A method for preparing amide

Abstract

The invention discloses a method for preparing an amide compound, wherein the method comprises the following steps: mixing a carboxylic acid compound, an amine compound, a difluorocarbene reagent and an alkaline substance in an organic solvent, heating the mixture to 60-130°C for reaction for 6-15h, and obtaining an amide compound after the reaction is completed; the difluorocarbene reagent is used as a coupling reagent to directly condense a carboxylic acid and an amine to generate an amide compound. The raw materials used in the method are cheap and readily available, the reaction conditions are mild, the operation is simple, and the yield is high.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a method for directly preparing amide compounds by reacting carboxylic acid and amine compounds under the action of a difluorocarbene reagent and an alkaline substance. Background Art

[0002] Whether in natural molecules or synthetic drug molecules, amide bonds are very important chemical bonds, and the formation of amide bonds is one of the most important reactions in drug synthesis. In 2008, Stephen et al. counted 139 papers from three major pharmaceutical companies and found that the formation of amide bonds accounted for 16% of all reaction types [Stephen D. Roughley and Allan M. Jordan, J. Med. Chem., 2011, 54, 3451-3479]. Coincidentally, in 2016, Dean et al. compared the synthesis of amide bonds in chemical reactions used in the total synthesis of natural products in 1984 and 2014, and found that the synthesis of amide bonds increased from 25% to about 50% [Dean G. Brown and Jonas J.Med.Chem., 2016, 59, 4443-44458]. Direct condensation of carboxylic acid and amine is the most common method for preparing amides. Common methods for synthesizing amides from acids / amines include carbodiimide condensation agent method, mixed acid anhydride method, urea salt condensation agent method, organic phosphonium salt condensation agent, acyl halide method, etc. At present, the method widely used in drug synthesis is the coupling reagent method. The commonly used condensation agents include: 1) carbodiimides, such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI); 2) uronium salts, such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HCTU); 3) organic phosphonium salts, such as ( 7-Azabenzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyAOP) and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP). Although the above three types of reagents have the advantages of mild reaction conditions, high reaction efficiency, and simple feeding, these condensation agents have large molecular weights and low atom economy. Most of the reagents are expensive, and the reaction produces equivalent organic byproducts (N-hydroxybenzotriazole, urea or phosphoramide), making it difficult to separate and purify the amide product. In addition, recent studies have shown that the three highly active condensation agents of carbodiimides, urea salts, and organic phosphonium salts are sensitizers of the human immune system. Long-term exposure to these reagents can lead to allergic reactions and even potential carcinogenic toxicity [Kate J.McKnelly, William Sokol, and James S.Nowick et al, J.Org.Chem.2020, 85, 1764-1768]. Therefore, it is necessary to develop a safe, green, and highly atom-economical amide synthesis method. Summary of the invention

[0003] In order to meet the demand for amide condensation in medicinal chemistry, the present invention provides a method for preparing amide compounds by direct condensation of carboxylic acid and amine compounds in the presence of a difluorocarbene reagent. The raw materials used in the method are cheap and readily available, the reaction conditions are mild, and the operation is simple and practical.

[0004] To achieve the above object, the technical solution of the present invention is as follows:

[0005] A method for preparing an amide compound represented by formula (I), the preparation method comprising: adding a compound represented by formula (II) and a compound represented by formula (III) to an organic solvent, adding a difluorocarbene reagent to construct a reaction system, reacting at 60-130°C for 6-15h, and after the reaction, post-treating the obtained reaction solution to obtain the amide compound represented by formula (I); the difluorocarbene reagent is one or a mixture of two or more of difluorobromoethyl acetate, difluorochloroacetate, and difluoromonochloromethane; the molar ratio of the compound represented by formula (II), the compound represented by formula (III) to the difluorocarbene reagent is 1:0.8-2:1-80;

[0006]

[0007] Among them, in formula (I), formula (II) and formula (III), R 1 C 1-20 Alkyl, phenyl, halogen or C 1-4 Alkyl-substituted phenyl, benzyl, halogen, C 1-4 Alkyl or C 1-4 Alkoxy-substituted benzyl, 1-tert-butyloxycarbonyl-4-piperidinyl, a substituent represented by formula (X), a substituent represented by formula (Y), a substituent represented by formula (Z), or a styryl group; R 2 C 1-4 Alkyl, naphthyl, thiazolyl, pyridyl, phenyl or halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylcarbonyl, cyano, C 1-4 Alkylthio, nitro or C 1-4 Hydroxyalkyl substituted phenyl, R 3 is hydrogen or C 1-4 Alkyl, or R 2 , R 3 Combined with the N between the two, a piperidine ring or a morpholine ring is formed.

[0008] Furthermore, the organic solvent is one or a mixed solvent of two or more selected from N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), acetonitrile, toluene, chlorobenzene, dimethyl sulfoxide, ethanol, and 1,4-dioxane; the volume of the organic solvent is 3.3 to 4 mL / mmol based on the amount of the compound represented by formula (II).

[0009] Taking into account the source of the raw materials, the yield of the reaction and the representativeness of the product, as the most preferred, R 1is p-chlorobenzyl, benzyl, o-toluyl, o-chlorobenzyl, m-chlorobenzyl, p-methoxybenzyl, pentadecyl, 2-phenylvinyl, 1-tert-butoxycarbonyl-4-piperidinyl, phenyl, p-methylbenzyl, p-chlorobenzyl, a substituent represented by formula (X), a substituent represented by formula (Y), or a substituent represented by formula (Z); R 2 is o-methylphenyl, o-chlorophenyl, o-bromophenyl, m-methylphenyl, m-cyanophenyl, m-methylthiophenyl, m-nitrophenyl, m-hydroxymethylphenyl, p-tolyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl, p-methoxyphenyl, p-acetylphenyl, 1-naphthyl, 2-thienyl, 3-pyridyl, R 3 is hydrogen, or R 2 , R 3 and the N between them to form a piperidine ring or a morpholine ring. The final structure of compound (I) is as follows:

[0010]

[0011]

[0012] The structural formulas of ethyl difluorobromoacetate, sodium difluorochloroacetate, and difluorochloromethane are as follows:

[0013]

[0014] Furthermore, an alkaline substance is added to the reaction system, and the alkaline substance is one or a mixture of two or more of cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, potassium acetate, sodium acetate, triethylamine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DMAP (4-dimethylaminopyridine); the molar ratio of the compound represented by formula (II) to the alkaline substance is 1:0-4, wherein 0 is infinitely close to 0 but not 0. That is, the preparation method is as follows: adding the compound represented by formula (II) and the compound represented by formula (III) to an organic solvent, adding a difluorocarbene reagent to construct a reaction system under the action of an alkaline substance, reacting at 60-130° C. for 6-15 hours, and after the reaction is completed, the obtained reaction solution is post-treated to obtain the amide compound represented by formula (I); the alkaline substance is one or a mixture of two or more of cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, potassium acetate, sodium acetate, triethylamine, DBU, and DMAP; the difluorocarbene reagent is one or a mixture of two or more of difluoroethyl bromoacetate, sodium difluorochloroacetate, and difluoromonochloromethane; the molar ratio of the compound represented by formula (II), the compound represented by formula (III), the difluorocarbene reagent, and the alkaline substance is 1:0.8-2:1-80:0-4;

[0015] When the difluorocarbene reagent is (IV) ethyl difluorobromoacetate, the alkaline substance is preferably one or a mixture of two or more of cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, potassium acetate, sodium acetate, triethylamine, DBU, and DMAP; most preferably, the alkaline substance is triethylamine, the reaction solvent is N,N-dimethylformamide, the reaction temperature is 110° C., and the molar ratio of the compound represented by formula (II), the compound represented by formula (III), the difluorocarbene reagent, and the alkaline substance is 1:1.5:3:2; at this time, it is recommended that the reaction be carried out under a protective atmosphere, and the yield will be slightly higher than that without gas protection, and preferably the protective atmosphere is a nitrogen atmosphere.

