A method for synthesizing spirocyclic amide derivatives involving carbon dioxide

Abstract

The invention provides a method for synthesizing spirocyclic amide derivatives that carbon dioxide participates in, and belongs to the technical field of synthesis of compounds. The present invention has developed a method for participating in the synthesis of spirocyclic amide compounds using carbon dioxide, which uses carbon dioxide as a carbonylation reagent, using carbon dioxide and (2-aminophenyl) cyclohexyl ketone as raw materials, by adding alkali and solvent, and preparing the spirocyclic amide derivatives in the next step of reaction time and reaction temperature. Because carbon dioxide has the characteristics of non-toxicity, cheapness and reproducibility, it meets the strategic requirements of green chemistry and sustainable development. The synthetic method provided by the present invention is safe, environmentally friendly and practical, and the yield of target product is high, and it is suitable for industrialized production.

Description

Technical Field

[0001] The invention belongs to the technical field of compound synthesis, and particularly relates to a method for synthesizing spirocyclic amide derivatives with the participation of carbon dioxide.

[0002] This invention is funded by the following: Sichuan Natural Science Foundation of China (2022NSFSC0200), Sichuan Science and Technology Innovation Seedling Project (MZGC20230100). Background Art

[0003] Spiroamides are a class of important chemical building blocks, widely found in natural product and drug synthesis. They typically exhibit diverse biological activities and pharmacological actions, and therefore have attracted widespread attention in drug research and medicinal chemistry. They may exhibit antibacterial, antiviral, antitumor, anti-inflammatory, and antidepressant activities, and have significant application potential in areas such as neuroscience and drug delivery systems. However, due to the complex structures and diverse biological activities of spiroamides, their synthesis currently requires very demanding conditions, and the ability to efficiently synthesize these compounds has long been a focus of chemists.

[0004] Spiroamide compounds have the following structures:

[0005]

[0006] By modifying and optimizing the structures of the above-mentioned spirocyclic amide compounds, compounds with better biological activity, lower toxicity and better pharmacokinetic properties can be obtained, thereby developing more effective and safer drugs.

[0007] In general, these spirocyclic amide compounds have common advantages in drug molecules, such as structural diversity, biological activity, pharmacokinetic properties and drug development potential, which makes them have broad application prospects in the field of drug research and development.

[0008] Some existing methods for synthesizing spiroamide compounds use CO, but CO is toxic and its safety is difficult to guarantee. On the other hand, the process steps of existing synthesis methods are relatively complicated, the reaction process is difficult to control, and the yield of the prepared spiroamide compounds is not high.

[0009] Therefore, there is an urgent need to provide a new synthesis method of spirocyclic amide compounds that is safe, mild, green, environmentally friendly, and has high yield. Summary of the Invention

[0010] The present invention addresses the shortcomings and deficiencies of existing synthesis methods and provides a method for synthesizing spiroamide compounds. The present invention aims to utilize green and safe CO₂ and (2-aminophenyl)cyclohexyl ketone as raw materials for synthesizing spiroamide compounds, replacing toxic CO with CO₂, and synthesizing spiroamide compounds in high yields under safe and mild experimental conditions.

[0011] In order to achieve the above technical objectives, the technical solutions adopted by the present invention are as follows:

[0012] The present invention provides a method for synthesizing spirocyclic amide derivatives involving carbon dioxide, wherein carbon dioxide and (2-aminophenyl)cyclohexyl ketone are used as raw materials, and a base and a solvent are added to obtain the spirocyclic amide derivatives in a step under a certain reaction time and reaction temperature; wherein the structural formula of the spirocyclic amide derivatives is shown in the following formula or formula <II>:

[0013]

[0014] The reaction formula for preparing the above-mentioned spirocyclic amide compound by the one-step method of the present invention is as follows:

[0015]

[0016] in: 1.

[0018] Represents various aromatic compounds, R = hydrogen, methyl, ethyl, tert-butyl, alkenyl, alkynyl and other hydrocarbon groups and fluorinated hydrocarbons, methoxy, ethoxy and other alkoxy groups, alkylthio groups, fluorine, chlorine, bromine, iodine and other halogen groups; other ester groups, amides, other acyl groups, carbonyl groups (including keto and aldehyde groups), alkyl groups, aryl groups (including phenyl, substituted phenyl, biphenyl ether, benzidine, biphenol, thienyl, pyrazolyl, pyrrolyl, imidazolyl, pyridine, furan), nitrile groups, carboxyl groups, hydroxyl groups, thiol groups, nitro groups, various amino groups (including protected amino groups), phosphine groups (phosphino), silicon groups (silicon hydrogen, silicon oxygen, silicon halide), boron-containing groups (boronic acid, boron ester); elements appearing in the above groups include deuterium, 13 C. 31 P. 18 O. 11 B and other isotopes; the number of R can be 1, 2, or 3; the position of R can be 1, 2, 3, 4, or 5. If there are two, they can be ortho, meta, or para.

