FI111637B - Preparation of matairesinol useful in nutritional supplement for treating e.g. cancer involves either catalytic hydrogenolysis of hydroxymatairesinol or reduction of hydroxymatairesinol by hydrogen transfer reaction - Google Patents

Abstract

Preparation of matairesinol from hydroxymatairesinol involves either: (1) catalytic hydrogenolysis (M1) of the hydroxy group in 7-position of hydroxymatairesinol in a solvent (S1) as a pressurized hydrogenolysis, or (2) reduction (M2) of hydroxymatairesinol by a hydrogen transfer reaction from a hydrogen donor in the presence of a catalyst.

Description

111637

METHOD FOR PREPARING MATAIRESINOL FIELD OF THE INVENTION

This invention relates to a novel process for the preparation of plantignan matairesinol.

BACKGROUND OF THE INVENTION

The publications and other material used to explain the background of the invention, and in particular the individual cases detailing the practice, shall be considered to be incorporated by reference in the application.

Hydroxymatairesinol and matairesinol, the chemical structures of which are shown in Scheme 1, are both biologically active plant lignans.

Hydroxymatairesinol exists in two diastereomers, namely (-) hydroxymatairesinol (also called HMR 2 isomer) and (-) allo-hydroxymatairesinol (HMR 1 isomer).

EP 906761 mentions that mateiresinol is useful as a nutritional supplement for the prevention of cancer, coronary heart disease and hormonal disorders. It is also known that matairesinol is a precursor of mammalian lignan enterolactone (JD Ford et al., Plant Polyphenols 2: Chemistry, Biology, Pharmacology, Edited by Gross et al.

25 Kluwer Academic / Plenum Publisher, New York 1999, p. 675-694).

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Matairesinol, like many other lignans, occurs in different parts of plants and trees (roots, leaves, trunks, seeds, fruits) but mainly in small amounts. In many sources (seeds, fruits), lignans are present as glucoside conjugates combined with plant fiber components.

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The most common sources of nutrients for mammalian lignan precursors are unrefined cereal products. The highest concentrations are found in flax seed. The limited availability of large quantities of matairesinol is a problem that must be addressed before matairesinol can be used commercially more widely.

Considerable amounts of lignan have been found in conifers. Lignan types vary in species, and lignan levels vary in different parts of the tree.

Typical lignans in the heart tree of spruce (Picea abies) are 10 hydroxymataatiresinol (HMR), α-conidendrin, conidendric acid, matairesinol, isolariciresinol, secoisolariciresinol, lyovil, picearesinol, lariciresinol, and pinoresinol (R. Ekman, Abo, Ser. B, 39: 3.1-6 (1979). The most abundant single component of lignans in spruce wood is hydroxymatairesinol 15 (HMR), about 60 percent of the total amount of lignans present predominantly in unconjugated, free form. Thick roots have a lignan content of 2-3%. Lignans are abundant in branch heartwood (5-10%) and twisted tree, and in particular in branches, where the amount of lignans can be higher than 10% (R. Ekman, "Analysis of lignans in 20 Norway by mass gas chromatography",

Holzforschung 30, 79-85 (1976); R Ekman 1979; S. Willfor, J. Hemming, M.

Reunanen, C. Eckerman and B. Holmbom, "Hydrophilic and Lipophilic Extracts in Norway Spruce Knots". Presented at 11. ISWPC, Nice, France, 2001). These concentrations are about one hundred times higher than those found in powdered form. 25 linen powder, which is known as a lignan-rich material.

t

It has been suggested that hydroxymatairesinol could be recovered from the fibers of the lye tree. These fibers are derived from the lumber of the trunk and twigs (fraction of oversized chips) and are known to degrade paper quality (R. Ekman, 1976; S Willfor et al., 2001).

