Synthesis of 2,3,6-trimethylphenol from 5-methyl-1,3-dihydroisobenzofuran-4-ol or its ester, including ring-opening and reduction steps

Abstract

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

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to the synthesis of 2,3,6-trimethylphenol and its intermediates.

[0002] [Background of the invention] 2,3,6-Trimethylphenol is a key compound in the synthesis of α-tocopherol.

[0003] Various approaches to its synthesis have been proposed.

[0004] WO 2018 / 096152 A1 discloses that 2,3,6-trimethylphenol is not obtained as the desired hydrogenation product from 5-methyl-1,3-dihydroisobenzofuran-4-ol with hydrogen in the presence of a palladium complex.

[0005] However, 5-methyl-1,3-dihydroisobenzofuran-4-ol is available from renewable raw materials and therefore a particularly interesting compound and the possible synthesis of 2,3,6-trimethylphenol from this compound would be highly appreciated.

[0006] [Summary of the Invention] Therefore, the problem to be solved by the present invention is to provide a method for synthesizing 2,3,6-trimethylphenol from the starting material 5-methyl-1,3-dihydroisobenzofuran-4-ol or an ester thereof.

[0007] Surprisingly, it has been found that such a synthesis is possible using the method described in claim 1.

[0008] It is highly surprising that 5-methyl-1,3-dihydroisobenzofuran-4-ol or its ester can be converted to the desired 2,3,6-trimethylphenol in high yield and selectivity by using at least two steps: a ring-opening step and a reduction step. It is even more surprising that the ring-opening can result in the formation of a compound of formula (III). In a preferred embodiment of the present invention, it has been found that said intermediate of formula (III) can then be converted to 2,3,6-trimethylphenol by three different routes, each of which includes a hydrogenation step.

[0009] Thus, despite the negative results shown in WO 2018 / 096152 A1, it was possible to realize a short synthetic route including a hydrogenation step starting from the highly sustainable molecule 5-methyl-1,3-dihydroisobenzofuran-4-ol or its esters.

[0010] Further aspects of the invention are the subject matter of further independent claims. Particularly preferred embodiments are the subject matter of the dependent claims. [Brief explanation of the drawings]

[0011] [Figure 1] Two steps are shown: ring opening (step a) and reduction (step b). [Figure 2] A preferred synthetic route is shown schematically.

[0012] [Detailed Description of the Invention] In a first aspect, the present invention provides a process for preparing a compound of formula (I) from a compound of formula (II), comprising the steps of: [ka] a) a ring-opening step; b) a reduction step and Including, wherein R' represents either H or an acyl group.

[0013] For clarity, some terms used herein are defined as follows:

[0014] In this specification, "C x~y A "-alkyl" group is an alkyl group containing x to y carbon atoms, i.e., for example, C 1~3 An alkyl group is an alkyl group containing 1 to 3 carbon atoms. The alkyl group can be straight or branched. For example, -CH(CH3)-CH2-CH3 is considered a C4-alkyl group.

[0015] An "aryl group" is an aromatic substituent. x~y An "aryl group" is an aryl group containing x to y carbon atoms. Preferred aryl groups are phenyl or naphthyl groups.

[0016] A "heteroaryl" group is an aromatic substituent having at least one heteroatom. Preferred heteroaryl groups are pyridyl or methylpyridyl groups.

[0017] An "aralkyl" group is an alkyl group substituted with an aryl group.

[0018] Therefore, in this specification, "C x~y An "aralkyl" group is an aralkyl group containing x to y carbon atoms, i.e., for example, C 7~16 An aralkyl group is an aralkyl group containing 7 to 16 carbon atoms. The aralkyl group can be straight-chain or branched. For example, a benzyl group (—CH—C—H) is considered a C-aralkyl group.

[0019] An "alkylaryl" group is an aryl group substituted with an alkyl group.

[0020] Therefore, in this specification, "C x~y An "-alkylaryl" group is an alkylaryl group containing x to y carbon atoms, i.e., for example, C 7~16An alkylaryl group is an alkylaryl group containing 7 to 16 carbon atoms. The alkylaryl group may be linear or branched. For example, a tolyl group (-CHCH) is considered a C7-alkylaryl group, and a xylyl group (-CH(CH)) is considered a C8-alkylaryl group.

