WO2012003625A1

WO2012003625A1 - Process for preparing hydroxytyrosol

Info

Publication number: WO2012003625A1
Application number: PCT/CN2010/075006
Authority: WO
Inventors: Zhengyi Yang; Fengyu Tan; Heilam Wong; Paul Hanselmann
Original assignee: Lonza Ltd
Priority date: 2010-07-06
Filing date: 2010-07-06
Publication date: 2012-01-12
Also published as: CN103038203B; CN103038203A

Abstract

A process for preparing hydroxytyrosol from eugenol is disclosed. The eugenol can be converted to 4-(2-hydroxyethyl)-2-methoxyphenol, which is subsequently converted to hydroxytyrosol. The eugenol can also be initially demethylated, and the reaction product is subsequently converted to hydroxytyrosol. A process for producing 4-(2-hydroxyethyl)-2-methoxyphenol is also disclosed.

Description

PROCESS FOR PREPARING HYDROXYTYROSOL

The invention relates to a process for the production of hydroxytyrosol from eugenol. The invention also relates to a process for producing 4-(2-hydroxyethyl)-2-methoxyphenol.

Background of the invention

Hydroxytyrosol (3,4-dihydroxyphenylethanol; DOPET, CAS 10597-60-1) is a phy to chemical 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.

KR 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 hydro xytyrosol 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 hydroxy ethyl 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.

In summary, methods known in the art for producing hydroxytyrosol by organic synthesis are often tedious and also expensive. Further, they use starting materials which are often not readily available. Some reactions require high temperatures or pressure, which further increases the energy

consumption and costs.

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. Toxic side products, which are not desirable in a food additive, shall be avoided. Since reactions under mild conditions are

environmentally friendly, the problem underlying the invention is thus also to provide a method which does not affect the environment. 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 hydroxytyrosol, wherein eugenol is used as a starting material.

Eugenol (4-allyl-2-methoxyphenol; 2-methoxy-4-(2-propenyl)phenol; CAS 97-53-0^") is an allyl chain-substituted guaiacol. It is a member of the phenylpropanoids class of chemical compounds. It is an oily liquid an can be extracted from natural oils, such as clove oil, nutmeg, cinnamon, basil and bay leaf. Eugenol is available in large amounts and relatively inexpensive.

In a preferred embodiment of the invention, the eugenol is converted to 4-(2-hydroxyethyl)-2- methoxyphenol, which is subsequently converted to hydroxytyrosol.

In the overall reaction, the methoxy group of eugenol is converted to a hydro xyl group and the 4- allyl-group is converted to a 4-(2-hydroxyethyl) group.

Preferably, the process comprises a step

(a) oxidation of the allylic double bond of eugenol.

In the oxidation step (a), a mild oxidation of the allyl group is carried out. An oxidized intermediate is obtained. In the oxidation step, the allylic double bond of eugenol is cleaved or not cleaved and partially oxidized. The C=C double bond of the allyl group can be oxidatively cleaved into a substituted phenylacetaldehyde and formaldehyde. Alternatively, an oxidative addition to the C=C double bond can be carried out to yield an oxidized intermediate, such as a 1,2-diol, a derivative thereof, a 1,2-dihalide or a 2-haloethanol. After optional conversion of the halides into hydro xyl groups, the intermediate may be cleaved into a substituted phenylacetaldehyde. Preferably, the reagents and reaction conditions are chosen such that a selective transformation of the C=C double bond of eugenol occurs, while the remainder of the molecule, such as the methoxy group, remains unmodified.

In a preferred embodiment of the invention, the oxidation step (a) is carried out in the presence of an oxidizing agent selected from ozone, hydrogen peroxide, KMn0₄, Os0₄, Pd(II) salts in combination with oxygen (preferably as described in J. Am. Chem. Soc. 2009, 3848), halogens, optionally in the presence of water, Ru0₄ and Cr0₃. From the oxidizing agents, ozone is preferred, because it enables a clean, selective oxidative cleavage of the C=C double bond in eugenol, and does not lead to the formation of toxic by-products.

