阅读说明：本技术 一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法 (Synthesis method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone ) 是由 王涛 孔前广 方燕 涂司武 张芝平 毕强 董建生 于 2019-12-04 设计创作，主要内容包括：本发明涉及一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法,所述合成方法包括以下步骤：1)α-卤素取代对氯苄基膦酸酯与环丙基甲基酮在碱性条件下缩合,制得烯基卤化合物；2)将步骤1)制得的烯基卤化合物进行水解,即得1-(4-氯苯基)-2-环丙基-1-丙酮。本发明的1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法,α-卤素取代对氯苄基膦酸酯与环丙基甲基酮在碱性条件下缩合,得到烯基卤化合物,所得的烯基卤化合物进行水解,即得1-(4-氯苯基)-2-环丙基-1-丙酮,整个工艺过程简单流畅,反应条件温和,适合工业化放大生产；采用α-卤素取代对氯苄基膦酸酯和环丙基甲基酮为反应底物,原子经济性高,绿色环保,原料成本低。(The invention relates to a synthesis method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone, which comprises the following steps of 1) condensing α -halogen substituted p-chlorobenzylphosphonate and cyclopropyl methyl ketone under an alkaline condition to prepare an alkenyl halide compound, 2) hydrolyzing the alkenyl halide compound prepared in the step 1) to obtain 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone, condensing α -halogen substituted p-chlorobenzylphosphonate and cyclopropyl methyl ketone under an alkaline condition to obtain the alkenyl halide compound, and hydrolyzing the obtained alkenyl halide compound to obtain the 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone, wherein the whole process is simple and smooth, the reaction condition is mild, the method is suitable for industrial amplification production, and the α -halogen substituted p-chlorobenzylphosphonate and the cyclopropyl methyl ketone are adopted as reaction substrates, so that the atom economy is high, the environment is protected, and the raw material cost is low.)

The synthesis method of kinds of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone is characterized by comprising the following steps:

(1) condensing α -halogen substituted p-chlorobenzyl phosphonate with the structure shown in the formula (II) and cyclopropyl methyl ketone under the alkaline condition to prepare alkenyl halide compound with the structure shown in the formula (III);

(2) hydrolyzing the alkenyl halide compound prepared in the step (1) to prepare a compound 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone with a structure shown in a formula (I);

wherein R is₁Is methyl or ethyl; x is halogen substituent-Cl, -Br or-I.

2. The synthetic method of claim 1 wherein the halogen substituent is-Cl or-Br.

3. The synthesis method according to claim 1, wherein in the step (1), the alkali under basic condition is or more of sodium amide, sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide or lithium diisopropylamide.

4. The synthesis process according to claim 3, wherein the base is sodium amide or sodium methoxide.

5. The synthesis method according to claim 1, wherein in the step (1), the solvent for the condensation reaction is or more of polar solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, dimethylformamide and tetrahydrofuran, or the solvent is or a mixed solvent of the polar solvents and nonpolar solvents such as benzene, toluene or xylene.

6. The synthesis method of claim 1, wherein in the step (1), the reaction temperature of the condensation reaction is 0-50 ℃, and the molar ratio of the α -halogen substituted p-chlorobenzyl phosphonate, cyclopropyl methyl ketone and the base is (1.0-1.3): (1.0-1.3): (1.0-3.0).

7. The synthesis method of claim 6, wherein the condensation reaction is carried out at a reaction temperature of 0-30 ℃ and the molar ratio of the α -halogen substituted p-chlorobenzyl phosphonate, the cyclopropyl methyl ketone and the base is 1.0:1.0: 2.0.

8. The synthesis method according to claim 1, wherein in step (2), the hydrolysis reaction is performed under alkaline conditions, the base used is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate or butyl lithium, and the reaction solvent for the hydrolysis reaction is water or a mixture of water and methanol, ethanol, isopropanol or toluene.

9. The synthesis method according to claim 8, wherein the base used in the hydrolysis reaction is sodium hydroxide or potassium hydroxide.

10. The synthesis method of claim 1, wherein in step (2), the reaction temperature of the hydrolysis reaction is 0-60 ℃, and the molar ratio of the alkenyl halide compound having the structure of formula (III) to the base is (1.0-1.3): 1.0-2.0.

11. The synthesis method of claim 10, wherein in step (2), the reaction temperature of the hydrolysis reaction is 20-40 ℃, and the molar ratio of the alkenyl halide compound with the structure of formula (III) to the base is 1.0 (1.0-1.1).

12. The synthesis method according to claim 1, wherein after the hydrolysis reaction is finished, the reaction solution is directly neutralized under acidic conditions until the pH is 1.0-7.0, and the acid used is hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid.

13. The method of claim 12, wherein the reaction solution is neutralized under acidic conditions to a pH of 1.0 to 3.0 directly after the hydrolysis reaction is completed.

