A kind of synthetic method of 4-trifluoromethylpyridine

Abstract

The invention discloses a method for synthesizing 4-trifluoromethylpyridine, and relates to the technical field of 4-trifluoromethylpyridine synthesis. The method comprises the following steps: measuring bromoacetaldehyde diethyl acetal: magnesium chips: ethyl trifluoroacetate: ammonium acetate in a molar ratio of 1:1-1.1:0.4-0.5:1.3-2.6; adding magnesium chips and tetrahydrofuran into a reaction bottle; adding a small amount of substrate bromoacetaldehyde diethyl acetal; adding an initiator; controlling the temperature at 35°C; dripping a tetrahydrofuran solution of the remaining bromoacetaldehyde diethyl acetal and ethyl trifluoroacetate; and heating the bottle for reaction; The reaction flask is cooled with an ice-water bath, and a saturated ammonium chloride solution is added dropwise at low temperature to quench the reaction. The mixture is extracted with ethyl acetate, the organic phase is dried, and concentrated under reduced pressure to obtain 2-diethoxymethyl-3,3-dimethoxy-1,1,1-trifluoropropane-2-ol; acetic acid and ammonium acetate are added, and an appropriate amount of water is added. The pH of the aqueous phase is adjusted to greater than 7 with solid sodium bicarbonate, the mixture is filtered, and the organic phase is dried; S7, dichloromethane is removed by a water pump at low temperature, and the crude product is distilled to finally obtain a high-purity target product 4-trifluoromethylpyridine.

Description

Technical Field

[0001] The invention relates to the technical field of 4-trifluoromethylpyridine synthesis, in particular to a synthesis method of 4-trifluoromethylpyridine. Background Art

[0002] 4-Trifluoromethylpyridine, with the molecular formula C6H4F3 and a relative molecular mass of 147.10, is a light yellow transparent liquid and is an important raw material for chemical and pharmaceutical industries.

[0003] Currently, there are four main schemes for synthesizing 4-trifluoromethylpyridine: Scheme 1: Patent (99127004.5) uses 1,1,1-trifluoro-4-alkoxy-3-alkylbutene-2-one as a raw material, which reacts with a metal reagent of a 2-halogenated alkylnitrile to produce the corresponding carbonyl addition product, allyl alcohol. This product can be directly reacted with PX5 and / or HCl without separation to obtain the corresponding 4-trifluoromethylpyridine compound; Scheme 2: Reference J.CHEM.SOC.PERKIN TRANS.11990 (2293-2299) describes that crude 4-trifluoromethylpyridine can be obtained by filling trifluoromethyl bromide (pressure 13 bar) with substrates such as pyridine, water, dipotassium hydrogen phosphate and sodium disulfite at 65°C, and finally purified by distillation, fractionation and other methods; Scheme 3: Reference European Journal of Organic Chemistry (2011) Chemistry, 2002, #2, pp. 327-330 proposes using 4-iodopyridine, potassium fluoride, cuprous iodide, and trifluoromethyltrimethylsilane as raw materials, with anhydrous N,N-dimethylformamide and anhydrous N-methylpyrrolidone as solvents, and reacting at 25°C to synthesize 4-trifluoromethylpyridine. Scheme 4: The synthesis of 4-trifluoromethylpyridine in the literature (Organic Process Research & Development 2001, 5, 531-534) involves three steps. The first step involves using ethyl trifluoroacetate and allylmagnesium bromide in tetrahydrofuran as a solvent to produce 3-trifluoromethyl-penta-1,4-dien-3-ol. The second step involves oxidizing the product from the first step with ozone in dichloromethane and methanol to produce 2-hydroxy-2-trifluoromethylmalonaldehyde. The third step involves refluxing the product from the second step in an ammonia-methanol solution to ultimately produce 4-trifluoromethylpyridine. Existing methods for synthesizing 4-trifluoromethylpyridine in published patents and literature all have certain drawbacks. Among them, the method of Scheme 1 is complicated to operate, with low purity and low yield. Among the synthesis methods of the three documents, Scheme 2 uses trifluoromethyl bromide reagent as the trifluoromethyl source, and the reaction must be heated to 65°C under the pressure of trifluoromethyl bromide gas. The reagent has a low boiling point, is difficult to operate, and has high cost and high risk for industrial scale-up. Scheme 3 uses iodine, potassium fluoride, cuprous iodide, and trifluoromethyltrimethylsilane as the trifluoromethyl source for synthesis. Trifluoromethyltrimethylsilane is expensive and has poor stability, and the para-position yield of the reaction is low. The reaction conditions are relatively harsh, the cost is high, and the yield is low. Scheme 4 has a relatively long reaction route. The first step uses a format to obtain an intermediate, and the second step uses ozone, which is more dangerous and the intermediate is unstable. The yield of the third step reaction is low. The post-processing and purification of each step of the reaction are relatively cumbersome, cannot meet the requirements of industrial production, and have great safety hazards. For this reason, we propose a synthesis method for 4-trifluoromethylpyridine. Summary of the Invention

