阅读说明：本技术 一种制备4-氟苯基环氧乙烷的方法 (Method for preparing 4-fluorophenyl epoxy ethane ) 是由 刘昶 李世洪 左翔 程柯 于 2020-06-23 设计创作，主要内容包括：本发明涉及一种制备4-氟苯基环氧乙烷的方法,该方法包括以下步骤：a)在与水不混溶的有机溶剂中,使用碱金属硼氢化物、碱土金属硼氢化物或季铵硼氢化物还原ω-氯-4-氟苯乙酮得到含有2-氯-1-(4-氟苯基)乙-1-醇的反应液；b)使得到的反应液不经过中间体后处理与碱金属氢氧化物或碱土金属氢氧化物反应,得到4-氟苯基环氧乙烷。本发明的方法简单经济,可以以高产率制备4-氟苯基环氧乙烷。(The invention relates to a method for preparing 4-fluorophenyl epoxy ethane, which comprises the following steps: a) reducing omega-chloro-4-fluoroacetophenone with an alkali metal borohydride, alkaline earth metal borohydride or quaternary ammonium borohydride in a water-immiscible organic solvent to obtain a reaction solution containing 2-chloro-1- (4-fluorophenyl) ethan-1-ol; b) the obtained reaction solution is reacted with an alkali metal hydroxide or an alkaline earth metal hydroxide without intermediate post-treatment to obtain 4-fluorophenyl oxirane. The method of the invention is simple and economical and can prepare 4-fluorophenyl epoxy ethane with high yield.)

1. A process for the preparation of 4-fluorophenyloxirane comprising the steps of:

a) reducing omega-chloro-4-fluoroacetophenone with an alkali metal borohydride, alkaline earth metal borohydride or quaternary ammonium borohydride in a water-immiscible organic solvent to obtain a reaction solution containing 2-chloro-1- (4-fluorophenyl) ethan-1-ol;

b) the obtained reaction solution is reacted with an alkali metal hydroxide or an alkaline earth metal hydroxide without intermediate post-treatment to obtain 4-fluorophenyl oxirane.

2. The method of claim 1, wherein: in step a), the water-immiscible organic solvent is a haloalkane solvent.

3. The method of claim 2, wherein: the haloalkane solvent is dichloroethane, preferably 1, 2-dichloroethane.

4. The method of claim 1, wherein: sodium borohydride is used in said step a).

5. The method of claim 4, wherein: the molar ratio of sodium borohydride to omega-chloro-4-fluoroacetophenone is from 0.25 to 0.5 to 1.

6. The method of claim 1, wherein: the reaction temperature in step a) is 0 to 50 ℃, preferably 20 to 40 ℃.

7. The method according to any one of claims 1-6, wherein: said step b) uses sodium hydroxide.

8. The method of claim 7, wherein: the molar ratio of the sodium hydroxide to the omega-chloro-4-fluoroacetophenone is from 1 to 1.2 to 1.

9. The method according to any one of claims 1-6, wherein: the reaction temperature in step b) is 0 to 50 ℃, preferably 20 to 30 ℃.

10. The method of claim 1, wherein: and c), when the conversion rate of the omega-chloro-4-fluoro acetophenone is not less than 95%, performing the step b).

Technical Field

The invention relates to a preparation method of an epoxiconazole intermediate.

Background

4-fluorophenyl oxirane is an intermediate of the fungicide epoxiconazole.

US4933477 discloses a process for the preparation of 4-fluorophenyloxirane from omega-chloro-4-fluoroacetophenone. Although the method does not need to carry out post-treatment on the intermediate, the method has the disadvantages that an organic solvent which is miscible with water and an organic solvent which is not miscible with water are required to be simultaneously used in a reaction system, and at least two organic solvents are adopted, so that the processes of recovering and post-treating the reaction solvent are complicated, and the production cost is increased.

Disclosure of Invention

In order to solve the above problems, the present invention provides a simple and economical process for preparing 4-fluorophenyloxirane in high yield, which comprises the steps of:

a) reducing omega-chloro-4-fluoroacetophenone with an alkali metal borohydride, alkaline earth metal borohydride or quaternary ammonium borohydride in a water-immiscible organic solvent to obtain a reaction solution containing 2-chloro-1- (4-fluorophenyl) ethan-1-ol;

b) the obtained reaction solution is reacted with an alkali metal hydroxide or an alkaline earth metal hydroxide without intermediate post-treatment to obtain 4-fluorophenyl oxirane.

