U.S. patent application number 10/851270 was filed with the patent office on 2005-06-30 for production of isoflavone derivatives.
This patent application is currently assigned to Novogen Research Pty Ltd.. Invention is credited to Heaton, Andrew, Kumar, Naresh.
Application Number | 20050143588 10/851270 |
Document ID | / |
Family ID | 3812886 |
Filed Date | 2005-06-30 |
United States Patent
Application |
20050143588 |
Kind Code |
A1 |
Heaton, Andrew ; et
al. |
June 30, 2005 |
Production of isoflavone derivatives
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.
Inventors: |
Heaton, Andrew; (New South
Wales, AU) ; Kumar, Naresh; (New South Wales,
AU) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Assignee: |
Novogen Research Pty Ltd.
|
Family ID: |
3812886 |
Appl. No.: |
10/851270 |
Filed: |
May 20, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10851270 |
May 20, 2004 |
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09889701 |
Nov 5, 2001 |
|
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09889701 |
Nov 5, 2001 |
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PCT/AU00/00103 |
Feb 15, 2000 |
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Current U.S.
Class: |
549/403 |
Current CPC
Class: |
C07D 311/38 20130101;
C07D 311/56 20130101; C07D 311/36 20130101 |
Class at
Publication: |
549/403 |
International
Class: |
C07D 311/74 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 15, 1999 |
AU |
PP 8685 |
Claims
1. A method for the preparation of a compound of formula II
6wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7 and R.sub.8 are independently hydrogen, hydroxy, OR.sub.9,
OC(O)R.sub.9, OS(O)R.sub.9, alkyl, haloalkyl, aryl, arylalkyl,
thio, alkylthio, amino, alkylamino, dialkylamino, nitro, or halo,
and R.sub.9 is alkyl, haloalkyl, aryl, arylalkyl or alkylaryl,
comprising the step of hydrogenating a compound of formula I
7wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8 and R.sub.9 are as defined above to prepare a
compound of formula II.
2. A method of claim 1, wherein the hydrogenation step is performed
with hydrogen in the presence of a reduction catalyst and a
solvent.
3. A method of claim 2, wherein the reduction catalyst comprises
palladium, palladium hydroxide, platinum or platinum oxide.
4. A method of claim 3, wherein the reduction catalyst is palladium
on activated carbon, palladium on barium sulfate or
platinum(IV)oxide.
5. A method of claim 4, wherein the reduction catalyst is palladium
on activated carbon (1% Pd to 10% Pd).
6. A method of claim 5, wherein the reduction catalyst is about 5%
palladium on activated carbon.
7. A method of claim 2, wherein the solvent is a C.sub.1-C.sub.8
alcohol, an alkyl acetate or a C.sub.1-C.sub.3 carboxylic acid.
8. A method of claim 7, wherein the solvent is a methanol, ethanol
or C.sub.1-C.sub.6 alkyl acetate.
9. A method of claim 8, wherein the solvent is absolute methanol or
absolute ethanol.
10. A method of claim 1 which further comprises the step of
dehydrating and optionally deprotecting or transforming a compound
of formula II to prepare a compound of formula III 8R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8
are independently hydrogen, hydroxy, OR.sub.9, OC(O)R.sub.9,
OS(O)R.sub.9, alkyl, haloalkyl, aryl, arylalkyl, thio, alkylthio,
amino, alkylamino, dialkylamino, nitro, or halo, and R.sub.9 is
alkyl, haloalkyl, aryl, arylalkyl or alkylaryl.
11. A method of any one of claims 1 to 10, wherein the compounds of
formula I, II or III have the following substituents R.sub.1 is
hydroxy, OR.sub.9 or OC(O)R.sub.9, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6 and R.sub.7 are independently hydrogen, hydroxy,
OR.sub.9, OC(O)R.sub.9, alkyl, aryl or arylalkyl, R.sub.8 is
hydrogen, and R.sub.9 is methyl, ethyl, propyl, isopropyl or
trifluoromethyl.
12. A method of claim 11, wherein the compounds of formula I, II or
III have the following substituents R.sub.1 is hydroxy, OR.sub.9 or
OC(O)R.sub.9, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.7 are
independently hydrogen, hydroxy, OR.sub.9, OC(O)R.sub.9, alkyl,
aryl or arylalkyl, R.sub.6 and R.sub.8 are hydrogen, and R.sub.9 is
methyl.
13. A method of any one of claims 1 to 12, wherein the compound of
formula I is 4',7-diacetoxyisoflavone (daidzein diacetate) or
7-acetoxy-4'-methoxyisoflavone.
14. A method of any one of claims 1 to 13, wherein the compound of
formula II is 4',7-diacetoxyisoflavan-4-ol (tetrahydrodaidzein
diacetate) or 7-acetoxy4'-methoxyisoflavan-4-ol.
15. A method of any one of claims 10 to 14, wherein and the
compound of formula III is 4',7-diacetoxyisoflav-3-ene
(dehydroequol diacetate), 4',7-dihydroxyisoflav-3-ene
(dehydroequol), 7-acetoxy-4'-methoxyisoflav-3- -ene or
7-hydroxy-4'-methoxyisoflav-3-ene.
16. A method for the preparation of a compound of formula IV
9wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7 and R.sub.8 are independently hydrogen, hydroxy, OR.sub.9,
OC(O)R.sub.9, OS(O)R.sub.9, alkyl, haloalkyl, aryl, arylalkyl,
thio, alkylthio, amino, alkylamino, dialkylamino, nitro, or halo,
and R.sub.9 is alkyl, haloalkyl, aryl, arylalkyl or alkylaryl,
comprising the step of hydrogenating a compound of formula I
10wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8 and R.sub.9 are as defined above to prepare a
compound of formula IV.
17. A method of claim 16, wherein the hydrogenation step is
performed with hydrogen in the presence of a reduction catalyst and
a solvent.
18. A method of claim 17, wherein the reduction catalyst comprises
palladium, palladium hydroxide, platinum or platinum(IV)oxide.
19. A method of claim 18, wherein the reduction catalyst is
palladium on activated carbon (1% Pd to 10% Pd).
20. A method of claim 19, wherein the reduction catalyst is about
5% palladium on activated carbon.
21. A method of claim 17, wherein the solvent is a C.sub.1-C.sub.8
alcohol, a C.sub.1-C.sub.6 alkyl acetate or a C.sub.1-C.sub.3
carboxylic acid.
22. A method of claim 21, wherein the solvent is absolute methanol,
ethanol or ethyl acetate.
23. A method of any one of claims 16 to 22, wherein the compound of
formula I is 4',7-diacetoxyisoflavone (daidzein diacetate) or
7-acetoxy-4'-methoxyisoflavone.
24. A method of any one of claims 16 to 22, wherein the compound of
formula IV has the following substituents R.sub.1 is hydroxy,
OR.sub.9 or OC(O)R.sub.9, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6 l and R.sub.7 are independently hydrogen, hydroxy,
OR.sub.9, OC(O)R.sub.9, alkyl, aryl or arylalkyl, R.sub.8 is
hydrogen, and R.sub.9 is methyl, ethyl, propyl, isopropyl or
trifluoromethyl.
25. A method of claim 24, wherein the compound of formula IV has
the following substituents R.sub.1 is hydroxy, OR.sub.9 or
OC(O)R.sub.9, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.7 are
independently hydrogen, hydroxy, OR.sub.9, OC(O)R.sub.9, alkyl,
aryl or arylalkyl, R.sub.6 and R.sub.8 are hydrogen, and R.sub.9 is
methyl.
26. A method of claim 25, wherein the compound of formula IV is
4',7-diacetoxyisoflavan-4-one (diacetoxydihydrodaidzein) or
4',7-dihydroxyisoflavan-4-one (dihydrodaidzein).
27. A method for the preparation of a compound of formula V
11wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7 and R.sub.8 are independently hydrogen, hydroxy, OR.sub.9,
OC(O)R.sub.9, OS(O)R.sub.9, alkyl, haloalkyl, aryl, arylalkyl,
thio, alkylthio, amino, alkylamino, dialkylamino, nitro, or halo,
and R.sub.9 is alkyl, haloalkyl, aryl, arylalkyl or alkylaryl,
comprising the step of hydrogenating a compound of formula III
12wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8 and R.sub.9 are as defined above to prepare a
compound of formula V.
28. A method of claim 27, wherein the hydrogenation step is
performed with hydrogen in the presence of a reduction catalyst and
a solvent.
29. A method of claim 28, wherein the reduction catalyst comprises
palladium, palladium hydroxide, platinum or platinum(IV)oxide.
30. A method of claim 29, wherein the reduction catalyst is
palladium on activated carbon (1% Pd to 10% Pd).
31. A method of claim 30, wherein the reduction catalyst is about
5% palladium on activated carbon.
32. A method of claim 28, wherein the solvent is a C.sub.1-C.sub.8
alcohol, a C.sub.1-C.sub.6 alkyl acetate or a C.sub.1-C.sub.3
carboxylic acid.
33. A method of claim 32, wherein the solvent is a methanol,
ethanol or ethyl acetate.
34. A method of claim 33, wherein the solvent is ethyl acetate.
35. A method of any one of claims 27 to 34, wherein and the
compound of formula III is 4',7-diacetoxyisoflav-3-ene
(dehydroequol diacetate), 4',7-dihydroxyisoflav-3-ene
(dehydroequol), 7-acetoxy4'-methoxyisoflav-3-- ene or
7-hydroxy-4'-methoxyisoflav-3-ene.
36. A method of any one of claims 27 to 34, wherein the compound of
formula V has the following substituents R.sub.1 is hydroxy,
OR.sub.9 or OC(O)R.sub.9, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6 and R.sub.7 are independently hydrogen, hydroxy, OR.sub.9,
OC(O)R.sub.9, alkyl, aryl or arylalkyl, R.sub.8 is hydrogen, and
R.sub.9 is methyl, ethyl, propyl, isopropyl or trifluoromethyl.
37. A method of claim 36, wherein the compound of formula V has the
following substituents R.sub.1 is hydroxy, OR.sub.9 or
OC(O)R.sub.9, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.7 are
independently hydrogen, hydroxy, OR.sub.9, OC(O)R.sub.9, alkyl,
aryl or arylalkyl, R.sub.6 and R.sub.8 are hydrogen, and R.sub.9 is
methyl.
38. A method of claim 37, wherein the compound of formula V is
4',7-diacetoxyisoflavan (equol diacetate) or
4',7-dihydroxyisoflavan (equol).
39. Methods substantially as hereinbefore described especially with
reference to the Examples.
40. Compounds of formula II or formula III or formula IV or formula
V when prepared by a method of any preceding claim.
41. A compound of the formulae II, III, IV or V, wherein R.sub.1 is
hydroxy, OR.sub.9, OC(O)R.sub.9, thio, alkylthio, or halo, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are
independently hydrogen, hydroxy, OR.sub.9, OC(O)R.sub.9,
OS(O)R.sub.9, alkyl, aryl, thio, alkylthio or halo, and R.sub.9 is
alkyl, fluoroalkyl or arylalkyl with the proviso that at least one
of R.sub.5, R.sub.6 and R.sub.7 is not hydrogen, or when R.sub.5,
R.sub.6 and R.sub.7 are all hydrogen, then R.sub.3 is hydroxy,
OR.sub.9, OC(O)R.sub.9, OS(O)R.sub.9, alkyl aryl, thio, alkylthio
or halo, provided that compounds of the formula 13wherein R.sub.1
is hydroxy or acetoxy, R.sub.2 is hydrogen, hydroxy, acetoxy,
methoxy, methyl, isopropyl or halo, R.sub.3 is hydrogen, methoxy,
methyl, halo or trifluoromethyl, R.sub.6 is hydrogen, hydroxy or
acetoxy, and R.sub.7 is hydrogen, hydroxy, methyl or methoxy are
specifically excluded, provided that compounds of the formula
14wherein R.sub.3 is hydroxy or methoxy, and R.sub.4 is hydrogen or
methoxy are specifically excluded, provided that compounds of the
formulae 15wherein R.sub.1 is hydroxy, methoxy, ethoxy, methylthio
or halogen, and R.sub.2, R.sub.3 R.sub.4, R.sub.5, R.sub.6, and
R.sub.7 are independently hydrogen, hydroxy, methoxy, ethoxy,
methylthio or halogen, are specifically excluded, and provided that
the compounds 4',7-Dihydroxy-3 ',5'-dimethoxyisoflavan-4-one
4',5-Dimethoxy-7-hydroxy-8-methylisoflavan-- 4-one
2',7-Dihydroxy-4',8-dimethoxyisoflavan-3 -ene are specifically
excluded.
42. A compound of claim 41, wherein R.sub.1 is hydroxy, OR.sub.9 or
OC(O)R.sub.9, R.sub.2 and R.sub.3 are independently hydrogen,
hydroxy, OR.sub.9 or OC(O)R.sub.9, R.sub.4, R.sub.5, R.sub.6, and
R.sub.8 are hydrogen, R.sub.7 is hydroxy, OR.sub.9, OC(O)R.sub.9,
alkyl, aryl or halo, and R.sub.9 is methyl, ethyl, propyl,
isopropyl, trifluoromethyl or benzyl.
43. A compound of claim 41, wherein R.sub.1 is hydroxy, OR.sub.9 or
OC(O)R.sub.9, R.sub.2 and R.sub.3 are independently hydrogen,
hydroxy, OR.sub.9 or OC(O)R.sub.9, R.sub.5 is OR.sub.9,
OC(O)R.sub.9, alkyl, aryl or halo, R.sub.4, R.sub.6, R.sub.7, and
R.sub.8 are hydrogen, and R.sub.9 is methyl, ethyl, propyl,
isopropyl, trifluoromethyl or benzyl.