[0004] In view of the deficiencies in the prior art, the present invention provides a method for synthesizing 4-trifluoromethylpyridine, which solves the problems raised in the above background technology.

[0005] To achieve the above objectives, the present invention is implemented by the following technical solution: A method for synthesizing 4-trifluoromethylpyridine, comprising the following steps:

[0006] S1. Measure bromoacetaldehyde diethyl acetal: magnesium chips: ethyl trifluoroacetate: ammonium acetate in a molar ratio of 1:1-1.1:0.4-0.5:1.3-2.6;

[0007] S2. At 20-25°C, first add magnesium chips and tetrahydrofuran into the reaction flask, then add a small amount of substrate bromoacetaldehyde diethyl acetal, then add a small amount of initiator iodine particles, and slowly raise the temperature to 55°C;

[0008] S3, adding the remaining bromoacetaldehyde diethyl acetal and ethyl trifluoroacetate in tetrahydrofuran solution dropwise at 35°C, and then raising the temperature to react;

[0009] S4. Cool the reaction flask with an ice-water bath, add saturated ammonium chloride solution dropwise at low temperature to quench the reaction, extract with ethyl acetate, dry the organic phase, and concentrate under reduced pressure to obtain 2-diethoxymethyl-3,3-dimethoxy-1,1,1-trifluoropropan-2-ol;

[0010] S5. Add acetic acid and ammonium acetate, raise the temperature to 90-100°C, react for two hours, and then cool to room temperature;

[0011] S6. Add appropriate amount of water, adjust the pH of the aqueous phase to >7 with solid sodium bicarbonate, filter, extract the filtrate with dichloromethane, and dry the organic phase;

[0012] S7. Dichloromethane is removed by a water pump at low temperature, and the crude product is distilled to obtain the high-purity target product 4-trifluoromethylpyridine.

[0013] In the present invention, the molar ratio of bromoacetaldehyde diethyl acetal: magnesium chips: ethyl trifluoroacetate: ammonium acetate in S1 is 1:1:0.5:2.1.

[0014] Furthermore, in the present invention, the temperature rising reaction in S3 is carried out at 50° C. for 4 hours.

[0015] Furthermore, in the present invention, the cooling reaction temperature in S4 is 0-10°C.

[0016] The present invention provides a method for synthesizing 4-trifluoromethylpyridine, which has the following beneficial effects:

[0017] 1. The method for synthesizing 4-trifluoromethylpyridine comprises the following steps: using bromoacetaldehyde diethyl acetal and ethyl trifluoroacetate as starting materials, first preparing a Grignard reagent of bromoacetaldehyde diethyl acetal using bromoacetaldehyde diethyl acetal and magnesium chips, then subjecting the mixture to nucleophilic addition with ethyl trifluoroacetate to obtain 2-diethoxymethyl-3,3-dimethoxy-1,1,1-trifluoropropyl-2-ol, and then performing ring closure with ammonium acetate and acetic acid at 90-100° C. to finally obtain 4-trifluoromethylpyridine. The method avoids the use of expensive substrates and reagents, and also avoids obtaining the product through an ozone oxidation process, thereby reducing the risk of kilogram-scale production. At the same time, the raw materials are relatively cheap, thereby reducing the production cost. The use of relatively low-priced ammonium acetate for ring closure greatly reduces the production cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Schematic diagram of the process of the structure of the present invention;

[0019] Figure 2 is the calculated hydrogen spectrum of the present invention;

[0020] Figure 3 Schematic diagram of embodiment 1 of the present invention;

[0021] Figure 4 Schematic diagram of embodiment 2 of the present invention;

[0022] Figure 5 This is a schematic diagram of Example 3 of the present invention. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0024] See also Figures 1 to 5 The present invention provides a technical solution: a method for synthesizing 4-trifluoromethylpyridine.

