CN1616475A - Process for preparing cytidine-S'-phosphate - Google Patents
Process for preparing cytidine-S'-phosphate Download PDFInfo
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- CN1616475A CN1616475A CN 200410064715 CN200410064715A CN1616475A CN 1616475 A CN1616475 A CN 1616475A CN 200410064715 CN200410064715 CN 200410064715 CN 200410064715 A CN200410064715 A CN 200410064715A CN 1616475 A CN1616475 A CN 1616475A
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Abstract
The present invention relates to chemical synthesis process of cytidine-5'-monophosphate (5'-CMP). The preparation process includes the reaction between cytidine material with phosphorus oxychloride or other phosphation agent at the temperature of -15 deg.c to -5 deg.c and normal pressure, adding ice water to end the reaction after reaching conversion rate over 85 %, hydrolysis at 0-5 deg.c, extracting with alkyl halide, letting stand to laminate, and separating to obtain organic phase and water phase; distilling the organic phase to recover extracting agent and organic solvent, neutralizing water phase to pH 3-4 and cooling to crystallize and obtain 5'-CMP; refining and drying to obtain 5'-CMP product. The present invention has simplified technological process, short production period, high product yield, low cost and high product purity.
Description
Relate to the field
The present invention relates to a kind of preparation of Nucleotide, relate in particular to the preparation method of " Cytidine-5 '-one phosphoric acid ", particularly is the method preparation " Cytidine-5 '-one phosphoric acid " that raw material adopts chemosynthesis with the cytidine.
Technical background
Yeast Nucleic Acid (RNA) is a kind of biological polymeric compound, is the major ingredient that constitutes biomass cells.On structure, RNA is made of many repeating units, and these repeating units are Nucleotide.Therefore, Nucleotide and derivative thereof have multiple biologically active substance, can be directly or indirectly as drug use, its series compound is mainly used in field of medicaments, purposes is very extensive, product innovation emerges in an endless stream, and range of application also constantly enlarges, and has played important role to treating multiple disease.
" Cytidine-5 '-one phosphoric acid " involved in the present invention is a kind of basic Nucleotide that constitutes RNA, and be called again: " 5 '-cytidylic acid ", " 5 '-single cytidine phosphate " or " 5 '-CMP ", its molecular formula is C
9H
14N
3O
8P, structure is suc as formula shown in the I.
(formula I) (formula II)
5 '-CMP not only can use and production nutritious supplementary, nutritive food additive or makeup with other Nucleotide collocation, the more important thing is, it can be used as intermediate and is used for preparing biochemical drugs such as cytidine diphosphate, cytidine triphosphate(CTP), cytosine arabinoside, Polyinosinic-polycytidylic acid, wherein: cytidine diphosphate can the cerebral blood flow increasing amount, promote the recovery of brain injury and apoplexy, good curative effect is arranged at aspects such as treatment Parkinson's disease, senile dementia, dysthymia disorders and cardiovascular and cerebrovascular diseases; Cytidine triphosphate(CTP) is a kind of antiviral, and its effect is similar to Ancitabine, ATP (Triphosaden); Cytosine arabinoside also has antivirus action, is the medicine commonly used of treatment acute leukemia; Polyinosinic-polycytidylic acid is the double stranded RNA of synthetic, can induce low-level Interferon, rabbit, has antivirus action, energy adjuster body immunity function, impel the enhancing of human body non-specific immune function and some specific immune function, play anti-cell necrosis and antitumor action, be usually used in treating chronic viral liver class disease, herpes simplex and verruca plana etc.These biochemical drugs demand clinically are bigger, and at present domestic have tens tame pharmaceutical factories to produce, but because its initial raw materials for production---5 '-CMP relatively lacks, make that every year need be from the import of external high price in enormous quantities.
In the prior art, the method for preparation 5 '-CMP mainly contains nucleolysis method, enzymic synthesis method and chemical synthesis three major types.
