CN103387547B - A kind of method preparing phonetic mite amine - Google Patents

Abstract

The invention discloses a method for preparing pyrimethanil: firstly salting pyrimidinol under alkaline conditions, and then reacting with benzyl chloride to obtain a product. The preparation method of the invention avoids the generation of by-product N-alkylated isomers, the product obtained by the method has high yield and high purity, reduces production cost and is suitable for industrial production.

Description

A kind of method for preparing pyrimethan

technical field

The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing pyrimidan.

Background technique

Chinese patent application CN101906075A discloses pyrimethanil (compound I) with acaricidal activity, the structural formula is as follows:

The compound has excellent biological activity, not only against adult mites, but also against romanes and mite eggs, and has broad market prospects. The above-mentioned patent application also discloses the preparation method of the compound (the structural formula 1 is not marked), and the compound II (hereinafter referred to as pyrimidine phenol) reacts with the compound III (hereinafter referred to as benzyl chloride) to prepare pyrimidan (I):

However, the synthesis method reported in the literature has obvious disadvantages: low reaction yield, low product purity, long reaction time, N-alkylated isomers are easily generated during the reaction and product purification is difficult, so it is not suitable for industrial production.

Contents of the invention

In order to meet the needs of industrialized production, the present invention is committed to developing a method for preparing pyrimidan with higher yield and purity and lower cost.

After exhaustive research, the inventor first made pyrimidine phenol into a salt in the preparation process, that is, the target product was prepared by a salt-forming method, so as to solve the problems of low reaction yield, low product purity, long reaction time and long reaction time in the prior art. It is very easy to generate N-alkylated isomers, the product is difficult to purify, and is not suitable for industrial production.

Technical scheme of the present invention is as follows:

A method for preparing pyrimethanil, the reaction formula is as follows:

The reaction comprises the following reaction steps:

1) Adding reaction solvent A and alkali to pyrimidine phenol, and incubating at 20°C to 140°C for 1 to 10 hours to prepare pyrimidine phenol salt; after the reaction, remove reaction solvent A;

2) Add reaction solvent B, benzyl chloride and a catalyst to the reaction system, control the reaction temperature to 40°C to reflux temperature, and keep the reaction for 2 to 20 hours to prepare the crude pyrimidamide;

After the reaction is completed, the reaction solvent B is removed, and the crude product of pyrimidan is recrystallized to obtain the product pyrimidan.

Concrete operation of the present invention is:

Step 1) The reaction solvent A described in the reaction step is selected from alcohol solvents such as methanol, ethanol, and propanol, aromatic hydrocarbon solvents such as toluene, chlorobenzene, benzene, and xylene, or 1,4-dioxane, etc. Polar heterocyclic reaction solvent; the alkali is selected from alkali metal hydroxyl salts such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, or alkali metal alkoxy salts such as sodium methylate and sodium ethylate ; The molar ratio of pyrimidine phenol and base is 1:1; the reaction temperature is selected from 60°C to reflux temperature.

A further preferred reaction solvent A is selected from methanol, toluene, or 1,4-dioxane, etc.; a further preferred base is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, or sodium methoxide.

1) In the reaction step, when a non-water-soluble reaction solvent is used, the generated water can be removed during the reaction to speed up the reaction; while using a water-soluble reaction solvent such as alcohols, although it cannot be separated The water produced by the reaction is released, but the reaction speed is already very fast.

2) The reaction solvent B described in the step reaction step is selected from N,N dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide, etc.; the catalyst is selected from 4-dimethylaminopyridine, tris Ethylenediamine or polyethylene glycol (PEG) series, etc., the amount of catalyst added is usually 0.1%-10% of the weight of benzyl chloride; the molar ratio of pyrimidinol salt to benzyl chloride is 1-2:1; heat preservation reaction The temperature is 60-140° C., and the reaction time is 6-10 hours.

