WO2008012108A2

WO2008012108A2 - Process for the preparation of polyhydroxylated stilbenes via claisen condensation

Info

Publication number: WO2008012108A2
Application number: PCT/EP2007/006726
Authority: WO
Inventors: Jonathan William Wiffen; Raymond Mccague
Original assignee: Bial Portela and Cia SA
Current assignee: Bial Portela and Cia SA
Priority date: 2006-07-28
Filing date: 2007-07-30
Publication date: 2008-01-31
Anticipated expiration: 2009-01-28
Also published as: WO2008012108A3

Abstract

The invention relates to a process for the preparation of polyhydroxylated stilbenes starting from a compound of the formula (I) formula (VI) or formula (IX).

Description

Preparation of Polyhydroxylated Stilbenes

Polyhydroxylated trans-stilbenes have been found to exhibit interesting biological activities. TrøHS-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. J; Yus, M. J. Org. Chem. 1997, 62, 417-421; Thakkar, K; Geahlen, R. L.; Cushman, M. J. Med. Chem. 1993, 36(20), 2950-2955) and anti-tumor properties (He, K.; Zheng, Q. Y.; Zheng, B. L.; Kim, C. H. WO 2000/037021). Plant material containing /rαrcs-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). Further investigations led to identification of many important biological functions including inhibition of lypooxygenase activity (Kimma, Y. et al. Biochem. Biophys. Acta. 1985, 834, 275), inhibition of anaphylactoid (Ragazy et al. Pharmacol. Commun. 1988, 79, 20) and protection of lipoproteins against oxidative and free radical damage (Frankel E. N. et al. Lancet 1979, 1, 1017).

Despite the many varied biological activities of the polyhydroxylated trans- stilbenes, there have been surprisingly few methods reported for the synthesis of these compounds which mostly employ a Wittig reaction in the synthesis of res- veratrol. U.S. Pat. No. 6,048,903 describes the synthesis of (£)-resveratrol by the Wittig reaction of 3,5-dimethoxybenzyltriphenyl phosphonium salt with p- anisaldehyde in the presence of n-butyllithium. In this method the mixture of (Z)- and (£)-olefins so obtained is demethylated with boron tribromide which provides a low overall yield of the product. This method suffers from the low quality and use of expensive and hazardous reagents and the poor solubility of the phospho- nium salt which requires large volumes of solvent and results in a poor (E)-I(Z)- ratio, necessitating a separate isomerisation step to give pure trøws-resveratrol.

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. Cunningham, J.; Haslam, E.; Haworth, R. D. J. Chem. Soc. 1963, 2875-2883 disclosed a different route, which comprises reaction of 3,5- dihydroxyphenylacetate and 3,4-dihydroxybenzaldehyde in acetic anhydride, de- carboxylation of the ensuing 3,3',4,5'-tetraacetoxystilbene-[alpha]-carboxylic acid with copper and quinoline at high temperature, followed by hydrolysis of the resulting piceatannol tetraacetate with sodium hydroxide. The reported yields in these methods are moderate to low. AIi, M. A.; Kondo, K.; Tsuda, Y. Chem. Pharm. Bull. 1992, 40(5), 1130-1136 described the Wittig reaction, wherein the undesired (Z)-isomers are reported to form to the extent of 52% along with the desired (£)-isomers (48%) when potassium tert-butoxide is employed. Cushman, M.; Nagarathnam, D.; Gopal, D. et al. J. Med. Chem. 1992, 35 (12), 2293-2306; Chen, Yi-Ping; Lei, Tong-Kang. Zhongguo Yiyao Gongye Zazhi 2000, 31(7), 334-336 disclosed the formation of (Z)-isomers to the extent of 45% ((E): 55%) when sodium hydride is used. These processes are commercially and technically difficult to be implemented. To this date, no viable Wittig reaction has been found which ensures formation of the desired (£)-isomer. In addition, the main problems in the synthesis of these polyhydroxylated-l,2-diphenylethenes are caused by the instability of this polyphenols stilbene due to facile oxidation resulting in the formation of unstable radicals and quinones. Accordingly, it is the object of the present invention to develop an industrially viable method for producing resveratrol characterized by the use of cost-efficient, relatively low-toxic, non-hazardous starting materials and avoiding the formation of undesired side products and isomers. In addition, it is a further object of the invention to develop viable and cost-efficient ways of predominantly forming the desired trans-isomer.

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.

In one embodiment of the invention which employs a Claisen-type reaction, the process for the preparation of resveratrol comprises the steps of

a) reaction of a compound according to formula I

with a compound according to formula II - A -

(H)

to form a compound according to formula III

b) conversion of the compound according to formula III to a compound according to formula IV

(IV),

and, if necessary,

c) deprotection of the compound according to formula IV to resvera- trol, wherein Ri, R₂, and R₃ independently from each other represent hydrogen, a (Q- C₄)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl; (C₁-C₄)alkoxy(C₁-C₄)alkyl group such as methoxymethyl, meth- oxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl; (C₁- C₄)alkoxy(C]-C₄)alkoxy(Ci-C₄)alkyl group such as methoxyethoxymethyl, meth- oxyethoxyethyl; allyl, vinyl, silyl, formyl, acyl group such as acetyl, propanoyl, butanoyl or benzoyl; aryl(Cl-C4)alkyl or substituted aryl(Ci-C₄)alkyl group such as benzyl, phenethyl, diphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, p- methylbenzyl or o-chlorobenzyl; R₄ represents a (Cl-C₁₈)alkyl group such as methyl, ethyl, n-propyl, isopropyl, tert-butyl, decyl, optionally with additional substitution such as methoxyethyl, a (Ci-Cio)aryl group such as phenyl optionally with additional substituents on the aromatic residue such as 4-methylphenyl, 4- methoxyphenyl, or an aryl(C₁-C₄)alkyl group such as benzyl or phenethyl; R₅ represents hydrogen or a residue COOR₄; and M is a leaving group.

