CN110540555B - Method for dissociating nucleoside phosphate - Google Patents
Method for dissociating nucleoside phosphate Download PDFInfo
- Publication number
- CN110540555B CN110540555B CN201910444315.8A CN201910444315A CN110540555B CN 110540555 B CN110540555 B CN 110540555B CN 201910444315 A CN201910444315 A CN 201910444315A CN 110540555 B CN110540555 B CN 110540555B
- Authority
- CN
- China
- Prior art keywords
- formula
- calcium
- salt
- compound represented
- organic solvent
- 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.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 67
- -1 nucleoside phosphate Chemical class 0.000 title claims abstract description 26
- 229910019142 PO4 Inorganic materials 0.000 title abstract description 9
- 239000002777 nucleoside Substances 0.000 title abstract description 7
- 239000010452 phosphate Substances 0.000 title description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003729 cation exchange resin Substances 0.000 claims abstract description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 79
- 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 description 49
- 150000001875 compounds Chemical class 0.000 claims description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 31
- 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 description 25
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims description 25
- 229940045145 uridine Drugs 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 21
- 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 description 20
- 239000003960 organic solvent Substances 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- 159000000007 calcium salts Chemical class 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
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-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
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229910021645 metal ion Inorganic materials 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 4
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 159000000000 sodium salts Chemical class 0.000 claims description 4
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 claims description 3
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 claims description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- UNMYWSMUMWPJLR-UHFFFAOYSA-L Calcium iodide Chemical compound [Ca+2].[I-].[I-] UNMYWSMUMWPJLR-UHFFFAOYSA-L 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 159000000009 barium salts Chemical class 0.000 claims description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 2
- 239000001639 calcium acetate Substances 0.000 claims description 2
- 229960005147 calcium acetate Drugs 0.000 claims description 2
- 235000011092 calcium acetate Nutrition 0.000 claims description 2
- 229910001622 calcium bromide Inorganic materials 0.000 claims description 2
- 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 claims description 2
- 239000001354 calcium citrate Substances 0.000 claims description 2
- WGEFECGEFUFIQW-UHFFFAOYSA-L calcium dibromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 claims description 2
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 claims description 2
- 229910001634 calcium fluoride Inorganic materials 0.000 claims description 2
- 229940046413 calcium iodide Drugs 0.000 claims description 2
- 229910001640 calcium iodide Inorganic materials 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 2
- 235000011010 calcium phosphates Nutrition 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 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 claims description 2
- BWEYVLQUNDGUEC-UHFFFAOYSA-L calcium;methanesulfonate Chemical compound [Ca+2].CS([O-])(=O)=O.CS([O-])(=O)=O BWEYVLQUNDGUEC-UHFFFAOYSA-L 0.000 claims description 2
- 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 claims description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 2
- 159000000003 magnesium salts Chemical group 0.000 claims description 2
- 150000002696 manganese Chemical class 0.000 claims description 2
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 claims description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 235000013337 tricalcium citrate Nutrition 0.000 claims description 2
- 150000003751 zinc Chemical class 0.000 claims description 2
- 150000002505 iron Chemical class 0.000 claims 1
- 235000021317 phosphate Nutrition 0.000 abstract description 8
- 239000000243 solution Substances 0.000 description 19
- 239000011347 resin Substances 0.000 description 15
- 229920005989 resin Polymers 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- 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 9
- PGAVKCOVUIYSFO-UHFFFAOYSA-N uridine-triphosphate Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)OC1N1C(=O)NC(=O)C=C1 PGAVKCOVUIYSFO-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 238000010494 dissociation reaction Methods 0.000 description 5
- 230000005593 dissociations Effects 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- KURVIXMFFSNONZ-WFIJOQBCSA-L disodium;[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound [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 4