[0025] Example 1

[0026] At 20°C, add 20g of magnesium chips and 200g of THF into a four-necked flask equipped with a mechanical stirrer, add 20g of bromoacetaldehyde diethanol acetal, add 0.2g of iodine, replace with nitrogen, start stirring, and then slowly raise the temperature to 55°C. There are a lot of bubbles in the reaction flask, and the iodine color gradually disappears. After 10 minutes, the bubbles gradually disappear, and the temperature is lowered to 35°C. The remaining 144g of bromoacetaldehyde diethanol acetal and 59.2g of ethyl trifluoroacetate in tetrahydrofuran solution are slowly added dropwise in batches. The addition is done for 3h. After the addition is completed, the temperature is raised to 50°C and the reaction is carried out for 4h. The reaction solution was cooled to 0°C and poured into 800ml of saturated ammonium chloride solution, stirred for 5min, extracted with 800ml of ethyl acetate, separated, and the aqueous phase was extracted again with 400ml of ethyl acetate. The organic phases were combined and dried by adding 80g of anhydrous sodium sulfate. The organic phases were concentrated under reduced pressure to obtain 2-diethoxymethyl-3,3-dimethoxy-1,1,1-trifluoropropan-2-ol. At 20°C, 300ml of acetic acid and 68g of 2-diethoxymethyl-3,3-dimethoxy-1,1,1-trifluoropropan-2-ol was added to 62.4g of ammonium acetate. After addition, the temperature was raised to 90°C for 2h, cooled to 20°C, and 600ml of ice water was added. 800g of solid sodium bicarbonate was slowly added to adjust the pH of the aqueous phase to >7. A large amount of solid precipitated. The mixture was filtered through a Buchner funnel, and the filter cake was washed with water and dichloromethane. The filtrate was extracted twice with 500ml of dichloromethane. The organic phases were combined, dried over 200g of anhydrous sodium sulfate, and concentrated under reduced pressure at a low temperature of below 20°C to obtain a crude brown liquid. The crude product was then distilled under normal pressure, and the 110°C fraction was collected to obtain the highly pure target product, 4-trifluoromethylpyridine, with a GC yield of 98.84%. (1:1:0.5:1.3).

[0027] Example 2

[0028] At 25°C, add 43.8g of magnesium chips and 200g of THF into a four-necked flask equipped with a mechanical stirrer, add 40g of bromoacetaldehyde diethanol acetal, add 0.2g of iodine, replace with nitrogen, start stirring, and then slowly raise the temperature to 55°C. There are a lot of bubbles in the reaction flask, and the iodine color gradually disappears. After 10 minutes, the bubbles gradually disappear, and the temperature is lowered to 35°C. The remaining 288g of bromoacetaldehyde diethanol acetal and 117.86g of ethyl trifluoroacetate in tetrahydrofuran solution are slowly added dropwise in batches. The addition is done for 3h. After the addition is completed, the temperature is raised to 50°C and the reaction is carried out for 4h. The reaction solution was cooled to 5°C and poured into 800ml of saturated ammonium chloride solution, stirred for 5min, extracted with 800ml of ethyl acetate, separated, and the aqueous phase was extracted again with 400ml of ethyl acetate. The organic phases were combined and dried by adding 80g of anhydrous sodium sulfate. The organic phases were concentrated under reduced pressure to obtain 2-diethoxymethyl-3,3-dimethoxy-1,1,1-trifluoropropan-2-ol. At 25°C, 300ml of acetic acid and 68g of 2-diethoxymethyl-3,3-dimethoxy-1,1,1-trifluoropropan-2-ol was added to 195.88g of ammonium acetate. After addition, the temperature was raised to 100°C and the reaction was allowed to react for 2h. The mixture was then cooled to 25°C, followed by the addition of 600ml of ice water. 800g of solid sodium bicarbonate was slowly added to adjust the pH of the aqueous phase to >7. A large amount of solid precipitated. The mixture was filtered through a Buchner funnel, and the filter cake was washed with water and dichloromethane. The filtrate was extracted twice with 500ml of dichloromethane. The organic phases were combined, dried over 200g of anhydrous sodium sulfate, and concentrated under reduced pressure at a low temperature of below 25°C to obtain a crude brown liquid. The fraction at 110°C was then distilled under normal pressure to obtain the highly pure target product, 4-trifluoromethylpyridine, with a GC yield of 98.56%. (1:1.1:0.5:2).

