CN105601536B - A kind of preparation method of vilazodone intermediate - Google Patents
A kind of preparation method of vilazodone intermediate Download PDFInfo
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- CN105601536B CN105601536B CN201410662345.3A CN201410662345A CN105601536B CN 105601536 B CN105601536 B CN 105601536B CN 201410662345 A CN201410662345 A CN 201410662345A CN 105601536 B CN105601536 B CN 105601536B
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- 229960003740 vilazodone Drugs 0.000 title claims abstract description 20
- SGEGOXDYSFKCPT-UHFFFAOYSA-N vilazodone Chemical compound C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 SGEGOXDYSFKCPT-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- -1 aldehyde compound Chemical class 0.000 claims abstract description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 229920005556 chlorobutyl Polymers 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 9
- 239000012044 organic layer Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 150000007857 hydrazones Chemical class 0.000 claims description 4
- 239000010410 layer Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- DZUUSHCOMPROCJ-UHFFFAOYSA-N 4-hydrazinylbenzonitrile Chemical compound NNC1=CC=C(C#N)C=C1 DZUUSHCOMPROCJ-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 15
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 229910052782 aluminium Inorganic materials 0.000 abstract description 6
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 3
- 238000005917 acylation reaction Methods 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- SMBXFXNRGQKPKS-UHFFFAOYSA-N 2-(4-chlorobutyl)-1h-indole-5-carbonitrile Chemical class N#CC1=CC=C2NC(CCCCCl)=CC2=C1 SMBXFXNRGQKPKS-UHFFFAOYSA-N 0.000 abstract 1
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 150000001263 acyl chlorides Chemical class 0.000 abstract 1
- 239000004411 aluminium Substances 0.000 abstract 1
- 150000001448 anilines Chemical class 0.000 abstract 1
- 150000004031 phenylhydrazines Chemical class 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- RPZBRGFNBNQSOP-UHFFFAOYSA-N vilazodone hydrochloride Chemical compound Cl.C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 RPZBRGFNBNQSOP-UHFFFAOYSA-N 0.000 description 8
- 229960003381 vilazodone hydrochloride Drugs 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 229940076279 serotonin Drugs 0.000 description 5
- YHYLDEVWYOFIJK-UHFFFAOYSA-N 1h-indole-5-carbonitrile Chemical compound N#CC1=CC=C2NC=CC2=C1 YHYLDEVWYOFIJK-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- OFFSPAZVIVZPHU-UHFFFAOYSA-N 1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1 OFFSPAZVIVZPHU-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 3
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- QHKJIJXBJCOABP-UHFFFAOYSA-N 1-benzofuran-2-carboxamide Chemical class C1=CC=C2OC(C(=O)N)=CC2=C1 QHKJIJXBJCOABP-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000000697 serotonin reuptake Effects 0.000 description 2
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 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 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical class NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical class ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- UXDLLFIRCVPPQP-UHFFFAOYSA-N 4-hydrazinylbenzonitrile;hydrochloride Chemical compound [Cl-].[NH3+]NC1=CC=C(C#N)C=C1 UXDLLFIRCVPPQP-UHFFFAOYSA-N 0.000 description 1
- VYOHEOKELADMTR-UHFFFAOYSA-N 5-bromo-1-benzofuran-2-carboxamide Chemical class BrC1=CC=C2OC(C(=O)N)=CC2=C1 VYOHEOKELADMTR-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000007527 Autoreceptors Human genes 0.000 description 1
- 108010071131 Autoreceptors Proteins 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Substances [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000011938 amidation process Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- DLIJPAHLBJIQHE-UHFFFAOYSA-N butylphosphane Chemical compound CCCCP DLIJPAHLBJIQHE-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- ANNUBWNRUPBBFN-UHFFFAOYSA-N cyclohexanone ethyl formate Chemical compound C(=O)OCC.C1(CCCCC1)=O ANNUBWNRUPBBFN-UHFFFAOYSA-N 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- RGOPGRSAYPXWIG-UHFFFAOYSA-N pyridin-2-ylmethanesulfonic acid Chemical compound [O-]S(=O)(=O)CC1=CC=CC=[NH+]1 RGOPGRSAYPXWIG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000000376 reactant Chemical class 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000011091 sodium acetates Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The present invention provides a kind of preparation method of vilazodone intermediate.This method is using own aldehyde compound as starting material; reacted with phenylhydrazine class or amino benzenes compounds; the cyclization under the catalysis of acid of resulting compound obtains 3 (4 chlorobutyl) 5 cyanoindoles; the method, which has been evaded, uses acyl chlorides acylation reaction under lewis acidic catalysis in document; it also avoid red aluminium reducing carbonyl in document obtains methylene simultaneously, the step of this is difficult to realize in workshop.The compound is the key intermediate of synthesis vilazodone.This method raw material is easy to get, reaction condition is gentle, simple to operate, process is easily controllable, with low cost and is easy to industrialized production.
