EP4673422A1 - Synthesis of dimethylphenol or trimethylphenol from 2,5-dimethylfuran using a platinum catalyst - Google Patents

Synthesis of dimethylphenol or trimethylphenol from 2,5-dimethylfuran using a platinum catalyst

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Publication number
EP4673422A1
EP4673422A1 EP24707578.1A EP24707578A EP4673422A1 EP 4673422 A1 EP4673422 A1 EP 4673422A1 EP 24707578 A EP24707578 A EP 24707578A EP 4673422 A1 EP4673422 A1 EP 4673422A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
process according
catalyst
dimethylfuran
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24707578.1A
Other languages
German (de)
French (fr)
Inventor
Thomas Baldinger
Werner Bonrath
Alissa GOETZINGER
Rolf Kuenzi
Ulla Letinois
Jan Schuetz
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DSM IP Assets BV
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DSM IP Assets BV
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Filing date
Publication date
Application filed by DSM IP Assets BV filed Critical DSM IP Assets BV
Publication of EP4673422A1 publication Critical patent/EP4673422A1/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
    • C07C37/14—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by addition reactions, i.e. reactions involving at least one carbon-to-carbon unsaturated bond
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
    • C07C39/06—Alkylated phenols
    • C07C39/07—Alkylated phenols containing only methyl groups, e.g. cresols, xylenols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/828—Platinum

Definitions

  • the present invention relates to the synthesis of dimethylphenol or trimethylphenol.
  • Trimethylphenols and dimethylphenols are key compounds in the synthesis of tocopherols, particularly a-tocopherol, especially (all-rac)-a-tocopherol.
  • Several approaches to their synthesis have been suggested.
  • WO 2015/110654 A1 discloses the synthesis of 2,3,6-trimethylphenol from 2,5-dimethylfuran and propyne using a gold catalyst.
  • WO 2015/110655 A1 discloses the synthesis of 2,5-dimethylphenol from 2,5-dimethylfuran and acetylene using a gold catalyst.
  • Platinum catalysts are regularly used on industrial large scale, particularly in hydrogenation and oxidation reactions. Hence, the availability of suitable gold catalysts is significantly limited in volume and, hence, the use of cost of gold catalysts is significantly higher than for platinum catalysts.
  • the use of a catalyst which is an alternative to the gold catalyst has, therefore, a high impact on the cost and is of high financial interest in the production of 2,5-dimethylphenol and 2,3,6-trimethylphenol, respectively of tocopherols.
  • 2,5-dimethylfuran is very interesting as it can be obtained from a renewable source (cellulose) as known from the prior art such as Y. Roman- Leshkov, C. J. Barrett, Z. Y. Liu, J. A. Dumesic, Nature 2007, 447, 982-985 ).
  • the problem to be solved by the present invention is to offer a synthetic pathway towards dimethylphenols or trimethylphenols, particularly 2,3,6- trimethylphenol, which is based on platinum catalysts.
  • platinum catalysts which are available in large amounts from different suppliers can be used for this reaction as they are also known and used for other hydrogenation reactions in the synthesis of a-tocopherol. This of course is further advantageous in view of logistics, as the same catalyst can be used for different steps in the synthesis of vitamin E.
  • a further advantage of the invention is the formation dimethylphenols or trimethylphenols in high yields and selectivity in a single step reaction from 2,5- dimethylfuran, and, hence, is a very sustainable approach of dimethylphenols or trimethylphenols or a-tocopherol, respectively. Further aspects of the invention are subject of further independent claims.
  • the present invention relates to a process for manufacturing a mixture of the compound of the formula (la) and the compound of the formula (lb) comprising the step of reacting the compound of the formula (II) with the compound of the formula (III) X TM o
  • the propyne can be also mixed with propadiene.
  • MAF gas is a cheap process gas and can is commercially available from different suppliers.
  • Said platinum catalyst is either in the form of a platinum salt or platinum complex.
  • said platinum catalyst is preferably a Pt(ll) salt, particularly PtC .
  • said platinum catalyst is preferably a complex of Pt(ll), particularly a complex of Pt(ll) having at least one organic ligand comprising at least one phosphorous atom, particularly a ligand selected from the group consisting of phosphites, phosphates, phosphonates, and phosphines.
  • Pt catalyst is PtC I2 in the presence of an organic ligand comprising at least one phosphorous atom, particularly a ligand selected from the group consisting of phosphites, phosphates, phosphonates, and phosphines.
  • the amount of the Pt catalyst is present in an amount in the range of 0.1 - 25 mol %, particularly 6 -12 mol %, in respect to the compound of the formula (II).
  • molar ratio of the above-mentioned organic ligand comprising at least one phosphorous atom to Pt is in the range of 1 - 2, preferably 0.5 - 1 .5, more preferably 0.4 - 1 .2.
  • the molar ratio of compound of the formula (II) to compound of the formula (III) is in the range of 1 :1 to 1 :8, particularly of 1 :1 to 1 :8, preferably 1 :1 to 1 :3.
  • reaction is performed at a temperature of between 0°C and 80°, particularly of between 10°C and 60°C, preferably of between 20°C and 30°C.
  • the reaction is preferably performed under pressure.
  • the dimethyl phenol or trimethylphenol of formula (lb) is able to form the required hydroquinone of the formula (lb 1 ).
