CN112920079A - Preparation method of amide compound - Google Patents
Preparation method of amide compound Download PDFInfo
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- CN112920079A CN112920079A CN202110125455.6A CN202110125455A CN112920079A CN 112920079 A CN112920079 A CN 112920079A CN 202110125455 A CN202110125455 A CN 202110125455A CN 112920079 A CN112920079 A CN 112920079A
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- amide
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- -1 amide compound Chemical class 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 138
- 238000006243 chemical reaction Methods 0.000 claims abstract description 70
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 5
- 125000002252 acyl group Chemical group 0.000 claims abstract description 4
- 238000007112 amidation reaction Methods 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 63
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 32
- 150000001263 acyl chlorides Chemical class 0.000 claims description 31
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 21
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 claims description 17
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 16
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 claims description 6
- 150000007960 acetonitrile Chemical class 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- LTYRAPJYLUPLCI-UHFFFAOYSA-N glycolonitrile Chemical compound OCC#N LTYRAPJYLUPLCI-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 2
- FKTXDTWDCPTPHK-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical group FC(F)(F)[C](F)C(F)(F)F FKTXDTWDCPTPHK-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 238000009776 industrial production Methods 0.000 abstract description 6
- 238000004440 column chromatography Methods 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000006215 cyanomethylation reaction Methods 0.000 abstract description 4
- 150000002894 organic compounds Chemical class 0.000 abstract description 2
- 238000011112 process operation Methods 0.000 abstract description 2
- 230000035484 reaction time Effects 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- 239000000203 mixture Substances 0.000 description 46
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 45
- 238000010438 heat treatment Methods 0.000 description 45
- 238000001035 drying Methods 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 238000010992 reflux Methods 0.000 description 27
- 238000005406 washing Methods 0.000 description 27
- 239000000047 product Substances 0.000 description 26
- 238000001816 cooling Methods 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 238000004809 thin layer chromatography Methods 0.000 description 18
- 239000007787 solid Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- UOYDNSRSUSNCKS-UHFFFAOYSA-N methyl 3-amino-2-fluorobenzoate Chemical compound COC(=O)C1=CC=CC(N)=C1F UOYDNSRSUSNCKS-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 239000006227 byproduct Substances 0.000 description 9
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 239000007789 gas Substances 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 230000003301 hydrolyzing effect Effects 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 238000006386 neutralization reaction Methods 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 7
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical group [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- RAAGZOYMEQDCTD-UHFFFAOYSA-N 2-fluorobenzoyl chloride Chemical compound FC1=CC=CC=C1C(Cl)=O RAAGZOYMEQDCTD-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 241000426497 Chilo suppressalis Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241001477931 Mythimna unipuncta Species 0.000 description 1
- 241000500437 Plutella xylostella Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Abstract
The invention provides a preparation method of an amide compound, belonging to the field of synthesis of organic compounds. The method comprises the steps of sequentially carrying out primary substitution reaction, secondary substitution reaction, hydrolysis reaction, acyl chlorination reaction and amidation reaction on an initial compound to finally obtain the amide compound. The preparation method provided by the invention has the advantages of simple preparation process, advanced cyanomethylation step, direct reaction of the product in the next step without column chromatography step, simplified process operation flow, shortened reaction time, saved cost, high reaction yield, suitability for industrial production, good application prospect and industrial production potential.
Description
Technical Field
The invention belongs to the field of synthesis of organic compounds, and particularly relates to a preparation method of an amide compound.
Background
The amide compound has wide application in the fields of pesticides and medicines, and has wide application in agriculture such as insect killing, sterilization, weeding, virus resistance and the like because the compound has broad-spectrum biological activity.
The patent document with the publication number of CN110194726A reports a benzamide compound and application thereof, and the compound with the structure of the formula I has excellent insecticidal activity and can effectively control pests such as diamondback moth, armyworm, chilo suppressalis and the like under lower dosage.
However, the synthesis method has great defects, particularly, the reaction step of bromoacetonitrile and amide is adopted, the reaction conditions of potassium tert-butoxide, sodium hydride and the like are harsh, the yield is low, and the separation process of the reaction needs to be subjected to a column chromatography step, so that the industrial large-scale application of the reaction is limited.
For example, patent publication No. CN108840806A discloses a process for preparing benzamide compounds, which comprises mixing amino compounds and phenylacetonitrile, adding into a solvent, reacting under the action of a copper catalyst, and after the reaction is finished, performing column chromatography to obtain the target product, wherein the yield of the product obtained by the process is low.
In the past, the technical personnel have been devoted to continuously research and develop new, more advanced and more reasonable preparation methods more suitable for industrial production so as to obtain amide compounds with simpler preparation process, higher yield and lower price.
Therefore, the method for preparing the amide compound has the advantages of simple preparation process, capability of advancing the step of cyanomethylation, high reaction yield and suitability for industrial production, and the product can directly enter the next reaction without the step of column chromatography.