[0016]

[0017] When the difluorocarbene reagent is (V) sodium difluorochloroacetate, the alkaline substance is preferably cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium hydroxide, lithium hydroxide, potassium phosphate, potassium acetate, sodium acetate, triethylamine, DBU, DMAP or a mixture of two or more thereof; most preferably, the alkaline substance is cesium carbonate, the reaction solvent is N,N-dimethylformamide, the reaction temperature is 110° C., and the molar ratio of the compound represented by formula (II), the compound represented by formula (III), the difluorocarbene reagent and the alkaline substance is 1:1.2:2:1.5; at this time, it is recommended that the reaction be carried out under a protective atmosphere, and the yield will be slightly higher than that without gas protection, and preferably the protective atmosphere is a nitrogen atmosphere.

[0018]

[0019] When the difluorocarbene reagent is (VI) difluorochloromethane, the alkaline substance is preferably one or a mixture of two or more of cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium phosphate, potassium acetate, sodium acetate, triethylamine, DBU, and DMAP; most preferably, the alkaline substance is potassium carbonate, the reaction solvent is N,N-dimethylformamide, the reaction temperature is 80° C., and the molar ratio of the compound represented by formula (II), the compound represented by formula (III), difluorochloromethane, and the alkaline substance is 1:1:80:1.5.

[0020]

[0021] Preferably, when the difluorocarbene reagent is difluoroethyl bromoacetate or difluorochlorosodium acetate, the reaction is carried out under a protective atmosphere (such as nitrogen). The yield will be slightly higher than that without gas protection.

[0022] Furthermore, the post-treatment is as follows: after the reaction is completed, dilute with water, extract with ethyl acetate (three times), combine the organic layers, wash with saturated brine, then dry with anhydrous sodium sulfate, filter, concentrate, perform silica gel column chromatography with petroleum ether and ethyl acetate in a volume ratio of 0-9:1 as eluent, collect the eluate containing the target product, distill under reduced pressure, and dry to obtain the amide compound shown in formula (I).

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] The method of the present invention uses difluorocarbene reagent as a condensation agent, N,N-dimethylformamide as a solvent, adds a suitable base, and directly reacts in one pot to achieve the condensation of carboxylic acid and amine, thereby synthesizing an amide bond commonly used in pharmaceutical chemistry. The method has cheap and readily available raw materials, mild reaction conditions, simple preparation and separation methods, high reaction yield, and purity of more than 95%. DETAILED DESCRIPTION

[0025] The invention is described in detail below with reference to the embodiments, but the invention is not limited thereto.

[0026] When the difluorocarbene reagent used is ethyl bromodifluoroacetate (IV), the optimal condition optimization process is as follows.

[0027] Example 1

[0028] In a dry reaction tube equipped with magnetic stirring, add 0.0853g (0.5mmol) of p-chlorophenylacetic acid, 46μL (0.5mmol) of aniline and 0.3045g (1.5mmol) of difluoroethyl bromide, and finally add 2mL of N,N-dimethylformamide (DMF). The reaction tube is equipped with a three-way tube connected to a nitrogen balloon, and the reaction is stirred in a 90℃ oil bath under a nitrogen atmosphere for 6 hours; after the reaction, add 30mL of water to dilute, extract with ethyl acetate three times, 30mL each time, combine the organic layers, wash the organic phase with saturated brine, and then dry with anhydrous sodium sulfate, filter, concentrate, column chromatography (petroleum ether: ethyl acetate (v / v) = 4:1), collect the eluent with Rf value of 0.2, distill under reduced pressure, and dry to obtain the target compound (Ⅰ-1), 57.2mg of white solid, yield 47%, melting point 164-166℃, purity 96.24% (HPLC detection).

[0029] Embodiment 2-5

[0030] The reaction solvent was changed from DMF to DMA, toluene, acetonitrile, and NMP. The other conditions were the same as in Example 1. The reaction results are shown in Table 1-1:

[0031] Table 1-1 Effect of different reaction solvents on reaction yield

[0032] Example Reaction solvent Yield [mg] Yield [%] 2 DMA (2 mL) 33.1 27 3 Toluene (2 mL) 20.5 17 4 Acetonitrile (2 mL) 18.3 15 5 NMP (2 mL) 30.0 25

[0033] The results showed that the reaction yield was highest when DMF was used as the reaction solvent.

[0034] Embodiment 6-9

[0035] The reaction temperature was changed from 90°C to 50°C, 70°C, 110°C, and 130°C. Other operations were the same as in Example 1. The reaction results are shown in Table 1-2:

[0036] Table 1-2 Effect of different reaction solvents on reaction yield

[0037] Example Reaction temperature Yield [mg] Yield [%] 6 50℃ 36.0 29 7 70℃ 47.3 38 8 110℃ 65.4 53 9 130℃ 49.3 40

[0038] The results showed that the reaction yield was highest when the reaction temperature was 110℃.

[0039] Examples 10-12

[0040] The amount of ethyl bromodifluoroacetate (IV) was changed from the original 1.5 mmol to 0, 1 mmol, and 2 mmol. DMF was used as the solvent, the reaction temperature was 110° C., and the other operations were the same as in Example 1. The reaction results are shown in Table 1-3:

[0041] Table 1-3 Effect of the amount of ethyl bromodifluoroacetate (IV) on the reaction yield

[0042]

[0043]

[0044] The results show that when the dosage of ethyl bromodifluoroacetate (IV) is 0, no product is generated. When the dosage of ethyl bromodifluoroacetate (IV) is increased to 2 mmol, the reaction yield does not change significantly (Comparative Example 8), so the optimal dosage is still 1.5 mmol.

[0045] Examples 13-16

[0046] To explore the effect of alkaline substances on the reaction, 0.5 mmol of alkaline substances were added to the reaction: NaHCO3, Na2CO3, DMAP, triethylamine, DMF was used as solvent, the reaction temperature was 110°C, and other operations were the same as in Example 1. The reaction results are shown in Table 1-4:

[0047] Table 1-4 Effect of different bases on reaction yield

[0048] Example Types of alkali Yield [mg] Yield [%] 13 <![CDATA[NaHCO3(0.5mmol,42.0mg)]]> 38.2 31 14 <![CDATA[Na2CO3(0.5mmol,53.0mg)]]> 60.4 49 15 DMAP (0.5mmol, 61.1mg) 61.3 50 16 Triethylamine (0.5mmol, 50.6mg) 66.8 54

[0049] The results show that the reaction yield is higher when 0.5 mmol of triethylamine is added. Adding 0.5 mmol of sodium bicarbonate will increase the by-product difluorobromoacetanilide, reducing the yield of the product to 31%.

