CN109456329A - A kind of preparation method of famciclovir - Google Patents
A kind of preparation method of famciclovir Download PDFInfo
- Publication number
- CN109456329A CN109456329A CN201811375544.0A CN201811375544A CN109456329A CN 109456329 A CN109456329 A CN 109456329A CN 201811375544 A CN201811375544 A CN 201811375544A CN 109456329 A CN109456329 A CN 109456329A
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- Prior art keywords
- amino
- reaction
- ethyl
- pyrimidine
- preparation
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Links
- 229960004396 famciclovir Drugs 0.000 title claims abstract description 41
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 124
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 65
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 51
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims abstract description 48
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims abstract description 45
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000002994 raw material Substances 0.000 claims abstract description 27
- 239000001294 propane Substances 0.000 claims abstract description 24
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 22
- JPZOAVGMSDSWSW-UHFFFAOYSA-N 4,6-dichloropyrimidin-2-amine Chemical compound NC1=NC(Cl)=CC(Cl)=N1 JPZOAVGMSDSWSW-UHFFFAOYSA-N 0.000 claims abstract description 21
- -1 chloro- 5- nitroso pyrimidine-4-yl Chemical group 0.000 claims abstract description 21
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical class NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 13
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 12
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 12
- NDEMNVPZDAFUKN-UHFFFAOYSA-N guanidine;nitric acid Chemical compound NC(N)=N.O[N+]([O-])=O.O[N+]([O-])=O NDEMNVPZDAFUKN-UHFFFAOYSA-N 0.000 claims abstract description 11
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 8
- 230000009467 reduction Effects 0.000 claims abstract description 6
- 238000006298 dechlorination reaction Methods 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 39
- 239000002585 base Substances 0.000 claims description 36
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 229960000583 acetic acid Drugs 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 10
- 239000012362 glacial acetic acid Substances 0.000 claims description 10
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 235000019441 ethanol Nutrition 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000012445 acidic reagent Substances 0.000 claims description 5
- 230000008859 change Effects 0.000 claims description 5
- 238000005660 chlorination reaction Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- 238000005516 engineering process Methods 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical group N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 150000003863 ammonium salts Chemical class 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 230000020477 pH reduction Effects 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- UQOKRDJILZMZKU-UHFFFAOYSA-N 2-nitropyrimidine Chemical compound [O-][N+](=O)C1=NC=CC=N1 UQOKRDJILZMZKU-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 206010013786 Dry skin Diseases 0.000 claims description 2
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical compound OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 239000002274 desiccant Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000000428 dust Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229940093915 gynecological organic acid Drugs 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 150000003230 pyrimidines Chemical class 0.000 claims description 2
- 239000012265 solid product Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 claims 2
- 239000012046 mixed solvent Substances 0.000 claims 2
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 claims 1
- 239000012320 chlorinating reagent Substances 0.000 claims 1
- 230000000717 retained effect Effects 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 4
- 239000007806 chemical reaction intermediate Substances 0.000 abstract description 3
- 230000032050 esterification Effects 0.000 abstract description 3
- 238000005886 esterification reaction Methods 0.000 abstract description 3
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- 238000010792 warming Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000007605 air drying Methods 0.000 description 9
- 239000003651 drinking water Substances 0.000 description 9
- 235000020188 drinking water Nutrition 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 238000009413 insulation Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 239000012452 mother liquor Substances 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 230000006837 decompression Effects 0.000 description 7
- 239000012954 diazonium Substances 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 150000001989 diazonium salts Chemical class 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- LGZXYFMMLRYXLK-UHFFFAOYSA-N mercury(2+);sulfide Chemical compound [S-2].[Hg+2] LGZXYFMMLRYXLK-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- YWTPXFZSOUGVMT-UHFFFAOYSA-N 9-(2-bromoethyl)purin-2-amine Chemical compound NC1=NC=C2N=CN(CCBr)C2=N1 YWTPXFZSOUGVMT-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 235000021050 feed intake Nutrition 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000005360 mashing Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000010583 slow cooling Methods 0.000 description 3
- 238000007039 two-step reaction Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 208000007514 Herpes zoster Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000007034 nitrosation reaction Methods 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- KFUSEUYYWQURPO-UHFFFAOYSA-N 1,2-dichloroethene Chemical compound ClC=CCl KFUSEUYYWQURPO-UHFFFAOYSA-N 0.000 description 1
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical compound NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 description 1
- TUARVSWVPPVUGS-UHFFFAOYSA-N 5-nitrouracil Chemical compound [O-][N+](=O)C1=CNC(=O)NC1=O TUARVSWVPPVUGS-UHFFFAOYSA-N 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
Abstract
The present invention relates to a kind of preparation methods of famciclovir.Preparation method of the present invention, using guanidine nitrate and diethyl malonate as raw material, ring closure reaction obtains 2- amino -4 under alkaline condition, 6- pyrimidine glycol, 2-amino-4,6-dichloropyrimidine is obtained through hydroxy chloride again, afterwards and 2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl -1- amine reaction generate 6- it is chloro-N 4 (2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl) pyrimidine -2,4- diamines, it is reacted in acid condition with sodium nitrite again and obtains 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) propane -1, reduction/dechlorination, cyclization and esterification are finally obtained famciclovir by 3- glycol.The problems such as present invention solves current technique N- alkylated reaction poor selectivity, reaction intermediate needs additional purification.
Description
Technical field
The present invention relates to a kind of preparation methods of famciclovir, belong to pharmaceutical technology field.