  • the dimethyl phenol or trimethylphenol of the formula (la) has a methyl group in the para position to the phenolic group and, consequently, the direct formation of the needed hydroquinone is not possible.
  • the dimethyl phenol or trimethylphenol of formula (la) does not take part in the further reaction steps of the formation of a-tocopherols, respectively p-tocopherols, and is removed during the reaction processing and/or and purification from the a-tocopherols or p-tocopherols, respectively.
  • 2.3.6-trimethylphenol, respectively a-tocopherols is the most important embodiment of the present innovation, mainly due to the fact that the volume of 2,3,6-trimethylphenol, respectively a-tocopherols, produced worldwide is several magnitudes larger than the volume of 2,5-dimethylphenol (2,5-DMP), respectively P-tocopherols.
  • the methylation in step a’) can be performed by different methods.
  • the mixture of 2,4-DMP and 2,5-DMP is methylated for example in an autoclave with methanol in the presence of lithium hydroxide monohydrate at elevated temperatures as disclosed in EP 1 108 705 A1 , particularly by example 3 to yield a mixture of mesitol and 2,3,6-TMP, the whole disclosure of which is incorporated herein by reference.
  • the methylation of the mixture of 2,4- DMP and 2,5-DMP is achieved by gas phase methylation, particularly by subjecting the mixture of 2,4-DMP and 2,5-DMP to a mixture of methanol and, optionally, water in the presence of an oxidic catalyst in inert atmosphere at a temperature of between 300 and 500°C, to yield a mixture of mesitol and 2,3,6- TMP.
  • This process produces less of waste material, allows a continuous process and is, therefore, economically and ecologically highly advantageous.
  • the present invention relates to a process of comprising the following steps a) manufacturing a mixture of the compound of the formula (la) and the compound of the formula (lb) by a process as discussed above in detail,
  • any wavy line represents a carbon-carbon bond which when linked to the carbon-carbon double bond is either in the Z- or in the E- configuration.
  • Q represents a halide, preferably Q represents Cl.
  • the acyloxy is preferably a group of the formula wherein R 10 represents either an Ci -6-alkyl or an aryl group, which is optionally substituted, particularly by at least one Ci-6-alkyl group.
  • R 10 represents either an Ci -6-alkyl or to a phenyl group.
  • R 10 represents either a methyl or a phenyl group, most preferably a methyl group.
  • Particular examples for compounds of formula (X-A) are isophytol, isophytyl chloride, isophytyl bromide, isophytyl iodide, isophytyl acetate, isophytyl methanesulfonate, isophytyl ethanesulfonate, isophytyl benzenesulfonate, and isophytyl toluenesulfonate.
  • Particular examples for compounds of formula (X-B) are phytol, phytyl chloride, phytyl bromide, phytyl iodide, phytyl acetate, phytyl methanesulfonate, phytyl ethanesulfonate, phytyl benzenesulfonate, and phytyl toluenesulfonate.
  • the compound of formula (X-B) can be used as E/Z-mixture as well as in pure E- or pure Z-form. Preferred is their use as E/Z-mixtures.
  • Q represents preferably OH or Cl.
  • preferred as compound of formula (X-A) or (X-B) are phytol, isophytol, phytyl chloride or isophytyl chloride, more preferred phytol or isophytol. Most preferred is isophytol.
  • step a) The use of compounds of formula (X-A) are preferred over compounds of formula (X-B). Details for step a) as well as its preferred embodiments, amounts ratio and conditions have already been discussed above in detail.
  • Steps b) and c) are principally known by the person skilled in the art for example from W. Bonrath et al. Angew. Chem. Int. Ed. 2012, 51 , 12982-12985 or Bonrath, W. et al. (2021 ). Vitamins, 4. Vitamin E (Tocopherols, Tocotrienols). In Ullmann's Encyclopedia of Industrial Chem istry. https ://doi . orq/ 10.1002/14356007.o27 o07.pub2
  • step b) the compound of the formula (lb) is oxidized to the corresponding quinone, followed by reduction to the hydroquinone of the formula (lb 1 ).
  • This process of synthesizing tocopherol of the formula (XI) has the advantage that it is very sustainable.
  • the aromatic part is accessible from the compound of formula (lb) as discussed before in detail.
  • the building block of the side chain i.e. isophytol
  • the whole process of synthesizing said tocopherol is highly sustainable.
  • composition of 2,5-dimethylfuran and acetylene or propyne in the presence of a platinum catalyst leads to the manufacturing of a mixture of the compound of the formula (la) and the compound of the formula (lb), in a further aspect the present invention relates to a composition comprising
  • the compound of the formula (lb) represents a key intermediate in the new route of synthesis for a-tocopherols and p-tocopherols.
  • the present invention is further illustrated by the following experiments.
  • results of table 1 show that particularly the ligands having an aromatic substituent are suitable as part of the platinum catalyst.
  • the ligand P(PhsF)3 (tns(pentafluoro- phenyl)phosphine) is one of the most suitable ligands.
  • table 1 shows that acetone and 3-pentanone are particularly well suited as organic solvents.
  • 2,5-Dimethylfuran was reacted with propyne (2% by weight) in an organic solvent and a platinum catalyst as indicated in table 2.
  • the platinum chloride (6 mol%), 2,5-dimethylfuran (1.0 equivalent) and propyne (1.0 equivalent) dissolved (2% by weight) in the respective organic solvent were added to a 10 ml vial with a magnetic stirrer bar under argon atmosphere.