Description
Technical field
The present invention relates to the preparation method of pharmaceutical intermediate, and in particular in a kind of anti-depression drug Vilazodone Hydrochloride
The preparation method of mesosome.
Background technology
Depression (Depression) is a kind of mode of onset of manic-depressive psychosis, with hypothymergasia, retardation of thinking and
Speech action reduce, it is slow be classical symptom.Depression seriously perplexs the live and work of patient, brings heavy to family and society
The burden of weight, about 15% patients with depression dies from suicide.One joint of the World Health Organization, the World Bank and Harvard University
Research shows that depression has become the second largest cause of disease of Chinese Disease Spectrum.
Vilazodone Hydrochloride, chemical entitled 5- [4- [4- (5- cyano-1 H-indol -3- bases) butyl] -1- piperazinyls] -2-
Benzofuran carboxamides hydrochloride, be developed jointly by Trovis Pharma LLC companies of the U.S. and Merck ＆ Co., Inc., for controlling
The new drug of severe adult's depression is treated, its chemical constitution is as follows.
Vilazodone Hydrochloride is first indolyl amine antidepressants, is suppressed with selective serotonin reuptake
Agent and 5-HT1A acceptor portion agonist double actions.Vilazodone passes through selective depression serotonin in central nervous system
Reuptake, enables serotonin activity increase：The 5-HT1A of presynaptic membrane is pointed to by Giving play to physical strength serotonin neuron
Inhibition adjustment effect, selective partial agonist 5-HT1A acceptors can prevent to produce 5- because of the increase of synaptic cleft serotonin
The activation of HT1A autoreceptors, so as to prevent the generation of negative-feedback, enables the increase of postsynaptic serotonin neurotransmission, strengthens medicine
The serotonin reuptake transporter effect of thing.Clinical testing data shows, Vilazodone Hydrochloride has that rapid-action, curative effect is excellent, tolerance
The characteristics of good, adverse reaction is small etc., therefore, after listing is paid close attention to by major pharmaceutical manufacturers always, wherein vilazodone and wherein
The synthesis of mesosome is the focus of its research.
The method that patent CN94116585.X discloses two kinds of Vilazodone Hydrochlorides.Method one is using 5- cyanoindoles as starting
Raw material, under isobutyl group aluminum chloride-catalyzed, carries out friedel-crafts acylation reaction with 4- chlorobutanoylchlorides, obtains 3- (4- chlorobutyryls) Yin
Diindyl -5- first cyanogen, then activated through isobutyl group aluminium chloride, then use sodium borohydride selective reduction ketone carbonyl for methylene, obtain
Intermediate 3- (4- chlorobutyls) indoles -5- formonitrile HCNs, the intermediate carries out being condensed instead with 5- (1- piperazinyls) coumarilic acid
Should, 5- (4- (4- (5- cyanoindole -3- bases) butyl) piperazine -1- bases) coumarilic acid is obtained, then in the chloro- 1- methyl of 2-
In the presence of pyridine methanesulfonic acid and ammonia, 2 carboxylic acids are converted into acid amides, vilazodone is obtained, is finally obtained with hydrochloric acid into salt
Target product.The friedel-crafts acylation reaction and reduction reaction of this method employ that lewis acid is different and butyl aluminium chloride is urges
Agent, the reagent is difficult to buy and prepared, and its unstable chemcial property, easily fires in atmosphere, need to be defeated using duct type
Send, high is required to consersion unit.In addition, this method also needs to carry out acylation reaction using pyridine compounds, industry is not suitable with
Metaplasia is produced.Method two is hydrogenated using 5- nitrobenzofuran -2- Ethyl formates as initiation material using Raney's nickel as catalyst
Reaction, obtains 5- aminobenzofur class compounds, then with double (2- chloroethyls) amine cyclizations, generation 5- piperazine benzofurans -2-
Ethyl formate, adds di-tert-butyl dicarbonate and carries out amido protecting, obtain 5- [4- (tertbutyloxycarbonyl)] piperazine benzofuran -2-
Ethyl formate, adds formamide and sodium alkoxide carries out amidation process, sloughs protection group, obtains 5- piperazine benzofuran-2-carboxamides formamides
Afterwards, reacted with 3- (4- chlorobutyls) indoles -5- formonitrile HCNs, obtain vilazodone, finally into salt, obtain target product.This method is anti-
Answer step many, yield is low, synthesis cost is high.