Further preferred reaction solvent B is selected from N,N-dimethylformamide; the catalyst is selected from 4-dimethylaminopyridine, triethylenediamine, PEG-200, PEG-300 or PEG-600, etc., the catalyst The added amount of benzyl chloride is usually 0.5%-5% of the weight of benzyl chloride; the molar ratio of pyrimidine phenol to benzyl chloride is 1.0~1.2:1.

The amount of the reaction solvent A and the reaction solvent B used in the two-step reaction is not strictly limited, for those skilled in the art, just add an appropriate amount of solvent. This just means that the amount of solvent added can be adjusted within a wide range without affecting the smooth progress of the reaction. However, in order to improve the production capacity of the equipment and reduce the energy consumed for removing the solvent, the addition of the solvent should be controlled as much as possible, as long as the reaction can be guaranteed to proceed smoothly, which is familiar to those skilled in the art.

The method for purifying the crude product after the reaction is: remove the reaction solvent B in step 2) after the reaction, add toluene and water, stir for 0.5 to 1 hour, let stand to separate layers, and dissolve pyrimidan in toluene. After the toluene layer was washed twice with water, the toluene was removed to obtain a crude product of pyrimidan, which was recrystallized by adding methanol to obtain the product pyrimidan. The amount of toluene, water and recrystallization solvent methanol used in the product refining process is well known to those skilled in the art.

The raw materials pyrimidine phenol and benzyl chloride used in the above reaction are prepared according to the methods described in patents CN101906075A, US4723034 and US5554578, and the raw materials and reagents used in other reactions are commercially available.

The preparation method provided by the invention has the advantages of simple operation, high reaction yield, high product purity and mild conditions, and is difficult to generate N-alkylated isomers in the reaction process, and is suitable for industrial popularization and application.

detailed description

Embodiment 1,

Add 34 grams of pyrimidine phenol (0.1mol, 95%) into a 500ml reaction flask (with a stirring and condenser tube), add 3.2 grams of sodium methoxide and 200ml of methanol, heat and reflux for 2 hours to remove methanol. Cool down to 50°C, add 24 grams of benzyl chloride (0.1mol, 99%), 150ml of N,N-dimethylformamide, raise the temperature to 100°C and keep it warm for 6-10 hours, HPLC analysis shows that the content of benzyl chloride is <2%. complete. N,N-Dimethylformamide was removed under reduced pressure. Then add 270ml of toluene and 120ml of water, stir at 45°C for 30 minutes, and let stand to separate layers. The toluene layer was washed with 60ml×2 water. Toluene was removed by distillation, and 200ml of methanol was added to recrystallize the product. Obtain 49.5 grams of product, yield 92%, content 98.1%.

Embodiment 2,

Add 34 grams of pyrimidinol (0.1mol, 95%) into a 500ml reaction flask (with a stirring and condenser tube), add 5.3 grams of sodium carbonate, 200ml of 1,4-dioxane, heat and reflux for 4 hours, remove 1,4-Dioxane. Cool down to 50°C, add 24 grams of benzyl chloride (0.1mol, 99%), and 150ml of N-methylpyrrolidone, raise the temperature to 100°C and keep it warm for 6-10 hours. According to HPLC analysis, the content of benzyl chloride is <2%, and the reaction is complete. N-methylpyrrolidone was removed under reduced pressure. Then add 270ml of toluene and 120ml of water, stir at 45°C for 30 minutes, and let stand to separate layers. The toluene layer was washed with 60ml×2 water. Toluene was removed by distillation, and 200ml of methanol was added to recrystallize the product. Obtain 49.0 grams of product, yield 91.1%, content 98.1%.

Embodiment 3,

Add 34 grams of pyrimidine phenol (0.1mol, 95%) into a 500ml reaction bottle (with stirring, water separation device and condenser), add 4.0 grams of sodium hydroxide, 200ml of toluene, and heat up and reflux for 6 hours for dehydration until the water until it is no longer removed. Remove toluene. Cool down to 50°C, add 24g of benzyl chloride (0.1mol, 99%), 150ml of N,N-dimethylformamide, 0.8g of triethylenediamine, raise the temperature to 100°C and keep the reaction for 6-10 hours, HPLC analysis, chlorine Benzyl content < 2%, the reaction is complete. N,N-Dimethylformamide was removed under reduced pressure. Then add 270ml of toluene and 120ml of water, stir at 45°C for 30 minutes, and let stand to separate layers. The toluene layer was washed with 60ml×2 water. Toluene was removed by distillation, and 200ml of methanol was added to recrystallize the product. Obtain 49.8 grams of product, yield 93%, content 98.5%.

