CN111592539B - Preparation method of trifluoro-benzene pyrimidine - Google Patents
Preparation method of trifluoro-benzene pyrimidine Download PDFInfo
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- CN111592539B CN111592539B CN202010498427.4A CN202010498427A CN111592539B CN 111592539 B CN111592539 B CN 111592539B CN 202010498427 A CN202010498427 A CN 202010498427A CN 111592539 B CN111592539 B CN 111592539B
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a preparation method of trifluoro-benzene pyrimidine, which comprises the following steps: (1) Taking 30-35 parts of 2- (3- (trifluoromethyl) phenyl) malonate and 15-20 parts of N- (pyridine-5-ylmethyl) pyridine-2-amine, dissolving the two in a solvent, adding a catalyst, and carrying out sealed stirring reaction under the microwave condition to obtain a crude product; (2) And (3) decompressing the crude product to remove the solvent, adding ethyl acetate, stirring uniformly, and performing silica gel column chromatography to obtain the trifluoro-phenylpyrimidine. The invention utilizes 2- (3- (trifluoromethyl) phenyl) malonate and N- (pyridine-5-ylmethyl) pyridine-2-amine to directly react under the conditions of catalyst and microwave, the reaction process is only one step, the reaction process is greatly shortened, and the yield of the trifluoro-fluoropyrimidine is improved.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of trifluoro-phenylpyrimidine.
Background
Trifluoropyrimidine (Pemetrexed disc), chemically known as 3, 4-dihydro-2, 4-dioxo-1- (pyrimidin-5-ylmethyl) -3- (. Alpha.,. Alpha. -trifluoro-m-tolyl) -2H-pyrido [1, 2-. Alpha. ] pyrimidin-1-ium-3-salt, has the following structural formula 1:
trifluoropyrimidine is developed by DuPont, USA, for controlling rice planthopper, and acts on insect nicotinic acetylcholine receptor.
At present, trifluoro-benzene pyrimidine generally takes m-iodo trifluorotoluene and diethyl malonate as raw materials, and is subjected to Ullmann reaction and ester hydrolysis to synthesize active ester, and the active ester and substituted 2-aminopyridine are cyclized to generate a mesoionic compound 1, wherein the synthetic route is shown as the following formula:
in the existing synthesis process of trifluoro-phenylpyrimidine, complicated processes such as ester hydrolysis and active ester generation are carried out, the reaction process is long, the whole reaction yield is low, the wastewater generated by hydrolysis reaction is difficult to treat, and the like, so that the synthesis process is not beneficial to industrial production.
Disclosure of Invention
The invention aims to provide trifluoro-phenylpyrimidine with short reaction flow and high yield.
A preparation method of trifluoro-benzene pyrimidine comprises the following steps:
(1) Taking 30-35 parts of 2- (3- (trifluoromethyl) phenyl) malonate and 15-20 parts of N- (pyridine-5-ylmethyl) pyridine-2-amine, dissolving the two in a solvent, adding a catalyst, and carrying out sealed stirring reaction under the microwave condition to obtain a crude product;
(2) And (3) decompressing the crude product, removing the solvent, adding ethyl acetate, stirring uniformly, and performing silica gel column chromatography to obtain the trifluoro-phenylpyrimidine.
The beneficial effects of the invention are: 2- (3- (trifluoromethyl) phenyl) malonate and N- (pyridine-5-ylmethyl) pyridine-2-amine are directly reacted under the conditions of catalyst and microwave, the reaction process is only one step, the reaction process is greatly shortened, and the yield of the trifluoro-fluoropyrimidine is improved.