- 238000010828 elution Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 238000001728 nano-filtration Methods 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- OWTGMPPCCUSXIP-FNXFGIETSA-J tetrasodium;[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] [[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl]oxy-oxidophosphoryl] phosphate Chemical compound [Na+].[Na+].[Na+].[Na+].N1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)COP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OC[C@@H]2[C@H]([C@H]([C@@H](O2)N2C(NC(=O)C=C2)=O)O)O)C=CC(=O)NC1=O OWTGMPPCCUSXIP-FNXFGIETSA-J 0.000 description 3
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 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 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 102000015728 Mucins Human genes 0.000 description 1
- 108010063954 Mucins Proteins 0.000 description 1
- 241000590428 Panacea Species 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
- 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 1
- ODAFRNQYKNHQRI-UHFFFAOYSA-J [O-]P([O-])(=O)OP(=O)([O-])OP(=O)([O-])OP(=O)(O)O.[Na+].[Na+].[Na+].[Na+] Chemical compound [O-]P([O-])(=O)OP(=O)([O-])OP(=O)([O-])OP(=O)(O)O.[Na+].[Na+].[Na+].[Na+] ODAFRNQYKNHQRI-UHFFFAOYSA-J 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229950003529 diquafosol Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 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
- 231100001231 less toxic Toxicity 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 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
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
- 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 1
- 238000013022 venting 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
-
- 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 present invention provides a method for liberating nucleoside phosphates. Specifically, the present invention provides an environmentally friendly, novel method for liberating nucleoside phosphates, which avoids the use of a large amount of cation exchange resin and water, and reduces industrial costs.
Description
Technical Field
The invention relates to an environment-friendly and novel method for preparing free nucleoside phosphate.
Background
Diquafosol tetrasodium salt, also known as P 1 ,P 4 -bis (uridine 5' -) tetrasodium tetraphosphate, having the structure shown below,
diquafosol tetrasodium is a dibasic uridine nucleotide analog, which is a P2Y2 receptor agonist and a mucin secretion stimulator, and 3% of diquafosol tetrasodium salt eye drops have been developed by japan panacea corporation for the treatment of dry eye. In addition, it is possible to develop an expectorant or a therapeutic drug for pneumonia, which has an effect of inducing expectoration.
The prior art discloses a large number of documents relating to P 1 ,P 4- The synthesis of disodium bis (uridine 5' -) tetraphosphate, summarized basically as follows, comprises liberating disodium uridine-5 ' -monophosphate by cationic resin as uridine-5 ' -monophosphate, then forming n-butylamine uridine-5 ' -monophosphate salt (UMP-TBA), liberating trisodium uridine-5 ' -triphosphate by cationic resin as uridine-5 ' -triphosphate, then forming tri-n-butylamine uridine-5 ' -triphosphate salt (UTP-3 TBA), wherein the eluent is water when liberated, and reacting UMP-TBA with UTP-3TBA by condensing agent to obtain P-TBA 1 ,P 4- Bis (uridine 5'-) tetraphosphoric acid, and then converting the acid into a sodium salt to obtain a final product, as specifically disclosed in the prior art CN107056859A, CN1292795A and the like.
This process for the preparation of uridine phosphates typically requires the use of large amounts of cation exchange resin and water, while removing the water azeotropically by lyophilization or by large amounts of solvent over a long period of time, is a time, energy and solvent consuming process. In addition, high boiling tributylamine is required to neutralize uridine phosphates due to lyophilization and azeotropic water entrainment. Tributylamine is listed as a highly toxic chemical, and is not favorable for safe operation and environmental protection.
The present invention provides an environment-friendly, novel method for dissociating nucleoside phosphate, which avoids the use of a large amount of cation exchange resin and water, and reduces industrial costs.
Disclosure of Invention
The present invention provides an environment-friendly, novel method for dissociating nucleoside phosphate, which avoids the use of a large amount of cation exchange resin and water, and reduces industrial costs.
The present invention provides a process for liberating a compound represented by the formula (I) into an acid, which is characterized by the step of contacting a compound represented by the formula (I) in an organic solvent with a cation exchange resin,
wherein Y is selected from
Preference is given to
X is selected from Na + 、K + 、NH 4 + Preferably Na + ；
n and m are each independently selected from 1, 2, 3, 4, 5.