It was found that the ozonolysis of eugenol proceeds in higher yield when conducted in the presence of a base. Thus the oxidation step (a) is preferably carried out in the presence of a catalytic amount of a base. In specific embodiments, the base is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, phosphates and carboxylates, such as acetates, oxalates, formats and propionates. Specific examples include, but are not limited to, Ca(OH)₂, NaOH, MgC0₃, Na₃P0₄, sodium acetate, sodium oxalate and sodium formate. Preferably, the base is a carbonate or bicarbonate such as Na₂C0₃, K₂C0₃ or NaHC0₃.

In a preferred embodiment of the invention, the oxidation step (a) is followed by a step

(b) reduction of the reaction product with a reducing agent to obtain 4-(2-hydroxyethyl)-2-methoxyphenol.

The reducing agent can be any agent capable of reducing the oxidized intermediate resulting from step (a) to the 2-hydroxyalkyl compound. For example, the reducing agent may be a boron hydride, an aluminum hydride, a metal, such as sodium, aluminum, zinc or magnesium, an organic hydride source, such as a dihydropyridine or isopropanolate, or hydrogen in the presence of a hydrogenation catalyst.

In a preferred embodiment, the reduction of the phenylacetaldehyde resulting from step (a) to the corresponding alcohol is performed by catalytic hydrogenation in the presence of a catalyst selected from palladium, rhodium, ruthenium, platinum and nickel. Optionally, the hydrogenation catalyst is supported by a carrier, such as carbon or BaS0₄. The hydrogenation is carried out in a suitable solvent, such as water, alcohols, esters, ethers, carboxylic acids, or mixtures thereof. Preferably, the reaction is carried out at room temperature or at a higher temperature. In a further preferred embodiment of the invention, the reducing agent is selected from sodium, AIH3, B2H4, LiBH₄, KBH₄, NaBH₄, and L1AIH4.

In a preferred embodiment, the oxidation step (a) is carried out with ozone as the oxidizing agent and the subsequent reduction step (b) is carried out with NaBH₄ as the reducing agent. After the oxidation step (a), which preferably is followed by the reduction step (b), 4-(2-hydroxyethyl)-2- methoxyphenol (homovanillyl alcohol) is obtained.

In a preferred embodiment of the invention, the oxidation step (a) and/or the reduction step (b) are carried out in a solvent selected from methanol, dichloromethane, methylenechloride, ethanol, ethylacetate and mixtures thereof. In a preferred embodiment, the solvent is a mixture of methanol and dichloromethane. Preferably, the mixture is in a ratio between 1 :4 and 4: 1, preferably 1 : 1.

In a preferred embodiment of the invention, the oxidation step (a) and/or the reduction step (b) are carried out at a temperature below 25°C or below 0°C, preferably below 50°C. In a preferred embodiment, the oxidant is ozone and the oxidation is carried out at -78°C.

In a preferred embodiment of the invention, the oxidation step (a) and the reduction step (b) are carried out in the same reaction batch. Preferably, the reducing agent is added directly to the reaction mixture after the oxidation step (a). In this embodiment, an intermediate isolation of the oxidation product is not necessary.

Another subject of the invention is a process for the production of 4-(2-hydroxyethyl)-2- methoxyphenol from eugenol. As shown above, homovanillyl alcohol is a valuable intermediate in the synthesis of hydroxytyrosol. Further, homovanillyl alcohol is itself a valuable compound which can be used as an antioxidant or as a starting material for synthesizing other hydroxytyrosol derivatives.

In a preferred embodiment of the invention, the reduction step (b) is followed by a step

(c) demethylation of the 4-(2- hydroxyethy l)-2 -methoxyphenol . Preferably, the methoxy group is converted to the hydroxyl group without affecting the other two hydroxyl groups of the starting material.

The conversion of methoxyarenes into phenols can be accomplished with various reagents, either under acidic or basic reaction conditions. 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. Acidic conditions include treatment with HC1, HBr, or HI.

In a preferred embodiment of the invention, the nucleophilic cleavage of the methoxy group is carried out with a nucleophile selected from NaCN, Nal, thiourea, 2-mercaptobenzothiazole, sodium or potassium Ν,Ν-diethyldithiocarbamate (Et2N-C(=S)-SM; M = Na, K), cysteine, methionine, or an alkylmercaptane.

