CN102911229B - 1-Beta-D-ribofuranosyl cytosine preparation method - Google Patents
1-Beta-D-ribofuranosyl cytosine preparation method Download PDFInfo
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Abstract
The invention discloses a 1-Beta-D-ribofuranosyl cytosine chemical preparation method which comprises the following steps: adding an additive to promote double silanization protection of cytosine; performing glycosylation with tetraacetylribose under the catalysis of a high-polymer load Lewis acid catalyst so as to produce an intermediate 2,3,5-III-o-acetyl cytidine; and after the coarse product of the intermediate is deprotected under an alkaline condition, allowing the liquid reactant to be subjected to separation and purification so as to obtain a high-purity 1-Beta-D-ribofuranosyl cytosine. According to the method, during the silanization protection process of cytosine, N, N-dimethyl formamide is added, so as to avoid single protection of cytosine; the high-polymer load Lewis acid catalyst is stable in performance, is efficient, easy to separate from a reaction system, is free from contamination, and can be repeatedly used; and the obtained product has the reduced impurity content, and the technology is simple and feasible. Therefore, the method is more suitable for industrialized production.
Description
Technical field
The invention belongs to technical field of fine chemical synthesis, be specifically related to the chemical preparation process of 1-β-D-RIBOSE base cytosine(Cyt) that a kind of preparation technology is simple, cost is low, yield is high.
Background technology
1-β-D-RIBOSE base cytosine(Cyt) is cytidine (Cytidine), and cytidine is the structure fragment of RNA in human body and animal and plant body, plays in vivo important regulating and controlling effect in physiological and biochemical procedure, has many-sided physiologically active; Meanwhile, cytidine is again multiple antiviral, antitumor and the good intermediate of anti-AIDS drug and the important raw and processed materials of genetically engineered research such as 5-F cytidine, cytidylic acid, Ancitabine, cytidine diphosphate, cytidine triphosphate(CTP), lamivudine, cytosine arabinoside.As shown in the above, 1-β-D-RIBOSE base cytosine(Cyt) is a kind of important medicine intermediate, and the exploitation of its product is conducive to the development of genetically engineered research and pharmaceutical industries.
At present, the method for chemosynthesis 1-β-D-RIBOSE base cytosine(Cyt) is a lot, is mainly that to take cytosine(Cyt) or uridine be starting raw material.Wherein, take the preparation method that cytosine(Cyt) is raw material mainly contains following several:
(1) Chinese patent CN100999540 discloses a kind of cytosine(Cyt) and the glycosylation of 1,2,3,5-Tetra-O-Acetyl-D-Ribose under the catalysis of phosphoric acid phenolic ester compounds of ethanoyl protection; add again basic catalyst; deprotection obtains 1-β-D-RIBOSE base cytosine(Cyt), and reaction formula is as follows:
Solvent-free synthetic route:
There is solvent synthetic route:
(2) cytosine(Cyt) that Chinese patent CN102127136A discloses the protection of a kind of silanization is prepared the method for 1-β-D-RIBOSE base cytosine(Cyt) under alkali metal halide catalysis, and reaction formula is as follows:
(3) Chinese patent CN102633843A discloses the cytosine(Cyt) of a kind of dibenzoyl protection and 1,2,3,5-Tetra-O-Acetyl-D-Ribose carried out condensation under acidity or slant acidity ionic liquid-catalyzed; the method of preparing 1-β-D-RIBOSE base cytosine(Cyt) through saponification deprotection, reaction formula is as follows:
(4) Ji Yafei etc., chemistry world, has proposed the cytosine(Cyt) of ultrasonic auxiliary titanium tetrachloride catalysis benzoylation protection and reacting of 1,2,3,5-Tetra-O-Acetyl-D-Ribose in 2007,48 (1), 59, and reaction formula is as follows:
The synthetic route of 1-β-D-RIBOSE base cytosine(Cyt) is through constantly improving; its a large amount of production is mainly usingd 1,2,3,5-Tetra-O-Acetyl-D-Ribose as ribose donor; under extremely strong with the cytosine(Cyt) of silanization protection intense hydrolysis, corrodibility in expensive, air, to belong to hazardous chemical stannic chloride catalysis, carry out condensation; there is severe reaction conditions; the problems such as the large and raw materials cost height of environmental pollution; and; easily exist silanization to protect incomplete phenomenon; cause reaction system impurity to increase; the problems such as post-processing operation difficulty, are unfavorable for industrial production.
