JP2005206605A - ホスホジエステルを合成するためのプロセス - Google Patents
ホスホジエステルを合成するためのプロセス Download PDFInfo
- Publication number
- JP2005206605A JP2005206605A JP2005044872A JP2005044872A JP2005206605A JP 2005206605 A JP2005206605 A JP 2005206605A JP 2005044872 A JP2005044872 A JP 2005044872A JP 2005044872 A JP2005044872 A JP 2005044872A JP 2005206605 A JP2005206605 A JP 2005206605A
- Authority
- JP
- Japan
- Prior art keywords
- amino
- phosphino
- compound
- phosphodiester
- alcohol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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- 238000000034 method Methods 0.000 title claims description 44
- 150000004713 phosphodiesters Chemical class 0.000 title abstract description 14
- 230000002194 synthesizing effect Effects 0.000 title 1
- -1 phosphodiester compound Chemical class 0.000 claims abstract description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 150000001412 amines Chemical class 0.000 claims abstract description 9
- 230000003647 oxidation Effects 0.000 claims abstract description 8
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 8
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims description 24
- 230000008878 coupling Effects 0.000 claims description 11
- 238000010168 coupling process Methods 0.000 claims description 11
- 238000005859 coupling reaction Methods 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 125000002015 acyclic group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
- 108010043958 Peptoids Proteins 0.000 claims description 3
- 108091028664 Ribonucleotide Proteins 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000002738 chelating agent Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 239000002342 ribonucleoside Substances 0.000 claims description 3
- 239000002336 ribonucleotide Substances 0.000 claims description 3
- 125000002652 ribonucleotide group Chemical group 0.000 claims description 3
- 229940124530 sulfonamide Drugs 0.000 claims description 3
- 150000003456 sulfonamides Chemical class 0.000 claims description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 11
- 239000002872 contrast media Substances 0.000 abstract description 7
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000004215 Carbon black (E152) Substances 0.000 description 7
- 229930195733 hydrocarbon Natural products 0.000 description 7
- 150000002430 hydrocarbons Chemical class 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000007800 oxidant agent Substances 0.000 description 7
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 150000008300 phosphoramidites Chemical class 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- LWNLXVXSCCLRRZ-UHFFFAOYSA-N dichlorophosphane Chemical class ClPCl LWNLXVXSCCLRRZ-UHFFFAOYSA-N 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- 230000026731 phosphorylation Effects 0.000 description 5
