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A kind of method for preparing isoxazole compound

A technology for isoxazole compounds and copper compounds, which is applied in the field of preparing isoxazole compounds, can solve the problems of inconvenient large-scale industrial production, high solvent requirements, increased cost, etc., and achieves wide application range, simple post-processing, and reaction safe effect

Active Publication Date: 2020-08-04
SUZHOU UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0003] (1) Yoshimura et al. reported that 3,5-dimethyliodobenzene catalyzed the reaction of oxime and alkyne to prepare isoxazole compounds, but the reaction required the addition of a large amount of oxidant combined with iodobenzene to oxidize oxime to form a nitrone intermediate , and then undergo [3+2] cycloaddition reaction with alkyne to build the skeleton of isoxazole compound, and the reaction has high requirements on solvent, and the use of three mixed solvents greatly limits its application in industrial production (see: Org. Lett. 2013, 15 ,4010-4013; Org. Lett. 2011, 13 ,2966-2969);
[0004] (2) Miyata et al. reported the preparation of isoxazole compounds by gold-catalyzed cyclization reaction of allyl oxime ester, but the reaction raw materials need multi-step synthesis, and the reaction needs to be carried out under the catalysis of noble metal gold, so that the preparation process is easy The cost is greatly improved, and it is not easy for large-scale industrial production (see: Org. Lett. 2010, 12 , 2594-2597);
[0005] (3) Recently, Pal et al. reported that α-nitroketones reacted with alkynes and water and polyethylene glycol 400 as solvents to prepare isoxazole compounds without adding a catalyst. The reaction conditions were quite mild. However, the substrate range of the starting nitro compound greatly limits the application of this reaction (see: Adv. Synth. Catal. 2014, 356 , 160-164)

Method used

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  • A kind of method for preparing isoxazole compound
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  • A kind of method for preparing isoxazole compound

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Experimental program
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Embodiment 1

[0034]

[0035] The reaction flask was sequentially charged with CuI (0.15 mmol, 28 mg), Mg(OTf) 2 (0.2 mmol, 64 mg), DABCO (5 mmol, 560 mg), compound 1a (2 mmol, 384 mg), compound 2a (3 mmol, 342 mg), t BuONO (3 mmol, 309 mg), cyclohexane (10.0 mL). Then the system was heated at 80 °C in air for about 12 hours, extracted with ethyl acetate (40 mL × 3), and the product 3a was obtained by simple column chromatography with a yield of 63%. The main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthetic product is consistent with the theoretical analysis.

[0036] 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 – 7.87 (m, 2H), 7.58 – 7.45 (m, 3H), 4.48 (q, J = 7.1 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 171.4, 160.8, 159.7, 156.2, 131.7, 128.6, 128.4, 125.6, 108.4, 62.6, 61.7, 13.9, 13.7; HRMS (ESI-TOF): Anal. Calcd. For C 15 H 15 NO 5 : 312.0842,...

Embodiment 2

[0038]

[0039] Cu(OAc) was charged into the reaction flask in turn 2 (0.15 mmol, 27 mg), Mg(OTf) 2(0.2 mmol, 64 mg), DABCO (5 mmol, 560 mg), compound 1a (2 mmol, 384 mg), compound 2a (3 mmol, 342 mg), t BuONO (3 mmol, 309 mg), cyclohexane (10.0 mL). Then the system was heated at 80 °C in air for about 12 hours, extracted with ethyl acetate (40 mL × 3), and the product 3a was obtained by simple column chromatography with a yield of 71%. The main test data of the prepared product are as in Example 1, and the analysis shows that the actual synthetic product is consistent with the theoretical analysis.

Embodiment 3

[0041]

[0042] Cu(OAc) was charged into the reaction flask in turn 2 .H 2 O (0.15 mmol, 30 mg), Mg(OTf) 2 (0.2 mmol, 64 mg), DABCO (5 mmol, 560 mg), compound 1a (2 mmol, 384 mg), compound 2a (3 mmol, 342 mg), t BuONO (3 mmol, 309 mg), cyclohexane (10.0 mL). Then, the system was heated at 80 °C in air for about 12 hours, extracted with ethyl acetate (40 mL × 3), and the product 3a was obtained by simple column chromatography with a yield of 80%. The main test data of the prepared product are as in Example 1, and the analysis shows that the actual synthetic product is consistent with the theoretical analysis.

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Abstract

The invention discloses a method for preparing isoxazole compounds, using β-keto acid ester, α-diazoic acid ester and tert-butyl nitrite as reaction substrates, copper compounds as catalysts, Lewis acid as additives, three Ethylenediamine (DABCO) is a base, and the fully substituted oxazole product is prepared by a three-component reaction; the method used in the present invention has the following characteristics: the reactivity of the catalyst is high, the reaction conditions are mild, and the substrate has a wide range of applications. The post-treatment is convenient, the yield of the target product is high, the preparation process is simple, and the sources of raw materials used are extensive.

Description

technical field [0001] The present invention relates to a method for preparing isoxazole compounds. Background technique [0002] Isoxazoles are a kind of very important five-membered heterocyclic organic compounds, which are widely used in biology, medicine, pesticide, chemical industry and so on. A variety of isoxazole derivatives show broad medical prospects. For example: various parecoxib: COX-2 inhibitor, sulfamethoxazole: PABA antagonist, oxacillin: beta-lactam antibiotic, hydroxamic acid: 4-hydroxyphenylpyruvate bis-addition Oxygenase inhibitors, leflunomide: anti-rheumatism and other compounds containing isoxazole compound skeletons have shown very good prospects for medical applications. Therefore, the synthesis of isoxazole compounds has always been a research hotspot of chemists. At present, the methods for preparing isoxazole compounds have disadvantages such as harsh reaction conditions, cumbersome preparation of raw materials, and excessive use of oxidants. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D261/18C07D409/12B01J27/122B01J31/02B01J31/04
CPCC07D261/18C07D409/12B01J27/122B01J31/0225B01J31/04B01J2231/341
Inventor 万小兵陈荣祥陈继君方尚文龙文号
Owner SUZHOU UNIV
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