ORGANOMETALLIC COMPOUNDS

The invention relates to a process for the production of 4-(2-hydroxyalkyl)-l ,2-benzenediols, such as hydroxytyrosol.

Background of the invention

Hydroxytyrosol (4-(2-hydroxyethyl)-l,2-benzenediol; 3 ,4-dihydroxyphenyl-ethanol; DOPET, CAS 10597-60-1) is a phytochemical with strong antioxidant properties. In nature, hydroxytyrosol is found in olive oil in the form of its elenolic acid ester oleuropein and, especially after degradation, in its plain form. The olives, leaves and olive pulp contain small amounts of hydroxytyrosol, which can be recovered to produce hydroxytyrosol extracts. Hydroxytyrosol has been demonstrated to be a monoamine oxidase inhibitor (MAOI). It functions as a potent inhibitor of monoamine oxidase B. Hydroxytyrosol is also a metabolite of the neurotransmitter dopamine. Pharmacological functions of hydroxytyrosol are anti-inflammatory, vasodilatory, antihypertensive, antimicrobial and fungicide properties. Hydroxytyrosol also prevents thrombocyte aggregation and improves cognitive functions. Thus hydroxytyrosol can be used for various pharmaceutical uses and as a food supplement.

Besides isolating natural hydroxytyrosol from plants, it is desirable to provide an efficient organic synthesis route. Various methods for the synthesis of hydroxytyrosol have been described in the art.

WO2008/107109 discloses a method for the synthesis of hydroxytyrosol from 4- (chloroacetyl)catechol, which is reduced by hydrogenation in the presence of a metal catalyst, such as a palladium/carbon catalyst. The catechol precursor is synthesized in a reaction, which requires enhanced temperatures above 100°C for extended times.

WO 2007/009590 Al discloses a method, in which hydroxytyrosol is obtained from 3,4- dihydroxymandelic acid. The acid precursor is reduced by hydrogenation in the presence of a metal catalyst, such as a palladium/carbon catalyst, to yield a phenylacetic acid, followed by a reduction step. R 2007 038702 A discloses a method for obtaining hydroxytyrosol from styrene oxide. The precursor is reduced with hydrogen in the presence of a metal catalyst, such as a palladium/carbon catalyst.

In the hydrogenation reactions mentioned above, acid or ester analogues of hydroxytyrosol are reduced. Since this usually requires precious metal catalysts, the reactions are relatively expensive. Further, in the production of food ingredients and pharmaceuticals, there is generally a desire to avoid these metal catalysts, which subsequently have to be removed from the product.

Other methods have been described in the art, which start from 2-hydroxyethylphenol precursors and in which phenol substituents are introduced or modified.

WO 2008/110908 Al discloses a method starting from tyrosol. After protecting the hydroxyethyl group, a second hydroxyl group is introduced into the phenol ring. After deprotection,

hydroxytyrosol is obtained. However, the reaction starts from tyrosol, which is closely related to hydroxytyrosol and which is an expensive food additive. Further, due to the protection and deprotection step, the synthesis is inefficient.

WO 2009/153374 discloses a method starting from safrol. However, safrol is expensive and also toxic, and the method requires carcinogenic hexamethylphosphoric triamide (HMPT) in the last step.

Since hydroxytyrosol is a valuable pharmaceutical and food additive, there is a need for efficient synthesis methods. Besides, methods known in the art for producing hydroxytyrosol by organic synthesis are often tedious and expensive. Often starting materials are used, which are not readily available. Some reactions require high temperatures or pressure, which increases the energy consumption and costs. There is also a need for simple and efficient methods for the production of analogues having different β-hydroxy alkyl side chains.

Problem underlying the invention

The problem underlying the invention is to provide a method for producing hydroxytyrosol, which overcomes the above-mentioned problems. The invention shall provide a simple and efficient method for producing hydroxytyrosol. The yield of hydroxytyrosol shall be high. The process shall be applicable under mild conditions and with a low number of process steps. The starting materials, catalysts and further reagents used shall be easily available. The use of precious metals, such as platinum, shall be avoided. Specifically, a reaction shall be provided which allows the production of hydroxytyrosol derivatives, especially 4-(2-hydroxyalkyl)-l ,2-benzenediol.

Disclosure of the invention

Surprisingly, the problem underlying the invention is solved by the process according to the claims. Further inventive embodiments are disclosed throughout the description.

Subject of the invention is a process for the production of a 4-(2-hydroxyalkyl)-l,2-benzenediol, comprising the steps of

(a) providing protected 1,2-benzenediol having the 1 ,2-hydroxyl groups protected,

(b) halogenating the protected 1 ,2-benzenediol to obtain a protected 4-halo- 1 ,2-benzenediol having the 1,2-hydroxyl groups protected,

(c) reacting, in the presence of a metal or organometallic compound, the protected 4-halo-l,2- benzenediol to protected 4-(2-hydroxyalkyl)-l ,2-benzenediol having the 1 ,2-hydroxyl groups protected,

(d) deprotecting the protected 4-(2-hydroxyalkyl)-l,2-benzenediol to obtain the 4-(2- hydroxyalkyl)-l ,2-benzenediol.