Summary of the invention
For the above-mentioned problems in the prior art, the object of the present invention is to provide a kind of chemical preparation process of 1-β-D-RIBOSE base cytosine(Cyt).It is by adding a kind of additive to promote two silanizations of cytosine(Cyt) to protect; and provide a kind of efficient, stable; easy separated, pollution-free from reaction system, can repeatedly to use lewis acid catalyst; improve the production technique of 1-β-D-RIBOSE base cytosine(Cyt); reduce production costs; improve reaction yield, be applicable to suitability for industrialized production.
The preparation method of described a kind of 1-β-D-RIBOSE base cytosine(Cyt), is characterized in that comprising the following steps: first use additive
n,
n-dimethyl formamide promotes two silanization protections of cytosine(Cyt), obtains two silanization protection intermediates of cytosine(Cyt), and this protection intermediate carries out glycosylation with 1,2,3,5-Tetra-O-Acetyl-D-Ribose and makes intermediate 2,3 under the catalysis of macromolecule loading lewis acid catalyst, 5-tri--
o-acetylcytidine, this intermediate carries out deprotection reaction under alkaline condition, and the reaction solution obtaining makes highly purified 1-β-D-RIBOSE base cytosine(Cyt) through separated, purification, and catalyzer can repeatedly be used after separation.
The preparation method of described a kind of 1-β-D-RIBOSE base cytosine(Cyt), is characterized in that described macromolecule loading lewis acid catalyst is any one in macromolecule loading titanium tetrachloride, macromolecule loading tin tetrachloride, macromolecule loading iron trichloride, macromolecule loading zinc dichloride, macromolecule loading Nickel Chloride, macromolecule loading cupric chloride.
The preparation method of described a kind of 1-β-D-RIBOSE base cytosine(Cyt), is characterized in that described macromolecule loading lewis acid catalyst is macromolecule loading titanium tetrachloride or macromolecule loading tin tetrachloride.
The preparation method of described a kind of 1-β-D-RIBOSE base cytosine(Cyt), it is characterized in that described macromolecule loading lewis acid catalyst can reclaim, the filter residue that recovery method is filtration after reaction is completed is successively with ethanol, water, ether washing, oven dry, and the macromolecule loading lewis acid catalyst of recovery can be reused at least 20 times after reclaiming.
The preparation method of described a kind of 1-β-D-RIBOSE base cytosine(Cyt), is characterized in that the molar ratio of described cytosine(Cyt), hexamethyldisilazane and 1,2,3,5-Tetra-O-Acetyl-D-Ribose is 1:1 ~ 3:0.8 ~ 1.2; The quality of cytosine(Cyt) with
n,
nthe volume ratio of-dimethyl formamide is 1:0.05 ~ 1.5; The mass ratio that feeds intake of cytosine(Cyt) and macromolecule loading lewis acid catalyst is 1:0.1 ~ 2.
Its syntheti c route is shown below:
By adopting above-mentioned technology, compared with prior art, beneficial effect of the present invention is as follows:
1) the present invention is by using additive
n,
n-dimethyl formamide promotes two silanization protections of cytosine(Cyt), reduces the impurity in reaction system, reduces the difficulty of subsequent operations, improves the purity of product;
2) the invention provides a kind of efficient macromolecule loading lewis acid catalyst, catalyst performance stabilised, be easy to separation, pollution-free, can repeatedly use, avoided use expensive, high toxicity catalyzer, reduced cost;
3) preparation technology of the present invention is simple, easy handling, and production cost is low, low in the pollution of the environment, and the product 1-β-D-RIBOSE base cytosine(Cyt) yield obtaining can be up to 87%, 187 ~ 189 ℃ of fusing points, purity more than 99.5%, is applicable to suitability for industrialized production.
concrete embodiment
Below in conjunction with concrete case study on implementation, the present invention is further described.Be construed as; the preparation method of the invention process case is only for the present invention is described, rather than limitation of the present invention, and protection scope of the present invention is not limited in this; under design prerequisite of the present invention, preparation method's of the present invention simple modifications is all belonged to the scope of protection of present invention.
