CN104072539A - Tenofovir bis(4-acetaminophenoloxy)ester, and preparation method and application thereof - Google Patents
Tenofovir bis(4-acetaminophenoloxy)ester, and preparation method and application thereof Download PDFInfo
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- CN104072539A CN104072539A CN201310098149.3A CN201310098149A CN104072539A CN 104072539 A CN104072539 A CN 104072539A CN 201310098149 A CN201310098149 A CN 201310098149A CN 104072539 A CN104072539 A CN 104072539A
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- Prior art keywords
- tynofovir
- preparation
- combination
- solution
- method described
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Links
- 150000002148 esters Chemical class 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title abstract description 13
- 229960004556 tenofovir Drugs 0.000 title abstract 4
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 99
- 239000000243 solution Substances 0.000 claims description 64
- -1 4-acetoamidophenol oxygen Chemical compound 0.000 claims description 59
- 239000002585 base Substances 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000004821 distillation Methods 0.000 claims description 18
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 17
- 239000000725 suspension Substances 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 241000700605 Viruses Species 0.000 claims description 10
- 238000005660 chlorination reaction Methods 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- 230000003068 static effect Effects 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 6
- 150000004682 monohydrates Chemical class 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 235000002639 sodium chloride Nutrition 0.000 claims description 6
- 239000011782 vitamin Substances 0.000 claims description 6
- 229940088594 vitamin Drugs 0.000 claims description 6
- 229930003231 vitamin Natural products 0.000 claims description 6
- 235000013343 vitamin Nutrition 0.000 claims description 6
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-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
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 4
- 239000012267 brine Substances 0.000 claims description 4
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 claims description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 4
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- 241000700721 Hepatitis B virus Species 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 239000002274 desiccant Substances 0.000 claims description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- 229960005489 paracetamol Drugs 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
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 2
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 2
- 235000011151 potassium sulphates 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
- 239000000843 powder Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 239000007787 solid Substances 0.000 abstract description 11
- 229940002612 prodrug Drugs 0.000 abstract description 5
- 239000000651 prodrug Substances 0.000 abstract description 5
- 208000030507 AIDS Diseases 0.000 abstract description 2
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 abstract description 2
- 206010070863 Toxicity to various agents Diseases 0.000 abstract description 2
- 208000002672 hepatitis B Diseases 0.000 abstract description 2
- 230000000071 effect on fever Effects 0.000 abstract 1
- 238000001415 gene therapy Methods 0.000 abstract 1
- 230000009044 synergistic interaction Effects 0.000 abstract 1
- 239000010410 layer Substances 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- 238000001819 mass spectrum Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000002155 anti-virotic effect Effects 0.000 description 4
- 239000002777 nucleoside Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 230000001754 anti-pyretic effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- LTVDTKRMOQDRCH-UHFFFAOYSA-N furan;1h-pyrrole Chemical class C=1C=CNC=1.C=1C=COC=1 LTVDTKRMOQDRCH-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 125000003835 nucleoside group Chemical group 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- ADVGKWPZRIDURE-UHFFFAOYSA-N 2'-Hydroxyacetanilide Chemical compound CC(=O)NC1=CC=CC=C1O ADVGKWPZRIDURE-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000005340 bisphosphate group Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to tenofovir bis(4-acetaminophenoloxy)ester as shown in a formula I which is described in the specification, and a preparation method and application thereof. The tenofovir bis(4-acetaminophenoloxy)ester provided by the invention is in a solid state, improves dissolvability of a prodrug, reduces drug toxicity and exerts a synergistic interaction effect on fever and gene therapy of patients with hepatitis-B or AIDS. Compared with PMPA, the tenofovir bis(4-acetaminophenoloxy)ester provided by the invention has a more excellent antiviral effect.
Description
Technical field
[0001] the invention belongs to field of medicine preparing technology, be specifically related to two (4-acetoamidophenol oxygen base) esters of tynofovir and preparation method thereof and its application.
Background technology
Phosphonylmethoxy yl nucleosides acid-like substance is the known broad-spectrum antiviral compound of a class, has anti-AIDS (HIV) virus and the viral isoreactivity of anti-hepatitis b (HBV).Wherein, 9-[(R)-2-(phosphonylmethoxy base) propyl group] VITAMIN B4 (claiming again tynofovir) has been widely used in clinical antiviral therapy.But the phosphonate radical in phosphonylmethoxy yl nucleosides acid-like substance affects absorption of human body, and then affect the bioavailability of medicine.For this reason, phosphonylmethoxy yl nucleosides acid-like substance need to be changed into lipophilic prodrug and improve its bioavailability.First that the two pyrrole furan esters (TDF) of fumaric acid tynofovir are FDA Food and Drug Administration (FDA) approval is used for the treatment of the nucleoside analog that HIV-1 infects.TDF is the prodrug of tynofovir, is metabolised in vivo the parent drug tynofovir with antivirus action.