The compounds of formula (I) described in the present invention optionally contain one or more water.
The organic solvent in the present invention is selected from the group consisting of N, N-Dimethylformamide (DMF), dimethylacetamide (DMAC), dioxane, tetrahydrofuran, acetone, acetonitrile, dimethyl sulfoxide, dimethyl imidazolidinone, hexamethylphosphoric triamide, trimethyl phosphate, triethyl phosphate or a mixture thereof, preferably N, N-dimethylformamide.
The method provided by the invention further comprises a step of separating the organic solvent from the cation exchange resin, and the method can be filtration, throwing filtration and the like.
The method for dissociating the compound shown as the formula I into the corresponding acid is characterized in that the cation exchange resin is gel type strong acid cation exchange resin, such as DOWEX IR100S H type resin.
In the dissociation method provided by the invention, the mass ratio of the cation exchange resin to the compound shown in the formula I is selected from 1-30, preferably 2-10, and most preferably 3-5.
In the dissociation method provided by the invention, the dissociation temperature is selected from-15-70 ℃, preferably-5-30 ℃, and most preferably 10-15 ℃.
In the dissociation method provided by the invention, the mass-to-volume (g/mL) ratio of the compound represented by the formula (I) to the organic solvent is selected from 0.05 to 0.50, preferably 0.1 to 0.4, and most preferably 0.25 to 0.35.
The free method provided by the invention can be selected from the following operation modes:
a) Mixing the cation exchange resin with an organic solvent;
b) Adding a compound shown in a formula (I) under stirring;
c) The corresponding free acid is obtained by filtration.
In the dissociation method provided by the present invention, the compound represented by the formula (I) is preferably
The invention further provides a P 1 ,P 4 Process for the preparation of (uridine 5' -) tetraphosphate, characterised in that it comprises the free compound of formula (Ia) or (Ib) as defined aboveThe steps are performed in the presence of a compound represented by the formula (IIa) and a compound represented by the formula (IIb).
P provided by the invention 1 ,P 4 A process for the preparation of (E) -bis (uridine 5' -) tetraphosphate, further comprising the step of forming an amine salt of the compound of formula (IIa) and (IIb) in an aprotic organic solvent.
P provided by the invention 1 ,P 4 -bis (uridine 5' -) tetraphosphate, wherein said aprotic organic solvent is selected from the group consisting of N, N-Dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide, alone or in combination, preferably N, N-Dimethylformamide (DMF).
P provided by the invention 1 ,P 4 The amine of the amine salt in the process for the preparation of (uridine 5' -) tetraphosphoric acid is selected from the group consisting of triethylamine, N-diisopropylethylamine, tributylamine, trioctylamine, tetrabutylammonium, heterocyclic amines, preferably triethylamine.
In the preparation method provided by the invention, the water content in the aprotic organic solution of the amine salt of the compound shown in the formula (IIa) and the compound shown in the formula (IIb) is controlled to be less than 1.0%, preferably less than 0.7%, and more preferably less than 0.3%.
In the method provided by the invention, the water removal of the aprotic organic solution of the compounds represented by the formula (IIa) and the formula (IIb) can be carried out by using a molecular sieve, azeotropic method or freeze-drying method.
P provided by the invention 1 ,P 4 A process for producing (E) -bis (uridine 5' -) tetraphosphate, further comprising the step of reacting an amine salt of the compound represented by formula (IIa) or (IIb) with a condensing agent and a metal ion catalyst.
The condensing agent of the present invention is selected from: dicyclohexylcarbodiimide, water-soluble carbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or a hydrochloride thereof, carbonyldiimidazole, and preferably diisopropylcarbodiimide.
The metal salt catalyst is selected from magnesium salt, zinc salt, calcium salt, ferric salt, manganese salt and barium salt, and calcium salt is preferred.
