EP4673420A1 - Synthesis of 2,3,6-trimethylphenol from 5-methyl-1,3-dihydroisobenzofuran-4-ol or its ester comprising a ring opening and a reducing step - Google Patents

Synthesis of 2,3,6-trimethylphenol from 5-methyl-1,3-dihydroisobenzofuran-4-ol or its ester comprising a ring opening and a reducing step

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Publication number
EP4673420A1
EP4673420A1 EP24707576.5A EP24707576A EP4673420A1 EP 4673420 A1 EP4673420 A1 EP 4673420A1 EP 24707576 A EP24707576 A EP 24707576A EP 4673420 A1 EP4673420 A1 EP 4673420A1
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EP
European Patent Office
Prior art keywords
formula
compound
group
process according
iii
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.)
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EP24707576.5A
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German (de)
French (fr)
Inventor
Werner Bonrath
Alissa GOETZINGER
Ulla Letinois
Jonathan Alan Medlock
Jan Schuetz
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DSM IP Assets BV
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DSM IP Assets BV
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Publication of EP4673420A1 publication Critical patent/EP4673420A1/en
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    • 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
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/24—Preparation of carboxylic acid esters by reacting carboxylic acids or derivatives thereof with a carbon-to-oxygen ether bond, e.g. acetal, tetrahydrofuran
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/18—Acetic acid esters of trihydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans

Definitions

  • the present invention relates to the synthesis of 2,3,6-trimethylphenol and intermediates thereof.
  • 2,3,6-Trimethylphenol is a key compound in the synthesis of a-tocopherol.
  • Various approaches to its synthesis have been suggested.
  • WO 2018/096152 A1 discloses that 2,3,6-trimethylphenol was not obtained as a desired hydrogenation product by hydrogen in the presence of a palladium complex from 5-methyl-1 ,3-dihydroisobenzofuran-4-ol.
  • 5-Methyl-1 ,3-dihydroisobenzofuran-4-ol is accessible from renewable raw materials, and is, hence, a compound of big interest and a possible synthesis of 2,3,6-trimethylphenol from this compound would be highly appreciated.
  • the problem to be solved by the present invention is to offer a synthesis of 2,3,6-trimethylphenol from 5-methyl-1 ,3-dihydroisobenzofuran-4-ol or its ester as starting material.
  • the present invention relates to the process for the manufacturing the compound of the formula (I) from compound of the formula (II) a) a ring opening step b) a reducing step characterized in that R' represents either H or an acyl group.
  • a “C x -y-alkyl” group is an alkyl group comprising x to y carbon atoms, i.e. , for example, a Ci-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.
  • a “C x -y-aralkyl” group is an aralkyl group comprising x to y carbon atoms, i.e. , for example, a Cy- -aralkyl group is an aralkyl group comprising 7 to 16 carbon atoms.
  • the aralkyl group can be linear or branched.
  • benzyl group (-CH2-C6H5) is considered as a Cyaralkyl group.
  • alkylaryl is an aryl group which is substituted by an alkyl group.
  • a “C x-y -alkylaryl” group is an alkylaryl group comprising x to y carbon atoms, i.e., for example, a Cy- -alkylaryl group is an alkylaryl group comprising 7 to 16 carbon atoms.
  • the alkylaryl group can be linear or branched.
  • the tolyl group (-C6H4CH3) is considered as a Cy-alkylaryl group and the xylyl group (-CeH3(CH3)2) is considered as a Cs- alkylaryl group.
  • a " C x -y-alkoxy" group is a R 2 O group, in which the substituent R 2 is a C x.y - alkyl as defined above.
  • a " C x -y-aryloxy” group is a R 2 O group, in which the substituent R 2 is a C x -y-aryl group as defined above.
  • acyl group is the chemical substituent of the formula which R 1 is an alkyl or a cycloalkyl or an aryl or hetero aryl or an aralkyl or an alkylaryl group, particularly a Ci-20-alkyl or a Cs-w-cycloalkyl or a Ce-12-aryl or C6-12- hetero aryl or a Cy-24-aralkyl or a Cy-24-alkylaryl group.
  • the substituent R 1 is optionally substituted by a Ci-10-alkyloxy or aryloxy group.
  • the substituent R 1 in the acyl group is preferably, however, not substituted.
  • reducing step is referring to a step where a substance is chemically reduced.
  • any dotted line in formulae represents the bond by which a substituent is bound to the rest of a molecule.
  • step a it is a key element of the present invention that for a successful synthesis of 2,3,6-trimethylphenol from 5-methyl-1 ,3-dihydroisobenzofuran-4-ol or its ester the presence of both steps of a ring opening (step a) and reducing (step b) are necessary (figure 1 ).
  • the ring opening step a) is followed by the reducing step b). Principally the two steps a) and b) can performed quasi-simultaneously in the reaction if the ingredients for both the ring opening reaction and the reduction reaction are added to the compound of formula (II).
  • the two steps a) and b) are performed as separate steps.
  • the ring opening reaction of compound of the formula (II) yields a compound of the formula (III).
  • said compounds are esters and the process further comprises a step c) of hydrolysis of the ester group to a hydroxyl group, i.e. to a phenolic group.
  • the process of manufacturing 2,3,6-trimethylphenol comprises a ring opening step a).
  • the ring opening step a) is performed in the presence of the compound of the formula ROR and sulfamic acid yielding the intermediate of the formula (III) wherein R represents an acyl group, particularly an acetyl group.
  • R' R.
  • Sulfamic acid also known as amidosulfonic acid
  • ROR is a carboxylic acid anhydride, in which R is an acyl group of the formula which R 1 is an alkyl or a cycloalkyl or an aryl or a hetero aryl or an aralkyl or an alkylaryl group, particularly a Ci -20-alkyl or a Cs-w-cycloalkyl or a Ce-12-aryl or Ce-12-hetero aryl or a C?-24-aralkyl or a C?-24-alkylaryl group and is optionally substituted by a Ci-10-alkyloxy or aryloxy group.
  • the compound of the formula ROR is most preferably acetic anhydride.
