CN105601536A - Vilazodone intermediate preparation method - Google Patents
Vilazodone intermediate preparation method Download PDFInfo
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- CN105601536A CN105601536A CN201410662345.3A CN201410662345A CN105601536A CN 105601536 A CN105601536 A CN 105601536A CN 201410662345 A CN201410662345 A CN 201410662345A CN 105601536 A CN105601536 A CN 105601536A
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- Prior art keywords
- vilazodone
- acid
- compound
- formula
- structural formula
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Links
- 229960003740 vilazodone Drugs 0.000 title claims abstract description 19
- 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 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- NJJWMEJWFYRORL-UHFFFAOYSA-N 3-(4-chlorobutyl)-1h-indole-5-carbonitrile Chemical compound C1=C(C#N)C=C2C(CCCCCl)=CNC2=C1 NJJWMEJWFYRORL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 5
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 229960003381 vilazodone hydrochloride Drugs 0.000 claims description 14
- 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 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- QHKJIJXBJCOABP-UHFFFAOYSA-N 1-benzofuran-2-carboxamide Chemical class C1=CC=C2OC(C(=O)N)=CC2=C1 QHKJIJXBJCOABP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 229920005556 chlorobutyl Polymers 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims 1
- -1 caproaldehyde compound Chemical class 0.000 abstract description 10
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 abstract description 8
- 229910052782 aluminium Inorganic materials 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000005917 acylation reaction Methods 0.000 abstract description 4
- 230000009467 reduction Effects 0.000 abstract description 4
- 239000002841 Lewis acid Substances 0.000 abstract description 3
- JARKCYVAAOWBJS-UHFFFAOYSA-N caproic aldehyde Natural products CCCCCC=O JARKCYVAAOWBJS-UHFFFAOYSA-N 0.000 abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 2
- 150000007517 lewis acids Chemical class 0.000 abstract description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 abstract 1
- 229940067157 phenylhydrazine Drugs 0.000 abstract 1
- 238000004886 process control Methods 0.000 abstract 1
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000004411 aluminium Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 229940076279 serotonin Drugs 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 4
- 230000002194 synthesizing effect Effects 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
- 238000005660 chlorination reaction Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 150000007857 hydrazones Chemical class 0.000 description 3
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 3
- 230000000977 initiatory effect Effects 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
- 239000000463 material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 2
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- MJSICWJVLIZECN-UHFFFAOYSA-N C(=O)OCC.O1C=CC2=C1C=CC=C2 Chemical compound C(=O)OCC.O1C=CC2=C1C=CC=C2 MJSICWJVLIZECN-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000243 solution Substances 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
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- YHYLDEVWYOFIJK-UHFFFAOYSA-N 1h-indole-5-carbonitrile Chemical compound N#CC1=CC=C2NC=CC2=C1 YHYLDEVWYOFIJK-UHFFFAOYSA-N 0.000 description 1
- 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
- VKPPFDPXZWFDFA-UHFFFAOYSA-N 2-chloroethanamine Chemical compound NCCCl VKPPFDPXZWFDFA-UHFFFAOYSA-N 0.000 description 1
- YWBYYVAHAWQUDF-UHFFFAOYSA-N 3-(4-piperazin-1-ylbutyl)-1h-indole-5-carbonitrile Chemical compound C12=CC(C#N)=CC=C2NC=C1CCCCN1CCNCC1 YWBYYVAHAWQUDF-UHFFFAOYSA-N 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-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
- 102000007527 Autoreceptors Human genes 0.000 description 1
- 108010071131 Autoreceptors Proteins 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 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
- 238000005863 Friedel-Crafts acylation reaction Methods 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 compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium chloride Substances Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- ONVOIOVJDDVCPQ-UHFFFAOYSA-N aniline 1-benzofuran Chemical compound C1(=CC=CC=C1)N.O1C=CC2=C1C=CC=C2 ONVOIOVJDDVCPQ-UHFFFAOYSA-N 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- DLIJPAHLBJIQHE-UHFFFAOYSA-N butylphosphane Chemical class CCCCP DLIJPAHLBJIQHE-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexyloxide Natural products O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 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
- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 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
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 description 1
- 229920001084 poly(chloroprene) Polymers 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000010025 steaming 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
- 150000003462 sulfoxides Chemical class 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
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 238000003809 water extraction Methods 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 vilazodone intermediate preparation method. According to the method, a caproaldehyde compound is adopted as a starting material, and reacts with a phenylhydrazine or aniline compound, and the obtained compound is subjected to ring closure under catalysis of an acid to obtain 3-(4-chlorobutyl)-5-cyano indole. According to the present invention, the application of the acylation reaction catalyzed through the Lewis acid in the literature is avoided, and the step of the methylene obtaining through carbonyl reduction with red aluminum in the literature is avoided and is not easily achieved in the workshop; and the compound is the key vilazodone synthesis intermediate, and the method has characteristics of easily available raw materials, mild reaction condition, simple operation, easy process control, low cost, and easy industrial production.
