CN110218233B - P (P) 1 ,P 4 Preparation method of di (uridine 5' -tetraphosphate) - Google Patents
P (P) 1 ,P 4 Preparation method of di (uridine 5' -tetraphosphate) Download PDFInfo
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- CN110218233B CN110218233B CN201910148349.2A CN201910148349A CN110218233B CN 110218233 B CN110218233 B CN 110218233B CN 201910148349 A CN201910148349 A CN 201910148349A CN 110218233 B CN110218233 B CN 110218233B
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- uridine
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- iib
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- SBVYRQFJZOKNGO-XVFCMESISA-N [[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [hydroxy(phosphonooxy)phosphoryl] hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 SBVYRQFJZOKNGO-XVFCMESISA-N 0.000 title description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims abstract description 61
- 238000000034 method Methods 0.000 claims abstract description 36
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 claims abstract description 30
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229940045145 uridine Drugs 0.000 claims abstract description 30
- YDHWWBZFRZWVHO-UHFFFAOYSA-H [oxido-[oxido(phosphonatooxy)phosphoryl]oxyphosphoryl] phosphate Chemical compound [O-]P([O-])(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O YDHWWBZFRZWVHO-UHFFFAOYSA-H 0.000 claims abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- YDHWWBZFRZWVHO-UHFFFAOYSA-N [hydroxy(phosphonooxy)phosphoryl] phosphono hydrogen phosphate Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(O)=O YDHWWBZFRZWVHO-UHFFFAOYSA-N 0.000 claims description 13
- -1 amine salts Chemical class 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 10
- 239000002184 metal Substances 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 159000000007 calcium salts Chemical class 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical group [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 238000001728 nano-filtration Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000010828 elution Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000001179 sorption measurement Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims description 2
- 239000003957 anion exchange resin Substances 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 7
- 239000008213 purified water Substances 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- QTPILKSJIOLICA-UHFFFAOYSA-N bis[hydroxy(phosphonooxy)phosphoryl] hydrogen phosphate Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(O)=O QTPILKSJIOLICA-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- DJJCXFVJDGTHFX-UHFFFAOYSA-N Uridinemonophosphate Natural products OC1C(O)C(COP(O)(O)=O)OC1N1C(=O)NC(=O)C=C1 DJJCXFVJDGTHFX-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
- DJJCXFVJDGTHFX-ZAKLUEHWSA-N uridine-5'-monophosphate Chemical compound O[C@@H]1[C@@H](O)[C@H](COP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 DJJCXFVJDGTHFX-ZAKLUEHWSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- PGAVKCOVUIYSFO-XVFCMESISA-N UTP Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 PGAVKCOVUIYSFO-XVFCMESISA-N 0.000 description 2
- LSYVCAOPFHHUHM-UHFFFAOYSA-N [hydroxy-[hydroxy-[hydroxy(phosphonooxy)phosphoryl]oxyphosphoryl]oxyphosphoryl] phosphono hydrogen phosphate Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(O)=O LSYVCAOPFHHUHM-UHFFFAOYSA-N 0.000 description 2
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- KURVIXMFFSNONZ-WFIJOQBCSA-L disodium;[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical class [Na+].[Na+].O[C@@H]1[C@H](O)[C@@H](COP([O-])([O-])=O)O[C@H]1N1C(=O)NC(=O)C=C1 KURVIXMFFSNONZ-WFIJOQBCSA-L 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- WHQOKFZWSDOTQP-UHFFFAOYSA-N 2,3-dihydroxypropyl 4-aminobenzoate Chemical compound NC1=CC=C(C(=O)OCC(O)CO)C=C1 WHQOKFZWSDOTQP-UHFFFAOYSA-N 0.000 description 1
- PZBGMTRNNJMLGH-UHFFFAOYSA-L C1(=CC=CC=C1)CS(=O)(=O)[O-].[Ca+2].C1(=CC=CC=C1)CS(=O)(=O)[O-] Chemical compound C1(=CC=CC=C1)CS(=O)(=O)[O-].[Ca+2].C1(=CC=CC=C1)CS(=O)(=O)[O-] PZBGMTRNNJMLGH-UHFFFAOYSA-L 0.000 description 1
- UNMYWSMUMWPJLR-UHFFFAOYSA-L Calcium iodide Chemical compound [Ca+2].[I-].[I-] UNMYWSMUMWPJLR-UHFFFAOYSA-L 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 102000015728 Mucins Human genes 0.000 description 1
- 108010063954 Mucins Proteins 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 102000001744 Purinergic P2Y2 Receptors Human genes 0.000 description 1