  • ROR carboxylic acid anhydride
  • ROH carboxylic acid
  • the ring opening reaction a) is performed with a mixture of the compound of the formula ROH and the formula ROR, in which R is particularly an acetyl group, preferably in a molar ratio of ROH/ROR of 1 :3 to 2:1 , particularly of 1 :1 to 2:1 , preferably 1 .5:1 to 2:1 .
  • the molar ratio of the compound of the formula (II) to the compound of the formula ROR is in the range of 1 :3 to 1 :50, particularly of 1 :5 to 1 :40, preferably used of 1 :8 to 1 :30.
  • the molar ratio of the sulfamic acid to the compound of the formula (II) is in the range of 1 :50 to 1 :1 , particularly of 1 :50 to 1 :5, preferably of 1 :30 to 1 : 10, more preferably of 1 :20 to 1 :10.
  • the ring opening step a) is performed at a temperature of between 100°C and 140°C.
  • the ring opening step a) is performed under inert atmosphere, particularly under nitrogen or argon, particularly under argon.
  • composition of 5-methyl-1 ,3-dihydroisobenzofuran-4-ol or its ester of the formula (II) and the carboxylic acid anhydride of the formula ROR in the presence of sulfamic acid leads to the manufacturing of the compounds of the formula (III), respectively of the formula (I), in a further aspect the present invention relates to a composition comprising
  • R represents an acyl group, particularly an acetyl group
  • the compound of the formula (III) represents a key intermediate.
  • the process of manufacturing 2,3,6-trimethylphenol comprises, furthermore, a reducing step b).
  • the reduction, respectively hydrogenation, can be carried out in the presence or absence of solvents.
  • Suitable solvents are particularly those in which the compound of the formula (III) or (III 1 ) is soluble.
  • the solvent is particularly an organic solvent, preferably a solvent selected from the group consisting of alcohols, ethers, esters, acids, aromatic and aliphatic hydrocarbons, and carbonates. Preferred are aromatic hydrocarbons, ethers, esters, and carbonates.
  • the reduction, respectively hydrogenation, is performed typically at temperatures of between 20 and 200°C, particularly between 50 and 180°C, and preferably under pressure. In case of use of molecular hydrogen, it is preferred that the reduction is carried out under a pressure of hydrogen of between 2 and 30 bar, preferably of between 5 and 28 bar.
  • the reduction is performed in a suitable vessel.
  • the reduction can be performed batchwise or continuously.
  • Suitable reactors for industrial scale are known. It is preferred that the weight ratio of the heterogeneous metal catalyst to the compound of the formula (III) or (III 1 ) is 0.01 % to 20%, particularly 1 % to 10%.
  • the process for manufacturing the compound of the formula (I) from compound of the formula (II) comprises a ring opening step a), a reducing step b) and preferably a hydrolysis step c).
  • an ester group being present in the compound of the formula (II), respectively in the preferred intermediate of the formula (II) or (III) or (I 1 ) is hydrolysed to a hydroxyl group, more specially to a phenolic OH group.
  • Said hydrolysis is preferably performed by an acid.
  • hydrolysis can be achieved under reductive conditions by using metal hydrides, particularly complex hydrides such as LiAIH4.
  • reaction conditions for such a hydrolysis of an ester to a phenol are principally known by the person skilled in the art.
  • the compound of the formula (III) is formed by the ring opening step a) from compound of the formula (II).
  • said compound of the formula (III) is subsequently either reduced in step b') and then hydrolysed by step c') b') reducing compound of the formula (III) by a reducing agent in the presence of a heterogeneous metal catalyst to yield a compound of the formula (I 1 ); c') hydrolyzing the compound of the formula (I 1 ) to yield the compound of the formula (I); or hydrolysed in step c") and then reduced by step b") c") hydrolyzing the compound of the formula (III) to yield the compound of the formula (III 1 ); b") reducing the compound of the formula (III 1 ) by a reducing agent in the presence of a heterogeneous metal catalyst to yield a compound of the formula (I); wherein the metal of the heterogeneous metal catalyst is selected from the group consisting of Ni, Fe, Ir, Pd, Pt, Rh and Ru;
  • R represents an acyl group, particularly an acetyl group
  • R' represents either H or an acyl group.
  • step a the compound of formula (II) is ring opened in step a) to yield the compound of the formula (III), followed by a reduction in step b') to yield the compound of formula (I 1 ), followed by a hydrolysis in step c') to yield 2,3,6-trimethylphenol (formula (I).
  • step a the compound of formula (II) is ring opened in step a) to yield the compound of the formula (III), followed by a hydrolysis in step c") to yield the compound of the formula (III 1 ), followed by a reduction in step b") to yield 2,3,6-trimethylphenol (formula (I)).
  • hydrolysis steps c') and c") are as discussed above for hydrolysis step c).
  • the hydrolysis step and reducing step are performed simultaneously, c'") and b'").
  • the compound of the formula (III) is red uced/hydro lysed simultaneously.
  • an acid or base is added to the compound of formula (III) in the presence of the of the heterogeneous metal catalyst wherein the metal of the heterogeneous metal catalyst reduction and the reducing agent, particularly molecular hydrogen.
  • the starting product for the process for manufacturing 2, 3,6-trimethyl- phenol is the compound of the formula (II) as described above in great detail.
  • esters of compound 5-methyl-1 ,3-dihydroisobenzofuran-4-ol are presently not known to the person skilled in the art.
  • the invention relates to a compound of the formula (II') wherein R 1 is a Ci-20-alkyl or a Cs-w-cycloalkyl or a Ce-12-aryl or a C7-24- aralkyl or a C?-24-alkylaryl group and is optionally substituted by a C1-10- alkyloxy or aryloxy group, particularly a Ci -5-alkyl or a phenyl group.
  • the compound of the formula (II 1 ) can particularly be manufactured from 5-methyl-1 ,3-dihydroisobenzofuran-4-ol and a respective carboxylic acid R'OH (corresponding to R 1 COOH) or its anhydride R'OR' (corresponding to (R 1 C0)20) ).
  • the compound of the formula (II 1 ) can be particularly manufactured from 5-methyl-1 ,3-dihydroisobenzofuran-4-ol and acetic anhydride, preferably in a mixture of acetic anhydride and acetic acid.
  • the compounds of the formula (II 1 ) can be isolated and their structure and identity can be determined by standard methods.