The nucleolysis method is to utilize the core nucleolysis water yeast rna of nuclease P 1, obtains 5 '-adenylic acid (AMP), 5 '-guanylic acid, 5 '-uridylic acid and 5 '-Nucleotide such as CMP, separates with ion-exchange chromatography then, makes 5 '-CMP again through making with extra care.This is the main method that China produces 5 '-CMP at present, but this method production cycle is long, separates and the refining step complexity, and output is little, the tooling cost height.
The enzymic synthesis method is to adopt the production technology of microbial enzyme for the basis, is the enzyme source with polynucleotide phosphorylase and nucleoside phosphorylase, through repeatedly fermentation processing, finally is converted into the purpose product.The shortcoming of this method is a long reaction time, easily microbiological contamination, and transformation efficiency is lower.
The route of chemical synthesis is, carries out condensation reaction by cytosine(Cyt) and tetrem acyl ribose (α, β-mix tetrem acyl-D-ribose) under the effect of condensing agents such as tin tetrachloride earlier, and (molecular formula is C to make cytidine
9H
13N
3O
5, its structural formula is seen formula II).With cytidine and protection reagent 2 ', the reaction of 3 '-O-isopropylidene cytidine, cytidine intramolecularly 2 ', 3 ' the locational hydroxyl is protected earlier then, carry out acidification reaction with phosphoric acid agent again, remove protective material at last and just can make 5 '-CMP.
Clearly, chemosynthesis has more advantage than other two kinds of methods, and its DEVELOPMENT PROSPECT is also good.On the one hand; cytosine(Cyt) is the most cheap raw material in the middle of the production oligonucleotide product; on the other hand; the synthesis technique of cytidine reaches its maturity, and therefore, it is that the synthetic 5 '-CMP of raw material is last that people transfer to research emphasis gradually with the cytidine; better operational path and condition are explored in research; so that overcome the defective of the sort of protection earlier of prior art, acidifying again, last deprotection, thereby simplify technological process, make the highly purified Cytidine-5 of preparation ' technological process of-one phosphoric acid is more economical, efficiently.
Summary of the invention
The object of the present invention is to provide a kind of is the feedstock production Cytidine-5 with the cytidine ' method of-one phosphoric acid, this method technological process is short, transformation efficiency is high, product purity is high, can large-scale industrial production.
Purpose of the present invention realizes by following technical solution:
A kind of Cytidine-5 for preparing ' method of-one phosphoric acid, be starting raw material with the cytidine, comprise following operation steps successively:
1. cytidine is dissolved in organic solvent, adds phosphoric acid agent, carry out acidification reaction under-15 ℃ to-5 ℃, conventional barometric point, phosphoric acid agent is 1/1～1/1.5 with the ratio of the mole dosage of cytidine;
2. when the acidifying transformation efficiency of cytidine 〉=85%, add the frozen water termination reaction, and hydrolysis 1～3 hour under-5 ℃～5 ℃ temperature;
3. add extraction agent and extract, standing demix obtains organic phase and water respectively after the separation;
4. using in the dilute alkaline soln and water, is 3～4 until pH value, then at 10 ℃～0 ℃ following freezing and crystallizing, and solid-liquid separation gets Cytidine-5 '-one phosphoric acid crude product;
5. refining gained crude product, drying promptly gets Cytidine-5 '-one phosphoric acid finished product.
Purpose of the present invention also can further realize by following technology solution:
The aforesaid Cytidine-5 for preparing ' method of-one phosphoric acid, wherein step 5. the operation for the treatment of process be, crude product is added in the pure water, heating for dissolving adds activated carbon decolorizing, filters, the cooling back adds ethanol in filtrate, separate out white crystal, centrifugation obtains Cytidine-5 after the vacuum-drying '-one phosphoric acid finished product; Or, use the washing with alcohol crude product, add pure water then, regulating pH value with dilute alkaline soln is 5～6, adds activated carbon decolorizing after the heating for dissolving, filters, regulating pH value with dilute acid soln again after the cooling is 3～4, at 10 ℃～0 ℃ following freezing and crystallizing, and solid-liquid separation promptly gets Cytidine-5 '-one phosphoric acid finished product.
