CN103254179A - Preparation method of Avanafil - Google Patents
Preparation method of Avanafil Download PDFInfo
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- CN103254179A CN103254179A CN201310195728XA CN201310195728A CN103254179A CN 103254179 A CN103254179 A CN 103254179A CN 201310195728X A CN201310195728X A CN 201310195728XA CN 201310195728 A CN201310195728 A CN 201310195728A CN 103254179 A CN103254179 A CN 103254179A
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- CN
- China
- Prior art keywords
- preparation
- cutting down
- chloro
- reaction
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- WEAJZXNPAWBCOA-INIZCTEOSA-N avanafil Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=NC=CC=N1 WEAJZXNPAWBCOA-INIZCTEOSA-N 0.000 title claims abstract description 8
- 229960000307 avanafil Drugs 0.000 title abstract description 5
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims abstract description 44
- -1 3-chloro-4-methoxybenzyl halogen Chemical class 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940104302 cytosine Drugs 0.000 claims abstract description 9
- 238000007259 addition reaction Methods 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 238000005520 cutting process Methods 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 238000006482 condensation reaction Methods 0.000 claims description 8
- DVAHKWQEUJRPCN-UHFFFAOYSA-N ClC=1C=C(CNC2=NC(=NC=C2)N2C(CCC2)CO)C=CC=1OC Chemical compound ClC=1C=C(CNC2=NC(=NC=C2)N2C(CCC2)CO)C=CC=1OC DVAHKWQEUJRPCN-UHFFFAOYSA-N 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- XGGVVEBLYIACJO-UHFFFAOYSA-N 6-[(3-chloro-4-methoxyphenyl)methylamino]-1H-pyrimidin-2-one Chemical compound ClC=1C=C(CNC2=NC(NC=C2)=O)C=CC=1OC XGGVVEBLYIACJO-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 230000002140 halogenating effect Effects 0.000 claims description 6
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- MQRWBMAEBQOWAF-UHFFFAOYSA-N acetic acid;nickel Chemical compound [Ni].CC(O)=O.CC(O)=O MQRWBMAEBQOWAF-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229940078494 nickel acetate Drugs 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000012964 benzotriazole Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- IVDNCEPKBKOMER-UHFFFAOYSA-N phenoxyphosphane Chemical compound POC1=CC=CC=C1 IVDNCEPKBKOMER-UHFFFAOYSA-N 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000009833 condensation Methods 0.000 abstract description 3
- 230000005494 condensation Effects 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract 2
- 239000007858 starting material Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- OCNMSDZALRAYEX-UHFFFAOYSA-N (3-chloro-4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1Cl OCNMSDZALRAYEX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- BQNXHDSGGRTFNX-UHFFFAOYSA-N n-methylpyrimidin-2-amine Chemical compound CNC1=NC=CC=N1 BQNXHDSGGRTFNX-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 238000005935 nucleophilic addition reaction Methods 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- ZTVIKZXZYLEVOL-DGKWVBSXSA-N 2-hydroxy-2-phenylacetic acid [(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] ester Chemical group C([C@H]1CC[C@@H](C2)N1C)C2OC(=O)C(O)C1=CC=CC=C1 ZTVIKZXZYLEVOL-DGKWVBSXSA-N 0.000 description 1
- YEFXGSFLVHHYMA-UHFFFAOYSA-N 2-methyl-6-oxo-1H-pyrimidine-5-carbothioic S-acid Chemical compound OC1=NC(=NC=C1C(=S)O)C YEFXGSFLVHHYMA-UHFFFAOYSA-N 0.000 description 1
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical class ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 description 1
- BDYJMOYDXJQHFS-UHFFFAOYSA-N 4-(bromomethyl)-2-chloro-1-methoxybenzene Chemical compound COC1=CC=C(CBr)C=C1Cl BDYJMOYDXJQHFS-UHFFFAOYSA-N 0.000 description 1
- KJYHORVTWSYSQP-UHFFFAOYSA-N 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2C(CCC2)CO)=NC=C1C(O)=O KJYHORVTWSYSQP-UHFFFAOYSA-N 0.000 description 1
