CN102212096A - Method for preparing 5'-cytidylic acid from composite solvent and bind acid agent - Google Patents
Method for preparing 5'-cytidylic acid from composite solvent and bind acid agent Download PDFInfo
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- CN102212096A CN102212096A CN2011100877857A CN201110087785A CN102212096A CN 102212096 A CN102212096 A CN 102212096A CN 2011100877857 A CN2011100877857 A CN 2011100877857A CN 201110087785 A CN201110087785 A CN 201110087785A CN 102212096 A CN102212096 A CN 102212096A
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- acid
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- cytidylic
- double solvents
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Abstract
The invention relates to a method for preparing 5'-cytidylic acid from a composite solvent and a bind acid agent. The method comprises the following detailed steps of: (1) preparing the composite solvent which contains a sulfoxide solvent and alkyl three-low level phosphate; (2) adding a phosphorylation agent, namely at the temperature of -2 to 2 DEG C, dropwise adding the phosphorylation agent into the composite solvent to perform an intervention reaction, wherein the phosphorylation agent and a certain amount of water in the composite solvent react to generate a part of hydrate; (3) adding cytidine, namely gradually adding the cytidine at the temperature of 0 to 5 DEG C to perform reaction for 3 to 5 hours; and (4) adding the bind acid agent, namely adding the phosphorylation agent and the bind acid agent in a proportion of 100:0.8-100:0.6. The yield of the product obtained by the method is over 90 percent; the ultraviolet content of the generated 5'-cytidylic acid is over 98 percent; and the high-performance liquid chromatography (HPLC) content of the generated 5'-cytidylic acid is over 98 percent.
Description
Technical field
The present invention relates to make 5 '-method of cytidylic acid, especially a kind of utilize double solvents and acid binding agent make 5 '-method of cytidylic acid.
Background technology
Cytidylic acid, English name: cytidylic acid is the phosphoric acid ester of cytidine.Look phosphoric acid connecting portion difference, have cytidine 2 '-phosphoric acid (2 '-cytidylic acid), cytidine 3 '-phosphoric acid (3 '-cytidylic acid) and cytidine 5 '-three kinds of phosphoric acid (5 '-cytidylic acid).Intravital cytidylic acid is generally 5 '-cytidylic acid.Make at present 5 '-method of cytidylic acid adopts microorganism synthetic method usually, and though had certain scale, productive rate only is about 85%, and the quality instability of product, and ultraviolet content is about 97%, and HPLC content is about 97.5%.
Summary of the invention
The technical problem to be solved in the present invention is: overcome the deficiencies in the prior art, provide a kind of utilize double solvents and acid binding agent make 5 '-method of cytidylic acid, improve the productive rate of product, constant product quality.
The technical solution adopted for the present invention to solve the technical problems is: a kind of utilize double solvents and acid binding agent make 5 '-method of cytidylic acid, have following steps: (1) preparation double solvents: described double solvents contains sulfoxide kind solvent and tricresyl phosphate lower alkyl esters, and the ratio of described sulfoxide kind solvent and tricresyl phosphate lower alkyl esters is 1: 6～1: 14; (2) add phosphoric acid agent: under-2～2 ℃ temperature condition, phosphoric acid agent is added dropwise to carries out noiseless reaction in the double solvents, a certain amount of water reacts the generating portion hydrate in phosphoric acid agent and the double solvents; (3) add cytidine: under 0～5 ℃ temperature condition, add cytidine gradually and react, 3～5 hours reaction times; (4) add acid binding agent: add acid binding agent according to phosphoric acid agent and 100: 0.8～100: 0.6 ratio of acid binding agent, drip acid binding agent and finish back insulated and stirred 3～5 hours under 0～5 ℃ of temperature condition, entire reaction finishes the back termination reaction, the pH value of reaction solution is transferred to 3～4 obtain 5 '-the cytidylic acid crude product; (5) crystallization obtain 5 '-the cytidylic acid finished product.
Particularly, the ratio of described sulfoxide kind solvent and tricresyl phosphate lower alkyl esters is 1: 1-10.
Particularly, the ratio of described sulfoxide kind solvent and tricresyl phosphate lower alkyl esters is 50g: 500g.
Particularly, described phosphoric acid agent is a trihalophosporus oxide, and the reaction formula of cytidine and trihalophosporus oxide reaction is:
Particularly, described trihalophosporus oxide is phosphoryl chloride or phosphorus oxybromide.
