CN103880758B - The synthetic method of cytosine - Google Patents
The synthetic method of cytosine Download PDFInfo
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- CN103880758B CN103880758B CN201410110611.1A CN201410110611A CN103880758B CN 103880758 B CN103880758 B CN 103880758B CN 201410110611 A CN201410110611 A CN 201410110611A CN 103880758 B CN103880758 B CN 103880758B
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- cytosine
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- thiourea
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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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the synthetic method of a kind of cytosine, its step of preparation process is as follows: choose 3 hydroxy nitrile sodium salts with thiourea as raw material；During preparation, first catalyst and organic solvent are put in reactor, after stirring, be sequentially added into 3 hydroxy nitrile sodium salt and thiourea；It is 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 obtains midbody solution；In midbody solution, drip hydrogen peroxide, be warming up to 60～90 DEG C and be incubated 18～24 hours；Regulate pH value with sodium hydroxide solution, when pH is 7.0～7.5, be cooled to 10～15 DEG C；Carry out after having cooled down filtering, washing, after drying, i.e. can get cytosine.Advantage is: present invention process step is simple, with short production cycle and low cost；And feed stock conversion of the present invention is high, the good product quality of synthesis, yield are high, convenient post-treatment, are suitable for industrialized production.
Description
Technical field
The invention belongs to medicine intermediate synthesis technical field, especially relate to a kind of born of the same parents phonetic
The synthetic method of pyridine.
Background technology
Cytosine i.e. 4-amino-2-hydroxy pyrimidine, is one of pyrimidine Type base in nucleic acid, also
It it is the important intermediate of fine chemistry industry, pesticide and medicine；Especially mainly use at field of medicaments
In synthesizing anti-AIDS pharmaceutical and anti-hbv drug lamivudine, cancer therapy drug gemcitabine,
Enocitabine and 5-flurocytosine etc..The synthetic method of existing cytosine mainly includes
Functional group conversions's method and Pinner synthetic method；Functional group conversions's method is with 2-sulfydryl-6-pyrimidine
Ketone is Material synthesis cytosine, or with uracil or 2,4-bis-sulfur pyrimidine is substrate,
Through process synthesizing cytimidines such as hydrolysis；There is complex operation, produce week in this synthetic method
Phase length, the shortcomings such as by-product is many and environmental pollution is serious of generation；Pinner synthetic method
Being with 3-alkoxy propone nitrile or 3,3-alkoxypropionitrile is Material synthesis cytosine, this
It is the main method of current industrialized production cytosine, 3-alkoxy propone nitrile or 3,3-alkane
Epoxide propionitrile typically reacts generation 3-hydroxy by acetonitrile under sodium alkoxide effect with CO
Nitrile sodium salt, then be synthesized with hydrochloric acid alcoholic solution；But, produce in this way
Its cost of material of cytosine is more expensive, and total recovery ratio is relatively low；It is therefore desirable to changed
Enter.
Summary of the invention
It is an object of the invention to the deficiency existed for above-mentioned prior art, it is provided that a kind of born of the same parents
The synthetic method of pyrimidine, it is simple that it has processing step, and feed stock conversion is high, production
Good product quality, with short production cycle, and the feature of applicable industrialization large-scale continuous production.
To achieve these goals, the technical solution adopted in the present invention is: a kind of born of the same parents are phonetic
The synthetic method of pyridine, its step of preparation process is as follows: choose 3-hydroxy nitrile sodium salt with
Thiourea is as raw material；During preparation, first catalyst and organic solvent are put in reactor,
After stirring, it is sequentially added into 3-hydroxy nitrile sodium salt and thiourea；Be warmed up to 50～
90 DEG C and ring-closure reaction 6～10 hours, obtain ring-closure reaction liquid；Steam ring-closure reaction liquid
In solvent, add water and hydrochloric acid and obtain midbody solution；Midbody solution drips
Hydrogen peroxide, is warming up to 60～90 DEG C and is incubated 18～24 hours；Use sodium hydroxide solution
Regulation pH value, when pH is 7.0～7.5, is cooled to 10～15 DEG C；Cooling completes
After carry out filtering, washing, i.e. can get cytosine after drying.
