Process for the preparation of asymmetric disubstituted amides

Abstract

This invention provides a method for preparing asymmetric disubstituted amides, comprising the following steps: (1) a primary amine compound of formula I undergoes a condensation reaction with a carboxylic acid or carboxylic acid ester compound of formula II to obtain a compound of formula III; (2) a compound of formula III reacts with an alkylating agent to obtain a compound of formula IV. This invention synthesizes asymmetric disubstituted amides with high product purity, high yield, and good product quality. The raw materials used in the synthesis route are inexpensive and readily available, avoiding the use of expensive secondary asymmetric amines. The route is suitable for industrial production and has versatility, solving the problem of high prices and scarce supply of secondary asymmetric amines in the current market. All reactions in this invention are carried out at mild temperatures, are safe and controllable, and do not involve the use of flammable or explosive hazardous chemicals, making it more valuable for industrial applications.

Description

Technical Field

[0001] This invention belongs to the field of organic compound preparation technology, and specifically relates to a method for preparing asymmetric disubstituted amides. Background Technology

[0002] Asymmetric disubstituted amides are an important class of chemical intermediates, widely used in the synthesis of pharmaceutical and pesticide compounds.

[0003] Taisho Pharmaceutical Co., Ltd. disclosed a series of amidine compounds and salts in CN103797000, which have a special effect on killing fungi that cause deep-seated infections in the human body. Their synthesis requires an asymmetric disubstituted amide as an intermediate, and their general structural formula is as follows:

[0004]

[0005] Syngenta disclosed a series of phenylamidine derivative fungicides in CN110461156, which have very high activity in improving pesticide safety, reducing crop phytotoxicity, and combating, preventing and controlling plant pathogenic diseases. These fungicides require an asymmetric disubstituted amide as an intermediate, and their general structural formula is as follows:

[0006]

[0007] Taihe Group invented a class of pyrazole ether compounds in CN116003322A, which have significant effects on the prevention and control of diseases in agriculture and forestry, especially on cucumber powdery mildew, cucumber downy mildew, soybean rust, and wheat scab. An asymmetric disubstituted amide is an important intermediate in this process, and its general formula is as follows:

[0008]

[0009] Syngenta also disclosed a class of amidine-substituted benzoic acid amides in WO2021175822, which exhibit good activity as insecticides against nematode pests, especially those in the orders Hemiptera, Lepidoptera, Arachnida, Glandularia, and Cryptorchidia. The synthesis of this class of insecticides is inseparable from the intermediate asymmetric disubstituted amide, whose general formula is as follows:

[0010]

[0011] It is evident that asymmetric disubstituted amides have important applications in pharmaceuticals, agricultural applications, and the creation of highly active compounds. Currently, the commonly used preparation methods for asymmetric disubstituted amides all use asymmetric secondary amines as starting materials, which are condensed with carboxylic acids or carboxylic esters. The asymmetric secondary amines required by this method are generally not commodities and are expensive. Asymmetric secondary amines with slightly complex substituent group structures may even lack procurement channels.

[0012] For example, WO2012146125 and WO2013018735 disclose methods for preparing N-ethyl-N-methylformamide, which involves the condensation of methyl ethylamine with formic acid or formate ester. The raw material methyl ethylamine is not produced on a large scale and is currently only available in reagent grade, priced as high as 3590 yuan / kg (based on recent transactions by Qianyan Chemical). ,https: / / www.biochemsafebuy.com), The large-scale production of downstream products is severely limited. For the synthesis of N-ethyl-N-methylformamide, the reported yield of the amino transesterification method is generally around 90%, while the yield of the carboxylic acid dehydration method is lower, only around 80%, due to the decomposition of the ammonium carboxylate salt. Overall, the yield is low. The specific route is as follows:

[0013]

[0014] The existing synthetic route for the intermediate methyl ethylamine is also quite complex. Generally, it involves the dehydration of methylamine with formaldehyde to obtain an imine, followed by hydrogenation reduction with a noble metal catalyst to obtain methyl ethylamine, as shown in the following route:

[0015]

[0016] This route involves a hydrogenation reduction reaction with high safety risks, and the use of precious metal catalysts also keeps the cost high. According to reports in literature such as DE4230402 and WO2010001055, the yield is unstable, ranging from 47% to 93%. It can be seen that the existing synthetic route of methyl ethylamine is not an ideal route for industrialization.

[0017] Existing routes for the synthesis of asymmetric disubstituted amides have the following common problems: low reaction yield, expensive and scarce asymmetric secondary amines used as raw materials, high difficulty in synthesis, and high reaction safety risks. Therefore, it is essential to develop new technologies and methods for the synthesis of asymmetric disubstituted formamides. Summary of the Invention

[0018] In view of the shortcomings of the prior art, the purpose of this invention is to provide a method for preparing asymmetric disubstituted amides.

[0019] To achieve this objective, the present invention adopts the following technical solution:

[0020] On one hand, the present invention provides a method for preparing an asymmetric disubstituted amide, the method comprising the following steps:

[0021] (1) The primary amine compound shown in Formula I undergoes a condensation reaction with the carboxylic acid or carboxylic acid ester compound shown in Formula II to obtain the compound shown in Formula III, as shown in the following reaction formula:

[0022]

[0023] (2) The compound shown in Formula III reacts with an alkylating agent to give the compound shown in Formula IV; the reaction formula is as follows:

[0024]

[0025] R1 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl and C3-C8 halocycloalkyl; R2 is selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 halocycloalkyl, C6-C20 aryl or haloC6-C20 aryl; R3 is selected from hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl.

[0026] In this invention, asymmetric disubstituted amides are prepared by reacting a primary amine compound with a compound containing a carboxyl or ester group, followed by alkylation. The product of this invention has high purity, high yield, and good product quality. The raw materials used in this synthetic route are inexpensive and readily available, avoiding the use of expensive secondary asymmetric amines. For example, the price of 70% ethylamine aqueous solution used in this route is 7900 yuan / ton, chloromethane is 2000 yuan / ton, and sodium hydroxide is 3000 yuan / ton (related quotations are obtained from recent price quotes on Business Society). ,https: / / www.100ppi.com), Methyl formate is a byproduct of our company's pyraclostrobin project, with a total comprehensive cost of approximately RMB 15,000 per ton. In contrast, the existing technology uses methyl ethylamine, a more expensive raw material, with a synthesis cost of approximately RMB 2.72 million per ton for N-ethyl-N-methylformamide, far exceeding the cost of this route. Therefore, this route is suitable for industrial production and possesses versatility, solving the current market problem of high prices and scarce supply of asymmetric secondary amines. The reaction in this invention is mild, safe, and controllable, without the use of flammable or explosive hazardous chemicals, making it more valuable for industrial applications.

[0027] As used in this invention, the term "C1-C6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms, and non-limitingly includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, n-hexyl, etc. The term "C3-C8 cycloalkyl" as used in this invention refers to a cyclic alkyl group having 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms on a ring, and non-limitingly includes cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. As used in this invention, the term "C1-C6 haloalkyl" refers to a straight-chain or branched alkyl group having 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms substituted with at least one halogen. This term, without limitation, includes halogenated methyl, halogenated ethyl, halogenated n-propyl, halogenated isopropyl, halogenated n-butyl, halogenated isobutyl, halogenated sec-butyl, halogenated n-pentyl, halogenated isopentyl, and halogenated n-hexyl, wherein the halogen can be F, Cl, Br, or I. The term "C3-C8 halocycloalkyl" as used in this invention refers to a cyclic alkyl group having 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms on the ring substituted with at least one halogen. This term, without limitation, includes halogenated cyclopropyl, halogenated cyclopropylmethyl, halogenated cyclobutyl, halogenated cyclopentyl, and halogenated cyclohexyl.

