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Preparation method of alpha, alpha-di-substituted iso-chroman compound

An isochroman and compound technology, which is applied in the field of preparation of α,α-disubstituted isochroman compounds, can solve problems such as sensitivity, and achieve the effects of simple operation, short reaction steps and mild reaction conditions

Active Publication Date: 2019-10-15
XI'AN PETROLEUM UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the DDQ oxidizer used is sensitive to water and releases highly toxic substances, and the substrate used involves toxic cyanide

Method used

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  • Preparation method of alpha, alpha-di-substituted iso-chroman compound
  • Preparation method of alpha, alpha-di-substituted iso-chroman compound
  • Preparation method of alpha, alpha-di-substituted iso-chroman compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Taking the preparation of the compound 1-nitromethyl-1-phenylisochroman as an example, the raw materials used and the preparation method are as follows:

[0037]

[0038] Mix 161mg (0.6mmol) of 1-phenylisochromatium (0.6mmol) and 238mg (0.72mmol) of triphenylmethyltetrafluoroborate in dichloroethane at 20°C, stir and react for 1 hour, add 160uL (3.0mmol) ) Nitromethane, react at 80°C for 24 hours. When the reaction is over, add 2 mL of distilled water to the system, extract three times with 10 mL of dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, filter with suction, concentrate, and give the crude product Column chromatography separation (dichloromethane and n-hexane) was performed to obtain 1-nitromethyl-1-phenyl isochroman as a white solid with a yield of 95%.

[0039] The NMR characterization data are: 1 H NMR(600MHz, CDCl 3 )δ7.40–7.39(m,2H),7.36–7.26(m,7H),5.06(d,J=12.1Hz,1H), 4.88(d,J=12.1Hz,1H),4.05(ddd,J = 11.6, 6.0, 1.8 Hz, 1H), 3.6...

Embodiment 2

[0041] Taking the preparation of 1-nitromethyl-1-p-tert-butylphenyl isochroman as an example, the raw materials used and the preparation method are as follows:

[0042]

[0043] In Example 2, the 1-phenyl isochroman used in Example 1 was replaced with an equimolar 1-tert-butyl phenyl isochroman. The other steps were the same as in Example 1, and a white solid was prepared. The yield was 92%.

[0044] The NMR characterization data are: 1 H NMR(600MHz, CDCl 3 )δ8.20(d,J=8.8Hz,2H), 7.65(d,J=8.8Hz,2H), 7.36–7.26(m,4H), 5.10(d,J=12.1Hz,1H), 4.84( d, J = 12.1Hz, 1H), 4.03 (ddd, J = 11.6, 6.0, 1.8 Hz, 1H), 3.69 (td, J = 11.4, 3.7 Hz, 1H), 3.06–3.01 (m, 1H), 2.64 –2.60(m,1H),1.37(s,9H); 13 C NMR(151MHz, CDCl 3 )δ145.5,139.8,139.0,132.4,128.5,128.4,126.9,125.7,123.7,122.8,82.0,79.2,61.1,35.2,31.1.HRMS(ESI)m / z:C 20 H 23 NNaO 3 [M+Na] + The theoretical value is 348.1576, and the measured value is 348.1558.

Embodiment 3

[0046] Taking the preparation of the compound 1-nitromethyl-1-p-chlorophenyl isochroman as an example, the raw materials used and the preparation method are as follows:

[0047]

[0048] In Example 3, the 1-phenyl isochroman used in Example 1 was replaced with an equimolar 1-chlorophenyl isochroman. The other steps were the same as in Example 1, and the white solid was prepared. The yield Is 92%.

[0049] The NMR characterization data are: 1 H NMR(600MHz, CDCl 3 )δ7.36–7.29(m,4H),7.26–7.22(m,4H),5.07(d,J=12.1Hz,1H), 4.93(d,J=12.1Hz,1H),4.05–3.98(m ,1H), 3.71–3.67(m,1H),3.06–3.01(m,1H), 2.64–2.60(m,1H); 13 C NMR(151MHz, CDCl 3 )δ139.8,138.6,133.8,132.4,128.4,128.0,127.7,126.9,125.7,122.8,81.7,78.4,59.6,26.9.HRMS(ESI)m / z:C 16 H 14 ClNNaO 3 [M+Na] + The theoretical value is 326.0560, and the measured value is 326.0579.

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Abstract

The invention discloses a preparation method of an alpha, alpha-di-substituted iso-chroman compound. The alpha,alpha-di-substituted iso-chroman compound is obtained by directly synthesizing a raw material alpha-monosubstituted iso-chroman compound, which is diverse in structure and easy to synthesize, and nitromethane in one step. The method has the advantages of short reaction steps, mild reaction conditions, high efficiency and simple operation. According to the preparation method, the C-H bond on the alpha-site carbon of the alpha-mono-substituted iso-chroman compound can directly form theC-C bond, so that the use of an intermediate in a redundant synthesis step is avoided, which is consistent with the concept of green synthetic chemistry of economy and sustainable development of atomspursued at present. The prepared alpha, alpha-disubstituted iso-chroman compound can be subjected to a series of chemical conversion to generate various substituted iso-chroman derivatives; the method has great application potential in preparation of medicines and active natural products.

Description

Technical field [0001] The invention relates to a preparation method of α,α-disubstituted heterochroman compounds. Background technique [0002] α,α-disubstituted heterochroman compounds are common structural units of many natural products and synthetic drugs with multiple biological activities. The current synthesis mainly relies on the construction of a cyclization reaction involving the O-heterocyclic pre-functionalized alcohol group. For example, in formula 1, a terminal alkyne-substituted methoxy-functionalized heterochroman compound obtains a terminal alkyne-functionalized α,α-disubstituted heterochroman compound (Angew.Chem.Int.Ed.2015,54,14154– 14158). [0003] [0004] The intermediate alcohol-based functionalized isochroman compounds used above are usually prepared through the route shown in Formula 2 (J. Am. Chem. Soc. 2008, 130, 7198-7199). However, the synthesis steps are lengthy and air-sensitive organolithium reagents are used, and the reaction conditions are hars...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/76
CPCC07D311/76
Inventor 吴亚林智伟陈刚李浩
Owner XI'AN PETROLEUM UNIVERSITY
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