44. A compound of formula I selected from the group consisting of:
4',7,8-Triacetoxyisoflavone 7,8-Diacetoxy-4'-methoxyisoflavone
4',7-Diacetoxy-8-methylisoflavone 3',7-Diacetoxy-8-methylisoflavone
7-Acetoxy-4'-methoxy-8-methylisoflavone 4',7-Diacetoxy-3
'-methoxy-8-methylisoflavone 4',5,7-Triacetoxyisoflavone
45. A compound of formula II selected from the group consisting of:
4',7,8-Triacetoxyisoflavan-4-ol
7,8-Diacetoxy-4-methoxyisoflavan-4-ol
4',7-Diacetoxy-8-methylisoflavan-4-ol
3',7-Diacetoxy-8-methylisoflavan-4-- ol
7-Acetoxy-4'-methoxy-8-methylisoflavan-4-ol
4',7-Diacetoxy-3'-methoxy-8- -methylisoflavan-4-ol
4',5,7-Triacetoxyisoflavan-4-ol 4',7,8-Trihydroxyisoflavan-4-ol
7,8-Dihydroxy-4-methoxyisoflavan-4-ol
4',7-Dihydroxy-8-methylisoflavan-4-ol
3',7-Dihydroxy-8-methylisoflavan-4-- ol
7-Hydroxy-4'-methoxy-8-methylisoflavan-4-ol 4',7-Dihydroxy-3
'-methoxy-8-methylisoflavan-4-ol
4',5,7-Trihydroxyisoflavan-4-ol
46. A compound of formula III selected from the group consisting
of: 4',7,8-Triacetoxydehydroequol (4',7,8-Triaceioxyisoflav-3-ene)
7,8-Di acetoxy-4-methoxydehydroequol
(7,8-Diacetoxy-4-methoxyisoflav-3-ene)
4',7-Diacetoxy-g-methylisoflav-3 -ene
3',7-Diacetoxy-8-methylisoflav-3-en- e
7-Acetoxy-4'-methoxy-8-methylisoflav-3-ene
4',7-Diacetoxy-3'-methoxy-8-m- ethylisoflav-3-ene
4',5,7-Triacetoxyisoflav-3-ene Isoflav-3-ene-4',7,8-tri- ol
4'-Methoxyisoflav-3-ene-7,8-diol 8-Methylisoflav-3-ene-4',7-diol
8-Methylisoflav-3-ene-3',7-diol 4'-Methoxy-8-methylisoflav-3
-ene-7-ol 3'-Methoxy-8-methylisoflav-3 -ene-4',7-diol
Isoflav-3-ene-4',5,7-triol
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 difficult to control and lead to
mixtures of different products.
[0004] The reduction of 5,7-dihydroxyisoflavylium salts have been
reported to give mixtures of isoflav-2-enes, isoflav-3-enes and
isoflavans. The individual compounds are difficult to separate and
can be obtained only in low yields. Sodium borohydride reductions
of isoflavones are known, see dm Major et al. 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.
[0005] 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.
[0006] Solvents used in hydrogenation reactions of isoflavones
reported in the literature include N-methylpyrrolidinone, see
Liepa, A. J., Aust. J Chem., 1981, 34, 2647-55. 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.
[0007] Isoflavan-4-ols are key intermediates in the synthesis of
isoflavenes and accordingly there is a need for more efficient and
reliable syntheses of isoflavan-4-ols, or at least comparable
alternatives, acceptable than those known in the art. There is also
a need for synthetic methods for isoflavone hydrogenation which
utilise solvents pharmaceutically more acceptable than those
previously reported. Therefore it is an object of the present
invention to overcome or at least alleviate one or more of the
above-mentioned disadvantages of the prior art. It is an other
object of the present invention to synthesise novel isoflavone
metabolites and derivatives.
[0008] Surprisingly hydrogenation conditions have been found by the
present inventors which enable the synthesis of isoflavone
derivatives in good to excellent yields. In particular the
conditions found by the present inventors allow for the
hydrogenation of isoflavones to relatively pure
tetrahydroisoflavan-4-ol products in excellent yields, and without
the need for pharmaceutically unsuitable solvents and extensive
chromatography in the hydrogenation reactions.
SUMMARY OF THE INVENTION
[0009] Thus the present invention provides a method for the
hydrogenation of a compound of formula I 1
[0010] wherein
[0011] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7 and R.sub.8 are independently hydrogen, hydroxy, OR.sub.9,
OC(O)R.sub.9, OS(O)R.sub.9, alkyl, haloalkyl, aryl, arylalkyl,
thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halo,
and
[0012] R.sub.9 is alkyl, haloalkyl, aryl, arylalkyl or
alkylaryl,
[0013] to prepare a compound of formula II 2
[0014] wherein
[0015] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8 and R.sub.9 are as defined above.
[0016] The present invention also provides a method for the
dehydration of a compound of formula II, which method may
optionally include deprotection or transformation steps, to prepare
a compound of the formula III 3
[0017] wherein
[0018] R.sub.1, R.sub.2, R.sub.3, R.sub.4R.sub.5, R.sub.6R.sub.7
and R.sub.8 are independently hydrogen, hydroxy, OR.sub.9,
OC(O)R.sub.9, OS(O)R.sub.9, alkyl, haloalkyl, aryl, arylalkyl,
thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halo,
and
[0019] R.sub.9 is alkyl, haloalkyl, aryl, arylalkyl or
alkylaryl.
[0020] The present invention also provides a method for the
hydrogenation of a compound of formula I to prepare a compound of
formula IV 4
[0021] wherein
[0022] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8 and R.sub.9 are as defined above
[0023] The present invention also provides a method for the
hydrogenation of a compound of formula III to prepare a compound of
formula V 5
[0024] wherein
[0025] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8 and R.sub.9 are as defined above.
[0026] The present invention also provides compounds of formulae
II, III, IV and V when prepared by a method described above and
compositions comprising same.
[0027] The present invention also provides novel compounds of the
formulae I, II, III, IV and V and compositions comprising same.
DETAILED DESCRIPTION OF THE INVENTION
[0028] In the methods of the present invention, the starting
isoflavone of formula I, the hydrogenation products isoflavan4-ol
of formula II, isoflavan4-one of formula IV and isoflavan of
formula V, and the dehydration product isoflav-3-ene of formula III
preferably have the following substituents wherein
[0029] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7 and R.sub.8 are independently hydrogen, hydroxy, OR.sub.9,
OC(O)R.sub.9, OS(O)R.sub.9, alkyl, aryl, arylalkyl, thio,
alkylthio, bromo, chloro or fluoro, and R.sub.9 is alkyl,
fluoroalkyl or arylalkyl;
[0030] more preferably they have the following substituents
wherein
[0031] R.sub.1 is hydroxy, OR.sub.9 or OC(O)R.sub.9,
[0032] R.sub.2, R.sub.3, R.sub.4R.sub.5, R.sub.6 and R.sub.7 are
independently hydrogen, hydroxy, OR.sub.9, OC(O)R.sub.9, alkyl,
aryl or arylalkyl,
[0033] R.sub.8 is hydrogen, and
[0034] R.sub.9 is methyl, ethyl, propyl, isopropyl or
trifluoromethyl; and
[0035] most preferably they have the following substituents
wherein
[0036] R.sub.1 is hydroxy, OR.sub.9 or OC(O)R.sub.9,
[0037] R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.7 are
independently hydrogen, hydroxy, OR.sub.9, OC(O)R.sub.9, alkyl,
aryl or arylalkyl,
[0038] R.sub.6 and R.sub.8 are hydrogen, and
[0039] R.sub.9 is methyl.
[0040] The particularly preferred compounds of formula I are
4',7-diacetoxyisoflavone (daidzein diacetate) and
7-acetoxy4'-methoxyisof- lavone;
[0041] the particularly preferred compounds of formula II are
4',7-diacetoxyisoflavan-4-ol (tetrahydrodaidzein diacetate) and
7-acetoxy-4'-methoxyisoflavan4-ol;
[0042] the particularly preferred compounds of formula III are
4',7-diacetoxyisoflav-3-ene (dehydroequol diacetate),
4',7-dihydroxyisoflav-3-ene (dehydroequol),
7-acetoxy-4'-methoxyisoflav-3- -ene and
7-hydroxy-4'-methoxyisoflav-3-ene;
[0043] the particularly preferred compounds of formula IV are
4',7-diacetoxyisoflavan-4-one (diacetoxydihydrodaidzein) and
4',7-dihydroxyisoflavan-4-one (dihydrodaicizein); and
[0044] the particularly preferred compounds of formula V are
4',7-diacetoxyisoflavan (equol diacetate) and
4',7-dihydroxyisoflavan (equol).
[0045] The novel compounds of the formulae I, II, III, IV and V
preferably have the following substituents wherein
[0046] R.sub.1 is hydroxy, OR.sub.9, OC(O)R.sub.9, thio, alkylthio,
or halo,
[0047] R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and
R.sub.8 are independently hydrogen, hydroxy, OR.sub.9,
OC(O)R.sub.9, OS(O)R.sub.9, alkyl, aryl, thio, alkylthio or halo,
and
[0048] R.sub.9 is alkyl, fluoroalkyl or arylalkyl
[0049] with the proviso that
[0050] at least one of R.sub.5, R.sub.6 and R.sub.7 is not
hydrogen, or
[0051] when R.sub.5, R.sub.4 and R.sub.7 are all hydrogen, then
R.sub.3 is hydroxy, OR.sub.9, OC(O)R.sub.9, OS(O)R.sub.9, alkyl,
aryl, thio, alkylthio or halo; and
[0052] more preferably they have the following substituents
wherein
[0053] R.sub.1 is hydroxy, OR.sub.9 or OC(O)R.sub.9,
[0054] R.sub.2 and R.sub.3 are independently hydrogen, hydroxy,
OR.sub.9 or OC(O)R.sub.9,
[0055] R.sub.4, R.sub.5, R.sub.6, and R.sub.8 are hydrogen,
[0056] R.sub.7 is hydroxy, OR.sub.9, OC(O)R.sub.9, alkyl, aryl or
halo, and
[0057] R.sub.9 is methyl, ethyl, propyl, isopropyl, trifluoromethyl
or benzyl; or
[0058] wherein
[0059] R.sub.1 is hydroxy, OR.sub.9, OC(O)R.sub.9,
[0060] R.sub.2 and R.sub.3 are independently hydrogen, hydroxy,
OR.sub.9 or OC(O)R.sub.9,
[0061] R.sub.5 is OR.sub.9, OC(O)R.sub.9, alkyl, aryl or halo,
[0062] R.sub.4, R.sub.6, R.sub.7, and R.sub.8 are hydrogen, and
[0063] R.sub.9 is methyl, ethyl, propyl, isopropyl, trifluoromethyl
or benzyl.
[0064] Most preferably the novel compounds of formulae I, II and
III are:
[0065] 4',7,8-Triacetoxyisoflavone
[0066] 7,8-Diacetoxy-4'-methoxyisoflavone
[0067] 4',7-Diacetoxy-8-methylisoflavone
[0068] 3',7-Diacetoxy-8-methylisoflavone
[0069] 7-Acetoxy-4'-methoxy-8-methylisoflavone
[0070] 4',7-Diacetoxy-3'-methoxy-8-methylisoflavone
[0071] 4',5,7-Triacetoxyisoflavone
[0072] 4',7,8-Triacetoxyisoflavan4-ol
[0073] 7,8-Diacetoxy-4-methoxyisoflavan-4-ol
[0074] 4',7-Diacetoxy-8-methylisoflavan-4-ol
[0075] 3',7-Diacetoxy-8-methylisoflavan4-ol
[0076] 7-Acetoxy-4'-methoxy-8-methylisoflavan-4-ol
[0077] 4',7-Diacetoxy-3'-methoxy-8-methylisoflavan-4-ol
[0078] 4',5,7-Triacetoxyisoflavan-4-ol
[0079] 4',7,8-Trihydroxyisoflavan-4-ol
[0080] 7,8-Dihydroxy-4-methoxyisoflavan-4-ol
[0081] 4',7-Dihydroxy-8-methylisoflavan-4-ol
[0082] 3',7-Dihydroxy-8-methylisoflavan-4-ol
[0083] 7-Hydroxy-4'-methoxy-8-methylisoflavan-4-ol
[0084] 4',7-Dihydroxy-3'-methoxy-8-methylisoflavan-4-ol
[0085] 4',5,7-Trihydroxyisoflavan-4-ol
[0086] 4',7,8-Triacetoxydehydroequol
(4',7,8-Triacetoxyisoflav-3-ene)
[0087] 7,8-Diacetoxy4-methoxydehydroequol
(7,8-Diacetoxy4-methoxyisoflav-3- -ene)
[0088] 4',7-Diacetoxy-8-methylisoflav-3-ene
[0089] 3',7-Diacetoxy-8-methylisoflav-3-ene
[0090] 7-Acetoxy4'-methoxy-8-methylisoflav-3 -ene
[0091] 4',7-Diacetoxy-3'-methoxy-8-methylisoflav-3-ene
[0092] 4',5,7-Triacetoxyisoflav-3-ene
[0093] Isoflav-3-ene-4',7,8-triol
[0094] 4'-Methoxyisoflav-3-ene-7,8-diol
[0095] 8-Methylisoflav-3-ene-4',7-diol
[0096] 8-Methylisoflav-3-ene-3',7-diol
[0097] 4'-Methoxy-8-methylisoflav-3 -ene-7-ol
[0098] 3'-Methoxy-8-methylisoflav-3-ene4',7-diol
[0099] Isoflav-3-ene4',5,7-triol
[0100] 4',7-Dihydroxy-8-methylisoflavan4-ol
[0101] 7-Hydroxy-4'-methoxy-8-methylisoflavan-4-ol
[0102] The term "alkyl" is taken to mean both straight chain and
branched chain alkyl groups such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, secbutyl, tertiary butyl, and the like.
Preferably the alkyl group is a lower alkyl of 1 to 6 carbon atoms.
The alkyl group may optionally be substituted by one or more of
fluorine, chlorine, bromine, iodine, carboxyl,
C.sub.1-C.sub.4-alkoxycarbonyl, C.sub.1-C.sub.4-alkylam-
ino-carbonyl, di-(C.sub.1-C.sub.4-alkyl)-amino-carbonyl, hydroxyl,
C.sub.1-C.sub.4-alkoxy, formyloxy,
C.sub.1-C.sub.4-alkyl-carbonyloxy, C.sub.1-C.sub.4-alkylthio,
C.sub.3-C.sub.6-cylcoalkyl or phenyl.
