Synthesis of 2, 3, 6-trimethylphenol from 5-methyl-1, 3-dihydroisobenzofuran-4-ol or esters thereof comprising ring opening and reduction steps

Abstract

The invention relates to a method for synthesizing 2, 3, 6-trimethylphenol from 5-methyl-1, 3-dihydroisobenzofuran-4-alcohol or ester thereof, which comprises a ring opening step and a reduction step.

Description

Technical Field

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

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

[0003] Various methods for its synthesis have been proposed.

[0004] WO 2018 / 096152 A1 discloses a method for preparing 5-methyl-1,3-dihydroisobenzofuran-4-ol by hydrogenation in the presence of a palladium complex. No 2,3,6-Trimethylphenol was obtained as the desired hydrogenation product.

[0005] However, 5-methyl-1,3-dihydroisobenzofuran-4-ol is obtainable from renewable raw materials and is therefore a very interesting compound, and the possibility of synthesizing 2,3,6-trimethylphenol from this compound would be highly appreciated. Summary of the Invention

[0006] Therefore, the problem to be solved by the present invention is to provide a method for synthesizing 2,3,6-trimethylphenol using 5-methyl-1,3-dihydroisobenzofuran-4-ol or its ester as a raw material.

[0007] Surprisingly, it has been found that this synthesis can be carried out by using the process according to claim 1 .

[0008] It is very surprising that 5-methyl-1,3-dihydroisobenzofuran-4-ol or an ester thereof can be converted to the target 2,3,6-trimethylphenol in high yield and selectivity by using at least two steps, namely a ring opening step and a reduction step. It is further surprising that as a result of the ring opening, a compound of formula (III) can be formed. It has been found that in a preferred embodiment of the present invention, the intermediate of formula (III) can then be converted to 2,3,6-trimethylphenol via three different pathways, each of which includes a hydrogenation step.

[0009] Thus, despite the negative results indicated by WO 2018 / 096152 A1, a short synthetic route involving a hydrogenation step starting from the highly sustainable molecule 5-methyl-1,3-dihydroisobenzofuran-4-ol or its esters can be achieved.

[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. DETAILED DESCRIPTION

[0011] In a first aspect, the present invention relates to a process for producing a compound of formula (I) from a compound of formula (II),

[0012]

[0013] a) Opening loop steps and

[0014] b) Reduction step

[0015] Characterized in that R' represents H or acyl.

[0016] For the sake of clarity, some terms used in this document are defined below:

[0017] In this document, “C x-y -alkyl" groups are alkyl groups containing x to y carbon atoms, i.e., for example, C 1-3 -Alkyl is an alkyl group containing 1 to 3 carbon atoms. Alkyl groups can be straight or branched. For example, -CH(CH3)-CH2-CH3 is considered a C4-alkyl group.

[0018] "Aryl" is an aromatic substituent. Thus, a"C x-y "-aryl" is an aryl group containing x to y carbon atoms. Preferred aryl groups are phenyl or naphthyl.

[0019] A "heteroaryl" group is an aromatic substituent having at least one heteroatom. Preferred heteroaryl groups are pyridyl or methylpyridyl.

[0020] "Aralkyl" is an alkyl group substituted with an aryl group.

[0021] Therefore, in this document, “C x-y -aralkyl" groups are aralkyl groups containing x to y carbon atoms, i.e., for example, C 7-16 -Aralkyl is an aralkyl group containing 7 to 16 carbon atoms. Aralkyl groups can be straight-chain or branched. For example, benzyl (-CH3-C6H3) is considered a C7-aralkyl group.

[0022] "Alkylaryl" is an aryl group substituted with an alkyl group.

[0023] Therefore, in this document, “C x-y -alkylaryl" groups are alkylaryl groups containing x to y carbon atoms, i.e., for example, C 7-16 -alkylaryl is an alkylaryl group containing 7 to 16 carbon atoms. Alkylaryl can be straight or branched. For example, tolyl (-C6H4CH3) is considered to be a C7-alkylaryl group, and xylyl (-C6H3(CH3)2) is considered to be a C8-alkylaryl group.

[0024] “C x-y -alkoxy" group is R2 O group, where the substituent R 2 is C as defined above x-y -alkyl.

[0025] “C x-y -aryloxy" group is R 2 O group, where the substituent R 2 is C as defined above x-y -Aryl is an aryl group as defined above.