The alkyl moiety may be linear, branched or cyclic. It may comprise 1 to 20, preferably 2 to 10 or 2 to 6 carbon atoms. Preferably, the 2-hydroxyalkyl moiety in the product is a hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl group. In a preferred embodiment of the invention, the 4-(2-hydroxyalkyl)-l ,2-benzenediol is hydroxytyrosol.

The trivial name for 1,2-dihydroxybenzene is catechol. Catechol is produced in basic industrial processes and available in high amounts.

In step (a), a protected 1,2-benzenediol (catechol) derivative is used, which has the 1,2-hydroxyl groups protected with an appropriate protective group. Protective groups are covalently attached to the oxygen of the 1,2-hydroxyl group and replace the hydrogen atoms. The protective group can be any known protective group, which is stable in the subsequent halogenating step (b). Protecting groups can be attached to the 1,2-hydroxyl groups through reactions with protective agents. Appropriate protective groups, protective agents and reactions with aromatic hydroxyl groups are known in the art (see for example T.W. Green, P.G.M. Wuts,

Protective Groups in Organic Synthesis, 2nd edition, Wiley Interscience 1991).

In a preferred embodiment of the invention, the process comprises before step (a) an additional step (al) reacting 1,2-benzenediol with a protective agent to obtain a protected 1,2-benzenediol having the 1,2-hydroxyl groups protected.

Alternatively, a protected 1,2-benzendilol is selected which is available from other sources, such as natural sources or fractionation of mineral oil, or commercially available.

In preferred embodiments of the invention, the protective groups are independently selected from alkyl, alkylidene, preferably methylene, cycloalkylidene, alkylene, cycloalkyl, acyl, acetyl, alkoxyalkyl, alkoxycarbonyl, dialkylaminocarbonyl, methanesulfonyl, benzenesulfonyl, 4- toluenesulfonyl, silyl, trityl. benzoyl, benzyl, benzyl substituted with lower alkyl or lower alkoxy, β-methoxyethoxymethyl (MEM), methoxymethyl (MOM), methoxytrityl (MMT), p-methoxybenzyl (PMB), methylthiomethyl, tetrahydropyran-2-yl and pivaloyl. The alkyl, alkoxy, alkylene groups etc. may be linear, branched or cyclic, and/or substituted with heteroatomic groups, such as halogen, amine, hydroxyl, thiol etc. The groups may comprise 1 to 20, preferably 1 to 10 or 1 to 6 carbon atoms.

Although it is generally more practical, it is not necessary to attach the same protective groups to each hydroxyl group. When the protective group is alkyl, the catechol derivative provided in step (a) is a dialkoxy compound.

The protective group may be an alkyl group. As an example, when the protective groups are methyl group, the protected catechol derivative is an ether comprising two methoxy groups instead of the hydroxyl groups. Preferred alkyl groups are methyl, ethyl, propyl and isobutyl groups. For example, alkyl protective groups can be introduced through SN2 reactions with alkyl halides.

The protective group may be an alkylidene group. An alkylidene group bridges both oxygen atoms of the catechol 1,2 hydroxyl groups. The catechol derivative protected with an alkylidene group comprises a phenyl ring and a second ring, the latter formed of the two oxygen atoms, the two adjacent arylic carbon atoms and the alkylidene group. The alkylidene group may be a methylene, ethylidene or propylidene group. In a preferred embodiment of the invention, both oxygen atoms of the hydroxyl groups are bridged by a methylene group. The one or more carbon atoms bridging the oxygen atoms may be substituted once or twice, preferably with lower alkyl groups, such as methyl or ethyl groups. Thus, the protective group may be isopropylidene (dimethylmethylene), 2- pentylidene (methylpropylmethylene) or 3-pentylidene (diethylmethylene).

In a preferred embodiment of the invention, the protective agent is an aldehyde or ketone. The aldehyde or ketone reacts with the two hydroxy groups to form an acetal. In accordance with the standard nomenclature, the term "acetal" as used herein relates to the reaction products of aldehydes and ketones and comprises "ketals". The protected 1,2-benzendiol used in step (a) and (b) is preferably an acetal. The protective group linking the two oxygen atoms is a methylene group, which is not substituted when derived from formaldehyde, or a methylene group substituted with one residue when derived from an aldehyde, or substituted with two residues, when derived from a ketone.

The protective group may be a cycloalkylidene group, such as cyclopentylidene, cyclohexylidene or cyclobutylidene, optionally substituted once or several times with lower alkyl. The protective group is a cycloalkylidene group, when being derived from a cyclic ketone as protective agent.