[0103] The term "aryl" is taken to include phenyl and naphthyl and
may be optionally substituted by one or more C.sub.1-C.sub.4-alkyl,
hydroxy, C.sub.1-C.sub.4-alkoxy, carbonyl,
C.sub.1-C.sub.4-alkoxycarbonyl , C.sub.1-C.sub.4-alkylcarbonyloxy
or halo.
[0104] The term "halo" is taken to mean one or more halogen
radicals selected from fluoro, chloro, bromo, iodo and mixtures
thereof, preferably fluoro and chloro, more preferably fluoro.
Reference to for example "haloalkyl" includes monohalogenated,
dihalogenated and up to perhalogenated alkyl groups. Preferred
perhalogenated groups are trifluoromethyl and pentafluoroethyl.
[0105] The compounds of the invention include all salts, such as
acid addition salts, anionic salts and zwitterionic salts, and in
particular include pharmaceutically acceptable salts.
[0106] Throughout this specification and the claims which follow,
unless the context requires otherwise, the word "comprise", and
variations such as "comprises" or "comprising", will be understood
to imply the inclusion of a stated integer or step or group of
integers or steps but not the exclusion of any other integer or
step or group of integers or steps.
[0107] The hydrogenation is ideally preformed with hydrogen in the
presence of a reduction catalyst and a solvent. The reaction is
preferably conducted under hydrogen at a pressure of 1-20
atmospheres, more preferably 1-5 atmospheres. The reaction may be
performed from 10 to 60.degree. C. and is typically carried out at
room temperature.
[0108] The reaction time may range from 12 hours to 96 hours or
more and is typically about 55 hours or more. Generally better
yields and cleaner reactions are achieved with longer reaction
times. It will be appreciated that reaction conditions may be
varied depending on the individual nature of the compounds and the
progress of the hydrogenation reaction.
[0109] The reduction catalysts may be selected from heterogeneous
catalysts (whereby the catalyst is insoluble in the reaction
medium) or homogenous catalysts (whereby the catalyst is soluble in
the reaction medium). Examples of heterogeneous reduction catalysts
include Raney nickel, palladium black, palladium hydroxide on
carbon, palladium on activated carbon (1% Pd to 30% Pd), palladium
on alumina powder, palladium on various barium salts, sodium
borohydride reduced nickel, platinum metal, platinum black,
platinum on activated carbon (1% Pt to 10% Pt), platinum oxide,
rhodium salts, ruthenium salts and their chiral salts and zinc
oxide. Preferably the catalyst is palladium on activated carbon (1%
Pd to 10% Pd), more preferably about 5% palladium on carbon.
Platinum oxide (Adam's catalyst) is also a very useful
hydrogenation catalyst for the methods of the present invention to
produce predominantly cis-isomers of isoflavan4-ols.
[0110] Examples of homogeneous reduction catalysts include
chlorotris (triphenylphosphine)rhodium,
chloro(trisphenylphosphine)hydridoruthenium (II) and
pentacyanocobaltate (II).
[0111] The solvents suitable for use in the present invention
include but are not limited to C.sub.1-C.sub.8 alcohols and
polyols, alkyl acetates, tetrahydrofuran, ethers, dioxane and
C.sub.1-C.sub.3 acids. Preferably the solvent is a C.sub.1-C.sub.6
alcohol or C.sub.1-C.sub.6 alkyl acetate, more preferably methanol,
ethanol or ethyl actate, as well as propanol, isopropanol, butanol,
isobutanol, secbutanol, tertiary butanol, methyl formate, ethyl
formate and methly acetate. Most preferably the solvent is absolute
methanol, ethanol or ethyl acetate.
[0112] The present inventors have found that with a judicious
choice of catalysts, solvents and optionally protecting groups,
isoflavones are reduced cleanly and in high yields to corresponding
isoflavanols. In particular the use of absolute methanol or ethanol
as a solvent provided for very clean catalytic hydrogenation over
5% palladium on charcoal of isoflavones to afford up to
quantitative yields of isoflavanols. In methods where, for example,
10% palladium on charcoal is employed, the reaction can proceed
more rapidly, at times being complete within 12 hours. The ratio of
cis- and trans-isomers of the isoflavan-4-ol hydrogenation product
can vary with the choice of catalysts and the nature of the
isoflavone substitute. By varying the methods of the present
invention it is possible to influence the isomeric ratio achieved
during the reduction process.
[0113] Of particular interest are isoflavones with oxygen
substitution (or precursors to oxygen substitution) at the 4'- and
7-positions as reduction of these compounds leads to the
biologically important dehydroequol or precursors thereof. A
convenient starting material is daidzein which is readily obtained
by established routes.
[0114] It will be understood that some moieties on the isoflavone
rings may require protection or derivatisation prior to being
subjected to hydrogenation. For example it may be desirable to
protect free hydroxy moieties with groups such as an acetoxy group
to assist in the solubility of the substituted isoflavones and/or
their susceptibility to hydrogenation. Protecting groups can be
carried out be well established methods known in the art, for
example as described in Protective Groups in Organic Synthesis, T.
W. Greene.
[0115] In particular the present inventors have found it is useful
to protect hydroxy groups when present as esters or ethers prior to
reduction, with acetoxy or methoxy groups most favoured. Acylation
is preferably carried out with the hydroxy compounds in a solvent
mixture of a carboxylic acid anhydride and base. Protecting free
hydroxy groups prior to hydrogenation increases yields up to and
including quantitative yields. The reaction products are generally
cleaner and do not require a chromatography step in the
purification and isolation of the hydrogenation products.
[0116] Thus surprisingly, tetrahydrodaidzein diacetate was obtained
in quantitative yield when the catalytic hydrogenation of
diacetoxydaidzein in ethanol was continued for 55 h. Spectroscopic
analysis established the product to be a 1:1 mixture of cis- and
trans-isomers. Pleasingly, no further reduction of
tetrahydrodaidzein was observed even if the reduction was continued
for longer periods of time.
[0117] In a similar manner it was also surprisingly found that the
protected isoflavone 7-acetoxy-4'-methoxydaidzein smoothly and
cleanly underwent hydrogenation in ethanol to afford a quantitative
yield of a 1:1 mixture of cis- and trans-isomers of
7-acetoxy-4'-methoxyisoflavan-4-- ol. This reaction appears to be
quite general and was repeated on many different substrates in
amounts of up to one half gram and more.
[0118] In this regard the inventors have found conditions which
allow for the large scale generation of clean and near quantitative
yields of isoflavan-4-ols compounds by hydrogenation of
corresponding isoflavones. In particular, it has been found that
kilogram quantities of diacetoxy daidzein undergo smooth and
efficient reduction to the isomeric cis- and
trans-4',7-diacetoxyisoflavan-4-ols. The isomeric ratios can be
influenced by the percentage of palladium in the catalyst.
[0119] The cis-/trans-isomeric mixtures are able to be dehydrated
to isoflav-3-enes without the need for separation. However, is
desired, the mixtures are able to be separated by a variety of
methods as set out below.
[0120] The mixture of cis- and trans-tetrahydrodaidzein compounds
are able to be separated by preparative HPLC. This mode of
separation is quite tedious and limited to small amounts of
material. Since reasonable quantities of the diacetoxy isoflavanols
were able to be prepared, fractional crystallisation was attempted
to separate the cis- and trans-isomers. A single recrystallisation
of the 1:1 mixture from ethanol gave predominantly
trans-diacetoxytetrahydrodaidzein (50% yield: 73% purity)
(cis-isomer 27%). Subsequent recrystallisations from ethanol
afforded the pure trans-isomer in 25% overall yield.
[0121] Likewise the 7-acetoxy-4'-methoxyisoflavan-4-ol was able to
be fractionally recrystallised to give the pure trans-isomer, with
the filtrate containing increased proportions of the
cis-isomer.
[0122] Most hydrogenations yielded 1:1 mixtures of cis- and
trans-isoflavan-4-ols. However one derivative of note was
7-hydroxy-4'-methoxy-8-methylisoflavone, the hydrogenation of which
afforded predominantly the trans-isomer in excellent yield.
[0123] Synthesis of tetrahydrodaidzein and related derivatives was
achieved by removal of the protecting acetoxy groups under mild
conditions, preferably with imidazole in ethanol at reflux.
Tetrahydrodaidzein was isolated in 80% yield after crystallisation
from aqueous ethanol.
[0124] Dehydration of isoflavan-4-ols leads to the unsaturated
isoflav-3-enes. Thus reaction of a cis-/trans-mixture of
isoflavan-4-ols with benzoyl chloride/dimethylformamide at
100.degree. C. has been reported in the literature by Liepa to give
the desired isoflav-3-ene dehydration product. However this
reaction could only be repeated in low yield. Dehydration may also
be effected by treatment with acids such as sulfuric acid,
hydrochloric acid, polyphosphoric acid, thionyl chloride and the
like. Alternative methods of dehydration using p-toluenesulfonic
acid or trifluoroacetic acid in refluxing dichloromethane were also
investigated, but these methods also afforded the isoflavenes in
low yields.
[0125] Generally the present inventors found the dehydration
reagent of choice to be phosphorus pentoxide in dichloromethane,
which can yield isoflavenes in yields of greater than 60%. The
dehydration reactions can be carried out on the hydrogenation
products directly, or deprotected derivatives thereof.
[0126] Synthesis of dehydroequol was achieved by removal of the
protecting acetoxy groups under mild conditions as described for
the synthesis of tetrahydrodaidzein, and dehydroequol was purified
by standard crystallisation solvent mixtures such as ethanol/water.
Other isoflav-3-ene derivatives may be prepared by similar
methods.
[0127] Hydrogen reduction of 4',7-diacetoxydaidzein with Adam's
catalyst (platinum(IV)oxide) in ethyl acetate under an atmosphere
of hydrogen afforded 4',7-diacetoxytetrahydrodaidzein. However
unlike the palladium-on-charcoal reduction in ethanol, reductions
with Adam's catalyst gave predominantly the cis-isomer of
4',7-diacetoxytetrahydrodai- dzein.
[0128] In another embodiment of the invention, hydrogenation of
4',7-diacetoxy daidzein with 5% palladium-on-charcoal in ethyl
acetate as solvent under an atmosphere of hydrogen gave
4',7-diacetoxydihydrodaidzei- n in excellent yield (80%). These
conditions provide access to isoflavan-4-ones from the
corresponding isoflavones in good to excellent yields.
[0129] Access to isoflavan derivatives such as equol is possible by
hydrogenation of isoflav-3-enes with, preferably,
palladium-on-charcoal in an alkyl acetate solvent under an
atmosphere of hydrogen. Excellent yields of 75% and more of the
hydrogenated products are obtainable by these methods. The products
are clean and are readily recrystallised.
[0130] 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.
[0131] The invention is further described in and illustrated by the
following Examples. The Examples are not to be construed as
limiting the invention in any way.
EXAMPLES
[0132] Acetylation Reactions
Example 1
4',7 Diacetoxydaidzein
[0133] Method A
[0134] 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.times.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%). .sup.1H NMR (CDCl.sub.3): .delta. 2.32 (s, 3H,
OCOCH.sub.3), 2.36 (s, 3H, OCOCH.sub.3), 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).
[0135] Method B
[0136] 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
crystallised from the solution. The product was filtered, washed
thoroughly with water and recrystallised from methanol to yield
daidzein diacetate as colourless prisms (2.4 g, 90%).
Example 2
7-acetoxy-4'-methoxyisoflavone
[0137] 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.times.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%). .sup.1H NMR (CDCl.sub.3): .delta. 2.36 (s, 3H,
OCOCH.sub.3), 3.84 (s, 3H, OCH.sub.3), 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
[0138] 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.degree. C. 1H NMR (CDCl.sub.3):
.delta. 2.31 and 2.36 (each s, 3H, OCOCH.sub.3), 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).
Example 4
7-Acetoxy-3'-methoxyisoflavone
[0139] 7-Acetoxy-3'-methoxyisoflavone was prepared from
7-hydroxy-3'-methoxyisoflavone (1.7 g, 6.3 mmol), acetic anhydride
(6 ml) and pyridine (1.0 ml) as described for
4',7-diacetoxydaidzein. Yield: (1.6 g, 81%) m.p. 118.degree. C. 1H
NMR (CDCl.sub.3): .delta. 2.36 (s, 3H, OCOCH.sub.3), 3.85 (s, 3H,
OMe), 6.95 (dd, 1H, J 2.0 Hz 8.3 Hz, H6), 6.70-7.40 (m, 5H, ArH),
8.01 (s, 1H, H2), 8.32 (d, 1H, J 8.7 Hz, H5).
Example 5
4',7-Diacetoxy-3'-methoxyisoflavone
[0140] 4',7-Diacetoxy-3'-methoxyisoflavone was prepared from
4',7-dihydroxy-3'-methoxyisoflavone (0.37 g, 1.3 mmol), acetic
anhydride (2.5 ml) and pyridine (0.4 ml) as described for
4',7-diacetoxydaidzein. Yield: (0.36 g, 75%) m.p. 197.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 2.33, 2.36 (each s, 3H,
OCOCH.sub.3), 3.88 (s, 3H, OMe), 7.06-7.17 (m, 2H, ArH), 7.19 (dd,
1H, J 2.3 Hz 9.0 Hz, ArH), 7.32 (dd, 2H, J 2.3 Hz 7.6 Hz, ArH),
8.03 (s, 1H, H2), 8.32 (d, 1H, J 8.6 Hz, H5).
Example 6
7-Acetoxyisoflavone
[0141] 7-Acetoxyisoflavone was prepared from 7-hydroxyisoflavone
(2.6 g, 10.9 mmol), acetic anhydride (16 ml) and pyridine (3.0 ml)
as described for 4',7-diacetoxydaidzein. Yield: (2.5 g, 82%) m.p.
133.degree. C. 1H NMR (CDCl.sub.3): .delta. 2.36 (s, 3H,
OCOCH.sub.3), 7.18 (dd, 1H, J 2.2 Hz 8.6 Hz, H6), 7.31 (d, 1H, J
2.2 Hz H8), 7.39-7.57 (m, 5H, ArH), 8.00 (s, 1H, H2), 8.33 (d, 1H,
J 8.6 Hz, H5). Mass spectrum: m/z 280 (M, 28%); 237-(98); 238
(57).
