CN115215816B - A kind of synthesis method of lactam compounds - Google Patents

Abstract

The invention provides a synthesis method of lactam compounds, which uses sodium chlorite as an oxidant to oxidize cyclic amine compounds into lactam compounds under the catalysis of carbon dioxide. The synthesis method provided by the invention has the characteristics of green and high efficiency, mild reaction conditions, high yield, high purity, convenient post-treatment and easy industrial application.

Description

A kind of synthesis method of lactam compounds

Technical field

The invention belongs to the technical field of chemical synthesis, and specifically relates to a synthesis method for oxidizing cyclic amine compounds into lactam compounds.

Background technique

Lactam compounds are key intermediates for many drugs and have wide applications in the field of drug synthesis. For example, the commonly used clinical antithrombotic drugs rivaroxaban and apixaban have lactam structures in their molecular structures. Lactam compounds can be introduced into the target drug structure as intermediates, and their synthesis method can be obtained by directly oxidizing cyclic amine compounds, thereby simplifying the synthesis process of raw materials.

Commonly used methods to obtain lactams by oxidizing cyclic amine compounds include transition metal catalytic oxidation and non-metal catalytic oxidation. The transition metal catalytic oxidation method uses transition heavy metals as catalysts, resulting in high process costs and excessive residual metal elements in the product. risks and is not suitable for industrial applications; the non-metal catalytic oxidation method uses non-metal oxidants to oxidize cyclic amines. Compared with the transition metal catalytic oxidation method, it avoids the use of transition heavy metals, and the process cost is relatively reduced, making it more suitable for industrial applications. .

Femando Sartillo-Piscil et al. published in J.Org.Chem. (2018, 83, 15333-15346) in 2018 described a method of using a non-metal catalytic oxidation method to oxidize morpholine compounds to obtain morpholinone compounds. This method uses sodium chlorite (3 equivalents) and sodium hypochlorite (0.7 equivalents) as oxidants, TEMPO (tetramethylpiperidine nitrogen oxide) (0.1 equivalents) as a catalyst, and a pH adjuster NaH ₂ PO ₄ (3 equivalents). ) as an oxidation system, realizing non-metal catalytic oxidation. However, the disadvantages of this reaction are also obvious. Too many salts are added to the entire reaction system, which will produce a large amount of solid waste or waste liquid during industrialization. In addition, TEMPO is expensive, toxic, can be absorbed through the skin, and has It is irritating and poses certain risks to experimenters, and its structure is unstable under acid and alkali conditions and is easy to decompose, resulting in many impurities in the product, making it difficult to recycle and easily polluting the environment. Therefore, this method is expensive and does not meet the current green and environmentally friendly chemical industry requirements.

Eric PATalbot et al. published in Org. Lett. (2017, 19, 870-873) in 2017 described a method of using a non-metal catalytic oxidation method to oxidize cyclic amine compounds to generate lactam compounds. This method uses up to 7.5 equivalents of iodine element as the oxidant. The price of iodine is high and the dosage is large, resulting in high process costs; and 10 equivalents of NaHCO ₃ are used as the pH adjuster, which will generate a large amount of solid waste during industrialization. It is also not conducive to the chemical industry requirements of green environmental protection.

The above-mentioned process has shortcomings such as high production cost, high "three wastes", non-environmental protection, poor reaction selectivity and unsafe reaction during process amplification, which is not conducive to industrial production. Therefore, the study of alternative synthesis of lactam compounds has very important practical value and significance.

In the patent application CN201911264060.3 applied by the applicant in 2019, acid or acid salt was used as the pH regulator and sodium chlorite was used as the oxidant to successfully realize the rivaroxaban intermediate 4-(4-aminophenyl )-Synthesis of 3-morpholinone. Specifically, the patent application provides a method for synthesizing 4-(4-aminophenyl)-3-morpholinone, which includes the following steps: using p-halonitrobenzene and morpholine as starting materials, condensation to generate 4 -(4-nitrophenyl)morpholine, then use halide or chlorine dioxide as the oxidant, adjust the pH value of the reaction system with acid or acid salt to be less than 7, and convert 4-(4-nitrophenyl) ) morpholine is oxidized to generate 4-(4-nitrophenyl)-3-morpholinone, and finally reduced to generate the target product 4-(4-aminophenyl)-3-morpholinone. This synthesis method shows good application value. However, in this method, pH control is difficult. At the beginning of the reaction, the reaction speed is too fast and generates more heat, resulting in poor selectivity. In the later stage of the reaction, the pH increases and the reaction rate decreases. The reaction speed during the entire reaction process is unstable. When the process is scaled up, outstanding problems such as poor reaction selectivity and incomplete reactions occur, which is not conducive to industrial production. Therefore, the alternative synthesis of lactam compounds still needs further improvement.