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It has recently been found that large amounts of hydroxymatairesinol can be produced - by extraction of finely divided wood material, preferably spruce twig, with a polar solvent or solvent mixture and precipitation of hydroxymatairesinol as a complex from the extract. Suitable solvents for use in the extraction step include, for example, pure ethanol or a mixture of ethanol and ethyl acetate. After the extraction step, at least part of the solvent is preferably removed before the addition of a complexing agent, which is preferably a carboxylate of an alkali metal such as potassium, alkaline earth metal or ammonium such as acetate. Such carboxylates form crystallizable adducts with hydroxymatairesinol. A particularly suitable complexing agent is potassium acetate, which gives the potassium acetate adduct of hydroxymatairesinol, which is easily crystallizable. This adduct also contains a large amount of the diastereomer of (-) hydroxymatairesinol.

In Freudenberg K and Knof L, "Lignanes des Fichtenholzes". Chem. Ber. 90,2857-69, 1957 describes a laboratory method for the preparation of matairesinol from hydroxymatairesinol using palladium in acetic acid ester.

OBJECTIVE AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a process for the synthesis of matairesinol 25 from a starting material obtainable in large quantities, namely hydroxymatairesinol, in particular hydroxymatairesinol, derived from wood.

This invention relates to a process for the preparation of matairesinol by catalytic hydrolysis of the hydroxy group at position 7 of hydroxymatairesinol. The process is characterized in that the reaction is carried out by pressurized hydrogenolysis in a suitable solvent.

> BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1 and 5 show the evolution of the concentration of the matairesinol (end product) and the concentration of the diastereomer (starting material) of hydroxymatairesinol as a function of time in pressurized hydrogenolysis using Pd on carbon as catalyst.

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Figures 2-4 show the evolution of the concentration of matairesinol (end product) and the concentration of the diastereomer of hydroxymatairesinol (starting material) over time in pressurized hydrogenolysis using Raney Nickel as catalyst.

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FURTHER DESCRIPTION OF THE INVENTION

Hydroxymatairesinol exists in two diastereomers, namely (-) hydroxymatairesinol and (-) allo-hydroxymatairesinol. The term 20 '' hydroxymatairesinol 'as used in the definition of this invention encompasses any pure geometric isomer or pure stereoisomer or pure diastereomer or mixture of diastereomers or a mixture of diastereomers.

The term is to be understood to include salts, adducts and complexes of a compound.

25 • <<

In one embodiment, catalytic hydrogenolysis is heterogeneous catalysis.

One suitable catalyst is a metal, a metal oxide, a metal alloy and / or a metal oxide alloy. The catalyst may be a metal or metal oxide powder, or the catalyst may be attached to a support. Suitable elements in the carrier include Si, Al and C. The carrier may be, for example, solid particles such as powders, granules or extrudates.

The process can be carried out using known reactor technology. It may thus be a slurry process in which the catalyst particles are suspended in the liquid phase. Alternatively, structured catalysis may be used. Examples of structured catalysts include monolithic technologies, packed columns, droplet layers, Sulzer-type catalysts or fiber-bound catalysts.

The catalyst is preferably a Pd, Pt, Ni, Rh, Ru, Co, Raney-type catalyst such as Raney-Ni, or oxide of the aforementioned elements. Alloys of these metals and / or their oxides may also be used.

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Particularly suitable catalysts include Raney-Ni or palladium on carbon (PdC).

On a laboratory scale, without a separate hydrogen source, the reaction may be carried out, for example, using excess Raney-Nickel catalyst. However, on a production scale, a separate hydrogen source (hydrogen gas) must be used to reduce the amount of expensive catalyst.

The term "pressurized hydrogenolysis" is to be understood as including. 25 includes any suitable pressure higher than normal • · atmospheric pressure, that is, in the range of 2 to 200 bar. However, a pressure range of 5-70 bar, or even higher, preferably 15-70 bar is recommended.

The temperature is preferably maintained in the range of 50-150 ° C.

30 i 6 111637

Suitable solvents include, for example, alcohols, ethers, esters, ketones, hydrocarbons, or halogenated hydrocarbons. According to an embodiment, the solvent is an alcohol such as ethanol, 2-propanol or a mixture thereof.