[0019] 2. R 1 、R 2 There are two cases:

[0020] (1)R 1、R 2 =Hydrogen, methyl, ethyl, tert-butyl, alkenyl, alkynyl and other hydrocarbon groups and fluorinated hydrocarbons, methoxy, ethoxy and other alkoxy groups, alkylthio groups, fluorine, chlorine, bromine, iodine and other halogen groups; other ester groups, amides, other acyl groups, carbonyl groups (including keto and aldehyde groups), nitrile groups, carboxyl groups, hydroxyl groups, thiol groups, nitro groups, various amino groups (including protected amino groups), phosphino groups (phosphinooxy groups), silicon groups (silicon hydrogen groups, silicon oxygen groups, silicon halide groups), boron-containing groups (boric acid groups, boron ester groups), elements appearing in the above groups include deuterium, 13 C. 31 P. 18 O. 11 B and other isotopes.

[0021] (2) It can also be R=hydrogen, methyl, ethyl, tert-butyl, alkenyl, alkynyl and other hydrocarbon groups and fluorinated hydrocarbons, methoxy, ethoxy and other alkoxy groups, alkylthio groups, fluorine, chlorine, bromine, iodine and other halogen groups; other ester groups, amides, other acyl groups, carbonyl groups (including ketone groups and aldehyde groups), nitrile groups, carboxyl groups, hydroxyl groups, thiol groups, nitro groups, various amino groups (including protected amino groups), phosphine groups (phosphino groups), silicon groups (silicon hydrogen groups, silicon oxygen groups, silicon halide groups), boron groups (boric acid groups, boron ester groups), elements appearing in the above groups include deuterium, 13 C. 31 P. 18 O. 11 B and other isotopes.

[0022] (3) represents a 3-n membered ring, including aliphatic rings and derivatized aliphatic rings containing heteroatoms.

[0023] 3. Base = potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, potassium hydrogen phosphate, sodium acetate, cesium acetate, butyl lithium, phenyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide, magnesium tert-butoxide and other alkali metal and alkaline earth metal alkoxides, cesium fluoride, potassium fluoride, sodium fluoride, as well as potassium hydroxide, sodium hydroxide, lithium hydroxide, etc., of course, also including other organic bases such as amine compounds, DBU (1,8-diazabicycloundec-7-ene), TBD (1,5,7-triazabicyclo[4.4.0]-5-decene), etc.

[0024] 4. Solvent = water, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, benzene, tetrahydrofuran, cyclohexane, decahydronaphthalene, xylene, chlorobenzene, trimethylbenzene, 1,2-dioxane, 1,2-dichloroethane, 1,2-dimethoxyethane, dimethoxyfuran, 2-methyltetrahydrofuran, 2,2,2-trifluoroethanol, acetonitrile, N-methylpyrrolidone, diethylene glycol dimethyl ether, etc.

[0025] 5. Base equivalent = 1.0-4.5 equivalents

[0026] 6. Reaction temperature = 50℃-140℃

[0027] 7. Reaction time = 2 hours - 48 hours

[0028] The synthesis method provided by the present invention uses carbon dioxide and (2-aminophenyl)cyclohexyl ketone as raw materials and produces the spiroamide compound in a single step under heating conditions. This method is a green and clean method for synthesizing spiroamide compounds, which has inexpensive raw materials, simple operation, and a wide range of substrate applications.

[0029] Such spirocyclic amide compounds have the following uses:

[0030] (1) Spiroamide compounds may exhibit biological activity and therefore may be used as a starting point for drug design. They may have pharmacological activities such as anti-inflammatory, antibacterial, and anti-tumor activities and can be used to develop new drug treatment options.

[0031] (2) Certain spirocyclic amide compounds may have special polymerization properties and can therefore be used to prepare high-performance polymer materials. These materials may be used to prepare materials with high strength, high heat resistance or other specific performance requirements, such as fibers, films, coatings, etc.

[0032] (3) Since spirocyclic amide compounds may have diverse structures and properties, they may be used to prepare materials with specific functions, such as fluorescent materials, optoelectronic materials, sensors, etc.

[0033] (4) Some spirocyclic amide compounds may have the ability to interact with specific molecules in the body and therefore may be used as biomarkers in biological research, medical diagnosis and other fields.

[0034] The beneficial effects of the present invention are as follows:

[0035] 1. This patent uses green and economical CO2 as raw material. CO2 is easy to obtain and environmentally friendly. It is non-toxic, abundant, usable and recyclable, and has great potential to turn waste CO2 into treasure, which meets the requirements of green chemistry and sustainable development strategies and avoids the safety issues of using CO2 before.