Background technique
The famciclovir (Famciclovir, 1) that the 1990s is developed by SmithKline Beecham company is one
The new ucleosides broad-spectrum antiviral medicament of kind, is widely used in the diseases such as serious shingles zoster and primary genitalia herpes.Its
Chemical name are as follows: 2- [2- (2- amino -9H- purine -9- base) ethyl] -1,3-PD-diethylester, the following institute of chemical structure
Show:
。
Current existing famciclovir synthetic method patent mainly has: EP 182024, EP 0302644, US 5138057,
CN 108314685A, CN 101195622A, CN 100455583C；WO2004/110343, US5917041, CN
101555249B, CN 102924455A etc..
According to the design feature of famciclovir, its synthetic method mainly has two major classes:
The first kind is to synthesize general former times Lip river from different alkane side chain connections respectively using 2- amido-6-chloropurine as starting material
Wei.
Patent EP 182024, EP 0302644, US 5138057, CN 108314685A, CN 101195622A, CN
100455583C etc., the ratio around N-9/N-7 when improving N- alkylated reaction construct different types of alkane side respectively
Chain, relevant synthetic route are as follows:
Route (1-1) step is shorter, but raw material carboxylate side chain is not easy to obtain, and synthesis step is comparatively laborious.First step condensation
The N-7 position isomer (1/3 or so is accounted in reaction solution) generated in reaction is close with famciclovir property, it is not easy to remove, need
It to be separated using column chromatography technology, operation is complicated, needs a large amount of organic solvent.Therefore this method exists applied to industrial production
Very big difficulty.
Route (1-2) moderate length, raw material are easily obtained or synthesize, and each reaction condition that walks is mild, are not necessarily to special installation；Phase
Than route (1-1), though the route can reduce the ratio of N-7 isomer impurities to a certain extent, the impurity is still accounted in reaction solution
1/6 or so.
Second class is then to introduce alkane side chain in specific position using the pyrimidine ring of different substituents as starting material,
Famciclovir is synthesized finally by cyclization.Such as patent WO2004/110343, US5917041, CN 101555249B, CN
102924455A etc., relevant synthetic route are as follows:
Route (2-1) is using 5- nitrouracil as raw material, successively through chlorination, N- alkylation, ammonolysis, reduction, cyclization, halogenated etc.
6 steps, which are reacted, is made 2- amino -9- bromoethyl purine, can position and generate 9 purine substitution products, avoid N-7 position isomer
Generation.Therefore the patent report is a kind of preferable method for preparing famciclovir.But the patent reaction step is long, total to receive
Rate is 8%.
Step 6 bromo-reaction will use expensive carbon tetrabromide, and 2- amino -9- bromoethyl purine is unstable, meeting
Self-condensation (such as above formula), reduces product purity.
Route (2-2) is using 2-amino-4,6-dichloropyrimidine as raw material, successively through N- alkylation, esterification, diazotising, hydrogen
6 steps such as change, cyclization and dechlorination reaction synthesis famciclovir.The route steps are longer, wherein the object of 2-amino-4,6-dichloropyrimidine
Expect that price is higher；Parachloroanilinum diazonium salt needs current existing system, stability and safety be not high, and furthermore the diazonium salt makes
With the Material Cost that also will increase route.
In summary, inevitably there is N- alkylated reaction poor selectivity in existing first kind route, generate compared with
More N-7 position isomer impurity generally requires column chromatography or additional purification process to remove this impurity to ensure finished product
Quality it is unaffected, certainly will will lead in this way yield decline, cost increase, it is cumbersome the problems such as, be unfavorable for industrial metaplasia
It produces.Though the second class route can avoid the generation of N-7 position isomer impurity, there are steps to grow partially for route (2-1), and yield is low, four
The disadvantage that bromination carbon is expensive and intermediate 2-amino -9- bromoethyl purine is unstable；That there are steps is longer for route (2-2),
The material price of material 2-amino-4,6-dichloropyrimidine is higher, and parachloroanilinum diazonium salt needs current existing system, and it is hidden to there is safety
The deficiencies of suffering from.
Summary of the invention
The technical problem to be solved by the present invention is based on above-mentioned route there are the problem of, a kind of system of famciclovir is provided
Preparation Method needs additional purification, technique to solve N- alkylated reaction poor selectivity, reaction intermediate present in above-mentioned route
It is cumbersome, intermediate is unstable, the use of diazonium salt the problems such as there are security risk and productions at high cost.
Technical solution
The technical scheme is that a kind of preparation method of famciclovir, using guanidine nitrate and diethyl malonate as raw material,
Ring closure reaction obtains 2- amino -4,6- pyrimidine glycol under alkaline condition, then through hydroxy chloride to obtain 2- amino -4,6- dichloro phonetic
Pyridine, afterwards and 2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl -1- amine reaction generate 6- it is chloro-N 4 (2-(2,2- dimethyl-
1,3- dioxanes -5- base) ethyl) pyrimidine -2,4- diamines, then reacted in acid condition with sodium nitrite and obtain 2- (2- ((2-
The chloro- 5- nitroso pyrimidine-4-yl of amino -6-) amino) ethyl) propane -1,3- glycol, finally by reduction/dechlorination, cyclization and ester
Change reaction and obtains famciclovir with one pot process.Synthetic route described in the technical solution is as follows:
The preparation method of famciclovir of the present invention, comprising the following steps:
The preparation of first step 2- amino -4,6- pyrimidine glycol, that is, 5 compound of formula:
Using guanidine nitrate described in formula 6 and diethyl malonate as starting material, thermal dehydration cyclization is closed in organic alkali alcosol
It at 2- amino -4,6- pyrimidine glycol, is concentrated under reduced pressure after completion of the reaction, water dissolution, subsequent dilute hydrochloric acid solution is added into residue
Acidification, obtains 5 compound of formula.Wherein, the molar ratio of guanidine nitrate, diethyl malonate and organic base is 1:1 ~ 1.2:2 ~ 3, excellent
Select 1:1.04:2.5；Reaction temperature is 60 ~ 100 DEG C, preferably 60 ~ 80 DEG C；It is common that the organic base is selected from sodium methoxide, sodium ethoxide etc.