[0026] "Acyl" is a A chemical substituent, where R 1 is alkyl or cycloalkyl or aryl or heteroaryl or aralkyl or alkylaryl, especially C 1-20 -alkyl or C 5-10 -cycloalkyl or C 6-12 -aryl or C 6-12 -heteroaryl or C 7-24 -aralkyl or C 7-24 -alkylaryl. Substituent R 1 Optionally C 1-10 - substituted with alkoxy or aryloxy.

[0027] 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).

[0028] However, the substituent R in the acyl group 1 Preferably it is unsubstituted.

[0029] The substituent R in the acyl group 1 Especially C 1-20 -alkyl or phenyl, preferably C 1-10 -alkyl, especially C 1-3 -alkyl, most preferably methyl.

[0030] Herein, the term "ring opening" refers to the opening of the ring containing the oxygen atom of 5-methyl-1,3-dihydroisobenzofuran-4-ol or an ester thereof.

[0031] As used herein, the term "reduction step" refers to a step in which a substance is chemically reduced.

[0032] In this document, any dashed line in a formula represents a bond connecting a substituent to the rest of the molecule.

[0033] In case the same labeled symbol or group is present in several formulae, in this document the definition of said group or symbol given in the context of one specific formula also applies to the other formulae containing the same said symbol.

[0034] In WO 2018 / 096152 A1, as disclosed, it has been found that 5-methyl-1,3-dihydroisobenzofuran-4-ol or its esters cannot be reduced directly to 2,3,6-trimethylphenol.

[0035]

[0036] The key element of the present invention is that the presence of two steps, ring opening (step A) and reduction (step b), is necessary for the successful synthesis of 2,3,6-trimethylphenol from 5-methyl-1,3-dihydroisobenzofuran-4-ol or its esters. Figure 1 ).

[0037]

[0038] The ring-opening step a) is followed by the reduction step b). Primarily, the two steps a) and b) can be carried out quasi-simultaneously in the reaction if the components for the ring-opening reaction and the reduction reaction are added to the compound of formula (II).

[0039] However, preferably the two steps a) and b) are performed as separate steps.

[0040] Therefore, in a preferred embodiment, in the first step, the ring-opening reaction of the compound of formula (II) produces the compound of formula (III).

[0041]

[0042] In case an acyl group is present in the compound of formula (I) or the compound of formula (III), the compound is an ester and the process further comprises a step c) of hydrolyzing the ester group to a hydroxyl group, ie to a phenolic group.

[0043] Open-loop steps

[0044] The process for producing 2,3,6-trimethylphenol comprises a ring-opening step a).

[0045] Particularly preferably, the ring-opening step a) is carried out in the presence of a compound of formula ROR and sulfamic acid to give an intermediate of formula (III),

[0046]

[0047] wherein R represents an acyl group, in particular an acetyl group.

[0048] Preferably, R'=R.

[0049] Sulfamic acid, also known as amidosulfonic acid, is a compound of the formula It is a strongly acidic, colorless, water-soluble compound. Sulfamic acid is commercially available in large quantities from various suppliers.

[0050] The compound of formula ROR is a carboxylic acid anhydride wherein R is an acyl group of the formula

[0051] where R 1 is alkyl or cycloalkyl or aryl or heteroaryl or aralkyl or alkylaryl, especially C 1-20 Alkyl or C 5-10 Cycloalkyl or C 6-12 Aryl or C 6-12 Heteroaryl, C 7-24 Aralkyl or C 7-24 alkylaryl, and optionally C 1-10 Alkoxy or aryloxy substituted.

[0052] Most preferably, the compound of formula ROR is acetic anhydride.

[0053] Preferably, the carboxylic anhydride (ROR) is present in combination with its corresponding carboxylic acid (ROH).

[0054] Furthermore, it is preferred that the ring-opening reaction a) is carried out with a mixture of compounds of the formula ROH and ROR, wherein 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.

[0055] Preferably, the 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.

[0056] It is further preferred that the molar ratio of aminosulfonic acid to the compound of formula (II) is in the range of 1:50 to 1:1, particularly 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.

[0057] Preferably, the ring-opening step a) is carried out at a temperature between 100°C and 140°C.

[0058] It is further preferred that the ring-opening step a) is carried out under an inert atmosphere, in particular under nitrogen or argon, in particular under argon.