  • the vial was then sealed with a cap and the mixture was stirred in an aluminium block at 23°C during a time as indicated in table 2.
  • the reaction mixture was then filtered to remove the catalyst and ligand.
  • a gas-phase flow reactor was filled with an iron oxide-based catalyst (13 g). The reactor was closed and heated under nitrogen to 350 °C in the reactor.
  • the feed consisted of a mixture of 2,5-dimethyl phenol and 2,4-dimethyl phenol (example 2) and methanol and water in a molar ratio of 0.35 : 0.65 : 30 : 1 .7.
  • the mixture was pumped at 0.39 ml/min from top to bottom into the gas-phase reactor. After the heated zone the reaction mixture was cooled to room temperature and collected in a bottle. The bottle was emptied and analysed after each 24 h for five days.

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
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Abstract

The present invention relates to the manufacturing of dimethylphenols, particularly 2,5-dimethylphenol, respectively trimethylphenols, particularly 2,3,6-trimethylphenol, from 2,5-dimethylfuran and acetylene, respectively propyne, particularly in MAP gas, in the presence of a platinum catalyst. This invention offers a sustainable synthesis of β-tocopherols, respectively α-tocopherols.

Description

SYNTHESIS OF DIMETHYLPHENOL OR TRIMETHYLPHENOL FROM 2,5- Dl METHYLFURAN USING A PLATINUM CATALYST
Technical Field
The present invention relates to the synthesis of dimethylphenol or trimethylphenol.
Background of the invention
Trimethylphenols and dimethylphenols are key compounds in the synthesis of tocopherols, particularly a-tocopherol, especially (all-rac)-a-tocopherol. Several approaches to their synthesis have been suggested.
WO 2015/110654 A1 discloses the synthesis of 2,3,6-trimethylphenol from 2,5-dimethylfuran and propyne using a gold catalyst.
WO 2015/110655 A1 discloses the synthesis of 2,5-dimethylphenol from 2,5-dimethylfuran and acetylene using a gold catalyst.
The formation of phenolic compounds from 2,5-dimethylfuran and certain substituted alkynes in the presence of a gold (I) catalyst has been disclosed by N. Huguet et al., Chem. Eur. J. 2013, 19, 6581-6585. Disadvantageous is the formation of hydroarylation side products, which are regularly formed at significant amounts.
Platinum catalysts are regularly used on industrial large scale, particularly in hydrogenation and oxidation reactions. Hence, the availability of suitable gold catalysts is significantly limited in volume and, hence, the use of cost of gold catalysts is significantly higher than for platinum catalysts. The use of a catalyst which is an alternative to the gold catalyst has, therefore, a high impact on the cost and is of high financial interest in the production of 2,5-dimethylphenol and 2,3,6-trimethylphenol, respectively of tocopherols.
In the methods described in the state of the art, expensive catalyst with limited selectivity are applied and the described procedures need separation methods for product isolation. The use of 2,5-dimethylfuran is very interesting as it can be obtained from a renewable source (cellulose) as known from the prior art such as Y. Roman- Leshkov, C. J. Barrett, Z. Y. Liu, J. A. Dumesic, Nature 2007, 447, 982-985 ).
Sustainability of chemical processes has gained tremendous importance in the public and marketplace.
Therefore, there is a high interest in a synthesis of 2,5-dimethylphenol and 2,3,6-trimethylphenol from renewable sources.
Summary of the invention
Therefore, the problem to be solved by the present invention is to offer a synthetic pathway towards dimethylphenols or trimethylphenols, particularly 2,3,6- trimethylphenol, which is based on platinum catalysts.
Surprisingly, it was found that the process according to claim 1 offers a solution to this problem.
Surprisingly, it was found that the disadvantage of the procedures of the state of the art can be circumvented by applying platinum-based catalysts in the reaction of 2,5-dimethylfuran and ethyne or propyne, particularly in MAF gas.
It was found that a catalyst based on platinum can be used for this synthesis, although up to now it has not been known that platinum catalysts can be used for the reaction of 2,5-dimethylfuran and alkynes to dimethylphenols or trimethylphenols in excellent selectivity. Surprisingly, the formation of hydroary- lation products, as regularly encountered for the respective gold catalysed reaction, has not been found.
Therefore, platinum catalysts, which are available in large amounts from different suppliers can be used for this reaction as they are also known and used for other hydrogenation reactions in the synthesis of a-tocopherol. This of course is further advantageous in view of logistics, as the same catalyst can be used for different steps in the synthesis of vitamin E.
A further advantage of the invention is the formation dimethylphenols or trimethylphenols in high yields and selectivity in a single step reaction from 2,5- dimethylfuran, and, hence, is a very sustainable approach of dimethylphenols or trimethylphenols or a-tocopherol, respectively. Further aspects of the invention are subject of further independent claims.
Particularly preferred embodiments are subject of dependent claims.
Detailed description of the invention In a first aspect the present invention relates to a process for manufacturing a mixture of the compound of the formula (la) and the compound of the formula (lb) comprising the step of reacting the compound of the formula (II) with the compound of the formula (III) X ™ o
HC^ C - R (III) wherein R represents H or CH3, preferably CH3; in the presence of a Pt catalyst, which is either in the form of a Pt salt or of a Pt complex.
For sake of clarity, it is stressed that 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.
