阅读说明：本技术 一种制备2-环丙基苯酚衍生物的方法 (Method for preparing 2-cyclopropyl phenol derivative ) 是由 梁全德 戴耀 王荣良 王延波 刘玲玲 张小红 赵鑫 于 2021-09-28 设计创作，主要内容包括：本发明涉及一种制备2-环丙基苯酚衍生物的方法,属于有机化学领域。本发明所述方法包括如下步骤：①以苯酚衍生物为原料,与乙二醛发生环合反应生成内酯中间体1；②将内酯中间体1与二溴乙烷发生环合反应生成环丙基中间体2；③将环丙基中间体2脱羧反应生成2-环丙基苯酚衍生物。本发明所述方法使用的原料价廉易得、安全环保。(The invention relates to a method for preparing a 2-cyclopropyl phenol derivative, belonging to the field of organic chemistry. The method comprises the following steps: firstly, taking a phenol derivative as a raw material, and carrying out cyclization reaction with glyoxal to generate a lactone intermediate 1; secondly, performing cyclization reaction on the lactone intermediate 1 and dibromoethane to generate a cyclopropyl intermediate 2; ③ decarboxylation reaction of the cyclopropyl intermediate 2 to generate the 2-cyclopropyl phenol derivative. The method has the advantages of cheap and easily obtained raw materials, safety and environmental protection.)

1. A process for producing a 2-cyclopropylphenol derivative, which comprises: the method comprises the following steps:

firstly, taking a general formula I as a raw material, and carrying out cyclization reaction with glyoxal to generate a general formula II;

wherein, R in the general formula I is H or CH₃；

Carrying out cyclization reaction on the general formula II and dibromoethane to generate a general formula III;

thirdly, decarboxylation reaction is carried out on the general formula III to generate a general formula IV;

2. the process for producing a 2-cyclopropylphenol derivative according to claim 1, characterized in that: the steps are as follows: taking a general formula I and glyoxal as raw materials, and carrying out cyclization reaction in an acetic acid water solution in the presence of ammonium chloride to generate a general formula II.

3. The process for producing a 2-cyclopropylphenol derivative according to claim 2, characterized in that: in the step (i), the molar ratio of the general formula I, glyoxal, ammonium chloride and acetic acid is 1.0: 1.0-1.5: 0.05-0.15: 2.0-4.0.

4. The process for producing a 2-cyclopropylphenol derivative according to claim 2, characterized in that: the steps are as follows: mixing the general formula I with acetic acid, heating to 50-60 ℃, synchronously dropwise adding a glyoxal solution and an ammonium chloride solution, wherein the concentration of the glyoxal solution is 40 wt%, the concentration of the ammonium chloride solution is 30 wt%, the dropwise adding process is 1h, the temperature is controlled to be 50-60 ℃, then reacting for 2-5h at 50-60 ℃, cooling to 5-10 ℃ after reaction, filtering to obtain a wet cake of the general formula II, and drying to obtain the general formula II.

5. The process for producing a 2-cyclopropylphenol derivative according to claim 1, characterized in that: the second step is: taking a general formula II and dibromoethane as raw materials, and carrying out cyclization reaction on sulfolane and toluene in a mixed solution in the presence of potassium carbonate to generate a general formula III.

6. The process for producing a 2-cyclopropylphenol derivative according to claim 5, characterized in that: in the step (II), the mol ratio of dibromoethane, potassium carbonate and sulfolane is 1.0: 1.0-1.5: 2.0-3.0: 2.0-3.0, wherein the mass ratio of sulfolane to toluene is 1.0: 0.5-2.0, and the mesh number of the potassium carbonate is 200-300 meshes.

7. The process for producing a 2-cyclopropylphenol derivative according to claim 5, characterized in that: the second step is: sequentially adding potassium carbonate, sulfolane, toluene and dibromoethane into the general formula II, reacting for 4-12h at 90-110 ℃, cooling to room temperature after reaction, and filtering to remove salt to obtain the sulfolane and toluene mixed solution of the general formula III.

