Preparation method and application of aromatic amide compound

Abstract

The invention relates to a preparation method and application of an aromatic amide compound, in particular to an aromatic amide compound obtained by realizing amidation reaction of a triazine ester compound under the catalysis of metallic iron (0), and the aromatic amide compound is simple in process condition, good in yield and wide in functional group tolerance by using iron which is low in cost and wide in reserves as a catalyst.

Description

Technical Field

[0001] This invention belongs to the field of chemical and pharmaceutical engineering, and relates to a method for preparing aromatic amide compounds and their applications. Background Technology

[0002] Amides are an important class of molecules, widely found not only in natural products, bioactive compounds, and functional materials, but also as a key component of synthetic organic chemistry. Typically, amides are synthesized by coupling carbonyl compounds (such as carboxylic acids and esters) with amines. In recent decades, the use of nitroaromatics as an attractive nitrogen source for ester coupling to amides has attracted considerable attention because nitroaromatics are readily available and more stable than arylamines. For example, in 2017, Hu et al. semi-finished the reductive amidation of esters with nitroaromatics in the presence of Zn and TMSCl (Nat. Commun. 2017, 8, 14878–14888 and ACS Catal. 2020, 10, 2845–2854).

[0003] In 2019, the Cheung / Ma and Luo / Zeng groups reported that the same type of amidation could also be performed by using Mn / TMSCl and CrCl3 / / Mg / TMSCl, respectively (Org. Chem. Front. 2019, 6, 756–761 and Org. Lett. 2019, 21, 1912–1916.).

[0004] In addition, the reductive conversion of amides with nitroaromatics has also been developed for the preparation of amides, mainly by using reducing metals (such as Zn, Mn) and TMSCl, as disclosed by Hu, Ma, Li et al. (ACS Catal. 2017, 7, 7092–7096, J. Am. Chem. Soc. 2018, 140, 6789–6792 and Chem. Sci. 2018, 9, 655–659, etc.).

[0005] This invention provides a method for the amidation reaction of triazine esters under the catalysis of metallic iron (O) to obtain aromatic amides. Summary of the Invention

[0006] This invention provides a method for preparing the compound shown in Formula I.

[0007]

[0008] This includes the step of reacting the compounds shown in Formula II and Formula III in the presence of metallic iron.

[0009] ,

[0010] Among them, Ar 1 Selected from aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 3-6 One or more substituents in the cycloalkyl group are substituted;

[0011] Ar 2 Selected from aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, ester (e.g., methyl formate CH3COO-), C 3-6 It is substituted by one or more substituents in a cycloalkyl or phenyl group.

[0012] In some embodiments, Ar in the compound shown in Formula II 1 Selected from phenyl, wherein the phenyl group is optionally selected from halogen, cyano, C 1-6 Alkyl or C 1-6 One or more substituents in the alkoxy group are replaced.

[0013] In some embodiments, Ar in the compound shown in Formula II 1 Selected from phenyl, wherein the phenyl group is optionally selected from halogenated C. 1-6 Alkyl or halogenated C 1-6 One or more substituents in the alkoxy group are replaced.

[0014] In some embodiments, Ar in the compound shown in Formula II 1 The phenyl group is selected from phenyl, wherein the phenyl group is optionally substituted with one or more substituents selected from cyano, halogen (such as fluorine, chlorine or bromine), methyl, tert-butyl, methoxy, trifluoromethyl or trifluoromethoxy.

[0015] In some embodiments, the compound represented by Formula II in the method is selected from:

[0016] , , , , , , , , , or .

[0017] In some embodiments, Ar in the compound shown in Formula III 2 Selected from phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally selected from halogen, cyano, C 1-6 Alkyl or C 1-6 One or more substituents in the alkoxy group are replaced.

[0018] In some embodiments, Ar in the compound shown in Formula III 2 Selected from phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally selected from a halogenated C. 1-6 Alkyl or halogenated C 1-6 One or more substituents in the alkoxy group are replaced.