Description
Technical field
The present invention relates to the preparation method of pharmaceutical intermediate, be specifically related to a kind of anti-depression drug Vilazodone Hydrochloride intermediatePreparation method.
Background technology
Depression (Depression) is a kind of mode of onset of manic-depressive psychosis, with hypothymergasia, retardation of thinking and speechAction reduce, slow be classical symptom. Depression seriously perplexs patient's live and work, brings heavy to family and societyBurden, approximately 15% patients with depression is died from suicide. A joint study of the World Health Organization, the World Bank and Harvard UniversityShow, depression has become the second largest cause of disease of Chinese disease burden.
Vilazodone Hydrochloride, chemistry 5-[4-[4-(5-cyano-1 H-indol--3-yl) butyl by name]-1-piperazinyl]-2-benzofuran formylAmine hydrochlorate, develops, is used for the treatment of adult's severe depression jointly by TrovisPharmaLLC company of the U.S. and Merck & Co., Inc.The new drug of disease, its chemical constitution is as follows.
Vilazodone Hydrochloride is first indolyl amine antidepressants, have selective serotonin reuptake inhibitor and5-HT1A acceptor portion agonist double action. Vilazodone is taken the photograph by selective inhibition serotonin in central nervous system againGet, serotonin can actively be increased: be subject to the neuronic inhibition of Giving play to physical strength serotonin to being positioned at the 5-HT1A of presynaptic membraneProperty regulating action, the selective exciting 5-HT1A acceptor of part, can stop because synaptic cleft serotonin increases and produce 5-HT1AThe activation of autoreceptor, thus degenerative generation stoped, postsynaptic serotonin energy neurotransmission is increased, enhancing medicineSerotonin reuptake transporter effect. Clinical testing data shows, that Vilazodone Hydrochloride has is rapid-action, curative effect is excellent, better tolerance,The feature of the little grade of bad reaction, therefore, the concern of Shou Ge great pharmaceutical manufacturer always, wherein vilazodone and intermediate thereof after listingSynthetic be the focus of its research.