- 108010029812 Purinergic P2Y2 Receptors Proteins 0.000 description 1
- XCCTYIAWTASOJW-XVFCMESISA-N Uridine-5'-Diphosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 XCCTYIAWTASOJW-XVFCMESISA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229910001622 calcium bromide Inorganic materials 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- WGEFECGEFUFIQW-UHFFFAOYSA-L calcium dibromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 description 1
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 description 1
- 229910001634 calcium fluoride Inorganic materials 0.000 description 1
- 229940046413 calcium iodide Drugs 0.000 description 1
- 229910001640 calcium iodide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- RCPKXZJUDJSTTM-UHFFFAOYSA-L calcium;2,2,2-trifluoroacetate Chemical compound [Ca+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F RCPKXZJUDJSTTM-UHFFFAOYSA-L 0.000 description 1
- BWEYVLQUNDGUEC-UHFFFAOYSA-L calcium;methanesulfonate Chemical compound [Ca+2].CS([O-])(=O)=O.CS([O-])(=O)=O BWEYVLQUNDGUEC-UHFFFAOYSA-L 0.000 description 1
- PUQLFUHLKNBKQQ-UHFFFAOYSA-L calcium;trifluoromethanesulfonate Chemical compound [Ca+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F PUQLFUHLKNBKQQ-UHFFFAOYSA-L 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- CZMAIROVPAYCMU-UHFFFAOYSA-N lanthanum(3+) Chemical compound [La+3] CZMAIROVPAYCMU-UHFFFAOYSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 229910001631 strontium chloride Inorganic materials 0.000 description 1
- AHBGXTDRMVNFER-UHFFFAOYSA-L strontium dichloride Chemical compound [Cl-].[Cl-].[Sr+2] AHBGXTDRMVNFER-UHFFFAOYSA-L 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/02—Phosphorylation
- C07H1/04—Introducing polyphosphoric acid radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
Abstract
The application provides a P 1 ,P 4 -a process for the preparation of bis (uridine 5' -) tetraphosphate. Specifically, the method has the advantages of high yield and obviously reduced generation amount of impurities with large molecular weight, which are not easy to remove, in the industrial production process, and is easy to purify, and the method is P 1 ,P 4 The industrial production of di (uridine 5' -) tetraphosphate is made possible.
Description
Technical Field
The application relates to a P 1 ,P 4 -bis (uridine 5' -) tetraphosphoric acid (UP 4U) salt.
Background
Diquafos tetrasodium is also known as P 1 ,P 4 Bis (uridine 5' -) tetraphosphate, having the structure shown in (Ia), is a second-generation uridine nucleotide analogue, which is a P2Y2 receptor agonist and mucin secretion stimulator, and 3% diquassia tetrasodium salt eye drops have been developed by Japanese Korea pharmaceutical Co., ltd, for the treatment of dry eye. In addition, as an expectorant or a therapeutic agent for pneumonia having an effect of inducing sputum excretion, there is a possibility of further development.
Regarding P 1 ,P 4- Synthesis of di (uridine 5 '-) tetraphosphate, chinese patent CN101495497B discloses a method of using uridine 5' -triphosphateA process for the preparation of uridine 5 '-cyclic triphosphate by dehydration condensation of phosphoric acid (UTP) followed by docking with uridine 5' -monophosphate (UMP) using a metal salt selected from magnesium, manganese and iron as catalyst.
The preparation method disclosed in CN1147502C does not use a catalyst, but the yield of the target product is extremely low, and the method cannot be practically used. The process disclosed in CN105026414a is carried out by reacting a phosphoric acid active compound with a phosphoric acid compound selected from UMP, UDP, UTP and pyrophosphate, or a salt thereof, in the presence of a metal ion selected from 2-valent iron ion, 3-valent aluminum ion, 3-valent lanthanum ion, and 3-valent cerium ion, in water or a hydrophilic organic solvent to obtain P 1 ,P 4- Bis (uridine 5' -) tetraphosphoric acid, the method disclosed in this application uses very few metal salts which remain at a later stage, which is not known. CN107056859a claims a high purity P 1 ，P 4 The preparation method of the-di (uridine-5' -tetraphosphate) salt, the specification discloses a preparation method using strontium chloride as a metal salt catalyst, but the reaction yield is only 56%, and the method is not used for industrially producing P 1 ,P 4 The preferred method of di (uridine 5' -) tetraphosphoric acid, how to increase the yield of the reaction while reducing the impurity content, remains a problem to be solved.