Technical Field

The invention relates to the field of chemical synthesis, in particular to a synthesis method of kinds of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone.

Background

The 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone is an important intermediate of the bactericide cyproconazole, and in the existing intermediate synthesis process, the process is complex, the reaction steps are multiple, raw materials or intermediates are not easy to obtain, the raw material cost is high, the industrial amplification production difficulty is high, and the like. The key steps reported in patent CN201210479107 require silica gel column chromatography or reduced pressure distillation purification, and the industrial amplification operation is difficult; the condensation reaction is carried out by adopting benzyl or dihydropyran as protecting group to protect hydroxyl group reported in patents CN201710478581 and CN201710049273, the cost of raw materials is high, and the atom economy is poor; as the synthesis route reported in patent CN201410822089 is too long, magnesium powder is also used for reduction, and the process safety is not high; the raw materials reported in patents CN201810555411 and CN201810556624 are not easy to obtain, the production cost is high, magnesium is required to be used as a grignard reagent, and the safety is not high.

Therefore, the search for synthesis processes of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone which has simple and smooth process and low cost and is suitable for industrial scale-up production is a problem which needs to be solved urgently by the technical personnel in the field.

Disclosure of Invention

The invention provides a synthesis method of kinds of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone, aiming at solving the problems of complex process, multiple reaction steps, difficult obtainment of raw materials or intermediates, high raw material cost and high difficulty of industrial amplification production in the existing synthesis process of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone.

In order to achieve the purpose, the invention adopts the following technical scheme:

the invention provides a synthesis method of kinds of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone, which comprises the following steps:

(1) condensing α -halogen substituted p-chlorobenzyl phosphonate with the structure shown in the formula (II) and cyclopropyl methyl ketone under the alkaline condition to prepare alkenyl halide compound with the structure shown in the formula (III);

(2) hydrolyzing the alkenyl halide compound prepared in the step (1) to prepare a compound 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone with a structure shown in a formula (I);

X＝Cl，Br，I

wherein R is₁Is methyl or ethyl; x is halogen substituent-Cl, -Br or-I.

Further , the halogen substituent is-Cl or-Br.

, in step (1), the alkali of the alkaline condition is or more of sodium amide, sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide or lithium diisopropylamide.

Further , preferably, the base is sodium amide or sodium methoxide.

, in the step (1), the solvent of the condensation reaction is or more of polar solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, dimethylformamide and tetrahydrofuran, or the solvent is or a mixed solvent of the polar solvents and non-polar solvents such as benzene, toluene or xylene.

, in the step (1), the reaction temperature of the condensation reaction is 0-50 ℃, and the molar ratio of the α -halogen substituted p-chlorobenzyl phosphonate, the cyclopropyl methyl ketone and the alkali is (1.0-1.3): (1.0-1.3): (1.0-3.0).

preferably, the condensation reaction has a reaction temperature of 0-30 deg.C and the molar ratio of α -halogen substituted p-chlorobenzyl phosphonate, cyclopropyl methyl ketone and base is 1.0:1.0: 2.0.

, in step (2), the hydrolysis reaction is carried out under alkaline conditions, the base used is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate or butyl lithium, and the reaction solvent for the hydrolysis reaction is water or a mixture of water and methanol, ethanol, isopropanol or toluene.

preferably, the alkali used in the hydrolysis reaction is sodium hydroxide or potassium hydroxide.

, in the step (2), the reaction temperature of the hydrolysis reaction is 0-60 ℃, and the molar ratio of the alkenyl halide compound with the structure of the formula (III) and the alkali is (1.0-1.3): 1.0-2.0.

preferably, in step (2), the hydrolysis reaction is carried out at a temperature of 20-40 deg.C and the molar ratio of the alkenyl halide compound of formula (III) to the base is 1.0 (1.0-1.1).

, directly neutralizing the reaction liquid under acidic condition to pH 1.0-7.0, and using hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid.

preferably, the reaction solution is neutralized to pH 1.0-3.0 under acidic condition directly after the hydrolysis reaction.

By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:

according to the synthesis method of the 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone, α -halogen substituted p-chlorobenzyl phosphonate and cyclopropyl methyl ketone are condensed under an alkaline condition to obtain the alkenyl halide compound, the obtained alkenyl halide compound is hydrolyzed to obtain the 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone, the whole process is simple and smooth, the reaction condition is mild, the method is suitable for industrial amplification production, α -halogen substituted p-chlorobenzyl phosphonate and cyclopropyl methyl ketone are adopted as reaction substrates, the atom economy is high, the method is green and environment-friendly, and the raw material cost is low.

Detailed Description

The present invention will be described in detail and specifically with reference to the following examples to facilitate better understanding of the present invention, but the following examples do not limit the scope of the present invention.