CN102030715B - Method for synthetizing cytosine - Google Patents
Method for synthetizing cytosine Download PDFInfo
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Abstract
The invention discloses a method for synthetizing cytosine, comprising: adding 3-ethyoxyl acrylonitrile, thiourea, a catalyst and a solvent into a cyclizing agent, and stirring at constant temperature for 5-8 hours; heating to the temperature of 40-70 DEG C; keeping warm and stirring for 9-17 hours; distilling to obtain a solvent at normal pressure; adding a certain quantity of water, heating to the temperature of 95 DEG C, and clarifying; then, cooling to the temperature of 10-20 DEG C; cooling, devitrifying and filtering to obtain a wet product; adding the wet product into water; then, adding 10mol/L of hydrochloric acid, stirring and dropwise adding 28% of hydrogen peroxide; after dropwise adding, keeping warm at the temperature of 80 DEG C for 18-36 hour; cooling to the temperature of 10-20 DEG C; dropwise adding 10mol/L of sodium hydroxide solution until pH reaches 7.5; cooling to the temperature of 5-10 DEG C; and slowly dissolving out a great quantity of solids; pumping for filtering, rinsing, and drying to obtain cytosine, wherein the yield reaches above 88.5%, and HPLC (high performance liquid chromatography) is above 99.36%. The technology is simple and reasonable, has good safety, is convenient in operation and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of method of synthesizing cytimidine.
Background technology
Cytosine(Cyt) is the important intermediate of fine chemistry industry, agricultural chemicals and medicine.It is widely used, and especially at field of medicaments, is mainly used in synthesizing anti-AIDS pharmaceutical, hepatitis B medicine lamivudine, cancer therapy drug gemcitabine, BH-AC and 5-flurocytosine etc.
Gemcitabine also has the property of appeasing curative effect to multiple solid tumor, treatment the elderly late malignant tumour, and sure, the better tolerance of curative effect benefits the patient.Along with the development of medicine industry, and to the deepening continuously of life science genomic medicine research, cytosine(Cyt) has become the focus product that market is paid close attention to.At present, the method for synthesizing cytimidine mainly is functional group's conversion method and Pinner synthesis method, and wherein the single stage method in the Pinner synthesis method is a most widely used compound method on the current industrial.
Functional group's conversion method is with uridylic or 2, and 4-two sulphur pyrimidines are substrate, through process synthesizing cytimidines such as hydrolysis; According to relevant, the research of this method just began from 1903, and synthesis step is lengthy and tedious, productive rate is low but still exist so far; Problems such as environmental pollution is serious fail to realize industriallization.
The Pinner synthesis method is to get cytosine(Cyt) through 5-formyloxy cytosine(Cyt), cytosine(Cyt) vitriol etc. through hydrolysis; Nineteen eighty-three, human 3-ethoxy propylene nitriles and 3 such as Peeters, 3-diethoxy propene dried meat mixture and the urea single stage method that direct cyclization makes cytosine(Cyt) in the t-butanol solution of potassium tert.-butoxide also is a kind of of Pinner method.
The technology of preparation patent (CN101597264) the report synthesizing cytimidine of the method for a kind of synthesizing cytimidine of Shanghai Puredu Bio-Tech Co., Ltd. application is to be starting raw material with 3-ethoxy propylene nitrile, urea; Toluene is solvent; Sodium tert-butoxide is done catalyst reaction, does recrystallization with acetate then and obtains product.This method shortcoming is that the three wastes are high, yield is low, reaction time is long, cost is high.
Chinese patent (CN1594287) report acetonitrile and manthanoate are in the metal alkoxide effect, and the 3-hydroxyl vinyl cyanide metal-salt that under certain condition, is condensed into, the solution of this material with the urea cyclization, prepare cytosine(Cyt) after reacting with the hydrochloric acid alcoholic solution.This method has used toxic acetonitrile to do reaction raw materials, uses 1～5 pressure to be condition, adopts band press operation risk level higher, and reaction time is longer.
Summary of the invention
To the problems referred to above that prior art exists, the objective of the invention is to design provides that a kind of synthesis technique advantages of simple, transformation efficiency height, convenient post-treatment, production cost are low, the technical scheme of the novel method of the synthesizing cytimidine of environmental protection.
