CN102180925B - Method for treating emulsion layer in process for synthesizing 5-methyluridine - Google Patents
Method for treating emulsion layer in process for synthesizing 5-methyluridine Download PDFInfo
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- CN102180925B CN102180925B CN 201110069670 CN201110069670A CN102180925B CN 102180925 B CN102180925 B CN 102180925B CN 201110069670 CN201110069670 CN 201110069670 CN 201110069670 A CN201110069670 A CN 201110069670A CN 102180925 B CN102180925 B CN 102180925B
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Abstract
The invention discloses a method for treating an emulsion layer in a process for synthesizing 5-methyluridine. By the method, the process of treating the colloidal emulsion layer produced in the conventional process for producing the 5-methyluridine is optimized, and hydrolyzate 5-methyl-2',3',5'-O-triacetyl-beta-D-ribose uridine in the emulsion layer is directly converted into a target product, namely the 5-methyluridine. The conventional complicated process is saved, anhydrous magnesium sulfate and diatomite are not required to be used, the product is easier to separate, and the solvent-containing emulsion layer is not required to be directly filtered or centrifuged, so that the production environment is clean and safe, and labor intensity is reduced; and the method improves process yield, saves production cost and is suitable for industrial production.
Description
Technical field
The present invention relates to the chemicals synthesis technical field, be specifically related to the treatment process of emulsion layer in the 5-methyl-uridin synthesis technique.
Background technology
5-methyl-uridin (5-methyl-uridin) molecular formula is C
10h
14n
2o
6, be the important intermediate of nucleosides and deoxynucleoside medicine.Nucleosides and deoxynucleoside series derivates have various bioactivators, can be directly or indirectly as drug use, at the multiple major disease important role for the treatment of.5-methyl-uridin is the intermediate of synthesizing anti-AIDS pharmaceutical AZT (AZT), D4T (D4T).Current global AIDS patient increases increasingly, and therefore greatly developing the 5-methyl-uridin pharmaceutical intermediate has market outlook preferably.Traditional 5-methyl-uridin production technique be adopt 1,2,3,5-Tetra-O-Acetyl-D-Ribose and under the katalysis of thymus pyrimidine at anhydrous stannic chloride of silanization protection the condensation hydrolysis generate 5-methyl-2 '; 3 '; 5 '-O-triacetyl-β-D-ribose uridine, then make through alcoholysis.The method technical maturity is the production technique generally adopted at present.But, in this building-up process because a large amount of anhydrous stannic chlorides is used in condensation reaction, so, in the hydrolysis extraction sepn process, the catalyzer tin tetrachloride can be hydrolyzed equally and produce stannic acid (SnO
2h
2o), the stannic acid of colloidal state very easily the particulate matter in absorption system as the solvent of unreacted thymus pyrimidine and system and the product in solvent and form the emulsion layer of gluey state, in industrialized production, the amount of the emulsion layer of this gluey state is very large, not only reduce process recovery ratio, and the discharge of stannic acid and solvent has serious pollution to environment, traditional treatment process is to adopt anhydrous magnesium sulfate to add diatomite to collect solvent through vacuum filtration or centrifuging emulsion layer, the recovery product, so just produced the more substantial useless solid thing containing above-mentioned solvent and stannic acid, cause operating environment seriously polluted, production cost is high and useless solid thing is difficult.
The 5-methyl-uridin building-up process is as follows:
In above-mentioned reaction process; at first; the thymus pyrimidine (III) (two trimethylsilyl thymus pyrimidine) of 1,2,3,5-Tetra-O-Acetyl-D-Ribose (II) and silanization carries out condensation and obtains condensation product (IV) under the effect of catalyzer anhydrous stannic chloride; then; condensation product (IV) through hydrolysis remove silylation obtain hydrolysate (V) 5-methyl-2 '; 3 '; 5 '-O-triacetyl-β-D-ribose uridine and stannic acid (VI); then, this hydrolysate (V) obtains target product (I) 5-methyl-uridin after alcoholysis reagent effect deacetylation.