5

Although both diastereomers of hydroxymatairesinol can be used in the synthesis of this invention, it may be desirable to use the diastereomer of (-) hydroxymatairesinol. According to a preferred embodiment, the hydroxymatairesinol is in complex or adduct form, precipitated from an extract obtained by extraction of wood material with a polar solvent, such as the potassium acetate adduct of hydroxymatairesinol.

The hydroxymatairesinol or adduct thereof in the starting material used in the synthesis need not necessarily be purified from other components.

However, the starting material should not contain components which are detrimental to the catalyst.

The invention will be described in more detail in the following non-limiting experimental section.

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EXPERIMENTAL PART

In the examples below, the following abbreviations are used: MR = matairesinol; HMR1 = diastereomer of (-) allohydroxymatairesinol; HMR2, 25 = diastereomer of (-) hydroxymatairesinol; and HMR = a mixture of the diastereomer of (-) allohydroxy-matairesinol and the diastereomer of (-) hydroxymatairesinol.

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Examples 1-2 are comparative examples describing catalytic hydrogenolysis at atmospheric pressure. Examples 3-9 illustrate the process of this invention using pressurized conditions.

Example 1

A mixture of 1 g HMR and 5 g Raney Nickel (50% slurry in water, Acros) was stirred in 50 ml ethanol at 50 ° C. After 24 hours, 5 g of Raney-Ni catalyst was added and the mixture was stirred for an additional 24 hours.

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The mixture was then filtered and the solvent was removed under reduced pressure. GC and GC-MS analyzes showed that only 3% of the HMR had been converted to mateiresinol and no other products could be detected.

Example 2 HMR (300 mg) was soaked in 5 mL of benzene and 5 mL of THF. To the solution was added 300 mg of Raney-Ni (50% slurry) at room temperature. The mixture was stirred for 1 hour and then H2 gas was allowed to flow through the mixture.

The mixture was then warmed to 50 ° C and stirred for 24 hours under H 2 atmosphere at atmospheric pressure (balloon). Raney-Ni (300 mg) was further added and stirring was continued under H 2 for 5 days. The mixture was then filtered and the solvent was removed under reduced pressure. GC and GC-MS analyzes indicated that about 2% of the HMR had been converted to MR.

25 * <

The Raney Nickel catalyst (50% slurry in water) used in Examples 1 and 2 was washed several times with ethanol before being added to the reaction mixture.

Example 3 8 111637

An isothermal, laboratory-scale pressure autoclave (without spacers) of 64mm stainless steel and 5,103mm internal diameter was filled with 150ml of 1,2-dichloroethane in which 19.35g of cosmic HMR was dissolved. 1.5 g of catalyst with 10% Pd on activated carbon (Acros Chemicals) was added to the reactor vessel with the reaction mixture and the heating turned on. Hydrogen (purity 99.999%, AGA Corporation) was passed through the mixture for two minutes to remove oxygen from the vessel. During heating, the mixer was not switched on. During heating in an oil bath (1-2 h), the reactor temperature reached the desired reaction temperature of 50 ° C (323 K). The stirrer was turned on (1000 rpm) and held at the time of the start of hydrogenation of the batch. The pressure was adjusted to 80 PSI (about 5.5 bar).

The reaction was allowed to proceed for 4 hours and small volumes of the reaction mixture were sampled every 30 min. for subsequent GC analyzes (GC = gas chromatography). Samples (a few ml) were taken through a 5 μητ.η metal sinter filter by bursting the sample valve, immediately covered with aluminum foil to protect from light, and transferred to a freezer at 20 (-20 ° C, 253 K).

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After four hours, the MR initial concentration 0.18 wt% increased to 58.9 wt%, while the HMR initial concentration (HMR1 36.4 wt%, HMR2 61.7 wt%) decreased 8.5 resp. 28.8% by weight (HMR1, HMR2).

