CN108503592A - A kind of synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of fluorine-containing miazines medicine intermediate 2,4- - Google Patents
A kind of synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of fluorine-containing miazines medicine intermediate 2,4- Download PDFInfo
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- CN108503592A CN108503592A CN201810338370.4A CN201810338370A CN108503592A CN 108503592 A CN108503592 A CN 108503592A CN 201810338370 A CN201810338370 A CN 201810338370A CN 108503592 A CN108503592 A CN 108503592A
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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
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Abstract
The present invention relates to a kind of synthetic methods of fluorine-containing 2,4 dichloro of miazines medicine intermediate, 5 trifluoromethyl pyrimidine, include the following steps：(1) uracil, Sodium trifluoromethanesulfinate, persulfate and water are added in the reaction vessel, controlling reaction temperature obtains 5 trifluoromethyl uracils after reaction；(2) 5 trifluoromethyl uracils, phosphorus oxychloride, diisopropyl ethyl amine are added in pressure reacting container, are reacted at being 150~220 DEG C in reaction temperature, product is obtained after reaction.Only with water as solvent in the preparation process of 5 trifluoromethyl uracils of the invention, any other organic solvent or organic radical initiator are not used, post-processing is simple, and product purity is high, can directly carry out the reaction of next step, easy to operate, and pollution is few, at low cost；By using pressure reacting container, reaction temperature is improved, and the dosage of phosphorus oxychloride is greatly reduced, reduces the three wastes and generate, meet Atom economy.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of fluorine-containing miazines medicine intermediate 2, bis- chloro- 5- tri- of 4-
The synthetic method of fluoromethyl pyrimidine.
Background technology
Bis- chloro- 5- trifluoromethyl pyrimidines of the 2,4- medicine intermediate useful as one is widely used in various containing fluoropyrimidine
In the preparation of class drug.
So far, synthetic method includes mainly：
Chinese patent CN106117149A is disclosed and is first carried out then method that the chloro of pyrimidine carries out trifluoromethylation, this
Kind method needs to use toxic chlorine, and the narration of related patents is all very simple.European patent EP 2213663 by 2,
The fluoro of bis- chloro- 5- trichloromethyls pyrimidines of 4- prepares 2,4-, bis- chloro- 5- trifluoromethyl pyrimidines and needs to use in this process
It is bigger to react and environmental pollution very high to requirement of experiment for hydrofluoric acid or hydrofluoric acid complex.In order to overcome drawbacks described above, specially
Sharp CN106083828A, CN105461695A, US20140135497, CN102060782A etc. pass through phosphorus pentachloride or trichlorine oxygen
The chlorinating agents such as phosphorus, the chloro to 5- trifluoromethyl uracils are to prepare the most general side of 2,4-, bis- chloro- 5- trichloromethyls pyrimidines
Method, but such method generally existing chlorinating agent is significantly excessive (3 times or 3 times of mole dosage or more), post-processing trouble, ring
Pollute the problems such as big in border.
Synthesis for chloro raw material 5- trifluoromethyl uracils, document are mainly reacted by the trifluoromethylation of uracil
It is made.But it is required for using organic radical initiator or organic radical initiator in the synthesis of existing literature or patent
Auxiliary agent carries out in presence of organic solvent, and most organic free radical reactions are difficult to control, and the use of organic solvent is but also anti-
The pollution answered increases.
Invention content
In order to overcome the shortcomings of the prior art, the present invention provides a kind of fluorine-containing miazines medicine intermediate 2,4- bis-
The synthetic method of chloro- 5- trifluoromethyl pyrimidines (II) and its precursor 5- trifluoromethyl uracils (I).
The technical solution adopted by the present invention is as follows：
A kind of fluorine-containing miazines medicine intermediate 2, the synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of 4-, including following steps
Suddenly：
(1) uracil, Sodium trifluoromethanesulfinate, persulfuric acid are added in the reaction vessel equipped with thermometer, blender
Salt and water, 30~90 DEG C of controlling reaction temperature, reaction 1~9h times post-process to obtain 5- trifluoromethyl uracils (I)；
(2) 5- trifluoromethyl uracils (I), phosphorus oxychloride, the diisopropyl ethyl amine (DIPEA) obtained step (1)
It is added in pressure reacting container, 3~15h of heating reaction under conditions of reaction temperature is 150~220 DEG C, after reaction
It is cooled to room temperature, post-processes, obtain product.