[0019] In some embodiments, Ar in the compound shown in Formula III 2 The group is selected from phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally substituted by one or more substituents selected from cyano, halogen (such as fluorine, chlorine or bromine), methyl, tert-butyl, methoxy, trifluoromethyl, methyl formate (CH3COO-), trifluoromethoxy or phenyl.

[0020] In some embodiments, Ar in the compound shown in Formula III 2 Selected from thiophene groups, wherein the thiophene group is optionally selected from halogens, cyano groups, C... 1-6 Alkyl or C 1-6 One or more substituents in the alkoxy group are replaced.

[0021] In some embodiments, Ar in the compound shown in Formula III 2 Selected from thiophene groups, wherein the thiophene group is optionally selected from halogenated C. 1-6 Alkyl or halogenated C 1-6 One or more substituents in the alkoxy group are replaced.

[0022] In some embodiments, Ar in the compound shown in Formula III 2 The group is selected from thienyl, wherein the thienyl group is optionally substituted by one or more substituents selected from cyano, halogen (such as fluorine, chlorine or bromine), methyl, tert-butyl, methoxy, trifluoromethyl, methyl formate (CH3COO-), trifluoromethoxy or phenyl.

[0023] In some embodiments, the compound represented by Formula III in the method is selected from:

[0024] , , , , , , , , , , , or .

[0025] To ensure the smooth progress of the reaction, the amount of metallic iron used in the method of this invention is 2 to 5 times the molar amount of the compound of formula II, and can be 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.8, 4.9, 5.0, or any value between any two numbers. In some embodiments, the amount of metallic iron used in the method is 3.0 to 4.5 times the molar amount of the compound of formula II. In some embodiments, the amount of metallic iron used in the method is 4 times the molar amount of the compound of formula II.

[0026] On the other hand, the reaction described in this invention also contains Lewis acids, such as trimethylchlorosilane or boron trifluoride ether.

[0027] In some embodiments, the amount of Lewis acid used in the reaction is 2 to 4 times the molar amount of compound II, and can be 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.8, 3.9, 4.0, or any value between any two numbers. In some embodiments, the amount of Lewis acid used in the reaction is 2.5 to 3.5 times the molar amount of compound II. In some embodiments, the amount of trimethylchlorosilane used in the reaction is 2 times the molar amount of compound II.

[0028] Furthermore, the reaction described in this invention is carried out in a solvent selected from N-methylpyrrolidone, N,N-dimethylformamide, or N,N-dimethylacetamide.

[0029] In some embodiments, the reaction is carried out in N,N-dimethylformamide.

[0030] On the other hand, in the method, the molar ratio of the compound represented by Formula II to the compound represented by Formula III is 1:1 to 1:4 (including 1:1, 1:2, 1:3, 1:4 or any value between them). In some embodiments, the molar ratio of the compound represented by Formula II to the compound represented by Formula III is selected to be 1:1.5 to 1:3. In some embodiments, the molar ratio of the compound represented by Formula II to the compound represented by Formula III is selected to be 1:2.5.

[0031] The reaction temperature can be 80~140℃ (it can be 80℃, 85℃, 90℃, 95℃, 100℃, 110℃, 115℃, 120℃, 130℃ or 140℃).

[0032] In some implementations, the reaction temperature is 120°C.

[0033] In a preferred embodiment, the method for preparing the compound of formula I includes the step of reacting the compound of formula II and the compound of formula III in the presence of metallic iron, trimethylchlorosilane, and N,N-dimethylformyl solvent.

[0034] .

[0035] The present invention also provides the use of the method for preparing the aforementioned aromatic amide compounds, such as those shown in Formula I, in the preparation of pharmaceuticals, fragrances, or pesticides.

[0036] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0037] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, and their various branched isomers. Alkyl groups can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable junction, preferably one or more of the following groups: halogens.

[0038] The term "cycloalkyl" refers to a substituent in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon ring containing 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl.

[0039] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0040] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, cyano groups, C... 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, ester, C 3-6 Cycloalkyl or phenyl.

[0041] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, tetrazolyl, pyridinyl, etc., preferably imidazolyl, pyrazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl or thiazolyl.