Most preferably, in formula I, R₁ and R₂ represent methyl.

Most preferably, in formula II, R₃ represents methyl, and R₄ 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. In a preferred embodiment 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.

In an alternative preferred embodiment, prior to the Claisen-type reaction 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. In this case, the above described use of 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.

The choice of 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. The 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 R₄ 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.

In a preferred embodiment, 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 R₅ represents COOR₄. The carboxylic ester moiety COOR₄ is hydrolysed and decarboxylated in a subsequent step. Preferably, 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.

The reaction conditions for the hydrolysis/decarboxylation are also not particu- larly limited and primarily depend on the choice of the protective groups R₁ to R₄ 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.

In an alternative preferred embodiment, 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 R₅ 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.

In still an alternative preferred embodiment, the groups Ri to R₄ are changed prior to conducting the reaction steps in order to facilitate the reactions in reaction step b). In particular, it is envisaged to deprotect or transesterify the groups Ri to R₄ or to introduce protective groups in cases where groups R₁ to R₄ represent hydroxyl groups.

The reaction step b) includes the conversion of the compound according to the formula III to the hydroxyl compound according to the formula IV.

In a preferred embodiment, 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:

(V),

wherein RK R₂ and R₃ 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. In a preferred embodiment, the reduction is conducted by using an ionic hydride reducing agent such as sodium borohydride or by hydrogenation such as with a PdVC catalyst. When using sodium borohydride alcoholic solvents, such as methanol, ethanol and isopropanol, and water or mixtures thereof are preferred. When using 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.

Processes for the dehydration of the hydroxyl compound of formula V are known in the art. In a preferred embodiment, the hydroxyl compound of formula V is heated in an inert solvent, such as toluene, in the presence of catalytic amounts of iodine. 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.

In an alternative preferred embodiment, 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. Preferably, 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. Preferably, 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.

Most preferably, 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. In the course of the reaction 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. In a preferred embodiment, in which in formula IV Ri, R₂ and R₃ represent methyl, the protective groups are removed by treatment with BBr₃ in an inert solvent, preferably toluene, at -20 °C to 30 °C, preferably -10 to 10 ⁰C, and most preferably at 0 to 5 °C, for 0.5 to 3 h, preferably 1 to 2 h.

In an alternative embodiment which employs a Heck reaction, the process for the preparation of resveratrol comprises the steps of

a) reacting a compound according to formula VI

(VI),

with a compound according to formula VII

(VII) to form a compound according to formula VIII

(VIII)

b) optionally converting the (Z)-isomer of the compound according to formula VIII to its (E)-isomer,

and, if necessary,

c) deprotecting of the compound according to formula VIII to resveratrol,

wherein R₁, R₂, and R₃ independently from each other represent hydrogen, a (C₁- C₄)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl; (Ci-C₄)alkoxy-(C₁-C₄)alkyl group such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl; (C₁-C₄)alkoxy-(C₁- C₄)alkoxy-(Ci-C₄)alkyl group such as methoxyethoxymethyl, methoxyeth- oxyethyl; allyl, vinyl, silyl, formyl, acyl group such as acetyl, propanoyl, butanoyl or benzoyl; aryl-(Cl-C4)alkyl or substituted aryl-(C₁-C₄)alkyl group such as ben- zyl, phenethyl, diphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, p-methylbenzyl or o-chlorobenzyl; and wherein Z represents chloro, bromo, iodo, triflate, hexaflate, nonaflate, tosylate, nosylate, or a diazonium group.

Most preferably, in formula VI, Ri and R₂ represent methyl.

Most preferably, in formula VII, R₃ represents methyl. Most preferably, in formula VII, 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.

Examples for non-ligand Heck-type reactions are known in the art. Non-limiting examples of such catalyst systems are mentioned in Reetz et al, Chem Commun, 2004, 1559-63 and Reetz et al, Tetrahedron Lett., 1998, 39, 8449.

Various other catalyst compositions are established in the art for the carrying out of Heck reactions, any of which may be applied to this invention. For example, the following publications exemplify suitable catalyst compositions: Littke & Fu, Angew. Chem. hit. Ed. 41 : 4176-4211 (2002), J. Org. Chem., 64: 10 (1999), Choudary et al, JACS 124:14127-36 (2002).

Preferably the catalyst is a palladium or palladium complex catalyst. However, other suitable catalysts, such as nickel catalysts, will be evident to those skilled in the art.

Preferably, 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. Alternatively 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.

Preferably, 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. 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.

Preferably, 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 ,4-bis(diphenylphosphino)butane (dppb) and 2,2'-bis(diphenylphosphino)-l,l '-binaphthalene (BINAP). Optionally, when the Heck-type reaction is operated in water, or in the presence of water, the phosphine ligand may be a water-soluble ligand such as, for example, triphenyl- phosphine m-trisulphonate sodium salt (TPPTS).