The method of described a kind of synthesizing cytimidine is characterized in that being made up of following steps:
1) of the 3 - ethoxy acrylonitrile and said thiourea of formula (I), (II) shown below:
（I） （II）；
2) catalyzer and solvent are dropped into reaction kettle, the back that stirs is dropped into suc as formula the 3-ethoxy propylene nitrile shown in (I), is continued to stir down and drop into suc as formula the thiocarbamide shown in (II), stirring at normal temperature reaction 5～8h; Reheat is warming up to 40～70 ℃, and insulated and stirred reaction 9～17h is after normal pressure steams and desolventizes; Adding consumption to reaction kettle is 2～4 times water of 3-ethoxy propylene nitrile weight; Be warming up to 95 ℃ of dissolving clarifications, be cooled to 10～20 ℃ then, cooling crystallization; Cross and filter the wet article of crystallization, described catalyzer is potassium tert.-butoxide, sodium methylate or sodium isopropylate;
3) in another reaction kettle, put into 1～3 times the water as solvent that consumption is a 3-ethoxy propylene nitrile weight, stir the hydrochloric acid that adds a small amount of 10mol/L down, add step 2 again) the wet article of crystallization that obtain; Stir 1h, drip consumption and be 1.5～2.5 times of 3-ethoxy propylene nitrile weight 28% ydrogen peroxide 50, after dripping off; In 80 ℃ of insulation 18～36h, be cooled to 10～20 ℃ after the end, the sodium hydroxide that drips 10mol/L is transferred PH to 7.5; Be cooled to 5～10 ℃, slowly separate out a large amount of solids;
4) reaction solution that step 3) is obtained carries out suction filtration, and washing is dried suc as formula the product shown in (III)
（III）。
The method of described a kind of synthesizing cytimidine is characterized by and is step 2) described input raw material 3-ethoxy propylene nitrile is 1:1.029 with the ratio of thiocarbamide amount of substance.
The method of described a kind of synthesizing cytimidine is characterized in that step 2) described in catalyst levels be 1.75 ~ 2.5 times of 3-ethoxy propylene nitrile weight.
The method of described a kind of synthesizing cytimidine; It is characterized in that step 2) described solvent is a kind of in the trimethyl carbinol, methyl alcohol or the Virahol; Consumption is 5～10 times of 3-ethoxy propylene nitrile weight; The solvent of being selected for use is corresponding with catalyzer, and catalyzer is that potassium tert.-butoxide, solvent correspond to the trimethyl carbinol; Catalyzer is that sodium methylate, solvent correspond to methyl alcohol; Catalyzer is that sodium isopropylate, solvent correspond to Virahol.
The method of described a kind of synthesizing cytimidine is characterized in that the described stirring at normal temperature reaction of step 3) 6～7h, is warming up to 40～70 ℃, insulated and stirred reaction 10～13h.
The method of described a kind of synthesizing cytimidine, the consumption that it is characterized in that the described aqueous solvent of step 3) are 2 times of 3-ethoxy propylene nitrile weight.
The method of described a kind of synthesizing cytimidine, the hydrochloric acid consumption that it is characterized in that adding 10mol/L under the described stirring of step 3) are 1 times of 3-ethoxy propylene nitrile weight.
The method of described a kind of synthesizing cytimidine, the ydrogen peroxide 50 consumption that it is characterized in that the described dropping 28% of step 3) be 3-ethoxy propylene nitrile weight 2 times.
The method of described a kind of synthesizing cytimidine is characterized in that the described 80 ℃ of insulation reaction 20～28h of step 3).
The method of described a kind of synthesizing cytimidine is characterized in that the described 80 ℃ of insulation reaction 24h of step 3).
The synthetic route that the present invention adopts is:
Utilization of the present invention be simple and easy to 3-ethoxy propylene nitrile, thiocarbamide be raw material, under catalyst action, make cytosine(Cyt) through reactions such as cyclization, hydrolysis.The present invention compared with prior art, major advantage is embodied in:
(1) this synthesis technique advantages of simple, good stability, production process safety, easy to operate;
(2) in ring-closure reaction, catalyst efficiency is higher, and can apply mechanically repeatedly for several times, and cyclizing agent efficient is higher, and raw material is easy to get, cost is low, and aftertreatment is simple, and is environmentally friendly, process stabilizing;
(3) transformation efficiency is high, yield>88.5%; Product purity is high, HPLC>99.36%.
