CN1133633C - Method for preph. of citalopram - Google Patents
Method for preph. of citalopram Download PDFInfo
- Publication number
- CN1133633C CN1133633C CNB998148962A CN99814896A CN1133633C CN 1133633 C CN1133633 C CN 1133633C CN B998148962 A CNB998148962 A CN B998148962A CN 99814896 A CN99814896 A CN 99814896A CN 1133633 C CN1133633 C CN 1133633C
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- formula
- compound
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- reaction
- citalopram
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 36
- 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 28
- 229960001653 citalopram Drugs 0.000 title claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- -1 3-(N, N-dimethylamino)-propyl magnesium halide Chemical class 0.000 claims abstract description 23
- 125000002252 acyl group Chemical group 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 17
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 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 claims description 7
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001336 alkenes Chemical class 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 3
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- BRKADVNLTRCLOW-UHFFFAOYSA-M magnesium;fluorobenzene;bromide Chemical compound [Mg+2].[Br-].FC1=CC=[C-]C=C1 BRKADVNLTRCLOW-UHFFFAOYSA-M 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000026030 halogenation Effects 0.000 claims 1
- 238000005658 halogenation reaction Methods 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 abstract 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000006798 ring closing metathesis reaction Methods 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- PCOFIIVWHXIDGT-UHFFFAOYSA-N 3-(hydroxymethyl)benzonitrile Chemical compound OCC1=CC=CC(C#N)=C1 PCOFIIVWHXIDGT-UHFFFAOYSA-N 0.000 description 5
- 238000003747 Grignard reaction Methods 0.000 description 5
- 239000000935 antidepressant agent Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 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
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 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
- 235000019502 Orange oil Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 150000003840 hydrochlorides Chemical class 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
- 239000010502 orange oil Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229960000278 theophylline Drugs 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 230000001519 thymoleptic effect Effects 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 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
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- AITNMTXHTIIIBB-UHFFFAOYSA-N 1-bromo-4-fluorobenzene Chemical compound FC1=CC=C(Br)C=C1 AITNMTXHTIIIBB-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 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
- NYYRRBOMNHUCLB-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCCl NYYRRBOMNHUCLB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 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
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-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
- 239000007818 Grignard reagent Substances 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 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
- 241000872931 Myoporum sandwicense Species 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241001635574 Sabatia angularis Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- ALIGTYPNWJPIKT-UHFFFAOYSA-M [Cl-].FC1=CC=C([Mg+])C=C1 Chemical compound [Cl-].FC1=CC=C([Mg+])C=C1 ALIGTYPNWJPIKT-UHFFFAOYSA-M 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
- 239000002671 adjuvant Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 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
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 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
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 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
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 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
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 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
- 229950006191 gluconic acid Drugs 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000012155 injection solvent Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 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
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- NGPAITITALWALP-UHFFFAOYSA-M magnesium;n,n-dimethylpropan-1-amine;chloride Chemical compound [Mg+2].[Cl-].CN(C)CC[CH2-] NGPAITITALWALP-UHFFFAOYSA-M 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
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- SFLGSKRGOWRGBR-UHFFFAOYSA-N phthalane Chemical class C1=CC=C2COCC2=C1 SFLGSKRGOWRGBR-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 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
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a method for preparing citalopram, which comprises a compound of a formula (IV), wherein R is C1-6 alkyl, acyl, C1-6 alkyl sulfonyl or aryl sulfonyl, and R reacts with 3-(N, N-dimethylamino)-propyl magnesium halide to prepare citalopram.
Description
The antidepressant drug citalopram that the present invention relates to know, be 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1, the preparation method of 3-dihydro-5-isobenzofurancarboniderivatives.
Background of invention
Citalopram is the thymoleptic of knowing, and has gone on the market for many years, has following array structure:
Formula I
It is a selectivity central action thrombotonin (serotonin; Therefore 5-HT) reuptake inhibitor has antidepressant activity.The antidepressant activity of this compound is existing report in many pieces of documents, J.Hyttel for example, Prog.Neuro-Psychopharmcol.﹠amp; Biol.Psychiat. (" nerve-psychopharmacology and biological psychiatry progress ") 1982,6,277-295 and A.Gravem, Acta Psychiatr.Scand. (" Scandinavia psychiatry journal ") 1987,75,478486.It is effective to the treatment of dull-witted and cerebrovascular disease that EP-A 474580 further discloses this compound.
