WO2008012108A2 - Préparation de stilbènes polyhydroxylés - Google Patents

Préparation de stilbènes polyhydroxylés Download PDF

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WO2008012108A2
WO2008012108A2 PCT/EP2007/006726 EP2007006726W WO2008012108A2 WO 2008012108 A2 WO2008012108 A2 WO 2008012108A2 EP 2007006726 W EP2007006726 W EP 2007006726W WO 2008012108 A2 WO2008012108 A2 WO 2008012108A2
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formula
butyl
process according
compound according
alkyl group
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PCT/EP2007/006726
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WO2008012108A3 (fr
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Jonathan William Wiffen
Raymond Mccague
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Portela & Ca., S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C07C45/676—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton by elimination of carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms

Definitions

  • Tr ⁇ HS-resveratrol which in IUPAC nomenclature corresponds to (E)-I- (3,5-dihydroxyphenyl)-2-(4-hydroxyphenyl)ethene has been found to raise the level of high-density lipoproteins (HDL) and lower the level of low-density lipoproteins (LDL) in human beings thereby reducing the risk of clogging arteries and consequent myocardial infarctions (Toppo, F. U.S. Pat. No. 6,048,903). Many 5- alkenyl resorcinols show antileukemic activity (Alonso, E; Ramon, D.
  • Plant material containing /r ⁇ rcs-resveratrol has been used as herbal medicine for the treatment of hyperlu- pemia and liver diseases in China and Japan for many centuries (Kimura, K. M. et al. Shoyqakugaku Zasshi 1987, 83, 35-58).
  • WO 00/21368 describes the condensation of phosphonate esters with aromatic aldehydes followed by demethylation using pyridine hydrochloride. In this method also the yields are low & the process is not commercially attractive.
  • Drewes, S. E.; Fletcher, I. P J. Chem. Soc. Perkin Trans. I 1974, 961-962 & Bajaj, R.; Gill, M. T.; McLaughlin, J. L. Rev. Latinoamer Quim. 1987, 18, 79-80 reported the synthesis of analogs of (£)-resveratrol wherein a mixture of (E)- & (Z)- isomer is obtained.
  • the present invention relates to processes and intermediates for the industrially viable preparation of resveratrol characterized by the use of cost-efficient, rela- tively low-toxic, non-hazardous starting materials and avoiding the formation of undesired side products during the reaction sequence.
  • the process for the preparation of resveratrol comprises the steps of
  • Ri, R 2 , and R 3 independently from each other represent hydrogen, a (Q- C 4 )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl; (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl group such as methoxymethyl, meth- oxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl; (C 1 - C 4 )alkoxy(C]-C 4 )alkoxy(Ci-C 4 )alkyl group such as methoxyethoxymethyl, meth- oxyethoxyethyl; allyl, vinyl, silyl, formyl, acy
  • R 1 and R 2 represent methyl.
  • R 3 represents methyl
  • R 4 represents, methyl, ethyl, n-propyl or isopropyl.
  • Preferred examples of suitable leaving groups M in formula I include fluoride, chloride, bromide, iodide, methoxy, ethoxy, n-propoxy, isopropoxy, n-butanoxy, sec-butoxy, tert-butoxy, phenoxy, 4-chlorophenoxy, 4-bromophenoxy, 4- nitrophenoxy, imidazolyl, acetoxy, trifluorocarboxy, tosylate and mesylate.
  • the reaction step a) includes a Claisen-type reaction or acylation of a compound according to formula I with a compound according to formula II to form a compound according to formula III.
  • the Claisen-type reaction or acylation of a compound according to formula I with a compound according to formula II is conducted in the presence of a suitable base.
  • the compound of formula II is converted to its corresponding enolate which may optionally be silylated.
  • the enolate is formed by deprotonation with a suitable base.
  • the preferred silylating agent for silylating the enolate is trimethylsilyl chloride.
  • a base in reaction step a) is not necessary. If a silylated enolate is used an activating compound such as a Lewis acid or trimethylsilyltriflate may also be employed, as is well known in the art.