[0050] Examples 17-18

[0051] To explore the optimal amount of triethylamine, 1 mmol or 1.5 mmol of triethylamine was added to the reaction, DMF was used as solvent, the reaction temperature was 110° C., and other operations were the same as in Example 1. The reaction results are shown in Table 1-5:

[0052] Table 1-5 Effect of different triethylamine dosage on reaction yield

[0053] Example Triethylamine dosage Yield [mg] Yield [%] 17 Triethylamine (1mmol, 101.2mg) 71.9 59 18 Triethylamine (1.5mmol, 151.8mg) 63.3 52

[0054] The results showed that the reaction yield was highest when the amount of triethylamine was increased to 1 mmol.

[0055] Examples 19-21

[0056] The molar ratio of carboxylic acid and amine in the reaction was changed, DMF was used as solvent, the reaction temperature was 110° C., 1 mmol of triethylamine was added during the reaction, and other operations were the same as in Example 1. The reaction results are shown in Table 1-6:

[0057] Table 1-6 Effect of the ratio of the amount of carboxylic acid to amine on the reaction yield

[0058] Example p-Chlorophenylacetic acid: aniline Yield [mg] Yield [%] 19 1.5:1(0.75mmol:0.5mmol; 128.0mg:46.6mg) 75.9 63 20 1:1.5(0.5mmol:0.75mmol; 85.3mg:69.8mg) 81.1 66 21 1:2(0.5mmol:1mmol; 85.3mg:93.1mg) 81.2 66

[0059] The results show that the reaction yield is higher when the molar ratio of p-chlorophenylacetic acid to aniline is 1:1.5, and the yield remains basically unchanged when the amount of aniline is increased.

[0060] After the above series of condition screening, the optimal conditions are the conditions used in Example 20, and the specific operations are as follows:

[0061] In a dry reaction tube equipped with magnetic stirring, add 0.0853g (0.5mmol) of p-chlorophenylacetic acid, 68μL (0.75mmol) of aniline, 0.3045g (1.5mmol) of ethyl difluorobromoacetate and 0.1012g (1mmol) of triethylamine, and finally add 2mL of N,N-dimethylformamide. The reaction tube is equipped with a three-way tube connected to a nitrogen balloon, and the reaction is stirred in an oil bath at 110°C under a nitrogen atmosphere for 6 hours; after the reaction, add 30mL of water to dilute, extract with ethyl acetate three times, 30mL each time, combine the organic layers, wash the organic phase with saturated brine, then dry with anhydrous sodium sulfate, filter, concentrate, column chromatography (petroleum ether: ethyl acetate = 4:1), collect R fThe eluent with a pH value of 0.2 was distilled under reduced pressure and dried to obtain the target compound (I-1) as a white solid (81.1 mg). The yield was 66%, the melting point was 164-166°C, and the purity was 97.14% (HPLC detection).

[0062] When the difluorocarbene reagent used is ethyl bromodifluoroacetate (IV), the substrate applicability is investigated

[0063] Examples 22-39

[0064] The type of the reaction amine was changed, and aniline was replaced with p-methylaniline, p-fluoroaniline, p-chloroaniline, p-bromoaniline, p-iodoaniline, p-methoxyaniline, p-acetanilide, o-methylaniline, o-chloroaniline, o-bromoaniline, m-methylaniline, m-aminobenzonitrile, m-aminothioanisole, m-nitroaniline, α-naphthylamine, morpholine, piperidine, and 2-aminothiophene. The other reaction results were shown in Table 1-7 as in Example 20.

[0065] Table 1-7 Effect of different amines on reaction yield

[0066]

[0067] The results show that changing the para- and meta-substituents of aniline compounds has little effect on the reaction yield; for ortho-substituted aniline, the yield decreases with the increase of steric hindrance; changing aniline to α-naphthylamine, 2-aminothiophene or fatty secondary amine still has a good yield.

[0068] Examples 40-53

[0069] The type of the reaction carboxylic acid was changed, and p-chlorophenylacetic acid was changed to phenylacetic acid, o-methylphenylacetic acid, o-chlorophenylacetic acid, p-methoxyphenylacetic acid, m-chlorophenylacetic acid, 2-(6-methoxy-2-naphthyl)propionic acid, 2-methyl-4-(2-methylpropyl)phenylacetic acid, benzoic acid, p-chlorobenzoic acid, p-toluic acid, cinnamic acid, hexadecanoic acid, 1-tert-butoxycarbonyl-4-piperidinic acid or 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetic acid. The other reactions were the same as in Example 20. The reaction results are shown in Table 1-8:

[0070] Table 1-8 Effect of different carboxylic acids on reaction yield

[0071]

[0072]

[0073] The results showed that the reaction yields were high when phenylacetic acid compounds and aliphatic carboxylic acids with different substituents were used; however, the reaction yield decreased significantly when p-chlorophenylacetic acid was replaced with aromatic carboxylic acids of the benzoic acid class.

[0074] Embodiment 53

[0075] The types of carboxylic acid and amine were changed at the same time. The other operations were the same as Example 20, except that p-chlorophenylacetic acid was replaced with 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetic acid (140.2 mg, 0.5 mmol), and 33% aqueous dimethylamine solution (1366.2 mg, 10 mmol) was used instead of aniline. The reaction was carried out for 15 hours instead of 6 hours to obtain the target compound (Ⅰ-28), 77.4 mg of white solid, and the yield was 50%.

[0076] When the difluorocarbene reagent used is sodium difluorochloroacetate (V), the optimal condition optimization process is as follows.

[0077] Embodiment 54

[0078] In a dry reaction tube equipped with magnetic stirring, add 0.0853g (0.5mmol) of p-chlorophenylacetic acid, 46μL (0.5mmol) of aniline, 0.2287g (1.5mmol) of sodium difluorochloroacetate and 0.1012g (1mmol) of triethylamine, and finally add 2mL of N,N-dimethylformamide. The reaction tube is equipped with a three-way tube connected to a nitrogen balloon, and the reaction is stirred in an oil bath at 110°C under a nitrogen atmosphere for 6 hours; after the reaction, add 30mL of water to dilute, extract with ethyl acetate three times, 30mL each time, combine the organic layers, wash the organic phase with saturated brine, then dry with anhydrous sodium sulfate, filter, concentrate, column chromatography (petroleum ether: ethyl acetate = 4:1), collect R f The eluent with a pH value of 0.2 was distilled under reduced pressure and dried to obtain the target compound (I-1) as a white solid (103.0 mg). The yield was 84%, with a melting point of 164-165°C and a purity of 97.73% (HPLC detection).

[0079] Examples 55-62

[0080] To explore the effect of alkaline substances on the reaction, 1 mmol of alkaline substances: Cs2CO3, DMAP, Na2CO3, K2CO3, Li2CO3, K3PO4, NaHCO3, LiOH were added to the reaction instead of 1 mmol of triethylamine. Other operations were the same as those in Example 54. The reaction results are shown in Table 2-1:

[0081] Table 2-1 Effect of different bases on reaction yield

[0082] Example Types of alkali Yield [mg] Yield [%] 55 <![CDATA[Cs2CO3(1mmol,325.8mg)]]> 106.3 87 56 DMAP (1mmol, 122.2mg) 101.7 83 57 <![CDATA[Na2CO3(1mmol,106.6mg)]]> 75.6 62 58 <![CDATA[K2CO3(1mmol,207.3mg)]]> 75.3 61 59 <![CDATA[Li2CO3(1mmol,73.9mg)]]> 91.0 74 60 <![CDATA[K3PO4(1mmol,163.9mg)]]> 84.7 69 61 <![CDATA[NaHCO3(1mmol,84.0mg)]]> 33.9 28 62 LiOH (1mmol, 24.0mg) 91.0 74

[0083] The results showed that the reaction yield was higher when 1 mmol of Cs2CO3 was added into the reaction.