[0059] The compounds of formula (III), in particular (3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate (R'=R=acetyl), are novel and not yet known. They can be isolated and their identity and structure determined by standard methods.

[0060] Therefore, in another aspect, the present invention relates to compounds of formula (III),

[0061]

[0062] wherein R and R' represent acyl groups, and R' is in particular acetyl. Furthermore, it is preferred that R'=R.

[0063] Since the composition of 5-methyl-1,3-dihydroisobenzofuran-4-ol or an ester thereof of formula (II) and a carboxylic anhydride of formula ROR in the presence of sulfamic acid leads to the production of a compound of formula (III) and a compound of formula (I), in another aspect, the present invention relates to a composition comprising

[0064] -Compound of formula (II)

[0065]

[0066] - a compound of formula ROR;

[0067] in

[0068] R represents an acyl group, especially an acetyl group;

[0069] and

[0070] -Aminosulfonic acid.

[0071] All ingredients and their preferred embodiments and corresponding amounts and ratios have been discussed above in considerable detail.

[0072] In the preferred novel synthetic route to 2,3,6-trimethylphenol, the compound of formula (III) represents a key intermediate.

[0073] Restore steps

[0074] Furthermore, the method for producing 2,3,6-trimethylphenol comprises a reduction step b).

[0075] Preferably, the reduction step b) is carried out 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.

[0076] Preferably, the compound actually reduced is a compound of formula (III) or (III').

[0077]

[0078]

[0079] In a preferred embodiment, the reducing agent is molecular hydrogen. In other words, in one embodiment of each embodiment, the reducing step is carried out by molecular hydrogen as the reducing agent in the presence of a heterogeneous metal catalyst. Hydrogenation is the preferred reduction.

[0080] In another preferred embodiment, the reducing agent is a transfer hydrogenation agent. In other words, in another embodiment, the reduction step is carried out by a transfer hydrogenation agent in the presence of a heterogeneous metal catalyst. The transfer hydrogenation agent is preferably formic acid and / or a formate salt.

[0081] The metal in the heterogeneous metal catalyst is selected from the group consisting of Ni, Fe, Ir, Pd, Pt, Rh and Ru.

[0082] Preferably, the metal of the heterogeneous metal catalysis comprises at least one metal selected from the group consisting of Ni, Fe, Ir, Pd, Pt and Rh. The heterogeneous metal catalyst may be a catalyst comprising more than one of the mentioned metals.

[0083] In particular, the heterogeneous metal catalyst comprises Pd and Pt as metals.

[0084] More preferably, the metal of the heterogeneous metal catalyst is palladium.

[0085] A wide variety of heterogeneous metal catalysts are known. Particularly useful are heterogeneous metal catalysts on a carrier or support material. Such a support material is typically a solid material having a high surface area to which the metal is attached. The support may be inert or participate in the catalytic reaction. Typical support / carrier materials include various carbons, aluminum oxides, and silicon dioxides. A preferred support / carrier material is carbon.

[0086] The heterogeneous metal catalyst can also be attached or fixed on the surface of a larger object, which is usually in the form of a structured packing element, which can be a part of the reactor in which the reduction is carried out or an element inserted into the reactor. The structured packing element can be a pouring filler, a knitted fabric, an open-cell foam structure, preferably made of plastic (for example polyurethane or melamine resin) or ceramic, or a structured packing element as known in principle (i.e. by its geometry) from distillation and extraction technology. However, for the purposes of the present invention, the hydraulic diameter of the structured packing is in principle much smaller than the hydraulic diameter of comparable internals in the field of distillation and extraction technology, typically 1 / 10 to 1 / 2 of 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 designed as Montz A3, Sulzer BX, DX and EX. Instead of metal fabric packings, structured packings made of other woven, knitted or felt materials can also be used. Other useful structured packings are flat or corrugated sheets, preferably without perforations or other relatively large openings, for example designs corresponding to Montz BI or Sulzer Mellapak. Structured packings made of expanded metal are also advantageous, for example structured packings of the Montz BSH type.

[0087] Preferably, the heterogeneous metal catalyst is a palladium catalyst, particularly a palladium-on-carbon catalyst (Pd / C).