[0021] "C x~y -alkoxy" group is a substituent R 2 is the C defined above. x~y - R is alkyl 2 It is an O group.

[0022] "C x~y The "-aryloxy" group is a group containing the substituent R 2 is the C defined above. x~y - R is an alkyl group 2 It is an O group.

[0023] An "acyl group" is a group of the formula [ka] where R 1 is an alkyl or cycloalkyl or aryl or heteroaryl or aralkyl or alkylaryl group, in particular C 1~20 -alkyl or C 5~10 Cycloalkyl or C 6~12 -aryl, or C 6~12 -heteroaryl, or C 7~24 -aralkyl group, or C 7~24 -alkylaryl group. 1 is C 1~10 It is optionally substituted with an alkyloxy or aryloxy group.

[0024] Thus, for example, the group CH3OCH2CO is considered to be a C1-acyl group (R1 = C1-alkyl) and CH3-O-C6H4-CO is considered to be a C6-acyl group (R1 = C6-aryl).

[0025] However, the substituent R in the acyl group 1 is preferably unsubstituted.

[0026] Substituent R in the acyl group 1 is especially C 1~20 - an alkyl or phenyl group, preferably C 1~10 -Alkyl groups, especially C 1~3 - an alkyl group, most preferably a methyl group.

[0027] As used herein, the term "ring opening" refers to the cleavage of the ring containing the oxygen atom of 5-methyl-1,3-dihydroisobenzofuran-4-ol or its ester.

[0028] As used herein, the term "reduction step" refers to a step in which a substance is chemically reduced.

[0029] As used herein, a dotted line in a formula represents the bond by which a substituent is attached to the remainder of the molecule.

[0030] In this specification, where the same symbol appears for a symbol or group in more than one formula, the definition of said group or symbol given in relation to one particular formula also applies to other formulas containing the same symbol.

[0031] In WO 2018 / 096152 A1, it was found that 5-methyl-1,3-dihydroisobenzofuran-4-ol or its ester cannot be directly reduced to 2,3,6-trimethylphenol as disclosed. [ka]

[0032] A key element of the present invention is that the successful synthesis of 2,3,6-trimethylphenol from 5-methyl-1,3-dihydroisobenzofuran-4-ol or its ester requires the presence of both ring-opening (step a) and reduction (step b) steps (Figure 1). [ka]

[0033] The ring-opening step a) is followed by the reduction step b). In principle, if the components of both the ring-opening and reduction reactions are added to the compound of formula (II), the two steps a) and b) can occur almost simultaneously during the reaction.

[0034] However, it is preferred that the two steps a) and b) are carried out as separate steps.

[0035] Thus, in a preferred embodiment, in a first step, a compound of formula (III) is obtained by ring-opening reaction of a compound of formula (II). [ka]

[0036] When an acyl group is present in the compound of formula (I) or the compound of formula (III), said compound is an ester and the method further comprises a step c) of hydrolyzing the ester group to a hydroxyl group, i.e., a phenol group.

[0037] [Ring-opening step] The process for preparing 2,3,6-trimethylphenol comprises a ring-opening step a).

[0038] The ring-opening step (a) is carried out in the presence of a compound of formula ROR and sulfamic acid to give a compound of formula (III) [ka] It is particularly preferred to produce an intermediate of the formula: in which R represents an acyl group, in particular an acetyl group.

[0039] It is preferred that R'=R.

[0040] Sulfamic acid, also known as amidosulfonic acid, has the formula [ka] It is a strongly acidic, colorless, water-soluble compound. Sulfamic acid is commercially available in large quantities from a variety of sources.

[0041] Compounds of formula ROR are carboxylic acid anhydrides, where R is a group of formula [ka] where R 1 is an alkyl or cycloalkyl or aryl or heteroaryl or aralkyl or alkylaryl group, in particular C 1~20 -alkyl or C 5~10 Cycloalkyl or C 6~12 -aryl, or C 6~12 -heteroaryl, or C 7~24 -aralkyl group, or C 7~24 - an alkylaryl group, C 1~10 -Optionally substituted by alkyloxy or aryloxy groups.