Contents of the invention

In view of the above-mentioned shortcomings in the synthesis of lactam compounds, the purpose of the present invention is to provide a synthetic method of lactam compounds that is green and efficient, has mild reaction conditions, has high yield and purity, and is convenient for post-processing and is easy for industrial application. In the present invention, carbon dioxide is used as a catalyst to participate in the oxidation reaction for the first time. Carbon dioxide is a cheap and easily available weakly acidic gas. It can stably control the pH value of the reaction system at around 6, well control the reaction process and reaction selectivity, and is an effective supplement and great improvement to the existing technology.

According to the purpose of the present invention, the present invention provides a method for synthesizing lactam compounds, which is characterized in that the method uses sodium chlorite as an oxidizing agent to oxidize cyclic amine compounds into lactam compounds under the catalysis of carbon dioxide. compound.

The method for synthesizing lactam compounds of the present invention is not limited to oxidizing cyclic amine compounds with specific structures into lactam compounds. For example, the 4-(4-nitro group mentioned in patent application CN201911264060.3 Phenyl)morpholine is oxidized to 4-(4-nitrophenyl)-3-morpholinone. As a more preferred solution of the present invention, the method of the present invention oxidizes the cyclic amine compound represented by formula II into a lactam compound represented by formula I. The chemical reaction equation is as follows:

in

When n=0 or 1, X is CH2,

When n=2, X is O or CH ₂ ;

R is optionally one or more selected from hydrogen, halogen, nitro, trifluoromethyl, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ acyl, C ₁ -C ₆ alkoxy Substituted phenyl, benzyl, or pyridyl, where "multiple" means substituted by two or more groups.

As an example, the cyclic amine compound is, for example, 4-(4-nitrophenyl)morpholine, 4-phenylmorpholine, 4-(2-methyl-4-nitrophenyl)morpholine 4-(4-cyanophenyl)morpholine, 4-(2-chloro-4-nitrophenyl)morpholine, 4-(4-nitrobenzyl)morpholine, 4-(4- Chlorophenyl)morpholine, 4-(2-nitro-4-cyanophenyl)morpholine, 4-(pyridin-2-yl)morpholine, 4-(2-nitro-4-trifluoromethyl methylphenyl)morpholine, 4-(3-nitro-5-trifluoromethylphenyl)morpholine, 1-(4-nitrophenyl)piperidine, 4-(3-nitrophenyl) Morpholine, 1-(4-nitrophenyl)tetrahydropyrrole, 1-(2-methylphenyl)piperidine, 1-(3-fluoro-4-bromophenyl)piperidine, 1-(4 -Trifluoromethylphenyl)piperidine, 1-(4-nitrophenyl)azetidine, etc.

In the method for synthesizing lactam compounds of the present invention, sodium chlorite is added dropwise to the reaction system in the form of sodium chlorite aqueous solution.

In the method for synthesizing lactam compounds of the present invention, the reaction system does not react without adding carbon dioxide, but the reaction can be catalyzed and carried out rapidly in the presence of carbon dioxide. On the one hand, carbon dioxide gas can be directly introduced into the reaction vessel below the reaction liquid level, or into the reaction vessel above the reaction liquid level. On the other hand, during the process of dripping the sodium chlorite aqueous solution, carbon dioxide is continuously introduced into the reaction system. After the dripping is completed, carbon dioxide is optionally continued to be continuously introduced into the reaction system, carbon dioxide is stopped, or carbon dioxide is introduced intermittently. Enter carbon dioxide. Any of the above carbon dioxide introduction methods can achieve the purpose of carbon dioxide catalytic reaction, and there is no obvious difference in the reaction effect.

In the method for synthesizing lactam compounds of the present invention, the molar ratio of the cyclic amine compound and the oxidant sodium chlorite is 1:1 to 1:10, preferably 1:2 to 1:6, for example, 1:2, 1:3, 1:4, 1:5, 1:6. As a stable oxidant, sodium chlorite is widely used in industrial fields. It is easily available, cheap, and soluble in water. It can be easily removed by washing and layering post-processing. In addition, sodium chlorite is an alkali. Metal salts will not cause the problem of excessive impurities of transition heavy metal elements.

In the method for synthesizing lactam compounds of the present invention, the reaction temperature is 0-100°C, preferably 20-80°C. For example, the reaction temperature can be 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃.