Document Bioorganic＆Medicinal Chemistry Letters, 2004,14 (10)：2681-2684 is reported
Method using 2- hydroxy-4-aminobenzoic acids as initiation material, with 2- cyclohexanone Ethyl formate react, then by glacial acetic acid catalysis
Rearrangement, hydrolysis of ester group, decarboxylation, esterification, reduction, amidatioon, sulfonylation and piptonychia sulfonyl etc. react, and obtain vilazodone,
Finally into salt, target product is obtained.This method reaction scheme is long, and total recovery is low, is unfavorable for industrialized production.
Patent CN200680013816 is closed using 5- bromobenzofuran -2- formamides as raw material in three (dibenzalacetones)
Coupling reaction is directly carried out with 3- [4- (1- piperazinyls) butyl] -5- cyanoindoles under the catalysis of two palladiums and tri-butyl phosphine, is obtained
To vilazodone, then into salt, target product is obtained.Palladium class and butyl phosphine catalyst used in this method is expensive.
Document Journal ofMedicinal Chemistry, 2004,47 (19)：The method of 4684-4692 reports is with 5-
Cyanoindole is raw material, isobutyl aluminium dichloride catalysis under carry out Friedel Crafts actlation, obtain 3- (4- chlorobutyryls) indoles-
5- first cyanogen, then through red aluminum [two (methoxy ethoxy) aluminum dihydrides] selective reduction carbonyl, obtain 3- (4- chlorobutyls) indoles-
5- formonitrile HCNs, then react with 5- piperazine benzofuran -2- Ethyl formates, and products therefrom obtains 5- (4- (4- (5- cyano group through hydrolysis
Indol-3-yl) butyl) piperazine -1- bases) coumarilic acid, then in the chloro- 1- picolines methanesulfonic acids of 2- and ammonia
Under effect, 2 carboxylic acids are converted into acid amides, vilazodone is obtained, finally target product are obtained into salt with hydrochloric acid.Fu of the route-
In gram acylation reaction step, it is catalyst equally to have used seldom used lewis acid isobutyl group aluminium chloride, in reduction reaction step
In, using red aluminum alternatively property reducing agent, but the weighing and charging of red aluminum be not easy to operate in workshop, yield is low, and only 27%,
And need to be purified by column chromatography, it is not suitable for industrialization production.
The content of the invention
In order to overcome the shortcomings of in above-mentioned synthetic method, it is easy to get the invention provides a kind of raw material, reaction condition is gentle, behaviour
Work is simple, process is easily controllable, with low cost and is easy to the preparation method of the vilazodone hydrochloride intermediate of industrialized production.Adopt
Vilazodone is synthesized with such intermediate, with low excellent of product purity and high income, mild condition, with short production cycle, cost
Point.
The preparation method of the vilazodone hydrochloride intermediate, be specially：
Compound shown in structural formula I is in the presence of alkali, with the compound and its reactant salt shown in formula II, life
Into the compound and its salt shown in formula II I or structural formula IV：
Wherein, R1For-Cl or-Br, R2Selected from-COOH ,-COOR ' ,-CONH2Or-CN, R3For-NH2Or-NH-NH2, R ' choosings
From-CH3、-CH2-CH3, substituted or unsubstituted phenyl ring.
In preparation method of the present invention, described alkali is organic base or inorganic base, such as sodium hydroxide, potassium hydroxide, hydrogen-oxygen
Change lithium, tetrabutylammonium, triethylamine, diethylamine, pyridine, piperidines etc..
In preparation method of the present invention, reaction dissolvent used be selected from dichloromethane, chloroform, methanol, ethanol, isopropanol,
Ethyl acetate, methyl acetate, tetrahydrofuran, dioxane, DMF, DMA or dimethyl
Sulfoxide.
A kind of intermediate for synthetic hydrochloric acid vilazodone, the i.e. compound as shown in formula II I.