[0042] The compound of formula ROR is most preferably acetic anhydride.

[0043] The carboxylic acid anhydride (ROR) is preferably present together with the corresponding carboxylic acid (ROH).

[0044] Furthermore, the ring-opening reaction a) is preferably carried out with a mixture of compounds of the formula ROH and ROR, where R is in particular an acetyl group, preferably in a molar ratio ROH / ROR of 1:3 to 2:1, in particular 1:1 to 2:1, preferably 1.5:1 to 2:1.

[0045] It is preferred to use a molar ratio of the compound of formula (II) to the compound of formula ROR in the range of 1:3 to 1:50, in particular in the range of 1:5 to 1:40, preferably 1:8 to 1:30.

[0046] Furthermore, it is further preferred that the molar ratio of sulfamic acid to the compound of formula (II) is in the range of 1:50 to 1:1, in particular in the range of 1:50 to 1:5, preferably in the range of 1:30 to 1:10, more preferably in the range of 1:20 to 1:10.

[0047] The ring-opening step a) is preferably carried out at a temperature between 100°C and 140°C.

[0048] It is further preferred that the ring-opening step a) is carried out under an inert atmosphere, in particular under nitrogen or argon, especially under argon.

[0049] The compounds of formula (III), in particular (3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate (R' = R = acetyl), are novel and previously unknown. They can be isolated and their identity and structure determined by standard methods.

[0050] Thus, in a further aspect, the present invention provides a compound of formula (III) [ka] in which R and R' represent an acyl group, R' in particular an acetyl group. It is further preferred that R'=R.

[0051] In a further aspect, the present invention provides a method for preparing a compound of formula (III), respectively formula (I), by the composition of 5-methyl-1,3-dihydroisobenzofuran-4-ol or its ester of formula (II) with a carboxylic acid anhydride of formula ROR in the presence of sulfamic acid, - a compound of formula (II) [ka] and, - a compound of formula ROR, (wherein R represents an acyl group, particularly an acetyl group). and; - Sulfamic acid and The present invention relates to a composition comprising:

[0052] All components and their preferred embodiments as well as their respective amounts and ratios have already been described in great detail above.

[0053] In a preferred novel synthetic route to 2,3,6-trimethylphenol, the compound of formula (III) represents a key intermediate.

[0054] [Reduction step] The process for preparing 2,3,6-trimethylphenol comprises a reduction step b).

[0055] The reduction step b) is preferably carried out with a reducing agent in the presence of a heterogeneous metal catalyst, the metal of which 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.

[0056] The compound that is actually reduced is preferably a compound of formula (III) or (III'). [ka]

[0057] In a preferred embodiment, the reducing agent is molecular hydrogen. In other words, in one embodiment, the reduction step is carried out with molecular hydrogen as the reducing agent in the presence of a heterogeneous metal catalyst. Hydrogenation is the preferred reduction.

[0058] In another preferred embodiment, the reducing agent is a transfer hydrogenation agent. In other words, in another embodiment, the reduction step is carried out with a transfer hydrogenation agent in the presence of a heterogeneous metal catalyst. The transfer hydrogenation agent is preferably formic acid and / or formate.

[0059] The metal in the heterogeneous metal catalyst is selected from the group consisting of Ni, Fe, Ir, Pd, Pt, Rh and Ru.

[0060] The metal of the heterogeneous metal catalyst preferably contains at least one metal selected from Ni, Fe, Ir, Pd, Pt and Rh, and the heterogeneous metal catalyst may contain two or more of the above metals.

[0061] In particular, the heterogeneous metal catalyst comprises Pd and Pt as metals.

[0062] More preferably, the metal of the heterogeneous metal catalyst is palladium.

