Patent Application
20240209132
The present invention relates to the field of the synthesis of chromanes and chromenes, particularly, of 3,4-dehydrotocotrienols, tocotrienols and tocopherols.
Chromane compounds comprising olefinic carbon-carbon double bonds are an important class of chemicals. Particularly, α-tocotrienol is an highly important member of this class.
The corresponding compound having a saturated side chain, i.e. α-tocopherol, is known to be prepared from 2,3,6-trimethylhydroquinone and isophytol in the presence of Lewis and/or Brønsted acids.
For example, WO 2004/063182 A1 discloses the formation of α-tocopheryl acetate from 2,3,6-trimethylhydroquinone-1-acetate and isophytol in the presence of a large variety of metal triflates. Isophythol has only one carbon-carbon double bond which is used for the coupling reaction, however, has no further double bond(s) which might lead to secondary ring formations, i.e. ring formation in the side chain.
WO 2004/046126 A1 discloses the formation of α-tocopheryl acetate from 2,3,6-trimethylhydroquinone-1-acetate and isophytol in the presence of a large variety of sulfonic acids, particularly triflic acid or p-toluenesulfonic acid. As isophythol is used, no secondary ring formation is possible.
EP 949255 A1 discloses the coupling of TMHQ with isophythol using sulfuric acid or a few sulfonic acids, particularly triflic acid or p-toluenesulfonic acid.
However, it has been shown that the use of those acidic catalysts are generally not suitable for the reaction of 2,3,6-trimethylhydroquinone (TMHQ) or its protected form with the respective unsaturated alcohols, such as geranylgeraniol or farnesol, because undesired cyclic compounds are formed.
This finding is completely in line with Kabbe and Heitzer, Synthesis 1978, 12, 888-889, who has reported that using the known synthetic pathway for vitamin E (i.e. α-tocopherol) from TMHQ and isophytol is not suitable for the synthesis of tocotrienols (i.e. from TMHQ and geranyllinalool) because the isoprenoid side chain undergoes acid-catalyzed secondary ring closure reactions.
The synthesis of tocotrienol and its precursors, however, is still of great importance.
Therefore, the problem to be solved by the present invention is to find a suitable process for the manufacturing of the compound of the formula (I) from TMHQ or its protected form with unsaturated alcohols of the formula (IIIa) or (IIIb).
It has been very surprising that despite the teaching of the prior art, a few members of the metal triflates and sulfonic acids are suitable catalysts for this reaction and yield the compound of formula (I) in high yield and selectivity, particularly with low tendency of forming cyclic compounds by the isoprenoid side chains as side products.
Further aspects of the invention are subject of further independent claims. Particularly preferred embodiments are subject of dependent claims.
In a first aspect, the present invention relates to a process of manufacturing the compound of the formula (I)
It is preferred, that any wavy lines when linked to a carbon-carbon double bond is in the E-configuration.
For sake of clarity, some terms used in the present document are defined as follows:
In the present document, a “Cx-y-alkyl” group is an alkyl group comprising x to y carbon atoms, i.e., for example, a C1-3-alkyl group is an alkyl group comprising 1 to 3 carbon atoms. The alkyl group can be linear or branched. For example —CH(CH3)—CH2—CH3 is considered as a C4-alkyl group.
An “aralkyl” group is an alkyl group which is substituted by an aryl group.
Accordingly, in the present document, a “Cx-y-aralkyl” group is an aralkyl group comprising x to y carbon atoms, i.e., for example, a C7-16-aralkyl group is an aralkyl group comprising 7 to 16 carbon atoms. The aralkyl group can be linear or branched. For example, benzyl group (—CH2-C6H5) is considered as a C7-aralkyl group.
In case identical labels for symbols or groups are present in several formulae, in the present document, the definition of said group or symbol made in the context of one specific formula applies also to other formulae which comprises the same said label.
The term “independently from each other” in this document means, in the context of substituents, moieties, or groups, that identically designated substituents, moieties, or groups can occur simultaneously with a different meaning in the same molecule.
