WO2017149017A1

WO2017149017A1 - Method for preparation of hydroxytyrosol

Info

Publication number: WO2017149017A1
Application number: PCT/EP2017/054780
Authority: WO
Inventors: Leo Schmid; Daniel Zollinger; Florencio ZARAGOZA
Original assignee: Lonza Ltd
Priority date: 2016-03-03
Filing date: 2017-03-01
Publication date: 2017-09-08
Also published as: TW201731806A

Abstract

The invention discloses a method for the preparation of (3,4-dihydroxyphenyl)acetic acid or its ester starting from the respective nitrile, and the conversion of (3,4-dihydroxyphenyl)acetic acid ester to hydroxytyrosol.

Description

Method for Preparation of Hydroxytyrosol

BACKGROUND OF THE INVENTION

Hydroxytyrosol is an antioxidant present in olive oil and is used as food supplement. US 2014/0256989 Al discloses a process for preparation of hydroxytyrosol by reaction of 2- (3,4-dimethoxyphenyl)ethanol with triisobutylaluminun. According to example 1 the reaction time is 20 h and the reaction is done under reflux in the solvent cumene, which has a boiling point of ca. 152°C. Gambacorta et al, Molecules, 2007, 12, 1762-1770, discloses the reduction of (3,4- dihydroxyphenyl)acetic acid methyl ester, wherein the two hydroxyl residues are protected by a prior reaction with orthoformate in form of an acetale, with L1AIH4. L1AIH4 is an expensive reagent, and the use of a protecting group requires additional steps and reagents, whereby the overall costs of the synthesis are increased.

WO 2008/136037 A2 disclose in Fig. 5 the reduction of (3,4-dihydroxyphenyl)acetic acid ethyl ester with sodium borohydride in water.

Bianco et al, Synthetic Communications, 1988, 18, 1765-1771, disclose the reduction of (3,4- dihydroxyphenyl)acetic acid methyl ester with sodium borohydride in water.

DE 37 37 825 Al discloses the didemethylation of homoveratronitril with pyridinium hydrochloride. However, no convenient preparation of (3,4-dihydroxyphenyl)acetic acid esters has been reported. Known syntheses are based on the enzymatic or electrochemical hydroxylation of phenylacetic acid or hydroxyphenylacetic acid, often product mixtures are obtained and such synthesis are not well suited for large scale preparation. There was a need for a method for preparation of hydroxytyrosol without the use of common disadvantages, such as the use of toxic reagents or intermediates, harsh reaction conditions or expensive reagents. Disclosed herein is a method for the preparation of (3,4-dihydroxyphenyl)acetic acid esters, which can be used as an intermediate in the preparation of hydroxytyrosol, the method starts from (3,4-dihydroxyphenyl)acetonitrile, and the subsequent conversion to hydroxytyrosol.

(3,4-Dihydroxyphenyl)acetonitrile is readily accessible by demethylation of

(3,4-dimethoxyphenyl)acetonitrile as disclosed in DE 37 37 825 Al .

(3,4-Dimethoxyphenyl)acetonitrile is a readily available intermediate for the industrial preparation of verapamil.

Thereby disadvantages of the known preparations methods can be avoided, for example readily available starting materials can be used, the method does not require enzymes, thiols, toxic solvents or expensive organometallic reagents, and the method is well suited for the large scale preparation of the intermediate and therefore also for the large scale preparation of hydroxytyrosol.

SUMMARY OF THE INVENTION

Subject of the invention is a method for the preparation of compound of formula (I);

is H or C 1-4 alkyl;

a reaction REAC1 of compound of formula (2) with an acid ACI in the presence of Rl- OH;

ACI is selected from the group consisting of H2SO4, HCl, H3PO4, formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, borontrifluoride etherate, and mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION

Preferably, Rl is

alkyl, more preferably, Rl is methyl or ethyl; even more preferably Rl is methyl.