[0028] Preferably, the primary amine compound represented by Formula I is selected from methylamine, ethylamine, isopropylamine, cyclopropylamine, or cyclopropylmethylamine.

[0029] Preferably, the carboxylic acid or carboxylic acid ester compound represented by Formula II is selected from formic acid, acetic acid, methyl formate, ethyl formate, methyl acetate, ethyl acetate, benzoic acid, 4-halobenzoic acid, 2-methyl-4-fluorobenzoic acid, 2-methyl-4-fluoro-5-acetaminobenzoic acid, benzoic acid ester, 4-halobenzoic acid ester, 2-methyl-4-fluorobenzoic acid ester or 2-methyl-4-fluoro-5-acetaminobenzoic acid ester.

[0030] Preferably, the molar ratio of the primary amine compound of Formula I to the carboxylic acid or carboxylic acid ester compound of Formula II in step (1) is 1:(0.8 to 2.0), for example, it can be 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.0, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, and it is further preferred to be 1:1.1.

[0031] In this invention, the mixing method of the primary amine compound shown in Formula I and the carboxylic acid or carboxylic acid ester compound shown in Formula II in step (1) is to add Formula I dropwise to Formula II, or add Formula II dropwise to Formula I, or add Formula I and Formula II dropwise simultaneously, or feed them in one pot. More preferably, Formula I is added dropwise to Formula II.

[0032] Preferably, when Formula II is a carboxylic acid, the solvent for the condensation reaction is an organic solvent that can be refluxed to remove water. Preferably, the organic solvent that can be refluxed to remove water is selected from any one or a combination of at least two of aromatic hydrocarbons, alkanes, or ester solvents. More preferably, it is toluene, xylene, butyl acetate, dichloroethane, or o-dichlorobenzene. Toluene is even more preferred.

[0033] Preferably, when Formula II is a carboxylic acid, the condensation reaction requires a water separation device and the use of an organic solvent for reflux to remove water.

[0034] Preferably, when Formula II is a carboxylic acid, the temperature of the condensation reaction is 70℃~140℃ (e.g. 70℃, 80℃, 90℃, 100℃, 110℃, 120℃, 130℃ or 140℃), depending on the aqueous solvent. If necessary, dehydration under pressure or negative pressure can be selected. More preferably, toluene is refluxed under normal pressure to remove water at a temperature of 85-110℃.

[0035] Preferably, when Formula II is a carboxylic acid, the condensation reaction time is 0.5 to 5 hours, for example 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours or 5 hours, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, and 3 hours is further preferred.

[0036] Preferably, when Formula II is a carboxylic acid ester, the solvent for the condensation reaction is water or an organic solvent, or no solvent is used.

[0037] Preferably, when Formula II is a carboxylic acid ester, the solvent for the condensation reaction is any one or a combination of at least two of the following solvents: water, aromatic hydrocarbons, alkanes, alcohols, nitrile solvents, ethers, or amides. More preferably, it is any one or a combination of at least two of the following solvents: toluene, xylene, methanol, ethanol, methyl tert-butyl ether, dichloroethane, dichloromethane, acetonitrile, or DMF.

[0038] Preferably, when Formula II is a carboxylic acid ester, the temperature of the condensation reaction is 0℃ to 100℃, for example, 0℃, 10℃, 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃ or 100℃, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, but it is further preferred to be 20-30℃.

[0039] Preferably, when Formula II is a carboxylic acid ester, the condensation reaction time is 0.5 to 5 hours, for example 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours or 5 hours, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, and 2 hours is further preferred.

[0040] Preferably, the alkylating agent in step (2) is selected from haloalkanes or alkyl sulfate esters.

[0041] Preferably, the alkylating agent is selected from any one or a combination of at least two of iodomethane, bromomethane, chloromethane, iodoethane, bromoethane, chloroethane, dimethyl sulfate, or diethyl sulfate.

[0042] Preferably, the molar ratio of the compound represented by Formula III in step (2) to the alkylating agent is 1:(1.0 to 3.0), for example, it can be 1:1.0, 1:1.2, 1:1.5, 1:1.8, 1:2.0, 1:2.2, 1:2.5, 1:2.8, 1:3.0, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, and it is further preferred to be 1:1.5.

[0043] Preferably, the reaction in step (2) is carried out in the presence of an alkaline substance.

[0044] Preferably, the alkaline substance is selected from any one or a combination of at least two of sodium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, or sodium bicarbonate, and more preferably sodium hydroxide.

[0045] Preferably, the molar ratio of the compound shown in Formula III to the alkaline substance is 1:(1.0 to 3.0), for example, it can be 1:1.00, 1:1.25, 1:1.50, 1:1.85, 1:2.00, 1:2.25, 1:2.50, 1:2.80, 1:3.00, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, and it is further preferred to be 1:1.25.

[0046] Preferably, the temperature of the reaction in step (2) is -10℃ to 30℃, for example -10℃, -5℃, -0℃, 5℃, 10℃, 15℃, 20℃, 25℃ or 30℃, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 20℃.

[0047] Preferably, the reaction time in step (2) is 1 to 16 hours, for example 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours or 16 hours, and specific values ​​between the above-mentioned values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, but it is more preferably 6 to 10 hours.

[0048] Preferably, the reaction in step (2) is carried out in an organic solvent.

[0049] Preferably, the organic solvent is selected from any one or a combination of at least two of aromatic hydrocarbons, alkanes, amides, sulfoxides, ethers, ketones, nitriles, or alcohols. More preferably, it is selected from any one or a combination of at least two of toluene, acetonitrile, dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, methyl tert-butyl ether, methyl isobutyl ketone, tert-butanol, sulfolane, N-ethyl-N-methylformamide, or N-ethylformamide. More preferably, it is selected from any one or a combination of at least two of DMF, acetonitrile, or tert-butanol.

[0050] Preferably, the mass ratio of the compound shown in Formula III to the organic solvent is 1:(1.0 to 3.0), for example, it can be 1:1.0, 1:1.25, 1:1.50, 1:1.85, 1:2.0, 1:2.25, 1:2.50, 1:2.80, 1:3.0, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, and it is further preferred to be 1:2.0.

[0051] In this invention, when the alkylating agent is a gas, such as bromomethane or chloromethane, the reaction described in step (2) needs to be carried out in a high-pressure reactor.

[0052] Preferably, after the reaction in step (2) is completed, a post-processing procedure for the product is also included.

[0053] Preferably, the post-processing method includes: filtering the reaction solution after the reaction is complete, washing the filter cake with toluene, combining the washing liquid and the filtrate, distilling the combined solution, and collecting the corresponding fraction, which is the product, the asymmetric disubstituted amide.

[0054] In this invention, as a preferred technical solution, the preparation method includes the following steps:

[0055] (1) The primary amine compound shown in Formula I undergoes a condensation reaction with the carboxylic acid or carboxylic acid ester compound shown in Formula II to obtain the compound shown in Formula III; the primary amine compound shown in Formula I is selected from methylamine, ethylamine, isopropylamine, cyclopropylamine, or cyclopropylmethylamine; the carboxylic acid or carboxylic acid ester compound shown in Formula II is selected from formic acid, acetic acid, methyl formate, ethyl formate, methyl acetate, ethyl acetate, benzoic acid, 4-halobenzoic acid, 2-methyl-4-fluorobenzoic acid, 2-methyl-4-fluoro-5-acetaminobenzoic acid, benzoic acid ester, 4-halobenzoic acid, ethyl benzoic acid ester ... The benzoate, 2-methyl-4-fluorobenzoate or 2-methyl-4-fluoro-5-acetaminobenzoate, wherein the molar ratio of the primary amine compound of formula I to the carboxylic acid or carboxylic acid ester compound of formula II in step (1) is 1:(0.8 to 2.0), and when formula II is a carboxylic acid, the temperature of the condensation reaction is 70℃ to 140℃ and the time of the condensation reaction is 0.5 to 5h; when formula II is a carboxylic acid ester, the temperature of the condensation reaction is 0℃ to 100℃ and the time of the condensation reaction is 0.5 to 5h.