[0084] Examples 63-67

[0085] To explore the optimal amount of Cs2CO3, 0.25mmol, 0.5mmol, 0.75mmol, 1.25mmol, and 1.5mmol of Cs2CO3 were added to the reaction instead of 1mmol of triethylamine. The other operations were the same as those in Example 54. The reaction results are shown in Table 2-2:

[0086] Table 2-2 Effect of different Cs2CO3 dosage on reaction yield

[0087] Example Dosage of alkali Yield [mg] Yield [%] 63 <![CDATA[Cs2CO3(0.25mmol,81.5mg)]]> 65.9 54 64 <![CDATA[Cs2CO3(0.5mmol,162.9mg)]]> 100.2 82 65 <![CDATA[Cs2CO3(0.75mmol,244.4mg)]]> 105.2 86 66 <![CDATA[Cs2CO3(1.25mmol,407.3mg)]]> 107.2 87 67 <![CDATA[Cs2CO3(1.5mmol,488.7mg)]]> 109.5 89

[0088] The results show that when the amount of Cs2CO3 is increased to 0.75mmol, the reaction yield does not change significantly when the amount of Cs2CO3 is further increased, so 0.75mmol of Cs2CO3 is chosen.

[0089] Examples 68-73

[0090] The solvent used in the reaction was changed. DMA, NMP, DMSO, chlorobenzene, toluene, and dioxane were used as solvents instead of DMF. 0.75 mmol of Cs2CO3 was used instead of 1 mmol of triethylamine. Other operations were the same as those in Example 54. The reaction results are shown in Table 2-3:

[0091] Table 2-3 Effect of reaction solvent on reaction yield

[0092] Example Solvents Yield [mg] Yield [%] 68 DMA(2ml) 85.8 70 69 NMP(2ml) 94.1 77 70 DMSO(2ml) 67.6 55 71 Chlorobenzene (2ml) 87.3 71 72 Toluene (2ml) 97.1 79 73 Dioxane (2ml) 89.1 73

[0093] The results showed that the reaction yield was higher when other solvents were used than when DMF was used as the solvent (Comparative Example 65), and DMF was finally used as the reaction solvent.

[0094] Examples 74-76

[0095] To explore the optimal reaction temperature, the reaction was carried out at 70°C, 90°C, and 130°C instead of 110°C, 0.75 mmol of Cs2CO3 was used instead of 1 mmol of triethylamine, and other operations were the same as in Example 54. The reaction results are shown in Table 2-4:

[0096] Table 2-4 Effect of reaction temperature on reaction yield

[0097] Example Solvents Yield [mg] Yield [%] 74 70℃ 98.0 80 75 90℃ 95.1 77 76 130℃ 100.4 82

[0098] The results show that whether the temperature is increased or decreased, the reaction yield is not as high as the yield at 110°C (Comparative Example 65), and the final reaction temperature is 110°C.

[0099] Examples 77-81

[0100] The amount of sodium difluorochloroacetate (V) was changed from the original 1.5 mmol to 0.5 mmol, 0.75 mmol, 1 mmol, 1.25 mmol, and 1.75 mmol. 0.75 mmol of Cs2CO3 was used instead of 1 mmol of triethylamine. The other operations were the same as those in Example 54. The reaction results are shown in Table 2-5:

[0101] Table 2-5 Effect of the dosage of sodium difluorochloroacetate (V) on the reaction yield

[0102]

[0103]

[0104] The results showed that when the dosage of sodium difluorochloroacetate (V) increased to 1 mmol, the reaction yield did not change significantly, so the optimal dosage was 1 mmol.

[0105] Examples 82-83

[0106] The molar ratio of carboxylic acid and amine in the reaction was changed, 0.75 mmol of Cs2CO3 was used instead of 1 mmol of triethylamine, 1 mmol of sodium difluorochloroacetate (V) was used instead of 1.5 mmol of sodium difluorochloroacetate (V), and other operations were the same as those in Example 54. The reaction results are shown in Table 2-6:

[0107] Table 2-6 Effect of the ratio of the amount of carboxylic acid and amine on the reaction yield

[0108] Example p-Chlorophenylacetic acid: aniline Yield [mg] Yield [%] 82 1.2:1(0.6mmol:0.5mmol; 102.4mg:46.6mg) 103.2 84 83 1:1.2(0.5mmol:0.6mmol; 85.3mg:55.9mg) 110.1 90

[0109] The results showed that the reaction yield was highest when the molar ratio of p-chlorophenylacetic acid to aniline was 1:1.2.

[0110] After the above series of condition screening, the optimal conditions are the conditions used in Example 83, and the specific operations are as follows:

[0111] In a dry reaction tube equipped with magnetic stirring, add 0.0853g (0.5mmol) of p-chlorophenylacetic acid, 55μL (0.6mmol) of aniline, 0.1525g (1mmol) of sodium difluorochloroacetate and 0.2444g (0.75mmol) of cesium carbonate, and finally add 2mL of N,N-dimethylformamide. The reaction tube is equipped with a three-way tube connected to a nitrogen balloon, and the reaction is stirred in an oil bath at 110°C under a nitrogen atmosphere for 6 hours; after the reaction, add 30mL of water to dilute, extract with ethyl acetate three times, 30mL each time, combine the organic layers, wash the organic phase with saturated brine, then dry with anhydrous sodium sulfate, filter, concentrate, column chromatography (petroleum ether: ethyl acetate = 4:1), collect R fThe eluate with a pH of 0.2 was distilled under reduced pressure and dried to obtain the target compound (I-1) as a white solid (110.1 mg) with a yield of 90%.

[0112] Examples 84-103

[0113] The type of the reaction amine was changed, and aniline was replaced with p-methylaniline, p-fluoroaniline, p-chloroaniline, p-bromoaniline, p-iodoaniline, p-methoxyaniline, p-acetanilide, o-methylaniline, o-chloroaniline, o-bromoaniline, m-methylaniline, m-aminobenzonitrile, m-aminothioanisole, m-nitroaniline, 3-aminobenzyl alcohol, α-naphthylamine, morpholine, piperidine, 2-aminothiophene, and 3-aminopyridine. The other reaction results were shown in Table 2-7 as in Example 83.

[0114] Table 2-7 Effect of different amines on reaction yield

[0115]

[0116]

[0117] The results show that for aniline compounds, changing the para- and meta-substituents has little effect on the reaction yield; for ortho-substituted aniline, the yield decreases with the increase of steric hindrance; when aniline is changed to α-naphthylamine or fatty secondary amine, the reaction still has a good yield, and when aniline is changed to 2-aminothiophene or 3-aminopyridine, the reaction yield is greatly reduced.

[0118] Examples 104-118

[0119] The type of the reacted carboxylic acid was changed, and p-chlorophenylacetic acid was replaced with phenylacetic acid, o-methylphenylacetic acid, o-chlorophenylacetic acid, p-methoxyphenylacetic acid, m-chlorophenylacetic acid, 2-(6-methoxy-2-naphthyl)propionic acid, 2-methyl-4-(2-methylpropyl)phenylacetic acid, benzoic acid, p-chlorobenzoic acid, p-toluic acid, cinnamic acid, hexadecanoic acid, 1-tert-butoxycarbonyl-4-piperidinic acid or 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetic acid. The other reactions were the same as in Example 83. The reaction results are shown in Table 2-8:

[0120] Table 2-8 Effect of different carboxylic acids on reaction yield

[0121]

[0122] The results showed that the reaction yields were higher when phenylacetic acid compounds and aliphatic carboxylic acids with different substituents were used, while the reaction yields were relatively lower when p-chlorophenylacetic acid was changed to aromatic carboxylic acids of the benzoic acid class.