A methylene or substituted methylene protective group is preferred, because the protected acetal for step (a) is obtainable relatively conveniently. The reaction of the dihydroxy compound with the aldehyde or ketone can be carried out in a simple acid catalysed reaction. Alkylidene and cycloalkylidene protective groups are further preferred, because it was found that they can be cleaved off in step (d) under mild conditions, for example by treatment with an acid.

Catechol derivatives having the 1,2-hydroxyl groups protected are known in the art. For example, veratrol (1,2-dimethoxybenzene), which has both hydroxyl groups of catechol protected with methyl groups, can be used as a protected starting compound in steps (a) and (b). In preferred embodiments of the invention, the catechol having the 1,2-hydroxyl groups protected is selected from veratrole, 2,2-dimethylbenzo-[l,3]-dioxole, 1 ,2 -dibenzyloxy benzene and spiro[l,3- benzodioxole-2,1 '-cyclohexane]. In halogenation step (b), a halogen atom is selectively introduced in the 4-position of the benzyl ring of the protected catechol derivative. Preferably, the halogenation is carried out without affecting the protective groups or other groups of the substrate.

In a preferred embodiment of the invention, the halogenation step (b) is carried out in the presence of a halogenation agent. Preferably, the halogenation reaction is carried out in the presence of a strong oxidant, preferably a peroxide, preferably hydrogen peroxide. Preferably, the brominating agent is selected from Bn, NaOBr, N-bromosuccinimide, N-bromodimethylhydantoin, NH4Br or other bromide salts, which are preferably used in the presence of an oxidant, preferably a strong oxidant, such as hydrogen peroxide. Other halogenation agents are NH4CI, preferably used in the presence of hydrogen peroxide, N-chlorosuccinimide, NaOCl, Cl ₂ and I2. Preferably, the halogen is bromine and the halogenation agent is NH ₄ Br in combination with an oxidant. Especially preferred is a combination of ammonium bromide, potassium bromide, or sodium bromide with hydrogen peroxide. The ammonium halide may be diluted with acetic acid.

The halogenation reaction is carried out for an appropriate time, for example 1 to 40 hours or 5 to 25 hours. After the halogenation reaction, the product can be extracted, isolated, and purified using standard techniques.

In step (c), the 4-haloatom is replaced by a 2-hydroxyalkyl group, preferably a 2-hydroxyethyl group. According to the invention, it was found that the 2 rydroxylalkyl moiety can be introduced by a Grignard reaction or a corresponding organometallic reaction in the presence of a metal or organometallic compound. At first, a reactive metal or an organometallic reagent, such as butyllithium or an isopropylmagnesium halide, is added to the halogenated substrate in order to induce a halogen-metal exchange. Preferably, the organometallic reagent comprises 3 to 6 carbon atoms. An organometallic metal halide intermediate is thus obtained. Subsequently, an alkyl reactant is added, such as alkylene oxide. In principle, organometallic reactions and Grignard reactions are known in the art. They are described in detail in the literature, for example Omae, "Applications of Organometallic Compounds", 1 ^st edition 1998, editor Wiley-VCH. The skilled person thus may select appropriate metals, solvents, process conditions and optionally additives.

In a preferred embodiment of the invention, the metal in step (c) is selected from magnesium, lithium, aluminum, calcium and zinc. In a further preferred embodiment, the organometallic reagent is butyllithium or an isopropylmagnesium halide. Step (c) is conducted in an appropriate solvent, preferably an ether, such as tetrahydrofuran (THF). Optionally, step (c) is carried out in the presence of a catalyst, such as TiCU, BiCb, PbCb, iodine or 1,2-dibromoethane, and/or in the presence of an additive, such as LiCl or hexamethylphosphoric acid triamide.

The halogen-metal exchange may be performed at low temperatures below 10°C, such as -78 °C or at 0 °C. Alternatively, the reaction may be carried out at room temperature or higher temperature, for example at 66 °C or even higher temperatures. Optionally, ultrasound is applied to accelerate the reaction or pressure to increase the reaction temperature above the atmospheric boiling point of the solvent chosen.

In a further embodiment, after an initial halogen-metal exchange with a reactive metal, such as lithium, magnesium or aluminum, a transmetallation to a less reactive metal, such as zinc, titanium, or zirconium, is performed by addition of an alkoxide, sulfonate, or halide salt of said less reactive metal to the reaction mixture. Such transmetallations may improve the yield of the final hydroxyethylated product.

After formation of the organometallic intermediate, the reactive alkyl compound is added. In a preferred embodiment of the invention, the alkyl reactant is an alkylene oxide. Preferably, a reactive ethyl compound is used, such as ethylene oxide or a synthetic equivalent thereof, such as ethylene carbonate, l-bromo-2-benzyloxyethane, 1 -bromo-2-tert-butyloxyethane or other related reagents. Most preferred is the use of ethylene oxide. Preferably, the metal is magnesium and the reactant is ethylene oxide.

In step (d), the protective groups are cleaved off. As a result, the corresponding 1 ,2-dihydroxy compound is obtained. Preferably, the deprotecting step (d) does not affect the residual molecule.