[0029] Example 3

[0030] At 23°C, add 21.9g of magnesium chips and 200g of THF into a four-necked flask equipped with a mechanical stirrer, add 20g of bromoacetaldehyde diethanol acetal, add 0.2g of iodine, replace with nitrogen, start stirring, and then slowly raise the temperature to 55°C. There are a lot of bubbles in the reaction flask, and the iodine color gradually disappears. After 10 minutes, the bubbles gradually disappear, and the temperature is lowered to 35°C. The remaining 144g of bromoacetaldehyde diethanol acetal and 47.14g of ethyl trifluoroacetate in tetrahydrofuran solution are slowly added dropwise in batches. The addition is done for 3h. After the addition is completed, the temperature is raised to 50°C and the reaction is carried out for 4h. The reaction solution was cooled to 0°C and poured into 800ml of saturated ammonium chloride solution, stirred for 5min, extracted with 800ml of ethyl acetate, separated, and the aqueous phase was extracted again with 400ml of ethyl acetate. The organic phases were combined and dried by adding 80g of anhydrous sodium sulfate. The organic phases were concentrated under reduced pressure to obtain 2-diethoxymethyl-3,3-dimethoxy-1,1,1-trifluoropropan-2-ol. At 23°C, 300ml of acetic acid and 68g of 2-diethoxymethyl-3,3-dimethoxy-1,1,1-trifluoropropan-2-ol was added to 62.4g of ammonium acetate. After addition, the temperature was raised to 95°C for 2h, cooled to 23°C, and 600ml of ice water was added. 800g of solid sodium bicarbonate was slowly added to adjust the pH of the aqueous phase to >7. A large amount of solid precipitated. The mixture was filtered through a Buchner funnel, and the filter cake was washed with water and dichloromethane. The filtrate was extracted twice with 500ml of dichloromethane. The organic phases were combined, dried over 200g of anhydrous sodium sulfate, and concentrated under reduced pressure at a low temperature of below 23°C to obtain a crude brown liquid. The fraction was then distilled at atmospheric pressure, and the 110°C fraction was collected to obtain the highly pure target product, 4-trifluoromethylpyridine, with a GC yield of 98.47%. (1:1:0.4:2.6).

[0031] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A method for synthesizing 4-trifluoromethylpyridine, characterized in that: The following steps are involved: S1. Measure bromoacetaldehyde diethyl acetal: magnesium chips: ethyl trifluoroacetate: ammonium acetate in a molar ratio of 1:1-1.1:0.4-0.5:1.3-2.6; S2. At 20-25°C, first add magnesium chips and tetrahydrofuran into the reaction flask, then add a small amount of substrate bromoacetaldehyde diethyl acetal, then add a small amount of initiator iodine particles, and slowly raise the temperature to 55°C; S3, adding the remaining bromoacetaldehyde diethyl acetal and ethyl trifluoroacetate in tetrahydrofuran solution dropwise at 35°C, and then raising the temperature to react; S4. Cool the reaction flask with an ice-water bath, add saturated ammonium chloride solution dropwise at low temperature to quench the reaction, extract with ethyl acetate, dry the organic phase, and concentrate under reduced pressure to obtain 2-diethoxymethyl-3,3-dimethoxy-1,1,1-trifluoropropan-2-ol; S5. Add acetic acid and ammonium acetate, raise the temperature to 90-100°C, react for two hours, and then cool to room temperature; S6. Add appropriate amount of water, adjust the pH of the aqueous phase to >7 with solid sodium bicarbonate, filter, extract the filtrate with dichloromethane, and dry the organic phase; S7. Dichloromethane is removed by a water pump at low temperature, and the crude product is distilled to obtain the high-purity target product 4-trifluoromethylpyridine.

2. A method for synthesizing 4-trifluoromethylpyridine according to claim 1, characterized in that: In the S1, the molar ratio of bromoacetaldehyde diethyl acetal: magnesium chips: ethyl trifluoroacetate: ammonium acetate is 1:1:0.5:2.

1.

3. A method for synthesizing 4-trifluoromethylpyridine according to claim 1, characterized in that: The temperature reaction in S3 is carried out at 50° C. for 4 hours.

4. A method for synthesizing 4-trifluoromethylpyridine according to claim 1, characterized in that: The cooling reaction temperature in S4 is 0-10°C.

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