[0063] A wide variety of heterogeneous metal catalysts are known. Particularly useful are heterogeneous metal catalysts on a carrier or support material. Such carrier materials are solid materials, particularly those with a high surface area, onto which the metal is deposited. The support may be inert or may participate in the catalytic reaction. Typical support / support materials include various types of carbon, alumina, and silica. A preferred support / support material is carbon.

[0064] Heterogeneous metal catalysts may also be attached to or fixed on the surface of larger bodies, typically in the form of structured packing elements, which may be part of the reactor in which the reduction takes place or elements inserted into said reactor. These structured packing elements may be random packings, meshes, open-cell structures, preferably made of plastics, such as polyurethane or melamine resins, or ceramics, or structured packing elements originating from distillation and extraction technology, i.e., those already known in principle by their geometry. However, for the purposes of the present invention, structured packings generally have significantly smaller hydraulic diameters, often two to ten times smaller, than similar internal structures in the distillation and extraction technology. Useful structured packing elements are, in particular, woven metal packings and wire mesh packings, such as those of the Montz A3, Sulzer BX, DX, and EX designs. Instead of woven metal packings, structured packings made of other woven, mesh, or nonwoven materials can also be used. Further useful structured packings are preferably unperforated flat or corrugated sheets or other relatively large orifices, such as those of the Montz BI or Sulzer Mellapak designs. Structured packings made of expanded metal, such as those of the Montz BSH type, are also advantageous.

[0065] The heterogeneous metal catalyst is preferably a palladium catalyst, particularly a palladium on carbon catalyst (Pd / C).

[0066] The catalyst metal loading (i.e., weight of metal / weight (metal + support)) is typically 1-20% by weight, preferably 4-11%, and more preferably 4-6%. A highly preferred heterogeneous metal catalyst is palladium on carbon (Pd / C), of which 5% by weight is palladium (i.e., loading=5%).

[0067] The reduction, respectively the hydrogenation, can be carried out with or without a solvent. Suitable solvents are those in which the compound of formula (III) or (III') is soluble. The solvent is in particular an organic solvent, preferably a solvent selected from alcohols, ethers, esters, acids, aromatic and aliphatic hydrocarbons, and carbonates. Aromatic hydrocarbons, ethers, esters, and carbonates are preferred.

[0068] Preferred solvents used in the hydrogenation are selected from the group consisting of toluene, 2-methyl-tetrahydrofuran (=2-methyl-THF), cyclopropyl methyl ether, isopropyl acetate, ethyl acetate and propylene carbonate.

[0069] The reduction, i.e., hydrogenation, is usually carried out at a temperature in the range of 20 to 200°C, particularly 50 to 180°C, preferably under pressure. When molecular hydrogen is used, the reduction is preferably carried out under a hydrogen pressure of 2 to 30 bar, preferably 5 to 28 bar.

[0070] The reduction, i.e., hydrogenation, is carried out in a suitable vessel. The reduction can be carried out batchwise or continuously. Reactors suitable for industrial scale are known.

[0071] The weight ratio of the heterogeneous metal catalyst to the compound of formula (III) or (III') is preferably 0.01% to 20%, particularly preferably 1% to 10%.

[0072] [Hydrolysis step] The process for preparing compounds of formula (I) from compounds of formula (II) comprises a ring-opening step a), a reduction step b), and preferably a hydrolysis step c).

[0073] In said hydrolysis step, the ester group present in the compound of formula (II), the preferred intermediate of formula (II) or (III) or (I'), respectively, is hydrolyzed to a hydroxy group, more particularly a phenolic OH group.

[0074] The hydrolysis is preferably carried out with an acid.

[0075] Furthermore, the hydrolysis can be achieved under reducing conditions by using metal hydrides, especially complex hydrides such as LiAlH4.

[0076] The reaction conditions for such hydrolysis of esters to phenols are primarily known to those skilled in the art.

[0077] As pointed out above, compounds of formula (III) are preferably formed from compounds of formula (II) by ring-opening step a).

