CN103880758A - Synthesis method of cytosine - Google Patents
Synthesis method of cytosine Download PDFInfo
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- CN103880758A CN103880758A CN201410110611.1A CN201410110611A CN103880758A CN 103880758 A CN103880758 A CN 103880758A CN 201410110611 A CN201410110611 A CN 201410110611A CN 103880758 A CN103880758 A CN 103880758A
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- cytosine
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- sodium salt
- vinyl cyanide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention discloses a synthesis method of cytosine. The preparation process comprises the following steps: selecting 3-hydroxy acrylonitrile sodium salt and thiourea as raw materials; when preparing, adding a catalyst and an organic solvent to a reaction kettle, uniformly stirring, and sequentially adding the 3-hydroxy acrylonitrile sodium salt and the thiourea; raising temperature to 50-90 DEG C and carrying out a cyclization reaction for 6-10 hours to obtain a cyclization reaction solution; evaporating out the solvent in the cyclization reaction solution, and adding water and hydrochloric acid to obtain an intermediate product solution; dropping hydrogen peroxide to the intermediate product solution, raising temperature to 60-90 DEG C and preserving heat for 18-24 hours; regulating pH value through a sodium hydroxide solution, and cooling to 10-15 DEG C when the pH value is 7.0-7.5; and after cooling, filtering, washing and drying to obtain the cytosine. The synthesis method disclosed by the invention has the advantages that the process is simple in step, short in production cycle and low in cost; moreover, a raw material conversion rate is high, and the synthesized product is good in quality, high in yield, convenient in post-treatment and applicable to industrial production.
Description
Technical field
The invention belongs to medicine intermediate synthesis technical field, especially relate to a kind of synthetic method of cytosine(Cyt).
Background technology
Cytosine(Cyt) is 4-amino-2-hydroxy pyrimidine, is one of pyrimidine Type base in nucleic acid, is also the important intermediate of fine chemistry industry, agricultural chemicals and medicine; Especially be mainly used in synthesizing anti-AIDS pharmaceutical and anti-hbv drug lamivudine, cancer therapy drug gemcitabine, enocitabine and 5-flurocytosine etc. at field of medicaments.The synthetic method of existing cytosine(Cyt) mainly comprises functional group's conversion method and Pinner synthesis method; Functional group's conversion method is taking 2-sulfydryl-6-pyrimidone as raw material synthesizing cytimidine, or with uridylic or 2,4-, bis-sulphur pyrimidines for substrate, through process synthesizing cytimidines such as hydrolysis; There is the shortcomings such as the by product of complex operation, production cycle length, generation is many and environmental pollutions are serious in this synthetic method; Pinner synthesis method is with 3-alkoxy propone nitrile or 3,3-alkoxypropionitrile is raw material synthesizing cytimidine, this is the main method of current suitability for industrialized production cytosine(Cyt), 3-alkoxy propone nitrile or 3,3-alkoxypropionitrile generally reacts with CO under sodium alkoxide effect by acetonitrile and generates 3-hydroxyl vinyl cyanide sodium salt, then react with hydrochloric acid alcoholic solution and synthesize; But its cost of material of cytosine(Cyt) of producing is in this way more expensive, and total recovery is lower; Therefore be necessary to be improved.
Summary of the invention
The object of the invention is the deficiency existing for above-mentioned prior art, a kind of synthetic method of cytosine(Cyt) is provided, it is simple that it has processing step, and feed stock conversion is high, the good product quality of production, with short production cycle, and applicable large-scale industrialization quantity-produced feature.
To achieve these goals, the technical solution adopted in the present invention is: a kind of synthetic method of cytosine(Cyt), and its step of preparation process is as follows: choose 3-hydroxyl vinyl cyanide sodium salt and thiocarbamide as raw material; When preparation, first catalyzer and organic solvent are dropped in reactor, after stirring, add successively 3-hydroxyl vinyl cyanide sodium salt and thiocarbamide; Be warmed up to 50～90 DEG C and ring-closure reaction 6～10 hours, obtain ring-closure reaction liquid; Steam the solvent in ring-closure reaction liquid, add water and hydrochloric acid to obtain midbody solution; In midbody solution, drip hydrogen peroxide, be warming up to 60～90 DEG C and be incubated 18～24 hours; By sodium hydroxide solution adjusting pH value, in the time that pH is 7.0～7.5, be cooled to 10～15 DEG C; After cooling completing, filter, wash, after oven dry, can obtain cytosine(Cyt).
