CN100395256C - Crystallization process of 5'-nucleoside-sodium phosphate - Google Patents
Crystallization process of 5'-nucleoside-sodium phosphate Download PDFInfo
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- CN100395256C CN100395256C CNB2006100853813A CN200610085381A CN100395256C CN 100395256 C CN100395256 C CN 100395256C CN B2006100853813 A CNB2006100853813 A CN B2006100853813A CN 200610085381 A CN200610085381 A CN 200610085381A CN 100395256 C CN100395256 C CN 100395256C
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- 238000002425 crystallisation Methods 0.000 title claims abstract description 60
- 230000008025 crystallization Effects 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title abstract description 16
- 229910000162 sodium phosphate Inorganic materials 0.000 title abstract 4
- 239000001488 sodium phosphate Substances 0.000 title abstract 4
- 230000008569 process Effects 0.000 title description 9
- 239000013078 crystal Substances 0.000 claims abstract description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 238000000967 suction filtration Methods 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 9
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 7
- 239000002777 nucleoside Substances 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- 229910052708 sodium Inorganic materials 0.000 claims description 12
- 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 11
- 238000002156 mixing Methods 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 7
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 229960004249 sodium acetate Drugs 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 19
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- 239000012467 final product Substances 0.000 abstract description 3
- 238000003756 stirring Methods 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 229910019142 PO4 Inorganic materials 0.000 abstract 3
- 239000010452 phosphate Substances 0.000 abstract 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 12
- 229950006790 adenosine phosphate Drugs 0.000 description 12
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 6
- 238000009826 distribution Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
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- 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 5
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- RQFCJASXJCIDSX-UHFFFAOYSA-N 14C-Guanosin-5'-monophosphat Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(O)=O)C(O)C1O RQFCJASXJCIDSX-UHFFFAOYSA-N 0.000 description 3
- ZRWPTARDKZMNQK-IAIGYFSYSA-N [(2r,3s,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate;sodium Chemical compound [Na].O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(O)=O)O1 ZRWPTARDKZMNQK-IAIGYFSYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
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- 239000013558 reference substance Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- RAJMXAZJKUGYGW-POYBYMJQSA-N 2',3'-dideoxycytidine-5'-monophosphate Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP(O)(O)=O)CC1 RAJMXAZJKUGYGW-POYBYMJQSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 230000008859 change Effects 0.000 description 2
- 238000001514 detection method 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
- 230000006911 nucleation Effects 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- IERHLVCPSMICTF-XVFCMESISA-N CMP group Chemical group P(=O)(O)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)N=C(N)C=C1)O)O IERHLVCPSMICTF-XVFCMESISA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
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- 238000007710 freezing Methods 0.000 description 1
- 235000013928 guanylic acid Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
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- 230000002906 microbiologic effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
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- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a method for crystalizing 5'-nucleoside-sodium phosphate, which comprises: inorganic sodium salts with the solute mass percentage of 1 to 10% and a solution educing agent are added to a 5'-nucleoside-phosphate water solution with a pH value of 5.0 to 9.0 and the concentration of 5 to 30% by mass percentage, wherein the initial volume of the solution educing agent is 0.5 to 10 times of that of the 5'-nucleoside-phosphate water solution; a crystallization temperature is controlled between 15 DEG C and 40 DEG C, and a stirring speed is controlled between 20 to 200 rpm; suction filtration is carried out after complete crystalization; ethanol is used for washing the crystals, and the crystals are dried in a vacuum mode; the 5'-nucleoside-sodium phosphate crystals are obtained. The quality of a final product produced by the method of the present invention is obviously improved, and a crystalization yield is stably increased. The 5'-nucleoside-sodium phosphate crystals with controllable sizes can be obtained by controlling the crystallization technological conditions and states of a flow field. The present invention has the advantages of simple operation and good repeatability, and is suitable for the industrialized production of 5'-nucleoside-phosphate products.
Description
Technical field
The invention belongs to the separation and purification field of engineering technology, relate to a kind of new crystallization method of producing high-purity crystal 5 '-nucleoside monophosphate sodium salt from 5 '-nucleoside monophosphate aqueous solution.