The two pyrrole furan esters (TDF) of fumaric acid tynofovir
At present, the prodrug of tynofovir is all modified into dibasic acid esters by tynofovir phosphonate group, and modified outcome is oily more, and existence and stability is poor, is unfavorable for the defects such as the preparation of medicine and preparation thereof and storage.For this reason, the mode of oily matter acid adding (as fumaric acid, toxilic acid, the succsinic acid etc.) salify after modifying need be solidified, but be brought thus into some invalid components, and then be affected drug effect, security and the consumption of medicine.
Summary of the invention
The object of the present invention is to provide structure suc as formula two (4-acetoamidophenol oxygen base) the phosphonylmethoxy base propyl group of (the R)-9-[2-shown in I] VITAMIN B4 (abbreviation Compound I),
(formula I)
Another object of the present invention is to provide a kind of (R)-9-[2-two (paracetamol base) phosphonylmethoxy base propyl group] preparation method of VITAMIN B4, comprise the steps:
1) tynofovir (II) or its monohydrate are suspended in solvent, under catalyzer exists, in tynofovir or its monohydrate suspension, drip chlorination reagent, after dropwising, return stirring, after reacting completely, reaction solution is cooled to room temperature, vacuum rotary steam is removed after volatile matter, make the two phosphonyl chlorides (III) of tynofovir, wherein, tynofovir or its monohydrate: the mol ratio of chlorination reagent is 1:1～10, is preferably 1:5;
2) under alkali, catalyzer existence condition, the two phosphonyl chlorides of tynofovir and acamol (IV) are placed in to solvent, after condensation reaction completes, add salt brine solution cancellation reaction, wherein, the two phosphonyl chlorides of tynofovir: the mol ratio of acamol is 1:2～5, is preferably 1:3; The two phosphonyl chlorides of tynofovir: the mol ratio of alkali is 1:3～10, is preferably 1:5;
3) reaction solution static layering, get organic layer, by after organic layer successively water, saturated common salt water washing, then drying agent dry after, filter, remove siccative, collect filtrate, vacuum rotary steam, distillation leftover solvent crystallization, dry, make two (the 4-acetoamidophenol oxygen base) esters of tynofovir.
In the preferred technical solution of the present invention, step 1) chlorination reagent described in is selected from any or its combination of Acetyl Chloride 98Min., oxalyl chloride, thionyl chloride, phosphorus oxychloride.
In the preferred technical solution of the present invention, step 1) solvent described in is selected from methylene dichloride, 1,2-ethylene dichloride, N, any or its combination in dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, benzene,toluene,xylene.
In the preferred technical solution of the present invention, step 1) described in, catalyzer is selected from DMF, N, any or its combination in N-diethylformamide, N,N-dimethylacetamide, titanium tetrachloride, tin tetrachloride, aluminum chloride, iron trichloride.
In the preferred technical solution of the present invention, step 1) chlorination reaction temperature described in is 20 ~ 80 ℃, is preferably 40 ~ 60 ℃.
In the preferred technical solution of the present invention, step 1) the chlorination reaction time described in is 2 ~ 8h, is preferably 6h.
In the preferred technical solution of the present invention, step 2) alkali described in is selected from triethylamine, tripropyl amine, Tributylamine, diisopropyl ethyl amine, pyridine, 2, any or its combination in 6-lutidine, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride KH, hydrolith, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide.
In the preferred technical solution of the present invention, step 2) catalyzer described in is selected from any or its combination in titanium tetrachloride, tin tetrachloride, aluminum chloride, iron trichloride.
In the preferred technical solution of the present invention, step 2) solvent described in is selected from methylene dichloride, 1,2-ethylene dichloride, N, any or its combination in dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, benzene,toluene,xylene.
In the preferred technical solution of the present invention, step 2) described in, the temperature of condensation reaction is-50 ~ 80 ℃, is preferably-10 ~ 30 ℃.
In the preferred technical solution of the present invention, step 2) described in, the reaction times of condensation reaction is 1 ~ 10h, is preferably 5 ~ 8h.
In the preferred technical solution of the present invention, step 2) salt brine solution described in is selected from any or its combination of sodium chloride aqueous solution, potassium chloride solution, aqueous sodium persulfate solution, potassium sulfate solution.