[0123] Embodiment 118

[0124] The types of carboxylic acid and amine were changed at the same time. The other operations were the same as Example 83, except that p-chlorophenylacetic acid was replaced with 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetic acid (140.2 mg, 0.5 mmol), and 33% aqueous dimethylamine solution (1366.2 mg, 10 mmol) was used instead of aniline. The reaction was carried out for 15 hours instead of 6 hours to obtain the target compound (Ⅰ-28), 69.4 mg of white solid, and the yield was 45%.

[0125] When the difluorocarbene reagent used is difluorochloromethane (VI), the optimal condition optimization process is as follows.

[0126] Embodiment 119

[0127] In a dry reaction tube equipped with magnetic stirring, add 0.0853g (0.5mmol) of p-chlorophenylacetic acid, 46μL (0.5mmol) of aniline and 0.4887g (1.5mmol) of cesium carbonate, and finally add 2mL of N-methylpyrrolidone (NMP). The reaction tube is equipped with a three-way tube connected to a difluorochloromethane balloon (difluorochloromethane is about 40mmol), and stirred in an 80℃ oil bath for 6 hours; after the reaction is completed, add 30mL of water to dilute, extract with ethyl acetate three times, 30mL each time, combine the organic layers, wash the organic phase with saturated brine, then dry with anhydrous sodium sulfate, filter, concentrate, column chromatography (petroleum ether: ethyl acetate = 4:1), collect R f The eluent with a pH of 0.2 was distilled under reduced pressure and dried to obtain the target compound (I-1), 108.5 mg of white solid, with a yield of 88%. Melting point 165-166°C, purity 98.11% (HPLC detection)

[0128] Examples 120-126

[0129] To explore the effect of alkaline substances on the reaction, 1.5 mmol of alkaline substances were added to the reaction: KOH, KO t Bu, K2CO3, Na2CO3, NaHCO3, K3PO4, DBU instead of 1.5mmol Cs2CO3, other operations were the same as in Example 119, and the reaction results are shown in Table 3-1:

[0130] Table 3-1 Effect of different bases on reaction yield

[0131] Example Types of alkali Yield [mg] Yield [%] 120 KOH (1.5 mmol, 84.2 mg) 54.1 44 121 <![CDATA[KO t This is(1.5mmol,168.3mg)]]> 62.1 44 122 <![CDATA[K2CO3(1.5mmol,207.3mg)]]> 111.8 91 123 <![CDATA[Na2CO3(1.5mmol,159.0mg)]]> 109.9 89 124 <![CDATA[NaHCO3(1mmol,126.0mg)]]> 77.2 63 125 <![CDATA[K3PO4(1mmol,318.4mg)]]> 77.7 63 126 DBU (1mmol, 24.0mg) 228.4 74

[0132] The results showed that the reaction yield was higher when 1.5 mmol K2CO3 was added into the reaction.

[0133] Examples 127-130

[0134] To explore the optimal amount of K2CO3, 0.5mmol, 0.75mmol, 1mmol, and 2mmol of K2CO3 were added to the reaction instead of 1.5mmol of Cs2CO3. Other operations were the same as those in Example 119. The reaction results are shown in Table 3-2:

[0135] Table 3-2 Effect of different K2CO3 dosage on reaction yield

[0136] Example Dosage of alkali Yield [mg] Yield [%] 127 <![CDATA[K2CO3(0.5mmol,69.1mg)]]> 91.9 75 128 <![CDATA[K2CO3(0.75mmol,103.7mg)]]> 111.8 91 129 <![CDATA[K2CO3(1mmol,138.2mg)]]> 112.8 92 130 <![CDATA[K2CO3(2mmol,276.4mg)]]> 111.3 91

[0137] The results show that when the amount of K2CO3 is increased to 0.75mmol, the reaction yield does not change significantly when the amount of K2CO3 is further increased, so 0.75mmol of K2CO3 is chosen.

[0138] Examples 131-133

[0139] The solvent used in the reaction was changed. DMF, DMA, and DMSO were used as solvents instead of NMP. 0.75 mmol of K2CO3 was used instead of 1.5 mmol of Cs2CO3. Other operations were the same as those in Example 119. The reaction results are shown in Table 3-3:

[0140] Table 3-3 Effect of reaction solvent on reaction yield

[0141] Example Solvents Yield [mg] Yield [%] 131 DMF(2ml) 116.4 95 132 DMA(2ml) 81.8 67 133 DMSO(2ml) 100.9 82

[0142] The results showed that the reaction yield was the highest when DMF was used as the solvent, and DMF was finally used as the reaction solvent.

[0143] Examples 134-136

[0144] The optimal reaction temperature was explored, the reaction was carried out at 25°C, 60°C, and 100°C instead of 80°C, 0.75 mmol of K2CO3 was used instead of 1.5 mmol of Cs2CO3, DMF was used as solvent instead of NMP, and other operations were the same as in Example 119. The reaction results are shown in Table 3-4:

[0145] Table 3-4 Effect of reaction temperature on reaction yield

[0146] Example Solvents Yield [mg] Yield [%] 134 25℃ 26.5 22 135 60℃ 46.0 37 136 100℃ 108.0 88

[0147] The results show that no matter whether the temperature is increased or decreased, the reaction yield is not as high as the yield at 80°C (Comparative Example 131), and the final reaction temperature is 80°C.

[0148] Examples 137-138

[0149] The molar ratio of carboxylic acid and amine in the reaction was changed, 0.75 mmol of K2CO3 was used instead of 1.5 mmol of Cs2CO3, DMF was used as solvent instead of NMP, and other operations were the same as those in Example 119. The reaction results are shown in Table 3-5:

[0150] Table 3-5 Effect of the ratio of the amount of carboxylic acid to amine on the reaction yield

[0151] Example p-Chlorophenylacetic acid: aniline Yield [mg] Yield [%] 137 1.2:1(0.6mmol:0.5mmol; 102.4mg:46.6mg) 116.8 95 138 1:1.2(0.5mmol:0.6mmol; 85.3mg:55.9mg) 114.6 93

[0152] The results show that changing the molar ratio of p-chlorophenylacetic acid and aniline has little effect on the reaction yield (Comparative Example 131), so the molar ratio of carboxylic acid and amine is still 1:1.

[0153] After the above series of condition screening, the optimal conditions are the conditions used in Example 131, and the specific operations are as follows:

[0154] In a dry reaction tube equipped with magnetic stirring, add 0.0853g (0.5mmol) of p-chlorophenylacetic acid, 46μL (0.5mmol) of aniline and 0.1037g (0.75mmol) of potassium carbonate, and finally add 2mL of N,N-dimethylformamide. The reaction tube is equipped with a three-way tube connected to a difluorochloromethane balloon (difluorochloromethane is about 40mmol), and stirred in an 80℃ oil bath for 6 hours; after the reaction is completed, add 30mL of water to dilute, extract with ethyl acetate three times, 30mL each time, combine the organic layers, wash the organic phase with saturated brine, then dry with anhydrous sodium sulfate, filter, concentrate, column chromatography (petroleum ether: ethyl acetate = 4:1), collect R f The eluate with a pH of 0.2 was distilled under reduced pressure and dried to obtain the target compound (I-1) as a white solid (116.4 mg) with a yield of 95%.