- 238000006366 phosphorylation reaction Methods 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 239000013522 chelant Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- MGYUXEVPJWBUEE-UHFFFAOYSA-N dichloro-(4,4-diphenylcyclohexyl)oxyphosphane Chemical compound C1CC(OP(Cl)Cl)CCC1(C=1C=CC=CC=1)C1=CC=CC=C1 MGYUXEVPJWBUEE-UHFFFAOYSA-N 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 229960003330 pentetic acid Drugs 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- UUQQLWRHPNEFIG-UHFFFAOYSA-N 4,4-diphenylcyclohexan-1-ol Chemical compound C1CC(O)CCC1(C=1C=CC=CC=1)C1=CC=CC=C1 UUQQLWRHPNEFIG-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- BHYPTCSVPKCUME-UHFFFAOYSA-N [2-(2-aminoethylamino)ethylamino]methyl (4,4-diphenylcyclohexyl) hydrogen phosphate Chemical compound C1CC(OP(O)(=O)OCNCCNCCN)CCC1(C=1C=CC=CC=1)C1=CC=CC=C1 BHYPTCSVPKCUME-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000007822 coupling agent Substances 0.000 description 3
- 238000002059 diagnostic imaging Methods 0.000 description 3
- 125000005265 dialkylamine group Chemical group 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 230000000865 phosphorylative effect Effects 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- LSIPOGMNALRESU-UHFFFAOYSA-N (4-diaminophosphanyloxy-1-phenylcyclohexyl)benzene Chemical compound C1CC(OP(N)N)CCC1(C=1C=CC=CC=1)C1=CC=CC=C1 LSIPOGMNALRESU-UHFFFAOYSA-N 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 2
- LLPKQRMDOFYSGZ-UHFFFAOYSA-N 2,5-dimethyl-1h-imidazole Chemical compound CC1=CN=C(C)N1 LLPKQRMDOFYSGZ-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001983 dialkylethers Chemical class 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- NALMPLUMOWIVJC-UHFFFAOYSA-N n,n,4-trimethylbenzeneamine oxide Chemical compound CC1=CC=C([N+](C)(C)[O-])C=C1 NALMPLUMOWIVJC-UHFFFAOYSA-N 0.000 description 1
- QBLCHHSGJTUNSJ-UHFFFAOYSA-N n-bis(prop-2-enoxy)phosphanyl-n-propan-2-ylpropan-2-amine Chemical compound C=CCOP(N(C(C)C)C(C)C)OCC=C QBLCHHSGJTUNSJ-UHFFFAOYSA-N 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical class OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 229940067626 phosphatidylinositols Drugs 0.000 description 1
- 238000006368 phosphinylation reaction Methods 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011697 sodium iodate Substances 0.000 description 1
- 229940032753 sodium iodate Drugs 0.000 description 1
- 235000015281 sodium iodate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- QBVXKDJEZKEASM-UHFFFAOYSA-M tetraoctylammonium bromide Chemical compound [Br-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC QBVXKDJEZKEASM-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/117—Esters of phosphoric acids with cycloaliphatic alcohols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
【解決手段】1)アルコールを三塩化リンと反応させ、ジクロロホスフィン化合物を形成する工程、2)ジクロロホスフィン化合物をアミン塩基と反応させ、ビス(アミノ)ホスフィノ化合物を形成する工程、3)該ビス(アミノ)ホスフィノ化合物をアルコールと反応させ(アミノ)ホスフィノ化合物を形成する工程、4)該(アミノ)ホスフィノ化合物を加水分解および酸化する工程を含むホスホジエステルの製造方法。
【選択図】なし
Description
P(III)の化学に基づいた、多数のホスホジエステル化合物の作成法が知られている。一般に、リン酸化はホスホジエステル化合物の合成において、重要な役割を務める。しかし、公知のホスホジエステル合成法は全て、どのようにリン酸化が達成されるかということを含めて多数の問題を欠点として持つ。
本発明は、ホスホジエステル化合物、およびより詳細には以下の式を有するホスホジエステルを調製するための、より安全で、より効率的で、そしてより安価なプロセスに関する:
(a)PCl3をアルコールとカップリングして置換ジクロロホスフィンを得る工程;
(b)前述のジクロロホスフィンをアミン塩基とカップリングしてビス(アミノ)ホスフィノを得る工程;
(c)前述のビス(アミノ)ホスフィノを第二のアルコール(これは工程(a)で使用されたアルコールと同じであるかまたは異なるものであり得る)とカップリングして二置換(アミノ)ホスフィノを得る工程;
(d)および、前述の(アミノ)ホスフィノを水および酸化剤と反応させて所望のホスホジエステル化合物を得る工程。
本発明によるプロセスは、不安定なリン酸化剤の使用ならびに保護基またはカップリング剤を使用することの必要性を回避している。それ故、本発明の方法は脱保護およびカップリング試薬の合成のような不必要なプロセスの工程を回避する。本発明の好適な実施態様において、ホスホジエステル合成プロセスは1個の反応容器中で行われ、複数の単離および/または精製工程の必要性を回避する。