In the preferred technical solution of the present invention, step 3) siccative described in is selected from any or its combination of anhydrous sodium sulphate, anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, Vanadium Pentoxide in FLAKES.
In the preferred technical solution of the present invention, the recrystallisation solvent described in step 3) is selected from any or its combination of methylene dichloride, ethyl acetate, methyl alcohol, ethanol, Virahol, sherwood oil, normal hexane, normal heptane, toluene.
Another object of the present invention is to provide two (the 4-acetoamidophenol oxygen base) esters of tynofovir for the preparation of the application in the medicine of any or its combination of antiviral, antipyretic-antalgic.
In the preferred technical solution of the present invention, described virus is selected from any or its combination of hepatitis B virus, HIV virus.
The present invention obtain hydrogen spectrum (
1hNMR) instrument that data are used is the 400 megahertz nuclear magnetic resonance analyser (Bruker Advance II 400 MHz) of Brooker company.Tetramethylsilane (TMS) is marked in doing, and room temperature is collected.Chemical shift (δ) is 1,000,000/(ppm).The unimodal s that is denoted as, doublet is denoted as d, and triplet is denoted as t, and quartet is denoted as q, and multiplet is denoted as m, the wide unimodal brs that is denoted as.Coupling constant is denoted as J, and unit is ppm.Deuterated solvent is deuterated dimethyl sulfoxide (DMSO-
d 6).
It is Shimadzu LC-MS instrument (Shimadzu LCMS 2010EV) that the present invention obtains the instrument that mass spectrum (MS) data are used, and forward (positive) provides the quasi-molecular ions (MH of molecular weight hydrogenation
+).
Except as otherwise noted, while the present invention relates to the per-cent between liquid and liquid, described per-cent is volume/volume per-cent; While the present invention relates to the per-cent between liquid and solid, described per-cent is volume/weight per-cent; While the present invention relates to the per-cent between solid and liquid, described per-cent is weight/volume percent; All the other are weight/weight percent.
Compared with prior art, the present invention has following useful technique effect:
1, two (4-acetoamidophenol oxygen base) esters of tynofovir that the present invention makes are solid state, and have modified biconjugate acetyl amino phenyl phenolic ester on the phosphoric acid position of tynofovir, have improved the solvability of prodrug, have reduced drug toxicity;
2, after two (the 4-acetoamidophenol oxygen base) esters of tynofovir of the present invention are absorbed by the body, meta-bolites is to have the tynofovir bisphosphate of pharmacologically active and to acetaminophenol, the two has synergistic function to the fever of hepatitis B patient and aids patient and viral therapy;
3, two (the 4-acetoamidophenol oxygen base) esters of tynofovir of the present invention, with respect to the easier crystallization of the two pyrrole furan of tynofovir ester, are prepared more easy.
Accompanying drawing explanation
The preparation process of two (the 4-acetoamidophenol oxygen base) esters of Fig. 1 tynofovir of the present invention.
Embodiment
Below in conjunction with embodiment, the present invention is further described, but scope of the present invention is not limited to following embodiment.
embodiment 1the preparation of two (the 4-acetoamidophenol oxygen base) esters of tynofovir
The preparation method of two (the 4-acetoamidophenol oxygen base) esters of tynofovir, comprises the steps:
1) 6.1g tynofovir is suspended in the mixed solvent of 10ml DMF and 100ml methylene dichloride composition, makes tynofovir suspension; In tynofovir suspension, drip 15ml oxalyl chloride, after dropwising, after return stirring reaction 2h, reaction solution is cooled to room temperature, vacuum rotary steam is removed after volatile matter, adds DMF 10ml in distillation leftover, make the DMF solution of the two phosphonyl chlorides of tynofovir;
2) 10g acamol is dissolved in to 100ml methylene dichloride, in the dichloromethane solution of the acetoamidophenol making, slowly add 20ml triethylamine, stirring at room 0.5h, drip again the N of the two phosphonyl chlorides of tynofovir that step 1) makes, dinethylformamide solution, during dropping, controlling temperature is-5
-0 ℃, after dropwising, under room temperature, stir 2h, add 5% ice-cold salt solution 100ml cancellation reaction;
3) reaction solution static layering, gets dichloromethane layer, by after dichloromethane layer successively water, saturated common salt water washing, again after anhydrous sodium sulfate drying, filter, remove anhydrous sodium sulphate, collect filtrate, vacuum rotary steam, methylene dichloride-normal hexane for distillation leftover (1:3, v/v) crystallization, obtains two (4-acetoamidophenol oxygen base) the ester 7.0g of tynofovir, the solid that is white in color, yield is 60%.
