CN114230513A - Synthetic method of 3-chloro-2-methyl-5-trifluoromethylpyridine - Google Patents
Synthetic method of 3-chloro-2-methyl-5-trifluoromethylpyridine Download PDFInfo
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- CN114230513A CN114230513A CN202210020379.7A CN202210020379A CN114230513A CN 114230513 A CN114230513 A CN 114230513A CN 202210020379 A CN202210020379 A CN 202210020379A CN 114230513 A CN114230513 A CN 114230513A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
Abstract
The invention discloses a synthetic method of 3-chloro-2-methyl-5-trifluoromethylpyridine, which comprises the following steps: s1: alkaline decarboxylation: adding an organic solvent or adding no organic solvent or alkali solution into 2- [ 3-chloro-5- (trifluoromethyl) pyridine-2-yl ] -1, 3-malonic acid diester, continuously stirring, and keeping the temperature unchanged until the raw materials are completely reacted to obtain an intermediate solution; s2: acid decarboxylation: and (3) adding an acid solution into the intermediate solution in the step S1, continuously stirring, keeping the temperature unchanged until the intermediate reaction is complete, and layering, washing and concentrating the reaction solution to obtain the target product. The synthesis method disclosed by the invention obtains a target product through a conventional post-treatment method after alkaline and acidic two-step hydrolysis decarboxylation reaction. The method has the advantages of reasonable and simple technical route selection, mild reaction conditions, simple post-treatment and easy industrial production, and the separation yield reaches more than 98%.
Description
Technical Field
The invention relates to the technical field of fine chemical engineering, in particular to a synthetic method of 3-chloro-2-methyl-5-trifluoromethylpyridine.
Background
The fluorine-containing organic compound has high fat solubility and hydrophobicity, can promote the absorption and transmission speed of the fluorine-containing organic compound in organisms, and changes the physiological action, so that a plurality of fluorine-containing medicines and pesticides have the characteristics of small dosage, low toxicity, high drug effect, strong metabolic capability and the like in performance, and the proportion of the fluorine-containing organic compound in new medicines and pesticide varieties is higher and higher. Among them, 3-chloro-2-methyl-5-trifluoromethylpyridine is an important fluorine-containing fine chemical intermediate, but the synthetic method literature is rarely reported.
Disclosure of Invention
The invention provides a synthetic method of 3-chloro-2-methyl-5-trifluoromethylpyridine, and provides a synthetic method of 3-chloro-2-methyl-5-trifluoromethylpyridine.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a synthetic method of 3-chloro-2-methyl-5-trifluoromethylpyridine comprises the following steps:
s1: alkaline decarboxylation: adding an alkali solution and/or an organic solvent into 2- [ 3-chloro-5- (trifluoromethyl) pyridine-2-yl ] -1, 3-malonic diester, continuously stirring, and keeping the temperature unchanged until the raw materials are completely reacted to obtain an intermediate solution;
s2: acid decarboxylation: and (3) adding an acid solution into the intermediate solution in the S1, continuously stirring, keeping the temperature unchanged until the intermediate reaction is complete, and carrying out layering, water washing and concentration on the reaction solution to obtain the 3-chloro-2-methyl-5-trifluoromethylpyridine.
Further, in the step S1, the molar ratio of the 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonic acid diester to the alkali solution is 1: 2-10, the concentration of the alkali solution is 1-8M, and the temperature is 0-100 ℃.
Further, in the step S2, the molar ratio of the 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonic acid diester to the acid solution is 1: 2-10, the acid solution has a concentration of 1-8M, and the temperature is 0-100 ℃.
Further, in the step S1, the diester of 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-propanedioic acid is dimethyl 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-propanedioic acid or diethyl 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-propanedioic acid.
Further, the organic solvent is one or more of aromatic hydrocarbon, halogenated alkane, alkane and cyclane.