Preferably, ACI is selected from the group consisting of H2SO4, HCl, H3PO4, formic acid, acetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, and mixturese thereof;

more preferably, ACI is selected from the group consisting of H2SO4, HCl, H3PO4, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, and mixturese thereof.

Preferably, in case that Rl is C1-4 alkyl then ACI is selected from the group consisting of H2SO4, H3PO4, formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, borontrifluoride etherate, and mixturese thereof;

more preferably, in case that Rl is C1-4 alkyl then ACI is selected from the group consisting of H2SO4, H3PO4, formic acid, acetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and mixturese thereof;

even more preferably, in case that Rl is C1-4 alkyl then ACI is selected from the group

consisting of H2SO4, H3PO4, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, and mixturese thereof.

ACI is H2SO4, HCl or H3PO4, in case that Rl is H or CM alkyl.

HCl is preferably used as aqueous HCl or as gaseous HCl.

In principle and in case that Rl is H also a saponification of compound of formula (2) under alkaline conditions is possible. Preferably, the molar amount of Rl-OH is from 1 to 60 times, more preferably 1 to 40 times, even more preferably from 1 to 20 times, based on the molar amount of compound of formula (2). It is also possible to use Rl-OH as solvent.

Preferably, the molar amount of ACI is from 1 to 10 times, more preferably 1.5 to 10 times, even more preferably from 2 to 10 times, based on the molar amount of compound of formula (2).

In another preferred embodiment, the molar amount of ACI is from 1 to 5 times, more

preferably 1.5 to 5 times, even more preferably from 1 to 5 times, based on the molar amount of compound of formula (2).

REACl can be done in a solvent SOLV1, SOLV1 is preferably Rl-OH, THF, methyl-THF, dioxane, more preferably, SOLV1 is Rl-OH.

Preferably, the reaction temperature TEMPI of REACl is from ambient temperature to

150°C, more preferably from 30 to 125°C, even more preferably from 40 to 100°C, especially from 40 to 80°C.

Preferably, the pressure PRESS 1 of REACl is adjusted according to the vapor pressure of the reaction mixture at the chosen TEMPI of REACl ; but PRESS 1 can also be adjusted to a higher pressure than the vapor pressure of the reaction mixture at the chosen TEMPI . A PRESS 1 higher than the vapor pressure of the reaction mixture at the chosen TEMPI can be adjusted for example by applying inert gas such a nitrogen or argon to the reaction vessel.

Preferably, the reaction time TIME1 of REACl is from 1 to 48 h, more preferably from 5 to 36 h, even more preferably from 10 to 30 h, especially from 12 to 25 h.

After REACl, compound of formula (I) can be isolated and purified by methods well-known to those skilled in the art. These include, for instance, distillation, preferably fractional distillation, which can be done under reduced pressure, crystallization, extraction, or a combination of these methods. Further subject of the invention is a method for the preparation of compound of formula (HYDROXTYR);

(HYDROXTYR)

the method comprises two steps, a step STEP1 and a step STEP2,

STEP1 comprises the reaction REACl ;

with REACl as defined above, also with all it embodiments,

REACl provides compound of formula (I);

STEP2 comprises a reaction REAC2, wherein compound of formula (I) is reduced to provide compound of formula (HYDROXTYR). Preferably, the reduction in REAC2 is done with a reducing agent REDUC;

REDUC is selected from the group consisting of L1AIH4, NaBH₄, borane, Na and H₂.

Borane can adopt various forms such as a monomeric, a dimeric form or a complex with a solvent, if it is provided in form of a solution.

In case that REDUC is H₂ then REAC2 is actually a catalytic hydrogenation. Suitable

catalysts for this catalytic hydrogenation are known to the skilled person and comprise for example copper chromite.

Preferably, the molar amount of REDUC is from 1 to 20 times, more preferably 2 to 15 times, even more preferably from 3 to 10 times, based on the molar amount of compound of formula (I).

Of course H₂ in a catalytic hydrogenation can also be used in larger excess.

Borane as REDUC is preferably used in case that Rl is H.