The calcium salt according to the present invention is not particularly limited, and specifically, calcium fluoride, calcium chloride, calcium bromide, calcium iodide, calcium sulfate, calcium nitrate, calcium phosphate, calcium perchlorate, calcium tetrafluoroborate, calcium trifluoromethanesulfonate, calcium methanesulfonate, calcium toluenesulfonate, calcium acetate, calcium trifluoroacetate, calcium stearate, and calcium citrate can be exemplified, and calcium chloride is preferable.
In the preparation method provided by the invention, the molar ratio of the metal ion catalyst to the compound shown in the formula (IIb) is selected from 0.1-5, preferably 1.0-2, and most preferably 1.1-1.5.
The optimal method provided by the invention is specifically carried out by a process shown in Scheme 1:
in the method provided by the invention, after the reaction is finished, P for the synthetic target substance 1 ,P 4 The di (uridine 5' -) tetraphosphate can be isolated and purified by appropriately combining methods used in the isolation and purification of a usual nucleotide (for example, recrystallization, ion exchange column chromatography, adsorption column chromatography, activated carbon column chromatography, etc.), and then prepared in the form of a sodium salt.
The invention provides a P 1 ,P 4 Process for the preparation of tetrasodium (uridine 5' -) tetraphosphate, characterized in that it comprises the above-mentioned preparation of P 1 ,P 4 -bis (uridine 5' -) tetraphosphate.
The invention provides a method for synthesizing P 1 ,P 4 Preparation of P from-bis (uridine 5' -) tetraphosphate 1 ,P 4 Process for the adsorption of P-tetra sodium-bis (uridine 5' -) tetraphosphate using an anion exchange resin 1 ,P 4 -bis (uridine 5' -) tetraphosphate followed by a fast elution with sodium chloride solution as eluent.
The invention provides a process for preparing P 1 ,P 4 The process for the production of sodium-bis (uridine 5' -) tetraphosphate further comprises one or more operations selected from nanofiltration, activated carbon adsorption, recrystallization.
The method provided by the invention avoids nanofiltration, freeze-drying or azeotropic dehydration, and shortens the total synthesis time by 40%. Meanwhile, the usage amount of resin is reduced by 60%, the usage amount of water and solvent is greatly reduced, and the yield of the target product is as high as 73.9%. (calculated as the conversion of UTP)
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and the spirit and scope of the present invention are not limited thereto.
Uridine-5 '-monophosphate disodium salt and uridine-5' -triphosphate trisodium salt were used in the experiments and were purchased commercially.
Example 1
1. Preparation of intermediate Compound (IIIa) (UMP-TEA)
60mL of Dowex IR100s H type resin was added to a 150mL glass suction filter funnel, suction filtered, rinsed twice with 20mL of N, N-Dimethylformamide (DMF), and suction filtered until no droplets were evident. The resin was transferred to a 250ml single neck flask, 55ml of N, N-Dimethylformamide (DMF) was added, uridine 5' -monophosphate disodium salt (54.3 mmol,20.0 g) was added in one portion with magnetic stirring, reacted at room temperature (15 ℃) for 2h, filtered through a glass suction filter funnel, stirred with 55ml of 2N, N-dimethylformamide and combined in N, N-dimethylformamide solution. Triethylamine (54.3 mmol,5.5 g) was added dropwise to the N, N-dimethylformamide solution while stirring, and the temperature was raised slightly, after the addition, the reaction was stirred at room temperature for 30min to obtain a N, N-dimethylformamide solution of UMP-TEA. Adding activated molecular sieve
The form (90.0 g) was dried and the water content was determined to be not more than 0.2%, and the filtered liquid was directly transferred to the next step.