[0078] The compound of formula (III) is then reduced in step b') and then hydrolyzed in step c') [b'] reducing the compound of formula (III) with a reducing agent in the presence of a heterogeneous metal catalyst to obtain a compound of formula (I') [ka] to produce a compound of; c') hydrolyzing a compound of formula (I') to form a compound of formula (I); or or It is hydrolyzed in step c'') and then reduced in step b''). [c''] hydrolyzing a compound of formula (III) to obtain a compound of formula (III') [ka] to produce a compound of b'') reduction of a compound of formula (III') with a reducing agent in the presence of a heterogeneous metal catalyst to give a compound of formula (I), During the ceremony, 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, in particular an acetyl group; R' represents either H or an acyl group.

[0079] These preferred synthetic routes are shown schematically in FIG.

[0080] In the first pathway (left side of Figure 2), a compound of formula (II) is ring-opened in step a) to give a compound of formula (III), which is then reduced in step b') to give a compound of formula (I'), which is then hydrolyzed in step c') to give 2,3,6-trimethylphenol (formula (I)).

[0081] In the second pathway (right side of Figure 2), the compound of formula (II) is ring-opened in step a) to give the compound of formula (III), which is then hydrolyzed in step c'') to give the compound of formula (III'), which is then reduced in step b'') to give 2,3,6-trimethylphenol (formula (I)).

[0082] The reduction steps b') and b'') are as described above for the reduction step b).

[0083] The hydrolysis steps c') and c'') are as described above for the hydrolysis step c).

[0084] In a third pathway (middle part of FIG. 2), hydrolysis step c''') and reduction step b''') are carried out simultaneously. In this embodiment, which is less preferred than the other two embodiments of FIG. 2, the compound of formula (III) is reduced / hydrolyzed simultaneously. This can be achieved by having the components for reduction step b) and hydrolysis step c) present in the same vessel. In particular, an acid or base (as described above) is added to the compound of formula (III) in the presence of a heterogeneous metal catalyst, here the metal of the heterogeneous metal catalyzed reduction, and a reducing agent, in particular molecular hydrogen.

[0085] Most preferably, the conversion of the compound of formula (III) to 2,3,6-trimethylphenol (formula (I)) follows a route using steps b') and c') (see Figure 2).

[0086] The starting product for the process for preparing 2,3,6-trimethylphenol is the compound of formula (II), which has been described in great detail above. The compound of formula (II) is either 5-methyl-1,3-dihydroisobenzofuran-4-ol (R' = H) or its ester (R' = acyl).

[0087] Esters of the compound 5-methyl-1,3-dihydroisobenzofuran-4-ol are currently unknown to those skilled in the art.

[0088] Thus, in a further aspect, the present invention provides a compound of formula (II') [ka] In the compound of formula R 1 is C 1~20 -alkyl or C 5~10 -cycloalkyl or C 6~12 -aryl or C 7~24 -aralkyl or C 7~24 - an alkylaryl group, C 1~10 -Alkyloxy or aryloxy groups, especially C 1~5 - optionally substituted by alkyl or phenyl groups.

[0089] As noted above, these compounds are suitable for use in the synthesis of 2,3,6-trimethylphenol or compounds of formula (III).

[0090] Compounds of formula (II') are in particular 5-methyl-1,3-dihydroisobenzofuran-4-ol and the corresponding carboxylic acid R'OH(R 1 COOH) or its anhydride R'OR'((R 1 It can be prepared from HCl (corresponding to HClO).

[0091] It has been shown that the compound of formula (II') can in particular be prepared from 5-methyl-1,3-dihydroisobenzofuran-4-ol and acetic anhydride, preferably in a mixture of acetic anhydride and acetic acid.

[0092] Furthermore, it has been observed that the addition of small amounts (typically 5-15 mol % relative to 5-methyl-1,3-dihydroisobenzofuran-4-ol) of trifluoroacetic acid is beneficial in the synthesis of compounds of formula (II'), particularly 5-methyl-1,3-dihydroisobenzofuran-4-yl acetate.

[0093] Compounds of formula (II') can be isolated and their structure and identity determined by standard methods.

[0094] [Example] The present invention is further illustrated by the following experiments.