In an alternative preferred embodiment, 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. In an alternative preferred embodiment, 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-μ-chlorobis(tris(2,4-di-t- butylphenyl)phosphite-2-C,P)-dipalladium (II), bis(tri-tert-butylphosphine)- palladium (0), trans-di(μ-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.

Preferably, 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.

In a preferred alternative embodiment, a 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.

In another preferred alternative embodiment, 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. 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.

Preferably, for each mole of the compound of formula (VII), 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.

In order to facilitate the purification of the compound of formula (VIII), the reaction mixture is heated while stirring under an inert atmosphere until less than 2% of the compound of formula (VII) remains.

Preferably, 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 %.

Methods for converting the (Z)-isomer of the compound according to formula VIII to its (E)-isomer in reaction step b) are known in the art and described e.g. in US 6,844,471.

The optional reaction step c) of the Heck-reaction scheme may be carried out as described for step c) of the Claisen-type reaction.

Methods for preparing compounds according to formulas (VI) and (VII) are known in the art. A method for preparing a compound according to formula (VI) is also described in the experimental section. Furthermore, it has now surprisingly been found that resveratrol can be efficiently produced by a Wadsworth-Emmons variant of the Wittig olefination reaction, wherein the use of certain Wittig reagents produces products which are substantially isomerically pure (E)-isomers of resveratrol thereby eliminating the need to isomerize (Z)-resveratrol in a separate additional step. Furthermore, it has been surprisingly found that by use of Wittig reagents according to the invention higher yields, and purer end-products can be obtained. Therefore, in another embodiment of the invention which employs a HWE-type reaction, the process for the preparation of resveratrol comprises the steps of

b) reacting a compound according to formula IX

(IX),

with a compound according to formula X

(X)

in presence of a suitable base to form a compound according to formula XI

(XI)

and, if necessary,

b) deprotecting of the compound according to formula XI to resveratrol,

wherein R₁, R₂, and R₃ independently from each other represent hydrogen, a (C₁- C₄)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl (Ci-C₄)alkoxy-(Ci-C₄)alkyl group such as methoxymethyl, meth- oxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl; (Q- C₄)alkoxy-(C₁-C₄)alkoxy-(C₁-C₄)alkyl group such as methoxyethoxymethyl, methoxyethoxyethyl; allyl, vinyl, silyl, formyl, acyl group such as acetyl, pro- panoyl, butanoyl or benzoyl; aryl-(Cl-C4)alkyl or substituted aryl-(Ci-C₄)alkyl group such as benzyl, phenethyl, diphenylmethyl, p-methoxybenzyl, p- nitrobenzyl, p-methylbenzyl, 2,6-dimethylbenzyl or o-chlorobenzyl; and wherein Y is the group P(O)(OR₄)?, wherein R₄ is selected from (CrC₄)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl; and a substituted or unsubstituted aryl or alkylaryl group such as phenyl, benzyl, phenethyl, diphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, p-methylbenzyl o-chlorobenzyl, 4-chlorophenyl or 4-chlorobenzyl. Most preferably, in formula IX, Ri and R₂ represent methyl.

Most preferably, in formula X, R₃ represents methyl and R₄ 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-O₂, provide higher yields, superior purity and greater stereoselectivity.

Preferably, 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.

Preferably, 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.

The 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. Preferably, 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

Preferably, 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 %.

Preferably, the reaction product of step a) is substantially free of the (Z)-isomer of the compound of formula XI. Preferably, the reaction product of step a) contains less than 5% (Z)-isomer, preferably less than 3% (Z)-isomer, more preferably 0 to

2 % of the (Z)-isomer, even more preferably less than 2% of the (Z)-isomer, still further preferred 0.1 to 0.5 % of the (Z)-isomer, and most preferred less than 0.5% of the (Z)-isomer.

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.

Methods for preparing compounds according to formulas (IX) and (X) are known in the art. A method for preparing a compound according to formula (IX) is also described in the examples section.

Examples

Example 1 : Preparation of 3-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)-3-oxo- propionic acid methyl ester

A solution of methyl 4-methoxyphenyl acetate (1Og, 0.055mol) in dry THF (40ml) was added dropwise over 6h to a suspension of methyl 3,5- dimethoxybenzoate (14.2g, 0.072mol) and NaH (6g, 60% suspension in oil pre- washed with hexane) at 65°C under N₂. The reaction mixture was then allowed to stir at 65°C overnight. Reaction progress was monitored by TLC and ¹H NMR analyses. After complete reaction, the mixture was cooled to room temperature before concentration to half the original volume under reduced pressure. The mix- ture was quenched by careful addition to ice/lN HCl (150ml) followed by extraction with ethyl acetate (3 x 50ml). The combined organic extracts were washed with 10% aq. K₂CO₃ (100ml) followed by water (100ml), then dried (Na₂SO₄), filtered and concentrated yielding a viscous brown oil (18.3g, 96% crude yield). This material was used in the subsequent step without purification.

Example 2: Preparation of l-(3.5-dimethoxyphenyl)-2-(4-methoxyphenyl)- ethanone

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. K₂CO₃ (150ml) followed by water (100ml) before drying (Na₂SO₄), 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.