Described 3-hydroxy nitrile sodium salt is 1:1.05～1.5 with the molar ratio of thiourea.
Described 3-hydroxy nitrile sodium salt is 1:1.1～1.5 with the molar ratio of catalyst.
Described 3-hydroxy nitrile sodium salt is 1:1.2～2 with the molar ratio of hydrogen peroxide.
Described catalyst is Feldalat NM, Sodium ethylate, sodium isopropylate, sodium tert-butoxide or tertiary fourth
Any one in potassium alcoholate；Described organic solvent is methanol, ethanol, isopropanol, tertiary fourth
Any one in alcohol, toluene or dimethylbenzene.
The mass fraction of described hydrogen peroxide is 20%～30%.
The synthesis equation of the present invention is as follows:
Wherein, I is 3-hydroxy nitrile sodium salt；II is thiourea；III is intermediate.
The present invention is the most advantageously: the present invention is with 3-hydroxyl third
Alkene nitrile sodium salt is raw material, directly carries out ring-closure reaction, decreases 3-hydroxy nitrile sodium salt
Generation 3-alkoxy propone nitrile or this step of 3,3-alkoxypropionitrile is reacted with hydrochloric acid alcoholic solution
Suddenly, processing step is simple, and production cost is low, and greatly reduces labor operations and energy consumption；
3-hydroxy nitrile sodium salt substitutes 3-alkoxy propone nitrile or 3,3-alkoxypropionitrile not only drops
Low reaction temperature, shorten the response time, and reaction condition milder, even if
Primary alconol can also well carry out ring-closure reaction；The feed stock conversion of the present invention is high, raw
The convenient post-treatment in puerperal, produces yield and is up to 93%, HPLC ＞ 99.0%, be suitable for work
Industry metaplasia is produced.
Detailed description of the invention
The following stated is only presently preferred embodiments of the present invention, the most therefore limits the present invention
Protection domain.
Embodiment 1: the synthetic method of a kind of cytosine, its step of preparation process is as follows:
Feldalat NM (24.3g, 0.45mol) is put in reactor with 180mL methanol and stirs
Uniformly；Be sequentially added into 3-hydroxy nitrile sodium salt (27.3g, 0.3mol) and thiourea (24.0g,
0.315mol)；It is warming up to 60 DEG C of also ring-closure reaction 10 hours, obtains ring-closure reaction liquid；
Steam methanol at ambient pressure, and addition 80mL water and 95mL concentrated hydrochloric acid obtain slowly
Midbody solution；The hydrogen peroxide (40.8g, 0.36mol) of 30% is dripped in midbody solution,
The mass fraction of hydrogen peroxide is 30% to obtain preferably effect, if certain mass fraction
Also similar effect can be obtained between 20%～30%；After dropping, rise
Temperature is incubated 24 hours to 60 DEG C；It is cooled to room temperature, the sodium hydroxide of dropping 10mol/L
Solution regulation pH value, when pH is 7.5, is cooled to 10 DEG C；Carry out after cooling filtering,
Washing, i.e. can get cytosine 30.7g, yield 92.1%, HPLC content after drying
99.2%。
Embodiment 2: Feldalat NM (24.3g, 0.45mol) is put into 180mL methanol
In reactor and stir；Be sequentially added into 3-hydroxy nitrile sodium salt (27.3g,
0.3mol) with thiourea (34.2g, 0.45mol), it is warming up to 60 DEG C and ring-closure reaction 8 is little
Time；Steam methanol at ambient pressure, and add 50mL water and 95mL concentrated hydrochloric acid slowly
Obtain midbody solution；In midbody solution drip 30% hydrogen peroxide (68.0g,
0.6mol), after dropping, it is warming up to 90 DEG C and is incubated 18 hours；It is cooled to room temperature,
The sodium hydroxide solution regulation pH value of dropping 10mol/L, when pH is for during for 7.0, cold
But to 15 DEG C；Carry out after cooling filtering, washing, after drying, i.e. can get cytosine 30.9g,
Yield 92.8%, HPLC content 99.0%.