[0042] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, cyano groups, C... 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, ester, C 3-6 Cycloalkyl or phenyl.

[0043] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, etc. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, such as halogens.

[0044] The term "cyano" refers to -CN.

[0045] The term "nitro" refers to -NO2.

[0046] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0047] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0048] The reagents used in this invention can be purchased commercially. Detailed Implementation

[0049] The present invention will be explained in detail below with specific examples, so that those skilled in the art can have a more comprehensive understanding of the present invention. The specific examples are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention in any way.

[0050] Example 1: Screening of preparation conditions

[0051]

[0052] Nitrobenzene (1a, 0.4 mmol, 1 equiv.), 4,6-dimethoxy-1,3,5-triazine-2-ylbenzoate (2a), catalyst, and trimethylchlorosilane (TMSCl) were added to the solution, and the mixture was stirred and heated to react. After the reaction was completed, the target product was purified by silica gel column chromatography, and the yields were calculated. The specific data are shown in the table below:

[0053] Table 1

[0054]

[0055] a Separation yield; b No TMSCl.

[0056] Example 2

[0057]

[0058] 49.3 mg of nitrobenzene (1a, 0.4 mmol, 1 equiv.), 329 mg of 4,6-dimethoxy-1,3,5-triazine-2-yl-4-(trifluoromethyl)benzoate (2b, 1 mmol), 89.6 mg of iron powder, and trimethylchlorosilane (TMSCl, 0.8 mmol) were added to 1 mL of N,N-dimethylformamide. The mixture was stirred and heated to 120 °C for approximately 24 h. After the reaction was completed, the product was purified by silica gel column chromatography with a yield of 71%.

[0059] Example 3

[0060] Following the method in Example 2, nitrobenzene, compound 2c-2m, iron powder, trimethylchlorosilane, and N,N-dimethylformamide were added sequentially to a reaction flask. The reaction was heated and stirred at 120°C. After the reaction was complete, the target product was purified using silica gel column chromatography, and the yields were calculated. The specific data are as follows:

[0061]

[0062]

[0063] Example 4

[0064] Following the method in Example 2, compounds 1b-1k, 4,6-dimethoxy-1,3,5-triazine-2-ylbenzoate (2a), iron powder, trimethylchlorosilane, and N,N-dimethylformamide were added sequentially to a reaction flask. The reaction was heated and stirred at 120°C. After the reaction was complete, the target product was purified using silica gel column chromatography, and the yields were calculated. The specific data are as follows:

[0065]

[0066] .

Claims

1. A method for preparing the compound shown in Formula I, This includes the step of reacting the compounds shown in Formula II and Formula III in the presence of metallic iron. ， in, Ar 1 Selected from aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 3-6 One or more substituents in the cycloalkyl group are substituted; Ar 2 Selected from aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, ester, C 3-6 It is substituted by one or more substituents in a cycloalkyl or phenyl group.

2. The method of claim 1, wherein the reaction further comprises a Lewis acid, preferably trimethylchlorosilane.

3. The method of claim 1 or 2, wherein the solvent used in the reaction is selected from N-methylpyrrolidone, N,N-dimethylformamide or N,N-dimethylacetamide.

4. The method according to any one of claims 1-3, wherein the amount of metallic iron is 2 to 5 times, for example 4 times, the molar amount of the compound shown in Formula II.

5. The method according to any one of claims 1-4, wherein the compound represented by formula II is selected from: , , , , , , , , , or .

6. The method according to any one of claims 1-5, wherein the compound represented by formula III is selected from: , , , , , , , , , , , or .

7. The method according to any one of claims 1-6, wherein the molar ratio of the compound of formula II to the compound of formula III is 1:1 to 1:4, preferably 1:1.5 to 1:3, for example 1:2.

5.

8. The method according to any one of claims 1-7, wherein the reaction temperature is 80-140°C, preferably 100-130°C, for example 120°C.

9. Use of the method according to any one of claims 1-8 in the preparation of a pharmaceutical, fragrance, or pesticide.

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