δ(
1HNMR,DMSO-
d 6):?1.26(d,?
J=6.4Hz,?3H),?2.08(s,?3H),?2.12（s,?3H）,?3.02(m,?1H),?3.52(brs,?2H),?3.86(m,?2H),?6.20(m,?2H),?6.70(d,?
J=6.8Hz,?2H),?6.78(d,?
J=6.8Hz,?2H),?7.42(d,?
J=6.8Hz,?2H),?7.50(d,?
J=6.8Hz,?2H),?11.42(s,?1H),11.45(s,?1H)ppm;?MS:?554(MH
+)。
embodiment 2the preparation of two (the 4-acetoamidophenol oxygen base) esters of tynofovir
The preparation method of two (the 4-acetoamidophenol oxygen base) esters of tynofovir, comprises the steps:
1) 6.1g tynofovir is suspended in the mixed solvent of 10ml DMF and 100ml methylene dichloride composition, makes tynofovir suspension; In tynofovir suspension, drip 15ml oxalyl chloride, after dropwising, after return stirring reaction 2h, reaction solution is cooled to room temperature, vacuum rotary steam is removed after volatile matter, adds 10ml DMF in distillation leftover, make the DMF solution of the two phosphonyl chlorides of tynofovir;
2) 10g acamol is dissolved in to 100ml methylene dichloride, in the molten dichloromethane solution of the acamol making, adds 1g titanium tetrachloride and 20ml triethylamine, after dropwising, stirring at room 0.5h; Drip again the DMF solution of the two phosphonyl chlorides of tynofovir that step 1) makes, temperature control-5 during dropping
-0 ℃, after dropwising, under room temperature, stir 2h, add 5% ice-cold salt solution 100ml cancellation reaction;
3) reaction solution static layering, gets dichloromethane layer, by after dichloromethane layer successively water, saturated common salt water washing, again after anhydrous sodium sulfate drying, filter, remove sodium sulfate, collect filtrate, vacuum rotary steam, methylene dichloride-normal hexane for distillation leftover (1:3, v/v) crystallization, obtains two (the 4-acetoamidophenol oxygen base) esters of 8.9g tynofovir, the solid that is white in color, yield is 76%.
δ(
1HNMR,DMSO-
d 6):?1.26(d,?
J=6.4Hz,?3H),?2.08(s,?3H),?2.12（s,?3H）,?3.02(m,?1H),?3.52(brs,?2H),?3.86(m,?2H),?6.20(m,?2H),?6.70(d,?
J=6.8Hz,?2H),?6.78(d,?
J=6.8Hz,?2H),?7.42(d,?
J=6.8Hz,?2H),?7.50(d,?
J=6.8Hz,?2H),?11.42(s,?1H),11.45(s,?1H)ppm;?MS:?554(MH
+)。
embodiment 3the preparation of two (the 4-acetoamidophenol oxygen base) esters of tynofovir
The preparation method of two (the 4-acetoamidophenol oxygen base) esters of tynofovir, comprises the steps:
1) 6.1g tynofovir is suspended in the mixed solvent of 10ml DMF and 100ml methylene dichloride composition, makes tynofovir suspension; In tynofovir suspension, drip 15ml oxalyl chloride, after dropwising, after return stirring reaction 2h, reaction solution is cooled to room temperature, vacuum rotary steam is removed after volatile matter, adds 10ml DMF in distillation leftover, make the DMF solution of the two phosphonyl chlorides of tynofovir;
2) in the DMF solution of the two phosphonyl chlorides of tynofovir that make in step 1), add 1g titanium tetrachloride, then drip the solution that is dissolved in 100ml methylene dichloride by 10g acamol and 20ml triethylamine, temperature control-5 during dropping
-0 ℃, after dropwising, stirring at room 2.5h, adds 5% ice-cold salt solution 100ml cancellation reaction;
3) reaction solution static layering, gets dichloromethane layer, by after dichloromethane layer successively water, saturated common salt water washing, again after anhydrous sodium sulfate drying, filter, remove sodium sulfate, collect filtrate, vacuum rotary steam, methylene dichloride-normal hexane for distillation leftover (1:3, v/v) crystallization, obtains two (the 4-acetoamidophenol oxygen base) esters of 9.2g tynofovir, the solid that is white in color, yield is 78%.
δ(
1HNMR,DMSO-
d 6):?1.26(d,?
J=6.4Hz,?3H),?2.08(s,?3H),?2.12（s,?3H）,?3.02(m,?1H),?3.52(brs,?2H),?3.86(m,?2H),?6.20(m,?2H),?6.70(d,?
