4-carboxamide oxazole compound and preparation method and application thereof

Abstract

The application relates to a 4-formamide oxazole compound and a preparation method and application thereof, and a structural formula of the 4-formamide oxazole compound is as follows: wherein R 1 is any one selected from phenyl, 2-(phenyl ethynyl)phenyl, 2-biphenyl, 2-bromophenyl, 3-(methoxy)phenyl, 4-((trimethylsilyl)ethynyl)phenyl, 4-(trifluoromethylthio)phenyl and dibenzo[b,d] furan-4-yl; R 2 is any one selected from adamantyl and tert-butyl; R 3 is any one selected from hydrogen, methyl and chloromethyl. Compared with the prior art, the application uses simple and easily obtained aldehyde and amide compound as raw materials, isocyanide as the nitrogen source of the oxazole skeleton in the product and the source of the amide functional group, and one-step modular synthesis of 4-formamide oxazole series compounds is realized. The application has the advantages of cheap and easily obtained raw materials, environmental friendliness, simple operation and the like, and has good development potential and application prospect in the fields of organic synthesis and biological medicine.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a 4-carboxamide oxazole compound and a preparation method and application thereof. BACKGROUND

[0002] Oxazole is an important five-membered nitrogen-containing heterocycle and is also an important core structure in many drugs and natural products (see the literature: Bharti, R. et al. Tetrahedron 2022, 119, 132813). Oxazole compounds are relatively easy to bind to receptors or enzymes in the body through various non-covalent interactions, thereby exhibiting biological activity. Among them, 4-carboxamide oxazole compounds are widely present in drug and bioactive molecules. For example, the drug molecule Dalfopristin is an important antibiotic and can be used for the treatment of severe staphylococcus and vancomycin-resistant enterococcus faecalis infections; Griseovirdin is a streptomycin antibiotic with antibacterial effect; and GSK-3 inhibitor can also be used for the diagnosis of Alzheimer's disease.

[0003]

[0004] In the past few decades, the main method for synthesizing 4-carboxamide oxazole compounds is still to introduce an amide functional group on the oxazole ring or to use amide compounds to construct the oxazole heterocyclic skeleton, but the method for simultaneously constructing the oxazole heterocycle and the amide functional group is very limited. Therefore, from the perspective of synthesis method and application prospect, it is of great significance to efficiently synthesize 4-carboxamide oxazole compounds using simple and readily available reagents.

[0005] The synthesis methods reported in the literature mainly include the following:

[0006] (I) Synthesis of 4-carboxamide oxazole from oxazole compounds

[0007] In 2020, Ma Xiaoyun et al. used 4-cyano oxazole compounds as raw materials to hydrolyze the cyano group under the action of hydrogen peroxide to obtain 4-carboxamide oxazole compounds (see the literature: Ma, X. et al. Synth. Commun. 2023, 53, 503-510).

[0008]

[0009] In 2021, Liu Ning et al. synthesized 4-carboxamide oxazole compounds by condensation reaction of ester and amine catalyzed by manganese (see the literature: Liu, L. et al. J. Org. Chem. 2021, 86, 2339-2358).

[0010]

[0011] (ii) Synthesis of 4-carboxamide oxazoles from amides

[0012] In 2010, the Ila group first used a fully substituted push-pull alkene as a raw material to synthesize a polysubstituted oxazole compound through an intramolecular cyclization process mediated by silver carbonate. The raw material required by this method is not easy to obtain, which limits its application (see literature: Ila, H. et al. J. Org. Chem. 2010, 75, 5195-5202).

[0013]

[0014] In 2012, Hulme et al. realized the Ugi / Robinson-Gabriel reaction to directly synthesize fully substituted 4-carboxamide oxazoles. The reaction condition is mild and easy to operate. However, this reaction has a greater limitation on the substrate, and requires two-step reaction to synthesize 4-carboxamide oxazoles, which is not enough for synthesis application (see literature: Hulme, C. et al. Tetrahedron Lett. 2012, 53, 1998-2000).

[0015]

[0016] In 2014, Chang Junbiao et al. developed a copper / amino acid catalyzed intramolecular C-O coupling reaction, using a push-pull alkene with bromine atom as a leaving group as a reactant, to synthesize polysubstituted 4-carboxamide oxazoles (see literature: Chang, J. et al. Org. Biomol. Chem. 2014, 12, 3912-3923).

[0017]

[0018] In 2020, the Hashmi group used α-alkynyl amide and nitrile compounds as raw materials to obtain fully substituted 4-carboxamide oxazoles (see literature: Hashmi, A. S. K. et al. Eur. J. Org. Chem. 2020, 2020, 2384-2388).