[0155] Examples 139-157

[0156] The type of the reaction amine was changed, and aniline was replaced with p-methylaniline, p-fluoroaniline, p-chloroaniline, p-bromoaniline, p-iodoaniline, p-methoxyaniline, p-acetanilide, o-methylaniline, o-chloroaniline, o-bromoaniline, m-methylaniline, m-aminobenzonitrile, m-aminothioanisole, m-nitroaniline, 3-aminobenzyl alcohol, α-naphthylamine, morpholine, piperidine, and 3-aminopyridine. The other reaction results were shown in Table 3-6 as in Example 119.

[0157] Table 3-6 Effect of different amines on reaction yield

[0158]

[0159]

[0160] The results show that for aniline compounds, changing the para- and meta-substituents has little effect on the reaction yield; for aniline with greater steric hindrance at the ortho-position, the yield is lower; when aniline is changed to α-naphthylamine or aliphatic secondary amine, the reaction still has a good yield, and when aniline is changed to 3-aminopyridine, the reaction yield is greatly reduced.

[0161] Examples 158-172

[0162] The type of the reacted carboxylic acid was changed, and p-chlorophenylacetic acid was replaced with phenylacetic acid, o-methylphenylacetic acid, o-chlorophenylacetic acid, p-methoxyphenylacetic acid, m-chlorophenylacetic acid, 2-(6-methoxy-2-naphthyl)propionic acid, 2-methyl-4-(2-methylpropyl)phenylacetic acid, benzoic acid, p-chlorobenzoic acid, p-toluic acid, cinnamic acid, hexadecanoic acid, 1-tert-butoxycarbonyl-4-piperidinic acid or 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetic acid. The other reactions were the same as in Example 119. The reaction results are shown in Table 3-7:

[0163] Table 3-7 Effect of different carboxylic acids on reaction yield

[0164]

[0165]

[0166] The results showed that the reaction yields were higher when phenylacetic acid compounds and aliphatic carboxylic acids with different substituents were used, while the reaction yields were relatively lower when p-chlorophenylacetic acid was changed to aromatic carboxylic acids of the benzoic acid class.

[0167] Embodiment 172

[0168] The types of carboxylic acid and amine were changed at the same time. The other operations were the same as Example 119, except that p-chlorophenylacetic acid was replaced with 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetic acid (140.2 mg, 0.5 mmol), and 33% aqueous dimethylamine solution (1366.2 mg, 10 mmol) was used instead of aniline. The reaction was carried out for 15 hours instead of 6 hours to obtain the target compound (Ⅰ-28), 85.5 mg of white solid, and the yield was 56%.

[0169] The melting points and NMR data of all products are as follows:

[0170]

[0171] mp:165-166℃. 1H NMR(400MHz,CDCl3)δ7.43(d,J=7.8Hz,2H),7.36(d,J=8.3Hz,2H),7.31-7.27(m,4H),7.12-7.08(m,2H),3.69(s,2H).

[0172]

[0173] mp:191-192℃. 1 H NMR(400MHz,CDCl3)δ7.36(d,J=8.4Hz,2H),7.31-7.28(m,4H),7.09(d,J=8.3Hz,2H),7.04(br,1H),3.68(s,2H),2.29(s,3H).

[0174]

[0175] mp:157-158℃. 1 H NMR(400MHz,CDCl3)δ7.40-7.35(m,4H),7.26(d,J=7.9Hz,2H),7.16(br,1H),6.98(t,J=8.5Hz,2H),3.68(s,2H); 13 C NMR(101MHz,CDCl3)δ168.55,159.53(J=244.96Hz),133.71,133.41(J=2.5Hz),132.70,130.82,129.34,121.81(J=8.0Hz),115.66(J=22.6Hz),43.84.

[0176]

[0177] mp:187-188℃. 1 H NMR(400MHz,CDCl3)δ7.39-7.36(m,4H),7.28-7.23(m,4H),7.04(br,1H),3.70(s,2H).

[0178]

[0179] mp:202-203℃. 1 H NMR(400 MHz,d6-DMSO)δ10.31(s,1H),7.58-7.55(m,2H),7.50-7.46(m,2H),7.40-7.33(m,4H),3.65(s,2H); 13C NMR(101 MHz,d6-DMSO)δ169.74,139.33,135.59,132.39,132.21,131.90,129.09,121.94,115.71,43.27.

[0180]

[0181] mp:212-213℃. 1 H NMR(400 MHz,d6-DMSO)δ10.30(s,1H),7.63(d,J=8.0 Hz,2H),7.44-7.33(m,6H),3.64(s,2H); 13 C NMR(101 MHz,d6-DMSO)δ169.86,139.88,138.33,135.68,132.27,132.02,129.18,122.24,87.70,43.36.

[0182]

[0183] mp:185-186℃. 1 H NMR(400 MHz,CDCl3)δ7.38-7.29(m,6H),6.97(s,1H),6.83(d,J=8.5Hz,2H),3.78(s,3H),3.69(s,2H).

[0184]

[0185] mp:145-146℃. 1 H NMR(400 MHz,CDCl3)δ7.90(d,J=8.2 Hz,2H),7.66(s,1H),7.57(d,J=8.3 Hz,2H),7.35(d,J=7.8 Hz,2H),7.26(d,J=6.4 Hz,2H),3.72(s,2H),2.57(s,3H); 13 CNMR(101 MHz,CDCl3)δ197.13,168.91,141.96,133.75,133.04,132.40,130.78,129.70,129.32,118.99,44.01,26.49.

[0186]

[0187] mp:184-185℃. 1H NMR(400 MHz,d6-DMSO)δ9.52(s,1H),7.41-7.35(m,5H),7.19(d,J=7.3 Hz,1H),7.14(t,J=6.6 Hz,1H),7.07(t,J=7.4 Hz,1H),3.68(s,2H),2.16(s,3H); 13 C NMR(101 MHz,d6-DMSO)δ169.57,137.06,136.17,132.67,132.10,131.83,131.15,129.10,126.79,126.15,125.98,42.79,18.66.

[0188]

[0189] mp:170-171℃. 1 H NMR(400 MHz,CDCl3)δ8.34(d,J=8.1 Hz,1H),7.62(br,1H),7.38(d,J=8.1 Hz,2H),7.31-7.29(m,3H),7.25(td,J=7.4,1.2 Hz,1H),7.02(td,J=7.9,1.3 Hz,1H),3.76(s,2H); 13 C NMR(101 MHz,CDCl3)δ168.43,134.29,133.86,132.45,130.96,129.40,128.97,127.74,124.87,122.82,121.39,44.35.

[0190]

[0191] mp:173-174℃. 1 H NMR(400 MHz,CDCl3)δ8.33(d,J=7.6 Hz,1H),7.60(br,1H),7.47(dd,J=8.0,1.4 Hz,1H),7.41-7.38(m,2H),7.32-7.27(m,3H),6.95(td,J=7.9,1.5,1H),3.76(s,2H); 13 C NMR(101 MHz,CDCl3)δ168.49,135.38,133.89,132.39,132.21,131.09,129.44,128.39,125.38,121.59,113.33,44.40.