Citalopram is disclosed in DE 2,657 for the first time, in 271, is equivalent to US 4,136,193.This patent gazette has been described a kind of preparation method of citalopram, has summarized the another kind of method that can be used for preparing citalopram.
According to described method, in the presence of methanesulfinyl methide condensing agent, make corresponding 1-(4-fluorophenyl)-1, the reaction of 3-dihydro-5-isobenzofurancarboniderivatives and 3-(N, N-dimethylamino) propyl chloride.Raw material is from the prepared in reaction of corresponding 5-br-derivatives and cuprous cyanide.
According to the method for only doing general general introduction, in the presence of dewatering agent, by the ring closure of following compounds
With cuprous cyanide exchange 5-bromine group, can obtain citalopram subsequently.Formula II raw material obtains by two step successive Grignard reactions from 5-bromo-2-benzo [c] furanone, just respectively with 4-fluorophenyl magnesium chloride and N, N-dimethylamino-propyl magnesium chloride.
US Patent No 4,650,884 have described preparation method and intermediate novel and surprising citalopram, according to this method, the following formula intermediate
Formula III carries out ring-closure reaction, to obtain citalopram by with the strength sulfuric acid dehydration.The formula III intermediate prepares by two step successive Grignard reactions from 5-cyano group-2-benzo [c] furanone, just respectively with 4-fluorophenyl magnesium halide and N, the reaction of N-dimethylamino-propyl magnesium halide.
Further method is disclosed among international patent application Nos.WO 98019511, WO 98019512 and the WO 98019513.WO 98019512 and WO 98019513 relate to such method, make that 5-amino, 5-carboxyl-or 5-(secondary amino group carbonyl)-2-benzo [c] furanone carries out the successive Grignard reaction of two steps, ring closure and with gained 1,3-dihydroisobenzofuran derivative is converted into corresponding 5-cyano compound, i.e. citalopram.International patent application No.WO 98019511 discloses a kind of preparation method of citalopram, wherein make (4-replaces-and 2-hydroxymethyl phenyl-(4-fluorophenyl) carbinol compound carries out ring closure, the 1-(4-fluorophenyl)-1 that gained 5-replaces, the 3-dihydroisobenzofuran is converted into corresponding 5-cyano derivative, the latter is with the alkylation of (3-dimethyl hydrogen-based) propyl group halogenide, to obtain citalopram.
At last, the method for indivedual enantiomers of preparation citalopram is disclosed in US Patent No 4,943, in 590, can also find out obviously that therefrom the ring closure of formula III intermediate can be undertaken by unsettled ester and alkali.
Find shockingly that now utilize suitable raw material, citalopram can be prepared by novel, smooth and safe method.
Summary of the invention
Therefore, the present invention relates to the preparation method of novel citalopram, comprise formula IV compound
Formula IV wherein R is an acyl group, with 3-(N, N-dimethylamino) propyl group magnesium halide, be preferably 3-(N, N-dimethylamino) propyl group magnesium chloride, obtains citalopram
Formula I separation obtains alkali or its pharmacy acceptable salt.
The present invention relates to the method for preparation formula IV intermediate aspect further.
According to method of the present invention, citalopram obtains from formula IV compound by the single step Grignard reaction, and R is an acyl group among the formula IV,
Surprisingly, the Grignard reaction product spontaneously carries out ring closure, directly obtains citalopram, and therefore, being reflected in the step of formula IV compound and Grignard reagent generates citalopram.
And according to the present invention, formula IV compound can be prepared by three kinds of diverse ways.
One of these methods comprise the protection of the methylol alcohol of formula VI's (4-cyano group-2-hydroxymethyl phenyl) (4-fluorophenyl) methyl alcohol:
Oxidation then obtains formula IV compound, and wherein R is an acyl group.
The oxidation of formula V compound can be carried out with any conventional oxidant, preferably uses Na
2WO
4Carry out.
Formula VI raw materials of compound can be prepared as described in international patent application No.PCT/DK97/00511.