Example 7
4',7,8-Triacetoxyisoflavone
[0142] A mixture of 4',7,8-trihydroxyisoflavone (1.4 g, 5.2 mmol),
acetic anhydride (8.4 ml) and pyridine (2 ml) was heated on an oil
bath at 105-110.degree. C. for 1 h. After cooling the mixture to
room temperature, it was stirred for a further 30 min during which
time the diacetate crystallised from the solution. The product was
filtered, washed thoroughly with water and recrystallised from
ethyl acetate to yield 4',7,8-triacetoxyisoflavone as colourless
prisms (1.49 g, 73%) m.p. 190-192.degree. C. 1H NMR (CDCl.sub.3):
.delta. 2.32, 2.36, 2.42 (each s, 3H, OCOCH.sub.3), 7.18 (d, 2H, J
8.6 Hz, ArH), 7.28 (d, 1H, J 8.9 Hz, H6), 7.56 (d, 2H, J 8.6 Hz
H8), 7.98 (s, 1H, ArH), 8.18 (d, 1H, J 8.9 Hz, H5).
Example 8
7,8-Diacetoxy-4'-methoxyisoflavone
[0143] 7,8-Diacetoxy-4'-methoxyisoflavone was prepared from
7,8-dihydroxy-4'-methoxyisoflavone (0.82 g, 2.9 mmol), acetic
anhydride (4.9 ml) and pyridine (0.9 ml) as described for
4',7,8-triacetoxyisoflavo- ne. Yield: (0.9 g, 85%) m.p. 165.degree.
C. 1H NMR (CDCl.sub.3): .delta. 2.36, 2.42 (each s, 3H,
OCOCH.sub.3), 3.84 (s, 3H, OCH.sub.3), 6.98 (d, 2H, J 9.0 Hz, ArH),
7.25 (d, 1H, J 8.7 Hz, H6), 7.48 (d, 2H, J 9.0 Hz H8), 7.95 (s, 1H,
H2), 8.20 (d, 1H, J 9.1 Hz, H5). Mass spectrum: m/z 368 (M, 20%);
326 (15); 312 (18); 284 (80).
Example 9
4',7-Diacetoxy-methylisoflavone
[0144] A mixture of 4',7-dihydroxy-8-methylisoflavone (2.9 g, 10.8
mmol), acetic anhydride (18 ml) and pyridine (3 ml) was heated on
an oil bath at 105-110.degree. C. for 1 h. After cooling the
mixture to room temperature, it was stirred for a further 30 min
during which time the diacetate crystallised from the solution. The
product was filtered, washed thoroughly with water and
recrystallised from ethyl acetate to yield
4',7-diacetoxy-8-methylisoflavone as colourless prisms (3.2 g,
84%). 1H NMR (CDCl.sub.3): .delta. 2.31 (s, 3H, CH.sub.3), 2.32,
2.39 (each s, 3H, OCOCH.sub.3), 7.13 (d, 1H, J 9.0 Hz, H6), 7.17
(d, 2H, J 8.7 Hz, ArH), 7.59 (d, 2H, J 8.7 Hz, ArH), 8.07 (s, 1H,
H2), 8.19 (d, 1H, J 8.7 Hz, H5).
Example 10
3',7-Diacetoxy-8-methylisoflavone
[0145] 3',7-Diacetoxy-8-methylisoflavone was prepared from
3',7-dihydroxy-8-methylisoflavone (1.3 g, 4.8 mmol), acetic
anhydride (8 ml) and pyridine (1.5 ml) as described for
4',7-diacetoxy-8-methylisoflav- one. Yield: (1.2 g, 70%) m.p.
112.degree. C. .sup.1H NMR (CDCl.sub.3): .delta. 2.31 (s, 3H,
CH.sub.3), 2.32, 2.39 (each s, 3H, OCOCH.sub.3), 7.13 (m, 2H, ArH),
7.37-7.45 (m, 3H, ArH), 8.1 (s, 1H, H2), 8.18 (d, 1H, J 8.7 Hz,
H5). Mass spectrum: m/z 352 (M, 6%); 310 (35); 268 (100); 267
(60).
Example 11
7-Acetoxy-4'-methoxy-8-methylisoflavone
[0146] 7-Acetoxy4'-methoxy-8-methylisoflavone was prepared from
7-hydroxy4'-methoxy-8-methylisoflavanone (3.0 g, 10.6 mmol), acetic
anhydride (10 ml) and pyridine (2.0 ml) as described for
4',7-diacetoxy-8-methylisoflavone. Yield: (2.0 g, 58%) m.p.
190-192.degree. C. 1H NMR (CDCl.sub.3): .delta. 2.31 (s, 3H,
CH.sub.3), 2.38 (s, 3H, OCOCH.sub.3), 3.84 (s, 3H, OMe), 6.98 (d,
2H, J 8.7 Hz, ArH), 7.12 (d, 1H, J 8.6 Hz, H6), 7.52 (d, 2H, J 8.7
Hz, ArH), 8.03 (s, 1H, H2), 8.18 (d, 1H, J 8.6 Hz, H5). Mass
spectrum: 325 (M+1, 13%); 324 (M, 58%); 282 (100); 281 (42).
Example 12
4',7-Diacetoxy-3'-methoxy-8-methylisoflavone
[0147] 4',7-Diacetoxy-3'-methoxy-8-methylisoflavone was prepared
from 4',7-dihydroxy-3'-methoxy-8-methylisoflavone (0.42 g, 1.4
mmol), acetic anhydride (2.6 ml) and pyridine (0.5 ml) as described
for 4',7-diacetoxy-8-methylisoflavone. Yield: (0.4 g, 74%) m.p.
209.degree. C. 1H NMR (CDCl.sub.3): .delta. 2.22 (s, 3H, CH.sub.3),
2.32, 2.39 (each s, 3H, OCOCH.sub.3), 3.89 (s, 3H, OMe), 7.07-7.11
(m, 2H, ArH), 7.13 (d, 1H, J 8.6 Hz, H6), 7.32 (d, 1H, J 1.5 Hz,
ArH), 8.09 (s, 1H, H2), 8.18 (d, 1H, J 8.7 Hz, H5).
[0148] Hydrogenation Reactions:--Isoflavone.fwdarw.Isoflavan4ol
Example 13
4',7-diacetoxytetrahydrodaidzein (4'7-Diacetoxyisoflavan4-ol)
[0149] Method A
[0150] Palladium-on-charcoal (5%, 0.08 g) was added to a suspension
of 4',7-diacetoxydaidzein (0.5 g, 1.5 mmol) in absolute ethanol
(400 ml) and the mixture was stirred at room temperature under a
hydrogen atmosphere for 55 hours. The catalyst was removed by
filtration through Celite and the filtrate was evaporated in vacuo
to yield 4',7-diacetoxytetrahydrodai- dzein (0.51 g, 100%) in
quantitative yield. A nuclear magnetic resonance spectrum revealed
the product to be a clean 1:1 mixture of cis- and
trans-4',7-diacetoxytetrahydrodaidzein.
[0151] The cis- and trans-isomers were able to be separated by
fractional recrystallisation. A 1:1 mixture of cis- and
trans-4',7-diacetoxytetrahyd- rodaidzein (0.17 g), prepared as
above, was dissolved in excess absolute ethanol and concentrated on
a rotary evaporator. At the first sign of crystallisation, further
concentration of ethanol was stopped and the flask was cooled in an
ice-bath. The resulting crystals were filtered and washed with a
small amount of cold absolute ethanol. A nuclear magnetic resonance
spectrum of the product (0.08 g) revealed it to be a mixture
trans4',7-diacetoxytetrahydrodaidzein (73%) and
cis-4',7-diacetoxytetrahy- drodaidzein (27%). Further
recrystallisations of the mixture from ethanol yielded the pure
trans-4',7-diacetoxytetrahydrodaidzein (0.04 g, 24%).
[0152] The filtrate yielded predominantly cis-isomer. Nuclear
magnetic resonance spectroscopic analysis revealed the substance to
be a mixture of cis4',7-diacetoxytetrahydrodaidzein (73%) and
trans4',7-diacetoxytetra- hydrodaidzein (27%).
[0153] For trans4',7-Diacetoxyisoflavan-4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.28 (s, 3H, OCOCH.sub.3), 2.29 (s, 3H
OCOCH.sub.3), 3.14 (ddd, 1H, J 3.7 Hz, 7.9 Hz, 9.1 Hz, H3), 4.24
(dd, 1H, J 9.1 Hz, 11.3 Hz, H2); 4.35 (dd, 1H, J 3.7 Hz, 11.3 Hz,
H2), 4.87 (d, 1H, J 7.9 Hz, H4), 6.61 (d, 1H, J 2.3 Hz, H8), 6.70
(dd, 1H, J 2.3 Hz, 8.4 Hz, H6), 7.06 (d, 2H, J 8.6 Hz, ArH), 7.23
(d, 2H, J 8.4 Hz, ArH), 7.44 (dd, 1H, J 0.8 Hz, 8.4 Hz, H5).
.sup.13C NMR (CDCl.sub.3): 20.98 (OCOCH.sub.3), 46.18 (C3), 68.04
(C2), 69.01 (C4), 109.67 (C8), 114.26 (C6), 121.96, 128.96 (ArCH),
129.40 (C5).
[0154] For cis-4',7-Diacetoxyisoflavan-4-ol: .sup.1H NMR
(CDCl.sub.3): .delta. 2.28 (s, 3H, OCOCH.sub.3), 2.29 (s, 3H,
OCOCH.sub.3), 3.30 (dt, 1H, J 3.4 Hz, J 11.8 Hz, H3), 4.31 (ddd,
1H, J 1.4 Hz, 3.6 Hz, 10.5 Hz, H2); 4.56 (dd, 1H, J 10.5 Hz, 11.8
Hz, H2), 4.75 (dd, 1H, J 1.3 Hz, 3.2 Hz, H4). 6.66 (dd, 1H, J 2.3
Hz, 8.7 Hz, H6), 6.69 (d, 1H, J 2.3 Hz, H8), 7.08 (d, 2H, J 8.6 Hz,
ArH), 7.26 (d, 1H, 8.4 Hz, H5), 7.29 (d, 2H, J 8.6 Hz ArH).
.sup.13C NMR (CDCl.sub.3); 20.98 (OCOCH.sub.3), 43.52 (C3), 64.10
(C2), 66.46 (C4), 110.08 (C6), 114.09 (C8), 121.82, 129.40 (ArCH),
131.10 (C5).
[0155] Method B
[0156] Palladium-on-charcoal (5%, 3.1 g) was added to a suspension
of 4',7-diacetoxydaidzein (30.0 g) in absolute methanol (3600 ml)
and the mixture was stirred at room temperature under a hydrogen
atmosphere for 55 hours. The catalyst was removed by filtration
through Celite and the filtrate was evaporated in vacuo to yield
4',7-diacetoxytetrahydrodaidzei- n (29.5 g, 96%). A nuclear
magnetic resonance spectrum revealed the product to be a clean 2:1
mixture of cis- and trans-4',7-diacetoxytetrahy- drodaidzein.
[0157] Method C
[0158] Palladium-on-charcoal (10%, 3.0 g) was added to a suspension
of 4',7-diacetoxydaidzein (30.1 g) in absolute methanol (3600 ml)
and the mixture was stirred at room temperature under a hydrogen
atmosphere for 15 hours. The catalyst was removed by filtration
through Celite and the filtrate was evaporated in vacuo to yield
4',7-diacetoxytetrahydrodaidzei- n (28.5 g, 94%). A nuclear
magnetic resonance spectrum revealed the product to be a clean 1:1
mixture of cis- and trans4',7-diacetoxytetrahyd- rodaidzein.
[0159] Method D
[0160] Palladium-on-charcoal (5%, 100 g) was added to a suspension
of 4',7-diacetoxydaidzein (980 g) in absolute methanol (100 L) and
the mixture was stirred at room temperature under a hydrogen
atmosphere for 78 hours. The catalyst was removed by filtration
through a ceramic candle filtratation apparatus and the filtrate
was evaporated in vacuo to yield 4',7-diacetoxytetrahydrodaidzein
(820 g, 83%). A nuclear magnetic resonance spectrum revealed the
product to be a clean 2:1 mixture of cis- and
trans-4',7-diacetoxytetrahydrodaidzein.
Example 14
Synthesis of 7-Acetoxy-4'-methoxyisoflavan-4-ol
[0161] Palladium-on-charcoal (5%, 0.08 g) was added to a suspension
of 7-acetoxy-4'-methoxyisoflavone (0.5 g, 1.6 mmol) in absolute
ethanol (400 ml) and the mixture was stirred at room temperature
under a hydrogen atmosphere for 55 hours. The catalyst was removed
by filtration through Celite and the filtrate was evaporated in
vacuo to yield 7-acetoxy-4'-methoxyisoflavan-4-ol (0.51 g, 100%) in
quantitative yield. A nuclear magnetic resonance spectrum revealed
the product to be a clean 1:1 mixture of cis- and
trans-7-acetoxy-4'-methoxyisoflavan-4-ol.
[0162] The cis- and trans-isomers were able to be separated by
fractional recrystallisation. A 1:1 mixture of cis- and
trans-4',7-diacetoxytetrahyd- rodaidzein, prepared as above, was
recrystallised three times from ethanol to yield pure
trans-7-acetoxy-4'-methoxyisoflavan4-ol. The filtrate yielded
predominantly cis-isomer.
[0163] For trans-7-Acetoxy-4'-methoxyisoflavan-4-ol; 1H NMR (CDCl
.sub.3): 8 2.31 (s, 3H, OCOCH.sub.3), 3.14 (dt, 1H, J 3.8 Hz, 8.6
Hz, H3), 3.82 (s, 3H, OCH.sub.3), 4.25 (dd, 1H, J 9.4 Hz, 11.3 Hz,
H2); 4.37 (dd, 1H, J 4.1 Hz, 11.3 Hz, H2), 4.93 (d, 1H, J 7.8 Hz,
H4), 6.63 (d, 1H, J 2.3 Hz, H8), 6.73 (dd, 1H, J 2.3 Hz, 8.3 Hz,
H6), 6.93 (d, 2H, J 8.7 Hz, ArH), 7.19 (d, 2H, J 8.7 Hz, ArH), 7.51
(d, 1H, J 7.9 Hz, H5).