Preferably, in step (1), the persulfate is potassium peroxydisulfate, persulfuric acid calcium, sodium peroxydisulfate, persulfuric acid
It is one or more in magnesium, ammonium persulfate, persulfuric acid ferrous iron, persulfuric acid copper, persulfuric acid lithium, persulfuric acid zinc, AMMONIUM PER SULFATE.
Preferably, in step (1), the mass ratio of the water and uracil is 10~30：1.
Preferably, in step (1), the molar ratio of the uracil and Sodium trifluoromethanesulfinate is 1：1~3.
Preferably, in step (1), the molar ratio of the uracil and persulfate is 1：1~3.
Preferably, in step (1), it is 50~70 DEG C to answer temperature.
Preferably, in step (2), the molar ratio of the 5- trifluoromethyl uracils and phosphorus oxychloride is 1：0.75~
2。
Preferably, in step (2), the molar ratio of the 5- trifluoromethyl uracils and diisopropyl ethyl amine is 5
~10：1.
Preferably, in step (2), reaction temperature is 160~170 DEG C.
Preferably, the fluorine-containing miazines medicine intermediate 2, the synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of 4-, packet
Include following step：
(1) 11.2 grams of uracils, 23.4 grams of trifluoromethyl Asia sulphurs are added in the reaction vessel equipped with thermometer, blender
Sour sodium is added 150 milliliters of water and makes it dissolve, and increases temperature to 60 DEG C, controlling reaction temperature is added portionwise 50 grams at 60~65 DEG C
Sodium peroxydisulfate and 5 grams of persulfuric acid copper mixtures, after reacting 6 hours, cooling to be precipitated after boiling off 100 milliliters of water, filtration drying obtains
To 5- trifluoromethyl uracils；
(2) 16 grams of 5- trifluoromethyl uracils, 23 grams of trichlorine oxygen are added in the pressure vessel equipped with thermometer, blender
Phosphorus, 0.19 gram of diisopropyl ethyl amine, 165 DEG C of controlling reaction temperature, heating reaction 9 hours are cooled to room temperature after reaction,
It is evaporated under reduced pressure to product.
The beneficial effects of the present invention are：
(1) only with water as solvent in the preparation process of 5- trifluoromethyl uracils (I) of the present invention, any other is not used
Organic solvent or organic radical initiator, post-processing is simple, and product purity is high, can directly carry out the reaction of next step, grasps
Make simply, pollution is few, at low cost；
(2) by using pressure reacting container, reaction temperature is improved, and the dosage of phosphorus oxychloride is greatly reduced, subtracted
Few three wastes generate, and meet Atom economy.
Specific implementation mode
The present invention is further explained in the light of specific embodiments, but invention which is intended to be protected is not limited to
This.
Embodiment 1
11.2 grams of uracils (0.1 mole), 23.4 grams of fluoroforms are added in the reaction vessel equipped with thermometer, blender
Base sulfinic acid sodium (0.15 mole) is added 150 milliliters of water and makes it dissolve, and increases temperature to 60 DEG C, controlling reaction temperature 60~
65 DEG C, 50 grams of sodium peroxydisulfates and 5 grams of persulfuric acid copper mixtures are added portionwise, it is cooling after boiling off 100 milliliters of water after reacting 6 hours
It is precipitated, filtration drying, obtains 14.7 grams of 5- trifluoromethyl uracils (I), HPLC is more than 99%, yield 91.9%.
16 grams of 5- trifluoromethyl uracils (I) (0.1 mole) are added in the pressure vessel equipped with thermometer, blender,
23 grams of phosphorus oxychloride (0.15 mole), 0.19 gram of DIPEA (0.015 mole), 165 DEG C of controlling reaction temperature, heating reaction 9 are small
When, it is cooled to room temperature after reaction, is evaporated under reduced pressure to 20.6 grams of product, HPLC is more than 99.5%, yield 94.9%.
Embodiment 2
11.2 grams of uracils (0.1 mole), 15.6 grams of fluoroforms are added in the reaction vessel equipped with thermometer, blender
Base sulfinic acid sodium (0.1 mole) is added 112 milliliters of water and makes it dissolve, and increases temperature to 30 DEG C, controlling reaction temperature is 30~40
DEG C, 81 grams of potassium peroxydisulfates (0.3 mole) are added portionwise, it is cooling to be precipitated after boiling off 60 milliliters of water after reacting 9 hours, it crosses and is filtered dry
It is dry, 13.4 grams of 5- trifluoromethyl uracils (I) are obtained, HPLC is more than 99%, yield 83.7%.