Disclosure of Invention
Aiming at the defects of the prior amide compound preparation method, the invention provides the amide compound preparation method which has simple preparation process and high reaction yield and is suitable for industrial production.
The invention is realized by the following technical scheme:
a process for producing an amide compound represented by the following reaction formula:
in the formula:
R1、R2each independently selected from hydrogen, halogen, C1-C6Alkyl of (C)1-C6Halogenoalkyl of, C1-C6Alkoxy or C1-C6Haloalkoxy of (a);
R3selected from heptafluoroisopropyl or nonafluoro-2-butyl;
R4selected from hydrogen, C1-C6Alkyl of (C)1-C6Haloalkyl or cyanomethyl of (a);
R5selected from hydrogen, halogen, cyano, nitro, C1-C6Alkyl of (C)1-C6Halogenoalkyl of, C1-C6Alkoxy group of (C)1-C6Halogenoalkoxy of (C)1-C6Alkylthio or C of1-C6Haloalkylthio of (a);
X1、X2、X3each independently selected from hydrogen, halogen, cyano or C1-C6Alkoxy group of (a);
the reaction steps are as follows:
the method comprises the following steps: carrying out primary substitution reaction on the compound of the formula (2) and substituted acetonitrile to prepare a compound of a formula (3);
secondly, the step of: carrying out secondary substitution reaction on the compound shown in the formula (3) and benzoyl chloride to obtain a compound shown in a formula (4);
③: the compound of the formula (4) is hydrolyzed under alkaline conditions to prepare a compound of a formula (5);
fourthly, the method comprises the following steps: the amide compound of formula (1) is prepared by amidation reaction of acyl chloride obtained by acyl chlorination of the compound of formula (5) with the compound of formula (6).
Preferably, in the step (i), the substituted acetonitrile is one of chloroacetonitrile, bromoacetonitrile and hydroxyacetonitrile, and the molar ratio of the compound of formula (2) to the substituted acetonitrile is 1: 1-2.
Preferably, the molar ratio of the compound in the formula (3) to benzoyl chloride in the step (c) is 1: 1-3.
Preferably, the alkali reacted in the step (c) is one of potassium carbonate, sodium carbonate and sodium bicarbonate, the molar ratio of the compound of the formula (4) to the alkali is 1:0.5-3, and the temperature of the hydrolysis reaction is 25-80 ℃.
Preferably, the molar ratio of the acyl chloride to the compound of formula (6) in the step (iv) is 1: 0.5-2.
Preferably, the solvent used for acyl chlorination of the compound in the formula (5) in the step (iv) is oxalyl chloride or thionyl chloride.
Preferably, in the step (iv), the acyl chloride is reacted with the compound of formula (6) in acetonitrile solvent under the catalysis of potassium iodide.
Preferably, the solvent for preparing the compound of formula (3) from the compound of formula (2) and the solvent for preparing the compound of formula (4) from the compound of formula (3) are selected from one of toluene, acetone, acetonitrile, dichloromethane, dioxane and dimethylformamide.
As a technical scheme, the compound in the formula (2) in the step (r) can also react with formaldehyde and hydrocyanic acid to prepare the compound in the formula (3).
Preferably, the molar ratio of the compound in the formula (2), formaldehyde and hydrocyanic acid in the step (i) is 1:5-6: 4-5.
Compared with the prior art, the invention has the advantages and beneficial effects that:
1. the novel method for preparing the amide compound avoids the harsh reaction conditions of potassium tert-butoxide, sodium hydride and the like used in the reaction step of bromoacetonitrile and amide in the prior art, and also leads the step of cyanomethylation to be advanced, and the product directly carries out the next reaction without the step of column chromatography, thereby shortening the process operation flow and greatly improving the reaction efficiency.
2. The method for preparing the amide compound has reasonable design, mild reaction conditions, easily obtained raw materials, convenient operation and high product yield, is suitable for large-scale production, has important market value and economic benefit for industrial production of the amide compound, and lays a foundation for further research of the amide compound.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to the scope of the present invention.