Example 3: Preparation of l-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)ethanol

To a suspension of the product of Example 2 (5g, 0.017mol) in ethanol (40ml) was added NaBH₄ (0.73g, 1.1 eq.) portionwise over 2 mins. The reaction mixture was then heated to 50⁰C and monitored by thin layer chromatography (dichloro- methane eluent) until completion (ca. Ih). The reaction mixture was then concentrated to one-third of the original volume before dilution with ethyl acetate (75ml) and water (50ml). The organic portion was washed further with brine (2 x 50ml) before drying (Na₂SO₄), filtration and concentration to yield an off-white solid (5g, 99%).

Example 4: Preparation of 3,5,4'-trimethoxystilbene

To a solution of the product of Example 3 (1.8g, 6.25mmol) in dry toluene containing Et₃N (8.8ml, 0.55mol) at 0⁰C was added mesyl chloride (0.58ml, 7.5mmol) dropwise. The reaction was allowed to stir at this temperature for 0.5h before heating to 8O⁰C. The progress of the reaction was monitored by thin layer chromatography until completion (ca. 4-8h). The reaction mixture was then diluted with ethyl acetate (40ml) and IN HCl (30ml). The organic portion was then washed further with IN HCl (30ml) and brine (30ml) before drying (Na₂SO₄), filtration and concentration. This yielded a brown oil that was purified by flash chromatography (dichloromethane:hexane 1 :1) affording a viscous colourless oil (1.2g, 71 %) that solidified on standing yielding a white solid.

Example 5: E-3,5,4'-trihvdroxystilbene (ResveratroD

To a solution of the product of Example 4 (0.5g, 1.85mmol) in dry toluene (5ml) at 0⁰C under N₂ was added BBr₃ (0.58ml, 5.55mmol) dropwise over 2 mins. The reaction mixture was then allowed to stir at 0⁰C for 0.5h and room temperature for

1.5h. Progress of the reaction was monitored by thin layer chromatography

(methanol :dichloromethane 1 :9). The reaction was then cooled to 0⁰C before the careful addition of saturated aq. NaHCO₃ (15ml). This mixture was allowed to stir for 20mins before addition of ethyl acetate (25ml). Stirring was continued for

15mins before separation of the layers. The organic portion was washed further with brine (2 x 15ml) before drying (Na₂SO₄), filtration and concentration in vacuo yielding an off-white solid. This was slurried in diethyletherhexane (1:1)

(20ml), filtered and air-dried yielding resveratrol as a beige solid (0.39g, 92%). Example 6: Preparation of a compound according to formula (VI): 1,3-dimethoxy- 5-vinyl-benzene

a) 3,5-Dimethoxybenzylalcohol

To a stirred solution of methyl 3,5-dimethoxybenzoate (2.0Og, O.Olmol) in THF (32mL) at room temperature was added NaBH₄ (2.3g, O.Oόmol) in portions. The resulting reaction mixture was heated at 65⁰C under a nitrogen atmosphere for 15min, whereupon MeOH (8mL) was added dropwise over lhr. The reaction was then stirred for a further 3hr at 65°C at which point the reaction was complete. To the reaction mixture was slowly added saturated aqueous NH₄Cl solution (15mL). The reaction mixture was filtered through celite™ and the filter cake was washed with THF. The solvent was evaporated under vacuum and the aqueous residue was diluted with H₂O (2OmL) and extracted with EtOAc (3x20mL). The com- bined organic extracts were dried (MgSO₄), filtered and concentrated in vacuo to afford a colourless oil that solidified on standing to give a white solid.

Yield: 1.38g (81%), pure product by ¹H NMR.

b) 3,5-Dimethoxy-benzaldehyde

To 3,5-dimethoxybenzylalcohol (8.0Og, 0.05mol) in EtOAc (17OmL) was added IBX (26.7g, O.lmol) with stirring. The heterogeneous reaction mixture was then heated to 8O⁰C for 2hr whereupon the reaction was complete. After cooling to room temperature, the insoluble material was removed by filtration and the filtrate concentrated in vacuo to afford an orange oil which solidified on standing.

Yield: quantitative, pure product by ¹H NMR.

c) Methyltriphenylphosphonium iodide A mixture of triphenylphosphine (20.0Og, 0.08mol) and iodomethane (10.8Og, 0.08mol) in toluene (20OmL) was refluxed under N₂ overnight during which time a white solid precipitated. The reaction mixture was allowed to cool to room temperature and the solid collected by filtration, washed with ether and dried.

Yield: Quantitative.

d) l,3-Dimethoxy-5-vinyl-benzene

To a stirred solution of 3,5-dimethoxybenzaldehyde (2.0Og, 12mmol) in THF (2OmL) was added methyl triphenyl phosphonium iodide (5.38g, 13mmol). The resulting mixture was then cooled to O⁰C and 'BuOK was added under N₂. After 2hr the reaction was complete. The product was purified by chromatography using a hexane/EtOAc 95:5 mixture as eluent. Homogenous fractions were pooled and evaporated to dryness to afford the product as a colourless oil.

