A kind of synthesis process of 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone

Abstract

The invention discloses a synthesis process method of 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone, and belongs to the technical field of chemical synthesis. 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester or 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester is used as a raw material, and the source is wide, and the preparation is simple and convenient, which is conducive to industrial production. A low eutectic solvent is adopted, and the low eutectic solvent is green and recyclable. Methyl chloride is added for reaction, and then heating decarboxylation reaction, secondary methyl chloride reaction and hydrogenation reduction are carried out. The process steps are simple, the use of harmful organic solvents and toxic catalysts is avoided, the cost is saved, the loss of products in the post-treatment process is avoided, the total yield of the target product is high, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and specifically relates to a synthesis process method of 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone. Background Art

[0002] There are several reports on the synthetic route of 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone, including Aislabie et al., who used 1-bromo-3-chloropropane and isobutyronitrile for condensation, cyanation, and ring-transposition to generate amines. The amines reacted with nitrous acid at low temperature to generate diazo compounds, which were hydrolyzed to generate secondary alcohols, which were transposed to ketones, and then para-chlorobenzylated and hydrolyzed to decarboxylate to obtain the target product. This route has many steps and requires distillation and separation of multiple products, which has high requirements. Since the toxic compound sodium cyanide is used as a raw material, the process faces huge challenges in terms of environmental protection and storage, which are one of the key difficulties currently faced in achieving industrialization. Using ethyl 2-oxocyclopentanecarboxylate as a raw material, the compound can be prepared by para-chlorobenzylated, methylated, and hydrolyzed decarboxylation to prepare the target product. This synthetic route is relatively short, but it needs to be carried out under alkaline conditions because two carbonyl carbon negatives will be generated in the process. Side reactions may occur during the chlorobenzylation process. During the methylation stage, the chlorobenzyl group may shift, resulting in the generation of by-products. In addition, the by-products and product structures are similar, making separation difficult, which also makes it difficult to achieve industrial production. Zeng Minghua et al. used 2-dimethylcyclopentanone as a raw material, reacted with dimethyl carbonate, and then carried out benzylation and hydrolysis decarboxylation reaction to finally obtain the target product. However, the raw material 2-dimethylcyclopentanone used in the reaction is prepared by Dickmann condensation, methylation and decarboxylation of adipic acid ester compounds. This preparation process contains many side reactions and is not suitable for large-scale industrial production. Other reactions use complex and used synthetic routes, such as Mirnyi et al. using sodium hydride for reaction, which is highly dangerous to operate, or HBr aqueous solution, which is highly toxic and easy to pollute the environment after treatment. The above methods not only have complex synthetic routes, many steps, and many side reactions, but also have high process costs and are harmful to the environment. Those skilled in the art are in urgent need of developing a synthesis process for 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone to meet existing usage requirements and market demands. Summary of the invention

[0003] The purpose of the present invention is to provide a synthesis process of 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone to solve the above technical problems.

[0004] A synthetic process for 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone comprises the following steps: in a reaction kettle, under nitrogen protection, 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester or 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester is added as a raw material into a low eutectic solvent, methyl chloride is added for reaction, and then heating decarboxylation reaction, secondary methyl chloride reaction and hydrogenation reduction are carried out to obtain the product.

[0005] Furthermore, the mass volume ratio of the methyl 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylate or ethyl 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylate to the low eutectic solvent is 1:10-12.

[0006] Furthermore, the low eutectic solvent is a low eutectic solvent in which the molar ratio of benzyltriethylammonium chloride to n-heptanol is 1:1.

[0007] Furthermore, in the methyl chloride reaction, the amount of methyl chloride used is 1 to 1.05 moles relative to 1 mole of 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester or 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester added, and after reacting with methyl chloride, water is added to separate the lower organic phase, and anhydrous sodium sulfate is added to dry it.

[0008] Furthermore, the reaction temperature of the reaction of adding chloroform is 25-30° C., the reaction time is 2-3 hours, the reaction conditions are sodium methoxide alkaline catalysis, and the mass volume ratio of sodium methoxide to the low eutectic solvent is 1:8-10.

[0009] Furthermore, in the secondary chloroform reaction, the amount of chloroform used is 1 to 1.05 moles relative to 1 mole of the added 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester or 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester, the reaction temperature is 25 to 30° C., the reaction time is 2 to 3 hours, the reaction conditions are sodium methoxide alkaline catalysis, and the mass volume ratio of sodium methoxide to the low eutectic solvent is 1:8 to 10.

[0010] 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester or 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester is used as a raw material, which has wide sources and low costs.

[0011] In production practice, due to operator error, the hydrolysis and removal of carboxyl groups were omitted. It was unexpectedly found that the decarboxylation reaction could be achieved without using acid or alkali for hydrolysis reaction, and the by-products were less, thus improving the purity of the product.