Highly basic；The alcoholic solution is C1 ~ C4 alcohol, is chosen in particular from methanol, ethyl alcohol, tert-butyl alcohol etc.；Reaction time is 0.5 ~ 12h；Acidification
Terminal is pH=6.
The preparation of second step 2- amino -4,6- dichloro pyrimidine:
2- amino -4,6- pyrimidine glycol is mixed with chlorination reagent, 4 compound 2-amino-4,6-dichloropyrimidine of preparation formula, with two
For the solution that chloromethanes and methanol volume ratio are 10:1 as solvent, TLC method detects raw material 2-amino-4,6-dichloropyrimidine without surplus
Reaction solution is poured into ice water and is quenched by Yu Hou, and solid product is precipitated.The chlorination reagent is selected from thionyl chloride, phosphorus oxychloride etc.,
Its dosage is 1 ~ 5 times of 2- amino -4,6- pyrimidine glycol mole；Reaction dissolvent is selected from non-protonic solvent such as bis- chloroethene of 1,2-
Alkane or not solubilizer；Reaction temperature is 60 ~ 100 DEG C, preferably 70 ~ 90 DEG C；Product should sufficiently elute filter cake when filtering, in order to avoid influence
The quality of product and next step are reacted when dry, and efflux pH value is advisable with 7.
Third step 6- is chloro-N 4 (2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl) pyrimidine -2,4- diamines system
It is standby:
With 2-amino-4,6-dichloropyrimidine and 2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl -1- amine be raw material, tiing up
In the presence of sour agent, 3 compound 6- of preparation formula is chloro-N 4 (2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl) pyrimidine -2,
4- diamines.Wherein, 2-amino-4,6-dichloropyrimidine and 2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl -1- amine throwing
Material molar ratio is 1:1 ~ 2, preferably 1:1 ~ 1.1；The acid binding agent is selected from the inorganic bases such as sodium carbonate, potassium carbonate, and feed intake mole
Usually 1 ~ 2 times of 2- amino -4,6- dichloro pyrimidine；Reaction dissolvent is selected from polar aprotic solvent, such as acetonitrile, N, N- diformazan
Base formamide etc.；Reaction temperature is 60 ~ 100 DEG C, preferably 70 ~ 90 DEG C；Reaction time is 18 ~ 22h.
4th step 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) propane -1,3- glycol is
Preparation:
Acid reagent is chloro- with 6-N 4 (2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl) pyrimidine -2,4- diamines crude product
It is sufficiently mixed under stiring, sodium nitrite solution, 2 compound 2- of preparation formula (2- ((the chloro- 5- nitrous of 2- amino -6- is then added
Yl pyrimidines -4- base) amino) ethyl) propane -1,3- glycol.Wherein, the inventory of sodium nitrite is that 6- is chloro-N 4 (2-(2,2- bis-
Methyl-1,3- dioxanes -5- base) ethyl) 1 ~ 3 times, preferably 1 ~ 2 times of pyrimidine -2,4- diamines mole；The acid reagent choosing
From the inorganic acids such as the organic acids such as formic acid, glacial acetic acid or dilute hydrochloric acid, dust technology, mole dosage is that raw material 6- is chloro-N 4 (2-(2,
2- dimethyl -1,3- dioxanes -5- base) ethyl) 3 ~ 4 times of pyrimidine -2,4- diamines mole；Reaction temperature is 60 ~ 100 DEG C,
Preferable temperature is 60 ~ 80 DEG C；Reaction time is 1 ~ 5h.
The preparation of 5th step famciclovir, that is, 1 compound of formula:
The reaction of this step divides three phases to carry out:
First stage is with 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) propane -1,3- glycol
Raw material, ethyl acetate make solvent, and dechlorination and nitroso reduction are completed under the action of ammonium formate/palladium carbon system；TLC(dichloro
Methane/methanol=4:1, V/V) detection raw material 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) third
After alkane -1,3- glycol is without residue, palladium carbon and ammonium salt are filtered out, filtrate filters out solid again after drying, retains filtrate；
The inventory of ammonium formate is 4 ~ 10 times, preferably 5 ~ 6 times of raw material glycol mole；Palladium carbon specification is selected from 3%, 5%, 10% etc.
Different model, preferably 5%, inventory are raw material 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl)
0.05 ~ 0.1 times of propane -1,3- glycol quality；Reaction temperature is 20 ~ 100 DEG C, preferably 60 ~ 80 DEG C；；Desiccant is selected from anhydrous
The conventional dryings reagent such as sodium sulphate, anhydrous magnesium sulfate；
Triethyl orthoformate and glacial acetic acid reaction are added into first step filtrate for second stage, and the structure of purine ring is completed through cyclization
It builds；
Raw material 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) propane -1,3- glycol and orthoformic acid
Triethyl, glacial acetic acid molar ratio be 1:1 ~ 1.5:1: ~ 1.5；Reaction temperature is 0 ~ 50 DEG C, and preferable temperature is 25 ~ 35 DEG C；Reaction
Time be 12 ~ for 24 hours；
Phase III, excessive acid binding agent was added into second step reaction solution, 4-dimethylaminopyridine and acetic anhydride was added, through ester
Change reaction and generates famciclovir.