Patent CN94116585.X discloses the method for two kinds of Vilazodone Hydrochlorides. Method one is taking 5-cyanoindole as initiation material,Under the catalysis of isobutyl group chlorination aluminium, carry out friedel-crafts acylation reaction with 4-chlorobutanoylchloride, obtain 3-(4-chlorobutyryl) indoles-5-first cyanogen,Through the activation of isobutyl group chlorination aluminium, then adopting sodium borohydride selective reduction ketone carbonyl is methylene, obtains intermediate 3-(4-chlorine againButyl) indoles-5-formonitrile HCN, this intermediate and 5-(1-piperazinyl) coumarilic acid carries out condensation reaction, obtains 5-(4-(4-(5-cyanogenBase indol-3-yl) butyl) piperazine-1-yl) coumarilic acid, then in the effect of 2-chloro-1-picoline methanesulfonic acid and ammoniaUnder, 2 carboxylic acids are converted into acid amides, obtain vilazodone, last and hydrochloric acid salify obtains target product. Fu-Ke acyl of the methodIt is catalyst that glycosylation reaction and reduction reaction have all adopted the different and butyl aluminium chloride of lewis acid, and this reagent is difficult to buy and preparation,And its unstable chemcial property, very easily combustion in air, needs to adopt duct type to carry, and requires high to consersion unit. In addition,The method also needs to adopt pyridine compounds to carry out acylation reaction, is not suitable with industrialization and produces. Method two is with 5-nitro benzo furanMutter-2-Ethyl formate is initiation material, carries out hydrogenation using Raney's nickel as catalyst, obtains 5-aminobenzene benzofuran chemical combinationThing, then with two (2-chloroethyl) amine cyclization, generate 5-piperazine benzofuran-2-Ethyl formate, add di-tert-butyl dicarbonate to carry outAmido protecting, obtains 5-[4-(tertbutyloxycarbonyl)] piperazine benzofuran-2-Ethyl formate, add formamide and sodium alkoxide to carry out acid amidesChange reaction, slough protecting group, obtain after 5-piperazine benzofuran-2-formamide, react with 3-(4-chlorobutyl) indoles-5-formonitrile HCN,To vilazodone, last salify, obtains target product. The method reactions steps is many, and yield is low, and synthetic cost is high.
Document Bioorganic&MedicinalChemistryLetters, 2004,14 (10): the method for 2681-2684 report with2-hydroxy-4-aminobenzoic acid is initiation material, reacts, then pass through glacial acetic acid catalytically rearranging, ester group with 2-cyclohexanone Ethyl formateThe reactions such as hydrolysis, decarboxylation, esterification, reduction, amidatioon, sulfonylation and piptonychia sulfonyl, obtain vilazodone, finally becomeSalt, obtains target product. The method reaction scheme is long, and total recovery is low, is unfavorable for suitability for industrialized production.
Patent CN200680013816 is taking 5-bromine benzofuran-2-formamide as raw material, three (dibenzalacetones) close two palladiums andUnder the catalysis of tri-butyl phosphine with 3-[4-(1-piperazinyl) butyl]-5-cyanoindole directly carries out coupling reaction, obtains vilazodone,Salify again, obtains target product. Palladium class and butyl phosphine class catalyst that the method is used are expensive.
Document JournalofMedicinalChemistry, 2004,47 (19): the method for 4684-4692 report is with 5-cyano group YinDiindyl is raw material, carries out Fu-Ke acylation reaction under the catalysis of isobutyl group al dichloride, obtains 3-(4-chlorobutyryl) indoles-5-first cyanogen, thenThrough red aluminium [two (methoxy ethoxy) aluminum dihydride] selective reduction carbonyl, obtain 3-(4-chlorobutyl) indoles-5-formonitrile HCN, thenReact with 5-piperazine benzofuran-2-Ethyl formate, products therefrom obtains 5-(4-(4-(5-cyanoindole-3-yl) butyl) piperazine through hydrolysisPiperazine-1-yl) coumarilic acid, then under the effect of 2-chloro-1-picoline methanesulfonic acid and ammonia, 2 carboxylic acids are transformedFor acid amides, obtain vilazodone, last and hydrochloric acid salify obtains target product. In Fu-Ke acylation reaction step of this route, sameHaving used seldom used lewis acid isobutyl group chlorination aluminium is catalyst, in reduction reaction step, adopts red aluminium as also selectiveFormer dose, but the weighing of red aluminium and feed in raw material not easy to operately in workshop, yield is low, is only 27%, and needs by column chromatography purification, noBeing applicable to industrialization produces.