In the present document, any dotted line in formulae represents the bond by which a substituent is bound to the rest of a molecule.
In the present document any bond having dotted line () in a chemical formula represents independently from each other either a carbon-carbon single bond or a carbon-carbon double bond.
Any wavy line in any formula of this document represents a carbon-carbon bond and which when linked to the carbon-carbon double bond is either in the Z or in the E-configuration. It is preferred in all molecules that the carbon-carbon double bond is in the E-configuration.
The term “OTf”, as used in this document, means trifluoromethanesulfonate.
The “pKa” is commonly known as negative decadic logarithm of the acid dissociation constant (pKa=−log10 Ka). When the organic acid has several protons the pKa as used in this document relates to the dissociation constant of the last proton. For example, for a base having two basic sites the “pka” relates to pKa2. The pKa are measured at standard temperature and pressure.
The compound of formula (II) is either 2,3,5-trimethyl hydroquinone (=2,3,5-trimethylbenzene-1,4-diol, TMHQ) (R═H) or the mono-protected derivative thereof (R≠H; R═R′).
A phenol protecting group is a group which protects the phenolic group (OH) in any of the formulae in this document having R═H in said formulae and the protecting group can be easily removed, i.e. by state-of-the-art methods, resulting to the respective compound with the free phenolic group again.
The phenol protecting group R′ is introduced by a chemical reaction of the compound of the respective formula having H as R with a protecting agent.
The protecting agents leading to the corresponding phenol protecting groups are known to the person skilled in the art, as well as the chemical process and conditions for this reaction. If, for example, the phenol protecting group forms with the rest of the molecule an ester, the suitable protecting agent is for example an acid, an anhydride, or an acyl halide.
The phenol protecting group R′ is particularly selected from the groups consisting of
If R′ is equal to R10, the respective compound is an ether, which can be formed by the reaction of the respective protecting agent with the phenolic group (OH). In this case, the protecting agent may be for example an alkylation agent such as the respective C1-15-alkyl or fluorinated C1-15-alkyl or C1-15-cycloalkyl or C7-15-aralkyl halide, particularly iodide.
In one of the preferred embodiments R10 is a methyl group.
In another preferred embodiment R10 is a C7-15-aralkyl group, preferably a benzyl group or a substituted benzyl group, particularly preferred a benzyl group.
If R′ is represented by
the respective compound is an ester of a carboxylic acid or dicarboxylic acid, which can be formed by the reaction of the respective protecting agent with the phenolic group (OH). In this case, the protecting agent may be for example an anhydride or halide of the respective carboxylic acid (1) or dicarboxylic acid (2).
If the compound of the respective formula is an ester of a carboxylic acid or dicarboxylic acid, it is preferred that R′ is an C1-7-acyl, preferably acetyl, trifluoroacetyl, propionyl or benzoyl group, or a substituted benzoyl group.
If R′ is
the respective compound is an acetal, which can be formed by the reaction of the respective protecting agent with the phenolic group (OH). In this case, the protecting agent may be for example, a respective aldehyde, alkyl halide, e.g. MeO(CH2)2OCH2Cl, or an enol ether, e.g. 3,4-dihydro-2H-pyran.
In this case, the substituent R′ is preferably
with n=0 or 1.
In some instances, acetals are also called “ethers”, particularly in the cases mentioned above: methoxymethyl ether (MOM-ether), β-methoxyethoxy-methyl ether (MEM-ether) or tetrahydropyranyl ether (THP-ether).
In another preferred embodiment, the respective compound is an ester of phosphoric acid, pyrophosphoric acid, phosphorous acid, sulphuric acid or sulphurous acid.
Depending on the reaction conditions, the esterification is either complete or partial, leaving some residual acid groups of the respective acid non-esterified.
It is most preferred that the protecting group R′ is a benzoyl group or a C1-4-acyl group, particularly acetyl or trifluoroacetyl group, more particularly acetyl group. The molecules in which R′ represents an acyl group, particularly an acetyl group, can be easily prepared from the corresponding unprotected molecule by esterification, and the unprotected phenolic compound can be obtained from the corresponding ester by ester hydrolysis.