The method of another kind of preparation formula IV compound comprises 5-cyano group-2-benzo [c] furanone and 4-fluorophenyl magnesium halide, is preferably the reaction of 4-fluorophenyl magnesium bromide, and with the R-X reaction, wherein R is as defined above then, and X is a leavings group.
This reaction is described below:
Raw material 5-cyano group-2-benzo [c] furanone can be as Tirouflet J., 26,1959,35 described preparations of Bull.Soc.Sci. (" section association circular ") Bretagne.
According to the method for the third preparation formula IV compound, a kind of enantiomer of formula III compound, be that the R-enantiomer is protected and dehydration, obtain formula VII compound, latter's oxidation obtains the ketone of formula IV.
In this manner, the R-enantiomer of formula III can be used for the preparation of racemize citalopram.
The oxicracking of formula VII compound is undertaken by oxygenizement, preferably uses MnO
4 -(permanganate) or ozone, RuCl
3, OsO
4Carry out.
Citalopram as the thymoleptic listing is the form of racemoid.But, in the near future, the active S-enantiomer of citalopram also plans to introduce market.
The active S-enantiomer of citalopram can prepare like this, from the formula III compound, separates S-enantiomer and R-enantiomer, carries out the ring closure of S-enantiomer then, as described in US Patent No 4943590.The R-enantiomer of formula III compound was not used after separation in the past.
Other reaction conditionss, solvent etc. that are used for above-mentioned reaction are the normal conditions of this class reaction, are easily determined by those skilled in the art.
The term C that spreads all over specification sheets and claims
1-6Alkyl refers to have a branch or a unbranched alkyl to six carbon atom, for example comprises methyl, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, 2-methyl-2-propyl group, 2,2-dimethyl-1-ethyl and 2-methyl 1-propyl group.
Term aryl refers to list or bicyclic carbocyclic aromatic group, for example phenyl and naphthyl, particularly phenyl or cyclosubstituted phenyl.
The term heteroaryl refers to list or bicyclic heterocyclic aromatic group, for example indyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuryl, benzothienyl, pyridyl and furyl, particularly pyrimidyl, indyl and thienyl.
Acyl group is used in C
1-6Alkyl-or aryl-or the implication of heteroaryl carbonyl in, C wherein
1-6Alkyl and aryl and heteroaryl are as defined above.
Halogen refers to chlorine, bromine or iodine.
Preferably, leavings group refers to halogenide or sulfonate.
In preferred implementation of the present invention, R is an acyl group, is preferably valeryl, ethanoyl or optional substituted benzoyl.
Compound of Formula I can be used its free alkali or pharmaceutically-acceptable acid addition.As acid salt, can use and the formed salt of organic or inorganic acid.The example of organic salt be with following acid formed those: toxilic acid, fumaric acid, phenylformic acid, xitix, succsinic acid, oxalic acid, dimethylene Whitfield's ointment, methylsulfonic acid, ethionic acid, acetate, propionic acid, tartrate, Whitfield's ointment, citric acid, glyconic acid, lactic acid, oxysuccinic acid, mandelic acid, styracin, citraconic acid, aspartic acid, stearic acid, palmitinic acid, methylene-succinic acid, oxyacetic acid, para-amino benzoic acid, L-glutamic acid, Phenylsulfonic acid and theophylline acetate, and 8-halogen theophylline, for example 8-bromine theophylline.The example of inorganic salt be with hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid and nitric acid formed those.
The acid salt of compound can be prepared according to methods known in the art.The acid of alkali and calculated amount is reacted in water miscible solvent, and acetone or alcohol for example by concentrating and refrigerated separation salt, perhaps reacts in water immiscible solvent with excessive acid subsequently, for example ether, ethyl acetate or methylene dichloride, and salt spontaneously separates.
Pharmaceutical composition of the present invention can be in any suitable manner, with any suitable form administration, for example with the form oral administration of tablet, capsule, powder agent or syrup, perhaps with the form administered parenterally of common aseptic injectable solution.
Pharmaceutical preparation of the present invention can be prepared according to the ordinary method of this area.For example, tablet can prepare like this, and is with activeconstituents and ordinary adjuvants and/or mixing diluents, in conventional tabletting machine that the mixture compacting is in blocks subsequently.The example of auxiliary agent or thinner comprises: W-Gum, yam starch, talcum, Magnesium Stearate, gelatin, lactose, natural gum etc.Can use any other auxiliary agent or additive, for example tinting material, spices, sanitas etc. are as long as they can be compatible with activeconstituents.
