A process for the preparation of 4-tert-butylcyclohexanone

Abstract

The present application relates to the field of synthesis of pesticide intermediates, in particular to a preparation method of 4-tert-butyl cyclohexanone, by reaction of compound 1 with oxygen under catalysis of a catalyst to generate a target product (TM), the process greatly reduces the cost and the amount of three wastes while maintaining high yield, overcomes the shortcomings of the prior art, realizes green production, and has the value of industrialization.

Description

Technical Field

[0001] This invention relates to the field of pesticide intermediate synthesis, and more particularly to a method for preparing 4-tert-butylcyclohexanone. Background Technology

[0002] tert-butylcyclohexanone is an intermediate of the pesticide Spiroxamine, whose chemical name is N-ethyl-N-propyl-8-tert-butyl-1,4-dioxaspiro[4.5]decane-2-methylamine, and English name (R,S)-N-[(8-tert-butyl-1,4-dioxaspiro[4.5]dec-2-yl)methyl]-N-ethylpropylamine. It is a novel systemic foliar fungicide developed by Bayer, belonging to the sterol biosynthesis inhibitor class. It inhibits the synthesis of C-14 demethylase and is mainly used to control wheat powdery mildew and various rust diseases, barley cloud stripe and stripe diseases, and is particularly effective against powdery mildew. The structure of Spiroxamine is as follows:

[0003] In addition, 4-tert-butylcyclohexanone is also a key intermediate in the veterinary drug Buparvaquone, chemically named 2-[(4-tert-butylcyclohexyl)methyl]-3-hydroxy-1,4-naphthalenedione, and its English name is 3-[(4-tert-butylcyclohexyl)methyl]-4-hydroxynaphthalene-1,2-dione. The structure of Buparvaquone is as follows:

[0004] The methods for preparing 4-tert-butylcyclohexanone reported in the literature are mainly as follows: (1) Using TEMPO as a catalyst and adding other oxidants, such as Organic Letters, 2014, 16(1), 58-61; Synlett, 2025, 36(12), 1775-1779; Journal of Chemical Society. Perkin transaction II, 1988, 533-536, etc.; (2) Using some very special catalysts as catalysts and hydrogen peroxide as oxidant, such as Arkivoc, 2012, 8, 187-197, etc. These processes either have expensive oxidants, complex catalysts with no cheap industrial products available, or generate a large amount of waste pollution; (3) The methods reported in the literature all use batch oxidation. Since the oxidation reaction itself is a high-risk process, the traditional batch oxidation process has obvious safety hazards. For the above reasons, the methods reported in the literature are difficult to meet the requirements of economy and environmental protection at the same time, and therefore have low industrialization value. Summary of the Invention

[0005] The purpose of this invention is to address the problems existing in the prior art by providing a low-cost, safe, and environmentally friendly preparation method for 4-tert-butylcyclohexanone, which significantly reduces the amount of waste generated and aligns with the contemporary theme of safety and environmental protection.

[0006] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: Preferably, a method for preparing 4-tert-butylcyclohexanone, the method comprising: a continuous oxidation reaction of compound 1 with oxygen (or air) in an organic solvent (or solvent-free state) in a tubular reactor catalyzed by Cu salt, ligand, and TEMPO (2,2,6,6-tetramethylpiperidine oxide) to obtain the target product 4-tert-butylcyclohexanone (TM), the reaction formula being as follows:

[0007] Preferably, the O2 or air pressure is 1~40 atm; the molar ratio of oxygen to the substrate 4-tert-butylcyclohexanol is 5:1~20:1, and when air is used, it is calculated based on the pure oxygen content. The reaction temperature is 70~110℃.

[0008] Preferably, the copper salt is a divalent copper salt, including copper chloride, copper bromide, copper sulfate, copper trifluoromethanesulfonate, copper acetate, and copper nitrate. Alternatively, a corresponding monovalent copper salt can be oxidized in situ to generate divalent copper. The ligand is a bipyridine ligand or acetylacetone. Bipyridine ligands include substituted or unsubstituted 2,2'-bipyridine and substituted or unsubstituted 2,2':6',2''-terpyridine. Preferred ligands include: 2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 2,2':6',2''-terpyridine, 4'-chloro-2,2':6',2''-terpyridine, and 4'-methyl-2,2':6',2''-terpyridine. ''-Tripyridine, 4'-tert-butyl-2,2':6',2''-terpyridine; the molar ratio of copper salt to ligand is 1:1 to 1.5:1; the molar ratio of copper salt to substrate 4-tert-butylcyclohexanol is 1:100 to 1:1000; preferably, the molar ratio of copper salt to substrate 4-tert-butylcyclohexanol is 1:100 to 1:500; the molar ratio of TEMPO to 4-tert-butylcyclohexanol is 1:500 to 1500; preferably, the molar ratio of TEMPO to 4-tert-butylcyclohexanol is 1:500 to 1000; the general structural formula of 2,2':6',2''-terpyridine is as follows:

[0009] R = hydrogen, halogen, C1-C4 alkyl; Preferably, the reaction can be carried out in a solvent-free or solvent-containing state. When an organic solvent is used, the reaction solvent is an organic solvent that does not react with the raw materials or products. Preferred solvents include 1,2-dichloroethane, chlorobenzene, acetic acid, tert-butanol, ethyl acetate, nitrobenzene, α,α,α-trifluorotoluene, etc. Since most organic solvents can be used, no further limitations are made here. The amount of the same solvent used only affects the reaction rate and has a negligible effect on the yield.

[0010] In this invention, if there is a conflict between the Chinese name and the structural formula of a compound, the structural formula shall prevail, unless the structural formula is obviously incorrect.