Further, the organic solvent is one or more of toluene, xylene, chlorobenzene, dichloromethane, dichloroethane, n-hexane, n-heptane and cyclohexane.
Further, the base is one or more of alkali metal hydroxide, carbonate, bicarbonate and carboxylate.
Further, the alkali is one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium formate and sodium acetate.
Further, the acid is an inorganic acid or an organic acid.
Further, the inorganic acid is one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid; the organic acid is one or more of formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, citric acid, trifluoroacetic acid and cyanoacetic acid.
The invention discloses a synthesis method of 3-chloro-2-methyl-5-trifluoromethylpyridine, which comprises the steps of taking 2- [ 3-chloro-5- (trifluoromethyl) pyridine-2-yl ] -1, 3-malonic diester as a raw material, respectively carrying out alkaline and acidic two-step hydrolysis decarboxylation reactions in an organic solvent system (or in the absence of a solvent), and carrying out a conventional post-treatment method to obtain a 3-chloro-2-methyl-5-trifluoromethylpyridine product. The technical route disclosed by the invention is reasonable and simple to select, mild in reaction condition, simple in post-treatment step and easy for industrial production, and the separation yield of the method reaches more than 98%.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed to be used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a nuclear magnetic resonance spectrum of 3-chloro-2-methyl-5-trifluoromethylpyridine obtained in example 1 of the present invention;
FIG. 2 is a GC-MS spectrum of 3-chloro-2-methyl-5-trifluoromethylpyridine obtained in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Step S1, adding 31.8g (0.1mol, 98% and 1.0eq) of 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonic acid dimethyl ester, 200ml of toluene and 250ml (0.5mol, 2M and 5.0eq) of potassium carbonate aqueous solution into a 1000ml four-neck flask, heating the system to 60 ℃, carrying out heat preservation reaction for 4 hours, and sampling LC (liquid chromatography) to detect that the 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonic acid dimethyl ester completely reacts to obtain an intermediate solution.
Step S2, adding 267ml (0.4mol, 1.5M and 4.0eq) of citric acid aqueous solution into the intermediate solution system, then continuing to keep the temperature at 60 ℃ for reaction for 4 hours, and performing LC tracking reaction until the intermediate reaction is completely finished to obtain a product system containing 3-chloro-2-methyl-5-trifluoromethylpyridine; the product system is cooled to 20-25 ℃, then is layered, washed and concentrated to obtain 19.5g of 3-chloro-2-methyl-5-trifluoromethylpyridine with the content of 98.5 percent, and the yield of the 3-chloro-2-methyl-5-trifluoromethylpyridine is calculated to be 98.2 percent.
Example 2
Step S1, putting 34.7g (0.1mol, 98% and 1.0eq) of diethyl 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonate, 200ml of dichloroethane and 200ml (0.8mol, 4M and 8.0eq) of aqueous sodium hydroxide solution into a 1000ml four-neck flask, heating the system to 30 ℃, carrying out heat preservation reaction for 4 hours, and sampling LC (liquid chromatography) to detect that the diethyl 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonate is completely reacted to obtain an intermediate solution.
Step S2, adding 106ml (0.85mol, 8M, 8.5eq) of acetic acid aqueous solution into the intermediate solution system, heating to 40 ℃, keeping the temperature and reacting for 5 hours, and performing LC tracking reaction until the intermediate reaction is completed to obtain a product system containing 3-chloro-2-methyl-5-trifluoromethylpyridine; the product system is cooled to 20-25 ℃, then is layered, washed and concentrated to obtain 19.5g of 3-chloro-2-methyl-5-trifluoromethylpyridine with the content of 98.2 percent, and the yield of the 3-chloro-2-methyl-5-trifluoromethylpyridine is calculated to be 98.0 percent.