2,5-Dimethylfuran is reacted with either propyne (R=CH3) or with acetylene (R=H). Both propyne and acetylene are gases. Their handling is different as compared to liquid alkynes. Particularly the dosage, respectively pressure control, requires respective due care and knowledge.
In case of R representing CH3, the propyne can be also mixed with propadiene. A particular mixture comprising propyne and propadiene is known as MAF gas (MAF = methylacetylene-allene fraction) to the person skilled in the art. MAF gas is a cheap process gas and can is commercially available from different suppliers.
In order to enable the reaction of 2,5-dimethylfuran with propyne or acetylene to occur, the presence of a platinum catalyst is required. It is a key element that this process is using a platinum catalyst and not a gold catalyst and is, hence, a platinum-based and gold-free process.
Said platinum catalyst is either in the form of a platinum salt or platinum complex.
In one embodiment, said platinum catalyst is preferably a Pt(ll) salt, particularly PtC .
In another embodiment said platinum catalyst is preferably a complex of Pt(ll), particularly a complex of Pt(ll) having at least one organic ligand comprising at least one phosphorous atom, particularly a ligand selected from the group consisting of phosphites, phosphates, phosphonates, and phosphines.
Particularly preferred as Pt catalyst is PtC I2 in the presence of an organic ligand comprising at least one phosphorous atom, particularly a ligand selected from the group consisting of phosphites, phosphates, phosphonates, and phosphines.
Said organic ligand is preferably selected from the group consisting of triphenylphosphite (P(OPh)3), diphenylphosphate ((PhO)2P=O(OH)), triphenylphosphate ((PhO)3P=O), triethylphosphate ((EtO)3P=O), dibenzylphosphite ((PhCH2O)2P=O(H)), methyldiphenylphosphite ((Me0)P(0Ph)2), triphenylphosphine (P(Ph)3), P(Ph5F)3, bis-(2,2,2-trifluorethyl)-phosphite ((CF3CH2O)2P=O(H)), triethyl 2-fluoro-2-phosphonoacetate ((CHFCOOEt)(EtO)2P=O), tris(2-tolyl)- phosphite, ethyl 3-(diethoxyphosphoryl)propanoate (=triethyl 3-phosphono- propionate) ((CH2CH2COOEt)(EtO)2P=O), 2-(diphenylphosphino)benzoic acid (P(Ph)2CeH4COOH), 3,9-Bis(2,4-di-tert-butylphenoxy)-2,4,8, 10-tetraoxa-3,9- diphosphaspiro[5.5]undecane (Ultranox 626), P(O-isooctyl)3), P(O-isopropyl)3), P(O/-PrFe)3, P(0n-Bu)3, bis(2,4-di-tert-butylphenoxy)-X2-phosphane, CH3P(EtO)2, 1 , 1 '-binaphthy I-2 , 2'-d iy I hydrogenphosphate (=4-hydroxydinaphtho[2, 1 -d 1 ' ,2'- f][1 ,3,2]dioxaphosphepine 4-oxide), VAPOL hydrogen phosphate (=18-hydroxy- 8,9-diphenyldiphenanthro[4,3-c/:3',4'-f][1 ,3,2]dioxaphosphepine 18-oxide), methyltriphenoxyphosphonium iodide ([CH3P(OPh)3]+l; 4-ethyl-2,6,7-trioxa-1- phosphabicyclo[2.2.2]octane ((CH2CH2COOEt)(EtO)2P=O, trimethylolpropane phosphite), trisodium triphenylphosphine trisulfonate (=TPPTS), disodium triphenylphosphinedisulfonate (= TPPDS) and sodium triphenylphosphinemonosulfonate (= TPPMS); wherein Ph represents phenyl, PhsF represents pentafluorophenyl and Et represents ethyl and Me represents methyl.
The organic ligand is more preferably selected from the group consisting of triphenylphosphite (P(OPh)3), diphenylphosphate ((PhO)2P=O(OH)), dibenzylphosphite ((PhCH2O)2P=O(H)), triphenylphosphate ((PhO)3P=O), methyldiphenylphosphite ((Me0)P(0Ph)2), trisodium triphenylphosphine trisulfonate (=TPPTS), P(PhsF)3, bis-(2,2,2-trifluorethyl)-phosphite ((CF3CH2O)2P=O(H)), tris(2-tolyl)phos- phite, ethyl 3-(diethoxyphosphoryl)propanoate (=triethyl 3-phosphonopropionate) ((CH2CH2COOEt)(EtO)2P=O), 2-(diphenylphosphino)benzoic acid (P(Ph)2CeH4COOH) and 9-Bis(2,4-di-tert-butylphenoxy)-2,4,8, 10-tetraoxa-3,9- diphosphaspiro[5.5]undecane (Ultranox 626); wherein Ph represents phenyl, PhsF represents pentafluorophenyl and Et represents ethyl and Me represents methyl.
It is preferred that said reaction between 2,5-dimethylfuran and propyne or acetylene is performed in the presence of an ether or a ketone, particularly a cyclic ether, preferably tetrahydrofuran, or acetone or methyl ethyl ketone or diethyl ketone (=3-pentanone), preferably acetone or diethyl ketone, more preferably diethyl ketone.
It is further preferred that the amount of the Pt catalyst is present in an amount in the range of 0.1 - 25 mol %, particularly 6 -12 mol %, in respect to the compound of the formula (II).