In preferred embodiments of the invention, the deprotection step (d) is carried out in the presence of an acid, a base, a nucleophile and/or a combination of molecular hydrogen and a suitable catalyst. The selection of the deprotecting agent and process conditions depends on the specific protective groups.

Alkylidene and cycloalkylidene protective groups (acetals) can be hydrolyzed by treatment with a weak acid, such as dilute hydrochloric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, optionally diluted with a suitable solvent. Alternatively, a //%%y-acetalization may be performed by treating the acetal with a ketone (such as acetone or methylethylketone) in the presence of catalytic amounts of an acid, such as sulfuric acid or 4-toluenesulfonic acid. When using a carboxylic acid as deprotection reagent, acylation of the resulting phenol or the hydroxyethyl group may occur and necessitate an additional saponification (e.g. treatment with NaOH) to generate the desired alcohol.

In a preferred embodiment, the protective group is a cycloalkylidene group and the deprotection is carried out by the acetolysis with acetic acid followed by saponification with sodium hydroxide.

Alternatively, the deprotection step (d) can be carried out with molecular hydrogen in the presence of a metal catalyst. This method is preferred if the protective agent is a benzyl group, for example an unsubstituted benzyl group or a substituted benzyl group, such as a methylated or alkoxylated benzyl group.

It was found that alkyl groups and cycloalkyl groups can be cleaved off in the presence of a strong acid or a strong nucleophile. Preferred acids used in this reaction step are aluminum chloride or boron trihalides.

Nucleophilic cleavage of methoxy groups can be attained by treatment with strong nucleophiles, such as thioethers, thiols, cyanide, or iodide, e.g. sodium iodide in pyridine or another suitable solvent. Nucleophilic cleavage can be carried out under acidic conditions. Acidic conditions include treatment with HC1, HBr, or HI. The use of nucleophilic cleavage agents is especially preferred if the protective groups are alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl or cycloalkyl groups.

In a preferred embodiment of the invention, the nucleophilic cleavage of the alkoxy group is carried out with a nucleophile selected from NaCN, Nal, thiourea, 2-mercaptobenzothiazole, sodium or potassium Ν,Ν-diethyldithiocarbamate (Et ₂ N-C(=S)-SM; M = Na, ), cysteine, methionine, or an alkylmercaptane .

In a preferred embodiment of the invention, the deprotection step (d) is carried out in the presence of a thiol in combination with a Lewis acid, a metal thiolate and/or a metal alkoxide. Especially preferred is a combination of a Lewis base and a thiol. This combination of a hard acid and a soft nucleophile is known in the art (Node et al., J. Org. Chem. 1980, 45, 4275-4277). Specific alkoxy cleavage methods with combinations of thiols and metal alkoxides or metal thiolates are known from Frey et al, Tetrahedron, 2003, 59, 6363-6373.

In a preferred embodiment of the invention, the Lewis acid is a metal halide, preferably AlCb or AlBr3, and the thiol is an alkanethiol, preferably ethanethiol or dodecanethiol. In a preferred embodiment of the invention, the demethylation is carried out in the presence of AlCb and ethanethiol. Preferably, the metal alkoxide is sodium methoxide, the metal thiolate is sodium ethanethiolate and the thiol is ethanethiol or 1 -dodecanethiol.

According to the invention, depending on the reactive alkyl species introduced into the benzene ring in step (c), catechol derivatives with various 4-(2-hydroxyalkyl) groups can be obtained. For example, the product can be 4-(2-hydroxypropyl)-l,2-benzenediol, 4-(2-hydroxybutyl)-l,2- benzenediol or 4-(2-hydroxydecyl)-l,2-benzenediol.

Another subject of the invention is a process for the production of hydroxytyrosol, comprising the steps of

(a) providing a protected 1 ,2-benzenediol having the 1 ,2-hydroxyl groups protected with alkyl, alkylidene or cycloalkylidene groups,

(b) halogenating the protected 1 ,2-benzenediol to obtain a 4-halo- 1,2-benzenediol having the 1,2-hydroxyl groups protected with alkyl, alkylidene or cycloalkylidene groups,

(c) reacting, in the presence of a metal, the 4-halo- 1,2-benzenediol into a protected 4-(2- hydroxyethyl)- 1 ,2-benzenediol, having the 1,2-hydroxyl groups protected with alkyl, alkylidene or cycloalkylidene groups,

(d) deprotecting the protected 4-(2-hydroxyethyl)-l,2-benzenediol to obtain hydroxytyrosol.

In this process, the reactants, conditions etc. are preferably selected as outlined above.

In preferred embodiments, the protective groups are alkyl groups and the halogenating step (b) is carried out in the presence of ammonium bromide and hydrogen peroxide followed by a Grignard reaction with magnesium and ethylene oxide. In this embodiment, the cleavage of the protective group is preferably carried out with aluminum chloride and ethanethiol.

