CN102977146B - A kind of synthetic method of adenine derivative - Google Patents
A kind of synthetic method of adenine derivative Download PDFInfo
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- CN102977146B CN102977146B CN201210473810.XA CN201210473810A CN102977146B CN 102977146 B CN102977146 B CN 102977146B CN 201210473810 A CN201210473810 A CN 201210473810A CN 102977146 B CN102977146 B CN 102977146B
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- Prior art keywords
- prodrug
- pmpa
- vitamin
- pivaloyloxymethyl
- phosphonylmethoxypropyl
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- FCZOVUJWOBSMSS-UHFFFAOYSA-N 5-[(6-aminopurin-9-yl)methyl]-5-methyl-3-methylideneoxolan-2-one Chemical compound C1=NC2=C(N)N=CN=C2N1CC1(C)CC(=C)C(=O)O1 FCZOVUJWOBSMSS-UHFFFAOYSA-N 0.000 title description 2
- 238000010189 synthetic method Methods 0.000 title description 2
- 229930003231 vitamin Natural products 0.000 claims abstract description 30
- 235000013343 vitamin Nutrition 0.000 claims abstract description 30
- 239000011782 vitamin Substances 0.000 claims abstract description 30
- 229940088594 vitamin Drugs 0.000 claims abstract description 30
- 150000003722 vitamin derivatives Chemical class 0.000 claims abstract description 30
- 229940002612 prodrug Drugs 0.000 claims abstract description 21
- 239000000651 prodrug Substances 0.000 claims abstract description 21
- 238000001308 synthesis method Methods 0.000 claims 1
- 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 abstract description 20
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 11
- -1 adefovir ester Chemical class 0.000 abstract description 9
- JFVZFKDSXNQEJW-UHFFFAOYSA-N [1-(6-aminopurin-9-yl)propan-2-yloxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate Chemical compound N1=CN=C2N(CC(C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-UHFFFAOYSA-N 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 229920000858 Cyclodextrin Polymers 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 abstract description 7
- 229960001355 tenofovir disoproxil Drugs 0.000 abstract description 7
- 229960001997 adefovir Drugs 0.000 abstract description 5
- 230000000840 anti-viral effect Effects 0.000 abstract description 5
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 abstract description 5
- 238000001727 in vivo Methods 0.000 abstract description 4
- 231100000252 nontoxic Toxicity 0.000 abstract description 4
- 230000003000 nontoxic effect Effects 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 4
- 238000003756 stirring Methods 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000000967 suction filtration Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 238000009413 insulation Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000002777 nucleoside Substances 0.000 description 4
- 125000003835 nucleoside group Chemical group 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 208000002672 hepatitis B Diseases 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 2
- DNNIMMTYNOWWHP-UHFFFAOYSA-N C1=CC=C(C=C1)S(=O)(=O)OCOP(O)(O)=O Chemical compound C1=CC=C(C=C1)S(=O)(=O)OCOP(O)(O)=O DNNIMMTYNOWWHP-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 239000001116 FEMA 4028 Substances 0.000 description 2
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- LWEKFDHXJHJYGB-RXMQYKEDSA-N [(2r)-1-(2,6-diaminopurin-9-yl)propan-2-yl]oxymethylphosphonic acid Chemical compound N1=C(N)N=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N LWEKFDHXJHJYGB-RXMQYKEDSA-N 0.000 description 2
- HXNWVLBCIOHKBZ-UHFFFAOYSA-M [NH4+].[Br-].C(CCC)[P+](CC1=CC=CC=C1)(CCCC)CCCC.[Br-] Chemical compound [NH4+].[Br-].C(CCC)[P+](CC1=CC=CC=C1)(CCCC)CCCC.[Br-] HXNWVLBCIOHKBZ-UHFFFAOYSA-M 0.000 description 2
- 229960005305 adenosine Drugs 0.000 description 2
- 229950005162 benexate Drugs 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- IAXUQWSLRKIRFR-SAABIXHNSA-N chembl2104696 Chemical compound C1C[C@@H](CNC(=N)N)CC[C@@H]1C(=O)OC1=CC=CC=C1C(=O)OCC1=CC=CC=C1 IAXUQWSLRKIRFR-SAABIXHNSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 235000007715 potassium iodide Nutrition 0.000 description 2
- 229960004839 potassium iodide Drugs 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- MZSBWBNMVOPWIU-UHFFFAOYSA-N C(C)OP(OCC)(O)C.[O] Chemical compound C(C)OP(OCC)(O)C.[O] MZSBWBNMVOPWIU-UHFFFAOYSA-N 0.000 description 1
- 208000035240 Disease Resistance Diseases 0.000 description 1
- 241001269524 Dura Species 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 239000006002 Pepper Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 230000009246 food effect Effects 0.000 description 1
- 235000021471 food effect Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000004845 hydriding Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses one and belong to technical field of pharmaceuticals, it specifically discloses prodrug, the cyclodextrin inclusion compound of this prodrug, the non-toxic pharmacy acceptable salt of this prodrug of a kind of new (R)-9-[2-(phosphonylmethoxy base) propyl group] VITAMIN B4.This prodrug can be metabolized to PMPA in vivo, bioavailability about 39%, and this has more outstanding bioavailability than tenofovir disoproxil (Bis-(POC)-PMPA); Meanwhile, compare adefovir ester, this prodrug has more excellent antiviral activity and better security.<!--1-->
Description
Technical field
The present invention relates to prodrug, the cyclodextrin inclusion compound of this prodrug, the non-toxic pharmacy acceptable salt of this prodrug of new (R)-9-[2-(phosphonylmethoxy base) propyl group] VITAMIN B4.