It is further preferred that molar ratio of the above-mentioned organic ligand comprising at least one phosphorous atom to Pt is in the range of 1 - 2, preferably 0.5 - 1 .5, more preferably 0.4 - 1 .2.
It is preferred that the molar ratio of compound of the formula (II) to compound of the formula (III) is in the range of 1 :1 to 1 :8, particularly of 1 :1 to 1 :8, preferably 1 :1 to 1 :3.
It is further preferred that the reaction is performed at a temperature of between 0°C and 80°, particularly of between 10°C and 60°C, preferably of between 20°C and 30°C.
At temperatures being above the boiling point of the solvent, the reaction is preferably performed under pressure.
The above process produces a mixture of the compound of the formula (la) and of the formula (lb).
This, however, is largely irrelevant as in the further reaction sequence towards tocopherols only the compound of the formula (lb) is reactive. Dimethyl phenol, respectively trimethyl phenol, is transformed to the dimethyl or trimethyl hydroquinone, which is then reacted with isophytol (X) or phytol to the respective a-tocopherols or p-tocopherols (XI) as is schematically shown in figure 2.
However, only the dimethyl phenol or trimethylphenol of formula (lb) is able to form the required hydroquinone of the formula (lb1). The dimethyl phenol or trimethylphenol of the formula (la) has a methyl group in the para position to the phenolic group and, consequently, the direct formation of the needed hydroquinone is not possible.
Therefore, the dimethyl phenol or trimethylphenol of formula (la) does not take part in the further reaction steps of the formation of a-tocopherols, respectively p-tocopherols, and is removed during the reaction processing and/or and purification from the a-tocopherols or p-tocopherols, respectively.
In case of R being H, typically, 2,4-DMP (la) is predominantly formed. Hence, the molar ratio of 2,4-DMP : 2,5-DMP is typically larger than 50:50.
Due to the presence of a methyl group in the para position to the phenolic OH group in 2,4-DMP, the formation of a high content in 2,5-DMP is preferred, as indicated above.
It has been observed that the molar ratio of compound of formula (la) (=2,4-dimethylphenol = 2,4-DMP) : compound of formula (lb) (=2,5-dimethylphenol = 2,5-DMP) of typically < 70 : 30, particularly < 60:40, preferably < 50:50.
In case of R being CH3, typically, 2,3,6-TMP (lb) is predominantly formed. Hence, the molar ratio of 2,4,6-TMP : 2,3,6-TMP is typically smaller than 50:50. Hence, the molar ratio of compound of formula (la) (=2,4,6-trimethylphenol =
2.4.6-TMP) : compound of formula (lb) (=2,3,6-trimethylphenol = 2,3,6-TMP) is preferably < 50 : 50, particularly < 10 : 90, more particularly < 5 : 95, preferably < 3 : 97, more preferably < 2 : 98.
This finding is particularly interesting in the context of that the formation of
2.3.6-trimethylphenol, respectively a-tocopherols, is the most important embodiment of the present innovation, mainly due to the fact that the volume of 2,3,6-trimethylphenol, respectively a-tocopherols, produced worldwide is several magnitudes larger than the volume of 2,5-dimethylphenol (2,5-DMP), respectively P-tocopherols.
Therefore, it is very advantageous to minimize the loss due by the formation of the unreactive 2,4,6-trimethylphenol or 2,4-dimethylphenol, respectively,
As a consequence of this, it is preferred to use propyne over acetylene in the above process. Furthermore, it is also advantageous to use MAF as source of propyne
As described above, the mixture of 2,4,6-trimethylphenol (= 2,4,6-TMP, compound of the formula (la)) and 2,3,6-trimethylphenol (= 2,3,6-TMP, compound of formula (lb)) can be prepared from 2,5-dimethylfuran (formula (II)) and propyne or MAF gas (compound of the formula (III) with R=methyl) as pointed out by step aO) in figure 1 .
In a further embodiment, the mixture of 2,4,6-trimethylphenol (= 2,4,6- TMP, compound of the formula (la)) and 2,3,6-trimethylphenol (= 2,3,6-TMP, compound of formula (lb)) can be prepared by methylation of a mixture of 2,4-di- methylphenol (= 2,4-DMP, compound of the formula (la-1 H)) and 2,5-dimethyl- phenol (= 2,5-DMP, compound of formula (lb-1 H)), as pointed out by step a’) in figure 1. Said mixture of 2,4-dimethylphenol (= 2,4-DMP, compound of the formula (la-1 H)) and 2,5-dimethylphenol (= 2,5-DMP, compound of formula (lb-1 H)), can be prepared, as described above, from 2,5-dimethylfuran (formula (II)) and acetylene (compound of the formula (III) with R=H) as pointed out by step aO’) in figure 1 .
The methylation in step a’) can be performed by different methods.
In a preferred manner, the mixture of 2,4-DMP and 2,5-DMP is methylated for example in an autoclave with methanol in the presence of lithium hydroxide monohydrate at elevated temperatures as disclosed in EP 1 108 705 A1 , particularly by example 3 to yield a mixture of mesitol and 2,3,6-TMP, the whole disclosure of which is incorporated herein by reference.