[0011] The beneficial effects of this invention are as follows: This invention uses compound 1 as raw material and achieves the conversion of 4-tert-butylcyclohexanol to 4-tert-butylcyclohexanone by continuous oxidation reaction of oxygen or air catalyzed by inexpensive copper salt catalyst. The raw materials used are inexpensive and readily available, avoiding the use of expensive reagents, reducing costs and waste. The reaction and post-treatment are simple, overcoming the shortcomings of the prior art and having industrial value. Attached Figure Description

[0012] Figure 1 It is the product of Example 1, 4-tert-butylcyclohexanone. 1 H NMR spectrum. Detailed Implementation

[0013] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention.

[0014] Example 1: Preparation of product 4-tert-butylcyclohexanone The substrate 4-tert-butylcyclohexanol (2 mol), cuprous chloride (5 mmol), 2,2'-bipyridine (4 mmol), and TEMPO (2 mmol) were dissolved in 1,2-dichloroethane (2 L) with stirring. The oil bath was heated to 90°C, the back pressure valve was set to 20 atm, and oxygen was introduced from the cylinder. The feed pump was started to pump the substrate solution into the tubular reactor (1.2 L capacity), allowing the gas and liquid to react simultaneously. The molar ratio of oxygen to substrate was 10:1. After exiting the reactor, the solution was cooled and collected. The solvent was recovered by vacuum concentration, and the product was obtained by vacuum distillation: 4-tert-butylcyclohexanone was obtained with a yield of 92.3% and a GC purity of 99.2%. The retention times of the product and the standard were consistent on gas chromatography (GC). The 1H NMR spectrum is shown below. Figure 1 The results obtained by adjusting different process parameters (copper salt, ligand, and temperature, while keeping other parameters constant) are shown in the table below. Table 1: Ligand and Reaction Temperature Screening

[0015] Note: The ratios in the table above refer to the molar ratio of copper salt to ligand.

[0016] Based on the study in the table above, the ligands described in this invention can achieve a yield of 90% and a purity of over 99% under most conditions, which is comparable to the results of the hydrogen peroxide oxidation method reported in the literature, but the amount of waste generated is less than 10% of that of the literature method.

[0017] Example 2: Solvent, gas type and pressure screening Using the method of Example 1, with other conditions unchanged, the solvent, gas type, oxygen amount (a multiple of the amount of the substrate 4-tert-butylcyclohexanol), and pressure were screened, and the following results were obtained: Table 2

[0018] Note: When using air, the amount of oxygen used is the amount of pure oxygen in the air.

[0019] The above results indicate that this type of catalytic system exhibits good solvent adaptability, and high yields can be obtained with all the aforementioned solvent systems. Good results can be achieved using either air or oxygen; however, the low oxygen concentration in air necessitates multiple gas replenishments and a longer reaction time. Under the same conditions, higher oxygen pressure and a higher oxygen concentration are beneficial for improving the yield.

[0020] Example 3: Screening of copper salt and TEMPO dosage Using the method of Example 1, the amount of copper salt and TEMPO was screened, with the ratio of copper salt to ligand kept constant and other conditions unchanged. The following results were obtained: Table 3

[0021] The above research results indicate that when the amount of either copper salt or TEMPO is too low, the yield of the product will be significantly affected, even if the amount of the other species is increased. Therefore, the two have a synergistic catalytic effect, and appropriate concentrations must be maintained to achieve good results in the reaction.

[0022] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several modifications and improvements can be made without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A method for preparing 4-tert-butylcyclohexanone, characterized in that, The method includes: compound 1 reacting with oxygen or air in a tubular reactor under the catalysis of copper salt and ligands and TEMPO to generate compound TM, namely 4-tert-butylcyclohexanone, as shown in the following reaction formula: 。 2. The preparation method according to claim 1, characterized in that, The pressure of the oxygen or air is 1~40 atm.

3. The preparation method according to claim 1, characterized in that, The molar ratio of oxygen to 4-tert-butylcyclohexanol is 5:1 to 20:1, and when air is used, it is calculated based on the amount of pure oxygen contained therein.

4. The preparation method according to claim 1, characterized in that, The reaction temperature is 70~110℃.

5. The preparation method according to claim 1, characterized in that, The copper salt is a divalent copper salt.

6. The preparation method according to claim 5, characterized in that, The copper salt is one or more of copper chloride, copper bromide, copper sulfate, copper trifluoromethanesulfonate, copper acetate, and copper nitrate.

7. The preparation method according to claim 1, characterized in that, The copper salt is one or more of cuprous chloride, cuprous bromide, cuprous sulfate, cuprous trifluoromethanesulfonate, cuprous acetate, and cuprous nitrate.

8. The preparation method according to claim 1, characterized in that, The ligand is selected from acetylacetone, substituted or unsubstituted 2,2'-bipyridine, substituted or unsubstituted 2,2':6',2''-terpyridine, and the substituent is selected from halogens and C1-C4 alkyl groups.

9. The preparation method according to claim 1, characterized in that, The molar ratio of the copper salt to the ligand is 1:1 to 1.5:1; the molar ratio of the copper salt to compound 1 is 1:100 to 1:1000; and the molar ratio of TEMPO to compound 1 is 1:500 to 1500.

10. The preparation method according to claim 1, characterized in that, The reaction is carried out in the presence of a solvent, which is selected from one or more of 1,2-dichloroethane, chlorobenzene, acetic acid, tert-butanol, ethyl acetate, nitrobenzene, and α,α,α-trifluorotoluene.

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