In the method for synthesizing lactam compounds of the present invention, the solvents used are aprotic solvents such as nitrile solvents, ether solvents, toluene, acetone, and methylene chloride. Nitrile solvents can be selected from acetonitrile, propionitrile, butyronitrile, etc.; ether solvents can be selected from tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, etc.

Preferably, the present invention provides a method for synthesizing lactam compounds represented by Formula I, which method uses sodium chlorite as an oxidizing agent to catalyze cyclic amine compounds represented by Formula II under carbon dioxide catalysis. Oxidized to lactam compounds as shown in formula I

in

When n=0 or 1, X is CH ₂ ,

When n=2, X is O or CH ₂ ;

R is optionally one or more selected from hydrogen, halogen, nitro, trifluoromethyl, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ acyl, C ₁ -C ₆ alkoxy substituted phenyl, benzyl, or pyridyl,

"Multiple" means substituted by two or more groups, and the type of the cyclic amine compound, the adding method of catalyst carbon dioxide, the molar ratio of the cyclic amine compound and the oxidant sodium chlorite, The reaction temperatures and solvents used were as described above.

In the method for synthesizing lactam compounds of the present invention, high conversion rate and selectivity of the reaction can be achieved under CO ₂ catalysis during the reaction process. Using CO ₂ as a catalyst was the applicant's accidental discovery that CO ₂ itself, as a common gas in nature, has many applications, but it has not been directly used as a catalyst in oxidation reactions; as a stable gas, CO ₂ has After being dissolved in water, carbonic acid is generated. The reaction itself is also a reversible reaction. The generated trace amount of carbonic acid catalyzes the oxidation reaction. Under the catalysis of _CO2 , the reaction system can maintain a stable carbonic acid microenvironment, thereby ensuring that the reaction proceeds smoothly and gently; in addition, the reaction After completion, CO ₂ leaves the reaction system, which reduces post-processing steps and does not cause environmental pollution, making it more suitable for industrial applications.

In the method of synthesizing lactam compounds of the present invention, after the reaction is completed, a reducing agent such as sodium bisulfite or sodium sulfite is added to quench the reaction, the solvent is concentrated and recovered, and the lactam compound can be obtained by filtering and washing with water, with a yield of up to 85 to 98%. , HPLC purity can reach up to 99% or more.

In the prior art, when non-metal catalytic oxidation is used to synthesize lactam compounds, the oxidation methods in the literature are not suitable for industrial application. On the one hand, a large amount of oxidants are used, resulting in a large amount of solid waste or waste liquid, which increases the cost of oxidation and is not environmentally friendly; on the other hand, when the process is scaled up, problems such as poor reaction selectivity and incomplete reactions are highlighted, and the product quality is not high.

The method for synthesizing lactam compounds of the present invention has significant advantages: sodium chlorite is used as the oxidant and _CO2 is used as the catalyst. The entire reaction process is mild and controllable, the reaction selectivity is high and the reaction is thorough, and the product yield is high and the purity is high. . The post-treatment is convenient and simple. Only sodium chlorite is added as the oxidant. The dosage is controllable. The oxidant is easily soluble in water and can be removed by conventional water washing and layering operations, avoiding the generation of a large amount of solid waste. The entire reaction operation process is simple. Products are easily available, more efficient and green.

Detailed ways

The embodiments of the present invention are described in detail below with reference to specific examples. However, those skilled in the art should understand that the examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.

The preparation of cyclic amine compounds can refer to the method described in J.Org.Chem (2018, 83, 15333-15346).

Reagents and solvents: All are commercially available; the solvents used are domestic analytically pure reagents, purchased from Sinopharm Chemical Reagent Co., Ltd., and were not treated in any way before use. Commercially available sodium chlorite is a solid with a mass fraction of 80%. It can be prepared into an aqueous solution with a mass concentration of 10 to 60% as needed, such as a mass concentration of 10%, 20%, 30%, 40%, 50% or 60%. aqueous solution.

Liquid Chromatography: Agilent 1206.

Nuclear magnetic resonance instrument: Bruker DRX-400FT (Germany), ¹ HNMR was measured in CDCl ₃ , the chemical shift was based on tetramethylsilane (TMS), and the unit was ppm.

Example 1: Synthesis of 4-(4-nitrophenyl)-3-morpholinone

Add 2.08g (0.01mol) of 4-(4-nitrophenyl)morpholine and 20ml of acetonitrile to a 100ml reaction flask, heat it to 50°C, and in the presence of CO ₂ , add 2.26g (0.02mol) of submers dissolved in 5g of water. Sodium chlorate is prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 3 hours. After the reaction is completed, add 2.5g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 30 ml of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 2.14 g of 4-(4-nitrophenyl)-3-morpholinone, yield 96.4%, HPLC purity 99.7%.