[0164] For cis-7-Acetoxy4'-methoxyisoflavan-4-ol; 1H NMR
(CDCl.sub.3): 8 2.30 (s, 3H, OCOCH.sub.3), 3.28 (dt, 1H, J 3.4 Hz,
J 12.1 Hz, H3), 3.84 (s, 3H, OCH3), 4.36 (ddd, 1H, J 1.4 Hz, 3.8
Hz, 10.1 Hz, H2); 4.57 (dd, 1H, J 10.1 Hz, 11.3 Hz, H2), 4.75 (bs,
1H, H4), 6.58 (d, 1H, J 2.3 Hz, H8), 6.75 (dd, 1H, J 2.3 Hz, 8.3
Hz, H6), 6.96 (d, 2H, J 8.6 Hz, ArH), 7.25 (d, 2H, 8.6 Hz, ArH),
7.34 (d, 1H, J 8.3 Hz, H5).
Example 15
3'-7-Diacetoxyisoflavan4-ol
[0165] Palladium-on-charcoal (5%, 0.03 g) was added to a suspension
of 3',7-diacetoxyisoflavanone (0.2 g, 0.6 mmol) in methanol (50 ml)
and the mixture was stirred at room temperature under a hydrogen
atmosphere for 55 h. The catalyst was removed by filtration through
Celite and the filtrate was evaporated in vacuo to yield
3'-7-diacetoxyisoflavan-4-ol in quantitative yield. A nuclear
magnetic resonance spectrum revealed the product to be a clean 1:1
mixture of cis- and trans-3'-7-diacetoxyisoflav- an-4-ol.
[0166] For trans-3'-7-diacetoxyisoflavan-4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.31 and 2.32 (each s, 3H, OCOCH.sub.3), 3.17
(ddd, 1H, J 3.6 Hz, 8.6 Hz, 11.2 Hz, H3), 4.26 (dd, 1H, J 9.2 Hz,
11.6 Hz, H2); 4.33 (m, 1H, H2), 4.91 (d, 1H, J 7.9 Hz, H4),
6.60-6.73 (m, ArH), 6.97-7.16 (m, ArH), 7.25-7.48 (m, ArH).
[0167] For cis-3'-7-diacetoxyisoflavan-4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.30 and 2.31 (each s, 3H, OCOCH.sub.3), 3.31
(dt, 1H, J 3.3 Hz, J 11.6 Hz, H3), 4.31 (m, 1H, H2); 4.57 (dd, 1H,
J 10.6 Hz, 11.9 Hz, H2), 4.79 (bs, 1H, H4), 6.60-6.73 (m, ArH),
6.97-7.16 (m, ArH), 7.25-7.48 (m, ArH).
Example 16
7-Acetoxy-3'-methoxyisoflavan-4-ol
[0168] Cis- and trans-7-acetoxy-3'-methoxyisoflavan-4-ol was
prepared from 7-acetoxy-3'-methoxyisoflavone (0.5 g, 1.6 mmol) and
palladium-on-charcoal (5%, 0.12 g) in methanol (100 ml) by the
method described above.
[0169] For trans-7-acetoxy-3'-methoxyisoflavan4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.28 (s, 3H, OCOCH.sub.3), 3.15 (ddd, 1H, J
3.8 Hz, 8.3 Hz, 12.0 Hz, H3), 3.80 (s, 3H, OMe), 4.26 (dd, 1H, J
9.4 Hz, 11.3 Hz, H2); 4.32 (m, 1H, H2), 4.95 (d, 1H, J 7.9 Hz, H4),
6.60-6.93 (m, ArH), 7.23-7.33 (m, ArH), 7.49 (d, J 8.7 Hz,
ArH).
[0170] For cis-7-acetoxy-3'-methoxyisoflavan-4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.28 (s, 3H, OCOCH.sub.3), 3.30 (dt, 1H, J
3.3 Hz, J 11.7 Hz, H3), 4.31 (m, 1H, H2); 4.58 (dd, 1H, J 10.5 Hz,
11.7 Hz, H2), 4.81 (bs, 1H, H4), 6.60-6.93 (m, ArH), 7.23-7.33 (m,
ArH), 7.49 (d, J 8.7 Hz, ArH).
Example 17
4',7-Diacetoxy-3'-methoxyisoflavan-4ol
[0171] Cis- and trans-4'-7-diacetoxy-3'-methoxyisoflavan-4-ol was
prepared from 4'-7-diacetoxy-3'-methoxyisoflavone (0.25 g, 0.7
mmol) and palladium-on-charcoal (5%, 0.06 g) in methanol (50 ml) by
the method described above.
[0172] For trans-4'-7-diacetoxy-3'-methoxyisoflavan-4-ol; .sup.1H
NMR (CDCl .sub.3): 8 2.29, 2.31 (each s, 3H, OCOCH.sub.3), 3.17
(ddd, 1H, J 3.8 Hz, 8.7 Hz, 12.5 Hz, H3), 3.79 (s, 3H, OMe), 4.26
(dd, 1H, J 9.4 Hz, 11.3 Hz, H2); 4.32 (m, 1H, H2), 4.93 (d, 1H, J
7.9 Hz, H4), 6.62-6.73 (m, ArH), 6.81-6.91 (m, ArH), 6.99-7.05 (m,
ArH), 7.30 (d, J 8.3 Hz, ArH), 7.48 (d, J 9.0 Hz, ArH).
[0173] For cis-7-acetoxy-3'-methoxyisoflavan-4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.31,2.32 (each s, 3H, OCOCH.sub.3), 3.33
(dt, 1H, J 3.3 Hz, J 11.3 Hz, H3), 3.83 (s, 3H, OMe), 4.31 (m, 1H,
H2); 4.58 (t, 1H, J 10.5 Hz, H2), 4.82 (bs, 1H, H4), 6.62-6.73 (m,
ArH), 6.81-6.91 (m, ArH), 6.99-7.05 (m, ArH), 7.30 (d, J 8.3 Hz,
ArH), 7.48 (d, J 9.0 Hz, ArH).
Example 18
7-Acetoxyisoflavan4-ol
[0174] Cis- and trans-7-acetoxyisoflavan-4-ol was prepared from
7-acetoxyisoflavone (0.4 g, 1.4 mmol) and palladium-on-charcoal
(5%, 0.09 g) in absolute methanol (60 ml). m.p. 90.degree. C. Mass
spectrum: m/z 284 (M, 10%); 226 (42); 138 (100); 137 (58).
[0175] For trans-7-acetoxyisoflavan4-ol; .sup.1H NMR (CDCl.sub.3):
.delta. 2.29 (s, 3H, OCOCH.sub.3), 3.17 (m, 1H, H3), 4.27 (t, 1H, J
10.6 Hz, H2); 4.30 (m, 1H, H2), 4.97 (d, 1H, J 8.3 Hz, H4).
6.60-6.73 (m, ArH), 7.08 (d, J 8.7 Hz, ArH), 7.23-7.37 (m, ArH),
7.49 (d, J 8.7 Hz, ArH).
[0176] For cis-7-acetoxyisoflavan-4-ol; .sup.1H NMR (CDCl.sub.3):
.delta. 2.30 (s, 3H, OCOCH.sub.3), 3.33 (dt, 1H, J 3.4 Hz, J 11.7
Hz, H3), 4.36 (m, 1H, H2); 4.62 (t, 1H, J 10.5 Hz, H2), 4.80 (bs,
1H, H4), 6.60-6.73 (m, ArH), 7.08 (d, J 8.7 Hz, ArH), 7.23-7.37 (m,
ArH), 7.49 (d, J 8.7 Hz, ArH).
Example 19
4',7,8-Triacetoxyisoflavan-4-ol
[0177] Palladium-on-charcoal (5%, 0.07 g) was added to a suspension
of 4',7,8-triacetoxyisoflavone (0.5 g, 1.3 mmol) in methanol (100
ml) and the mixture was stirred at room temperature under a
hydrogen atmosphere for 55 h. The catalyst was removed by
filtration through Celite and the filtrate was evaporated in vacuo
to yield 4',7,8-triacetoxyisoflavan-4-ol in quantitative yield. A
nuclear magnetic resonance spectrum revealed the product to be a
clean 1:1 mixture of cis- and trans-4',7,8-triacetoxyisof-
lavan-4-ol. Mass spectrum: m/z 400 (M, 5%); 358 (12); 298 (12); 256
(24); 196 (20); 162 (70); 154 (100); 120 (80).
[0178] For trans4',7,8-triacetoxyisoflavan-4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.28, 2.29. 2.31 (each s, 3H, OCOCH.sub.3),
3.20 (m, 1H, H3), 4.27 (dd, 1H, H2); 4.37 (m, 1H, H2), 4.93 (d, 1H,
J 7.9 Hz, H4), 6.78 (d, 1H, J 8.3 Hz, H8), 7.09 (m, ArH), 7.11-7.31
(m, ArH), 7.39 (d, 1H, 1H, J 8.7 Hz, ArH).
[0179] For cis-4',7,8-triacetoxyisoflavan4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.30, 2.31, 2.32 (each s, 3H, OCOCH.sub.3),
3.35 (m, 1H, H3), 4.38 (m, 1H, H2); 4.57 (t, 1H, J 10.6 Hz, H2),
4.75 (bs, 1H, H4), 6.78 (d, 1H, J 8.3 Hz, H8), 7.09 (m, ArH),
7.11-7.31 (m, ArH), 7.39 (d, 1H, J 8.7 Hz, ArH).
Example 20
7,8-Diacetoxy4-methoxyisoflavan-4-ol
[0180] 7,8-Diacetoxy4-methoxyisoflavan4-ol was prepared from
7,8-dihydroxy-4'-methoxyisoflavone (0.4 g, 1.1 mmol) in methanol
(120 ml) using palladium-on-charcoal (5%, 0.08 g) by the method
described above.
[0181] For trans-7,8-diacetoxy-4-methoxyisoflavan-4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.29, 2.30 (each s, 3H, OCOCH.sub.3), 3.14
(ddd, 1H, J 3.9 Hz, 9.2 Hz, 12.5 Hz, H3), 3.79 (s, 3H, OCH.sub.3),
4.24 (dd, 1H, J 9.6 Hz, 11.2 Hz, H2); 4.35 (m, 1H, H2), 4.92 (d,
1H, J 7.8Hz, H4), 6.78 (d, 1H, J 8.6 Hz, H6), 6.90 (m, ArH),
7.13-7.22 (m, ArH), 7.38 (d, J 8.6 Hz, ArH).
[0182] For cis-7,8-diacetoxy-4-methoxyisoflavan-4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.30, 2.31 (each s, 3H, OCOCH.sub.3), 3.29
(dt, 1H, J 3.0 Hz, J 12.0 Hz, H3), 3.80 (s, 3H, OCH.sub.3), 4.36
(m, 1H, H2); 4.57 (t, 1H, J 10.6 Hz, H2), 4.75 (bs, 1H, H4), 6.77
(d, 1H, J 8.6 Hz, H6), 6.90 (m, ArH), 7.13-7.22 (m, ArH), 7.38 (d,
J 8.6 Hz, ArH).
Example 21
4',7-Diacetoxy-8-methylisoflavan4-ol
[0183] Palladium-on-charcoal (5%, 0.12 g) was added to a suspension
of 4',7-diacetoxy-8-methylisoflavone (1.0 g, 2.8 mmol) in methanol
(200 ml) and the mixture was stirred at room temperature under a
hydrogen atmosphere for 55 h. The catalyst was removed by
filtration through Celite and the filtrate was evaporated in vacuo
to yield 4',7-diacetoxy-8-methylisoflavan-4-ol in quantitative
yield, m.p. 135-37.degree. C. A nuclear magnetic resonance spectrum
revealed the product to be a clean 1:1 mixture of cis- and
trans4',7-diacetoxy-8-methy- lisoflavan4-ol. Mass spectrum: 356 (M,
53%); 254 (86); 253 (100); 240 (80); 196 (37).
[0184] For trans-4',7-diacetoxy-8-methylisoflavan-4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.02 (s, 3H, CH.sub.3), 2.30, 2.31 (each s,
3H, OCOCH.sub.3), 3.15 (ddd, 1H, J 3.8 Hz, 8.6 Hz, 11.7, H3), 4.27
(dd, 1H, J 9.4 Hz, 11.3 Hz, H2); 4.39 (m, 1H, H2), 4.92 (d, 1H, J
7.5 Hz, H4), 6.64 (d, 1H, J 8.0 Hz, H6), 7.06-7.32 (m, ArH).
[0185] For cis-4',7-diacetoxy-8-methylisoflavan4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.02 (s, 3H, CH.sub.3), 2.31, 2.32 (each s,
3H, OCOCH.sub.3), 3.28 (dt, 1H, J 3.4 Hz, J 11.7 Hz, H3), 4.40 (m,
1H, H2); 4.58 (dd, 1H, J 10.1 Hz, 11.7 Hz, H2), 4.78 (bs, 1H, H4),
6.67 (d, 1H, J 8.0 Hz, H6), 7.06-7.32 (m, ArH).
Example 22
3',7-Diacetoxy-8-methylisoflavan4-ol
[0186] 3',7-Diacetoxy-8-methylisoflavan-4-ol was prepared from
3',7-diacetoxy-8-methylisoflavone (0.25 g, 0.7 mmol) in methanol
(50 ml) using palladium-on-charcoal (5%, 0.06 g) by the method
described above.
[0187] For trans-3',7-diacetoxy-8-methylisoflavan-4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.03 (s, 3H, CH.sub.3), 2.30, 2.32 (each s,
3H, OCOCH.sub.3), 3.18 (ddd, 1H, J 3.8 Hz, 8.3 Hz, 12.1 Hz, H3),
4.28 (dd, 1H, J 9.0 Hz, 10.9 Hz, H2); 4.39 (m, 1H, H2), 4.94 (d,
1H, J 8.7 Hz, H4), 6.65 (d, 1H, J 7.9 Hz, H6), 6.98-7.39 (m,
ArH).