Case study on implementation 1
Intermediate 2,3,5-tri--
othe preparation of-acetylcytidine
Cytosine(Cyt) (111g, 1mol) is suspended in 180ml dry toluene, adds 15ml anhydrous
n,
n-dimethyl formamide, hexamethyldisilazane (218ml, 1mol), be heated to the 3h that refluxes, be cooled to 70 ℃, evaporated under reduced pressure, adds 1,2,3,5-Tetra-O-Acetyl-D-Ribose (286g under room temperature condition, 0.9mol), the anhydrous methylene chloride of macropore polystyrene storng-acid cation exchange resin load titanium tetrachloride (30g) and 1200ml reacts 3h, filtration, filtrate washing (80ml * 3), organic phase anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated into dry, obtains intermediate 2,3,5-tri--
o-acetylcytidine 316g, yield 95.1%.
In above-described embodiment, any one for macromolecule loading lewis acid catalyst in macromolecule loading titanium tetrachloride new or that recycle, macromolecule loading tin tetrachloride, macromolecule loading iron trichloride, macromolecule loading zinc dichloride, macromolecule loading Nickel Chloride, macromolecule loading cupric chloride replaces macropore polystyrene storng-acid cation exchange resin load titanium tetrachloride, all can obtain same technique effect.
Case study on implementation 2
Intermediate 2,3,5-tri--
othe preparation of-acetylcytidine
Cytosine(Cyt) (111g, 1mol) is suspended in 150ml dry toluene, adds 8ml anhydrous
n,
n-dimethyl formamide, hexamethyldisilazane (240ml, 1.1mol), be heated to the 3h that refluxes, be cooled to 80 ℃, evaporated under reduced pressure, adds 1,2,3,5-Tetra-O-Acetyl-D-Ribose (254g under room temperature condition, 0.8mol), the immobilized titanium tetrachloride of macropore polystyrene storng-acid cation exchange resin (50g) and 1200ml anhydrous 1,2-ethylene dichloride reaction 2h, filters, filtrate washing (80ml * 3), organic phase anhydrous sodium sulfate drying, filters, filtrate decompression is concentrated into dry, obtain intermediate 2,3,5-tri--
o-acetylcytidine 283g, yield 95.9%.
Case study on implementation 3
Intermediate 2,3,5-tri--
othe preparation of-acetylcytidine
To in cytosine(Cyt) (111g, 1mol), add 150ml anhydrous
n,
n-dimethyl formamide, hexamethyldisilazane (655ml, 3mol), be heated to the 2h that refluxes, be cooled to 70 ℃, evaporated under reduced pressure, adds 1,2,3,5-Tetra-O-Acetyl-D-Ribose (581g under room temperature condition, 1.2mol), the anhydrous methylene chloride of the immobilized titanium tetrachloride of macropore polystyrene storng-acid cation exchange resin (222g) and 1200ml reacts 2h, filtration, filtrate washing (80ml * 3), organic phase anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated into dry, obtains intermediate 2,3,5-tri--
o-acetylcytidine 351g, yield 95.1%.
Case study on implementation 4
Intermediate 2,3,5-tri--
othe preparation of-acetylcytidine
Cytosine(Cyt) (111g, 1mol) is suspended in 240ml anhydrous acetonitrile, adds 8ml anhydrous
n,
n-dimethyl formamide, hexamethyldisilazane (436ml, 2mol), be heated to the 4h that refluxes, be cooled to 65 ℃, evaporated under reduced pressure, adds 1,2,3,5-Tetra-O-Acetyl-D-Ribose (286g under room temperature condition, 0.9mol), the anhydrous methylene chloride of the immobilized titanium tetrachloride of macropore polystyrene storng-acid cation exchange resin (20g) and 1200ml reacts 3.5h, filtration, filtrate washing (80ml * 3), organic phase anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated into dry, obtains intermediate 2,3,5-tri--
o-acetylcytidine 290g, yield 87.2%.
