CN110218233A - A kind of P1,P4The preparation method of-two (uridine 5`-) tetraphosphates - Google Patents
A kind of P1,P4The preparation method of-two (uridine 5`-) tetraphosphates Download PDFInfo
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- CN110218233A CN110218233A CN201910148349.2A CN201910148349A CN110218233A CN 110218233 A CN110218233 A CN 110218233A CN 201910148349 A CN201910148349 A CN 201910148349A CN 110218233 A CN110218233 A CN 110218233A
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- Prior art keywords
- calcium
- preparation
- iii
- uridine
- formula
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- 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 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 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 title 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 title claims abstract description 30
- 229940045145 uridine Drugs 0.000 title claims abstract description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 18
- -1 metals calcium salt Chemical class 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 10
- 239000002184 metal Substances 0.000 claims description 10
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 7
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- 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
- 159000000007 calcium salts Chemical class 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
- 238000001728 nano-filtration Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- BREXUOXCEDKPCA-UHFFFAOYSA-N [Ca].OB(O)O Chemical compound [Ca].OB(O)O BREXUOXCEDKPCA-UHFFFAOYSA-N 0.000 claims description 2
- 230000004913 activation Effects 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000003957 anion exchange resin Substances 0.000 claims description 2
- 229910052786 argon Inorganic materials 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
- 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
- KWUXWMAPDYIJDD-UHFFFAOYSA-N calcium;methanesulfonic acid Chemical compound [Ca].CS(O)(=O)=O KWUXWMAPDYIJDD-UHFFFAOYSA-N 0.000 claims description 2
- CFSYYJNGCPTQRE-UHFFFAOYSA-N calcium;trifluoromethanesulfonic acid Chemical compound [Ca].OS(=O)(=O)C(F)(F)F CFSYYJNGCPTQRE-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000071 diazene Inorganic materials 0.000 claims description 2
- 150000002012 dioxanes Chemical class 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 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
- 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
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 claims 1
- UHWJJLGTKIWIJO-UHFFFAOYSA-L calcium iodate Chemical compound [Ca+2].[O-]I(=O)=O.[O-]I(=O)=O UHWJJLGTKIWIJO-UHFFFAOYSA-L 0.000 claims 1
- 238000001179 sorption measurement Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 25
- 239000012535 impurity Substances 0.000 abstract description 6
- 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 abstract description 3
- 229920002521 macromolecule Polymers 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 7
- 239000008213 purified water Substances 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 239000003480 eluent Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 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 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
- DJJCXFVJDGTHFX-XVFCMESISA-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-XVFCMESISA-N 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 239000002997 ophthalmic solution Substances 0.000 description 2
- 229940054534 ophthalmic solution Drugs 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
- 238000005070 sampling Methods 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical class [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- MMJGIWFJVDOPJF-LLWADOMFSA-K trisodium;[[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl]oxy-oxidophosphoryl] hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].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 MMJGIWFJVDOPJF-LLWADOMFSA-K 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LSIXBBPOJBJQHN-UHFFFAOYSA-N 2,3-Dimethylbicyclo[2.2.1]hept-2-ene Chemical compound C1CC2C(C)=C(C)C1C2 LSIXBBPOJBJQHN-UHFFFAOYSA-N 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
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical group [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 102000015728 Mucins Human genes 0.000 description 1
- 108010063954 Mucins Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 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
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 description 1
- 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 class 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 description 1
- 239000002253 acid Substances 0.000 description 1
- REDXJYDRNCIFBQ-UHFFFAOYSA-N aluminium(3+) Chemical compound [Al+3] REDXJYDRNCIFBQ-UHFFFAOYSA-N 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940046413 calcium iodide Drugs 0.000 description 1
- 229910001640 calcium iodide Inorganic materials 0.000 description 1
- 238000003763 carbonization Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 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
- 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 1
- 239000003814 drug Substances 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- CZMAIROVPAYCMU-UHFFFAOYSA-N lanthanum(3+) Chemical compound [La+3] CZMAIROVPAYCMU-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 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
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 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
- 229940048102 triphosphoric acid Drugs 0.000 description 1
- 210000002700 urine Anatomy 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 kind of P1,P4The preparation method of-two (uridine 5 ' -) tetraphosphates.Specifically, this method high income and is not easy the production quantity of impurity of the macromolecule removed and is substantially reduced in industrial processes, it is easy to purify, is P1,P4- two (uridine 5 ' -) tetraphosphate industrial productions provide may.