In an even more preferred manner, the methylation of the mixture of 2,4- DMP and 2,5-DMP is achieved by gas phase methylation, particularly by subjecting the mixture of 2,4-DMP and 2,5-DMP to a mixture of methanol and, optionally, water in the presence of an oxidic catalyst in inert atmosphere at a temperature of between 300 and 500°C, to yield a mixture of mesitol and 2,3,6- TMP.
This process produces less of waste material, allows a continuous process and is, therefore, economically and ecologically highly advantageous.
In a further aspect, the present invention relates to a process of comprising the following steps a) manufacturing a mixture of the compound of the formula (la) and the compound of the formula (lb) by a process as discussed above in detail,
HC^=C - R (III)
b) transforming the compound of the formula (lb) to the hydroquinone of the formula (lb1) c) condensing the hydroquinone of the formula (Ib’)of step b) with a compound of the formula (X-A) or of the formula (X-B) to yield the tocopherol of the formula (XI) wherein R represents H or CH3, preferably CH3, and wherein Q is a substituent selected from the group consisting of OH, halide, acyloxy, particularly acetoxy or benzoyloxy, methanesulfonyloxy
(=mesyloxy), ethanesulfonyloxy, benzenesulfonyloxy and toluenesulfonyloxy (=tosyloxy); and wherein any wavy line represents a carbon-carbon bond which when linked to the carbon-carbon double bond is either in the Z- or in the E- configuration. In case Q represents a halide, preferably Q represents Cl.
In case Q represents an acyloxy, the acyloxy is preferably a group of the formula wherein R10 represents either an Ci -6-alkyl or an aryl group, which is optionally substituted, particularly by at least one Ci-6-alkyl group.
Preferably R10 represents either an Ci -6-alkyl or to a phenyl group.
More preferably, R10 represents either a methyl or a phenyl group, most preferably a methyl group.
Particular examples for compounds of formula (X-A) are isophytol, isophytyl chloride, isophytyl bromide, isophytyl iodide, isophytyl acetate, isophytyl methanesulfonate, isophytyl ethanesulfonate, isophytyl benzenesulfonate, and isophytyl toluenesulfonate.
Particular examples for compounds of formula (X-B) are phytol, phytyl chloride, phytyl bromide, phytyl iodide, phytyl acetate, phytyl methanesulfonate, phytyl ethanesulfonate, phytyl benzenesulfonate, and phytyl toluenesulfonate.
The compound of formula (X-B) can be used as E/Z-mixture as well as in pure E- or pure Z-form. Preferred is their use as E/Z-mixtures.
Q represents preferably OH or Cl.
Hence, preferred as compound of formula (X-A) or (X-B) are phytol, isophytol, phytyl chloride or isophytyl chloride, more preferred phytol or isophytol. Most preferred is isophytol.
The use of compounds of formula (X-A) are preferred over compounds of formula (X-B). Details for step a) as well as its preferred embodiments, amounts ratio and conditions have already been discussed above in detail.
Steps b) and c) are principally known by the person skilled in the art for example from W. Bonrath et al. Angew. Chem. Int. Ed. 2012, 51 , 12982-12985 or Bonrath, W. et al. (2021 ). Vitamins, 4. Vitamin E (Tocopherols, Tocotrienols). In Ullmann's Encyclopedia of Industrial Chem istry. https ://doi . orq/ 10.1002/14356007.o27 o07.pub2
In step b) the compound of the formula (lb) is oxidized to the corresponding quinone, followed by reduction to the hydroquinone of the formula (lb1).
This process of synthesizing tocopherol of the formula (XI) has the advantage that it is very sustainable. The aromatic part is accessible from the compound of formula (lb) as discussed before in detail. In case that also the building block of the side chain, i.e. isophytol, is based on renewable sources, the whole process of synthesizing said tocopherol is highly sustainable.
As the composition of 2,5-dimethylfuran and acetylene or propyne in the presence of a platinum catalyst leads to the manufacturing of a mixture of the compound of the formula (la) and the compound of the formula (lb), in a further aspect the present invention relates to a composition comprising
- a compound of the formula (II);
- a compound of the formula (III); and
- Pt catalyst which is either in the form a Pt salt or of a Pt complex;
HC^ C - R (III) wherein R represents H or CH3, preferably CH3.
All the ingredients and their preferred embodiments as well as amounts and ratios have been discussed already above in detail.
The compound of the formula (lb) represents a key intermediate in the new route of synthesis for a-tocopherols and p-tocopherols. Examples
The present invention is further illustrated by the following experiments.
First experimental seriesfexamples 7-26): Reaction of 2,5-dimethylfuran with acetylene 2,5-Dimethylfuran was reacted with acetylene (2% by weight) in an organic solvent and a platinum catalyst as indicated in table 1 .
For this, the platinum chloride (6 mol%), 2,5-dimethylfuran (1.0 equivalent) and acetylene (1.0 equivalent) dissolved (2% by weight) in the respective organic solvent were added to a 10 ml vial with a magnetic stirrer bar under argon atmosphere. The vial was then sealed with a cap and the mixture was stirred in an aluminium block at 23°C during a time as indicated in table 1. The reaction mixture was then filtered to remove the catalyst and ligand. All volatiles (including nonreacted 2,5-dimethylfuran) were removed in vacuo at 50 °C/ <30 mbar to give an oily residue. The amounts of 2,4- and 2,5-dimethylphenol were determined by GC (gas chromatography). The ratio as well as the yield are indicated in table 1 .