In another preferred embodiment, the protective group is a 2,2-dimethyl methylene group, which can be introduced by treating catechol with acetone in the presence of catalytic amounts of an acid. In this embodiment, the halogenation is preferably carried out with ammonium bromide and hydrogen peroxide and a Grignard reaction is preferably carried out with magnesium and ethylene oxide. The deprotection step (d) is preferably carried out with acetic acid, followed by an optional saponification with a sodium hydroxide solution.

In another embodiment, the protective groups are benzyl groups, which can be attached to catechol by treatment of the latter with NaH and benzyl chloride. Preferably, the halogenation is carried out with ammonium bromide and hydrogen peroxide, and a Grignard reaction is carried out with magnesium and ethylene oxide. The deprotection step (d) is preferably carried out with hydrogen in the presence of a metal catalyst, such as palladium/carbon.

In another embodiment, the protected catechol in step (a) is preferably a cycloalkylidene acetal. In this embodiment, the protected catechol is a spiro-compound For example, catechol may be protected as a cycloalkylidene acetal by treating catechol with a cyclic ketone, preferably a cyclic alkanone, preferably cyclohexanone, in the presence of catalytic amounts of an acid. In this embodiment, the halogenation of the protected catechol is preferably carried out with ammonium bromide and hydrogen peroxide, and the Grignard reaction is preferably carried out with magnesium and ethylene oxide. The deprotection is preferably carried out by mild acidolysis.

In a preferred embodiment of the invention, the reaction steps (a) to (d) are carried out without intermediate purification of the reaction products. In other preferred embodiments, at least reaction steps (a) to (c) or (c) and (d) are carried out in one batch without intermediate isolation of the reaction product. Alternatively, intermediates obtained in step (b) and/or step (c) can be isolated and optionally purified.

After steps (b), (c) and/or (d), common treatments may be carried out to neutralize or remove residual reactants. The final product, and if desired also any intermediate products, can be isolated and purified by known methods, such as extraction, distillation, filtration or recrystallization.

Subject of the invention is also the use of protected 1,2-benzenediol having the 1 ,2-hydroxyl groups protected for the production of hydroxytyrosol. Preferably, the 1,2-hydroxyl groups are protected with groups selected from alkyl, alkylidene and cycloalkylidene. Preferably, the overall yield of 4-(2-hydroxyalkyl)-l,2-benzenediol, preferably hydroxytyrosol, is at least 20%, preferably at least 40%, more preferably at least 60%, most preferably at least 70% or 80%, based on the total amount of protected 1,2-benzenediol used in step (a) or based on the total amount of 1,2-benzenediol used in step (al).

The inventive process solves the problems underlying the invention. The invention provides a simple and efficient method for producing hydroxytyrosol. According to the invention,

hydroxytyrosol can be obtained using an efficient and mild reaction sequence and in a relatively high yield. The starting compound may be catechol, which is readily available and relatively inexpensive. The reaction only requires a low number of process steps.

The method can be performed with reagents and catalysts which are readily available and inexpensive.

The inventive process does not require harsh reaction conditions. The process steps can be carried out at low temperatures. It is not necessary to carry out reaction steps at high temperatures, high pressures or other extreme conditions. The inventive process can be carried out under mild conditions and without or with only low amounts of undesired side products.

Examples

Grignard route:

Veratrole 91 % 1 55 % 2

20 h Hydroxytyrosol

95.4 %

Scheme 1: Hydroxytyrosol synthesis according to examples 1 to 4.

Example 1 : Preparation of 4-bromo-1.2-dimethoxybenzene (1) from veratrole A 3.0 L reactor was charged with veratrole (142 g, 1.03 mol) and ammonium bromide (110 g, 1.12 mol, 1.10 equiv) in acetic acid (1.6 L). Aqueous hydrogen peroxide (30%) (180 mL, 1.76 mol, 1.67 equiv) was added dropwise to the reaction mixture and the contents allowed to stir at room temperature. After 20 h, the reaction mixture was treated with saturated sodium bicarbonate solution and extracted with dichloromethane (3 ^χ 200 mL). The combined organic extract was washed with water (2 ^χ 200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to give a yellow liquid. After distillation, the pure product (202.7 g, b.p. 128-133 °C/10 mbar, 91%) was obtained. ¾ NMR (400 MHz, DMSO-</_r): δ 7.09 (d, J= 2.0 Hz, 1 H), 7.05 (dd, J= 8.6, 2.0 Hz, 1 H), 6.9 (d, J= 8.6 Hz, 1 H), 3.76 (s, 3 H), 3.73 (s, 3 H). ¹³ C NMR (100 MHz, DMSO-«¾): δ 150.3, 148.8, 123.5, 115.3, 113.8, 112.3, 56.2, 56.0.