The molar ratio of described 3-hydroxyl vinyl cyanide sodium salt and thiocarbamide is 1:1.05～1.5.
The molar ratio of described 3-hydroxyl vinyl cyanide sodium salt and catalyzer is 1:1.1～1.5.
The molar ratio of described 3-hydroxyl vinyl cyanide sodium salt and hydrogen peroxide is 1:1.2～2.
Described catalyzer is any one in sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide or potassium tert.-butoxide; Described organic solvent is any one in methyl alcohol, ethanol, Virahol, the trimethyl carbinol, toluene or dimethylbenzene.
The massfraction of described hydrogen peroxide is 20%～30%.
Synthetic equation of the present invention is as follows:
Wherein, I is 3-hydroxyl vinyl cyanide sodium salt; II is thiocarbamide; III is intermediate.
The advantage that compared to the prior art the present invention had is: the present invention is taking 3-hydroxyl vinyl cyanide sodium salt as raw material, directly carry out ring-closure reaction, reduce 3-hydroxyl vinyl cyanide sodium salt and reacted generation 3-alkoxy propone nitrile or 3 with hydrochloric acid alcoholic solution, this step of 3-alkoxypropionitrile, processing step is simple, production cost is low, and greatly reduces work operation and energy consumption; 3-hydroxyl vinyl cyanide sodium salt to replace 3-alkoxy propone nitrile or 3,3-alkoxypropionitrile have not only reduced temperature of reaction, have shortened the reaction times, and reaction conditions milder, even if also can well carry out ring-closure reaction in primary alconol; Feed stock conversion of the present invention is high, and the convenient post-treatment after production is produced yield up to 93%, HPLC > 99.0%, is applicable to suitability for industrialized production.
Embodiment
The following stated is only preferred embodiment of the present invention, does not therefore limit protection scope of the present invention.
Embodiment 1: a kind of synthetic method of cytosine(Cyt), its step of preparation process is as follows: sodium methylate (24.3g, 0.45mol) and 180mL methyl alcohol are dropped in reactor and stirred; Add successively 3-hydroxyl vinyl cyanide sodium salt (27.3g, 0.3mol) and thiocarbamide (24.0g, 0.315mol); Be warming up to 60 DEG C and ring-closure reaction 10 hours, obtain ring-closure reaction liquid; Under normal pressure, steam methyl alcohol, and add slowly 80mL water and 95mL concentrated hydrochloric acid to obtain midbody solution; In midbody solution, drip 30% hydrogen peroxide (40.8g, 0.36mol), the massfraction of hydrogen peroxide is 30% can obtain preferably effect, and massfraction is as long as the words between 20%～30% also can obtain similar effect certainly; After dropwising, be warming up to 60 DEG C of insulations 24 hours; Be cooled to room temperature, the sodium hydroxide solution that drips 10mol/L regulates pH value, in the time that pH is 7.5, is cooled to 10 DEG C; After cooling, filter, wash, after oven dry, can obtain cytosine(Cyt) 30.7g, yield 92.1%, HPLC content 99.2%.
Embodiment 2: sodium methylate (24.3g, 0.45mol) and 180mL methyl alcohol are dropped in reactor and stirred; Add successively 3-hydroxyl vinyl cyanide sodium salt (27.3g, 0.3mol) and thiocarbamide (34.2g, 0.45mol), be warming up to 60 DEG C and ring-closure reaction 8 hours; Under normal pressure, steam methyl alcohol, and add slowly 50mL water and 95mL concentrated hydrochloric acid to obtain midbody solution; In midbody solution, drip 30% hydrogen peroxide (68.0g, 0.6mol), after dropwising, be warming up to 90 DEG C of insulations 18 hours; Be cooled to room temperature, the sodium hydroxide solution that drips 10mol/L regulates pH value, when pH is when being 7.0, is cooled to 15 DEG C; After cooling, filter, wash, after oven dry, can obtain cytosine(Cyt) 30.9g, yield 92.8%, HPLC content 99.0%.
Embodiment 3: sodium ethylate (25.5g, 0.375mol) and 180mL ethanol are dropped in reactor and stirred; Add successively 3-hydroxyl vinyl cyanide sodium salt (27.3g, 0.3mol) and thiocarbamide (24.0g, 0.315mol), be warming up to 70 DEG C and ring-closure reaction 8 hours; Under normal pressure, steam ethanol, and add slowly 85mL water and 80mL concentrated hydrochloric acid to obtain midbody solution; In midbody solution, drip 30% hydrogen peroxide (51.0g, 0.45mol), dropwise, be warming up to 80 DEG C of insulations 20 hours; Be cooled to room temperature, the sodium hydroxide solution that drips 10mol/L regulates pH value, in the time that pH is 7.5, is cooled to 10 DEG C; After cooling, filter, wash, after oven dry, can obtain cytosine(Cyt) 30.7g, yield 92.1%, HPLC content 99.1%.