Background technology
5 '-nucleoside monophosphate (UMP, GMP, CMP and AMP, hereinafter to be referred as NMP) have the height biological activity, can the enhancing body immunologic function, regulate the whole nutrition and the metabolic balance of human body, promote growing of body, have auxiliary antineoplastic biological regulating effect.The metabolism of lipid be can also promote simultaneously, intelligence, memory improved, and the infringement part that can repair organs such as liver and small intestine, the microorganism species that improves in the enteron aisle is formed.Its sodium salt purposes relates to fields such as medicine, chemical industry, food, healthcare products and agricultural.
Chinese patent CN 1616475A proposes to adopt chemosynthesis-freeze crystallization preparation 5 '-cytidine monophosphate, with 5 '-cytidine is raw material, is being lower than under zero degree, the condition of normal pressure, with the reaction of phosphoric acid agent such as Phosphorus Oxychloride, after hydrolysis, distillation, water is transferred the pH3-4 freezing and crystallizing again.Though product through twice crystallization after purity can reach more than 98%, this method complex process, yield is very low, is not suitable for suitability for industrialized production.
Patent KR9500259 proposes to adopt strategic point dilution crystallization 5 '-guanosine monophosphate, starting soln pH is controlled at 8.4-8.6, improve the solution degree of supersaturation by adding methyl alcohol or ethanol, change when nucleus is about to produce that stream adds form and speed obtains 5 '-sodium guanylate crystal.This method is had relatively high expectations to crystallization operation, and crystallisation process is wayward, also is not suitable for suitability for industrialized production.
Conventional ethanol dissolved technology is all adopted in known domestic 5 '-nucleoside monophosphate crystallization at present.Utilize the difference of 5 '-nucleoside monophosphate and different solvents intermolecular interaction, by changing its solubility change of property effect of solvent.Because it is very remarkable that alcohol solvent turns the solubleness influence of using 5 '-nucleoside monophosphate into, the easily rapid nucleation of 5 '-nucleoside monophosphate sodium, outburst are separated out in the crystallisation process, cause crystalline product powdery indefiniteness, and water absorbability is strong, problems such as the filtering separation difficulty is big, and the high yield of foreign matter content is low.
Summary of the invention
The objective of the invention is to provides a kind of crystallization method of 5 '-nucleoside monophosphate sodium salt at present 5 '-nucleoside monophosphate dilution crystallization poor product quality, shortcoming that yield is low.
Purpose of the present invention can reach by following measure:
A kind of crystallization method of 5 '-nucleoside monophosphate sodium salt, this method be the pH value be 5.0～9.0 and mass percent be in 5 '-nucleoside monophosphate aqueous solution of 5～30% concentration, add the solute mass percent and be the dissolved agent of 0.5～10 times of 1～10% inorganic sodium and initial 5 '-nucleoside monophosphate aqueous solution volume, Tc is controlled at 15 ℃～40 ℃, mixing speed is controlled at 20～200rpm, suction filtration after the crystallization, washing with alcohol, vacuum-drying promptly gets 5 '-nucleoside monophosphate crystals of sodium salt.
Described crystallization method, wherein inorganic sodium refers to one or more in sodium-acetate, yellow soda ash, sodium sulfate, the sodium-chlor.
Described crystallization method, wherein the dissolved agent refers to one or more in the organic solvents such as ethanol, methyl alcohol, acetone, ether.
Described crystallization method, wherein the pH value is preferably 5.5～7.5.
Described crystallization method, wherein Tc control is preferably at 20 ℃～35 ℃.
Described crystallization method, wherein the add-on of dissolved agent is preferably 1～4 times of initial 5 '-nucleoside monophosphate aqueous solution volume.
Described crystallization method, wherein the adding mode of dissolved agent adopts disposable adding mode or fed-batch mode.
