CN106883266B - Preparation method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone and intermediate thereof - Google Patents
Preparation method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone and intermediate thereof Download PDFInfo
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Abstract
The invention relates to a preparation method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone, which is prepared from α -hydroxy p-chlorobenzyl phosphonate shown in formula I and 3,4-2HThe preparation method comprises the following steps of (1) -dihydropyran as a raw material, preparing a compound shown in a formula II in the presence of a catalyst, reacting the compound shown in the formula II with cyclopropyl methyl ketone in the presence of alkali and a solvent to obtain a compound shown in a formula III, and hydrolyzing the compound shown in the formula III in an acidic condition to obtain 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone, wherein α -hydroxy p-chlorobenzyl phosphonate and 3, 4-2-propyl phosphonate shown in the formula IHThe dihydropyran is used as a raw material, the raw material is cheap and easy to obtain, the steps are simple, the cost is low, the three-waste pollution is less, the environment is protected, the method is suitable for industrial production, and the finally prepared 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone has high purity, the content of more than 96 percent, high yield and the yield of more than 83 percent.
Description
Technical Field
The invention relates to a preparation method of a fungicide cyproconazole intermediate, in particular to a preparation method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone and an intermediate thereof.
Background
Cyproconazole (cyproconazole) is a triazole bactericide developed by Sandoz AG, switzerland, is a systemic bactericide, has protective, therapeutic and virus-eradicating effects, and is widely used in western europe and north america. 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone is a key intermediate for the synthesis of cyproconazole. At present, various methods for preparing 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone have been reported, for example, chinese patent CN201110432969 discloses a method for preparing 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone, which has the following reaction formula:
US4973767 discloses a method for synthesizing 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone by a Grignard reagent method. Chloropropene and magnesium are adopted to generate a Grignard reagent, the Grignard reagent reacts with p-chlorobenzaldehyde to obtain 4- (4-chlorphenyl) -1-butene-4-ol, the Grignard reagent and dibromomethane are cyclized under the action of zinc and cuprous chloride to obtain 1- (4-chlorphenyl) -2-cyclopropyl ethanol, the cyclization is carried out under the action of oxalyl chloride, triethylamine and the like to obtain 4-chlorphenyl cyclopropyl methyl ketone, and the 4-chlorphenyl cyclopropyl methyl ketone reacts with sodium hydride and methyl iodide in a tetrahydrofuran solvent to obtain the target. The use of a Grignard reagent and sodium hydride is required, the requirement on the water content of a reaction system is high, and the method is not suitable for industrial production.
CN101786948 discloses a method for obtaining 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone by condensation, hydrogenation and oxidation of raw materials comprising cyclopropyl methyl ketone, p-chlorobenzene acetonitrile and sodium hydride, wherein the method also needs to use sodium hydride, has strict requirements for the water content of a reaction system, has unsafe factors in magnesium powder reduction operation, is easy to self-polymerize, and is not suitable for industrial large-scale production.
The reported methods for the preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone also include: for example, CN102603508, CN101125807A, CN101857576A, CN102942465, etc. However, the method has the problems of high production cost, use of dangerous chemicals, difficult control of reaction conditions, potential safety hazards, non-conformity with green environmental protection requirements and the like, and is not beneficial to industrial production.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide an economical, green and environment-friendly preparation method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone suitable for industrial production.
Another object of the present invention is to provide an intermediate of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone and a preparation method thereof.
In order to solve the technical problems, the invention adopts the following technical scheme:
an intermediate of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone, which is a compound shown as II,
wherein R is an alkyl group having 1 to 5 carbon atoms,
or the intermediate is an alkoxy propylene derivative shown in a formula III,
the other technical scheme adopted by the invention is as follows: a method for preparing an intermediate of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone, said method comprising the steps of:
(1) α -hydroxy p-chlorobenzyl phosphonate shown in the formula I and 3, 4-2H-dihydropyran react under the conditions of catalyst, solvent and 20-120 ℃ to obtain the compound shown in the formula II,
wherein R is alkyl with 1-5 carbon atoms, preferably, R is methyl or ethyl.