[0088] The catalytic metal loading (i.e., metal weight / (metal + support) weight) is typically 1-20% by weight, preferably 4-11% by weight, and more preferably 4-6% by weight. A highly preferred heterogeneous metal catalyst is a palladium-on-carbon catalyst (Pd / C), wherein 5% by weight is palladium (i.e., loading = 5%).

[0089] The reduction or hydrogenation can be carried out in the presence or absence of a solvent. Suitable solvents are in particular 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 the group consisting of alcohols, ethers, esters, acids, aromatic and aliphatic hydrocarbons and carbonates. Preferred are aromatic hydrocarbons, ethers, esters and carbonates.

[0090] Preferred solvents for 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.

[0091] The reduction or hydrogenation is generally carried out at a temperature of 20-200° C., in particular 50-180° C., and preferably under pressure. When molecular hydrogen is used, the reduction is preferably carried out at a hydrogen pressure of 2-30 bar, preferably 5-28 bar.

[0092] The reduction or hydrogenation is carried out in a suitable vessel. The reduction can be carried out batchwise or continuously. Suitable reactors for industrial scale are known.

[0093] Preferably, the weight ratio of the heterogeneous metal catalyst to the compound of formula (III) or (III') is 0.01% to 20%, in particular 1% to 10%.

[0094] Hydrolysis step

[0095] The process for preparing a compound of formula (I) from a compound of formula (II) comprises a ring-opening step a), a reduction step b) and preferably a hydrolysis step c).

[0096] In the hydrolysis step, ester groups present in the compound of formula (II) or in the preferred intermediates of formula (II) or (III) or (I′) are hydrolyzed to hydroxyl groups, more particularly to phenolic OH groups.

[0097] The hydrolysis is preferably carried out by means of an acid.

[0098] Furthermore, by using metal hydrides, in particular complex hydrides such as LiAlH4, hydrolysis can be achieved under reducing conditions.

[0099] The reaction conditions for the hydrolysis of such esters to phenols are largely known to the person skilled in the art.

[0100] As indicated above, it is preferred that the compound of formula (III) is formed from the compound of formula (II) by a ring-opening step a).

[0101] It is highly preferred that the compound of formula (III) is subsequently

[0102] or

[0103] is reduced in step b') and then hydrolyzed in step c')

[0104] 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');

[0105]

[0106] c') hydrolyzing the compound of formula (I') to obtain the compound of formula (I);

[0107] or

[0108] Hydrolyzed in step c") and then reduced in step b")

[0109] c") hydrolyzing the compound of formula (III) to obtain a compound of formula (III');

[0110]

[0111] 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);

[0112] in

[0113] The metal of the heterogeneous metal catalyst is selected from the group consisting of Ni, Fe, Ir, Pd, Pt, Rh and Ru;

[0114] R represents an acyl group, in particular an acetyl group; and

[0115] R' represents H or an acyl group.

[0116] These preferred synthetic routes are schematically shown in Figure 2 middle.

[0117] In the first approach ( Figure 2 In the left part of the figure), the compound of formula (II) is ring-opened in step a) to produce a compound of formula (III), which is then reduced in step b') to produce a compound of formula (I'), which is then hydrolyzed in step c') to produce 2,3,6-trimethylphenol (formula (I)).

[0118] In the second approach ( Figure 2 In the right part of the figure), the compound of formula (II) is ring-opened in step a) to produce a compound of formula (III), which is then hydrolyzed in step c") to produce a compound of formula (III'), which is then reduced in step b") to produce 2,3,6-trimethylphenol (formula (I)).

[0119] Reduction steps b') and b") are as discussed above for reduction step b).

[0120] The hydrolysis steps c') and c") are as discussed above for the hydrolysis step c).

[0121] In the third way ( Figure 2 In the middle part of the embodiment (the hydrolysis step and the reduction step are carried out simultaneously, c') and b'). In this embodiment (which is not as good as Figure 2 In the other two preferred embodiments, the compound of formula (III) is reduced / hydrolyzed simultaneously. This can be achieved by having the components of the reduction step b) and the hydrolysis step c) present in the same container. 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 (wherein a metal reduction of the heterogeneous metal catalyst) and a reducing agent (in particular molecular hydrogen).

[0122] Most preferably, the method according to the method using steps b') and c') is carried out (see Figure 2 ) to convert the compound of formula (III) into 2,3,6-trimethylphenol (formula (I)).