J=6.8Hz,?2H),?6.78(d,?
J=6.8Hz,?2H),?7.42(d,?
J=6.8Hz,?2H),?7.50(d,?
J=6.8Hz,?2H),?11.42(s,?1H),11.45(s,?1H)ppm;?MS:?554(MH
+)。
embodiment 4the preparation of two (the 4-acetoamidophenol oxygen base) esters of tynofovir
The preparation method of two (the 4-acetoamidophenol oxygen base) esters of tynofovir, comprises the steps:
1) 6.1g tynofovir is suspended in the mixed solvent of 10ml DMF and 100ml methylene dichloride composition, makes tynofovir suspension; In tynofovir suspension, drip 10ml sulfur oxychloride, after dropwising, after return stirring reaction 2h, reaction solution is cooled to room temperature, vacuum rotary steam is removed after volatile matter, adds DMF 10ml in distillation leftover, make the DMF solution of the two phosphonyl chlorides of tynofovir;
2) 10g acamol is dissolved in to 100ml methylene dichloride, in the acamol dichloromethane solution making, slowly add 20ml triethylamine, stirring at room 0.5h, then drip the N of the two phosphonyl chlorides of tynofovir that step 1) makes, dinethylformamide solution, temperature control-5 during dropping
-0 ℃, after dropwising, stirring at room 2h, adds 5% ice-cold salt solution 100ml cancellation reaction;
3) reaction solution static layering, gets dichloromethane layer, by after dichloromethane layer successively water, saturated common salt water washing, again after anhydrous sodium sulfate drying, filter, remove sodium sulfate, collect filtrate, vacuum rotary steam, methylene dichloride-normal hexane for distillation leftover (1:3, v/v) crystallization, obtains two (the 4-acetoamidophenol oxygen base) esters of 7.6g tynofovir, the solid that is white in color, yield is 65%.
δ(
1HNMR,DMSO-
d 6):?1.26(d,?
J=6.4Hz,?3H),?2.08(s,?3H),?2.12（s,?3H）,?3.02(m,?1H),?3.52(brs,?2H),?3.86(m,?2H),?6.20(m,?2H),?6.70(d,?
J=6.8Hz,?2H),?6.78(d,?
J=6.8Hz,?2H),?7.42(d,?
J=6.8Hz,?2H),?7.50(d,?
J=6.8Hz,?2H),?11.42(s,?1H),11.45(s,?1H)ppm;?MS:?554(MH
+)。
embodiment 5the preparation of two (the 4-acetoamidophenol oxygen base) esters of tynofovir
The preparation method of two (the 4-acetoamidophenol oxygen base) esters of tynofovir, comprises the steps:
1) 6.1g tynofovir is suspended in the mixed solvent of 10ml DMF and 100ml methylene dichloride composition, makes tynofovir suspension; In tynofovir suspension, drip 10ml sulfur oxychloride, after dropwising, after return stirring reaction 2h, reaction solution is cooled to room temperature, vacuum rotary steam is removed after volatile matter, adds 10ml DMF in distillation leftover, make the DMF solution of the two phosphonyl chlorides of tynofovir;
2) 10g acamol is dissolved in to 100ml methylene dichloride, in the acamol dichloromethane solution making, adds 1g titanium tetrachloride and 20ml triethylamine, finish stirring at room 0.5h; Drip again the DMF solution of the two phosphonyl chlorides of tynofovir that step 1) makes, temperature control-5 during dropping
-0 ℃; After dropwising, stirring at room 2h, adds 5% ice-cold salt solution 100ml cancellation reaction;
3) reaction solution static layering, gets dichloromethane layer, by after dichloromethane layer successively water, saturated common salt water washing, again after anhydrous sodium sulfate drying, filter, remove sodium sulfate, collect filtrate, vacuum rotary steam, methylene dichloride-normal hexane for distillation leftover (1:3, v/v) crystallization, obtains two (the 4-acetoamidophenol oxygen base) esters of 9.2g tynofovir, the solid that is white in color, yield is 78%.
δ(
1HNMR,DMSO-
d 6):?1.26(d,?
J=6.4Hz,?3H),?2.08(s,?3H),?2.12（s,?3H）,?3.02(m,?1H),?3.52(brs,?2H),?3.86(m,?2H),?6.20(m,?2H),?6.70(d,?
J=6.8Hz,?2H),?6.78(d,?
J=6.8Hz,?2H),?7.42(d,?
J=6.8Hz,?2H),?7.50(d,?