Description
Technical field
This application involves a kind of P1,P4The preparation method of-two (uridine 5 ' -) tetraphosphate (UP4U) salt.
Background technique
Four sodium of ophthalmic solution also known as P1,P4- two (uridine 5 ' -) tetraphosphates, structure are such as a kind of two generations urine shown in (I a)
Glycosides nucleotide analog is P2Y2 receptor stimulating agent and mucin secretion stimulant, and Japanese Santen Pharmaceutical Co. Ltd. has opened
The ophthalmic solution tetrasodium salt eye drops for having sent out 3%, for treating scheroma.In addition, as the eliminating the phlegm with induction expectoration effect
Agent or pneumonia therapeutic agent have a possibility that further exploitation.
About P1,P4-The synthesis of two (uridine 5 ' -) tetraphosphates, Chinese patent CN101495497B disclose a kind of utilization
The dehydration condensation of uridine 5 '-triphosphoric acid (UTP) prepares the cyclic annular triphosphoric acid of uridine 5 '-, afterwards with uridine 5 '-monophosphate (UMP)
The method for docking preparation, this method, which is used, makees catalyst selected from magnesium, violent, ferrous metal salt.
Catalyst is not used in preparation method disclosed in CN1147502C, but the yield of target product is extremely low, it can not
Method as actual use.Method disclosed in CN105026414A with phosphatase activity compound with selected from UMP, UDP, UTP and
Phosphate cpd or its salt in pyrophosphate are being selected from divalent iron ion, trivalent iron ion, trivalent aluminium ion, trivalent lanthanum ion and 3
It reacts to obtain P in water or hydrophilic organic solvent in the presence of metal ion in valence cerium ion1,P4-Two (uridines
5 ' -) tetraphosphate, some non-common metal salts have been arrived in use in method disclosed in this application, and whether these metal salt later periods can
Residual is unknown.A kind of high-purity P is claimed in CN107056859A1, P4The preparation side of-two (uridine -5 '-tetraphosphate) salt
Method discloses the preparation method for making metal salt catalyst using strontium chloride in specification, but reaction yield only has 56%, is not
It is industrial to generate P1,P4How the preferred method of-two (uridine 5 ' -) tetraphosphates, improve the yield of reaction while reducing impurity
Content is still a problem to be solved.
Summary of the invention
The application provides a kind of P1,P4The preparation method of-two (uridine 5 ' -) tetraphosphates, this method is on the basis for improving yield
On significantly reduce P1,P5- two (uridine 5 ' -) five phosphoric acid (UP5U), P1,P6-The life of two (uridine 5 ' -) six phosphoric acid (UP6U) impurity
Cheng Liang.
The application provides P shown in a kind of formula (I)1, P4The preparation method of-two (uridine 5 ' -) tetraphosphates (UP4U) includes
Following steps:
A) using compound shown in condensing agent activation formula (III b)；
B) compound shown in the formula (III b) being activated under the action of catalyst metals calcium salt and chemical combination shown in formula (III a)
Object reaction.
Metal calcium salt of the present invention, is not particularly limited, specifically may be exemplified for calcirm-fluoride, calcium chloride, calcium bromide,
Calcium iodide, calcium sulfate, calcium nitrate, calcium phosphate, Calcium perchlorate, tetrafluoro boric acid calcium, trifluoromethanesulfonic acid calcium, methanesulfonic acid calcium, toluene sulphur
Sour calcium, calcium acetate, calcium trifluoroacetate, calcium stearate, calcium citrate, preferably calcium chloride, it should be noted that used calcium salt
It can be anhydride and be also possible to hydrate, preferably anhydride.