16 grams of 5- trifluoromethyl uracils (I) (0.1 mole) are added in the pressure vessel equipped with thermometer, blender,
11.5 grams of phosphorus oxychloride (0.075 mole), 0.26 gram of DIPEA (0.02 mole), 220 DEG C of controlling reaction temperature, heating reaction 15
Hour, it is cooled to room temperature after reaction, is evaporated under reduced pressure to 18.4 grams of product, HPLC is more than 99.5%, yield 84.8%.
Embodiment 3
11.2 grams of uracils (0.1 mole), 46.8 grams of fluoroforms are added in the reaction vessel equipped with thermometer, blender
Base sulfinic acid sodium (0.3 mole) is added 336 milliliters of water and makes it dissolve, and increases temperature to 85 DEG C, controlling reaction temperature is 85~90
DEG C, 27 grams of potassium peroxydisulfates (0.1 mole) are added portionwise, it is cooling to be precipitated after boiling off 270 milliliters of water after reacting 5 hours, it crosses and is filtered dry
It is dry, 11.4 grams of 5- trifluoromethyl uracils (I) are obtained, HPLC is more than 99%, yield 71.2%.
16 grams of 5- trifluoromethyl uracils (I) (0.1 mole) are added in the pressure vessel equipped with thermometer, blender,
30.6 grams of phosphorus oxychloride (0.2 mole), 0.13 gram of DIPEA (0.01 mole), 150 DEG C of controlling reaction temperature, heating reaction 3 are small
When, it is cooled to room temperature after reaction, is evaporated under reduced pressure to 18.2 grams of product, HPLC is more than 99.5%, yield 83.9%.
Embodiment 4
11.2 grams of uracils (0.1 mole), 23.4 grams of fluoroforms are added in the reaction vessel equipped with thermometer, blender
Base sulfinic acid sodium (0.15 mole) is added 150 milliliters of water and makes it dissolve, and increases temperature to 60 DEG C, controlling reaction temperature 60~
65 DEG C, 54 grams of potassium peroxydisulfates and 5 grams of persulfuric acid ferrous iron mixtures are added portionwise, it is cold after boiling off 100 milliliters of water after reacting 6 hours
But it is precipitated, filtration drying, obtains 14.4 grams of 5- trifluoromethyl uracils (I), HPLC is more than 99%, yield 90%.
16 grams of 5- trifluoromethyl uracils (I) (0.1 mole) are added in the pressure vessel equipped with thermometer, blender,
16.9 grams of phosphorus oxychloride (0.11 mole), (0.02 mole, 165 DEG C of controlling reaction temperature, it is small that heating reacts 5 to 0.26 gram of DIPEA
When, it is cooled to room temperature after reaction, is evaporated under reduced pressure to 18.4 grams of product, HPLC is more than 99.5%, yield 84.8%.
Embodiment 5
11.2 grams of uracils (0.1 mole), 23.4 grams of fluoroforms are added in the reaction vessel equipped with thermometer, blender
Base sulfinic acid sodium (0.15 mole) is added 150 milliliters of water and makes it dissolve, and increases temperature to 60 DEG C, controlling reaction temperature 60~
65 DEG C, 54 grams of sodium peroxydisulfates and 5 grams of persulfuric acid calcium compounds are added portionwise, it is cooling after boiling off 100 milliliters of water after reacting 6 hours
It is precipitated, filtration drying, obtains 14.1 grams of 5- trifluoromethyl uracils (I), HPLC is more than 99%, yield 88.1%.
16 grams of 5- trifluoromethyl uracils (I) (0.1 mole) are added in the pressure vessel equipped with thermometer, blender,
16.9 grams of phosphorus oxychloride (0.11 mole), 0.26 gram of DIPEA (0.02 mole), 170 DEG C of controlling reaction temperature, heating reaction 5 are small
When, it is cooled to room temperature after reaction, is evaporated under reduced pressure to 19.2 grams of product, HPLC is more than 99.5%, yield 88.5%.
Embodiment 6
11.2 grams of uracils (0.1 mole), 23.4 grams of fluoroforms are added in the reaction vessel equipped with thermometer, blender
Base sulfinic acid sodium (0.15 mole) is added 150 milliliters of water and makes it dissolve, and increases temperature to 60 DEG C, controlling reaction temperature 60~
65 DEG C, 54 grams of potassium peroxydisulfates and 5 grams of ammonium persulfate mixtures are added portionwise, it is cooling after boiling off 100 milliliters of water after reacting 6 hours
It is precipitated, filtration drying, obtains 12.7 grams of 5- trifluoromethyl uracils (I), HPLC is more than 99%, yield 79.4%.