[0192] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0193] <h2 style=";text-align:left;direction:ltr"> mp:128-129℃.<h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR (400 MHz, CDCl3)δ7.33(d, J = 8.1 Hz, 2H),7.27-7.13(m, 6H),6.91(d, J = 7.3 Hz, 1H),3.64(s, 2H),2.29(s, 3H).<h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C NMR(101 MHz,CDCl3)δ168.57,138.93,137.45,133.53,132.99,130.77,129.21,128.79,125.43,120.61,117.04,43.97,21.40.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0194] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0195] <h2 style=";text-align:left;direction:ltr"> mp:146-147℃.<h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR(400 MHz,CDCl3)δ7.88(s,1H),7.65-7.64(m,1H),7.43-7.36(m,5H),7.27(d,J=5.3 Hz,2H),3.72(s,2H);<h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C NMR(101 MHz,CDCl3)δ168.90,138.37,133.89,132.22,130.78,129.90,129.42,127.98,123.93,122.91,118.39,112.93,43.86.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0196] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0197] <h2 style=";text-align:left;direction:ltr"> mp:136-137℃.<h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR (400 MHz, CDCl3)δ7.48-7.41(m, 1H), 7.36(d, J = 8.3 Hz, 2H), 7.26(d, J = 8.3 Hz, 2H), 7.21-7.12(m, 3H), 6.98(d, J = 7.6 Hz, 1H), 3.68(s, 2H), 2.45(s, 3H);<h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C NMR(101 MHz,CDCl3)δ168.51,139.73,138.03,133.70,132.72,130.80,129.32,129.23,122.61,117.58,116.39,44.05,15.68.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0198] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0199] mp:187-188℃. 1 H NMR(400 MHz,d6-DMSO)δ10.68(s,1H),8.62(t,J=2.1 Hz,1H),7.91(dd,J=8.2,2.2 Hz,2H),7.61(t,J=8.2 Hz,1H),7.41-7.35(m,4H),3.71(s,2H); 13 CNMR(101 MHz,d6-DMSO)δ170.39,148.84,141.07,135.28,132.33,131.99,131.09,129.14,125.94,118.68,114.11,43.27.

[0200]

[0201] mp:168-169℃. 1 H NMR(400 MHz,d6-DMSO)δ10.15(s,1H),7.56(s,1H),7.47(d,J=8.1Hz,1H),7.40-7.34(m,4H),7.23(t,J=7.8 Hz,1H),6.98(d,J=7.5 Hz,1H),5.09(br,1H),4.46(s,2H),3.64(s,2H); 13 C NMR(101 MHz,d6-DMSO)δ168.68,143.26,139.02,135.08,131.29,131.02,128.41,128.25,121.30,117.45,117.17,62.81,42.51.

[0202]

[0203] mp:189-190℃. 1 H NMR(400 MHz,d6-DMSO)δ10.17(s,1H),8.12-8.06(m,1H),7.94(d,J=8.0 Hz,1H),7.76(d,J=8.1 Hz,1H),7.69-7.67(m,1H),7.58-7.41(m,7H),3.85(s,2H); 13CNMR(101 MHz,d6-DMSO)δ169.40,135.20,133.65,133.35,131.24,131.00,128.21,128.10,127.66,125.96,125.79,125.47,125.27,122.50,121.61,41.97.

[0204]

[0205] mp:107-108℃. 1 H NMR(400 MHz,CDCl3)δ7.30(d,J=8.4 Hz,2H),7.18(d,J=8.4Hz,2H),3.69(s,2H),3.65(s,4H),3.54-3.42(m,4H).

[0206]

[0207] mp:89-90℃. 1 H NMR(400 MHz,CDCl3)δ7.29-7.17(m,4H),3.68(s,2H),3.64-3.28(m,4H),1.59-1.39(m,6H); 13 C NMR(101 MHz,CDCl3)δ168.73,133.95,132.52,130.08,128.73,47.20,42.95,40.25,26.28,25.47,24.40.

[0208]

[0209] mp:174-175℃. 1 H NMR(400 MHz,d6-DMSO)δ12.36(s,1H),7.47(d,J=3.6 Hz,1H),7.41-7.34(m,4H),7.21(d,J=3.5 Hz,1H),3.78(s,2H).

[0210]

[0211] mp:117-118℃. 1H NMR(400 MHz,CDCl3)δ8.50(d,J=2.5 Hz,1H),8.31(d,J=4.7Hz,1H),8.11(d,J=8.4 Hz,2H),7.33(d,J=8.4 Hz,2H),7.25-7.23(m,2H),3.69(s,2H); 13 C NMR(101 MHz,CDCl3)δ169.26,145.31,141.09,134.77,133.71,132.51,130.72,129.27,127.47,123.78,43.69.

[0212]

[0213] mp:118-119℃. 1 H NMR(400 MHz,CDCl3)δ7.41(d,J=8.1 Hz,2H),7.38-7.24(m,8H),7.07(t,J=7.4 Hz,1H),3.71(s,2H).

[0214]

[0215] mp:131-132℃. 1 H NMR(400 MHz,CDCl3)δ7.38(d,J=7.6 Hz,2H),7.29-7.25(m,6H),7.07(t,J=7.4 Hz,1H),7.04(br,1H),3.74(s,2H),2.34(s,3H).

[0216]

[0217] mp:141-142℃. 1 H NMR(400 MHz,d6-DMSO)δ10.20(s,1H),7.60-7.58(m,2H),7.46-7.41(m,2H),7.33-7.28(m,4H),7.04(t,J=7.4 Hz,1H),3.83(s,2H).

[0218]

[0219] mp:118-119℃. 1H NMR (400 MHz, CDCl3) δ7.41 (d, J = 8.0 Hz, 2H), 7.29-7.23 (m, 5H), 7.07 (t, J = 7.4 Hz, 1H), 6.92 (d, J = 8.5 Hz, 2H), 3.82 (s, 3H), 3.66 (s, 2H).

[0220]

[0221] mp:129-130℃. 1 H NMR (400 MHz, CDCl3) δ7.51-7.40(m,3H),7.32-7.25(m,5H),7.20(br,1H),7.09(t,J=7.4 Hz,1H),3.65(s,2H). 13 C NMR (101 MHz, CDCl3) δ168.38,137.52,136.41,134.85,130.28,129.56,128.99,127.77,127.57,124.67,120.06,44.21.

[0222]

[0223] mp:171-172℃. 1 H NMR (400 MHz, CDCl3) δ8.19 (s, rotamer, 0.5H), 8.06 (s, rotamer, 0.5H), 7.78 (s, 1H), 7.60-7.58 (m, 2H), 7.47 -7.42 (m, 3H), 7.28-7.19 (m, 4H), 7.08 (t, J = 7.4 Hz, 1H), 7.04-7.01 (m, 1H), 8.19 (s, rotamer, 1.2H), 8.19 (s, rotamer, 0.8H), 2.36 (s, 3H), 2.31 (s, 3H); 13 C NMR (101MHz, CDCl3) δ166.96,144.71,144.31,137.98,137.51,130.83,129.57,128.96, 128.21,128.05,124.72,122.78,121.05,120.26,116.63,112.66,33.53,21.25,18.38.

[0224]

[0225] mp:188-189℃. 1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.55-7.52(m,3H),7.26(d,J=7.9Hz,2H),7.04(d,J=9.2Hz,1H),4.07(s,2H),2.94(s,3H),2.88(s,3H),2.39(s,3H),2.34(s,3H).

[0226]

[0227] mp:144-145℃. 1 H NMR(400MHz,CDCl3)δ7.74(t,J=9.3Hz,3H),7.43(dd,J=8.4,1.7Hz,1H),7.39(d,J=7.9Hz,2H),7.27-7.23(m,2H),7.18(dd,J=8.9,2.5Hz,1H),7.14(d,J=2.4Hz,1H),7.05(t,J=7.4Hz,2H),3.93(s,3H),3.85(q,J=7.1Hz,1H),1.67(d,J=7.1Hz,3H).