The acid binding agent is selected from the organic bases such as triethylamine, pyridine；(((the chloro- 5- of 2- amino -6- is sub- by 2- by raw material 2- in the stage
Nitro-pyrimidine -4- base) amino) ethyl) propane -1,3- glycol and acid binding agent, 4-dimethylaminopyridine, acetic anhydride feed intake mole
Than for 1:3 ~ 6:0.05 ~ 0.15:5 ~ 8, preferably 1:3 ~ 3.5:0.05 ~ 0.1:6；Reaction temperature is 10 ~ 40 DEG C, preferable temperature 20
~30℃；Reaction temperature is 1 ~ 4h.
The invention has the advantages that providing a kind of preparation method of famciclovir, solve universal in current route
Existing N- alkylated reaction poor selectivity, reaction intermediate need that additional purification, technological operation are cumbersome, intermediate is unstable,
The use of diazonium salt the problems such as there are security risk and productions at high cost.The present invention is with guanidine nitrate and diethyl malonate
Starting material has synthesized famciclovir, each to walk that reaction condition is mild, simple and safe operation, reacts required material, reagent is
It large chemicals and is readily synthesized, production cost is low, is convenient for industrialized production.
In technical solution of the present invention, alkane side chain is (that is, 2-(2,2- dimethyl -1,3- dioxanes -5- in step 3 reaction
Base) ethyl -1- amine) double hydroxyls protected with propylidene, in this way can be to avoid the generation of by-product ether when alkylated reaction, to mention
The high selectivity and Atom economy of reaction；And propylidene protection can in the nitrosation reaction of next step simultaneous removing, be not necessarily to
Additional solution protects operation.Step 4 reaction using sodium nitrite be raw material introducing nitroso, instead of in route (2-4) to chlorobenzene
The use of amine diazonium salt (needing current existing system).Sodium nitrite has many advantages, such as that cheap, property is stable, highly-safe, so that
The step operation is simple, avoids the introducing of the impurity such as by-product such as parachloroanilinum.Final step uses one pot reaction, first
Removing and nitroso reduction that palladium carbon/ammonium formate completes 6- chlorine through catalytic transfer hydrogenation are first passed through, reaction solution is through filtering out palladium
Directly complete the building of imidazole ring after carbon, ammonium salt and drying through ring closure reaction with the triethyl orthoformate of addition and glacial acetic acid,
Suitable acid binding agent such as triethylamine and acetic anhydride is added into reaction solution again, the reaction was continued complete hydroxyl esterification be finally made general
VACV；The simplicity of operation can be played sharpest edges, extremely suitable industrialized production with reactive mode by this feed intake.
Compared with other existing routes, the advantage of the technical solution is: (1) route completely avoids N-7 isomery
The generation of body impurity, makes Atom economy be greatly improved；(2) each step reacts material used and is easy to get or easily prepared,
It is cheap, reduce the production cost of famciclovir；(3) respectively step reaction condition is mild, of less demanding to production equipment, is convenient for
Industrialized production；(4) four-step reactions replace diazonium salt to carry out nitrosation reaction using sodium nitrite, and safety coefficient is high；(5)
The reaction of five steps uses the strategy of one kettle way to collapse multistep reaction for a step, simplifies operation, shortens the production of famciclovir
Period.
Specific embodiment:
Content for a better understanding of the present invention is described further combined with specific embodiments below, but the present invention is not only limited to
This.
Embodiment 1
The first step, the synthesis of 2- amino -4,6- pyrimidine glycol
5 DEG C of temperature control, 30.52g(0.25mol is put into 500ml four-hole bottle) guanidine nitrate and 100ml methanol, stirring is opened, to solid
Body slowly instills the methanol solution 250ml, insulated and stirred 0.5h of 2.5M sodium methoxide after all dissolving；Then in above-mentioned reaction flask
Slowly instill 41.64g(0.26mol) diethyl malonate, drop is complete, is warming up to back flow reaction 6h.After reaction, it is concentrated under reduced pressure
Off-white powder is obtained afterwards.It is added into reaction flask after 60ml drinking water dissolves solid, with 10% dilute hydrochloric acid solution by system pH
Value is adjusted to 6, and a large amount of solids are precipitated at this time；It filters, and is eluted with drinking water, pressed dry, wet cake, to constant weight, is obtained in 60 DEG C of forced air dryings
Off-white color product 29.74g, this step yield are that 93.6%, HPLC purity is 99.2%.
Embodiment 2
The first step, the synthesis of 2- amino -4,6- pyrimidine glycol
5 DEG C of temperature control, 30.52g(0.25mol is put into 500ml four-hole bottle) guanidine nitrate and 100ml dehydrated alcohol, stirring is opened,
The ethanol solution 250ml, insulated and stirred 0.5h of 2.5M sodium methoxide are slowly instilled after the solid is completely dissolved；Then to above-mentioned reaction
41.64g(0.26mol is slowly instilled in bottle) diethyl malonate, drop is complete, is warming up to 65 DEG C of reaction 6h.After reaction, it depressurizes
Off-white powder is obtained after concentration.It is added into reaction flask after 60ml drinking water dissolves solid, with 10% dilute hydrochloric acid solution by body
It is that pH value is adjusted to 6, a large amount of solids is precipitated at this time；It filters, and is eluted with drinking water, pressed dry, wet cake is in 60 DEG C of forced air dryings to perseverance
Weight, obtains off-white color product 30.56g, this step yield is that 96.10%, HPLC purity is 99.7%.
