CN103265534A - 阿伐那非的制备方法 - Google Patents
阿伐那非的制备方法 Download PDFInfo
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- CN103265534A CN103265534A CN2013101958545A CN201310195854A CN103265534A CN 103265534 A CN103265534 A CN 103265534A CN 2013101958545 A CN2013101958545 A CN 2013101958545A CN 201310195854 A CN201310195854 A CN 201310195854A CN 103265534 A CN103265534 A CN 103265534A
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- 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 9
- 238000000034 method Methods 0.000 title abstract description 10
- 229960000307 avanafil Drugs 0.000 title abstract description 6
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000002360 preparation method Methods 0.000 claims abstract description 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006482 condensation reaction Methods 0.000 claims abstract description 9
- 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
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- -1 3-chloro-4-methoxybenzyl halogen Chemical class 0.000 claims description 28
- 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
- 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
- 229910052757 nitrogen Inorganic materials 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
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 150000002148 esters Chemical class 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
- 230000002140 halogenating effect Effects 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 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
- 238000006467 substitution reaction Methods 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
- 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
- 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
- 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
- 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
- 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-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
- 229910052794 bromium Inorganic materials 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
- 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
- 238000005516 engineering process Methods 0.000 abstract description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract 2
- 239000000463 material Substances 0.000 abstract 2
- 230000003321 amplification Effects 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- OCNMSDZALRAYEX-UHFFFAOYSA-N (3-chloro-4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1Cl OCNMSDZALRAYEX-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004519 manufacturing process Methods 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