  • the present invention is further illustrated by the following experiments.
  • reaction was quenched by pouring into ice water (ca. 50 mL) and the resulting mixture was acidified to pH 1-2 with diluted H2SO4, saturated with solid NaCI, and extracted with EtOAc (3 x). The combined organic phases were washed with sat. aq. NaHCOs and brine, dried (Na2SO4), and concentrated under reduced pressure.
  • the product i.e. 2,3,6-trimethylphenol, was identified by comparison to a commercial sample.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to the synthesis of 2,3,6-trimethylphenol from 5-methyl-1,3-dihydroisobenzofuran-4-ol or its ester comprising a ring opening step and a reducing step.

Description

SYNTHESIS OF 2,3,6-TRIMETHYLPHENOL FROM 5-METHYL-1,3- DIHYDROISOBENZOFURAN-4-OL OR ITS ESTER COMPRISING A RING OPENING AND A REDUCING STEP
Technical Field
The present invention relates to the synthesis of 2,3,6-trimethylphenol and intermediates thereof.
Background of the invention
2,3,6-Trimethylphenol is a key compound in the synthesis of a-tocopherol. Various approaches to its synthesis have been suggested.
WO 2018/096152 A1 discloses that 2,3,6-trimethylphenol was not obtained as a desired hydrogenation product by hydrogen in the presence of a palladium complex from 5-methyl-1 ,3-dihydroisobenzofuran-4-ol.
5-Methyl-1 ,3-dihydroisobenzofuran-4-ol, however, is accessible from renewable raw materials, and is, hence, a compound of big interest and a possible synthesis of 2,3,6-trimethylphenol from this compound would be highly appreciated.
Summary of the invention
Therefore, the problem to be solved by the present invention is to offer a synthesis of 2,3,6-trimethylphenol from 5-methyl-1 ,3-dihydroisobenzofuran-4-ol or its ester as starting material.
Surprisingly, it has been found that such synthesis is possible by using a process according to claim 1 .
It was very surprising that by using at least 2 steps, i.e. , a ring opening step and a reduction step, 5-methyl-1 ,3-dihydroisobenzofuran-4-ol or its ester could be converted to the targeted 2,3,6-trimethylphenol in high yields and selectivity. It was further surprising that as a result of the ring opening a compound of the formula (III) could be formed. It has been found that in a preferred embodiment of the invention said intermediate of the formula (III) can then be transformed to 2,3,6-trimethylphenol by three different routes, each of which comprises a hydrogenation step. Hence, despite the negative result indicated by WO 2018/096152 A1 , a short synthetic pathway starting from of the highly sustainable molecule 5-methyl- 1 ,3-dihydroisobenzofuran-4-ol or its ester involving a hydrogenation step could be realized.
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 the process for the manufacturing the compound of the formula (I) from compound of the formula (II) a) a ring opening step b) a reducing step characterized in that R' represents either H or an acyl group.
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 Ci-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 "aryl group" is an aromatic substituent. Accordingly, a " Cx-y aryl group" is an aryl group comprising x to y carbon atoms. Preferred aryl groups are phenyl or naphthyl groups. A "hetero aryl" group is an aromatic substituent having at least one hetero atom. Preferred hetero aryl groups are pyridyl or methylpyridyl groups.
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 Cy- -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 Cyaralkyl group.
An "alkylaryl" group is an aryl group which is substituted by an alkyl group.
Accordingly, in the present document, a “Cx-y-alkylaryl” group is an alkylaryl group comprising x to y carbon atoms, i.e., for example, a Cy- -alkylaryl group is an alkylaryl group comprising 7 to 16 carbon atoms. The alkylaryl group can be linear or branched. For example, the tolyl group (-C6H4CH3) is considered as a Cy-alkylaryl group and the xylyl group (-CeH3(CH3)2) is considered as a Cs- alkylaryl group.
A " Cx-y-alkoxy" group is a R2O group, in which the substituent R2 is a Cx.y- alkyl as defined above.
A " Cx-y-aryloxy" group is a R2O group, in which the substituent R2 is a Cx-y-aryl group as defined above.
An "acyl group" is the chemical substituent of the formula which R1 is an alkyl or a cycloalkyl or an aryl or hetero aryl or an aralkyl or an alkylaryl group, particularly a Ci-20-alkyl or a Cs-w-cycloalkyl or a Ce-12-aryl or C6-12- hetero aryl or a Cy-24-aralkyl or a Cy-24-alkylaryl group. The substituent R1 is optionally substituted by a Ci-10-alkyloxy or aryloxy group.
Hence, for example, the group CH3OCH2CO is regarded as Ci-acyl group (Ri=Ci -alkyl) and CH3-O-C6H4-CO is regarded as a Ce-acyl group (Ri=Ce-aryl).
The substituent R1 in the acyl group is preferably, however, not substituted.
The substituent R1 in the acyl group is particularly a Ci-20-alkyl or a phenyl group, preferably a Ci-10-alkyl group, particularly a Ci-3-alkyl group, most preferably a methyl group. ln the present document the term "ring opening" is referring to an opening of the ring comprising the oxygen atom of the 5-methyl-1 ,3-dihydroisobenzofuran- 4-ol or its ester.
In the present document the term "reducing step" is referring to a step where a substance is chemically reduced.
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 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.
In WO 2018/096152 A1 it has been found that 5-methyl-1 ,3- dihydroisobenzofuran-4-ol or its ester cannot be reduced directly to 2,3,6- trimethylphenol as disclosed.
It is a key element of the present invention that for a successful synthesis of 2,3,6-trimethylphenol from 5-methyl-1 ,3-dihydroisobenzofuran-4-ol or its ester the presence of both steps of a ring opening (step a) and reducing (step b) are necessary (figure 1 ).
The ring opening step a) is followed by the reducing step b). Principally the two steps a) and b) can performed quasi-simultaneously in the reaction if the ingredients for both the ring opening reaction and the reduction reaction are added to the compound of formula (II).
It is, however, preferred that the two steps a) and b) are performed as separate steps. Hence, in a preferred embodiment, in a first step, the ring opening reaction of compound of the formula (II) yields a compound of the formula (III).