Background technology
Phosphonylmethoxy yl nucleosides acid-like substance is the known broad-spectrum disease resistance cytotoxic compound of a class, has the activity of the viruses such as AntiHIV1 RT activity, HBV, CMV, HSV-1, HSV-2 and human body herpes virus.9-[2-(phosphatidyl methoxy) ethyl] adenosine (being called for short PMEA) and 9-[(R)-2-(phosphatidyl methoxy) propyl group] adenosine (being called for short PMPA) are two examples for clinical antiviral therapy in this compounds.Because phosphonate radical contained in phosphonylmethoxy yl nucleosides acid-like substance affects the absorption of human body to it, generally need phosphonylmethoxy yl nucleosides acid-like substance to change into lipophilic prodrug to improve its bioavailability.Such as be used for the AD for the treatment of hepatitis B by FDA approval and be the lipotropy prodrug of phosphonylmethoxy yl nucleosides acid-like substance PMEA and PMPA respectively for the tenofovir disoproxil (tenofovirdisoproxilfumarate) (Bis-(POC)-PMPA) for the treatment of AIDS, treating hepatitis B.AD and tenofovir disoproxil can be metabolised to parent drug PMEA and PMPA having antivirus action accordingly in vivo.
U.S. FDA approval is 300mg/ days for the dosage of the tenofovir disoproxil (Bis-(POC)-PMPA) for the treatment of AIDS, treating hepatitis B, the dosage used due to this medicine is comparatively large, is very large burden to the liver of the patient of long-term taking and kidney and other organs.Although compared with PMPA, the bioavailability of Bis-(POC)-PMPA significantly improves, the bioavailability about 25% that people is oral, but this index is far below similar medicine adefovir ester (bioavailability about 59%), and the bioavailability of Bis-(POC)-PMPA is by food effect.
Up to now, the report about (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4 and preparation method thereof is not also had in existing document.
Summary of the invention
The object of this invention is to provide the new PMPA prodrug representated by formula (I), this prodrug can be metabolized to PMPA in vivo, bioavailability about 39%, this has more outstanding bioavailability than tenofovir disoproxil (Bis-(POC)-PMPA); Meanwhile, compare adefovir ester, this prodrug has more excellent antiviral activity and better security.
The present invention also provides the non-toxic pharmacy acceptable salt of this prodrug, the cyclodextrin inclusion compound of this prodrug.The cyclodextrin inclusion compound of described prodrug, the quality mol ratio of prodrug and cyclodextrin is 1: (1 ~ 10).
The present invention also provides the non-toxic pharmacy acceptable salt of this prodrug, and structural formula is as follows:
Wherein HR is acid; A is the mol ratio of acid and (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4, and a is between 0.5 ~ 3.
Wherein acid (HR) be mineral acid, organic sulfonic acid, organic carboxyl acid or containing acidic-group and there is organic compound or the natural product of protection liver effect.
Compared with prior art, the present invention is new PMPA prodrug, and this prodrug can be metabolized to PMPA in vivo, bioavailability about 39%, and this has more outstanding bioavailability than tenofovir disoproxil (Bis-(POC)-PMPA); Meanwhile, compare adefovir ester, this prodrug has more excellent antiviral activity and better security.
Embodiment
The following examples can conduct further description the present invention, but these embodiments should as the restriction of scope of the present invention.