[0188] For cis-3',7-diacetoxy-8-methylisoflavan-4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.05 (s, 3H, CH.sub.3), 2.30, 2.32 (each s,
3H, OCOCH.sub.3), 3.32 (dt, 1H, J 3.4 Hz, J 12.0 Hz, H3), 4.39 (m,
1H, H2); 4.59 (dd, 1H, J 10.5 Hz, 11.7 Hz, H2), 4.80 (bs, 1H, H4),
6.68 (d, 1H, J 8.3 Hz, H6), 6.98-7.39 (m, ArH).
Example 23
7-Acetoxy-4'-methoxy-8-methylisoflavan-4-ol
[0189] 7-Acetoxy-4'-methoxy-8-methylisoflavan-4-ol was prepared
from 7-hydroxy-4'-methoxy-8-methylisoflavone (0.25 g, 0.8 mmol) in
methanol (50 ml) using palladium-on-charcoal (5%, 0.08 g) by the
method described above. This hydrogenation reaction predominantly
yielded the trans-isomer.
[0190] For trans-7-Acetoxy4'-methoxy-8-methylisoflavan4-ol; .sup.1H
NMR (CDCl.sub.3): .delta. 2.02 (s, 3H, CH.sub.3), 2.32 (s, 3H,
OCOCH.sub.3), 3.11 (ddd, 1H, J 3.8 Hz, 9.4 Hz, 12.1 Hz, H3), 3.80
(s, 3H, OMe), 4.25 (dd, 1H, J 9.4 Hz, 11.3 Hz, H2); 4.40 (dd, 1H, J
3.8 Hz, 12.6 Hz, H2), 4.92 (bd, 1H, H4), 6.67 (d, 1H, J 8.3 Hz,
H6), 6.89 (d, 2H, J 8.7 Hz, ArH), 7.16 (d, 2H, J 8.7 Hz, ArH), 7.34
(d, 1H, J 8.3 Hz, H5).
Example 24
4',7-Diacetoxy-3'-methoxy-8-methylisoflavan-4-ol
[0191] 4',7-Diacetoxy-3'-methoxy-8-methylisoflavan4-ol was prepared
from 4',7-diacetoxy-3'-methoxy-8-methylisoflavone (0.25 g, 0.7
mmol) in methanol (50 ml) using palladium-on-charcoal (5%, 0.07 g)
by the method described above.
[0192] For trans-4',7-diacetoxy-3'-methoxy-8-methylisoflavan4-ol;
.sup.1H NMR (CDCl.sub.3): .delta. 2.05 (s, 3H, CH.sub.3), 2.30,
2.32 (each s, 3H, OCOCH.sub.3), 3.18 (ddd, 1H, J 3.8 Hz, 8.3 Hz,
11.4 Hz, H3), 3.79 (s, 3H, OMe), 4.28 (dd, 1H, J 9.0 Hz, 11.3 Hz,
H2); 4.41 (m, 1H, H2), 4.93 (d, 1H, J 7.9 Hz, H4), 6.64 (d, 1H, J
7.9 Hz, H6), 6.75-6.92 (m, ArH), 7.00 (d, 1H, J 7.9 Hz, ArH), 7.16
(d, 1H, J 8.3 Hz, ArH).
[0193] For cis-3',7-diacetoxy-8-methylisoflavan4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.05 (s, 3H, CH.sub.3), 2.30, 2.32 (each s,
3H, OCOCH.sub.3), 3.29 (dt, 1H, J 3.4 Hz, J 11.7 Hz, H3), 4.40 (m,
1H, H2); 4.59 (t, 1H, J 10.5 Hz, H2), 4.81 (bs, 1H, H4), 6.67 (d,
1H, J 7.9 Hz, H6), 6.75-6.92 (m, ArH), 7.03 (d, 1H, J 8.3 Hz, ArH),
7.33 (d, 1H, J 8.3 Hz, ArH).
[0194] Dehydration Reactions
Example 25
4',7-Diacetoxydehydroequol (4',7-Diacetoxyisoflav-3-ene)
[0195] Method A
[0196] Distilled trifluoroacetic acid (0.1 ml) was added to a
solution of cis- and trans-4',7-diacetoxytetrahydrodaidzein (0.1 g)
in dry distilled dichloromethane (15 ml) and the mixture was
refluxed under argon. Progress of the reaction was monitored by
thin layer chromatography and further 0.1 ml portions of
trifluoroacetic acid were added. After refluxing for 4 hours, the
reaction mixture was cooled and washed successively with saturated
sodium bicarbonate solution, water and brine. The resulting organic
phase was dried, concentrated, chromatographed and crystallised to
yield 4',7-diacetoxydehydroequol as colourless prisms (0.034 g,
35%). .sup.1H NMR (CDCl.sub.3+d.sub.6-DMSO): .delta. 2.29 (s, 3H,
OCOCH.sub.3), 2.31 (s, 3H, OCOCH.sub.3), 5.15 (s, 2H, H2), 6.62
(bs, 1H, H4), 6.65 (dd, 1H, J 2.1 Hz 8.2 Hz, H6), 6.75 (bs, 1H,
H8), 7.06 (d, 1H, J 8.2 Hz H5), 7.12 (d, 2H, J 8.2 Hz, ArH), 7.43
(d, 2H, J 8.2 Hz, ArH).
[0197] Method B
[0198] p-Toluenesulfonic acid (0.02 g) was added to a solution of
cis- and trans-4'7-diacetoxytetrahydrodaidzein (0.1 g) in dry
distilled dichloromethane (15 ml) and the mixture was refluxed
under argon. Progress of the reaction was monitored by thin layer
chromatography and after 4 h at reflux, the reaction mixture was
passed through a short column of silica gel and the eluant
recrystallised from ethanol to yield 4',7-diacetoxydehydroequol as
colourless prisms (0.025 g, 26%).
[0199] Method C
[0200] Phosphorous pentoxide (5 g) was added with stirring to a
solution of cis- and trans-4',7-diacetoxytetrahydrodaidzein (1.0 g)
in dry dichoromethane (80 ml). The mixture was stirred at room
temperature for 2 hours and filtered through a pad of Celite. The
dichoromethane solution was concentrated and chromatographed on
silica gel to yield 4',7-diacetoxydehydroequol as colourless prisms
(0.64 g, 67%).
Example 26
7-Acetoxy4'-methoxyisoflav-3-ene
[0201] Phosphorus pentoxide (1.0 g) was added with stirring to a
solution of cis- and trans-7-acetoxy-4'-methoxyisoflavan-4-ol (0.1
g, 0.3 mmol) in dry dichloromethane (20 ml). The mixture was
stirred at room temperature for 2 hours and filtered through a pad
of Celite. The organic phase was concentrated and chromatographed
on silica gel to yield 7-acetoxy-4'-methoxyisoflav-3-ene (0.04 g,
42%). 1H NMR (CDCl.sub.3); .delta. 2.28 (s, 3H, OCOCH3), 3.83 (s,
3, OCH3), 5.14 (s, 2H, H2), 6.61 (dd, 1H, J 2.3 Hz 6.4 Hz, H6),
6.65 (d, 1H, J 2.3 Hz, H8), 6.69 (bs, 1H, H4), 6.92 (d, 2H, J 9.0
Hz ArH), 7.04 (d, 1H, J 7.9 Hz, H5), 7.37 (d, 2H, J 9.0 Hz,
ArH).
Example 27
3',7-Diacetoxydehydroequol (3',7-Diacetoxyisoflav-3-ene)
[0202] 3',7-Diacetoxyisoflav-3-ene was prepared from cis- and
trans-3',7-diacetoxyisoflavan-4-ol (0.2 g, 0.6 mmol) in dry
dichloromethane (50 ml) using phosphorus pentoxide (2.0 g). Yield:
(0.09 g, 48%). 1H NMR (CDCl.sub.3): .delta. 2.29 and 2.32 (each s,
3H, OCOCH.sub.3), 5.14 (s, 2H, H2), 6.61 (d, 1H, J 2.3 Hz, H8),
6.66 (dd, 1H, J 2.3 Hz 7.9 Hz, H6), 6.79 (bs, 1H, H4), 7.02-7.25
(m, 3H, ArH), 7.25-7.44 (m, 2H, ArH).
Example 28
7-Acetoxy-3'-methoxydehydroequol
(7-Acetoxy-3'-methoxyisoflav-3-ene)
[0203] 7-Acetoxy-3'-methoxyisoflav-3-ene was prepared from cis- and
trans-7-acetoxy-3'-methoxyisoflavan-4-ol (0.25 g, 0.8 mmol) in dry
dichloromethane (20 ml) using phosphorus pentoxide (2.0 g). Yield:
(0.15 g, 63%). .sup.1H NMR (CDCl.sub.3): .delta. 2.28 (s, 3H,
OCOCH.sub.3), 3.85 (s, 3H, OMe), 5.15 (s, 2H, H2), 6.60-6.67 (m,
2H, ArH), 6.78 (bs, 1H, H4), 6.84-7.06 (m, 4H, ArH), 7.35 (t, 1H, J
8.6 Hz, ArH).
Example 29
4',7-Diacetoxy-3'-methoxyisoflav-3-ene
[0204] 4',7-Diacetoxy-3'-methoxyisoflav-3-ene was prepared from
cis- and trans-4',7-diacetoxy-3'-methoxyisoflavan-4-ol (0.20 g, 0.5
mmol) in dry dichloromethane (20 ml) using phosphorus pentoxide
(2.0 g). Yield: (0.1 g, 58%).
Example 30
7-Acetoxyisoflav-3-ene
[0205] 7-acetoxyisoflav-3-ene was prepared from cis- and
trans-7-acetoxyisoflavan4-ol (0.4 g, 1.4 mmol) in dry
dichloromethane (60 ml) using phosphorus pentoxide (5.0 g). Yield:
(0.2 g, 53%). .sup.1H NMR (CDCl.sub.3): .delta. 2.29 (s, 3H,
OCOCH.sub.3), 5.18 (s, 2H, H2), 6.61-6.67 (m, 2H, ArH), 6.79 (bs,
1H, H4), 7.07 (d, 1H, J 7.9 Hz, H5), 7.23-7.45 (m, 5H, ArH).
Example 31
4',7,8-Triacetoxydehydroequol (4',7,8-Triacetoxyisoflav-3-ene)
[0206] Phosphorus pentoxide (5.0 g) was added with stirring to a
solution of cis- and trans4',7,8-triacetoxyisoflavan-4-ol (0.5 g,
1.3 mmol) in dry dichloromethane (50 ml). The mixture was stirred
at room temperature for 2 h and filtered through a pad of Celite.
The resulting solution was concentrated and chromatographed on
silica gel to yield 4',7,8-triacetoxyisoflav-3-ene (0.3 g, 63%).
.sup.1H NMR (CDCl.sub.3): .delta. 2.29, 2.31, 2.32, (each s, 3H,
OCOCH.sub.3), 5.15 (s, 2H, H2), 6.72 (d, 1H, J 8.3 Hz, H6), 6.75
(bs, 1H, H4), 6.97 (d, 1H, J 7.9 Hz, H5), 7.12 (d, 2H, J 8.7 Hz
ArH), 7.41 (d, 2H, J 8.7 Hz, ArH).
Example 32
7,8-Diacetoxy-4-methoxydehydroequol
(7,8-Diacetoxy-4-methoxyisoflav-3-ene)
[0207] 7,8-Diacetoxy4-methoxyisoflav-3-ene was prepared from cis-
and trans-7,8-diacetoxy-4-methoxyisoflavan-4-ol (0.4 g, 1.1 mmol)
in dry dichloromethane (60 ml) using phosphorus pentoxide (5.0 g).
Yield: (0.18 g, 47%). .sup.1H NMR (CDCl.sub.3): .delta. 2.29, 2.32
(each s, 3H, OCOCH.sub.3), 3.83 (s, 3H, OCH.sub.3), 5.14 (s, 2H,
H2), 6.69 (bs, 1H, H4), 6.71 (d, 1H, J 8.3 Hz, H6), 6.90 (d, 2H, J
8.6 Hz ArH), 6.95 (d, 1H, J 7.9 Hz, H5), 7.36 (d, 2H, J 8.6 Hz,
ArH).
Example 33
4',7-Diacetoxy-8-methylisoflav-3-ene
[0208] Phosphorus pentoxide (3.0 g) was added with stirring to a
solution of cis- and trans-4',7-diacetoxy-8-methylisoflavan-4-ol
(0.55 g, 1.5 mmol) in dry dichloromethane (25 ml). The mixture was
stirred at room temperature for 2 h and filtered through a pad of
Celite. The resulting solution was concentrated and chromatographed
on silica gel to yield 4',7-diacetoxy-8-methylisoflav-3-ene (0.25
g, 48%). m.p. 140.degree. C. .sup.1H NMR (CDCl.sub.3): .delta. 2.04
(s, 3H, CH.sub.3), 2.31, 2.32 (each s, 3H, OCOCH.sub.3), 5.16 (s,
2H, H2), 6.61 (d, 1H, J 8.3 Hz, H6), 6.75 (bs, 1H, H4), 6.94 (d,
1H, J 8.3 Hz, H5), 7.13 (d, 2H, J 8.7 Hz, ArH), 7.45 (d, 2H, J 8.7
Hz, ArH). Mass spectrum: m/z 339 (M+1, 6%); 338 (M, 26); 296 (48);
254 (90); 253 (100).
Example 34
3',7-Diacetoxy-8-methylisoflav-3-ene
[0209] 3',7-Diacetoxy-8-methylisoflav-3-ene was prepared from cis-
and trans-3',7-diacetoxy-8-methylisoflavan-4-ol (0.25 g, 0.7 mmol)
in dry dichloromethane (20 ml) using phosphorus pentoxide (2.0 g).