Further, the haloalkane-based solvent is dichloroethane, preferably 1, 2-dichloroethane.

Further, sodium borohydride is used in step a).

Further, the molar ratio of sodium borohydride to ω -chloro-4-fluoroacetophenone is from 0.25 to 0.5 to 1.

Further, the reaction temperature in step a) is 0 to 50 ℃, preferably 20 to 40 ℃. An excessively high reduction reaction temperature, for example, more than 50 ℃ may result in a decrease in the reaction yield.

In some embodiments, step b) uses sodium hydroxide. The sodium hydroxide can be in solid form or in the form of aqueous solution, preferably in the form of aqueous solution, and the sodium hydroxide aqueous solution with the concentration of 10-40 wt% can achieve better effect.

The molar ratio of sodium hydroxide to omega-chloro-4-fluoroacetophenone is from 0.25 to 0.5 to 1.

Further, the reaction temperature of step b) is 0 to 50 ℃, preferably 20 to 30 ℃.

Further, when the conversion rate of the omega-chloro-4-fluoroacetophenone is not less than 95%, the step b) is performed. The reaction time in step a) is generally from 1 to 24 hours.

According to the prior art, sodium borohydride is known to decompose easily in acidic and neutral solutions, and its decomposition can be suppressed by adding a base to the solution (see: Verlinden, M.; Baart, J.; Decstra, H.Talanta 1980,27(8), 633; Kingweiren, Qiuderen, university of double school newspaper (Nature's science edition), 1998,37(3), 276). In the process disclosed in US4933477, a base is mixed with sodium borohydride, thus favoring the effect of the reduction reaction.

However, we have surprisingly found that the overall yield of the two-step reaction of the present invention is not significantly affected by the process of the present invention even when no base is added to the reduction reaction of step a). Even when a mixed solution of 1, 2-dichloroethane and a water-miscible organic solvent is used, the addition of a base causes a decrease in the total yield of the two-step reaction.

In addition, the 1, 2-dichloroethane is an organic solvent particularly suitable for industrial production, has the advantages of moderate boiling point, good safety, low price and the like, and is an organic solvent particularly suitable for industrial production. However, we have found that, surprisingly, when the water-immiscible organic solvent used is a mixture of 1, 2-dichloroethane and a water-miscible organic solvent, as disclosed in US4933477, a large number of side reactions occur and the yield of the desired 4-fluorophenyloxirane is relatively low. This results in that the process disclosed in US4933477 is not suitable for using 1, 2-dichloroethane as solvent. However, 1, 2-dichloroethane is very suitable as solvent for carrying out the process according to the invention. In addition, when the organic solvent which is miscible with water can not be added in the step a), the final reaction effect is not obviously influenced, and the yield is even higher, so that the post-treatment is simpler and more convenient, and only one organic solvent is needed to be recycled instead of two organic solvents. Meanwhile, experiments show that if methanol is not added, the reaction temperature in the step a) can be controlled more conveniently, and the industrial production is facilitated.

Also, the present invention achieves better results with less reducing agent than the method disclosed in US 4933477. In some embodiments, the present invention may be effectively practiced with a molar ratio of sodium borohydride to ω -chloro-4-fluoroacetophenone of 0.26: 1, 0.28: 1, 0.33: 1, 0.40: 1, 0.44: 1, or 0.58: 1, with a reaction selectivity greater than 90%.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Detailed Description

Example 1

To a solution of 60 wt% chloro-p-fluoroacetophenone (17.26g,0.100mol,1eq) in 1, 2-dichloroethane was added NaBH in portions in a 100mL reaction flask, in a water bath at 20 ℃₄(1.06g,28mmol,0.28eq) and the temperature of the system was kept at 30 ℃ or below. After the completion of the addition, stirring was continued at room temperature for 7 hours, and a 30 wt% aqueous NaOH solution (containing 4.2g of NaOH, 0.105mol,1.05eq) was added to the reaction mixture. After stirring at room temperature for 4h, the organic phase is separated, washed with 10mL of water, dried and concentrated to obtain a crude product of 4-fluorophenyl epoxy ethane. The crude product was subjected to distillation under reduced pressure to give 12.84g of 4-fluorophenyl oxirane, having an absolute content of 98.1% and an isolation yield of 91.2%.