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Example 4

An isothermal, laboratory-scale pressure autoclave (without spacers) of 64 mm stainless steel and 30 103 mm internal diameter was filled with 100 ml of HPLC grade ethyl alcohol (EtOH), 9,11,163 g of 1.15 g of dried (overnight vacuum oven) HMR: was dissolved. 0.1725 g of catalyst, 10% Pd on activated carbon (Acros Chemicals) was added to the reactor vessel with the reaction mixture and the heating turned on. Hydrogen (purity 99.999%, AGA Corporation) was passed through the mixture for two to five minutes to remove oxygen from the vessel. The mixer was not switched on during heating. During heating in an oil bath (1-2 h), the reactor temperature reached the desired reaction temperature of 338 K (65 ° C).

The stirrer was turned on (1000 rpm) and held at the time of the start of hydrogenation of the batch. The pressure was adjusted to 80 PSI (about 5.5 bar).

10

The reaction was allowed to continue for 175 minutes and small portions of the reaction mixture were withdrawn at regular intervals for subsequent GC analyzes (GC = gas chromatography). Samples (a few ml) were taken through a 5 µm metal sinter filter by breaking the sample valve, immediately covered with 15 aluminum foils to protect from light and transferred to a freezer (-20 ° C, 253 K).

After 175 minutes, the initial MR concentration of 30.6 wt% increased to 88.2 wt%, while the initial HMR concentration (HMR1 20.6 wt%, 20 HMR2 40.9 wt%) decreased 6.19 resp. 3.81% by weight (HMR1, HMR2).

the evolution of concentration as a function of time is shown in Figure 1.

Example 5 25. An isothermal, laboratory-scale pressure autoclave (with baffles) of 64 mm internal diameter and 103 mm long stainless steel was filled with 100 ml of HPLC grade ethyl alcohol (EtOH) to which 1 g of potassium acetate HMR adduct (1: 1) was dissolved. 1.35 g of 30 commercial Raney nickel catalysts (enhanced with molybdenum; activated 10 111637 metals) were added to the reactor vessel with the reaction mixture and the heating turned on. Hydrogen (purity 99.999%, AGA Corporation) was passed through the mixture for two minutes to remove oxygen from the vessel. The mixer was not switched on during heating. After two minutes of electric coil heating, the temperature of the 5 reactors (equipped with a coil of refrigeration and a temperature controller) reached the desired reaction temperature of 373 K (100 ° C). The mixer was turned on (1700 rpm) and this was held at the start of the batch hydrogenation. The pressure was adjusted to 420 PSI (about 29 bar).

The reaction was allowed to continue for 90 minutes and small volumes of the reaction mixture were periodically sampled for subsequent GC analyzes (GC = gas chromatography). Samples (a few ml) were taken through a 5 µm metal sinter filter by breaking the sample valve, immediately covered with aluminum foil to protect them from light, and transferred to a freezer 15 (-20 ° C, 253 K).

After 90 minutes, the initial MR concentration of 1.4 wt% increased to 56.4 wt%, while the initial HMR concentration (HMR1 8.5 wt%, HMR2 78.5 wt%) decreased 15.6 resp. 9.8% by weight (HMR1, HMR2). The evolution of concentration 20 as a function of time is shown in Figure 2.

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Example 6

An isothermal, laboratory-scale pressure autoclave (without spacers) of 25 stainless steel, 64 mm internal diameter and 103 mm long, was filled with 100 ml of HPLC grade ethyl alcohol (EtOH) containing 3 g of potassium acetate HMR adduct (1: 1). dissolved. 3 g of commercial Raney nickel catalyst (enhanced with molybdenum; activated metals) were added to the reactor vessel with the reaction mixture and the heating turned on. Hydrogen (purity 99.999%, AGA Corporation) was passed through the mixture for 2 minutes 11111637 to remove oxygen from the vessel. The mixer was not switched on during heating. After 10 minutes of electric coil heating, the reactor temperature (equipped with cooling coil and temperature controller) reached the desired reaction temperature of 373 K (100 ° C). The mixer was turned on (1150 5 rpm) and this was held at the start of the batch hydrogenation. The pressure was adjusted to 280 PSI (about 19 bar).