Summary of the invention
The object of the present invention is to provide the treatment process of emulsion layer in a kind of 5-methyl-uridin synthesis technique.
For achieving the above object, the inventive method has been optimized the treating processes of the gluey state emulsion layer produced in traditional 5-methyl-uridin production technique.Particularly, treatment process of the present invention comprises the steps:
1) the gluey state emulsion layer vacuum concentration produced in the 5-methyl-uridin synthesis technique is extremely dry, reclaim organic solvent wherein;
2) add the alcoholysis reagent stirring and dissolving of 5～15 times of dry emulsion layer volumes above-mentioned in being concentrated into dry emulsion layer, then drip alcoholysis catalysts and regulate this mixture system pH value to 8～11, control 5～40 ℃ of temperature, stir, alcoholysis reaction 5～20h;
3) the mixture vacuum concentration after above-mentioned alcoholysis is reclaimed to alcoholysis reagent, then the mixture pH value of this vacuum concentration is adjusted to 2～4, control 0～10 ℃ of temperature, crystallization 5～10h;
4) above-mentioned solidliquid mixture is filtered to obtain to the 5-methyl-uridin crude product, by this crude product recrystallization in the mixed solution that methyl alcohol and water volume ratio are 1: 3～5, filter, the vacuum-drying of gained solid matter is obtained to the white crystalline powder of 5-methyl-uridin, by after the merging containing the filtrate of stannic acid of above-mentioned twice filtration for reclaiming tin wherein.
Further, step 1) temperature of described gluey state emulsion layer vacuum concentration is 45～80 ℃.
Further, step 2) dripping alcoholysis catalysts, to regulate this mixture system pH value be 10～11, controls 25～30 ℃ of temperature, stirring, alcoholysis reaction 10～15h.
Further, step 2) described alcoholysis reagent can be methyl alcohol, ethanol, propyl alcohol, Virahol or their combination.
Further, step 2) described alcoholysis catalysts can be ammonia, sodium methylate, sodium carbonate, sodium bicarbonate or their combination.
Further, step 3), the mixture pH value of this vacuum concentration is adjusted to 2～3,2～5 ℃ of control temperature.
Further, use 5～15% dilute hydrochloric acid adjusting pH value step 3).
Further, step 4) described in, the step of 5-methyl-uridin crude product recrystallization in methyl alcohol and water mixed liquid is, keeps 40～70 ℃ of system temperatures, filters the undissolved impurity of elimination (unreacted thymus pyrimidine etc.), and filtrate is cooled to 2～5 ℃ of crystallizations.
The inventive method has following advantage:
With existing traditional technology, compare, the present invention can by the hydrolysate in emulsion layer (V) 5-methyl-2 ', 3 ', 5 '-O-triacetyl-β-D-ribose uridine is converted into target product (I) 5-methyl-uridin; Because as long as the 5-methyl-uridin in water is controlled pH value and the Tc of mixture system well, just can by 5-methyl-uridin, Crystallization Separation be out effectively, the present invention has overcome the cumbersome procedure of former technique, without using anhydrous magnesium sulfate and diatomite and more easily separating, without to directly filtering containing the emulsion layer of solvent (ethylene dichloride, methylene dichloride, toluene etc.) or centrifugal, and can not produce a large amount of useless solid things, make the production environment clean and safe, alleviated labour intensity; The present invention has improved process recovery ratio, has saved production cost, is suitable for suitability for industrialized production.
Embodiment
Following examples are used for the present invention is described, but are not used for limiting the scope of the invention.
Synthesizing of embodiment 1 5-methyl-uridin
With agitator, thermometer, add 1,2,3,5-Tetra-O-Acetyl-D-Ribose 318g (1mol) in the 2000ml there-necked flask of dropping funnel, dichloromethane solvent 1000ml, be stirred to dissolving, add again the thymus pyrimidine 138.6g (1.1mol through the protection of (hexamethyldisilane amine) silanization, in thymus pyrimidine), temperature is controlled 10～15 ℃ and is added dropwise to catalyzer anhydrous stannic chloride 180g, then naturally be warming up to 25～30 ℃, stir condensation reaction 10h, TLC detection reaction terminal, obtain condensation product, add 1～3 times of process water to stir hydrolysis, then static layering, collect its middle layer emulsion layer (a), the organic phase of lower floor turns next step operation, the upper strata water is that stanniferous sour water can reclaim tin.
