CN116987136A - Preparation method of uridine trisodium triphosphate and product thereof - Google Patents
Preparation method of uridine trisodium triphosphate and product thereof Download PDFInfo
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- CN116987136A CN116987136A CN202310957227.4A CN202310957227A CN116987136A CN 116987136 A CN116987136 A CN 116987136A CN 202310957227 A CN202310957227 A CN 202310957227A CN 116987136 A CN116987136 A CN 116987136A
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- uridine
- reaction
- triphosphate
- trisodium
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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 50
- 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 25
- 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 25
- 229940045145 uridine Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- ZOEVNLTZXXOQCI-UHFFFAOYSA-K trisodium;[[hydroxy(oxido)phosphoryl]oxy-oxidophosphoryl] hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].OP([O-])(=O)OP(O)(=O)OP([O-])([O-])=O ZOEVNLTZXXOQCI-UHFFFAOYSA-K 0.000 title claims abstract 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 claims abstract description 40
- 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 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 239000002608 ionic liquid Substances 0.000 claims abstract description 19
- 229950010342 uridine triphosphate Drugs 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- 229940125904 compound 1 Drugs 0.000 claims abstract description 11
- WRMXOVHLRUVREB-UHFFFAOYSA-N phosphono phosphate;tributylazanium Chemical compound OP(O)(=O)OP([O-])([O-])=O.CCCC[NH+](CCCC)CCCC.CCCC[NH+](CCCC)CCCC WRMXOVHLRUVREB-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 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 claims abstract description 5
- 239000007806 chemical reaction intermediate Substances 0.000 claims abstract description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 14
- IQQRAVYLUAZUGX-UHFFFAOYSA-N 1-butyl-3-methylimidazolium Chemical compound CCCCN1C=C[N+](C)=C1 IQQRAVYLUAZUGX-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000001953 recrystallisation Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 239000011630 iodine Substances 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 238000005580 one pot reaction Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 239000002537 cosmetic Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 235000013305 food Nutrition 0.000 claims description 2
- 230000036541 health Effects 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000011160 research Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 239000000543 intermediate Substances 0.000 abstract description 7
- BVOITXUNGDUXRW-UHFFFAOYSA-N 2-chloro-1,3,2-benzodioxaphosphinin-4-one Chemical compound C1=CC=C2OP(Cl)OC(=O)C2=C1 BVOITXUNGDUXRW-UHFFFAOYSA-N 0.000 abstract description 4
- 238000007254 oxidation reaction Methods 0.000 abstract description 4
- 230000001737 promoting effect Effects 0.000 abstract description 3
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 abstract description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 abstract description 2
- 125000004122 cyclic group Chemical group 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000007142 ring opening reaction Methods 0.000 abstract description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 5
- PGAVKCOVUIYSFO-XVFCMESISA-K UTP(3-) Chemical compound O1[C@H](COP([O-])(=O)OP([O-])(=O)OP(O)([O-])=O)[C@@H](O)[C@@H](O)[C@@H]1N1C(=O)NC(=O)C=C1 PGAVKCOVUIYSFO-XVFCMESISA-K 0.000 description 5
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 5
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 150000001923 cyclic compounds Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 3
- HSCJRCZFDFQWRP-UHFFFAOYSA-N Uridindiphosphoglukose Natural products OC1C(O)C(O)C(CO)OC1OP(O)(=O)OP(O)(=O)OCC1C(O)C(O)C(N2C(NC(=O)C=C2)=O)O1 HSCJRCZFDFQWRP-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- -1 i.e. Chemical compound 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000001226 triphosphate Substances 0.000 description 3
- 230000006819 RNA synthesis Effects 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000005562 fading Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 108010062745 Chloride Channels Proteins 0.000 description 1
- 102000011045 Chloride Channels Human genes 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- CYKLRRKFBPBYEI-KBQKSTHMSA-N UDP-alpha-D-galactosamine Chemical compound O1[C@H](CO)[C@H](O)[C@H](O)[C@@H](N)[C@H]1OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 CYKLRRKFBPBYEI-KBQKSTHMSA-N 0.000 description 1
- HSCJRCZFDFQWRP-ABVWGUQPSA-N UDP-alpha-D-galactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 HSCJRCZFDFQWRP-ABVWGUQPSA-N 0.000 description 1
- HSCJRCZFDFQWRP-JZMIEXBBSA-N UDP-alpha-D-glucose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 HSCJRCZFDFQWRP-JZMIEXBBSA-N 0.000 description 1