NaBH₄ or Na as REDUC is preferably used in case that Rl is Ci_₄ alkyl. In case of REDUC being NaBH₄ or Na, preferably REAC2 is done in the presence of water, an C 1 -4 alkanol or both.

Preferably, REDUC is selected from the group consisting of L1AIH4, NaB¾, borane and H₂; more preferably, REDUC is selected from the group consisting of NaBH₄ and H₂. Preferably, REAC2 is done in a solvent SOLV2,

SOLV2 is preferably selected from the group consisting of THF, methyl-THF, dioxane, water, Ci-₄ alkanol, and mixtures thereof.

Preferably, the reaction temperature TEMP2 of REAC2 depends on the choice of REDUC and can be from -20 to 300°C, this is known to the skilled person.

In case of NaBH₄ as REDUC, TEMP2 is more preferably from 30 to 125°C, even more

preferably from 40 to 100°C, especially from 40 to 80°C.

In case of LiAlH₄ as REDUC, TEMP2 is more preferably from 0 to 80°C, even more

preferably from 5 to 60°C.

Preferably, the pressure PRESS2 of REAC2 is adjusted according to the vapor pressure of the reaction mixture at the chosen TEMP2 of REAC2; but PRESS2 can also be adjusted to a higher pressure than the vapor pressure of the reaction mixture at the chosen TEMP2. A PRESS2 higher than the vapor pressure of the reaction mixture at the chosen TEMP2 can be adjusted for example by applying inert gas such a nitrogen or argon to the reaction vessel.

Preferably, the reaction time TIME2 of REAC2 depends on the choice of REDCU, this is known to the skilled person, and is from 1 to 48 h, more preferably from 5 to 36 h, even more preferably from 10 to 30 h, especially from 12 to 25 h.

After REAC2, compound of formula (HYDROXTYR) can be isolated and purified by methods well-known to those skilled in the art. These include, for instance, distillation, preferably fractional distillation, which can be done under reduced pressure, crystallization, extraction, or a combination of these methods.

Preferably, compound of formula (2) is prepared in a step STEP0;

STEP0 comprises a reaction REACO, wherein compound of formula (III)

is reacted with HCl;

R2 and R3 are identical or different and independently from each other

alkyl. Preferably, R2 and R3 are identical.

Preferably, R2 and R3 are C_1-2 alkyl;

more preferably, R2 and R3 are methyl.

Preferably, REACO is done in the presence of pyridine, of pyridinium hydrochloride or of a mixture of pyridine and pyridinium hydrochloride.

Preferably, the molar amount of pyridine is from 2 to 5 times, more preferably 2 to 4 times, even more preferably 2 to 3 times, based on the molar amount of compound of formula

(III). Preferably, HCl is used in gaseous form.

Preferably, the molar amount of HCl is from 2 to 5 times, more preferably 2 to 4 times, even more preferably 2 to 3 times, based on the molar amount of compound of formula (III). When pyridine is used in the beginning of REACO and before the addition of HCl, the

pyridine is converted by the HCl to pyridinium hydrochloride. Depending on relative amounts of pyridine and HCl, either all pyridine is converted by the addition of HCl to pyridinium hydrochloride, or only part of pyridine is converted by the addition of HCl to pyridinium hydrochloride.

In one preferred embodiment, the pyridine is used in REACO in form of pyridinium

hydrochloride. Also the HCl can be used in REACO in form of pyridinium hydrochloride.

More preferably, the molar amount of pyridinium hydrochloride is from 2 to 5 times,

preferably 2 to 4 times, even more preferably 2 to 3 times, based on the molar amount of compound of formula (III).

Even more preferably, an excess of pyridine with respect to the pyridinium hydrochloride is used, especially the excess is 0.1 to 100%, more preferably 0.1 to 50%, even more preferably 0.1 to 20%>, especially 0.1 to 10%>, more especially 0.5 to 5%, the % being weight percent based on the amount of pyridinium hydrochloride. As disclosed in the D 37 37 825 Al, it is possible to charge the HC1 to a mixture of pyridine and compound of formula (III); or as disclosed in example 4 and 5, it is possible to use a mixture of pyridinium hydrochloride and compound of formula (III), said mixture can additionally contain the excess of pyridine.