(1)以下の式を有するホスホジエステル化合物を調製するためのプロセス:
該プロセスは、以下の工程を包含する:
(a)溶媒の存在下、アルコールROHをPCl3と反応して以下の式を有するジクロロホスフィン化合物を形成する工程;
(2)上記ホスホジエステル化合物が、1つの反応容器内で調製される、項目(1)に記載のプロセス。
(3)上記工程(a)で形成されたアルコキシジクロロホスフィン化合物を約5〜約6当量の上記アミン塩基と反応させる、項目(1)または(2)に記載のプロセス。
(4)上記アミン塩基が約5.0〜約11.0のpKa値を有する、項目(1)〜(3)のいずれか1項に記載のプロセス。
(5)上記塩基がイミダゾール、2,4−ジメチルイミダゾール、1H−テトラゾール、ジアルキルアミン(メチル、エチル、ブチル)、ピリジン、ピペラジン、ピペリジン、ピロール、1H−1,2,3−トリアゾール、および1,2,4−トリアゾールからなる群より選択される、項目(4)に記載のプロセス。
(6)上記塩基がイミダゾールである、項目(5)に記載のプロセス。
(7)約1当量のROHが約1当量のPCl3と反応する、項目(1)または(2)に記載のプロセス。
(8)上記工程(a)、(b)、および(c)で使用される溶媒が同じであるか異なるものであり得、そしてエーテルおよび炭化水素溶媒からなる群より選択される、項目(1)または(2)に記載のプロセス。
(9)上記溶媒が、ヘプタン、メチル−t−ブチルエーテル、ジオキサン、テトラヒドロフラン、1,3−ジオキソラン、ジグリム、ジエチルエーテル、ジアルキルエーテル、およびエチレングリコールジアルキルエーテルからなる群より選択される、項目(8)に記載のプロセス。
(10)上記溶媒がテトラヒドロフランである、項目(9)に記載のプロセス。
(11)上記工程(b)で形成されるアルコキシ(アミノ)ホスフィノ化合物が約1当量のR1OHとカップリングされる、項目(1)または(2)に記載のプロセス。
(12)上記工程(c)で形成されるジアルコキシ(アミノ)ホスフィノ化合物の加水分解および酸化が、溶媒中約−15℃〜約25℃の温度範囲で10〜24時間の間、水および酸化剤で行われる、項目(1)または(2)に記載のプロセス。
(13)上記酸化剤が過ヨウ素酸ナトリウムを含む、項目(12)に記載のプロセス。
(14)上記溶媒がテトラヒドロフラン、ヘプタン、およびトルエンの混合物を含む、項目(12)に記載のプロセス。
(15).以下の工程を含む、ホスホジエステル化合物を調製するためのプロセス:
(a) 4,4−ジフェニルシクロヘキサノール化合物をPCl3と反応して、以下の式を有する4,4−ジフェニルシクロヘキシルオキシジクロロホスフィンを得る工程;
(16)以下の工程を含む、[(4,4−ジフェニルシクロヘキシル)ホスホノオキシメチル]ジエチレントリアミン五酢酸を調製するためのプロセス:
(a)1.0当量の 4,4−ジフェニルシクロヘキサノールを約1当量の三塩化リン(phosphorous trichloride)でリン酸化して、以下の式を有する4,4−ジフェニルシクロヘキシルオキシジクロロホスフィンを得る工程;
(17)上記工程(d)で形成された[(4,4−ジフェニルシクロヘキシル)ホスホノオキシメチル]ジエチレントリアミン,ペンタt−ブチルエステルをHCl中で加水分解して、以下の式を有する[(4,4−ジフェニルシクロヘキシル)ホスホノオキシメチル]ジエチレントリアミン五酢酸を形成する工程をさらに含む、項目(16)に記載のプロセス:
本明細書中で記載される発明がより完全に理解され得るために、以下の詳細な説明を記述する。
本発明に従い、アルコールROH(ここでRは上記で記載されたのと同じ意味を有する)を、好ましくは1:1のモル比で、PCl3と反応させて、ジクロロホスフィン反応生成物(I)を形成する:
次いで、ジクロロホスフィン(I)を約5〜約6当量のアミン塩基と反応させて、ビス(アミノ)ホスフィノ反応生成物(II)を形成する:
上記のプロセスが画像診断法のための造影剤の調製において特に有用であることが見いだされている。この改良されたプロセスにより調製され得るホスホジエステル造影剤の例は、以下に示される化合物、ならびにPCT公開公報第WO96/23526号において記載される他のものを含む。
Claims (1)
- 以下の式を有するホスホジエステル化合物を調製するためのプロセス:
該プロセスは、以下の工程を包含する:
(a)溶媒の存在下、アルコールROHをPCl3と反応して以下の式を有するジクロロホスフィン化合物を形成する工程;
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US08/833,745 US5919967A (en) | 1997-04-11 | 1997-04-11 | Process for synthesizing phosphodiesters |
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JP2005044872A Withdrawn JP2005206605A (ja) | 1997-04-11 | 2005-02-21 | ホスホジエステルを合成するためのプロセス |
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US (1) | US5919967A (ja) |
EP (1) | EP1021452B1 (ja) |
JP (2) | JP4014231B2 (ja) |
KR (2) | KR20060066122A (ja) |
AT (1) | ATE236171T1 (ja) |
AU (1) | AU728902B2 (ja) |
BR (1) | BR9809084B1 (ja) |
CA (1) | CA2285417C (ja) |
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ES (1) | ES2195315T3 (ja) |
HU (1) | HU224257B1 (ja) |
IL (1) | IL131964A (ja) |
IS (1) | IS1994B (ja) |
NO (1) | NO325619B1 (ja) |
NZ (1) | NZ337921A (ja) |
PL (1) | PL188258B1 (ja) |
PT (1) | PT1021452E (ja) |
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AU717099B2 (en) * | 1995-03-08 | 2000-03-16 | Scripps Research Institute, The | Carbopeptoids and carbonucleotoids |
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WO2022185843A1 (ja) * | 2021-03-03 | 2022-09-09 | 国立大学法人東京工業大学 | 非対称型リン酸トリエステルの製造方法、対称型リン酸トリエステルの製造方法、リン酸エステルの製造方法、及び、有機リン化合物の製造方法 |
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