Then, organic phase again with saturated soda water extraction once, its middle layer emulsion layer (b) is collected in layering, and the organic phase of lower floor turns next step operation, and the emulsion layer (a) and rear being total to of emulsion layer (b) that merge above-mentioned layering collection to obtain gluey state emulsion layer 60g.
The processing of embodiment 2 emulsion layers
With agitator, thermometer, add the emulsion layer 120g by embodiment 1 operation gained in the 500ml there-necked flask of dropping funnel, be placed in thermostat water bath control temperature 60 C vacuum concentration and reclaim wherein all dichloromethane solvents to doing, add alcoholysis reagent methyl alcohol 120ml stirring and dissolving in emulsion layer after concentrating to this again, the pH value that drips the ammoniacal liquor adjusting said mixture system of alcoholysis catalysts 20% is 11, control 25 ℃ of temperature, stir, alcoholysis reaction 15h, make 5-methyl-2 in this mixture system ', 3 ', 5 '-generate 5-methyl-uridin soluble in water after O-triacetyl-β-D-ribose uridine deacetylation, TLC (thin-layer chromatography) detection reaction terminal.
Then, above-mentioned there-necked flask is placed in to thermostat water bath again and controls temperature 45 C vacuum concentration recovery alcoholysis reagent methanol solvate wherein, to adding 5% dilute hydrochloric acid to regulate this mixture system pH value in the mixture after concentrated, be 3 again, control 5 ℃ of temperature, crystallization 8h, filter to obtain the 5-methyl-uridin crude product by above-mentioned solidliquid mixture.Reclaim tin together with after the stanniferous filtrate of filtering can merge mutually with the stanniferous sour water in embodiment 1.
In the 500ml there-necked flask with agitator, thermometer, by above-mentioned dissolving crude product in the mixed solution that methyl alcohol and water volume ratio are 1: 4, be placed in again thermostat water bath and keep the system temperature 60 C, the undissolved impurity of vacuum filtration elimination (unreacted thymus pyrimidine etc.), filtrate is cooled to 4 ℃ of crystallizations, the gained solid matter is placed in to the white crystalline powder 6.2g that 80 ℃ of vacuum-drying 20h of vacuum drying oven obtain 5-methyl-uridin, after testing 184 ℃ of its fusing points, content (HPLC) >=99.0%, heavy metal≤10PPM.Can make the total recovery of 5-methyl-uridin production technique improve approximately 1.5% (yield calculates in thymus pyrimidine, is equivalent to every crowd of nearly 3.1g of volume increase in embodiment 1) than traditional technology.
The processing of embodiment 3 emulsion layers
With agitator, thermometer, add the emulsion layer 120g by embodiment 1 operation gained in the 500ml there-necked flask of dropping funnel, be placed in 80 ℃ of vacuum concentration of thermostat water bath control temperature and reclaim wherein all dichloromethane solvents to doing, add alcoholysis reagent propyl alcohol 100ml stirring and dissolving in emulsion layer after concentrating to this again, the pH value that the sodium methoxide solution of dropping 15% is regulated the said mixture system is 9, control 15 ℃ of temperature, stir, alcoholysis reaction 20h, make 5-methyl-2 in this mixture system ', 3 ', 5 '-generate 5-methyl-uridin soluble in water after O-triacetyl-β-D-ribose uridine deacetylation, TLC (thin-layer chromatography) detection reaction terminal.