The phenol protecting group can be cleaved by a deprotecting reaction step b), as discussed later.
It is preferred that R′ is a phenol protecting group of the formula
It is preferred that n=0 or 1 or 2, preferably 1 or 2, most preferably n=2.
Examples of preferred compounds of the formula (IIIa) are compounds selected from the group consisting of
particularly selected from the group consisting of
It is more preferred that all double bonds are in the E-configuration.
Most preferred compounds of formula (IIIa) are 3,7,11-trimethyldodeca-2,6,10-trien-1-ol, preferably (6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol, also known as farnesol; and 3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-ol, preferably (6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-ol, also known as geranylgeraniol. Particularly preferred are (2E,6E)-farnesol und (2E,6E,10E)-geranylgeraniol.
Examples for preferred compounds of the formula (IIIb) are compounds selected from the group consisting of
particularly selected from the group consisting of
Most preferred compounds of formula (IIIb) are 3,7,11-trimethyldodeca-1,6,10-trien-3-ol, preferably (E)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol, also known as nerolidol; and 3,7,11,15-tetramethylhexadeca-1,6,10,14-tetraen-3-ol, preferably (6E,10E)-3,7,11,15-tetramethylhexadeca-1,6,10,14-tetraen-3-ol, also known as geranyllinalool.
The compound of the formula (IIIa) and (IIIb), particularly geranyllinalool and geranylgeraniol, can either be prepared by known methods in industrial quantities or are also commercially available, for example from Sigma-Aldrich or from natural sources/bio-based sources, such as disclosed by John A. Hyatt et al., Organic Process Research and Development 2002, 6, 782-787.
The compound of the formula (II) is reacted with a compound of the formula (IIIa) or (IIIIb) in the presence of a acidic catalyst which is either camphorsulfonic acid or BiCl3 or Gd(OTf)3 or Tm(OTf)3 or Al(OTf)3 or Y(OTf)3 or Fe(OTf)2.
It has been found that only a very small number of Brønsted or Lewis acids are suitable as acidic catalyst for the reaction of this invention.
In one embodiment, the acidic catalyst is camphorsulfonic acid. Camphorsulfonic acid as used in this document is camphor-10-sulfonic acid:
Preferably, camphorsulfonic acid is in its (+) form.
In another embodiment, the acid catalyst is BiCl3.
In another embodiment, the acidic catalyst is the triflate of gadolinium or thulium or aluminum or yttrium or iron. Preferred triflates are Gd(OTf)3 and Al(OTf)3 and Fe(OTf)2.
It is preferred that in above reaction, the molar ratio of the compound of formula (II) to the compound of formula (IIIa) or (IIIb) is in the range of between 3 and 1, preferably between 2.5 and 1.1, more preferably between 2.0 and 1.2.
Furthermore, it is preferred that the molar ratio of the compound of the formula (II) to the acidic catalyst is 0.001 mol % to 1 mol %, preferably 0.005% to 1 mol %, more preferably 0.02 to 1 mol %.
Said reaction is performed at a temperature of between 20° C. and 160° C., preferably between 80 and 120° C.
Furthermore, the reaction is typically performed at ambient pressure.
It is preferred that said reaction is performed in one embodiment in the presence of a solvent which is a hydrocarbon, preferably toluene, or a C5-10 alkane, most preferred hexane or heptane.
It is preferred that said reaction is performed in another embodiment the presence of a solvent which is an organic carbonate, preferably a carbonate of the the formula (X)
Preferably the organic carbonate is ethylene carbonate or propylene carbonate. It is also possible that mixtures of different carbonate of the formula (X) are used, particularly as binary or ternary mixture of ethylene carbonate and/or propylene carbonate and/or butylene carbonate, most preferably as a binary mixture of ethylene carbonate and propylene carbonate. It is preferred that the ratio of ethylene carbonate to propylene carbonate is between 20:80 to 80:20, particularly 25:75 to 75:25.