A kind of intermediate for synthetic hydrochloric acid vilazodone, the i.e. compound as shown in structural formula IV.
Formula II I or structural formula IV carries out cyclization reaction under the catalysis of acid, obtains the 3- (4- as shown in structural formula V
Chlorobutyl) -5- cyanoindoles：
The acid of described catalytic action is selected from 20-37% hydrochloric acid, 20-100% sulfuric acid, phosphoric acid, polyphosphoric acids, trifluoro
Acetic acid, methanesulfonic acid or p-methyl benzenesulfonic acid, reaction solvent for use are selected from dichloromethane, chloroform, acetonitrile, methanol, ethanol, isopropyl
Alcohol, ethyl acetate, methyl acetate, tetrahydrofuran, dioxane, DMF, DMA or two
Methyl sulfoxide
3- (4- chlorobutyls) -5- cyanoindoles occur as follows with 5- (piperazine -1- bases) benzofuran-2-carboxamides
Reaction, generates vilazodone, it is sub- that reaction solvent for use is selected from DMF, DMA, dimethyl
Sulfone or acetonitrile：
Vilazodone and hydrochloric acid salt-forming reaction, obtain Vilazodone Hydrochloride.
Each step reaction of the present invention is carried out under normal conditions, and pressure is normal pressure, and reaction temperature is -8 DEG C -120 DEG C,
Reaction condition is gentle, it is easy to operation and control.
Synthetic method of the present invention, synthetic route is short, and reaction condition is gentle, and agents useful for same is conventional reagent, after
Processing is simple, and high income, cost is low, it is easy to industrialized production.
Embodiment
Embodiment 1
The synthesis of 6- chlorine hexanal -4- cyano group phenylhydrazones
4- cyanophenylhydrazine hydrochloride 21.40g (0.126mol) are taken to be added in 250mL there-necked flasks, in dry N2Under protection, plus
Enter 140mL methanol, 13.40g Et3N (0.133mol) stirs into solution, and 6- chlorine hexanals are added dropwise in 0~5 DEG C in ice bath cooling
(23.30g, 0.174mol), completion of dropping, in stirring at this temperature, 15 minutes or so, TLC show reaction finish (petroleum ether:
Ethyl acetate=1: 1), reaction is stopped.Reaction solution is poured into frozen water, keeping temperature -10~0 DEG C stirring separates out solid, mistake
Filter, vacuum drying obtains hydrazone 26.6g, yield 84%.The hydrazone of gained is the mixture of double strong cis and trans isomers, the ratio of the two
For 1: 4, wherein cis-structure appraising datum is as follows：
1H-NMR、(400MHz CDCl3Ppm) 7.48 (d, J=8.6Hz 2H), 7.13 (t, J=5.1Hz, 1H), 6.99
(d, J=8.6Hz2H), 3.57 (t J=6.6Hz 2H), 2.35 (q, J=6.6Hz 2H), 1.86-1.76 (m 2H), 1.62-
1.39 (m, 4H)；
Transconfiguration appraising datum is as follows：
1H-NMR(400MHz CDCl3Ppm) 7.50 (d, J=8.6Hz 2H), 7.06 (d, J=8.6Hz 2H), 6.59 (t,
J=5.1Hz, 1H), 3.65 (t J=6.6Hz 2H), 2.24 (q, J=6.6Hz 2H), 1.86-1.76 (m 2H), 1.62-
1.39 (m, 4H).
Embodiment 2
The synthesis of 3- (4- chlorobutyls) -5- cyanoindoles
10.00g hydrazones (40mmol) are placed in 500mL flasks, 150mL acetonitriles, polyphosphoric acids 14.80g is added
(44mmol), is heated to acetonitrile backflow.React after about hour, HPLC shows that reaction terminates (acetonitrile: water=80: 20).