[0095] [1. Synthesis of (3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate] [1a) Starting from 5-methyl-1,3-dihydroisobenzofuran-4-ol] [- Use of a mixture of acetic acid / acetic anhydride: Example 1] In a 100 mL three-necked round-bottom flask under argon, sulfamic acid (0.251 g, 2.56 mmol) was added to a solution of 5-methyl-1,3-dihydroisobenzofuran-4-ol (4 g, 25.6 mmol) in acetic acid (33 mL, 574 mmol) and acetic anhydride (33 mL, 346 mmol). The resulting clear yellow solution was refluxed at 127 °C for 17 h.

[0096] After cooling to 0 °C (water / ice bath), 5% aqueous HCl was added to the brown mixture, which was extracted several times with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO (2x), water, brine, dried (NaSO), and concentrated under reduced pressure to give 8.77 g of a brown oil.

[0097] The crude product was adsorbed onto Kinesis TELOS Flash Chromatography Bulk Sorbent, NM (diatomaceous earth) and purified by silica gel column chromatography using n-heptane / EtOAc as the eluent to give the desired product, i.e., 3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate, (1) (6.13 g, 20.7 mmol, 81%) as a pale yellow oil.

[0098] Analytical data for 3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate: 1 H NMR(300MHz,CDCl3)δ [ppm]=2.02(s,3H),2.08(s,3H),2.17(s,3H),2.35(s,3H),5.16(s,2H),5.23(s,2H),7.21-7.28(m,2H). 13 C NMR(75MHz,CDCl3)δ [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:ν ~ [cm -1 ]=778,820,914,1072,1023,1181,1212,1371,1435,1733,1763,2936. C 15 H 18 Calculated values ​​for O6(294.3): C61.22, H6.16; Measured values: C61.26, H6.32

[0099] [-Acetic anhydride used: Example 1a] In a 100 mL three-necked round-bottom flask under argon, 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 clear yellow solution was refluxed at 127 °C for 20 h.

[0100] After cooling to 0°C (water / ice bath), 5% aqueous HCl was added to the brown mixture, which was extracted several times with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO (2x), water, and brine, dried (NaSO), and concentrated under reduced pressure to give 1.22 g of a brown oil, 3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate (89% pure by q-NMR, 3.69 mmol, 92%). Analytical data were consistent with Example 1.

[0101] [-Acetic acid used: Reference Example 1:] In a 100 mL three-necked round-bottom flask under argon, 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 clear yellow solution was refluxed at 107 °C for 22 h. Reaction monitoring by GC and TLC showed no conversion of the 5-methyl-1,3-dihydroisobenzofuran-4-ol starting material.

[0102] [1b) Starting from 5-methyl-1,3-dihydroisobenzofuran-4-yl acetate] In a 25 mL three-necked round-bottom flask under argon, 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 clear yellow solution was refluxed at 127 °C for 20 h.

[0103] After cooling to 0°C (water / ice bath), 5% aqueous HCl was added to the brown mixture, which was extracted several times with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO (2x), water, and brine, dried (NaSO), and concentrated under reduced pressure to give 0.75 g of a brown oil, 3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate (91% pure by q-NMR, 2.30 mmol, 92%). Analytical data were consistent with Example 1.

[0104] [Synthesis of 5-methyl-1,3-dihydroisobenzofuran-4-yl acetate] In a 100 mL three-necked round-bottom flask under argon, 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 acetic acid (5.0 mL) and acetic anhydride (5.0 mL). The resulting clear yellow solution was refluxed at 127 °C for 23 h.

[0105] After cooling to 0 °C (water / ice bath), 5% aqueous HCl was added to the brown mixture, which was extracted several times with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO (2x), water, and brine, dried (NaSO), 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%).