Case study on implementation 5
Intermediate 2,3,5-tri--
othe preparation of-acetylcytidine
Cytosine(Cyt) (111g, 1mol) is suspended in 180ml dry toluene, adds 15ml anhydrous
n,
n-dimethyl formamide, hexamethyldisilazane (240ml, 1.1mol), be heated to the 3h that refluxes, be cooled to 70 ℃, evaporated under reduced pressure, under room temperature condition, add 1,2,3,5-Tetra-O-Acetyl-D-Ribose (286g, the immobilized titanium tetrachloride of macropore polystyrene storng-acid cation exchange resin (30g) that 0.9mol), the tenth time is reclaimed and the anhydrous methylene chloride of 1200ml react 4h, filtration, filtrate washing (80ml * 3), organic phase anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated into dry, obtains intermediate 2,3,5-tri--
o-acetylcytidine 277g, yield 83.5%.
Case study on implementation 6
Intermediate 2,3,5-tri--
othe preparation of-acetylcytidine
Cytosine(Cyt) (111g, 1mol) is suspended in 180ml dry toluene, adds 20ml anhydrous
n,
n-dimethyl formamide, hexamethyldisilazane (240ml, 1.1mol), be heated to the 2.5h that refluxes, be cooled to 70 ℃, evaporated under reduced pressure, adds 1,2,3,5-Tetra-O-Acetyl-D-Ribose (286g under room temperature condition, 0.9mol), the anhydrous methylene chloride of the immobilized tin tetrachloride of macropore polystyrene storng-acid cation exchange resin (50g) and 1200ml reacts 2.5h, filtration, filtrate washing (80ml * 3), organic phase anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated into dry, obtains intermediate 2,3,5-tri--
o-acetylcytidine 310g, yield 93.3%.
Case study on implementation 7
Intermediate 2,3,5-tri--
othe preparation of-acetylcytidine
Cytosine(Cyt) (111g, 1mol) is suspended in 180ml dry toluene, adds 20ml anhydrous
n,
n-dimethyl formamide, hexamethyldisilazane (240ml, 1.1mol), be heated to the 2.5h that refluxes, be cooled to 70 ℃, evaporated under reduced pressure, under room temperature condition, add 1,2,3,5-Tetra-O-Acetyl-D-Ribose (286g, the immobilized tin tetrachloride of macropore polystyrene storng-acid cation exchange resin (50g) that 0.9mol), the 20 time is reclaimed and the anhydrous methylene chloride of 1200ml react 2.5h, filtration, filtrate washing (80ml * 3), organic phase anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated into dry, obtains intermediate 2,3,5-tri--
o-acetylcytidine 175g, yield 52.5%.
Case study on implementation 8
Intermediate 2,3,5-tri--
othe preparation of-acetylcytidine
Cytosine(Cyt) (111g, 1mol) is suspended in 150ml dry toluene, adds 8ml anhydrous
n,
n-dimethyl formamide, hexamethyldisilazane (240ml, 1.1mol), be heated to the 3h that refluxes, be cooled to 80 ℃, evaporated under reduced pressure, adds 1,2,3,5-Tetra-O-Acetyl-D-Ribose (254g under room temperature condition, 0.8mol), the immobilized titanium tetrachloride of macropore polystyrene storng-acid cation exchange resin (11g) and 1200ml anhydrous 1,2-ethylene dichloride reaction 2h, filters, filtrate washing (80ml * 3), organic phase anhydrous sodium sulfate drying, filters, filtrate decompression is concentrated into dry, obtain intermediate 2,3,5-tri--
o-acetylcytidine 241g, yield 81.5%.
Case study on implementation 9
The preparation of 1-β-D-RIBOSE base cytosine(Cyt)
By 2,3,5-tri--
o-acetylcytidine (185g, 0.5mol) be dissolved in 500ml methyl alcohol, ice-water bath is cooled to below 10 ℃, the sodium hydroxide solution 120ml that adds 2mol/L, stirring at room 4h, the hydrochloric acid that drips 2mol/L regulates PH to neutral, evaporated under reduced pressure, in residuum, add 100ml water and the extraction of 420ml ethyl acetate, ethyl acetate for water layer (60ml * 2) is extracted, merge organic phase anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated into dry, to agitation and dropping 720ml sherwood oil crystallization in residuum, obtain white solid 1-β-D-RIBOSE base cytosine(Cyt) 110g, yield 90.6%, 187 ~ 189 ℃ of fusing points, purity 99.5%.