- NFZFYBRBQXQMGK-UHFFFAOYSA-N 4-chloro-2-methylpyrimidine-5-carbothioic S-acid Chemical compound ClC1=NC(=NC=C1C(=S)O)C NFZFYBRBQXQMGK-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- ROSKZJGILXBSFM-UHFFFAOYSA-N NCc1ncccn1 Chemical compound NCc1ncccn1 ROSKZJGILXBSFM-UHFFFAOYSA-N 0.000 description 1
- HVVNJUAVDAZWCB-UHFFFAOYSA-N OCC1NCCC1 Chemical compound OCC1NCCC1 HVVNJUAVDAZWCB-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229940046921 stendra Drugs 0.000 description 1
- NRTLTGGGUQIRRT-UHFFFAOYSA-N triethylazanium;bromide Chemical compound [Br-].CC[NH+](CC)CC NRTLTGGGUQIRRT-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a preparation method of Avanafil (I). Cytosine is taken as a starting material, and substitution, condensation and halogenated addition reactions are sequentially carried out by virtue of 3-chloro-4-methoxybenzyl halogen (III), S-hydroxymethyl pyrrolidine (II) and N-(2-methyl pyrimidine) formamide (IV), thus the target product Avanafil (I) can be obtained. The preparation method has the advantages of available raw materials, simple process, economy and environmental protection and is applicable to the requirement of industrialized production.
Description
Technical field
The invention belongs to organic synthesis highway route design and bulk drug thereof and intermediate preparation technical field, that non-preparation method of particularly a kind of Ah cutting down.
Background technology
Ah cutting down that non-(Avanafil) is the medicine that is used for the treatment of male erectile dysfunction of being authorized the exploitation of U.S. Wei Fusi (Vivus) drugmaker by Japanese Tanabe Mitsubishi Pharmaceutical Co.Ah cutting down that non-be a kind of oral quick-acting highly selective phosphodiesterase-5 (PDE-5) inhibitor, can suppress cyclic guanosine monophosphate metabolism in vivo, thereby the diastole effect of unstriated muscle is strengthened, the volume of blood flow of penis increases, and then helps to erect.Ah cutting down that non-in April 27 in 2012 the Nikkei drugs approved by FDA go on the market in the U.S., commodity are called Stendra.
That non-(Avanafil, I), chemistry is called (S)-4-[(3-chloro-4-methoxy-benzyl) amino of Ah cutting down]-2-[2-(methylol)-1-pyrrolidyl]-N-(2-Pyrimidylmethyl)-5-pyrimidine carboxamide.
The pharmacy former world patent that grinds in limit, field has been reported the preparation method of Ah cutting down Na Fei and analogue thereof for WO0183460 number and WO0119802 number.This method is to obtain Ah cutting down that non-(I) with side chain S-hydroxymethyl pyrrolidine (II), 3-chloro-4-methoxybenzylamine (VII) and 2-methylamino pyrimidine (VIII) prepared in reaction of 2-position, 4-position and 5-position respectively by pyrimidine ring parent nucleus (IX).
Particularly, obtain pyrimidine ring parent nucleus 4-hydroxyl-2-methylthiopyrimidine-5-carboxylic acid, ethyl ester (IX) with methylthio group urea (X) and ethoxy methyne diethyl malonate (XI) cyclization; Intermediate (IX) obtains 4-chloro-2-methylthiopyrimidine-5-carboxylic acid, ethyl ester (XII) through the phosphorus oxychloride chlorination; Substitution reaction takes place with side chain (VII) and obtains 4-(3-chloro-4-methoxybenzyl amido)-2-methylthiopyrimidine-5-carboxylic acid, ethyl ester (XIII) in intermediate (XII); Intermediate (XIII) obtains 4-(3-chloro-4-methoxybenzyl amido)-2-methanesulfonyl pyrimidine-5-carboxylic acid, ethyl ester (IXV) with the benzoyl hydroperoxide oxidation; Nucleophilic addition takes place with side chain (II) in intermediate (IXV), generates 4-[(3-chloro-4-methoxy-benzyl) amino]-2-[2-(methylol)-1-pyrrolidyl] pyrimidine-5-carboxylic acid's ethyl ester (XV); Intermediate (XV) makes Ah cutting down that non-(I) through hydrolysis and with side chain (VIII) generation acylation reaction.
