CN102977008A - Synthetic method of 2-chloro-5-methylpyridine - Google Patents

Abstract

The invention discloses a preparation method of a compound 2-chloro-5-picoline, which comprises the following steps: firstly, the compound 3-picoline oxide is used as a raw material, diluted with a solvent, and mixed with an electrophile and an organic nitrogen base React at -60-100°C to obtain an intermediate product, and then react it with a chlorinating agent at 40-200°C to obtain the compound 2-chloro-5-picoline. The production process of the present invention is simple and the yield is high , the yield can reach about 80% based on 3-picoline oxide.

Description

The synthetic method of 2-chloro-5-picoline compound

technical field

The invention belongs to the technical field of pesticides, and in particular relates to a preparation method of 2-chloro-5-picoline compound.

Background technique

2-Chloro-5-picoline is an important "three-drug" intermediate, which can be used to synthesize neonicotinoid insecticides such as imidacloprid and acetamiprid. These insecticides have systemic, broad-spectrum, Higher education, low toxicity, less dosage, long duration, good safety, strong drug resistance and other advantages. In addition, 2-chloro-5-methylpyridine is also used in the synthesis of herbicides such as fluazifop and haloxyfop.

The synthetic route of 2-chloro-5-picoline mainly includes cyclization method, diazotization method, 3-picoline oxidation method, one-step chlorination method and so on. Among them, the cyclization reaction step is longer, the yield is low, the raw materials are various, and the production cost is high; the diazotization process has strict requirements, serious pollution, and high production cost; the one-step chlorination process has high catalyst cost and difficult recovery, which cannot Recycling and other features.

The 3-picoline oxidation method is simple in operation, low in investment cost, easy to control the process, and low in production cost. Construct by-products, improve the yield of the main product.

At present, many chlorinating agents have been developed and used, and the combination of various electrophiles and chlorinating agents can produce a synergistic effect and increase the chlorination yield. This route has not been reported.

Contents of the invention

The purpose of the present invention is to provide a preparation method of 2-chloro-5-picoline compound, and overcome the problem of low yield in the prior synthesis technology.

In order to achieve the above object, the present invention adopts the following technical solutions:

The preparation method of 2-chloro-5-picoline (I) compound comprises the steps:

(I)

(1) First add the compound 3-picoline oxide of formula (II) into the diluent, after cooling, first slowly add the electrophile, then the organic nitrogen base, and stir when adding, 3-methylpyridine The base pyridine oxide reacts with the electrophile and the organic nitrogen base at a molar ratio of 1:1.5-5:1.5-5, and the molar ratio of the diluent to the electrophile is 1:1-10 at -60-100°C The reaction is carried out to obtain the compound of formula (Ⅲ),

(Ⅱ) (Ⅲ)

In formula (Ⅲ), X represents the electrophile of dechlorination or the corresponding group of decarboxylation;

(2) The compound of formula (Ⅲ) and the chlorinating agent are used as the reactant at a molar ratio of 1:0.1-20, with diluent or other excess chlorinating agent as the solvent, under normal pressure or high pressure, 40-200 The reaction was carried out under the condition of ℃ to obtain the compound 2-chloro-5-methylpyridine of the formula (I).

The electrophile is one or more of acid chloride, acid anhydride, phosphorus oxide, phosphorus oxychloride or cyanoyl chloride.

The electrophile is acetyl chloride, propionyl chloride, trichloroacetyl chloride, acetic anhydride, propionic anhydride, benzoyl chloride, benzenesulfonyl chloride, C ₁ -C ₄ alkyl substituted benzenesulfonyl chloride, phosphorus trichloride, penta One or more of phosphorus chloride, sulfurous acid, cyanuric chloride or sulfuryl chloride.

The electrophilic reagent is a composite reagent composed of phosphorus oxychloride and electrophilic reagents such as benzoyl chloride, phosphorus pentachloride, phosphorus trichloride and phthaloyl chloride respectively in a molar ratio of 1:0.1-2.

The organic nitrogen base is tri(C ₁ -C ₄ alkyl)amine, N,N-di(C ₁ -C ₄ alkyl)benzylamine, N,N-di(C ₁ -C ₄ alkyl) One or more of amine, N,N-di(C ₁ -C ₄ alkyl)cyclohexylamine, C1-C4 alkyl substituted or unsubstituted pyridine.

The organic nitrogen base is trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, pyridine or C ₁ - One or more of C ₄ alkyl substituted pyridines.

The chlorinating agent is one or more of phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, sulfuryl chloride, cyanuric chloride, phosgene, diphosgene or solid phosgene kind.