J=6.8Hz,?2H),?11.42(s,?1H),11.45(s,?1H)ppm;?MS:?554(MH
+)。
embodiment 6the preparation of two (the 4-acetoamidophenol oxygen base) esters of tynofovir
The preparation method of two (the 4-acetoamidophenol oxygen base) esters of tynofovir, comprises the steps:
1) 6.1g tynofovir is suspended in the mixed solvent of 10ml DMF and 100ml methylene dichloride composition, makes tynofovir suspension; In tynofovir suspension, drip 10ml sulfur oxychloride, after dropwising, after return stirring reaction 2h, reaction solution is cooled to room temperature, vacuum rotary steam is removed after volatile matter, adds 10ml DMF in distillation leftover, make the DMF solution of the two phosphonyl chlorides of tynofovir;
2) in the DMF solution of the two phosphonyl chlorides of tynofovir that make in step 1), add 1g titanium tetrachloride, then drip the solution that is dissolved in 100ml methylene dichloride by 10g acamol and 20ml triethylamine, temperature control-5 during dropping
-0 ℃, finish, stirring at room 2.5h, adds 5% ice-cold salt solution 100ml cancellation reaction;
3) reaction solution static layering, gets dichloromethane layer, by after dichloromethane layer successively water, saturated common salt water washing, again after anhydrous sodium sulfate drying, filter, remove sodium sulfate, collect filtrate, vacuum rotary steam, methylene dichloride-normal hexane for distillation leftover (1:3, v/v) crystallization, obtains two (the 4-acetoamidophenol oxygen base) esters of 10.2g tynofovir, the solid that is white in color, yield is 88%.
δ(
1HNMR,DMSO-
d 6):?1.26(d,?
J=6.4Hz,?3H),?2.08(s,?3H),?2.12（s,?3H）,?3.02(m,?1H),?3.52(brs,?2H),?3.86(m,?2H),?6.20(m,?2H),?6.70(d,?
J=6.8Hz,?2H),?6.78(d,?
J=6.8Hz,?2H),?7.42(d,?
J=6.8Hz,?2H),?7.50(d,?
J=6.8Hz,?2H),?11.42(s,?1H),11.45(s,?1H)ppm;?MS:?554(MH
+)。
embodiment 7the preparation of two (the 4-acetoamidophenol oxygen base) esters of tynofovir
The preparation method of two (the 4-acetoamidophenol oxygen base) esters of tynofovir, comprises the steps:
1) 6.1g tynofovir is suspended in the mixed solvent of 10ml DMF and 100ml methylene dichloride composition, makes tynofovir suspension; In tynofovir suspension, drip 10ml sulfur oxychloride, after dropwising, after return stirring reaction 2h, reaction solution is cooled to room temperature, vacuum rotary steam is removed after volatile matter, adds 10ml DMF in distillation leftover, make the DMF solution of the two phosphonyl chlorides of tynofovir;
2) in the suspension that the sodium hydride by 3.5g 60% and 50ml tetrahydrofuran (THF) form, dropping is dissolved in the solution of 30ml tetrahydrofuran (THF) by 15g acamol, temperature control 0-10 ℃ during dropping, after dropwising, stirring at room 2h, drip again the muriatic DMF solution of tynofovir that step 1) makes, temperature control 0-10 ℃ during dropping, after dropwising, stirring at room 2h, adds after Glacial acetic acid cancellation reaction, and volatile matter is removed in underpressure distillation;
3) in distillation leftover, add 60ml water, use successively 180ml methylene dichloride, 140ml methylene dichloride, 90ml dichloromethane extraction, get dichloromethane layer, by after dichloromethane layer successively water, saturated common salt water washing, then after anhydrous sodium sulfate drying, filter, remove sodium sulfate, collect filtrate, the vacuum rotary steam, (1:3 of methylene dichloride-normal hexane for distillation leftover, v/v) crystallization, obtain two (the 4-acetoamidophenol oxygen base) esters of 10g tynofovir, the solid that is white in color, yield is 85%.
δ(
1HNMR,DMSO-
d 6):?1.26(d,?
J=6.4Hz,?3H),?2.08(s,?3H),?2.12（s,?3H）,?3.02(m,?1H),?3.52(brs,?2H),?3.86(m,?2H),?6.20(m,?2H),?6.70(d,?
J=6.8Hz,?2H),?6.78(d,?
J=6.8Hz,?2H),?7.42(d,?
J=6.8Hz,?2H),?7.50(d,?
J=6.8Hz,?2H),?11.42(s,?1H),11.45(s,?1H)ppm;?MS:?554(MH
+)。
embodiment 8the antivirus action research of two (the 4-acetoamidophenol oxygen base) esters of tynofovir
1, material
Cell: HIV-1 (111B) (Shanghai Fudan-Yueda Bio-Tech Co., Ltd. provides).