In addition, the trifluorobenzene pyrimidine provided by the invention can also have the following additional technical characteristics:
the 2- (3- (trifluoromethyl) phenyl) malonate may be any one of dimethyl 2- (3- (trifluoromethyl) phenyl) malonate, diethyl 2- (3- (trifluoromethyl) phenyl) malonate, dipropyl 2- (3- (trifluoromethyl) phenyl) malonate, diphenyl 2- (3- (trifluoromethyl) phenyl) malonate, di- (2, 4, 6-trichloro) phenyl 2- (3- (trifluoromethyl) phenyl) malonate, tert-butyl 2- (3- (trifluoromethyl) phenyl) malonate, dihexyl 2- (3- (trifluoromethyl) phenyl) malonate, dibutyl 2- (3- (trifluoromethyl) phenyl) malonate and diisopropyl 2- (3- (trifluoromethyl) phenyl) malonate.
Further, the solvent is N-methylimidazole or toluene.
Further, the catalyst is any one of N, N '-dicyclohexylcarbodiimide, benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, N, N' -carbonyldiimidazole, 6-chloro-1-hydroxy-benzotriazole, 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate, tetramethylchlorourea hexafluorophosphate, and 3- (diethoxyphosphoryl) -oxy-1, 2, 3-benzotriazin-4 (3H) -one.
Furthermore, the dosage of the catalyst is 20-30 parts, and the solvent is added into 1L of solute per 150-160 g of solute.
Further, the microwave condition is 2-6 GHz microwave environment, the environment temperature is 20-30 ℃, and the stirring lasts for 30min at 100-500 r/min.
Further, the step of removing the solvent under reduced pressure comprises:
and (3) putting the crude product into an oil bath pan at the temperature of between 60 and 70 ℃, and keeping the environmental vacuum degree to be more than 50mmHg for 60min.
Further, the environmental vacuum degree is increased from 50mmHg at a rate of 0.5-2 mmHg/min until the environmental vacuum degree reaches 100 mmHg.
Further, the column chromatography uses 100g of silica gel, and the mobile phase is ethyl acetate, chloroform or methanol.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the following examples, wherein:
FIG. 1 is a liquid chromatography spectrum of the product of example 1 of the present invention;
FIG. 2 is a single crystal plot of the product of example 1 of the present invention.
Detailed Description
In order to make the objects, features and advantages of the present invention comprehensible, specific embodiments accompanied with examples are described in detail below. Several embodiments of the invention are given in the examples. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Example 1
A preparation method of trifluoro-benzene pyrimidine comprises the following steps:
(1) Taking 30.43g of 2- (3- (trifluoromethyl) phenyl) malonate and 18.62g of N- (pyridine-5-ylmethyl) pyridine-2-amine, dissolving the two in 0.5L of N-methylimidazole, adding 28.06g of tetramethyl chlorourea hexafluorophosphate serving as a catalyst, and reacting under sealed stirring under a microwave condition to obtain a crude product;
(2) And (3) decompressing the crude product to remove the N-methylimidazole, adding ethyl acetate, uniformly stirring, and performing silica gel column chromatography to obtain the trifluoro-phenylpyrimidine.
The synthetic route of this example is shown below:
the method has the advantages that the 2- (3- (trifluoromethyl) phenyl) malonate and the N- (pyridine-5-ylmethyl) pyridine-2-amine are directly reacted under the conditions of a catalyst and microwaves, the reaction flow is only one step, the reaction flow is greatly shortened, and the yield of the trifluoro-phenylpyrimidine is improved.
In this example, the 2- (3- (trifluoromethyl) phenyl) malonate was diethyl 2- (3- (trifluoromethyl) phenyl) malonate.
Specifically, the microwave condition is a 4GHz microwave environment, the stirring lasts for 30min at 300r/min, the column chromatography adopts 100g of silica gel, and the adopted mobile phase is ethyl acetate.
In addition, the step of removing the solvent under reduced pressure is to place the crude product in an oil bath kettle at 60-70 ℃, and maintain the environmental vacuum degree of 50 mmHg-60 mmHg for 60min, wherein the temperature of the oil bath kettle and the environmental vacuum degree are floating.