Reaction solution is cooled down to room temperature, decompression boils off acetonitrile, and add water (200mL) ethyl acetate (200mL) dissolution residual substance, separates water layer,
Aqueous layer with ethyl acetate extracts (3 × 150mL), merges organic layer, and organic layer is washed with water (2 × 200mL), and the sodium chloride of saturation is molten
Liquid is washed (200mL), and organic layer adds anhydrous sodium sulfate drying, filtering, and concentration filtrate obtains yellow solid.1: 1 (V/ is added to product
W methanol) is heated to reflux dissolving, is cooled to room temperature and separates out solid, filtering vacuum obtains 5.59g benzazolyl compounds, yield after drying
60%.The fusing point of 3- (4- chlorobutyls) -5- cyanoindoles is 99.0-99.5 DEG C, and its Structural Identification data is as follows：
1H-NMR(DMSO-d6Ppm) δ 11.33 (br s, 1H), 8.06 (s, 1H), 7.50 (d, 1H, J=8.4Hz), 7.38
(dd, 1H, J=1.5Hz and J=8.4Hz), 7.32 (d, 1H, J=2.1Hz), 3.67 (m, 2H), 2.75 (m, 2H), 1.78
(m, 4H).
Embodiment 3
The synthesis of vilazodone
3- (4- chlorobutyls) -5- cyanoindoles 36.10g (155mmol), 5- (piperazine -1- bases) are added in 1L single port bottles
Benzofuran-2-carboxamides 36.00g (147mmol), 25.50g sodium acetates (310mmol), is dissolved in 500mLDMAC under stirring,
Reacted 18 hours in 90 DEG C (outer temperature), reaction solution is cooled to room temperature, add 1L water, ethyl acetate extraction (3 × 400mL) merges
Organic layer, organic layer is washed with water (2 × 300mL), and saturated nacl aqueous solution is washed (200mL), anhydrous sodium sulfate drying, is filtered, filter
Liquid is concentrated to give yellow solid.Purified, solid is dissolved in THF using mixed solvent first, stirring is lower to add acetone, methanol, stirs
Precipitation solid is mixed, is filtered, is weighed after vacuum drying, obtain vilazodone.
Embodiment 4
The synthesis of vilazodone hydrochloride
8.0g (18mmol) is added into 40mL THF, is heated to reflux to being completely dissolved, is added acetone and be cooled to 55 DEG C, slowly
It is 7-8 that concentrated hydrochloric acid 2mL, pH, which is added dropwise, and it is about 1 to add 2.2mL pH, and stirring 30min filterings, solid is washed with a small amount of THF, vacuum
9.2g off-white powders, yield 99% are obtained after drying.
Claims (1)
1. a kind of preparation method of vilazodone intermediate 3- (4- chlorobutyls) -5- cyanoindoles, it is characterised in that step is as follows：
Prepare 6- chlorine hexanal -4- cyano group phenylhydrazones：4- cyanophenylhydrazine hydrochlorides 21.40g is taken to be added in 250mL there-necked flasks, in dry N2
Under protection, 140mL methanol, 13.40g Et are added3N stirs into solution, and 6- chlorine hexanals are added dropwise in 0~5 DEG C in ice bath cooling
23.30g, completion of dropping, in stirring 15 minutes or so at this temperature, TLC shows that reaction is finished, and stops reaction.Reaction solution is inclined
Enter in frozen water, keeping temperature -10~0 DEG C stirring separates out solid, and filtering, vacuum drying obtains hydrazone 26.6g, and yield 84% is obtained
The 6- chlorine hexanal -4- cyano group phenylhydrazones of the mixture of double strong cis and trans isomers, the ratio of the two is 1: 4；
Prepare 3- (4- chlorobutyls) -5- cyanoindoles：10.00g 6- chlorine hexanal -4- cyano group phenylhydrazones are placed in 500mL flasks,
150mL acetonitriles, polyphosphoric acids 14.80g are added, acetonitrile backflow is heated to；React after about hour, HPLC display reaction knots
Beam, cooling reaction solution to room temperature, decompression boils off acetonitrile, plus 200mL water and 200mL ethyl acetate dissolution residual substances, separates water layer,
Water layer is extracted with 3 × 150mL ethyl acetate, merges organic layer, and organic layer is washed with 2 × 200mL, and 200mL saturated sodium-chlorides are molten
Liquid is washed, and organic layer adds anhydrous sodium sulfate drying, filtering, and concentration filtrate obtains yellow solid；The methanol of 1: 1 volume is added to product
Dissolving is heated to reflux, room temperature is cooled to and separates out solid, filtering vacuum obtains 5.59g benzazolyl compounds after drying.
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| Title |
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| Alternative Approach to Synthesis of 3-(4-Chloro butyl)-1H-indole-5-carbonitrile: A Key Intermediate of Vilazodone Hydrochloride, an Antidepressant Drug;N. Anitha B et al.;《Synthetic Communications》;20141015;第44卷;第3563-3571页 * |
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