Example 2

In a 100mL reaction flask, 30 wt% NaBH was added dropwise to a solution of 3g of 60 wt% chloro-p-fluoroacetophenone (1.8g,10mmol,1eq) in 1, 2-dichloroethane in a water bath at 30 ℃₄(0.15g,4mmol,0.40eq) of an aqueous solution, and the temperature of the reaction mixture was controlled<At 40 ℃. After the addition was complete, stirring was continued for 4 h. Further, a 10 wt% aqueous NaOH solution (containing 0.44g,11mmol,1.1 eq. of NaOH) was added to the reaction mixture. Stirring is carried out for 3h at room temperature, HPLC detection shows that the reaction selectivity is calculated to be 93.46%. The reaction selectivity is the ratio of 4-fluorophenyl epoxy ethane to the converted chloro-p-fluoro acetophenone in the reaction liquid.

Example 3

In a 2L reaction flask, 690.3g of 60 wt% chloro-p-fluoroacetophenone (414.2g,2.4mol,1eq) in 1, 2-dichloroethane were added dropwise 25 wt% NaBH in a water bath at 20 deg.C₄(41.60g,1.06mmol,0.44eq) of the aqueous solution, the rate of addition being controlled to ensure the temperature of the reaction mixture<At 30 ℃. After the dropwise addition, stirring was continued for 20 h. Further, a 30 wt% aqueous NaOH solution (containing 100.8g of NaOH, 2.52mol,1.05eq) was added to the reaction mixture at room temperature. After 4 hours at room temperature, liquid separation is carried out, the organic phase is dried and concentrated to obtain 320.55g of crude orange oily liquid, and after reduced pressure distillation, 292.05g of 4-fluorophenyl epoxy ethane with the content of 99.31 percent and the separation yield of 87.5 percent is obtained.

Comparative example 1

NaBH is added to a 250mL reaction flask at 0 deg.C₄(3.89g,0.104mol, 0.26eq) was dissolved in 59.56g of an aqueous NaOH solution (containing 17.6g,0.44mol,1.1eq) and stirred for 20min, after which 50g of methanol was added. Chloro-p-fluoroacetophenone (68.34g,0.4mol,1eq) was dissolved in 60g of 1, 2-dichloroethane. After 1h, NaBH was added in a room temperature water bath₄And (3) beginning to dropwise add a 1, 2-dichloroethane solution containing chloro-p-fluoro acetophenone into the alkali solution, and controlling the dropwise adding speed to ensure that the temperature of the system does not exceed 30 ℃. After the addition was complete, stirring was continued for 2 h. With 50 wt% H₂SO₄The pH value is adjusted to be neutral, liquid separation is carried out, the organic phase is dried and concentrated, and 51.6g of crude orange oily liquid is obtained. Vacuum distillation was carried out to give 31.8g of 4-fluorophenyl oxirane product, content was 92.9%, isolation yield was 53.6%.

Comparative example 2

In a 100mL reaction flask, NaBH is added at 0 DEG C₄(0.10g,2.6mol, 0.26eq) was dissolved in 1.44g of an aqueous NaOH solution (containing 0.44g,11mmol,1.1eq) and stirred for 20min, after which 1.33g of tetrahydrofuran was added. Chloro-p-fluoroacetophenone (1.73g,10mmol,1eq) was dissolved in 1.44g of 1, 2-dichloroethane. After 1h, NaBH was added in a room temperature water bath₄1, 2-dichloroethane solution containing chloro-p-fluoro acetophenone is dripped into the alkali solution, and the maximum system temperature is not more than 30 ℃. After the dropwise addition, stirring was continued for 1 h. The reaction selectivity was calculated to be 35.37% by HPLC.

Comparative example 3

In a 100mL reaction flask, chloro-p-fluoroacetophenone (1.80g,10mol,1eq) was dissolved in a mixed solution of 1.5g of 1, 2-dichloroethane and 1.2g of methanol, and 20% wt of 0.5g of NaBH was added at 0 ℃ in a cold bath₄Aqueous NaOH solution (containing NaBH)₄0.10g,2.6mmol,0.26eq, NaOH 0.08g, 2mmol,0.2 eq). After the completion of the addition, stirring was continued for 1 hour, and a 20 wt% aqueous NaOH solution (containing 0.36g, 9mmol,0.9 eq.) was added to the reaction mixture. After stirring for 4h at room temperature, HPLC detection calculated a reaction selectivity of 80.66%.