¹ HNMR (CDCl ₃ , 400MHz): δ8.21 (d, J=8.8Hz, 2H), 7.55 (d, J=9.2Hz, 2H), 4.31 (s, 2H), 4.01 (t, J=5.2Hz , 2H), 3.79 (t, J=5.2Hz, 2H).

Example 2: Synthesis of 4-phenyl-3-morpholinone

Add 1.63g (0.01mol) of 4-phenylmorpholine and 20ml of tetrahydrofuran to a 100ml reaction flask, heat it to 60°C, and prepare 4.51g (0.04mol) of sodium chlorite dissolved in 14.16g of water in the presence of _CO2 The aqueous solution was added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 1.5 hours. After the reaction is completed, add 5g of sodium sulfite and stir at room temperature for 15 minutes. Concentrate under reduced pressure to obtain a light yellow solid, add 25 ml of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and obtain 1.53g of 4-phenyl-3-morpholinone after drying, yield 86.4%, HPLC purity 98.1%.

¹ HNMR (CDCl ₃ , 400MHz): δ7.48-7.36(m, 2H), 7.38-7.24(m, 3H), 4.35(s, 2H), 4.08-3.99(m, 2H), 3.82-3.72(m ,2H).

Example 3: Synthesis of 4-(2-methyl-4-nitrophenyl)-3-morpholinone

Add 2.22g (0.01mol) of 4-(2-methyl-4-nitrophenyl)morpholine and 25ml of methylene chloride into a 100ml reaction flask, heat it to 30°C, and dissolve it in 14.16g of water in the presence of CO ₂ 4.51g (0.04mol) of sodium chlorite was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 3 hours. After the reaction is completed, add 5g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a light yellow solid. Add 30 ml of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 4-(2-methyl-4-nitrophenyl)-3-morpholine. Ketone 2.18g, yield 92.4%, HPLC purity 98.9%.

¹ HNMR (CDCl ₃ , 400MHz): δ8.22-8.10 (m, 2H), 7.35 (d, J=8.6Hz, 1H), 4.37 (s, 2H), 4.08 (s, 2H), 3.67 (d, J＝71.8Hz, 2H), 2.35(s, 3H).

Example 4: Synthesis of 4-(4-cyanophenyl)-3-morpholinone

Add 1.88g (0.01mol) of 4-(4-cyanophenyl)morpholine and 15ml of dioxane into a 100ml reaction flask, heat it to 45°C, and dissolve 3.38g (0.03g) of 10.62g of water in the presence of _CO2 mol) sodium chlorite was prepared into an aqueous solution and added dropwise to the reaction system. After the dropping is completed, continue the reaction for about 3 hours. After the reaction is completed, add 3.8g of sodium sulfite and stir at room temperature for 12 minutes. Concentrate under reduced pressure to obtain a white solid, add 25 ml of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 1.87 g of 4-(4-cyanophenyl)-3-morpholinone, yield 92.6%, HPLC purity 98.1%.

¹ HNMR (CDCl ₃ , 400MHz): δ7.75-7.67(m, 2H), 7.59-7.50(m, 2H), 4.36(s, 2H), 4.10-4.03(m, 2H), 3.86-3.78(m ,2H).

Example 5: Synthesis of 4-(2-chloro-4-nitrophenyl)-3-morpholinone

Add 2.42g (0.01mol) of 4-(2-chloro-4-nitrophenyl)morpholine and 25ml of toluene to the 100ml reaction flask, heat it to 80°C, and in the presence of CO ₂ , dissolve 3.38g of 4-(2-chloro-4-nitrophenyl)morpholine in 10.62g of water. (0.03mol) sodium chlorite was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 5 hours. After the reaction is completed, add 3.8g of sodium sulfite and stir at room temperature for 15 minutes. Concentrate under reduced pressure to obtain a light yellow solid. Add 40 ml of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 4-(2-chloro-4-nitrophenyl)-3-morpholinone. 2.51g, yield 98.0%, HPLC purity 99.1%.

¹ HNMR (CDCl ₃ , 400MHz): δ8.42 (d, J=2.5Hz, 1H), 8.24 (dd, J=8.7, 2.5Hz, 1H), 7.54 (d, J=8.6Hz, 1H), 4.41 (s, 2H), 4.11 (dd, J=5.8, 4.2Hz, 2H), 3.74 (t, J=5.0Hz, 2H).