Then, above-mentioned there-necked flask is placed in to thermostat water bath again and controls temperature 60 C vacuum concentration recovery alcoholysis reagent propyl alcohol solvent wherein, to adding 15% dilute hydrochloric acid to regulate this mixture system pH value in the mixture after concentrated, be 2 again, control 0 ℃ of temperature, crystallization 5h, filter to obtain the 5-methyl-uridin crude product by above-mentioned solidliquid mixture.Reclaim tin together with after the stanniferous filtrate of filtering can merge mutually with the stanniferous sour water in embodiment 1.
In the 500ml there-necked flask with agitator, thermometer, by above-mentioned dissolving crude product in the mixed solution that methyl alcohol and water volume ratio are 1: 3, be placed in again thermostat water bath and keep the system temperature 70 C, the undissolved impurity of vacuum filtration elimination (unreacted thymus pyrimidine etc.), filtrate is cooled to 2 ℃ of crystallizations, the gained solid matter is placed in to the white crystalline powder 5.5g that 80 ℃ of vacuum-drying 15h of vacuum drying oven obtain 5-methyl-uridin, after testing 182 ℃ of its fusing points, content (HPLC) >=99.0%, heavy metal≤10PPM.
The processing of embodiment 4 emulsion layers
With agitator, thermometer, add the emulsion layer 120g by embodiment 1 operation gained in the 500ml there-necked flask of dropping funnel, be placed in thermostat water bath control temperature 45 C vacuum concentration and reclaim wherein all dichloromethane solvents to doing, add alcoholysis reagent alcohol 160ml stirring and dissolving in emulsion layer after concentrating to this again, the pH value that the sodium carbonate solution of dropping 10% is regulated the said mixture system is 10, control 40 ℃ of temperature, stir, alcoholysis reaction 5h, make 5-methyl-2 in this mixture system ', 3 ', 5 '-generate 5-methyl-uridin soluble in water after O-triacetyl-β-D-ribose uridine deacetylation, TLC (thin-layer chromatography) detection reaction terminal.
Then, above-mentioned there-necked flask is placed in to thermostat water bath again and controls temperature 60 C vacuum concentration recovery alcoholysis reagent alcohol solvent wherein, to adding 10% dilute hydrochloric acid to regulate this mixture system pH value in the mixture after concentrated, be 4 again, control 10 ℃ of temperature, crystallization 10h, filter to obtain the 5-methyl-uridin crude product by above-mentioned solidliquid mixture.Reclaim tin together with after the stanniferous filtrate of filtering can merge mutually with the stanniferous sour water in embodiment 1.
In the 500ml there-necked flask with agitator, thermometer, by above-mentioned dissolving crude product in the mixed solution that methyl alcohol and water volume ratio are 1: 5, be placed in again thermostat water bath and keep the system temperature 50 C, the undissolved impurity of vacuum filtration elimination (unreacted thymus pyrimidine etc.), filtrate is cooled to 5 ℃ of crystallizations, the gained solid matter is placed in to the white crystalline powder 5.8g that 80 ℃ of vacuum-drying 10h of vacuum drying oven obtain 5-methyl-uridin, after testing 186 ℃ of its fusing points, content (HPLC) >=99.0%, heavy metal≤10PPM.
Although the present invention is described in detail above to have used general explanation and specific embodiment, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements, all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (7)
1.5-in the methyluridine synthesis technique, the treatment process of emulsion layer, is characterized in that, comprises the steps:
1) the gluey state emulsion layer vacuum concentration produced in the 5-methyl-uridin synthesis technique is extremely dry, reclaim organic solvent wherein;
2) add the alcoholysis reagent stirring and dissolving of 5 ~ 15 times of dry emulsion layer volumes above-mentioned in being concentrated into dry emulsion layer, then drip alcoholysis catalysts and regulate this mixture system pH value to 8 ~ 11, control 5 ~ 40 ℃ of temperature, stir, alcoholysis reaction 5 ~ 20h;
3) the mixture vacuum concentration after above-mentioned alcoholysis is reclaimed to alcoholysis reagent, then the mixture pH value of this vacuum concentration is adjusted to 2 ~ 4, control 0 ~ 10 ℃ of temperature, crystallization 5 ~ 10h;
4) above-mentioned solidliquid mixture is filtered to obtain to the 5-methyl-uridin crude product, by this crude product recrystallization in the mixed solution that methyl alcohol and water volume ratio are 1 ︰ 3 ~ 5, filter, the vacuum-drying of gained solid matter is obtained to the white crystalline powder of 5-methyl-uridin, by after the merging containing the filtrate of stannic acid of above-mentioned twice filtration for reclaiming tin wherein;
Wherein, step 2) described alcoholysis catalysts is ammonia, sodium methylate, sodium carbonate, sodium bicarbonate or their combination.
