Preparation method of fluoro-alpha-methylbenzyl alcohol

Abstract

The invention relates to a preparation method of fluoro-alpha-methylbenzyl alcohol, which is characterized in that in the presence of a strong alkali reagent and an organic solvent, a compound shown in a formula II reacts with acetaldehyde to obtain fluoro-alpha-methylbenzyl alcohol shown in a formula I. The target product is directly obtained through a one-step method, the reaction is efficient, the product purity is high, and the method is suitable for industrial production. The method can be directly used for next-step reaction, and has the characteristics of cheap and easily available raw materials, no expensive reagent, environment friendliness, mild reaction conditions, simplicity in operation, low cost, high yield and easiness in industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of fluoro-α-methylbenzyl alcohol. Background Art

[0002] With the development of modern pesticides and pharmaceuticals, fluorine-containing compounds have shown an increasingly important position. Fluorine-containing pesticides have advantages such as high activity, low toxicity, and environmental friendliness, and have become one of the key development directions of world pesticides. Fluorine-containing herbicides are the pesticides with the largest number of varieties developed in recent years; fluorine-containing pharmaceuticals have characteristics such as high efficiency, low toxicity, and easy metabolism, and are increasingly commonly used in the pharmaceutical field. Common ones include anti-infective quinolone drugs, cardiovascular and cerebrovascular drugs, and anti-inflammatory and anti-rheumatic drugs, etc. Therefore, the market demand for fluorine-containing pesticide and pharmaceutical intermediates is increasing. Among them, fluoro-α-methylbenzyl alcohol is an important intermediate for pesticides and drugs and plays an important role in the synthesis process.

[0003] Taking the synthesis of 2,6-difluoro-α-methylbenzyl alcohol as an example, its synthesis route requires two or more steps, specifically as follows:

[0004] First, react expensive 2,6-difluorobenzonitrile (market price is about 120,000 yuan / ton) with a Grignard reagent, and then obtain 2,6-difluoroacetophenone through a hydrolysis reaction. Finally, obtain 2,6-difluoro-α-methylbenzyl alcohol through reduction with sodium borohydride. Its disadvantages are that the prices of 2,6-difluorobenzonitrile and the Grignard reagent are expensive, and the yield of the reaction between the nitrile and the Grignard reagent is low, only 40-70%. The process operation is cumbersome, and a large amount of waste salt generated by the reaction is not friendly to industrial production.

[0005]

[0006] In addition, 2,6-difluoroacetophenone can also be obtained by reacting 2,6-difluorobenzoic acid raw material with thionyl chloride and then through a condensation reaction and decarboxylation with monoethyl malonate. This method uses 2,6-difluorobenzoic acid as a raw material, which is usually hydrolyzed from 2,6-difluorobenzonitrile, and the raw material price is expensive; a large amount of sulfur dioxide and by-product hydrochloric acid are generated during the preparation of the acyl chloride, and monoethyl malonate potassium salt is also expensive. In the second-step reaction, first condensation is carried out, and then high-temperature decarboxylation is carried out. There are also more waste gases generated by the reaction. The reaction steps are many and the operation is cumbersome, which is not conducive to production.

[0007]

[0008] It has also been reported in relevant literature that 2,6-difluoroacetophenone can be obtained using m-difluorobenzene as a raw material. Bernard Bennetau et al. disclosed the specific scheme. To improve the yield, a trimethylsilylated intermediate is first generated and then acetylated to produce 2,6-difluoroacetophenone. This method has harsh reaction conditions, a long reaction time, and high raw material costs. (Fonctionnalisation régiosélective en position 2 de benzènes 1,3-disubstitués, Tetrahedron, 1993, 49(47): 10843-10854).

[0009]

[0010] For the reaction of reducing to obtain 2,6-difluoro-α-methylbenzyl alcohol, US Patent Application US4438271A discloses that 2,6-difluoroacetophenone reacts under the action of a NaBH4 reducing agent to generate 2,6-difluoro-α-methylbenzyl alcohol, and then the product is obtained by rectification. This method has a long reaction time, high raw material costs, and a large amount of three wastes, and is also not conducive to industrial production.

