US20050143588A1 - Production of isoflavone derivatives - Google Patents

Production of isoflavone derivatives Download PDF

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US20050143588A1
US20050143588A1 US10/851,270 US85127004A US2005143588A1 US 20050143588 A1 US20050143588 A1 US 20050143588A1 US 85127004 A US85127004 A US 85127004A US 2005143588 A1 US2005143588 A1 US 2005143588A1
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hydroxy
ene
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alkyl
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Andrew Heaton
Naresh Kumar
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Kazia Research Pty Ltd
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Novogen Research Pty Ltd
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Priority to US11/442,369 priority patent/US7906660B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
    • C07D311/56—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 without hydrogen atoms in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/38—2,3-Dihydro derivatives, e.g. isoflavanones

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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 wherein
  • the present invention also provides a method for the hydrogenation of a compound of formula I to prepare a compound of formula IV wherein
  • the present invention also provides a method for the hydrogenation of a compound of formula III to prepare a compound of formula V wherein
  • the present invention also provides compounds of formulae II, III, IV and V when prepared by a method described above and compositions comprising same.
  • the present invention also provides novel compounds of the formulae I, II, III, IV and V and compositions comprising same.
  • 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
  • the particularly preferred compounds of formula I are 4′,7-diacetoxyisoflavone (daidzein diacetate) and 7-acetoxy4′-methoxyisoflavone;
  • novel compounds of the formulae I, II, III, IV and V preferably have the following substituents wherein
  • novel compounds of formulae I, II and III are:
  • 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.
  • 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 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylamino-carbonyl, di-(C 1 -C 4 -alkyl)-amino-carbonyl, hydroxyl, C 1 -C 4 -alkoxy, formyloxy, C 1 -C 4 -alkyl-carbonyloxy, C 1 -C 4 -alkylthio, C 3 -C 6 -cylcoalkyl or phenyl.
  • aryl is taken to include phenyl and naphthyl and may be optionally substituted by one or more C 1 -C 4 -alkyl, hydroxy, C 1 -C 4 -alkoxy, carbonyl, C 1 -C 4 -alkoxycarbonyl , C 1 -C 4 -alkylcarbonyloxy or halo.
  • 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.
  • 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.
  • 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° C. and is typically carried out at room temperature.
  • 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.
  • 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).
  • 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.
  • 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.
  • homogeneous reduction catalysts examples include chlorotris (triphenylphosphine)rhodium, chloro(trisphenylphosphine)hydridoruthenium (II) and pentacyanocobaltate (II).
  • the solvents suitable for use in the present invention include but are not limited to C 1 -C 8 alcohols and polyols, alkyl acetates, tetrahydrofuran, ethers, dioxane and C 1 -C 3 acids.
  • the solvent is a C 1 -C 6 alcohol or C 1 -C 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.
  • the solvent is absolute methanol, ethanol or ethyl acetate.
  • isoflavones are reduced cleanly and in high yields to corresponding isoflavanols.
  • 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.
  • 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.
  • isoflavones with oxygen substitution or precursors to oxygen substitution
  • oxygen substitution or precursors to oxygen substitution
  • a convenient starting material is daidzein which is readily obtained by established routes.
  • moieties on the isoflavone rings may require protection or derivatisation prior to being subjected to hydrogenation.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Tetrahydrodaidzein and related derivatives were 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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° C.
  • 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° C.
  • 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° C.
  • 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-triacetoxyisoflavone. Yield: (0.9 g, 85%) m.p. 165° C.
  • 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-methylisoflavone. Yield: (1.2 g, 70%) m.p. 112° C.
  • 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° C.
  • 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° C.
  • the cis- and trans-isomers were able to be separated by fractional recrystallisation.