Preferably, the solvent of the formula is a carbonate solvent as commercialized by Huntsman under the trademark Jeffsol®, particularly the blends of ethylene carbonate with propylene carbonate Jeffsol® EC-75, Jeffsol® EC-50 and Jeffsol® EC-25.
In a further, even more preferred, embodiment said reaction is performed in the presence of a two-phase solvent mixture comprising at least one hydrocarbon and at least one organic carbonate. Said hydrocarbon is preferably toluene, or a C5-10 alkane, most preferred hexane or heptane. Said organic carbonate is preferably a carbonate of the formula (X). Also in this embodiment the organic carbonate used can be a mixture of different carbonates of the formula (X), particularly as binary or ternary mixture of ethylene carbonate and/or propylene carbonate and/or butylene carbonate, most preferably as a binary mixture of ethylene carbonate and propylene carbonate. If mixtures of ethylene carbonate and propylene carbonate are used together with the hydrocarbon, it is preferred that the ratio of ethylene carbonate to propylene carbonate is between 20:80 to 80:20, particularly 25:75 to 75:25.
Most preferably, the reaction is performed in a two-phase solvent mixture of hexane and/or heptane with ethylene carbonate and/or propylene carbonate.
It is preferred that all bonds having dotted lines in formula (I) and (IIIa) and (IIIb) represent carbon-carbon double bonds.
The compound of the formula (I) can be oxidized to the compound of the formula (V) and cyclized to the compound of formula (VI).
Hence, in a further aspect, the present invention relates to a process of manufacturing the compound of the formula (VI)
When the compound of the formula (I) has phenolic groups in a protected form, i.e. R═R′, the respective protection group needs to be removed by a deprotection reaction in a step b) to yield the respective deprotected compound of the formula (I′)
The conditions for said deprotection reaction in step b) depend on the kind of phenol protecting group and are known to the person skilled in the art. For example, esters can be easily deprotected under the influence of an acid or a base or acetals can be easily deprotected under the influence of acids.
Esters, such as acetate, are particularly cleaved to yield the respective unprotected phenol by lithium aluminum hydride.
The oxidation in step c) can be performed by the use of a suitable oxidizing agent, preferably with silver oxide in the presence of an acid, particularly acetic acid, or with oxygen or air in methanol.
In step d), the compound of the formula (V) is cyclized to the compound of the formula (VI) in the presence of a basic catalyst.
Said basic catalyst is preferably either an organic amine, preferably an organic tertiary amine, or a metal hydroxide or carbonate, particularly an organic tertiary amine or an alkali metal hydroxide.
It has been shown that the conjugated acids of said basic catalysts having a pKa of between 8.6 and 15.7, particularly of between 9 and 15.7, measured in water, are particularly suitable. This means that the basic catalyst has preferably a pKb of between 5.4 and 0, particularly of between 5 and 0.
A few, non-limiting, examples of pka of the corresponding acids for:
1pka of the corresponding conjugated acid
2H. Ripin; D. A. Evans (2002). “pKa's of Nitrogen Acids” https://organicchemistrydata.org/hansreich/resources/pka/pka data/evans
3https://www.aatbio.com/data-sets/pka-and-pkb-reference-table
4basic catalysts which are less preferred (pka < 8.6)
In one embodiment the basic catalyst is an organic amine, particularly selected from the group consisting of 4-dimethylaminopyridine (=DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (=DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (=DBN), 1,4-diazabicyclo[2.2.2]octane (=DABCO), 1-azabicyclo[2.2.2]octane (=quinuclidine) and sparteine, preferably from the group consisting of 4-dimethylaminopyridine (=DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (=DBU) and 1-azabicyclo[2.2.2]-octane (=quinuclidine).
In another embodiment the basic catalyst is preferably a hydroxide or a carbonate, preferably a hydroxide, of an alkali metal or an earth alkali metal, particularly an alkali metal hydroxide. In this embodiment, most preferably, the basic catalyst is NaOH or KOH.