[0012] Due to the strong solvation effect, heating of the low eutectic solvent can accelerate the one-step decarboxylation without the need for alkaline hydrolysis and then acidic decarboxylation. The steps are simple and avoid the condensation between the molecules in the previous hydrolysis reaction. In addition, the use of sulfuric acid requires the use of additional expensive organic solvent extraction and the addition of acids and bases at additional cost, and the acids and bases are difficult to recycle, avoiding the use of harmful organic solvents and toxic catalysts.

[0013] Furthermore, the heating decarboxylation reaction is heated to 60-80° C. for 4-6 hours, and then water is added to separate the liquids, and after the lower organic phase is obtained, anhydrous sodium sulfate is added to dry it.

[0014] Furthermore, the hydrogenation reaction is performed by adding a catalyst of palladium carbon, introducing hydrogen gas to 0.8-0.9 MPa at 80-90° C. and reacting for 4-6 hours.

[0015] The present invention has the following beneficial effects:

[0016] The invention discloses a synthetic process method for 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone. 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester or 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester is used as a raw material, which has a wide source and is easy to prepare and is conducive to industrial production. A low eutectic solvent is used, which is green and recyclable. Methyl chloride is added for reaction, and then heating decarboxylation reaction, secondary methyl chloride reaction and hydrogenation reduction are carried out. The process steps are simple, the use of harmful organic solvents and toxic catalysts is avoided, the cost is saved, the loss of products in the post-treatment process is avoided, the total yield of the target product is high, and the method is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Attached Figure 1 is the quantitative analysis chromatogram of the sample of Example 1, Figure 2 This is a photo of the actual object of 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone of Example 1. DETAILED DESCRIPTION

[0018] The present invention is described below with specific examples, but is not intended to be limiting of the present invention. Example 1

[0019] Raw materials: Longxi Biotechnology 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester; Dingyuan Saidi Chemical first-class benzyl triethylammonium chloride; Sinopharm Group 99.5% n-heptanol; Suzhou Yidun Technology 99.5% monochloromethane; Lai'an Jinbang Medical Chemical superior sodium methoxide; Runyue superior anhydrous sodium sulfate. Equipment: S30408 ​​material reactor, glass-lined mother liquor layering reactor; PLD1250NF centrifuge.

[0020] Preparation of low eutectic solvent: A mixture of benzyltriethylammonium chloride and n-heptanol in a molar ratio of 1:1 is placed in a high-speed mixer, heated to 60°C, and stirred at 500 rpm for 0.8 h to form a uniform transparent liquid to obtain; the mass volume ratio of methyl 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylate to the low eutectic solvent is 1:10.

[0021] A synthetic process for 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone, comprising the following steps: (1) in a reaction kettle, 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester is added as a raw material into a low eutectic solvent under nitrogen protection, and chloroform is added for reaction. In the chloroform reaction, the amount of chloroform is 1 mol relative to 1 mol of the added 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester or 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester. The reaction temperature of the chloroform reaction is 25°C, the reaction time is 2h, the reaction conditions are sodium methoxide alkaline catalysis, and the mass volume ratio of the amount of sodium methoxide to the low eutectic solvent is 1:1. ∶8; (2) heating decarboxylation reaction, heating to 60℃, heating for 4h, adding water to separate, separating to obtain the lower organic phase, adding anhydrous sodium sulfate to dry; (3) secondary chloroform reaction, the amount of chloroform is 1 mol relative to 1 mol of 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester added, the reaction temperature is 25℃, the reaction time is 2h, the reaction conditions are sodium methoxide alkaline catalysis, and the mass volume ratio of sodium methoxide to low eutectic solvent is 1:8; (4) hydrogenation reduction, the hydrogenation reaction is to add catalyst palladium carbon, fill hydrogen to replace the air in the kettle 3 times, and then, introduce hydrogen at 80℃ to 0.8MPa for 4h to obtain, with a yield of 89.8%.

[0022] The above reaction route is as follows:

[0023]

[0024] Product: 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone, purity 97.0%, water content 0.1%, appearance light yellow oily liquid. Example 2

[0025] Raw materials: Longxi Biotechnology 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester; Dingyuan Saidi Chemical first-class benzyl triethyl ammonium chloride; Sinopharm Group 99.5% n-heptanol; Zhonglian Zenong Chemical 99.5% n-heptanol. Suining Guineng Chemical 99.5% monochloromethane; Langheng Chemical superior sodium methoxide; Dingyuan Yunsen superior anhydrous sodium sulfate. Equipment: S30408 ​​material reactor, glass-lined mother liquor layering reactor; PLD1250NF centrifuge.