Example 6: Synthesis of 4-(4-chlorophenyl)-3-morpholinone

Add 1.98g (0.01mol) of 4-(4-chlorophenyl)morpholine and 20ml of acetone into a 100ml reaction flask, heat it to 20°C, and in the presence of CO ₂ , add 5.65g (0.05mol) of submers dissolved in 8.35g of water. Sodium chlorate is prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 2.5 hours. After the reaction is completed, add 6.3g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a light yellow solid, add 50 ml of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 1.81 g of 4-(4-chlorophenyl)-3-morpholinone, yield 85.4%, HPLC purity 98.1%.

¹ HNMR (CDCl ₃ , 400MHz): δ7.43-7.32(m, 2H), 7.32-7.26(m, 2H), 4.34(s, 2H), 4.07-4.00(m, 2H), 3.79-3.71(m ,2H).

Example 7: Synthesis of 4-(2-nitro-4-cyanophenyl)-3-morpholinone

Add 2.33g (0.0lmol) of 4-(2-nitro-4-cyanophenyl)morpholine and 35ml of propionitrile to a 100ml reaction flask, heat it to 55°C, and in the presence of _CO2 , dissolve 14.16g of water 4.51g (0.04mol) sodium chlorite was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 6 hours. After the reaction is completed, add 4.2g of sodium bisulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid. Add 30 ml of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 4-(2-nitro-4-cyanophenyl)-3-morpholinone. 2.42g, yield 98.0%, HPLC purity 99.1%.

¹ HNMR (CDCl ₃ , 400MHz): δ8.30 (d, J=1.9Hz, 1H), 7.97 (dd, J=8.3, 1.9Hz, 1H), 7.54 (d, J=8.3Hz, 1H), 4.33 (s, 2H), 4.12 (t, J=5.0Hz, 2H), 3.87 (s, 2H).

Example 8: Synthesis of 4-(2-nitro-4-trifluoromethylphenyl)-3-morpholinone

Add 2.76g (0.01mol) of 4-(2-nitro-4-trifluoromethylphenyl)morpholine and 40ml of butyronitrile to a 100ml reaction flask, heat it to 65°C, and dissolve 14.16g of it in the presence of _CO2 4.51g (0.04mol) sodium chlorite in water was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 4 hours. After the reaction is completed, add 4.2g of sodium bisulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a light yellow solid. Add 20 ml of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 4-(2-nitro-4-trifluoromethylphenyl)-3- Morlinone 2.85g, yield 98.3%, HPLC purity 99.1%.

¹ HNMR (CDCl ₃ , 400MHz): δ8.29 (d, J=2.0Hz, 1H), 7.96 (ddd, J=8.3, 2.0, 0.7Hz, 1H), 7.56 (dd, J=8.3, 0.9Hz, 1H), 4.33(s, 2H), 4.12(t, J=5.0Hz, 2H), 3.87(s, 2H).

Example 9: Synthesis of 4-(3-nitro-5-trifluoromethylphenyl)-3-morpholinone

Add 2.76g (0.01mol) of 4-(3-nitro-5-trifluoromethylphenyl)morpholine and 40ml of 2-methyltetrahydrofuran to a 100ml reaction flask, and heat it to 60°C. In the presence of CO ₂ , dissolve in 4.51g (0.04mol) sodium chlorite in 14.16g water was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 4.5 hours. After the reaction is completed, add 5g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a light yellow solid. Add 35 ml of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 4-(3-nitro-5-trifluoromethylphenyl)-3- Morlinone 2.82g, yield 97.2%, HPLC purity 99.1%.

1HNMR (CDCl ₃ , 400MHz): δ8.49 (s, J=2.1Hz, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 4.40 (s, 2H), 4.15-4.07 (m, 2H ), 3.91 (dd, J=5.9, 4.1Hz, 2H).

Example 10: Synthesis of 1-(4-nitrophenyl)-2-piperidone

Add 2.06g (0.01mol) of 1-(4-nitrophenyl)piperidine and 30ml of butyronitrile to a 100ml reaction flask, heat it to 55°C, and in the presence of _CO2 , dissolve 4.51g (0.04mol) of 14.16g of water. ) Sodium chlorite is prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 3 hours. After the reaction is completed, add 4.2g of sodium bisulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a light yellow solid, add 30 ml of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, dry to obtain 1.98 g of 1-(4-nitrophenyl)-2-piperidone, and collect The yield is 90.0% and the HPLC purity is 98%.

¹ HNMR (CDCl ₃ , 400MHz): δ 8.29-8.20 (m, 2H), 7.53-7.45 (m, 2H), 3.77-3.69 (m, 2H), 2.61 (t, J=6.5Hz, 2H), 2.07-1.92(m,4H).