[0228]

[0229] mp:143-145℃. 1 H NMR(400MHz,CDCl3)δ7.41(d,J=8.0Hz,2H),7.27-7.23(m,4H),7.14(d,J=8.0Hz,2H),7.05(t,J=7.4Hz,1H),3.69(q,J=7.1Hz,1H),2.47(d,J=7.2Hz,2H),1.93-1.79(m,1H),1.58(d,J=7.2Hz,3H),0.91(d,J=6.6Hz,6H).

[0230]

[0231] mp:164-165℃. 1 H NMR(400MHz,CDCl3)δ7.87(d,J=7.2Hz,2H),7.84(br,1H),7.64(d,J=7.7Hz,2H),7.55(t,J=7.3Hz,1H),7.48(t,J=7.3Hz,2H),7.37(t,J=7.9Hz,2H),7.15(t,J=7.4Hz,1H).

[0232]

[0233] mp:200-201℃. 1 H NMR(400MHz,CDCl3)δ7.82(d,J=8.6Hz,2H),7.75(br,1H),7.62(d,J=7.6Hz,2H),7.47(d,J=8.6Hz,2H),7.41-7.36(m,2H),7.17(t,J=7.4Hz,1H).

[0234]

[0235] mp:145-146℃. 1 H NMR(400MHz,CDCl3)δ7.84-7.76(m,3H),7.64(d,J=7.7Hz,2H),7.37(t,J=7.9Hz,2H),7.29(d,J=8.0Hz,2H),7.14(t,J=7.4Hz,1H),2.43(s,3H).

[0236]

[0237] mp:150-151℃. 1 H NMR(400MHz,CDCl3)δ7.76(d,J=15.5Hz,1H),7.71-7.46(m,4H),7.37-7.33(m,5H),7.13(t,J=7.3Hz,1H),6.57(d,J=15.5Hz,1H).

[0238]

[0239] mp:87-88℃. 1 H NMR(400MHz,CDCl3)δ7.51(d,J=7.9Hz,2H),7.31(t,J=7.9Hz,2H),7.18(br,1H),7.09(t,J=7.4Hz,1H),2.35(t,J=7.6Hz,2H),1.76-1.69(m,2H),1.45-1.25(m,24H),0.88(t,J=6.8Hz,3H).

[0240]

[0241] mp:158-159℃. 1H NMR(400MHz,CDCl3)δ7.51(d,J=7.9Hz,2H),7.31(t,J=7.5Hz,2H),7.10(t,J=7.2Hz,1H),4.25-4.11(m,2H),2.80-2.75(m,2H),2.42-2.34(m,1H),1.90-1.69(m,4H),1.47(s,9H).

Claims

1. A method for preparing an amide compound represented by formula (I), characterized in that The preparation method comprises: adding a compound represented by formula (II) and a compound represented by formula (III) into an organic solvent, adding a difluorocarbene reagent to construct a reaction system, reacting at 60-130° C. for 6-15 hours, and after the reaction is completed, post-treating the obtained reaction solution to obtain the amide compound represented by formula (I); the difluorocarbene reagent is one or a mixture of two or more of difluoroethyl bromoacetate, difluorochloroacetate, and difluoromonochloromethane; the molar ratio of the compound represented by formula (II), the compound represented by formula (III) and the difluorocarbene reagent is 1:0.8-2:1-80; Among them, in formula (I), formula (II) and formula (III), R 1 C 1-20 Alkyl, phenyl, halogen or C 1-4 Alkyl-substituted phenyl, benzyl, halogen, C 1-4 Alkyl or C 1-4 Alkoxy-substituted benzyl, 1-tert-butyloxycarbonyl-4-piperidinyl, a substituent represented by formula (X), a substituent represented by formula (Y), a substituent represented by formula (Z), or a styryl group; R 2 C 1-4 Alkyl, naphthyl, thiazolyl, pyridyl, phenyl or halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylcarbonyl, cyano, C 1-4 Alkylthio, nitro or C 1-4 Hydroxyalkyl substituted phenyl, R 3 is hydrogen or C 1-4 Alkyl, or R 2 , R 3 Combined with the N between the two, a piperidine ring or a morpholine ring is formed.

2. The method for preparing the amide compound represented by formula (I) as claimed in claim 1, characterized in that: The organic solvent is one or a mixed solvent of two or more selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, toluene, chlorobenzene, dimethyl sulfoxide, ethanol, and 1,4-dioxane; the volume of the organic solvent is 3.3 to 4 mL / mmol based on the amount of the compound represented by formula (II).

3. The method for preparing the amide compound represented by formula (I) as claimed in claim 1, characterized in that: The amide compound represented by formula (I) is one of the following:

4. The method for preparing the amide compound represented by formula (I) according to any one of claims 1 to 3, characterized in that: An alkaline substance is also added to the reaction system, and the alkaline substance is one or a mixture of two or more of cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium hydroxide, lithium hydroxide, potassium phosphate, triethylamine, DBU, and DMAP.

5. The method for preparing the amide compound represented by formula (I) as claimed in claim 4, characterized in that: The molar ratio of the compound represented by formula (II) to the alkaline substance is 1:0-4, wherein 0 is infinitely close to 0 but not 0.

6. The method for preparing the amide compound represented by formula (I) as claimed in claim 4, characterized in that: When the difluorocarbene reagent is ethyl difluorobromoacetate, the alkaline substance is triethylamine, the reaction solvent is N,N-dimethylformamide, the reaction temperature is 110° C., and the molar ratio of the compound represented by formula (II), the compound represented by formula (III), the difluorocarbene reagent and the alkaline substance is 1:1.5:3:

2.

7. The method for preparing the amide compound represented by formula (I) as claimed in claim 4, characterized in that: When the difluorocarbene reagent is sodium difluorochloroacetate, the alkaline substance is cesium carbonate, the reaction solvent is N,N-dimethylformamide, the reaction temperature is 110° C., and the molar ratio of the compound represented by formula (II), the compound represented by formula (III), the difluorocarbene reagent and the alkaline substance is 1:1.2:2:1.

5.

8. The method for preparing the amide compound represented by formula (I) as claimed in claim 4, characterized in that: When the difluorocarbene reagent is difluorochloromethane, the alkaline substance is potassium carbonate, the reaction solvent is N,N-dimethylformamide, the reaction temperature is 80°C, and the molar ratio of the compound represented by formula (II), the compound represented by formula (III), difluorochloromethane and the alkaline substance is 1:1:80:1.

5.

9. The method for preparing the amide compound represented by formula (I) as claimed in claim 1, characterized in that: When the difluorocarbene reagent is ethyl difluorobromoacetate or sodium difluorochloroacetate, the reaction is carried out under a protective atmosphere.

10. The method for preparing the amide compound represented by formula (I) according to claim 1, characterized in that: The post-treatment is as follows: after the reaction is completed, dilute with water, extract with ethyl acetate, combine the organic layers, wash with saturated brine, then dry with anhydrous sodium sulfate, filter, concentrate, perform silica gel column chromatography with petroleum ether and ethyl acetate in a volume ratio of 0-9:1 as eluent, collect the eluate containing the target product, distill under reduced pressure, and dry to obtain the amide compound shown in formula (I).

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