- HDYANYHVCAPMJV-UHFFFAOYSA-N Uridine diphospho-D-glucuronic acid Natural products O1C(N2C(NC(=O)C=C2)=O)C(O)C(O)C1COP(O)(=O)OP(O)(=O)OC1OC(C(O)=O)C(O)C(O)C1O HDYANYHVCAPMJV-UHFFFAOYSA-N 0.000 description 1
- STIMNHRZMRZOHW-SQOUGZDYSA-N [(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoyl]phosphonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)P(O)(O)=O STIMNHRZMRZOHW-SQOUGZDYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 238000001994 activation Methods 0.000 description 1
- 210000001552 airway epithelial cell Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 210000004081 cilia Anatomy 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000006571 energy metabolism pathway Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000002175 goblet cell Anatomy 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 108700021021 mRNA Vaccine Proteins 0.000 description 1
- 229940126582 mRNA vaccine Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940005657 pyrophosphoric acid Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- HDYANYHVCAPMJV-USQUEEHTSA-N udp-glucuronic acid Chemical compound O([P@](O)(=O)O[P@](O)(=O)OC[C@H]1[C@@H]([C@H]([C@@H](O1)N1C(NC(=O)C=C1)=O)O)O)[C@H]1O[C@@H](C(O)=O)[C@H](O)[C@@H](O)[C@@H]1O HDYANYHVCAPMJV-USQUEEHTSA-N 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
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- 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
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/60—Sugars; Derivatives thereof
- A61K8/606—Nucleosides; Nucleotides; Nucleic acids
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- A61P11/02—Nasal agents, e.g. decongestants
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07H1/04—Introducing polyphosphoric acid radicals
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Abstract
The invention relates to a preparation method of uridine trisodium triphosphate and a product thereof. According to the invention, ionic liquid is used as a reaction solvent, 2-chloro-4H-1, 3, 2-benzodioxaphosphorin-4-one (compound 1) reacts with tributylammonium pyrophosphate to generate a cyclic intermediate 2, uridine is reacted, and then oxidation and alkaline hydrolysis ring opening steps are carried out to obtain trisodium uridine triphosphate. The ionic liquid is used as a solvent for promoting the reaction to react with the hydroxyl in the ribose structure of uridine in site selectivity, so that the reaction intermediate 2 can react with the hydroxyl at the 5' position of uridine in high selectivity to obtain UTP in high yield. The invention solves the problems of long steps and low yield in the synthesis of UTP by adopting a chemical synthesis method in the prior art.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of uridine triphosphate trisodium and a product thereof.
Background
Uridine triphosphate, also known as uridine-5 '-triphosphate (UTP), is a uracil nucleotide, consisting of a uracil, a ribose, and three phosphates attached to the ribose 5' -OH carbon, and UTP is usually stored as the trisodium salt, i.e., trisodium uridine triphosphate. UTP is closely related to carbohydrate metabolism, and UDP-glucose and pyrophosphoric acid are generated by enzyme catalysis of UTP and 1-phosphoglucose; in addition, UDP-galactose, UDP-galactosamine, UDP-glucuronic acid and the like are also produced.
UTP is involved in pyrimidine ribonucleotide synthesis and is a raw material for RNA synthesis (transcription). In addition, UTP can also be used as an energy source, functionally similar to ATP, but less common than ATP. UTP is also involved in many energy metabolic pathways in organisms. UTP is also involved in the activation process of certain G protein-coupled receptors (e.g., P2Y, P Y2, P2Y11, etc.), thereby activating the chloride ion channel of the epithelial cells, increasing the frequency of cilia oscillation, inducing degranulation of goblet cells in airway epithelial cells, and also affecting inflammatory cell action and vascular responsiveness. In addition, UTP is also commonly used in the diagnosis and treatment of certain diseases (e.g., INS316, lung cancer, etc.). It also plays an important role in sinusitis, chronic bronchitis, otitis media, dry eye and gastrointestinal disorders. UTP is one of the main substrates for RNA synthesis, and is essential in the development of mRNA vaccines.
A variety of methods for preparing UTP have been reported in the prior art, with enzymatic, fermentative and other biological methods being most commonly used. It has also been reported to prepare UTP or its analogues by purely chemical synthesis, but chemical synthesis methods generally require protection of certain reaction sites of the starting materials and intermediates to avoid by-product formation, and finally removal of protecting groups, and the synthesis steps are generally very tedious and inefficient. For example, the one-Pot synthesis of2 '-Deoxynucleoside-5' -triphosphate was reported by the ZhenHuang group under the article "Protection-FreeOne-Pot synthesis 2'-Deoxynucleoside5' -triphosphates" and the reaction steps and the products obtained and yields are shown below.