Example 11: Synthesis of 1-(4-nitrophenyl)-2-tetrahydropyrrolidone

Add 1.92g (0.01mol) of 1-(4-nitrophenyl)tetrahydropyrrole and 30ml of methylene chloride to the 100ml reaction flask, heat it to 30°C, and in the presence of CO ₂ , dissolve 4.51g (0.01mol) of 14.16g of water. 0.04mol) sodium chlorite was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 6 hours. After the reaction is completed, add 5g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a light yellow solid, add 35 ml of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, dry to obtain 2.02 g of 1-(4-nitrophenyl)-2-tetrahydropyrrolidone, and collect The yield is 98.1% and the HPLC purity is 99.1%.

¹ HNMR (CDCl ₃ , 400MHz): δ 8.28-8.19 (m, 2H), 7.89-7.81 (m, 2H), 3.93 (t, J=7.1Hz, 2H), 2.68 (dd, J=8.6, 7.7 Hz, 2H), 2.23 (tt, J=7.8, 6.9Hz, 2H).

Example 12: Synthesis of 1-(4-nitrophenyl)-azetidin-2-one

Add 1.78g (0.01mol) of 1-(4-nitrophenyl) azetidine and 25ml of tetrahydrofuran to the 100ml reaction flask, and heat it to 45°C. In the presence of CO ₂ , dissolve 4.51g (0.04mol) of 14.16g of water. ) Sodium chlorite is prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 2.5 hours. After the reaction is completed, add 4.2g of sodium bisulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 25 ml of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 1.68g of 1-(4-nitrophenyl)-azetidin-2-one. The yield was 87.5%, and the HPLC purity was 99.1%.

¹ HNMR (CDCl ₃ , 400MHz): δ 8.30-8.22 (m, 2H), 7.51-7.43 (m, 2H), 3.76 (t, J=4.7Hz, 2H), 3.25 (t, J=4.7Hz, 2H).

Example 13: Synthesis of 1-(3-fluoro-4-bromophenyl)piperidin-2-one

Add 2.57g (0.01mol) of 1-(3-fluoro-4-bromophenyl)piperidine and 40ml of toluene into the 100ml reaction flask, heat it to 80°C, and in the presence of _CO2 , dissolve 2.26g (0.02g) of 1-(3-fluoro-4-bromophenyl)piperidine in 5g of water. mol) sodium chlorite was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 3 hours. After the reaction is completed, add 2.5g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure, add 20ml of water, extract with dichloromethane (20ml*3), combine the organic phases, and concentrate to obtain 2.33g of colorless oily substance 1-(3-fluoro-4-bromophenyl)piperidin-2-one. The yield was 85.7%, and the HPLC purity was 99.3%.

¹ HNMR (CDCl ₃ , 400MHz): δ7.55 (t, J=8.1Hz, 1H), 7.16-7.09 (m, 1H), 6.99 (dd, J=8.5, 2.3Hz, 1H), 3.64 (t, J＝5.5Hz, 2H), 2.57(t, J＝6.3Hz, 2H), 2.03-1.88(m, 4H).

Example 14: Synthesis of 1-(4-trifluoromethylphenyl)piperidin-2-one

Add 2.29g (0.01mol) of 1-(4-trifluoromethylphenyl)piperidine and 40ml of propionitrile to the 100ml reaction flask, heat it to 65°C, and in the presence of CO ₂ , dissolve 3.38g (0.01mol) of 10.62g of water. 0.03mol) sodium chlorite was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 1.5 hours. After the reaction is completed, add 3.8g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 60 ml of water, stir for 20 minutes, filter and dry to obtain 2.17g of white solid 1-(4-trifluoromethylphenyl)piperidin-2-one, yield 89.3%, HPLC Purity 99.6%.

¹ HNMR (CDCl ₃ , 400MHz): δ7.66 (t, J=8.3Hz, 2H), 7.42 (d, J=8.2Hz, 2H), 3.69 (t, J=5.5Hz, 2H), 2.60 (t , J=6.3Hz, 2H), 2.00 (ddt, J=11.7, 8.54.5Hz, 4H).

Example 15: Synthesis of 4-(3-nitrophenyl)-3-morpholinone

Add 2.08g (0.01mol) of 4-(3-nitrophenyl)morpholine and 20ml of dihydromethane into the 100ml reaction flask, heat it to 30°C, and in the presence of _CO2 , dissolve 4.51g (0.04 mol) sodium chlorite was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 5 hours. After the reaction is completed, add 5g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 25 ml of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 2.01 g of 4-(3-nitrophenyl)-3-morpholinone as a yellow solid. The yield was 90.5%, and the HPLC purity was 99.7%.