Example 2: Preparation of 2-(3.4-dimethoxyphenyl)ethanol (2) from 4-bromo-l ,2- dimethoxybenzene (1)

Magnesium turnings (3.9 g, 0.160 mol, 1.0 equiv) and I ₂ (5 mg) was charged to a 250 mL three- neck round-bottom flask, one neck of which was equipped with a cooling condenser, one with a dropping funnel, the other with a thermometer. The reaction system was protected with N2 gas. A small portion of 4-bromo-l,2-dimethoxybenzene (35 g, 0.155 mol) in anhydrous THF (160 mL) was added to the flask. After the reaction was initiated by heating the reaction mixture at 70 °C, the residual solution of the bromide was added slowly at a rate sufficient to maintain the reaction solution under slight reflux. When the addition was finished, the mixture was maintained at 70 °C for 2 h and then cooled to 0 °C. Ethylene oxide (15 mL, 0.30 mol, 2.0 equiv) was added dropwise and the reaction mixture was heated to 70 °C for 1 h. When a sticky gel hat formed, a saturated NH4CI solution (100 mL) was added. After phase separation, the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (2 * 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to give a red oil. Distillation yielded a colorless oil (15.3 g, b.p. 155-160 °C/10 mbar, 55%), which solidified upon standing. ¾ NMR (400 MHz, DMSO-^): δ 6.83 (d, J= 8.2 Hz, 1 H), 6.80 (d, J= 2.0 Hz, 1 H), 6.71 (dd, J= 8.2, 2.0 Hz, 1 H), 4.60 (t, J= 5.2 Hz, 1 H, -OH), 3.73 (s, 3 H), 3.70 (s, 3 H), 3.57 (m, 2 H), 2.65 (t, J= 7.2 Hz, 2 H). ¹³ C MR (100 MHz, DMSO-afc): δ 148.7, 147.2, 132.1, 120.7, 113.0, 112.0, 62.5, 55.6, 55.4, 38.7.

Example 3: Preparation of hydroxytyrosol from 2-(3.4-dimethoxyphenyl)-ethanol (2)

To a stirred solution of anhydrous aluminium chloride (29 g, 0.22 mol, 7.6 equiv) in ethanethiol (81 mL), cooled with an ice-water bath, was added 2-(3,4-dimethoxyphenyl)ethanol (5.2 g, 28.5 mmol). The mixture was stirred at 0 °C for 2 h and at room temperature for 1 h. The mixture was poured into ice water (100 mL) and acidified with dilute HC1 (20 mL). Ethanethiol was removed by evaporation and brine was added. The mixture was extracted with ethyl acetate (3 ^x 100 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated to give a red oil (4.2 g, 95%). 'H NMR (400 MHz, DMSO-/&): δ 8.69 (br s, 1 H), 8.59 (br s, 1 H), 6.60 (d, J= 7.8 Hz, 1 H), 6.58 (d, J= 2.0 Hz, 1 H), 6.42 (dd, J= 7.8, 2.0 Hz, 1 H), 4.55 (t, J= 5.2 Hz, 1 H, -OH), 3.50 (m, 2 H), 2.53 (t, J= 7.3 Hz, 2 H). ¹³ C NMR (100 MHz, DMSO-ofc): δ 144.9, 143.4, 130.31, 119.6, 116.4, 115.5, 62.7, 38.6.

2

Hydroxytyrosol

Scheme 2: Hydroxytyrosol synthesis according to examples 4 to 7

Example 4: Preparation of 2,2-dimethylbenzo-[l ,31-dioxole (3) from catechol

Phosphorus trichloride (11 g, 0.08 mol, 0.4 equiv) was added dropwise with stirring over a period of 20 min to a solution of catechol (22 g, 0.2 mol) and acetone (18 mL, 0.25 mol, 1.24 equiv) in toluene (40 mL). The reaction mixture was neutralized with triethylamine (20 mL) and washed with 10% aqueous NaOH (20 mL) and water (3 ^x 20 mL). The organic layer was dried over magnesium sulfate and vacuum-distilled. A colorless liquid (15.2 g, 50%), b.p.110-1 15 °C/20 mbar, was obtained. Ή NMR (400 MHz, DMSO-«¾): δ 6.78 (m, 4 H), 1.62 (s, 6 H).

Example 5: Preparation of 5-bromo-2.2-dimethylbenzo-[1.3]-dioxole (4) from 2.2-dimethylbenzo- ri .31-dioxole (3)

The method described in Example 1 is applied with the alteration that 21.58 g (0.144 moL) of 2, 2- dimethylbenzo-[l,3]-dioxole is used. After distillation, 28 g (85%) of pure product, b.p. 125-129 °C/ 8 mbar, was obtained. ¾ NMR (400 MHz, DMSO-«¾: δ 7.05 (d, J= 2.0 Hz, 1 H), 6.95 (dd, J= 8.0, 2.0 Hz, 1 H), 6.78 (d, J= 8.0 Hz, 1 H), 1.63 (s, 6 H). ¹³ C NMR (100 MHz, DMSO-^): δ 148.0, 146.4, 123.5, 119.0, 111.6, 11 1.5, 109.6, 25.3.