2. Preparation of intermediate Compound (IIIb) (UTP-3 TEA)
60ml of Dowex IR100s H-type resin was added to a 150mL glass suction filter funnel, suction filtered, rinsed twice with 20ml of N, N-dimethylformamide, and suction filtered until no significant droplets were present. The resin was transferred to a 250ml single-neck flask, 55ml of N, N-dimethylformamide was added, and uridine 5' -triphosphate trisodium salt (48.9mmol, 27.0 g) was added in one portion under magnetic stirring, and the mixture was inverted at room temperature (15 ℃ C.)The reaction solution is filtered by a glass suction filter funnel for 2 hours, and then is stirred and washed by 55mx 2N and N-dimethylformamide, and the N, N-dimethylformamide solution is combined. To the above DMF solution was added dropwise triethylamine (163mmol, 16.5 g) with stirring, and after the addition, the reaction was stirred at room temperature for 30min to obtain a DMF solution of UTP-3 TEA. Adding activated molecular sieve
The form (90.0 g) was dried and the water content was determined to be not more than 0.2%, and the filtered liquid was directly transferred to the next step.
3.P 1 ,P 4 Preparation of-bis (uridine 5' -) tetraphosphate
The prepared UTP-3TEA in N, N-dimethylformamide (UTP-3 TEA 3.80g, 4.83mmol) was placed in a 100ml three-necked flask, and diisopropylcarbodiimide (554mg, 5.80mmol), N-diisopropylcarbodiimide (554mg, 5.80mmol) was added 2 After 2 times of replacement, reacting for 5 hours at 25-30 ℃; to the reaction solution were added a solution of UMP-TEA in N, N-dimethylformamide (UMP-TEA 2.46g, 5.80mmol), anhydrous calcium chloride (484mg, 5.80mmol), followed by reaction at 25 to 30 ℃ for 5 hours, followed by sampling and HPLC analysis, and the UP4U content was calculated by area normalization in terms of the UTP conversion (yield: 73.9%).
Comparative example 1
1. Preparation of uridine-5' -monophosphoric tri-n-butylamine (UMP-TBA)
Adding uridine-5' -monophosphate disodium salt (54.3mmol, 20.0g) and purified water (100 g) into a 250mL glass beaker, dissolving completely under stirring, and filtering to obtain a filtrate for later use; loading 200mL of DOWEX IR100S resin converted into hydrogen form into a chromatographic column, washing with purified water (400 g), compacting the resin, discharging bubbles, discharging the washing solution, and closing a liquid discharge switch; slowly introducing the filtrate into a column, allowing the upper liquid level to just submerge the resin, standing, adding purified water (950 g) into the column for column chromatography, stopping elution when the pH of the eluent is 6.5-7.5, mixing the eluates, adding into a 2L reaction bottle, stirring, and dropwise adding tri-n-butylamine (9.2 g) to pH6.5-7.5 at 15-25 deg.C; the reaction solution was concentrated to a small volume by nanofiltration, and then lyophilized to remove water to obtain 25.3g. The residue was dissolved in N, N-dimethylformamide (85 mL) to make a solution of about 0.65mol/L IIa, and the activated molecule was addedSieve
Drying, measuring water content not more than 0.2%, filtering, and transferring the liquid to next step.
2. Preparation of uridine-5' -triphosphate, tri-n-butylamine salt (UTP-3 TBA)
Adding uridine-5' -triphosphate trisodium salt (45.4 mol, 25g) and purified water (125 g) into a 250mL plastic bucket, dissolving completely under stirring, and filtering to obtain filtrate for later use; 300mL of DOWEX IR100S resin converted to the hydrogen form was loaded into a chromatography column, washed with purified water (600 g), the resin was compacted, the wash was drained after venting the gas bubbles, and the drain switch was closed. Slowly introducing the filtrate into a column to ensure that the liquid level of the upper layer just submerges the resin, standing, adding purified water (1.30 kg) into the column for column-passing elution, controlling the flow rate until the pH value of the eluent is 6.5-7.5, stopping elution, combining the eluents, adding the eluates into a 2L reaction bottle, starting stirring, and dropwise adding tri-n-butylamine (22.7 g) to the pH value of 6.5-7.5 at 15-25 ℃; the reaction solution was concentrated by nanofiltration to a small volume and then lyophilized to remove water to obtain 42.5g. The residue was dissolved in N, N-dimethylformamide (140 mL) to prepare an about 0.32mol/L IIb solution, and activated molecular sieves were added
Drying, measuring water content not more than 0.2%, filtering, and transferring the liquid to next step.