However, the reaction of preparing 2 '-deoxynucleoside-5' -triphosphate by the one-pot method in the above-mentioned ZhenHuang group of subjects is clearly limited to the reaction substrate, and there is no attempt to prepare UTP using a non-deoxynucleoside such as uridine as the reaction substrate, only some 2 '-deoxynucleoside-5' -triphosphate is obtained, and the yield of the 2 '-deoxynucleoside-5' -triphosphate obtained is also relatively low.
Chinese patent CN103314001B also reports a similar method for preparing 2' -deoxynucleoside-5 ' -triphosphate and nucleoside-5 ' -triphosphate, which states that the isolation yield is greatly improved by optimizing the conditions. However, the reaction conditions for preparing nucleoside triphosphates in this patent are substantially identical to those described in the above-mentioned article, and the reaction yields for preparing UTP are likewise not explicitly described.
Indeed, the ZhenHuang group of problems has been mentioned in the paper that the hydroxyl group at the 3 'carbon position on ribose reacts with intermediate 2 as a major side reaction when it is reacted from intermediate 2 and 2' -deoxynucleosides. That is, when intermediate 2 is reacted with 2'-deoxynucleoside, it lacks specific selectivity for the hydroxyl group at the 5' carbon position, resulting in an increase in byproducts. When a non-deoxynucleoside such as uridine is reacted with intermediate 2, there are 3 hydroxyl reactive sites on ribose, and the reaction yield for preparing UTP using this reaction is very low due to poor selectivity of the reactive sites.
The ionic liquid is used as a solvent or a catalyst and the like to be applied to organic chemical reactions, and the ionic liquid has many reports on promoting the site selectivity of the organic reactions, and the reports show that the ionic liquid is used as the solvent to improve the reaction selectivity of hydroxyl groups on ribose, but the ionic liquid is not used in the synthesis of UTP.
Disclosure of Invention
The invention solves the problems of long steps and low yield in the synthesis of UTP by adopting a chemical synthesis method in the prior art. The invention relates to a preparation method of uridine trisodium triphosphate and a product thereof. According to the invention, ionic liquid is used as a reaction solvent, 2-chloro-4H-1, 3, 2-benzodioxaphosphorin-4-one (compound 1) reacts with tributylammonium pyrophosphate to generate a cyclic intermediate 2, uridine is reacted, and then oxidation and alkaline hydrolysis ring opening steps are carried out to obtain trisodium uridine triphosphate.
Specifically, the invention provides a preparation method of uridine trisodium triphosphate, which has the following reaction equation:
wherein, ionic liquid is used as a reaction solvent in the step 1) and the step 2).
Further, the ionic liquid in steps 1) and 2) is selected from [ Bmim ]]PF 6 、[Bmim]BF 4 、[Bmim]Any of TfO, preferably [ Bmim ]]PF 6 。
Further, the reaction steps 1), 2), 3) and 4) are all carried out at 25-35 ℃.
Further, the reaction steps 1), 2), 3) and 4) are all carried out under the protection of inert gas.
Further, the preparation method is a one-pot reaction, and the reaction steps 1), 2) and 3) do not need post-treatment of the reaction liquid or separation of reaction intermediates.
Further, the reaction time of the reaction step 1) is 0.5-1.5h, the reaction time of the step 2) is 1-2h, the reaction time of the step 3) is 15-30min, and the reaction time of the step 4) is 1-3h.
Further, the reagent reacting with the compound 1 in the step 1) is tributylammonium pyrophosphate, and the molar ratio of the compound 1 to the tributylammonium pyrophosphate is 1:1.5-2.5, preferably 1:2.
Further, the molar amount of uridine in the reaction step 2) is the same as the molar amount of compound 1.
Further, in the step 3), the iodine simple substance is dissolved in a mixed solution of pyridine and water, and the mass concentration of the iodine solution is 3-8%, preferably 5%; the volume ratio of pyridine to water is 12:1-6:1, preferably 9:1.
Further, the NaOH in step 4) is in the form of an aqueous solution.
Further, the step 4) further comprises the steps of refrigerating, filtering and recrystallizing after the reaction.