Embodiment 3: Sodium ethylate (25.5g, 0.375mol) is put into 180mL ethanol
In reactor and stir；Be sequentially added into 3-hydroxy nitrile sodium salt (27.3g,
0.3mol) with thiourea (24.0g, 0.315mol), it is warming up to 70 DEG C and ring-closure reactions 8
Hour；Steam ethanol at ambient pressure, and add 85mL water and the dense salt of 80mL slowly
Acid obtains midbody solution；In midbody solution drip 30% hydrogen peroxide (51.0g,
0.45mol), drip complete, be warming up to 80 DEG C and be incubated 20 hours；It is cooled to room temperature,
The sodium hydroxide solution regulation pH value of dropping 10mol/L, when pH is 7.5, cooling
To 10 DEG C；Carry out after cooling filtering, washing, after drying, i.e. can get cytosine 30.7g,
Yield 92.1%, HPLC content 99.1%.
Embodiment 4: by sodium isopropylate (30.8g, 0.375mol) and 180mL isopropanol
Put in reactor and stir；Be sequentially added into 3-hydroxy nitrile sodium salt (27.3g,
0.3mol) with thiourea (24.0g, 0.315mol), it is warming up to 70 DEG C and ring-closure reactions 6
Hour；Steam isopropanol at ambient pressure, and addition 85mL water and 80mL are dense slowly
Hydrochloric acid obtains midbody solution；In midbody solution drip 30% hydrogen peroxide (51.0g,
0.45mol), drip complete, be warming up to 80 DEG C and be incubated 20 hours；It is cooled to room temperature,
The sodium hydroxide solution regulation pH value of dropping 10mol/L, when pH is 7.5, cooling
To 10 DEG C；Carry out after cooling filtering, washing, after drying, i.e. can get cytosine 30.8g,
Yield 92.4%, HPLC content 99.4%.
Embodiment 5: by sodium tert-butoxide (31.7g, 0.33mol) and the 150mL tert-butyl alcohol
Put in reactor and stir；Be sequentially added into 3-hydroxy nitrile sodium salt (27.3g,
0.3mol) with thiourea (24.0g, 0.315mol), it is warming up to 50 DEG C and ring-closure reactions 8
Hour；Steam the tert-butyl alcohol at ambient pressure, and addition 95mL water and 72mL are dense slowly
Hydrochloric acid obtains midbody solution；In midbody solution drip 30% hydrogen peroxide (51.0g,
0.45mol), drip complete, be warming up to 80 DEG C and be incubated 20 hours；It is cooled to room temperature,
The sodium hydroxide solution regulation pH value of dropping 10mol/L, when pH is 7.5, continues
It is cooled to 10 DEG C；Carry out after cooling filtering, washing, after drying, i.e. can get cytosine
31.0g, yield 93.0%, HPLC content 99.4%.
Embodiment 6: by potassium tert-butoxide (37.0g, 0.33mol) and the 150mL tert-butyl alcohol
Put in reactor and stir；Be sequentially added into 3-hydroxy nitrile sodium salt (27.3g,
0.3mol) with thiourea (27.4g, 0.36mol), it is warming up to 50 DEG C and ring-closure reaction 6 is little
Time；Steam the tert-butyl alcohol at ambient pressure, and add 95mL water and the dense salt of 72mL slowly
Acid obtains midbody solution；In midbody solution drip 30% hydrogen peroxide (51.0g,
0.45mol), drip complete, be warming up to 80 DEG C and be incubated 20 hours；It is cooled to room temperature,
The sodium hydroxide solution regulation pH value of dropping 10mol/L, when pH is 7.5, cooling
To 10 DEG C；Carry out after cooling filtering, washing, after drying, i.e. can get cytosine 30.9g,
Yield 92.8%, HPLC content 99.4%.
Embodiment 7: Feldalat NM (24.3g, 0.45mol) is put into 150mL toluene
In reactor and stir；Be sequentially added into 3-hydroxy nitrile sodium salt (27.3g,
0.3mol) with thiourea (27.4g, 0.36mol), it is warming up to 90 DEG C and ring-closure reaction 8 is little
Time；Decompression steams toluene, and addition 70mL water and 95mL concentrated hydrochloric acid obtain slowly
Midbody solution；The hydrogen peroxide (51.0g, 0.45mol) of 30% is dripped in midbody solution,
Drip complete, be warming up to 80 DEG C and be incubated 20 hours；It is cooled to room temperature, drips 10mol/L
Sodium hydroxide solution regulation pH value, when pH is 7.5, be cooled to 15 DEG C；Cooling
After carry out filtering, washing, i.e. can get cytosine 30.3g after drying, yield 91.0%,
HPLC content 99.1%.