It is preferred that the ring closing step is performed in a hydrocarbon solvent, particularly in toluene.
In case a hydrocarbon solvent is used, the solvent is preferably used in such an amount that the solution with the compound of the formula (V) is between 0.05 and 5 molar, more preferred between 0.1 and 1 molar, in respect to the compound of the formula (V).
In case of water being present, it is preferred that the ring closure reaction is performed in a two-phase system, i.e. water phase and organic phase, particularly with a water and organic solvent phase
It is preferred that the basic catalyst is present in catalytical amounts, i.e. the basic catalyst is not present in stoichiometric amounts relative to the compound of the formula (V), but in significantly lower amounts, i.e. the molar ratio of the basic catalyst to the compound of the formula (V) is preferably 1:1′000 to 1:5, particularly 1:100 to 1:10.
The ring closing step is typically performed under stirring preferably at a temperature of between 40 and 200° C., preferably between 90 and 150° C., more preferably at the reflux temperature of the organic solvent when an organic solvent is used, and/or at a pressure of between 1 bara and 10 bara. It is further preferred that this reaction is performed under inert atmosphere, preferably under nitrogen.
The compound of the formula (VI) can be hydrogenated by means of a hydrogenation agent either compound of the formula (VIIII) (partial hydrogenation) or (IX) (complete hydrogenation)
Hence, in a further aspect the present invention relates to a process of manufacturing a compound of the formula (VIII)
In the partial hydrogenation of step ii) only the carbon-carbon double bond in the ring is hydrogenated whereas the olefinic carbon-carbon double bonds are not hydrogenated (“partial hydrogenation”), so that the hydrogenation leads to the compound of the formula (VIII).
The hydrogenating agent used in step ii) is a hydrogenating agent which only hydrogenates the carbon-carbon double bond of the ring in formula (VIII). Particularly suitable as hydrogenating agent is sodium/ethanol such as described by Schudel, Mayer, Isler, Helv. Chim. Acta 46, 2517-2526 (1963), particularly in the last paragraph on page 2524.
This process particularly leads to α-tocotrienol, which has three double bonds in the side chain. α-Tocotrienol is an important compound in natural vitamin E.
Hence, in a further aspect the present invention relates to a process of manufacturing a compound of the formula (IX)
The hydrogenating agent used in step ii′) is a hydrogenating agent which hydrogenates all olefinic carbon-carbon double bond of the ring in formula (VI). Particularly suitable as hydrogenating agent is hydrogen in the presence of a transition metal from the groups 7, 8, 9 or 10, particularly selected form the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co, and Ni, more preferably Pd.
The heterogenous transition metal catalyst is preferably a heterogenous supported transition metal catalyst.
Such hydrogenation is disclosed for example by Kabbe and Heitzer, Synthesis 1978, 12, 888-889.
In this embodiment, the transition metal is supported on a carrier, i.e. palladium is attached to/or deposited on a carrier. The carrier is a solid material.
Preferably said carrier is carbon or an inorganic carrier. Preferred inorganic carriers are oxides or carbonates. Preferred oxides are oxides of Si, Al, Ce, Ti or Zr, particularly of Al or Si. Particularly preferred are silicon dioxide, alumina and titanium dioxide and ceria.
In case the support is Ce, the preferred oxide is CeO2. Preferably, the oxide of Al is Al2O3 and AlO(OH). Particularly preferred is Al2O3.
It is preferred to perform the hydrogenation under pressure, particularly under a hydrogen pressure of 2 to 20 bar. It is further preferred to perform the hydrogenation at a temperature between 0° C. and 100° C.
This process particularly leads to α-tocopherol, which has a completely saturated side chain. α-Tocopherol is an important compound in natural vitamin E.
