CN113773246A - Preparation method of 2-substituted-4-trifluoromethylpyridine - Google Patents
Preparation method of 2-substituted-4-trifluoromethylpyridine Download PDFInfo
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- CN113773246A CN113773246A CN202111086895.1A CN202111086895A CN113773246A CN 113773246 A CN113773246 A CN 113773246A CN 202111086895 A CN202111086895 A CN 202111086895A CN 113773246 A CN113773246 A CN 113773246A
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Abstract
The invention belongs to a production method of chemical intermediates, and particularly relates to a preparation method of 2-substituted-4-trifluoromethylpyridine. The method isThe method takes 2-chloro-4-trichloromethylpyridine as a raw material, and obtains the 2-substituted-4-trifluoromethylpyridine through hydrolysis, halogenation, trifluoromethylation and nucleophilic substitution; the reaction route is as follows:
wherein Y is amino, hydroxyl, thiol, hydrazino, cyano, fluorine, bromine or iodine; x is chlorine or bromine. The method takes cheap and easily-obtained 2-chloro-4-trichloromethyl pyridine as a raw material, greatly reduces the preparation cost, and has the characteristics of high yield, simple steps, less side reactions, stability and reliability.
Description
Technical Field
The invention belongs to a production method of chemical intermediates, and particularly relates to a preparation method of 2-substituted-4-trifluoromethylpyridine.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Since trifluoromethylpyridines or derivatives thereof exhibit remarkable biological activities, they are widely used in the fields of medicines and agricultural chemicals. For example, 2-chloro or 2, 6-dichloro-4-trifluoromethylated pyridines are common trifluoromethyl-containing compounds that mediate biological activity. However, to date, there are only a limited number of methods by which substituted trifluoromethylpyridines can be prepared. Among them, 2-substituted 4-trifluoromethylpyridine is particularly difficult to obtain in large quantities due to its special electronic effect, resulting in high price. At present, the common 2-substituted-4-trifluoromethyl pyridine can be obtained by the following methods, wherein the application value is as follows:
(1) fluorination was carried out by trichloromethylation of the corresponding 4-methylpyridine by reaction with chlorine, followed by reaction with HF under catalysis of antimony or molybdenum at elevated temperature and pressure. However, the method has harsh reaction conditions, high temperature and high pressure, serious by-products and low yield.
(2) The corresponding 4-iodo/bromopyridine or 4-pyridineboronic acid and copper triflate, sodium triflate, trifluoromethyl substituted silane or hydrofluorocarbon are fluorinated catalytically by heating in a polar aprotic solvent in the presence of a base. However, the method has high raw material cost and is not easy to obtain.
(3) Under the action of 4-ethoxy-1, 1, 1-trifluoro-3-butene-2-ketone and acetonitrile-butyl lithium or chloroacetonitrile-metal zinc, 5-ethoxy-3-hydroxy-3- (trifluoromethyl) -pent-4-enenitrile is obtained, and then ring closure is carried out by chlorination to obtain 2-chloro-4-trifluoromethylpyridine, and if the 2-amino-4-trifluoromethylpyridine is further aminated, 2-amino-4-trifluoromethylpyridine is obtained; if the ring is condensed before chlorination, 2-hydroxy-4-trifluoromethyl pyridine is obtained. However, the method has the disadvantages of high price of reaction raw materials, low temperature requirement of butyl lithium, expensive reagent, difficult operation, high requirement on corrosion resistance of equipment, unstable raw materials, high price and relative feasibility.
(4) Ethyl trifluoroacetate and allyl bromide Grignard reagent undergo addition-elimination reaction to generate 4- (trifluoromethyl) hepta-1, 6-diene-4-alcohol, and then ozonization-reduction, ammoniation cyclization, nitrogen oxidation and chlorination are carried out to obtain the 2-chloro-4-trifluoromethylpyridine. This method requires the use of a large amount of ozone, but the supply of ozone is a problem.
(5) 4-ethoxy-1, 1, 1-trifluoro-3-butene-2-ketone or 4-chloro-4-ethoxy-1, 1, 1-trifluoro-3-butyl-2-ketone reacts with diethoxy ethyl phosphonoacetate (obtained by the reaction of halogenated ethyl acetate and triethyl phosphite) to obtain 5, 5-diethoxy-3- (trifluoromethyl) penta-2-enoate, and then reacts with ammonia at the high temperature of 250 ℃ or ammonium acetate and formamide at the temperature of about 155 ℃ to obtain 2-hydroxy-4-trifluoromethyl pyridine. The method has high reaction temperature, inconvenient operation and low yield, and generates a large amount of phosphorus-containing substances to be treated.
(6) Corresponding isonicotinic acid reacts for 40 hours at 180 ℃ under the catalysis of molybdenum hexafluoride, and the trifluoromethylation of carboxyl is completed. The method has harsh reaction conditions, severe side reactions and poor effect.
(7) The corresponding isonicotinic acid reacts with sulfur tetrafluoride in anhydrous hydrogen fluoride at the temperature of 75-150 ℃ to obtain the corresponding 4-trifluoromethyl pyridine. The method is used for preparing the 4-trifluoromethyl pyridine compound which is difficult to obtain, has good effect, theoretically, the sulfur element is finally converted into sulfur dioxide, and the byproduct is mainly a small amount of substituted bis (difluoromethylene ether) and is easy to separate. Sulfur tetrafluoride is a toxic gas and is inconvenient to operate, and research on trifluoromethylation by using sulfur tetrafluoride is focused on how to convert carboxyl into trifluoromethyl.