Embodiment
Below the utility model is done further to describe, but protection scope of the present invention is not limited in through specific embodiment:
Embodiment 1: t-butanol solution 170mL, potassium tert.-butoxide 52.5g are dropped into reaction kettle, and the back that stirs is dropped into 3-ethoxy propylene nitrile 30g, is stirred and drop into thiocarbamide 24.2g down, and normal temperature stirs 6h down; Be warming up to 40 ℃, insulated and stirred 10h, air distillation goes out the trimethyl carbinol; Add 90mL water, be warming up to 95 ℃ of dissolving clarifications, be cooled to 20 ℃ then; Cooling crystallization is crossed and is filtered the wet article 36.6g of crystallization.
In reaction kettle, put into 60mL water, stir the hydrochloric acid that adds 83mL10mol/L down, the dissolving back adds above-mentioned wet article 36.6g, stirs 1h; The ydrogen peroxide 50 of Dropwise 5 5mL28% after dripping off, in 80 ℃ of insulation 18h, is cooled to 20 ℃; The sodium hydroxide that drips about 113mL10mol/L is transferred PH to 7.5, is cooled to 10 ℃, slowly separates out a large amount of solids, filters; The washing, dry cytosine(Cyt) product 30.8g, total recovery is 89.7%, HPLC99.42%.
Embodiment 2: t-butanol solution 150mL, potassium tert.-butoxide 52.5g are dropped into reaction kettle, and the back that stirs is dropped into 3-ethoxy propylene nitrile 30g, is stirred and drop into thiocarbamide 24.2g down, and normal temperature stirs 8h down; Be warming up to 45 ℃, insulated and stirred 13h, air distillation goes out the trimethyl carbinol; Add 60mL water, be warming up to 95 ℃ of dissolving clarifications, be cooled to 10 ℃ then; Cooling crystallization is crossed and is filtered the wet article 36.7g of crystallization.
In reaction kettle, put into 30mL water, stir the hydrochloric acid that adds 83mL10mol/L down, the dissolving back adds above-mentioned wet article 36.7g, stirs 1h; The ydrogen peroxide 50 of Dropwise 5 5mL28% after dripping off, in 80 ℃ of insulation 24h, is cooled to 10 ℃; The sodium hydroxide that drips about 113.5mL10mol/L is transferred PH to 7.5, is cooled to 5 ℃, slowly separates out a large amount of solids, filters; The washing, dry cytosine(Cyt) product 30.9g, yield is 89.9%, HPLC99.42%.
Embodiment 3: t-butanol solution 300mL, potassium tert.-butoxide 75.0g are dropped into reaction kettle, and the back that stirs is dropped into 3-ethoxy propylene nitrile 30g, is stirred and drop into thiocarbamide 24.2g down, and normal temperature stirs 7h down; Be warming up to 50 ℃, insulated and stirred 9h, air distillation goes out the trimethyl carbinol; Add 120mL water, be warming up to 95 ℃ of dissolving clarifications, be cooled to 15 ℃ then; Cooling crystallization is crossed and is filtered the wet article 36.9g of crystallization.
In reaction kettle, put into 90mL water, stir the hydrochloric acid that adds 83mL10mol/L down, the dissolving back adds above-mentioned wet article 36.9g, stirs 1h; Drip the ydrogen peroxide 50 of 82mL28%, after dripping off,, be cooled to 14 ℃ in 80 ℃ of insulation 36h; The sodium hydroxide that drips about 113.6mL10mol/L is transferred PH to 7.5, is cooled to 8 ℃, slowly separates out a large amount of solids, filters; The washing, dry cytosine(Cyt) product 31.1g, yield is 90.7%, HPLC99.57%.
Embodiment 4: t-butanol solution 250mL, potassium tert.-butoxide 60.6g are dropped into reaction kettle, and the back that stirs is dropped into 3-ethoxy propylene nitrile 30g, is stirred and drop into thiocarbamide 24.2g down, and normal temperature stirs 8h down; Be warming up to 70 ℃, insulated and stirred 17h, air distillation goes out the trimethyl carbinol; Add 90mL water, be warming up to 95 ℃ of dissolving clarifications, be cooled to 18 ℃ then; Cooling crystallization is crossed and is filtered the wet article 37.7g of crystallization.