(2) Carrying out Horner-Wadsworth-Emmons reaction on the compound shown in the formula II prepared in the step (1) and cyclopropyl methyl ketone under the conditions of alkali, solvent and-78-120 ℃ to obtain a compound shown in a formula III, namely the intermediate,
further, in the step (1), the feeding molar ratio of the α -hydroxy-p-chlorobenzyl phosphonate, the 3, 4-2H-dihydropyran and the catalyst is 1: 1.0-3: 0.01-1.
Further preferably, the feeding molar ratio of the α -hydroxy-p-chlorobenzyl phosphonate, the 3, 4-2H-dihydropyran and the catalyst is 1: 1.0-2.5: 0.01-0.50.
Further, in the step (1), the catalyst is p-toluenesulfonic acid.
Further, in the step (1), the solvent is one or more of toluene, tetrahydrofuran, chloroform, 1, 2-dichloroethane and 1, 4-dioxane.
Further preferably, in the step (1), the solvent is one or a combination of several of toluene, tetrahydrofuran and 1, 2-dichloroethane.
Further, in the step (1), the reaction is carried out at 30 to 110 ℃.
Further preferably, the reaction is carried out at 30 ℃ to 60 ℃.
Further, the specific implementation mode of the step (1) is that α -hydroxy-p-chlorobenzyl phosphonate is dissolved in a solvent, then the 3, 4-2H-dihydropyran and a catalyst are sequentially added, and the reaction is carried out for 1-12 hours at the temperature of 30-60 ℃.
Further, the preparation method also comprises a step of carrying out post-treatment after the reaction in the step (1) is finished, and the preparation method is implemented specifically as follows: and washing and layering the reaction solution after the reaction by using a sodium hydroxide solution, drying and concentrating the organic phase to obtain the compound shown in the formula II, and further purifying the compound shown in the formula II or directly using the compound shown in the next step.
Further, in the step (2), the compound shown in the formula II, the cyclopropyl methyl ketone and the base are fed in a molar ratio of 1: 1.0-2: 1.0 to 2.
Further preferably, the compound shown in the formula II, the cyclopropyl methyl ketone and the base are fed in a molar ratio of 1: 1.1-1.8: 1.1 to 1.8.
Further, in the step (2), the base is one or more of n-butyl lithium, lithium diisopropylamide, sodium hydride, sodium amide, sodium tert-butoxide and potassium tert-butoxide.
Further, in the step (2), the Horner-Wadsworth-Emmons reaction is carried out at-78 ℃ to 100 ℃.
Further preferably, in the step (2), the Horner-Wadsworth-Emmons reaction is carried out at-78 ℃ to 50 ℃.
Further, in the step (2), the solvent is one or a combination of several of toluene, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, N-methylpyrrolidone, N-butanol, isobutanol and tert-butanol.
Further preferably, in the step (2), the solvent is one or a combination of several of toluene, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide and tert-butanol.
Further, the specific implementation manner of step (2) is as follows: dissolving the compound shown in the formula II prepared in the step (1) and cyclopropyl methyl ketone in a solvent, adding the alkali at the temperature of-78-15 ℃, and reacting for 2-16 hours at the temperature of 15-120 ℃ after the addition is finished.
Further, the preparation method further comprises a step of carrying out post-treatment after the reaction in the step (2) is finished, and the preparation method is implemented specifically as follows: after the Horner-Wadsworth-Emmons reaction is finished, adding water to extract and kill the reaction product, and concentrating the reaction product to obtain a crude compound shown in a formula III.
Further preferably, the crude compound shown in the formula III can be directly used for preparing 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone.