Results of table 1 show that particularly the ligands having an aromatic substituent are suitable as part of the platinum catalyst. The ligand P(PhsF)3 (tns(pentafluoro- phenyl)phosphine) is one of the most suitable ligands. Furthermore, table 1 shows that acetone and 3-pentanone are particularly well suited as organic solvents.
All examples of table 1 yield a mixture of 2,4 DMP and 2,5 DMP.
Tab e 1 Reaction of 2,5-dimethylfuran with acetylene in different solvents and different catalysts
1 acetylene 2% in mentioned organic solvent
2 relative to 2,5-dimethylfuran
3 combined yield of 2,4-DMP and 2,5-DMP
42, 4:2, 5: ratio 2,4-DMP : 2,5-DMP (area %)
5 molar ratio acetylene : 2,5-DMF = 2:1
6 molar ratio acetylene : 2,5-DMF = 3:1
6 molar ratio acetylene : 2,5-DMF = 5:1
7 n.d. : not determined Second experimental series (examples 27-36). Reaction of 2,5-dimethylfuran with propyne
2,5-Dimethylfuran was reacted with propyne (2% by weight) in an organic solvent and a platinum catalyst as indicated in table 2. For this, the platinum chloride (6 mol%), 2,5-dimethylfuran (1.0 equivalent) and propyne (1.0 equivalent) dissolved (2% by weight) in the respective organic solvent were added to a 10 ml vial with a magnetic stirrer bar under argon atmosphere. The vial was then sealed with a cap and the mixture was stirred in an aluminium block at 23°C during a time as indicated in table 2. The reaction mixture was then filtered to remove the catalyst and ligand. All volatiles (including nonreacted 2,5-dimethylfuran) were removed in vacuo at 50 °C/ <30 mbar to give an oily residue. The amounts of 2,4,6-TMP and 2,3,6-TMP were determined by GC (gas chromatography). The ratio as well as the yield are indicated in table 2.
Tab e 2 Reaction of 2,5-dimethylfuran with propyne in different solvents and different catalysts
1 propyne 2% in mentioned organic solvent
2 relative to 2,5-dimethylfuran
3 combined yield of 2,4,6-TMP and 2,3,6-TMP
42, 4, 6:2, 3, 6: ratio 2,4,6-TMP and 2,3,6-TMP (area %)) Third experimental series (examples 37-43). Reaction of 2,5-dimethylfuran with MAF 2,5-dimethylfuran was reacted with MAF gas (2% by weight) in an organic solvent and a platinum catalyst as indicated in table 2.
For this, the platinum chloride (6 mol%), 2,5-dimethylfuran (1.0 equivalent) and MAF gas (1.0 equivalent) dissolved (2% by weight) in the respective organic solvent were added to a 10 ml vial with a magnetic stirrer bar under argon atmosphere. The vial was then sealed with a cap and the mixture was stirred in an aluminium block at 23°C during a time as indicated in table 3. The reaction mixture was then filtered to remove the catalyst and ligand. All volatiles (including non- reacted 2,5-dimethylfuran) were removed in vacuo at 50 °C/ <30 mbar to give an oily residue. The amounts of 2,4,6-TMP and 2,3,6-TMP were determined by GC (gas chromatography). The ratio as well as the yield are indicated in table 2.
Tab e 3 Reaction of 2,5-dimethylfuran with propyne/propadiene (MAF) in different solvents and different catalysts
1 MAF 2% in mentioned organic solvent
2 relative to 2,5-dimethylfuran
3 combined yield of 2,4,6-TMP and 2,3,6-TMP
42, 4, 6:2, 3, 6: ratio 2,4,6-TMP and 2,3,6-TMP (area %)
Example 44: Methylation: step a’)
A gas-phase flow reactor was filled with an iron oxide-based catalyst (13 g). The reactor was closed and heated under nitrogen to 350 °C in the reactor. The feed consisted of a mixture of 2,5-dimethyl phenol and 2,4-dimethyl phenol (example 2) and methanol and water in a molar ratio of 0.35 : 0.65 : 30 : 1 .7. The mixture was pumped at 0.39 ml/min from top to bottom into the gas-phase reactor. After the heated zone the reaction mixture was cooled to room temperature and collected in a bottle. The bottle was emptied and analysed after each 24 h for five days.
The average conversion and selectivity over the five days were: Conversion of 2,5-dimethyl phenol: 16%
Conversion of 2,4-dimethyl phenol: 32% Selectivity to 2,3,6-trimethyl phenol: 95% Selectivity to 2,4,6-trimethyl phenol: 89%

Claims

Claims
1 . A process for manufacturing a mixture of the compound of the formula (la) and the compound of the formula (lb) comprising the step of reacting the compound of the formula (II) with the compound of the formula (III) X ■ o
HC^ C - R (III) wherein R represents H or CH3, preferably CH3; in the presence of a Pt catalyst, which is either in the form of a Pt salt or of a
Pt complex.
2. The process according to claim 1 characterized in that in case R represents CH3 the propyne is used in said reaction in combination with propadiene, particularly in the form of MAF gas.
3. The process according to claim 1 or 2, characterized in that the Pt catalyst is a Pt(ll) salt, particularly PtCh
4. The process according to claim 1 or 2, characterized in that the Pt catalyst is a complex of Pt(ll) having at least one organic ligand comprising at least one phosphorous atom, particularly a ligand selected from the group consisting of phosphites, phosphates, phosphonates, and phosphines.
