CN104163842A - Method for producing cytidine monophosphate disodium salt - Google Patents
Method for producing cytidine monophosphate disodium salt Download PDFInfo
- Publication number
- CN104163842A CN104163842A CN201410333718.2A CN201410333718A CN104163842A CN 104163842 A CN104163842 A CN 104163842A CN 201410333718 A CN201410333718 A CN 201410333718A CN 104163842 A CN104163842 A CN 104163842A
- Authority
- CN
- China
- Prior art keywords
- hydrolysis
- water layer
- disodium salt
- reaction
- add
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a method for producing cytidine monophosphate disodium salt, which comprises the following steps: A)respectively adding cytidine, triethyl phosphate and pyridine in a reaction container, uniformly mixing and adjusting the reaction temperature to -15-5 DEG C, slowly adding a certain amount of phosphorous oxychloride at the temperature condition, continuously stirring for reacting for 10-30 hours after the addition is completed; B)sampling and analyzing HPLC, when the conversion rate is greater or equal to 99%, adding 10-15% of brine ice for hydrolysis, wherein the hydrolysis temperature is controlled at 0-5 DEG C, and the hydrolysis time is 10-20 hours; C)after hydrolysis is completed, standing and layering, removing an organic phase to obtain a water layer for standby; D)adjusting the pH value of the water layer to 7.0-8.0 by using 30% of sodium hydroxide, then dropping 95% of alcohol with amount of two times of the water layer, precipitating and crystallizing, and filtering to obtain the crude product; and E)dissolving the crude product, adding active carbon for decolouring, continuously dropping the 95% of alcohol with volume amount of two times of a solution to precipitate and crystallize, filtering, rinsing and drying to obtain the finished product. The method for producing cytidine monophosphate disodium salt has the advantages of fast reaction rate, short reaction time, high product purity and high yield.
Description
Technical field
The present invention relates to a kind of production method of cytidylic acid disodium salt, belong to food and medicine technical field.
Background technology
Cytidylic acid disodium salt is comparatively extensive in field application such as food and medicines, but current highly purified cytidylic acid disodium salt is difficult to production, and product yield is lower, and production cost is high.
Summary of the invention
The production method that the object of this invention is to provide the cytidylic acid disodium salt of a kind of high purity, high yield.
The technical solution used in the present invention is:
The production method of cytidylic acid disodium salt, the steps include:
A, in reaction vessel, add respectively cytidine, triethyl phosphate and pyridine, mix rear adjusting temperature of reaction for-15-5 ℃, under this temperature condition, slowly add a certain amount of phosphorus oxychloride, add rear continuation stirring reaction 10-30h;
B, sampling analysis HPLC, when transformation efficiency >=99%, add the icy salt solution of 10-15% to be hydrolyzed, and hydrolysis temperature is controlled as 0-5 ℃, hydrolysis time 10-20h;
After c, hydrolysis finish, stratification, removes organic phase, obtains water layer stand-by;
D, 30% sodium hydroxide for water layer is regulated to PH7.0-8.0, then drip 95% alcohol of liquor capacity doubling dose, crystallization, filters to obtain crude product.
E, by dissolving crude product, add activated carbon decolorizing, continue to drip 95% alcohol crystallization of liquor capacity doubling dose, filtration, rinsing, dry to obtain finished product.
The weight ratio of described cytidine and triethyl phosphate, pyridine, phosphorus oxychloride is 1:10-20:1-5:2-5.
The weight ratio of described cytidine and icy salt solution is 1:4-10.
The present invention adopts pyridine, and the effect that it not only has catalyzer is more cut at the end reaction, and reaction conversion ratio can reach more than 99%, greatly improves product yield, and its HCl producing in can also absorption reaction process.
The present invention adopts icy salt solution to be hydrolyzed, and replaces traditional trichloromethane class haloalkane reagent, reduces secondary pollution, makes whole process economics environmental protection, simplifies working process.
The present invention adopts the mode crystallization control process that drips alcohol, and secondary crystal purifying improves product purity.
Advantage of the present invention is: speed of reaction is fast, the reaction times is short, product purity is high, yield is high.