[0011]

[0012] In summary, the existing technologies all synthesize fluoro-α-methylbenzyl alcohol through a two-step or multi-step method, with disadvantages such as a long reaction time, high production costs, complex operations, and a large amount of three wastes generated. Based on the above disadvantages, it is necessary to propose a new method for preparing fluoro-α-methylbenzyl alcohol, making the main raw materials inexpensive and easily available, having fewer synthesis steps, and less three wastes. Summary of the Invention

[0013] To solve the above problems existing in the prior art, the present invention provides a method for preparing fluoro-α-methylbenzyl alcohol. The raw materials of the present invention are inexpensive and easily available (such as m-difluorobenzene, m-fluorobenzotrifluoride, m-bis(trifluoromethyl)benzene), and the target product can be directly obtained in one step. The reaction is efficient, the operation is simple, the yield is high, the product purity is high, the production cost is low, and the by-product lithium can be easily made into lithium carbonate for battery materials and is easy to separate, which is conducive to industrial production.

[0014] To achieve the above object, the present invention adopts the following technical scheme:

[0015] A method for preparing fluoro-α-methylbenzyl alcohol, the method comprising the following steps:

[0016] In the presence of a strong base reagent and an organic solvent, reacting a compound of formula II with acetaldehyde to obtain fluoro-α-methylbenzyl alcohol of formula I.

[0017]

[0018] Among them, R1 and R2 are each independently selected from fluorine or trifluoromethyl, or when R1 is trifluoromethyl, R2 is chlorine.

[0019] Furthermore, the strong base reagent is selected from alkyllithium and lithamide. Preferably, it can be selected from one or more of n-butyllithium, LDA, and NaNH2;

[0020] Furthermore, the organic solvent is selected from one or more of tetrahydrofuran, methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, cyclohexane, n-hexane, methylcyclohexane, toluene, xylene, and liquid ammonia;

[0021] In the present invention, the reaction temperature is -20 to -90 °C, and the elevated temperature is -40 to 0 °C;

[0022] In the present invention, the reaction time is 0.1 to 8 h, preferably 0.5 to 2 h;

[0023] In the present invention, the molar ratio of the compound of formula II to the strong base reagent is 1:1 to 1:2, and the molar ratio of the compound of formula II to acetaldehyde is 1:1.1 to 1:2.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] The method of the present invention uses fluorine-substituted benzene as a raw material and directly obtains the target product through a one-step method. The reaction is efficient, and the product has high purity and can be directly used in the next step reaction. It has the characteristics of cheap and easily available raw materials, no expensive reagents, environmental friendliness, mild reaction conditions, simple operation, low cost, high yield, and easy industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the compound in Example 1 of the present invention 1 1H NMR spectrum DETAILED DESCRIPTION OF THE INVENTION

[0027] The technical solutions of the present invention will be further described below through specific embodiments.

[0028] Example 1

[0029] The preparation method of 2,6-difluoro-α-methylbenzyl alcohol in this example includes the following steps:

[0030] Under the conditions of a temperature of -70°C and nitrogen protection, 50 mL of n-butyllithium / hexane solution (2.5 M, 0.125 mol) was added to a four-necked flask, and a solution of 12.96 g (0.114 mol) of m-difluorobenzene in 50 mL of THF was added dropwise, with the temperature maintained at -70 to -80°C. After keeping warm for 1 hour, a solution of 6.5 g (0.147 mol) of acetaldehyde in 6.5 mL of THF was added dropwise at this temperature. After the addition was complete, it was kept warm for 1 hour. The temperature was naturally raised to -20°C, and the reaction solution was added to ice-cold 20% hydrochloric acid, extracted twice with toluene / MIBK (methyl isobutyl ketone), filtered, and the filtrate was concentrated to dryness to obtain 16.5 g of the target product. The content detected by HPLC was 99.5%, and the yield was 91.09%.