3.P 1 ,P 4 Preparation of-bis (uridine 5' -) tetraphosphate
The prepared UTP-3TBA in N, N-dimethylformamide (UTP-3 TBA 5.02g, 4.83mmol) was placed in a 100ml three-necked flask and diisopropylcarbodiimide (562mg, 4.44mmol), N-dimethylformamide, added 2 After 2 times of replacement, reacting for 5 hours at 25-30 ℃; a solution of UMP-TBA in N, N-dimethylformamide (UMP-TBA 2.96g, 5.80mmol) and anhydrous calcium chloride (492mg, 4.43mmol) were added to the reaction mixture, and the mixture was reacted at 25 to 30 ℃ for 5 hours, followed by sampling and HPLC analysis, and the UP4U content was calculated by area normalization based on the conversion of UTP (yield: 75.9%).
The yields of the examples and comparative examples were substantially identical. However, the reaction time of the examples only needs 12The hour was 62 hours compared to the comparative example. The examples were carried out without water, whereas the comparative examples used 2176g of water. The examples only require 1/4 of the resin of the comparative example. The examples use triethylamine, which is less toxic, instead of tributylamine, which is highly toxic. Therefore, the invention provides an environment-friendly, energy-saving and time-saving P 1 ,P 4 A synthetic preparation method of (uridine 5' -) tetraphosphate.
Comparing the experimental results of the examples and comparative examples:
Claims (32)
1. a process for liberating a compound represented by the formula (I) into an acid, which comprises the step of contacting a compound represented by the formula (I) with a cation exchange resin in an organic solvent,
wherein Y is selected from
X is selected from Na + 、K + 、NH 4 + ；
n and m are each independently selected from 1, 2, 3, 4, 5;
the organic solvent is selected from N, N-dimethylformamide, dimethylacetamide, dioxane, tetrahydrofuran, acetone, acetonitrile, dimethyl sulfoxide, dimethyl imidazolidinone, hexamethylphosphoric triamide, trimethyl phosphate, triethyl phosphate or a mixture thereof;
the cation exchange resin is gel type strong acid cation exchange resin.
2. A process for liberating a compound represented by the formula (I) into an acid, which comprises the step of contacting a compound represented by the formula (I) with a cation exchange resin in an organic solvent,
wherein Y is
X is Na + ；
n and m are each independently selected from 1, 2, 3, 4, 5;
the organic solvent is selected from N, N-dimethylformamide, dimethylacetamide, dioxane, tetrahydrofuran, acetone, acetonitrile, dimethyl sulfoxide, dimethyl imidazolidinone, hexamethylphosphoric triamide, trimethyl phosphate, triethyl phosphate or a mixture thereof;
the cation exchange resin is gel type strong acid cation exchange resin.
3. The process according to any one of claims 1-2, characterized in that the organic solvent is N, N-dimethylformamide.
4. The method according to any one of claims 1 to 2, characterized by further comprising a step of separating the organic solvent from the cation exchange resin.
5. The process according to any one of claims 1-2, characterized in that the mass ratio of the cation exchange resin to the compound of formula (i) is selected from the range of 1 to 30.
6. The process according to any one of claims 1-2, characterized in that the mass ratio of the cation exchange resin to the compound of formula (i) is selected from the range of 2 to 10.
7. The process according to any one of claims 1-2, characterized in that the mass ratio of the cation exchange resin to the compound of formula (i) is selected from 3 to 5.
8. The method according to any one of claims 1-2, wherein the temperature of liberation is selected from the group consisting of-15 to 70 ℃.
9. The method according to any one of claims 1-2, wherein the temperature of liberation is-5 to 30 ℃.
10. The method according to any one of claims 1-2, characterized in that the temperature of liberation is selected from 10-15 ℃.