Therefore, how to prepare the 2-substituted-4-trifluoromethylpyridine compound in a general way with few steps and convenient operation by using simple and easily obtained raw materials is of great significance.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides a general preparation method of 2-substituted-4-trifluoromethylpyridine, which takes cheap and easily obtained 2-chloro-4-trichloromethylpyridine as a raw material and can conveniently and stably obtain the 2-substituted-4-trifluoromethylpyridine compound through the processes of hydrolysis, halogenation, trifluoromethylation, nucleophilic substitution and the like.
The following scheme is provided specifically:
a preparation method of 2-substituted-4-trifluoromethylpyridine takes 2-chloro-4-trichloromethylpyridine as a raw material, and 2-substituted-4-trifluoromethylpyridine is obtained through hydrolysis, halogenation, trifluoromethylation and nucleophilic substitution;
the reaction route is as follows:
wherein Y is amino, hydroxyl, thiol, hydrazino, cyano, fluorine, bromine or iodine;
x is chlorine or bromine.
The preparation method specifically comprises the following steps:
(1) in a strong alkali or strong protonic acid water solution, 2-chloro-4-trichloromethylpyridine is hydrolyzed to be converted into 2-hydroxypyridine-4-formic acid;
(2) halogenating 2-hydroxypyridine-4-formic acid with a halogenating reagent to obtain 2-halopyridine-4-formic acid;
(3) carrying out fluorination reaction on 2-halopyridine-4-formic acid and a fluorination reagent to obtain 2-halogeno-4-trifluoromethylpyridine;
(4) reacting the 2-halogenated-4-trifluoromethylpyridine with a nucleophilic reagent capable of providing Y to obtain the 2-substituted-4-trifluoromethylpyridine compound.
One or more embodiments of the present invention have at least the following advantageous effects:
(1) the preparation method of the 2-substituted-4-trifluoromethylpyridine compound provided by the invention takes cheap and easily available 2-chloro-4-trichloromethylpyridine as a raw material, thereby greatly reducing the preparation cost.
(2) The preparation method of the 2-substituted-4-trifluoromethylpyridine compound provided by the invention has the advantages of simple process, easiness in operation, stable process, contribution to industrial production, high yield and easiness in purification.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a gas mass spectrum of 2-chloro-4-trichloromethylpyridine prepared in example 1;
FIG. 2 is a gas mass spectrum of 2-chloro-4-trifluoromethylpyridine prepared in example 1;
FIG. 3 is a gas mass spectrum of 2-hydroxy-4-trifluoromethylpyridine prepared in example 1;
FIG. 4 is a gas mass spectrum of 2-amino-4-trifluoromethylpyridine prepared in example 1.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As introduced in the background art, the method for preparing 2-substituted-4-trifluoromethylpyridine in the prior art has the problems of harsh reaction conditions, serious by-products, high raw material price, low yield and the like, and restricts the wide application of the 2-substituted-4-trifluoromethylpyridine.
In order to solve the technical problems, the invention provides a preparation method of 2-substituted-4-trifluoromethylpyridine, which takes 2-chloro-4-trichloromethylpyridine as a raw material and obtains the 2-substituted-4-trifluoromethylpyridine through hydrolysis, halogenation, trifluoromethylation and nucleophilic substitution;
the reaction route is as follows:
wherein Y is amino, hydroxyl, thiol, hydrazino, cyano, fluorine, bromine or iodine;
x is chlorine or bromine.
Wherein the physical properties of the 2-chloro-4-trifluoromethylpyridine are as follows:
the molecular formula is as follows: c6H3ClF3N
Molecular weight: 181.54
Density: 1.411g/mL at 25 deg.C
Boiling point: 146- & lt147- & gt
Melting point: -19 deg.C
The method takes cheap and easily-obtained 2-chloro-4-trichloromethylpyridine as a raw material, has lower price and is easier to obtain compared with 4-iodine/bromopyridine, 4-pyridine boric acid, 4-ethoxy-1, 1, 1-trifluoro-3-butene-2-ketone and the like, can conveniently and stably obtain the 2-substituted-4-trifluoromethylpyridine compound through the subsequent processes of hydrolysis, halogenation, trifluoromethylation, nucleophilic substitution and the like, and has the advantages of easily-obtained raw material, higher yield, simple steps, less side reactions, stability, reliability and the like.
The preparation method specifically comprises the following steps:
(1) in a strong alkali or strong protonic acid water solution, 2-chloro-4-trichloromethylpyridine is hydrolyzed to be converted into 2-hydroxypyridine-4-formic acid;
(2) 2-hydroxypyridine-4-formic acid is subjected to halogenation reaction by a halogenating reagent to obtain 2-halopyridine-4-formic acid;
(3) carrying out fluorination reaction on 2-halopyridine-4-formic acid and a fluorination reagent to obtain 2-halogeno-4-trifluoromethylpyridine;
(4) reacting the 2-halogenated-4-trifluoromethylpyridine with a nucleophilic reagent capable of providing Y to obtain the 2-substituted-4-trifluoromethylpyridine compound.