[0123] The starting product of the process for producing 2,3,6-trimethylphenol is a compound of formula (II) as described in greater detail above.The compound of formula (II) is 5-methyl-1,3-dihydroisobenzofuran-4-ol (R'=H) or an ester thereof (R'=acyl).

[0124] Esters of the compound 5-methyl-1,3-dihydroisobenzofuran-4-ol are currently unknown to those skilled in the art.

[0125] Therefore, in another aspect, the present invention relates to compounds of formula (II')

[0126]

[0127] where R 1 It is C 1-20 -alkyl or C 5-10 -cycloalkyl or C 6-12 -aryl or C 7-24 -aralkyl or C 7-24 -alkylaryl, and optionally C 1-10 - alkoxy or aryloxy substituted, especially C 1-5 -alkyl or phenyl.

[0128] As shown above, these compounds are suitable for the synthesis of 2,3,6-trimethylphenol or compounds of formula (III).

[0129] The compound of formula (II') can be prepared in particular from 5-methyl-1,3-dihydroisobenzofuran-4-ol and the corresponding carboxylic acid R'OH (corresponding to R 1 COOH) or its anhydride R'OR' (corresponding to (R 1 CO)2O)) to produce.

[0130] It has been shown that the compound of the formula (II′) can be prepared, inter alia, from 5-methyl-1,3-dihydroisobenzofuran-4-ol and acetic anhydride, preferably in a mixture of acetic anhydride and acetic acid.

[0131] Furthermore, it has been observed that the admixture of small amounts (typically 5-15 mol % relative to 5-methyl-1,3-dihydroisobenzofuran-4-ol) of trifluoroacetic acid facilitates the synthesis of compounds of formula (II'), in particular the synthesis of 5-methyl-1,3-dihydroisobenzofuran-4-yl acetate.

[0132] Compounds of formula (II') can be isolated and their structure and identity determined by standard methods.

[0133] Example

[0134] The present invention is further illustrated by the following experiments.

[0135] 1. Synthesis of (3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate 1a) from 5-methyl- Starting from 1,3-dihydroisobenzofuran-4-ol

[0136] - Using a mixture of acetic acid / acetic anhydride: Example 1

[0137] In a 100 mL three-necked round-bottom 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 (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 hours.

[0138] After cooling to 0°C (water / ice bath), 5% aqueous HCl was added to the brown mixture and 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.

[0139] The crude product was adsorbed onto Kinesis TELOS Flash Chromatography Bulk adsorbent NM (Celite) and purified by silica gel column chromatography using n-heptane / EtOAc as eluent to give the desired product, 3-acetoxy-4-methyl-1,2-phenylene)bis(methylene) diacetate, (1) (6.13 g, 20.7 mmol, 81%), as a light yellow oil.

[0140] Analytical data of (3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate:

[0141] 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).

[0142] 13C 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.

[0143] eiFI+MS:252[M + -OAc], 234, 192, 174, 150, 122, 105, 91, 43.

[0144] FT-IR: [cm -1 ]=778,820,914,1072,1023,1181,1212,1371,1435,1733,1763,2936.

[0145] For C 15 H 18 Anal. Calcd. for O6 (294.3): C 61.22, H 6.16; Found: C 61.26, H 6.32.

[0146] - Using acetic anhydride: Example 1a

[0147] In a 100 mL three-necked round-bottom flask, under 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) and the resulting yellow clear solution was refluxed at 127° C. for 20 hours.

[0148] After cooling to 0°C (water / ice bath), 5% aqueous HCl was added to the brown mixture and extracted several times with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO₃ (twice), water, and brine, dried (Na₂SO₄), and concentrated under reduced pressure to yield 1.22 g of (3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate as a brown oil (89% purity by q-NMR, 3.69 mmol, 92%). Analytical data were consistent with Example 1.

[0149] - Using acetic acid: Example Reference 1:

[0150] In a 100 mL three-necked round-bottom 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 mmol) and water (4.20 ml, 233 mmol). The resulting yellow clear solution was refluxed at 107 ° C for 22 hours. Reaction control by GC and TLC showed that the 5-methyl-1,3-dihydroisobenzofuran-4-ol starting material was not converted.