11. The process according to any one of claims 1-2, wherein the mass to volume (g/mL) ratio of the compound of formula (i) to the organic solvent is selected from 0.05 to 0.55.
12. The process according to any one of claims 1-2, characterized in that the mass to volume (g/mL) ratio of the compound of formula (i) to the organic solvent is selected from 0.1 to 0.4.
13. The process according to any one of claims 1-2, characterized in that the mass to volume (g/mL) ratio of the compound of formula (i) to the organic solvent is selected from the range of 0.25 to 0.35.
14. The method according to any one of claims 1-2, wherein the compound of formula (i) is selected from the group consisting of
15. P 1 ,P 4 -a process for the preparation of di (uridine 5' -) tetraphosphate comprising the process according to claim 14, wherein said compound of formula (Ia) or (Ib) is free as the corresponding acid, a compound of formula (IIa) or (IIb),
16. the method according to claim 15, further comprising a step of forming an amine salt of the compound represented by the formula (IIa) or (IIb) in an aprotic organic solvent.
17. The method according to claim 16, wherein the aprotic organic solvent is selected from the group consisting of N, N-dimethylformamide, dimethylacetamide and dimethylsulfoxide.
18. The method according to claim 16, wherein the aprotic organic solvent is N, N-dimethylformamide.
19. The method of claim 17, wherein the amine forming salt of an amine is selected from the group consisting of triethylamine, N-diisopropylethylamine, tributylamine, trioctylamine, tetrabutylammonium, and heterocyclic amines.
20. The method of claim 17, wherein the amine forming amine salt is triethylamine.
21. The process according to claim 19, wherein the water content of the aprotic organic solution of the amine salt of the compound represented by the formula (IIa) or (IIb) is controlled to less than 1.0%.
22. The process according to claim 19, wherein the water content of the aprotic organic solution of the amine salt of the compound represented by the formula (IIa) or (IIb) is controlled to less than 0.7%.
23. The process according to claim 19, wherein the water content of the aprotic organic solution of the amine salt of the compound represented by the formula (IIa) or (IIb) is controlled to less than 0.3%.
24. The method according to any one of claims 15 to 23, further comprising the step of reacting an amine salt of a compound represented by the formula (iia) and (iib) with a condensing agent selected from dicyclohexylcarbodiimide, water-soluble carbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or a hydrochloride thereof, carbonyldiimidazole; the metal salt catalyst is selected from magnesium salt, zinc salt, calcium salt, iron salt, manganese salt and barium salt.
25. The method according to any one of claims 15 to 23, further comprising the step of reacting an amine salt of a compound represented by the formula (iia) and (iib) with a condensing agent which is diisopropylcarbodiimide; the metal salt catalyst is calcium salt.
26. The method of claim 24, wherein the calcium salt is selected from the group consisting of 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.
27. The method of claim 24, wherein the calcium salt is calcium chloride.
28. The method according to claim 24, wherein the molar ratio of the metal ion catalyst to the compound represented by the formula (IIb) is selected from the range of 0.1 to 5.
29. The method according to claim 24, wherein the molar ratio of the metal ion catalyst to the compound represented by the formula (IIb) is selected from the range of 1.0 to 2.
30. The method according to claim 24, wherein the molar ratio of the metal ion catalyst to the compound represented by the formula (IIb) is selected from the range of 1.1 to 1.5.
31. P 1 ,P 4 Process for the preparation of tetrasodium (uridine 5' -) tetraphosphate, comprising the preparation of P according to claim 24 1 ,P 4 -bis (uridine 5' -) tetraphosphate, further comprising a step of forming a sodium salt.