Example 1
Synthesis of a compound of formula (1):
step A: adding 1.5 g of 2-fluoro-3-aminobenzoic acid methyl ester, 1.2 g of bromoacetonitrile, 0.2 g of potassium iodide and 10 ml of dimethylformamide into a round-bottom flask in sequence, slowly heating the mixture, heating up, refluxing for reaction for 10 hours, tracking by using a thin layer chromatography, cooling to room temperature after the reaction is finished, distilling the obtained mixture, washing the product with petroleum ether and water in sequence, extracting with ethyl acetate, and drying in vacuum to obtain 1.5 g of the compound shown in the formula (3), wherein the yield is 81%;
and B: adding 1 g of the compound shown in the formula (3) as a product in the step A, 15 g of acetonitrile and 0.8 g of benzoyl chloride into a round-bottom flask in sequence, slowly heating the mixture, heating up for reflux reaction for 15h, tracking by using thin-layer chromatography, cooling to room temperature after the reaction is finished, distilling the obtained mixture, collecting solids, washing with isooctane, a sodium carbonate aqueous solution and water in sequence, and drying in vacuum at 40 ℃ to obtain 1.2 g of the compound shown in the formula (4), wherein the yield is 80%;
and C: adding 1 g of the compound of the formula (4), 2 g of dioxane, 4 g of water and 0.6 g of potassium carbonate into a round-bottom flask in sequence, hydrolyzing at 30 ℃ for 2 hours, adding 10% hydrochloric acid to adjust the pH value to 6, extracting with ethyl acetate, washing an organic phase with saturated salt water, drying with anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain 1.3 g of the compound of the formula (5), wherein the yield is 85%;
step D: sequentially adding 1 g of the compound shown in the formula (5) as a product in the step 3 and 10 g of dichloromethane into a flask, dropwise adding 20 g of oxalyl chloride under ice bath, stirring for 5h at normal temperature, absorbing the generated hydrogen chloride gas with water to obtain a byproduct hydrochloric acid, distilling under reduced pressure, and drying to obtain the acyl chloride of the compound shown in the formula (5) for later use;
step E: 10 g of acetonitrile, 0.7 g of 2, 6-dibromo-4-heptafluoroisopropyl aniline of the formula (5) and 0.5 g of potassium iodide are sequentially added into a flask, 0.6 g of acyl chloride of the compound of the formula (5) is stirred and added, the mixture is slowly heated, heated and refluxed for 8 hours, the rest of acyl chloride is added after the temperature is reduced, the mixture is heated and refluxed again, a point plate is tracked until the amine reaction is complete, the reaction solution is poured into a saturated sodium bicarbonate solution, the precipitated solid is filtered, and the compound of the formula (1) 1.1 g is obtained after vacuum drying, wherein the yield is 71%.
Example 2
Synthesis of a compound of formula (1):
step A: adding 1.8 g of 2-fluoro-3-aminobenzoic acid methyl ester, 1.5 g of bromoacetonitrile, 0.3 g of potassium iodide and 15 ml of acetone into a round-bottom flask in sequence, slowly heating the mixture, heating up, refluxing for reaction for 10 hours, tracking by using a thin layer chromatography, cooling to room temperature after the reaction is finished, distilling the obtained mixture, collecting a product, washing with petroleum ether and water in sequence, and drying in vacuum at 40 ℃ to obtain 1.7 g of a compound shown in the formula (3), wherein the yield is 83%;
and B: adding 1.2 g of the compound of formula (3) as a product in the step A, 15 g of dichloroethane and 1.0 g of benzoyl chloride into a round-bottom flask in sequence, slowly heating the mixture, heating up, refluxing for 8 hours, tracking by using thin-layer chromatography, cooling to room temperature after the reaction is finished, distilling the mixture obtained by the reaction, collecting solids, washing with isooctane, water, sodium carbonate and water in sequence, and drying in vacuum at 40 ℃ to obtain 1.2 g of the compound of formula (4), wherein the yield is 80%;
and C: adding 1.2 g of the compound of the formula (4), 3 g of dioxane, 6 g of water and 0.8 g of sodium carbonate into a round-bottom flask in sequence, hydrolyzing for 2 hours at 40 ℃, adding hydrochloric acid for neutralization, extracting with ethyl acetate, washing an organic phase with saturated salt, drying with anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure to obtain 1.3 g of the compound of the formula (5), wherein the yield is 84%;
step D: adding 1.2 g of the compound shown in the formula (5) as a product in the step 3 and 15 g of dichloromethane into a flask in sequence, dropwise adding 10 g of thionyl chloride under ice bath, stirring for 5 hours at normal temperature, absorbing the generated hydrogen chloride gas with water to obtain a byproduct hydrochloric acid, distilling under reduced pressure, and drying to obtain the acyl chloride of the compound shown in the formula (5) for later use;
step E: adding 15 g of acetonitrile, 0.8 g of 2, 6-dibromo-4-heptafluoroisopropyl aniline and 0.7 g of potassium iodide into a flask in sequence, stirring and adding 0.7 g of acyl chloride of the compound of the formula (5), slowly heating the mixture, heating up and refluxing for reaction for 10 hours, cooling, adding the rest of acyl chloride, heating up and refluxing again, tracking until the amine reaction is complete, pouring the reaction liquid into a saturated sodium bicarbonate solution, filtering out the precipitated solid, and drying in vacuum to obtain 1.3 g of the compound of the formula (1) with the yield of 76%.