[0019]

[0020] In 2022, the Neochoritis group reported the ring-opening reaction of active methylene isocyanide containing amide groups with cyclic anhydrides and lactones in the presence of butyllithium, obtaining disubstituted 4-formamide oxazole compounds. This reaction needs to be carried out at low temperature, which limits its synthetic application (see literature: Neochoritis, C. G. et al. Synlett 2022, 33, 1913-1916).

[0021]

[0022] In summary, there are still few methods for directly synthesizing 4-formamide oxazoles reported in the literature, and in these reactions, there are disadvantages such as complex synthesis of reaction raw materials, harsh reaction conditions, and large substrate range limitations. Therefore, it is of important application value to develop a one-step efficient synthesis method for constructing an oxazole ring skeleton containing an amide group using simple and readily available compounds. SUMMARY

[0023] The purpose of the present application is to overcome the shortcomings of the prior art, such as complex synthesis of reaction raw materials, harsh reaction conditions, and large substrate range limitations, and to provide a 4-formamide oxazole compound and a preparation method and application thereof.

[0024] The purpose of the present application can be achieved by the following technical solutions:

[0025] One of the technical solutions of the present application is to provide a 4-formamide oxazole compound, the structure formula of which is as follows:

[0026]

[0027] Among them, R 1 is any one selected from the group consisting of phenyl, 2-(phenylacetylenyl)phenyl, 2-biphenyl, 2-bromophenyl, 3-(methoxy)phenyl, 4-((trimethylsilyl)ethynyl)phenyl, 4-(trifluoromethylthio)phenyl, and dibenzo[b,d]furan-4-yl;

[0028] R 2 is any one selected from the group consisting of adamantyl and tert-butyl;

[0029] R 3 is any one selected from the group consisting of hydrogen, methyl, and chloromethyl.

[0030] The second technical solution of the present application is to provide a preparation method of the 4-formamide oxazole compound according to the above-mentioned one of the technical solutions, comprising the following steps:

[0031] S1, under an inert atmosphere, an aldehyde compound containing R 1 group, an aldehyde compound containing R 3amide compound of a group, R 2 The isonitrile compound of a group, boron trifluoride diethyl ether and adamantanol are mixed in toluene to react, to obtain a crude product.

[0032] S2, the crude product obtained in S1 is separated and purified to obtain the 4-formamide oxazole compound.

[0033] In some embodiments, in S1, the aldehyde compound is selected from any one or more of benzaldehyde, 2-biphenylylcarboxaldehyde, 2-(phenylethynyl)phenylcarboxaldehyde, 2-bromobenzaldehyde, 3-methoxybenzaldehyde, 4-(trimethylsilyl)ethynylbenzaldehyde, 4-trifluoromethylthiobenzaldehyde, and dibenzo[b,d]furane-4-carboxaldehyde.

[0034] In some embodiments, in S1, the amide compound is selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and 2-chloro-N,N-dimethylacetamide.

[0035] In some embodiments, in S1, the isonitrile compound is selected from any one or more of adamantyl isonitrile and tert-butyl isonitrile.

[0036] In some embodiments, in S1, the molar ratio of the aldehyde compound, the amide compound, the isonitrile compound, boron trifluoride diethyl ether and adamantanol is 1.0:(3.0-3.5):(2.5-4.0):(1.5-2.0):(1.0-1.5).

[0037] The amount ratio of the aldehyde compound and toluene is 0.3 mmol:(0.6-1.0 mL).

[0038] In some embodiments, in S1, the inert atmosphere is nitrogen.

[0039] In some embodiments, in S1, the temperature of the mixing reaction is 80-110°C, the time is 9-12 h, and the stirring speed is 400-500 rpm.

[0040] In some embodiments, in S2, the separation and purification is performed by silica gel column chromatography, and the developing agent is a mixed solvent of petroleum ether, ethyl acetate and triethylamine in a volume ratio of 100:5:1-100:2:1.

[0041] The reaction mechanism of the preparation method is as follows:

[0042]

[0043] The third technical scheme of the present application provides an application of the 4-carboxamide oxazole compound in one of the above technical schemes, and the 4-carboxamide oxazole compound is applied to the field of organic synthesis and biological medicine.

[0044] In some specific embodiments, the 4-carboxamide oxazole compound is used for synthesizing a drug molecule, a bioactive molecule, such as a small molecule agonist of a receptor FPR2 / ALXR involved in inflammation resolution.