Embodiment
Embodiment 1
First the pyridine that adds respectively the cytidine of 1 weight part, the triethyl phosphate of 10 weight parts and 1 weight part in reaction vessel, mix rear adjusting temperature of reaction and be-15 ℃, under this temperature condition, slowly add the phosphorus oxychloride of 2 weight parts, add rear continuation stirring reaction 10h; Then sampling analysis HPLC, when transformation efficiency >=99%, adds the icy salt solution of 4 weight parts 10% to be hydrolyzed, and it is 0 ℃ that hydrolysis temperature is controlled, hydrolysis time 10h; After hydrolysis finishes, stratification, removes organic phase, obtains water layer stand-by; Water layer is regulated to PH to 7.0 with 30% sodium hydroxide, then drip 95% alcohol of liquor capacity doubling dose, crystallization, filter to obtain crude product, by dissolving crude product, add activated carbon decolorizing, continue to drip 95% alcohol crystallization of liquor capacity doubling dose, filtration, rinsing, dry to obtain product, molar product yield can reach more than 95%, and traditional production technique can only reach 85% left and right.
Embodiment 2
First the pyridine that adds respectively the cytidine of 1 weight part, the triethyl phosphate of 20 weight parts and 5 weight parts in reaction vessel, mixing rear adjusting temperature of reaction is 5 ℃, under this temperature condition, slowly add the phosphorus oxychloride of 5 weight parts, add rear continuation stirring reaction 30h; Then sampling analysis HPLC, when transformation efficiency >=99%, adds the icy salt solution of 10 weight parts 15% to be hydrolyzed, and it is 5 ℃ that hydrolysis temperature is controlled, hydrolysis time 20h; After hydrolysis finishes, stratification, removes organic phase, obtains water layer stand-by; Water layer is regulated to PH to 8.0 with 30% sodium hydroxide, then drip 95% alcohol of liquor capacity doubling dose, crystallization, filter to obtain crude product, by dissolving crude product, add activated carbon decolorizing, continue to drip 95% alcohol crystallization of liquor capacity doubling dose, filtration, rinsing, dry to obtain product, molar product yield can reach more than 95%, and product liquid content reaches more than 99.9%.
Embodiment 3
First the pyridine that adds respectively the cytidine of 1 weight part, the triethyl phosphate of 15 weight parts and 3 weight parts in reaction vessel, mix rear adjusting temperature of reaction and be-10 ℃, under this temperature condition, slowly add the phosphorus oxychloride of 3 weight parts, add rear continuation stirring reaction 20h; Then sampling analysis HPLC, when transformation efficiency >=99%, adds the icy salt solution of 6 weight parts 13% to be hydrolyzed, and it is 3 ℃ that hydrolysis temperature is controlled, hydrolysis time 15h; After hydrolysis finishes, stratification, removes organic phase, obtains water layer stand-by; Water layer is regulated to PH to 7.5 with 30% sodium hydroxide, then drip 95% alcohol of liquor capacity doubling dose, crystallization, filter to obtain crude product, by dissolving crude product, add activated carbon decolorizing, continue to drip 95% alcohol crystallization of liquor capacity doubling dose, filtration, rinsing, dry to obtain product, molar product yield can reach more than 95%, and product liquid content reaches more than 99.9%.
Claims (3)
1. the production method of cytidylic acid disodium salt, is characterized in that: the steps include:
A, in reaction vessel, add respectively cytidine, triethyl phosphate and pyridine, mix rear adjusting temperature of reaction for-15-5 ℃, under this temperature condition, slowly add a certain amount of phosphorus oxychloride, add rear continuation stirring reaction 10-30h;
B, sampling analysis HPLC, when transformation efficiency >=99%, add the icy salt solution of 10-15% to be hydrolyzed, and hydrolysis temperature is controlled as 0-5 ℃, hydrolysis time 10-20h;
After c, hydrolysis finish, stratification, removes organic phase, obtains water layer stand-by;
D, 30% sodium hydroxide for water layer is regulated to PH7.0-8.0, then drip 95% alcohol of water layer amount two volumes, crystallization, filters to obtain crude product;
E, by dissolving crude product, add activated carbon decolorizing, continue to drip 95% alcohol crystallization of liquor capacity doubling dose, filtration, rinsing, dry to obtain finished product.