The chlorination agent is a composite reagent composed of phosphorus oxychloride and electrophiles such as benzoyl chloride, phosphorus pentachloride, phosphorus trichloride and phthaloyl chloride respectively in a molar ratio of 1:0.1-2.

The diluent is aliphatic or aromatic halogenated hydrocarbon.

The diluent is one or more of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene or dichlorobenzene.

The preparation method of 2-chloro-5-picoline compound, the preferred reaction temperature of step (1) is -40-10°C, the preferred diluent is dichloromethane, 3-picoline oxide, electrophile and organic The nitrogen base is reacted at a molar ratio of 1:1.5-5:1.5-5; the preferred reaction temperature of step (2) is 100-140°C, the preferred diluent is chlorobenzene, and the compound of formula (Ⅲ) and the chlorinating agent are molar The ratio is 1:0.2-5 for the ratio reaction.

The compound of formula (Ⅲ) in the present invention can be isolated from the reaction system in the form of an intermediate, or can be directly subjected to the next chlorination reaction without isolation. The preferred way is to use this crude intermediate directly in the second step reaction.

According to the present invention, the compound 2-chloro-5-picoline of formula (I) can be obtained in relatively high yields, and therefore, the process according to the present invention represents a valuable improvement over the prior art.

If the composite system of phosphorus oxychloride and phosphorus pentachloride is used as the electrophile and the chlorination agent in the second step, and diisopropylamine is used as the organic nitrogen base, the reaction equation can be expressed as follows:

The mixed use of various electrophilic reagents and chlorinating agents produces a synergistic effect, and then improves the chlorination yield, which is a new method that constitutes the subject of the present invention.

Beneficial effects of the present invention:

The production process of the invention is convenient and the yield is high, and the yield can reach about 80% based on 3-picoline oxide.

Detailed ways

In order to understand the present invention better, illustrate by following example:

Example 1:

Add 50g, 0.4587mol of 3-picoline oxide into 600g of dichloromethane, cool the mixture to -30°C, slowly add 82.05g, 0.5351mol of phosphorus oxychloride, 37.61g, 0.2676mol of benzoyl chloride and 92.65 g, 0.9174 mol of diisopropylamine, after the dropwise addition, stirred at room temperature for 1 hour, filtered with suction, and distilled off dichloromethane. Add 500mL of chlorobenzene, slowly add 27.97g, 0.1824mol of phosphorus oxychloride and 12.82g, 0.0912mol of benzoyl chloride dropwise, and heat up to reflux for a total of 9 hours. After the reaction, it was hydrolyzed, neutralized with liquid caustic soda, and steam distilled to obtain the compound of formula (I), with a yield of 75.2%.

Example 2:

Add 50g, 0.4587mol of 3-picoline oxide into 600g of dichloromethane, cool the mixture to -30°C, slowly add 102.56g, 0.6689mol of phosphorus oxychloride, 27.85g, 0.1338mol of phosphorus pentachloride (Phosphorus pentachloride is dissolved in 60 g of dichloromethane) and 92.65 g, 0.9174 mol of diisopropylamine. After the dropwise addition, stir at room temperature for 1 hour, filter with suction, and distill off the dichloromethane. Add 500mL of chlorobenzene, slowly add 34.86g, 0.2271mol of phosphorus oxychloride and 9.51g, 0.0456mol of phosphorus pentachloride (dissolved in 20 g of chlorobenzene) dropwise, and raise the temperature to reflux for a total of 9 hours. After the reaction, it was hydrolyzed, neutralized with liquid caustic soda, and steam distilled to obtain the compound of formula (I), with a yield of 80.3%.

Example 3:

Add 50g, 0.4587mol of 3-picoline oxide into 600g of dichloromethane, cool the mixture to -30°C, slowly add 63.34g, 0.4460mol of phosphorus oxychloride, 48.76g, 0.3567 of phosphorus trichloride and 92.65 g, 0.9174 mol of diisopropylamine, after the dropwise addition, stirred at room temperature for 1 hour, filtered with suction, and distilled off dichloromethane. Add 500mL of chlorobenzene, slowly dropwise add 23.34g, 0.1520mol of phosphorus oxychloride and 16.72g, 0.1216mol of phosphorus trichloride, and heat up to reflux for a total of 9 hours. After the reaction, it was hydrolyzed, neutralized with liquid caustic soda, and steam distilled to obtain the compound of formula (I), with a yield of 78.2%.

