CN1129593C - 西酞普兰的制备方法 - Google Patents
西酞普兰的制备方法 Download PDFInfo
- Publication number
- CN1129593C CN1129593C CN99816768A CN99816768A CN1129593C CN 1129593 C CN1129593 C CN 1129593C CN 99816768 A CN99816768 A CN 99816768A CN 99816768 A CN99816768 A CN 99816768A CN 1129593 C CN1129593 C CN 1129593C
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- Prior art keywords
- compound
- nickel
- citalopram
- formula
- acid
- 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.)
- Expired - Fee Related
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- 238000000034 method Methods 0.000 title claims abstract description 38
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 title claims abstract description 24
- 229960001653 citalopram Drugs 0.000 title claims abstract description 24
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- -1 5-cyano compound Chemical class 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 239000011701 zinc Substances 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 229910052759 nickel Inorganic materials 0.000 claims description 8
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 8
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052725 zinc Inorganic materials 0.000 claims description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 238000011065 in-situ storage Methods 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 229910052748 manganese Inorganic materials 0.000 claims description 2
- 239000011572 manganese Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 10
- 238000002955 isolation Methods 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000935 antidepressant agent Substances 0.000 description 5
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 description 5
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 3
- KTGRHKOEFSJQNS-UHFFFAOYSA-N Citalopram Oxalate Chemical compound OC(=O)C(O)=O.O1CC2=CC(C#N)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 KTGRHKOEFSJQNS-UHFFFAOYSA-N 0.000 description 3
- 238000003747 Grignard reaction Methods 0.000 description 3
- 230000001430 anti-depressive effect Effects 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- NOYCNNBKNIAAHS-UHFFFAOYSA-N FC1=CC=C([Mg])C=C1 Chemical compound FC1=CC=C([Mg])C=C1 NOYCNNBKNIAAHS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- LVHBHZANLOWSRM-UHFFFAOYSA-N itaconic acid Chemical compound OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 description 1
- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical compound C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 description 1
- YXCRMKYHFFMNPT-UHFFFAOYSA-N 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile Chemical compound C1=CC(F)=CC=C1C1C2=CC=C(C#N)C=C2CO1 YXCRMKYHFFMNPT-UHFFFAOYSA-N 0.000 description 1
- KHEVPDFAQFJIGK-UHFFFAOYSA-N 2-sulfooxyethanesulfonic acid Chemical compound OS(=O)(=O)CCOS(O)(=O)=O KHEVPDFAQFJIGK-UHFFFAOYSA-N 0.000 description 1
