CN1243009C - Technique for preparing 5'nucleotide bi-sodium - Google Patents
Technique for preparing 5'nucleotide bi-sodium Download PDFInfo
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- CN1243009C CN1243009C CN 200310106155 CN200310106155A CN1243009C CN 1243009 C CN1243009 C CN 1243009C CN 200310106155 CN200310106155 CN 200310106155 CN 200310106155 A CN200310106155 A CN 200310106155A CN 1243009 C CN1243009 C CN 1243009C
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- Prior art keywords
- disodium
- trialkylphosphate
- ribonucleotide
- nucleotide
- small amount
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Links
- 239000002773 nucleotide Substances 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title abstract description 9
- 125000003729 nucleotide group Chemical group 0.000 title description 2
- 229910052708 sodium Inorganic materials 0.000 title 1
- 239000011734 sodium Substances 0.000 title 1
- 239000000243 solution Substances 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229910001868 water Inorganic materials 0.000 claims abstract description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 239000002777 nucleoside Substances 0.000 claims abstract description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 9
- 239000006227 byproduct Substances 0.000 claims abstract description 9
- 230000007062 hydrolysis Effects 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 239000004193 disodium 5'-ribonucleotide Substances 0.000 claims description 20
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 16
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 14
- 229910052698 phosphorus Inorganic materials 0.000 claims description 14
- 239000011574 phosphorus Substances 0.000 claims description 14
- 238000005917 acylation reaction Methods 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 125000003835 nucleoside group Chemical group 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 239000012266 salt solution Substances 0.000 claims description 7
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- 150000003016 phosphoric acids Chemical class 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 3
- 235000019800 disodium phosphate Nutrition 0.000 claims description 3
- 229940045641 monobasic sodium phosphate Drugs 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 abstract description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract description 6
- 239000011780 sodium chloride Substances 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 2
- 229910019142 PO4 Inorganic materials 0.000 abstract 5
- 239000010452 phosphate Substances 0.000 abstract 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract 5
- 238000006366 phosphorylation reaction Methods 0.000 abstract 2
- 239000012267 brine Substances 0.000 abstract 1
- 150000003833 nucleoside derivatives Chemical class 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 abstract 1
- 229960003786 inosine Drugs 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 6
- 229930010555 Inosine Natural products 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical class CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 4
- 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 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229910017053 inorganic salt Inorganic materials 0.000 description 3
- 239000003456 ion exchange resin Substances 0.000 description 3
- 229920003303 ion-exchange polymer Polymers 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 description 3
- 235000011008 sodium phosphates Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 2
- 102100024304 Protachykinin-1 Human genes 0.000 description 2
- 101800003906 Substance P Proteins 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- PVBRXXAAPNGWGE-LGVAUZIVSA-L disodium 5'-guanylate Chemical compound [Na+].[Na+].C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP([O-])([O-])=O)[C@@H](O)[C@H]1O PVBRXXAAPNGWGE-LGVAUZIVSA-L 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 description 2
- 239000004223 monosodium glutamate Substances 0.000 description 2
- 235000013923 monosodium glutamate Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- 229930183912 Cytidylic acid Natural products 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- -1 alkali metal salt Chemical class 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000020247 cow milk Nutrition 0.000 description 1
- IERHLVCPSMICTF-XVFCMESISA-N cytidine 5'-monophosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(O)=O)O1 IERHLVCPSMICTF-XVFCMESISA-N 0.000 description 1
- IERHLVCPSMICTF-UHFFFAOYSA-N cytidine monophosphate Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(COP(O)(O)=O)O1 IERHLVCPSMICTF-UHFFFAOYSA-N 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 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
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 210000004251 human milk Anatomy 0.000 description 1
- 235000020256 human milk Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940061671 uridine 5-mo-phos disod Drugs 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Abstract
The present invention relates to a preparation process for 5'-nucleotide disodium, which is a preparation process for a strong fresh assistant, more specially to a simple and practical post-treatment process of a preparation process for 5'-nucleotide disodium. The preparation process comprises the following steps: a phosphorylation reaction is carried out by using nucleoside as raw material and using trialkyl phosphate as a solvent; a phosphorylation reaction liquid is hydrolyzed in a brine ice to obtain a hydrolysis liuqid containing trialkyl phosphate, water, phosphoric acid, hydrochloric acid, 5'-nucleotide, salt and a small amount of byproduct; the hydrolysis liquid stands to be naturally divided into a trialkyl phosphate layer and a water solution layer containing phosphoric acid, hydrochloric acid, 5'-nucleotide and a small amount of byproduct; the water solution layer with sodium hydroxide is neutralized until all of acid become salts, cooled and filtered to eliminate most of phosphate in order to obtain a water solution containing sodium chloride, 5'-nucleotide disodium, a small amount of byproducts and a small amount of phosphate; and the water solution is regulated by hydrochloric acid until the pH is 8, concentrated and crystallized to obtain 5'-nucleotide disodium.
