RU2581045C2 - Производные эфиров фосфоновых кислот и способы их синтеза - Google Patents
Производные эфиров фосфоновых кислот и способы их синтеза Download PDFInfo
- Publication number
- RU2581045C2 RU2581045C2 RU2013114370/04A RU2013114370A RU2581045C2 RU 2581045 C2 RU2581045 C2 RU 2581045C2 RU 2013114370/04 A RU2013114370/04 A RU 2013114370/04A RU 2013114370 A RU2013114370 A RU 2013114370A RU 2581045 C2 RU2581045 C2 RU 2581045C2
- Authority
- RU
- Russia
- Prior art keywords
- propyl
- methyl
- hexadecyloxy
- mono
- phosphonic acid
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 125
- 230000015572 biosynthetic process Effects 0.000 title claims description 38
- 238000003786 synthesis reaction Methods 0.000 title claims description 33
- 150000003008 phosphonic acid esters Chemical class 0.000 title description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 162
- 150000001875 compounds Chemical class 0.000 claims abstract description 129
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims abstract description 70
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 49
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 47
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 40
- 229940104302 cytosine Drugs 0.000 claims abstract description 35
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims abstract description 33
- 150000002148 esters Chemical class 0.000 claims abstract description 30
- 238000001953 recrystallisation Methods 0.000 claims abstract description 27
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 21
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 18
- RTKCPZYOLXPARI-UHFFFAOYSA-N magnesium;2-methylpropan-2-olate Chemical compound [Mg+2].CC(C)(C)[O-].CC(C)(C)[O-] RTKCPZYOLXPARI-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052751 metal Inorganic materials 0.000 claims abstract description 16
- 239000002184 metal Substances 0.000 claims abstract description 16
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims abstract description 10
- XFSXUCMYFWZRAF-UHFFFAOYSA-N 2-(trityloxymethyl)oxirane Chemical compound C1OC1COC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 XFSXUCMYFWZRAF-UHFFFAOYSA-N 0.000 claims abstract description 8
- RUGJMMHJSZPVQO-UHFFFAOYSA-N C(CCCCCCCCCCCCCCC)OCCCOCCCOCCCCCCCCCCCCCCCC Chemical compound C(CCCCCCCCCCCCCCC)OCCCOCCCOCCCCCCCCCCCCCCCC RUGJMMHJSZPVQO-UHFFFAOYSA-N 0.000 claims abstract description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 8
- 125000006239 protecting group Chemical group 0.000 claims abstract description 8
- -1 [[(S) -2- (4-amino-2-oxo-1 (2H) -pyrimidinyl) -1- (hydroxymethyl) ethoxy] methyl] mono [3- (hexadecyloxy) propyl] ester Chemical class 0.000 claims description 119
- 239000000203 mixture Substances 0.000 claims description 89
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 87
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- 239000011541 reaction mixture Substances 0.000 claims description 47
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 239000000047 product Substances 0.000 claims description 40
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 32
- YDCSFYSJEYSCBP-UHFFFAOYSA-N 3-hexadecoxypropan-1-ol Chemical compound CCCCCCCCCCCCCCCCOCCCO YDCSFYSJEYSCBP-UHFFFAOYSA-N 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 23
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims description 17
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- 238000002360 preparation method Methods 0.000 claims description 17
- 239000012634 fragment Substances 0.000 claims description 16
- FESYLDKBOOCXRD-UHFFFAOYSA-N hexadecyl methanesulfonate Chemical compound CCCCCCCCCCCCCCCCOS(C)(=O)=O FESYLDKBOOCXRD-UHFFFAOYSA-N 0.000 claims description 16
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 14
- 230000002194 synthesizing effect Effects 0.000 claims description 12
- 238000000746 purification Methods 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 9
- 230000003993 interaction Effects 0.000 claims description 9
- 230000000877 morphologic effect Effects 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000012312 sodium hydride Substances 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 8
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 7
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 7
- 238000010791 quenching Methods 0.000 claims description 7
- 230000000171 quenching effect Effects 0.000 claims description 7
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims description 6
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 5
- 229960000541 cetyl alcohol Drugs 0.000 claims description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 4
- FDDNSMNKXPSQCN-BNABKKBVSA-N CCCCCCCCCCCCCCCCOCCCP(O)(OC[C@H](CO)C(N(C=CC(N)=N1)C1=O)OC(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1)=O Chemical compound CCCCCCCCCCCCCCCCOCCCP(O)(OC[C@H](CO)C(N(C=CC(N)=N1)C1=O)OC(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1)=O FDDNSMNKXPSQCN-BNABKKBVSA-N 0.000 claims description 3
- 125000000847 cytosin-1-yl group Chemical group [*]N1C(=O)N=C(N([H])[H])C([H])=C1[H] 0.000 claims description 3
- LKQURIXXQZXEQD-VWLOTQADSA-N CCCCCCCCCCCCCCCCOCCCP(O)(OCO[C@@H](CN(C=CC(N)=N1)C1=O)CO)=O Chemical compound CCCCCCCCCCCCCCCCOCCCP(O)(OCO[C@@H](CN(C=CC(N)=N1)C1=O)CO)=O LKQURIXXQZXEQD-VWLOTQADSA-N 0.000 claims description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 2
- 229910052749 magnesium Inorganic materials 0.000 claims 2
- 239000011777 magnesium Substances 0.000 claims 2
- 229960005235 piperonyl butoxide Drugs 0.000 claims 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 abstract 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 abstract 1