Example 6: Preparation of 2-(2.2-dimemylbenzo-[1.3]-dioxol-5-yl)-ethanol (5) from 5-bromo-2,2- dimethylbenzo-[1.31-dioxole (4)

Magnesium turnings (1.17 g, 49 mmol, 1.1 equiv) and h (10 mg) was charged into a 250 mL three- neck round-bottom flask, one neck of which was equipped with a cooling condenser, one with a charging funnel, the other with a thermometer. The reaction system was protected with N ₂ gas. A small portion of 5-bromo-2,2-dimethylbenzo-[l,3]-dioxole (10.2 g, 44.5 mmol) in anhydrous THF (50 mL) was added to the flask. After the reaction was initiated by heating the reaction mixture to 55 °C, the residual solution was added slowly at a rate sufficient to maintain the reaction solution under reflux slightly. When the addition was finished, the reaction was maintained at 55 °C for 2 h and then cooled to 0 °C. Ethylene oxide (10 mL, 0.2 mol, 4.4 equiv) was added dropwise and the reaction mixture was heated at 55 °C for 0.5 h. When a sticky gel had formed, a saturated NH4CI solution (100 mL) was added. After phase separation, the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to give a yellow oil. Distillation yielded a colorless oil (6.0 g, 70%). ¾ NMR (400 MHz, DMSO-<¾: δ 6.68 (d, J= 7.8 Hz, 1 H), 6.68 (d, J= 1.7 Hz, 1 H), 6.59 (dd, J= 7.8, 1.7 Hz, 1 H), 4.58 (t, J= 5.2 Hz, 1 H, -OH), 3.55 (m, 2 H), 2.61 (t, J= 7.1 Hz, 2 H), 1.60 (s, 6 H). ¹³ C NMR (100 MHz, DMSO- d6): δ 147.2, 145.5, 133.1, 121.5, 117.8, 109.5, 108.1, 62.9, 39.2, 26.0.

Example 7: Preparation of hydroxytyrosol from 2-(2,2-dimethylbenzo-rL31-dioxol-5-yl)ethanol (5) Into a 50 mL round-bottom flask, 2-(2,2-dimethylbenzo-[l,3]-dioxol-5-yl)-ethanol (1.76 g, 9.06 mmol), water (7 mL), and acetic acid (7 mL) were charged. The mixture was heated to 120 °C for 20 h. After evaporation of the solvent, a yellow oil was obtained, which was dissolved in water (10 mL) and 95% ethanol (10 mL), and then NaOH (1.17 g, 29 mmol, 3.2 equiv) was added. The mixture was stirred at room temperature for 3 h and acidified with 6 N HC1. Evaporation of the solvent under reduced pressure resulted in a gray solid, which was dissolved in ethyl acetate (20 mL). An insoluble solid was removed by filtration and the filtrate was concentrated to give a red oil (1.3 g, 94%). Ή NMR (400 MHz, DMSO-ώ): δ 8.69 (br s, 1 H), 8.59 (br s, 1 H), 6.60 (d, J= 7.8 Hz, 1 H), 6.58 (d, J= 2.0 Hz, 1 H), 6.42 (dd, J= 7.8, 2.0 Hz, 1 H), 4.55 (t, J= 5.2 Hz, 1 H, -OH), 3.50 (m, 2 H), 2.53 (t, J= 7.3 Hz, 2 H). ¹³ C NMR (100 MHz, DMSO-ώ): δ 144.9, 143.4, 130.31, 119.6, 116.4, 115.5, 62.7, 38.6.

Catechol 6

Combined Yield: 85 %

2)

32 % 8 96% Hydroxytyrosol

Scheme 3: Hydroxytyrosol synthesis according to examples 8 to 11.

Example 8: Preparation of 1, 2-dibenzyloxybenzene (6 from catechol

Into a 1.0 L round-bottom flask, catechol and DMF were charged. While stirring, NaH was added in portions whereby a solid precipitated. Benzyl chloride was added to the reaction solution and stirring at room temperature was continued for 3 h. Water was added to the reaction mixture, followed by extraction with ethyl acetate (3 ^χ 300 mL). The combined ethyl acetate extracts were washed with water (2 x 300 mL) and brine (150 mL), dried over anhydrous MgS04, and concentrated to give a brown solid (30 g), which was directly used in the next step without purification. ¾ NMR (400 MHz, DMSO-<¾): δ 7.28-7.50 (m, 10 H), 7.02-7.09 (m, 2 H), 6.85-6.91 (m, 2 H), 5.12 (s, 4 H).