8. The process for producing a 2-cyclopropylphenol derivative according to claim 1, characterized in that: the third step is as follows: heating sulfolane and toluene mixed solution in a general formula III as a raw material to 100-105 ℃, dropwise adding sodium methoxide and methanol solution, azeotropically removing the toluene and methanol mixed solution, reacting at 100-105 ℃ for 1-6h, cooling to room temperature after reaction, filtering to obtain sodium salt in a general formula IV, adding water for dissolution, regulating the pH value to 11-12, separating an organic layer, and carrying out reduced pressure distillation to obtain the sodium salt in the general formula IV.

9. The process for producing a 2-cyclopropylphenol derivative according to claim 8, characterized in that: in the step (c), the molar ratio of the general formula III to sodium methoxide is 1.0: 1.0-1.5, the concentration of sodium methoxide methanol solution is 30 wt%.

Technical Field

The invention relates to a method for preparing a 2-cyclopropyl phenol derivative, belonging to the field of organic chemistry.

Background

2-cyclopropyl phenol derivatives have a wide range of applications in the field of pesticides, for example: it can be used as an important intermediate of 3-phenoxy-4-pyridazinol derivatives (see: CN 102510857).

The methods for synthesizing 2-cyclopropylphenol derivatives reported in the prior literature mainly comprise the following steps:

1) patent CN101151234 reports that phenol derivatives as raw materials undergo ortho-position aldehyde reaction with paraformaldehyde, then undergo addition reaction with vinyl magnesium chloride, then undergo dibromo-reaction with hydrogen bromide, then undergo grignard cyclization reaction with magnesium, and finally undergo deprotection to obtain the target product. The method has multiple steps, wherein two steps relate to the Grignard reaction, and the waste amount is large.

2) Document bioorg.med.chem.2008,16,762 reports that o-bromophenol is used as a raw material, firstly, allyl halide and phenolic hydroxyl are subjected to etherification reaction, and then, tert-butyl lithium is used for lithiation under a low temperature condition, so that a target product is obtained through migration. Although the process steps are few, the low temperature conditions required for lithiation are too severe and the use of tert-butyllithium must be very careful. If the method is used in large-scale production, the method has great limitation in both raw material cost and safety.

3) Patent CN110041253 reports that o-bromophenol is taken as a raw material and undergoes a coupling reaction with cyclopropyl boronic acid under the catalysis of palladium to obtain a target product. Although the method has few steps, the cost of the cyclopropyl boronic acid and the palladium catalyst is high, and the large-scale production is unlikely.

Therefore, it is necessary to find a method which is cheap in raw materials, safe and environment-friendly and more suitable for industrial scale-up.

Disclosure of Invention

The invention solves the problems by synthesizing the 2-cyclopropyl phenol derivative by a novel method.

The invention provides a method for preparing a 2-cyclopropylphenol derivative, which comprises the following steps:

firstly, taking a general formula I as a raw material, and carrying out cyclization reaction with glyoxal to generate a general formula II;

wherein, R in the general formula I is H or CH₃；

Carrying out cyclization reaction on the general formula II and dibromoethane to generate a general formula III;

thirdly, decarboxylation reaction is carried out on the general formula III to generate a general formula IV;

the invention preferably comprises the following steps: taking a general formula I and glyoxal as raw materials, and carrying out cyclization reaction in an acetic acid water solution in the presence of ammonium chloride to generate a general formula II.

The invention preferably selects the mol ratio of the general formula I, the glyoxal, the ammonium chloride and the acetic acid in the step (I) as 1.0: 1.0-1.5: 0.05-0.15: 2.0-4.0.

