Production of isoflavone derivatives

a technology of isoflavone and derivatives, applied in the field of isoflavone derivative production, can solve the problems of difficult control and lead to mixtures of different products, difficult to separate individual compounds, and general method suitable for large-scale synthesis of these metabolites

Inactive Publication Date: 2005-06-30
NOVOGEN RES
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  • Summary
  • Abstract
  • Description
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Benefits of technology

[0125] The surprising results obtained by the present inventors are in sharp contrast to those reported in the literature for other attempted hydrogenations of isoflavones. One such marked advantage is the use of alkyl acetates or alcohol solvents such as absolute methanol or ethanol in the hydrogenation reactions. The isoflavanols prepared by the methods of the present invention are typically very crystalline and can be isolated in good purity, and without the need for chromatography. The isoflavanols can be converted to isoflav-3-enes by dehydration. Further deprotection or derivatisation steps can be employed by those skilled in the art to obtain natural isoflavan4-ones, isoflavans, isoflavenes, metabolites and novel derivatives thereof as required.

Problems solved by technology

In spite of the recently discovered biological significance of isoflavone metabolites there is not at present a general method suitable for the large scale synthesis of these metabolites.
These reduction reactions are found to be non-selective, extremely difficult to control and lead to mixtures of different products.
The individual compounds are difficult to separate and can be obtained only in low yields.
Liebigs Ann. Chem. (1988) 555-558, however the reactions are low yielding, typically not clean and substituents on the basic isoflavone ring structure require tedious protective groups not affected by metal hydrides.
Chromatography is often required to separate the reaction products and only low yields of isoflavanones, isoflavan-4-ols, isoflavenes and isoflavans are obtained.
The chromatography required is tedious and often impracticable for large scale reactions Furthermore, attempts to improve the yield and purity of products obtained from hydrogenation reactions has been met with limited success as evidenced by published results which are largely contradictory.
However this solvent is unsuitable for pharmaceutical preparations of isoflavone metabolites and derivatives because N-methylpyrrolidinone is a severe eye irritant and a possible carcinogen.
Furthermore the high boiling point of the solvent makes it extremely difficult to remove after the reduction.

Method used

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  • Production of isoflavone derivatives
  • Production of isoflavone derivatives
  • Production of isoflavone derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

4′,7 Diacetoxydaidzein

Method A

[0127] A mixture of daidzein (1.0 g, 3.9 mmol), acetic anhydride (5 ml) and pyridine (5 ml) was left in the dark at room temperature for 24 h. The reaction mixture was poured into water (100 ml), stirred for 2 h and then extracted with dichloromethane (3×50 ml). The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The white residue was crystallised from methanol to yield daidzein diacetate as white prisms (1.1 g, 83%). 1H NMR (CDCl3): δ 2.32 (s, 3H, OCOCH3), 2.36 (s, 3H, OCOCH3), 7.18 (d, 2H, J 9.2 Hz, ArH), 7.19 (d, 1H, J 9.0 Hz, H6), 7.31 (d, 1H, J 20 Hz H8), 7.59 (d, 2H, J 9.2 Hz, ArH), 8.00 (s, 1H, H2), 8.33 (d, 2H, J 8.2 Hz, ArH).

Method B

[0128] A mixture of daidzein (2.0 g, 7.9 mmol), acetic anhydride (10 ml) and pyridine (2 ml) was heated on an oil bath at 105-110 C for 1 h. After cooling the mixture to room temperature, it was stirred for a further 30 min during which time the diacetate crysta...

example 2

7-acetoxy-4′-methoxyisoflavone

[0129] A mixture of 7-hydroxy-4′-methoxyisoflavanone (2.0 g, 7.5 mmol), acetic anhydride (10 ml) and pyridine (2 ml) was heated on an oil bath at 105-110 C for 1 hour. After cooling the mixture to room temperature, it was poured into water (100 ml), stirred for 2 hours and then extracted with dichloromethane (3×50 ml). The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The white residue was crystallised from methanol to yield 7-acetoxy-4′-methoxyisoflavone as colourless prisms (2.1 g, 91%). 1H NMR (CDCl3): δ 2.36 (s, 3H, OCOCH3), 3.84 (s, 3H, OCH3), 6.98 (d, 2H, J 8.7 Hz, ArH), 7.16 (dd, 1H, J 1.9 Hz 8.6 Hz, H6), 7.30 (d, 1H, J 1.9 Hz H8), 7.50 (d, 2H, J 8.7 Hz, ArH), 8.00 (s, 1H, H2), 8.32 (d, 1H, J 8.6 Hz, HS).

example 3

3′,7-Diacetoxyisoflavone

[0130] 3′,7-Diacetoxydaidzein was prepared from 3′,7-dihydroxyisoflavone (0.98 g, 3.9 mmol), acetic anhydride (6 ml) and pyridine (1.1 ml) as described for 4′,7-diacetoxydaidzein. Yield: (1.0 g, 77%) m.p. 152° C. 1H NMR (CDCl3): δ 2.31 and 2.36 (each s, 3H, OCOCH3), 7.14 (m, 1H, ArH), 7.18 (dd, 1H, J 2.0 Hz 8.6 Hz, H6), 7.31 (d, 1H, J 2.0 Hz H8), 7.37-7.45 (m, 3H, ArH), 8.03 (s, 1H, H2), 8.32 (d, 1H, J 8.6 Hz, H5). Mass spectrum:r m / z 338 (M, 8%); 296 (53); 254 (100); 253 (60).

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Abstract

Methods for the hydrogenation of isoflavones are described which provide access to workable quantities of isoflavan-4-ols, isoflav-3-enes, and isoflavans. The isoflavone derivatives can be obtained in high purity and in near quantitative yields whilst employing pharmaceutically acceptable reagents and solvents.

Description

INTRODUCTION [0001] The present invention relates to the hydrogenation of isoflavones and products thereof. The invention also relates to the synthesis of phytoestrogenic isoflavone metabolites and derivatives from the hydrogenation products of isoflavones. BACKGROUND OF THE INVENTION [0002] Isoflavone metabolites possess a very wide range of important biological properties including oestrogenic effects (WO 98 / 08503). Isoflavone metabolites can be isolated from the urine of human volunteers subjected to diets rich in plant isoflavanoids such as soya, lentils, peas and beans. [0003] In spite of the recently discovered biological significance of isoflavone metabolites there is not at present a general method suitable for the large scale synthesis of these metabolites. The few reported syntheses of these metabolites utilise either catalytic hydrogenation or hydrogen transfer reduction of the corresponding isoflavones. These reduction reactions are found to be non-selective, extremely d...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07B61/00C07D311/04C07D311/36C07D311/38C07D311/56C07D311/58
CPCC07D311/36C07D311/56C07D311/38
Inventor HEATON, ANDREWKUMAR
Owner NOVOGEN RES
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