Injection solution can prepare like this, and activeconstituents and possible additive are dissolved in a part of injection solvent, and preferred sterilized water is adjusted solution to volume required, and with solution sterilization, can is in ampoule that is fit to or bottle.Can add this area any suitable additive commonly used, for example opening property agent, sanitas, antioxidant etc.
Embodiment
The following example is further set forth the present invention.
Embodiment 1
2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-1-hydroxyl-methyl]-benzyl ester
To (4-cyano group-2-hydroxymethyl phenyl) (4-fluorophenyl) methyl alcohol that is stirring (9.2g, 0.037mol) with triethylamine (4.0g, add in solution 0.04mol) pivalyl chloride (4.2g, 0.39mol).Stir after 60 minutes, reaction mixture be poured on ice, with diethyl ether extraction (2 * 75ml), dry (MgSO
4), concentrating under reduced pressure obtains colourless oil (12.0g).Compound is through chromatogram purification, and (eluent is hexane/ethyl acetate 1: 9) obtains title compound (8.2g, 70%).
1H?NMR(DMSO-D
6)：1.1(s，9H)，5.15(m，2H)，6(bs，1H)，6.25(d，J＝6Hz，1H)，7.1-7.2(m，2H)，7.3-7.4(m，2H)，7.7-7.9(m，3H).
Embodiment 2
2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-formyl radical]-benzyl ester
To stirring 2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-1-hydroxyl-methyl]-benzyl ester (8.0g, add in ethyl acetate 0.025mol) (20ml) solution 30%wt superoxol (10g, 0.079mol), Na
2WO
4.2H
2(0.15g is 0.0005mol) with (n-octyl) 3NCH for O
3.HSO
4(0.23g, 0.0005mol).Mixture heating 4 hours under refluxing then is cooled to room temperature, pour among rare HCl, with the diethyl ether extraction (2 * 50ml), dry (MgSO
4), concentrating under reduced pressure obtains title ketone compound (7.8g, 97.5%).
Embodiment 3
Acetate 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester and oxalate thereof
Method 3A. under 20 ℃, with diacetyl oxide (103g 1mol) is added drop-wise to 4-[4-dimethylamino-1-(4-fluoro-the phenyl)-1-hydroxyl-butyl that is stirring]-(72g is in acetonitrile 0.21mol) (438g) solution for 3-methylol-benzonitrile.In case add fully, (stirring is spent the night for 5.5g, 0.05mol) (cause thermopositive reaction, temperature rises to 28 ℃ from 20 ℃) to drip trimethylsilyl chloride.Then with dense H
2SO
4(14.5g 0.14mol) joins in the reaction mixture, and reaction mixture heats 30 minutes (the HPLC Indicator Reaction is complete) down at 50 ℃ then.After the cooling, the reaction mixture concentrating under reduced pressure is with ammonia soln (23%) neutralization, with toluene extraction (2 times).Organic phase drying (MgSO
4), concentrating under reduced pressure obtains title compound, is light orange oil (69.5g, 85%).
Be called oxalate.(1.g, methyl alcohol 0.0177mol) (50ml) solution join the title ene compound that is stirring, and (6.63g is in methyl alcohol 0.0173mol) (50ml) solution with warm oxalic acid.After the cooling, filtering separation crystal (7.4g) is with cold methanol (10ml) washing.M.p.168℃
1H?NMR(DMSO-D
6)：1.9(s，3H)，2.2(m，2H)，2.62(s，6H)，3.1(t，J＝6.2Hz，2H)，4.8(s，2H)，6.35(t，J＝7Hz，1H)7.1-7.25(m，4H)，7.42(d，J＝7Hz，1H)，7.9-8(m，2H).
13C；NMR(DMSO-D6)：20.35，24.98，42.16，55.54，62.51，111.17，115.25，115.59，118.51，124.85，128.0，128.18，131.32，132.43，132.73，135.65，135.99，138.68，142.9，164.72.169.96.