[0056] (2) The compound shown in Formula III reacts with the alkylating agent in an organic solvent in the presence of an alkaline substance at -10℃ to 30℃ for 1 to 16 h to obtain the compound shown in Formula IV.

[0057] The alkylating agent is selected from haloalkanes or alkyl sulfates; the basic substance is selected from any one or a combination of at least two of sodium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, or sodium bicarbonate; the organic solvent is selected from any one or a combination of at least two of toluene, acetonitrile, dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, methyl tert-methyl ether, methyl isobutyl ketone, tert-butanol, sulfolane, N-ethyl-N-methylformamide, or N-ethylformamide; the molar ratio of the compound of Formula III to the alkylating agent is 1:(1.0–3.0); the molar ratio of the compound of Formula III to the basic substance is 1:(1.0–3.0); and the mass ratio of the compound of Formula III to the organic solvent is 1:(1.0–3.0).

[0058] Compared with the prior art, the present invention has the following beneficial effects:

[0059] The method for preparing asymmetric disubstituted amides provided by this invention avoids the use of expensive and scarce asymmetric secondary amines. It utilizes inexpensive and readily available raw materials, employs mild reaction temperatures, and avoids the use of flammable or explosive hazardous chemicals, ensuring high safety. The resulting product exhibits high yield and purity, making it an extremely suitable method for the long-term, stable, safe, and economical industrial production of asymmetric disubstituted amides. Taking N-ethyl-N-methylformamide as an example, the two-step reaction yield is greater than 95%, and the purity, as determined by HPLC external standard method, is greater than 99.0%. Detailed Implementation

[0060] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0061] In the following specific embodiments of the present invention, all raw materials for which preparation methods are not provided were purchased from the market; the reaction conversion rate was determined by gas chromatography (GC) normalization method, the purity (content) of the product was determined by HPLC external standard method, and all yields were mass yields. The molecular structure of the product was determined by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) and / or nuclear magnetic resonance (NMR) spectroscopy. 1 Characterized and confirmed by H-NMR.

[0062] Example 1: Synthesis of N-ethyl-N-methylformamide

[0063]

[0064] Add 135.2 g of ethylamine aqueous solution (50%, 1.50 mol) to the reaction vessel, start stirring, and slowly add 104.3 g of methyl formate (95%, 1.65 mol) dropwise over 3 hours, keeping the temperature below 30°C. After the addition is complete, maintain the temperature for another 3 hours. After the reaction is complete, distill at a negative pressure of 35 kPa to remove low-boiling-point substances. Stop distillation when the vessel temperature reaches 110°C. The resulting pale yellow oily substance in the vessel is N-ethylformamide, with a mass of 111.8 g, a purity of 97.4%, and a yield of 99.3%.

[0065] 75.0 g of synthesized N-ethylformamide (97.4%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of acetonitrile and 52.6 g of sodium hydroxide solid (95%, 1.25 mol). After closing the reactor, 76.5 g of chloromethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-ethylformamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washings and filtrates were combined, and the combined solution was distilled. First, the acetonitrile was recovered by distillation under normal pressure for use in the reaction and for salt washing. Then, the solution was distilled under negative pressure (6 kPa, 74-76 °C) to obtain 84.6 g of N-ethyl-N-methylformamide, with a quantitative content of 99.1% and a yield of 96.2%. GC-MS (m / z): 87; theoretical value: 87. 1 H-NMR (CDCl3, 400MHZ) δ (ppm): 1.127 (t, J=7.2Hz, 3H, CH3 CH2); 2.918 (m, 2H, CH3) CH2 ); 3.347 (s, 3H, CH3); 9.952 (s, 1H, COH).

[0066] Example 2: Synthesis of N-ethyl-N-methylformamide

[0067]

[0068] 135.2 g of ethylamine aqueous solution (50%, 1.50 mol) and 150 g of toluene were added to the reaction vessel. Stirring was started, and 86.3 g of formic acid aqueous solution (88%, 1.65 mol) was added dropwise over 30 min. After the addition was complete, the mixture was heated and refluxed to separate the water. The reaction was stopped when no obvious water separation occurred. The total reaction time was 3 h. After the reaction was complete, the mixture was distilled under negative pressure (35 kPa) to remove low-boiling-point substances. Distillation was stopped when the vessel temperature reached 110 °C. The resulting pale yellow oily substance in the vessel was N-ethylformamide, with a mass of 109.2 g, a purity of 95.5%, and a yield of 95.1%.

[0069] 76.5 g of synthesized N-ethylformamide (95.5%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of acetonitrile and 73.8 g of potassium hydroxide solid (95%, 1.25 mol). After closing the reactor, 76.5 g of chloromethane gas (99%, 1.50 mol) was introduced, and the reaction was maintained at a temperature below 20 °C for 6 hours. The reaction was stopped when the N-ethylformamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washing liquid and filtrate were combined, and the combined solution was distilled. First, the acetonitrile was recovered by distillation under normal pressure for use in the reaction and for washing salts. Then, the solution was distilled under negative pressure (6 kPa, 74-76 °C) to obtain 85.0 g of N-ethyl-N-methylformamide, with a quantitative content of 98.9% and a yield of 96.5%.

[0070] Example 3: Synthesis of N-ethyl-N-methylformamide

[0071]

[0072] Add 93.2 g of methylamine aqueous solution (50%, 1.50 mol) and 150 g of toluene to the reaction vessel, start stirring, and add 86.3 g of formic acid aqueous solution (88%, 1.65 mol) dropwise over 30 min. After the addition is complete, heat and reflux to separate water until no obvious water is separated, then stop the reaction. The total reaction time is 3 h. After the reaction is complete, distill at a negative pressure of 35 kPa to remove low-boiling substances. Stop distillation when the vessel temperature reaches 110 °C. The pale yellow oily substance in the vessel is N-methylformamide, with a mass of 87.0 g, a purity of 96.2%, and a yield of 94.5%.

[0073] 61.4 g of synthesized N-methylformamide (96.2%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of acetonitrile and 52.6 g of sodium hydroxide solid (95%, 1.25 mol). After closing the reactor, 97.7 g of monochloroethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-methylformamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washing liquid and filtrate were combined, and the combined solution was distilled. First, the acetonitrile was recovered by distillation under normal pressure for use in the reaction and for salt washing. Then, the solution was distilled under negative pressure (6 kPa, 74-76 °C) to obtain 85.4 g of N-ethyl-N-methylformamide with a quantitative content of 99.1% and a yield of 97.1%.

[0074] Example 4: Synthesis of N-methyl-N-cyclopropylformamide

[0075]

[0076] Add 171.3 g of cyclopropylamine aqueous solution (50%, 1.50 mol) to the reaction vessel, start stirring, and slowly add 104.3 g of methyl formate (95%, 1.65 mol) dropwise over 3 hours, keeping the temperature below 30°C. After the addition is complete, maintain the temperature for another 3 hours. After the reaction is complete, distill at a negative pressure of 10 kPa to remove low-boiling-point substances. Stop distillation when the vessel temperature reaches 110°C. The resulting pale yellow oily substance in the vessel is N-cyclopropylformamide, weighing 132.2 g, with a purity of 95.4% and a yield of 98.8%.