The invention preferably comprises the following steps: mixing the general formula I with acetic acid, heating to 50-60 ℃, synchronously dropwise adding a glyoxal solution and an ammonium chloride solution, wherein the concentration of the glyoxal solution is 40 wt%, the concentration of the ammonium chloride solution is 30 wt%, the dropwise adding process is 1h, the temperature is controlled to be 50-60 ℃, then reacting for 2-5h at 50-60 ℃, cooling to 5-10 ℃ after reaction, filtering to obtain a wet cake of the general formula II, and drying to obtain the general formula II.

The invention preferably comprises the following steps: taking a general formula II and dibromoethane as raw materials, and carrying out cyclization reaction on sulfolane and toluene in a mixed solution in the presence of potassium carbonate to generate a general formula III.

The invention preferably selects the mol ratio of the general formula II, dibromoethane, potassium carbonate and sulfolane in the step (II) as 1.0: 1.0-1.5: 2.0-3.0: 2.0-3.0, wherein the mass ratio of sulfolane to toluene is 1.0: 0.5-2.0, and the mesh number of the potassium carbonate is 200-300 meshes.

The invention preferably comprises the following steps: sequentially adding potassium carbonate, sulfolane, toluene and dibromoethane into the general formula II, reacting for 4-12h at 90-110 ℃, cooling to room temperature after reaction, and filtering to remove salt to obtain the sulfolane and toluene mixed solution of the general formula III.

The invention preferably adopts the following steps: heating sulfolane and toluene mixed solution in a general formula III as a raw material to 100-105 ℃, dropwise adding sodium methoxide and methanol solution, azeotropically removing the toluene and methanol mixed solution, reacting at 100-105 ℃ for 1-6h, cooling to room temperature after reaction, filtering to obtain sodium salt in a general formula IV, adding water for dissolution, regulating the pH value to 11-12, separating an organic layer, and carrying out reduced pressure distillation to obtain the sodium salt in the general formula IV.

Preferably, in the step (c), the molar ratio of the general formula III to the sodium methoxide is 1.0: 1.0-1.5, the concentration of sodium methoxide methanol solution is 30 wt%.

The invention has the beneficial effects that:

the raw materials used by the method are cheap and easily available, and are safe and environment-friendly;

the method has the advantages of few steps, simple operation and more suitability for industrial amplification.

Detailed Description

The following non-limiting examples are presented to enable those of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way.

Example 1

Mixing o-cresol (108.1g, 1.0mol) and acetic acid (180.1g, 3.0mol), heating to 50-60 ℃, synchronously dropwise adding glyoxal solution (174.1g, 1.2mol, 40 wt%) and ammonium chloride solution (17.8g, 0.1mol, 30 wt%), controlling the temperature to be 50-60 ℃ for 1h, reacting at 50-60 ℃ for 2h, cooling to 5-10 ℃ after reaction, filtering to obtain an intermediate 1 wet cake, and performing vacuum drying at 40-50 ℃ to obtain a light yellow solid 105.2g, the purity is 97%, and the yield is 71%;

secondly, sequentially adding potassium carbonate (241.9g, 1.75mol, 200 meshes, 300 meshes), sulfolane (210.3g, 1.75mol), toluene (210.3g) and dibromoethane (157.8g, 0.84mol) into the intermediate 1(103.7g, 0.7mol, 97% purity), reacting at 100 ℃ for 5 hours, cooling to room temperature after reaction, and filtering to remove salt to obtain 531g of a sulfolane and toluene mixed solution of the intermediate 2 with the purity of 91%;

③ heating the sulfolane and toluene mixed solution (531g, 0.7mol) of the intermediate 2 to 100-.

1H NMR(400MHz,CDCl3)δppm 7.01(d,1H),6.96(d,1H),6.76(t,1H),5.55(s,1H),2.26(s,3H),1.79-1.73(m,1H),0.99-0.94(m,2H),0.65-0.62(m,2H).

