash accent pH is 8-9.Separate each layer, water layer 500ml xylene extraction.Merge organic (dimethylbenzene reaction solvent) layer, with 2 * 500ml water washing.Heat up in a steamer the dereaction solvent in 70-80 ℃ of following vacuum, get 60g oily matter.HPLC area %:99.5%.
Embodiment 3:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine
Add 50g (0.2mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine and 500ml propyl carbinol in the 2L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, mixture at room temperature stirs 15min.Gained solution is mixed with 39g (0.22mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine (II), 56.2g (0.40mol) salt of wormwood and 16.89g (0.10mol) potassiumiodide.Reaction mixture heated 12 hours under gentle reflux, with HPLC analyze reaction mixture sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture is handled with 1000ml 1N hydrochloric acid soln to room temperature, obtains pH 1-2.Separate each layer (water and non-aqueous reaction solvent), water layer 500ml methylbenzene extraction, adding yellow soda ash accent pH is 8-9.Separate each layer, water layer is once more with the extraction of 500ml toluene.Merge organic layer (propyl carbinol and toluene), with 2 * 500ml water washing.At 70-80 ℃ of following vacuum distilling solvent, get 47.5g oily matter, HPLC area %:98.9%.
Embodiment 4:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine
Add 10g (0.04mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine and 100ml toluene in the 1L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.Gained solution is mixed with 7.7g (0.044mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine (II), 8.5g (0.08mol) yellow soda ash and 1.6g (0.01mol) sodium iodide.Reaction mixture heated 15 hours under gentle reflux, with HPLC analyze reaction mixture sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture is handled with 175ml 1N hydrochloric acid soln to room temperature, obtains pH 1-2.Separate each layer, water layer 100ml dilution with toluene, adding yellow soda ash accent pH is 8-9.Separate each layer, water layer extracts with 100ml toluene.Merge organic layer, with 2 * 100ml water washing.At 70-80 ℃ of following vacuum distilling solvent, get 11g oily matter, HPLC area %:98.3%.
Embodiment 5 (comparative): 11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine
Add 10g (0.04mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine and 100ml toluene in the 1L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.With gained solution and 7.0g (0.04mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine) and 3.2g (0.08mol) sodium hydroxide mix.Reaction mixture heated 20 hours under gentle reflux, with HPLC analyze reaction mixture sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture is handled with the 70ml1N hydrochloric acid soln to room temperature, obtains pH 1-2.Separate each layer, water layer 100ml dilution with toluene, adding yellow soda ash accent pH is 8-9.Separate each layer, water layer extracts with 100ml toluene.Merge organic layer, with 2 * 100ml water washing.At 70-80 ℃ of following vacuum distilling solvent, get 12g oily matter, HPLC area %:66.47%.
Embodiment 6:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine
Add 10g (0.04mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine and 100ml toluene in the 1L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.With gained solution and 7.0g (0.04mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine), 9.7g (0.08mol) N, accelerine mixes.Reaction mixture heated 40 hours under gentle reflux, used the HPLC analytic sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture is handled with 175ml 1N hydrochloric acid soln to room temperature, obtains pH 1-2.Separate each layer, water layer 100ml dilution with toluene, adding yellow soda ash accent pH is 8-9.Separate each layer, water layer extracts with 100ml toluene.Merge organic layer, with 2 * 100ml water washing.At 70-80 ℃ of following vacuum distilling solvent, get 12g oily matter, HPLC area %:96.52%.
Embodiment 7:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] dibenzo [b, f[] 1,4] preparation of thia azepine
Add 10g (0.04mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine and 100ml toluene in the 1L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.With gained solution and 7.0g (0.04mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine), 10.3g (0.08mol) N, N-di-isopropyl ethylaniline is mixed.Reaction mixture heated 38 hours under gentle reflux, used the HPLC analytic sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture is handled with the 175ml1N hydrochloric acid soln to room temperature, obtains pH 1-2.Separate each layer, water layer 100ml dilution with toluene, adding yellow soda ash accent pH is 8-9.Separate each layer, water layer extracts with 100ml toluene.Merge organic layer, with 2 * 100ml water washing.At 70-80 ℃ of following vacuum distilling solvent, get 12g oily matter, HPLC area %:90.64%.