Embodiment 4: sodium isopropylate (30.8g, 0.375mol) and 180mL Virahol are dropped in reactor and stirred; Add successively 3-hydroxyl vinyl cyanide sodium salt (27.3g, 0.3mol) and thiocarbamide (24.0g, 0.315mol), be warming up to 70 DEG C and ring-closure reaction 6 hours; Under normal pressure, steam Virahol, and add slowly 85mL water and 80mL concentrated hydrochloric acid to obtain midbody solution; In midbody solution, drip 30% hydrogen peroxide (51.0g, 0.45mol), dropwise, be warming up to 80 DEG C of insulations 20 hours; Be cooled to room temperature, the sodium hydroxide solution that drips 10mol/L regulates pH value, in the time that pH is 7.5, is cooled to 10 DEG C; After cooling, filter, wash, after oven dry, can obtain cytosine(Cyt) 30.8g, yield 92.4%, HPLC content 99.4%.
Embodiment 5: sodium tert-butoxide (31.7g, 0.33mol) and the 150mL trimethyl carbinol are dropped in reactor and stirred; Add successively 3-hydroxyl vinyl cyanide sodium salt (27.3g, 0.3mol) and thiocarbamide (24.0g, 0.315mol), be warming up to 50 DEG C and ring-closure reaction 8 hours; Under normal pressure, steam the trimethyl carbinol, and add slowly 95mL water and 72mL concentrated hydrochloric acid to obtain midbody solution; In midbody solution, drip 30% hydrogen peroxide (51.0g, 0.45mol), dropwise, be warming up to 80 DEG C of insulations 20 hours; Be cooled to room temperature, the sodium hydroxide solution that drips 10mol/L regulates pH value, in the time that pH is 7.5, continues to be cooled to 10 DEG C; After cooling, filter, wash, after oven dry, can obtain cytosine(Cyt) 31.0g, yield 93.0%, HPLC content 99.4%.
Embodiment 6: potassium tert.-butoxide (37.0g, 0.33mol) and the 150mL trimethyl carbinol are dropped in reactor and stirred; Add successively 3-hydroxyl vinyl cyanide sodium salt (27.3g, 0.3mol) and thiocarbamide (27.4g, 0.36mol), be warming up to 50 DEG C and ring-closure reaction 6 hours; Under normal pressure, steam the trimethyl carbinol, and add slowly 95mL water and 72mL concentrated hydrochloric acid to obtain midbody solution; In midbody solution, drip 30% hydrogen peroxide (51.0g, 0.45mol), dropwise, be warming up to 80 DEG C of insulations 20 hours; Be cooled to room temperature, the sodium hydroxide solution that drips 10mol/L regulates pH value, in the time that pH is 7.5, is cooled to 10 DEG C; After cooling, filter, wash, after oven dry, can obtain cytosine(Cyt) 30.9g, yield 92.8%, HPLC content 99.4%.
Embodiment 7: sodium methylate (24.3g, 0.45mol) and 150mL toluene are dropped in reactor and stirred; Add successively 3-hydroxyl vinyl cyanide sodium salt (27.3g, 0.3mol) and thiocarbamide (27.4g, 0.36mol), be warming up to 90 DEG C and ring-closure reaction 8 hours; Decompression steams toluene, and adds slowly 70mL water and 95mL concentrated hydrochloric acid to obtain midbody solution; In midbody solution, drip 30% hydrogen peroxide (51.0g, 0.45mol), dropwise, be warming up to 80 DEG C of insulations 20 hours; Be cooled to room temperature, the sodium hydroxide solution that drips 10mol/L regulates pH value, in the time that pH is 7.5, is cooled to 15 DEG C; After cooling, filter, wash, after oven dry, can obtain cytosine(Cyt) 30.3g, yield 91.0%, HPLC content 99.1%.