Embodiment 3
The first step, the synthesis of 2- amino -4,6- pyrimidine glycol
5 DEG C of temperature control, 30.52g(0.25mol is put into 500ml four-hole bottle) guanidine nitrate and 100ml dehydrated alcohol, stirring is opened,
The ethanol solution 250ml, insulated and stirred 0.5h of 2.5M sodium ethoxide are slowly instilled after the solid is completely dissolved；Then to above-mentioned reaction
41.64g(0.26mol is slowly instilled in bottle) diethyl malonate, drop is complete, is warming up to back flow reaction 4h.After reaction, it depressurizes
Off-white powder is obtained after concentration.It is added into reaction flask after 60ml drinking water dissolves solid, with 10% dilute hydrochloric acid solution by body
It is that pH value is adjusted to 6, a large amount of solids is precipitated at this time；It filters, and is eluted with drinking water, pressed dry, wet cake is in 60 DEG C of forced air dryings to perseverance
Weight, obtains off-white color product 28.78g, this step yield is that 90.59%, HPLC purity is 99.7%.
Embodiment 4
Second step, the synthesis of 2-amino-4,6-dichloropyrimidine
At room temperature, 2- amino -4,6- pyrimidine glycol 28.00g(0.22mol), thionyl chloride 80ml(1.1mol) is put into 250ml
In four-hole bottle, it is warming up to back flow reaction 4h.After reaction, heating is closed, is cooled to room temperature and reaction solution is slowly poured into ice water
In be quenched.A large amount of solids are precipitated at this time, filter, it is 7 that filter cake, which is eluted with drinking water to pH value,.Wet cake is in 60 DEG C of forced air dryings to perseverance
Weight, obtains light yellow product 33.45g, this step yield is that 92.7%, HPLC purity is 99.1%.
Embodiment 5
Second step, the synthesis of 2-amino-4,6-dichloropyrimidine
At room temperature, 2- amino -4,6- pyrimidine glycol 28.00g(0.22mol), phosphorus oxychloride 80ml(0.86mol) is put into
In 250ml four-hole bottle, it is warming up to 80 DEG C of reaction 4h.After reaction, heating is closed, is cooled to room temperature and slowly pours into reaction solution
It is quenched in ice water.A large amount of solids are precipitated at this time, filter, it is 7 that filter cake, which is eluted with drinking water to pH value,.Wet cake is in 60 DEG C of forced air dryings
To constant weight, light yellow product 32.66g is obtained, this step yield is that 90.5%, HPLC purity is 88.9%.
Embodiment 6
Second step, the synthesis of 2-amino-4,6-dichloropyrimidine
At room temperature, by 2- amino -4,6- pyrimidine glycol 28.00g(0.22mol), 1,2- dichloroethanes 100ml, phosphorus oxychloride
It 20ml(0.28mol) puts into 250ml four-hole bottle, is warming up to back flow reaction 6h.After reaction, heating is closed, room temperature is down to
Reaction solution is slowly poured into ice water afterwards and is quenched.A large amount of solids are precipitated at this time, filter, it is 7 that filter cake, which is eluted with drinking water to pH value,.
Wet cake obtains light yellow product 32.98g in 60 DEG C of forced air dryings to constant weight, this step yield is that 91.4%, HPLC purity is 99.3%.
Embodiment 7
Third step, 6- are chloro-N 4 (2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl) pyrimidine -2,4- diamines synthesis
At room temperature, into 1000ml four-hole bottle put into 2-amino-4,6-dichloropyrimidine 29.51g(0.18mol), potassium carbonate
37.32g(0.27mol), 2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl -1- amine 30.25g(0.19mol) and 600ml
DMF opens stirring, is warming up to 80 DEG C, insulation reaction 18h.End of reaction closes heating, wait be cooled to room temperature, filters, decompression
DMF is fallen in concentration, obtains brown color heat-bodied oil, this step yield directly casts single step reaction in terms of 100%.
Embodiment 8
Third step, 6- are chloro-N 4 (2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl) pyrimidine -2,4- diamines synthesis
At room temperature, into 1000ml four-hole bottle put into 2-amino-4,6-dichloropyrimidine 29.51g(0.18mol), potassium carbonate
37.32g(0.27mol), 2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl -1- amine 30.25g(0.19mol) and 600ml
Acetonitrile opens stirring, is warming up to reflux, insulation reaction 20h.End of reaction closes heating, wait be cooled to room temperature, filters, decompression
Acetonitrile is fallen in concentration, obtains brown color heat-bodied oil, this step yield directly casts single step reaction in terms of 100%.
Embodiment 9
Third step, 6- are chloro-N 4 (2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl) pyrimidine -2,4- diamines synthesis
At room temperature, into 1000ml four-hole bottle put into 2-amino-4,6-dichloropyrimidine 29.51g(0.18mol), sodium carbonate
28.62g(0.27mol), 2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl -1- amine 30.25g(0.19mol) and 600ml
DMF opens stirring, is warming up to 80 DEG C, insulation reaction 22h.End of reaction closes heating, wait be cooled to room temperature, filters, decompression
DMF is fallen in concentration, obtains brown color heat-bodied oil, this step yield directly casts single step reaction in terms of 100%.