The invention adopts another technical scheme that: a process for the preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone comprising the steps of:
(a) preparing a compound represented by formula III according to the method;
(b) carrying out hydrolysis reaction on the compound shown in the formula III prepared in the step (a) under an acidic condition to obtain a compound shown in a formula IV, namely the 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone,
further, in the step (b), the acid selected for the acidic condition is one or a combination of acetic acid, hydrochloric acid, p-toluenesulfonic acid and sulfuric acid.
Further, in the step (b), the hydrolysis reaction is carried out at 0-80 ℃.
Further preferably, the hydrolysis reaction is carried out at 10 ℃ to 60 ℃.
Further, in the step (b), the solvent is one or a combination of several of water, methanol, ethanol, isopropanol, tert-butanol, 1, 4-dioxane, tetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane, N-dimethylformamide and dimethylsulfoxide.
Further preferably, in the step (b), the solvent is one or a combination of several of water, methanol, ethanol, tetrahydrofuran and toluene.
Further, the specific implementation manner of the step (b) is as follows: dissolving the compound shown in the formula III prepared in the step (a) in a solvent, dropwise adding acid, and reacting for 0.5-3 hours at 0-80 ℃ after dropwise adding.
Further, the preparation method of the 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone further comprises the step of carrying out post-treatment after the reaction in the step (b), and the preparation method is implemented specifically as follows: after the reaction is finished, concentrating the reaction solution, separating and purifying to obtain the 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone.
Due to the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:
the 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone is prepared by using α -hydroxy p-chlorobenzyl phosphonate shown in formula I and 3, 4-2H-dihydropyran as raw materials, the raw materials are cheap and easy to obtain, the steps are simple, the cost is low, the three-waste pollution is less, the method is green and environment-friendly and suitable for industrial production, and the finally prepared 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone has high purity, the content is more than 96%, the yield is high, and the yield is more than 83%.
Detailed Description
The present invention will be described in further detail with reference to specific examples. It is to be understood that these embodiments are provided to illustrate the basic principles, essential features and advantages of the present invention, and the present invention is not limited by the following embodiments. The implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
Example one
This example provides a method for preparing 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone, which comprises the following steps:
(1) α -hydroxy-p-chlorobenzylphosphonic acid dimethyl ester (prepared from p-chlorobenzaldehyde and dimethyl phosphite by the method described in J.Organomet.Chem.2016,804, 59-65; Phosphorus, Sulfur Silicon Relat.Elem.2014,189,812-818 or J.Org.Chem.2014,79, 6172-6178) (2.51g,10.0mmol) was dissolved in toluene (50mL), followed by addition of 3, 4-2H-dihydropyran (841mg,10.0mmol) and p-toluenesulfonic acid (190mg,1.0 mmol). after the reaction was stirred at 50 ℃ for 5 hours, the reaction solution was washed with sodium hydroxide solution (20mL) and the organic layer was concentrated under reduced pressure to remove toluene.the crude product was purified by column chromatography (petroleum ether: ethyl acetate 3:1) to give the compound of formula II (R is methyl) (3.05% yield 95%).
1H NMR(400MHz,CDCl3)δ(ppm)7.43(1H,dd,J1＝1.6Hz,J2＝8.4Hz),7.38(1H,dd,J1＝1.6Hz,J2＝8.4Hz),7.32(2H,d,J＝8.4Hz),5.11(0.46H,s),5.06(0.65H,d,J＝17.2Hz),4.97 (0.47H,d,J＝12.0Hz),4.49(0.65H,s),3.96-4.17(6H,m),3.13-3.55(1H,m),3.33-3.38(1H,m), 1.40-1.85(6H,m).
(2) The compound represented by the formula II (1.67g,5.0mmol) obtained in step (1) was dissolved in N, N-dimethylformamide (5.0mL), followed by the addition of cyclopropylmethyl ketone (505mg,6.0mmol) and sodium amide (234mg,6.0mmol) in that order. The reaction solution was stirred at 40 ℃ for 3 hours. After completion of the reaction, water (10mL) was added to the reaction, and the resulting mixture was extracted with ethyl acetate (three times 10mL each). The resulting organic phases were combined, dried over sodium sulfate and concentrated to give a crude compound represented by formula III (1.51g), content 80.1%, yield 83%.