Description
Technical field
The present invention is a kind of preparation technology of powerful fragrance adding agent, and what be specifically related to is a kind of preparation technology's of simple and easy to do 5 '-disodium 5 '-ribonucleotide aftertreatment technology.
Background technology
Nucleotide and derivative thereof be at medicine, food, and fields such as agricultural are widely used.5 '-inosine acid disodium and 5 '-Sodium guanylate all is powerful fragrance adding agents, and the two is used to mix monosodium glutamate, and its delicate flavour exceeds 40-100 doubly than general monosodium glutamate, and local flavor is better, obtains human consumer's welcome after this product puts goods on the market.Cytidylic acid disodium and uridine monophosphate disodium can be used for replenishing the nucleic acid in the cow's milk, to produce the humanized milk near human milk, can strengthen baby's immunizing power.
5 '-disodium 5 '-ribonucleotide all is very important in fields such as food and medicines as mentioned above, and its preparation technology has also had continuous development for many years, now looks back as follows:
With corresponding nucleosides and phosphorus oxychloride at pyridine, under the existence of alkaline mediums such as triethylamine, at certain polar organic solvent such as dimethyl formamide, dimethyl sulfoxide (DMSO) is reacted in the acetonitrile.1. reaction transfers to this hydrolyzed solution suitable substance P H value in finishing to fall back then, directly with active carbon column absorption, alkali lye wash-out; Or 2. use organic solvent in the insoluble organic solvent extracting of other water hydrolyzed solution, water transfers to suitable substance P H value, carries out separation and purification with anion-exchange resin column or active carbon column.(Gulland?et?al.，J.Chem.Soc.，1940；Tsumshima?Masaaki?et?al.，JP59167599，1984)。
2. 2 ' of nucleosides-and 3 '-position hydroxyl protection is got up; make solvent with trialkylphosphate; with phosphorus oxychloride reaction; deprotection again after the phosphorylated; salify adds ethanol crystallization is separated out, and recrystallization obtains 5 '-disodium 5 '-ribonucleotide (Masaharu Yoshikawa et al. again; US 3347846,1967).
3. with corresponding nucleosides and phosphorus oxychloride direct phosphorylated in trialkylphosphate; reaction is poured in the frozen water after finishing; the hydrolyzed solution neutralization is after anion-exchange column absorption; wash-out; condensing crystal obtains 5 '-disodium 5 '-ribonucleotide (Masaharu Yoshikawa et al.; US 3413282,1968).
4. using an alkali metal salt of inosine and guanosine, or contain the salt of one of them at least, mix and carry out phosphorylated, is solvent with the trialkylphosphate.Reaction is poured hydrolysis in the frozen water into after finishing, and uses the organic solvent extraction trialkylphosphate, and the aqueous solution adsorbs through active carbon column, wash-out, condensing crystal obtains 5 '-inosine acid disodium and 5 '-Sodium guanylate mixture (Shigemitsu Abe et al., EP 453597,1991).
5. corresponding nucleosides and trialkylphosphate reaction are earlier formed a kind of mixture, add phosphorus oxychloride then and carry out phosphorylated.Reaction finishes posthydrolysis, separates with active carbon column or ion exchange resin column and purifies, and last crystallization goes out product (Tomomi Ikemoto et al., Chem. Pharm. Bull., 1995; Akira Haze et al., CA2100027,1994).