[0077] 89.2 g of synthesized N-cyclopropylformamide (95.4%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of DMF and 52.6 g of sodium hydroxide solid (95%, 1.25 mol). After closing the reactor, 76.5 g of chloromethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-cyclopropylformamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of DMF. The washings and filtrates were combined, and the combined solution was distilled. First, DMF was recovered by distillation under normal pressure for use in the reaction and for salt washing. Then, N-pressure distillation (3 kPa, 99-101 °C) was performed to obtain 96.9 g of N-methyl-N-cyclopropylformamide, with a quantitative content of 98.8% and a yield of 96.6%. GC-MS (m / z): 99; theoretical value: 99. 1 H-NMR (CDCl3, 400MHZ) δ (ppm): 0.097 (m, 2H, CH2); 0.432 (m, 2H, CH2); 2.543 (m, 1H, CH); 3.352 (s, 3H, CH3); 9.957 (s, 1H, COH).

[0078] Example 5: Synthesis of N-ethyl-N-isopropylformamide

[0079]

[0080] Add 126.7 g of isopropylamine aqueous solution (50%, 1.50 mol) to the reaction vessel, start stirring, and slowly add 104.3 g of methyl formate (95%, 1.65 mol) dropwise over 3 hours, keeping the temperature below 30°C. After the addition is complete, maintain the temperature for another 3 hours. After the reaction is complete, distill at a negative pressure of 25 kPa to remove low-boiling-point substances. Stop distillation when the vessel temperature reaches 110°C. The resulting pale yellow oily substance in the vessel is N-isopropylformamide, weighing 133.7 g, with a purity of 96.5% and a yield of 98.7%.

[0081] 90.3 g of synthesized N-isopropylformamide (96.5%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of acetonitrile and 52.6 g of sodium hydroxide solid (95%, 1.25 mol). After closing the reactor, 97.7 g of monochloroethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-isopropylformamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washings and filtrates were combined, and the combined solution was distilled. First, the acetonitrile was recovered by distillation under normal pressure for use in the reaction and for washing salts. Then, the solution was distilled under negative pressure (5 kPa, 98-100 °C) to obtain 111.6 g of N-ethyl-N-isopropylformamide, with a quantitative content of 98.6% and a yield of 95.5%. GC-MS (m / z): 115; theoretical value: 115. 1 H-NMR (CDCl3, 400MHZ) δ (ppm): 0.875 (d, J=7.2Hz, 6H, CH3CH); 1.127 (t, J=7.2Hz, 3H, CH3CH2); 2.632 (m, 1H, CH); 2.918 (m, 2H, CH3CH2); 9.882 (s, 1H, COH).

[0082] Example 6: Synthesis of N-methyl-N-isopropylformamide

[0083]

[0084] Add 177.3 g of isopropylamine aqueous solution (50%, 1.50 mol) to the reaction vessel, start stirring, and slowly add 104.3 g of methyl formate (95%, 1.65 mol) dropwise over 3 hours, maintaining the temperature below 30°C. After the addition is complete, maintain the temperature for another 3 hours. After the reaction is complete, distill at a negative pressure of 30 kPa to remove low-boiling-point substances. Stop distillation when the vessel temperature reaches 110°C. The resulting pale yellow oily substance in the vessel is N-isopropylformamide, with a mass of 134.3 g, a purity of 96.2%, and a yield of 98.9%.

[0085] 90.6 g of synthesized N-isopropylformamide (96.2%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of acetonitrile and 52.6 g of sodium hydroxide solid (95%, 1.25 mol). After closing the reactor, 76.5 g of chloromethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-isopropylformamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washings and filtrates were combined, and the combined solution was distilled. First, the acetonitrile was recovered by distillation under normal pressure for use in the reaction and for salt washing. Then, the solution was distilled under negative pressure (6 kPa, 95-97 °C) to obtain 96.9 g of N-methyl-N-isopropylformamide, with a quantitative content of 98.9% and a yield of 94.7%. GC-MS (m / z): 101; theoretical value: 101. 1 H-NMR (CDCl3, 400MHZ) δ (ppm): 0.834 (d, J=7.2Hz, 6H, CH3 CH); 2.612 (m, 1H, CH); 3.366 (s, 3H, CH3); 9.927 (s, 1H, COH).

[0086] Example 7: Synthesis of N-methyl-N-cyclopropylmethylformamide

[0087]

[0088] 108.9 g of cyclopropylmethylamine (98%, 1.50 mol) was added to the reaction vessel, and stirring was started. Over 3 hours, 104.3 g of methyl formate (95%, 1.65 mol) was slowly added dropwise, maintaining the temperature below 30°C. After the addition was complete, the reaction was maintained at this temperature for 3 hours. After the reaction was complete, the mixture was distilled under a negative pressure of 7 kPa to remove low-boiling-point substances. Distillation was stopped when the vessel temperature reached 110°C. The resulting pale yellow oily substance in the vessel was N-cyclopropylmethylformamide, weighing 152.6 g, with a purity of 96.2% and a yield of 98.7%.

[0089] 103.1 g of synthesized N-cyclopropylmethylformamide (96.2%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of acetonitrile and 52.6 g of sodium hydroxide solid (95%, 1.25 mol). After closing the reactor, 76.5 g of chloromethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-cyclopropylmethylformamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washing liquid and filtrate were combined, and the combined solution was subjected to distillation. First, the solution was distilled at atmospheric pressure (2 kPa, 99-101 °C) to recover acetonitrile for use in the reaction and for salt washing. Then, the solution was distilled under negative pressure to obtain 108.2 g of N-methyl-N-cyclopropylmethylformamide, with a quantitative content of 99.1% and a yield of 94.8%. GC-MS (m / z): 113; Theoretical value: 113. 1 H-NMR (CDCl3, 400MHZ) δ (ppm): 0.081 (m, 2H, CH2); 0.410 (m, 2H, CH2); 1.043 (m, 1H, CH); 2.708 (d, J=8Hz, 2H, CH); 3.378 (s, 3H, CH3); 9.739 (s, 1H, COH).

[0090] Example 8: Synthesis of N-methyl-N-cyclopropylmethylacetamide

[0091]

[0092] 108.9 g of cyclopropylmethylamine (98%, 1.50 mol) was added to the reaction vessel, and stirring was started. 128.7 g of methyl formate (95%, 1.65 mol) was slowly added dropwise over 3 hours, maintaining the temperature below 30°C. After the addition was complete, the reaction was maintained at this temperature for 3 hours. After the reaction was complete, the vessel was heated under a negative pressure of 5 kPa to remove low-boiling-point substances by distillation. Distillation was stopped when the vessel temperature reached 110°C. The resulting pale yellow oily substance in the vessel was N-cyclopropylmethylformamide, weighing 150.9 g, with a purity of 96.3% and a yield of 97.7%.

[0093] 102.9 g of synthesized N-cyclopropylmethylacetamide (96.3%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of DMF and 52.6 g of sodium hydroxide solid (95%, 1.25 mol). After closing the reactor, 76.5 g of chloromethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-cyclopropylmethylacetamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of DMF. The washings and filtrates were combined, and the combined solution was distilled. First, DMF was recovered by distillation under normal pressure for use in the reaction and for salt washing. Then, the solution was distilled under negative pressure (5 kPa, 100-102 °C) to obtain 121.7 g of N-methyl-N-cyclopropylmethylacetamide, with a quantitative content of 98.8% and a yield of 94.5%. GC-MS (m / z): 127; theoretical value: 127. 1 H-NMR (CDCl3, 400MHZ) δ (ppm): 0.121 (m, 2H, CH2); 0.440 (m, 2H, CH2); 1.032 (m, 1H, CH); 2.621 (s, 3H, COCH3); 2.722 (d, J=8Hz, 2H, CH); 3.447 (s, 3H, CH3).