, method
With 9-[(R)-2-(phosphatidyl methoxy) propyl group] the positive contrast of VITAMIN B4 (PMPA), and virus control group is set (only adds virus, do not add medicine), cell control group (not adding virus, medicine), the antivirus action of two (the 4-acetoamidophenol oxygen base) esters of comparative studies tynofovir.
PMPA, formula I compound, with after dmso solution, are diluted to table 1 with phosphoric acid buffer and are recorded concentration.
Centrifugal collection virocyte liquid adds the cell suspending liquid 100 μ l of desired concn in each hole of 96 orifice plates.According to table 1, record, add the solution of PMPA, formula I compound, and virus control group (only add virus, do not add medicine), cell control group (not adding virus, medicine) are set in each test group, every group arranges 4 repeating holes.After adding, 96 orifice plates are placed in to 37 ℃, 5%CO
2hatch and cultivate 5 days.Get supernatant liquor, supernatant liquor, after high speed centrifugation, then is got supernatant liquor, to measure the IC50(50% effective concentration of MT-2 cell), CC50(50% has poison cell to kill concentration).
The viral inhibiting rate of comparative studies Compound I group, positive controls, virus control group and cell control group, the results are shown in Table 1.
Table 1
| Compound | IC 50（uM） | CC 50（uM） |
| PMPA | 0.5 | 250 |
| Compound I | 0.02 | 0.23 |
From table 1, PMPA compares with positive control drug, and Compound I of the present invention has more excellent antivirus action.
embodimentthe antipyretic effect research of two (the 4-acetoamidophenol oxygen base) esters (I) of 9 tynofovirs
1, oral anti-inflammatory (antipyretic experiment)
Get the adaptation of regular grade laboratory after 3 days, carry out prerun.After Success in Experiment, get with 60 of batch Kunming mouses, be divided at random 3 groups, i.e. negative control group, positive controls (Asprin), Compound I group.
Each is organized after mouse stomach administration 1h, with dimethylbenzene, processes mouse right ear, and left ear is done self-blank contrast, after 15min, the dislocation of mouse cervical vertebra is put to death, and with 6mm punch tool, samples, weighs, and calculates inhibitory rate of intumesce, the results are shown in Table 2.
Table 2
| Medicine | Quantity (only) | Dosage | Swelling (mg) | Inhibiting rate (%) |
| Physiological saline | 20 | 0.2ml/10g | 76 | ? |
| Asprin | 20 | 1mg/10g | 2.54 | 46.6% |
| Compound I | 20 | 1mg/10g | 1.50 | 64.3% |
2, analgesia research (mouse writhing reaction)
Get the adaptation of regular grade laboratory after 3 days, carry out prerun.After Success in Experiment, get with 60 of batch Kunming mouses, be divided at random 3 groups, i.e. negative control group, positive controls (Asprin), Compound I group.
Each is organized after mouse stomach administration 1h, and the tartrate of abdominal injection 0.2% ladder potassium 0.15ml/10g, records the writhing number of times of every mouse in 15min and the average time of each group, calculates pain inhibiting rate, the results are shown in Table 3.
Table 3
| Medicine | Quantity (only) | Dosage | Average time | Inhibiting rate (%) |
| Physiological saline | 20 | 0.2ml/10g | 38 | ? |
| Asprin | 20 | 1mg/10g | 6.1 | 84.2 |
| Compound I | 20 | 1mg/10g | 7.9 | 78.2 |
From table 2 and table 3 result, to compare with positive control drug Asprin, Compound I of the present invention has more excellent antipyretic town analgesic effect.
Claims (15)
- A structure suc as formula shown in I ( rtwo (4-acetoamidophenol oxygen base) the phosphonylmethoxy base propyl group of)-9-[2-] VITAMIN B4,(formula I)A kind of ( rtwo (paracetamol base) the phosphonylmethoxy base propyl group of)-9-[2-] preparation method of VITAMIN B4, comprise the steps:1) tynofovir or its monohydrate are suspended in solvent, under catalyzer exists, in tynofovir or its monohydrate suspension, drip chlorination reagent, after dropwising, return stirring, after reacting completely, reaction solution is cooled to room temperature, vacuum rotary steam is removed after volatile matter, make the two phosphonyl chlorides of tynofovir, wherein, tynofovir or its monohydrate: the mol ratio of chlorination reagent is 1:1 ~ 10, is preferably 1:5;2), under alkali, catalyzer existence condition, the two phosphonyl chlorides of tynofovir and acamol are placed in to solvent, after condensation reaction completes, add salt brine solution cancellation reaction, wherein, the two phosphonyl chlorides of tynofovir: the mol ratio of acamol is 1:2 ~ 5, is preferably 1:3; The two phosphonyl chlorides of tynofovir: the mol ratio of alkali is 1:3 ~ 10, is preferably 1:5;3) by reaction solution static layering, get organic layer, by after organic layer successively water, saturated common salt water washing, then drying agent dry after, filter, remove siccative, collect filtrate, vacuum rotary steam, distillation leftover solvent crystallization, dry, make two (the 4-acetoamidophenol oxygen base) esters of tynofovir.