Preferably, the reaction temperature TEMPO of REACO is from 100 to 300°C, more

preferably from 100 to 250°C, even more preferably from 125 to 225°C.

Preferably, the pressure PRESSO of REACO is adjusted according to the vapor pressure of the reaction mixture at the chosen TEMPO of REACO; but PRESSO can also be adjusted to a higher pressure than the vapor pressure of the reaction mixture at the chosen TEMPO. A

PRESSO higher than the vapor pressure of the reaction mixture at the chosen TEMPO can be adjusted for example by applying inert gas such a nitrogen or argon to the reaction vessel.

Preferably, the reaction time TIMEO of REACO is from 1 to 100 h, more preferably from 10 to 80 h.

REACO can be done in the presence of KI.

After REACO, compound of formula (2) can be isolated and purified by methods well-known to those skilled in the art. These include, for instance, distillation, preferably fractional distillation, which can be done under reduced pressure, crystallization, extraction, or a combination of these methods.

Examples

Internal standard for ^JH NMR: Triisobutyl phosphate, if not otherwise stated

THF tetrahydrofuran

DMSO dimethyl sulfoxide

Example 1: (3,4-Dihydroxyphenyl)acetic acid methyl ester

A mixture of (3,4-dihydroxyphenyl)acetonitrile (1.49 g, 10.0 mmol; prepared according to example 4), methanol (5 ml), and sulfuric acid (2.0 ml, 37 mmol) was stirred at 65°C for 18 h. The mixture was then poured into brine (50 ml), and the product was extracted with ethyl acetate (5 times with 25 ml). The combined extracts were dried (MgS0₄) and concentrated under reduced pressure to yield 1.49 g (yield 82%) of (3,4-dihydroxyphenyl)acetic acid methyl ester as an oil. Ή NMR (DMSO, 400 MHz) delta = 8.8 (s, br, 2H), 6.66 (m, 2H), 6.49 (m, 1H), 3.58 (s, 3H), 3.45 (s, 2H).

Example 2: 2-(3,4-Dihydroxyphenyl)ethanol

To a mixture of (3,4-dihydroxyphenyl)acetic acid methyl ester (0.91 g, 5.0 mmol), prepared according to example 1, THF (10 ml), and sodium borohydride (0.82 g, 22 mmol) having a temperature of 65 °C, was added within 6 h a mixture of methanol (4.0 ml, 99 mmol) and THF (4.0 ml). Then the mixture was stirred at 65 °C overnight. The mixture was then concentrated under reduced pressure, and the residue was mixed with THF (10 ml), ethanol (10 ml), and concentrated aqueous HCl (2.14 ml, 26 mmol). After stirring at room

temperature for 3 h the mixture was filtered, and the solid was washed with THF (20 ml). The combined filtrates were concentrated and the residue mixed with 1 N aqueous HCl (5 ml). After stirring at room temperature for 47 h the mixture was extracted with ethyl acetate (3 times with 30 ml), the combined extracts were washed with brine (1 time with 40 ml), dried (MgS0₄), and concentrated under reduced pressure, to yield 695 mg (yield 90%) of hydroxytyrosol.

Ή NMR (DMSO, 400 MHz) delta

(t, J = 7 Hz, 2H). Example 3: (3,4-Dihydroxyphenyl)acetic acid

A mixture of (3,4-dihydroxyphenyl)acetonitrile (75 mg, 0.5 mmol, prepared according to example 4) and concentrated aqueous hydrochloric acid (0.5 ml) was stirred at 65 °C for 16 h. The mixture was diluted with brine (5 ml), extracted with AcOEt (3 ml), and 1BU3PO4 (0.04 ml, 0.146 mmol) was added as NMR standard. Analysis by ^JH NMR of a concentrated sample indicated, that (3,4-dihydroxyphenyl)acetic acid had been formed in 70% yield.