In case of the presence of an acyl group in the compound of the formula
(I) or the compound of the formula (III), said compounds are esters and the process further comprises a step c) of hydrolysis of the ester group to a hydroxyl group, i.e. to a phenolic group.
Ring opening step
The process of manufacturing 2,3,6-trimethylphenol comprises a ring opening step a).
It is particularly preferred that the ring opening step a) is performed in the presence of the compound of the formula ROR and sulfamic acid yielding the intermediate of the formula (III) wherein R represents an acyl group, particularly an acetyl group.
It is preferred that R' = R.
Sulfamic acid, also known as amidosulfonic acid, is the compound of the formula . It is a strongly acidic, colorless, and water-soluble compound. Sulfamic acid is commercially available in bulk amounts from different suppliers. The compound of the formula ROR is a carboxylic acid anhydride, in which R is an acyl group of the formula which R1 is an alkyl or a cycloalkyl or an aryl or a hetero aryl or an aralkyl or an alkylaryl group, particularly a Ci -20-alkyl or a Cs-w-cycloalkyl or a Ce-12-aryl or Ce-12-hetero aryl or a C?-24-aralkyl or a C?-24-alkylaryl group and is optionally substituted by a Ci-10-alkyloxy or aryloxy group.
The compound of the formula ROR is most preferably acetic anhydride.
It is preferred that said a carboxylic acid anhydride (ROR) is present in combination with its corresponding carboxylic acid (ROH).
It is, furthermore, preferred that that the ring opening reaction a) is performed with a mixture of the compound of the formula ROH and the formula ROR, in which R is particularly an acetyl group, preferably in a molar ratio of ROH/ROR of 1 :3 to 2:1 , particularly of 1 :1 to 2:1 , preferably 1 .5:1 to 2:1 .
It is preferred that the molar ratio of the compound of the formula (II) to the compound of the formula ROR is in the range of 1 :3 to 1 :50, particularly of 1 :5 to 1 :40, preferably used of 1 :8 to 1 :30.
It is further preferred that the molar ratio of the sulfamic acid to the compound of the formula (II) is in the range of 1 :50 to 1 :1 , particularly of 1 :50 to 1 :5, preferably of 1 :30 to 1 : 10, more preferably of 1 :20 to 1 :10.
It is preferred that the ring opening step a) is performed at a temperature of between 100°C and 140°C.
It is further preferred that the ring opening step a) is performed under inert atmosphere, particularly under nitrogen or argon, particularly under argon.
The compounds of the formula (III), particularly (3-acetoxy-4-methyl-1 ,2- phenylene)bis(methylene) diacetate ( R'=R= acetyl), are novel and have not been known yet. They can be isolated, and their identity and structure can be determined by standard methods.
Hence, in a further aspect the present invention relates to the compound of the formula (III) wherein R and R' represents an acyl group, and R' particularly an acetyl group. It is furthermore preferred that R' = R.
As the composition of 5-methyl-1 ,3-dihydroisobenzofuran-4-ol or its ester of the formula (II) and the carboxylic acid anhydride of the formula ROR in the presence of sulfamic acid leads to the manufacturing of the compounds of the formula (III), respectively of the formula (I), in a further aspect the present invention relates to a composition comprising
- a compound of the formula (II)
- a compound of the formula ROR; wherein R represents an acyl group, particularly an acetyl group; and
- sulfamic acid.
All the ingredients and their preferred embodiments, as well the respective amounts and ratios, have been discussed already above in great detail.
In the preferred, new, route of synthesis for 2,3,6-trimethylphenol, the compound of the formula (III) represents a key intermediate.
Reducing step
The process of manufacturing 2,3,6-trimethylphenol comprises, furthermore, a reducing step b).
It is preferred that in that the reduction step b) is performed by a reducing agent in the presence of a heterogeneous metal catalyst wherein the metal of the heterogeneous metal catalyst is selected from the group consisting of Ni, Fe, Ir, Pd, Pt, Rh and Ru, preferably selected from the group consisting of Ni, Fe, Ir, Pd, Pt and Rh.
It is preferred that the compound which is actually reduced is the compound of the formula (III) or (III'). ln a preferred embodiment, the reducing agent is molecular hydrogen. In other words, in one of the embodiments, the reduction step is performed by molecular hydrogen as reducing agent in the presence of a heterogeneous metal catalyst. Hydrogenation is the preferred reduction.
In another preferred embodiment the reducing agent is a transfer hydrogenation agent. In other words, in another embodiment, the reduction step is performed by a transfer hydrogenation agent in the presence of presence of a heterogeneous metal catalyst. Said transfer hydrogenation agent is preferably formic acid and/or a formic acid salt.
The metal in the heterogeneous metal catalyst is selected from the group consisting of Ni, Fe, Ir, Pd, Pt, Rh and Ru.
It is preferred that the metal of the heterogeneous metal catalyst comprises at least one of the metals selected from the group consisting of Ni, Fe, Ir, Pd, Pt and Rh. The heterogeneous metal catalyst can be a catalyst comprising more than one of the mentioned metals.
Particularly, the heterogeneous metal catalyst comprises Pd and Pt as metal.
It is more preferred that the metal of the heterogeneous metal catalyst is palladium.
A wide variety of heterogeneous metal catalysts are known. Particularly useful are heterogeneous metal catalyst which are on a carrier or support material. Such carrier material is particularly a solid material having a high surface area, to which the metal is affixed. The support may be inert or participate in the catalytic reactions. Typical supports/camer material include various kinds of carbon, alumina, and silica. The preferred support/carrier material is carbon. The heterogeneous metal catalyst may also be affixed or immobilized on a surface of a larger object typically in form of a structured packing element which might be a part of the reactor in which the reduction takes place or an element which is inserted into said reactor. This structured packing element may be a dumped packing, a knit, an open-celled foam structure, preferably made of plastic, for example polyurethane or melamine resin, or ceramic, or a structured packing element, as already known in principle, i.e. by its geometric shape, from distillation and extraction technology. However, for the purposes of the present invention, structured packings in principle have a substantially smaller hydraulic diameter, frequently by a factor of from 2 to 10, than comparable internals in the field of distillation and extraction technology. Useful structured packing elements are in particular metal fabric packings and wire fabric packings, for example of the design Montz A3, Sulzer BX, DX and EX. Instead of metal fabric packings, it is also possible to use structured packings made of other woven, knitted or felted materials. Further useful structured packings are of flat or corrugated sheets, preferably without perforation, or other relatively large orifices, for example corresponding to the designs Montz Bl or Sulzer Mellapak. The structured packings made of expanded metal are also advantageous, for example structured packings of the type Montz BSH.