1 is the acylation reaction technology of comparison classics in the above technology, and bad to the selectivity of 5 '-position, yield is affected.Use pyridine, triethylamine etc. are made catalyzer, and this compounds is water-soluble fabulous, therefore can produce serious water and pollute.The 2nd, earlier with 2 ' of nucleosides-and 3 '-position hydroxyl protection get up, carry out the phosphorylated of 5 '-position again, also want deprotection at last, step is loaded down with trivial details.Even found afterwards not 2 '-and 3 '-position hydroxyl protection get up; in the trialkylphosphate solvent system 5 '-and the phosphorylated of position also has very high selectivity (3 and 5), and therefore phosphorus acylation reaction all adopts in the trialkylphosphate solvent system and carries out in the production technique of present 5 '-disodium 5 '-ribonucleotide.
Although the technology of phosphorus acylation reaction has had very big improvement, post-reaction treatment technology is never too big change but: pour reaction solution in frozen water hydrolysis, directly adsorb with active carbon column then or after the hydrolysis, the alkali lye wash-out has a large amount of organic solvents to need further to handle in the effluent liquid; After the insoluble organic solvent extracting of water used in solvent taken out, separate with active carbon column or ion exchange resin column again and purify.Also have boric acid silicagel column partition method (Analytical Biochem., 1982), ion pair inverse permutation chromatography (Chem.Eng.Sci., 1992) in addition.But it is loaded down with trivial details that above method is all operated, time-consuming many, and separator column regeneration will produce a large amount of waste water.
Summary of the invention
Technical problem: the object of the present invention is to provide a kind of preparation technology of easy 5 '-disodium 5 '-ribonucleotide, complicated operations is simplified in the past, simplified equipment, and reduce and consume, reduce and pollute.
Technical scheme: the preparation technology of 5 '-disodium 5 '-ribonucleotide of the present invention is specific as follows:
A, be raw material with the nucleosides, trialkylphosphate is that solvent carries out phosphorus acylation reaction; Nucleosides: trialkylphosphate=1: 8-20 (w/w), nucleosides: phosphorus oxychloride=1: 1.5-4.0 (mol/mol);
B, phosphorus acylation reaction liquid is hydrolyzed in icy salt solution, obtains containing the hydrolyzed solution of trialkylphosphate, water, phosphoric acid, hydrochloric acid, 5 '-Nucleotide and salt and a small amount of by product;
C, hydrolyzed solution are separated into the trialkylphosphate layer and contain phosphoric acid through leaving standstill natural layering, hydrochloric acid, the aqueous layer of 5 '-Nucleotide and a small amount of by product;
D, above aqueous layer is neutralized to all acid salify fully with sodium hydroxide, cold filtration is removed most phosphoric acid salt, obtains containing sodium-chlor, the aqueous solution of 5 '-disodium 5 '-ribonucleotide and a small amount of by product and carbamate additives for low phosphorus hydrochlorate;
E, the above aqueous solution is transferred to PH=8 with hydrochloric acid, condensing crystal promptly gets 5 '-disodium 5 '-ribonucleotide.When nucleosides and trialkylphosphate carried out phosphorus acylation reaction, temperature of reaction was-10 ℃～+ 20 ℃.When phosphorus acylation reaction liquid was hydrolyzed in icy salt solution, hydrolysis temperature was-5 ℃～+ 10 ℃; Brinish concentration is 5～15% (w/w), and used salt is a kind of in sodium-chlor or SODIUM PHOSPHATE, MONOBASIC or Sodium phosphate dibasic or the sodium sulfate.Trialkylphosphate in the hydrolyzed solution can be through leaving standstill nature and water layering, and do not need with an organic solvent to extract.
Utilize the difference of solubleness,, and do not need to separate with chromatography column or ion exchange column with most phosphoric acid salt filtering separation.When the aqueous solution is adjusted to PH 〉=13, because the difference of solubleness, most phosphoric acid salt will be separated out from the aqueous solution, and filtering separation.