  • Suitable bases for deprotonating a compound according to formula II prior or in the course of the Claisen-type reaction are such bases which are strong enough to convert (at least part of) the compound according to formula II into its corresponding enolate.
  • Preferred examples include, sodium hydride, potassium hydride, lithium diisopropylamide (LDA), lithium hexamethyldisilylamide (LHMDSA), butyl lithium, methyl lithium, potassium butoxide, alkaline alkoxides and earth alkaline alkoxides, such as sodium ethoxide, sodium methoxide, magne- sium ethoxide; amidines, guanidines, tetramethylammoniumhydroxide, tetrabu- tylammoniumhydroxide, combinations of alkaline hydroxides, such as sodium hydroxide and potassium hydroxide, with phase transfer catalysts, and mixtures thereof.
  • LDA lithium diisopropylamide
  • LHMDSA lithium
  • a solvent for carrying out the reaction step a) is not particularly limited. The exact choice will inter alia depend on the nature and solubility of the base employed. Suitable solvents include tetrahydrofuran, dioxane, dimeth- oxyethane, toluene, xylenes, acetonitrile, dimethysulfoxide, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. Preferred solvents for carrying out the reaction step a) include tetrahydrofuran and dimethoxyethane.
  • reaction conditions in reaction step a) are also not particularly limited and primarily depend on the choice of the leaving group M, the steric and electronic effect of the protective groups Rj to R 4 and the type of solvent employed.
  • Suitable temperature ranges include -70 to 100 °C, preferably -20 to 80 °C, most prefera- bly 45 to 75 °C.
  • Suitable reaction times range from 1 h to 48 h, preferably 2 h to 24 h, and most preferably 3 h to 18 h.
  • the Claisen-type reaction or acylation of a compound according to formula I with a compound according to formula II yields a com- pound of formula III in which R 5 represents COOR 4 .
  • the carboxylic ester moiety COOR 4 is hydrolysed and decarboxylated in a subsequent step.
  • both hydrolysis and decarboxylation are conducted in the same step under either acidic or alkaline conditions.
  • Preferred solvents for the hydrolysis/decarboxylation are alcohols such as methanol, ethanol, propanol, isopropanol, water and mixtures thereof. It is also possible to use the crude reaction mixture obtained in the above step of reacting as a compound according to formula II with a compound according to formula III. In such a case, it is preferred to add one of the preferred solvents for the hydroly- sis/decarboxylation a second solvent to further facilitate the reaction. Suitable mixing ratios of these solvents are readily determined by the person skilled in the art.
  • reaction conditions for the hydrolysis/decarboxylation are also not particu- larly limited and primarily depend on the choice of the protective groups R 1 to R 4 and the type of solvent employed. Suitable temperature ranges include room temperature to the boiling point of the particular solvent, preferably 40 to 110°C, more preferably 60 to 90 °C and most preferably 70 to 80 °C.
  • the Claisen-type reaction or acylation of a compound according to formula I with a compound according to formula II yields a compound of formula III wherein R 5 represents H, i.e. the carboxylic ester moiety originating from the compound according to formula II is lost in situ under the reaction conditions of the Claisen-type reaction or acylation.
  • the groups Ri to R 4 are changed prior to conducting the reaction steps in order to facilitate the reactions in reaction step b).
  • the reaction step b) includes the conversion of the compound according to the formula III to the hydroxyl compound according to the formula IV.
  • the conversion of the compound according to the for- mula III to the compound according to the formula IV is conducted by reducing the carbonyl function and dehydrating the resulting hydroxyl compound of formula V:
  • RK R 2 and R 3 are defined as in formulas I and II.
  • Suitable reducing agents and reaction conditions for preparing a compound of formula V are known in the art.
  • the reduction is conducted by using an ionic hydride reducing agent such as sodium borohydride or by hydrogenation such as with a PdVC catalyst.
  • an ionic hydride reducing agent such as sodium borohydride or by hydrogenation such as with a PdVC catalyst.
  • sodium borohydride alcoholic solvents such as methanol, ethanol and isopropanol, and water or mixtures thereof are preferred.