In one or more embodiments of the present invention, when the final target product is 2-hydroxy-4-trifluoromethylpyridine, steps (2) and (4) are omitted, and 2-hydroxy-4-trifluoromethylpyridine is directly reacted with a fluorinating agent to obtain 2-hydroxy-4-trifluoromethylpyridine, and the reaction route is as follows:
in one or more embodiments of the present invention, the strong base of step (1) and a strong protic acid, the strong base is preferably sodium hydroxide, potassium hydroxide or barium hydroxide; the addition amount of the strong base is as follows: 4-6 chemical molar equivalents, and the concentration of the strong alkali aqueous solution is as follows: 5-40% mass concentration.
The strong protonic acid refers to non-volatile acid and solid super acid and acidic ion exchange resin, the concentration of the non-volatile acid is 60% or more, preferably sulfuric acid, phosphoric acid, bisulfate, chlorosulfonic acid, fluorosulfonic acid and the like, and more preferably the concentration of the sulfuric acid, acidic ion exchange resin and solid super acid is 70% or more; the dosage of the strong protonic acid is preferably 1 to 3 times of the molar amount of 2-chloro-4-trichloromethylpyridine; the mass concentration of the aqueous solution of the strong protonic acid is as follows: 60 to 90 percent.
Further, in step (1), the hydrolysis is carried out with the aid of a phase transfer catalyst in an amount of 0.1% to 5.0%, preferably 0.5% to 1.5% by mass of 2-chloro-4-trichloromethylpyridine, including, but not limited to, long-chain linear or branched alkyl sulfonic acid alkali metal salts (e.g., sodium dodecylsulfonate), long-chain linear or branched quaternary ammonium/phosphonium salts (e.g., didodecyldimethylammonium bromide, tetraphenylphosphonium bromide), polymeric polyethylene glycols (e.g., polyethylene glycol 400).
Further, the hydrolysis reaction temperature is 150-.
Furthermore, the hydrolysis reaction time is 6-18 h.
Further, when hydrolyzing in strong protonic acid, the hydrolysis pressure is normal pressure; when the hydrolysis is carried out in strong alkali, the hydrolysis pressure is 0.1-2.0 MPa.
In one or more embodiments of the present invention, the halogenating agent in step (2) is any one or a combination of two or more of phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, phosphorus tribromide, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide and triphosgene.
Further, in the step (2), a halogenating reagent is used as a solvent to carry out a solvent-free reaction, or a solvent is added to carry out a reaction;
when the solventless reaction is carried out, the amount of the halogenating agent is 3 to 5 times the molar amount required for the chemical reaction.
When a solvent is added to carry out the reaction, the solvent is a halogenated hydrocarbon, preferably carbon tetrachloride, dichloroethane or chlorobenzene.
Further, the mass of the added solvent is preferably 2 to 5 times of that of the halogenated raw material; at this time, the amount of the halogenating agent to be added needs to be reduced, and is preferably 1.05 to 2.00 times, more preferably 1.2 to 1.5 times, the molar amount required for the chemical reaction.
In one or more embodiments of the present invention, the halogenation reaction temperature is in the range of 70 to 120 ℃ and the reaction time is in the range of 8 to 24 hours, preferably 10 to 12 hours.
In one or more embodiments of the present invention, in the fluorination reaction in step (3), anhydrous hydrogen fluoride, triethylamine trifluoride or pyridine fluoride is reacted as a reaction solvent in an amount of 0.5 to 3 times the mass of 2-halopyridine-4-carboxylic acid.
Further, the fluorinating agent is phenyl sulfur trifluoride, substituted sulfur trifluoride or sulfur tetrafluoride.
Furthermore, the adding amount of the fluorinating agent is 2.0 to 3.5 times of the molar amount of the 2-halopyridine-4-carboxylic acid.
Further, the fluorination reaction temperature is 85-150 ℃.
Further, the fluorination reaction time is 8 to 24 hours, preferably 10 to 14 hours.
Furthermore, the fluorination reaction pressure is 0.1-5.0 MPa.
Further, after the fluorination reaction is finished, the post-treatment mode is as follows: and (2) at 35-45 ℃, decompressing, absorbing and neutralizing anhydrous hydrogen fluoride, removing residual solvent and fluorinating reagent, blowing nitrogen to remove residual hydrogen fluoride to an absorption device for absorption, neutralizing by using sodium carbonate, sodium bicarbonate, ammonia water and the like, and performing post-treatment to obtain the required 2-halogeno-4-trifluoromethylpyridine.
In one or more embodiments of the present invention, the nucleophilic reagent in step (4) includes, but is not limited to, sodium alkoxide, sodium phenoxide, sodium amide, liquid ammonia, aqueous ammonia, sodium sulfide, sodium hydrosulfide, sodium thiolate, sodium thiocyanate, sodium/potassium cyanide, hydrazine hydrochloride or sulfate, hydrazine hydrate, alkali metal fluoride, alkali metal iodide, alkali metal bromide.
Furthermore, the amount of the nucleophilic reagent added is 1.05 to 15 times of the molar amount of the 2-halo-4-trifluoromethylpyridine, and is determined by the activity of the nucleophilic reagent, whether the nucleophilic reagent is easy to remove and whether the nucleophilic reagent is used as a solvent.