Embodiment 8:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine
Add 10g (0.04mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine and 100ml toluene in the 1L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.With gained solution and 7.0g (0.04mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine), 8.0g (0.08mol) triethylamine mixes.Reaction mixture heated 35 hours under gentle reflux, used the HPLC analytic sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture is handled with 175ml 1N hydrochloric acid soln to room temperature, obtains pH 1-2.Separate each layer, water layer mixes with 100ml toluene, and adding yellow soda ash accent pH is 8-9.Separate each layer, water layer extracts with 100ml toluene.Merge organic layer, with 2 * 100ml water washing.At 70-80 ℃ of following vacuum distilling solvent, get 15g oily matter, HPLC area %:97.7%.
Embodiment 9:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine
Add 10g (0.04mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine and 100ml toluene in the 1L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.With gained solution with 7.0g (0.04mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine), 6.7g (0.08mol) sodium bicarbonate handles.Reaction mixture heated 35 hours under gentle reflux, used the HPLC analytic sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture is handled with 175ml 1N hydrochloric acid soln to room temperature, obtains pH 1-2.Separate each layer, water layer 100ml dilution with toluene, adding yellow soda ash accent pH is 8-9.Separate each layer, water layer extracts with 100ml toluene.Merge organic layer, with 2 * 100ml water washing.Heat up in a steamer in 70-80 ℃ of following vacuum and to desolvate, 14g oily matter, HPLC area %:94.68%.
Embodiment 10:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine
Add 10g (0.04mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine and 100ml toluene in the 1L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.With gained solution and 7.0g (0.04mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine), 8.0g (0.08mol) saleratus mixes.Reaction mixture heated 35 hours under gentle reflux, used the HPLC analytic sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture with the nursing of 175ml 1N hydrochloric acid soln, obtains pH 1-2 to room temperature.Separate each layer, water layer 100ml dilution with toluene, adding yellow soda ash accent pH is 8-9.Separate each layer, water layer extracts with 100ml toluene.Merge organic layer, with 2 * 100ml water washing.Heat up in a steamer in 70-80 ℃ of following vacuum and to desolvate, 15g oily matter.HPLC area %:98.54%.
Embodiment 11:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine
Add 10g (0.04mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine and 100ml toluene in the 1L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.With gained solution and 7.7g (0.044mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine), 8.5g (0.08mol) yellow soda ash and 7.7g (0.026mol) Tetrabutylammonium bromide mix.Reaction mixture heated 22 hours under gentle reflux, used the HPLC analytic sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture is handled with 175ml 1N hydrochloric acid soln to room temperature, obtains pH 1-2.Separate each layer, water layer 100ml methylbenzene extraction, adding yellow soda ash accent pH is 8-9.Separate each layer, water layer extracts with 100ml toluene.Merge organic layer, with 2 * 100ml water washing.At 70-80 ℃ of following vacuum distilling solvent, get 12g oily matter, HPLC area %:98.87%.
Embodiment 12:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine
Add 10g (0.04mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine and 100ml toluene in the 1L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.With gained solution and 77g (0.044mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine), 8.5g (0.08mol) yellow soda ash and 4.0g (0.02mol) trimethyl silyl iodine mixes.Reaction mixture heated 18 hours under gentle reflux, used the HPLC analytic sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture is handled with 175ml 1N hydrochloric acid soln to room temperature, obtains pH 1-2.Separate each layer, water layer 100ml dilution with toluene, adding yellow soda ash accent pH is 8-9.Separate each layer, water layer extracts with 100ml toluene.Merge organic layer, with 2 * 100ml water washing.At 70-80 ℃ of following vacuum distilling solvent, get 0.9g oily matter, HPLC area %:98.9%.