The aforesaid Cytidine-5 for preparing ' method of-one phosphoric acid, wherein step 1. described in phosphoric acid agent be Phosphorus Oxychloride, described organic solvent is halogenated alkane, organic nitrile, dimethyl formamide or phosphoric acid ester.
The aforesaid Cytidine-5 for preparing ' method of-one phosphoric acid, wherein 1. preferred-10 ℃ to-5 ℃ of temperature in the acidification reaction process of step is participated in the central water content of all material raw materials of acidification reaction and all should be no more than 0.1Wt%.
The aforesaid Cytidine-5 for preparing ' method of-one phosphoric acid, wherein the 3. used extraction agent of step is haloalkane, more preferably alkyl chloride.
The aforesaid Cytidine-5 for preparing ' method of-one phosphoric acid, wherein the organic phase that 3. step obtains after the extracting and separating can be distilled, reclaim the extraction agent and the acidification reaction organic solvent that are wherein contained, and reuse.
Outstanding substantive distinguishing features of the present invention and obvious improvement are embodied in following several respects:
At first, cytosine(Cyt) is the most cheap raw material of producing oligonucleotide product, and have up to a hundred tons output domestic every year now, and raw material sources are wide, price is low, and the cytidine price that makes is also comparatively cheap.Compare with nucleolysis method, enzymic synthesis method, advantage of the present invention is fairly obvious, and not only raw material sources are abundant, with short production cycle, product yield is high, tooling cost is low, and production process can microbiological contamination, reliable product quality.
Secondly, compare with the chemical synthesis process that prior art is adopted, the present invention passes through the optimization of acidification reaction choice of Solvent, reaction conditions, the control of reaction end, make the reaction of cytidine and phosphoric acid agent generate disposable the finishing of process of 5 '-CMP, simplify preparation technology, further reduced production cost.
The 3rd, the present invention provided cytidine after finishing acidification reaction in and excess acid and remove the optimum process condition of solvent, for making with extra care of crude product, the present invention has provided two kinds of technical schemes, can remove a large amount of salt, by product and unreacted cytidine that reaction generates well, about 98%, purity is very high with efficient liquid phase chromatographic analysis content for the product that makes.
In addition, the present invention can effectively prevent and overcome the normal material syrup phenomenon that takes place of prior art, and result of study shows the technical solution adopted in the present invention stable technical process, and each operation all can effectively be controlled, good reliability.
In a word, the invention provides a kind of more economical, prepare the method for 5 '-CMP efficiently, this method for exploitation 5 '-CMP complete producing technology, carry out from cytosine(Cyt) → cytidine → seriations such as cytidylic acid → biochemical drug processing and all have very important positive effect with being connected.This method can reduce production costs significantly, for scale operation cytidylic acid product is laid a good foundation.
Purpose of the present invention, advantage and characteristics will illustrate by the non-limitative illustration of following preferential embodiment and explain that these embodiment only provide as an example with reference to accompanying drawing.
Description of drawings
Fig. 1 is a process flow diagram of the present invention.
Embodiment
As shown in Figure 1, the present invention is a starting raw material with the cytidine, in organic solvent, under-15 ℃ to-5 ℃ temperature, reacts according to the ratio of 1/1～1/1.5 mole dosage with phosphoric acid agents such as Phosphorus Oxychlorides, '-one phosphoric acid that makes Cytidine-5.Reaction equation can be reduced to:
When the acidifying transformation efficiency of cytidine 〉=85%, add the frozen water termination reaction, and hydrolysis 1～3 hour under 0 ℃～5 ℃ temperature; Add extraction agents such as haloalkane then and extract, standing demix obtains organic phase and water respectively after the separation; Organic phase reclaims through distillation, obtains extraction agent and acidification reaction organic solvent, can reuse; Water is with dilute alkaline solns such as NaOH neutralizations, to pH value be 3～4 o'clock freezing and crystallizings, solid-liquid separation obtains 5 '-CMP crude product; Crude product promptly gets 5 '-CMP finished product through refining and drying treatment.