In reaction kettle, put into 60mL water, stir the hydrochloric acid that adds 83mL10mol/L down, the dissolving back adds above-mentioned wet article 37.7g, stirs 1h; Drip the ydrogen peroxide 50 of 72mL28%, after dripping off,, be cooled to 11 ℃ in 80 ℃ of insulation 36h; The sodium hydroxide that drips about 113.6mL10mol/L is transferred PH to 7.5, is cooled to 6 ℃, slowly separates out a large amount of solids, filters; The washing, dry cytosine(Cyt) product 31.5g, yield is 91.7%, HPLC99.58%.
Embodiment 5: aqueous isopropanol 190mL, sodium isopropylate 52.5g are dropped into reaction kettle, and the back that stirs is dropped into 3-ethoxy propylene nitrile 30g, is stirred and drop into thiocarbamide 24.2g down, and normal temperature stirs 5h down; Be warming up to 60 ℃, insulated and stirred 16h, air distillation goes out Virahol; Add 80mL water, be warming up to 95 ℃ of dissolving clarifications, be cooled to 17 ℃ then; Cooling crystallization is crossed and is filtered the wet article 36.6g of crystallization.
In reaction kettle, put into 60mL water, stir the hydrochloric acid that adds 83mL10mol/L down, the dissolving back adds above-mentioned wet article 36.6g, stirs 1h; The ydrogen peroxide 50 of Dropwise 5 5mL28% after dripping off, in 80 ℃ of insulation 20h, is cooled to 12 ℃; The sodium hydroxide that drips about 113.6mL10mol/L is transferred PH to 7.5, is cooled to 9 ℃, slowly separates out a large amount of solids, filters; The washing, dry cytosine(Cyt) product 30.4g, yield is 88.5%, HPLC99.47%.
Embodiment 6: aqueous isopropanol 250mL, sodium isopropylate 60g are dropped into reaction kettle, and the back that stirs is dropped into 3-ethoxy propylene nitrile 30g, is stirred and drop into thiocarbamide 24.2g down, and normal temperature stirs 8h down; Be warming up to 60 ℃, insulated and stirred 11h, air distillation goes out Virahol; Add 90mL water, be warming up to 95 ℃ of dissolving clarifications, be cooled to 10 ℃ then; Cooling crystallization is crossed and is filtered the wet article 36.8g of crystallization.
In reaction kettle, put into 60mL water, stir the hydrochloric acid that adds 83mL10mol/L down, the dissolving back adds above-mentioned wet article 36.8g, stirs 1h; The ydrogen peroxide 50 of Dropwise 5 5mL28% after dripping off, in 80 ℃ of insulation 24h, is cooled to 20 ℃; The sodium hydroxide that drips about 114mL10mol/L is transferred PH to 7.5, is cooled to 6 ℃, slowly separates out a large amount of solids, filters; The washing, dry cytosine(Cyt) product 30.6g, yield is 89.2%, HPLC99.46%.
Embodiment 7: aqueous isopropanol 280mL, sodium isopropylate 75.0g are dropped into reaction kettle, and the back that stirs is dropped into 3-ethoxy propylene nitrile 30g, is stirred and drop into thiocarbamide 24.2g down, and normal temperature stirs 8h down; Be warming up to 50 ℃, insulated and stirred 11h, air distillation goes out Virahol; Add 90mL water, be warming up to 95 ℃ of dissolving clarifications, be cooled to 16 ℃ then; Cooling crystallization is crossed and is filtered the wet article 37.1g of crystallization.
In reaction kettle, put into 60mL water, stir the hydrochloric acid that adds 83mL10mol/L down, the dissolving back adds above-mentioned wet article 37.1g, stirs 1h; Drip the ydrogen peroxide 50 of 82mL28%, after dripping off,, be cooled to 20 ℃ in 80 ℃ of insulation 28h; The sodium hydroxide that drips about 113.6mL10mol/L is transferred PH to 7.5, is cooled to 10 ℃, slowly separates out a large amount of solids, filters; The washing, dry cytosine(Cyt) product 30.9g, yield is 89.9%, HPLC99.39%.
