CN111039874A - Zero-wastewater preparation method of 2-amino-4-methylpyrimidine compound - Google Patents
Zero-wastewater preparation method of 2-amino-4-methylpyrimidine compound Download PDFInfo
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- CN111039874A CN111039874A CN201911288970.5A CN201911288970A CN111039874A CN 111039874 A CN111039874 A CN 111039874A CN 201911288970 A CN201911288970 A CN 201911288970A CN 111039874 A CN111039874 A CN 111039874A
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- 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 invention discloses a zero wastewater preparation method of a 2-amido-4-methylpyrimidine compound, in particular to a method for preparing a product by reacting 4, 4-dimethoxy-2-butanone and guanidine hydrochloride under the alkali condition and simply post-treating. The method solves the problem of a large amount of wastewater generated in the prior production because no process wastewater is generated. The operation process is simple and stable, the safety is high, the energy consumption is low, and the industrial implementation is easy.
Description
Technical Field
The invention discloses a preparation method of a 2-amido-4-methylpyrimidine compound.
Background
2-amido-4-methylpyrimidine is a nitrogen heterocyclic compound with good biological activity, has important physiological action in organisms, and is widely applied to the synthesis of medicines and pesticides. Shephard et al reported bactericidal activity in 1968 in a manner that interferes with the translocation process of cellular endocrine proteins. Has excellent control effect on apple brown rot, scab and gray mold, and has good control effect on powdery mildew, citrus resina diseases, black spot, leaf spot and diseases generated by alternaria. Meanwhile, the 2-amido-4-methylpyrimidine is also an intermediate of the ultra-efficient sulfonylurea herbicides monosulfuron-methyl and monosulfuron-ester.
The synthesis of 2-amino-4-methylpyrimidine has been reported in a number of documents, for example: mark C.Bagley et al, Synlett 2003,2, 259-261, have proposed the reaction of a methyl alkynyl ketone as a starting material with guanidine under the action of a base to obtain 2-amino-4-methylpyrimidine, but this method has significant limitations, such as the difficulty in obtaining the starting material, the need for microwave reaction, and the disadvantage of industrialization. The method for preparing the product by using the toluene as a solvent in CN101851229A by Liu Hai et al has the defects that the yield is low and can only reach 50 percent after being optimized by authors, and the acetone and ethyl formate are condensed under the condition of sodium alkoxide and then are subjected to ring closure with guanidine hydrochloride. Meanwhile, when distilling low boiling substances, a large amount of solvent needs to be taken out due to azeotropy of toluene and raw materials, and a large amount of water washing is needed in the process of recovering the solvent, thus generating wastewater. And the pouring operation is not well realized in the production process.
Disclosure of Invention
Based on the problems, the invention provides a simple preparation method of 2-amido-4-methylpyrimidine, which has simple process and mild conditions and can solve the existing wastewater problem and the technical problem that industrialization is difficult to realize.
The purpose of the invention is realized by the following scheme:
a method for preparing 2-amino-4-methylpyrimidine shown in the figure comprises the following steps: in a solvent, 4, 4-dimethoxy-2-butanone and guanidine hydrochloride undergo a ring-closing reaction under the alkali condition to obtain a product.
The reaction equation is as follows:
the specific preparation method provided by the invention comprises the following steps:
the solvent is stirred with addition of the sodium alkoxide in portions. Triturated guanidine hydrochloride (guanidine nitrate) was added in portions to allow thorough contact of the materials. After stirring for a period of time, the temperature is gradually increased, and neutralization reaction is carried out under a certain temperature to release free guanidine.
The raw material 4, 4-dialkoxy-2-butanone is added. The temperature was increased to continue stirring. Then heated to reflux for 2 hours. Heating, rectifying and steaming low-boiling-point substances, gradually raising the temperature of the solution, and stopping heating when the temperature of the solution reaches 110 ℃. Starting hot filtration, keeping the whole filtration system at a certain temperature, adding the reaction solution, hot filtering, removing salt, and cooling and crystallizing the filtrate to obtain the product.
4, 4-dialkoxy-2-butanone described in the present invention: sodium alcoholate: the feeding molar ratio of guanidine is 1: 1-1.5, preferably 1: 1-1.1: 1-1.2.
The solvent is toluene, xylene or chlorobenzene, preferably toluene, and the amount of the solvent is 5-10 times of that of the raw material sodium alkoxide.
The sodium alkoxide in the invention is sodium methoxide, sodium ethoxide, sodium isopropoxide and sodium tert-butoxide, and sodium methoxide or sodium ethoxide is preferred.
The guanidine in the invention is guanidine hydrochloride or guanidine nitrate.
The alkyl in the 4, 4-dialkoxy-2-butanone disclosed by the invention is methyl, ethyl and isopropyl. Methyl is preferred.
The neutralization reaction temperature is 10-50 ℃, the preferable temperature is 20-40 ℃, and the reaction time is 0.5-5 h.
The temperature of the ring closing reaction is 30-100 ℃, preferably 50-70 ℃, and the reaction time is 1-5 h.
The hot filtration temperature in the invention is 60-150 ℃, and preferably 80-110 ℃.
Compared with the prior art, the invention has the following advantages: the whole reaction does not produce waste water, belongs to a zero waste water process, and is easy for industrial production. Has good application value.
Description of the drawings:
FIG. 1: a preparation method of a 2-amino-4-methylpyrimidine compound, and a reaction equation.
Detailed Description
In order to better describe the invention, through the following examples to specific representation, but the invention is not limited by these examples.