The above-mentioned refining drying process that reaches can adopt one of following two kinds of methods:
One adds crude product in the pure water, and heating for dissolving adds activated carbon decolorizing, filters, and the cooling back adds ethanol in filtrate, separate out white crystal, centrifugation final vacuum drying;
Its two, use the washing with alcohol crude product, add pure water then, regulating pH value with dilute alkaline soln is 5～6, adds activated carbon decolorizing after the heating for dissolving, filters, regulating pH value with dilute acid soln again after the cooling is 3～4, centrifugation behind the freezing and crystallizing, vacuum-drying.
Long influential to product yield, when transformation efficiency reaches after 85%, along with time lengthening, the content of 5 '-CMP is on a declining curve on the contrary in the reaction solution.Its reason may be because under strong acid environment, the glycosidic bond in 5 '-CMP molecule ruptures.Therefore in the acidification reaction process, can get sample one time, analyze,, can add the frozen water termination reaction when the transformation efficiency of determining cytidine reaches after 85% with above-mentioned " electrophoretic method " every half an hour.
For preventing that the glycosidic bond fracture from influencing product yield, acidification reaction should carry out at a lower temperature.By discovering, temperature of reaction is between-15 ℃ to-5 ℃, and yield is more stable; Temperature is during greater than-5 ℃, and yield begins to descend.Usually, with more suitable between-10 ℃ to-5 ℃.
After acidification reaction finished, through hydrolysis, extraction, neutralization, crystallization, 5 '-CMP separated out simultaneously with a large amount of salt and side reaction product, and wherein the part by weight of 5 '-CMP only accounts for about 40～50%, and therefore, ensuing treating process is extremely important.The front has provided two kinds of methods of purified, and the 5 '-CMP finished product purity after making with extra care is very high, and high performance liquid chromatography (HPLC) analytical results is about 98%, and UV spectrum (UV) analytical results illustrates that the effect of two kinds of process for purification is all fine about 96%.
The purpose that adds gac in the treating process is decolouring, makes the product that makes whiter.
Embodiment 1
In dry, clean building-up reactions bottle, add the 140ml triethyl phosphate, drop into 20 gram cytidines, stir, cool to-5～-10 ℃.Slowly drip the 12ml Phosphorus Oxychloride, keep temperature of reaction between-5～-10 ℃, finish. insulation reaction under this temperature.Every sampling half an hour, carry out electrophoretic analysis after two hours.When the cytidine transformation efficiency reaches more than 85%, in reaction system, add 80ml frozen water termination reaction, maintain the temperature between 0～5 ℃, hydrolysis 1 hour is then with ethylene dichloride extraction, standing demix.Organic layer reclaims through distillation, obtains ethylene dichloride and triethyl phosphate, and is reusable; Water layer is 3～4 with the NaOH neutralization of 30% weight concentration up to pH value, is cooled to 10 ℃～0 ℃ then and carries out freezing and crystallizing, obtains thick product after the centrifugation.
Add 3～10 times and measure pure water in thick product, heating for dissolving is used activated carbon decolorizing, filters, and the cooling back adds 95% ethanol in filtrate, separate out crystal, and mother liquid recycle after the centrifugation, crystal get Cytidine-5 '-one phosphoric acid finished product through vacuum-drying.Product appearance: white crystals or powder; Purity: the HPLC analytical results is 97.8%, and the UV analytical results is 95.7%; Total recovery 81.75%, wherein the acidification reaction transformation efficiency 85%, refining yield 96.17%.
Embodiment 2
In dry, clean building-up reactions bottle, add the 30ml tributyl phosphate, drop into 40 gram cytidines, stir, cool to-5～-10 ℃.Slowly drip the 30ml Phosphorus Oxychloride,, keep temperature of reaction between-5～-10 ℃, finish insulation reaction under this temperature.Every sampling half an hour, carry out electrophoretic analysis after two hours.When the cytidine transformation efficiency reaches more than 85%, in reaction system, add 200ml frozen water termination reaction, maintain the temperature between 0～5 ℃, hydrolysis 1 hour is used chloroform extraction, standing demix then.Organic layer reclaims through distillation, obtains trichloromethane and tributyl phosphate, and is reusable; Water layer is 3～4 with the NaOH neutralization of 30% weight concentration up to pH value, is cooled to 10 ℃～0 ℃ then and carries out freezing and crystallizing, obtains thick product after the centrifugation.