Yield: 2.0Og (79%), pure product by ¹H NMR

Example 7: Preparation of a compound according to formula (VIII): 3,5,4'- trimethoxystilbene

A mixture of l,3-dimethoxy-5-vinyl-benzene (200mg, 1.2mmol), 4-bromoanisole (152mg, O.δmmol), and triethylamine (170μL, 1.2mmol) in N₁N- Dimethylacetamide (3mL) was degassed with N₂ for 3min. Bis(tri-tert- butylphosphine)palladium (0) (0.1mol%) was then added and the mixture was heated at 100⁰C overnight. The reaction mixture was then diluted with H₂O (2OmL) and extracted with EtOAc (3x1 OmL). The combined organic layers were washed with H₂O (2x1 OmL), dried (MgSO₄), filtered and concentrated in vacuo to afford an orange oil. The oil was purified by chromatography (dichloro- methane:hexane 1 :1) affording a viscous colourless oil that solidified on standing yielding a white solid. Yield 98%, pure product by ¹H NMR.

Example 8: Deprotection to 3,5,4'-trihydroxystilbene

To a solution of 3,5,4'-trimethoxystilbene (0.5g, 1.85mmol) in dry toluene (5ml) at 0⁰C under N₂ was added BBr₃ (0.58ml, 5.55mmol) dropwise over 2 mins. The reaction mixture was then allowed to stir at 0⁰C for 0.5h, then at room temperature for a further 1.5h. The reaction mixture was then cooled to O⁰C before the careful addition of saturated aqueous NaHCO₃ solution (15ml). This mixture was allowed to stir for 20mins before addition of ethyl acetate (25ml). Stirring was continued for 15mins before separation of the layers. The organic portion was washed further with brine (2 x 15ml) before drying (Na₂SO₄), filtration and concentration in vacuo to provide an off-white solid. This was slurried in diethyletherhexane (1 :1) (20ml), filtered and air-dried yielding 3,5,4'-trihydroxystilbene as a beige solid.

Yield: 0.39g, (92%), pure product by ¹H NMR.

Example 9: Preparation of a compound according to formula (IX): 3,5-dimethoxy- benzaldehyde

a) 3,5-Dimethoxybenzylalcohol

To the methyl 3,5-dimethoxybenzoate (2.0Og, O.Olmol) in THF (32mL) at room temperature was charged NaBH₄ (2.3g, O.Oόmol) by portion. The resulting reaction mixture was heated at 65⁰C under N₂ for 15min. whereupon MeOH (8mL) was slowly added dropwise over lhr. Effervescence was observed. The reaction was then stirred for 3hr at 65°C. To the reaction mixture was added saturated aqueous NH₄Cl solution (15mL) slowly under N₂. The reaction mixture was fil- tered through celite™ and the filter cake was washed with THF. The THF was evaporated from the filtrate under vacuum and the remaining aqueous residue was diluted with H₂O (2OmL) and extracted with EtOAc (3x20mL). The combined organic extracts were dried (MgSO₄), filtered and concentrated in vacuo to afford a colourless oil that solidified on standing to give a white solid.

Yield: 1.38g (81 %) pure product by ¹H NMR.

b) 3,5-Dimethoxy-benzaldehyde

To 3,5-dimethoxybenzylalcohol (8.0Og, 0.05mol) in EtOAc (17OmL) was charged IBX (26.7g, O.lmol). The heterogeneous reaction mixture was then heated at 80⁰C for 2hr. After cooling to room temperature, the insoluble material was removed by filtration and the filtrate concentrated in vacuo to afford an orange oil that solidified on standing.

Yield: quant, pure product by ¹H NMR.

Example 10: Preparation of a compound according to formula (XI): £-3,5,4'- trimethoxystilbene

To a solution of diethyl 4-methoxybenzylphosphonate (310mg, 1.2mmol) in dry THF (2mL) at 0°C under N₂ was charged NaOMe (130mg, 2.4mmol) and the mixture was stirred for 5 min at room temperature. A solution of aldehyde obtained in Example 9, step b) above (240mg, 1.4mmol) in dry THF (ImL) was then added and the reaction mixture was refiuxed for 3hr under N₂. After cooling the reaction was quenched by the addition of ice under N₂, followed by the addition Of H₂O (15mL). The THF was removed in vacuo, and the remaining aqueous residue was extracted with EtOAc (3x1 OmL). The combined organic extracts were washed with water (1OmL), dried (MgSO₄), filtered and concentrated in vacuo to afford an orange oil that solidified upon standing. Yield: 214mg (66%, after chromatography, pure product by ¹H NMR). Examples 11 to 18 and Comparative Examples 1 to 3

The compounds according to Examples 11 to 18 and Comparative Examples 1 to 3 were produced according to the procedure described for Example 9 with the exception of the changes indicated in table 1.

Table 1

Annotations to table 1 :

DEMBP: Diethyl 4-methoxybenzylphosphonate MBDPO: 4-Methoxybenzyl diphenylphosphine oxide

All products obtained from Examples 11 to 18 were isomerically pure as determined by ¹H NMR of the row reaction product, whereas the products of Compara- tive Examples 1 to 3 contained amounts of (2)-isomer as estimated by ¹H NMR. In addition, the content of impurities arising from competing side reactions was higher in the comparative examples as estimated by ¹H NMR.