Beneficial effect of the present invention:
Inorganic sodium provided by the invention adds dissolved agent crystallizing system, the synergy of utilizing dissolved and saltouing, can stablize and improve 5 '-nucleoside monophosphate sodium salt quality product and crystallization yield, can obtain 5 '-nucleoside monophosphate crystals of sodium salt by crystallization control processing condition and flow field state, good reproducibility simple to operate, the suitability for industrialized production of suitable 5 '-nucleoside monophosphate product.
The present invention compared with prior art has following advantage:
1, the crystalline product particle diameter is even, and purity surpasses 98%.Because the adding of inorganic sodium is the potential of hydrogen of crystallization control process effectively, influence the ionization equilibrium of 5 '-nucleoside monophosphate, the micro of crystal nucleation and growth had greatly improves, guarantee high-purity quality of the finished product and good medicinal character, the product water absorbability be improved significantly.
2, crystallization yield is stabilized in more than 90%.Because the influence of the common-ion effcet of sodium ion, crystallization yield obtain stable the raising.Can obtain the granular crystal of 5 '-nucleoside monophosphate sodium by reasonable crystallization control processing condition and flow field state, effectively improve the suction filtration and the washing situation of postorder, further guarantee final quality product and crystallization yield.
3, process stabilizing, good reproducibility.The crystallization operation time is short, and production process is carried out at normal temperatures, has reduced the biological degradation and the pigment impurity increase of 5 '-nucleoside monophosphate in the crystallisation process, and need not special heating and cooling device, save cost of investment, operating process is easy to control, good reproducibility more.
4, safe.Adopt appropriate organic solvent as the dissolved agent, can guarantee the microbiological indicator requirement of the finished product.
5, finished product is attractive in appearance.Utilize present method crystallization 5 '-nucleoside monophosphate, its sodium salt product is a particulate state, even particle size, and glossiness is good, and drift sand is strong.
Embodiment
Following examples will the invention will be further described, but to the present invention without limits.
Embodiment 1:
With concentration is two parts of 5 '-uridylic acid (UMP) aqueous solution of 100g/L, and each 10L adopts conventional dilution crystallization and this patent preparation method to carry out crystallization respectively.The former directly transfers pH to 7.5 with sodium hydroxide, slowly adds ethanol 10L, and the latter transfers to pH6.0 with sodium hydroxide, adds sodium-acetate 30g and ethanol 10L.Both crystallization processes term harmonizations all are controlled at 25 ℃, mixing speed 50rpm.After the crystallization fully suspension liquid is distinguished suction filtration, the washing with alcohol with 85%, vacuum-drying.Table 1 is that two kinds of crystallizing system quality producies and crystallization yield compare.
Two kinds of crystallizing system quality producies of table 1 and crystallization yield are relatively
| Project | Conventional dilution crystallization method | This patent preparation method |
| Product appearance | White crystalline powder | The white particulate crystal |
| HPLC | Should to go out the peak situation consistent with reference substance | Consistent |
| Moisture (%) | 16.8 | 22.8 |
| A250/260nm | 0.73 | 0.74 |
| A280/260nm | 0.37 | 0.37 |
| Content (%) (by anhydrous) | 96.7 | 98.6 |
| Crystallization yield (%) | 89.3 | 94.8 |
Embodiment 2
With concentration is 5 '-uridylic acid (UMP) aqueous solution 100L of 100g/L, transfers to pH6.0 with sodium hydroxide, adds yellow soda ash 300g and methyl alcohol 100L, controls stirring velocity 100rpm down at 25 ℃.After the crystallization fully with the suspension liquid suction filtration, the white crystal of washing with alcohol gained with 85%, vacuum-drying can obtain 5 '-sodium uridilate crystal 13.7kg.Finished product detection purity is 98.3%, moisture 19.8%, and last crystallization yield is 95.1%.Detected result sees Table 2.