In a preferred embodiment of the invention, the demethylation step (c) 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 demethylations 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 AICI3 and ethanethiol.

Preferably, the metal alkoxide is sodium methoxide, the metal thiolate is sodium ethanethiolate and the thiol is ethanethiol or 1 -dodecanethiol.

In a preferred embodiment of the invention, the process comprises a step

(a) oxidation of the double-bond of eugenol with ozone,

(b) reduction of the reaction product with a reducing agent, preferably NaBFL, and (c) demethylation of the 4-(2- hydroxyethol)-2-methoxyphenol obtained in step (b) with a metal halide and thiol, preferably aluminum chloride and ethanethiol.

As outlined above, it is preferred that the oxidation step (a) in the present inventive process is carried out with ozone. The ozone is preferably bubbled through the reaction mixture at a predetermined rate whilst stirring. After a reaction time of preferably between 30 minutes and 5 hours, more preferably between 1 and 3 hours, the ozone addition is stopped. Preferably, the residual ozone is removed with an inert gas. Subsequently, the reducing agent is added in order to convert the intermediate product to the ethylhydroxy compound. The ozone reaction is preferably carried out at a temperature below 0°C or below -50°C.

In a preferred embodiment, the reduction step (b) is carried out whilst the temperature is increased to room temperature. In general, it is preferred that the reduction step (b) is carried out at a temperature below 25°C. It is further preferred that the intermediate product is extracted with an organic solvent.

When converting the intermediate hydroxyethyl compound to hydroxytyrosol, it is preferred to provide at first a solution or suspension of the metal halide in the thiol. Subsequently, the hydroxyethyl intermediate is added slowly. It is preferred that the demethylation reaction is carried out at a temperature below 50°C, preferably at room temperature. The reaction time could be between 30 minutes and 72 hours, preferably between 10 and 50 hours. Preferably, the product is extracted with an organic solvent, such as ethyl acetate.

In another embodiment of the invention, the eugenol is demethylated in a first step and the reaction product is subsequently converted to hydroxytyrosol. For the demethylation reaction, the conditions and reactants disclosed above for step (c) can be used. As a result, 4-allyl-2-hydroxyphenol is obtained. This intermediate can be further converted to hydroxytyrosol by oxidation and optionally reduction, preferably according to steps (a) and (b) as outlined above.

Preferably, the overall yield of the conversion of eugenol to hydroxytyrosol according to the present invention is at least 60%, more preferably at least 70% or 80%.

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 in an efficient and mild reaction and at a relatively high yield. The starting compound is the natural product eugenol, which is readily available and relatively inexpensive. The reaction only requires a limited number of process steps. In this respect, the oxidation (a) and reduction (b) can be carried out subsequently in the same batch and thus could be considered as one reaction step.

The method can be performed with reagents and catalysts which are readily available, inexpensive and relatively innoxious in food applications.

Further, the intermediate homovanillyl alcohol can be obtained in a simple and efficient reaction.

The inventive process does not require harsh reaction conditions. The process steps can be carried out at room temperature or lower 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, especially when using ozone as the oxidizing agent. Since the inventive process uses mild chemicals and does not require high energy consumption, the overall process is environmentally friendly. Since the starting compound eugenol is a natural product, the overall process avoids petroleum-derived starting materials and is sustainable.

Examples

Ozonolysis Route:

OH

Hydroxytyrosol

Scheme 1: Example of ozonolysis reaction route

Example 1 : Preparation of 4-(2-hydroxyethyl)-2-methoxyphenol (12) from eugenol

Into a solution of eugenol (5.0 g, 30.5 mmol) and a catalytic amount of NaHCC"3 (0.1 g) in methanol-dichloromethane (1 : 1 , 200 mL), ozone gas was bubbled at -78 °C. After 2.0 h of stirring at that temperature, the ozone was replaced by nitrogen. After 15 min, NaBH₄ (1.21 g, 32 mmol, 1.05 equiv) was added in portions to the reaction mixture. When the addition was finished, the dry ice-acetone bath was removed and the reaction mixture was slowly warmed to room temperature. After stirring at room temperature for 2 h, the solvent was evaporated under reduced pressure. Brine (100 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 100 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated to give an orange oil (4.0 g, 80 %). ¾ NMR (400 MHz, DMSO-d6): δ 8.64 (br s, 1 H), 6.76 (d, J = 2.0 Hz, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 6.58 (dd, J = 8.0, 2.0 Hz, 1 H), 4.56 (t, J = 5.1 Hz, 1 H, -OH), 3.74 (s, 3 H), 3.55 (m, 2 H), 2.61 (t, J = 7.3 Hz, 2 H). ¹³C NMR (100 MHz, DMSO-d6): δ 147.4, 144.8, 130.4, 121.1, 1 15.4, 113.2, 62.7, 55.6, 38.8.