Example 3
Synthesis of a compound of formula (1):
step A: adding 2.0 g of 2-fluoro-3-aminobenzoic acid methyl ester, 1.8 g of bromoacetonitrile, 0.5 g of potassium iodide and 18 ml of acetonitrile into a round-bottom flask in sequence, slowly heating the mixture, heating up, refluxing for reaction for 8 hours, tracking by using a thin layer chromatography, cooling to room temperature after the reaction is finished, distilling the obtained mixture, collecting solids, washing with petroleum ether and water in sequence, and drying in vacuum at 40 ℃ to obtain 2.1 g of the compound shown in the formula (3), wherein the yield is 85%;
and B: adding 1.5 g of the compound of formula (3) as a product in the step A, 20 g of toluene and 1.2 g of benzoyl chloride into a round-bottom flask in sequence, slowly heating the mixture, heating up, refluxing for reaction for 8 hours, tracking by using thin-layer chromatography, cooling to room temperature after the reaction is finished, distilling the mixture obtained by the reaction, collecting solids, washing with isooctane, water, sodium carbonate and water in sequence, and drying in vacuum at 40 ℃ to obtain 1.6 g of the compound of formula (4), wherein the yield is 82%;
and C: adding 1.5 g of the compound of the formula (4), 4 g of dimethyl imide, 8 g of water and 1.2 g of sodium bicarbonate into a round-bottom flask in sequence, hydrolyzing at 50 ℃ for 2 hours, adding hydrochloric acid for neutralization, extracting with ethyl acetate, washing an organic phase with saturated common salt, drying with anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure to obtain 1.3 g of the compound of the formula (5), wherein the yield is 65%;
step D: adding 1.2 g of the compound shown in the formula (5) as a product in the step 3 and 10 g of dichloromethane into a flask in sequence, dropwise adding 20 g of oxalyl chloride under ice bath, stirring for 5h at normal temperature, absorbing the generated hydrogen chloride gas with water to obtain a byproduct hydrochloric acid, distilling under reduced pressure, and drying to obtain the acyl chloride of the compound shown in the formula (5) for later use;
step E: 10 g of acetonitrile, 1.0 g of 2, 6-dibromo-4-heptafluoroisopropyl aniline and 0.5 g of potassium iodide are sequentially added into a flask, 0.8 g of acyl chloride of the compound shown in the formula (5) is stirred and added, the mixture is slowly heated, heated and refluxed for 8 hours, the rest of acyl chloride is added after the temperature is reduced, the mixture is heated and refluxed again, a point plate is tracked until the amine is completely reacted, the reaction liquid is poured into a saturated sodium bicarbonate solution, the precipitated solid is filtered, and the compound shown in the formula (1) is obtained after vacuum drying, wherein the yield is 73%.
Example 4
The procedure is as in example 3, except that 1.8 g of bromoacetonitrile in step A are replaced by 1.6 g of chloroacetonitrile, giving a yield of 70% of the compound of formula (3).
Example 5
The procedure was as in example 3, except that 1.4 g of bromoacetonitrile in step A was replaced with 1.1 g of hydroxyacetonitrile to obtain the compound of formula (3) in a yield of 69%.
Example 6
The procedure as in example 3, except that bromoacetonitrile in step A was replaced with formaldehyde and hydrocyanic acid. The specific mode is as follows: 1.5 g of methyl 2-fluoro-3-aminobenzoate is added into a round bottom flask in sequence, 1.5 g of formaldehyde and 1 g of hydrocyanic acid are contained in a constant pressure funnel, the temperature is controlled to be about 75 ℃, the dropwise addition is finished at the same time for 2 hours, and the temperature is kept for 3 hours. Standing for 10 min, removing water phase, extracting oil phase with water twice, extracting with organic solvent once, and crystallizing to obtain the product with yield of 71%.
Example 7
The procedure was as in example 3 except that 1.8 g of bromoacetonitrile in step A was replaced with 1.6 g of chloroacetonitrile, potassium iodide was replaced with sodium bromide and the final product of formula (3) was obtained in 75% yield.
The results are shown in the following table:
TABLE 1. examples 4-7 yield of formula (3) in step A
The results of the above examples 4 to 7 show that the yields of the compound of formula (3) obtained when methyl 2-fluoro-3-aminobenzoate is reacted with chloroacetonitrile, hydroxyacetonitrile, formaldehyde and hydrocyanic acid, chloroacetonitrile and sodium bromide, respectively, are high, which indicates that these substances can react with methyl 2-fluoro-3-aminobenzoate, so that the step of cyanomethylation in the reaction process is advanced and the reaction achieves a good effect.