  • Pd/C with hydrogen ethyl acetate and alcoholic solvents such as methanol, ethanol and isopropanol, are preferred solvents.
  • Suitable reaction temperatures range from 0 to 70 °C, preferably 20 to 60 °C, and most preferably 30 to 50 °C.
  • Suitable reaction times range from 0.5 to 60 h, preferably 1 to 5 h, and most preferably 1.5 to 3 h.
  • Suitable catalytic amounts of iodine range from 3 to 50 mol%, preferably 4 to 30 mol%, more preferably 5 to 20 mol%, of the hydroxyl compound.
  • the hydroxyl group of formula V is con- verted into a leaving group and subsequently or concomitantly the double bond is formed by elimination which is effected by the addition of a base.
  • the hydroxyl group is converted into a mesyl, tosyl, bromo, triflate, acetate or chloride moiety.
  • Suitable bases for the elimination reaction which yields the double bond are known in the art.
  • amine bases such as trimethylamine and triethylamine, are used.
  • Suitable solvent systems are known in the art and preferably toluene or an ether solvent are used.
  • Suitable reaction temperatures range from 0 to 100 °C, preferably 20 to 90 °C, and most preferably 30 to 80 °C.
  • Suitable reaction times range from 0.5 to 5 h, preferably 1 to 4 h, and most preferably 2 to 3 h.
  • the hydroxyl compound is treated with 1 to 1.5 equivalents, preferably 1.1 to 1.4 equivalents, most preferably with 1.2 to 1.3 equivalents, mesyl chloride, and an excess, preferably 1.5 to 10 equivalents, preferably 2 to 8 equivalents, more preferably 3 to 6 equivalents, of triethylamine in toluene at 60 to 100°C, preferably 70 to 90°C, more preferably 70 to 80°C, for 3 to 8 h, preferably 4 to 7 h, more preferably 5 to 6 h.
  • a favourable E- to Z-isomer ratio is obtained.
  • the optional reaction step c) relates to the deprotection of the compound according to formula IV to resveratrol.
  • Suitable reaction conditions for the removal of protecting groups are known in the art.
  • the protective groups are removed by treatment with BBr 3 in an inert solvent, preferably toluene, at -20 °C to 30 °C, preferably -10 to 10 0 C, and most preferably at 0 to 5 °C, for 0.5 to 3 h, preferably 1 to 2 h.
  • the process for the preparation of resveratrol comprises the steps of
  • R 1 , R 2 , and R 3 independently from each other represent hydrogen, a (C 1 - C 4 )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl; (Ci-C 4 )alkoxy-(C 1 -C 4 )alkyl group such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl; (C 1 -C 4 )alkoxy-(C 1 - C 4 )alkoxy-(Ci-C 4 )alkyl group such as methoxyethoxymethyl, methoxyeth- oxyethyl; allyl, vinyl, silyl, formyl, acyl group such as acetyl, propanoyl, butanoyl or benzoyl;
  • Ri and R 2 represent methyl.
  • R 3 represents methyl.
  • Z represents bromo or chloro.
  • the reaction step a) includes a Heck-type reaction of a compound according to formula VI with a compound according to formula VII to form a compound according to formula VIII.
  • the Heck-type reaction is preferably conducted at temperatures above room temperature in a suitable solvent in the presence of supported or non-supported catalyst optionally with a ligand, for example a phosphine-based ligand, and a base.
  • the catalyst is a palladium or palladium complex catalyst.
  • suitable catalysts such as nickel catalysts, will be evident to those skilled in the art.
  • suitable solvents for said Heck-type reactions are selected from dipolar aprotic solvents, comprising dimethylformamide, dimethylacetamide, N- methylpyrrolidone and hexamethylphosphotriamide, dimethylsulfoxide and other polar solvents, such as acetonitrile.
  • hydrocarbon solvents can be employed such as, for example, toluene, mesitylene, xylenes and the like, ethereal solvents such as, for example, tetrahydrofuran, dioxane, anisole and the like, chlorinated solvents such as, for example, chloroform, dichloromethane, dichloro- ethane and the like or ionic liquids such as tetrabutylammonium bromide. These solvents may optionally be used alone or in combination and optionally also in combination with water. However, it is preferred to employ essentially water-free conditions.
  • the palladium metal is selected from Pd(O) and Pd(I) and Pd(II) salts or complexes which may optionally be supported on a carrier such as charcoal, graphite, polystyrene, clay or glass.
  • a carrier such as charcoal, graphite, polystyrene, clay or glass.