Yield: (0.13 g, 54%) m.p. 116.degree. C. .sup.1H NMR (CDCl.sub.3):
.delta. 2.04 (s, 3H, CH.sub.3), 2.31, 2.32 (each s, 3H,
OCOCH.sub.3), 5.16 (s, 2H, H2), 6.61 (d, 1H, J 8.3 Hz, H6), 6.79
(bs, 1H, H4), 6.92 (d, 1H, J 8.3 Hz, ArH), 7.05 (dd, 1H, J 2.0 Hz,
8.0 Hz, ArH), 7.15 (s, 1H, ArH), 7.26 (d, 1H, J 8.0 Hz, ArH), 7.37
(t, 1H, J 8.0 Hz, ArH). Mass spectrum: m/z 339 (M+1, 15%); 338 (M,
22); 296 (54); 254 (30).
Example 35
7-Acetoxy-4'-methoxy-8-methylisoflav-3-ene
[0210] 7-Acetoxy4'-methoxy-8-methylisoflav-3-ene was prepared from
cis- and trans-7-acetoxy-4'-methoxy-8-methylisoflavan-4-ol (0.25 g,
0.7 mmol) in dry dichloromethane (20 ml) using phosphorus pentoxide
(2.0 g). Yield: (0.11 g, 46%) m.p. 107.degree. C. .sup.1H NMR
(CDCl.sub.3): .delta. 2.04 (s, 3H, CH.sub.3), 2.31 (s, 3H,
OCOCH.sub.3), 3.83 (s, 3H, OMe), 5.16 (s, 2H, H2), 6.59 (d, 1H, J
8.3 Hz, H6), 6.68 (bs, 1H, H4), 6.90 (d, 1H, J 8.3 Hz, H5), 6.93
(d, 2H, J 9.0 Hz, ArH), 7.37 (d, 2H, J 9.0 Hz, ArH). Mass spectrum:
m/z 311 (M+1, 13%); 310 (M, 68); 267 (100); 152 (68); 135 (90).
Example 36
4',7-Diacetoxy-3'-methoxy-8-methylisoflav-3-ene
[0211] 4',7-Diacetoxy-3'-methoxy-8-methylisoflav-3-ene was prepared
from cis- and trans-4',7-diacetoxy-3'-methoxy-8-methylisoflavan4-ol
(0.25 g, 0.6 mmol) in dry dichloromethane (25 ml) using phosphorus
pentoxide (2.0 g). Yield: (0.14 g, 58%) m.p. 123.degree. C. .sup.1H
NMR (CDCl.sub.3): .delta. 2.05 (s, 3H, CH.sub.3), 2.31. 2.32 (each
s, 3H, OCOCH.sub.3), 3.88 (s, 3H, OMe), 5.16 (s, 2H, H2), 6.61 (d,
1H, J 8.3 Hz, H6), 6.73 (bs, 1H, H4), 6.94 (d, 1H, J 8.3 Hz, H5),
6.97 (dd, 1H, J 1.9 Hz, 8.3 Hz, ArH), 7.03 (d, 1H, J 1.9 Hz, ArH),
7.05 (d, 1H, J 7.9 Hz, ArH).
[0212] Deprotection Reactions
Example 37
Dehydroequol (Isoflav-3-ene4',7-diol)
[0213] Imidazole (0.09 g) was added to a suspension of
4',7-diacetoxydehydroequol (0.03 g, 0.09 mmol) in absolute ethanol
(2.0 ml) and the mixture was refluxed for 45 min under argon. The
solution was concentrated under reduced pressure and the product
was precipitated by addition of distilled water (10 ml). The
mixture was left overnight in the fridge and filtered to yield
dehydroequol. The crude product was reprecipitated from methanol by
addition of benzene to yield dehydroequol as fluffy white solid
(0.012 g, 55%). .sup.1H NMR (CDCl.sub.3+d.sub.6-DMS- O): .delta.
4.93 (s, 2H, H2), 6.26 (bs, 1H, H4), 6.29 (dd, 1H, J 2.0 Hz, 8.2
Hz, H6), 6.50 (bs, 1H, H8), 6.73 (d, 2H, J 8.2 Hz, ArH), 6.76 (d,
2H, J 8.2 Hz, H5), 7.13 (d, 2H, J 8.2 Hz, ArH).
Example 38
7-Hydroxy-4'-methoxyisoflav-3-ene
[0214] Imidazole (0.18 g) was added to a suspension of
7-acetoxy-4'-methoxyisoflav-3-ene (0.06 g, 0.02 mmol) in absolute
ethanol (5.0 ml) and the mixture was refluxed for 45 minutes under
argon. The solution was concentrated under reduced pressure and the
product was precipitated by addition of distilled water (10 ml).
The mixture was left overnight in the fridge and filtered to yield
isoflav-3-ene. The crude product was recrystallised from
methanol/benzene to yield 7-hydroxy4'-methoxyisoflav-3-ene (0.034
g, 66%). .sup.1H NMR (CDCl.sub.3+d.sub.6-DMSO): .delta. 3.74 (s,
31H, OCH.sub.3), 4.99 (s, 2H, H2), 6.21 (d, 1H, J 2.3 Hz, H8), 6.29
(dd, 1H, J 2.3 Hz, 8.3 Hz, H6), 6.67 (bs, 1H, H4), 6.85 (d, 1H, J
8.3 Hz, H5 ), 6.86 (d, 2H, J 8.7 Hz, ArH), 7.33 (d, 2H, J 8.7 Hz,
ArH).
Example 39
Isoflav-3-ene-3',7-diol
[0215] Isoflav-3-ene-3',7-diol was prepared from
3',7-diacetoxyisoflav-3-e- ne (0.09 g, 0.3 mmol) and imidazole (0.3
g) in ethanol (2.0 ml) as described for isoflav-3-ene-4',7-diol.
Yield: (0.04 g, 60%). .sup.1H NMR (CDCl.sub.3+d.sub.6-DMSO):
.delta. 4.94 (s, 2H, H2), 6.21 (d, 1H, J 2.0 Hz, H8), 6.29 (dd, 1H,
J 2.3 Hz, 8.3 Hz, H6), 6.62 (m, 1H, ArH), 6.64 (bs, 1H, H4),
6.75-6.82 (m, 3H, ArH), 7.07 (t, 1H, J 7.9 Hz, ArH), 8.99-9.17 (bs,
2H, OH).
Example 40
3'-Methoxylsoflav-3-ene-7-ol
[0216] 3'-Methoxylsoflav-3-ene-7-ol was prepared from
7-acetoxy-3'-methoxyisoflav-3-ene (0.1 g, 0.3 mmol) and imidazole
(0.15 g) in ethanol (2.0 ml) as described for
isoflav-3-ene-4',7-diol. Yield: (0.06 g, 70%) m.p. 75.degree. C. 1H
NMR (CDCl.sub.3): .delta. 3.84 (s, 3H, OMe), 5.12 (s, 2H, H2), 6.38
(d, 1H, J 2.0 Hz, H8), 6.40 (dd, 1H, J 2.0 Hz, 8.3 Hz, H6), 6.76
(bs, 1H, H4), 6.84 (dd, 1H, J 1.9 Hz, 8.3 Hz, ArH), 6.95 (m, 3H,
ArH), 7.29 (t, 1H, J 8.3 Hz, ArH).
Example 41
3'-Methoxylsoflav-3-ene-4',7-diol
[0217] 3'-Methoxylsoflav-3-ene4',7-diol was prepared from
4',7-diacetoxy-3-methoxyisoflav-3-ene (0.11 g, 0.3 mmol) and
imidazole (0.3 g) in ethanol (2.0 ml) as described for
isoflav-3-ene-4',7-diol. Yield: (0.06 g, 71%). .sup.1H NMR
(d.sub.6-acetone): .delta. 3.90 (s, 3H, OMe), 5.07 (s, 2H, H2),
6.31 (d, 1H, J 2.3 Hz, H8), 6.40 (dd, 1H, J 2.3 Hz, 8.3 Hz, H6),
6.78 (bs, 1H, H4), 6.83 (d, 1H, J 8.3 Hz, ArH), 6.92 (dd, 2H, J 1.9
Hz, 8.3 Hz, ArH), 7.14 (d, 1H, J 1.9 Hz, ArH), 7.04,7.63 (each s,
1H, OH).
Example 42
Isoflav-3-ene-7-ol
[0218] Isoflav-3-ene-7-ol was prepared from 7-acetoxyisoflav-3-ene
(0.2 g, 0.75 mmol) and imidazole (0.24 g) in ethanol (3.5 ml) as
described for isoflav-3-ene4',7-diol. Yield: (0.11 g, 66%) m.p.
120.degree. C. .sup.1H NMR (d.sub.6-DMSO): .delta. 5.07 (s, 2H,
H2), 6.24 (d, 1H, J 2.2 Hz, H8), 6.33 (dd, 1H, J 1.9 Hz, 7.9 Hz,
H6), 6.96 (d, 1H, J 7.9 Hz, H5), 7.00 (s, 1H, H4), 7.26-7.47 (m,
5H, ArH), 9.65 (bs, 1H, OH). Mass spectrum: m/z 224 (m, 74%); 223
(100), 175 (28); 165 (23); 147 (41).
Example 43
Isoflav-3-ene-4',7,8-triol
[0219] Imidazole (0.6 g) was added to a suspension of
4',7,8-triacetoxyisoflav-3-ene (0.16 g, 0.4 mmol) in absolute
ethanol (5.0 ml) and the mixture was refluxed for 45 min under
argon. The solution was concentrated under reduced pressure and the
product was precipitated by addition of distilled water (10 ml).
The mixture was left overnight in the fridge and filtered to yield
isoflav-3-ene. The crude product was recrystallised from
methanol/benzene to yield Isoflav-3-ene-4',7-8-triol (0.08 g, 75%).
.sup.1H NMR (CDCl.sub.3+d.sub.6-DMSO): .delta. 4.97 (s, 2H, H2),
6.30 (d, 1H, J 8.2 Hz, H6), 6.36 (d, 1H, J 8.3 Hz, H5), 6.55 (bs,
1H, H4), 6.72 (d, 1H, J 8.7 Hz, ArH), 7.17 (d, 2H, J 8.7 Hz,
ArH).
Example 44
4'-Methoxyisoflav-3-ene-7,8-diol
[0220] 4'-Methoxyisoflav-3-ene-7,8-diol was prepared from
7,8-diacetoxy-4-methoxyisoflav-3-ene (0.15 g, 0.4 mmol) and
imidazole (0.4 g) in ethanol (1.6 ml) as described for
isoflav-3-ene-4',7-8-triol. Yield: (0.73 g, 61%). .sup.1H NMR
(CDCl.sub.3+d.sub.6-DMSO): .delta. 3.83 (s, 3H, OCH.sub.3), 5.15
(s, 2H, H2), 6.51 (d, 1H, J 8.3 Hz, H6), 6.58 (d, 1H, J 8.3 Hz,
H5), 6.68 (bs, 1H, H4), 6.92 (d, 1H, J 8.7 Hz, ArH), 7.35 (d, 2H, J
8.7 Hz, ArH). Mass spectrum: m/z 270 (M, 5%); 256 (100); 255 (70);
239 (20); 181 (25).
Example 45
8-Methylisoflav-3-ene4',7-diol
[0221] Imidazole (0.6 g) was added to a suspension of
4',7-diacetoxy-8-methylisoflav-3-ene (0.25 g, 0.7 mmol) in absolute
ethanol (5.0 ml) and the mixture was refluxed for 45 min under
argon. The solution was concentrated under reduced pressure and the
product was precipitated by addition of distilled water (10 ml).
The mixture was left overnight in the fridge and filtered to yield
isoflav-3-ene. The crude product was recrystallised from
methanol/benzene to yield 8-methylisoflav-3-ene-4',7-diol (0.13 g,
68%). m.p. 190-93.degree. C. .sup.1H NMR (CDCl.sub.3+d.sub.6-DMSO):
.delta. 1.94 (s, 3H, CH.sub.3), 4.98 (s, 2H, H2), 6.32 (d, 1H, J
7.9 Hz, H6), 6.58 (bs, 1H, H4), 6.67 (bd, 1H, H5), 6.72 (d, 2H, J
8.7 Hz, ArH), 7.21 (bd, 2H, ArH). Mass spectrum: m/z 255 (M+1,
16%); 254 (M, 79); 253 (100); 161 (32).
Example 46
8-Methylisoflav-3-ene-3',7-diol
[0222] 8-Methylisoflav-3-ene-3',7-diol was prepared from
3',7-diacetoxy-8-methylisoflav-3-ene (0.12 g, 0.4 mmol) and
imidazole (0.3 g) in ethanol (2.5 ml) as described for
8-methylisoflav-3-ene-4',7-d- iol. Yield: (0.07 g, 77%) m.p.
130.degree. C. .sup.1H NMR (CDCl.sub.3+d.sub.6-DMSO): .delta. 1.95
(s, 3H, CH.sub.3), 4.98 (s, 2H, H2), 6.34 (d, 1H, J 8.0 Hz, H6),
6.61-6.94 (m, 5H, ArH), 7.08 (bt, 1H, ArH). Mass spectrum: m/z 254
(M, 100%); 253 (96); 161 (45).
Example 47
4'-Methoxy-8-methylisoflav-3-ene-7-ol
[0223] 4'-Methoxy-8-methylisoflav-3-ene-7-ol was prepared from
7-acetoxy-4'-methoxy-8-methylisoflav-3-ene (0.11 g, 0.3 mmol) and
imidazole (0.14 g) in ethanol (1.5 ml) as described for
8-methylisoflav-3-ene-4',7-diol. Yield: (0.05 g, 53%) m.p.
103.degree. C. .sup.1H NMR (d.sub.6-acetone): .delta. 1.99 (s, 3H,
CH.sub.3), 3.81 (s, 3H, OMe), 5.11 (s, 2H, H2), 6.43 (d, 1H, J 8.3
Hz, H6), 6.77 (bs, 1H, H4), 6.80 (d, 1H, J 8.3 Hz, H5), 6.95 (d,
2H, J 9.0 Hz, ArH), 7.44 (d, 2H, J 9.0 Hz, ArH). Mass spectrum: 282
(M, 9%); 267 (100); 268 (95); 134 (52).