Example 4:

Add 50g, 0.4587mol 3-picoline oxide to 600g dichloromethane, cool the mixture to -30°C, slowly add 87.86g, 0.5734mol phosphorus oxychloride, 46.53g, 0.2293 phthaloyl chloride dropwise And 92.65g, 0.9174mol of diisopropylamine, after the dropwise addition, stirred at room temperature for 1 hour, filtered with suction, and distilled off dichloromethane. Add 500mL of chlorobenzene, slowly add 30.00g, 0.1954mol of phosphorus oxychloride and 15.89g, 0.0782mol of phthaloyl chloride dropwise, and heat up to reflux for a total of 9 hours. After the reaction, it was hydrolyzed, neutralized with liquid caustic soda, and steam distilled to obtain the compound of formula (I), with a yield of 76.7%.

Claims (10)

1. A preparation method of 2-chloro-5-picoline (I) compound, characterized in that it comprises the steps: (I) (1) First add the compound 3-picoline oxide of formula (II) into the diluent, after cooling, first slowly add the electrophile, then the organic nitrogen base, and stir when adding, 3-methylpyridine The base pyridine oxide reacts with the electrophile and the organic nitrogen base at a molar ratio of 1:1.5-5:1.5-5, and the molar ratio of the diluent to the electrophile is 1:1-10 at -60-100°C The reaction is carried out to obtain the compound of formula (Ⅲ),

(Ⅱ) (Ⅲ) In formula (Ⅲ), X represents the electrophile of dechlorination or the corresponding group of decarboxylation; (2) The compound of formula (Ⅲ) and the chlorinating agent are used as the reactant at a molar ratio of 1:0.1-20, with diluent or other excess chlorinating agent as the solvent, under normal pressure or high pressure, 40-200 The reaction was carried out under the condition of ℃ to obtain the compound 2-chloro-5-methylpyridine of the formula (I). 2. the preparation method of 2-chloro-5-picoline compound according to claim 1 is characterized in that: described electrophile is one in acyl chloride, acid anhydride, phosphorus oxide compound, phosphorus oxychloride or cyanoyl chloride one or more species. 3. the preparation method of 2-chloro-5-picoline compound according to claim 2 is characterized in that: described electrophile is acetyl chloride, propionyl chloride, trichloroacetyl chloride, acetic anhydride, propionic anhydride , one or more of benzoyl chloride, benzenesulfonyl chloride, C ₁ -C ₄ alkyl substituted benzenesulfonyl chloride, phosphorus trichloride, phosphorus pentachloride, sulfurous acid, cyanuric chloride or sulfuryl chloride. 4. the preparation method of 2-chloro-5-picoline compound according to claim 3 is characterized in that: described electrophile is phosphorus oxychloride and benzoyl chloride, phosphorus pentachloride, three Phosphorus chloride and one of the electrophilic reagents such as phthaloyl chloride are composite reagents with a molar ratio of 1:0.1-2. 5. The preparation method of 2-chloro-5-picoline compound according to claim 1, characterized in that: the organic nitrogen base is tri(C ₁ -C ₄ alkyl)amine, N,N- Di(C ₁ -C ₄ alkyl)benzylamine, N,N-di(C ₁ -C ₄ alkyl)amine, N,N-di(C ₁ -C ₄ alkyl)cyclohexylamine, C1-C4 One or more of alkyl-substituted or unsubstituted pyridines. 6. the preparation method of 2-chloro-5-picoline compound according to claim 5 is characterized in that: described organic nitrogen base is trimethylamine, triethylamine, tripropylamine, tributylamine, diisocyanurate One or more of propylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, pyridine or C ₁ -C ₄ alkyl substituted pyridine. 7. the preparation method of 2-chloro-5-picoline compound according to claim 1 is characterized in that: described chlorination agent is phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, One or more of sulfuryl chloride, sulfuryl chloride, cyanuric chloride, phosgene, diphosgene or solid phosgene. 8. the preparation method of 2-chloro-5-picoline compound according to claim 7, is characterized in that: described chlorination agent is phosphorus oxychloride and benzoyl chloride, phosphorus pentachloride, three Phosphorus chloride and phthaloyl chloride and other electrophiles are composite reagents with a molar ratio of 1:0.1-2. 9. the preparation method of 2-chloro-5-picoline compound according to claim 9 is characterized in that: described diluent is methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride, chlorine One or more of benzene or dichlorobenzene. 10. The preparation method of 2-chloro-5-picoline compound according to claim 1, characterized in that: the preferred reaction temperature of the step (1) is -40-10 °C, and the preferred diluent is di Chloromethane, the preferred reaction temperature of step (2) is 100-140°C, the preferred diluent is chlorobenzene, and the compound of formula (Ⅲ) reacts with the chlorinating agent at a molar ratio of 1:0.2-5.