Particularly, the reaction times of adding cytidine is 4 hours.
Particularly, described phosphoric acid agent and acid binding agent ratio are 100: 0.7.
Particularly, described acid binding agent is a triethylamine, drips triethylamine and finishes back insulated and stirred 4 hours under 0～5 ℃ of temperature condition, and entire reaction finishes the back termination reaction, the pH value of reaction solution is transferred to 3.5 obtain 5 '-the cytidylic acid crude product.
The invention has the beneficial effects as follows: when reaction, adopt sulfoxide kind solvent and tricresyl phosphate lower alkyl esters as double solvents, utilized double solvents can improve solubleness or this character of dissolution rate of solute, guarantee in ensuing reaction noiseless, i.e. this reaction has directional property, when specifying in cytidine phosphates 5 of cytidine '-position on import phosphate.When phosphorylation, use be the trihalophosporus oxide that is transformed into the portion water compound, directly do not use trihalophosporus oxide, being transformed into portion water compound trihalophosporus oxide can be to 5 '-cytidylic acid (C
9H
14N
3O
8P) preparation provides higher selectivity and reduces 2 '-phosphoric acid ester or 3 '-phosphoric acid ester and this class production of by-products of bisphosphate.Add a certain amount of acid binding agent after cytidine has been thrown again, accelerate the speed of acylation reaction, prevent the generation of alkyl halide.Adopt product yield that method of the present invention obtains more than 90%, 5 of production '-cytidylic acid ultraviolet content is more than 98%, and HPLC content is more than 98%.
Embodiment
Embodiment one: a kind of utilize double solvents and acid binding agent make 5 '-method of cytidylic acid, have following steps:
(1) preparation double solvents: double solvents contains sulfoxide kind solvent and tricresyl phosphate lower alkyl esters, and the ratio of sulfoxide kind solvent and tricresyl phosphate lower alkyl esters is 50g: 500g.When reaction, adopt sulfoxide kind solvent and tricresyl phosphate lower alkyl esters as double solvents, utilized double solvents can improve solubleness or this character of dissolution rate of solute, guarantee in ensuing reaction noiseless, i.e. this reaction has directional property, when specifying in cytidine phosphates 5 of cytidine '-position on import phosphate.
(2) add phosphoric acid agent: phosphoric acid agent is a trihalophosporus oxide, trihalophosporus oxide is phosphoryl chloride or phosphorus oxybromide, under-2～2 ℃ temperature condition, trihalophosporus oxide is added dropwise to carries out noiseless reaction in the double solvents, a certain amount of water reaction generating portion hydrate in trihalophosporus oxide and the double solvents.
(3) add cytidine: under 0～5 ℃ temperature condition, add cytidine gradually and react, 4 hours reaction times; The reaction formula of cytidine and trihalophosporus oxide reaction is:
When phosphorylation, use be the trihalophosporus oxide that is transformed into the portion water compound, directly do not use trihalophosporus oxide, being transformed into portion water compound trihalophosporus oxide can be to 5 '-cytidylic acid (C
9H
14N
3O
8P) preparation provides higher selectivity and reduces 2 '-phosphoric acid ester or 3 '-phosphoric acid ester and this class production of by-products of bisphosphate.
(4) add acid binding agent: acid binding agent is a triethylamine, add triethylamine according to trihalophosporus oxide and 100: 0.7 ratio of triethylamine, drip triethylamine and finish back insulated and stirred 4 hours under 0～5 ℃ of temperature condition, entire reaction finishes the back termination reaction, the pH value of reaction solution is transferred to 3.5 obtain 5 '-the cytidylic acid crude product.Add a certain amount of acid binding agent after cytidine has been thrown again, accelerate the speed of acylation reaction, prevent the generation of alkyl halide.
(5) crystallization obtain 5 '-the cytidylic acid finished product.
Adopt product yield that method of the present invention obtains more than 90%, 5 of production '-cytidylic acid ultraviolet content is more than 98%, and HPLC content is more than 98%.