Disclosure of Invention
The application provides a P 1 ,P 4 Preparation method of-di (uridine 5' -) tetraphosphoric acid, which obviously reduces P on the basis of improving yield 1 ,P 5 -di (uridine 5' -) pentaphosphoric acid (UP 5U), P 1 ,P 6- Production amount of di (uridine 5' -) hexaphosphoric acid (UP 6U) impurity.
The application provides a P shown in formula (I) 1 ，P 4 A process for the preparation of di (uridine 5' -) tetraphosphoric acid (UP 4U) comprising the steps of:
a) Activating a compound represented by formula (IIIb) using a condensing agent;
b) The compound of formula (IIIb) activated by the action of a catalyst metal calcium salt is reacted with the compound of formula (IIIa).
The metal calcium salt according to the present application is not particularly limited, and examples thereof include calcium fluoride, calcium chloride, calcium bromide, calcium iodide, calcium sulfate, calcium nitrate, calcium phosphate, calcium perchlorate, calcium tetrafluoroborate, calcium triflate, calcium methanesulfonate, calcium toluenesulfonate, calcium acetate, calcium trifluoroacetate, calcium stearate, and calcium citrate, preferably calcium chloride, and the calcium salt used may be anhydrous or hydrated, preferably anhydrous.
In the preparation method provided by the application, the molar ratio of the metal calcium salt to the compound shown in the formula (IIIb) is selected from 0.1-5, preferably 1.0-2, and most preferably 1.1-1.5.
The preparation method provided by the application further comprises the step of preparing a solution of the compound shown in the formula (IIIa) and an aprotic organic solvent of an amine salt of the compound shown in the formula (IIIb).
In the method provided by the magic, after the catalyst is added, the reaction temperature is selected from 0-50 ℃, preferably/25-40 ℃, and the reaction time is 4-24 hours, preferably 4-8 hours. In the process provided by the application, the aprotic organic solution of the amine salts of IIIa, IIIb has a moisture content of less than 1.0%, preferably less than 0.7%, more preferably less than 0.3%.
In the method provided by the application, molecular sieve mode can be used for removing water from the aprotic organic solution of the amine salts of IIIa and IIIb.
The preparation method provided by the application is characterized in that the reaction is carried out under the protection of inert gas, wherein the inert gas is selected from helium, argon and nitrogen, and nitrogen is preferred.
In the method provided by the application, the aprotic organic solvent is selected from single or mixed solvents of Dimethylformamide (DMF), dimethylacetamide (DMA), pyridine, dioxane and dimethyl sulfoxide.
In the method provided by the application, the condensing agent is selected from Dicyclohexylcarbodiimide (DCC), water-soluble carbodiimide (WSC), diisopropylcarbodiimide (DIPC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) or hydrochloride thereof, carbonyldiimidazole (CDI), preferably diisopropylcarbodiimide.
In the process provided by the application, the amine forming salt is selected from triethylamine, tributylamine, trioctylamine, tetrabutylammonium, heterocyclic amine, preferably tributylamine.
The method provided by the application is specifically carried out by a flow shown in Scheme 1:
in the method provided by the application, after the reaction is finished, P of a synthetic target object 1 ,P 4 The bis (uridine 5' -) tetraphosphoric acid may be isolated and purified by a suitable combination of methods used for isolation and purification of usual nucleotides (e.g., recrystallization, ion-exchange column chromatography, adsorption column chromatography, activated carbon column chromatography, etc.), and then prepared as a sodium salt.
The application provides a method for preparing P 1 ,P 4 Preparation of P from di (uridine 5' -) tetraphosphoric acid 1 ,P 4 Process for adsorbing P using anion exchange resin 1 ,P 4 After the bis (uridine 5' -) tetraphosphoric acid, a rapid elution was performed using sodium chloride solution as eluent.
The application provides the preparation P 1 ,P 4 The method of sodium bis (uridine 5' -) tetraphosphate further comprises one or more operations selected from nanofiltration, activated carbon adsorption, recrystallization.
The method provided by the application has the advantages that the yield of the target product is up to 75%, and the P is obviously reduced 1 ,P 5 -di (uridine 5' -) pentaphosphoric acid (UP 5U), P 1 ,P 6 -amount of di (uridine 5' -) hexaphosphoric acid (UP 6U) impurity.