Example 3
Step S1, adding 31.8g (0.1mol, 98% and 1.0eq) of 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonic acid dimethyl ester, 200ml of n-heptane and 50ml (0.2mol, 4M and 2.0eq) of sodium formate aqueous solution into a 1000ml four-neck flask, heating the system to 90 ℃, carrying out heat preservation reaction for 1h, sampling LC (liquid chromatography) to detect that the 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonic acid dimethyl ester completely reacts, and obtaining an intermediate solution.
Step S2, 100ml of formic acid aqueous solution (0.2mol, 2M and 2.0eq) is added into the intermediate solution system, then the temperature is kept for 3 hours under 90 ℃, LC tracking reaction is carried out until the intermediate reaction is completed to obtain a product system containing 3-chloro-2-methyl-5-trifluoromethylpyridine, the product system is cooled to 20-25 ℃, then layering, washing and concentrating are carried out to obtain 19.6g of 3-chloro-2-methyl-5-trifluoromethylpyridine with the content of 98.5%, and the yield of the 3-chloro-2-methyl-5-trifluoromethylpyridine is calculated to be 98.9%.
Example 4
Step S1, adding 31.8g (0.1mol, 98% and 1.0eq) of 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonic acid dimethyl ester, 200ml of cyclohexane and 250ml (0.5mol, 2M and 5.0eq) of potassium carbonate aqueous solution into a 1000ml four-neck flask, adjusting the temperature of the system to 20 ℃, carrying out heat preservation reaction for 6 hours, and detecting the completion of the reaction of the 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonic acid dimethyl ester by sampling LC to obtain an intermediate solution.
Step S2, adding 400ml (0.6mol, 1.5M and 6.0eq) of hydrochloric acid into the intermediate solution system, heating to 60 ℃, keeping the temperature for reaction for 2 hours, performing LC tracking reaction until the intermediate reaction is completed to obtain a product system containing 3-chloro-2-methyl-5-trifluoromethylpyridine, cooling the product system to 20-25 ℃, then layering, washing and concentrating to obtain 19.6g of 3-chloro-2-methyl-5-trifluoromethylpyridine with the content of 98.4%, and calculating that the yield of the 3-chloro-2-methyl-5-trifluoromethylpyridine is 98.5%.
Example 5
Step S1, adding 34.7g (0.1mol, 98% and 1.0eq) of diethyl 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonate, 200ml of chlorobenzene and 200ml (0.4mol, 2M and 4.0eq) of potassium hydroxide aqueous solution into a 1000ml four-neck flask, adjusting the temperature of the system to 10 ℃, carrying out heat preservation reaction for 5 hours, and sampling LC (liquid chromatography) to detect that the diethyl 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonate completely reacts to obtain an intermediate solution.
Step S2, adding 75ml (0.3mol, 4M, 3.0eq) of sulfuric acid into the intermediate solution system, then continuing to keep the temperature for 5 hours at 10 ℃, tracking and reacting by LC until the intermediate reaction is completed to obtain a product system containing 3-chloro-2-methyl-5-trifluoromethylpyridine, layering, washing and concentrating the product system to obtain 19.4g of 3-chloro-2-methyl-5-trifluoromethylpyridine with the content of 98.6 percent, and calculating the yield of the 3-chloro-2-methyl-5-trifluoromethylpyridine to be 98.0 percent.
Example 6
Step S1, adding 31.8g (0.1mol, 98 percent and 1.0eq) of 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonic acid dimethyl ester and 250ml (0.5mol, 2M and 5.0eq) of potassium carbonate aqueous solution into a 1000ml four-mouth bottle, heating the system to 60 ℃, carrying out heat preservation reaction for 4 hours, and sampling LC (liquid chromatography) to detect that the 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonic acid dimethyl ester completely reacts to obtain an intermediate solution.