[0106] Analytical data for 5-methyl-1,3-dihydroisobenzofuran-4-yl acetate: 1 H NMR(300MHz,CDCl3)δ [ppm]=2.20(s,3H),2.32(s,3H),4.97-5.03(m,2H),5.09-5.14(m,2H),6.98-7.05(m,1H),7.11-7.19(m,1H). 13C NMR(75MHz,CDCl3)δ [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:ν ~ [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 value [C 11 H 12 O3 + ]:192.0786; Actual value 192.0790

[0107] [2. Synthesis of 2,3,6-trimethylphenylacetate by reduction of (3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate] [-Various solvents used] (3-Acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate (1, 130 mg, 0.442 mmol) was dissolved in 10 mL of the solvent shown in Table 1, and Pd / C (5% Evonik E 101N / D, 100 mg) was added. The reactor was sealed and purged three times with N and three times with H. The mixture was stirred overnight at 150 °C under 25 bar H pressure. It was cooled, the pressure was released, and a sample was analyzed by GCMS.

[0108] [Table 1]

[0109] To isolate the product, the reaction was carried out using 1.85 g of substrate and 550 mg of catalyst in 73 mL of EtOAc under 15 bar H pressure for 4 hours. 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-trimethylphenylacetate (2), with 95% purity (q-NMR): 1H NMR(300MHz,CDCl3)δ [ppm]=2.07(s,3H),2.13(s,3H),2.27(s,3H),2.36(s,3H),6.92-7.02(m,2H).

[0110] [-Various heterogeneous metal catalysts] The synthesis was also evaluated using various 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 shown in Table 2. The reactor was sealed and purged three times with N and three times with H. The mixture was stirred overnight at 150 °C under 25 bar H pressure. It was cooled, the pressure was released, and a sample was analyzed by GCMS.

[0111] [Table 2]

[0112] [3. Synthesis of 2,3,6-trimethylphenol by hydrolysis of 2,3,6-trimethylphenyl acetate] In a 50 mL three-necked round-bottom flask under an argon atmosphere, 2,3,6-trimethylphenylacetate (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 hydrogen sulfate (857 mg, 2.50 mmol). The resulting yellow mixture was stirred under argon at room temperature for 5 hours and 15 minutes, during which time it turned deep purple.

[0113] The mixture was filtered through Celite, and the filtrate was neutralized with 4N HCl. It was extracted three times with diethyl ether, and the combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. Drying under 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. Analytical data were consistent with that of a commercially available sample: 1 H NMR(300MHz,CDCl3)δ [ppm]= 2.19(s,3H),2.24(s,3H),2.27(s,3H),4.62(brs,1H),6.69(d,J=7.53Hz,1H),6.89(d,J=7.53Hz,1H).

[0114] [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-necked round-bottom flask under argon, LiAlH (1.07 g, 26.7 mmol) was suspended in anhydrous THF (12 mL) and cooled to 0 °C (water / ice bath). (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. Check by TLC immediately after the addition was complete indicated complete conversion of the substrate.

[0115] The reaction was quenched by pouring into ice water (ca. 50 mL), and the resulting mixture was acidified with dilute H2SO4 to pH 1-2, saturated with solid NaCl, and extracted with EtOAc (3x). The combined organic phases were washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and concentrated under reduced pressure.

[0116] The crude product was adsorbed onto Kinesis TELOS Flash Chromatography Bulk Sorbent, NM (diatomaceous earth) and purified by silica gel column chromatography using n-heptane / EtOAc as the eluent to give 1.27 g (7.43 mmol, 75%) of the desired product, i.e., (3-hydroxy-4-methyl-1,2-phenylene)dimethanol, (3), as a colorless solid.

[0117] Analytical data for 3-hydroxy-4-methyl-1,2-phenylene)dimethanol: 1H NMR(300MHz,DMSO-d6)δ [ppm]=2.14(s,3H),4.42-4.50(m,2H),4.72(s,2H),4.86-5.08(m,1H),5. 52(brs,1H),6.75(d,J=7.53Hz,1H)6.96(d,J=7.72Hz,1H)8.86(brs,1H). 13 C NMR(75MHz,DMSO-d6)δ [ppm]=16.7,57.4,61.7,119.2,124.1,124.5,129.3,136.9,154.5. eiFI+MS, after silylation: 294 [M + +3TMS-CH3],279,251,221,191,147,105.

[0118] [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 the catalyst was added as shown in Table 3. The reactor was sealed and purged three times with N and three times with H. The mixture was stirred overnight at the indicated temperature and H pressure. It was cooled, the pressure was released, and a sample was analyzed by GCMS. The product, 2,3,6-trimethylphenol, was identified by comparison with a commercially available sample.