The above-mentioned former patent of grinding has also disclosed a kind of with 2, the 4-dichloro pyrimidine is the method for feedstock production analogue: 2, the 4-dichloro pyrimidine forms carbanion under the effect of n-Butyl Lithium and Diisopropylamine, under-78 ℃ condition of ultralow temperature, with carbonic acid gas or other carbonyl compound generation nucleophilic addition, generate 5-and replace-2,4-dichloro pyrimidine derivative (XVI).This derivative (XVI) reacts phosphodiesterase-5 (PDE-5) inhibitor that can prepare with target compound (I) similar by the side chain with 2-position, 4-position or 5-position again.
Find out thus, no matter adopting first sulfydryl substituted pyrimidines or dichloro pyrimidine is starting raw material, defective, especially condition of ultralow temperature, the condition of high voltage of carbonic acid gas carbonylation and the anhydrous and oxygen-free conditions that the multistep metal reagent reacts such as whole preparation process all exists raw material be difficult for to obtain, synthesis step is many, complex process and separation difficulty make the whole piece synthetic route be difficult to realize industrialization.
Summary of the invention
The objective of the invention is to seek new preparation approach, according to the synthetic theory of the Atom economy of Green Chemistry, a kind of improved Ah cutting down is provided that non-preparation method, this method is starting raw material with very inexpensive and industrial raw material cytosine(Cyt) (Cytosine) that be easy to get, that is non-to make Ah cutting down by processes such as halo, condensation and replacements, succinct, the economic environmental protection of this preparation method's technology is beneficial to suitability for industrialized production.
To achieve these goals, the invention provides a kind of following main technical schemes: that non-preparation method of a kind of Ah cutting down, that non-chemistry of described Ah cutting down is called (S)-4-[(3-chloro-4-methoxy-benzyl) amino]-2-[2-(methylol)-1-pyrrolidyl]-N-(2-Pyrimidylmethyl)-5-pyrimidine carboxamide (I).
It is characterized in that it is raw material that described preparation method comprises the steps: with the cytosine(Cyt), substitution reaction takes place in described cytosine(Cyt) and 3-chloro-4-methoxybenzyl halogen (III), generates N-(3-chloro-4-methoxy-benzyl) cytosine(Cyt) (V); Condensation reaction takes place and makes 4-[(3-chloro-4-methoxy-benzyl in described N-(3-chloro-4-methoxy-benzyl) cytosine(Cyt) (V) and S-hydroxymethyl pyrrolidine (II)) amino]-2-[2-(methylol)-1-pyrrolidyl] pyrimidine (VI), described 4-[(3-chloro-4-methoxy-benzyl) amino]-2-[2-(methylol)-1-pyrrolidyl] pyrimidine (VI) through halogenating reaction and and side chain N-(2-methylpyrimidine) methane amide (IV) generation addition reaction make Ah cutting down that non-(I).
In addition, the present invention also comprises following attached technical scheme:
Halogen X in the described 3-chloro-4-methoxybenzyl halogen (III) is chlorine, bromine or iodine.
The acid binding agent of described substitution reaction is salt of wormwood, potassium hydroxide, potassium tert.-butoxide, sodium methylate, sodium ethylate, triethylamine, diisopropylamine, pyridine or sodium hydroxide, preferred triethylamine or pyridine.
The condensing agent of described condensation reaction is N, N,-dicyclohexylcarbodiimide (DCC), carbonyl dimidazoles (CDI), N, N '-DIC (DIC), 1-hydroxyl-benzotriazole (HOBt), O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), O-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N ' N '-tetramethyl-urea phosphofluoric acid ester (HBTU) or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP), preferred benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU) or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP).
The alkali promotor of described condensation reaction is triethylamine, pyridine, 2,6-lutidine, 4-Dimethylamino pyridine, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0]-11-7-alkene or 1,4-diazabicylo [2.2.2] octane, preferred three (2,4-di-t-butyl) phenoxy group phosphine.
The temperature of described condensation reaction is 0-120 ℃, preferred 50-60 ℃.
Halogenating agent in the described halogenating reaction is chlorine, liquid bromine or iodine, preferred liquid bromine or iodine.