Example 8
Synthesis of a compound of formula (1):
step A: adding 1.5 g of 2-fluoro-3-aminobenzoic acid methyl ester, 1.2 g of bromoacetonitrile, 0.2 g of potassium iodide and 10 ml of dioxane into a round bottom flask in sequence, slowly heating the mixture, heating to 70 ℃, carrying out reflux reaction for 10h, tracking by using a thin layer chromatography, cooling to room temperature after the reaction is finished, distilling the obtained mixture, washing with petroleum ether and water in sequence, and drying in vacuum to obtain 1.5 g of a compound shown as a formula (3), wherein the yield is 83%;
and B: adding 1 g of the compound shown in the formula (3) as a product in the step A, 15 g of dimethylformamide and 0.8 g of benzoyl chloride into a round-bottom flask in sequence, slowly heating the mixture, heating up, carrying out reflux reaction for 10 hours, cooling to room temperature after the reaction is finished, tracking by using a thin layer chromatography, distilling the obtained mixture, washing by using isooctane, water, sodium carbonate and water in sequence, and drying in vacuum at 40 ℃ to obtain 1.2 g of the compound shown in the formula (4), wherein the yield is 80%;
and C: adding 1 g of the compound of the formula (4), 2 g of dioxane, 4 g of water and 0.6 g of potassium carbonate into a round-bottom flask in sequence, hydrolyzing at 40 ℃ for 2 hours, adding hydrochloric acid for neutralization, extracting with ethyl acetate, washing an organic phase with saturated common salt, drying with anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure to obtain 1.3 g of the compound of the formula (5), wherein the yield is 85%;
step D: sequentially adding 1 g of the compound shown in the formula (5) as a product in the step 3 and 10 g of dichloromethane into a flask, dropwise adding 20 g of oxalyl chloride under ice bath, stirring for 5h at normal temperature, absorbing the generated hydrogen chloride gas with water to obtain a byproduct hydrochloric acid, distilling under reduced pressure, and drying to obtain the acyl chloride of the compound shown in the formula (5) for later use;
step E: 10 g of acetonitrile, 0.73 g of 2-iodo-6-bromo-4-heptafluoroisopropyl aniline and 0.3 g of potassium iodide are sequentially added into a flask, 0.6 g of acyl chloride of the compound shown in the formula (5) is stirred and added, the mixture is slowly heated, heated and refluxed for reaction for 8 hours, the rest acyl chloride is added after cooling, the mixture is heated again for reflux, a point plate is tracked until the amine reaction is complete, the reaction solution is poured into a saturated sodium bicarbonate solution, the precipitated solid is filtered, and the compound shown in the formula (1) 1.3 g is obtained after vacuum drying, wherein the yield is 78%.
Example 9
Synthesis of a compound of formula (1):
step A: adding 1.5 g of 2-fluoro-3-aminobenzoic acid methyl ester, 1.2 g of bromoacetonitrile, 0.2 g of potassium iodide and 10 ml of acetone into a round-bottom flask in sequence, slowly heating the mixture, heating to 60 ℃, carrying out reflux reaction for 10h, tracking by using a thin layer chromatography, cooling to room temperature after the reaction is finished, distilling the obtained mixture, washing with petroleum ether and water in sequence, and drying in vacuum to obtain 1.5 g of a compound shown as a formula (3), wherein the yield is 82%;
and B: adding 1 g of the compound shown in the formula (3) as a product in the step A, 15 g of dimethylformamide and 0.8 g of benzoyl chloride into a round-bottom flask in sequence, slowly heating the mixture, heating to 70 ℃, carrying out reflux reaction for 10 hours, tracking by using thin-layer chromatography, cooling to room temperature after the reaction is finished, distilling the obtained mixture, washing with isooctane, water, sodium carbonate and water in sequence, and drying in vacuum at 40 ℃ to obtain 1.2 g of the compound shown in the formula (4), wherein the yield is 80%;
and C: adding 1 g of the compound of the formula (4), 2 g of dioxane, 4 g of water and 0.6 g of sodium carbonate into a round-bottom flask in sequence, hydrolyzing at 30 ℃ for 2 hours, adding hydrochloric acid for neutralization, extracting with ethyl acetate, washing an organic phase with saturated common salt, drying with anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure to obtain 1.3 g of the compound of the formula (5), wherein the yield is 83%;
step D: sequentially adding 1 g of the compound shown in the formula (5) as a product in the step 3 and 10 g of dichloromethane into a flask, dropwise adding 20 g of oxalyl chloride under ice bath, stirring for 5h at normal temperature, absorbing the generated hydrogen chloride gas with water to obtain a byproduct hydrochloric acid, distilling under reduced pressure, and drying to obtain the acyl chloride of the compound shown in the formula (5) for later use;
step E: 10 g of acetonitrile, 0.78 g of 2-iodo-6-bromo-4-heptafluoroisopropyl aniline and 0.3 g of potassium iodide are sequentially added into a flask, 0.7 g of acyl chloride of the compound shown in the formula (5) is stirred and added, the mixture is slowly heated, heated and refluxed for reaction for 9 hours, the rest acyl chloride is added after cooling, the mixture is heated again for reflux, a point plate is tracked until the amine reaction is complete, the reaction solution is poured into a saturated sodium bicarbonate solution, the precipitated solid is filtered, and the compound shown in the formula (1) is obtained after vacuum drying, wherein the yield is 75%.