Calculate C
24H
25N
2O
6FC, 63.14; H, 5.53; N, 6.14. actual measurement, C, 63.1; H, 5.58; N, 6.12
Acetate 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester
Method 3B. is under 20 ℃, with diacetyl oxide (1112g, 10.8mol) be added drop-wise to 4-[4-dimethylamino-1-(4-fluoro-the phenyl)-1-hydroxyl-butyl that is stirring]-3-methylol-benzonitrile (1000g, 2.9mol) acetonitrile (1000g) solution in (cause thermopositive reaction, temperature rises to 50 ℃ from 20 ℃), stirred 2 hours.With dense H
2SO
4(300g 3mol) joins in the reaction mixture, and reaction mixture heats 3 hours (the HPLC Indicator Reaction is complete) down at 50 ℃ then.After the cooling, reaction mixture is with ammonia soln (25%) neutralization, with toluene extraction (2 times).Organic phase drying (MgSO
4), concentrating under reduced pressure obtains title compound, is light orange oil (1023g, 92%).
Embodiment 4
2,2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester and oxalate thereof
Method 4A. is under 20 ℃, with pivalyl chloride solution (26.0g, 0.215mol) join 4-[4-dimethylamino-1-(4-fluoro-the phenyl)-1-hydroxyl-butyl that is stirring]-(72g, 0.21mol) (25.0g is in acetonitrile 0.247mol) (438g) solution with triethylamine for 3-methylol-benzonitrile.After 60 minutes, drip dense H
2SO
4(40ml), reaction mixture heated 180 minutes down at 70 ℃.Reaction mixture is cooled to room temperature, with ammoniacal liquor (25%) neutralization, extracts with diethyl ether.Organic phase drying (MgSO
4), concentrating under reduced pressure obtains title compound, is xanchromatic oil (82g, 96%).
Be called oxalate.(acetone) M.p.188 ℃
1H NMR (DMSO-D
6): 1.07 (s, 9H), 2.2 (m, 2H), 2.6 (s, 6H), 3.05 (t, J=6.2Hz, 2H), 4.725 (d, J=12Hz, 1H), 4.85 (d, J=12Hz, 1H), 6.3 (t, J=6.3Hz, 1H) 7.1-7.3 (m, 4H), 7.42 (d, J=7Hz, 1H), 7.9-8 (m, 2H).
13C; NMR (DMSO-D
6): 25.1.26.71,42.3; 55.67,62.55,111.21,115.3,115.64,128.17,131.33,132.28,136.13,138.58,142.76,164.4
Calculate C
27H
31N
2O
6F:C, 65.04; H, 6.28; N, 5.62. actual measurement, C, 64.86; H, 6.63; N, 5.6
2,2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester and hydrogen chloride salt thereof
Method 4B. under 0 ℃, with pivalyl chloride solution (30.1g 0.25mol) joins 4-[4-dimethylamino-1-(4-fluoro-the phenyl)-1-hydroxyl-butyl that is stirring]-(85.5g is in acetonitrile 0.21mol) (290ml) solution for 3-methylol-benzonitrile.Reaction mixture stirred 60 minutes, added dense H then
2SO
4(32.5g, 0.33mol).In case add fully, be reflected at 70 ℃ and heated 180 minutes down.Reaction mixture is cooled to room temperature, under reduced pressure removes acetonitrile (220ml), uses ammoniacal liquor (23%) neutralization then, extracts with diethyl ether.Organic phase drying (MgSO
4), concentrating under reduced pressure obtains the pink oil (102.1g) of title compound.
(50.0g, methanol solution 0.11mol) join in the methanol solution (200ml) of the anhydrous HCl that is stirring with title ene compound II.After at room temperature stirring 30 minutes, under reduced pressure remove and desolvate, add diethyl ether, filter the gained white solid,, obtain HCl salt (48.1g) with the diethyl ether washing.Mp＝165℃
2,2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester, hydrosulfate
Method 4C. under 0 ℃, with pivalyl chloride solution (29g 0.24mol) joins 4-[4-dimethylamino-1-(4-fluoro-the phenyl)-1-hydroxyl-butyl that is stirring]-(85.5g is in acetonitrile 0.21mol) (290ml) solution for 3-methylol-benzonitrile.Reaction mixture stirred 60 minutes, added dense H then
2SO
4(32.5g, 0.33mol).In case add fully, be reflected at 70 ℃ and heated 180 minutes down.Reaction mixture is cooled to room temperature, under reduced pressure removes acetonitrile, adds toluene (200ml) and also under reduced pressure removes, and obtains title compound, is rose pink oil (112.4g).