Further, the recrystallization is to use an ethanol solution as a recrystallization solvent.
Further, the operation of the recrystallization is: dissolving and filtering the obtained crude product of uridine triphosphate with a proper amount of water, regulating the pH to 3-4 with dilute hydrochloric acid, adding ethanol until the mass fraction of the ethanol is 70-85%, stirring for 15-30min, placing in a refrigerator at 4-8 ℃ for 8-12h, filtering, and vacuum drying at low temperature to obtain a pure product of uridine triphosphate.
Further, in order to further improve the purity of uridine triphosphate trisodium, the recrystallization step may be repeated 2-3 times.
In addition, the invention also provides a product of the uridine triphosphate trisodium obtained by the preparation method, which is used for preparing scientific research reagents, medicines, foods, health care products and cosmetics.
The beneficial effects obtained by the invention are as follows: the ionic liquid is introduced into the chemical synthesis of UTP as a solvent for promoting the site selectivity of the reaction to the hydroxyl in the ribose structure of uridine, which can lead the reaction intermediate 2 to react with the hydroxyl at the 5' position of uridine with high selectivity so as to obtain UTP with high yield. In the prior art, when UTP is prepared by a chemical synthesis method, due to low reaction yield, UTP or trisodium salt thereof is difficult to directly purify by a recrystallization method, and is usually purified by a separation column.
Detailed Description
The present invention will be described in more detail with reference to specific examples.
Example 1
40mmol (2 eq) tributylammonium pyrophosphate was weighed out and dissolved in a suitable amount of ionic liquid [ Bmim]PF 6 Adding 20mL tributyl anhydrous tri-n-butylamine, and stirring at 25 ℃; 20mmol (1 eq) of 2-chloro-4H-1, 3, 2-benzodioxaphosphorin-4-one (i.e. compound 1) is weighed into a reaction flask and a proper amount of ionic liquid [ Bmim ] is used]PF 6 Dissolving in water; slowly dropwise adding the solution of the compound 1 into the solution of tributylammonium pyrophosphate, and after the dropwise adding is completed, keeping the temperature of 25 ℃ and stirring to react for 1h to generate the cyclic compound 2. Then, 20mmol (1 eq) of uridine was weighed, dissolved in an appropriate amount of ionic liquid, and added to the reaction solution containing cyclic compound 2, followed by stirring at 25℃for 1.5 hours, to thereby yield compound 3. Then slowly adding 5% iodine solution (iodine simple substance is dissolved in Py: H of 9:1) 2 O) until the reaction solution turns dark red without fading, indicating that the oxidation reaction is completed. Then, naOH aqueous solution (containing NaOH in a molar amount of 80 mmol) was added thereto, and the mixture was stirred at 25℃for 2 hours, whereby a large amount of solids was precipitated in the reaction liquid. All the reactions are carried out under the protection of inert gas.
The reaction system is placed at 8 ℃ for 2 hours, filtered, and the solid is washed by cold ethanol to obtain crude uridine triphosphate trisodium. Dissolving the crude product of uridine triphosphate obtained by filtering with a proper amount of water, regulating the pH to 3-4 with dilute hydrochloric acid, adding ethanol until the mass fraction of the ethanol is 75%, stirring for 30min, placing in a refrigerator at 8 ℃ for 10h, filtering, and vacuum drying at low temperature to obtain 15.3mmol of pure uridine triphosphate with a yield of 76.5% and a purity of 97%.
Example 2
40mmol (2 eq) tributylammonium pyrophosphate was weighed out and dissolved in a suitable amount of ionic liquid [ Bmim]BF 4 20mL of tributyl anhydrous tri-n-butylamine is added and stirred at 35 DEG CThe method comprises the steps of carrying out a first treatment on the surface of the 20mmol (1 eq) of 2-chloro-4H-1, 3, 2-benzodioxaphosphorin-4-one (i.e. compound 1) is weighed into a reaction flask and a proper amount of ionic liquid [ Bmim ] is used]BF 4 Dissolving in water; slowly dropwise adding the solution of the compound 1 into the solution of tributylammonium pyrophosphate, and after the dropwise adding is completed, keeping the temperature of 35 ℃ and stirring to react for 1h to generate the cyclic compound 2. Then, 20mmol (1 eq) of uridine was weighed, dissolved in an appropriate amount of ionic liquid, and added to the reaction solution containing cyclic compound 2, followed by stirring at 35℃for 1 hour, to thereby yield compound 3. Then slowly adding 3% iodine solution (iodine simple substance is dissolved in Py: H of 6:1) 2 O) until the reaction solution turns dark red without fading, indicating that the oxidation reaction is completed. Then, naOH aqueous solution (containing NaOH in a molar amount of 80 mmol) was added thereto, and the mixture was stirred at 35℃for 1 hour, whereby a large amount of solids was precipitated in the reaction liquid. All the reactions are carried out under the protection of inert gas.