[0026] Preparation of low eutectic solvent: A mixture of benzyltriethylammonium chloride and n-heptanol in a molar ratio of 1:1 is placed in a high-speed mixer, heated to 60°C, and stirred at 500 rpm for 0.8 h to form a uniform transparent liquid, thereby obtaining a mass volume ratio of ethyl 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylate to the low eutectic solvent of 1:12.

[0027] A synthesis process for 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone, comprising the following steps: (1) in a reaction kettle, 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester is added as a raw material into a low eutectic solvent under nitrogen protection, and chloroform is added for reaction. In the chloroform reaction, the amount of chloroform is 1.05 mol relative to 1 mol of the added 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester. The reaction temperature of the chloroform reaction is 30°C, the reaction time is 3h, the reaction conditions are sodium methoxide alkaline catalysis, and the mass volume ratio of the amount of sodium methoxide to the low eutectic solvent is 1:10; (2) heating Decarboxylation reaction, heating to 80°C, heating for 6 hours, adding water to separate, separating the lower organic phase, adding anhydrous sodium sulfate to dry; (3) secondary chloroform reaction, the amount of chloroform used is 1.05 mol relative to 1 mol of 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester added, the reaction temperature is 30°C, the reaction time is 3 hours, the reaction conditions are sodium methoxide alkaline catalysis, and the mass volume ratio of sodium methoxide to low eutectic solvent is 1:10; (4) hydrogenation reduction, the hydrogenation reaction is to add catalyst palladium carbon, fill hydrogen to replace the air in the kettle 3 times, and then, introduce hydrogen to 0.9MPa at 90°C for 6 hours to obtain, with a yield of 90.2%.

[0028] Product: 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone, purity 96.5%, water content 0.08%, appearance light yellow oily liquid.

[0029] Note: Appearance is visually inspected. Content determination, instrument name: gas chromatograph, equipped with hydrogen flame ionization detector; chromatographic column: CP-Sil8CB30m×0.25mm×1.0μm; operating conditions: detector: FID detector temperature: 300℃ flow rate: 2.0mL / min column temperature: 150℃ for 2min, then increase the temperature to 300℃ at 15℃ / min, and maintain for 9min carrier gas: nitrogen; gas components: hydrogen: 30mL / min; air: 300mL / min; make-up gas: 25mL / min. Injection volume: 1μL; injector temperature: 295℃; injector split ratio: 20:1; running time: 21min; operating steps a. Preparation of standard sample solution Accurately weigh 50mg of 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone standard sample in a 10mL volumetric flask, dissolve it to volume with methanol, and mix well. b. Preparation of sample solution Accurately weigh 50 mg of 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone sample into a 10 mL volumetric flask, dissolve it in methanol to make up the volume, and mix well. The calculation formula is as follows: F external standard = A 表样（平均） / C 标样 ×P; 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (%) = A / f 外标 ×C; where: f external standard: correction factor, A 标样（平均） : Average value of the peak area of ​​the standard sample, C 标样 : concentration of standard sample, P: purity of standard sample, A: peak area of ​​sample to be tested, C: concentration of sample to be tested. Water content was determined by Karl Fischer reagent.

Claims

1. A method for synthesizing 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone, characterized in that: include: In a reaction kettle, 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester or 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester is added as a raw material to a low eutectic solvent under nitrogen protection, chloroform is added for reaction, and then subjected to heating decarboxylation reaction, secondary chloroform reaction, and hydrogenation reduction to obtain a low eutectic solvent, wherein the low eutectic solvent is a low eutectic solvent in which the amount ratio of benzyltriethylammonium chloride to n-heptanol is 1:1, and the mass volume ratio of the 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester or 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester to the low eutectic solvent is 1:10-12, the heating decarboxylation reaction is heated to 60-80°C for 4-6h, and then water is added to separate, and after the lower organic phase is obtained, anhydrous sodium sulfate is added for drying; in the chloroform reaction, the amount of chloroform used is relative to the amount of the added 3-(4-chlorobenzyl)-2 -Oxocyclopentanecarboxylic acid methyl ester or 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester is 1 to 1.05 moles; the reaction temperature of the reaction of adding chloroform is 25 to 30° C., the reaction time is 2 to 3 hours, the reaction conditions are sodium methoxide alkaline catalysis, and the mass volume ratio of sodium methoxide to the low eutectic solvent is 1: 8 to 10; in the secondary chloroform reaction, the amount of chloroform is 1 to 1.05 moles relative to 1 mole of the added 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid methyl ester or 3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylic acid ethyl ester, the reaction temperature is 25 to 30° C., the reaction time is 2 to 3 hours, the reaction conditions are sodium methoxide alkaline catalysis, and the mass volume ratio of sodium methoxide to the low eutectic solvent is 1: 8 to 10; the hydrogenation reduction is to pass hydrogen to 0.8 to 0.9 MPa at 80 to 90° C. and react for 4 to 6 hours.

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