The reaction was allowed to continue for 240 minutes and small volumes of the reaction mixture were periodically sampled for subsequent GC analyzes (GC = 10 gas chromatography). Samples (a few ml) were taken through a 5 µm metal sinter filter by breaking the sample valve, immediately covered with aluminum foil to protect from light and transferred to a freezer (-20 ° C, 253 K).

After 240 minutes, the initial MR concentration of 1.95 wt% increased to 57.5 wt%, while the initial HMR concentration (HMR1 6.1 wt%, HMR2 66 wt%) decreased 11.6 resp. 5.9% by weight (HMR1, HMR2).

The evolution of concentration as a function of time is shown in Figure 3.

Example 7

An isothermal, laboratory-scale pressure autoclave (without spacers) of stainless steel, 64 mm internal diameter and 103 mm long, was filled with 100 ml of HPLC grade ethyl alcohol (EtOH); 2.38 g of potassium acetate HMR adduct (1: 1) were dissolved. 2.38 µg of commercial Raney nickel catalyst (enhanced with molybdenum; activated metals) was added to the reactor vessel with the reaction mixture and the heating turned on. Hydrogen (purity 99.999%, AGA Corporation) was passed through the mixture for two minutes to remove oxygen from the vessel. During heating, the mixer was not turned on. After heating the electric coil for 10 minutes, the temperature of reactor 12111637 (equipped with cooling coil and temperature control) reached the desired reaction temperature of 393 K (120 ° C). The mixer was turned on (1150 rpm) and this was held at the start of the batch hydrogenation. The pressure was adjusted to 250 PSI (about 17 bar).

5

The reaction was allowed to continue for more than 300 minutes and small amounts of the reaction mixture were periodically sampled for subsequent GC analyzes (GC = gas chromatography). However, it turned out that the maximum yield of MR was obtained after about 200 minutes. Samples (a few ml) were taken through a 5 μιη: η 10 metal sinter filter by breaking the sample valve, immediately covered with aluminum foil to protect from light, and transferred to a freezer (-20 ° C, 253 K).

After 197 minutes, the initial MR concentration of 1.65 wt% increased to 76 wt% to 15%, while the initial HMR concentration (HMR1 6.91 wt%, HMR2 75.6 wt%) decreased 0.60 resp. 0.53% by weight (HMR1, HMR2). The evolution of concentration as a function of time is shown in Figure 4.

Example 8 20

An isothermal, laboratory-scale pressure autoclave (without baffle) of stainless steel having an internal diameter of 64 mm and a length of 103 mm was charged with 100 ml of HPLC grade ethyl alcohol (EtOH) containing 3.0 g of potassium acetate HMR adduct (1: 1). ) was dissolved. 0.3 g of 25 commercial Pd catacytes with activated carbon (Acros) were added to the reactor vessel

reaction mixture and heating was turned on. Hydrogen (purity 99.999%, AGA Corporation) was passed through the mixture several times to remove oxygen from the vessel. The mixer was not switched on during heating. After 10 minutes of electric coil heating, the temperature of the reactor (equipped with cooling coil 30 and temperature control) reached the desired reaction temperature of 100 ° C.

13 111637 (373 K). The mixer was turned on (1150 rpm) and this was held at the start of the batch hydrogenation. The pressure was adjusted to 435 PSI (about 30 bar).

The reaction was allowed to continue for more than 240 minutes and 5 small aliquots of the reaction mixture were withdrawn at regular intervals for subsequent GC analyzes (GC = gas chromatography). However, it turned out that the maximum yield of MR was obtained after about 210 minutes. Samples (a few ml) were taken through a 5 µm metal sinter filter by breaking the sample valve, immediately covered with aluminum foil to protect from light, and transferred to freezer 10 (-20 ° C, 253 K).