2,2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester, hydrogen chloride salt
Method 4D. at room temperature, with pivalyl chloride (7.6g 0.63mol) is added drop-wise to 4-[4-dimethylamino 1-(4-fluoro-the phenyl)-1 hydroxyl-butyl that is stirring]-(21.35g is in acetonitrile 0.052mol) (21.35g) solution for 3-methylol-benzonitrile.In case add fully, add methylsulfonyl chloride (6.1g, CH 0.053mol)
2Cl
2(50ml) solution, add then triethylamine (10.6g, 0.105mol).Reaction mixture further stirred 30 minutes, poured in the water, used CH
2Cl
2Extraction, organic phase drying (MgSO
4), concentrating under reduced pressure.Oil with gained is dissolved in dehydrated alcohol/HCl then, and concentrating under reduced pressure is handled with diethyl ether, filters, and obtains the HCl salt (22.6g, 98%) of alkene.
Embodiment 5
2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-formyl radical]-benzyl ester
Method 5A. is to the alkene 2 that is stirring, 2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-HCl salt (165g, H 0.337mol) of benzyl ester
2So that remaining on 45-50 ℃ of a kind of like this speed, temperature of reaction adds NaMnO in O (1100ml) solution
4H
2O solution (40%vv) (3.7mol).In case add fully, reaction mixture is cooled to room temperature, filter.Solid filtering thing cold water washing (3 * 150ml), solid residue is stirred in acetone (2000ml), filter, evaporation obtains thick ketone, and (eluent is a hexane: ethyl acetate 8: 2) to filter purifying by the silicon-dioxide plug, obtain title ketone, be pure compound 82g (75%).MP＝81℃
1H?NMR(DMSO-D
6)：0.9(s，9H)，5.1(s，2H)，7.35-7.5(m，3H)，7.65(d，J＝7Hz1H)，7.8-7.9(m，2H)，8.0(m，1H)，8.1(s，1H)
13C；NMR(DMSO-D6)：26.5，63.01，113.183，116.0，116.36，118.02，129.35，132.19，132.58，133.03，133.18，133.34，135.98，141.7，163.62，167.65，176.87，193.94
Calculate C
20H
18NO
3F:C, 70.79; H, 5.35; N, 4.13. actual measurement, C, 70.49; H, 5.30; N, 4.07
2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-formyl radical]-benzyl ester
Method 5B. will contain the O of ozone
2The alkene 2 that feeding is being stirred, 2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester (38.0g, H 0.093mol)
2In O (1300ml) and dense HCl (70ml) solution, carry out HPLC after the reaction.Between the reaction period, the adularescent precipitation generates, and when reaction finishes white solid is filtered, and washes with water, and drying under reduced pressure obtains protected title ketone, is pure compound (22.5g, 72%).
2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-formyl radical]-benzyl ester
Method 5C. is to alkene 2,2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester, H
2SO
4(11.0g adds NaIO in water 0.022mol) (250ml) and ethyl acetate (100ml) suspension
4(30g, 0.14mol) and RuCl
3Hydrate (0.35).Suspension is vigorous stirring 16 hours at ambient temperature.The gained suspension filters by the silicon-dioxide plug.Separate organic phase, water (50ml) washing.Evaporating solvent obtains title compound in a vacuum, is a kind of oil, places post crystallization.Yield: 7.4g (99%).
Embodiment 6
2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-formyl radical]-benzyl ester
Will (19.2g, 0.11mol) (3.2g, 0.13mol) anhydrous THF (100ml) drips of solution of Zhi Bei 4-fluorophenyl magnesium bromide be added to 5-cyano group-2-benzo [c] furanone (15.9g is in anhydrous THF (150ml) suspension 0.1mol) with magnesium chips from the 4-bromofluorobenzene.Temperature remains on below 5 ℃.After adding fully, reaction mixture at room temperature stirs and spends the night.
