Synthesis method of chiral spiro[chroman-4,1'-dihydroindene] molecule

A synthesis method, the technology of dihydroindene, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of many synthetic wastes, low practical value, poor atom economy, etc., and achieve a simple synthesis method and a green and efficient separation method Effect

Active Publication Date: 2021-10-12
NANKAI UNIV
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  • 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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  • Synthesis method of chiral spiro[chroman-4,1'-dihydroindene] molecule
  • Synthesis method of chiral spiro[chroman-4,1'-dihydroindene] molecule
  • Synthesis method of chiral spiro[chroman-4,1'-dihydroindene] 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 synthesis method of chiral spiro[chroman-4,1'-dihydroindene] molecule. Using phenylpropionic acid as the starting material, react with monoethylmagnesium malonate to obtain β-ketoester, and then construct the spirolide structure through acid-catalyzed series Friedel-Crafts reaction in one pot, and then through trifluoroform The sulfonate ester activates the phenolic hydroxyl group, and finally removes the occupying atom and the sulfonate group by palladium-carbon hydrogenation to complete the synthesis of the chiral spiro[chroman-4,1'-dihydroindene] molecule. The racemate was optically resolved under the action of N-benzylhalogenated cinchonidine. The synthesis method overcomes the problems of poor atom economy, many synthetic wastes, and low practical value of the original method, and realizes simple and economical large-scale preparation of the target molecule; the separation method is green and efficient, and the separation reagent, solvent It can be used multiple times; the product molecule and synthesis method have important application value and potential in catalyst skeleton design and natural product drug 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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Patent Type & Authority Patents(China)
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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