Example 1: a clean and dry four-necked flask was charged with 350ml of toluene, and 50g of sodium methoxide was added thereto in portions with stirring. The temperature of the kettle is adjusted to be between 28 and 32 ℃ through a water bath, 85g of ground guanidine hydrochloride is added in batches, the temperature of the water bath is controlled to be between 28 and 35 ℃, and stirring is carried out for 2 hours at the temperature. 110g of raw material 4, 4-dimethoxy-2-butanone is added. The temperature is raised to 55-60 ℃ and stirred. Stirring was continued for 1 hour. Then heated to reflux for 2 hours. Heating, rectifying and steaming low-boiling-point substances, gradually raising the temperature of the solution, and stopping heating when the temperature of the solution reaches 110 ℃. Starting thermal filtration, keeping the temperature of the whole filtration system to about 100 ℃, adding the reaction solution, filtering, removing salt, cooling the filtrate to 10 ℃, crystallizing to obtain a product, and reheating and filtering the salt with toluene mother liquor twice. Drying the product obtained by twice crystallization to obtain the product 2-amido-4-methylpyrimidine: 77g, purity 93.5%.
Example 2: a clean and dry four-mouth bottle is taken, 200ml of dimethylbenzene is added, and 31.5g of sodium ethoxide is added in batches under stirring. The temperature of the kettle is adjusted to be between 28 and 32 ℃ through a water bath, 42.5g of ground guanidine hydrochloride is added in batches, the temperature of the water bath is controlled to be between 28 and 35 ℃, and stirring is carried out for 2 hours at the temperature. Adding raw material 4, 4-dimethoxy-2-butanone. The temperature is raised to 55-60 ℃ and stirred. Stirring was continued for 1 hour. Then heated to reflux for 2 hours. Heating, rectifying and steaming low-boiling-point substances, gradually raising the temperature of the solution, and stopping heating when the temperature of the solution reaches 110 ℃. Starting thermal filtration, keeping the temperature of the whole filtration system to be about 100 ℃, adding the reaction solution, filtering, removing salt, cooling the filtrate to be about 10 ℃, crystallizing to obtain a product, and reheating and filtering the salt by using xylene mother liquor twice to obtain the relatively pure sodium chloride. Drying the product obtained by twice crystallization to obtain the product 2-amido-4-methylpyrimidine: 37.4g, purity 94.1%.
Claims (9)
1. A zero wastewater preparation method of 2-amido-4-methylpyrimidine is characterized by comprising the following steps:
the method comprises the following steps: adding sodium methoxide into a solvent in batches under stirring, adding smashed guanidine hydrochloride into the solvent in batches, fully contacting the materials, stirring for a period of time, gradually raising the temperature, controlling the stirring at a certain temperature, adding the raw material 4, 4-alkyl methoxyl-2-butanone, raising the temperature, continuously stirring, heating and refluxing for 2 hours, heating, rectifying and steaming low-boiling-point substances, gradually raising the temperature of the solution, stopping heating when the temperature of the solution reaches 110 ℃, starting thermal filtration, keeping the whole filtration system at a certain temperature, adding the reaction solution, filtering, removing salt, and cooling and crystallizing the filtrate to obtain the product.
2. The process of claim 1, wherein the ratio of 4, 4-dimethoxy-2-butanone: sodium methoxide: the feeding molar ratio of the guanidine hydrochloride is 1: 1-1.5, preferably 1: 1-1.1: 1-1.2.
3. The method according to claim 1, characterized in that the solvent is toluene, xylene or chlorobenzene, preferably toluene, and the amount of the solvent is 5 to 10 times of the amount of the sodium methoxide.
4. A process according to claim 1, characterized in that the sodium alkoxide is sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, preferably sodium methoxide or sodium ethoxide.
5. The method of claim 1, wherein the guanidine is guanidine hydrochloride or guanidine nitrate.
6. A process according to claim 1, wherein the alkyl group in the 4, 4-dialkoxy-2-butanone is methyl, ethyl or isopropyl. Methyl is preferred.
7. The process according to claim 1, wherein the neutralization reaction is carried out at a temperature of 10 to 50 ℃, preferably 20 to 40 ℃, for a time of 0.5 to 5 hours.
8. The process according to claim 1, wherein the temperature of the ring closure reaction is 30 to 100 ℃, preferably 50 to 70 ℃, and the reaction time is 1 to 3 hours.
9. A process according to claim 1, characterized in that the hot filtration temperature is 60 to 150 ℃, preferably 80 to 110 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101851229A (en) * | 2010-06-11 | 2010-10-06 | 浙江工业大学 | N-substituted pyridine acyl-N-substituted pyrimidyl thiourea derivant as well as preparation and application thereof |
| CN107108644A (en) * | 2014-11-11 | 2017-08-29 | 皮奎尔治疗公司 | Difluoromethyl aminopyridine and difluoromethyl aminopyrimidine |
| CN107619388A (en) * | 2016-07-13 | 2018-01-23 | 南京天印健华医药科技有限公司 | Heterocyclic compound as FGFR inhibitor |
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2019
- 2019-12-13 CN CN201911288970.5A patent/CN111039874B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101851229A (en) * | 2010-06-11 | 2010-10-06 | 浙江工业大学 | N-substituted pyridine acyl-N-substituted pyrimidyl thiourea derivant as well as preparation and application thereof |
| CN107108644A (en) * | 2014-11-11 | 2017-08-29 | 皮奎尔治疗公司 | Difluoromethyl aminopyridine and difluoromethyl aminopyrimidine |
| CN107619388A (en) * | 2016-07-13 | 2018-01-23 | 南京天印健华医药科技有限公司 | Heterocyclic compound as FGFR inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| PIERRE BANNWARTH ET AL.: "Flexible Synthesis of Pyrimidines with Chiral Monofluorinated and Difluoromethyl Side Chains", 《J. ORG. CHEM.》 * |
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