Case study on implementation 10
The preparation of 1-β-D-RIBOSE base cytosine(Cyt)
By 2,3,5-tri--
o-acetylcytidine (185g, 0.5mol) be dissolved in 500ml methyl alcohol, ice-water bath is cooled to below 5 ℃, add 10g sodium methylate, stirring at room 3h, the hydrochloric acid that drips 2mol/L regulates PH to neutral, evaporated under reduced pressure, in residuum, add 150ml water and 320ml dichloromethane extraction, methylene dichloride for water layer (50ml * 2) extracts, merge organic phase anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated into dry, to agitation and dropping 600ml normal hexane crystallization in residuum, obtain white solid 1-β-D-RIBOSE base cytosine(Cyt) 111g, yield 91.5%, 187 ~ 189 ℃ of fusing points, purity 99.7%.
Claims (4)
1. a preparation method for 1-β-D-RIBOSE base cytosine(Cyt), is characterized in that comprising the following steps: first use additive
n,
n-dimethyl formamide promotes two silanization protections of cytosine(Cyt), obtains two silanization protection intermediates of cytosine(Cyt), and this protection intermediate carries out glycosylation with 1,2,3,5-Tetra-O-Acetyl-D-Ribose and makes intermediate 2,3 under the catalysis of macromolecule loading lewis acid catalyst, 5-tri--
o-acetylcytidine, this intermediate carries out deprotection reaction under alkaline condition, and the reaction solution obtaining makes highly purified 1-β-D-RIBOSE base cytosine(Cyt) through separated, purification, and catalyzer can repeatedly be used after separation; Described macromolecule loading lewis acid catalyst is any one in macromolecule loading titanium tetrachloride, macromolecule loading tin tetrachloride, macromolecule loading iron trichloride, macromolecule loading zinc dichloride, macromolecule loading Nickel Chloride, macromolecule loading cupric chloride; The quality of described cytosine(Cyt) with
n,
nthe volume ratio of-dimethyl formamide is 1:0.05 ~ 1.5; The mass ratio that feeds intake of cytosine(Cyt) and macromolecule loading lewis acid catalyst is 1:0.1 ~ 2.
2. the preparation method of a kind of 1-β-D-RIBOSE base cytosine(Cyt) according to claim 1, is characterized in that described macromolecule loading lewis acid catalyst is macromolecule loading titanium tetrachloride or macromolecule loading tin tetrachloride.
3. the preparation method of a kind of 1-β-D-RIBOSE base cytosine(Cyt) according to claim 1, it is characterized in that described macromolecule loading lewis acid catalyst can reclaim, the filter residue that recovery method is filtration after reaction is completed is successively with ethanol, water, ether washing, oven dry, and the macromolecule loading lewis acid catalyst of recovery can be reused at least 20 times after reclaiming.
4. the preparation method of a kind of 1-β-D-RIBOSE base cytosine(Cyt) according to claim 1, is characterized in that the molar ratio of described cytosine(Cyt), hexamethyldisilazane and 1,2,3,5-Tetra-O-Acetyl-D-Ribose is 1:1 ~ 3:0.8 ~ 1.2.
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| CN102216315A (en) * | 2008-08-08 | 2011-10-12 | 台湾神隆股份有限公司 | Process for making 5-azacytosine nucleosides and their derivatives |
| CN102690311A (en) * | 2012-05-24 | 2012-09-26 | 上虞市华科化工有限公司 | Preparation method for cytidine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102216315A (en) * | 2008-08-08 | 2011-10-12 | 台湾神隆股份有限公司 | Process for making 5-azacytosine nucleosides and their derivatives |
| CN102690311A (en) * | 2012-05-24 | 2012-09-26 | 上虞市华科化工有限公司 | Preparation method for cytidine |
Non-Patent Citations (2)
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| 程先超，刘新泳.《5-氟胞嘧啶核苷的合成》.《中国医药工业杂志》.2005,第36卷(第11期),669、696. * |
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