It is preferred that the heterogeneous metal catalyst is a palladium catalyst, particularly a palladium on carbon catalyst (Pd/C).
The catalytic metal loading (i.e. weight metal I weight (metal+carrier)) is typically between 1 to 20%, preferably between 4 and 11 %, more preferably between 4 and 6%, by weight. A very preferred heterogeneous metal catalyst is palladium on carbon catalyst (Pd/C) of which 5 % by weight is palladium (i.e. loading = 5%).
The reduction, respectively hydrogenation, can be carried out in the presence or absence of solvents. Suitable solvents are particularly those in which the compound of the formula (III) or (III1) is soluble. The solvent is particularly an organic solvent, preferably a solvent selected from the group consisting of alcohols, ethers, esters, acids, aromatic and aliphatic hydrocarbons, and carbonates. Preferred are aromatic hydrocarbons, ethers, esters, and carbonates. The preferred solvent used for the hydrogenation is selected from the group consisting of toluene, 2-methyl-tetrahydrofuran (= 2-methyl-THF), cyclopropyl methyl ether, isopropyl acetate, ethyl acetate and propylene carbonate. The reduction, respectively hydrogenation, is performed typically at temperatures of between 20 and 200°C, particularly between 50 and 180°C, and preferably under pressure. In case of use of molecular hydrogen, it is preferred that the reduction is carried out under a pressure of hydrogen of between 2 and 30 bar, preferably of between 5 and 28 bar.
The reduction, respectively hydrogenation, is performed in a suitable vessel. The reduction can be performed batchwise or continuously. Suitable reactors for industrial scale are known. It is preferred that the weight ratio of the heterogeneous metal catalyst to the compound of the formula (III) or (III1) is 0.01 % to 20%, particularly 1 % to 10%.
Step of hydrolysis
The process for manufacturing the compound of the formula (I) from compound of the formula (II) comprises a ring opening step a), a reducing step b) and preferably a hydrolysis step c).
In said hydrolysis step, an ester group being present in the compound of the formula (II), respectively in the preferred intermediate of the formula (II) or (III) or (I1) is hydrolysed to a hydroxyl group, more specially to a phenolic OH group.
Said hydrolysis is preferably performed by an acid.
Furthermore, hydrolysis can be achieved under reductive conditions by using metal hydrides, particularly complex hydrides such as LiAIH4.
The reaction conditions for such a hydrolysis of an ester to a phenol are principally known by the person skilled in the art.
As pointed out above, it is preferred that the compound of the formula (III) is formed by the ring opening step a) from compound of the formula (II).
It is highly preferred that said compound of the formula (III) is subsequently either reduced in step b') and then hydrolysed by step c') b') reducing compound of the formula (III) by a reducing agent in the presence of a heterogeneous metal catalyst to yield a compound of the formula (I1); c') hydrolyzing the compound of the formula (I1) to yield the compound of the formula (I); or hydrolysed in step c") and then reduced by step b") c") hydrolyzing the compound of the formula (III) to yield the compound of the formula (III1); b") reducing the compound of the formula (III1) by a reducing agent in the presence of a heterogeneous metal catalyst to yield a compound of the formula (I); wherein the metal of the heterogeneous metal catalyst is selected from the group consisting of Ni, Fe, Ir, Pd, Pt, Rh and Ru;
R represents an acyl group, particularly an acetyl group; and
R' represents either H or an acyl group.
These preferred synthetic pathways are schematically shown in figure 2.
In the first pathway (left part in figure 2) the compound of formula (II) is ring opened in step a) to yield the compound of the formula (III), followed by a reduction in step b') to yield the compound of formula (I1), followed by a hydrolysis in step c') to yield 2,3,6-trimethylphenol (formula (I).
In the second pathway (right part in figure 2) the compound of formula (II) is ring opened in step a) to yield the compound of the formula (III), followed by a hydrolysis in step c") to yield the compound of the formula (III1), followed by a reduction in step b") to yield 2,3,6-trimethylphenol (formula (I)).
The reduction steps b') and b") are as discussed above for reduction step b).
The hydrolysis steps c') and c") are as discussed above for hydrolysis step c).
In a third pathway (middle part in figure 2), the hydrolysis step and reducing step are performed simultaneously, c'") and b'"). In this embodiment, which is less preferred then the other two embodiments of figure 2, the compound of the formula (III) is red uced/hydro lysed simultaneously. This can be achieved by that the ingredients for the reducing step b) and the hydrolysis step c) are present in the same vessel. Particularly, an acid or base (as described above) is added to the compound of formula (III) in the presence of the of the heterogeneous metal catalyst wherein the metal of the heterogeneous metal catalyst reduction and the reducing agent, particularly molecular hydrogen.
Most preferred, the transformation of the compound of the formula (III) to 2,3,6-trimethylphenol (formula (I)) follows the pathway using the steps b') and c') (see figure 2).
The starting product for the process for manufacturing 2, 3,6-trimethyl- phenol is the compound of the formula (II) as described above in great detail. The compound of formula (II) is either 5-methyl-1 ,3-dihydroisobenzofuran-4-ol (R'=H) or its ester (R'=acyl).
The esters of compound 5-methyl-1 ,3-dihydroisobenzofuran-4-ol are presently not known to the person skilled in the art.
Hence, in a further aspect, the invention relates to a compound of the formula (II') wherein R1 is a Ci-20-alkyl or a Cs-w-cycloalkyl or a Ce-12-aryl or a C7-24- aralkyl or a C?-24-alkylaryl group and is optionally substituted by a C1-10- alkyloxy or aryloxy group, particularly a Ci -5-alkyl or a phenyl group.