16 grams of 5- trifluoromethyl uracils (I) (0.1 mole) are added in the pressure vessel equipped with thermometer, blender,
16.9 grams of phosphorus oxychloride (0.11 mole), 0.13 gram of DIPEA (0.01 mole), 175 DEG C of controlling reaction temperature, heating reaction 5 are small
When, it is cooled to room temperature after reaction, is evaporated under reduced pressure to 18.9 grams of product, HPLC is more than 99.5%, yield 87.1%.
Embodiment 7
11.2 grams of uracils (0.1 mole), 23.4 grams of fluoroforms are added in the reaction vessel equipped with thermometer, blender
Base sulfinic acid sodium (0.15 mole) is added 150 milliliters of water and makes it dissolve, and increases temperature to 60 DEG C, controlling reaction temperature 60~
65 DEG C, 50 grams of persulfuric acid lithiums and 5 grams of AMMONIUM PER SULFATE mixtures are added portionwise, it is cooling after boiling off 100 milliliters of water after reacting 6 hours
It is precipitated, filtration drying, obtains 11.9 grams of 5- trifluoromethyl uracils (I), HPLC is more than 99%, yield 74.4%.
16 grams of 5- trifluoromethyl uracils (I) (0.1 mole) are added in the pressure vessel equipped with thermometer, blender,
16.9 grams of phosphorus oxychloride (0.11 mole), 0.26 gram of DIPEA (0.02 mole), 180 DEG C of controlling reaction temperature, heating reaction 7 are small
When, it is cooled to room temperature after reaction, is evaporated under reduced pressure to 19.5 grams of product, HPLC is more than 99.5%, yield 89.9%.
Embodiment 8
11.2 grams of uracils (0.1 mole), 23.4 grams of fluoroforms are added in the reaction vessel equipped with thermometer, blender
Base sulfinic acid sodium (0.15 mole) is added 150 milliliters of water and makes it dissolve, and increases temperature to 60 DEG C, controlling reaction temperature 60~
65 DEG C, 54 grams of potassium peroxydisulfates and 5 grams of persulfuric acid zinc mixtures are added portionwise, it is cooling after boiling off 100 milliliters of water after reacting 6 hours
It is precipitated, filtration drying, obtains 12.8 grams of 5- trifluoromethyl uracils (I), HPLC is more than 99%, yield 80%.
16 grams of 5- trifluoromethyl uracils (I) (0.1 mole) are added in the pressure vessel equipped with thermometer, blender,
23 grams of phosphorus oxychloride (0.15 mole), 0.26 gram of DIPEA (0.02 mole), 185 DEG C of controlling reaction temperature, heating reaction 6 hours,
It is cooled to room temperature after reaction, is evaporated under reduced pressure to 19.9 grams of product, HPLC is more than 99.5%, yield 91.7%.
Above-described embodiment is not for the limitation of the present invention, and the present invention is not limited only to above-described embodiment, as long as meeting
The present invention claims all belong to the scope of protection of the present invention.
Claims (10)
1. a kind of fluorine-containing miazines medicine intermediate 2, the synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of 4-, it is characterised in that packet
Include following step：
(1) be added uracil in the reaction vessel equipped with thermometer, blender, Sodium trifluoromethanesulfinate, persulfate and
Water, 30~90 DEG C of controlling reaction temperature, reaction 1~9h times post-process to obtain 5- trifluoromethyl uracils；
(2) 5- trifluoromethyl uracils, phosphorus oxychloride, diisopropyl ethyl amine that step (1) obtains are added to stress reaction
In container, 3~15h of heating reaction, is cooled to room temperature after reaction under conditions of reaction temperature is 150~220 DEG C, rear to locate
Reason, obtains product.
2. fluorine-containing miazines medicine intermediate 2 according to claim 1, the synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of 4-,
It is characterized in that：In step (1), the persulfate is potassium peroxydisulfate, persulfuric acid calcium, sodium peroxydisulfate, persulfuric acid magnesium, over cure
It is one or more in sour ammonium, persulfuric acid ferrous iron, persulfuric acid copper, persulfuric acid lithium, persulfuric acid zinc, AMMONIUM PER SULFATE.
3. fluorine-containing miazines medicine intermediate 2 according to claim 1, the synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of 4-,
It is characterized in that：In step (1), the mass ratio of the water and uracil is 10~30：1.
4. fluorine-containing miazines medicine intermediate 2 according to claim 1, the synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of 4-,
It is characterized in that：In step (1), the molar ratio of the uracil and Sodium trifluoromethanesulfinate is 1：1~3.