¹ HNMR (CDCl ₃ , 400MHz): δ8.27 (t, J=2.2Hz, 1H), 8.16 (ddd, J=8.2, 2.2, 1.0Hz, 1H), 7.82 (ddd, J=8.1, 2.1, 1.0 Hz, 1H), 7.62 (t, J=8.1Hz, 1H), 4.40 (s, 2H), 4.11 (dd, J=5.9, 4.1Hz, 2H), 3.88 (dd, J=5.9, 4.1Hz, 2H ).

Example 16: Synthesis of 4-(pyridin-2-yl)-3-morpholinone

Add 1.64g (0.01mol) of 4-(pyridin-2-yl)morpholinone and 25ml of dioxane to the 100ml reaction flask, heat it to 40°C, and in the presence of _CO2 , dissolve 4.51g ( 0.04mol) sodium chlorite was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 5.5 hours. After the reaction is completed, add 5g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 35 ml of water, stir for 20 minutes, filter, and dry to obtain 1.52 g of white solid 4-(pyridin-2-yl)-3-morpholinone, yield 85.4%, HPLC purity 99.6% .

¹ HNMR (CDCl ₃ , 400MHz): δ8.44 (dd, J=5.0, 1.9Hz, 1H), 8.11 (dt, J=8.3, 1.0Hz, 1H), 7.73 (ddd, J=8.4, 7.3, 2.0 Hz, 1H), 7.13 (ddd, J=7.3, 4.9, 1.0Hz, 1H), 4.37 (s, 2H), 4.16-4.09 (m, 2H), 4.09-4.02 (m, 2H).

Example 17: Synthesis of 4-(4-nitrobenzyl)-3-morpholinone

Add 2.22g (0.01mol) of 4-(4-nitrobenzyl)morpholine and 20ml of 2-methyltetrahydrofuran to the 100ml reaction flask, heat it to 50°C, and in the presence of _CO2 , dissolve 3.38g of 10.62g of water. (0.03mol) sodium chlorite was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 5 hours. After the reaction is completed, add 3.8g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 25 ml of water, stir for 20 minutes, and concentrate under reduced pressure to obtain 2.04 g of light yellow solid 4-(4-nitrobenzyl)-3-morpholinone, yield 86.4%, HPLC Purity 98.3%.

¹ HNMR (CDCl ₃ , 400MHz): δ8.24 (dd, J=9.0, 2.1Hz, 2H), 7.51-7.44 (m, 2H), 4.74 (s, 2H), 4.30 (s, 2H), 3.95- 3.87 (m, 2H), 3.35 (dd, J=5.9, 4.4Hz, 2H).

Example 18: Synthesis of 1-(2-methylphenyl)piperidin-2-one

Add 1.75g (0.01mol) of 1-(2-methylphenyl)piperidine and 25ml of acetone into the 100ml reaction flask, heat it to 30°C, and in the presence of CO ₂ , dissolve 4.51g (0.04mol) in 14.16g of water. Sodium chlorite is prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 4.5 hours. After the reaction is completed, add 5g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 30 ml of water, stir for 20 minutes, filter and dry to obtain 1.66g of white solid 1-(2-methylphenyl)piperidin-2-one, yield 87.8%, HPLC purity 99.3 %.

¹ HNMR (CDCl ₃ , 400MHz): δ7.32-7.29 (m, 1H), 7.27-7.22 (m, 2H), 7.15-7.10 (m, 1H), 4.66-4.57 (m, 2H), 2.48-2.36 (m, 4H), 2.26 (s, 3H), 1.96 (m, 2H).

Example 19: Synthesis of 4-(3-nitrophenyl)-3-morpholinone

Add 2.08g (0.01mol) of 4-(3-nitrophenyl)morpholine and 20mL of methylene chloride into the 100mL reaction flask, raise the temperature to 30°C, pass CO ₂ into the system, and at the same time dissolve 14.16g of water. 4.51g (0.04mol) sodium chlorite was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the flow of CO ₂ is stopped and the reaction is continued for about 5 hours. After the reaction is completed, add 5g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 25 mL of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 2.05 g of 4-(3-nitrophenyl)-3-morpholinone as a yellow solid. The yield was 92.3%, and the HPLC purity was 99.7%.

Example 20: Synthesis of 4-(3-nitrophenyl)-3-morpholinone

Add 2.08g (0.01mol) of 4-(3-nitrophenyl)morpholine and 20mL of methylene chloride into the 100mL reaction flask, raise the temperature to 30°C, introduce CO ₂ into the system, and at the same time, dissolve 14.16g of water into the reaction flask. 4.51g (0.04mol) sodium chlorite was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the flow of CO ₂ is stopped, and the reaction is continued for about 5 hours, during which time CO ₂ is flowed in intermittently. After the reaction is completed, add 5g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 25 mL of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 2.03 g of 4-(3-nitrophenyl)-3-morpholinone as a yellow solid. The yield was 91.4%, and the HPLC purity was 99.6%.