Embodiment 8: aqueous isopropanol 300mL, sodium isopropylate 60.6g are dropped into reaction kettle, and the back that stirs is dropped into 3-ethoxy propylene nitrile 30g, is stirred and drop into thiocarbamide 24.2g down, and normal temperature stirs 8h down; Be warming up to 70 ℃, insulated and stirred 10h, air distillation goes out Virahol; Add 90mL water, be warming up to 95 ℃ of dissolving clarifications, be cooled to 15 ℃ then; Cooling crystallization is crossed and is filtered the wet article 37.7g of crystallization.
In reaction kettle, put into 60mL water, stir the hydrochloric acid that adds 83mL10mol/L down, the dissolving back adds above-mentioned wet article 37.7g, stirs 1h; Drip the ydrogen peroxide 50 of 72mL28%, after dripping off,, be cooled to 15 ℃ in 80 ℃ of insulation 36h; The sodium hydroxide that drips about 113.5mL10mol/L is transferred PH to 7.5, is cooled to 56 ℃, slowly separates out a large amount of solids, filters; The washing, dry cytosine(Cyt) product 31.1g, yield is 90.7%, HPLC99.51%.
Embodiment 9: methanol solution 190mL, sodium methylate 52.5g are dropped into reaction kettle, and the back that stirs is dropped into 3-ethoxy propylene nitrile 30g, is stirred and drop into thiocarbamide 24.2g down, and normal temperature stirs 5h down; Be warming up to 40 ℃, insulated and stirred 10h, air distillation goes out the trimethyl carbinol; Add 90mL water, be warming up to 95 ℃ of dissolving clarifications, be cooled to 12 ℃ then; Cooling crystallization is crossed and is filtered the wet article 36.6g of crystallization.
In reaction kettle, put into 60mL water, stir the hydrochloric acid that adds 83mL10mol/L down, the dissolving back adds above-mentioned wet article 36.6g, stirs 1h; The ydrogen peroxide 50 of Dropwise 5 5mL28% after dripping off, in 80 ℃ of insulation 18h, is cooled to 12 ℃; The sodium hydroxide that drips about 113mL10mol/L is transferred PH to 7.5, is cooled to 7 ℃, slowly separates out a large amount of solids, filters; The washing, dry cytosine(Cyt) product 30.4g, yield is 88.6%, HPLC99.36%.
Embodiment 10: methanol solution 370mL, sodium methylate 75g are dropped into reaction kettle, and the back that stirs is dropped into 3-ethoxy propylene nitrile 30g, is stirred and drop into thiocarbamide 24.2g down, and normal temperature stirs 6h down; Be warming up to 50 ℃, insulated and stirred 17h, air distillation goes out the trimethyl carbinol; Add 90mL water, be warming up to 95 ℃ of dissolving clarifications, be cooled to 14 ℃ then; Cooling crystallization is crossed and is filtered the wet article 36.8g of crystallization.
In reaction kettle, put into 60mL water, stir the hydrochloric acid that adds 83mL10mol/L down, the dissolving back adds above-mentioned wet article 36.8g, stirs 1h; The ydrogen peroxide 50 of Dropwise 5 5mL28% after dripping off, in 80 ℃ of insulation 24h, is cooled to 14 ℃; The sodium hydroxide that drips about 114mL10mol/L is transferred PH to 7.5, is cooled to 10 ℃, slowly separates out a large amount of solids, filters; The washing, dry cytosine(Cyt) product 30.8g, yield is 89.6%, HPLC99.46%.
Embodiment 11: the sodium methylate 60.6g that will be dissolved in methanol solution 250mL drops into reaction kettle, and the back that stirs is dropped into 3-ethoxy propylene nitrile 30g, stirred and drop into thiocarbamide 24.2g down, and normal temperature stirs 8h down; Be warming up to 70 ℃, insulated and stirred 17h, air distillation goes out the trimethyl carbinol; Add 90mL water, be warming up to 95 ℃ of dissolving clarifications, be cooled to 20 ℃ then; Cooling crystallization is crossed and is filtered the wet article 37.1g of crystallization.
In reaction kettle, put into 60mL water, stir the hydrochloric acid that adds 83mL10mol/L down, the dissolving back adds above-mentioned wet article 37.1g, stirs 1h; Drip the ydrogen peroxide 50 of 72mL28%, after dripping off,, be cooled to 20 ℃ in 80 ℃ of insulation 36h; The sodium hydroxide that drips about 113mL10mol/L is transferred PH to 7.5, is cooled to 10 ℃, slowly separates out a large amount of solids, filters; The washing, dry cytosine(Cyt) product 31.1g, yield is 90.7%, HPLC99.42%.