In preparation method provided by the present application, the molar ratio of compound shown in metal calcium salt and formula (III b) is selected from 0.1~
5, preferably 1.0~2, most preferably 1.1~1.5.
It further include compound shown in compound shown in preparation formula (III a) and formula (III b) in preparation method provided by the present application
Amine salt sprotic organic solvent solution the step of.
In the method that this mystery provides, after catalyst is added, reaction temperature is selected from 0~50 DEG C, preferably/25~40 DEG C, instead
Between seasonable for 4~for 24 hours, preferably 4~8h.In method provided by the invention, III a, III b amine salt sprotic organic solution
Middle moisture content is less than 1.0%, and preferably smaller than 0.7%, more preferably less than 0.3%.
In method provided by the present application, III a, III b the sprotic organic solution moisture removal of amine salt can be used point
The mode of son sieve.
Preparation method provided by the present application, it is characterised in that it reacts under the protection of inert gas, the indifferent gas
Body is selected from helium, argon gas, nitrogen, preferably nitrogen.
In method provided by the present application, the sprotic organic solvent is selected from dimethylformamide (DMF), diformazan
Yl acetamide (DMA), pyridine, dioxanes, dimethyl sulfoxide independent or mixed solvent.
In method provided by the present application, the condensing agent is selected from dicyclohexyl carbodiimide (DCC), water-soluble carbonization
Diimine (WSC), Diisopropylcarbodiimide (DIPC), 1- (3- dimethylaminopropyl) -3- ethylcarbodiimine
(EDC) or its hydrochloride, carbonyl dimidazoles (CDI), preferably Diisopropylcarbodiimide.
In method provided by the present application, triethylamine, tri-butylamine, trioctylphosphine amine, tetrabutylammonium, miscellaneous is selected from the amine of amine salt
Cyclammonium, preferably tri-butylamine.
Method provided by the present application is specifically with the progress of process shown in Scheme 1:
In method provided by the present application, after the completion of reaction, for synthesizing the P of object1,P4- two (uridine 5 ' -) four phosphorus
Acid, can be with method (such as the recrystallization method, ion exchange column layer used in the isolating and purifying of appropriately combined common nucleotide
Analysis method, adsorpting column chromatography method, Rhizoma curcumae longae by activated etc.) it is isolated and purified, the form of sodium salt is then made.
The application provides a kind of by P1,P4- two (uridine 5 ' -) tetraphosphates are prepared into P1,P4- two (uridine 5 ' -) tetraphosphates
Method, use anion exchange resin adsorb P1,P4After-two (uridine 5 ' -) tetraphosphates, then it is used as and is washed using sodium chloride solution
De- liquid is quickly eluted.
Preparation P provided by the present application1,P4The method of-two (uridine 5 ' -) Magcophos further includes inhaling selected from nanofiltration, active carbon
Attached, recrystallization a step or many more manipulations.
Method provided by the invention, the yield of target product is up to 75%, and significantly reduces P1,P5- two (uridines 5 ' -)
Five phosphoric acid (UP5U), P1,P6The production quantity of-two (uridine 5 ' -) six phosphoric acid (UP6U) impurity.
Specific embodiment
Embodiment
Embodiment given below illustrates the application, but the application is not by any restriction of these embodiments.
- 5 '-monophosphate disodium salt of uridine used, uridine -5 '-triphosphoric acid trisodium salt are from commercially available in embodiment.