Example 9: Preparation of 4-bromo-l .2-dibenzyloxybenzene (7) from 1.2-dibenzyloxybenzene (6) The method described in Example 1 was applied with the alteration that 30 g (0.1 moL) of 1,2- dibenzyloxybenzene was used. 32.8 g (85 %) of 4-bromo-l, 2-dibenzyloxybenzene was obtained. ^] H NMR (400 MHz, DMSO-d¾: δ 7.28-7.46 (m, 10 H), 7.23 (d, J= 2.2 Hz, 1 H), 7.05 (dd, J= 8.9, 2.2 Hz, 1 H), 7.00 (d, J= 8.9 Hz, 1 H), 5.14 (s, 2 H), 5.11 (s, 2 H). ¹³ C NMR (100 MHz, DMSO-/a¾): δ 149.3, 147.7, 136.8, 136.7, 128.3, 128.2, 127.7, 127.6, 127.4, 127.3, 123.6, 117.3, 116.1, 112.4, 70.3, 70.2. Example 10: Preparation of 2-(3,4-bis(benzyloxy)phenyl)ethanol (8) from 4-bromo-l,2- dibenzyloxybenzene (7)

The method described in Example 2 is applied with the alteration that 10.4 g (28.2 mmoL) of 4- bromo-l ,2-dibenzyloxybenzene and 10 mL (0.2 mol, 7.0 equiv) of ethylene oxide liquid are used. After purification by silica-gel chromatography, 3.0 g (32 %) of 2-(3,4-bisbenzyloxyphenyl)ethanol was obtained. ¾ NMR (400 MHz, DMSO-^): δ 7.30-7.50 (m, 10 H), 6.95 (d, J= 2.0 Hz, 1 H), 6.94 (d, J= 8.0 Hz, 1 H), 6.72 (dd, J= 8.0, 2.0 Hz, 1 H), 5.10 (s, 2 H), 5.08 (s, 2 H), 4.59 (t, J= 5.2 Hz, 1 H, -OH), 3.51-3.60 (m, 2 H), 2.64 (t, J= 12 Hz, 2 H). ¹³ C MR (100 MHz, DMSO-afc): δ 148.3, 146.7, 137.5, 137.4, 132.8, 128.3, 127.7, 127.6, 127.5, 127.4, 121.5, 115.6, 114.8, 70.4, 70.3, 62.4, 38.6.

Example 1 1: Preparation of hydro xytyrosol from 2-(3.4-bisbenzyloxy-phenyl)ethanol (8)

To a 50 mL round-bottom flask, 2-(3,4-bisbenzyloxyphenyl)ethanol (1.04 g, 3.11 mmol) and ethyl acetate (15 mL) were charged. The reaction system was protected by N ₂ gas and 10% Pd/C (0.33 g) was quickly added to the flask. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen gas (balloon) for 2 h. After filtration of the catalyst and evaporation of the solvent, 0.46 g (96%) of a light yellow oil was obtained.

¾ NMR (400 MHz, DMSO-<¾): δ 8.69 (br s, 1 H), 8.59 (br s, 1 H), 6.60 (d, J= 7.8 Hz, 1 H), 6.58 (d, J= 2.0 Hz, 1 H), 6.42 (dd, J= 7.8, 2.0 Hz, 1 H), 4.55 (t, J= 5.2 Hz, 1 H, -OH), 3.50 (m, 2 H), 2.53 (t, .7= 7.3 Hz, 2 H). ¹³ C NMR (100 MHz, DMSO-«¾): δ 144.9, 143.4, 130.31, 119.6, 116.4, 115.5, 62.7, 38.6.

according to examples 12 and 13.

Example 12: Preparation of spiro[l,3-benzodioxole-2,l '-cyclohexane] (9) from catechol Catechol (10.9 g, 0.1 mol), cyclohexanone (10 g, 0.1 mol, 1.0 equiv), and p-toluenesulfonic acid (10 mg) were heated under reflux in toluene (100 mL) for 24 h. Water (1 mL) collected in the trap during this time. The cooled reaction mixture was extracted with 10% sodium hydroxide (50 mL), washed with water (2 ^χ 50 mL) and dried (anhydrous Na2SC ). The solvent was removed to leave a yellow oil. Distillation gave a colorless oil (14.0 g, 74%), b.p.100-105 °C/ 5 mbar, which solidified on standing. 'H NMR (400 MHz, DMSO-ώ): δ 6.73-6.85 (m, 4 H), 1.82-1.89 (m, 4 H), 1.60-1.70 (m, 4 H), 1.42-1.50 (m, 2 H).

Example 13: Preparation of 5-bromospirori ,3-benzodioxole-2,l'-cvclohexanel (10) from spiro[l,3- benzodioxole-2.1 '-cyclohexane] (9)

The method described in Example 1 is applied with the alteration that 3.82 g (0.1 moL) of spiro[l,3-benzodioxole-2,l '-cyclohexane] was used. 5.0 g (92 %) of 5-bromospiro[l,3- benzodioxole-2,l'-cyclohexane] was obtained. 'H NMR (400 MHz, DMSO-<¾: 57.06 (d, J= 2.0 Hz, 1 H), 6.94 (dd, .7= 8.2, 2.0 Hz, 1 H), 6.80 (d, J= 8.2 Hz, 1 H), 1.82-1.89 (m, 4 H), 1.58-1.67 (m, 4 H), 1.40-1.48 (m, 2 H).