  • Suitable palladium salts or complexes include palladium black, palladium (II) acetate, palladium (II) chloride, palladium (II) acetylacetonate, palladium (0) dibenzylideneacetone, palladium (II) trifluoro- acetate, dichlorobis(acetonitrile)palladium (II), dichlorobis(benzonitrile)palladium (II), tris(dibenzylideneacetone)dipalladium (0) and tris(dibenzylideneacetone)- dipalladium (0) chloroform adduct.
  • the phosphine ligand is mono- or bidentate and is selected from the group comprising tri-o-tolylphosphine, tri-o-furylphosphine, triphenylphosphine, tris(2,4-dimethoxyphenyl)phosphine, tris(2,4,6-trimethoxyphenyl)phosphine, 2- (dicyclohexylphosphino)biphenyl, 2-(di-t-butylphosphino)biphenyl, 1,1 -bis- (diphenylphosphino)ferrocene (dppf), (oxy-2, 1 -phenyl ene)bis(diphenylphosphine) (DPEPHOS), tricyclohexylphosphine, tri-t-butylphosphonium tetrafluoroborate, 1 ,3-bis(diphenylphosphino)propane (dppp), 1 ,
  • the phosphine ligand may be a water-soluble ligand such as, for example, triphenyl- phosphine m-trisulphonate sodium salt (TPPTS).
  • TPTS triphenyl- phosphine m-trisulphonate sodium salt
  • non-phosphine ligands are used. Such non-phosphine ligands are readily known in the art and examples are described in Najera et al (2003), Org. Lett 5:1451-4; Consorti et al (2003) Org. Lett 5:983-6; and CaIo et al (2003), J. Org. Chem. 68:2929-33.
  • the palladium metal and the phosphine ligand are added as a complex.
  • Preferred embodiments include dichlorobis(tri- ortho-tolylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0), dibromobis(tri-tert-butylphosphine)dipalladium (I), di- ⁇ -chlorobis(tris(2,4-di-t- butylphenyl)phosphite-2-C,P)-dipalladium (II), bis(tri-tert-butylphosphine)- palladium (0), trans-di( ⁇ -acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II), dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium (II) and trans- dichlorobis(triphenylphosphine)palladium (II).
  • the most preferred complexes of the palladium metal and the phosphine ligand include dibromobis(tri-tert-butylphosphine)dipalladium (I) and bis(tri-tert- butylphosphine)palladium (0), with the latter one being particularly preferred.
  • the base is selected from amine bases, such as triethylamine, tribu- tylamine, trimethylamine, ethyldiisopropylamine, N-ethylmorpholine, benzyldi- methylamine, 2,2,5,5,6-pentamethylpiperidine and the like, or from alkali metal carboxylates, alkoxides or carbonate bases, such as sodium acetate, potassium acetate, potassium tert-butoxide, cesium carbonate, lithium carbonate, calcium carbonate, sodium carbonate and potassium carbonate.
  • amine bases such as triethylamine, tribu- tylamine, trimethylamine, ethyldiisopropylamine, N-ethylmorpholine, benzyldi- methylamine, 2,2,5,5,6-pentamethylpiperidine and the like
  • alkali metal carboxylates such as sodium acetate, potassium acetate, potassium tert-butoxide
  • phase transfer catalyst in particular a quaternary ammonium salt such as tetrabutylammonium bromide, tetrabutyl ammonium chloride, benzyltriethylammonium chloride and the like is employed in the Heck reaction.
  • an additive in particular an inorganic salt such as lithium chloride, sodium chloride, nickel (II) bromide, sodium bromide, sodium iodide, silver carbonate, silver nitrate, silver phosphate, silver acetate, silver trifluoroacetate, thallium (II) carbonate and thallium acetate is em- ployed in the Heck reaction.
  • an inorganic salt such as lithium chloride, sodium chloride, nickel (II) bromide, sodium bromide, sodium iodide, silver carbonate, silver nitrate, silver phosphate, silver acetate, silver trifluoroacetate, thallium (II) carbonate and thallium acetate is em- ployed in the Heck reaction.
  • the Heck reaction is conveniently conducted so that for each mole of the compound of formula (VII), the amount of dipolar aprotic solvent ranges from 0.5 to 2 L; the amount of compound of formula (I) ranges from 1.05 to 2.5 equivalents; the amount of the palladium metal ranges from 0.005 to 0.1 equivalents; the amount of the phosphine ligand ranges from 0.01 to 0.1 equivalents; the amount of base ranges from 1 to 1.5 equivalents; and the amount of salt ranges from 0.5 to 1.5 equivalents.
  • the amount of sol- vent is about IL; the amount of the compound of formula (VI) is about 1.5 equivalents; the amount of palladium metal is about 0.01 equivalents; the amount of phosphine is about 0.02 equivalents; and the amount of base is about 1.5 equivalents.