1 P of embodiment1,P4The preparation of-two (uridine 5 ' -) tetraphosphates
The preparation (UMP-TBA) of compound shown in step 1. intermediate formula (II a)
Uridine -5 '-monophosphate disodium salt (5.43mol, 2.0kg) and purified water (10.0kg) are added into 20L plastic barrel,
Filtering after the lower dissolution completely of stirring, filtrate are stand-by；The 20.0L DOWEX IR100S resin for being converted to Hydrogen is encased in chromatographic column
In, it is rinsed with purified water (40.0kg), is compacted resin, drained washing lotion after bubble is discharged, close draining switch；Above-mentioned filtrate is delayed
Slowly it imported into column, upper layer liquid level is made just to flood resin, purified water (95.0kg) is added after standing into column carried out column and wash
It is de-, stop elution after eluent pH becomes to 6.5-7.5, merges eluent, be added in 200L reaction kettle, start stirring,
Tri-n-butylamine (0.92kg) is added dropwise at 15-25 DEG C to pH6.5-7.5；Water removal is lyophilized after reaction solution nanofiltration is concentrated into small size
Obtain 2.53kg, yield 91.4%.Residue is dissolved in n,N-Dimethylformamide, II a that about 0.65mol/L is made is molten
Liquid, and activated molecular sieve 4A type drying is added, moisture is not more than 0.2% after measured, and filtered fluid is directly transferred to lower step.
The preparation (UTP-3TBA) of compound shown in step 2. intermediate formula (II b)
Uridine -5 '-triphosphoric acid trisodium salt (4.54mol, 2.5kg) and purified water (12.5kg) are added into 20L plastic barrel,
Filtering after the lower dissolution completely of stirring, filtrate are stand-by；The 30.0L DOWEX IR100S resin for being converted to Hydrogen is encased in chromatographic column
In, it is rinsed with purified water (60.0kg), is compacted resin, drained washing lotion after bubble is discharged, close draining switch.Upper step filtrate is delayed
Slowly it imported into column, upper layer liquid level is made just to flood resin, purified water (130.0kg) is added after standing into column carried out column and wash
De-, coutroi velocity stops elution after eluent pH6.5-7.5, merges eluent, is added in 200L reaction kettle, starts and stir
It mixes, tri-n-butylamine (2.27kg) is added dropwise at 15-25 DEG C to pH6.5-7.5；It is lyophilized after reaction solution nanofiltration is concentrated into small size
Remove water to obtain 4.25kg, yield 89.9%.Residue is dissolved in n,N-Dimethylformamide, is made about 0.32mol/L's
II b solution, and activated molecular sieve 4A type drying is added, moisture is not more than 0.2% after measured, and filtered fluid is directly transferred to down
Step.
Step 3.P1,P4The preparation of-two (uridine 5 ' -) tetraphosphates
The n,N-Dimethylformamide solution (UTP-3TBA 3.85g, 3.69mmol) of the UTP-3TBA prepared is taken to be placed in
In 100ml there-necked flask, it is added diisopropylcarbodiimide (562mg, 4.44mmol), N25 are reacted in 25~30 DEG C after displacement 2 times
Hour；The n,N-Dimethylformamide solution (UMP-TBA 2.23g, 4.43mmol) of UMP-TBA is added into reaction solution, it is anhydrous
Calcium chloride (492mg, 4.43mmol) reacts 5 hours at 25~30 DEG C later, and sampling HPLC detection, area normalization method calculates
UP4U content and macromolecule impurity P1, P5Two (uridine 5 ' -) five phosphoric acid (UP5U) and P1, P6- two (uridine 5 ' -) six phosphoric acid
(UP6U) content.
2 P of embodiment1,P4The preparation of-two (uridine 5 ' -) tetraphosphates
The n,N-Dimethylformamide solution (UTP-3TBA 3.84g, 3.69mmol) of the UTP-3TBA prepared is taken to be placed in
In 100ml there-necked flask, it is added diisopropylcarbodiimide (564mg, 4.44mmol), N25 are reacted in 25~30 DEG C after displacement 2 times
Hour.The n,N-Dimethylformamide solution (UMP-TBA 2.23g, 4.43mmol) of UMP-TBA is added into reaction solution, it is anhydrous
Magnesium chloride (422mg, 4.43mmol) reacts 5 hours at 25~30 DEG C later, and sampling HPLC detection, area normalization method calculates
UP4U content and macromolecule impurity P1, P5Two (uridine 5 ' -) five phosphoric acid (UP5U) and P1, P6- two (uridine 5 ' -) six phosphoric acid
(UP6U) content.