[0094] Example 9: Synthesis of N-methyl-N-ethylcyclopropionamide

[0095]

[0096] Add 135.2 g of ethylamine aqueous solution (50%, 1.50 mol) to the reaction vessel, start stirring, and slowly add 149.5 g of methyl cyclopropionate (95%, 1.65 mol) dropwise over 3 hours, keeping the temperature below 30°C. After the addition is complete, maintain the temperature for another 3 hours. After the reaction is complete, distill at a negative pressure of 5 kPa to remove low-boiling-point substances. Stop distillation when the vessel temperature reaches 110°C. The resulting pale yellow oily substance in the vessel is N-ethylcyclopropionamide, weighing 175.6 g, with a purity of 95.8% and a yield of 99.1%.

[0097] 118.1 g of synthesized N-ethylcyclopropaneformamide (95.8%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of acetonitrile and 52.6 g of sodium hydroxide solid (95%, 1.25 mol). After closing the reactor, 76.5 g of chloromethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-ethylcyclopropaneformamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washings and filtrates were combined, and the combined solution was distilled. First, the acetonitrile was recovered by distillation under normal pressure for use in the reaction and for salt washing. Then, the solution was distilled under negative pressure (4 kPa, 101-103 °C) to obtain 124.4 g of N-methyl-N-ethylcyclopropaneformamide, with a quantitative content of 98.7% and a yield of 96.5%. GC-MS (m / z): 127; theoretical value: 127. 1 H-NMR (CDCl3, 400MHZ) δ (ppm): 0.121 (m, 2H, CH2); 0.440 (m, 2H, CH2); 1.032 (m, 1H, CH); 2.621 (s, 3H, COCH3); 2.722 (d, J=8Hz, 2H, CH); 3.447 (s, 3H, CH3).

[0098] Example 10: Synthesis of N-methyl-N-ethyl-p-chlorobenzamide

[0099]

[0100] Add 135.2 g of ethylamine aqueous solution (50%, 1.50 mol) to the reaction vessel, start stirring, and slowly add 296.3 g of methyl p-chlorobenzoate (95%, 1.65 mol) dropwise over 3 hours, keeping the temperature below 30°C. After the addition is complete, maintain the temperature for another 3 hours. After the reaction is complete, distill at a negative pressure of 4 kPa to remove low-boiling-point substances. Stop distillation when the vessel temperature reaches 110°C. The resulting pale yellow oily substance in the vessel is N-ethyl-p-chlorobenzamide, with a mass of 281.4 g, a purity of 96.7%, and a yield of 98.8%.

[0101] 189.9 g of synthesized N-ethyl-p-chlorobenzamide (96.7%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of acetonitrile and 52.6 g of sodium hydroxide solid (95%, 1.25 mol). After closing the reactor, 76.5 g of chloromethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-ethyl-p-chlorobenzamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washings and filtrates were combined, and the combined solution was distilled. First, the acetonitrile was recovered by atmospheric distillation for use in the reaction and for salt washing. Then, the solution was distilled under negative pressure (0.3 kPa, 126-128 °C) to obtain 191.1 g of N-methyl-N-ethyl-p-chlorobenzamide with a quantitative content of 99.0% and a yield of 95.7%. UHPLC-MS (m / z, ESI): 198.0683 (M+H)+; Theoretical value: 198.0680. 1 H-NMR (CDCl3, 400MHZ) δ (ppm): 1.127 (t, J=7.2Hz, 3H, CH3CH2); 2.918 (m, 2H, CH3C H2); 3.347 (s, 3H, CH3); 7.512 (d, J=8.8Hz, 2H, ArH); 7.744 (d, J=8.8Hz, 2H, ArH).

[0102] Example 11: Synthesis of N-methyl-N-ethyl-p-fluorobenzamide

[0103]

[0104] Add 135.2 g of ethylamine aqueous solution (50%, 1.50 mol) to the reaction vessel, start stirring, and slowly add 259.5 g of methyl p-fluorobenzoate (98%, 1.65 mol) dropwise over 3 hours, maintaining the temperature below 30°C. After the addition is complete, maintain the temperature for another 3 hours. After the reaction is complete, distill at a negative pressure of 4 kPa to remove low-boiling-point substances. Stop distillation when the vessel temperature reaches 110°C. The resulting pale yellow oily substance in the vessel is N-ethyl p-fluorobenzoamide, weighing 256.5 g, with a purity of 96.3% and a yield of 98.5%.

[0105] 173.6 g of synthesized N-ethyl-p-fluorobenzamide (96.3%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of acetonitrile and 52.6 g of sodium hydroxide solid (95%, 1.25 mol). After closing the reactor, 76.5 g of chloromethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-ethyl-p-fluorobenzamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washings and filtrates were combined, and the combined solution was distilled. First, the acetonitrile was recovered by distillation under normal pressure for use in the reaction and for washing salts. Then, the solution was distilled under negative pressure (0.6 kPa, 119-121 °C) to obtain 176.1 g of N-methyl-N-ethyl-p-fluorobenzamide, with a quantitative content of 98.7% and a yield of 95.9%. UHPLC-MS (m / z, ESI): 182.0973 (M+H)+; Theoretical value: 182.0976. 1 H-NMR (CDCl3, 400MHZ) δ (ppm): 1.236 (t, J=7.2Hz, 3H, CH3CH2); 2.942 (m, 2H, CH3 CH2); 3.347 (s, 3H, CH3); 7.491 (d, J=8.8Hz, 2H, ArH); 7.633 (t, J=8Hz, 2H, ArH).

[0106] Example 12: Synthesis of N-methyl-N-ethyl-p-fluoro-o-methylbenzamide

[0107]

[0108] Add 135.2 g of ethylamine aqueous solution (50%, 1.50 mol) to the reaction vessel, start stirring, and slowly add 283.1 g of methyl 4-fluoro-2-methylbenzoate (98%, 1.65 mol) dropwise over about 3 hours, keeping the temperature below 30°C. After the addition is complete, maintain the temperature for 3 hours. After the reaction is complete, distill at a negative pressure of 4 kPa to remove low-boiling substances. Stop distillation when the vessel temperature reaches 110°C. The resulting pale yellow oily substance in the vessel is N-ethyl-p-fluoro-o-methylbenzamide, with a mass of 274.1 g, a purity of 97.1%, and a yield of 97.9%.

[0109] 186.6 g of synthesized N-ethyl-p-fluoro-o-methylbenzamide (97.1%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of acetonitrile and 52.6 g of solid sodium hydroxide (95%, 1.25 mol). After closing the reactor, 76.5 g of chloromethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-ethyl-p-fluorobenzamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washing liquid and filtrate were combined, and the combined solution was distilled. First, the acetonitrile was recovered by distillation under normal pressure for use in the reaction and for washing salts. Then, the solution was distilled under negative pressure (0.3 kPa, 126-128 °C) to obtain 191.2 g of N-methyl-N-ethyl-p-fluoro-o-methylbenzamide with a purity of 97.2% and a yield of 95.2%. UHPLC-MS (m / z, ESI): 196.1130 (M+H)+; Theoretical value: 196.1132. 1 H-NMR (CDCl3, 400MHZ) δ (ppm): 1.237 (t, J=7.2Hz, 3H, CH3CH2); 2.361 (s, 3H, CH3); 2.941 (m, 2H, CH3CH2 ); 3.346 (s, 3H, CH3); 7.493 (d, J=8.8Hz, 1H, ArH); 7.531 (d, J=8Hz, 1H, ArH); 7.635 (t, J=8Hz, 1H, ArH).