  • reaction mixture is heated while stirring under an inert atmosphere until less than 2% of the compound of formula (VII) remains.
  • the yield of the Heck-type reaction is 60 to 100%, more preferably 70 to 98 %, even more preferably 75 to 95 % and most preferably 80 to 92 %.
  • step c) of the Heck-reaction scheme may be carried out as described for step c) of the Claisen-type reaction.
  • the process for the preparation of resveratrol comprises the steps of
  • R 1 , R 2 , and R 3 independently from each other represent hydrogen, a (C 1 - C 4 )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl (Ci-C 4 )alkoxy-(Ci-C 4 )alkyl group such as methoxymethyl, meth- oxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl; (Q- C 4 )alkoxy-(C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl group such as methoxyethoxymethyl, methoxyethoxyethyl; allyl, vinyl, silyl, formyl, acyl group such as acetyl, pro- panoyl, butanoyl or
  • R 3 represents methyl and R 4 is selected from methyl, ethyl and phenyl.
  • the reaction step a) includes a Wittig-type reaction of a compound according to formula IX with a compound according to formula X to form a compound according to formula XI. It was surprisingly found that in contrast to the prior art phos- phonium salts disclosed in U.S. Pat. No. 6,048,903 and similar phosphorus com- pounds, the compounds according to formula X of the invention, especially those bearing the residue -P(O)(OR-O 2 , provide higher yields, superior purity and greater stereoselectivity.
  • suitable solvents for said Wittig-reactions are selected from dipolar aprotic solvents, comprising dimethylformamide, dimethylacetamide, N- methylpyrrolidone, dimethylsulfoxide and hexamethylphosphotriamide, and other polar solvents, such as acetonitrile THF, dioxane, DME and the like. These solvents are preferably substantially dried in order to suppress the unwanted side- reactions.
  • the base in reaction step a) is selected from lithiated bases such as n- butyllithium, t-butyllithium, methylithium, phenylithium, lithiumhexa- methyldisilazide and lithiumdiisopropylamide, hydrides, such as sodium hydride, potassium hydride and calcium hydride, or alkoxides such as sodium methoxide, sodium ethoxide, magnesium ethoxide, potassium tert-butoxide and the like.
  • lithiated bases such as n- butyllithium, t-butyllithium, methylithium, phenylithium, lithiumhexa- methyldisilazide and lithiumdiisopropylamide
  • hydrides such as sodium hydride, potassium hydride and calcium hydride
  • alkoxides such as sodium methoxide, sodium ethoxide, magnesium ethoxide, potassium tert-butoxide and
  • reaction in step a) is conveniently conducted so that for each mole of the compound of formula (X), the amount of dipolar aprotic solvent ranges from 0.5 to 2 L; the amount of compound of formula (IX) ranges from 1 to 2.5 equivalents and the amount of base ranges from 1 to 3 equivalents.
  • reaction in step a) is conveniently conducted so that for each mole of the compound of formula (X), the amount of dipolar aprotic solvent ranges from 0.7 to 1 L; the amount of compound of formula (IX) ranges from 1.05 to 1.3 equivalents and the amount of base ranges from 1.1 to 1.5 equivalents
  • the yield of the reaction of step a) is 80 to 100%, more preferably 83 to 95 %, even more preferably 85 to 92 % and most preferably 87 to 91 %.
  • the reaction product of step a) is substantially free of the (Z)-isomer of the compound of formula XI.
  • the reaction product of step a) contains less than 5% (Z)-isomer, preferably less than 3% (Z)-isomer, more preferably 0 to
  • the optional reaction step c) of the HWE-type reaction scheme may be carried out as described for step c) of the Claisen-type reaction.
  • Example 1 The crude product of Example 1 (18.3g, 0.53mol) was dissolved in a mixture of ethanol (100ml) and 15% aq. HCl (50ml). The mixture was heated at reflux for 4h before cooling to room temperature and dilution with ethyl acetate (200ml) and water (200ml). The organic portion was then washed with 10% aq. K 2 CO 3 (150ml) followed by water (100ml) before drying (Na 2 SO 4 ), filtration and concentration in vacuo. This yielded a viscous brown oil that was recrystallised from hot isopropanol (50ml). The resultant white solid was collected by vacuum filtration and air-dried to yield 9.1g (60%) of product.