Embodiment 4,

Add 34 grams of pyrimidinol (0.1mol, 95%) into a 500ml reaction bottle (with stirring, water separation device and condenser), add 4.0 grams of sodium hydroxide, 200ml of toluene, heat up and reflux for 6 hours, until the water until it is no longer removed. Remove toluene. Cool down to 50°C, add 24 grams of benzyl chloride (0.1mol, 99%), and 150ml of dimethyl sulfoxide, heat up to 100°C and keep the reaction for 6-10 hours. According to HPLC analysis, the content of benzyl chloride is <2%, and the reaction is complete. The reaction solution was poured into 1000ml of water. Then 270ml of toluene was added, stirred at 45°C for 30 minutes, and allowed to stand to separate layers. The toluene layer was washed with 60ml×2 water. Toluene was removed by distillation, and 200ml of methanol was added to recrystallize the product. Obtain 49.3 grams of product, yield 91.8%, content 98.2%.

Claims (5)

1. prepare a method for phonetic mite amine, reaction formula is as follows:

Reaction comprises the following steps: 1) in pyrimidine phenol, add reaction solvent A and alkali, in 20 DEG C ~ 140 DEG C scope inside holding reactions 1 ~ 10 hour, prepares the salt of pyrimidine phenol; React complete, remove reaction solvent A; 2) in reaction system, reaction solvent B, benzyl chlorine and catalyzer is added, controlling temperature of reaction is 40 DEG C ~ 140 DEG C, insulation reaction 2 ~ 20 hours, prepare phonetic mite amine crude product, catalyzer is selected from DMAP, triethylene diamine or polyoxyethylene glycol series, and the add-on of catalyzer is the 0.1%-10% of benzyl chlorine weight; React complete, remove reaction solvent B, phonetic mite amine crude product, through recrystallization, obtains the phonetic mite amine of product.

2. the method for the phonetic mite amine of preparation according to claim 1, is characterized in that: the 1st) reaction solvent A described in step is selected from methyl alcohol, ethanol, propyl alcohol, toluene, chlorobenzene, benzene, dimethylbenzene or Isosorbide-5-Nitrae-dioxane; Described alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium methylate or sodium ethylate; The mol ratio of pyrimidine phenol and alkali is 1:1, and temperature of reaction is selected from 60 DEG C ~ 140 DEG C.

3. the method for the phonetic mite amine of preparation according to claim 2, is characterized in that: the 1st) reaction solvent described in step is selected from methyl alcohol, toluene or Isosorbide-5-Nitrae-dioxane; Described alkali is selected from sodium hydroxide, potassium hydroxide, salt of wormwood or sodium methylate.

4. the method for the phonetic mite amine of preparation according to claim 1, is characterized in that: the reaction solvent B the 2nd) described in step is selected from DMF, N-Methyl pyrrolidone or methyl-sulphoxide; The charged molar ratio of pyrimidine phenol and benzyl chlorine is 1 ~ 2:1; Temperature of reaction is 60 ~ 140 DEG C, and the reaction times is 6 ~ 10 hours.

5. the method for the phonetic mite amine of preparation according to claim 4, is characterized in that: the reaction solvent B the 2nd) described in step is selected from DMF; Described catalyzer is selected from DMAP, triethylene diamine, PEG-200, PEG-300 or PEG-600, and the add-on of catalyzer is the 0.5%-5% of benzyl chlorine weight; The salt of pyrimidine phenol and the charged molar ratio of benzyl chlorine are 1.0 ~ 1.2:1.