Embodiment 10
4th step, the synthesis of 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) propane -1,3- glycol
It is 0 DEG C of temperature control, 6- is chloro-N 4 (2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl) pyrimidine -2,4- diamines
(0.18mol), 25% glacial acetic acid solution 150ml are successively put into the four-hole bottle of 500ml, are uniformly mixed, are then slowly added dropwise
25% sodium nitrite in aqueous solution 100ml(0.36mol), drop finishes, and is warming up to 80 DEG C of reaction 1h.Reaction terminates to be down to 0 to reaction solution
DEG C, with 10% sodium hydroxide solution tune pH=7, when being concentrated under reduced pressure into no working fluid, repeated to extract product 2 with 150ml n-butanol
It is secondary, merge organic phase；After anhydrous sodium sulfate is dry, it is concentrated to dryness, obtains Chinese red heat-bodied oil, as 2- (2- ((2- amino -6-
Chloro- 5- nitroso pyrimidine-4-yl) amino) ethyl) and propane -1,3- glycol crude product.
Acetone 100ml is put into above-mentioned crude product, is handled 3h in 25 DEG C of mashing, is then filtered, press dry, it is dry to set 40 DEG C of decompressions
Dry to obtain 45.17g Chinese red product to constant weight, it be 91.12%, HPLC purity is 98.6% that two-step reaction, which merges yield,.
Embodiment 11
4th step, the synthesis of 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) propane -1,3- glycol
It is 0 DEG C of temperature control, 6- is chloro-N 4 (2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl) pyrimidine -2,4- diamines
(0.18mol), 10% dilute hydrochloric acid solution 230ml are successively put into the four-hole bottle of 500ml, are uniformly mixed, are then slowly added dropwise
25% sodium nitrite in aqueous solution 100ml(0.36mol), drop finishes, 60 DEG C of reaction 3h of temperature control.Reaction terminates to be down to 0 to reaction solution
DEG C, with 10% sodium hydroxide solution tune pH=7, when being concentrated under reduced pressure into no working fluid, repeated to extract product 2 with 150ml n-butanol
It is secondary, merge organic phase；After anhydrous sodium sulfate is dry, it is concentrated to dryness, obtains Chinese red heat-bodied oil, as 2- (2- ((2- amino -6-
Chloro- 5- nitroso pyrimidine-4-yl) amino) ethyl) and propane -1,3- glycol crude product.
Acetone 100ml is put into above-mentioned crude product, is handled 3h in 25 DEG C of mashing, is then filtered, press dry, it is dry to set 40 DEG C of decompressions
Dry to obtain 44.82g Chinese red product to constant weight, it be 90.38%, HPLC purity is 98.3% that two-step reaction, which merges yield,.
Embodiment 12
4th step, the synthesis of 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) propane -1,3- glycol
It is 0 DEG C of temperature control, 6- is chloro-N 4 (2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl) pyrimidine -2,4- diamines
(0.18mol), 10% dilute nitric acid solution 230ml are successively put into the four-hole bottle of 500ml, are uniformly mixed, are then slowly added dropwise
25% sodium nitrite in aqueous solution 100ml(0.36mol), drop finishes, 60 DEG C of reaction 3h of temperature control.Reaction terminates to be down to 0 to reaction solution
DEG C, with 10% sodium hydroxide solution tune pH=7, when being concentrated under reduced pressure into no working fluid, repeated to extract product 2 with 150ml n-butanol
It is secondary, merge organic phase；After anhydrous sodium sulfate is dry, it is concentrated to dryness, obtains Chinese red heat-bodied oil, as 2- (2- ((2- amino -6-
Chloro- 5- nitroso pyrimidine-4-yl) amino) ethyl) and propane -1,3- glycol crude product.
Acetone 100ml is put into above-mentioned crude product, is handled 3h in 25 DEG C of mashing, is then filtered, press dry, it is dry to set 40 DEG C of decompressions
Dry to obtain 44.96g Chinese red product to constant weight, it be 90.66%, HPLC purity is 98.2% that two-step reaction, which merges yield,.
Embodiment 13
5th step, the synthesis of famciclovir
By 35.00g 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) propane -1,3- glycol
(0.13mol), ethyl acetate 350.00g, ammonium formate 49.16g(0.78mol) and 5% palladium carbon 3.50g put into four mouthfuls of reaction flasks
In, 65 DEG C are warming up to, insulation reaction 22h；Reaction terminates, and filters, and then to anhydrous sodium sulfate 20.00g is put into mother liquor, stirs
0.5h retains mother liquor after filtering again.Triethyl orthoformate 22.23g(0.15mol is put into above-mentioned mother liquor) and glacial acetic acid
9.00g(0.15mol), in 30 DEG C of insulation reaction 20h；Reaction terminates, and triethylamine 43.51g(0.43mol is added into reaction flask)
With DMAP 1.47g(0.012mol), acetic anhydride 79.64g(0.78mol is added dropwise in 30 DEG C of subsequent temperature control), drop is complete, and the reaction was continued
To terminal, with continuing to be quenched 1h behind 10% sodium carbonate liquor tune pH=7,25 DEG C of standing liquid separations retain ethyl acetate phase, decompression to 1.5h
It is concentrated to give off-white powder, obtains famciclovir crude product 38.02g, this step yield is 91.01%.
N-butanol 60.00g is put into above-mentioned crude product, is heated to flowing back, is heated to flowing back, after the solid is completely dissolved,
Slow cooling crystallization is filtered, is pressed dry, wet product sets 60 DEG C of forced air dryings to constant weight, obtains 34.96g white crystals in 25 DEG C of growing the grain 2h
Powder, this step yield are 92.12%, and final product quality meets USP quality standard.
