Synthetic method of chiral spiro [chroman-4, 1'-indane] molecule

A technology of dihydroindene and chroman, which is applied in the field of synthesis of chiral compounds, can solve the problems of many synthetic wastes, low practical value, and poor atom economy, and achieve the effect of simple synthesis method and green and efficient separation method

Active Publication Date: 2019-07-05
NANKAI UNIV
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  • Abstract
  • Description
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Problems solved by technology

[0003] The object of the present invention is to provide a method for synthesizing chiral spiro[chroman-4,1′-indene] molecules, which can overcome the problems of poor atom economy, many synthetic wastes and low practical value of the original method. The simple and economical large-scale preparation of target molecules is realized; moreover, the resolution method is green and efficient, and the resolution reagents and solvents can be used multiple times; the product molecule and synthesis method have important application value in the design of catalyst skeleton and the synthesis of natural product drugs with potential

Method used

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  • Synthetic method of chiral spiro [chroman-4, 1'-indane] molecule
  • Synthetic method of chiral spiro [chroman-4, 1'-indane] molecule
  • Synthetic method of chiral spiro [chroman-4, 1'-indane] molecule

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Synthesis of ethyl 5-(2-bromo-5-hydroxyphenyl)-3-carbonylvalerate (b):

[0024]

[0025] To a 3000 mL dry reaction flask, add 3-(2-bromo-5-hydroxyphenyl)-propionic acid a (40 g, 163 mmol) and carbonyldiimidazole CDI (28.6 g, 176 mmol), and add tetrahydrofuran (700 mL) to dissolve. The atmosphere was replaced by argon, and the reaction was stirred at room temperature for 8 hours. A tetrahydrofuran (300 mL) solution of monoethyl malonate magnesium salt (39 g, 253 mmol) was added to the reaction system, and the reaction was continued to stir at room temperature for 12 hours, and the reaction was complete as monitored by TLC. The system was acidified by adding 1N HCl, extracted with ether (2×150 mL), and the combined organic phases were washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Add diatomaceous earth for suction filtration, precipitation under reduced pressure, and column chromatography (petroleum ether / ethyl aceta...

Embodiment 2

[0026] Example 2: Synthesis of 4'-bromo-5-hydroxyl-7'-hydroxyl-spiro[chroman-4,1'-indane]-2-one (c):

[0027]

[0028] Add ethyl 5-(2-bromo-5-hydroxyphenyl)-3-carbonylpentanoate b (17.8 g, 56.5 mmol) into a 1000 mL dry reaction flask, and add dichloromethane (300 mL) to dissolve. Replace the inside of the system with an argon atmosphere, and use an ice-water bath to control the temperature inside the system to below 5°C. Then trifluoromethanesulfonic acid (15.0 mL, 169 mmol) was slowly added dropwise. After the dropwise addition was completed, the ice bath was removed, and the system was stirred and reacted at room temperature for 0.5 hour. TLC monitored that all the raw materials had been converted completely, and a large amount of yellow solids were precipitated out in the system. Resorcinol (6.2 g, 56.5 mmol) was added to the reaction system, and the reaction was continued to stir at room temperature for 1 hour, and TLC monitored that all intermediates were converted co...

Embodiment 3

[0029] Example 3: Synthesis of 4'-bromo-7-hydroxyl-7'-methoxy-2',3'-dihydrospiro[chroman-4,1'-indene]-2-one:

[0030]

[0031] The preparation method is the same as that of Example 2, and the yield is 97% as light yellow solid. 1 H NMR (400MHz, DMSO) δ9.70(s,1H),7.45(d,J=8.6Hz,1H),6.82(d,J=8.7Hz,1H),6.66–6.59(m,1H),6.46 (m,2H),3.60(s,3H),3.26(d,J=15.9Hz,1H),3.03–2.95(m,2H),2.95–2.89(m,1H),2.29–2.15(m,2H ).

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Abstract

The invention relates to a synthetic method of a chiral spiro [chroman-4, 1'-indane] molecule. The method comprises the following steps of using phenylpropionic acid as a starting material to react with malonic acid monoethyl magnesium salt to obtain beta-ketone ester, constructing a spiro lactone structure through an acid catalysis series Friedel-Crafts reaction one-pot method, then activating phenol hydroxyl through triflate, finally removingan occupation atom and sulfonic ester group through palladium carbon hydrogenation to synthesizethe chiral spiro [chroman-4, 1'-indane] molecule. The optical resolution of a racemate is realized under the action of the N-benzyl halogenated cinchonine. The synthetic method solves the problems that an original method has poor atom economy, a pluralityof synthetic wastes and a low practical value, and realizes compact and economical large-scale preparation of target molecules; the resolution method is green and efficient, and resolution reagents and solvents can be used for a plurality of times; and the product molecules and the synthesis method have important application values and potentials in the aspects of catalyst framework design and natural product medicine synthesis.

Description

technical field [0001] The invention belongs to the synthesis of chiral compounds, in particular to a synthesis method of chiral spiro[chroman-4,1'-dihydroindene] molecules. Background technique [0002] The chiral spiro [chroman-4,1′-dihydroindene] structure exists in drugs and natural product molecules with physiological activity, and the corresponding chiral spiro ring molecules are also used in the synthesis of chiral ligands and natural product molecules. It has extremely high application value. However, the synthesis methods of chiral spiro[chroman-4,1′-dihydroindene] are still limited. The synthesis method reported in the literature is mainly obtained by Friedal-Crafts type tandem cyclization reaction of α,β-unsaturated ester derived from indanone and substituted phenol (Niharika, P.; Satyanarayana, G. RSCAdv.2016, 6, 837; Ramulu, B.V.; Satyanarayana, G. RSCAdv. 2015, 5, 70972; Niharika, P.; Ramulu, B.V.; Satyanarayana, G. Org. Biomol. Chem. 2014, 12, 4347). Since ...

Claims

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Application Information

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IPC IPC(8): C07D311/96
CPCC07B2200/07C07D311/96
Inventor 谢建华张洋铭周其林王庆仙郭淑敏王立新
Owner NANKAI UNIV
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