- 2. the chlorination reagent preparation method according to claim 2, step 1) is selected from any or its combination of Acetyl Chloride 98Min., oxalyl chloride, thionyl chloride, phosphorus oxychloride.
- 3. according to the preparation method described in claim 2 or 3, step 1) solvent described in is selected from methylene dichloride, 1,2-ethylene dichloride, N, any or its combination in dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, benzene,toluene,xylene.
- 4. according to the preparation method described in claim 2-4 any one, step 1) described in, catalyzer is selected from N, dinethylformamide, N, any or its combination in N-diethylformamide, N,N-dimethylacetamide, titanium tetrachloride, tin tetrachloride, aluminum chloride, iron trichloride.
- 5. according to the preparation method described in claim 2-5 any one, step 1) described in chlorination reaction temperature be 20 ~ 80 ℃, be preferably 40 ~ 60 ℃.
- 6. according to the preparation method described in claim 2-6 any one, step 1) described in the chlorination reaction time be 2 ~ 8h, be preferably 6h.
- 7. according to the preparation method described in claim 2-7 any one, step 2) alkali described in is selected from triethylamine, tripropyl amine, Tributylamine, diisopropyl ethyl amine, pyridine, 2, any or its combination in 6-lutidine, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride KH, hydrolith, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide.
- 8. according to the preparation method described in claim 2-8 any one, step 2) described in catalyzer be selected from any or its combination in titanium tetrachloride, tin tetrachloride, aluminum chloride, iron trichloride.
- 9. according to the preparation method described in claim 2-9 any one, step 2) solvent described in is selected from methylene dichloride, 1,2-ethylene dichloride, N, any or its combination in dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, benzene,toluene,xylene.
- 10. according to the preparation method described in claim 2-10 any one, step 2) described in the temperature of condensation reaction be-50 ~ 80 ℃, be preferably-10 ~ 30 ℃.
- 11. according to the preparation method described in claim 2-11 any one, step 2) described in reaction times of condensation reaction be 1 ~ 10h, be preferably 5 ~ 8h.
- 12. according to the preparation method described in claim 2-12 any one, step 2) described in salt brine solution be selected from any or its combination of sodium chloride aqueous solution, potassium chloride solution, aqueous sodium persulfate solution, potassium sulfate solution.
- 13. according to the preparation method described in claim 2-13 any one, step 3) described in siccative be selected from any or its combination of anhydrous sodium sulphate, anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, Vanadium Pentoxide in FLAKES.
- 14. according to the preparation method described in claim 2-14 any one, and the recrystallisation solvent described in step 3) is selected from any or its combination of methylene dichloride, ethyl acetate, methyl alcohol, ethanol, Virahol, sherwood oil, normal hexane, normal heptane, toluene.
- Two (the 4-acetoamidophenol oxygen base) esters of 15. tynofovirs are for the preparation of the application in the medicine of any or its combination of antiviral, antipyretic-antalgic, and preferably described virus is selected from any or its combination of hepatitis B virus, HIV virus.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
| CN112358503A (en) * | 2020-05-14 | 2021-02-12 | 南京天海医药科技有限公司 | Preparation method and application of tenofovir derivatives |
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| CN1443189A (en) * | 2000-07-21 | 2003-09-17 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1443189A (en) * | 2000-07-21 | 2003-09-17 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
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| 冷玲颖，等: "核苷类抗病毒前药的研究进展", 《中国药物化学杂志》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
| CN112358503A (en) * | 2020-05-14 | 2021-02-12 | 南京天海医药科技有限公司 | Preparation method and application of tenofovir derivatives |
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Denomination of invention: Tenofovir bis (4-acetylaminophenoxy) ester and its preparation method and Application Effective date of registration: 20220530 Granted publication date: 20170329 Pledgee: China Construction Bank Taihe sub branch Pledgor: Anhui Baker Pharmaceutical Co.,Ltd. Registration number: Y2022340000007 |