Ή NMR (DMSO, 400 MHz) delta = 6.64 (m, 2H), 6.48 (m, 2H), 3.34 (s, 2H). Example 4: (3,4-Dihydroxyphenyl)acetonitrile

A mixture of (3,4-dimethoxyphenyl)acetonitrile (8.90 g, 50 mmol, purchased from Aldrich) and pyridine hydrochloride (28.3 g, 250 mmol) was stirred at 200°C for 18 h. The mixture was dissolved in water (20 ml), 1 N aqueous HC1 (5 ml) was added, and the mixture was extracted with AcOEt (5 times with 40 ml). The combined extracts were dried (MgS0₄) and concentrated under reduced pressure. 4.56 g (yield 61%>) of (3,4-dihydroxyphenyl)acetonitrile were obtained as a solid, which was used without further purification.

Ή NMR (DMSO, 400 MHz) delta = 6.73 (m, 2H), 6.57 (m, 1H), 3.81 (s, 2H). Example 5: (3,4-Dihydroxyphenyl)acetonitrile

A mixture of (3,4-dimethoxyphenyl)acetonitrile (17.8 g, 101 mmol, purchased from Aldrich), pyridine hydrochloride (29.4 g, 254 mmol), potassium iodide (0.83 g, 5.0 mmol), and pyridine (1 ml) was stirred at 150°C for 18 h and then at 160 °C for 48 h. The mixture was dissolved in 1 N aqueous HC1 (30 ml) and brine (30 ml), and the mixture was extracted with AcOEt (four times with 60 ml). The combined extracts were dried (MgS0₄) and concentrated under reduced pressure; 12.1 g (yield 80%>) of (3,4-dihydroxyphenyl)acetonitrile was obtained as a solid, which was used without further purification.

Claims

1. Method for the preparation of compound of formula (HYDROXTYR);

(HYDROXTYR)

the method comprises two steps, a step STEPl and a step STEP2,

STEPl comprises a reaction REACl of compound of formula (2) with an acid ACI in the presence of Rl-OH;

Rl is H or CM alkyl;

ACI is selected from the group consisting of H2SO4, HCl, H3PO4, formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, borontrifluoride etherate, and mixtures thereof;

REACl provides compound of formula (I);

STEP2 comprises a reaction REAC2, wherein compound of formula (I) is reduced to provide compound of formula (HYDROXTYR).

2. Method according to claim 1, wherein

the reduction in REAC2 is done with a reducing agent REDUC;

REDUC is selected from the group consisting of L1AIH4, NaB¾, borane, Na and H₂.

3. Method according to claim 1 or 2, wherein

REDUC is selected from the group consisting of LiAlH₄, NaBH₄, borane and H₂.

4. Method according to one or more of claims 1 to 3, wherein

Rl is Ci-4 alkyl.

5. Method according to one or more of claims 1 to 4, wherein

Rl is methyl or ethyl.

6. Method according to one or more of claims 1 to 5, wherein

ACI is selected from the group consisting of H₂S0₄, HCl, H3PO4, formic acid, acetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and mixturese thereof.

7. Method according to one or more of claims 1 to 6, wherein

ACI is selected from the group consisting of H₂S0₄, HCl, H3PO4, acetic acid,

methanesulfonic acid, p-toluenesulfonic acid, and mixturese thereof.

8. Method according to one or more of claims 1 to 7, wherein

compound of formula (2) is prepared in a step STEPO;

STEPO comprises a reaction REACO, wherein compound of formula (III)

is reacted with HCl;

R2 and R3 are identical or different and independently from each other Ci_₄ alkyl.

9. Method according to claim 8, wherein

REACO is done in the presence of pyridine, of pyridinium hydrochloride or of a mixture of pyridine and pyridinium hydrochloride.