[0045] Compared with the prior art, the present application has the following beneficial effects:

[0046] (1) The present application uses simple and readily available aldehydes and amide compounds as raw materials, isocyanides as the nitrogen source of the oxazole skeleton in the product and the source of the amide functional group, and synthesizes a series of 4-carboxamide oxazole compounds in a modular one-step manner.

[0047] (2) The method has the advantages of low-cost and readily available raw materials, environmental friendliness, and simple operation.

[0048] (3) The 4-carboxamide oxazole compound synthesized by the method of the present application has good development potential and application prospect in the field of organic synthesis and biological medicine. DETAILED DESCRIPTION

[0049] The present application will be described in detail below in conjunction with specific examples. The present embodiment is implemented on the premise of the technical scheme of the present application, and detailed implementation modes and specific operation processes are given, but the protection scope of the present application is not limited to the following examples.

[0050] In the following examples, if no special instructions are given for the raw materials or processing techniques, it is indicated that they are all conventional commercially available raw material products or conventional processing techniques in the art.

[0051] Example 1

[0052] The present embodiment provides a preparation method of an N-((3s,5s,7s)-adamantane-1-yl)-2-methyl-5-phenyloxazole-4-carboxamide compound, and the specific steps are as follows:

[0053] (1) Under nitrogen protection, 15 mL of a sealed tube was sequentially added with solvent toluene (0.6 mL), N,N-dimethylacetamide (91.5 mg, 1.05 mmol), boron trifluoride ether (63.9 mg, 0.45 mmol), adamantyl isocyanide (120.9 mg, 0.75 mmol), 1-adamantanol (45.7 mg, 0.3 mmol), and benzaldehyde (31.8 mg, 0.3 mmol), and the reaction was carried out at an oil bath temperature of 110℃ and a stirring speed of 500 rpm for 12 hours;

[0054] (2) After the reaction is completed and cooled to room temperature, the solvent is removed to obtain the crude product;

[0055] (3) The crude product is purified by silica gel column chromatography, and the developing agent is a mixture of petroleum ether, ethyl acetate and triethylamine in a volume ratio of 100:2:1. A white solid (70.7 mg, yield 70%) is obtained, which is N-((3s,5s,7s)-adamantane-1-yl)-2-methyl-5-phenyloxazole-4-carboxamide compound, and the structural formula is:

[0056]

[0057] The melting point is 159-161°C.

[0058] The basic parameters of the compound are as follows:

[0059] 1 H NMR (400 MHz, CDCI3): δ 8.26-8.19 (m, 2H), 7.46-7.40 (m, 2H), 7.39-7.33 (m, 1H), 7.04 (s, 1H), 2.49 (s, 3H), 2.15-2.09 (m, 9H), 1.76-1.66 (m, 6H).

[0060] 13 C NMR (101 MHz, CDCI3): δ 160.7, 158.3, 152.0, 130.2, 129.5, 128.4, 128.2, 127.7, 52.0, 41.8, 36.5, 29.6, 13.9.

[0061] HRMS (ESI) m / z: calcd for C 21 H 24 O2N2Na[M+Na] + 359.1730, found 359.1724.

[0062] Example 2:

[0063] This embodiment provides a preparation method of a 5-([1,1'-biphenyl]-2-yl)-N-((3s,5s,7s)-adamantane-1-yl)-2-methyl oxazole-4-carboxamide compound, and the specific steps are as follows:

[0064] (1) Under nitrogen protection, 15 mL of sealed tube was added with solvent toluene (0.6 mL), N,N-dimethylacetamide (91.5 mg, 1.05 mmol), boron trifluoride etherate (63.9 mg, 0.45 mmol), adamantyl isocyanide (120.9 mg, 0.75 mmol), 1-adamantanol (45.7 mg, 0.3 mmol) and 2-biphenylcarboxaldehyde (54.7 mg, 0.3 mmol) in sequence, and reacted at 80°C in oil bath under stirring speed of 500 rpm for 12 hours;

[0065] (2) After reaction was completed and cooled to room temperature, the solvent was removed to obtain the crude product;

[0066] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixture of petroleum ether, ethyl acetate and triethylamine in a volume ratio of 100:2:1, to obtain white solid (62.8 mg, yield 51%) which was 5-([1,1'-biphenyl]-2-yl)-N-((3s,5s,7s)-adamantane-1-yl)-2-methyloxazole-4-carboxamide compound, and the structural formula was:

[0067]

[0068] The melting point was 159-161°C.