As a result:
Claims (13)
1. a kind of P1,P4The preparation method of-two (uridine 5 ' -) tetraphosphates comprising the steps of:
A) using compound shown in condensing agent activation formula (III b)；
B) compound shown in the formula (III b) being activated under the action of catalyst metals calcium salt and compound shown in formula (III a) are anti-
It answers.
2. preparation method according to claim 1, the metal calcium salt is selected from calcirm-fluoride, calcium chloride, calcium bromide, iodate
Calcium, calcium sulfate, calcium nitrate, calcium phosphate, Calcium perchlorate, tetrafluoro boric acid calcium, trifluoromethanesulfonic acid calcium, methanesulfonic acid calcium, calcium cresylsulfonate,
Calcium acetate, calcium trifluoroacetate, calcium stearate, calcium citrate, preferably calcium chloride, most preferably anhydrous calcium chloride.
3. the molar ratio of preparation method according to claim 1, the metal calcium catalyst and III b are selected from 0.1~5,
It is preferred that 1.0~2, most preferably 1.1~1.5.
4. preparation method according to claim 1-3, also comprising compound and formula (III shown in preparation formula (III a)
B) the step of solution of the sprotic organic solvent of the amine salt of compound shown in.
5. the preparation method according to claim 4, III a, III b amine salt sprotic organic solution in moisture
Content should be controlled less than 1.0%, and preferably smaller than 0.7%, more preferably less than 0.3%.
6. the reaction temperature of preparation method according to claim 5, step b) is selected from 0~50 DEG C, preferably 25~40 DEG C.
7. preparation method according to claim 6 reacts under the protection of inert gas, the inert gas is selected from
Helium, argon gas, nitrogen, preferably nitrogen.
8. preparation method according to claim 7, the sprotic organic solvent is selected from dimethylformamide, two
Methylacetamide, pyridine, dioxanes, dimethyl sulfoxide independent or mixed solvent, preferred dimethylformamide.
9. preparation method according to claim 8, the condensing agent is selected from dicyclohexyl carbodiimide, water-soluble carbon
Change diimine, Diisopropylcarbodiimide, 1- (3- dimethylaminopropyl) -3- ethylcarbodiimine or its hydrochloride,
Carbonyl dimidazoles, preferably Diisopropylcarbodiimide.
10. the preparation method according to claim 4, the amine at amine salt is selected from triethylamine, tri-butylamine, trioctylphosphine
Amine, tetrabutylammonium, heterocyclic amine, preferably tri-butylamine.
11. a kind of P1,P4The preparation method of four sodium of-two (uridine 5 ' -) tetraphosphates, it is described in any item comprising claim 1-10
Step.
12. preparation method according to claim 11 adsorbs P using anion exchange resin1,P4- two (uridine 5 's -) four
It is eluted after phosphoric acid with sodium chloride solution.
13. preparation method according to claim 12, including selected from nanofiltration, activated carbon adsorption, recrystallization a step or
Many more manipulations.
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| CN111253456A (en) * | 2020-03-13 | 2020-06-09 | 广东先强药业有限公司 | Preparation method of denufosol sodium |
| CN111574576A (en) * | 2020-05-13 | 2020-08-25 | 广东先强药业有限公司 | Refining method of diquafosol sodium |
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| 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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| 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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| CN111253456A (en) * | 2020-03-13 | 2020-06-09 | 广东先强药业有限公司 | Preparation method of denufosol sodium |
| CN111574576A (en) * | 2020-05-13 | 2020-08-25 | 广东先强药业有限公司 | Refining method of diquafosol sodium |
| CN111574576B (en) * | 2020-05-13 | 2021-07-06 | 广东先强药业有限公司 | Refining method of diquafosol sodium |
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