The catalyzer of described addition reaction is Palladous chloride, palladium, three (dibenzalacetone) two palladiums, nickelous chloride, nickel acetate, preferred nickel acetate.
The promotor of described addition reaction is triphenylphosphine, tri-n-butyl phosphine, tri-butyl phosphine, tricyclohexyl phosphine, triethoxy phosphine, triple phenoxyl phosphine, 1,1 '-two (diphenylphosphine) ferrocene, 4, the two diphenylphosphines-9 of 5-, 9-dimethyl oxa-is feared or three (2, the 4-di-t-butyl) phenoxy group phosphine, preferred three (2,4-di-t-butyl) phenoxy group phosphine.
Than prior art, that non-preparation method of Ah cutting down involved in the present invention, its method is starting raw material with inexpensive and industrial raw material cytosine(Cyt) that be easy to get, that is non-to make Ah cutting down by processes such as replacement, condensation and halo additions, so mainly being raw material, advantage of the present invention is easy to get, technology is succinct, and economic environmental protection is beneficial to suitability for industrialized production.
Embodiment
Below in conjunction with several preferred embodiments technical solution of the present invention is done further nonrestrictive detailed description.
Embodiment one:
In there-necked flask, add cytosine(Cyt) (2.22g, 20mmol), triethylamine (2.0g, 20mmol), (0.2g 1%eq) and dehydrated alcohol 50mL, is warming up to 50-55 ℃ to potassiumiodide, is stirred to system dissolving homogeneous.(5.60g is 24mol) to reaction solution slowly to drip 3-chloro-4-methoxybenzyl bromine (III).Be warming up to 80 ℃, continue reaction 3 hours, the TLC detection reaction finishes.Be down to room temperature, remove by filter triethylamine hydrobromide.Filtrate is regulated pH to 4-5 with hydrochloric acid.Decompression recycling ethanol, the residuum re-crystallizing in ethyl acetate obtains off-white color solid N-(3-chloro-4-methoxy-benzyl) cytosine(Cyt) (V) 4.78g, yield 90.2%.
Embodiment two:
Under the nitrogen protection, in there-necked flask, add N-(3-chloro-4-methoxy-benzyl) cytosine(Cyt) (V) (2.65g, 10mmol), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 50mL.Stir down, (2.28g 15mmol), drips and finishes room temperature reaction 12 hours to drip 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU).Be warming up to 60 ℃, continue reaction 12 hours.The underpressure distillation desolventizing adds ethyl acetate 100mL dissolving, and washs with 2M sodium hydroxide 20mL.Tell organic phase, drying, concentrating under reduced pressure.Resistates is with the dissolving of 100mL tetrahydrofuran (THF), add S-hydroxymethyl pyrrolidine (II) (1.31g, 13mmol) and sodium hydride (0.32g 13mmol), is warming up to 55 ℃, stirring reaction 5 hours, the end of TLC monitoring reaction.With saturated aqueous common salt cancellation reaction, tell organic phase, drying, vacuum distillation recovered solvent.The gained solid gets off-white color solid 4-[(3-chloro-4-methoxy-benzyl with ethyl alcohol recrystallization) amino]-2-[2-(methylol)-1-pyrrolidyl] pyrimidine (VI) 2.85g, yield is 81.9%.
Embodiment three:
In microwave reactor, add 4-[(3-chloro-4-methoxy-benzyl) amino]-2-[2-(methylol)-1-pyrrolidyl] pyrimidine (VI) (1.74g, 5mmol), bromine (0.94g, 6mmol) with 2.0M sodium hydroxide solution 25mL, 200W microwave radiation 5 minutes, be cooled to room temperature, the adularescent solid is separated out.After filtration, the drying, add glycol dimethyl ether 25mL dissolving and also be transferred in three mouthfuls of reaction flasks.Add four hydration nickel acetate (13mg; 0.05mmol), three (2; the 4-di-t-butyl) phenoxy group phosphine (32mg; 0.05mmol), sodium methylate (0.54g, 10mmol) and N-(2-methylpyrimidine) methane amide (IV) (2.05g, 15mmol); under the nitrogen protection; be warming up to 120 ℃, stirring reaction 10 hours, the TLC detection reaction finishes.Reaction solution is inclined to the 25mL saturated ammonium chloride solution, use ethyl acetate extraction three times.Merge organic phase, anhydrous magnesium sulfate drying, decompression and solvent recovery, residuum gets that non-(I) 1.96g of white solid Ah cutting down with recrystallizing methanol, and yield is 81.1%.