Embodiment 8: sodium methylate (24.3g, 0.45mol) and dimethylbenzene are dropped in reactor and stirred; Add successively 3-hydroxyl vinyl cyanide sodium salt (27.3g, 0.3mol) and thiocarbamide (27.4g, 0.36mol), be warming up to 90 DEG C and ring-closure reaction 8 hours; Decompression steams dimethylbenzene, and adds slowly water and hydrochloric acid to obtain midbody solution; In midbody solution, drip 30% hydrogen peroxide (51.0g, 0.45mol), dropwise, be warming up to 80 DEG C of insulations 20 hours; Be cooled to room temperature, drip sodium hydroxide solution and regulate pH value, in the time that pH is 7.5, be cooled to 15 DEG C; After cooling, filter, wash, after oven dry, can obtain cytosine(Cyt) 30.5g, yield 91.5%, HPLC content 99.0%.
Use the present invention to prepare cytosine(Cyt), its processing step of preparing is simpler, with short production cycle, cost is low, and greatly reduces work operation and energy consumption; And feed stock conversion of the present invention is high, synthetic good product quality, yield is high, convenient post-treatment, is applicable to suitability for industrialized production.
Claims (6)
1. a synthetic method for cytosine(Cyt), is characterized in that: its step of preparation process is as follows: choose 3-hydroxyl vinyl cyanide sodium salt and thiocarbamide as raw material; When preparation, first catalyzer and organic solvent are dropped in reactor, after stirring, add successively 3-hydroxyl vinyl cyanide sodium salt and thiocarbamide; Be warmed up to 50～90 DEG C and ring-closure reaction 6～10 hours, obtain ring-closure reaction liquid; Steam the solvent in ring-closure reaction liquid, add water and hydrochloric acid to obtain midbody solution; In midbody solution, drip hydrogen peroxide, be warming up to 60～90 DEG C and be incubated 18～24 hours; By sodium hydroxide solution adjusting pH value, in the time that pH is 7.0～7.5, be cooled to 10～15 DEG C; After cooling completing, filter, wash, after oven dry, can obtain cytosine(Cyt).
2. the synthetic method of cytosine(Cyt) according to claim 1, is characterized in that: the molar ratio of described 3-hydroxyl vinyl cyanide sodium salt and thiocarbamide is 1:1.05～1.5.
3. the synthetic method of cytosine(Cyt) according to claim 2, is characterized in that: the molar ratio of described 3-hydroxyl vinyl cyanide sodium salt and catalyzer is 1:1.1～1.5.
4. the synthetic method of cytosine(Cyt) according to claim 3, is characterized in that: the molar ratio of described 3-hydroxyl vinyl cyanide sodium salt and hydrogen peroxide is 1:1.2～2.
5. according to the synthetic method of the cytosine(Cyt) described in claim 1 or 4, it is characterized in that: described catalyzer is any one in sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide or potassium tert.-butoxide; Described organic solvent is any one in methyl alcohol, ethanol, Virahol, the trimethyl carbinol, toluene or dimethylbenzene.
6. the synthetic method of cytosine(Cyt) according to claim 5, is characterized in that: the massfraction of described hydrogen peroxide is 20%-30%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111646947A (en) * | 2020-07-14 | 2020-09-11 | 新乡瑞诺药业有限公司 | Preparation process for replacing sodium methoxide by metal sodium in cytosine cyclization process |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3434142A1 (en) * | 1984-09-18 | 1986-03-27 | Dynamit Nobel Ag, 5210 Troisdorf | Process for the preparation of cytosine |
| CN1594287A (en) * | 2004-07-16 | 2005-03-16 | 杭州科本化工有限公司 | Process for the preparation of 3-hydroxyacrylonitrile metal salts |
| JP2010024205A (en) * | 2008-07-23 | 2010-02-04 | Ube Ind Ltd | Method for preparing 5-methylcytosine |
| CN102030715A (en) * | 2010-12-08 | 2011-04-27 | 浙江先锋科技有限公司 | Method for synthetizing cytosine |
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2014
- 2014-03-24 CN CN201410110611.1A patent/CN103880758B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3434142A1 (en) * | 1984-09-18 | 1986-03-27 | Dynamit Nobel Ag, 5210 Troisdorf | Process for the preparation of cytosine |
| CN1594287A (en) * | 2004-07-16 | 2005-03-16 | 杭州科本化工有限公司 | Process for the preparation of 3-hydroxyacrylonitrile metal salts |
| JP2010024205A (en) * | 2008-07-23 | 2010-02-04 | Ube Ind Ltd | Method for preparing 5-methylcytosine |
| CN102030715A (en) * | 2010-12-08 | 2011-04-27 | 浙江先锋科技有限公司 | Method for synthetizing cytosine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111646947A (en) * | 2020-07-14 | 2020-09-11 | 新乡瑞诺药业有限公司 | Preparation process for replacing sodium methoxide by metal sodium in cytosine cyclization process |
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