5. fluorine-containing miazines medicine intermediate 2 according to claim 1, the synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of 4-,
It is characterized in that：In step (1), the molar ratio of the uracil and persulfate is 1：1~3.
6. fluorine-containing miazines medicine intermediate 2 according to claim 1, the synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of 4-,
It is characterized in that：In step (1), it is 50~70 DEG C to answer temperature.
7. fluorine-containing miazines medicine intermediate 2 according to claim 1, the synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of 4-,
It is characterized in that：In step (2), the molar ratio of the 5- trifluoromethyl uracils and phosphorus oxychloride is 1：0.75~2.
8. fluorine-containing miazines medicine intermediate 2 according to claim 1, the synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of 4-,
It is characterized in that：In step (2), the molar ratio of the 5- trifluoromethyl uracils and diisopropyl ethyl amine is 5~10：1.
9. fluorine-containing miazines medicine intermediate 2 according to claim 1, the synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of 4-,
It is characterized in that：In step (2), reaction temperature is 160~170 DEG C.
10. the synthesis side of bis- chloro- 5- trifluoromethyl pyrimidines of fluorine-containing miazines medicine intermediate 2,4- according to claim 1
Method, it is characterised in that include the following steps：
(1) 11.2 grams of uracils, 23.4 grams of trifluoromethanesulpacidc acidcs are added in the reaction vessel equipped with thermometer, blender
Sodium is added 150 milliliters of water and makes it dissolve, and increases temperature to 60 DEG C, 50 grams of mistakes are added portionwise at 60~65 DEG C in controlling reaction temperature
Sodium sulphate and 5 grams of persulfuric acid copper mixtures, after reacting 6 hours, cooling to be precipitated after boiling off 100 milliliters of water, filtration drying obtains
5- trifluoromethyl uracils；
(2) 16 grams of 5- trifluoromethyl uracils of addition in the pressure vessel equipped with thermometer, blender, 23 grams of phosphorus oxychloride,
0.19 gram of diisopropyl ethyl amine, 165 DEG C of controlling reaction temperature, heating reaction 9 hours are cooled to room temperature, subtract after reaction
Pressure distills to obtain product.
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| CN201810338370.4A CN108503592A (en) | 2018-04-16 | 2018-04-16 | A kind of synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of fluorine-containing miazines medicine intermediate 2,4- |
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| CN201810338370.4A CN108503592A (en) | 2018-04-16 | 2018-04-16 | A kind of synthetic method of bis- chloro- 5- trifluoromethyl pyrimidines of fluorine-containing miazines medicine intermediate 2,4- |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102060782A (en) * | 2010-11-18 | 2011-05-18 | 孙智华 | Method for preparing chloropyrimidines or analogues thereof |
| CN103539747A (en) * | 2013-09-24 | 2014-01-29 | 重庆紫光化工股份有限公司 | Preparation method of 4,6-dichloropyrimidine |
| US20140135497A1 (en) * | 2012-11-13 | 2014-05-15 | Boehringer Ingelheim International Gmbh | Synthesis of 2,4-dichloro-5-trifluoromethyl-pyrimidine |
| CN103880760A (en) * | 2014-04-18 | 2014-06-25 | 南京安源生物医药科技有限公司 | Synthesis method of 5-(trifluoromethyl) uracil |
| CN107652341A (en) * | 2017-11-10 | 2018-02-02 | 上海兆维科技发展有限公司 | The improved method that one kind prepares " Trifluridine " |
-
2018
- 2018-04-16 CN CN201810338370.4A patent/CN108503592A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102060782A (en) * | 2010-11-18 | 2011-05-18 | 孙智华 | Method for preparing chloropyrimidines or analogues thereof |
| US20140135497A1 (en) * | 2012-11-13 | 2014-05-15 | Boehringer Ingelheim International Gmbh | Synthesis of 2,4-dichloro-5-trifluoromethyl-pyrimidine |
| CN103539747A (en) * | 2013-09-24 | 2014-01-29 | 重庆紫光化工股份有限公司 | Preparation method of 4,6-dichloropyrimidine |
| CN103880760A (en) * | 2014-04-18 | 2014-06-25 | 南京安源生物医药科技有限公司 | Synthesis method of 5-(trifluoromethyl) uracil |
| CN107652341A (en) * | 2017-11-10 | 2018-02-02 | 上海兆维科技发展有限公司 | The improved method that one kind prepares " Trifluridine " |
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