Example 48
3'-Methoxy-8-methylisoflav-3-ene4',7-diol
[0224] 3'-Methoxy-8-methylisoflav-3-ene-4',7-diol was prepared from
4',7-diacetoxy-3'-methoxy-8-methylisoflav-3-ene (0.21 g, 0.6 mmol)
and imidazole (0.52 g) in ethanol (4 ml) as described for
8-methylisoflav-3-ene4',7-diol. Yield: (0.1 g, 63%). .sup.1H NMR
(CDCl.sub.3): .delta. 2.14 (s, 3aH, CH.sub.3), 3.94 (s, 3H, OMe),
5.11 (s, 2H, H2), 6.42 (d, 1H, J 8.3 Hz, H6), 6.64 (bs, 1H, ArH),
6.80 (d, 1H, J 7.9 Hz, ArH), 6.94 (m, 2H, ArH), 7.12 (m, 1H, ArH),
7.26, 7.70 (each bs, 1H, OH).
[0225] Deprotection Reactions
Example 49
cis- and trans-Tetrahydrodaidzein
[0226] Imidazole (0.2 g) was added to a suspension of
4',7-diacetoxytetrahyrodaidzein (0.10 g, 0.3 mmol) in absolute
ethanol (4.0 ml) and the mixture refluxed for 45 min under argon.
The solution was concentrated under reduced pressure and distilled
water (10 ml) was added. The mixture was left overnight in the
fridge and the crystalline product was filtered to yield cis- and
trans-tetrahydrodaidzein (0.06 g, 80%).
Example 50
trans-Tetrahydrodaidzein (trans-4',7-Dihydroxyisoflavan-4-ol)
[0227] Trans-4',7-dihydroxyisoflavan-4-ol was prepared from
trans4',7-dihydroxyisoflavan-4-ol and imidazole in ethanol as
described for cis- and trans-tetrahydrodaidzein. .sup.1H NMR
(d.sub.6-acetone): .delta. 2.99 (ddd, 1H, J 3.4 Hz, 6.8 Hz, 10.6
Hz, H3), 4.13 (dd, 1H, J 7.0 Hz, 10.9 Hz, H2); 4.24 (dd, 1H, J 3.8
Hz, 11.3 Hz, H2), 4.70 (d, 1H, J 6.4 Hz, H4), 6.20 (d, 1H, J 2.6
Hz, H8), 6.38 (dd, 1H, J 2.3 Hz, 8.3 Hz, H6), 6.71 (d, 2H, J 8.7
Hz, ArH), 7.04 (d, 2H, J 8.7 Hz, ArH), 7.18 (d, 1H, J 8.3 Hz,
H5).
Example 51
cis- and trans-7-Hydroxy-4'-methoxyisoflavan-4-ol
[0228] Imidazole (0.4 g) was added to a suspension of
7-acetoxy-4'-methoxyisoflavan-4-ol (0.20 g, 0.6 mmol) in absolute
ethanol (8.0 ml) and the mixture refluxed for 45 minutes under
argon. The solution was concentrated under reduced pressure and
distilled water (10 ml) was added. The mixture was left overnight
in the fridge and the crystalline product was filtered to yield
cis- and trans-7-hydroxy-4'-methoxyisoflavan-4-ol (0.16 g,
79%).
Example 52
cis- and trans-7-Hydroxyisoflavan4-ol
[0229] 7-hydroxyisoflavan-4-ol was prepared from
7-acetoxyisoflavan-4-ol (0.14 g, 0.5 mmol) and Imidazole (0.1 7 g)
in ethanol (3.0 ml) as described for cis- and
trans-tetrahydrodaidzein.
[0230] For trans-7-hydroxyisoflavan-4-ol; .sup.1H NMR
(d.sub.6-acetone): .delta. 3.08 (m, 1H, H3), 4.00 (t, 1 H, J 10.2
Hz, H2); 4.30 (m, 1H, H2), 4.81 (d, 1H, J 7.2 Hz, H4), 6.25-6.43
(m, ArH), 6.89 (d, J 8.3 Hz, ArH), 7.07 (d, J 8.3 Hz, ArH),
7.22-7.64 (m, ArH).
[0231] For cis-7-acetoxyisoflavan-4-ol; .sup.1H NMR
(d.sub.6-acetone): .delta. 3.20 (m, 1H, H3), 4.36 (m, 1H, H2); 4.57
(dd, 1H, J 10.2 Hz, 12.0 Hz, H2), 4.68 (bs, 1H, H4), 6.25-6.43 (m,
ArH), 6.89 (d, J 8.3 Hz, ArH), 7.07 (d, J 8.3 Hz, ArH), 7.22-7.64
(m, ArH).
Example 53
cis- and trans-4',7-Dihydroxy-8-methylisoflavan-4ol
[0232] 4',7-Dihydroxy-8-methylisoflavan-4-ol was prepared from
4',7-diacetoxy-8-methylisoflavan-4-ol (0.4 g, 1.1 mmol) and
imidazole (1.0 g) in ethanol (7.0 ml) as described for cis- and
trans-tetrahydrodaidzein.
[0233] For trans-4',7-dihydroxy-8-methylisoflavan-4-ol; .sup.1H NMR
(d.sub.6-acetone): .delta. 1.98 (s, 3H, CH.sub.3), 2.98 (ddd, 1H, J
3.8 Hz, 10.9 Hz, 12.0 Hz, H3), 4.18 (m, 1H, H2); 4.27 (m, 1H, H2),
4.75 (d, 1H, J 6.4 Hz, H4), 6.42 (m, ArH), 6.75 (m, ArH), 7.05-7.19
(m, ArH), 7.66 (bs, OH).
[0234] For cis4',7-dihydroxy-8-methylisoflavan4-ol; .sup.1H NMR
(d.sub.6-acetone): .delta. 1.99 (s, 3H, CH.sub.3), 3.01 (dt, 1H, J
3.4 Hz, 12.0 Hz, H3), 4.31 (m, 1H, H2); 4.52 (dd, 1H, J 10.2 Hz,
12.0 Hz, H2), 4.60 (bs, 1H, H4), 6.42 (m, ArH), 6.75 (m, ArH),
7.05-7.19 (m, ArH), 7.66 (bs, OH).
Example 54
trans-7-Hydroxy-4'-methoxy-8-methylisoflavan-4-ol
[0235] trans-7-Hydroxy-4'-methoxy-8-methylisoflavan-4-ol was
prepared from trans-7-acetoxy4'-methoxy-8-methylisoflavan-4-ol
(0.23 g, 0.7 mmol) and imidazole (0.28 g) in ethanol (2.1 ml) as
described for cis- and trans-tetrahydrodaidzein. m.p. 162.degree.
C. Mass spectrum: 285 M, 5%); 268 (10); 151 (20); 135 (20); 134
(100); 119 (20). .sup.1H NMR (d-.sub.6-acetone): .delta. 1.97 (s,
3H, CH.sub.3), 3.00 (ddd, 1H, J 3.4 Hz, 7.2 Hz, 10.2 Hz, H3), 3.72
(s, 3H, OMe), 4.20 (dd, 1H, J 7.5 Hz, 10.9 Hz, H2); 4.27 (m, 1H,
H2), 4.73 (d, 1H, J 6.8 Hz, H4), 6.45 (d, 1H, J 8.3 Hz, H6), 6.85
(d, 2H, J 8.6 Hz, ArH), 7.10 (d, 1H, J 8.7 Hz, H5), 7.18 (d, 2H, J
8.6 Hz, ArH).
[0236] Hydrogenation Reactions:--Isoflavone"cis-Isoflavan-4-ol
Example 55
cis-4',7-Diacetoxyisoflavan-4-ol
[0237] Platinum(IV)oxide (Adam's catalyst) (0.05 g) was added to a
solution of of 4',7-diacetoxyisoflavanone (0.25 g, 0.7 mmol) in
ethyl acetate (40 ml) and the mixture was stirred at room
temperature under a hydrogen atmosphere for 55 h. The catalyst was
removed by filtration through Celite and the filtrate was
evaporated in vacuo to yield predominantly the
cis-4',7-diacetoxyisoflavan-4-ol.
[0238] For cis-4',7-diacetoxyisoflavan-4-ol; .sup.1H NMR
(CDCl.sub.3): .delta. 2.28 (s, 3H, OCOCH.sub.3), 2.29 (s, 3H,
OCOCH.sub.3), 3.30 (dt, 1H, J 3.4 Hz, J 11.8 Hz, H3), 4.31 (ddd,
1H, J 1.4 Hz, 3.6 Hz, 10.5 Hz, H2); 4.56 (dd, 1H, J 10.5 Hz, 11.8
Hz, H2), 4.75 (dd, 1H, J 1.3 Hz, 3.2 Hz, H4), 666 (dd, 1H, J 2.3
Hz, 8.7 Hz, H6),6.69 (d, 1H, J 2.3 Hz, H8), 7.08 (d, 2H, J 8.6 Hz,
ArH), 7.26 (d, 1H, 8.4 Hz, H5), 7.29 (d, 2H, J 8.6 Hz, ArH).
.sup.13C NMR (CDCl.sub.3): .delta. 20.98 (OCOCH .sub.3), 43.52
(C3), 64.10 (C2), 66.46 (C4), 110.08 (C6), 114.09 (C8), 121.82,
129.40 (OCOCH.sub.3), 131.10 (C5).
[0239] Hydrogenation
Reactions:--Isoflavone.fwdarw.Isoflavan4-one
Example 56
4',7-Diacetoxydihydrodaidzein (4',7-Diacetoxyisoflavan-4-one)
[0240] Palladium-on-charcoal (5%, 0.02 g) was added to a solution
of 4',7-diacetoxydaidzein (0.50 g, 1.5 mmol) in ethyl acetate (80
ml) and the mixture was stirred at room temperature under a
hydrogen atmosphere for 72 h. The catalyst was removed by
filtration through Celite and the resulting filtrate was evaporated
in vacuo. The residue was recrystallised from ethanol to yield
4',7-diacetoxydihydrodaidzein (0.40 g, 80%) as colotirless )lates.
.sup.1H NMR (CDCl.sub.3): .delta. 2.29 (s, 3H, OCOCH.sub.3), 2.23
(s, 3H, OCOCH.sub.3), 3.98 (dd, 1H, J 6.2 Hz, 8.2 Hz, H3), 4.69 (m,
2H, H2), 6.78-6.82 (m, 2H, ArH), 7.08 (d, 2H, J 9.2 Hz, ArH), 7.30
(d, 2H, J 8.2 Hz, ArH), 7.98 (d, 1H, J 9.2 Hz H5).
[0241] Hydrogenation
Reactions:--Isoflavan-3-ene.fwdarw.Isoflavan
Example 57
O,O-Diacetylequol
[0242] Palladium-on-charcoal (5%, 0.02 g) was added to a solution
of 4',7-diacetoxyisoflav-3-ene (0.20 g, 0.06 ml) in ethyl acetate
(60 ml) and the mixture was stirred at room temperature under a
hydrogen atmosphere for 24 h. The catalyst was removed by
filtration through Celite and the resulting filtrate was evaporated
in vacuo. The residue was recrystallised from dichloromethane/light
petroleum to yield O,O-diacetylequol (0.15 g, 75%). .sup.1H NMR
(CDCl.sub.3): .delta. 2.29 (s, 3H, OCOCH.sub.3), 2.31 (s, 3H,
OCOCH.sub.3), 3.00 (d, 2H, J 8.3 Hz, H4), 3.25 (m, 1H, H3), 4.00
(t, 1H, H2), 4.34 (dd, 1H, J 3.4 Hz, 10.9 Hz, H2), 6.61 (d, J 7.5
Hz, 1H, ArH), 6.60 (s, 1H, ArH), 7.06 (bd, 3H, J 8.3 Hz, ArH), 7.24
(d, 3H, J 8.3 Hz, ArH).
[0243] Deprotection Reactions
Example 58
Dihydrodaidzein (4',7-Dihydroxyisoflavan4-one)
[0244] Imidazole (0.63 g) was added to a suspension of
4',7-diacetoxydihydrodaidzein (0.26 g, 0.08 mmol) in absolute
ethanol (5.0 ml) and the mixture was refluxed for 45 min under
argon.
[0245] The solution was concentrated under reduced pressure and
distilled water (10 ml) was added to the residue. The mixture was
left overnight in the fridge and the resulting precipitate was
filtered. The crude product was recrystallised from ethyl
aceate/dichloromethane to yield 4',7-diacetoxydihydrodaidzein (0.14
g, 71%) as a white powder. .sup.1H NMR (d.sub.6-acetone): .delta.
3.83 (t, 1H, J 7.2 Hz, H3), 4.60 (d, 2H, J 6.2 Hz, 1H2), 6.39 (d,
1H, J 2.0 Hz, H8), 6.55 (dd, 1H, J 8.2, J 2.0 Hz, ArH), 6.80 (d,
2H, J 8.2 Hz, ArH), 7.10 (d, 1H, J 8.2 Hz, ArH), 7.74 (d, 1H, J 8.2
Hz, H5).
Example 59
Equol (4',7-Dihydroxyisoflavan)
[0246] Imidazole 0.5 g) was added to a suspension of
(O,O-diacetylequol (0.15 g, 0.08 mmol) in absolute ethanol (5.0 ml)
and the mixture was refluxed for 45 min under argon. The solution
was concentrated under reduced pressure and distilled water (10 ml)
was added to the residue. The mixture was left overnight in the
fridge and the resulting product was filtered to yield equol (0.09
g, 80%) as a white powder. .sup.1H NMR (d.sub.6-DMSO): .delta. 2.70
(d, 2H, J 9.2 Hz, H4), 2.92 (m, 1H, H3), 3.73 (t, 1H, J 10.3 Hz,
H2), 4.06 (dd, 1H, J 3.0 Hz, 11.2 Hz, H2), 6.16 (bs, 1H, ArH), 6.21
(bd, J 8.2 Hz, 1H, ArH), 6.63 (d, 2H, J 8.2 Hz, ArH), 6.69 d, 1H, J
8.2 Hz, ArH), 6.87 (d, 2H, J 8.2 Hz, ArH)
[0247] Those skilled in the art will appreciate that the invention
described herein is susceptible to variations and modifications
other than those specifically described. It is to be understood
that the invention includes all such variations and modifications.
The inventions also includes all of the steps, features,
compositions and compounds referred to or indicated in the
specification, individually or collectively, and any and all
combinations of any two or more of said steps or features.
* * * * *