Liquid chromatogram and single crystal pattern were obtained for the product obtained in this example, as shown in fig. 1 and 2, which are patterns of trifluorobenzene pyrimidine, indicating that the product of this example is trifluorobenzene pyrimidine of higher purity.
Example 2
A preparation method of trifluoro-benzene pyrimidine comprises the following steps:
(1) Taking 30.56g of 2- (3- (trifluoromethyl) phenyl) malonate and 18.07g of N- (pyridine-5-ylmethyl) pyridine-2-amine, dissolving the two in 0.5L of toluene, adding 28.12g of tetramethyl chlorourea hexafluorophosphate serving as a catalyst, and carrying out sealed stirring reaction under the microwave condition to obtain a crude product;
(2) And decompressing the crude product to remove toluene, adding ethyl acetate, stirring uniformly, and performing silica gel column chromatography to obtain the trifluoro-phenylpyrimidine.
In this example, the 2- (3- (trifluoromethyl) phenyl) malonate was diethyl 2- (3- (trifluoromethyl) phenyl) malonate, and toluene was used as a solvent.
Specifically, the microwave condition is a 4GHz microwave environment, the stirring lasts for 30min at 300r/min, the column chromatography adopts 100g of silica gel, and the adopted mobile phase is ethyl acetate chloroform.
In addition, the step of removing the solvent under reduced pressure is to place the crude product in an oil bath kettle at 60-70 ℃, and keep the environmental vacuum degree at 50-60 mmHg for 60min, wherein the temperature of the oil bath kettle and the environmental vacuum degree are floating.
Example 3
This embodiment is substantially the same as embodiment 2 except that:
during the reduced pressure removal of the solvent, the ambient vacuum was increased at a rate of 1mmHg/min starting at 50mmHg until the ambient vacuum reached 100mmHg for a total duration of 60min.
Example 4
This example is substantially the same as example 3, except that:
the catalyst adopts N, N' -dicyclohexylcarbodiimide.
Comparative example 1
A preparation method of trifluoro-benzene pyrimidine comprises the following steps:
(1) Taking 30.63g of 2- (3- (trifluoromethyl) phenyl) malonate, adding sodium hydroxide solution, and performing hydrolysis reaction to obtain 2- (3- (trifluoromethyl) phenyl) malonic acid;
(2) Reacting 2- (3- (trifluoromethyl) phenyl) malonic acid with 2,4, 6-trichlorophenol to obtain oxalyl chloride, wherein the mass of the 2,4, 6-trichlorophenol is 20.63g;
(3) Taking 18.22g of N- (pyridine-5-ylmethyl) pyridine-2-amine to react with 2,4, 6-trichlorophenol to obtain trifluoro-phenylpyrimidine.
The route for the preparation of oxalyl chloride in this control is shown below:
comparative example 2
This comparative example is substantially the same as example 3 except that:
the step (1) does not adopt the microwave condition, and the sealing and stirring are carried out at the temperature of 25 ℃.
Comparative example 3
This comparative example is substantially identical to example 3, except that:
the step (1) does not adopt the microwave condition, and the sealing and stirring are carried out under the condition that the electric heating wire is heated to 60 ℃.
The total mass of the product, the content of the trifluoropyrimidine and the reaction time length are measured by adopting the methods of the above examples and comparative examples for multiple times, wherein the reaction time length is obtained by taking a large amount of yellow precipitates generated in the preparation process as the reaction finishing time point, and the average results of the numerical values are shown in table 1.