It is pointed out that above-described embodiment only is explanation technical conceive of the present invention and characteristics, its purpose is to allow the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (9)
1. that non-preparation method of Ah cutting down, that non-chemistry of described Ah cutting down is called (S)-4-[(3-chloro-4-methoxy-benzyl) amino]-2-[2-(methylol)-1-pyrrolidyl]-N-(2-Pyrimidylmethyl)-5-pyrimidine carboxamide (I),
It is characterized in that it is raw material that described preparation method comprises the steps: with the cytosine(Cyt), substitution reaction takes place in described cytosine(Cyt) and 3-chloro-4-methoxybenzyl halogen (III), generates N-(3-chloro-4-methoxy-benzyl) cytosine(Cyt) (V); Condensation reaction takes place and makes 4-[(3-chloro-4-methoxy-benzyl in described N-(3-chloro-4-methoxy-benzyl) cytosine(Cyt) (V) and S-hydroxymethyl pyrrolidine (II)) amino]-2-[2-(methylol)-1-pyrrolidyl] pyrimidine (VI), described 4-[(3-chloro-4-methoxy-benzyl) amino]-2-[2-(methylol)-1-pyrrolidyl] pyrimidine (VI) through halogenating reaction and and side chain N-(2-methylpyrimidine) methane amide (IV) generation addition reaction make Ah cutting down that non-(I).
2. according to that non-preparation method of described Ah the cutting down of claim 1, it is characterized in that: the halogen X in the described 3-chloro-4-methoxybenzyl halogen (III) is chlorine, bromine or iodine.
3. according to that non-preparation method of described Ah the cutting down of claim 1, it is characterized in that: the acid binding agent of described substitution reaction is salt of wormwood, potassium hydroxide, potassium tert.-butoxide, sodium methylate, sodium ethylate, triethylamine, diisopropylamine, pyridine or sodium hydroxide.
4. according to that non-preparation method of described Ah the cutting down of claim 1, it is characterized in that: the condensing agent of described condensation reaction is N, N,-dicyclohexylcarbodiimide, carbonyl dimidazoles, N, N '-DIC, 1-hydroxyl-benzotriazole, O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester, O-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate.
5. according to that non-preparation method of described Ah the cutting down of claim 1, it is characterized in that: the alkali promotor of described condensation reaction is triethylamine, pyridine, 2,6-lutidine, 4-Dimethylamino pyridine, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0]-11-7-alkene or 1,4-diazabicylo [2.2.2] octane.
6. according to that non-preparation method of described Ah the cutting down of claim 1, it is characterized in that: the temperature of described condensation reaction is 0-120 ℃.
7. according to that non-preparation method of described Ah the cutting down of claim 1, it is characterized in that: the halogenating agent in the described halogenating reaction is chlorine, liquid bromine or iodine.
8. according to that non-preparation method of described Ah the cutting down of claim 1, it is characterized in that: the catalyzer of described addition reaction is Palladous chloride, palladium, three (dibenzalacetone) two palladiums, nickelous chloride, nickel acetate.
9. according to that non-preparation method of described Ah the cutting down of claim 1, it is characterized in that: the promotor of described addition reaction is triphenylphosphine, tri-n-butyl phosphine, tri-butyl phosphine, tricyclohexyl phosphine, triethoxy phosphine, triple phenoxyl phosphine, 1,1 '-two (diphenylphosphine) ferrocene, 4, the two diphenylphosphines-9 of 5-, 9-dimethyl oxa-is feared or three (2,4-di-t-butyl) phenoxy group phosphine.