Example 10
Synthesis of a compound of formula (1):
step A: adding 1.8 g of 2-fluoro-3-aminobenzoic acid methyl ester, 1.4 g of bromoacetonitrile, 0.4 g of potassium iodide and 15 ml of dimethylformamide into a round-bottom flask in sequence, slowly heating the mixture, heating up, refluxing for 10 hours, tracking by using a thin layer chromatography, cooling to room temperature after the reaction is finished, distilling the reaction mixture, washing with petroleum ether and water in sequence, and drying in vacuum to obtain 1.7 g of a compound shown as a formula (3), wherein the yield is 81%;
and B: adding 1.3 g of the compound shown in the formula (3) as a product in the step A, 18 g of toluene and 1.0 g of o-fluorobenzoyl chloride into a round-bottom flask in sequence, slowly heating the mixture, heating up, refluxing for 10 hours, tracking by using a thin layer chromatography, distilling the reaction mixture, washing by using isooctane, water, sodium carbonate and water in sequence, and drying in vacuum to obtain 1.5 g of the compound shown in the formula (4), wherein the yield is 82%;
and C: adding 1.3 g of the compound of the formula (4), 2.2 g of dioxane, 6 g of water and 0.8 g of potassium carbonate into a round-bottom flask in sequence, hydrolyzing at 50 ℃ for 2 hours, adding hydrochloric acid for neutralization, extracting with ethyl acetate, washing an organic phase with saturated salt water, drying with anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure to obtain 1.4 g of the compound of the formula (5), wherein the yield is 81%;
step D: adding 1.2 g of the compound shown in the formula (5) serving as a product in the step C and 15 g of dichloromethane into a flask in sequence, dropwise adding 23 g of oxalyl chloride under ice bath, stirring for 5 hours at normal temperature, absorbing generated hydrogen chloride gas with water to obtain a byproduct hydrochloric acid, distilling under reduced pressure, and drying to obtain an acyl chloride of the compound shown in the formula (5) for later use;
step E: adding 15 g of acetonitrile, 0.8 g of 2, 6-dibromo-4-heptafluoroisopropyl aniline and 0.6 g of potassium iodide into a flask in sequence, stirring and adding 0.6 g of acyl chloride of the compound of the formula (5), slowly heating the mixture, heating up and refluxing for reaction for 10 hours, cooling, adding the rest of acyl chloride, heating up and refluxing again, tracking until the amine reaction is complete, pouring the reaction liquid into a saturated sodium bicarbonate solution, filtering out the precipitated solid, and drying in vacuum to obtain 1.2 g of the compound of the formula (1) with the yield of 73%.
Example 11
Synthesis of a compound of formula (1):
step A: adding 1.8 g of methyl 2-fluoro-3-aminobenzoate, 1.4 g of bromoacetonitrile, 0.5 g of potassium iodide and 15 ml of acetonitrile into a round-bottom flask in sequence, slowly heating the mixture, heating to reflux for reaction for 9 hours, tracking by using a thin-layer chromatography, cooling to room temperature after the reaction is finished, distilling the reaction mixture, washing with petroleum ether and water in sequence, and drying in vacuum at 40 ℃ to obtain 1.7 g of a compound shown as a formula (3), wherein the yield is 81%;
and B: adding 1.5 g of the compound of formula (3) as a product in the step A, 20 g of dioxane and 1.2 g of o-fluorobenzoyl chloride into a round-bottom flask in sequence, slowly heating the mixture, heating up, refluxing for 8 hours, performing tracking by using a thin layer chromatography, distilling the reaction mixture, washing with isooctane, water, sodium carbonate and water in sequence, and performing vacuum drying to obtain 1.4 g of the compound of formula (4), wherein the yield is 80%;
and C: adding 1.5 g of the compound of the formula (4), 4 g of dioxane, 6 g of water and 1.8 g of sodium carbonate into a round-bottom flask in sequence, hydrolyzing at 50 ℃ for 2 hours, adding hydrochloric acid for neutralization, extracting with ethyl acetate, washing an organic phase with saturated salt water, drying with anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure to obtain 1.8 g of the compound of the formula (5), wherein the yield is 85%;
step D: adding 1.5 g of the compound shown in the formula (5) serving as a product in the step C and 20 g of dichloromethane into a flask in sequence, dropwise adding 23 g of oxalyl chloride under ice bath, stirring for 5 hours at normal temperature, absorbing generated hydrogen chloride gas with water to obtain a byproduct hydrochloric acid, distilling under reduced pressure, and drying to obtain an acyl chloride of the compound shown in the formula (5) for later use;
step E: adding 15 g of acetonitrile, 1.0 g of 2, 6-dibromo-4-heptafluoroisopropyl aniline and 0.8 g of potassium iodide into a flask in sequence, stirring and adding 0.8 g of acyl chloride of the compound shown in the formula (5), slowly heating the mixture, heating up and refluxing for reaction for 8 hours, cooling, adding the rest of acyl chloride, heating up and refluxing again, tracking until the amine reaction is complete, pouring the reaction liquid into a saturated sodium bicarbonate solution, filtering out the precipitated solid, and drying in vacuum to obtain 1.4 g of the compound shown in the formula (1), wherein the yield is 76%.