1H NMR(400MHz,CDCl3)δ(ppm)7.44(2H,d,J＝6.0Hz),7.20(2H,d,J＝6.0Hz),4.88(1H, t,J＝4.8Hz),3.72-3.76(1H,m),3.63-3.66(1H,m),1.96-2.01(1H,m),1.71-1.77(2H,m),1.66 (3H,s),1.55-1.65(3H,m),1.19-1.27(1H,m),0.47-0.56(2H,m),0.25-0.31(2H,m).
(3) The compound represented by the formula III (1.51g) obtained in step (2) was dissolved in tetrahydrofuran (5.0mL), and a hydrochloric acid solution (6N, 1.5mL) was added to the solution. The reaction solution was stirred at 25 ℃ for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (0.86g) as a colorless oily compound with a content of 98% and a yield of 83%.
Example two
This example provides a method for preparing 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone, which comprises the following steps:
(1) α -diethyl p-chlorobenzylphosphonate (prepared from p-chlorobenzaldehyde and diethyl phosphite as described in Tetrahedron Lett.2004,45, 9233-.
1H NMR(400MHz,CDCl3)δ(ppm)7.43(1H,dd,J1＝1.6Hz,J2＝8.4Hz),7.38(1H,dd,J1＝1.6Hz,J2＝8.4Hz),7.32(2H,d,J＝8.4Hz),5.10(0.46H,s),5.05(0.65H,d,J＝17.2Hz),4.96 (0.47H,d,J＝12.0Hz),4.48(0.66H,s),3.96-4.17(4.3H,m),3.53-3.55(0.69H,m),3.33-3.38 (1H,m),1.40-1.85(6H,m),1.22-1.30(6H,m).
(2) The compound represented by the formula II (1.81g,5.0mmol) obtained in step (1) was dissolved in N, N-dimethylformamide (5.0mL), followed by the addition of cyclopropylmethyl ketone (505mg,6.0mmol) and sodium amide (234mg,6.0mmol) in that order. The reaction solution was stirred at 40 ℃ for 3 hours. After completion of the reaction, water (10mL) was added to the reaction, and the resulting mixture was extracted with ethyl acetate (three times 10mL each). The resulting organic phases were combined, dried over sodium sulfate and concentrated to give a crude compound of formula III (1.55g), 82% in content and 87% in yield.
(3) The compound represented by the formula III (1.55g) obtained in step (2) was dissolved in tetrahydrofuran (5.0mL), and a hydrochloric acid solution (6N, 1.5mL) was added to the solution. The reaction solution was stirred at 25 ℃ for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (0.90g) as a colorless oily compound with a content of 97% and a yield of 87%.
EXAMPLE III
This example provides a method for preparing 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone, which comprises the following steps:
(1) a tetrahydrofuran (10.0mL) solution containing diisopropylamine (0.51g, 5.0mmol) was cooled to-78 deg.C, and n-butyllithium (3.1mL,1.6M) was added dropwise to the solution, and the resulting solution was stirred at 0 deg.C for 30 minutes and then cooled to-40 deg.C. Subsequently, the compound represented by the formula II (1.81g,5.0mmol) obtained in the second step (1) of example and cyclopropylmethyl ketone (505mg,6.0mmol) were added dropwise to the reaction system in this order, and the reaction mixture was allowed to spontaneously rise to 0 ℃ and stirred at that temperature for 3 hours. After the reaction, the reaction solution was cooled to 0 ℃ and saturated ammonium chloride solution (10mL) was added dropwise to quench the reaction. Extract with ethyl acetate (three times 15mL each). The resulting organic phases were combined, dried over sodium sulfate and concentrated to give a crude compound of formula III (1.50g), 86% in content and 88% in yield.