[0069] The basic parameters of the compound were as follows:

[0070] 1 H NMR (400 MHz, CDCl3): δ 7.82-7.74 (m, 1H), 7.50-7.37 (m, 3H), 7.29-7.23 (m, 3H), 7.22-7.17 (m, 2H), 6.68 (s, 1H), 2.17 (s, 3H), 2.06 (s, 9H), 1.73-1.62 (m, 6H).

[0071] 13 C NMR (101 MHz, CDCl3): δ 160.0, 158.7, 152.1, 142.2, 141.3, 131.7, 131.4, 130.0, 129.9, 128.8, 127.9, 127.1, 126.8, 126.4, 51.8, 41.6, 36.4, 29.5, 13.5.

[0072] HRMS (ESI) m / z: calcd for C 27 H 29 O2N2[M+H] + 413.2224, found 413.2219.

[0073] Example 3:

[0074] This embodiment provides a preparation method of N-((3s,5s,7s)-adamantane-1-yl)-2-methyl-5-(2-(phenyl ethynyl)phenyl)oxazole-4-carboxamide compound, and the specific steps are as follows:

[0075] (1) Under the protection of nitrogen, 15 mL of a sealed tube was added with solvent toluene (0.6 mL), N,N-dimethylacetamide (91.5 mg, 1.05 mmol), boron trifluoride ether (63.9 mg, 0.45 mmol), adamantyl isocyanide (120.9 mg, 0.75 mmol), 1-adamantanol (45.7 mg, 0.3 mmol) and 2-(phenyl ethynyl)phenyl benzaldehyde (61.9 mg, 0.3 mmol) in sequence, and the reaction was carried out at an oil bath temperature of 80°C and a stirring speed of 500 rpm for 12 hours;

[0076] (2) After the reaction was completed and cooled to room temperature, the solvent was removed to obtain a crude product;

[0077] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixed solvent of petroleum ether, ethyl acetate and triethylamine in a volume ratio of 100:2:1, to obtain a white solid (79.7 mg, yield 61%), which was N-((3s,5s,7s)-adamantane-1-yl)-2-methyl-5-(2-(phenyl ethynyl)phenyl)oxazole-4-carboxamide compound, and the structural formula was as follows:

[0078]

[0079] The melting point is 160-162°C.

[0080] The basic parameters of the compound are as follows:

[0081] 1 H NMR (400 MHz, CDCl3): δ 7.81-7.72 (m, 1H), 7.65-7.58 (m, 1H), 7.44-7.36 (m, 4H), 7.34-7.27 (m, 3H), 6.83 (s, 1H), 2.50 (s, 3H), 2.05 (s, 9H), 1.68-1.62 (m, 6H).

[0082] 13C NMR (101 MHz, CDC13): δ 160.1, 159.2, 151.0, 132.7, 131.8, 131.7, 131.1, 129.9, 129.5, 128.37, 128.40, 128.1, 123.5, 123.2, 92.8, 88.3, 51.9, 41.7, 36.4, 29.5, 14.0.

[0083] HRMS (ESI) m / z: calcd for C 29 H 29 O2N2[M+H] + 437.2224, found 437.2220.

[0084] Example 4:

[0085] This embodiment provides a preparation method of N-((3s,5s,7s)-adamantane-1-yl)-5-(2-bromophenyl)-2-methyl oxazole-4-carboxamide compound, and the specific steps are as follows:

[0086] (1) Under the protection of nitrogen, 15 mL of a sealed tube was sequentially added with solvent toluene (0.6 mL), N,N-dimethylacetamide (91.5 mg, 1.05 mmol), boron trifluoride ether (63.9 mg, 0.45 mmol), adamantyl isocyanide (120.9 mg, 0.75 mmol), 1-adamantanol (45.7 mg, 0.3 mmol) and 2-bromobenzaldehyde (55.5 mg, 0.3 mmol), and then the mixture was reacted at an oil bath of 110°C and a stirring speed of 500 rpm for 12 hours;

[0087] (2) After the reaction was completed and cooled to room temperature, the solvent was removed to obtain a crude product;

[0088] (3) The crude product was purified by silica gel column chromatography, and a mixed solvent of petroleum ether, ethyl acetate and triethylamine in a volume ratio of 100:2:1 was used as the developing agent to obtain a white solid (65.6 mg, a yield of 53%), namely N-((3s,5s,7s)-adamantane-1-yl)-5-(2-bromophenyl)-2-methyl oxazole-4-carboxamide compound, and the structural formula was as follows:

[0089]

[0090] The melting point is 152-154°C.