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 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
- 230000007613 environmental effect Effects 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
- 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
- 125000004429 atom Chemical group 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
- 229960004756 ethanol Drugs 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
- 125000002924 primary amino group Chemical group [H]N([H])* 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
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明揭示了一种阿伐那非(Avanafil，I)的制备方法，其以胞嘧啶(Cytosine)为起始原料，依次通过与侧链3-氯-4-甲氧基苄卤素(III)、N-(2-甲基嘧啶)甲酰胺(IV)和S-羟甲基吡咯烷(II)进行取代、卤代加成以及缩合反应，即可得到目标产物阿伐那非(I)。该制备方法原料易得、工艺简洁、经济环保，适合工业化放大的要求。
Description
技术领域
本发明属于有机合成路线设计及其原料药和中间体制备技术领域，特别涉及一种阿伐那非的制备方法。
背景技术
阿伐那非(Avanafil)是由日本田边三菱制药株式会社授权美国维福斯(Vivus)制药公司开发的用于治疗男性***功能障碍的药物。阿伐那非是一种口服速效的高选择性磷酸二酯酶-5(PDE-5)抑制剂，能抑制环磷酸鸟苷在体内的代谢，从而使平滑肌的舒张作用得以加强，***的血流量增加，进而帮助***。阿伐那非于2012年4月27日经美国FDA批准在美国上市，商品名为Stendra。
阿伐那非(Avanafil，I)，化学名为(S)-4-[(3-氯-4-甲氧基苄基)氨基]-2-[2-(羟甲基)-1-吡咯烷基]-N-(2-嘧啶基甲基)-5-嘧啶甲酰胺。
田边制药原研的世界专利第WO0183460号和第WO0119802号报道了阿伐那非及其类似物的制备方法。该方法是通过嘧啶环母核(IX)分别与2-位、4-位和5-位的侧链S-羟甲基吡咯烷(II)、3-氯-4-甲氧基苄胺(VII)和2-甲胺基嘧啶(VIII)反应制备得到阿伐那非(I)。
具体地，以甲硫基脲(X)和乙氧次甲基丙二酸二乙酯(XI)环合得到嘧啶环母核4-羟基-2-甲硫基嘧啶-5-羧酸乙酯(IX)；中间体(IX)经三氯氧磷氯化得到4-氯-2-甲硫基嘧啶-5-羧酸乙酯(XII)；中间体(XII)与侧链(VII)发生取代反应得到4-(3-氯-4-甲氧基苄胺基)-2-甲硫基嘧啶-5-羧酸乙酯(XIII)；中间体(XIII)用过氧苯甲酸氧化得到4-(3-氯-4-甲氧基苄胺基)-2-甲磺酰基嘧啶-5-羧酸乙酯(IXV)；中间体(IXV)与侧链(II)发生亲核加成反应，生成4-[(3-氯-4-甲氧基苄基)氨基]-2-[2-(羟甲基)-1-吡咯烷基]嘧啶-5-羧酸乙酯(XV)；中间体(XV)经水解并与侧链(VIII)发生酰化反应制得阿伐那非(I)。
上述原研专利还揭示了一种以2，4-二氯嘧啶为原料制备类似物的方法：2，4-二氯嘧啶在正丁基锂和二异丙胺的作用下形成碳负离子，在-78℃的超低温条件下，与二氧化碳或其它羰基化合物发生亲核加成反应，生成5-取代-2，4-二氯嘧啶衍生物(XVI)。该衍生物(XVI)再通过与2-位、4-位或5-位的侧链反应可制备得到与目标化合物(I)结构类似的磷酸二酯酶-5(PDE-5)抑制剂。
由此看出，无论采用甲巯基取代嘧啶或二氯嘧啶为起始原料，整个制备工艺均存在原料不易获得、合成步骤多、工艺复杂以及分离困难等缺陷，尤其是超低温条件、二氧化碳羰基化的高压条件以及多步金属试剂反应的无水无氧条件使得整条合成路线难以实现工业化。
发明内容
本发明的目的在于寻求新的制备途径，按照绿色化学的原子经济性合成理念，提供一种改进的阿伐那非的制备方法，该方法以非常价廉和易得的工业原料胞嘧啶(Cytosine)为起始原料，通过卤代、缩合和取代等过程制得阿伐那非，该制备方法工艺简洁、经济环保，利于工业化生产。
为了实现上述目的，本发明提供了如下主要技术方案：一种阿伐那非的制备方法，所述阿伐那非的化学名为(S)-4-[(3-氯-4-甲氧基苄基)氨基]-2-[2-(羟甲基)-1-吡咯烷基]-N-(2-嘧啶基甲基)-5-嘧啶甲酰胺(I)，
其特征在于所述制备方法包括如下步骤：以胞嘧啶为原料，所述胞嘧啶和3-氯-4-甲氧基苄卤(III)发生取代反应，生成N-(3-氯-4-甲氧基苄基)胞嘧啶(V)；所述N-(3-氯-4-甲氧基苄基)胞嘧啶(V)经过卤代反应并和侧链N-(2-甲基嘧啶)甲酰胺(IV)发生加成反应生成6-(3-氯-4-甲氧基苄胺基)-1，2-二氢嘧啶-2-酮-5-(N-2-嘧啶基甲基)甲酰胺(VI)；所述6-(3-氯-4-甲氧基苄胺基)-1，2-二氢嘧啶-2-酮-5-(N-2-嘧啶基甲基)甲酰胺(VI)与S-羟甲基吡咯烷(II)发生缩合反应制得阿伐那非(I)。
此外，本发明还包括如下附属技术方案：
所述3-氯-4-甲氧基苄卤(III)中的卤素X为氯、溴或碘。
所述取代反应的缚酸剂为碳酸钾、氢氧化钾、叔丁醇钾、甲醇钠、乙醇钠、三乙胺、二异丙基胺、吡啶或氢氧化钠，优选三乙胺或吡啶。