Embodiment 14
5th step, the synthesis of famciclovir
By 35.00g 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) propane -1,3- glycol
(0.13mol), ethyl acetate 350.00g, ammonium formate 49.16g(0.78mol) and 10% palladium carbon 1.75g put into four mouthfuls of reaction flasks
In, 65 DEG C are warming up to, insulation reaction 12h；Reaction terminates, and filters, and then to anhydrous sodium sulfate 20.00g is put into mother liquor, stirs
0.5h retains mother liquor after filtering again.Triethyl orthoformate 22.23g(0.15mol is put into above-mentioned mother liquor) and glacial acetic acid
9.00g(0.15mol), in 30 DEG C of insulation reaction 20h；Reaction terminates, and triethylamine 43.51g(0.43mol is added into reaction flask)
With DMAP 1.47g(0.012mol), acetic anhydride 79.64g(0.78mol is added dropwise in 25 DEG C of subsequent temperature control), drop finishes the reaction was continued 2h
To terminal, with continuing to be quenched 1h behind 10% sodium carbonate liquor tune pH=7,25 DEG C of standing liquid separations retain ethyl acetate phase, are concentrated under reduced pressure
Off-white powder is obtained, famciclovir crude product 38.51g is obtained, this step yield is 92.23%.
N-butanol 60.00g is put into above-mentioned crude product, is heated to flowing back, after the solid is completely dissolved, slow cooling analysis
Crystalline substance is filtered, is pressed dry, wet product sets 60 DEG C of forced air dryings to constant weight, obtains 34.67g white crystalline powder, this step in 25 DEG C of growing the grain 2h
Yield is 90.02%, and final product quality meets USP quality standard.
Embodiment 15
5th step, the synthesis of famciclovir
By 35.00g 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) propane -1,3- glycol
(0.13mol), ethyl acetate 350.00g, ammonium formate 49.16g(0.78mol) and 10% palladium carbon 3.50g put into four mouthfuls of reaction flasks
In, 65 DEG C are warming up to, insulation reaction 5h；Reaction terminates, and filters, and then to anhydrous magnesium sulfate 20.00g is put into mother liquor, stirs
0.5h retains mother liquor after filtering again.Triethyl orthoformate 22.23g(0.15mol is put into above-mentioned mother liquor) and glacial acetic acid
9.00g(0.15mol), in 30 DEG C of insulation reaction 20h；Reaction terminates, and pyridine 34.00g(0.43mol is added into reaction flask) and
DMAP 1.47g(0.012mol), acetic anhydride 79.64g(0.78mol is added dropwise in 20 DEG C of subsequent temperature control), drop finishes the reaction was continued 2.5h
To terminal, with continuing to be quenched 1h behind 10% sodium carbonate liquor tune pH=7,25 DEG C of standing liquid separations retain ethyl acetate phase, are concentrated under reduced pressure
Off-white powder is obtained, famciclovir crude product 39.38g is obtained, this step yield is 94.32%.
N-butanol 60.00g is put into above-mentioned crude product, is heated to flowing back, after the solid is completely dissolved, slow cooling analysis
Crystalline substance is filtered, is pressed dry, wet product sets 60 DEG C of forced air dryings to constant weight, obtains 35.73g white crystalline powder, this step in 25 DEG C of growing the grain 2h
Yield is 90.73%, and final product quality meets USP quality standard.
Claims (10)
1. a kind of preparation method of famciclovir, spy is being, comprising the following steps:
The preparation of first step 2- amino -4,6- pyrimidine glycol, that is, 5 compound of formula:
,
Using guanidine nitrate described in formula 6 and diethyl malonate as starting material, thermal dehydration cyclization is closed in organic alkali alcosol
It at 2- amino -4,6- pyrimidine glycol, is concentrated under reduced pressure after completion of the reaction, water dissolution is added into residue, then with dilute hydrochloric acid acid
Change reaction solution, obtain 5 compound of formula, the organic base is selected from the common highly basic such as sodium methoxide, sodium ethoxide, the alcoholic solution be C1 ~
The solution of C4 alcohol, reaction temperature are 60 ~ 100 DEG C, the molar ratio of guanidine nitrate, diethyl malonate and organic base be 1:1 ~
1.2:2 ~ 3；
The preparation of second step 2- amino -4,6- dichloro pyrimidine:
,
2- amino -4,6- pyrimidine glycol is mixed with chlorination reagent, 4 compound 2-amino-4,6-dichloropyrimidine of preparation formula, with two
The mixed solvent that chloromethanes and methanol volume ratio are 10:1 detects raw material 2-amino-4,6-dichloropyrimidine as solvent, TLC method
After residue, reaction solution is poured into ice water and is quenched, solid product is precipitated, the chlorination reagent is selected from thionyl chloride, trichlorine oxygen
Phosphorus etc., reaction dissolvent are selected from non-protonic solvent or not solubilizer；Reaction temperature is 60 ~ 100 DEG C；
Third step 6- is chloro-N 4 (2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl) pyrimidine -2,4- diamines preparation:
,
With 2-amino-4,6-dichloropyrimidine and 2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl -1- amine be raw material, tiing up
In the presence of sour agent, 3 compound 6- of preparation formula is chloro-N 4 (2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl) pyrimidine -2,
4- diamines, wherein 2-amino-4,6-dichloropyrimidine and 2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl -1- amine throwing
Material molar ratio is 1:1 ~ 2, and the acid binding agent is selected from the inorganic bases such as sodium carbonate, potassium carbonate, and the mole that feeds intake of acid binding agent is 2- ammonia