Table 2 sodium uridilate final product quality detected result: C
9H
11N
2O
9PNa
2(molecular weight 368.15)
| Test item | Detect index | Detected result |
| Outward appearance | Should be white or off-white color crystalline powder | The white particulate crystal |
| HPLC | Should to go out the peak situation consistent with reference substance | Consistent |
| Moisture (%) | ≤26.0 | 19.8 |
| A250/260nm | 0.71～0.77 | 0.74 |
| A280/260nm | 0.36～0.40 | 0.37 |
| Content (%) (by anhydrous) | ≥97.0 | 98.3 |
Embodiment 3
With concentration is 5 '-guanosine monophosphate aqueous solution 100L of 150g/L, transfers to pH6.8 with sodium hydroxide, adds yellow soda ash 200g, at 25 ℃ of control stirring velocity 70rpm down, adds ethanol 120L with the flow velocity stream of 10L/h.After the crystallization with the suspension liquid suction filtration, the white crystal of washing with alcohol gained with 85%, vacuum-drying can obtain 5 '-guanylic acid sodium salt crystal 18.2kg.Finished product detection purity is 99.7%, moisture 11%, and last crystallization yield is 95.5%.Detected result sees Table 3.
Table 3 sodium guanylate final product quality detected result: C
10H
12N
5O
8PNa
2(molecular weight 407.19)
| Test item | Detect index | Detected result |
| Outward appearance | Should be white or off-white color crystalline powder | The white particulate crystal |
| HPLC | Should to go out the peak situation consistent with reference substance | Consistent |
| Moisture (%) | 25.0 | 11.0 |
| A250/260(pH7.0) | 1.13～1.19 | 1.16 |
| A280/260(pH7.0) | 0.64～0.68 | 0.65 |
| pH | 7.0～8.5 | 7.95 |
| Content (by anhydrous) (%) | 97.0 | 99.7 |
Embodiment 4
With concentration is 5 '-cytidine monophosphate aqueous solution 6L of 100g/L, transfers to pH6.5 with sodium hydroxide, adds sodium-acetate 20g and ether 9L, stable to system 25 ℃ of insulated and stirred.The mixing solutionss that processing is obtained etc. divide 3 parts, every part of 5L, and controlling mixing speed respectively is 50rpm, 100rpm and 150rpm.After the crystallization fully with suspension liquid suction filtration, washing with alcohol, vacuum-drying.Table 4 has provided 5 '-cytidylic acid sodium crystal size-grade distribution.
By data in the table as seen, mixing speed is bigger to the influence of 5 '-cytidylic acid sodium crystal size and distribution.Mixing speed increases to 150rpm from 50rpm, 100rpm, and crystalline mean particle size difference reaches 52 μ m, therefore, can reach the purpose of control crystal grain size by the flow field situation of crystallization control.
Table 4 mixing speed is to the influence of 5 '-cytidylic acid sodium crystal size distribution
| Mixing speed (rpm) | Crystallization time (branch) | M.S./C.V. (μm/％) | Crystallization yield (%) | Finished product purity (%) |
| 50 | 430 | 178/35.5 | 95.1 | 98.9 |
| 100 | 370 | 152/36.1 | 94.9 | 98.8 |
| 150 | 345 | 126/38.9 | 94.6 | 98.6 |
Embodiment 5
With concentration is 5 '-adenylic acid aqueous solution 6L of 100g/L, transfers to pH6.0 with sodium hydroxide, adds sodium-acetate 15g and acetone 12L, and the uniform and stable back of the system for the treatment of is waited and divided 3 parts, every part of 6L.Be placed on crystallization in 20 ℃, 25 ℃, the 30 ℃ water-baths respectively, mixing speed all is controlled at 100rpm.After the crystallization fully with suspension liquid suction filtration, washing with alcohol, vacuum-drying.Table 5 has provided 5 '-adenylic acid (AMP) sodium crystal size-grade distribution.