Example 12
Synthesis of a compound of formula (1):
step A: adding 2.2 g of 2-fluoro-3-aminobenzoic acid methyl ester, 2.0 g of bromoacetonitrile, 0.8 g of potassium iodide and 20 ml of dioxane into a round bottom flask in sequence, slowly heating the mixture, heating up, refluxing for reaction for 8 hours, tracking by using a thin layer chromatography, cooling to room temperature after the reaction is finished, distilling the reaction mixture, washing with petroleum ether and water in sequence, and drying in vacuum at 40 ℃ to obtain 2.3 g of a compound shown as a formula (3), wherein the yield is 83%;
and B: adding 1.8 g of the compound of formula (3) as a product in the step A, 25 g of dichloromethane and 1.5 g of o-fluorobenzoyl chloride into a round-bottom flask in sequence, slowly heating the mixture, heating up for reflux reaction for 10 hours, tracking by using thin-layer chromatography, cooling to room temperature after the reaction is finished, distilling the obtained mixture, collecting solids, washing with isooctane, water, sodium carbonate and water in sequence, and drying in vacuum to obtain 2.0 g of the compound of formula (4), wherein the yield is 82%;
and C: adding 1.8 g of the compound of the formula (4), 2 g of dioxane, 4 g of water and 0.6 g of sodium carbonate into a round-bottom flask in sequence, hydrolyzing at 45 ℃ for 2 hours, adding hydrochloric acid for neutralization, extracting with ethyl acetate, washing an organic phase with saturated salt water, drying with anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure to obtain 1.3 g of the compound of the formula (5), wherein the yield is 84%;
step D: adding 1.8 g of the compound shown in the formula (5) serving as a product in the step C and 20 g of dichloromethane into a flask in sequence, dropwise adding 28 g of oxalyl chloride under ice bath, stirring for 5 hours at normal temperature, absorbing generated hydrogen chloride gas with water to obtain a byproduct hydrochloric acid, distilling under reduced pressure, and drying to obtain an acyl chloride of the compound shown in the formula (5) for later use;
step E: 20 g of acetonitrile, 1.2 g of 2, 6-dibromo-4-heptafluoroisopropyl aniline and 0.8 g of potassium iodide are sequentially added into a flask, 0.8 g of acyl chloride of the compound shown in the formula (5) is stirred and added, the mixture is slowly heated, heated and refluxed for 10 hours, the rest of acyl chloride is added after the temperature is reduced, the mixture is heated and refluxed again, a point plate is tracked until the amine reaction is complete, the reaction liquid is poured into a saturated sodium bicarbonate solution, the precipitated solid is filtered, and the compound shown in the formula (1) is obtained after vacuum drying, wherein the yield is 78%.
Example 13
Synthesis of a compound of formula (1):
step A: adding 2.5 g of 2-fluoro-3-aminobenzoic acid methyl ester, 2 g of bromoacetonitrile, 0.4 g of potassium iodide and 25 ml of dichloromethane into a round-bottom flask in sequence, slowly heating the mixture, heating up, refluxing for 10 hours, tracking by using a thin-layer chromatography, cooling to room temperature after the reaction is finished, distilling the obtained mixture, washing by using petroleum ether and water in sequence, and drying in vacuum to obtain 2.6 g of a compound shown as a formula (3), wherein the yield is 83%;
and B: adding 2 g of the compound of formula (3) as a product in the step A, 30 g of acetone and 1.6 g of benzoyl chloride into a round-bottom flask in sequence, slowly heating the mixture, heating up and refluxing for reaction for 8 hours, tracking by using thin-layer chromatography, cooling to room temperature after the reaction is finished, distilling the obtained mixture, washing with isooctane, water, sodium carbonate and water in sequence, and drying in vacuum at 40 ℃ to obtain 2.3 g of the compound of formula (4), wherein the yield is 82%;
and C: adding 2 g of the compound of the formula (4), 4 g of dioxane, 8 g of water and 1.2 g of sodium carbonate into a round-bottom flask in sequence, hydrolyzing at 35 ℃ for 2h, adding hydrochloric acid for neutralization, extracting with ethyl acetate, washing an organic phase with saturated common salt, drying with anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure to obtain 1.8 g of the compound of the formula (5), wherein the yield is 85%;
step D: adding 1.5 g of the compound shown in the formula (5) as a product in the step 3 and 10 g of dichloromethane into a flask in sequence, dropwise adding 30 g of oxalyl chloride under ice bath, stirring for 5h at normal temperature, absorbing the generated hydrogen chloride gas with water to obtain a byproduct hydrochloric acid, distilling under reduced pressure, and drying to obtain the acyl chloride of the compound shown in the formula (5) for later use;
step E: 20 g of acetonitrile, 1.46 g of 2-iodo-6-bromo-4-heptafluoroisopropyl aniline and 0.6 g of potassium iodide are sequentially added into a flask, 1.2 g of acyl chloride of the compound shown in the formula (5) is stirred and added, the mixture is slowly heated, heated and refluxed for reaction for 8 hours, the rest acyl chloride is added after being cooled, the mixture is heated again for reflux, a point plate is tracked until the amine reaction is complete, the reaction solution is poured into a saturated sodium bicarbonate solution, the precipitated solid is filtered, and the compound shown in the formula (1) is obtained after vacuum drying, wherein the yield is 74%.