- WXJFKKQWPMNTIM-VWLOTQADSA-N [(2s)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethyl-(3-hexadecoxypropoxy)phosphinic acid Chemical compound CCCCCCCCCCCCCCCCOCCCOP(O)(=O)CO[C@H](CO)CN1C=CC(N)=NC1=O WXJFKKQWPMNTIM-VWLOTQADSA-N 0.000 description 92
- 239000002904 solvent Substances 0.000 description 54
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- 125000003118 aryl group Chemical group 0.000 description 34
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- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 229960000724 cidofovir Drugs 0.000 description 20
- 125000005842 heteroatom Chemical group 0.000 description 20
- 230000001225 therapeutic effect Effects 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
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- 241000700605 Viruses Species 0.000 description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 125000001183 hydrocarbyl group Chemical group 0.000 description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
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- 125000000304 alkynyl group Chemical group 0.000 description 11
- 125000003710 aryl alkyl group Chemical group 0.000 description 11
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- LVOASXNJWPROPP-UHFFFAOYSA-N (4-methylphenyl)sulfonyloxymethylphosphonic acid Chemical compound CC1=CC=C(S(=O)(=O)OCP(O)(O)=O)C=C1 LVOASXNJWPROPP-UHFFFAOYSA-N 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
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- 229940011051 isopropyl acetate Drugs 0.000 description 10
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000011321 prophylaxis Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
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- SLYMJSGMJWGMJB-OAWRCXNGSA-N 4-amino-1-[[(5s)-2-(3-hexadecoxypropoxy)-2-oxo-1,4,2$l^{5}-dioxaphosphinan-5-yl]methyl]pyrimidin-2-one Chemical compound C1OP(OCCCOCCCCCCCCCCCCCCCC)(=O)CO[C@H]1CN1C(=O)N=C(N)C=C1 SLYMJSGMJWGMJB-OAWRCXNGSA-N 0.000 description 7
- 150000004703 alkoxides Chemical class 0.000 description 7
- UXQPXWNAHMNXOR-UHFFFAOYSA-N diethoxyphosphorylmethyl phenylmethanesulfonate Chemical compound CCOP(=O)(OCC)COS(=O)(=O)CC1=CC=CC=C1 UXQPXWNAHMNXOR-UHFFFAOYSA-N 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
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- C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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| SG10201800188SA (en) | 2013-03-15 | 2018-02-27 | Univ California | Acyclic nucleoside phosphonate diesters |
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| US10160778B2 (en) | 2014-10-27 | 2018-12-25 | Concert Pharmaceuticals, Inc. | Pyrimidine phosphonic acid esters |
| EP3350191B9 (en) | 2015-09-15 | 2021-12-22 | The Regents of the University of California | Nucleotide analogs |
| AU2017290703B2 (en) | 2016-06-28 | 2023-03-30 | Emergent Biodefense Operations Lansing Llc | Formulations of brincidofovir |
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| US6716825B2 (en) * | 1999-12-03 | 2004-04-06 | The Regents Of The University Of California | Phosphonate compounds |
| US20070003516A1 (en) * | 2005-04-08 | 2007-01-04 | Almond Merrick R | Compounds, compositions and methods for the treatment of poxvirus infections |
| WO2008133966A1 (en) * | 2007-04-27 | 2008-11-06 | Chimerix, Inc. | Methods of reducing nephrotoxicity in subjects administered with nucleoside |
| EA011948B1 (ru) * | 2003-06-16 | 2009-06-30 | Инститьют Оф Оргэник Кемистри Энд Байокемистри, Экэдеми Оф Сайэнс Оф Зе Чек Рипаблик | Фосфонатзамещенные пиримидиновые соединения (варианты), способ их получения (варианты), фармацевтическая композиция на их основе и способ лечения вирусной инфекции |
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| ES2401285T3 (es) * | 2004-12-16 | 2013-04-18 | The Regents Of The University Of California | Fármacos con el pulmón como diana |
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2011
- 2011-08-31 WO PCT/US2011/050099 patent/WO2012031045A2/en not_active Ceased
- 2011-08-31 AU AU2011295937A patent/AU2011295937B2/en active Active
- 2011-08-31 EP EP15193479.1A patent/EP3020720B1/en active Active
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- 2011-08-31 CN CN201610571915.7A patent/CN105998039A/zh active Pending
- 2011-08-31 RU RU2013114370/04A patent/RU2581045C2/ru active
- 2011-08-31 US US13/223,249 patent/US8569321B2/en active Active
- 2011-08-31 CN CN201180051834.XA patent/CN103209985B/zh active Active
- 2011-08-31 ES ES15193479T patent/ES2700117T3/es active Active
- 2011-08-31 RU RU2015141024A patent/RU2015141024A/ru unknown
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- 2011-08-31 CN CN201510533631.4A patent/CN105218580A/zh active Pending
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2013
- 2013-02-27 IL IL224955A patent/IL224955A/en active IP Right Grant
- 2013-10-18 US US14/057,391 patent/US20140046085A1/en not_active Abandoned
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2015
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2016
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2017
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6716825B2 (en) * | 1999-12-03 | 2004-04-06 | The Regents Of The University Of California | Phosphonate compounds |
| EA011948B1 (ru) * | 2003-06-16 | 2009-06-30 | Инститьют Оф Оргэник Кемистри Энд Байокемистри, Экэдеми Оф Сайэнс Оф Зе Чек Рипаблик | Фосфонатзамещенные пиримидиновые соединения (варианты), способ их получения (варианты), фармацевтическая композиция на их основе и способ лечения вирусной инфекции |
| US20070003516A1 (en) * | 2005-04-08 | 2007-01-04 | Almond Merrick R | Compounds, compositions and methods for the treatment of poxvirus infections |
| WO2008133966A1 (en) * | 2007-04-27 | 2008-11-06 | Chimerix, Inc. | Methods of reducing nephrotoxicity in subjects administered with nucleoside |
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