Wash thick product twice with 80% ethanol by 3 times of consumptions, and then heating for dissolving is used activated carbon decolorizing in the middle of the pure water of 3 times of consumptions, filter, the cooling back adds 95% ethanol in filtrate, separate out crystal, mother liquid recycle after the centrifugation, crystal get Cytidine-5 '-one phosphoric acid finished product through vacuum-drying.Product appearance: white crystals or powder; Purity: the HPLC analytical results is 98.2%, and the UV analytical results is 96.1%; Total recovery 80%, wherein the acidification reaction transformation efficiency 86%, refining yield 93%.
Embodiment 3
In dry, clean synthesis reaction vessel, add 560 gram triethyl phosphates, drop into 80 gram cytidines, stir, cool to-5～-10 ℃.Slowly drip the 48L Phosphorus Oxychloride, keep temperature of reaction between-5～-10 ℃, finish insulation reaction under this temperature.Every sampling half an hour, carry out electrophoretic analysis after two hours.When the cytidine transformation efficiency reaches more than 85%, in reaction system, add 80L frozen water termination reaction, maintain the temperature between 0～5 ℃, hydrolysis 1 hour is then with ethylene dichloride extraction, standing demix.Organic layer reclaims through distillation, obtains ethylene dichloride and triethyl phosphate, and is reusable; Water layer is 3～4 with the NaOH neutralization of 30% weight concentration up to pH value, is cooled to 10 ℃～0 ℃ then and carries out freezing and crystallizing, obtains thick product after the centrifugation.
Wash thick product twice with 80% ethanol by 3 times of consumptions, thick product after then alcohol being washed is dissolved in pure water, and regulating pH value with 10%NaOH is 5～6, heating for dissolving, add activated carbon decolorizing, filtering, is 3～3.5 with dilute concentration HCL adjusting PH again after the cooling, separates out crystallization after freezing, centrifugation, mother liquid recycle, crystal get Cytidine-5 '-one phosphoric acid finished product through vacuum-drying.Product appearance: white crystals or powder; Purity: the HPLC analytical results is 98.5%, and the UV analytical results is 96.3%; Total recovery 82.5%, wherein the acidification reaction transformation efficiency 86%, refining yield 96%.
In addition to the implementation, the present invention can also have other embodiment.All employings are equal to the technical scheme of replacement or equivalent transformation formation, all drop within the scope of protection of present invention.
Claims (8)
1. one kind prepares Cytidine-5 ' method of-one phosphoric acid, be starting raw material with the cytidine, comprise following operation steps successively:
1. cytidine is dissolved in organic solvent, adds phosphoric acid agent, carry out acidification reaction under-15 ℃ to-5 ℃, conventional barometric point, phosphoric acid agent is 1/1～1/1.5 with the ratio of the mole dosage of cytidine;
2. when the acidifying transformation efficiency of cytidine 〉=85%, add the frozen water termination reaction, and hydrolysis 1～3 hour under-5 ℃～5 ℃ temperature;
3. add extraction agent and extract, standing demix obtains organic phase and water respectively after the separation;
4. using in the dilute alkaline soln and water, is 3～4 until pH value, then at 10 ℃～0 ℃ following freezing and crystallizing, and solid-liquid separation gets Cytidine-5 '-one phosphoric acid crude product;
5. refining gained crude product, drying gets Cytidine-5 '-one phosphoric acid finished product.
2. by the described Cytidine-5 for preparing of claim 1 ' method of-one phosphoric acid, it is characterized in that: described step 5. refining step is, crude product is added in the pure water, heating for dissolving adds activated carbon decolorizing, filters, the cooling back adds ethanol in filtrate, separate out white crystal, centrifugation, '-one phosphoric acid finished product that promptly gets Cytidine-5 after the vacuum-drying.