As shown above, these compounds are suitable for being used in the synthesis of 2,3,6-trimethylphenol or the compound of the formula (III). The compound of the formula (II1) can particularly be manufactured from 5-methyl-1 ,3-dihydroisobenzofuran-4-ol and a respective carboxylic acid R'OH (corresponding to R1COOH) or its anhydride R'OR' (corresponding to (R1C0)20) ).
It has been shown that the compound of the formula (II1) can be particularly manufactured from 5-methyl-1 ,3-dihydroisobenzofuran-4-ol and acetic anhydride, preferably in a mixture of acetic anhydride and acetic acid.
It has been furthermore observed that admixture of small quantities (typically 5-15 mol-% relative to 5-methyl-1 ,3-dihydroisobenzofuran-4-ol) of trifluoracetic acid are beneficial for said synthesis of the compound of the formula (II1), particularly of 5-methyl-1 ,3-dihydroisobenzofuran-4-yl acetate.
The compounds of the formula (II1) can be isolated and their structure and identity can be determined by standard methods.
Examples
The present invention is further illustrated by the following experiments.
1 . Synthesis of (3-acetoxy-4-methyl-1 ,2-phenylene)bis(methylene) diacetate
1a) starting from 5-methyl-1 ,3-dihydroisobenzofuran-4-ol -Using a mixture of acetic acid/acetic anhydride: Example 1
In a 100 mL three neck round-bottomed flask under an argon atmosphere, sulfamic acid (0.251 g, 2.56 mmol) was added to a solution of 5-methyl-1 ,3- dihydroisobenzofuran-4-ol (4g, 25.6 mmol) in acetic acid (33 mL, 574 mmol) and acetic anhydride (33 mL, 346 mmol). The resulting yellow, clear solution was refluxed at 127 °C for 17 h.
After cooling to 0 °C (water/ice bath), 5 % aq. HCI was added to the brown mixture and it was extracted several times with EtOAc. The combined organic layers were washed with sat. aq. NaHCOs (2 x), water, brine, dried (Na2SO4), and concentrated under reduced pressure bar to give 8.77 g of a brown oil.
The crude product was adsorbed on Kinesis TELOS Flash Chromatography Bulk Sorbent, NM (diatomaceous earth) and purified by silica gel column chromatgraphy using n-heptane/EtOAc as eluent, giving the desired product, i.e. 3- acetoxy-4-methyl-1 ,2-phenylene)bis(methylene) diacetate, (7) (6.13 g, 20.7 mmol, 81 %) as a light yellow oil.
Analytical data for 3-acetoxy-4-methyl-1 ,2-phenylene)bis(methylene) diacetate: 1H NMR (300 MHz, CDCI3) 6 [ppm] = 2.02 (s, 3 H), 2.08 (s, 3 H), 2.17 (s, 3 H), 2.35 (s, 3 H), 5.16 (s, 2 H), 5.23 (s, 2 H), 7.21-7.28 (m, 2 H).
13C NMR (75 MHz, CDCI3) 6 [ppm] = 16.3, 20.5, 20.7, 20.9, 57.7, 63.4, 127.0, 127.8, 131.5, 131.6, 134.6, 149.0, 168.9, 170.5. eiFI + MS: 252 [M+ - OAc], 234, 192, 174, 150, 122, 105, 91 , 43.
FT-IR: v [cm’1] = 778, 820, 914, 1072, 1023, 1181 , 1212, 1371 , 1435, 1733, 1763, 2936.
Anal, calcd. for CI5HI8O6 (294.3): C 61 .22, H 6.16; Found: C 61 .26, H 6.32. -Using acetic anhydride: Example 1a
In a 100 mL three neck round-bottomed flask under an argon atmosphere, sulfamic acid (39.2 mg, 0.400 mmol) was added to a solution of 5-methyl-1 ,3- dihydroisobenzofuran-4-ol (608 mg, 4.00 mmol) in acetic anhydride (10.3 mL, 108 mmol). The resulting yellow, clear solution was refluxed at 127 °C for 20 h.
After cooling to 0 °C (water/ice bath), 5 % aq. HCI was added to the brown mixture and it was extracted several times with EtOAc. The combined organic layers were washed with sat. aq. NaHCOs (2 x), water and brine, dried (Na2SO4), and concentrated under reduced pressure bar to give 1 .22 g of a brown oil of 3-acetoxy- 4-methyl-1 ,2-phenylene)bis(methylene) diacetate (89% purity by q-NMR, 3.69 mmol, 92%). The analytic data was in agreement with Example 1.
-Using acetic acid: Example Ref. 1:
In a 100 mL three neck round-bottomed flask under an argon atmosphere, sulfamic acid (0.324 g, 3.30 mmol) was added to a solution of 5-methyl-1 ,3- dihydroisobenzofuran-4-ol (0.502 g, 3.30 mmol) in acetic acid (4.20 ml, 73.0 mmol) and water (4.20 ml, 233 mmol). The resulting yellow, clear solution was refluxed at 107 °C for 22 h. Reaction control by GC and TLC showed no conversion of the 5-methyl-1 ,3-dihydroisobenzofuran-4-ol starting material.
1b) starting from 5-methyl-1 ,3-dihydroisobenzofuran-4-yl acetate
In a 25 mL three neck round-bottomed flask under an argon atmosphere, sulfamic acid (24.7 mg, 0.252 mmol) was added to a solution of 5-methyl-1 ,3- dihydroisobenzofuran-4-yl acetate (490 mg, 2.52 mmol) (synthesis see below) in a mixture of acetic anhydride (3.26 mL, 34.2 mmol) and acetic acid (3.26 mL, 56.6 mmol). The resulting yellow, clear solution was refluxed at 127 °C for 20 h.
After cooling to 0 °C (water/ice bath), 5 % aq. HCI was added to the brown mixture and it was extracted several times with EtOAc. The combined organic layers were washed with sat. aq. NaHCOs (2 x), water, and brine, dried (Na2SO4), and concentrated under reduced pressure bar to give 0.75 g of a brown oil of 3-acetoxy- 4-methyl-1 ,2-phenylene)bis(methylene) diacetate (91 % purity by q-NMR, 2.30 mmol, 92%). The analytic data was in agreement with Example 1. Synthesis of 5-methyl-1 ,3-dihydroisobenzofuran-4-yl acetate
In a 100 mL three neck round-bottomed flask under an argon atmosphere, trifluoroacetic acid (45.6 mg, 0.400 mmol) was added to a solution of 5-methyl-1 ,3- dihydroisobenzofuran-4-ol (608 mg, 4.00 mmol) in in acetic acid (5.0 mL) and acetic anhydride (5.0 mL). The resulting yellow, clear solution was refluxed at 127 °C for 23 h.