所述卤代反应中的卤代试剂为氯气、液溴或碘，优选液溴或碘。
所述加成反应的催化剂为氯化钯、醋酸钯、三(二亚苄基丙酮)二钯、氯化镍、醋酸镍，优选醋酸镍。
所述加成反应的助催化剂为三苯基膦、三正丁基膦、三叔丁基膦、三环己基膦、三乙氧基膦、三苯氧基膦、1，1′-双(二苯基膦)二茂铁、4，5-双二苯基膦-9，9-二甲基氧杂葸或三(2，4-二叔丁基)苯氧基膦，优选三(2，4-二叔丁基)苯氧基膦。
所述缩合反应的缩合剂为N，N，-二环己基碳二亚胺(DCC)、羰基二咪唑(CDI)、N，N′-二异丙基碳二亚胺(DIC)、1-羟基-苯并三氮唑(HOBt)、O-苯并三氮唑-N，N，N′，N′-四甲基脲四氟硼酸酯(TBTU)、O-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N，N，N′，N′-四甲基脲六氟磷酸酯(HBTU)或苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)，优选苯并三氮唑-N，N，N′，N′-四甲基脲六氟磷酸酯(HBTU)或苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)。
所述缩合反应的碱促进剂为三乙胺、吡啶、2，6-二甲基吡啶、4-二甲氨基吡啶、N-甲基吗啉、N-乙基吗啉、二异丙基乙胺、1，5-二氮杂二环[4.3.0]-壬-5-烯、1，8-二氮杂双环[5.4.0]-十一-7-烯或1，4-二氮杂二环[2.2.2]辛烷，优选三(2，4-二叔丁基)苯氧基膦。
所述缩合反应的温度为0-120℃，优选60-70℃。
比于现有技术，本发明所涉及的阿伐那非的制备方法，其方法以价廉和易得的工业原料胞嘧啶为起始原料，通过取代、卤代加成和缩合等过程制得阿伐那非，故而本发明的优点主要是原料易得，工艺简洁，经济环保，利于工业化生产。
具体实施方式
以下结合数个较佳实施例对本发明技术方案作进一步非限制性的详细说明。
实施例一：
于三口瓶中加入胞嘧啶(2.22g，20mmol)、三乙胺(2.0g，20mmol)、碘化钾(0.2g，1％eq)和无水乙醇50mL，升温至50-55℃，搅拌至体系溶解均一。缓慢滴加3-氯-4-甲氧基苄溴(III)(5.60g，24mol)至反应液中。升温至80℃，继续反应3小时，TLC检测反应结束。降至室温，过滤除去三乙胺氢溴酸盐。滤液用盐酸调节pH至4-5。减压回收乙醇，剩余物用乙酸乙酯重结晶，得到类白色固体N-(3-氯-4-甲氧基苄基)胞嘧啶(V)4.78g，收率90.2％。
实施例二：
于微波反应器中加入N-(3-氯-4-甲氧基苄基)胞嘧啶(V)(2.56g，10mmol)、碘(3.04g，12mmol)和2.0M氢氧化钠溶液50mL，300W微波辐射5分钟，冷却至室温，有白色固体析出。过滤、干燥后，加入乙二醇二甲醚50mL溶解并转移至三口反应瓶中。加入四水合醋酸镍(25mg，0.1mmol)、三(2，4-二叔丁基)苯氧基膦(64mg，0.1mmol)、甲醇钠(1.08g，20mmol)和N-(2-甲基嘧啶)甲酰胺(IV)(4.11g，30mmol)，氮气保护下，加入升温至110℃，搅拌反应10小时，TLC检测反应结束。将反应液倾至50mL饱和氯化铵溶液中，用乙酸乙酯萃取三次。合并有机相，无水硫酸镁干燥，减压回收溶剂，剩余物用丙酮重结晶得白色固体6-(3-氯-4-甲氧基苄胺基)-1，2-二氢嘧啶-2-酮-5-(N-2-嘧啶基甲基)甲酰胺(VI)3.35g，收率为83.8％。
实施例三：
氮气保护下，于三口瓶中加入6-(3-氯-4-甲氧基苄胺基)-1，2-二氢嘧啶-2-酮-5-(N-2-嘧啶基甲基)甲酰胺(VI)(2.0g，5mmol)、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)(3.31g，7.5mmol)和乙腈25mL。搅拌下，滴加1，8-二氮杂双环[5.4.0]-十一-7-烯(DBU)(1.15g，7.5mmol)，滴毕，室温反应12小时。升温至60℃，继续反应12小时。减压蒸馏除去溶剂，加入乙酸乙酯50mL溶解，并用2M氢氧化钠10mL洗涤。分出有机相，干燥，减压浓缩。残余物用50mL四氢呋喃溶解，加入S-羟甲基吡咯烷(II)(0.61g，6mmol)和氢化钠(0.16g，6mmol)，升温至65℃，搅拌反应5小时，TLC监测反应结束。用饱和食盐水淬灭反应，分出有机相，干燥，减压蒸馏回收溶剂。所得固体用甲醇重结晶得白色固体阿伐那非1.96g，收率为81.3％。
需要指出的是，上述实施例仅为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
Claims (9)
1.一种阿伐那非的制备方法，所述阿伐那非的化学名为(S)-4-[(3-氯-4-甲氧基苄基)氨基]-2-[2-(羟甲基)-1-吡咯烷基]-N-(2-嘧啶基甲基)-5-嘧啶甲酰胺(I)，
其特征在于所述制备方法包括如下步骤：以胞嘧啶为原料，所述胞嘧啶和3-氯-4-甲氧基苄卤(III)发生取代反应，生成N-(3-氯-4-甲氧基苄基)胞嘧啶(V)；所述N-(3-氯-4-甲氧基苄基)胞嘧啶(V)经过卤代反应并和侧链N-(2-甲基嘧啶)甲酰胺(IV)发生加成反应生成6-(3-氯-4-甲氧基苄胺基)-1，2-二氢嘧啶-2-酮-5-(N-2-嘧啶基甲基)甲酰胺(VI)；所述6-(3-氯-4-甲氧基苄胺基)-1，2-二氢嘧啶-2-酮-5-(N-2-嘧啶基甲基)甲酰胺(VI)与S-羟甲基吡咯烷(II)发生缩合反应制得阿伐那非(I)。
2.根据权利要求1所述阿伐那非的制备方法，其特征在于：所述3-氯-4-甲氧基苄卤(III)中的卤素X为氯、溴或碘。
3.根据权利要求1所述阿伐那非的制备方法，其特征在于：所述取代反应的缚酸剂为碳酸钾、氢氧化钾、叔丁醇钾、甲醇钠、乙醇钠、三乙胺、二异丙基胺、吡啶、或氢氧化钠。
4.根据权利要求1所述阿伐那非的制备方法，其特征在于：所述卤代反应中的卤代试剂为氯气、液溴或碘。