Embodiment 13: fumaric acid 11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine
Add 50g (0.2mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine (I) and 500ml toluene in the 2L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.Gained solution is mixed with 39g (0.22mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine (II), 56.2g (0.40mol) salt of wormwood and 16.89g (0.10mol) potassiumiodide.Reaction mixture heated 12 hours under gentle reflux, with HPLC analyze reaction mixture sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture is mixed with 1000ml 1N hydrochloric acid soln to room temperature, obtains pH 1-2.Separate each layer, water layer 500ml dilution with toluene, adding yellow soda ash accent pH is 8-9.Separate each layer (water and non-aqueous reaction solvent toluene), water layer extracts with 500ml toluene.Merge organic (toluene) layer, with 2 * 500ml water washing.Heat up in a steamer dereaction solvent (toluene) in 70-80 ℃ of following vacuum, remaining 50-60ml toluene.In this solution, add the 950-1000ml dehydrated alcohol, and gac 5-6g, reflux 90 minutes.Reaction solution is cooled to 55-60 ℃ then, filters.Filtrate is cooled to 25-30 ℃, adds the 8-9g fumaric acid while stirring.Mixture heating up refluxed 120 minutes, slowly cooled to 25-30 ℃, was incubated 120 minutes, filtered, and used the 175-200ml absolute ethanol washing.The wet feed that obtains gets quetiapine fumarate (50-55g) 50-60 ℃ of following vacuum-drying.
Embodiment 14:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine fumarate
Add 50g (0.2mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine (I) and 500ml dimethylbenzene in the 2L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.Gained solution is mixed with 39g (0.22mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine (II), 56.2g (0.40mol) salt of wormwood and 16.89g (0.10mol) potassiumiodide.Reaction mixture heated 12 hours under gentle reflux, with HPLC analyze reaction mixture sample.Analysis revealed starting raw material I residue is less than 1%.Reaction mixture is mixed with 1000ml 1N hydrochloric acid soln to room temperature, obtains the solution of pH 1-2.Separate each layer, water layer adds 500ml dimethylbenzene, and stirs, and adding yellow soda ash accent pH is 8-9.Separate organic layer and water layer, water layer 500ml xylene extraction.Merge organic layer (reaction solvent dimethylbenzene), with 2 * 500ml water washing.Remove most of solvent in 70-80 ℃ of following vacuum, remaining 50-60ml.In this solution, add the 950-1000ml dehydrated alcohol, and gac 5-6g, reflux 90 minutes.Reaction solution is cooled to 55-60 ℃ then, filters, and filtrate is cooled to 25-30 ℃, adds the 8-9g fumaric acid while stirring.Mixture heating up refluxed 120 minutes, slowly cooled to 25-30 ℃, was incubated 120 minutes, filtered, and used the 175-200ml absolute ethanol washing.The gained wet feed gets quetiapine fumarate (50-55g) 50-60 ℃ of following vacuum-drying.
Embodiment 15:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine fumarate
Add 50g (0.2mol) 1 1-chlorodiphenyl also [b, f] [1,4] thia azepine (I) and 500ml propyl carbinol in the 2L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.Gained solution is mixed with 39g (0.22mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine (II), 56.2g (0.40mol) salt of wormwood and 16.89g (0.10mol) potassiumiodide.Reaction mixture heated 12 hours under gentle reflux, with HPLC analyze reaction mixture sample.Analysis revealed starting raw material I residue is less than 1%.Reaction mixture is mixed with 1000ml 1N hydrochloric acid soln to room temperature, obtains the solution of pH 1-2.Separate each layer (water layer and non-aqueous reaction solvent layer), water layer extracts with 500ml toluene, and adding yellow soda ash accent pH is 8-9.Separate organic layer and water layer, water layer extracts with 500ml toluene.Merge organic layer (propyl carbinol and toluene), with 2 * 500ml water washing.70-80 ℃ of following solvent removed in vacuo, obtain oily matter.In this oily matter, add toluene 50-75m, dehydrated alcohol 950-1000ml, gac 5-6g, reflux 90 minutes.Reaction mixture is cooled to 55-60 ℃, filters, filtrate further is cooled to 25-30 ℃, adds the 7-7.5g fumaric acid while stirring.Mixture heating up refluxed 120 minutes, slowly cooled to 25-30 ℃, was incubated 120 minutes, filtered.Filter cake 125-150ml absolute ethanol washing.Wet feed gets quetiapine fumarate (40-45g) 50-60 ℃ of following vacuum-drying.