2. treatment process according to claim 1, is characterized in that step 1) temperature of described gluey state emulsion layer vacuum concentration is 45 ~ 80 ℃.
3. treatment process according to claim 1, is characterized in that step 2) drip alcoholysis catalysts and regulate this mixture system pH value to 10 ~ 11, control 25 ~ 30 ℃ of temperature, stirring, alcoholysis reaction 10 ~ 15h.
4. treatment process according to claim 1, is characterized in that step 2) described alcoholysis reagent is methyl alcohol, ethanol, propyl alcohol or their combination.
5. treatment process according to claim 1, is characterized in that step 3) in the mixture pH value of this vacuum concentration is adjusted to 2 ~ 3, control 2 ~ 5 ℃ of temperature.
6. treatment process according to claim 1 or 5, is characterized in that step 3) in use 5 ~ 15% dilute hydrochloric acid to regulate the pH value.
7. treatment process according to claim 1, it is characterized in that step 4) described in the step of 5-methyl-uridin crude product recrystallization in methyl alcohol and water mixed liquid be to keep 40 ~ 70 ℃ of system temperatures, filter the undissolved impurity of elimination, filtrate is cooled to 2 ~ 5 ℃ of crystallizations.
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| DE102012203881A1 (en) | 2012-03-13 | 2013-09-19 | Wacker Chemie Ag | Use of inorganic materials for the production of composites |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4914233A (en) * | 1988-03-01 | 1990-04-03 | Ethyl Corporation | Synthesis of beta-thymidine |
| CN1112123A (en) * | 1993-11-15 | 1995-11-22 | 布里斯托尔-迈尔斯斯奎布公司 | 5-methyluridine process for large-scale preparation of 2',3'-didehydro-3'-deoxythymidine (d4T) |
| CN1216766A (en) * | 1998-10-06 | 1999-05-19 | 中国人民解放军第二军医大学 | Method for preparing beta-thymidine |
| CN1634959A (en) * | 2004-10-28 | 2005-07-06 | 浙江沙星医药化工有限公司 | Industrial process for preparing beta-thymidine |
-
2011
- 2011-03-22 CN CN 201110069670 patent/CN102180925B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4914233A (en) * | 1988-03-01 | 1990-04-03 | Ethyl Corporation | Synthesis of beta-thymidine |
| CN1112123A (en) * | 1993-11-15 | 1995-11-22 | 布里斯托尔-迈尔斯斯奎布公司 | 5-methyluridine process for large-scale preparation of 2',3'-didehydro-3'-deoxythymidine (d4T) |
| CN1216766A (en) * | 1998-10-06 | 1999-05-19 | 中国人民解放军第二军医大学 | Method for preparing beta-thymidine |
| CN1634959A (en) * | 2004-10-28 | 2005-07-06 | 浙江沙星医药化工有限公司 | Industrial process for preparing beta-thymidine |
Non-Patent Citations (2)
| Title |
|---|
| Nobuaki Hori，等.Production of 5-methyluridine by immobilized thermostable purine nucleoside phosphorylase and pyrimidine nucleoside phosphorylase from bacillus stearothermophilus JTS 859.《Journal of biotechnology》.1991,第17卷(第2期),121-131. * |
| 靳立人,等.司他夫定的合成.《厦门大学学报(自然科学版)》.2002,第41卷(第2期),207-210. * |
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