[0036] 2. The synthesis method provided by the present invention has few experimental steps and is simple to operate;

[0037] 3. The reaction cost of the present invention is low and has certain economic efficiency.

[0038] 4. The synthetic reaction of the present invention has good functional group tolerance and a wide range of substrates.

[0039] 5. The target product obtained by the synthesis method of the present invention has a high yield and is atom-economical. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is described in detail below with reference to the following embodiments. It is necessary to point out that the following embodiments are only used to explain and illustrate the present invention and are not intended to limit the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above invention content still fall within the scope of protection of the present invention.

[0041] Example 1

[0042] A method for synthesizing spirocyclic amide compounds with the participation of carbon dioxide, the reaction equation of which is shown below:

[0043]

[0044] in:

[0045] A is the raw material of the reaction, and the amount used in the reaction is 1.0 equivalent;

[0046] B is the base in the reaction, lithium tert-butoxide, used in the reaction in an amount of 4.5 equivalents;

[0047] C is the reaction solvent in the reaction, which is a mixed solution of N,N-dimethylformamide and o-xylene in a ratio of 1:1 (v:v).

[0048] The specific reaction operation is:

[0049] First, select a suitable sealed tube reactor, add a stirrer, and dry the reaction tube with a high-temperature heating gun until it is free of water and oxygen. After cooling, add raw material A. Weigh 4.5 equivalents of lithium tert-butoxide in the glove box. After taking it out of the glove box, replace the inert gas in the reaction tube with carbon dioxide. Under a carbon dioxide atmosphere, add a 1:1 (v:v) mixed solution of N,N-dimethylformamide and o-xylene. After closing the reaction tube, mix well, and place it at 120°C for stirring and reaction for 24 hours.

[0050] The post-treatment of the reaction is as follows: after the reactant is cooled, it is quenched with water, extracted three times with ethyl acetate, and then dried over anhydrous sodium sulfate. The solvent is then removed in vacuo and purified by column chromatography.

[0051] Template reaction:

[0052]

[0053] A 10-ml sealed tube reactor was dried using a high-temperature heat gun to anhydrous and oxygen-free conditions. After cooling, raw material A (40.6 mg, 0.2 mmol) was added. Lithium tert-butoxide (72 mg, 0.9 mmol) was weighed into a glove box. After removing the reactor from the glove box, the inert gas in the reaction tube was replaced with carbon dioxide. Under a carbon dioxide atmosphere, a mixture of N,N-dimethylformamide and o-xylene (1:1, v:v, 1 ml + 1 ml) was added. The reaction tube was tightly sealed, mixed thoroughly, and stirred at 120°C for 24 hours.

[0054] The reaction was post-processed as follows: after cooling, the reactants were quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was removed in vacuo before purification by column chromatography. The TCL developing solvent was petroleum ether:ethyl acetate = 4:1 (v:v), with an Rf value of 0.38. The column chromatography eluent was petroleum ether:ethyl acetate in the following ratios: 20:1 (v:v, 105 mL); 16:1 (v:v, 85 mL); 14:1 (v:v, 75 mL); and 12:1 (v:v) until the product was completely recovered. The product was white crystals with a yield of 98%.

[0055] Example 2

[0056] Referring to the synthesis steps of Example 1, the reaction conditions and yields of different substrates composed of other substituents are as follows:

[0057]

[0058] Note: The data below the compound are the yields of different substrates under the reaction conditions.

Claims

1. A method for synthesizing spirocyclic amide derivatives involving carbon dioxide, characterized in that: Carbon dioxide and or As a raw material, the spirocyclic amide derivative is prepared in one step by adding a base and a solvent under a reaction time and a reaction temperature; the base is lithium tert-butoxide, the solvent is a mixture of DMF and o-xylene in a volume ratio of 1:1, and the reaction temperature is 120°C; The structural formula of the spirocyclic amide derivative is shown in the following formula <Ⅰ> or formula <Ⅱ>: ； in, is phenyl, R is selected from any one of the following groups: hydrogen, hydrocarbon, alkoxy or alkylthio, halogen, aryl, nitrile, hydroxy, thiol, nitro; the hydrocarbon is methyl, ethyl or tert-butyl; the alkoxy is methoxy or ethoxy; the alkylthio is methylthio or ethylthio; the halogen is fluorine, chlorine, bromine or iodine; the aryl is phenyl; the number of R is 1, 2 or 3; Among them, R 1 、R 2 All are methyl; in, represents a 5-membered aliphatic ring or a 6-membered aliphatic ring.

2. The synthesis method according to claim 1, wherein The equivalent weight of the base is 4.5 equivalents, and the reaction time is 24 hours.

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