Embodiment 16:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine fumarate
Add 10g (0.04mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine and 100ml toluene in the 1L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.Gained solution is mixed with 7.7g (0.044mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine (II), 8.5g (0.08mol) salt of wormwood and 1.6g (0.01mol) potassiumiodide.Reaction mixture heated 15 hours under gentle reflux, with HPLC analyze reaction mixture sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture is mixed with 175ml 1N hydrochloric acid soln to room temperature, obtains the solution of pH 1-2.Separate each layer, water layer 100ml dilution with toluene, adding yellow soda ash accent pH is 8-9.Separate organic layer and water layer, water layer extracts with 100ml toluene.Merge organic layer, with 2 * 100ml water washing.Remove most of solvent in 70-80 ℃ of following vacuum, remaining 10-15ml toluene.In this solution, add the 175-200ml dehydrated alcohol, and gac 1-1.5g, reflux 90 minutes.Reaction mixture is cooled to 55-60 ℃, filters, filtrate further is cooled to 25-30 ℃, adds the 1.5-2.0g fumaric acid while stirring.Mixture heating up refluxed 120 minutes, slowly cooled to 25-30 ℃, was incubated 120 minutes, filtered.Filter cake 30-40ml absolute ethanol washing.The gained wet feed gets quetiapine fumarate (8-10g) 50-60 ℃ of following vacuum-drying.
Embodiment 17:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine
Add 10g (0.04mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine (I) and 100ml toluene in the 1L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.Gained solution is mixed with 7.7g (0.044mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine (II), 8.5g (0.08mol) salt of wormwood and 7.7g (0.24mol) Tetrabutyl amonium bromide.Reaction mixture heated 22 hours under gentle reflux, with HPLC analyze reaction mixture sample.Analysis revealed starting raw material residue is less than 2%.Reaction mixture is mixed with 300ml 1N hydrochloric acid soln to room temperature, obtains the solution of pH 1-2.Separate each layer, water layer 100ml dilution with toluene, adding yellow soda ash accent pH is 8-9.Separate organic layer and water layer (water layer and non-aqueous reaction solvent toluene layer), water layer extracts with 100ml toluene.Merge organic layer (toluene), with 2 * 100ml water washing.In 70-80 ℃ of following solvent removed in vacuo (toluene), get 12g oily matter, HPLC area %:98.87%.
[0001] embodiment 18:11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] preparation of dibenzo [b, f] [1,4] thia azepine .
Add 50g (0.2mol) 11-chlorodiphenyl also [b, f] [1,4] thia azepine (I) and 500ml toluene in the 2L round-bottom reaction flask of band stirring rod, thermometer pocket, reflux exchanger and nitrogen inlet, reaction mixture at room temperature stirs 15min.Gained solution is mixed with 39g (0.22mol) 1-(2-hydroxyl-oxethyl) ethyl piperazidine (II), 56.2g (0.40mol) salt of wormwood and 16.89g (0.10mol) potassiumiodide.Reaction mixture heated 12 hours under gentle reflux, with HPLC analyze reaction mixture sample.Analysis revealed starting raw material residue is less than 1%.Reaction mixture is mixed with 1000ml 1N hydrochloric acid soln to room temperature, obtains the solution of pH 1-2.Separate each layer, water layer 500ml dilution with toluene, adding yellow soda ash accent pH is 8-9.Separate organic layer and water layer (water layer and non-aqueous reaction solvent toluene layer), water layer extracts with 500ml toluene.Merge organic layer (toluene), with 2 * 500ml water washing.In 70-80 ℃ of following solvent removed in vacuo (toluene), get 60g oily matter, with ethyl acetate oily matter is carried out recrystallization, obtain 11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] dibenzo [b, f] [1,4] thia azepine 55g.
Claims (29)
1. one kind prepares Quetiapine, be 11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] dibenzo [b, f] [1,4] method of thia azepine , described method comprises the steps: in reaction solvent, with the 11-chlorodiphenyl also [b, f] [1,4] thia azepine (I), be about the 1-1.5 molar equivalent of (I) 1-(2-hydroxyl-oxethyl) ethyl piperazidine (II),
Alkali and halogenide are that alkali metal halide or silyl halides mixing obtain reaction mixture, and arrive under the temperature of reaction of reflux temperature in about room temperature, and reaction mixture is heated certain reaction times.
