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A kind of synthetic method of 2,4-dichloro-5-methoxypyrimidine

A technology of methoxypyrimidine and a synthesis method, applied in the field of fine chemical industry, can solve the problems of no economical efficiency, unfavorable industrialization, complicated post-processing and the like, and achieves the effects of reasonable selection of process conditions, easy operation and control, and avoidance of hydrolysis side reactions

Active Publication Date: 2016-06-08
DALIAN JOIN KING FINE CHEM CO LTD
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Problems solved by technology

The disadvantage of this method is that the amount of phosphorus oxychloride is too large, and the post-treatment is directly added to ice water after concentration or concentrated, so the heat release is very large, which is not conducive to industrialization, and when water is added under strong acidity, the product will undergo hydrolysis side reactions, resulting in a low yield. , only 20.8-75%
[0005] 2) solvent-free reaction, phosphorus oxychloride equivalent, and 2,4-dihydroxy-5-methoxypyrimidine react in a closed ceramic reactor under the action of equivalent alkali, the yield is 92%, but the reaction temperature It is a reaction at a high temperature of 180°C, and the reaction pressure reaches 0.12 MPa. Under such high temperature and high pressure, the corrosion of equipment by strong acidic substances is not conducive to industrial production [J.Org.Chem., 2011, 76, 4149-4153; CN102060782]
The disadvantage of this method is that it is difficult to extract and separate layers. The viscous substance in the water layer needs to be extracted with dichloroethane multiple times. The content of the product obtained by concentration is low, and recrystallization is required. Supplement to Volume 29 (1)]
[0007] Currently, there is no cost-effective, simple-to-operate, and industrially-suitable method report

Method used

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  • A kind of synthetic method of 2,4-dichloro-5-methoxypyrimidine
  • A kind of synthetic method of 2,4-dichloro-5-methoxypyrimidine

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preparation example Construction

[0020] 2,4-dichloro-5-methoxypyrimidine synthetic method of the present invention, its reaction principle is as shown in formula (1), and the concrete steps of this synthetic method are as follows:

[0021]

[0022] (1) Add 2,4-dihydroxy-5-methoxypyrimidine, solvent and phosphorus oxychloride to the reaction flask after nitrogen replacement and mix uniformly, and carry out reflux reaction after adding alkaline substance under stirring condition; The ratio of 2,4-dihydroxy-5-methoxypyrimidine, solvent and phosphorus oxychloride is 1moL: (500~1000) mL: (2.0~2.5) mol; the basic substance and 2,4- The molar ratio of dihydroxy-5-methoxypyrimidine is (1.0~1.5): 1, and the basic substance is triethylamine, pyridine or N,N dimethylaniline; the solvent is toluene, xylene or trimethylbenzene; the reaction temperature of the reflux reaction is 100-160° C., and the reaction time is 2-6 hours.

[0023] (2) After cooling the system after the reflux reaction in the reaction bottle to 0-4...

Embodiment 1

[0025] Put 14.3g (0.1mol, 99.5%, 1.0eq) of 2,4-dihydroxy-5-methoxypyrimidine, 100ml of toluene and 31.0g of phosphorus oxychloride (0.2mol, 99% , 2.0eq), start stirring, put in 12.0g of pyridine (0.15mol, 99%, 1.5eq), heat the system to 160°C for reflux reaction for 6h, the system becomes a brown-black solution, and LC detects that the reaction of raw materials is complete. The system was cooled to 10°C, 100ml of water was slowly added, stirred for 30min, separated into layers, the water layer was extracted once with 50ml of toluene, and the oil layers were combined for desolvation under reduced pressure to obtain 16.4g of the target product ( figure 1 ), the state is light yellow solid, the content (purity) is 98.6%, and the yield is 90.3%. 1H-NMR (400MHz, d6-DMSO) δ: 8.634 (1H, s), 4.015 (3H, s).

Embodiment 2

[0027] Put into 2,4-dihydroxy-5-methoxypyrimidine 14.3g (0.1mol, 99.5%, 1.0eq), xylene 80ml and phosphorus oxychloride 34.1g (0.22mol, 99 %, 2.2eq), stirring was started, and 12.3g (0.12mol, 99%, 1.2eq) of triethylamine was dropped in, and the system was heated to 160°C for reflux reaction for 4h, and the system became a brown-black solution, and the reaction of raw materials was detected by LC. Cool the system to 20°C, slowly add 80ml of water, stir for 30min, separate layers, extract the water layer once with 40ml of xylene, combine the oil layers and carry out desolvation under reduced pressure to obtain 17.0g of the target product in the form of a light yellow solid with a content of 98.5%. Yield 93.5%.

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Abstract

Belonging to the technical field of fine chemical technologies, the invention discloses a synthesis method for 2, 4-dichloro-5-methoxy pyrimidine. The process is summarized as: adding 2, 4-dihydroxyl-5-methoxy pyrimidine, a solvent and phosphorous oxychloride into a nitrogen replaced reaction system, starting stirring, adding an alkaline substance, and conducting heating reflux reaction. At the end of the reaction, a simple quenching aftertreatment process is carried out, and a high yield and high purity target product can be obtained. The method provided by the invention has the advantages of reasonable selection process conditions, mild reaction conditions, easy operation and control, and easy realization of industrialized production.

Description

technical field [0001] The invention relates to the technical field of fine chemicals, in particular to a method for synthesizing 2,4-dichloro-5-methoxypyrimidine. Background technique [0002] Chloropyrimidines are widely used in the synthesis of many medicines and pesticides. They can perform functional group conversion, and can also replace activated carbon atoms with chlorine to achieve various carbon-carbon bond couplings. 2,4-dichloro-5-methoxypyrimidine is an important intermediate of anti-tumor active compounds, and also an important intermediate for the preparation of sulfonamide super-efficient herbicide penoxsulam. [0003] In the literature related to the preparation of this compound, there are mainly three methods: [0004] 1) Phosphorus oxychloride is not only used as a reactant, but also as a reaction solvent. Under the effect of N,N-dimethylaniline, it reacts with 2,4-dihydroxy-5-methoxypyrimidine, and phosphorus oxychloride greatly Excess [WO2008092049; JM...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/34
CPCC07D239/34
Inventor 王俊春李雨于滨张永杰王荣良
Owner DALIAN JOIN KING FINE CHEM CO LTD
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