[0110] Example 13: Synthesis of N-methyl-N-cyclopropylmethyl-p-fluorobenzamide

[0111]

[0112] 108.9 g of cyclopropylmethylamine (98%, 1.50 mol) was added to the reaction vessel, and stirring was started. 259.5 g of methyl p-fluorobenzoate (98%, 1.65 mol) was slowly added dropwise over 3 hours, with the temperature controlled below 30°C. After the addition was complete, the reaction was maintained at this temperature for 3 hours. After the reaction was complete, the vessel was heated under negative pressure (4 kPa) to remove low-boiling-point substances by distillation. Distillation was stopped when the vessel temperature reached 110°C. The resulting pale yellow oily substance in the vessel was N-cyclopropylmethyl p-fluorobenzoamide, weighing 295.8 g, with a purity of 96.7% and a yield of 98.7%.

[0113] 199.8 g of synthesized N-cyclopropylmethyl-p-fluorobenzamide (96.7%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of acetonitrile and 52.6 g of sodium hydroxide solid (95%, 1.25 mol). After closing the reactor, 76.5 g of chloromethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-cyclopropylmethyl-p-fluorobenzamide concentration was controlled to <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washings and filtrates were combined, and the combined solution was distilled. First, the acetonitrile was recovered by distillation under normal pressure for use in the reaction and for salt washing. Then, the solution was distilled under negative pressure (0.3 kPa, 126-128 °C) to obtain 199.9 g of N-methyl-N-cyclopropylmethyl-p-fluorobenzamide, with a quantitative content of 98.8% and a yield of 95.3%. UHPLC-MS (m / z, ESI): 208.1135 (M+H)+; Theoretical value: 208.1132. 1 H-NMR (CDCl3, 400MHZ) δ (ppm): 0.099 (m, 2H, CH2); 0.442 (m, 2H, CH2); 1.029 (m, 1H, CH); 2.711 (d, J=8Hz, 2H, CH); 3.423 (s, 3H, CH3); 7.496 (d, J=8.8Hz, 2H, ArH); 7.645 (t, J=8Hz, 2H, ArH).

[0114] Example 14: Synthesis of N-methyl-N-ethyltrifluoroacetamide

[0115]

[0116] Add 135.2 g of ethylamine aqueous solution (50%, 1.50 mol) to the reaction vessel, start stirring, and slowly add 215.6 g of methyl trifluoroacetate (98%, 1.65 mol) dropwise over 3 hours, keeping the temperature below 30°C. After the addition is complete, maintain the temperature for another 3 hours. After the reaction is complete, distill at a negative pressure of 4 kPa to remove low-boiling-point substances. Stop distillation when the vessel temperature reaches 60°C. The resulting pale yellow oily substance in the vessel is N-ethyltrifluoroacetamide, weighing 216.9 g, with a purity of 96.4% and a yield of 98.8%.

[0117] 146.4 g of synthesized N-ethyltrifluoroacetamide (96.4%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of acetonitrile and 52.6 g of sodium hydroxide solid (95%, 1.25 mol). After closing the reactor, 76.5 g of chloromethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-ethyltrifluoroacetamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washings and filtrates were combined, and the combined solution was distilled. First, the acetonitrile was recovered by distillation under normal pressure for use in the reaction and for salt washing. Then, the solution was distilled under negative pressure (6 kPa, 54-56 °C) to obtain 147.6 g of N-methyl-N-ethyltrifluoroacetamide, with a quantitative content of 99.1% and a yield of 94.3%. GC-MS (m / z): 155; theoretical value: 155. 1 H-NMR (CDCl3, 400MHZ) δ (ppm): 1.029 (t, J=7.2Hz, 3H, CH3 CH2); 2.818 (m, 2H, CH3) CH2 ); 3.326 (s, 3H, CH3).

[0118] Example 15: Synthesis of N-methyl-N-ethyldifluoroacetamide

[0119]

[0120] Add 135.2 g of ethylamine aqueous solution (50%, 1.50 mol) to the reaction vessel, start stirring, and slowly add 185.3 g of methyl difluoroacetate (98%, 1.65 mol) dropwise over 3 hours, keeping the temperature below 30°C. After the addition is complete, maintain the temperature for another 3 hours. After the reaction is complete, distill at a negative pressure of 1 kPa to remove low-boiling-point substances. Stop distillation when the vessel temperature reaches 60°C. The resulting pale yellow oily substance in the vessel is N-ethyldifluoroacetamide, weighing 188.9 g, with a purity of 96.3% and a yield of 98.5%.

[0121] 127.8 g of synthesized N-ethyldifluoroacetamide (99.54%, 1.00 mol) was placed in a high-pressure reactor, along with 200 g of acetonitrile and 52.6 g of sodium hydroxide solid (95%, 1.25 mol). After closing the reactor, 76.5 g of chloromethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-ethyldifluoroacetamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washings and filtrates were combined, and the combined solution was distilled. First, the acetonitrile was recovered by distillation under normal pressure for use in the reaction and for salt washing. Then, the solution was distilled under negative pressure (6 kPa, 56-58 °C) to obtain 130.6 g of N-methyl-N-ethyldifluoroacetamide, with a purity of 98.8% and a yield of 94.1%. GC-MS (m / z): 137; theoretical value: 137. 1 H-NMR (CDCl3, 400MHZ) δ (ppm): 1.137 (t, J=7.2Hz, 3H, CH3 CH2); 2.957 (m, 2H, CH3) CH2 ); 3.355 (s, 3H, CH3);; 7.261 (m, 1H, CF2H).

[0122] Example 16: Synthesis of N-ethyl-N-methylformamide

[0123]

[0124] 76.5 g of N-ethylformamide (95.5%, 1.00 mol), synthesized using the ethylamine and formic acid method, was placed in a high-pressure reactor. 200 g of acetonitrile and 52.6 g of sodium hydroxide solid (95%, 1.25 mol) were added. After closing the reactor, 143.8 g of bromomethane gas (99%, 1.50 mol) was introduced, and the temperature was maintained below 20 °C for 6 hours. The reaction was stopped when the N-ethylformamide concentration was controlled to be <0.2%. After opening the reactor, the reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washings and filtrates were combined, and the combined solution was distilled. First, acetonitrile was recovered by atmospheric distillation for use in the reaction and for salt washing. Then, negative pressure distillation (6 kPa, 74-76 °C) yielded 84.1 g of N-ethyl-N-methylformamide with a purity of 98.9% and a yield of 95.5%.

[0125] Example 17: Synthesis of N-ethyl-N-methylformamide

[0126]

[0127] 61.4 g of N-methylformamide (96.2%, 1.00 mol), synthesized using the methylamine and formic acid method, was placed in a reaction vessel. 200 g of acetonitrile and 52.6 g of solid sodium hydroxide (95%, 1.25 mol) were added. 165.1 g of liquid monobromoethane (99%, 1.50 mol) was added dropwise while maintaining the temperature below 20 °C. The mixture was kept at this temperature for 6 hours. The reaction was stopped when the N-methylformamide concentration was controlled to be <0.2%. The reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washings and filtrates were combined, and the combined solution was distilled. First, acetonitrile was recovered by atmospheric distillation for use in the reaction and for salt washing. Then, negative pressure distillation (6 kPa, 74-76 °C) yielded 83.4 g of N-ethyl-N-methylformamide, with a purity of 98.5% and a yield of 94.3%.

[0128] Example 18: Synthesis of N-ethyl-N-methylformamide

[0129]

[0130] 76.5 g of N-ethylformamide (95.50%, 1.00 mol), synthesized using the ethylamine and formic acid method, was placed in a reaction vessel. 250 g of acetonitrile and 214.1 g of sodium carbonate (99%, 2.00 mol) were added. The temperature was lowered to below 10 °C, and 165.6 g of dimethyl sulfate (99%, 1.30 mol) was added dropwise. After reacting for 10 h, the reaction was stopped when the N-ethylformamide content was controlled to be <0.2%. The reaction solution was filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washings and filtrates were combined, and the combined solution was distilled. First, acetonitrile was recovered by distillation under normal pressure for use in the reaction and for salt washing. Then, N-pressure distillation (6 kPa, 74-76 °C) yielded 73.9 g of N-ethyl-N-methylformamide, with a purity of 98.5% and a yield of 83.5%.