(2) The compound represented by the formula III (1.50g) obtained in step (1) was dissolved in tetrahydrofuran (5.0mL), and a 30% dilute sulfuric acid solution (1.0mL) was added to the solution. The reaction solution was stirred at 25 ℃ for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (0.93g) as a colorless oily compound with a content of 96% and a yield of 89%.
Example four
This example provides a method for preparing 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone, which comprises the following steps:
(1) the compound represented by the formula II (1.81g,5.0mmol) obtained in example two step (1) was dissolved in N, N-dimethylformamide (5.0mL), followed by the addition of cyclopropylmethyl ketone (505mg,6.0mmol) and potassium tert-butoxide (673mg,6.0mmol) in that order. The reaction solution was stirred at 40 ℃ for 3 hours. After completion of the reaction, water (10mL) was added to the reaction, and the resulting mixture was extracted with ethyl acetate (three times 10mL each). The resulting organic phases were combined, dried over sodium sulfate and concentrated to give a crude compound of formula III (1.60g), 80% in content and 88% in yield.
(2) The compound represented by the formula III (1.60g) obtained in step (1) was dissolved in ethanol (5.0mL), and p-toluenesulfonic acid (95.1mg,0.5mmol) was added to the solution. The reaction solution was stirred at 40 ℃ for 1 hour. After the reaction was completed, the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (0.96g) as a colorless oily compound, content 96%, yield 92%.
The present invention is described in detail in order to make those skilled in the art understand the content and practice the invention, and the invention is not limited to the above embodiments, and all equivalent changes or modifications made according to the spirit of the invention should be covered by the scope of the invention.
Claims (5)
1. A preparation method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone is characterized by comprising the following steps:
(1) α -hydroxy-p-chlorobenzyl phosphonate shown in the formula I and 3, 4-2H-dihydropyran react under the conditions of catalyst, solvent and 20-50 ℃ to obtain a compound shown in the formula II, the feeding molar ratio of α -hydroxy-p-chlorobenzyl phosphonate, 3, 4-2H-dihydropyran and catalyst is 1: 1.0-3: 0.01-1, the catalyst is p-toluenesulfonic acid,
wherein R is an alkyl group having 1-5 carbon atoms;
(2) carrying out Horner-Wadsworth-Emmons reaction on the compound shown in the formula II prepared in the step (1) and cyclopropyl methyl ketone under the conditions of alkali, solvent and-78-120 ℃ to obtain a compound shown in a formula III, namely the intermediate, wherein the alkali is one or a combination of more of n-butyl lithium, lithium diisopropylamide, sodium tert-butoxide and potassium tert-butoxide;
(3) carrying out hydrolysis reaction on the compound shown in the formula III prepared in the step (2) under an acidic condition to obtain a compound shown in a formula IV, namely the 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone,
2. the method for preparing an intermediate of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone according to claim 1, wherein the specific embodiment of step (1) is that α -hydroxy-p-chlorobenzyl phosphonate is dissolved in a solvent, and then the 3, 4-2H-dihydropyran and the catalyst are sequentially added to react for 1-12 hours at 30-50 ℃.
3. The process for producing an intermediate of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone according to claim 1, wherein in step (2), the compound represented by the formula II, cyclopropyl methyl ketone and base are fed in a molar ratio of 1: 1.0-2: 1.0 to 2.
4. The method for preparing 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone according to claim 1, wherein in step (3), the acid selected for use in said acidic conditions is one or a combination of acetic acid, hydrochloric acid, p-toluenesulfonic acid and sulfuric acid.
5. The process for preparing 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone according to claim 1, wherein the embodiment of step (b) is: dissolving the compound shown in the formula III prepared in the step (a) in a solvent, dropwise adding acid, and reacting for 0.5-3 hours at 0-80 ℃ after dropwise adding.
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