About being that the report and the patent of the solvent phosphorus acylation reaction that carries out nucleosides is existing many abroad with the trialkylphosphate.Document and patent as mentioning in " background technology " 3,4,5 just are not repeated here.
Beneficial effect: the present invention provides a kind of preparation technology of simple 5 '-disodium 5 '-ribonucleotide, and particularly simple aftertreatment technology consumes thereby reduce, and reduces and pollutes.
After phosphorus acylation reaction finishes; the present inventor is through studying repeatedly and testing; improved the method for hydrolysis in frozen water in the past; the employing icy salt solution is hydrolyzed; hydrolyzed solution leaves standstill the back layering as a result; can directly water layer be separated with organic solvent, thereby remove the process that extracts with the insoluble organic solvent of other water from, moreover such process must increase cost and can cause another kind of problem of solvent residue.The salt solution that the present invention adopts is the sodium-chlor of 5-20%, Sodium phosphate dibasic, SODIUM PHOSPHATE, MONOBASIC or other inorganic salt solutions.
Separate the hydrolyzed solution remove trialkylphosphate mostly was with active carbon column absorption 5 '-Nucleotide in the past, water flush away inorganic salt, and then use the alkali lye desorption, or spent ion exchange resin separates, and condensing crystal goes out 5 '-disodium 5 '-ribonucleotide at last.The present inventor is through a large amount of experiments and analyze discovery: under certain potential of hydrogen, can utilize the difference of solubleness at an easy rate the inorganic salt and 5 ' in the hydrolyzed solution-disodium 5 '-ribonucleotide to be separated.Concrete method is: earlier under strong alkaline condition with other component separating in sodium phosphate and the hydrolyzed solution, then under weak basic condition with other component separating in 5 '-disodium 5 '-ribonucleotide and the hydrolyzed solution, thereby obtain product.
Embodiment
Below in conjunction with embodiment the present invention is further described in detail.
Embodiment 1:
With 50 gram inosines, 500 restrain triethyl phosphates, and 3.4 gram water add respectively in the reactor, stir cooling, drip 87.5 in about 5 ℃ and restrain phosphorus oxychloride, drip off and continue reaction 1.5 hours;
900 grams, 10% sodium chloride solution is cooled to below 0 ℃, stirs down above-mentioned reaction solution to be poured into wherein to be hydrolyzed after 1 hour standing demix 20-60 minute;
Hydrolyzed solution is divided into triethyl phosphate and aqueous layer naturally, and the aqueous layer cooling is adjusted to PH 〉=13 with 50% sodium hydroxide solution down, in 0 ℃ of crystallization 2-3 hour, filters;
Filter solid be mainly sodium phosphate, filtrate is neutralized to PH=8～9 with concentrated hydrochloric acid, is evaporated to about 600 grams of residue, is cooled to 0～5 ℃, filters;
Filter solid be the inosine acid disodium crude product, the water recrystallization obtains inosine acid disodium.
Embodiment 2:
26.8 the gram inosine, 32.5 gram guanosines, 650 gram triethyl phosphates, 3.6 gram water add respectively in the reactor, and cooling in about 5 ℃ of droppings, 92 gram phosphorus oxychloride, drips off and continues reaction 3 hours;
The sodium chloride solution of 1000 grams 10% is cooled to below 0 ℃, stirs down above-mentioned reaction solution to be poured into wherein to be hydrolyzed standing demix after 1 hour;
Hydrolyzed solution is divided into triethyl phosphate layer and aqueous layer naturally, and the aqueous layer cooling is adjusted to PH 〉=13 with 50% sodium hydroxide solution down, in 0 ℃ of crystallization 2-3 hour, filters;
Filter solid be mainly sodium phosphate, filtrate is neutralized to PH=8～9 with concentrated hydrochloric acid, is evaporated to about 650 grams of residue, is cooled to 0～5 ℃, filters;
Filter solid be inosine acid disodium and Sodium guanylate crude product, the water recrystallization obtains inosine acid disodium and Sodium guanylate.