After cooling to 0 °C (water/ice bath), 5 % aq. HCI was added to the brown mixture and it was extracted several times with EtOAc. The combined organic layers were washed with sat. aq. NaHCOs (2 x), water, and brine, dried (Na2SO4), and concentrated under reduced pressure. After column chromatography (n- heptane/EtOAc), the product was identified as 5-methyl-1 ,3-dihydroisobenzofuran- 4-yl acetate and isolated as a colorless solid (600 mg, 3.12 mmol, 78%).
Analytical data for 5-methyl-1 ,3-dihydroisobenzofuran-4-yl acetate:
1H NMR (300 MHz, CDCI3) 6 [ppm] = 2.20 (s, 3 H), 2.32 (s, 3 H), 4.97-5.03 (m, 2 H), 5.09-5.14 (m, 2 H), 6.98-7.05 (m, 1 H), 7.11-7.19 (m, 1 H).
13C NMR (75 MHz, CDCI3) 6 [ppm] = 15.6, 20.5, 71.7, 73.8, 118.4, 128.9, 130.7, 131.9, 139.2, 143.4, 168.2.
FT-IR: v [cm’1] = 686, 737, 761 , 886, 897, 932, 984, 1050, 1154, 1190, 1222, 1367, 1375, 1433, 1486, 1487, 1592, 1631 , 1746, 2073, 2857.
HRMS (ESI) calculated for [CHHI2O3 +]: 192.0786; found 192.0790.
2. Synthesis of 2,3,6-trimethylphenyl acetate by reduction of (3-acetoxy-4-methyl- 1 ,2-phenylene)bis(methylene) diacetate
-Using different solvents
(3-Acetoxy-4-methyl-1 ,2-phenylene)bis(methylene) diacetate (1, 130 mg, 0.442 mmol) was dissolved in a solvent (10 mL) as indicated in table 1 and Pd/C (5% Evonik E 101 N/D, 100 mg) was added. The reactor was sealed and purged three times with N2 and three times with H2. The mixture was stirred over night at 150 °C and 25 bar H2 pressure. It was cooled, the pressure was released, and a sample was analyzed by GCMS.
Table 1 . Use of different solvents in the reduction step of (3-acetoxy-4-methyl-
1 ,2-phenylene)bis(methylene) diacetate.
1 yield of 2,3,6-trimethylphenyl acetate, measured as GCMS area-%.
To isolate the product, the reaction was executed with 1 .85 g of substrate and 550 mg of catalyst in 73 mL of EtOAc for 4 h at 15 bar H2 pressure. After completion of the reaction, the catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to give the desired product, i.e. 2,3,6- trimethylphenyl acetate (2), in 95% purity (q-NMR):
1H NMR (300 MHz, CDCI3) 6 [ppm] = 2.07 (s, 3 H), 2.13 (s, 3 H), 2.27 (s, 3 H), 2.36 (s, 3 H), 6.92-7.02 (m, 2 H). -Using different heterogeneous metal catalysts
The synthesis was also evaluated with different catalysts:
(3-Acetoxy-4-methyl-1 ,2-phenylene)bis(methylene) diacetate (1, 130 mg, 0.442 mmol) was dissolved in toluene (10 mL) and different heterogeneous metal catalysts were added as indicated in table 2. The reactor was sealed and purged three times with N2 and three times with H2. The mixture was stirred over night at 150 °C and 25 bar H2 pressure. It was cooled, the pressure was released, and a sample was analyzed by GCMS.
3. Synthesis of 2,3,6-trimethylphenol by hydrolysis of 2,3,6-trimethylphenyl acetate In a 50 mL three-necked round-bottomed flask under an argon atmosphere, 2,3,6-trimethylphenyl acetate (2, 938 mg, 5.00 mmol) was dissolved in THF (25 ml). Powdered NaOH (2.04 g, 50.0 mmol) was added followed by tetrabutylammonium hydrogensulfate (857 mg, 2.50 mmol). The resulting yellow mixture was stirred under argon at rt for 5 h 15 min, during which it turned deep violet.
It was filtered through Celite, and the filtrate was neutralized with 4 N HCI. It was extracted three times with diethylether, and the combined organic layers were washed with brine, dried with anhydrous MgSCU, and concentrated under reduced pressure. Drying in high vacuum gave 670 mg (85% purity by q- NMR, 4.18 mmol, 85%) of the desired product, i.e. 2,3,6-trimethylphenol, as an orange solid. The analytical data were in agreement with a commercial sample: 1H NMR (300 MHz, CDCI3) 6 [ppm] = 2.19 (s, 3 H), 2.24 (s, 3 H), 2.27 (s, 3 H), 4.62 (brs, 1 H), 6.69 (d, J = 7.53 Hz, 1 H), 6.89 (d, J = 7.53 Hz, 1 H). 4. Synthesis of (3-hydroxy-4-methyl-1 ,2-phenylene)dimethanol by hydrolysis of (3-acetoxy-4-methyl-1 ,2-phenylene)bis(methylene) diacetate
In a 50 mL three neck round-bottomed flask under an argon atmosphere, UAIH4 (1.07 g, 26.7 mmol) was suspended in anhydrous THF (12 mL) and cooled to 0 °C (water/ice bath). A solution of (3-acetoxy-4-methyl-1 ,2-phenylene)bis- (methylene) diacetate (1, 3.00 g, 9.90 mmol) in 9.0 mL of anhydrous THF was added dropwise via syringe. TLC control directly after completed addition showed complete conversion of substrate.
The reaction was quenched by pouring into ice water (ca. 50 mL) and the resulting mixture was acidified to pH 1-2 with diluted H2SO4, saturated with solid NaCI, and extracted with EtOAc (3 x). The combined organic phases were washed with sat. aq. NaHCOs and brine, dried (Na2SO4), and concentrated under reduced pressure.