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Abstract

L'invention concerne un procédé de préparation de stilbènes polyhydroxylés à partir d'un composé de la formule (I), de la formule (VI) ou de la formule (IX).
PCT/EP2007/006726 2006-07-28 2007-07-30 Préparation de stilbènes polyhydroxylés WO2008012108A2 (fr)

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Application Number Priority Date Filing Date Title
EP06015770.8 2006-07-28
EP06015772.4 2006-07-28
EP06015772 2006-07-28
EP06015773 2006-07-28
EP06015773.2 2006-07-28
EP06015770A EP1884508A1 (fr) 2006-07-28 2006-07-28 Procédé de préparation de stilbènes polyhydroxylés par condensation de claisen

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WO2008012108A3 WO2008012108A3 (fr) 2008-05-22

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Cited By (8)

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Publication number Priority date Publication date Assignee Title
US8841477B2 (en) 2004-01-20 2014-09-23 Brigham Young University Sirtuin activating compounds and processes for making the same
JP2009544663A (ja) * 2006-07-28 2009-12-17 クラリアント スペシャルティー ファイン ケミカルズ（フランス） レスベラトロールおよびピセアタンノールを得ることを可能にする（ｅ）−スチルベン誘導体を合成するための新規な方法
WO2010046926A2 (fr) * 2008-10-17 2010-04-29 Aptuit Laurus Pvt Ltd Nouveaux analogues de stilbene novel stilbene analogs
WO2010046926A3 (fr) * 2008-10-17 2011-03-31 Aptuit Laurus Pvt Ltd Nouveaux analogues de stilbène
EP2785673A4 (fr) * 2011-12-01 2015-07-01 Laurus Labs Private Ltd Procédé de préparation de composés polyhydroxystilbène par déprotection des éthers correspondants
CN104151232A (zh) * 2014-06-30 2014-11-19 北京万全德众医药生物技术有限公司 一种制备依托考昔的方法
CN111686817A (zh) * 2019-03-14 2020-09-22 凯惠药业(上海)有限公司 一种铜负载催化剂、其制备方法及应用
CN111686817B (zh) * 2019-03-14 2024-02-09 上海博腾智拓医药科技有限公司 一种铜负载催化剂、其制备方法及应用
CN109970517A (zh) * 2019-04-28 2019-07-05 杭州瑞树生化有限公司 一种白藜芦醇类化合物的制备方法
CN114195610A (zh) * 2022-01-05 2022-03-18 海南大学 一种e式内部烯烃类化合物的合成方法

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