3. by the described Cytidine-5 for preparing of claim 1 ' method of-one phosphoric acid, it is characterized in that: described step 5. refining step is, use the washing with alcohol crude product, add pure water then, regulating pH value with dilute alkaline soln is 5～6, adds activated carbon decolorizing after the heating for dissolving, filter, regulating pH value with dilute acid soln again after the cooling is 3～4, at 10 ℃～0 ℃ following freezing and crystallizing, and solid-liquid separation promptly gets Cytidine-5 '-one phosphoric acid finished product.
4. by claim 1 or the 2 or 3 described Cytidine-5s that prepare ' method of-one phosphoric acid, it is characterized in that: step 1. described in phosphoric acid agent be Phosphorus Oxychloride, described organic solvent is halogenated alkane, organic nitrile, dimethyl formamide or phosphoric acid ester.
5. by the described Cytidine-5 for preparing of claim 4 ' method of-one phosphoric acid, it is characterized in that: step 1. in the acidification reaction process temperature be-10 ℃ to-5 ℃, the central water content of all material raw materials of participation acidification reaction is no more than 0.1Wt%.
6. by claim 1 or the 2 or 3 described Cytidine-5s that prepare ' method of-one phosphoric acid, it is characterized in that: the 3. used extraction agent of step is a haloalkane.
7. by the described Cytidine-5 for preparing of claim 6 ' method of-one phosphoric acid, it is characterized in that: described haloalkane is an alkyl chloride.
8. by the described Cytidine-5 for preparing of claim 1 ' method of-one phosphoric acid, it is characterized in that: with step 3. the organic phase that obtains later on of extracting and separating distill, reclaim the extraction agent and the acidification reaction organic solvent that are wherein contained, reuse.
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Cited By (6)
| 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 |
| CN102115485A (en) * | 2009-12-30 | 2011-07-06 | 济南圣鲁金药物技术开发有限公司 | Prodrug based on cytosine arabinoside structure, and synthesis method and application thereof |
| CN102212096A (en) * | 2011-04-08 | 2011-10-12 | 南通香地生物有限公司 | Method for preparing 5'-cytidylic acid from composite solvent and bind acid agent |
| CN103483408A (en) * | 2013-09-18 | 2014-01-01 | 南京工业大学 | Method for continuous production of 5'-nucleotide by using micro-channel reaction device |
| CN114315934A (en) * | 2021-12-22 | 2022-04-12 | 成都市海通药业有限公司 | Synthesis and refining method of citicoline important intermediate cytidylic acid |
| CN114751949A (en) * | 2022-05-26 | 2022-07-15 | 南京工业大学 | 5' -cytidine monophosphate monohydrate crystal and preparation method thereof |
-
2004
- 2004-09-21 CN CN 200410064715 patent/CN1271080C/en not_active Expired - Fee Related
Cited By (7)
| 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 |
| CN102115485A (en) * | 2009-12-30 | 2011-07-06 | 济南圣鲁金药物技术开发有限公司 | Prodrug based on cytosine arabinoside structure, and synthesis method and application thereof |
| CN102212096A (en) * | 2011-04-08 | 2011-10-12 | 南通香地生物有限公司 | Method for preparing 5'-cytidylic acid from composite solvent and bind acid agent |
| CN103483408A (en) * | 2013-09-18 | 2014-01-01 | 南京工业大学 | Method for continuous production of 5'-nucleotide by using micro-channel reaction device |
| CN103483408B (en) * | 2013-09-18 | 2015-07-15 | 南京工业大学 | Method for continuous production of 5'-nucleotide by using micro-channel reaction device |
| CN114315934A (en) * | 2021-12-22 | 2022-04-12 | 成都市海通药业有限公司 | Synthesis and refining method of citicoline important intermediate cytidylic acid |
| 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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Assignee: Suzhou Dima Bio-Tech Development Co., Ltd. Assignor: Saikangdewanma Chemical Co., Ltd., Suzhou Industrial Garden Contract fulfillment period: 2009.7.28 to 2019.7.27 contract change Contract record no.: 2009990000917 Denomination of invention: Process for preparing cytidine-S'-phosphate Granted publication date: 20060823 License type: Exclusive license Record date: 2009.8.13 |
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