TABLE 1
Referring to table 1, it can be seen from comparative example 1, example 2 and example 3 that when toluene is used as a solvent, the content of the resulting trifluorobenzene pyrimidine is higher, and when the solvent is removed under reduced pressure, the content of trifluorobenzene pyrimidine can be further increased by gradually increasing the vacuum degree;
as can be seen from example 4, when N, N' -dicyclohexylcarbodiimide is used as the catalyst, the content of trifluorobenzene pyrimidine in the obtained product is reduced compared with that in example 3;
the comparative example 1 can be understood as a conventional preparation process, the product purity is far lower than that of the embodiment of the invention, and the reaction time is longer;
as can be seen from comparative examples 2 and 3, the invention adopts microwave conditions, thereby greatly improving the purity of the product and reducing the reaction time to a certain extent.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is specific and detailed, but not to be understood as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (5)
1. The preparation method of trifluoro-benzene pyrimidine is characterized by comprising the following steps:
(1) Taking 30-35 parts of 2- (3- (trifluoromethyl) phenyl) malonate and 15-20 parts of N- (pyridine-5-ylmethyl) pyridine-2-amine, dissolving the two in a solvent, adding a catalyst, and carrying out sealed stirring reaction under a microwave condition to obtain a crude product;
wherein the solvent is N-methylimidazole or toluene; the catalyst is any one of N, N '-dicyclohexylcarbodiimide, benzotriazole-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate, N, N' -carbonyldiimidazole, 6-chloro-1-hydroxy-benzotriazole, 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate, tetramethylchlorourea hexafluorophosphate and 3- (diethoxyphosphoryl) -oxygen-1, 2, 3-benzotriazine-4 (3H) -ketone;
(2) Decompressing the crude product, removing the solvent, adding ethyl acetate, stirring uniformly, and performing silica gel column chromatography to obtain the trifluoro-phenylpyrimidine;
wherein the step of removing the solvent under reduced pressure comprises:
putting the crude product into an oil bath pan at the temperature of 60-70 ℃, and keeping the environmental vacuum degree to be more than 50mmHg for 60min; the environmental vacuum degree is increased from 50mmHg at a rate of 0.5-2 mmHg/min until the environmental vacuum degree reaches 100 mmHg.
2. The method for producing trifluoropyrimidine according to claim 1, wherein the 2- (3- (trifluoromethyl) phenyl) malonate is any one of dimethyl 2- (3- (trifluoromethyl) phenyl) malonate, diethyl 2- (3- (trifluoromethyl) phenyl) malonate, dipropyl 2- (3- (trifluoromethyl) phenyl) malonate, diphenyl 2- (3- (trifluoromethyl) phenyl) malonate, di- (2, 4, 6-trichloro) phenyl 2- (3- (trifluoromethyl) phenyl) malonate, tert-butyl 2- (3- (trifluoromethyl) phenyl) malonate, dihexyl 2- (3- (trifluoromethyl) phenyl) malonate, dibutyl 2- (3- (trifluoromethyl) phenyl) malonate, and diisopropyl 2- (3- (trifluoromethyl) phenyl) malonate.
3. The method for preparing trifluorobenzene pyrimidine according to claim 1, characterized in that the amount of the catalyst is 20-30 parts, and the solvent is 1L per 150-160 g of solute.
4. The method for preparing trifluorobenzene pyrimidine according to claim 1, wherein the microwave condition is 2-6 GHz microwave environment, and the stirring is continued for 30min at 100-500 r/min.
5. The method for preparing trifluorobenzene pyrimidine according to claim 1, characterized in that the column chromatography uses 100g of silica gel and the mobile phase is ethyl acetate, chloroform or methanol.
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| CN113325120B (en) * | 2021-06-17 | 2022-04-19 | 湖南农业大学 | Method for detecting content of trifluoro-benzene pyrimidine by GC-MS |
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| WO2012106495A1 (en) * | 2011-02-03 | 2012-08-09 | E. I. Du Pont De Nemours And Company | Mesoionic pesticides |
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| CN103459387A (en) * | 2010-12-29 | 2013-12-18 | 杜邦公司 | Mesoionic pyrido [1,2 -A] pyrimidine pesticides |
| WO2012106495A1 (en) * | 2011-02-03 | 2012-08-09 | E. I. Du Pont De Nemours And Company | Mesoionic pesticides |
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