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A kind of method for preparing 1,4-dihydrooxazine

A technology for dihydrooxazine and derivatives, which is applied in the field of preparation of 1,4-dihydrooxazine, can solve the problems of inapplicability to the preparation of multi-substituted oxazine rings, high preparation costs, narrowing of the substrate range, etc., and achieve suitable It is suitable for large-scale industrial production, reduces the preparation cost, and has the effect of less reaction steps

Active Publication Date: 2020-12-08
SUZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] (1) Siegfried et al. reported that aminoalkyne compounds were prepared by intramolecular nucleophilic addition and cyclization to 1,4-dihydrooxazine, but the raw materials of aminoalkyne compounds required one or more steps of reaction to pre-prepare, so that the substrate narrow range and high preparation costs (cf.: Blechert, S., Angew. Chem. Int. Ed. 2005, 117 , 7972.);
[0004] (2) Urabe et al reported the preparation of 1,4-dihydrooxazine by intermolecular cycloaddition reaction between halogenated alkyne and hydroxylamine compound, but the reaction needs to be carried out at a higher temperature, and the reaction is not suitable for many Preparation of substituted oxazine rings (see: Urabe, H., J. Am. Chem. Soc. 2008, 130 , 1820.)

Method used

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  • A kind of method for preparing 1,4-dihydrooxazine
  • A kind of method for preparing 1,4-dihydrooxazine
  • A kind of method for preparing 1,4-dihydrooxazine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032]

[0033] The reaction flask was filled with compound 1a (0.2 mmol, 28.4 mg), compound 2a (0.6 mmol, 163.8 mg), AgOTf (0.03 mmol, 7.7 mg), Cu(OAc) 2 (0.02 mmol, 3.6 mg), NaHCO 3 (0.4 mmol, 33.6 mg), DCE (0.4 mL). Then the system was heated in the air at 40°C for about 12 hours, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and the product 3a was obtained by simple column chromatography with a yield of 70%. The main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

[0034] 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.35 (ddd, J = 8.3, 6.7, 4.6 Hz, 5H), 7.13 (dd, J = 7.5, 1.8 Hz, 2H) , 4.36 (dd, J = 10.2,2.9 Hz, 1H), 3.85 (s, 3H), 2.85 (dd, J = 14.6, 10.3 Hz, 1H), 2.45 (s, 3H), 2.26 (s, 3H); 13C NMR (101 MHz, CDCL3) Δ 166.12, 154.17, 144.66, 136.27,134.59, 129.92, 128.91, 128.28, 125.91, 106.08, 75.22, 52.06, 48.31.67,...

Embodiment 2

[0036]

[0037] The reaction flask was filled with compound 1b (7 mmol, 1.1 g), compound 2a (21 mmol, 1.9 g), AgOTf (0.7 mmol, 0.2 g), Cu(OAc) 2(1.1 mmol, 0.2 g), NaHCO 3 (14 mmol, 1.2 g), DCE (14 mL). Then the system was heated in the air at 40°C for about 12 hours, and the solvent was removed by a rotary evaporator, adsorbed on silica gel, and the product 3b was obtained by simple column chromatography with a yield of 73%. The main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

[0038] 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.2 Hz, 2H), 7.48 – 7.26 (m,5H), 7.14 (dd, J = 7.5, 1.6 Hz, 2H), 4.40 (dd, J = 10.2, 2.8 Hz, 1H), 4.34(dt, J = 13.8, 6.9 Hz, 2H), 3.82 (dd, J = 14.6, 3.0 Hz, 1H), 2.84 (dd, J = 14.6, 10.3 Hz, 1H), 2.45 (s, 3H), 2.26 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13CNMR (101 MHz, CDCl3) δ 165.70, 153.81, 144.58, 136.37, 134.65, 129.86, 128.87, 12...

Embodiment 3

[0040]

[0041] The reaction flask was filled with compound 1c (0.2 mmol, 25.2 mg), compound 2a (0.6 mmol, 163.9 mg), AgOTf (0.03 mmol, 7.7 mg), Cu(OAc) 2 (0.02 mmol, 3.6 mg), NaHCO 3 (0.4 mmol, 33.6 mg), DCE (0.4 mL). Then the system was heated at 40°C in the air for about 12 hours, and the solvent was removed by a rotary evaporator, adsorbed on silica gel, and the product 3a was obtained by simple column chromatography with a yield of 80%. The main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

[0042] 1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.0Hz, 2H), 7.36 – 7.31 (m, 3H), 7.04 – 6.98 (m, 2H), 4.03 (dd, J = 14.9, 3.1Hz, 1H), 3.72 (dd, J = 10.6, 3.1 Hz, 1H), 2.96 (dd, J = 14.9, 10.6 Hz, 1H), 2.48 (s, 3H), 2.47 (s, 3H), 2.14 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 197.15,152.15, 144.63, 135.52, 133.03, 129.75, 128....

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Abstract

The invention discloses a method for preparing 1,4-dihydrooxazine. An acyl diazo derivative and an acridine compound are taken as reaction substrates, AgOTf and Cu(OAc)2 are taken as reaction catalysts, NaHCO3 is used as an alkali, and the 1,4-dihydrooxazine is obtained through a ring addition reaction in an organic solvent. The method provided by the invention has the following characteristics that the reaction is more economical, functionalization in the later period is easier, reaction conditions are mild, the reaction can be carried out in the air, the use amount of the catalysts is small,post-treatment is simple and convenient, purification and large-scale industrial application of the product are facilitated, and one-step functionalization of commercial medicines is easier to carryout. Meanwhile, the raw materials such as the reactants, the catalysts and the like are cheap and easily available, the reaction composition is reasonable, a ligand is not needed, the atom economy ishigh, the reaction steps are few, and a relatively high yield can be obtained only by the one-step reaction, so that the method accords with requirements and directions of contemporary green chemistryand pharmaceutical chemistry and is suitable for screening high-activity 1,4-dihydrooxazine medicines, a gram-grade reaction can be well realized, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a method for preparing 1,4-dihydrooxazine, which belongs to the technical field of organic synthesis. Background technique [0002] 1,4-Dihydrooxazine is a ubiquitous core structure in many natural products, bioactive pharmaceuticals, and agrochemicals. Remarkably, 1,4-dihydrooxazine is often considered a privileged scaffold in medicinal chemistry for the discovery and optimization of new synthetic drug molecules. 1,4-Dihydrooxazine can also be used as a useful synthetic building block in the construction of heterocycles and as an additive in catalytic systems. At present, the method for preparing 1,4-dihydrooxazine has the disadvantages of harsh reaction conditions, cumbersome preparation of raw materials, large amount of raw materials, narrow substrate range, and low yield. E.g: [0003] (1) Siegfried et al. reported that aminoalkyne compounds were prepared by intramolecular nucleophilic addition and cyclization to 1,4-dih...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D265/30B01J31/02B01J31/04
Inventor 万小兵方尚文赵彦伟李海燕郑永高廉鹏程
Owner SUZHOU UNIV
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