Detailed Description
Examples
The present application is specifically illustrated by the following examples, but the present application is not limited to these examples.
The disodium uridine-5 '-monophosphate salt, uridine-5' -trisodium triphosphate salt used in the examples was commercially available.
Example 1P 1 ,P 4 Preparation of bis (uridine 5' -) tetraphosphoric acid
Step 1. Preparation of intermediate Compound of formula (IIa) (UMP-TBA)
Uridine-5' -monophosphate disodium salt (5.43 mol,2.0 kg) and purified water (10.0 kg) were added to a 20L plastic bucket, and after complete dissolution under stirring, the filtrate was filtered for use; loading 20.0L of DOWEX IR100S resin converted into hydrogen into a chromatographic column, flushing with purified water (40.0 kg), compacting the resin, discharging bubbles, discharging the flushing liquid, and closing a liquid discharge switch; slowly introducing the filtrate into a column, enabling the upper liquid level to just submerge the resin, standing, adding purified water (95.0 kg) into the column for column elution, stopping eluting when the pH of the eluent is changed to 6.5-7.5, combining the eluents, adding the eluents into a 200L reaction kettle, starting stirring, and dropwise adding tri-n-butylamine (0.92 kg) at 15-25 ℃ until the pH is 6.5-7.5; the reaction solution was concentrated to a small volume by nanofiltration and lyophilized to remove water to give 2.53kg with a yield of 91.4%. Dissolving the residue in N, N-dimethylformamide to obtain IIa solution of about 0.65mol/L, adding activated molecular sieve type 4A, drying, measuring water content not more than 0.2%, and filtering to obtain filtrate.
Step 2. Preparation of intermediate Compound of formula (IIb) (UTP-3 TBA)
Uridine-5' -trisodium triphosphate salt (4.54 mol,2.5 kg) and purified water (12.5 kg) were added to a 20L plastic bucket, and after complete dissolution under stirring, the filtrate was filtered for use; 30.0L of DOWEX IR100S resin converted into hydrogen form was charged into a column, washed with purified water (60.0 kg), compacted, the washing solution was discharged after the air bubbles were discharged, and the drain switch was turned off. Slowly introducing the filtrate obtained in the previous step into a column, enabling the upper liquid level to just submerge the resin, standing, adding purified water (130.0 kg) into the column for column passing and eluting, controlling the flow rate, stopping eluting when the pH value of the eluent is 6.5-7.5, mixing the eluates, adding the eluates into a 200L reaction kettle, starting stirring, and dropwise adding tri-n-butylamine (2.27 kg) at 15-25 ℃ until the pH value is 6.5-7.5; the reaction solution was concentrated to a small volume by nanofiltration and lyophilized to remove water to give 4.25kg with a yield of 89.9%. The residue was dissolved in N, N-dimethylformamide to give an IIb solution of about 0.32mol/L, and dried by adding activated molecular sieve type 4A, and the water content was measured to be not more than 0.2%, and the filtered liquid was directly transferred to the next step.
Step 3.P 1 ,P 4 Preparation of bis (uridine 5' -) tetraphosphoric acid
The prepared N, N-dimethylformamide (UTP-3TBA 3.85g,3.69mmol) of UTP-3TBA was put into a 100ml three-necked flask, and diisopropylcarbodiimide (562 mg,4.44 mmol) was added thereto, N 2 After 2 times of replacement, reacting for 5 hours at 25-30 ℃; n, N-dimethylformamide (UMP-TBA 2.23g,4.43 mmol) of UMP-TBA and anhydrous calcium chloride (492 mg,4.43 mmol) were added to the reaction mixture, followed by reaction at 25 to 30℃for 5 hours, detection by sampling HPLC, and calculation of UP4U content and high molecular weight impurity P by area normalization method 1 ，P 5 Di (uridine 5' -) pentaphosphoric acid (UP 5U) and P 1 ，P 6 -content of di (uridine 5' -) hexaphosphate (UP 6U).