[0091] The basic parameters of the compound are as follows:

[0092] 1H NMR (400 MHz, CDC13): δ 7.64 (dd, J = 8.1, 1.2 Hz, 1H), 7.58 (dd, J = 7.7, 1.7 Hz, 1H), 7.38 (td, J = 7.6, 1.2 Hz, 1H), 7.30-7.32 (m, 1H), 6.79 (s, 1H), 2.50 (s, 3H), 2.13-2.04 (m, 9H), 1.72-1.63 (m, 6H).

[0093] 13 C NMR (101 MHz, CDC13): δ 159.8, 159.6, 150.5, 133.2, 133.0, 132.1, 131.3, 129.4, 127.1, 123.7, 52.0, 41.7, 36.4, 29.5, 14.0.

[0094] HRMS (ESI) m / z: calcd for C 21 H 24 O2N2Br[M+H] + 415.1016, found 415.1009.

[0095] Example 5:

[0096] This example provides a method for preparing a N-((3s,5s,7s)-adamantane-1-yl)-5-(3- methoxyphenyl)-2-methyloxazole-4-carboxamide compound, the specific steps are as follows:

[0097] (1) Under the protection of nitrogen, 15 mL of a sealed tube was added with solvent toluene (0.6 mL), N,N-dimethylacetamide (91.5 mg, 1.05 mmol), boron trifluoride ether (63.9 mg, 0.45 mmol), adamantyl isocyanide (120.9 mg, 0.75 mmol), 1-adamantanol (45.7 mg, 0.3 mmol) and 3-methoxybenzaldehyde (40.8 mg, 0.3 mmol) in sequence, and reacted at 110°C of oil bath under the stirring speed of 500 rpm for 12 hours;

[0098] (2) After the reaction was completed and cooled to room temperature, the solvent was removed to obtain a crude product;

[0099] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixed solvent of petroleum ether, ethyl acetate and triethylamine in a volume ratio of 100:3:1, to obtain a white solid (44.8 mg, the yield was 41%) which was N-((3s,5s,7s)-adamantane-1-yl)-5-(3-methoxyphenyl)-2-methyloxazole-4-carboxamide compound, and the structural formula was as follows:

[0100]

[0101] Melting point: 133-135 °C.

[0102] The basic parameters of this compound are as follows:

[0103] 1 H NMR (400 MHz, CDC13): δ 7.91-7.86 (m, 1H), 7.81-7.78 (m, 1H), 7.34 (t, J = 8.1 Hz, 1H), 7.01 (s, 1H), 6.93-6.89 (m, 1H), 3.86 (s, 3H), 2.49 (s, 3H), 2.16-2.06 (m, 9H), 1.75-1.66 (m, 6H).

[0104] 13 C NMR (101 MHz, CDC13): δ 160.6, 159.5, 158.2, 151.7, 130.4, 129.5, 128.8, 120.8, 115.6, 113.2, 55.5, 51.9, 41.7, 36.5, 29.6, 13.9.

[0105] HRMS (ESI) m / z: calcd for C 22 H 27 O3N2[M+H] + 367.2016, found 367.2010.

[0106] Example 6:

[0107] This embodiment provides a preparation method of N-((3s,5s,7s)-adamantane-1-yl)-2-methyl-5-(4-((trimethylsilyl)ethynyl)phenyl)oxazole-4-carboxamide compound, and the specific steps are as follows:

[0108] (1) Under the protection of nitrogen, 15 mL of a sealed tube was added with solvent toluene (0.6 mL), N,N-dimethylacetamide (91.5 mg, 1.05 mmol), boron trifluoride ether (63.9 mg, 0.45 mmol), adamantyl isocyanide (120.9 mg, 0.75 mmol), 1-adamantanol (45.7 mg, 0.3 mmol) and 4-(trimethylsilyl)ethynylbenzaldehyde (60.7 mg, 0.3 mmol) in sequence, and then the reaction was carried out at an oil bath temperature of 110 °C and a stirring speed of 500 rpm for 12 hours;

[0109] (2) After the reaction was completed and cooled to room temperature, the solvent was removed to obtain a crude product;

[0110] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixture of petroleum ether, ethyl acetate and triethylamine in a volume ratio of 100:2:1. White solid (51.4 mg, yield 40%) was obtained, which was N-((3s,5s,7s)-adamantane-1-yl)-2-methyl-5-(4-((trimethylsilyl)ethynyl)phenyl)oxazole-4-carboxamide compound, and the structural formula was:

[0111]

[0112] The melting point is 140-142°C.

[0113] The basic parameters of the compound are as follows:

[0114] 1 H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.07 (s, 1H), 2.49 (s, 3H), 2.17-2.08 (m, 9H), 1.77-1.66 (m, 6H), 0.26 (s, 9H).