[0151] 1b) Starting from 5-methyl-1,3-dihydroisobenzofuran-4-yl acetate

[0152] In a 25 mL three-necked round-bottom flask, under an argon atmosphere, to a solution of 5-methyl-1,3-acetate hydroisobenzofuran-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) was added sulfamic acid (24.7 mg, 0.252 mmol). The resulting clear yellow solution was refluxed at 127° C. for 20 hours.

[0153] After cooling to 0°C (water / ice bath), 5% aqueous HCl was added to the brown mixture and extracted several times with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO₃ (twice), water, and brine, dried (Na₂SO₄), and concentrated under reduced pressure to afford 0.75 g of (3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate as a brown oil (91% purity by q-NMR, 2.30 mmol, 92%). Analytical data were consistent with Example 1.

[0154] Synthesis of 5-methyl-1,3-dihydroisobenzofuran-4-yl acetate

[0155] In a 100 mL three-necked round-bottom flask, under 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 acetic acid (5.0 mL) and acetic anhydride (5.0 mL). The resulting yellow clear solution was refluxed at 127° C. for 23 hours.

[0156] After cooling to 0°C (water / ice bath), 5% aqueous HCl was added to the brown mixture and extracted several times with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO (twice), 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%).

[0157] Analytical data of 5-methyl-1,3-dihydroisobenzofuran-4-yl acetate:

[0158] 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).

[0159] 13 C 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.

[0160] FT-IR: [cm -1 ]=686,737,761,886,897,932,984,1050,1154,1190,1222,1367,1375,1433,1486,1487,1592,1631,1746,2073,2857.

[0161] For [C 11 H 12 O3 + ] HRMS (ESI) calculated: 192.0786; found 192.0790. 2. By reducing (3-ethyl Acyloxy-4-methyl-1,2-phenylene)bis(methylene)diacetate

[0162] Synthesis of 2,3,6-trimethylphenyl acetate

[0163] -Use different solvents

[0164] (3-Acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate (1,130 mg, 0.442 mmol) was dissolved in the solvent shown in Table 1 (10 mL), and Pd / C (5% Evonik E101N / D, 100 mg) was added. The reactor was sealed and purged three times with N2 and three times with H2. The mixture was stirred overnight at 150°C under 25 bar H2 pressure. The mixture was cooled, the pressure was released, and a sample was analyzed by GCMS.

[0165] solvent <![CDATA[Yield [%] 1 > Toluene 94 2-Methyl-THF 95 Cyclopropyl methyl ether 97 Isopropyl acetate 97 Ethyl acetate 98 Propylene carbonate 94

[0166] Table 1. Use of different solvents in the reduction step of (3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate.

[0167] 1 Yield of 2,3,6-trimethylphenyl acetate, measured as GCMS area %.

[0168] To isolate the product, 1.85 g of substrate and 550 mg of catalyst were reacted in 73 mL of EtOAc under 15 bar H₂ pressure for 4 hours. After completion of the reaction, the catalyst was removed by filtration and the solvent was evaporated under reduced pressure to obtain the desired product, 2,3,6-trimethylphenyl acetate (2), with 95% purity (q-NMR):

[0169] 1 H 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).

[0170] -Use of different heterogeneous metal catalysts

[0171] The synthesis was also evaluated with different catalysts:

[0172] (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 N2 and three times with H2. The mixture was stirred at 150°C and 25 bar H2 pressure overnight. The mixture was cooled, the pressure was released, and a sample was analyzed by GCMS.

[0173]

[0174] 3. Synthesis of 2,3,6-trimethylphenol by hydrolysis of 2,3,6-trimethylphenyl acetate

[0175] Under argon atmosphere, in a 50 ml three-necked round-bottom flask, 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 at room temperature under argon for 5 hours and 15 minutes, during which time it turned dark purple.

[0176] It was filtered through celite and the filtrate was neutralized with 4N HCl. It was extracted three times with 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, 2,3,6-trimethylphenol, as an orange solid. The analytical data were consistent with the commercial sample:

[0177] 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).

[0178] 4. (3-Hydroxyphenyl)diacetate was synthesized by hydrolysis of (3-acetoxy-4-methyl-1,2-phenylene)bis(methylene)diacetate. 4-Methyl-1,2-phenylene)dimethanol

[0179] Under argon atmosphere, LiAlH4 (1.07 g, 26.7 mmol) was suspended in anhydrous THF (12 mL) in a 50 ml three-necked round-bottom flask 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 was performed immediately after the addition was complete, indicating complete conversion of the substrate.