Summary of the invention
In order to overcome the deficiency in above-mentioned synthetic method, the invention provides that a kind of raw material is easy to get, reaction condition gentleness, operation letterSingle, process is easy to control, with low cost and be easy to the preparation method of the Vilazodone Hydrochloride intermediate of suitability for industrialized production. Adopting shouldClass intermediate synthesizes vilazodone, has advantages of that product purity and yield are high, mild condition, with short production cycle, cost is low.
The preparation method of described Vilazodone Hydrochloride intermediate, is specially:
Compound shown in structural formula I is in the situation that alkali exists, with the compound shown in formula II and reactant salt thereof, generating structureCompound and salt thereof shown in formula III or structural formula IV:
Wherein, R1For-Cl or-Br, R2Be selected from-COOH ,-COOR ' ,-CONH2Or-CN, R3For-NH2Or-NH-NH2，Be selected from-CH of R '3、-CH2-CH3, have replace or without replace phenyl ring.
In preparation method of the present invention, described alkali is organic base or inorganic base, for example NaOH, potassium hydroxide, lithium hydroxide,Tetrabutylammonium, triethylamine, diethylamine, pyridine, piperidines etc.
In preparation method of the present invention, reaction dissolvent used is selected from carrene, chloroform, methyl alcohol, ethanol, isopropyl alcohol, secondAcetoacetic ester, methyl acetate, oxolane, dioxane, DMF, DMA or dimethylSulfoxide.
For the synthesis of an intermediate for Vilazodone Hydrochloride, i.e. compound as shown in formula II I.
For the synthesis of an intermediate for Vilazodone Hydrochloride, i.e. compound as shown in structural formula IV.
Formula II I or structural formula IV carry out cyclization reaction under sour catalysis, obtain 3-(the 4-neoprene as shown in structural formula VBase)-5-cyanoindole:
The acid of described catalytic action be selected from hydrochloric acid, the 20-100% of 20-37% sulfuric acid, phosphoric acid, polyphosphoric acids, trifluoracetic acid,Methanesulfonic acid or p-methyl benzenesulfonic acid, reaction solvent for use be selected from carrene, chloroform, acetonitrile, methyl alcohol, ethanol, isopropyl alcohol,Ethyl acetate, methyl acetate, oxolane, dioxane, DMF, DMA or diformazanBase sulfoxide
There is as follows reacting with 5-(piperazine-1-yl) benzofuran-2-carboxamides in 3-(4-chlorobutyl)-5-cyanoindole, generates dimensionDraw assistant ketone, reaction solvent for use is selected from DMF, DMA, dimethyl sulfoxide (DMSO) or acetonitrile:
Vilazodone and hydrochloric acid salt-forming reaction, obtain Vilazodone Hydrochloride.
Each step reaction of the present invention is all carried out under normal condition, and pressure is normal pressure, and reaction temperature is-8 DEG C-120 DEG C, reactionMild condition, easy operating and control.
Synthetic method of the present invention, synthetic route is short, reaction condition gentleness, agents useful for same is conventional reagent, post processingSimply, yield is high, and cost is low, is easy to suitability for industrialized production.