[0115] 13 C NMR (101 MHz, CDCl3): δ 160.6, 158.5, 151.2, 132.0, 130.9, 127.8, 127.5, 124.1, 105.1, 96.0, 52.0, 41.8, 36.5, 29.6, 13.9, 0.1.

[0116] HRMS (ESI) m / z: calcd for C 26 H 32 O2N2NaSi[M+Na] + 455.2125, found 455.2119.

[0117] Example 7:

[0118] A method for preparing an N-((3s,5s,7s)-adamantane-1-yl)-2-methyl-5-(4-(trifluoromethylthio)phenyl)oxazole-4-carboxamide compound, the specific steps are as follows:

[0119] (1) Under nitrogen protection, 15 mL of sealed tube was added with solvent toluene (0.6 mL), N,N-dimethylacetamide (91.5 mg, 1.05 mmol), boron trifluoride etherate (63.9 mg, 0.45 mmol), adamantyl isocyanide (120.9 mg, 0.75 mmol), 1-adamantanol (45.7 mg, 0.3 mmol) and 4-trifluoromethylthio benzaldehyde (61.9 mg, 0.3 mmol) in sequence, and reacted at 110°C in oil bath under stirring speed of 500 rpm for 12 hours;

[0120] (2) After reaction was completed and cooled to room temperature, the solvent was removed to obtain the crude product;

[0121] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixture of petroleum ether, ethyl acetate and triethylamine in a volume ratio of 100:2:1 to obtain white solid (98.5 mg, yield 75%), i.e. N-((3s,5s,7s)-adamantane-1-yl)-2-methyl-5-(4-(trifluoromethylthio)phenyl)oxazole-4-carboxamide compound, with structural formula:

[0122]

[0123] The melting point is 151-153°C.

[0124] The basic parameters of the compound are as follows:

[0125] 1 H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.08 (s, 1H), 2.51 (s, 3H), 2.13 (s, 9H), 1.77-1.66 (m, 6H).

[0126] 19 F NMR (376 MHz, CDCl3): δ -42.21.

[0127] 13 C NMR (101 MHz, CDCl3): δ 160.3, 159.0, 150.5, 136.1, 131.6, 130.0, 129.6 (q, J = 310.1 Hz), 129.0, 125.3, 52.1, 41.7, 36.5, 29.6, 13.9.

[0128] HRMS (ESI) m / z: calcd for C 22 H 23 O2N2F3NaS[M+Na] +459.1325, found 459.1318.

[0129] Example 8:

[0130] This example provides a method for preparing a N-((3s,5s,7s)-adamantane-1-yl)-5- (dibenzo[b,d]furan-4-yl)-2-methyloxazole-4-carboxamide compound, the specific steps are as follows:

[0131] (1) Under the protection of nitrogen, 15 mL of a sealed tube was added with solvent toluene (0.6 mL), N,N-dimethylacetamide (91.5 mg, 1.05 mmol), boron trifluoride ether (63.9 mg, 0.45 mmol), adamantyl isocyanide (120.9 mg, 0.75 mmol), 1-adamantanol (45.7 mg, 0.3 mmol) and dibenzo[b,d]furan-4-carboxaldehyde (58.9 mg, 0.3 mmol) in sequence, and reacted at 80°C in an oil bath for 12 hours under the stirring speed of 500 rpm;

[0132] (2) After the reaction was completed and cooled to room temperature, the solvent was removed to obtain a crude product;

[0133] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixed solvent of petroleum ether, ethyl acetate and triethylamine in a volume ratio of 100:5:1, to obtain a white solid (77.1 mg, yield 60%), which was N-((3s,5s,7s)-adamantane-1-yl)-5-(dibenzo[b,d]furan-4-yl)-2-methyloxazole-4-carboxamide compound, and the structural formula was as follows:

[0134]

[0135] The melting point is 195-197°C.

[0136] The basic parameters of the compound are as follows:

[0137] 1 H NMR (400 MHz, CDCl3): δ 8.23 (dd, J = 7.7, 1.3 Hz, 1H), 8.03-7.93 (m, 2H), 7.61-7.54 (m, 1H), 7.50-7.42 (m, 2H), 7.39-7.32 (m, 1H), 6.96 (s, 1H), 2.60 (s, 3H), 2.17-2.06 (m, 9H), 1.75-1.65 (m, 6H);

[0138] 13C NMR (101 MHz, CDC13): δ 160.2, 159.5, 156.2, 153.2, 148.4, 132.1, 129.1, 127.4, 124.9, 124.0, 123.0, 122.7, 122.2, 120.8, 112.7, 111.9, 52.0, 41.7, 36.5, 29.6, 14.1;

[0139] HRMS (ESI) m / z: calcd for C 27 H 27 O3N2[M+H] + 427.2016, found 427.2012.