[0119] [Table 3]

Claims

1. A process for preparing a compound of formula (I) from a compound of formula (II), comprising: a) a ring-opening step; b) a reduction step; Including, 【Chemistry 1】 wherein R' represents either H or an acyl group.

2. The ring-opening step a) is carried out in the presence of a compound of formula ROR and sulfamic acid to give a compound of formula (III) 【Chemistry 2】 2. The process according to claim 1, characterized in that it produces an intermediate of the formula: in which R represents an acyl group, in particular an acetyl group.

3. 3. The method according to claim 1 or 2, wherein the reduction step b) is carried out with a reducing agent in the presence of a heterogeneous metal catalyst, the metal of which 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 method comprises: c) hydrolyzing the ester groups to hydroxyl groups The method according to any one of claims 1 to 3, further comprising:

5. The compound of formula (III) is reduced in step b') and then hydrolyzed by step c') [b') reducing the compound of formula (III) with a reducing agent in the presence of a heterogeneous metal catalyst to obtain a compound of formula (I') 【Transformation 3】 to produce a compound of formula (I): c') hydrolyzing the compound of formula (I') to produce a compound of formula (I); or It is hydrolyzed in step c") and then reduced in step b") [c″] hydrolyzing the compound of formula (III) to obtain a compound of formula (III′): 【Chemistry 4】 to produce a compound of b″) reducing the compound of formula (III′) with a reducing agent in the presence of a heterogeneous metal catalyst to produce the compound of formula (I). (In the formula, the metal of the heterogeneous metal catalyst is selected from the group consisting of Ni, Fe, Ir, Pd, Pt, Rh and Ru; 5. The method according to claim 2, wherein R represents an acyl group, in particular an acetyl group.

6. 6. The process according to claim 2, wherein the ring-opening reaction a) is carried out by reacting with a mixture of compounds of formula ROH and formula ROR, where R is in particular an acetyl group, preferably in a molar ratio of ROH / ROR of from 1:3 to 2:1, in particular from 1:1 to 2:1, preferably from 1.5:1 to 2:

1.

7. 7. The method according to any one of claims 2 to 6, characterized in that a molar ratio of the compound of formula (II) to the compound of formula ROR is used in the range of 1:3 to 1:50, in particular in the range of 1:5 to 1:40, preferably 1:8 to 1:

30.

8. 8. The process according to any one of claims 2 to 7, characterized in that the molar ratio of the sulfamic acid to the compound of formula (II) is in the range of 1:50 to 1:1, in particular in the range of 1:50 to 1:5, preferably in the range of 1:30 to 1:10, more preferably in the range of 1:20 to 1:

10.

9. 9. The method of any one of claims 1 to 8, wherein the ring-opening step a) is carried out at a temperature of from 100°C to 140°C.

10. 10. The process according to any one of claims 1 to 9, characterized in that the ring-opening step a) is carried out under an inert atmosphere, in particular under nitrogen or argon, in particular under argon.

11. The method according to any one of claims 3 to 10, characterized in that the reducing agent in step b) is molecular hydrogen.

12. 12. The method according to any one of claims 3 to 11, characterized in that the heterogeneous metal catalyst of step b) is a palladium catalyst, in particular a palladium on carbon catalyst.

13. 1. A composition comprising: - Formula (II) 【Transformation 5】 and a compound of - a compound of formula ROR wherein R' represents an acyl group, in particular an acetyl group, and - sulfamic acid and A composition comprising:

14. Formula (II') 【Transformation 6】 (In the formula, R １ is C １～２０ -Alkyl or C ５～１０ -cycloalkyl or C ６～１２ -aryl or C ７～２４ -aralkyl or C ７～２４ - an alkylaryl group, C １～１０ - an alkyloxy or aryloxy group, in particular C １～５ - optionally substituted by alkyl or phenyl groups.

15. Formula (I) 【Transformation 7】 wherein R and R' represent an acyl group, in particular an acetyl group.

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