Claims (4)
1, a kind of preparation technology of 5 '-disodium 5 '-ribonucleotide is characterized in that concrete preparation technology is as follows:
A, be raw material with the nucleosides, trialkylphosphate is that solvent carries out phosphorus acylation reaction; Nucleosides: trialkylphosphate=1: 8-20w/w, nucleosides: phosphorus oxychloride=1: 1.5-4.0mol/mol;
B, phosphorus acylation reaction liquid is hydrolyzed in icy salt solution, obtains containing the hydrolyzed solution of trialkylphosphate, water, phosphoric acid, hydrochloric acid, 5 '-Nucleotide and salt and a small amount of by product;
C, hydrolyzed solution are separated into the trialkylphosphate layer and contain phosphoric acid through leaving standstill natural layering, hydrochloric acid, the aqueous layer of 5 '-Nucleotide and a small amount of by product;
D, above aqueous layer is neutralized to all acid salify fully with sodium hydroxide, cold filtration is removed most phosphoric acid salt, obtains containing sodium-chlor, the aqueous solution of 5 '-disodium 5 '-ribonucleotide and a small amount of by product and carbamate additives for low phosphorus hydrochlorate;
E, the above aqueous solution is transferred to PH=8 with hydrochloric acid, condensing crystal promptly gets 5 '-disodium 5 '-ribonucleotide.
2, the preparation technology of 5 '-disodium 5 '-ribonucleotide according to claim 1, when it is characterized in that nucleosides and trialkylphosphate carry out phosphorus acylation reaction, temperature of reaction is-10 ℃～+ 20 ℃.
3, the preparation technology of 5 '-disodium 5 '-ribonucleotide according to claim 1, when it is characterized in that phosphorus acylation reaction liquid is hydrolyzed in icy salt solution, hydrolysis temperature is-5 ℃～+ 10 ℃; Brinish concentration is 5～15%w/w, and used salt is a kind of in sodium-chlor or SODIUM PHOSPHATE, MONOBASIC or Sodium phosphate dibasic or the sodium sulfate.
4, the preparation technology of 5 '-disodium 5 '-ribonucleotide according to claim 1 is characterized in that trialkylphosphate in the hydrolyzed solution is through leaving standstill nature and water layering.
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Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100395256C (en) * | 2006-06-12 | 2008-06-18 | 南京工业大学 | Crystallization process of 5'-nucleoside-sodium phosphate |
| CN101293907B (en) * | 2008-06-24 | 2012-12-12 | 广东肇庆星湖生物科技股份有限公司 | Technique for preparing 5'-inosine acid disodium |
| CN101665525B (en) * | 2009-09-10 | 2013-05-01 | 广东肇庆星湖生物科技股份有限公司 | Synthetic method of nucleotide |
| CN101891772B (en) * | 2010-07-16 | 2012-11-28 | 广东肇庆星湖生物科技股份有限公司 | Method for preparing disodium 5'-ribonucleotide |
| CN101914125A (en) * | 2010-08-12 | 2010-12-15 | 广东肇庆星湖生物科技股份有限公司 | Extraction process of 5'-guanosine acidized reaction liquid |
| CN101993466B (en) * | 2010-10-14 | 2012-08-15 | 广东肇庆星湖生物科技股份有限公司 | Method for preparing 5'-disodium guanylate |
| CN102199182A (en) * | 2011-04-10 | 2011-09-28 | 浙江钱江生物化学股份有限公司 | One-step extraction method for disodium 5'-inosinate |
| CN102718823B (en) * | 2012-06-26 | 2014-11-12 | 华南理工大学 | Process method for elution, crystallization and refining of 5'-flavor nucleotide disodium |
| CN104163842A (en) * | 2014-07-15 | 2014-11-26 | 南通香地生物有限公司 | Method for producing cytidine monophosphate disodium salt |
| CN104163843A (en) * | 2014-07-15 | 2014-11-26 | 南通香地生物有限公司 | Adenosine 5'-monophosphoric acid disodium salt production method |
| CN104151383A (en) * | 2014-07-15 | 2014-11-19 | 南通香地生物有限公司 | Method for producing disodium uridylate |
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