(13.3g 0.11mol) joins in the reaction mixture, temperature is elevated to 60 ℃ reaches 2 hours with pivalyl chloride.Gained solution is joined NH
4Cl (100ml, aq) with ice (50g) saturated solution in.Add diethyl ether (100ml), separate each phase.Organic phase with 0.1N NaOH (2 * 100ml) and water (100ml) wash organic phase MgSO
4(20g) drying.Evaporating solvent obtains thick title compound (29.8g, 88%), is a kind of oil, is enough pure to further reaction.
Crystallization from EtOAc/ normal heptane (1: 9) obtains pure sample.The gained title compound is the yellow-white crystal.
Embodiment 7
1-(3-dimethylamino-propyl group)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-5-formonitrile HCN and oxalate thereof
Under 0 ℃; to 2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-formyl radical]-(28.5g adds 3-(N in anhydrous THF (150ml) solution 0.084mol) to benzyl ester; the N-dimethylamino) propyl group magnesium chloride solution (2.2 equivalent) carries out HPLC after the reaction.At 0 ℃ after following 1 hour, add saturated ammonium chloride, mixture ethyl acetate extraction, drying (Na
2SO
4), concentrating under reduced pressure obtains title compound, is a kind of oil.(28.0g, (purity 87%, HPLC)).Crystallization obtains oxalate from acetone.
Claims (10)
1, the method for preparing citalopram comprises making formula IV compound and 3-(N, N-dimethylamino) propyl group halogenation reactive magnesium, obtains citalopram,
Wherein R is an acyl group,
Separate and obtain alkali or its pharmacy acceptable salt.
2, the method for claim 1 is characterized in that, formula IV intermediate is the oxygenizement preparation by corresponding formula V compound,
Wherein R such as claim 1 definition.
3, the method for claim 2 is characterized in that, formula V compound is the provide protection preparation of the methylol alcohol of through type VI (4-cyano group-2-hydroxymethyl phenyl) (4-fluorophenyl) methyl alcohol.
4, the method for claim 1 is characterized in that, formula IV intermediate is the oxicracking preparation by corresponding formula VII compound,
Wherein R such as claim 1 definition.
5, the method for claim 4 is characterized in that, the oxicracking of formula VII compound is undertaken by oxygenizement, adopts MnO
4Or ozone, RuCl
3, OsO
4Carry out.
6, each method of claim 4-5 is characterized in that, formula VII intermediate alkene is that protection and the dehydration by corresponding formula III compound prepared,
Wherein the formula III compound is the R-enantiomer.
7, the method for claim 1, it is characterized in that formula IV intermediate is preparation like this: make the reaction of 5-cyano group-2-benzo [c] furanone and 4-fluorophenyl magnesium halide, then with the R-X reaction, with the ketone compound of preparation formula IV, wherein R is defined as claim 1, and X is a leavings group.
8. the method for claim 1 is characterized in that, formula IV compound and 3-(N, N-dimethylamino) propyl group magnesium chloride.
9. the method for claim 7 is characterized in that, formula IV compound is by making 5-cyano group-2-benzo [c] furanone and 4-fluorophenyl magnesium bromide prepared in reaction.
10. the method for one of claim 1-5 and 7-9, wherein R is valeryl, ethanoyl or optional substituted benzoyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB998148962A CN1133633C (en) | 1999-10-25 | 1999-10-25 | Method for preph. of citalopram |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB998148962A CN1133633C (en) | 1999-10-25 | 1999-10-25 | Method for preph. of citalopram |
| PCT/DK1999/000581 WO2000012044A2 (en) | 1999-10-25 | 1999-10-25 | Method for the preparation of citalopram |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03165033 Division CN1268621C (en) | 1999-10-25 | 1999-10-25 | Preparation of citalopram |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1331685A CN1331685A (en) | 2002-01-16 |
| CN1133633C true CN1133633C (en) | 2004-01-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998148962A Expired - Fee Related CN1133633C (en) | 1999-10-25 | 1999-10-25 | Method for preph. of citalopram |
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| CN (1) | CN1133633C (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101538257B (en) * | 2008-03-21 | 2012-10-17 | 浙江华海药业股份有限公司 | Method for preparing citalopram and S-citalopram |
| CN106928094A (en) * | 2017-02-10 | 2017-07-07 | 万全万特制药（厦门）有限公司 | The preparation method of escitalopram process contaminants |
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