Further, the step (4) is carried out by using a solvent, wherein the solvent is an aprotic dipolar solvent, and the aprotic dipolar solvent mainly plays a role of dissolving raw materials and providing a nucleophilic reagent for Y, and helps the reaction, and includes but is not limited to lower aliphatic nitriles (such as acetonitrile), lower aliphatic ethers/polyethers (such as ethylene glycol dimethyl ether, polyethylene glycol 600, tetraethylene glycol ether), lower aliphatic ketones (such as acetone and butanone), lower aliphatic amides (such as N, N-dimethylformamide; lower aliphatic sulfones, such as sulfolane), low molecular weight morpholines (such as N-formylmorpholine), and pyrrolidones (such as N-methylpyrrolidone); the aprotic dipolar solvent is added in a mass 1 to 5 times, more preferably 2 to 3 times the mass of 2-halo-4-trifluoromethylpyridine.
Further, the reaction temperature of the step (4) is 80-180 ℃.
Further, the reaction time of the step (4) is 6 to 48 hours.
Further, the reaction in the step (4) is carried out under the action of a catalyst, wherein the catalyst is one or more of cuprous chloride, cuprous bromide and cuprous iodide.
Preferably, the catalyst is used in combination with a phase transfer catalyst, and the phase transfer catalyst is selected in the same manner as in step (1).
Further, in the step (4), in order to promote the reaction to proceed smoothly, an acid-binding agent capable of binding hydrogen halide generated by the reaction is added, and the acid-binding agent includes, but is not limited to, tertiary amines (such as trimethylamine, triethylamine), pyridines (such as pyridine, 2-methylpyridine), alkali metal salts corresponding to inorganic or organic weak acids (such as potassium carbonate, trisodium phosphate, disodium hydrogen phosphate, sodium acetate), organic or inorganic weak bases (such as hexamethylenetetramine, aniline, benzylamine, magnesium hydroxide).
The process of the invention is further illustrated below:
in the step (1), in the acidolysis process, dynamic changes of raw materials and products are detected and tracked by adopting liquid chromatography, wherein the detection conditions are that the wavelength is 235nm, the flow is 1.0ml/min, and methanol: 80 parts of water: 20, adding 0.1% acetic acid into water, and separating with common C18 column with specification of 4.6 x 250mm, 5 um; calculated from the normalized contents according to the molar corresponding factors for 2-hydroxypyridine-4-carboxylic acid and 2-chloro-4-trichloromethylpyridine, the product and starting material are 98: 2, the reaction selectivity was about 92% at the end of the reaction control.
In the step (2), in the halogenation reaction process, after sampling, mixing and shaking with water, fully hydrolyzing, filtering, taking a small amount of sample, adding methanol for fully dissolving, and detecting by using the liquid chromatography detection method used in the step (1), wherein when 2-halopyridine-4-carboxylic acid and 2-hydroxypyridine-4-carboxylic acid are calculated according to normalized content, the product and the raw material are 98: 2, the reaction selectivity was about 88% at the end of the reaction control.
And (3) after the fluorination reaction is finished, reducing the temperature to 35-45 ℃, relieving the pressure, absorbing and neutralizing anhydrous hydrogen fluoride, removing residual solvent and fluorination reagent, adding an aqueous solution containing sodium carbonate for neutralization, and performing post-treatment to obtain the 2-halogeno-4-trifluoromethylpyridine, wherein the residual substances at the bottom of the kettle are mainly substances shown in a formula (I).
Wherein, X: cl or Br
In the step (4), the detection method used for tracking the reaction is the same as that in the step (1), and the content of the angelica normalized product is as follows: the raw materials are not less than 95: when 5, the reaction is regarded as the end point of the reaction; after the solvent is removed, post-treatment purification is carried out.
In order to make the technical solutions of the present invention more clearly understood by those skilled in the art, the technical solutions of the present invention will be described in detail below with reference to specific embodiments.
Example 1:
(1) hydrolysis reaction
A1000 ml stainless steel autoclave is added with 92.4g (0.40mol) of 2-chloro-4-trichloromethylpyridine, 1.0g of sodium dodecyl sulfate and 240.0g of 40% (w/w) sodium hydroxide aqueous solution, stirred, heated at 170 ℃ for 6 hours, followed by liquid chromatography, cooled to room temperature after the reaction is finished, added with about 20ml of concentrated hydrochloric acid to adjust the pH value to about 1.0, filtered, washed with 20ml of water for 3 times to obtain yellow powdery solid, and dried to obtain 51.2g of 2-hydroxypyridine-4-carboxylic acid with the yield of 92.1% and the content of 96% (HPLC235 nm).
(2) Halogenation reaction
55.6g (0.40mol) of 2-hydroxypyridine-4-carboxylic acid and 190.40g (1.60mol, 4.0eq.) of thionyl chloride and 5.0g of phosphorus pentachloride are added into a 500ml three-neck flask, stirred and heated under reflux at 80 ℃ for 10 hours to generate acid gas, the acid gas is absorbed by 30% liquid alkali, followed by liquid chromatography, after the reaction is finished, the unreacted thionyl chloride is evaporated under normal pressure, 100ml of water is added and stirred, the temperature is controlled at 45 ℃, the temperature is kept for 30 minutes, filtration is carried out to separate out yellow powdery solid, 100ml of saturated disodium hydrogen phosphate solution and 100ml of water are sequentially used for washing, filtration and drying are carried out to obtain 58.6g of 2-chloroisonicotinic acid, the yield is 93%, and the content is 98.5% (HPLC235 nm).