Claims (8)
- One kind utilize double solvents and acid binding agent make 5 '-method of cytidylic acid, it is characterized in that: have following steps: (1) preparation double solvents: described double solvents contains sulfoxide kind solvent and tricresyl phosphate lower alkyl esters, and the ratio of described sulfoxide kind solvent and tricresyl phosphate lower alkyl esters is 1: 6～1: 14; (2) add phosphoric acid agent: under-2～2 ℃ temperature condition, phosphoric acid agent is added dropwise to carries out noiseless reaction in the double solvents, a certain amount of water reacts the generating portion hydrate in phosphoric acid agent and the double solvents; (3) add cytidine: under 0～5 ℃ temperature condition, add cytidine gradually and react, 3～5 hours reaction times; (4) add acid binding agent: add acid binding agent according to phosphoric acid agent and 100: 0.8～100: 0.6 ratio of acid binding agent, drip acid binding agent and finish back insulated and stirred 3～5 hours under 0～5 ℃ of temperature condition, entire reaction finishes the back termination reaction, the pH value of reaction solution is transferred to 3～4 obtain 5 '-the cytidylic acid crude product; (5) crystallization obtain 5 '-the cytidylic acid finished product.
- 2. according to claim 1 utilize double solvents and acid binding agent make 5 '-method of cytidylic acid, it is characterized in that: the ratio of described sulfoxide kind solvent and tricresyl phosphate lower alkyl esters is 1: 1-10.
- 3. according to claim 2 utilize double solvents and acid binding agent make 5 '-method of cytidylic acid, it is characterized in that: the ratio of described sulfoxide kind solvent and tricresyl phosphate lower alkyl esters is 50g: 500g.
- 4. according to claim 1 utilize double solvents and acid binding agent make 5 '-method of cytidylic acid, it is characterized in that: described phosphoric acid agent is a trihalophosporus oxide, cytidine with the reaction formula that trihalophosporus oxide reacts is:
- 5. according to claim 4 utilize double solvents and acid binding agent make 5 '-method of cytidylic acid, it is characterized in that: described trihalophosporus oxide is phosphoryl chloride or phosphorus oxybromide.
- 6. according to claim 1 utilize double solvents and acid binding agent make 5 '-method of cytidylic acid, it is characterized in that: the reaction times that adds cytidine is 4 hours.
- 7. according to claim 1 utilize double solvents and acid binding agent make 5 '-method of cytidylic acid, it is characterized in that: described phosphoric acid agent and acid binding agent ratio are 100: 0.7.
- 8. according to claim 1 utilize double solvents and acid binding agent make 5 '-method of cytidylic acid, it is characterized in that: described acid binding agent is a triethylamine, drip triethylamine and finish back insulated and stirred 4 hours under 0～5 ℃ of temperature condition, entire reaction finishes the back termination reaction, the pH value of reaction solution is transferred to 3.5 obtain 5 '-the cytidylic acid crude product.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011100877857A CN102212096A (en) | 2011-04-08 | 2011-04-08 | Method for preparing 5'-cytidylic acid from composite solvent and bind acid agent |
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| CN2011100877857A CN102212096A (en) | 2011-04-08 | 2011-04-08 | Method for preparing 5'-cytidylic acid from composite solvent and bind acid agent |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0553821A1 (en) * | 1992-01-30 | 1993-08-04 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing cytidine diphosphate choline |
| CN1467216A (en) * | 2002-06-05 | 2004-01-14 | ������ѧ��ʽ���� | Method for purifying protected 2'-deoxycytidines |
| CN1616475A (en) * | 2004-09-21 | 2005-05-18 | 苏州工业园区赛康德万马化工有限公司 | Process for preparing cytidine-S'-phosphate |
-
2011
- 2011-04-08 CN CN2011100877857A patent/CN102212096A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0553821A1 (en) * | 1992-01-30 | 1993-08-04 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing cytidine diphosphate choline |
| CN1467216A (en) * | 2002-06-05 | 2004-01-14 | ������ѧ��ʽ���� | Method for purifying protected 2'-deoxycytidines |
| CN1616475A (en) * | 2004-09-21 | 2005-05-18 | 苏州工业园区赛康德万马化工有限公司 | Process for preparing cytidine-S'-phosphate |
Non-Patent Citations (1)
| Title |
|---|
| TOMOMI IKEMOTO,等: "Phosphorylation of Nucleoside with Phosphours Oxychloride in Trialkyl Phosphate", 《CHEM.PHARM.BUU.》, vol. 43, no. 2, 31 December 1995 (1995-12-31), pages 210 - 215 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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Application publication date: 20111012 |