5. The process according to any of the preceding claims characterized in that the Pt catalyst is PtC in the presence of an organic ligand having at least comprising at least one phosphorous atom, particularly a ligand selected from the group consisting of phosphites, phosphates, phosphonates, and phosphines.
6. The process according to claim 4 or 5, characterized in that the organic ligand is selected from the group consisting of triphenylphosphite (P(OPh)s), diphenylphosphate ((PhO)2P=O(OH)), triphenylphosphate ((PhO)3P=O), triethylphosphate ((EtO)3P=O), dibenzylphosphite ((PhCH2O)2P=O(H)), methyldiphenylphosphite ((MeO)P(OPh)2), triphenylphosphine (P(Ph)s), P(Ph5F)3, bis-(2,2,2-trifluorethyl)-phosphite ((CF3CH2O)2P=O(H)), triethyl 2- fluoro-2-phosphonoacetate ((CHFCOOEt)(EtO)2P=O), tris(2-tolyl)phosphite, ethyl 3-(diethoxyphosphoryl)propanoate (=triethyl 3-phosphonopropionate) ((CH2CH2COOEt)(EtO)2P=O), 2-(diphenylphosphino)benzoic acid (P(Ph)2CeH4COOH), 3,9-Bis(2,4-di-tert-butylphenoxy)-2,4,8, 10-tetraoxa-3,9- diphosphaspiro[5.5]undecane, P(O-isooctyl)3), P(O-isopropyl)3), P(O/-PrFe)3, P(On-Bu)3, bis(2,4-di-tert-butylphenoxy)-X2-phosphane, CH3P(EtO)2, 1 ,1 '- binaphthy I-2 , 2'-d iy I hydrogenphosphate (=4-hydroxydinaphtho[2, 1 -d: T ,2'- f][1 ,3,2]dioxaphosphepine 4-oxide), VAPOL hydrogen phosphate (=18- hydroxy-8,9-diphenyldiphenanthro[4,3-c/:3',4'-/][1 ,3,2]dioxaphosphepine 18- oxide), methyltriphenoxyphosphonium iodide ([CH3P(OPh)3] T, 4-ethyl-2,6,7- trioxa-1 -phosphabicyclo[2.2.2]octane ((CH2CH2COOEt)(EtO)2P=O, tri- methylolpropane phosphite), trisodium triphenylphosphine trisulfonate (=TPPTS), disodium triphenylphosphinedisulfonate (= TPPDS) and sodium triphenylphosphinemonosulfonate (= TPPMS); wherein Ph represents phenyl, PhsF represents pentafluorophenyl and Et represents ethyl and Me represents methyl.
7. The process according to any of the preceding claims characterized in that the reaction is performed in the presence of an ether or a ketone, particularly a cyclic ether, preferably tetrahydrofuran, or acetone or methyl ethyl ketone or diethyl ketone, preferably acetone or diethyl ketone, more preferably diethylketone.
8. The process according to any of the preceding claims characterized in that the amount of the Pt catalyst is in the range of 0.1 - 25 mol %, particularly 6 - 12 mol %, in respect to the compound of the formula (II).
9. The process according to any of the preceding claims characterized in that, in case of R being H, the molar ratio of compound of formula (la) : compound of formula (lb) is < 70 : 30, particularly < 60:40, preferably < 50:50.
10. The process according to any of the preceding claims characterized in that, in case of R being CH3, the molar ratio of compound of formula (la) : compound of formula (lb) is < 50 : 50, particularly < 10 : 90, more particularly < 5 : 95, preferably < 3 : 97, more preferably < 2 : 98.
11 . The process according to any of the preceding claims characterized in that the molar ratio of compound of the formula (II) to compound of the formula (III) is in the range of 1 : 1 to 1 :8, particularly of 1 : 1 to 1 :8, preferably 1 :1 to 1 :3.
12. The process according to any of the preceding claims characterized in that the reaction is performed at a temperature of between 0°C and 80°C, particularly of between 10°C and 60°C, preferably of between 20°C and 30°C.
13. A composition comprising
- a compound of the formula (II);
- a compound of the formula (III); and
- Pt catalyst which is either in the form a Pt salt or of a Pt complex;
HC^ C - R (III) wherein R represents H or CH3, preferably CH3. comprising the following steps a) manufacturing a mixture of the compound of the formula (la) and the compound of the formula (lb) by a process according to anyone of the preceding claims 1 to 12, b) transforming the compound of the formula (lb) to the hydroquinone of the formula (lb1) c) condensing the hydroquinone of the formula (lb’) of step b) with a compound of the formula (X-A) or of the formula (X-B) to yield the tocopherol of the formula (XI) wherein R represents H or CH3, preferably CH3, and wherein Q is a substituent selected from the group consisting of OH, halide, acyloxy, particularly acetoxy or benzoyloxy, methanesulfonyloxy (=mesyloxy), ethanesulfonyloxy, benzenesulfonyloxy and toluenesulfonyloxy (=tosyloxy); and wherein any wavy line represents a carbon-carbon bond which when linked to the carbon-carbon double bond is either in the Z- or in the E- configuration.
EP24707578.1A 2023-03-01 2024-03-01 Synthesis of dimethylphenol or trimethylphenol from 2,5-dimethylfuran using a platinum catalyst Pending EP4673422A1 (en)

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