(3) Fluorination reaction
In a 1000ml high-pressure autoclave, at low temperature of about 0 ℃, 157.50g (1.00mol) of 2-chloropyridine-4-formic acid, 324.0g (3.0mol) of sulfur tetrafluoride and 200.00g of anhydrous hydrogen fluoride are added, the temperature is raised to 120 ℃, the pressure is about 3.5MPa, the temperature is kept for 12 hours, the temperature is lowered to about 45 ℃, the pressure is released to absorb the anhydrous hydrogen fluoride, after that, 25 percent ammonia solution is added to neutralize the pH value to 7.0-8.0, the materials are discharged, the materials are transferred to a 500ml three-neck bottle and rectified to obtain 8.20g of 2-fluoro-4-trifluoromethylpyridine and 156.10g of 2-chloro-4-trifluoromethylpyridine, and the total yield is about 92.0 percent.
(4) Nucleophilic substitution reaction
Adding 181.5g (1.00mol) of 2-chloro-4-trifluoromethylpyridine, 9.9g (0.10mol) of cuprous chloride, 1.0g of tetraphenylphosphonium bromide and 637.5g of 40% ammonia water solution (15.0eq.) into a 1000ml autoclave, heating and stirring at 150 ℃ for reaction for 16 hours, reducing the temperature, opening the autoclave, adding 500ml of toluene, stirring and dissolving, filtering, recovering the cuprous chloride, separating liquid, adding 15g of anhydrous sodium sulfate, drying for 30 minutes, decolorizing with activated carbon, transferring an organic phase into a 1000ml flask, slowly introducing anhydrous hydrogen chloride gas, separating out a white solid which is the hydrochloride of 2-amino-4-trifluoromethylpyridine, filtering, washing with water and drying to obtain 150.65g of 2-amino-4-trifluoromethylpyridine with the yield of 93.0%; the remaining toluene was concentrated to give about 17g of an orange-red oily liquid, and 250ml of water was added to conduct steam distillation to obtain 3.50g of 2-chloro-4-trifluoromethylpyridine (2.0% mol), and the residue was subjected to steam distillation and dried to obtain 7.50g of a yellow solid which was mainly 2-hydroxy-4-trifluoromethylpyridine (4.60% mol) by gas chromatography.
Example 2:
(1) hydrolysis reaction
Adding 462g (2.0mol) of 2-chloro-4-trichloromethylpyridine, 1.0g of tetraphenyl phosphorus bromide and 533g of 75% (w/w) aqueous solution of sulfuric acid into a 1000ml three-neck flask, stirring, heating at 160 ℃ for 14 hours, continuously dropwise adding water, controlling the reaction temperature to fluctuate at 160 ℃, adding 65-75ml of water cumulatively, enabling the material color to be colorless and transparent-yellow-orange red-brown, tracking by liquid chromatography, reducing the reaction temperature to 100 ℃, adding 600ml of water, cooling to room temperature, stirring, filtering, washing a filter cake to the pH value of about 3.0 by 300ml of water, and drying to obtain 250.5g of 2-hydroxypyridine-4-formic acid, the yield is 90.11%, and the content is 97.5% (HPLC235 nm).
(2) Halogenation reaction
27.8g (0.20mol) of 2-hydroxypyridine-4-formic acid, 229.36g (0.80mol, 4.0eq.) of tribromophosphine, 3g of penta-phosphorus bromide and 123.07g (0.8mol) of carbon tetrachloride are added into a 500ml three-neck flask, the mixture is stirred and heated at 80 ℃ for reflux for 10 hours, generated acid gas is absorbed by 30% liquid alkali, followed by liquid chromatography, after the reaction is finished, the unreacted tribromophosphine oxide and carbon tetrachloride are evaporated out at normal pressure, 50ml of water is added into an ice water bath, the temperature is controlled at 45 ℃, the mixture is kept for 30min, the yellow powdery solid is separated out by filtration, 100ml of saturated disodium hydrogen phosphate solution and 100ml of water are sequentially used for washing, and the drying is carried out, so that 37.2g of 2-bromopyridine-4-formic acid is obtained, the yield is 92%, and the content is 98.7% (HPLC235 nm).
(3) Fluorination reaction
In a 1000ml autoclave, at a low temperature of about 0 ℃, 202.0g (1.00mol) of 2-bromopyridine-4-formic acid, 415.0g (2.5mol, 2.5eq.) of phenylsulfur trifluoride and 200.00g of anhydrous hydrogen fluoride are added, the temperature is raised to 120 ℃ by heating, the pressure is about 3.5MPa, the mixture is kept for 13 hours, the temperature is lowered to more than 35 ℃, the pressure is released to absorb the anhydrous hydrogen fluoride by decompression, after that, 25 percent ammonia water solution is added to neutralize the mixture to pH7.0-8.0, the mixture is discharged, the mixture is transferred into a 500ml three-mouth bottle and rectified to obtain 8.0g of 2-fluoro-4-trifluoromethylpyridine and 188.05g of 2-bromo-4-trifluoromethylpyridine, and the total yield is about 88.0 percent.