Compound of the present invention can be prepared according to following synthetic route:
(S)-Racemic glycidol 5% palladium-charcoal is carried out hydrogenation reduction, obtains (R)-1,2-PD.Then react with diethyl carbonate and sodium ethylate, obtain (R)-1,2-PD carbonic ether.Itself and VITAMIN B4, sodium hydroxide are dissolved in dimethyl formamide reaction, products therefrom and tolysulfonyl oxygen methyl-phosphorous acid diethyl ester react further, obtain (R)-9 [2-(diethoxy phosphonium mesitoyl ylmethoxy) propyl group] VITAMIN B4.Then trimethylchlorosilane, potassiumiodide reaction, obtain tynofovir (PMPA).PMPA and 1-Methyl-2-Pyrrolidone, triethylamine, pivaloyl chloride methyl esters are reacted (R)-9 [2-bis-(pivaloyloxymethyl phosphonium mesitoyl methoxy) propyl group] VITAMIN B4 (Bis-(POM)-PMPA), then react de-ester group with triethylamine and obtain PMPA monoesters.PMPA monoesters and 1-Methyl-2-Pyrrolidone, triethylamine, carbonic acid chloromethyl-2-propyl diester react, then salt-pepper noise removal of impurities is become with oxalic acid, oxalic acid is sloughed again ,-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4 (I) that crystallization obtains (R) with aqueous sodium carbonate.
The preparation of embodiment 1, (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4 (I)
1.1, the synthesis of p-benzenesulfonyloxymethyl phosphoric acid diethylester:
In 1000ml there-necked flask, add 200ml toluene, 400ml diethyl phosphite, 120g paraformaldehyde and 50ml triethylamine, be stirred and heated to 70 DEG C, insulation reaction 2 hours, then reaction is continued after being warmed up to backflow, until with TLC (developping agent normal hexane: ethyl acetate=1: reaction end when 4) can not detect diethyl phosphite.Solution is cooled to less than 10 DEG C, adds 560g Tosyl chloride, and then at about 5 DEG C, slowly add 560ml triethylamine, holding temperature is no more than 10 DEG C.Rise to room temperature after dropwising, anti-8h, can not detect till during toluene semi-annular jade pendant acyl chlorides until TLC.Suction filtration removing solid, uses q. s. toluene washing leaching cake.Washings and filtrate merge, and use 5%Na
2cO
3the aqueous solution and water wash 2 times, after anhydrous sodium sulfate drying respectively, underpressure distillation, and residual night is oily matter, weigh about: 600g.
1.2, the synthesis of (R)-carbonic acid-1,2-propylene diester:
1000ml hydriding reactor is vacuumized, then logical nitrogen, then 500ml ethanol, 2g5%Pd/C, 2.5g caustic soda is added, be cooled to-l0 DEG C, slowly add 50gS-Racemic glycidol, then pass into hydrogen (about 2 normal atmosphere) 4 hours, to no longer consuming hydrogen, filter, concentrated, obtain colorless oil 48g.
In 1000ml there-necked flask, the ethanolic soln of the colorless oil 200g that several hydrogenations are obtained, 380ml diethyl carbonate, 65ml20% sodium ethylate, stirring heating 80 DEG C, slow distillation removing ethanol, the process TLC of reaction detects, until when TLC can not detect (R)-1,2-PD.Then rectification under vacuum, rectifying under 20mmHg, collects the cut of 120 DEG C, obtains colorless oil compound 44.5g.
1.3, the synthesis of (R)-9-[2-(diethylphosphono methoxyl) propyl group] VITAMIN B4:
In 1000ml there-necked flask, add 100g VITAMIN B4,1.2g sodium hydroxide, 84g (R)-carbonic acid-1,2-propylene diester, 700mlDMF, stir and be warming up to 130 DEG C, insulation reaction 30hr.Reaction mixture is cooled to 25 DEG C, adds 8g lithium hydride, is then heated to 70 DEG C, insulation reaction reaction 2hr, is then cooled to room temperature, adds 300g p-benzenesulfonyloxymethyl phosphoric acid diethylester, reaction mixture maintains 60 DEG C, till TLC shows complete reaction.Be no more than vacuum concentration reaction mixture at the temperature of 80 DEG C, add 500ml water, stirring and dissolving, aqueous solution methylene dichloride extracts continuously, combined dichloromethane extract, vacuum concentration extract at not higher than 80 DEG C, obtain viscous orange oil 200g, HPLC analyzes (R)-9-[2-(the diethyl phosphonylmethoxy base) propyl group] VITAMIN B4 containing 65% in display orange, should can be directly used in subsequent reactions by (R)-9-[2-(diethyl phosphonylmethoxy base) propyl group] VITAMIN B4 crude product without purification.