Example 19: Deprotection to 3,5,4'-trihydroxystilbene

To a solution of 3,5,4'-trimethoxystilbene (0.5g, 1.85mmol) in dry toluene (5ml) at O⁰C under N₂ was added BBr₃ (0.58ml, 5.55mmol) dropwise over 2 mins. The reaction mixture was then allowed to stir at O⁰C for 0.5h followed by 1.5h at room temperature. The reaction was then cooled to 0⁰C before the careful addition of saturated aqueous NaHCO₃ (15ml) solution. This mixture was allowed to stir for 20mins before addition of ethyl acetate (25ml). Stirring was continued for a further 15mins before separation of the layers. The organic portion was washed with brine (2 x 15ml) before drying (Na₂SO₄), filtration and concentration in vacuo to yield an off-white solid. This was slurried in diethyletheπhexane (1:1) (20ml), filtered and air-dried yielding 3,5,4'-trihydroxystilbene as a beige solid (0.39g, 92%, pure product by ¹H NMR).

Claims

1. Process for the preparation of resveratrol, comprising the steps of a) reaction of a compound according to formula I

(I), with a compound according to formula II

to form a compound according to formula III

(IV),

and, if necessary,

c) deprotection of the compound according to formula IV to resveratrol,

wherein R₁, R₂, and R₃ independently from each other represent hydrogen, (C₁- C₄)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl; (C₁-C₄)alkoxy(C₁-C₄)alkyl group such as methoxymethyl, meth- oxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl; (C₁- C₄)alkoxy(Ci-C₄)alkoxy(Ci-C₄)alkyl group such as methoxyethoxymethyl, meth- oxyethoxyethyl; allyl, vinyl, silyl, formyl, acyl group such as acetyl, propanoyl, butanoyl or benzoyl; aryl(Ci-C₄)alkyl or substituted aryl(C_!-C₄)alkyl group such as benzyl, phenethyl, diphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, p- methylbenzyl or o-chlorobenzyl; R₄ represents a (Cl-Cig)alkyl group such as methyl, ethyl, n-propyl, isopropyl, tert-butyl, decyl, or said groups having an additional substitution such as methoxyethyl, a (C₁-Ci₀)aryl group such as phenyl optionally with additional substituents on the aromatic residue such as 4- methylphenyl, 4-methoxyphenyl, or an aryl(d-C₄)alkyl group such as benzyl or phenethyl; R₅ represents hydrogen or a residue COOR₄; and M is a leaving group or hydroxyl group.

2. Process according to claim 1, wherein as an intermediate reaction product in step b) a compound of formula V

(V),

wherein R₁, R₂ and R₃ and R₅ are defined as in claim 1, is formed.

3. Process according to claim 1 or 2, wherein M is selected from fluoride, chloride, bromide, iodide, methoxy, ethoxy, n-propoxy, isopropoxy, n-butanoxy, sec-butoxy, tert-butoxy, phenoxy, 4-chlorophenoxy, 4-bromophenoxy, 4- nitrophenoxy, imidazolyl, trifluorocarboxy, acetoxy, tosylate and mesylate.

4. Process according to claim 1 or 2, wherein M represents OH which is converted in situ to fluoride, chloride, bromide, iodide, methoxy, ethoxy, n-propoxy, isopropoxy, n-butanoxy, sec-butoxy, tert-butoxy, phenoxy, 4-chlorophenoxy, 4- bromophenoxy, 4-nitrophenoxy, imidazolyl, trifluorocarboxy, tosylate and mesylate.

5. Process according to any one of claims 1 to 4, wherein step a) is conducted in the presence of a base.

6. Process according to claim 5, wherein the base is selected from sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldis- ilylamide, butyl lithium, methyl lithium, potassium butoxide, alkaline alkoxides and earth alkaline alkoxides, such as sodium ethoxide, sodium methoxide, magnesium ethoxide; amidines, guanidines, tetramethylammonium hydroxide, tetrabu- tylammonium hydroxide, combinations of alkaline hydroxides, such as sodium hydroxide and potassium hydroxide, with phase transfer catalysts, and mixtures thereof.

7. Process according to claim 4, wherein the base is selected from sodium hydride, potassium hydride and calcium hydride.

8. Process according to any one of claims 1 to 4, wherein the compound of formula II is used in its enolate form which optionally may be silylated.

9. Process according to any one of claims 1 to 8, wherein R₅ represents a residue COOR₄.

10. Process according to claim 9, wherein the compound according to formula III is decarboxylated so that R₅ represents hydrogen.

11. Process according to any one of claims 2 to 10, wherein the compound according to formula III is reduced to the compound according to formula V by interaction with a reducing agent selected from NaBH₄ or by catalytic hydrogena- tion over Pd/C.

12. Process according to any one of claims 1 to 10, wherein the compound according to formula V is converted to the compound according to formula IV by using a catalytic amount of iodine in toluene.

13. Process according to any one of claims 1 to 10, wherein the compound according to formula V is converted to the compound according to formula IV by converting the hydroxyl group to be eliminated to the corresponding mesylate moiety and eliminating the mesylate moiety by using a base.

14. Process according to claim 13, wherein the base is selected from trimethylamine, triethylamine, ethyldiisopropylamine and tributylamine.

15. Process according to any one of claims 1 to 10, wherein the compound of formula IV is deprotected to resveratrol by action of BBr₃ in toluene in the temperature range of -5 to 5 °C.