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 1
- SKTFQHRVFFOHTQ-UHFFFAOYSA-N 8-bromo-1,3-dimethyl-7h-purine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC(Br)=N2 SKTFQHRVFFOHTQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- VYEYJCBEXFTGBN-UHFFFAOYSA-N acetic acid;1,3-dimethyl-7h-purine-2,6-dione Chemical compound CC(O)=O.O=C1N(C)C(=O)N(C)C2=C1NC=N2 VYEYJCBEXFTGBN-UHFFFAOYSA-N 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
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- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 description 1
- HNEGQIOMVPPMNR-IHWYPQMZSA-N citraconic acid Chemical compound OC(=O)C(/C)=C\C(O)=O HNEGQIOMVPPMNR-IHWYPQMZSA-N 0.000 description 1
- 229940018557 citraconic acid Drugs 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
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- 150000007522 mineralic acids Chemical class 0.000 description 1
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- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- SFLGSKRGOWRGBR-UHFFFAOYSA-N phthalane Chemical class C1=CC=C2COCC2=C1 SFLGSKRGOWRGBR-UHFFFAOYSA-N 0.000 description 1
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- 235000019260 propionic acid Nutrition 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
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- 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
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
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Abstract
一种制备西酞普兰的方法,它包括式(III)化合物,其中R为Cl或Br,与氧化物源在镍催化剂存在下的反应及相应的5-氰基化合物即西酞普兰的分离。
Description
本发明涉及熟知的抗抑郁药西酞普兰,1-[3-(二甲氨基)丙基]-1-(4-氟苯基)-1,3-二氢-5-异苯并呋喃腈(isobenzofurancarbonitrili)的制备方法。
本发明的背景
西酞普兰是一种上市多年的熟知的抗抑郁药,其结构如下:
式I
它是一种选择性的、中枢作用的5-羟色胺(5-羟基色胺;5-HT)再摄取抑制剂,并因而具有抗抑郁活性。该化合物的抗抑郁活性报道于一些出版物中,如,J.Hyttel,Prog的Neuro-Psychopharmacol.&Biol.Psychiat.,1982,6,277-295和A.Gravem的Acta Psychiatr.Scand,1987,75,478-486。EP-A 474580中进一步公开该化合物在治疗痴呆和脑血管疾病所显示的作用。
西酞普兰第一次公开于与US 4,136,193同时待审的DE 2,657,013中。该专利出版物描述了西酞普兰的一种制备方法,并概述了也可用于西酞普兰制备的另一方法。
根据所述的该方法,相应的1-(4-氟苯基)-1,3-二氢-5-异苯并呋喃腈在作为缩合剂的甲基亚磺酰甲基化物(methylsulfinylmethide)的存在下与3-(N,N-二甲氨基)丙基-氯反应。通过相应的5-溴衍生物与氰化亚铜的反应制备初始原料。
根据只是概括性地描述的该方法,西酞普兰可在脱水剂存在下通过化合物
式II的闭环作用,且接着经氰化亚铜用氰基替换5-溴基的情况下获得。用5-溴代2-苯并[c]呋喃酮经两步连续的格利雅反应,即分别与氯化4-氟苯基镁和氯化N,N-二甲氨基丙基镁反应来制备式II的初始原料。
式III经历由浓硫酸脱水所致的闭环反应以获得西酞普兰。通过两步连续的格利雅反应,即,由5-氰基2-苯并[c]呋喃酮分别与卤化4-氟苯基镁和卤化N,N-二甲氨基丙基镁反应制备式III中间体。
其它方法公开于国际专利申请号WO 9819511、WO 9819512和WO 9819513中。WO 9819512和WO 9819513涉及到一些方法,其中的5-氨基-、5-羧基-或5-(仲氨基羰基)2-苯并[c]呋喃酮经两步连续的格利雅反应,闭环并将生成的1,3-二氢异苯并呋喃衍生物转化为相应的5-氰基化合物,即西酞普兰。国际专利申请号WO 9819511公开了一种制备西酞普兰的方法,其中的(4-取代的-2羟甲基苯基-(4-氟苯基)甲醇化合物发生闭环作用,而将生成的5-取代的-1-(4-氟苯基)-1,3-二氢异苯并呋喃转化为相应的5-氰基衍生物,它经(3-二甲氨基)丙基卤化物烷基化以得到西酞普兰。
最后,制备西酞普兰单一对映体的方法公开于美国专利第4,943,590号,其中也表明可用碱经由不稳定的酯进行式III中间物的闭环反应。
就制备西酞普兰的上述方法而言,包括以氰基替换5-溴基的方法在大规模生产中被证明不是很方便,因为其得率颇低、产物不纯,特别是难于从相应的5-溴代化合物中分离出生成的西酞普兰。