1.4, the synthesis of (R)-9-[2-(phosphonic acids methoxyl group) propyl group] VITAMIN B4 (PMPA):
In 1000ml there-necked flask, add 100g (R)-9-[2-(diethyl phosphonylmethoxy base) propyl group] VITAMIN B4 crude product, 122ml acetonitrile, 50g potassiumiodide, 207g trimethylchlorosilane, then stir and be warming up to 70 DEG C, insulation reaction 4 hours.Then underpressure distillation is to oily matter, and resistates 200ml water dissolution, is cooled to 20 DEG C, separate lower floor's aqueous phase, aqueous phase 30% caustic soda regulates PH to 3.1 ~ 3.5, stirring at room temperature about 3 hours, filter, filter cake uses 50ml frozen water and 50ml washing with acetone respectively, obtains PMPA crude product 60g.In PMPA crude product, add 200ml pure water (being heated to 90 DEG C in advance), insulated and stirred 3hr, then stir and be cooled to 25 DEG C, suction filtration, by frozen water and acetone continuous washing, filter cake vacuum-drying at 50 DEG C, obtains PMPA45 gram.
1.5, the synthesis of (R)-9-[2-(pivaloyl oxygen methoxyl group phosphonic acids methoxyl group) propyl group] VITAMIN B4 (PMPA monoesters):
In 500ml there-necked flask, add 40gPMPA, 160mlN-methyl-2-pyrrolidone, 120ml triethylamine and 1g tributyl Benzylphosphonium Bromide ammonium, be heated with stirring to 50 DEG C, then drip 60ml chloromethyl pivalate, about 30min adds, then 50 ~ 55 DEG C of insulation reaction 8 hours.Stirring is cooled to room temperature, is joined by reaction solution in 4000ml ethyl acetate, stirs 1h, suction filtration.Filtrate NaHCO
3solution and water respectively wash three times, each 200ml.Organic phase adds oxalic acid, stirs 2h, and then vacuum rotary steam is to the about 500ml of residual volume at night, and be cooled to 2 DEG C, suction filtration, filter cake ethyl acetate washs 2 times, each 100ml.Filter cake adds in 300ml water, then adds 300ml chloroform, uses 10%NaHCO
3solution regulates PH to 6.5 ~ 7.0, then extracting and demixing, and aqueous phase uses 300ml chloroform extraction 2 times again, and organic phase mixes, and uses 20g anhydrous sodium sulfate drying, and then vacuum rotary steam is not to can distilling liquid, obtains oily matter 49g.Then add 300ml acetone, then add 80ml triethylamine, be heated to 50 ~ 55 DEG C, insulation reaction 16h.Then stir and be cooled to 25 DEG C, slowly drip 4500ml pure water, about 2h drips.Stirring is cooled to 2 DEG C, suction filtration, and filter cake frozen water washs 2 times, each 100ml.Wet product vacuum-drying at 50 DEG C, obtains PMPA monoesters 20g.
1.6, (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4
In 500ml there-necked flask, add 56gPMPA mono-pivaloyl oxygen methyl esters, 160mlN-methyl-2-pyrrolidone, 72ml triethylamine and 0.6g tributyl Benzylphosphonium Bromide ammonium, be heated with stirring to 50 DEG C, then 40ml carbonic acid chloromethyl-2-propyl diester is dripped, about 30min adds, then 50 ~ 55 DEG C of insulation reaction 8 hours.Stirring is cooled to room temperature, is joined by reaction solution in 4000ml ethyl acetate, stirs 1h, suction filtration.Filtrate NaHCO
3solution and water respectively wash three times, each 200ml.Organic phase adds oxalic acid, stirs 2h, and then vacuum rotary steam is to the about 500ml of residual volume at night, and be cooled to 2 DEG C, suction filtration, filter cake ethyl acetate washs 2 times, each 100ml.Filter cake adds in 300ml water, then adds 300ml chloroform, uses 10%NaHCO
3solution regulates PH to 6.5 ~ 7.0, then extracting and demixing, and aqueous phase uses 300ml chloroform extraction 2 times again, and organic phase mixes, and uses 20g anhydrous sodium sulfate drying, and then vacuum rotary steam is not to can distilling liquid, obtains colorless oil 50g.With 200ml acetone solution oily matter, then isopropyl ether 800ml is dripped, about 1h adds, adularescent crystallization in dropping process, stirring is cooled to 0 DEG C, suction filtration, washs 2 times with isopropyl ether, the vacuum-drying at 50 DEG C of each 100ml. wet product, obtains (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4 47g.