16. A compound of formula (III) wherein Ri, R₂, and R₃ independently from each other represent hydrogen, (C_!-C₄)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl; (C₁-C₄)alkoxy(C₁-C₄)alkyl group such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, eth- oxyethyl, ethoxypropyl; (C₁-C₄)alkoxy(Ci-C₄)alkoxy(C₁-C₄)alkyl group such as methoxyethoxymethyl, methoxyethoxyethyl; allyl, vinyl, silyl, formyl, acyl group such as acetyl, propanoyl, butanoyl or benzoyl; aryl(Ci-C₄)alkyl or substituted aryl(Ci-C₄)alkyl group such as benzyl, phenethyl, diphenylmethyl, p- methoxybenzyl, p-nitrobenzyl, p-methylbenzyl or o-chlorobenzyl; R₄ represents a (Cl-Cis)alkyl group such as methyl, ethyl, n-propyl, isopropyl, tert-butyl, decyl, or said groups having an additional substitution such as methoxyethyl, a (Ci- Ci_O)aryl group such as phenyl optionally with additional substituents on the aromatic residue such as 4-methylphenyl, 4-methoxyphenyl, or an aryl(Ci-C₄)alkyl group such as benzyl or phenethyl; and R₅ represents COOR₄.

17. Compound according to claim 16, wherein said compound is 3-(3,5- dimethoxyphenyl)-2-(4-methoxyphenyl)-3-oxopropionic acid methyl ester.

18. Compound according to claim 16, wherein said compound is 3-(3,5- dimethoxyphenyl)-2-(4-methoxyphenyl)-3-oxopropionic acid ethyl ester.

19. A process for the preparation of resveratrol, comprising the steps of

a) reacting a compound according to formula VI

(VI),

with a compound according to formula VII

(VII)

to form a compound according to formula VIII

(VIII)

b) optionally converting the (Z)-isomer of the compound according to formula VIII to its (£)-isomer,

and, if necessary, c) deprotecting of the compound according to formula VIII to resveratrol,

wherein Ri, R₂, and R₃ independently from each other represent hydrogen, a (Ci- C₄)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl; (Ci-C₄)alkoxy-(C₁-C₄)alkyl group such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl; (Ci- C₄)alkoxy-(Ci-C₄)alkoxy-(Ci-C₄)alkyl group such as methoxyethoxymethyl, methoxyethoxyethyl; allyl, vinyl, silyl, formyl, acyl group such as acetyl, pro- panoyl, butanoyl or benzoyl; aryl-(Cl-C4)alkyl or substituted aryl-(Ci-C₄)alkyl group such as benzyl, phenethyl, diphenylmethyl, p-methoxybenzyl, p- nitrobenzyl, p-methylbenzyl or o-chlorobenzyl; and wherein Z represents chloro, bromo, iodo, triflate, hexaflate, nonaflate, tosylate, nosylate, or a diazonium group.

20. A process according to claim 19 wherein the compound according to formula VI and the compound according to formula VII are reacted in the presence of a catalyst.

21. A process according to claim 19 or 20, wherein Ri, R₂, and R₃ represent methyl.

22. A process according to any one of claims 19 to 21, wherein Z represents bromo, chloro, triflate or tosylate.

23. A process according to any one of claims 19 to 22, wherein the reaction step a) comprises 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) and wherein the Heck-type reaction is conducted in a suitable solvent in the presence of supported or non-supported catalyst or in the presence of a supported or non-supported catalyst complex, said complex containing one or more ligands, and in the presence of a base and optionally a salt.

24. A process according to claim 23, wherein the Heck-type reaction is conducted in the presence of supported or non-supported palladium catalyst or palladium catalyst complex, said complex containing a phosphine ligand, and in the presence of a base and optionally a salt.

25. A process according to any one of claims 19 to 24, wherein the solvent for said Heck-reaction is a dipolar aprotic solvent selected from dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and hexamethyl- phosphotriamide, or other polar solvents, such as acetonitrile, water or combinations thereof.

26. A process according to any one of claims 19 to 25, wherein the solvent for said Heck-reaction is water-free.

27. A process according to any one of claims 19 to 26, wherein the palladium metal is selected from Pd(O) and Pd(I) and Pd(II) salts or complexes.

28. A process according to any one of claims 19 to 27, wherein the phosphine ligand is selected from the group comprising tri-o-tolylphosphine, tri-o- furylphosphine triphenylphosphine, tris(2,4-dimethoxyphenyl), tris(2,4,6- trimethoxyphenyl)phosphine, 2-(dicyclohexylphosphino)biphenyl, 2-(di-t- butylphosphino)biphenyl, l,l '-bis(diphenylphosphino)ferrocene (dppf), (oxy-2,1- phenylene)bis(diphenylphosphine) (DPEPHOS), tricyclohexylphosphine, tri-t- butylphosphonium tetrafluoroborate, l,3-bis(diphenylphosphino)propane (dppp), and l,4-bis(diphenylphosphino)butane (dppb).

29. A process according to any one of claims 19 to 28, wherein the palladium metal and the phosphine ligand are added as a complex selected from di- chlorobis(tri-ortho-tolylphosphine)palladium (II), tetrakis(triphenylphosphine)- palladium (0), dibromobis(tri-tert-butylphosphine)dipalladium (I), di-μ-chlorobis- (tris(2,4-di-t-butylphenyl)phosphite-2-C,P)-dipalladium (II), bis(tri-tert-butyl- phosphine)palladium (0) or trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)- benzyl]dipalladium (II).