The reaction system is placed at 8 ℃ for 2 hours, filtered, and the solid is washed by cold ethanol to obtain crude uridine triphosphate trisodium. Dissolving the crude product of uridine triphosphate obtained by filtering with a proper amount of water, regulating the pH to 3-4 with dilute hydrochloric acid, adding ethanol until the mass fraction of the ethanol is 75%, stirring for 30min, placing in a refrigerator at 8 ℃ for 10h, filtering, and vacuum drying at low temperature to obtain 13.6mmol of pure uridine triphosphate with a yield of 68% and a purity of 97%.
Example 3
This example differs from example 1 in that, with reference to the operation of the prior art, the ionic liquid solution is replaced with DMF, the product obtained by the final reaction system is more complex, the byproducts are more, and purification by recrystallization is difficult. A sample of the crude product was taken and quantified by high performance liquid analysis, with a UTP content of <30% in the product.
While certain specific forms of the invention have been described above, various obvious modifications and combinations thereof, without departing from the principles of the invention, should also be included within the scope of the invention.
Claims (10)
1. The preparation method of the uridine trisodium triphosphate is characterized by comprising the following reaction equations:
wherein, ionic liquid is used as a reaction solvent in the step 1) and the step 2).
2. The method for preparing tri-sodium uridine triphosphate according to claim 1, wherein said ionic liquid in steps 1) and 2) is selected from [ Bmim ]]PF 6 、[Bmim]BF 4 、[Bmim]Any of TfO, preferably [ Bmim ]]PF 6 。
3. The process for preparing uridine trisodium triphosphate according to claim 1 or 2, wherein the reaction steps 1), 2), 3), 4) are each carried out under the condition of 25-35 ℃ and are each carried out under the protection of inert gas.
4. The process for preparing uridine trisodium triphosphate according to claim 1 or 2, wherein the process is a one-pot reaction, and no post-treatment of the reaction solution or isolation of the reaction intermediate is required after the reaction steps 1), 2), 3).
5. The process for preparing trisodium uridine triphosphate according to claim 1 or 2, wherein the reaction time of the reaction step 1) is 0.5-1.5h, the reaction time of the step 2) is 1-2h, the reaction time of the step 3) is 15-30min, and the reaction time of the step 4) is 1-3h.
6. The process for the preparation of uridine trisodium triphosphate according to claim 1 or 2, wherein the reagent reacting with compound 1 in step 1) is tributylammonium pyrophosphate, the molar ratio of compound 1 to tributylammonium pyrophosphate being 1:1.5-2.5, preferably the molar ratio being 1:2; and/or the molar amount of uridine in said reacting step 2) is the same as the molar amount of compound 1; and/or the iodine simple substance in the step 3) is dissolved in a mixed solution of pyridine and water, wherein the mass concentration of the iodine solution is 3-8%, preferably 5%, and the volume ratio of the pyridine to the water is 12:1-6:1, preferably 9:1; and/or the NaOH in step 4) is in the form of an aqueous solution.
7. The method for preparing the uridine trisodium triphosphate according to claim 1 or 2, wherein said step 4) further comprises the steps of refrigerating, filtering and recrystallizing after the reaction.
8. The method for producing uridine trisodium triphosphate according to claim 7, wherein the recrystallization is performed using an ethanol solution as a recrystallization solvent.
9. The method for preparing uridine trisodium triphosphate of claim 8, wherein the recrystallization is performed by: dissolving and filtering the obtained crude product of uridine triphosphate with a proper amount of water, regulating the pH to 3-4 with dilute hydrochloric acid, adding ethanol until the mass fraction of the ethanol is 70-85%, stirring for 15-30min, placing in a refrigerator at 4-8 ℃ for 8-12h, filtering, and vacuum drying at low temperature to obtain a pure product of uridine triphosphate.
10. The preparation of the uridine trisodium triphosphate prepared by the preparation method of any one of claims 1-9, wherein the preparation is used in the preparation of scientific research reagents, medicines, foods, health products, cosmetics.
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