Step S2, 267ml (0.4mol, 1.5M and 4.0eq) of citric acid aqueous solution is added into the intermediate solution system, then the temperature is kept for reaction for 4 hours at 60 ℃, LC tracking reaction is carried out until the intermediate reaction is completed to obtain a product system containing 3-chloro-2-methyl-5-trifluoromethylpyridine, the product system is cooled to 20-25 ℃, then layering, water washing and drying are carried out to obtain 19.3g of 3-chloro-2-methyl-5-trifluoromethylpyridine with the content of 98.3%, and the yield of the 3-chloro-2-methyl-5-trifluoromethylpyridine is calculated to be 97.0%.
Nuclear magnetic and gas chromatography-mass spectrometry analysis of the structure of 3-chloro-2-methyl-5-trifluoromethylpyridine of example 1, as shown in fig. 1 and 2, nuclear magnetic data confirmed the correctness of 3-chloro-2-methyl-5-trifluoromethylpyridine, wherein the spectrum results shown in fig. 1 are: delta 2.692 (CH)3) δ 7.854 (4-position CH), δ 8.640 (6-position CH); the results of the spectra are shown in FIG. 2 as: m/z is 195. The above examples show that the yield of 3-chloro-2-methyl-5-trifluoromethylpyridine obtained by the synthesis method of the present application is 98% or more.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the technology of the embodiments of the present invention.
Claims (10)
1. A synthetic method of 3-chloro-2-methyl-5-trifluoromethylpyridine is characterized by comprising the following steps:
s1: alkaline decarboxylation: adding an alkali solution and/or an organic solvent into 2- [ 3-chloro-5- (trifluoromethyl) pyridine-2-yl ] -1, 3-malonic diester, continuously stirring, and keeping the temperature unchanged until the raw materials are completely reacted to obtain an intermediate solution;
s2: acid decarboxylation: and (3) adding an acid solution into the intermediate solution in the S1, continuously stirring, keeping the temperature unchanged until the intermediate reaction is complete, and carrying out layering, water washing and concentration on the reaction solution to obtain the 3-chloro-2-methyl-5-trifluoromethylpyridine.
2. The method for synthesizing 3-chloro-2-methyl-5-trifluoromethylpyridine according to claim 1, wherein in the step S1, the molar ratio of the 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonic diester to the alkali solution is 1: 2-10, the concentration of the alkali solution is 1-8M, and the temperature is 0-100 ℃.
3. The method for synthesizing 3-chloro-2-methyl-5-trifluoromethylpyridine according to claim 1, wherein in the step S2, the molar ratio of the 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-malonic acid diester to the acid solution is 1: 2-10, the concentration of the acid solution is 1-8M, and the temperature is 0-100 ℃.
4. The method of claim 1, wherein in step S1, the 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-propanedioic acid diester is 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-propanedioic acid dimethyl ester or 2- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -1, 3-propanedioic acid diethyl ester.
5. The method for synthesizing 3-chloro-2-methyl-5-trifluoromethylpyridine according to claim 1, wherein the organic solvent is one or more of aromatic hydrocarbon, halogenated alkane, alkane and cycloalkane.
6. The method for synthesizing 3-chloro-2-methyl-5-trifluoromethylpyridine according to claim 5, wherein the organic solvent is one or more of toluene, xylene, chlorobenzene, dichloromethane, dichloroethane, n-hexane, n-heptane, and cyclohexane.
7. The method for synthesizing 3-chloro-2-methyl-5-trifluoromethylpyridine according to claim 1, wherein the base is one or more of alkali metal hydroxide, carbonate, bicarbonate and carboxylate.
8. The method for synthesizing 3-chloro-2-methyl-5-trifluoromethylpyridine according to claim 7, wherein the base is one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium formate, and sodium acetate.
9. The method for synthesizing 3-chloro-2-methyl-5-trifluoromethylpyridine according to claim 1, wherein the acid is an inorganic acid or an organic acid.
10. The method for synthesizing 3-chloro-2-methyl-5-trifluoromethylpyridine according to claim 9, wherein the inorganic acid is one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid; the organic acid is one or more of formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, citric acid, trifluoroacetic acid and cyanoacetic acid.
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