The above-described embodiments are only intended to illustrate the inventive concept of the present invention and not to limit the protection of the claims of the present invention, and any simple modifications, equivalent changes and modifications made to the above-described embodiments according to the technical and methodological substance of the present invention still fall within the scope of the technical and methodological aspects of the present invention.
Claims (10)
1. A process for producing an amide compound represented by the following reaction formula:
in the formula:
R1、R2each independently selected from hydrogen, halogen, C1-C6Alkyl of (C)1-C6Halogenoalkyl of, C1-C6Alkoxy or C1-C6Haloalkoxy of (a);
R3selected from heptafluoroisopropyl or nonafluoro-2-butyl;
R4selected from hydrogen, C1-C6Alkyl of (C)1-C6Haloalkyl or cyanomethyl of (a);
R5selected from hydrogen, halogen, cyano, nitro, C1-C6Alkyl of (C)1-C6A haloalkyl group of,C1-C6Alkoxy group of (C)1-C6Halogenoalkoxy of (C)1-C6Alkylthio or C of1-C6Haloalkylthio of (a);
X1、X2、X3each independently selected from hydrogen, halogen, cyano or C1-C6Alkoxy group of (a);
the reaction steps are as follows:
the method comprises the following steps: carrying out primary substitution reaction on the compound of the formula (2) and substituted acetonitrile to prepare a compound of a formula (3);
secondly, the step of: carrying out secondary substitution reaction on the compound shown in the formula (3) and benzoyl chloride to obtain a compound shown in a formula (4);
③: the compound of the formula (4) is hydrolyzed under alkaline conditions to prepare a compound of a formula (5);
fourthly, the method comprises the following steps: the amide compound of formula (1) is prepared by amidation reaction of acyl chloride obtained by acyl chlorination of the compound of formula (5) with the compound of formula (6).
2. The method for preparing an amide compound according to claim 1, wherein the substituted acetonitrile in step (i) is one of chloroacetonitrile, bromoacetonitrile and hydroxyacetonitrile, and the molar ratio of the compound of formula (2) to the substituted acetonitrile is 1: 1-2.
3. The method for producing an amide compound according to claim 1, wherein the molar ratio of the compound of formula (3) to benzoyl chloride in step (2) is 1:1 to 3.
4. The method for preparing amide compounds according to claim 1, wherein the base reacted in step (c) is one of potassium carbonate, sodium carbonate and sodium bicarbonate, the molar ratio of the compound of formula (4) to the base is 1:0.5-3, and the temperature of the hydrolysis reaction is 25-80 ℃.
5. The process for producing an amide compound according to claim 1, wherein the molar ratio of the acid chloride to the compound of the formula (6) in the step (iv) is 1:0.5 to 2.
6. The process for producing an amide compound according to claim 1, wherein the solvent used for the acid chlorination of the compound of the formula (5) in the step (iv) is oxalyl chloride or thionyl chloride.
7. The process for producing an amide compound according to claim 1, wherein the acid chloride in the step (iv) is reacted with the compound of formula (6) in an acetonitrile solvent under the catalysis of potassium iodide.
8. The method for producing an amide compound according to claim 1, wherein the solvent for producing the compound of formula (3) from the compound of formula (2) and the solvent for producing the compound of formula (4) from the compound of formula (3) are each one selected from the group consisting of toluene, acetone, acetonitrile, dichloromethane, dioxane and dimethylformamide.
9. The process for producing an amide compound according to claim 1, wherein the compound of formula (2) in step (i) is further reacted with formaldehyde and hydrocyanic acid to produce a compound of formula (3).
10. The method for producing an amide compound according to claim 9, wherein the molar ratio of the compound of formula (2), formaldehyde and hydrocyanic acid in the step (i) is 1:5 to 6:4 to 5.
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| CN115724768A (en) * | 2021-08-26 | 2023-03-03 | 广西思钺生物科技有限责任公司 | Bisamide compound and preparation method and application thereof |
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