[0131] Example 19: Synthesis of N-ethyl-N-methylformamide

[0132]

[0133] 61.4 g of N-methylformamide (96.2%, 1.00 mol), synthesized using the methylamine and formic acid method, was placed in a reaction vessel. 250 g of acetonitrile and 279.2 g of potassium carbonate (99%, 2.00 mol) were added. The temperature was lowered to below 10 °C, and 202.5 g of diethyl sulfate (99%, 1.30 mol) was added dropwise. The reaction was stopped after 10 h when the N-methylformamide content was controlled to be <0.2%. The reaction solution was then filtered, and the filter cake was washed twice with 75 g of acetonitrile. The washings and filtrates were combined, and the combined solution was distilled. First, acetonitrile was recovered by atmospheric distillation for use in the reaction and for salt washing. Then, N-ethyl-N-methylformamide was obtained by negative pressure distillation (6 kPa, 74-76 °C), with a purity of 98.7% and a yield of 81.6%.

[0134] Example 20:

[0135] The amount of chloromethane introduced was changed to 102.0 g (99%, 2.00 mol, 2.00 eq), and other steps were the same as in Example 1. 84.5 g of N-ethyl-N-methylformamide was obtained, with a purity of 99.1% and a yield of 96.1%.

[0136] Example 21:

[0137] The substance used to maintain alkaline conditions was changed to potassium hydroxide, and the rest was the same as in Example 1. 84.9 g of the product N-ethyl-N-methylformamide was obtained, with a purity of 98.7% and a yield of 96.2%.

[0138] Example 22:

[0139] The substance used to maintain alkaline conditions was changed to sodium carbonate, and everything else was the same as in Example 1. 73.9 g of the product N-ethyl-N-methylformamide was obtained, with a purity of 98.7% and a yield of 83.7%.

[0140] Example 23:

[0141] The substance used to maintain alkaline conditions was changed to potassium carbonate, and the rest was the same as in Example 1. 81.3 g of N-ethyl-N-methylformamide was obtained, with a purity of 98.9% and a yield of 92.3%.

[0142] Example 24:

[0143] The amount of sodium hydroxide was changed to 40.4 g (95%, 1.00 mol, 1.00 eq), and other parameters were the same as in Example 1. 77.7 g of N-ethyl-N-methylformamide was obtained, with a purity of 99.0% and a yield of 88.3%.

[0144] Example 25:

[0145] The amount of sodium hydroxide was changed to 63.2 g (95%, 1.50 mol, 1.50 eq), and other parameters were the same as in Example 1. 80.4 g of N-ethyl-N-methylformamide was obtained, with a purity of 99.1% and a yield of 91.4%.

[0146] Example 26:

[0147] The alkylation temperature was maintained at 0°C, and other conditions were the same as in Example 1, yielding 84.8 g of N-ethyl-N-methylformamide with a purity of 99.0% and a yield of 96.4%.

[0148] Example 27:

[0149] The alkylation temperature was maintained at 35°C, and other conditions were the same as in Example 1, yielding 78.8 g of N-ethyl-N-methylformamide with a purity of 99.0% and a yield of 89.6%.

[0150] Comparative Example 1:

[0151]

[0152] Following the synthesis scheme of methyl ethylamine in CN102076652A: 93.2 g of methylamine aqueous solution (50%, 1.5 mol), 7.1 g of Raney nickel (82%, 0.09 mol), and 2 g of sodium hydroxide aqueous solution (30%, 0.015 mol) were added to a high-pressure reactor. The reactor was sealed and heated to 65–67 °C. Hydrogen gas was introduced until the pressure on the reactor gauge reached 3 MPa. Subsequently, over approximately 3.3 hours, 73.4 g of acetaldehyde (99%, 1.65 mol) was introduced into the reactor, while maintaining the hydrogen pressure at approximately 3 MPa throughout the reaction. After all the acetaldehyde was added, the reaction was maintained at the specified temperature and hydrogen pressure until hydrogen consumption ceased. Stirring was then stopped, and the reactor was degassed. The supernatant was then collected and distilled at atmospheric pressure, yielding 81.7 g of the fraction collected at 36–37 °C, with a purity of 98.4% and a yield of 90.7%.

[0153] Following the synthesis protocol for N-ethyl-N-methylformamide in WO2012146125: 60.1 g (98.4%, 1 mol) of the synthesized methyl ethylamine was added to a reaction vessel, followed by 200 g of toluene. The system temperature was maintained below 35°C, and 54.9 g of formic acid (88%, 1.05 mol) was added dropwise over 1 hour. After the addition was complete, the reaction mixture was stirred for 10 hours. Subsequently, the system was heated to reflux (oil temperature 135°C), and 24.9 g of the aqueous phase was removed using a Dean-Stark separator. The remaining reaction solution was subjected to vacuum distillation (8 kPa, 95-96°C) to obtain 78.3 g of N-ethyl-N-methylformamide, with a purity of 98.9% and a yield of 88.9%.

[0154] As shown in Comparative Example 1, the existing technical solutions for synthesizing N-ethyl-N-methylformamide have many shortcomings. First, the hydrogenation process is one of the 18 most dangerous reactions, using flammable and explosive hydrogen, which inherently poses a significant safety hazard. Second, the use of precious metal catalysts, coupled with low yields, results in high production costs. Furthermore, the intermediate methyl ethylamine has a low boiling point of only 36°C, and the purification, storage, and application procedures are all quite cumbersome. Even with these measures, the safety hazards remain significant, making it difficult, unsafe, and costly to achieve long-term, stable, and industrial-scale production of N-ethyl-N-methylformamide using this existing technical solution.

[0155] Similar shortcomings exist when using this existing technical solution to prepare other asymmetric disubstituted amides.

[0156] Comparative Example 2

[0157] The intermediate N-ethylformamide was prepared using this technical method: 135.2 g of ethylamine aqueous solution (50%, 1.50 mol) was added to a reaction vessel, and stirring was started. 104.3 g of methyl formate (95%, 1.65 mol) was slowly added dropwise over 3 hours, with the temperature controlled below 30°C. After the addition was complete, the reaction was maintained at this temperature for 3 hours. After the reaction was complete, the low-boiling components were removed by distillation under negative pressure and increased temperature, yielding 112.2 g of N-ethylformamide, with a quantitative purity of 96.9% and a yield of 99.2%.

[0158] Referring to the N-methylation scheme of dimethyl carbonate in Tundo P, Musolino M, Aricò F. GreenChem, 2018, 20:28–85: 75.4 g of synthesized N-ethylformamide (96.9%, 1.00 mol) was placed in a reactor, and 200 g of DMF, 3.7 g of CATB (99%, 0.01 mol) and 52.6 g of sodium hydroxide solid (95%, 1.25 mol) were added. The temperature was lowered to below 10 °C, and 118.3 g of dimethyl carbonate (99%, 1.30 mol) was added dropwise. After reacting for 10 h, the normalization of N-ethylformamide was >75%, and the reactants could not be converted further.

[0159] The comparison shows that dimethyl carbonate has poor methylation activity, and N-methylation reagents need to be selected from alkyl halides or sulfate esters, which have better methylation activity.

[0160] The applicant declares that the present invention illustrates the preparation method of the asymmetric disubstituted amide through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing an asymmetric disubstituted amide, characterized in that, The preparation method includes the following steps: (1) The primary amine compound shown in Formula I undergoes a condensation reaction with the carboxylic acid or carboxylic acid ester compound shown in Formula II to obtain the compound shown in Formula III, as shown in the following reaction formula: (2) The compound shown in Formula III reacts with an alkylating agent to give the compound shown in Formula IV; the reaction formula is as follows: R1 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl and C3-C8 halocycloalkyl, R2 is selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 halocycloalkyl, C6-C20 aryl or haloC6-C20 aryl, and R3 is selected from hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl.