Embodiment 8: Feldalat NM (24.3g, 0.45mol) is put into reactor with dimethylbenzene
In and stir；Be sequentially added into 3-hydroxy nitrile sodium salt (27.3g, 0.3mol) and
Thiourea (27.4g, 0.36mol), is warming up to 90 DEG C of also ring-closure reaction 8 hours；Decompression is steamed
Go out dimethylbenzene, and addition water and hydrochloric acid obtain midbody solution slowly；Molten at intermediate
Liquid drips the hydrogen peroxide (51.0g, 0.45mol) of 30%, drips complete, be warming up to 80 DEG C
It is incubated 20 hours；It is cooled to room temperature, dropping sodium hydroxide solution regulation pH value, works as pH
When being 7.5, it is cooled to 15 DEG C；Carry out after cooling filtering, washing, after drying
To cytosine 30.5g, yield 91.5%, HPLC content 99.0%.
Using the present invention to prepare cytosine, its processing step prepared is simpler, produce week
Phase is short, low cost, and greatly reduces labor operations and energy consumption；And raw material of the present invention
Conversion ratio is high, and the good product quality of synthesis, yield are high, convenient post-treatment, are suitable for industry
Metaplasia is produced.
Claims (5)
1. the synthetic method of a cytosine, it is characterised in that: its step of preparation process is as follows: choose 3-
Hydroxy nitrile sodium salt and thiourea are as raw material；During preparation, first catalyst and organic solvent are put into reaction
In still, after stirring, it is sequentially added into 3-hydroxy nitrile sodium salt and thiourea；It is warmed up to 50～90 DEG C also
Ring-closure reaction 6～10 hours, obtain ring-closure reaction liquid；Steam the solvent in ring-closure reaction liquid, add water
Midbody solution is obtained with hydrochloric acid；In midbody solution, drip hydrogen peroxide, be warming up to 60～90 DEG C and protect
Temperature 18～24 hours；Regulate pH value with sodium hydroxide solution, when pH is 7.0～7.5, be cooled to
10～15 DEG C；Carry out after having cooled down filtering, washing, after drying, i.e. can get cytosine；Described 3-hydroxyl
Base acrylonitrile sodium salt is 1:1.05～1.5 with the molar ratio of thiourea；Described catalyst is Feldalat NM, ethanol
Any one in sodium, sodium isopropylate, sodium tert-butoxide or potassium tert-butoxide.
The synthetic method of cytosine the most according to claim 1, it is characterised in that: described 3-hydroxyl
Acrylonitrile sodium salt is 1:1.1～1.5 with the molar ratio of catalyst.
The synthetic method of cytosine the most according to claim 2, it is characterised in that: described 3-hydroxyl
Acrylonitrile sodium salt is 1:1.2～2 with the molar ratio of hydrogen peroxide.
4. according to the synthetic method of the cytosine described in claim 1 or 3, it is characterised in that have described in:
Machine solvent is any one in methanol, ethanol, isopropanol, the tert-butyl alcohol, toluene or dimethylbenzene.
The synthetic method of cytosine the most according to claim 4, it is characterised in that: described hydrogen peroxide
Mass fraction be 20%-30%.
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| 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 (3)
| 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 |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010024205A (en) * | 2008-07-23 | 2010-02-04 | Ube Ind Ltd | Method for preparing 5-methylcytosine |
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Patent Citations (3)
| 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 |
| 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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Address after: 317021, Taizhou City, Zhejiang Province, Yongquan Town, Taizhou City, after the Jing Yan tou Applicant after: ZHEJIANG XIANFENG SCIENCE TECHNOLOGY CO., LTD. Address before: 317021, Taizhou City, Zhejiang Province, Yongquan Town, Taizhou City, after the Jing Yan tou Applicant before: Zhejiang Xianfeng Technology Co., Ltd. |
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