The crude product was adsorbed on Kinesis TELOS Flash Chromatography Bulk Sorbent, NM (diatomaceous earth) and purified by silica gel column chromatgraphy using n-heptane/EtOAc as eluent, giving 1.27 g (7.43 mmol, 75%) of the desired product, i.e. (3-hydroxy-4-methyl-1 ,2-phenylene)dimethanol, (3), as colorless solid.
Analytical data for 3-hydroxy-4-methyl-1 ,2-phenylene)dimethanol:
1H NMR (300 MHz, DMSO-d6) 6 [ppm] = 2.14 (s, 3 H), 4.42-4.50 (m, 2 H), 4.72 (s, 2 H), 4.86-5.08 (m, 1 H), 5.52 (brs, 1 H), 6.75 (d, J = 7.53 Hz, 1 H) 6.96 (d, J = 7.72 Hz, 1 H) 8.86 (brs, 1 H).
13C NMR (75 MHz, DMSO-d6) 6 [ppm] = 16.7, 57.4, 61 .7, 119.2, 124.1 , 124.5, 129.3, 136.9, 154.5. ei Fl + MS, after silylation: 294 [M+ + 3 TMS - CH3], 279, 251 , 221 , 191 , 147, 105. 5. Synthesis of 2,3,6-trimethylphenol by reduction of (3-hydroxy-4-methyl-1 ,2- phenylene)dimethanol
(3-Hydroxy-4-methyl-1 ,2-phenylene)dimethanol (3, 130 mg, 0.772 mmol) was dissolved in toluene (10 mL) and catalyst was added as indicated in table 3. The reactor was sealed and purged three times with N2 and three times with H2.
The mixture was stirred over night at the indicated temperature and H2 pressure. It was cooled, the pressure was released, and a sample was analyzed by GCMS.
The product, i.e. 2,3,6-trimethylphenol, was identified by comparison to a commercial sample.
Table 3. Use of different heterogeneous metal catalysts in the reduction step of (3-Hydroxy-4-methyl-1 ,2-phenylene)dimethanol.
1 yield of 2,3,6-trimethylphenol, measured as GCMS area-%.

Claims

Claims
1 . A process for manufacturing the compound of the formula (I) from compound of the formula (II) comprising a) a ring opening step and b) a reducing step characterized in that R' represents either H or an acyl group.
2. The process according to claim 1 , characterized in that the ring opening step a) is performed in the presence of the compound of the formula ROR and sulfamic acid yielding the intermediate of the formula (III) wherein R represents an acyl group, particularly an acetyl group.
3. The process according to claim 1 or 2, characterized in that the reduction step b) is performed by a reducing agent in the presence of a heterogeneous metal catalyst wherein the metal of the heterogeneous metal catalyst is selected from the group consisting of Ni, Fe, Ir, Pd, Pt, Rh and Ru, preferably selected from the group consisting of Ni, Fe, Ir, Pd, Pt and Rh. 4. The process according to any of the preceding claims, characterized in that the process furthermore comprises a step c) hydrolysis of an ester group to a hydroxyl group.
5. The process according to any of the preceding claims 2 to 4, characterized in that the compound of the formula (III) is either reduced in step b') and then hydrolysed by step c') b') reducing compound of the formula (III) by a reducing agent in the presence of a heterogeneous metal catalyst to yield a compound of the formula (I1); c') hydrolyzing the compound of the formula (I1) to yield the compound of the formula (I); or hydrolysed in step c") and then reduced by step b") c") hydrolyzing the compound of the formula (III) to yield the compound of the formula (III1); b") reducing the compound of the formula (III1) by a reducing agent in the presence of a heterogeneous metal catalyst to yield a compound of the formula (I); wherein the metal of the heterogeneous metal catalyst is selected from the group consisting of Ni, Fe, Ir, Pd, Pt, Rh and Ru;
R represents an acyl group, particularly an acetyl group. 6. The process according to any of the preceding claims 2 to 5 characterized in that the ring opening reaction a) is performed with a mixture of the compound of the formula ROH and the formula ROR, in which R is particularly an acetyl group, preferably in a molar ratio of ROH/ROR of 1 :3 to 2:1 , particularly of 1 :1 to 2:1 , preferably 1.5:1 to 2:1.
7. The process according to any of the preceding claims 2 to 6, characterized in that the molar ratio of the compound of the formula (II) to the compound of the formula ROR is in the range of 1 :3 to 1 :50, particularly of 1 :5 to 1 :40, preferably used of 1 :8 to 1 :30.
8. The process according to any of the preceding claims 2 to 7, characterized in that molar ratio of the sulfamic acid to the compound of the formula (II) is in the range of 1 :50 to 1 : 1 , particularly of 1 :50 to 1 :5, preferably of 1 :30 to 1 : 10, more preferably of 1 :20 to 1 : 10.
9. The process according to any of the preceding claims, characterized in that the ring opening step a) is performed at a temperature of between 100°C and 140°C.
10. The process according to any of the preceding claims, characterized in that the ring opening step a) is performed under inert atmosphere, particularly under nitrogen or argon, particularly under argon.
11 . The process according to any of the preceding claims 3 to 10, characterized in the reducing agent in step b) is molecular hydrogen.
12. The process according to any of the preceding claims 3 to 11 , characterized in that the heterogeneous metal catalyst in step b) is a palladium catalyst, particularly a palladium on carbon catalyst. A composition comprising
- a compound of the formula (II)
- a compound of the formula ROR; wherein
R' represents an acyl group, particularly an acetyl group and
- sulfamic acid.
14. A compound of the formula (II1) wherein R1 is a Ci-20-alkyl or a Cs-w-cycloalkyl or a Ce-12-aryl or a C7-24- aralkyl or a C?-24-alkylaryl group and is optionally substituted by a C1-10- alkyloxy or aryloxy group, particularly a Ci -5-alkyl or a phenyl group.
15. The compound of the formula (I) wherein R and R' represents an acyl group, particularly an acetyl group.
EP24707576.5A 2023-03-01 2024-03-01 Synthesis of 2,3,6-trimethylphenol from 5-methyl-1,3-dihydroisobenzofuran-4-ol or its ester comprising a ring opening and a reducing step Pending EP4673420A1 (en)

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