[0031] Example 2

[0032] The preparation method of 2,6-difluoro-α-methylbenzyl alcohol in this Example 2 includes the following steps:

[0033] Under the conditions of a temperature of -70°C and nitrogen protection, 50 mL of LDA / THF solution (2.5 M, 0.125 mol) was added to a four-necked flask, and a solution of 12.96 g (0.114 mol) of m-difluorobenzene in 50 mL of THF was added dropwise, with the temperature maintained at -70 to -80°C. After keeping warm for 1 hour, a solution of 6.5 g (0.147 mol) of acetaldehyde in 6.5 mL of THF was added dropwise at this temperature. After the addition was complete, it was kept warm for 1 hour. The temperature was naturally raised to -20°C, and the reaction solution was added to ice-cold 20% hydrochloric acid, extracted twice with toluene / MIBK (methyl isobutyl ketone), filtered, and the filtrate was concentrated to dryness to obtain 17 g of the target product. The content detected by HPLC was 99.3%, and the yield was 93.67%.

[0034] Example 3

[0035] The preparation method of 2,6-difluoro-α-methylbenzyl alcohol in this Example 2 includes the following steps:

[0036] Under the conditions of a temperature of -70°C and nitrogen protection, 50 mL of NaNH2 / toluene solution (2.5 M, 0.125 mol) was added to a four-necked flask, and a solution of 12.96 g (0.114 mol) of m-difluorobenzene in 50 mL of THF was added dropwise, with the temperature maintained at -70 to -80°C. After keeping warm for 0.5 hour, a solution of 6.5 g (0.147 mol) of acetaldehyde in 6.5 mL of THF was added dropwise at this temperature. After the addition was complete, it was kept warm for 1 hour. The temperature was naturally raised to -20°C, and the reaction solution was added to ice-cold 20% hydrochloric acid, extracted twice with toluene / MIBK (methyl isobutyl ketone), filtered, and the filtrate was concentrated to dryness to obtain 16.8 g of the target product. The content detected by HPLC was 99.5%, and the yield was 92.75%.

[0037] Example 4

[0038] The preparation method of 2-chloro-6-trifluoromethyl-α-methylbenzyl alcohol in this example comprises the following steps:

[0039] Under the conditions of a temperature of -70 °C and nitrogen protection, add a NaNH2 / xylene solution (2.5 M, 0.125 mol) to a four-necked flask, and dropwise add a solution of 18.06 g (0.1 mol) of m-chlorobenzotrifluoride in 50 mL of THF. Keep the temperature at -70 to -80 °C. Keep warm for 0.5 hour. At this temperature, dropwise add a solution of 5.7 g (0.13 mol) of acetaldehyde in 6 mL of THF. After the dropwise addition is completed, keep warm for 1.5 hours. Naturally raise the temperature to -20 °C, add the reaction solution to ice-cold 20% hydrochloric acid, extract twice with toluene / MIBK (methyl isobutyl ketone), filter, concentrate the filtrate to dryness, obtain 20.6 g of the target product, the content is 99.4% by HPLC detection, and the yield is 91.2%.

[0040] Example 5

[0041] The preparation method of 2-fluoro-6-trifluoromethyl-α-methylbenzyl alcohol in this example comprises the following steps:

[0042] Under the conditions of a temperature of -70 °C and nitrogen protection, add 50 mL of an LDA / THF solution (2.5 M, 0.125 mol) to a four-necked flask, and dropwise add a solution of 16.4 g (0.1 mol) of m-fluorobenzotrifluoride in 50 ml of THF. Keep the temperature at -70 to -80 °C. Keep warm for 0.5 hour. At this temperature, dropwise add a solution of 6.5 g (0.147 mol) of acetaldehyde in 6.5 ml of THF. After the dropwise addition is completed, keep warm for 1 hour. Naturally raise the temperature to -20 °C, add the reaction solution to ice-cold 20% hydrochloric acid, extract twice with toluene / MIBK (methyl isobutyl ketone), filter, concentrate the filtrate to dryness, obtain 19.2 g of the target product, the content is 99.5% by HPLC detection, and the yield is 91.8%.