2. the production method of cytidylic acid disodium salt according to claim 1, is characterized in that: the weight ratio of described cytidine and triethyl phosphate, pyridine, phosphorus oxychloride is 1:10-20:1-5:2-5.
3. the production method of cytidylic acid disodium salt according to claim 1, is characterized in that: the weight ratio of described cytidine and icy salt solution is 1:4-10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410333718.2A CN104163842A (en) | 2014-07-15 | 2014-07-15 | Method for producing cytidine monophosphate disodium salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410333718.2A CN104163842A (en) | 2014-07-15 | 2014-07-15 | Method for producing cytidine monophosphate disodium salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104163842A true CN104163842A (en) | 2014-11-26 |
Family
ID=51907841
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410333718.2A Pending CN104163842A (en) | 2014-07-15 | 2014-07-15 | Method for producing cytidine monophosphate disodium salt |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104163842A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS468854Y1 (en) * | 1968-02-13 | 1971-03-29 | ||
| JPH068854A (en) * | 1992-06-29 | 1994-01-18 | Mazda Motor Corp | Side part car body structure |
| CN1539846A (en) * | 2003-10-29 | 2004-10-27 | 徐昌洪 | Technique for preparing 5'nucleotide bi-sodium |
| CN102952167A (en) * | 2012-11-29 | 2013-03-06 | 南京工业大学 | Cytidine 5' -disodium phosphate elution crystallization method |
-
2014
- 2014-07-15 CN CN201410333718.2A patent/CN104163842A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS468854Y1 (en) * | 1968-02-13 | 1971-03-29 | ||
| JPH068854A (en) * | 1992-06-29 | 1994-01-18 | Mazda Motor Corp | Side part car body structure |
| CN1539846A (en) * | 2003-10-29 | 2004-10-27 | 徐昌洪 | Technique for preparing 5'nucleotide bi-sodium |
| CN102952167A (en) * | 2012-11-29 | 2013-03-06 | 南京工业大学 | Cytidine 5' -disodium phosphate elution crystallization method |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101781346B (en) | Method for separating uridylic acid from biocatalytic conversion solution | |
| EP2743259B1 (en) | Method for purifying (s)-oxiracetam | |
| CN105017360B (en) | A kind of preparation method of vitamin B12 | |
| CN103772432B (en) | A kind of production method of benfotiamine | |
| CN105859802A (en) | Sucralose crystallization and purification method | |
| CN102643238B (en) | A kind of preparation of new ornidazole optical antipode and purification process thereof | |
| CN106146560A (en) | A kind of process for purification of high-purity phosphoric acid specially azoles amine | |
| CN104163842A (en) | Method for producing cytidine monophosphate disodium salt | |
| CN1243009C (en) | Technique for preparing 5'nucleotide bi-sodium | |
| CN105439175A (en) | Method for directly producing potassium nitrate | |
| US20140303383A1 (en) | Method for purifying levo-oxiracetam | |
| CN103435651A (en) | Synthesis method and process of riboflavin sodium phosphate | |
| CN106335886A (en) | Method for recycling phosphorous acid from dimethyl ester rectification residual liquid | |
| CN102502570B (en) | Production method of medical sodium metavanadate | |
| CN102690222A (en) | Preparation method of (R,S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide | |
| CN103030599B (en) | Gefitinib intermediate and preparation method thereof | |
| CN102168123A (en) | Novel method for preparing deoxyribonucleoside triphosphate (dNMP) | |
| CN101993466A (en) | Method for preparing 5'-disodium guanylate | |
| CN105153232A (en) | Preparation method of minodronic acid for treating osteoporosis | |
| CN104151383A (en) | Method for producing disodium uridylate | |
| CN102154399A (en) | Production process flow of fructose diphosphate sodium | |
| CN104163843A (en) | Adenosine 5'-monophosphoric acid disodium salt production method | |
| CN102250018B (en) | Preparation method of 2-ehtyoxyl-4,6-dyhydroxypyrimidine | |
| CN104447273B (en) | A kind of recovery method of Zopiclone resolving agent D-(+)-oxysuccinic acid | |
| CN104262164A (en) | Preparation method of dinitolmide intermediate 3,5-dinitro-ortho-methyl benzoic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20141126 |