Example 2P 1 ,P 4 Preparation of bis (uridine 5' -) tetraphosphoric acid
Placing prepared N, N-dimethylformamide (UTP-3TBA 3.84g,3.69mmol) of UTP-3TBA into 100ml three-necked flask, adding diisopropylcarbodiimide (564 mg,4.44 mmol), and N 2 After 2 times of replacement, the reaction is carried out for 5 hours at 25-30 ℃. N, N-dimethylformamide (UMP-TBA 2.23g,4.43 mmol) of UMP-TBA and anhydrous magnesium chloride (422 mg,4.43 mmol) were added to the reaction mixture, followed by reaction at 25 to 30℃for 5 hours, detection by sampling HPLC, and calculation of UP4U content and high molecular weight impurity P by area normalization method 1 ，P 5 Di (uridine 5' -) pentaphosphoric acid (UP 5U) and P 1 ，P 6 -content of di (uridine 5' -) hexaphosphate (UP 6U).
Results:
Claims (14)
1. p (P) 1 ，P 4 -di (uridine 5)A process for preparing a (-) tetraphosphate comprising:
a) Preparing a solution of a compound of formula (IIa) and an aprotic organic solvent for the compound of formula (IIb);
b) Activating a compound represented by formula (IIb) with a condensing agent diisopropylcarbodiimide;
c) The compound shown in the formula (IIb) which is activated under the action of catalyst metal calcium salt reacts with the compound shown in the formula (IIa), the molar ratio of the metal calcium salt catalyst to the IIb is 1.1-1.5, and the metal calcium salt is calcium chloride.
2. The method according to claim 1, wherein the metal calcium salt is anhydrous calcium chloride.
3. The process according to claim 1, wherein the aprotic organic solution of the amine salts of IIa, IIb has a water content of less than 1.0%.
4. The process according to claim 1, wherein the aprotic organic solution of the amine salts of IIa, IIb has a water content of less than 0.7%.
5. The process according to claim 1, wherein the aprotic organic solution of the amine salts of IIa, IIb has a water content of less than 0.3%.
6. The process according to claim 3-5, wherein the reaction temperature in step c) is selected from the range of 0 to 50 ℃.
7. The process according to claim 6, wherein the reaction temperature in step c) is 25 to 40 ℃.
8. The process according to claim 6, wherein the reaction is carried out under the protection of an inert gas selected from helium, argon and nitrogen.
9. The preparation method according to claim 6, wherein the reaction is performed under the protection of an inert gas, wherein the inert gas is nitrogen.
10. The process according to claim 8, wherein the aprotic organic solvent is selected from dimethylformamide, dimethylacetamide, pyridine, dioxane and dimethylsulfoxide.
11. The process of claim 8 wherein the aprotic organic solvent is dimethylformamide.
12. P (P) 1 ，P 4 -a process for the preparation of tetra sodium di (uridine 5' -) tetraphosphate comprising the steps of any of the claims 1-11.
13. The process according to claim 12, wherein P is adsorbed by anion exchange resin 1 ，P 4 Di (uridine 5' -) tetraphosphoric acid followed by elution with sodium chloride solution.
14. The process according to claim 13, comprising one or more operations selected from nanofiltration, activated carbon adsorption, recrystallization.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101495497A (en) * | 2006-07-26 | 2009-07-29 | Yamasa酱油株式会社 | Process for producing di(pyrimidine nucleoside 5'-)polyphosphate |
| CN105026414A (en) * | 2012-12-28 | 2015-11-04 | Yamasa酱油株式会社 | Method for producing P1, P4-bis (uridine 5'-) tetraphosphate |
| CN107056859A (en) * | 2017-04-28 | 2017-08-18 | 广东众生药业股份有限公司 | A kind of high-purity P1, P4Two（The phosphoric acid of uridine 5 ' four）The preparation method of salt |
| KR20180091672A (en) * | 2017-06-21 | 2018-08-16 | 주식회사 종근당 | Method for Preparing a Dinucleoside Polyphosphate Compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101495497A (en) * | 2006-07-26 | 2009-07-29 | Yamasa酱油株式会社 | Process for producing di(pyrimidine nucleoside 5'-)polyphosphate |
| CN105026414A (en) * | 2012-12-28 | 2015-11-04 | Yamasa酱油株式会社 | Method for producing P1, P4-bis (uridine 5'-) tetraphosphate |
| CN107056859A (en) * | 2017-04-28 | 2017-08-18 | 广东众生药业股份有限公司 | A kind of high-purity P1, P4Two（The phosphoric acid of uridine 5 ' four）The preparation method of salt |
| KR20180091672A (en) * | 2017-06-21 | 2018-08-16 | 주식회사 종근당 | Method for Preparing a Dinucleoside Polyphosphate Compound |
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