32. P 1 ,P 4 Process for the preparation of tetrasodium-salt of (E) -bis (uridine 5' -) tetraphosphate, characterized in that it comprises the preparation of P according to any one of claims 25 to 30 1 ,P 4 -bis (uridine 5' -) tetraphosphate, further comprising a step of forming a sodium salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810521930 | 2018-05-28 | ||
| CN201810521930X | 2018-05-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110540555A CN110540555A (en) | 2019-12-06 |
| CN110540555B true CN110540555B (en) | 2023-01-24 |
Family
ID=68702734
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910444315.8A Active CN110540555B (en) | 2018-05-28 | 2019-05-27 | Method for dissociating nucleoside phosphate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110540555B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116694B (en) * | 2020-01-02 | 2021-10-08 | 上海方予健康医药科技有限公司 | P1，P4Process for the preparation of di (uridine 5' -) tetraphosphate |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU7623991A (en) * | 1990-05-17 | 1991-11-21 | Syntex (U.S.A.) Inc. | Antiviral agents |
| JP3723227B2 (en) * | 1997-07-25 | 2005-12-07 | インスパイアー ファーマシューティカルズ，インコーポレイティド | Process for large-scale production of di (uridine 5 ')-tetraphosphate and its salts |
| 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 |
-
2019
- 2019-05-27 CN CN201910444315.8A patent/CN110540555B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN110540555A (en) | 2019-12-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2017188042A1 (en) | Method for producing monomer for single-stranded nucleic acid molecule | |
| CN1302004C (en) | Preparing method for cytarabine | |
| CN1222147A (en) | Process for prepn. of tetraazamacrocycles | |
| KR20100103427A (en) | Improved process for preparing meropenem using zinc powder | |
| CN110540555B (en) | Method for dissociating nucleoside phosphate | |
| CN110218233B (en) | P (P) 1 ,P 4 Preparation method of di (uridine 5' -tetraphosphate) | |
| CN114516875A (en) | Preparation method of nucleoside analogue VV116 | |
| CN108976233A (en) | Impurity and its preparation, detection method of the Ba Rui for Buddhist nun | |
| WO2019143074A1 (en) | Method for producing calcobutrol | |
| EP4083039A1 (en) | Method for preparing isavuconazonium sulfate | |
| KR20230026411A (en) | Method for producing aromatic ether compounds | |
| CN106083539B (en) | A kind of synthetic method of list fluorine methoxyl group or the deuterated methoxy base class compound of single fluorine | |
| US20070208050A1 (en) | Process for preparing irinotecan | |
| CN106518939B (en) | Method for preparing Solithromycin compound | |
| CN103012176A (en) | Method for preparing long-chain alkyl 4-carboxyl anionic surfactant | |
| JP7405991B2 (en) | Method for producing uridine 5'-diphosphate (UDP), its salt or its hydrate | |
| CN101805339A (en) | Entecavir compound prepared in novel method | |
| CN113480465B (en) | Preparation method of 1- (2-nitrobenzyl) pyrrole-2-formaldehyde | |
| CN113754632A (en) | Preparation method of cancer treatment medicine | |
| CN110878108A (en) | Synthetic method of prazazolmitrin | |
| US10590136B2 (en) | Processes for the preparation of cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide | |
| CN111057052B (en) | Method for preparing minodronic acid intermediate 2- (imidazo [1, 2-alpha ] pyridine-3-yl) acetate compound | |
| CN106496192B (en) | A kind of preparation method of Crizotinib or deuterated Crizotinib | |
| CN117364252A (en) | Preparation method and application of On-DNA aromatic compound | |
| CN115710182A (en) | Preparation method of compound BCN |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240626 Address after: 222047 No. 7 Kunlun Shan Road, Lianyungang economic and Technological Development Zone, Jiangsu Patentee after: JIANGSU HENGRUI MEDICINE Co.,Ltd. Country or region after: China Patentee after: SUNCADIA PHARMACEUTICALS Co.,Ltd. Patentee after: Chengdu Xinyue Pharmaceutical Co.,Ltd. Address before: 222047 No. 7 Kunlun Shan Road, Lianyungang economic and Technological Development Zone, Jiangsu Patentee before: JIANGSU HENGRUI MEDICINE Co.,Ltd. Country or region before: China Patentee before: SUNCADIA PHARMACEUTICALS Co.,Ltd. |