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Polysubstituted tetrahydrofuran derivatives as well as synthesis method and application thereof

A technology of tetrahydrofuran and a synthetic method is applied in the field of preparation and application of pharmaceutical intermediates, and can solve the problems of many reaction steps, complicated operation and post-processing, long reaction time and the like

Active Publication Date: 2015-07-01
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many of these routes and synthetic methods have disadvantages such as complex synthesis of raw materials, many reaction steps, long reaction time, high cost, low yield, cumbersome operation and post-treatment, etc., and their practical and economic value are greatly limited.

Method used

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  • Polysubstituted tetrahydrofuran derivatives as well as synthesis method and application thereof
  • Polysubstituted tetrahydrofuran derivatives as well as synthesis method and application thereof
  • Polysubstituted tetrahydrofuran derivatives as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061]

[0062] The 3-hydroxy-1,3-diphenylpropan-1-one (0.30mmol, 1.0eq.), Molecular sieve (300mg) and rhodium acetate (0.003mmol) were dissolved in dichloromethane (1.5ml) at 25℃; then, phenyldiazomethyl ester (0.33mmol) dissolved in dichloromethane (1.5ml) , 1.1eq.) was added dropwise to the reaction system within 1h at 25°C. After the addition was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:30 to 1:10) to obtain a pure product. The yield is 80%, and the dr value is greater than 95:5.

[0063] 1 H NMR(400MHz, CDCl 3 )δ7.63(d, J=7.5Hz, 2H), 7.45(t, J=7.5Hz, 2H), 7.36(t, J=7.3Hz, 1H), 7.19(d, J=7.4Hz, 2H) , 7.10-7.00 (m, 8H), 5.74 (dd, J = 10.6, 5.2 Hz, 1H), 4.53 (s, 1H), 3.79 (s, 3H), 2.74-2.69 (m, 1H), 2.59 (dd , J=12.8, 5.2Hz, 1H); 13 C NMR(100MHz, CDCl 3 )δ173.62,140.77,140.18,137.96,128.61,127.88,127.63,127.39,127.31,1...

Embodiment 2

[0065]

[0066] The 3-hydroxy-1,3-diphenylpropan-1-one (0.30mmol, 1.0eq.), Molecular sieve (300mg) and palladium acetate (0.006mmol) were dissolved in toluene (1.5ml) at 0°C; then, phenyldiazomethyl ester (0.36mmol, 1.2eq.) dissolved in toluene (1.5ml). ) Add dropwise to the reaction system at 0°C within 1 hour, after the dropwise addition is completed, the solvent is removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:30 to 1:10) to obtain a pure product. The yield is 84%, and the dr value is greater than 95:5.

[0067] 1 H NMR(400MHz, CDCl 3 )δ7.63(d, J=7.5Hz, 2H), 7.45(t, J=7.5Hz, 2H), 7.36(t, J=7.3Hz, 1H), 7.19(d, J=7.4Hz, 2H) , 7.10-7.00 (m, 8H), 5.74 (dd, J = 10.6, 5.2 Hz, 1H), 4.53 (s, 1H), 3.79 (s, 3H), 2.74-2.69 (m, 1H), 2.59 (dd , J=12.8, 5.2Hz, 1H); 13 C NMR(100MHz, CDCl 3 )δ173.62,140.77,140.18,137.96,128.61,127.88,127.63,127.39,127.31,127.21,126...

Embodiment 3

[0069]

[0070] The 3-hydroxy-1,3-diphenylpropan-1-one (0.30mmol, 1.0eq.), Molecular sieve (300mg) and rhodium acetate (0.006mmol) were dissolved in chloroform (1.5ml) at 40℃; then, phenyldiazomethyl (0.42mmol) dissolved in chloroform (1.5ml) , 1.4eq.) was added dropwise to the reaction system within 1h at 40°C, and after the addition was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:30 to 1:10) to obtain a pure product. The yield was 87%, and the dr value was greater than 95:5.

[0071] 1 H NMR(400MHz, CDCl 3 )δ7.63(d, J=7.5Hz, 2H), 7.45(t, J=7.5Hz, 2H), 7.36(t, J=7.3Hz, 1H), 7.19(d, J=7.4Hz, 2H) , 7.10-7.00 (m, 8H), 5.74 (dd, J = 10.6, 5.2 Hz, 1H), 4.53 (s, 1H), 3.79 (s, 3H), 2.74-2.69 (m, 1H), 2.59 (dd , J=12.8, 5.2Hz, 1H); 13 C NMR(100MHz, CDCl 3 )δ173.62,140.77,140.18,137.96,128.61,127.88,127.63,127.39,127.31,127.21,126....

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Abstract

The invention relates to polysubstituted tetrahydrofuran derivatives and a chemical synthesis method thereof. The chemical synthesis method comprises the following steps: carrying out one-step reaction on raw materials (a diazo compound and a 3-hydroxyl-carbonyl flavone compound) in an organic solvent in the presence of a metal catalyst and an additive which is a molecular sieve shown in the specification; and carrying out column chromatography purification to obtain the target product. The chemical synthesis method of the polysubstituted tetrahydrofuran derivatives has the advantages of environmental benefit, step economy, atom economy, diastereoselectivity and high yield; in addition, the reaction conditions are mild, the applicability of the substrate range is wide and the operation is simple and safe. The invention discloses that the polysubstituted tetrahydrofuran derivatives with multiple chiral centers have PTPlB inhibiting effect; and therefore, the polysubstituted tetrahydrofuran derivatives are important chemical engineering, chemical and medical intermediates and have a wide prospect in the field of pharmaceutical chemicals.

Description

Technical field [0001] The invention relates to a novel multi-substituted tetrahydrofuran derivative and its synthesis method and application, belonging to the field of preparation and application of pharmaceutical intermediates. Background technique [0002] The multi-substituted tetrahydrofuran skeleton is an important skeleton structural unit for the construction of natural products and synthetic drugs. Many natural products and pharmaceutical active molecules contain such skeleton structures. For example, Muraymycins isolated from the fermentation broth of Streptomyces contains a multi-substituted tetrahydrofuran skeleton, which is a naturally occurring 6'-N-alkyl-5'-β-O-aminoribosyl-C- A member of the glycyluridine class of antibiotics. Muraymycins as a new peptidoglycan biosynthesis inhibitor has a good inhibitory effect on Gram-positive bacteria (J. Antibiot., 1985, 38, 1617; J. Antibiot., 1998, 51, 1099). Mucocin, as a kind of anticancer effect, contains such tetrahydro...

Claims

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Application Information

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IPC IPC(8): C07D307/24C07D409/04C07D493/10A61P3/04
Inventor 胡文浩荆常诚邢栋
Owner EAST CHINA NORMAL UNIVERSITY
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