(4) Nucleophilic substitution reaction
226.0g (1.00mol) of 2-bromo-4-trifluoromethylpyridine, 19.9g (0.10mol) of cuprous iodide, 1.0g of tetraphenylphosphonium bromide, 80.0g of 80% hydrazine hydrate solution (2.0eq.), 200ml of ethylene glycol dimethyl ether, 100g of anhydrous sodium acetate, heating and stirring at 150 ℃ for reaction for 16 hours, cooling, opening the kettle, filtering, washing a filter cake with 100ml of water, recovering the cuprous iodide, concentrating the liquid to obtain white-like solid powder, washing with 100ml of saturated sodium carbonate solution, filtering, washing with 100ml of clear water, filtering, and drying to obtain 164.8g of 2-hydrazino-4-trifluoromethylpyridine with the yield of 93.1% and the content of 99.2% (HPLC235nm) in a 1000ml autoclave.
Example 3:
(1) hydrolysis reaction
A1000 ml stainless steel autoclave is added with 92.4g (0.40mol) of 2-chloro-4-trichloromethyl pyridine, 1.0g of didodecyldimethylammonium bromide and 240.0g of 40% (w/w) aqueous solution of sodium hydroxide, stirred, heated at 160 ℃ for 12 hours, followed by liquid chromatography, cooled to room temperature after the reaction is finished, added with about 67ml of concentrated hydrochloric acid to adjust the pH to about 1.0, filtered, washed with 20ml of water for 3 times to obtain pale yellow powdery solid, and dried to obtain 53.0g of 2-hydroxypyridine-4-carboxylic acid with the yield of 95.3 percent and the content of 98.5 percent (HPLC235 nm).
(2) Halogenation reaction
Adding 55.6g (0.40mol) of 2-hydroxypyridine-4-formic acid and 245.0g (1.60mol, 4.0eq.) of phosphorus oxychloride into a 500ml three-neck flask, stirring and heating at 106 ℃ for reflux for 10 hours to generate acid gas, absorbing by using 30% liquid alkali, tracing by liquid chromatography, heating by using an oil bath at 80 ℃ after the reaction is finished, evaporating the unreacted phosphorus oxychloride by using a water pump under reduced pressure, dropping 50ml of water, stirring, violently releasing hydrogen chloride gas, cooling by using an ice water bath after the release is finished, stirring for 30 minutes, filtering under reduced pressure, separating out yellow powdery solid, and drying to obtain 56.70g of 2-chloroisonicotinic acid, wherein the yield is 90%, and the content is 95.5% (HPLC235 nm).
(3) Fluorination reaction
157.50g (1.00mol) of 2-chloropyridine-4-formic acid, 498.0g (3.0mol, 3.0eq.) of phenylsulfur trifluoride and 200.00g of anhydrous hydrogen fluoride are added into a 1000ml autoclave at a low temperature of about 0 ℃, heated to 120 ℃, kept at a pressure of about 3.5MPa for 10 hours, cooled to over 35 ℃, decompressed, absorbed and neutralized, and then added with 25% ammonia water solution to neutralize to a pH of 7.0-8.0, discharged, transferred into a 500ml three-neck flask, and rectified to obtain 8.60g of 2-fluoro-4-trifluoromethylpyridine and 163.0g of 2-chloro-4-trifluoromethylpyridine, wherein the total yield is about 95.0%.
(4) Nucleophilic substitution reaction
Adding 181.5g (1.00mol) of 2-chloro-4-trifluoromethylpyridine, 19.9g (0.10mol) of cuprous iodide, 350ml of N, N-dimethylformamide, 247g (3.0eq.) of 68% sodium hydrosulfide hydrate, 99g of triethylamine, heating, stirring and refluxing at 150 ℃ for 16 hours, introducing tail gas into an aqueous solution of sodium hydroxide for absorption, cooling, evaporating most of N, N-dimethylformamide under reduced pressure, adding 300ml of a saturated aqueous solution of ammonium chloride, stirring and washing, filtering to obtain yellow powder, heating, stirring and dissolving the yellow powder by 1000ml of methanol, filtering while hot, recovering the cuprous iodide, adding 10g of activated carbon into the filtrate, heating, refluxing and decoloring for 30min, cooling, filtering while hot, concentrating to obtain white solid powder, drying to obtain 147.0g of 2-mercapto-4-trifluoromethylpyridine, yield 82.1%, content 96.8% (HPLC235 nm).
Example 4:
(1) hydrolysis reaction
A1000 ml stainless steel autoclave is added with 92.4g (0.40mol) of 2-chloro-4-trichloromethylpyridine, 1.0g of polyethylene glycol 800 and 240.0g of 40% (w/w) sodium hydroxide aqueous solution, stirred, heated at 170 ℃ for 7 hours, tracked by liquid chromatography, cooled to room temperature after the reaction is finished, added with about 67ml of concentrated hydrochloric acid to adjust the pH value to about 1.0, filtered, washed with 20ml of water for 3 times to obtain pale yellow powdery solid, and dried to obtain 52.15g of 2-hydroxypyridine-4-formic acid with the yield of 93.8 percent and the content of 97.0 percent (HPLC235 nm).
(2) Halogenation reaction
55.6g (0.40mol) of 2-hydroxypyridine-4-formic acid and 203.2g (1.60mol, 4.0eq.) of oxalyl chloride and 5g of phosphorus pentachloride are added into a 500ml three-neck flask, the mixture is stirred and heated under reflux at 70 ℃ for 24 hours, generated acid gas is absorbed by 30% liquid alkali and tracked by liquid chromatography, after the reaction is finished, oxalyl chloride which cannot be reacted is evaporated under normal pressure, 50ml of water is added and stirred, the temperature is controlled at 45 ℃, the temperature is kept for 30min, filtering is carried out, yellow powdery solid is separated out, and drying is carried out to obtain 57.47g of 2-chloroisonicotinic acid, the yield is 91.2%, and the content is 98.5% (HPLC235 nm).