[0140] Example 9:

[0141] The present example provides a method for preparing N-(tert-butyl)-2-methyl-5- phenyloxazole-4-carboxamide compound, the specific steps are as follows:

[0142] (1) Under the protection of nitrogen, 15 mL of sealed tube was added with solvent toluene (0.6 mL), N,N-dimethylacetamide (91.5 mg, 1.05 mmol), boron trifluoride ether (63.9 mg, 0.45 mmol), tert-butyl isocyanide (99.8 mg, 1.2 mmol), 1-adamantanol (45.7 mg, 0.3 mmol) and benzaldehyde (31.8 mg, 0.3 mmol) in sequence, and reacted at 110°C of oil bath under the stirring speed of 500 rpm for 12 hours;

[0143] (2) After the reaction was completed and cooled to room temperature, the solvent was removed to obtain the crude product;

[0144] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixed solvent of petroleum ether, ethyl acetate and triethylamine in a volume ratio of 100:2:1, to obtain white solid (44.2 mg, yield 57%), which was N-(tert-butyl)-2-methyl-5-phenyloxazol-4-carboxamide compound, and the structural formula was as follows:

[0145]

[0146] The melting point is 61-63°C.

[0147] The basic parameters of the compound are as follows:

[0148] 1H NMR (400 MHz, CDC13): δ 8.26-8.20 (m, 2H), 7.46-7.41 (m, 2H), 7.40-7.34 (m, 1H), 7.14 (s, 1H), 2.49 (s, 3H), 1.47 (s, 9H);

[0149] 13 C NMR (101 MHz, CDC13): δ 160.9, 158.3, 152.0, 130.1, 129.6, 128.4, 128.2, 127.7, 51.2, 29.0, 13.9;

[0150] HRMS (ESI) m / z: calcd for C 15 H 18 O2N2Na[M+Na] + 281.1260, found 281.1258.

[0151] Example 10:

[0152] The present embodiment is a method for preparing a compound of N-((3s,5s,7s)-adamantane-1-yl)-2-(chloromethyl)-5-phenyloxazole-4-carboxamide, the specific steps are as follows:

[0153] (1) Under the protection of nitrogen, 15 mL of sealed tube was added with solvent toluene (0.6 mL), 2-chloro-N,N-dimethylacetamide (127.6 mg, 1.05 mmol), boron trifluoride ether (63.9 mg, 0.45 mmol), adamantyl isocyanide (120.9 mg, 0.75 mmol), 1-adamantanol (45.7 mg, 0.3 mmol) and benzaldehyde (31.8 mg, 0.3 mmol) in sequence, and reacted at 110°C in oil bath under the stirring speed of 500 rpm for 12 hours;

[0154] (2) After the reaction was completed and cooled to room temperature, the solvent was removed to obtain the crude product;

[0155] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixed solvent of petroleum ether, ethyl acetate and triethylamine in a volume ratio of 100:2:1, to obtain a white solid (57.7 mg, yield 52%), which was a compound of N-((3s,5s,7s)-adamantane-1-yl)-2-(chloromethyl)-5-phenyloxazole-4-carboxamide, and the structural formula was as follows:

[0156]

[0157] The melting point is 154-156°C.

[0158] The basic parameters of the compound are as follows:

[0159] 1 H NMR (400 MHz, CDC13): δ 8.30-8.19 (m, 2H), 7.50-7.38 (m, 3H), 7.00 (s, 1H), 4.62 (s, 2H), 2.20-2.05 (m, 9H), 1.76-1.68 (m, 6H);

[0160] 13 C NMR (101 MHz, CDC13): δ 160.0, 155.7, 153.6, 130.7, 130.2, 128.5 (2), 127.0, 52.2, 41.7, 36.5, 35.6, 29.6;

[0161] HRMS (ESI) m / z: calcd for C 21 H 23 O2N2ClNa[M+Na] + 393.1340, found 393.1341.