2. the process of claim 1 wherein that the molar weight of described 1-(2-hydroxyl-oxethyl) ethyl piperazidine (II) is about the also 1-1.2 molar equivalent of [b, f] [1,4] thia azepine (I) of 11-chlorodiphenyl.
3. each method in the aforementioned claim, wherein said temperature of reaction is a reflux temperature.
4. each method in the aforementioned claim, wherein said alkali is organic bases, i.e. amine.
5. the method for claim 4, wherein said amine is tertiary amine.
6. the process of claim 1 wherein that described alkali is mineral alkali, i.e. alkaline carbonate, supercarbonate or oxyhydroxide.
7. the method for claim 6, wherein said mineral alkali is selected from saleratus, sodium bicarbonate and sodium hydroxide.
8. the method for claim 6, wherein said alkali is alkaline carbonate, i.e. salt of wormwood.
9. each method in the aforementioned claim, the molar weight of wherein used alkali are about the also 1-3 molar equivalent of the molar weight of [b, f] [1,4] thia azepine (I) of 11-chlorodiphenyl used in the reaction.
10. the method for claim 9, wherein the molar weight of used alkali is about the also 1-2 molar equivalent of [b, f] [1,4] thia azepine (I) molar weight of 11-chlorodiphenyl.
11. each method in the aforementioned claim, wherein said halogenide are alkaline metal fluoride cpd, iodide or bromide.
12. the method for claim 11, wherein said alkali metal halide are alkaline metal iodide.
13. the method for claim 12, wherein said alkali metal halide are potassiumiodide.
14. each method in the aforementioned claim, wherein said halogenide consumption and 11-the chlorodiphenyl also mol ratio of [b, f] [1,4] thia azepine (I) consumption are at least about 0.2.
15. each method in the aforementioned claim, wherein said reaction solvent are the mixture or the alkyl alcohol of non-halogenated aromatic, alkyl ester, non-halogenated aromatic and alkyl ester.
16. the method for claim 15, wherein said reaction solvent are toluene, dimethylbenzene or its mixture.
17. the method for claim 15, wherein said reaction solvent are the mixture of alkyl alcohol or alkyl alcohol.
18. each method in the aforementioned claim, the wherein said reaction times is about 20 hours or still less.
19. the process of claim 1 wherein that the described reaction times is about 10 to about 14 hours.
20. each method in the aforementioned claim, the monitoring in wherein said reaction times are to realize by the disappearance with thin-layer chromatography, gas liquid chromatography or high performance liquid chromatography monitoring Compound I.
21. each method in the aforementioned claim further comprises the step that Quetiapine is converted into drug acceptable salt.
22. the method for claim 21, wherein said drug acceptable salt are quetiapine fumarate or half quetiapine fumarate, wherein said conversion is by mixing realization with fumaric acid with Quetiapine.
23. the method for claim 21, wherein said Quetiapine can mix in solvent with fumaric acid, and solvent can be reaction solvent or become salt solvent.
24. the method for claim 23, wherein said being blended in the reaction solvent carried out, and Quetiapine with need not from described reaction solvent, to separate before fumaric acid mixes.
25. the method for claim 23, wherein said solvent be for becoming salt solvent, i.e. one or more aromatic hydrocarbon or one or more C
1-C
4Alcohol.
26. the method for claim 25, wherein said one-tenth salt solvent is toluene or ethanol.
27. the method for claim 24 wherein with before fumaric acid mixes, is heated to about reflux temperature with the Quetiapine in the reaction solvent, is cooled to about 30 ℃ to about 60 ℃ then, mixes with fumaric acid then.
28. the purposes of each method in preparation Quetiapine or its drug acceptable salt in the aforementioned claim.
29. the purposes of claim 28, wherein said drug acceptable salt are fumarate.
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CN104447616A (en) * | 2014-12-23 | 2015-03-25 | 齐鲁天和惠世制药有限公司 | Preparation method of quetiapine fumarate impurity D |
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CN101676275B (en) * | 2008-09-17 | 2014-05-07 | 北京德众万全药物技术开发有限公司 | preparation method of quetiapine fumarate |
CN104447616A (en) * | 2014-12-23 | 2015-03-25 | 齐鲁天和惠世制药有限公司 | Preparation method of quetiapine fumarate impurity D |
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