已发现用新的催化方法来获得高得率的、纯度极高的西酞普兰产物,其中用5-氰基替换1-[3-(二甲氨基)丙基]-1-(4-氟苯基)-1,3-二氢-异苯并呋喃中的5-溴基或5-氯基,从而避免的老氰化物替换的老方法中的大量后处理。
本发明概述
式IV,其中R为Cl或Br,与氰化物源如KCN、NaCN或(R’4N)CN在镍催化剂存在下反应,其中R’4指四个可以是相同或不同的且选自氢、直链或支链C1-6烷基的基团,并分离出相应的5-氰基化合物,即为碱的或其药学上可接受的盐的西酞普兰。
式I
本发明另一方面涉及上述方法,其中式IV化合物为S-对映体。
本发明的又一个方面涉及含通过本发明的方法制备的西酞普兰的抗抑郁药用组合物。
通过本发明的方法可以高得率地获得纯产物的西酞普兰,因此免去了昂贵的提纯步骤。而且,与已知的氰基交换方法相比,本反应可在更适宜的溶剂中,在低温和低过量CN-中进行。本发明因只用少量的重金属(heavy)而具有环境方面的优势。最后,本方法产生易于转化为所需的盐的改良的晶状产物。
所用的氰化物源可以是任何有用的来源。优选的来源为KCN、NaCN或(R’4N)CN,其中的R’4定义如上。以化学计算的量或过量使用该类氰化物源,优选每当量式IV的初始原料用1-2当量。R’4N+适于为(Bu)4N+。氰化物化合物优选NaCN或KCN或Zn(CN)2。
镍催化剂可为任何合适的含可起催化剂作用的络合物的Ni(O)或Ni(II),如Ni(PPh3)3、(σ-芳基)-Ni(PPh3)2Cl等等。镍催化剂及其制备描述于WO 96/11906、EP-A-613720或EP-A-384392。
在本发明的一个实施方案中,该反应在催化量的Cu+或Zn2+的存在下进行。
在一个特别优选的实施方案中,镍(O)络合物是在氰化反应之前,在过量络合物配体(优选三苯膦)的存在下,通过用金属如锌、镁或锰还原镍(II)前体如NiCl2或NiBr2而原位制备的。
镍-催化剂适用量为0.5-10,优选2-6,最优选约4-5摩尔%。
Cu+和Zn2+的催化量各指低于化学计算量如0.1-5、优选1-3%。可用任何方便的Cu+和Zn2+的来源。优选采用CuI形式的Cu+,Zn2+可方便地作为Zn(CN)2盐或通过用锌还原镍(II)化合物而原位形成。
在本发明的优选实施方案中,R为氯。
在本发明特别优选的实施方案中,其中R为Cl的式IV化合物,在如上述优选原位制备的Ni(PPh3)3的存在下与NaCN或KCN反应。
其中R为溴或氯的式IV中间物可如DE 2,657,013和相关的US4,136,193中所述,可各自由溴代2-苯并[c]呋喃酮和氯代2-苯并[c]呋喃酮制得。
该反应可在任何合适的溶剂,优选乙腈、丙腈、四氢呋喃和乙酸乙酯中进行。
其它反应条件、溶剂等为这类反应的常规条件而易于为本领域的技术人员所确定。
总式I的化合物可用作游离碱或其药学上可接受的酸加成盐。作为酸加成盐,可使用与有机或无机酸形成的这类盐。这类有机盐的实例有与下列酸所形成的盐:马来酸、富马酸、苯甲酸、抗坏血酸、琥珀酸、草酸、二亚甲基水杨酸、甲磺酸、乙二磺酸、乙酸、丙酸、酒石酸、水杨酸、柠檬酸、萄糖酸、乳酸、苹果酸、扁桃酸、肉桂酸、柠康酸、天冬氨酸、硬脂酸、棕榈酸、衣康酸、乙醇酸、邻-氨基苯甲酸、谷氨酸、苯磺酸和茶碱乙酸以及8-卤代茶碱,如8-溴代茶碱。这类无机盐的实例有与氢氯酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸所形成的盐。
可通过本领域所熟知的方法制备该化合物的酸加成盐。所述碱与计算量的酸在水可混溶的溶剂如丙酮或乙醇中反应,接着通过浓缩和冷却分离所述盐;或与过量的酸在水不混溶的溶剂如***、乙酸乙酯或二氯甲烷中反应,而自然分离出盐。
本发明的药用组合物可采用任何合适的方式和任何合适的形式给药,例如,以片剂、胶囊、散剂或糖浆的形式口服;或以常用的无菌注射液经肠胃外给药。
可通过本领域的常规方法制备本发明的药物制剂。比如,可通过将活性成分与普通的辅助剂和/或稀释剂相混合,接着在常规的压片机内压制该混合物来制备片剂。辅助剂或稀释剂的实例包括:玉米淀粉、马铃薯淀粉、滑石粉、硬脂酸镁、明胶、乳糖、树胶等等。其它任何辅助剂或添加的着色剂、芳香剂、防腐剂等都可采用,只要它们与所述的活性成分适配。
将所述的活性成分和可能的添加物溶解于部分注射用溶剂,优选无菌水中,将溶液调节到所需的体积,将溶液灭菌并装入合适的安瓿瓶或管制瓶中,可制备注射液。可加入本领域常用的任何适用添加剂,如张度剂、防腐剂、抗氧化剂等。
实施例
通过下列实施例进一步说明本发明。
实施例1
西酞普兰草酸盐
在氮气氛围中将NiCl2(0.077克,0.006摩尔)和三苯膦(0.63克,0.0024摩尔)在乙腈(50毫升)中的混合物回流加热45分钟。冷却到室温后,在溶于乙腈(25毫升)的1-(4′-氟苯基)-1-(3-二甲氨基丙基)-5-氯酞(5.0克,0.015摩尔)溶液加入之前,加入锌粉(0.39克,0.006摩尔)搅拌15分钟。进一步搅拌10分钟后加入NaCN(0.32克,0.0065摩尔),并将该反应回流加热过夜、冷却、用***稀释,然后经硅藻土过滤。用盐水洗涤滤液、干燥(MgSO4)并减压浓缩。将残余物溶于丙酮(50毫升),再边搅拌边加入溶于丙酮(10毫升)中的草酸(1.35克,0.015摩尔)溶液。经过滤分离西酞普兰草酸盐,然后从乙醇中重结晶并真空干燥成纯的西酞普兰草酸盐(3.4克,55%)。
Claims (15)
2.权利要求1的方法,其中R为氯。
3.权利要求1或2的方法,其中氰化物源为KCN、NaCN、Zn(CN)2或(R’4N)CN,其中R’4指四个可以是相同或不同且选自氢、直链或支链C1-6烷基的基团。
4.权利要求1的方法,其中氰化物源为NaCN或KCN。
5.权利要求1的方法,其中镍催化剂为Ni(PPh3)3或(σ-芳基)-Ni(PPh)2Cl。
6.权利要求1的方法,其中镍催化剂为镍(O)络合物,它是在过量络合物配体的存在下,在氰化反应之前通过用金属还原镍(II)前体而原位制备的。
7.权利要求6的方法,其中所述金属为锌、镁或锰。
8.权利要求6的方法,其中所述镍(II)前体为NiCl2。
9.权利要求6的方法,其中镍(II)前体为NiCl2,金属为锌,络合物配体为三苯膦。
10.权利要求1的方法,其中R为Cl的式IV化合物与NaCN或KCN在Ni(PPh3)3催化剂存在下反应。
11.权利要求10的方法,其中Ni(PPh3)3是在氰化反应之前,在过量络合物三苯膦配体的存在下,通过用锌还原NiCl2而原位制备的。
12.权利要求1的方法,其中所述反应在催化量的Cu+存在下进行。
13.权利要求12的方法,其中所述Cu+是以CuI的形式存在。
14.权利要求1的方法,其中所述反应在催化量的Zn2+的存在下进行。
15.权利要求1的方法,其中式IV化合物为S-对映体。
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