[0162] Example 11:

[0163] This example provides a preparation method of an N-((3s,5s,7s)-adamantane-1-yl)-5- phenyloxazole-4-carboxamide compound, and the specific steps are as follows:

[0164] (1) Under the protection of nitrogen, 15 mL of a sealed tube was added with solvent toluene (0.6 mL), N,N-dimethylformamide (76.7 mg, 1.05 mmol), boron trifluoride ether (63.9 mg, 0.45 mmol), adamantyl isocyanide (120.9 mg, 0.75 mmol), 1-adamantanol (45.7 mg, 0.3 mmol) and benzaldehyde (31.8 mg, 0.3 mmol) in sequence, and the reaction was carried out at 110°C of oil bath under the stirring speed of 500 rpm for 12 hours;

[0165] (2) After the reaction was completed and cooled to room temperature, the solvent was removed to obtain a crude product;

[0166] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixed solvent of petroleum ether, ethyl acetate and triethylamine in a volume ratio of 100:2:1, to obtain a white solid (50.8 mg, the yield was 53%), which was an N-((3s,5s,7s)-adamantane-1-yl)-5-phenyloxazol-4-carboxamide compound, and the structural formula was as follows:

[0167]

[0168] Melting point: 118-120 °C.

[0169] The basic parameters of this compound are as follows:

[0170] 1 H NMR (400 MHz, CDC13): δ 8.27-8.22 (m, 2H), 7.80 (s, 1H), 7.48-7.38 (m, 3H), 7.07 (s, 1H), 2.15-2.10 (m, 9H), 1.77-1.67 (m, 6H);

[0171] 13 C NMR (101 MHz, CDC13): δ 160.3, 152.5, 147.6, 130.0, 129.8, 128.52, 128.48, 127.3, 52.1, 41.7, 36.5, 29.6;

[0172] HRMS (ESI) m / z: calcd for C 20 H 23 02N2[M+H] + 323.1754, found 323.1751.

[0173] The above description of the embodiments is for the purpose of enabling one of ordinary skill in the art to understand and use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein can be applied to other embodiments without the use of the inventive faculty. Thus, the present invention is not intended to be limited to the embodiments described herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein and limited solely by the appended claims.

Claims

1. A method for preparing a 4-carboxamide oxazole compound, characterized by, comprising the following steps: S1, under inert atmosphere, an aldehyde compound containing R 1 group, an amide compound containing R 3 group, an isonitrile compound containing R 2 group, boron trifluoride diethyl ether and adamantanol are mixed in toluene to react, to obtain a crude product; the aldehyde compound is selected from any one or more of benzaldehyde, 2-biphenylylcarboxaldehyde, 2-(phenylethynyl)phenylcarboxaldehyde, 2-bromobenzaldehyde, 3-methoxybenzaldehyde, 4-(trimethylsilyl)ethynylbenzaldehyde, 4-trifluoromethylthiobenzaldehyde, dibenz[ b , d ] furan-4-carboxaldehyde; The amide compound is selected from the group consisting of N,N - dimethylformamide, N,N - dimethylacetamide, 2-chloro- N,N - dimethylacetamide, any one or more of. The isonitrile compound is selected from any one or more of adamantyl isonitrile, t-butyl isonitrile; S2, the crude product obtained in step S1 is separated and purified to obtain a 4-carboxamide oxazole compound, and the structural formula of the 4-carboxamide oxazole compound is as follows: , Among them, R 1 Selected from phenyl, 2-(phenylethynyl)phenyl, 2-biphenyl, 2-bromophenyl, 3-(methoxy)phenyl, 4-((trimethylsilyl)ethynyl)phenyl, 4-(trifluoromethylthio)phenyl, dibenzo[ b , d Any one of furan-4-yl; R 2 any one selected from adamantyl, t-butyl; R 3 is selected from any one of hydrogen, methyl, chloromethyl.

2. The method for preparing 4-formamide oxazole compounds according to claim 1, characterized in that, In step S1, the molar ratio of the aldehyde compound, the amide compound, the isonitrile compound, boron trifluoride ether and adamantanol is 1.0: (3.0-3.5): (2.5-4.0): (1.5-2.0): (1.0-1.5). The amount ratio of the aldehyde compound and toluene is 0.3 mmol: (0.6-1.0 mL).

3. The method for preparing 4-formamide oxazole compounds according to claim 1, characterized in that, In step S1, the inert atmosphere is nitrogen.

4. The method for preparing 4-formamide oxazole compounds according to claim 1, characterized in that, In step S1, the temperature of the mixed reaction is 80-110°C, the time is 9-12 h, and the stirring speed is 400-500 rpm.

5. The method for preparing 4-formamide oxazole compounds according to claim 1, characterized in that, In step S2, the separation and purification method is silica gel column chromatography, and the developing agent is a mixed solvent of petroleum ether, ethyl acetate and triethylamine in a volume ratio of 100:5:1-100:2:1.

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