[0043] Example 6

[0044] The preparation method of 2,6-bis(trifluoromethyl)-α-methylbenzyl alcohol in this example comprises the following steps:

[0045] Under the conditions of a temperature of -70 °C and nitrogen protection, 50 mL of an LDA / THF solution (2.5 M, 0.125 mol) was added to a four-necked flask, and a solution of 17.13 g (0.08 mol) of m-bis(trifluoromethyl)benzene in 50 mL of THF was added dropwise, with the temperature maintained at -70 to -80 °C. After keeping the temperature for 10 min, a solution of 4 g (0.09 mol) of acetaldehyde in 5 mL of THF was added dropwise at this temperature. After the addition was complete, the temperature was kept for 20 min. The reaction solution was naturally warmed to -20 °C, added to ice-cold 20% hydrochloric acid, extracted twice with toluene / MIBK (methyl isobutyl ketone), filtered, and the filtrate was concentrated to dryness to obtain 19.2 g of the target product. The content detected by HPLC was 99.6%, and the yield was 92.6%.

[0046] Comparative Example 1

[0047] The preparation method of 2,6-difluoro-α-methylbenzyl alcohol in this Comparative Example 2 includes the following steps:

[0048] Referring to the synthetic route methods disclosed in the relevant literature "Fonctionnalisation régiosélective en position 2 de benzènes 1,3-disubstitués" and Patent US4438271A. Under the conditions of a temperature of -70 °C and nitrogen protection, 50 mL of a n-butyllithium / hexane solution (2.5 M, 0.125 mol) was added to a four-necked flask, and a solution of 12.96 g (0.114 mol) of m-difluorobenzene in 50 mL of THF was added dropwise, with the temperature maintained at -70 to -80 °C. After keeping the temperature for 1 hour, 14.12 g (0.13 mol) of trimethylchlorosilane was added dropwise at this temperature. After the addition was complete, the temperature was kept for 2 hours. After warming to room temperature, 18.26 g (0.137 mol) of anhydrous aluminum chloride was dissolved in 50 mL of dry dichloromethane, slowly added dropwise to the reaction solution, stirred evenly, and then added dropwise to a reaction system of 9.42 g (0.12 mol) of acetyl chloride. The reaction was carried out at 25 °C for 3 h. Finally, 4.92 g (0.13 mol) of sodium borohydride was added, and the reaction was carried out for 3 h to obtain 15.52 g of the final target product. The content detected by HPLC was 94.3%, and the yield was 81.2%.

Claims

1. A method for preparing fluoro-α-methylbenzyl alcohol, characterized in that, In the presence of a strong base reagent and an organic solvent, reacting a compound of formula II with acetaldehyde to obtain a fluoro-α-methylbenzyl alcohol of formula I: Wherein, R1 and R2 are each independently selected from fluorine or trifluoromethyl, or when R1 is trifluoromethyl, R2 is chlorine.

2. The preparation method of fluoro-α-methylbenzyl alcohol according to claim 1, characterized in that, The strong base reagent is an alkyllithium or lithium amide, and preferably, it can be selected from one or more of n-butyllithium, LDA, and NaNH2.

3. The preparation method of fluoro-α-methylbenzyl alcohol according to claim 1, characterized in that, The organic solvent is selected from one or more of tetrahydrofuran, methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, cyclohexane, n-hexane, methylcyclohexane, toluene, xylene, and liquid ammonia.

4. The preparation method of fluoro-α-methylbenzyl alcohol according to claim 1, characterized in that, The reaction temperature is -20 to -90 °C, and the elevated temperature is -40 to 0 °C. The reaction time is 0.1 to 8 h, preferably 0.5 to 2 h.

5. The preparation method of fluoro-α-methylbenzyl alcohol according to claim 1, characterized in that, The molar ratio of the compound of formula II to the strong base reagent is 1:1 to 1:2, and the molar ratio of the compound of formula II to acetaldehyde is 1:1.1 to 1:2.

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