Detailed description of the invention
Embodiment 1
Synthesizing of 6-chlorine hexanal-4-cyano group phenylhydrazone
Get 4-cyano group hydrazinobenzene hydrochloride salt 21.40g (0.126mol) and be added in 250mL there-necked flask, in dry N2Under protection, add140mL methyl alcohol, 13.40gEt3N (0.133mol) stirs into solution, and ice bath is cooling, in 0～5 DEG C drip 6-chlorine hexanal (23.30g,0.174mol), dropwise, at this temperature, stir, about 15 minutes, TLC shows the complete (benzinum: ethyl acetate of reaction=1: 1), stop reaction. By in reactant liquor impouring frozen water, keep temperature-10～0 DEG C stirring, separate out solid, filter vacuum dryingObtain hydrazone 26.6g, yield 84%. The hydrazone of gained is two mixtures suitable, trans isomer of being good for, and the ratio of the two is 1: 4, itsMiddle cis-structure appraising datum is as follows:
1H-NMR、(400MHzCDCl3ppm)7.48(d，J＝8.6Hz2H)，7.13(t，J＝5.1Hz，1H)，6.99(d，J＝8.6Hz2H)，3.57(tJ＝6.6Hz2H)，2.35(q，J＝6.6Hz2H)，1.86-1.76(m2H)，1.62-1.39(m，4H)；
Transconfiguration appraising datum is as follows:
1H-NMR(400MHzCDCl3ppm)7.50(d，J＝8.6Hz2H)，7.06(d，J＝8.6Hz2H)，6.59(t，J＝5.1Hz，1H)，3.65(tJ＝6.6Hz2H)，2.24(q，J＝6.6Hz2H)，1.86-1.76(m2H)，1.62-1.39(m，4H)。
Embodiment 2
Synthesizing of 3-(4-chlorobutyl)-5-cyanoindole
10.00g hydrazone (40mmol) is placed in to 500mL flask, adds 150mL acetonitrile, polyphosphoric acids 14.80g (44mmol),Being heated to acetonitrile refluxes. React after about one hour, HPLC shows that reaction finishes (acetonitrile: water=80: 20). Cooling reactant liquorTo room temperature, pressure reducing and steaming acetonitrile, (200mL) ethyl acetate (200mL) dissolution residual substance that adds water, point water-yielding stratum, water layer acetic acidEthyl ester extraction (3 × 150mL), merges organic layer, and organic layer washes (2 × 200mL) with water, and saturated sodium chloride solution is washed(200mL), organic layer adds anhydrous sodium sulfate drying, filters, and concentrated filtrate obtains yellow solid. Add 1: 1 (V/W) to productMethyl alcohol adds hot reflux and dissolves, and is cooled to room temperature and separates out solid, after filtration vacuum drying, obtains 5.59g benzazolyl compounds, yield 60%.The fusing point of 3-(4-chlorobutyl)-5-cyanoindole is 99.0-99.5 DEG C, and its Structural Identification data are as follows:
1H-NMR(DMSO-d6ppm)δ11.33(brs，1H)，8.06(s，1H)，7.50(d，1H，J＝8.4Hz)，7.38(dd，1H，J＝1.5HzandJ＝8.4Hz)，7.32(d，1H，J＝2.1Hz)，3.67(m，2H)，2.75(m，2H)，1.78(m，4H)。
Embodiment 3
Synthesizing of vilazodone
In 1L single port bottle, add 3-(4-chlorobutyl)-5-cyanoindole 36.10g (155mmol), 5-(piperazine-1-yl) benzofuran-2-Formamide 36.00g (147mmol), 25.50g sodium acetate (310mmol), is dissolved in 500mLDMAC under stirring, in 90 DEG C(temperature outward) reaction 18 hours, reactant liquor is cooled to room temperature, adds 1L water, and ethyl acetate extraction (3 × 400mL), merges organicLayer, organic layer washes (2 × 300mL) with water, and saturated nacl aqueous solution is washed (200mL), and anhydrous sodium sulfate drying filters filtrateThe concentrated yellow solid that obtains. Adopt mixed solvent purifying, first solid is dissolved in THF, under stirring, add acetone, methyl alcohol, stirMix and separate out solid, filter, after vacuum drying, weigh, obtain vilazodone.
Embodiment 4
Synthesizing of vilazodone hydrochloride
8.0g (18mmol) is added to 40mLTHF, and heating is back to completely dissolves, and adds acetone to be cooled to 55 DEG C, slowlyDrip concentrated hydrochloric acid 2mL, pH is 7-8, adds 2.2mLpH and is about 1, stirs 30min and filters, and solid is washed with a small amount of THFWash, after vacuum drying, obtain 9.2g off-white powder, yield 99%.