1 ~ 2 times of base -4,6- dichloro pyrimidine, reaction dissolvent are selected from acetonitrile, n,N-Dimethylformamide, and reaction temperature is 60 ~ 100 DEG C；
4th step 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) propane -1,3- glycol, that is, formula
(2) preparation of compound:
,
Acid reagent is chloro- with 6-N 4 (2-(2,2- dimethyl -1,3- dioxanes -5- base) ethyl) pyrimidine -2,4- diamines crude product
It is sufficiently mixed under stiring, sodium nitrite solution, 2 compound 2- of preparation formula (2- ((the chloro- 5- nitrous of 2- amino -6- is then added
Yl pyrimidines -4- base) amino) ethyl) propane -1,3- glycol, wherein the inventory of sodium nitrite is that 6- is chloro-N 4 (2-(2,2- bis-
Methyl-1,3- dioxanes -5- base) ethyl) 1 ~ 3 times of pyrimidine -2,4- diamines mole, the acid reagent is selected from formic acid, ice
The organic acids such as acetic acid or dilute hydrochloric acid, dust technology, the mole dosage of acid reagent are that raw material 6- is chloro-N 4 (2-(2,2- diformazan
Base -1,3- dioxanes -5- base) ethyl) 3 ~ 4 times of pyrimidine -2,4- diamines mole, reaction temperature is 60 ~ 100 DEG C, when reaction
Between be 1 ~ 5h；
The preparation of 5th step famciclovir, that is, 1 compound of formula:
,
This step reaction divides three phases to carry out:
First stage is with 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) propane -1,3- glycol
Raw material, ethyl acetate make solvent, and dechlorination and nitroso reduction are completed under the action of ammonium formate/palladium carbon system；With dichloromethane
The mixed solvent that the volume ratio of alkane and methanol is 4:1 is solvent, and TLC method detects raw material 2-, and (((the chloro- 5- of 2- amino -6- is sub- by 2-
Nitro-pyrimidine -4- base) amino) ethyl) and propane -1,3- glycol without residue after, filter out palladium carbon and ammonium salt, filtrate is after drying again
Solid is filtered out, filtrate is retained；
The inventory of ammonium formate is 4 ~ 10 times of raw material glycol mole, and palladium carbon inventory is raw material 2- (2- ((2- amino -6-
Chloro- 5- nitroso pyrimidine-4-yl) amino) ethyl) 0.05 ~ 0.1 times of propane -1,3- glycol quality；Reaction temperature is 60 ~ 80
℃；；Desiccant is selected from the conventional dryings reagents such as anhydrous sodium sulfate, anhydrous magnesium sulfate；
Triethyl orthoformate and glacial acetic acid reaction are added into first step filtrate for second stage, and the structure of purine ring is completed through cyclization
It builds；
Raw material 2- (2- ((the chloro- 5- nitroso pyrimidine-4-yl of 2- amino -6-) amino) ethyl) propane -1,3- glycol and orthoformic acid
Triethyl, glacial acetic acid molar ratio be 1:1 ~ 1.5:1: ~ 1.5；Reaction temperature is 25 ~ 35 DEG C；
Phase III, excessive acid binding agent was added into second step reaction solution, 4-dimethylaminopyridine and acetic anhydride was added, through ester
Change reaction and generate famciclovir, the acid binding agent is selected from triethylamine, pyridine, raw material 2- (2- ((the chloro- 5- nitroso of 2- amino -6-
Pyrimidine-4-yl) amino) ethyl) propane -1,3- glycol and the molar ratio of acid binding agent, 4-dimethylaminopyridine, acetic anhydride be
1:3 ~ 3.5:0.05 ~ 0.1:6；Reaction temperature is 20 ~ 30 DEG C.
2. the preparation method of famciclovir according to claim 1, spy is being, in first step reaction, guanidine nitrate, the third two
The molar ratio of diethyl phthalate and organic base is 1:1.04:2.5.
3. the preparation method of famciclovir according to claim 1, spy is being, reaction temperature is 60 in first step reaction
~ 80 DEG C, the acidification terminal is pH=6.
4. the preparation method of famciclovir according to claim 1, spy is being, the first step reacts the alcohol and is selected from first
Alcohol, ethyl alcohol, the tert-butyl alcohol.
5. the preparation method of famciclovir according to claim 1, spy is being, the dosage of second step chlorinating agent is 2- ammonia
1 ~ 5 times of base -4,6- pyrimidine glycol mole.
6. the preparation method of famciclovir according to claim 1, spy is being, second step reaction dissolvent is selected from 1,2- bis-
Chloroethanes, reaction temperature are selected from 70 ~ 90 DEG C.
7. the preparation method of famciclovir according to claim 1, spy is being that third step 2- amino -4,6- dichloro is phonetic
Pyridine and 2-(2,2- dimethyl -1,3- dioxanes -5- base) molar ratio of ethyl -1- amine is 1:1 ~ 1.1.
8. the preparation method of famciclovir according to claim 1, spy is being, third step reaction temperature is 70 ~ 90 DEG C.
9. the preparation method of famciclovir according to claim 1, spy is being, the throwing of the 5th step first stage ammonium formate
Doses is 5 ~ 6 times of raw material glycol mole.
10. the preparation method of famciclovir according to claim 1, spy is being, the 5th step first stage ammonium formate
Inventory is 5 ~ 6 times of raw material glycol mole.
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Cited By (3)
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| CN111620831A (en) * | 2020-07-06 | 2020-09-04 | 山东国邦药业有限公司 | Preparation method of cyromazine |
| CN112159408A (en) * | 2020-09-24 | 2021-01-01 | 天津市科莱博瑞科技有限公司 | Preparation method of bicyclic guanidine compound |
| CN112979653A (en) * | 2019-12-12 | 2021-06-18 | 上药康丽（常州）药业有限公司 | Method for synthesizing famciclovir by using microchannel reactor |
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