2. The preparation method according to claim 1, characterized in that, The primary amine compound shown in Formula I is selected from methylamine, ethylamine, isopropylamine, cyclopropylamine, or cyclopropylmethylamine.

3. The preparation method according to claim 1 or 2, characterized in that, The carboxylic acid or carboxylic acid ester compound represented by Formula II is selected from formic acid, acetic acid, methyl formate, ethyl formate, methyl acetate, ethyl acetate, benzoic acid, 4-halobenzoic acid, 2-methyl-4-fluorobenzoic acid, 2-methyl-4-fluoro-5-acetaminobenzoic acid, benzoic acid ester, 4-halobenzoic acid ester, 2-methyl-4-fluorobenzoic acid ester or 2-methyl-4-fluoro-5-acetaminobenzoic acid ester; Preferably, the molar ratio of the primary amine compound of Formula I to the carboxylic acid or carboxylic acid ester compound of Formula II in step (1) is 1:(0.8 to 2.0); more preferably, it is 1:1.

1.

4. The preparation method according to any one of claims 1-3, characterized in that, When Formula II is a carboxylic acid, the solvent for the condensation reaction is an organic solvent that can be refluxed to remove water. Preferably, the refluxing organic solvent is selected from any one or a combination of at least two of aromatic hydrocarbons, alkanes, or ester solvents, more preferably from any one or a combination of at least two of toluene, xylene, butyl acetate, dichloroethane, or o-dichlorobenzene, and more preferably from toluene; Preferably, when Formula II is a carboxylic acid, the condensation reaction requires a water separation device and the use of organic solvent reflux to remove water; Preferably, when Formula II is a carboxylic acid, the temperature of the condensation reaction is 70°C to 140°C, more preferably 85-110°C; Preferably, when Formula II is a carboxylic acid, the condensation reaction takes 0.5 to 5 hours, and more preferably 3 hours.

5. The preparation method according to any one of claims 1-4, characterized in that, When Formula II is a carboxylic acid ester, the solvent for the condensation reaction is water or an organic solvent or no solvent is used; Preferably, when Formula II is a carboxylic acid ester, the solvent for the condensation reaction is any one or a combination of at least two of the following solvents: water, aromatic hydrocarbons, alkanes, alcohols, nitrile solvents, ethers, or amides; more preferably, toluene, xylene, methanol, ethanol, methyl tert-butyl ether, dichloroethane, dichloromethane, acetonitrile, or DMF. Preferably, when Formula II is a carboxylic acid ester, the temperature of the condensation reaction is 0℃~100℃, more preferably 20-30℃; Preferably, when Formula II is a carboxylic acid ester, the condensation reaction time is 0.5 to 5 hours; more preferably, it is 2 hours.

6. The preparation method according to any one of claims 1-5, characterized in that, The alkylating agent in step (2) is selected from alkyl halogenated alkanes or alkyl sulfate esters; Preferably, the alkylating agent is selected from any one or a combination of at least two of iodomethane, bromomethane, chloromethane, iodoethane, bromoethane, chloroethane, dimethyl sulfate, or diethyl sulfate.

7. The preparation method according to any one of claims 1-6, characterized in that, The molar ratio of the compound of formula III to the alkylating agent in step (2) is 1:(1.0 to 3.0), more preferably 1:1.5; Preferably, the reaction in step (2) is carried out in the presence of an alkaline substance; Preferably, the alkaline substance is selected from any one or a combination of at least two of sodium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, or sodium bicarbonate, and more preferably sodium hydroxide; Preferably, the molar ratio of the compound shown in Formula III to the alkaline substance is 1:(1.0 to 3.0), and more preferably 1:1.

25.

8. The preparation method according to any one of claims 1-7, characterized in that, The reaction temperature in step (2) is -10℃ to 30℃, preferably 20℃; Preferably, the reaction in step (2) lasts for 1 to 16 hours, more preferably 6 to 10 hours; Preferably, the reaction in step (2) is carried out in an organic solvent; Preferably, the organic solvent is selected from any one or a combination of at least two of aromatic hydrocarbons, alkanes, amides, sulfoxides, ethers, ketones, nitriles, or alcohols. More preferably, it is selected from any one or a combination of at least two of toluene, acetonitrile, dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, methyl tert-butyl ether, methyl isobutyl ketone, tert-butanol, sulfolane, N-ethyl-N-methylformamide, or N-ethylformamide. More preferably, it is selected from any one or a combination of at least two of DMF, acetonitrile, or tert-butanol. Preferably, the mass ratio of the compound shown in Formula III to the organic solvent is 1:(1.0 to 3.0), and more preferably 1:2.

0.

9. The preparation method according to any one of claims 1-8, characterized in that, When the alkylating agent is a gas, the reaction described in step (2) is carried out in a high-pressure reactor; Preferably, after the reaction in step (2) is completed, a post-processing procedure for the product is also included; Preferably, the post-processing method includes: filtering the reaction solution after the reaction is complete, washing the filter cake with toluene, combining the washing liquid and the filtrate, distilling the combined solution, and collecting the corresponding fraction, which is the product, the asymmetric disubstituted amide.

10. The preparation method according to any one of claims 1-9, characterized in that, The preparation method includes the following steps: (1) The primary amine compound shown in Formula I undergoes a condensation reaction with the carboxylic acid or carboxylic acid ester compound shown in Formula II to obtain the compound shown in Formula III; the primary amine compound shown in Formula I is selected from methylamine, ethylamine, isopropylamine, cyclopropylamine, or cyclopropylmethylamine; the carboxylic acid or carboxylic acid ester compound shown in Formula II is selected from formic acid, acetic acid, methyl formate, ethyl formate, methyl acetate, ethyl acetate, benzoic acid, 4-halobenzoic acid, 2-methyl-4-fluorobenzoic acid, 2-methyl-4-fluoro-5-acetaminobenzoic acid, benzoic acid ester, 4-halobenzoic acid, ethyl benzoic acid ester ... The benzoate, 2-methyl-4-fluorobenzoate or 2-methyl-4-fluoro-5-acetaminobenzoate, wherein the molar ratio of the primary amine compound of formula I to the carboxylic acid or carboxylic acid ester compound of formula II in step (1) is 1:(0.8 to 2.0), and when formula II is a carboxylic acid, the temperature of the condensation reaction is 70℃ to 140℃ and the time of the condensation reaction is 0.5 to 5h; when formula II is a carboxylic acid ester, the temperature of the condensation reaction is 0℃ to 100℃ and the time of the condensation reaction is 0.5 to 5h. (2) The compound shown in Formula III reacts with the alkylating agent in an organic solvent in the presence of an alkaline substance at -10℃ to 30℃ for 1 to 16 h to obtain the compound shown in Formula IV. The alkylating agent is selected from haloalkanes or alkyl sulfate esters; the basic substance is selected from any one or a combination of at least two of sodium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, or sodium bicarbonate; the organic solvent is selected from any one or a combination of at least two of toluene, acetonitrile, dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, methyl tert-methyl ether, methyl isobutyl ketone, tert-butanol, sulfolane, N-ethyl-N-methylformamide, or N-ethylformamide; and the compound represented by Formula III is combined with the alkylating agent. The molar ratio is 1:(1.0~3.0), and the molar ratio of the compound shown in Formula III to the basic substance is 1:(1.0~3.0). The mass ratio of the compound shown in Formula III to the organic solvent is 1:(1.0 to 3.0).

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