Comparative Example 1: Synthesis of 4-(3-nitrophenyl)-3-morpholinone

Compared with Example 15, no catalyst CO ₂ was added.

Add 2.08g (0.01mol) of 4-(3-nitrophenyl)morpholine and 20mL of methylene chloride into a 100mL reaction flask, heat it to 30°C, and dissolve 4.51g (0.04mol) of chlorous acid in 14.16g of water. Sodium is prepared into an aqueous solution and added dropwise to the reaction system. After the dropping is completed and the reaction is continued for about 8 hours, 5g of sodium sulfite is added and stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 25 mL of water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 0.81 g of 4-(3-nitrophenyl)-3-morpholinone as a yellow solid. The yield is 36.47%, and the HPLC purity is 20.8%.

Comparative Example 2: Synthesis of 4-(pyridin-2-yl)-3-morpholinone

Compared with Example 16, the catalyst was changed from CO ₂ to formic acid.

Add 1.64g (0.01mol) of 4-(pyridin-2-yl)morpholinone, 25mL of dioxane, and 0.27g of formic acid (0.006mol) into a 100mL reaction flask, heat it to 40°C, and dissolve the 4.51g (0.04mol) sodium chlorite was prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction continues for about 6 hours. After the reaction is completed, add 5g of sodium sulfite and stir at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 35 mL of water, stir for 20 minutes, filter, and dry to obtain 1.42 g of white solid 4-(pyridin-2-yl)-3-morpholinone, yield 79.8%, HPLC purity 91.6% .

Comparative Example 3: Synthesis of 4-(3-nitrophenyl)-3-morpholinone

Amplified according to CN201911264060.3.

Add 104g (0.5mol) of 4-(3-nitrophenyl)morpholine, 234g of sodium dihydrogen phosphate dihydrate, and 3L of acetonitrile into the reaction kettle, heat it to 40°C, and add 169g of 80% chlorous acid dissolved in 650g of water. Sodium is prepared into an aqueous solution and added dropwise to the reaction system. After the dripping is completed, the reaction is continued for about 6 hours, and the reaction is monitored by HPLC. After the reaction is completed, let stand and separate the layers. Collect the organic layer. Add 700 mL of ethyl acetate to the aqueous layer and extract twice. Combine the organic layers and place in a cold water bath. Add about 1 L of saturated sodium sulfite aqueous solution and stir for 10 minutes. Add 500 mL of aqueous layer. Extract twice with ethyl acetate, combine the organic phases again, add anhydrous sodium sulfate to dry, and concentrate under reduced pressure to obtain a yellow solid. Add 240 mL of mixed solvent (petroleum ether: ethyl acetate = 5:1 (V: V)). Stir for 20 minutes and process to obtain 106g of yellow solid, with a yield of 95.9%, an HPLC purity of 95.7%, about 3.1% of raw materials, and a maximum impurity of 1.1%. When reacting for 6 hours, the purity of the reaction solution was 83.8%, the raw material was about 5.11%, and the maximum impurity was 2.6%.

Claims (6)

1. The synthesis method of the lactam compound is characterized in that sodium chlorite is used as an oxidant, and the cyclic amine compound shown in the formula II is oxidized into the lactam compound shown in the formula I under the catalysis of carbon dioxide:

wherein the method comprises the steps of

When n=0 or 1, X is CH ₂ ，

When n=2, X is O or CH ₂ ；

R is selected from phenyl, benzyl, pyridyl, said phenyl and benzyl optionally being substituted with one or moreA plurality of compounds selected from hydrogen, halogen, nitro, trifluoromethyl, cyano, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Acyl, C ₁ -C ₆ The substituent of the alkoxy group is substituted.

2. The method of claim 1, wherein the molar ratio of cyclic amine compound to oxidizer sodium chlorite is 1:1 to 1:10.

3. the method of claim 2, wherein the molar ratio of cyclic amine compound to oxidizer sodium chlorite is 1: 2-1: 6.

4. the synthesis according to claim 1, wherein the reaction temperature is 0 to 100 ℃.

5. The method according to claim 4, wherein the reaction temperature is 20 to 80 ℃.

6. The method according to claim 1, wherein the solvent is aprotic solvent selected from the group consisting of nitrile solvents, ether solvents, toluene, acetone, and methylene chloride.