After 210 minutes, MR initial concentration of 3.36 wt% increased to 77.4 Pamo%, while HMR initial concentration (HMR1 25.7 wt%, HMR2 61.1 wt%) decreased 3.05 resp. 2.15% by weight (HMR1, HMR2).

The evolution of concentration as a function of time is shown in Figure 5.

Example 9

An isothermal, laboratory-scale pressure autoclave (with baffles) of 20 stainless steel, 64 mm internal diameter and 103 mm long, was filled with 150 ml 1,2-dichloroethane (DCE, J.T. Baker p.a.). 1.5 g of HMR and 0.3 g of Pd-C catacyte (10%, Fluka) were added to the reaction vessel. The reaction mixture was heated on an electric coil to 50 ° C and N 2 gas (purity 99.999%, AGA Corporation) was passed through the mixture to remove oxygen; - 25 dishes (equipped with cooling coil and temperature control). The reaction mixture was stirred at 500 rpm and when the temperature of 36 ° C was reached at 1000 rpm. After the temperature of the reaction mixture had risen to 50 ° C, H2 gas (purity 99.999%, AGA Corporation) was introduced into the reaction mixture, followed by N2 gas to ensure that the oxygen had been completely removed from the reaction mixture. Subsequently, hydrogenolysis was performed by introducing H2-14111637 gas back into the vessel. The pressure was adjusted to 8 bar. The reaction was allowed to continue for 240 minutes, after which the reaction mixture was filtered through a paper filter. According to GC-MS analysis (HP-5890 Saija II gas chromatograph equipped with 5971 A mass-selective detector; column 30 m x 0.25 mm x 5 0.25 pm HP-IMS) the conversion of HMR to MR was quantitative.

It will be appreciated that the subject matter of the present invention can be applied in many forms, only a few of which are described herein. It will be apparent to one skilled in the art that other means exist and do not depart from the spirit of the invention. The embodiments described are thus illustrative in nature and do not limit the invention.

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Scheme I

r 0 π ηο ^^ Λ ^ 0 _. «Λ ^ ι ^ 7 γΝχ1 Y ^ OCii OH ° Π

Hydroxymatairesinol Matairesinol * <»·

Claims (13)

111637 A process for the preparation of matairesinol by catalytic hydrogenolysis of the hydroxy group in the 7-position of hydroxymatairesinol, characterized in that the reaction is carried out by pressurized hydrogenolysis in a suitable solvent. Process according to Claim 1, characterized in that the catalytic hydrogenolysis is heterogeneous catalysis. Process according to Claim 2, characterized in that the catalyst is a metal or metal oxide or a mixture of metals and / or metal oxides. 15 Process according to Claim 3, characterized in that the catalyst is a Pd, Pt, Ni, Rh, Ru, Co, Raney-type catalyst such as Raney-Ni, or oxide of the above mentioned elements or a mixture thereof. Process according to Claim 4, characterized in that the catalyst is Raney-Nickel. Process according to Claim 4, characterized in that the catalyst is palladium on carbon (PdC). : 25 Process according to one of the preceding claims, characterized in that the reaction is carried out at a pressure in the range of 5 to 70 bar. Process according to one of the preceding claims, characterized in that the solvent is an alcohol, an ether or a hydrocarbon. 111637 Process according to claim 8, characterized in that the solvent is an alcohol such as ethanol or 2-propanol. A process according to any one of the preceding claims, characterized in that the hydroxymatairesinol is a mixture of the diastereomer of (-) hydroxymatairesinol and the diastereomer of (-) allohydroximatiresinol. A process according to any one of claims 1 to 9, characterized in that the hydroxymatairesinol is a diastereomer of (-) hydroxymatairesinol. Process according to one of the preceding claims, characterized in that the hydroxymatairesinol is in the form of a complex or an adduct precipitated from an extract obtained by extraction of the wood material with a polar solvent. Process according to Claim 12, characterized in that the adduct is an adduct of potassium acetate with hydroxymatairesinol. • <«1 · 111637