Example 2

Mixing phenol (94.1g, 1.0mol) and acetic acid (180.1g, 3.0mol), heating to 50-60 ℃, synchronously dropwise adding glyoxal solution (174.1g, 1.2mol, 40 wt%) and ammonium chloride solution (17.8g, 0.1mol, 30 wt%), controlling the temperature to be 50-60 ℃ for 1h, reacting at 50-60 ℃ for 2h, cooling to 5-10 ℃ after reaction, filtering to obtain an intermediate 1 wet cake, and performing vacuum drying at 40-50 ℃ to obtain 103.3g of light yellow solid with the purity of 96% and the yield of 77%;

secondly, sequentially adding potassium carbonate (241.9g, 1.75mol, 200 meshes, 300 meshes), sulfolane (210.3g, 1.75mol), toluene (210.3g) and dibromoethane (157.8g, 0.84mol) into the intermediate 1(93.9g, 0.7mol, 96% of purity), reacting at 100 ℃ for 4 hours, cooling to room temperature after reaction, and filtering to remove salt to obtain 525g of a sulfolane-toluene mixed solution of the intermediate 2;

③ heating the sulfolane and toluene mixed solution (525g, 0.7mol) of the intermediate 2 to 100-.

1H NMR(400MHz,CDCl3)δppm 7.06-7.16(m,2H),6.82-6.88(m,2H),5.46(s,1H),1.74-1.86(m,1H),0.91-1.02(m,2H),0.59-0.69(m,2H).

Example 3

The method comprises the following steps: the results shown in Table 1 were obtained by changing the reaction conditions in accordance with the procedure of step (i) in example 1.

TABLE 1

Compared with the example 1, the purity and the yield of the intermediate 1 are influenced by increasing the adding amount of the glyoxal solution, and compared with the example 1, the purity and the yield of the intermediate 1 are not influenced greatly by reducing the adding amount of the glyoxal solution;

compared with the example 1, the addition amount of the ammonium chloride solution is increased, which affects the purity and the yield of the intermediate 1, and compared with the example 1, the addition amount of the ammonium chloride solution is reduced, which has little influence on the purity and the yield of the intermediate 1;

the purity and yield of the intermediate 1 are affected by reducing the addition amount of acetic acid compared with the example 1, and the purity and yield of the intermediate 1 are not affected greatly by increasing the addition amount of acetic acid compared with the example 1;

when the dropping manner of the glyoxal solution and the ammonium chloride solution is not simultaneous dropping, the purity and yield of the intermediate 1 are lower than those of example 1.

Step two: referring to the operation of step (II) of example 1, the results of Table 2 were obtained by changing the reaction conditions.

TABLE 2

The purity of the intermediate 2 is not greatly influenced by increasing the adding amount of the dibromoethane compared with the example 1, and the purity of the intermediate 2 is influenced by reducing the adding amount of the dibromoethane compared with the example 1;

compared with the embodiment 1, the purity of the intermediate 2 is not greatly influenced by increasing or reducing the addition amount of the potassium carbonate;

the purity of the intermediate 2 is affected by reducing the addition amount of sulfolane compared with example 1, and the purity of the intermediate 2 is not greatly affected by increasing the addition amount of sulfolane compared with example 1;

compared with the example 1, the purity of the intermediate 2 is not greatly influenced by increasing the addition of the toluene, and compared with the example 1, the purity of the intermediate 2 is influenced by reducing the addition of the toluene;

lowering the reaction temperature compared to example 1 affects the purity of intermediate 2, while raising the reaction temperature compared to example 1 has little effect on the purity of intermediate 2.

Step three: referring to the operation of step three of example 1, the reaction conditions were changed to obtain the results shown in Table 3.

TABLE 3

Compared with the example 1, the yield of the 2-cyclopropyl-6-methylphenol is not greatly influenced by increasing or decreasing the sodium methoxide;

compared with the example 1, the yield of the 2-cyclopropyl-6-methylphenol is influenced by pouring sodium methoxide methanol solution in one time;

increasing the reaction temperature compared to example 1 affected the yield of 2-cyclopropyl-6-methylphenol.