Example 2: Preparation of hydroxytyrosol from 4-(2-hydroxyethyl)-2-methoxyphenol (12

To a stirred solution of aluminum chloride (3.1 g, 23.3 mmol, 4.0 equiv) in ethanethiol (16 mL) cooled in an ice-water bath was added 4-(2-hydroxy-ethyl)-2-methoxyphenol (0.99 g, 5.9 mmol). The reaction was stirred at 0 °C for 2 h and at room temperature for 40 h. The reaction was poured into ice water (50 mL) and acidified with dilute HC1 (10 mL). Ethanethiol was removed by evaporation and brine was added. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated to give a red oil (0.86 g, 94.7 %). Ή NMR (400 MHz, DMSO-d6): 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). ¹³C NMR (100 MHz, DMSO-d6): δ 144.9, 143.4, 130.31, 119.6, 116.4, 1 15.5, 62.7, 38.6.

Claims

1 . A process for the production of hydroxytyrosol, wherein eugenol is used as a starting material.

2. The process of claim 1 , wherein the eugenol is converted to 4-(2-hydroxyethyl)-2-methoxyphenol, which is subsequently converted to hydroxytyrosol.

3. The process of claim 1 or 2, comprising a step

(a) oxidation of the allylic double bond of eugenol.

4. The process of claim 3, wherein the oxidation step (a) is carried out in the presence of an oxidizing agent selected from ozone, hydrogen peroxide, KMnC , OsC Pd(ll) salts in combination with oxygen, halogens, RuC and OO3.

5. The process of at least one of claims 3 and 4, wherein the oxidation step (a) is carried out in the presence of a catalytic amount of a base, preferably an alkali or alkaline earth metal hydroxide, carbonate, bicarbonate, phosphate or carboxylate.

6. The process of at least one of claims 3 to 5, wherein the oxidation step (a) is followed by a step

(b) reduction of the reaction product with a reducing agent to obtain 4-(2-hydroxyethyl)-2- methoxyphenol.

7. The process of claim 6, wherein the reducing agent is selected from a boron hydride, such as NaBhU, an aluminum hydride, such as LiAlhU, a metal, such as sodium, aluminum, zinc or magnesium, an organic hydride source, such as a dihydropyridine or isopropanolate, and hydrogen in the presence of a hydrogenation catalyst.

8. The process of at least one of claims 3 to 7, wherein the oxidation step (a) and/or the reduction step (b) are carried out in a solvent selected from methanol, dichloromethane, methylenechloride, ethanol, ethylacetate and mixtures thereof.

9. The process of at least one of claims 3 to 8, wherein the oxidation step (a) and/or the reduction step (b) are carried out at a temperature below 25°C, preferably below 0 °C.

10. The process of at least one of claims 6 to 9, wherein the oxidation step (a) and the reduction step (b) are carried out in the same reaction batch.

1 1. A process for the production of 4-(2-hydroxyethyl)-2-methoxyphenol according to any of claims 3 to10.

12. The process of at least one of claims 6 to 1 1 , wherein the reduction step (b) is followed by a step

(c) demethylation of the 4-(2-hydroxyethyl)-2-methoxyphenol.

13. The process of claim 12, wherein the demethylation step (c) is carried out in the presence of a thiol in combination with a Lewis acid , a metal thiolate and/or a metal alkoxide.

14. The process of claim 12 or 13, wherein the demethylation step (c) is carried out in the presence of AlC and ethanethiol.

15. The process of claim 1 , wherein the eugenol is demethylated in a first step and wherein the reaction product is subsequently converted to hydroxytyrosol.