Embodiment 2, (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl)
Phosphonylmethoxypropyl] preparation of Benexate Hydrochloride of VITAMIN B4
Take 20g (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4, add 40ml anhydrous alcohol solution.45g beta-cyclodextrin 567ml water is made into 60 DEG C of saturated aqueous solutions.By in the ethanolic soln of (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4 instillation beta-cyclodextrin saturated aqueous solution, insulated and stirred 30min, continues to stir 4h after stopping heating.Put into refrigerator and cooled and freeze 24 hours, suction filtration, use absolute ethanol washing filter cake, drying under reduced pressure, porphyrize, obtains the Benexate Hydrochloride 62.5 grams of (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4.
The preparation of embodiment 3, (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] adenine fumarate
Get 5.3g (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4 and be dissolved in 30ml ethanol, stir, slow dropping is containing the fumaric acid ethanolic soln 10ml of 1.16g, about 30min drips, and continues to stir 1h, suction filtration, filtrate stirring is cooled to 0 ~ 4 DEG C, continue stirring 5 hours, suction filtration, obtain the solid 4.8 grams of white.
The preparation of embodiment 4, (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4 hydrochloride
Getting 1.03g (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4 is dissolved in 10mlTHF, the hydrogenchloride THF solution 2.2ml of 1M is dripped at 0 DEG C, dropwise rear continuation stir about 2h, stirring is cooled to-2 DEG C of suction filtrations, obtains white solid 0.95 gram.
The preparation of embodiment 5, (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4 Hemisulphate
Getting 1.03g (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4 is dissolved in 10mlTHF, the methanolic solution 2.2ml of 1M is dripped at 0 DEG C, dropwise rear continuation stir about 2h, stirring is cooled to-2 DEG C of suction filtrations, obtains white solid 0.93 gram.
The preparation of embodiment 6, (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4 tosilate
Getting 1.03g (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4 is dissolved in 10mlTHF, the tosic acid methanol solution 2.2ml of 1M is dripped at 0 DEG C, dropwise rear continuation stir about 2h, solvent removed in vacuo obtains the foaming solid of white.
According to the medication that this area is conventional, by comprising per rectum, intranasal, locally (comprising eyes, oral cavity and sublingual) and the administration such as parenteral (comprising in subcutaneous, muscle, intravenously, intracutaneous, sheath and exterior dura), the medicine that preferred oral is drawn by the present embodiment mode.(reference: StarrettJE, etalJmedChem1994; The method of 37:1857-1864, by the content of active medicine (R)-PMPA or (R)-PMPDAP in urine after the administration of mensuration Oral Administration in Rats, compare with the content in urine after (R)-PMPA or (R)-PMPDAP intravenously administrable.Draw the bioavailability about more than 39% of the new PMPA prodrug representated by formula (I), this has more outstanding bioavailability than tenofovir disoproxil (Bis-(POC)-PMPA); Meanwhile, compare adefovir ester, this prodrug has more excellent antiviral activity and better security.
Claims (1)
1. the prodrug synthesis method shown in formula I, is obtained by following synthetic route, (R)-9-[2-(pivaloyloxymethyl)-(isopropoxy carbonyl oxygen ylmethyl) phosphonylmethoxypropyl] VITAMIN B4
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| US5663159A (en) * | 1990-09-14 | 1997-09-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
| CN1810816A (en) * | 2006-03-07 | 2006-08-02 | 中国医学科学院医药生物技术研究所 | Tenoforv monoester compounds with HIV-1/HBV virus copying inhibiting activity |
| CN1986553A (en) * | 2005-12-19 | 2007-06-27 | 北京美倍他药物研究有限公司 | Precursor medicine of acyclic nucleoside phosphonic acid |
| CN101659676A (en) * | 2009-09-07 | 2010-03-03 | 徐奎 | Sulfo-Adefovir and Tenofovir liver targeting ester prodrug |
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| US5663159A (en) * | 1990-09-14 | 1997-09-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
| CN1986553A (en) * | 2005-12-19 | 2007-06-27 | 北京美倍他药物研究有限公司 | Precursor medicine of acyclic nucleoside phosphonic acid |
| CN1810816A (en) * | 2006-03-07 | 2006-08-02 | 中国医学科学院医药生物技术研究所 | Tenoforv monoester compounds with HIV-1/HBV virus copying inhibiting activity |
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