[0180] The reaction is poured into cancellation in frozen water (about 50mL), and by the H of gained mixture dilution SO be acidified to pH 1-2, saturated with solid NaCl, and extracted with EtOAc (3x).By the saturated NaHCO of organic phase merging With salt water washing, dry (Na SO ), and concentrate under reduced pressure rod.

[0181] The crude product was adsorbed onto Kinesis TELOS Flash Chromatography Bulk adsorbent NM (Celite) and purified by silica gel column chromatography using n-heptane / EtOAc as eluent to give 1.27 g (7.43 mmol, 75%) of the desired product, (3-hydroxy-4-methyl-1,2-phenylene)dimethanol, (3), as a colorless solid.

[0182] Analytical data of (3-hydroxy-4-methyl-1,2-phenylene)dimethanol:

[0183] 1 H NMR (300MHz, DMSO-d6) δ [ppm] = 2.14 (s, 3H), 4.42–4.50 (m, 2H), 4.72 (s, 2H), 4.86–5.0 8 (m, 1H), 5.52 (brs, 1H), 6.75 (d, J = 7.53Hz, 1H) 6.96 (d, J = 7.72Hz, 1H) 8.86 (brs, 1H).

[0184] 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.

[0185] eiFI+MS after silylation: 294[M + +3TMS-CH3], 279, 251, 221, 191, 147, 105.

[0186] 5. Synthesis of 2,3,6-trimethylphenol by reduction of (3-hydroxy-4-methyl-1,2-phenylene) dimethanol

[0187] (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 N2 and three times with H2. The mixture was stirred overnight at the indicated temperature and H2 pressure. Cooled, the pressure was released, and the sample was analyzed by GCMS. The product, 2,3,6-trimethylphenol, was identified by comparison with a commercial sample.

[0188]

[0189] Table 3. Use of different heterogeneous metal catalysts in the reduction step of (3-hydroxy-4-methyl-1,2-phenylene)dimethanol.

[0190] 1Yield of 2,3,6-trimethylphenol, measured as GCMS area %.

Claims

1. A method for preparing a compound of formula (I) from a compound of formula (II), comprising: a) Opening loop steps and b) Reduction step It is characterized by: R' represents H or an acyl group.

2. The method according to claim 1, characterized in that The ring-opening step a) is carried out in the presence of a compound of formula ROR and aminosulfonic acid to obtain an intermediate of formula (III), wherein R represents an acyl group, in particular an acetyl group.

3. The method according to claim 1 or 2, characterized in that The reduction step b) is carried out 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 method according to any one of the preceding claims, characterized in that The method further comprises the following steps c) Ester groups are hydrolyzed to hydroxyl groups.

5. The method according to any one of the preceding claims 2 to 4, characterized in that The compound of formula (III): or is 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'); c') hydrolyzing the compound of formula (I') to obtain the compound of formula (I); or Hydrolyzed in step c") and then reduced in step b") c") hydrolyzing the compound of formula (III) to obtain a compound of formula (III'); 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); in 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.

6. The method according to any one of the preceding claims 2 to 5, characterized in that The ring-opening reaction a) is carried out with a mixture of compounds of the formula ROH and ROR, wherein R is in particular acetyl, 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.

7. The method according to any one of the preceding claims 2 to 6, characterized in that The 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. The method according to any one of the preceding claims 2 to 7, characterized in that The molar ratio of the aminosulfonic acid to the compound of formula (II) is in the range of 1:50 to 1:1, particularly 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. The method according to any one of the preceding claims, characterized in that The ring-opening step a) is carried out at a temperature of 100°C to 140°C.

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

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

13. A composition comprising: -Compound of formula (II) - a compound of formula ROR; in R' represents an acyl group, especially an acetyl group and -Aminosulfonic acid.

14. Compounds of formula (II') where R 1 It is C 1-20 -alkyl or C 5-10 -cycloalkyl or C 6-12 -aryl or C 7-24 -aralkyl or C 7-24 -alkylaryl, and optionally C 1-10 - alkoxy or aryloxy substituted, especially C 1-5 -alkyl or phenyl.

15. Compounds of formula (I) wherein R and R' represent acyl groups, in particular acetyl groups.

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