  • 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-diacetoxytetrahydrodaidzein (27%). Further recrystallisations of the mixture from ethanol yielded the pure trans-4′,7-diacetoxytetrahydrodaidzein (0.04 g, 24%).
  • 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.
  • 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.
  • 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° C. Mass spectrum: m/z 284 (M, 10%); 226 (42); 138 (100); 137 (58).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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° C.
  • 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° C.
  • 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%).
  • Isoflav-3-ene-3′,7-diol was prepared from 3′,7-diacetoxyisoflav-3-ene (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%).
  • 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° C.
  • 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%).
  • 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° C.
  • 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%).
  • 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%).
  • 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° C.
  • 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-diol. Yield: (0.07 g, 77%) m.p. 130° C.
  • 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° C.
  • 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%).
  • 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%).
  • 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.
  • 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%).
  • 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.
  • 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.
  • 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° C. Mass spectrum: 285 M, 5%); 268 (10); 151 (20); 135 (20); 134 (100); 119 (20).
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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US20030157225A1 (en) * 2000-01-21 2003-08-21 Husband Alan James Food product and process
US20030219499A1 (en) * 1998-03-26 2003-11-27 Novogen Research Pty Ltd Therapy of estrogen-associated disorders
US20040048812A1 (en) * 1992-05-19 2004-03-11 Novogen Research Pty. Ltd. Health supplement
US20040072765A1 (en) * 1999-04-28 2004-04-15 Novogen Research Pty Ltd. Cardiovascular and bone treatment using isoflavones
US20070149788A1 (en) * 2005-12-02 2007-06-28 Hyatt John A Preparation of Flavonoid Compounds
EP1919887A2 (en) * 2005-08-01 2008-05-14 Girindus America, Inc. Method for enantioselective hydrogenation of chromenes
WO2014145386A2 (en) * 2013-03-15 2014-09-18 University Of Florida Research Foundation Incorporated Novel allosteric inhibitors of thymidylate synthase
US20160159763A1 (en) * 2011-01-20 2016-06-09 Merck Patent Gmbh Polymerizable compounds and the use thereof in liquid-crystal displays
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US20070179099A1 (en) * 1992-05-19 2007-08-02 Novogen Research Pty Ltd. Methods of cholesterol reduction using isoflavones
US20020035074A1 (en) * 1997-05-01 2002-03-21 Novogen, Inc. Treatment or prevention of menopausal symptoms and osteoporosis
US20080038387A1 (en) * 1998-03-26 2008-02-14 Novogen Research Pty Ltd Therapy of estrogen-associated disorders
US20030219499A1 (en) * 1998-03-26 2003-11-27 Novogen Research Pty Ltd Therapy of estrogen-associated disorders
US20040072765A1 (en) * 1999-04-28 2004-04-15 Novogen Research Pty Ltd. Cardiovascular and bone treatment using isoflavones
US20030157225A1 (en) * 2000-01-21 2003-08-21 Husband Alan James Food product and process
EP1919887A2 (en) * 2005-08-01 2008-05-14 Girindus America, Inc. Method for enantioselective hydrogenation of chromenes
EP1919887A4 (en) * 2005-08-01 2011-01-19 Girindus America Inc METHOD FOR THE ENANTIOSELECTIVE HYDROGENATION OF CHROMENES
AU2006275587B2 (en) * 2005-08-01 2012-09-13 Children's Hospital Medical Center Method for enantioselective hydrogenation of chromenes
US20070149788A1 (en) * 2005-12-02 2007-06-28 Hyatt John A Preparation of Flavonoid Compounds
US7696363B2 (en) * 2005-12-02 2010-04-13 Yasoo Health Inc. Preparation of flavonoid compounds
US20160159763A1 (en) * 2011-01-20 2016-06-09 Merck Patent Gmbh Polymerizable compounds and the use thereof in liquid-crystal displays
US10414743B2 (en) * 2011-01-20 2019-09-17 Merck Patent Gmbh Polymerizable compounds and the use thereof in liquid-crystal displays
WO2014145386A2 (en) * 2013-03-15 2014-09-18 University Of Florida Research Foundation Incorporated Novel allosteric inhibitors of thymidylate synthase
WO2014145386A3 (en) * 2013-03-15 2014-12-24 University Of Florida Research Foundation Incorporated Novel allosteric inhibitors of thymidylate synthase
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US10835524B2 (en) 2015-06-24 2020-11-17 University Of Florida Research Foundation, Incorporated Compositions for the treatment of pancreatic cancer and uses thereof

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CA2362819A1 (en) 2000-08-24
HUP0105218A1 (hu) 2002-07-29
EP1153020A4 (en) 2002-08-21
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