Table 5 temperature is to the influence of 5 '-adenylic acid (AMP) sodium crystal size distribution
| Temperature (degree centigrade) | Crystallization time (branch) | M.S/C.V (μm/％) | Crystallization yield (%) | Finished product purity (%) |
| 20 | 320 | 135/36.9 | 95.1 | 99.3 |
| 25 | 375 | 162/38.1 | 94.9 | 99.1 |
| 30 | 435 | 197/40.6 | 94.6 | 98.8 |
By data in the table as seen, temperature is bigger to 5 '-adenylic acid (AMP) sodium crystalline influence, especially to the influence of 5 '-adenylic acid (AMP) crystals of sodium salt granular size.Tc is increased to 30 ℃ from 20 ℃, and crystal grain can be increased to 197 μ m from 135 μ m, therefore, can produce 5 '-adenylic acid (AMP) sodium particulate state crystal of different sizes by the method for regulating Tc.
Claims (7)
1. the crystallization method of 5 '-nucleoside monophosphate sodium salt, it is characterized in that the pH value be 5.0～9.0 and mass percent be in 5 '-nucleoside monophosphate aqueous solution of 5～30% concentration, add the solute mass percent and be the dissolved agent of 0.5～10 times of 1～10% inorganic sodium or sodium-acetate and initial 5 '-nucleoside monophosphate aqueous solution volume, Tc is controlled at 15 ℃～40 ℃, mixing speed is controlled at 20～200rpm, suction filtration after the crystallization, washing with alcohol, vacuum-drying promptly gets 5 '-nucleoside monophosphate crystals of sodium salt.
2. crystallization method according to claim 1 is characterized in that inorganic sodium refers to one or more in yellow soda ash, sodium sulfate, the sodium-chlor.
3. crystallization method according to claim 1 is characterized in that the dissolved agent refers to one or more in ethanol, methyl alcohol, acetone, the ether.
4. crystallization method according to claim 1 is characterized in that the pH value is 5.5～7.5.
5. crystallization method according to claim 1 is characterized in that Tc is controlled at 20 ℃～35 ℃.
6. crystallization method according to claim 1, the add-on that it is characterized in that the dissolved agent are 0.5～10 times of initial 5 '-nucleoside monophosphate aqueous solution volume.
7. crystallization method according to claim 1 is characterized in that the adding mode of dissolved agent adopts disposable adding mode or fed-batch mode.
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| WO2021101042A1 (en) | 2019-11-20 | 2021-05-27 | 씨제이제일제당 (주) | Method for refining nucleic acids |
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| CN101863943B (en) * | 2010-06-28 | 2014-03-12 | 大连珍奥生物技术股份有限公司 | Crystallizing method of 5'-guanosine-monophosphate disodium salt |
| CN102952167A (en) * | 2012-11-29 | 2013-03-06 | 南京工业大学 | Method for dilution crystallizationelution and crystallization of cytidine 5'-disodium phosphate |
| CN103319557A (en) * | 2013-07-17 | 2013-09-25 | 南京工业大学 | Crystallization method of cyclic adenosine monophosphate |
| CN103435669B (en) * | 2013-09-09 | 2016-03-09 | 南京工业大学 | The dilution crystallization method of 5 '-uridine monophosphate disodium |
| 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 |
| CN107712345B (en) * | 2017-10-17 | 2022-03-22 | 南京工业大学 | Nucleotide mixture crystal powder and preparation method thereof |
| KR102284843B1 (en) * | 2019-10-08 | 2021-08-02 | 씨제이제일제당 주식회사 | Method of producing 5'-guanylic acid disodium 7 hydrate crystals |
| CN112341503B (en) * | 2020-11-07 | 2022-05-20 | 潍坊华诺医药科技有限公司 | Method for separating and purifying deoxyribonucleoside triphosphate |
| CN113461745A (en) * | 2021-08-05 | 2021-10-01 | 南京工业大学 | Method for improving nucleotide crystal form |
| CN114751949A (en) * | 2022-05-26 | 2022-07-15 | 南京工业大学 | 5' -cytidine monophosphate monohydrate crystal and preparation method thereof |
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| WO2021101042A1 (en) | 2019-11-20 | 2021-05-27 | 씨제이제일제당 (주) | Method for refining nucleic acids |
| EP4047099A1 (en) | 2019-11-20 | 2022-08-24 | CJ Cheiljedang Corporation | Method for refining nucleic acids |
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