(3) Fluorination reaction
In a 1000ml autoclave, 157.50g (1.00mol) of 2-chloropyridine-4-formic acid, 498.0g (3.0mol, 3.0eq.) of phenylsulfur trifluoride and 163g of triethylamine trihydrofluoride are added at room temperature of 25-30 ℃, heated to 130 ℃, kept at a pressure of about 5MPa for 12 hours, cooled to about 35 ℃, the product is introduced into a sodium carbonate saturated solution in an ice water bath under stirring to neutralize to a pH of about 6-7, filtered, 250ml of dichloroethane is added each time, extracted for 2 times, transferred to a 1000ml three-necked flask, and rectified to obtain 7.95g of 2-fluoro-4-trifluoromethylpyridine and 151.0g of 2-chloro-4-trifluoromethylpyridine with a total yield of about 88.1%.
(4) Nucleophilic substitution reaction
In a 1000ml three-neck flask, 90.75g (0.5mol) of 2-chloro-4-trifluoromethylpyridine, 9.5g (0.05mol) of cuprous iodide, 350ml of N, N-dimethylformamide, 70.5(1.5eq.) of phenol, 74.3g of triethylamine and 180 ℃ are added in a nitrogen atmosphere, the mixture is heated, stirred and refluxed for 8 hours, the temperature is reduced, most of N, N-dimethylformamide is evaporated under reduced pressure, 300ml of saturated potassium carbonate aqueous solution is added, stirred and washed, and filtered to obtain an off-white powder, the off-white powder is heated, stirred and dissolved by 500ml of methanol, filtered while hot, the cuprous iodide is recovered, and the filtrate is concentrated to obtain an off-white solid powder, and the off-white solid powder is dried to obtain 108.8g of 2-phenoxy-4-trifluoromethylpyridine, the yield is 91.0%, and the content is 95.6% (HPLC235 nm).
Example 5:
adding 139.1g (1.00mol) of 2-hydroxypyridine-4-formic acid, 324.0g (3.0mol, 3.0eq.) of sulfur tetrafluoride and 163g of triethylamine trifluoride into a 1000ml autoclave at room temperature of 25-30 ℃, heating to 130 ℃, keeping for 12 hours, cooling to about 100 ℃, discharging gas after reaction, pouring the product into an ice water bath sodium carbonate saturated solution which is stirred, neutralizing to about 1-2 of pH, filtering, adding 250ml of n-butyl acetate each time, extracting for 3 times, concentrating, washing with 150ml of water for 3 times, and drying to obtain white powdery solid 2-hydroxy-4-trifluoromethylpyridine, wherein the total amount is 122.5g, and the yield is about 88.1%.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of 2-substituted-4-trifluoromethyl pyridine is characterized by comprising the following steps: 2-chloro-4-trichloromethylpyridine is taken as a raw material, and 2-substituted-4-trifluoromethylpyridine is obtained through hydrolysis, halogenation, trifluoromethylation and nucleophilic substitution;
the reaction route is as follows:
wherein Y is amino, hydroxyl, thiol, hydrazino, cyano, fluorine, bromine or iodine;
x is chlorine or bromine.
2. The method of claim 1, wherein: the method specifically comprises the following steps:
(1) in a strong alkali or strong protonic acid water solution, 2-chloro-4-trichloromethylpyridine is hydrolyzed to be converted into 2-hydroxypyridine-4-formic acid;
(2) halogenating 2-hydroxypyridine-4-formic acid with a halogenating reagent to obtain 2-halopyridine-4-formic acid;
(3) carrying out fluorination reaction on 2-halopyridine-4-formic acid and a fluorination reagent to obtain 2-halogeno-4-trifluoromethylpyridine;
(4) reacting the 2-halogenated-4-trifluoromethylpyridine with a nucleophilic reagent capable of providing Y to obtain the 2-substituted-4-trifluoromethylpyridine compound.
3. The method of claim 2, wherein: and (3) when the final target product is the 2-hydroxy-4-trifluoromethylpyridine compound, the steps (2) and (4) are omitted, and the 2-hydroxy-4-trifluoromethylpyridine directly reacts with a fluorinating reagent to obtain the 2-hydroxy-4-trifluoromethylpyridine compound.