Claims (9)
1. the method for a synthesizing cytimidine is characterized in that being made up of following steps:
1) described 3-ethoxy propylene nitrile and described thiocarbamide are suc as formula shown in (I), (II):
（I） （II）；
2) catalyzer and solvent are dropped into reaction kettle, the back that stirs is dropped into suc as formula the 3-ethoxy propylene nitrile shown in (I), is continued to stir down and drop into suc as formula the thiocarbamide shown in (II), stirring at normal temperature reaction 5～8h; Reheat is warming up to 40～70 ℃, and insulated and stirred reaction 9～17h is after normal pressure steams and desolventizes; Adding consumption to reaction kettle is 2～4 times water of 3-ethoxy propylene nitrile weight; Be warming up to 95 ℃ of dissolving clarifications, be cooled to 10～20 ℃ then, cooling crystallization; Cross and filter the wet article of crystallization, described catalyzer is potassium tert.-butoxide, sodium methylate or sodium isopropylate;
3) in another reaction kettle, put into 1～3 times the water as solvent that consumption is a 3-ethoxy propylene nitrile weight, stir the hydrochloric acid that adds 10mol/L down, add step 2 again) the wet article of crystallization that obtain; Stir 1h, drip consumption and be 1.5～2.5 times of 3-ethoxy propylene nitrile weight 28% ydrogen peroxide 50, after dripping off; In 80 ℃ of insulation 18～36h; Be cooled to 10～20 ℃ after the end, the sodium hydroxide that drips 10mol/L is transferred PH to 7.5, is cooled to 5～10 ℃; Slowly separate out a large amount of solids, the hydrochloric acid consumption that adds 10mol/L under the described stirring is 1 times of 3-ethoxy propylene nitrile weight;
4) reaction solution that step 3) is obtained carries out suction filtration, and washing is dried suc as formula the product shown in (III)
（III）。
2. the method for a kind of synthesizing cytimidine according to claim 1 is characterized by and is step 2) described input raw material 3-ethoxy propylene nitrile is 1:1.029 with the ratio of thiocarbamide amount of substance.
3. the method for a kind of synthesizing cytimidine according to claim 1 is characterized in that step 2) described in catalyst levels be 1.75 ~ 2.5 times of 3-ethoxy propylene nitrile weight.
4. the method for a kind of synthesizing cytimidine according to claim 1 is characterized in that step 2) described solvent is a kind of in the trimethyl carbinol, methyl alcohol or the Virahol, consumption is 5～10 times of 3-ethoxy propylene nitrile weight.
5. the method for a kind of synthesizing cytimidine according to claim 1 is characterized in that step 2) described stirring at normal temperature reaction 6～7h, be warming up to 40～70 ℃, insulated and stirred reaction 10～13h.
6. the method for a kind of synthesizing cytimidine according to claim 1, the consumption that it is characterized in that the described aqueous solvent of step 3) is 2 times of 3-ethoxy propylene nitrile weight.
7. the method for a kind of synthesizing cytimidine according to claim 1, the ydrogen peroxide 50 consumption that it is characterized in that the described dropping 28% of step 3) be 3-ethoxy propylene nitrile weight 2 times.
8. the method for a kind of synthesizing cytimidine according to claim 1 is characterized in that the described 80 ℃ of insulation reaction 20～28h of step 3).
9. the method for a kind of synthesizing cytimidine according to claim 1 is characterized in that the described 80 ℃ of insulation reaction 24h of step 3).
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| CN103880758B (en) * | 2014-03-24 | 2016-08-17 | 浙江先锋科技股份有限公司 | The synthetic method of cytosine |
| CN103896859B (en) * | 2014-03-24 | 2016-08-17 | 浙江先锋科技股份有限公司 | The technique of synthesizing cytimidine |
| CN115611815A (en) * | 2022-10-10 | 2023-01-17 | 新乡瑞诺药业有限公司 | Synthesis method of cytosine |
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| DE3906855A1 (en) * | 1989-03-03 | 1990-09-06 | Huels Chemische Werke Ag | METHOD FOR PRODUCING CYTOSINES |
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