Claims (10)
1. a preparation method for Vilazodone Hydrochloride intermediate, is characterized in that:
Compound shown in structural formula I in the situation that alkali exists, with the compound shown in formula II and reactant salt thereof, compound and the salt thereof shown in generating structure formula III or structural formula IV:
Wherein, R1For-Cl or-Br, R2Be selected from-COOH ,-COOR ' ,-CONH2Or-CN, R3For-NH2Or-NH-NH2, be selected from-CH of R '3、-CH2-CH3, have replace or without replace phenyl ring.
2. the method for claim 1, R1For Cl, R2For-NC, R3For-NH-NH2。
3. method as claimed in claim 1 or 2, is characterized in that described alkali is organic base or inorganic base, is selected from NaOH, potassium hydroxide, lithium hydroxide, tetrabutylammonium, triethylamine, diethylamine, pyridine or piperidines.
4. method as claimed in claim 3, is characterized in that, reaction dissolvent used is selected from carrene, chloroform, methyl alcohol, ethanol, isopropyl alcohol, ethyl acetate, methyl acetate, oxolane, dioxane, dimethyl formamide or dimethyl sulfoxide (DMSO).
5. for the synthesis of the intermediate of Vilazodone Hydrochloride, i.e. compound as shown in formula II I.
6. for the synthesis of the intermediate of vilazodone, i.e. 6-chlorine hexanal-4-cyano group phenylhydrazone.
7. a preparation method for Vilazodone Hydrochloride, is characterized in that, comprises the following steps:
(1) compound shown in structural formula I reacts compound and the salt thereof shown in generating structure formula III or structural formula IV in the situation that alkali exists with the compound shown in formula II and salt thereof:
(2) formula II I or structural formula IV carry out cyclization reaction under sour catalysis, obtain 3-(4-the chlorobutyl)-5-cyanoindole as shown in structural formula V:
(3) there is as follows reacting with 5-(piperazine-1-yl) benzofuran-2-carboxamides in 3-(4-chlorobutyl)-5-cyanoindole, generates vilazodone:
(4) vilazodone and hydrochloric acid salt-forming reaction, obtain Vilazodone Hydrochloride.
8. method as claimed in claim 7, is characterized in that, the described acid of step (2) is selected from sulfuric acid, phosphoric acid, polyphosphoric acids, trifluoracetic acid, methanesulfonic acid or the p-methyl benzenesulfonic acid of hydrochloric acid, 20%-100%.
9. method as claimed in claim 7, it is characterized in that, the solvent that step (2) is reacted used is selected from carrene, chloroform, acetonitrile, methyl alcohol, ethanol, isopropyl alcohol, ethyl acetate, methyl acetate, oxolane, dioxane, N, dinethylformamide, DMA or dimethyl sulfoxide (DMSO).
10. the method as described in claim 7-9 any one, is characterized in that, the solution that step (3) is reacted used is selected from DMA, DMF, dimethyl sulfoxide (DMSO) or acetonitrile.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101631769A (en) * | 2007-02-23 | 2010-01-20 | 日本瑞翁株式会社 | Liquid crystalline compound, liquid crystalline composition, optical film, and optical laminate |
| WO2014064715A2 (en) * | 2012-10-22 | 2014-05-01 | Cadila Healthcare Limited | Amorphous form of vilazodone hydrochloride and process for preparing thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101631769A (en) * | 2007-02-23 | 2010-01-20 | 日本瑞翁株式会社 | Liquid crystalline compound, liquid crystalline composition, optical film, and optical laminate |
| WO2014064715A2 (en) * | 2012-10-22 | 2014-05-01 | Cadila Healthcare Limited | Amorphous form of vilazodone hydrochloride and process for preparing thereof |
Non-Patent Citations (1)
| Title |
|---|
| N. ANITHA B ET AL.: "Alternative Approach to Synthesis of 3-(4-Chloro butyl)-1H-indole-5-carbonitrile: A Key Intermediate of Vilazodone Hydrochloride, an Antidepressant Drug", 《SYNTHETIC COMMUNICATIONS》 * |
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