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| PCT/CN2014/077632 WO2014187273A1 (en) | 2013-05-23 | 2014-05-16 | Avanafil preparation method |
| US14/948,387 US9453001B2 (en) | 2013-05-23 | 2015-11-23 | Avanafil preparation method |
| US15/247,383 US9593101B2 (en) | 2013-05-23 | 2016-08-25 | Avanafil preparation method |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014187273A1 (en) * | 2013-05-23 | 2014-11-27 | 苏州明锐医药科技有限公司 | Avanafil preparation method |
| CN104530015A (en) * | 2014-12-10 | 2015-04-22 | 齐鲁天和惠世制药有限公司 | Preparation method of avanafil |
| CN104557877A (en) * | 2013-10-28 | 2015-04-29 | 重庆安格龙翔医药科技有限公司 | Avanafil intermediate as well as preparation method and application thereof |
| CN104557730A (en) * | 2015-01-27 | 2015-04-29 | 江苏嘉逸医药有限公司 | Preparation method of avanafil key intermediate |
| CN104628707A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Amorphous form of avanafil, preparation method of, application and medicine composition of amorphous form of avanafil |
| CN104628708A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Avanaphil crystal form as well as preparation method, application and pharmaceutical composition thereof |
| CN104650045B (en) * | 2013-11-19 | 2017-04-19 | 苏州旺山旺水生物医药有限公司 | Preparation method of avanafil |
| CN112812101A (en) * | 2021-01-19 | 2021-05-18 | 山东省药学科学院 | Preparation method of avanafil impurity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1374953A (en) * | 1999-09-16 | 2002-10-16 | 田边制药株式会社 | Aromatic nitrogenous six-membered ring compounds |
| JP2002338466A (en) * | 2001-03-15 | 2002-11-27 | Tanabe Seiyaku Co Ltd | Medicinal composition |
| CN1440393A (en) * | 2000-04-28 | 2003-09-03 | 田边制药株式会社 | Cyclic compounds |
-
2013
- 2013-05-23 CN CN201310195728.XA patent/CN103254179B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1374953A (en) * | 1999-09-16 | 2002-10-16 | 田边制药株式会社 | Aromatic nitrogenous six-membered ring compounds |
| CN1440393A (en) * | 2000-04-28 | 2003-09-03 | 田边制药株式会社 | Cyclic compounds |
| JP2002338466A (en) * | 2001-03-15 | 2002-11-27 | Tanabe Seiyaku Co Ltd | Medicinal composition |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014187273A1 (en) * | 2013-05-23 | 2014-11-27 | 苏州明锐医药科技有限公司 | Avanafil preparation method |
| US9593101B2 (en) * | 2013-05-23 | 2017-03-14 | Suzhou Miracpharma Technology Co., Ltd. | Avanafil preparation method |
| US20160075693A1 (en) * | 2013-05-23 | 2016-03-17 | Suzhou Miracpharma Technology Co., Ltd. | Avanafil preparation method |
| US9453001B2 (en) | 2013-05-23 | 2016-09-27 | Suzhou Miracpharma Technology Co., Ltd. | Avanafil preparation method |
| CN104557877A (en) * | 2013-10-28 | 2015-04-29 | 重庆安格龙翔医药科技有限公司 | Avanafil intermediate as well as preparation method and application thereof |
| CN104557877B (en) * | 2013-10-28 | 2016-08-17 | 重庆安格龙翔医药科技有限公司 | A kind of avanaphil intermediate and its preparation method and application |
| CN104628707A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Amorphous form of avanafil, preparation method of, application and medicine composition of amorphous form of avanafil |
| CN104628708A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Avanaphil crystal form as well as preparation method, application and pharmaceutical composition thereof |
| CN104650045B (en) * | 2013-11-19 | 2017-04-19 | 苏州旺山旺水生物医药有限公司 | Preparation method of avanafil |
| CN104530015B (en) * | 2014-12-10 | 2017-01-04 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of avanaphil |
| CN104530015A (en) * | 2014-12-10 | 2015-04-22 | 齐鲁天和惠世制药有限公司 | Preparation method of avanafil |
| CN104557730A (en) * | 2015-01-27 | 2015-04-29 | 江苏嘉逸医药有限公司 | Preparation method of avanafil key intermediate |
| CN112812101A (en) * | 2021-01-19 | 2021-05-18 | 山东省药学科学院 | Preparation method of avanafil impurity |
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