5.根据权利要求1所述阿伐那非的制备方法，其特征在于：所述加成反应的催化剂为氯化钯、醋酸钯、三(二亚苄基丙酮)二钯、氯化镍、醋酸镍。
6.根据权利要求1所述阿伐那非的制备方法，其特征在于：所述加成反应的助催化剂为三苯基膦、三正丁基膦、三叔丁基膦、三环己基膦、三乙氧基膦、三苯氧基膦、1，1′-双(二苯基膦)二茂铁、4，5-双二苯基膦-9，9-二甲基氧杂葸或三(2，4-二叔丁基)苯氧基膦。
7.根据权利要求1所述阿伐那非的制备方法，其特征在于：所述缩合反应的缩合剂为N，N，-二环己基碳二亚胺、羰基二咪唑、N，N′二异丙基碳二亚胺、1-羟基-苯并三氮唑、O-苯并三氮唑-N，N，N′，N′-四甲基脲四氟硼酸酯、O-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯、苯并三氮唑-N，N，N′，N′-四甲基脲六氟磷酸酯或苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐。
8.根据权利要求1所述阿伐那非的制备方法，其特征在于：所述缩合反应的碱促进剂为三乙胺、吡啶、2，6-二甲基吡啶、4-二甲氨基吡啶、N-甲基吗啉、N-乙基吗啉、二异丙基乙胺、1，5-二氮杂二环[4.3.0]-壬-5-烯、1，8-二氮杂双环[5.4.0]-十一-7-烯或1，4-二氮杂二环[2.2.2]辛烷。
9.根据权利要求1所述阿伐那非的制备方法，其特征在于：所述缩合反应的温度为0-120℃。
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| WO2014187273A1 (zh) * | 2013-05-23 | 2014-11-27 | 苏州明锐医药科技有限公司 | 阿伐那非的制备方法 |
| WO2015001567A1 (en) * | 2013-07-01 | 2015-01-08 | Msn Laboratories Private Limited | Process for the preparation of (s)-4-[(3-chloro-4-methoxybenzyl)amino]-2-[2- (hydroxymethyl)-1-pyrrolidinyl]-n-(2-pyrimidinyl methyl-5-pyrimidine carboxamide |
| CN104557877A (zh) * | 2013-10-28 | 2015-04-29 | 重庆安格龙翔医药科技有限公司 | 一种阿伐那非中间体及其制备方法和应用 |
| CN104628708A (zh) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | 一种阿伐那非的晶型及其制备方法、用途和药物组合物 |
| CN104650045B (zh) * | 2013-11-19 | 2017-04-19 | 苏州旺山旺水生物医药有限公司 | 阿伐那非的制备方法 |
| CN112661705A (zh) * | 2021-01-21 | 2021-04-16 | 山东省药学科学院 | 一种阿伐那非杂质的合成方法 |
| CN112812101A (zh) * | 2021-01-19 | 2021-05-18 | 山东省药学科学院 | 一种阿伐那非杂质的制备方法 |
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| CN102584799A (zh) * | 1999-09-16 | 2012-07-18 | 田边三菱制药株式会社 | 含氮的6-员芳香环化合物 |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014187273A1 (zh) * | 2013-05-23 | 2014-11-27 | 苏州明锐医药科技有限公司 | 阿伐那非的制备方法 |
| US9453001B2 (en) | 2013-05-23 | 2016-09-27 | Suzhou Miracpharma Technology Co., Ltd. | Avanafil preparation method |
| WO2015001567A1 (en) * | 2013-07-01 | 2015-01-08 | Msn Laboratories Private Limited | Process for the preparation of (s)-4-[(3-chloro-4-methoxybenzyl)amino]-2-[2- (hydroxymethyl)-1-pyrrolidinyl]-n-(2-pyrimidinyl methyl-5-pyrimidine carboxamide |
| CN104557877A (zh) * | 2013-10-28 | 2015-04-29 | 重庆安格龙翔医药科技有限公司 | 一种阿伐那非中间体及其制备方法和应用 |
| CN104557877B (zh) * | 2013-10-28 | 2016-08-17 | 重庆安格龙翔医药科技有限公司 | 一种阿伐那非中间体及其制备方法和应用 |
| CN104628708A (zh) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | 一种阿伐那非的晶型及其制备方法、用途和药物组合物 |
| CN104650045B (zh) * | 2013-11-19 | 2017-04-19 | 苏州旺山旺水生物医药有限公司 | 阿伐那非的制备方法 |
| CN112812101A (zh) * | 2021-01-19 | 2021-05-18 | 山东省药学科学院 | 一种阿伐那非杂质的制备方法 |
| CN112661705A (zh) * | 2021-01-21 | 2021-04-16 | 山东省药学科学院 | 一种阿伐那非杂质的合成方法 |
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