The compound of the formula (I-A) is new. Hence, in a further aspect, the invention relates to a compound of the formula (I-A)
As already pointed out R′ represents a phenol protecting group and the wavy line represents a carbon-carbon bond which is linked to the carbon-carbon double bond which is either in the Z- or in the E-configuration. The protecting group has been discussed in great detail above. In this embodiment, the protecting group R′ is preferably an acetyl group.
It has been shown that an E/Z mixture is prepared from
in the presence of according to the process discussed above in great detail.
The E/Z mixture can be separated by chromatography, if needed.
As this invention demonstrates, the compound of the formula (I) is a very suitable agent for the synthesis of compound of the formula (V′), (VI′) and (VIII′) respectively (IX′)
The present invention is further illustrated by the following experiments.
Geranyllinalool (12.51 g (43 mmol)), 65 ml of a mixture ethylene carbonate/heptane (1.17/1 g/g) and 9.91 g (65 mmol) of 2,3,6-trimethylhydroquinone (TMHQ) have been added under stirring in the presence of the catalyst indicated in table 1 to yield 2,3,5-trimethyl-6-((2E,6E,10E)-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraen-1-yl)benzene-1,4-diol in conversion and yield as indicated in table 1.
1in all experiments of this document (+)-camphorsulfonic acid is used.
Geranylgeraniol (3.45 g (12 mmol)), 15 ml of a mixture ethylene carbonate/heptane (1.17/1 g/g) and 2.29 g (15 mmol) of 2,3,6-trimethylhydroquinone (TMHQ) have been added under stirring in the presence of the catalyst indicated in table 2 to yield 2,3,5-trimethyl-6-((2E,6E,10E)-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraen-1-yl)benzene-1,4-diol in conversion and yield as indicated in table 2.
Geranylgeraniol (3.42 g (12 mmol)), 15 ml of a mixture ethylene carbonate/heptane (1.17/1 g/g) and 2.91 g (15 mmol) of 2,3,6-trimethylhydroquinone-1-acetate have been added under stirring in the presence of the catalyst indicated in table 3 to yield 4-hydroxy-2,3,6-trimethyl-5-((2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl)phenyl acetate in conversion and yield as indicated in table 3.
Geranyllinalool (12.51 g (43 mmol)), 65 ml of a mixture ethylene carbonate/heptane (1.17/1 g/g) and 16.54 g (65 mmol) of 2,3,6-trimethylhydroquinone-1-benzoate have been added under stirring in the presence of the catalyst indicated in table 4 to yield 4-hydroxy-2,3,6-trimethyl-5-((2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl)phenyl benzoate in conversion and yield as indicated in table 4.
A solution of 2.19 g (11.3 mmol) of 2,3,6-trimethylhydroquinone-1-acetate and the amount of the catalyst indicated in table 5 in a mixture of 5.95 g of ethylene carbonate and 7.5 ml of n-heptane (ethylene carbonate/n-heptane 1.17/1 g/g) was heated to reflux under stirring. 2.2 g (7.5 mmol) of (all-E)-geranyllinalool were added. After removal of ethylene carbonate phase by extraction with heptane, 4-hydroxy-2,3,6-trimethyl-5-((6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl)phenyl acetate has been obtained in the yield as indicated in table 5.
1Yield in the E-isomer
2Yield in the Z-isomer
3Yield Total yield (E + Z) determined by GC using internal standard.
A solution of 2.19 g (11.3 mmol) of 2,3,6-trimethylhydroquinone-1-acetate and the amount of the catalyst indicated in table 6 in a mixture of 5.95 g of ethylene carbonate and 7.5 ml of n-heptane (ethylene carbonate/n-heptane 1.17/1 g/g) was heated to reflux under stirring. 1.69 g (7.5 mmol) of (all-E)-farnesol or E-nerolidol were added. After removal of ethylene carbonate phase by extraction with heptane, 4-hydroxy-2,3,6-trimethyl-5-((6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)phenyl acetate has been obtained in the yield as indicated in table 6.
1determined by GC using internal standard
| Number | Date | Country | Kind |
|---|---|---|---|
| 21170909.2 | Apr 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/061093 | 4/26/2022 | WO |