4. The method of claim 2, wherein: strong base and strong protonic acid in the step (1), wherein the strong base is preferably sodium hydroxide, potassium hydroxide or barium hydroxide; the addition amount of the strong base is as follows: 4-6 chemical molar equivalents, and the concentration of the strong alkali aqueous solution is as follows: 5-40% mass concentration;
the strong protonic acid refers to non-volatile acid and solid superacid and acidic ion exchange resin, the concentration of the non-volatile acid is 60% or more, preferably sulfuric acid, phosphoric acid, bisulfate, chlorosulfonic acid, fluorosulfonic acid and the like, more preferably the concentration of the sulfuric acid, acidic ion exchange resin and solid superacid is 70% or more, and the dosage is preferably 1-3 times of the molar amount of 2-chloro-4-trichloromethylpyridine; the mass concentration of the aqueous solution of the strong protonic acid is as follows: 60 to 90 percent;
or, the hydrolysis is carried out with the aid of a phase transfer catalyst in an amount of 0.1% to 5.0%, preferably 0.5% to 1.5% by mass of 2-chloro-4-trichloromethylpyridine, including, but not limited to, long-chain linear or branched alkyl alkali metal salts of alkyl sulfonic acids, long-chain linear or branched quaternary ammonium/phosphonium salts, polymeric polyethylene glycols;
preferably, the hydrolysis reaction temperature is 150-180 ℃;
further, the hydrolysis reaction time is 6-18 h;
further, when hydrolyzing in strong protonic acid, the hydrolysis pressure is normal pressure; when the hydrolysis is carried out in strong alkali, the hydrolysis pressure is 0.1-2.0 MPa.
5. The method of claim 2, wherein: in the step (2), the halogenating reagent is any one or two or more of phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, phosphorus tribromide, phosphorus tribromooxide, phosphorus pentachloride, phosphorus pentabromide or triphosgene.
6. The method of claim 2, wherein: in the step (2), a halogenating reagent is used as a solvent to carry out solvent-free reaction;
further, in the solvent-free reaction described in step (2), the amount of the halogenating agent used is 3 to 5 times the molar amount required for the chemical reaction.
7. The method of claim 2, wherein: in the step (2), adding a solvent for reaction, wherein the solvent is halogenated hydrocarbon, preferably carbon tetrachloride, dichloroethane or chlorobenzene;
further, the mass of the added solvent is preferably 2 to 5 times of that of the halogenated raw material; in this case, the amount of the halogenating agent to be added is preferably 1.05 to 2.00 times, more preferably 1.2 to 1.5 times the molar amount required for the chemical reaction.
8. The method of claim 2, wherein: the reaction temperature of the step (2) is 70-120 ℃, and the reaction time is 8-24 hours, preferably 10-12 hours.
9. The method of claim 2, wherein: in the fluorination reaction in the step (3), anhydrous hydrogen fluoride, triethylamine trifluoride or pyridine fluoride are used as reaction solvents for reaction, and the addition amount of the solvents is 0.5 to 3 times of the mass of 2-halopyridine-4-formic acid;
further, in the step (3), the fluorinating agent is phenylsulfur trifluoride, substituted sulfur trifluoride or sulfur tetrafluoride;
furthermore, the adding amount of the fluorinating agent is 2.0 to 3.5 times of the molar amount of the 2-halopyridine-4-formic acid;
further, the fluorination reaction temperature is 85-150 ℃;
further, the fluorination reaction time is 8 to 24 hours, preferably 10 to 14 hours;
further, the fluorination reaction pressure is 0.1-5.0 MPa;
further, after the fluorination reaction is finished, the post-treatment mode is as follows: and (2) at 35-45 ℃, decompressing, absorbing and neutralizing anhydrous hydrogen fluoride, removing residual solvent and fluorinating reagent, blowing nitrogen to remove residual hydrogen fluoride to an absorption device for absorption, neutralizing by using sodium carbonate, sodium bicarbonate, ammonia water and the like, and performing post-treatment to obtain the required 2-halogeno-4-trifluoromethylpyridine.
10. The method of claim 2, wherein: in step (4), the nucleophilic reagent includes, but is not limited to, sodium alkoxide, sodium phenoxide, sodium amide, liquid ammonia, ammonia water, sodium sulfide, sodium hydrosulfide, sodium mercaptide, sodium thiocyanate, sodium/potassium cyanide, hydrazine hydrochloride or sulfate, hydrazine hydrate, alkali metal fluoride, alkali metal iodide, alkali metal bromide;
furthermore, the adding amount of the nucleophilic reagent is 1.05 to 15 times of the molar amount of the 2-halogenated-4-trifluoromethylpyridine, and is determined according to the activity of the nucleophilic reagent, whether the nucleophilic reagent is easy to remove and whether the nucleophilic reagent is used as a solvent;
further, the step (4) adopts a solvent to carry out the reaction, wherein the solvent is an aprotic dipolar solvent which mainly plays a role in dissolving raw materials and providing a nucleophilic reagent for Y to help the reaction, and the aprotic dipolar solvent comprises but is not limited to lower aliphatic nitriles, lower aliphatic ethers/polyethers, lower aliphatic ketones, lower aliphatic amides, low molecular weight morpholines and pyrrolidones; the mass of the aprotic dipolar solvent added is 1 to 5 times, more preferably 2 to 3 times, the mass of the 2-halo-4-trifluoromethylpyridine;
further, the reaction temperature of the step (4) is 80-180 ℃;
further, the reaction time of the step (4) is 6-48 hours;
further, the reaction in the step (4) is carried out under the action of a catalyst, wherein the catalyst is one or more of cuprous chloride, cuprous bromide and cuprous iodide;
preferably, the catalyst is used in combination with a phase transfer catalyst;
further, in the reaction process in the step (4), in order to promote the reaction to proceed smoothly, an acid-binding agent capable of binding hydrogen halide generated by the reaction is added, wherein the acid-binding agent includes, but is not limited to, tertiary amines, pyridines, alkali metal salts corresponding to inorganic or organic weak acids, and organic or inorganic weak bases.
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