30. A process according to any one of claims 19 to 29, wherein the base is selected from amine bases, such as triethylamine, tributylamine, trimethylamine, ethyldiisopropylamine, or from alkali metal carboxylates or carbonate bases, such as sodium acetate, potassium acetate and cesium carbonate.

31. A process according to any one of claims 19 to 30, wherein a tetraal- kylammonium halide phase transfer catalyst is employed in the Heck reaction and is selected from tetrabutylammonium bromide, tetrabutyl ammonium chloride, benzyltriethylammonium chloride.

32. A process according to any one of claims 19 to 31, wherein an inorganic salt additive is employed in the Heck reaction and is selected from 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.

33. A compound of formula VI wherein Rj and R₂ independently from each other represent hydrogen, a (Cj-C-Oalkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl; (C₁-C₄)alkoxy-(C₁-C₄)alkyl group such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, eth- oxyethyl, ethoxypropyl; (C₁-C₄)alkoxy-(Ci-C₄)alkoxy-(C₁-C₄)alkyl group such as methoxyethoxymethyl, methoxyethoxyethyl; allyl, vinyl, silyl, formyl, acyl group such as acetyl, propanoyl, butanoyl or benzoyl; aryl-(Cl-C4)alkyl or substituted aryl-(Ci-C₄)alkyl group such as benzyl, phenethyl, diphenylmethyl, p- methoxybenzyl, p-nitrobenzyl, p-methylbenzyl or o-chlorobenzyl.

34. A compound of formula VI wherein R₁ and R₂ independently from each other represent hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl.

35. Process for the preparation of resveratrol, comprising the steps of

a) reacting a compound according to formula IX

(IX),

with a compound according to formula X

(X)

in presence of a suitable base in order to form a compound according to formula XI

(XI)

and, if necessary,

b) deprotecting of the compound according to formula XI to resveratrol,

wherein R₁, R₂, and R₃ independently from each other represent hydrogen, a (C₁- C4)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl; (C₁-C₄)alkoxy-(C₁-C₄)alkyl group such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl; (C₁- C₄)alkoxy-(Ci-C₄)alkoxy-(Ci-C₄)alkyl group such as methoxyethoxymethyl, methoxyethoxy ethyl; allyl, vinyl, silyl, formyl, acyl group such as acetyl, pro- panoyl, butanoyl or benzoyl; aryl-(Cl-C4)alkyl or substituted aryl-(Ci-C₄)alkyl group such as benzyl, phenethyl, diphenylmethyl, p-methoxybenzyl, p- nitrobenzyl, p-methylbenzyl, 2,6-dimethylbenzyl or o-chlorobenzyl; and wherein Y is the group P(O)(OR₄J₂, wherein R₄ is selected from (d-C₄)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl; and substituted or unsubstituted aryl or alkylaryl such as phenyl, benzyl, phenethyl, di- phenylmethyl, p-methoxybenzyl, p-nitrobenzyl, p-methylbenzyl or o- chlorobenzyl.

36. Process according to claim 35, wherein Ri, R₂, and R₃ independently from each other represent methyl, ethyl, phenyl or benzyl.

37. Process according to claim 35 or 36, wherein R₄ is selected from methyl, ethyl and phenyl.

38. Process according to any one of claims 35 to 37, wherein the base in reac- tion step a) is selected from lithiated bases, hydrides and alkoxides.

39. Process according to any one of claims 35 to 38, wherein the base in reaction step a) is selected from n-butyllithium, t-butyllithium, methylithium, phenylithium, lithiumhexamethyldisilazide, lithiumdiisopropylamide, sodium hydride, potassium hydride, calcium hydride, sodium methoxide, sodium ethox- ide, magnesium ethoxide and potassium tert-butoxide.

40. Process according to any one of claims 35 to 39, wherein the solvent for reaction step a) is selected from dimethylformamide, dimethyl acetamide, N- methylpyrrolidone, dimethylsulfoxide and hexamethylphosphotriamide, acetoni- trile, dioxane, dimethoxyethane and tetrahydrofuran.

41. Process according to any one of claims 35 to 40, wherein the yield of the reaction of step a) is 80 to 100 %, based on the amount of the employed Wittig reagent.

42. Process according to any one of claims 35 to 41, wherein the reaction product of step a) contains less than 5% (Z)-isomer of the compound of formula XI.

43. Compound of formula IX wherein Ri and R₂ independently from each other represent hydrogen, a (Cι-C₄)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl; (C_!-C₄)alkoxy-(Ci-C₄)alkyl group such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, eth- oxyethyl, ethoxypropyl; (C₁-C₄)alkoxy-(C₁-C₄)alkoxy-(Ci-C4)alkyl group such as methoxyethoxymethyl, methoxyethoxyethyl; allyl, vinyl, silyl, formyl, acyl group such as acetyl, propanoyl, butanoyl or benzoyl; aryl-(Cl-C4)alkyl or substituted aryl-(Ci-C₄)alkyl group such as benzyl, phenethyl, diphenylmethyl, p- methoxybenzyl, p-nitrobenzyl, p-methylbenzyl or o-chlorobenzyl.

44. Compound of formula IX wherein R₁ and R₂ independently from each other represent hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl.