Methylation of alcohols or thiols for the manufacturing of methylethers or methylthioethers

Abstract

The present invention relates to a process for the preparation of an aliphatic or aromatic methylether or methylthioether, preferably according to formula (I).

Description

[0001] Eisenfuhr Speiser

[0002] Munich, 29 November 2024

[0003] Our Ref.: SM 7001-01WO SOE / tko

[0004] Applicant: Symrise AG

[0005] Serial Number: New Application

[0006] Symrise AG

[0007] Mühlenfeldstraße 1, 37603 Holzminden,

[0008] Germany

[0009] METHYLATION OF ALCOHOLS OR THIOLS FOR THE MANUFACTURING OF METHYLETHERS OR METHYLTHIOETHERS

[0010] The present invention relates to a process for the preparation of an aliphatic or aromatic methylether or methylthioether, preferably according to formula (I) (as described herein).

[0011] Further aspects of the present invention will arise from the description below, in particular 5 from the examples, as well as from the attached patent claims.

[0012] Several methylation reagents are nowadays commercially available and suitable for a wide variety of applications. However, many of these reagents are presumed mutagens and / or carcinogens and therefore their use is associated with high risk. Moreover, most of these compounds cannot be sourced from renewable raw materials and are not sustainable.

[0013] 0 Quaternary ammonium salts are safer alternatives compared to other methylation reagents (e.g., methyliodide, dimethylsulfate). Due to their weaker methylation power, they are mainly used for the methylation of phenols (N. Maras, S. Polanc, M. Kocevar; Tetrahedron Lett. 2008, 64 (51), 11618-11624). One of these quaternary ammonium salts is betaine. Betaine is a by-product of the sugar industry and can therefore be sustainably sourced.

[0014] 5 There are a few examples describing the methylation of phenols with betaine (G. Kollenz, W. Maitz; Monatshefte fiir Chemie 1979, 110 (1), 89-95; H. Wittmann, G. Moller, E. Ziegler; Monatshefte fiir Chemie 1966, 97, 1207-1216). The use of CaO at very high temperatures (ca. 200 °C) yield in a methylation of phenols in the presence of betaine. Also, simple primary alcohols can be methylated under similar reaction conditions, however the yield is bad to moderate (5-50%) and the used alcohols are limited due to their physical properties. Only alcohols with boiling points >190 °C are successfully converted to their corresponding methyl ether (1 -Octanol, 1-Decanol).

[0015] WO 2020152579 describes a methylation process of resveratrol using trimethylglycine and folic acid.

[0016] The primary object of the present invention was to provide a novel process for methylation of primary and secondary alcohols or thiols, preferably with betaine, for the manufacturing of methylethers or methylthioethers. Furthermore, a process shall be provided which preferably offers a methylation process with raw materials from renewable sources and that are safe in handling. Preferably a process is provided which can be operated solvent-free.

[0017] Further objects underlying the present invention follow from the description below and the present patent claims.

[0018] According to a first aspect of the present invention, the stated object is achieved by a process for the preparation of an aliphatic or aromatic methylether or methylthioether, preferably according to formula (I)

[0019] 1

[0020] H3CXR1

[0021]

[0022] (I)

[0023] wherein X is O or S and R1is selected from the group consisting of primary, secondary or tertiary aliphatic or aromatic residues, preferably is selected from the group consisting of linear, substituted or cyclic Ci - CM alkyl residues, linear, substituted or cyclic Ci - CM heteroalkyl residues, C6 - C14 aromatic residues, or C4 - C14 heteroaromatic residues, more preferably is selected from the group consisting of

[0024]

[0025] or preferably according to formula (II)

[0026] H3CxAxCH3

[0027] (II)

[0028] wherein X is O or S and A is selected from the group consisting of primary, secondary or tertiary aliphatic or aromatic residues, preferably is selected from the group consisting of linear, substituted or cyclic Ci - CM alkyl residues, linear, substituted or cyclic Ci - CM heteroalkyl residues, C6 - C14 aromatic residues, or C4 - C14 heteroaro- matic residues,

[0029] more preferably A is

[0030]

[0031] comprising or consisting of the following steps:

[0032] (a) providing an aliphatic or aromatic primary, secondary or tertiary alcohol or thiol, preferably according to formula (III), HX - R1

[0033] (HI),

[0034] wherein X is O or S and R1is selected from the group consisting of

[0035]

[0036] or preferably according to formula (IV)

[0037] HxAxH

[0038] (IV)

[0039] wherein X is O or S and A is selected from the group consisting of primary, secondary or tertiary aliphatic or aromatic residues, preferably is selected from the group consisting of linear, substituted or cyclic Ci - CM alkyl residues, linear, substituted or cyclic Ci - CM heteroalkyl residues, C6 - C14 aromatic residues, or C4 - C14 heteroaromatic residues,

[0040] more preferably A is

[0041] o

[0042]

[0043] and

[0044] optionally adding (a) solvent / s

[0045] and / or

[0046] optionally melting the provided alcohol or thiol,

[0047] (b) mixing a base with the alcohol or thiol provided in step (a),

[0048] (c) reacting the mixture obtained in step (b) at a temperature in a range of from 30 - 100 °C, preferably in a range of from 40 - 70 °C, most preferably in a range of from 50 - 60 °C,

[0049] (d) adding betaine and / or betaine monohydrate to the mixture obtained in step (c),

[0050] (e) reacting the mixture obtained in step (d) at a temperature in a range of from 90 - 160 °C, preferably in a range of from 120 - 150 °C, most preferably in a range of from 130 - 140 °C, preferably for a period of 120 to 1440 min.

[0051] Surprisingly it was found that a process as described herein is particularly advantageous for the preparation of an aliphatic or aromatic methylether or methylthioether. The precise adjustment of the individual process parameters and the use of preferably sustainably produced betaine ensures an effective process in which the (thio)ethers are obtained in good yields.

[0052] Furthermore, it was surprisingly found that a process as described herein is particularly advantageous for the methylation of secondary aliphatic alcohols, e.g., menthol. To the best of our knowledge the methylation of this type of alcohols with betaine was not yet reported in literature.

[0053] According to a preferred embodiment of the present invention, a process as defined above is preferred wherein step (c) preferably is performed in two individual steps, more preferably wherein reacting the mixture obtained in step (b) at a temperature in a range of from 30 -100 °C, preferably in a range of from 40 - 70 °C, most preferably in a range of from 50 - 60 °C, is performed as a first step and subsequently reacting the mixture obtained in step (b) at a temperature in a range of from 105 - 150 °C is performed as a second step. The reaction temperature of step (c) and (e) depends on the physical properties of the alcohols / thiols. The preferred temperature of the reaction is between 105 and 150 °C, for alcohols preferably between 120 and 140 °C, more preferably 130-140 °C and for thiols preferably between 105 and 140 °C, more preferably 105 °C.

[0054] The reaction time of step (c) and (e) depends on the physical properties of the alcohols / thiols. The reaction time is preferably between 4 and 16 h, preferred 8 h.

[0055] A preferred embodiment of the present invention is a process as defined above, wherein the betaine and / or betaine monohydrate used in step (d) originate(s) from renewable sources, such as e.g. sugar beet, quinoa, beetroot.

[0056] A preferred embodiment of the present invention is a process as defined above, wherein CH3

[0057] I

[0058] 0H

[0059] the provided alcohol

[0060]

[0061] isH3CCH3, preferably wherein the provided alcohol is selected from the group consisting of (-)-menthol, (+)-menthol, (+)-neomenthol, (-)-neomenthol, (+)-isomenthol, (-)-isomenthol, (+)-neoisomenthol and (-)-neoisomenthol.

[0062] A preferred embodiment of the present invention is a process as defined above, wherein the prepared methylether or methylthioether is selected from the group consisting of

[0063]

[0064] A process as defined above is particularly advantageous for the manufacturing of the (thio)ethers as defined in the embodiment above.

[0065] A process as defined above is particularly preferred, wherein in step (b) 0.2 to 2 equivalents, preferably 0.8 to 1.2 equivalents, most preferably 1 equivalent of the base are mixed with the alcohol or thiol according to formula (III) provided in step (a), based on the total amount of alcohol or, respectively, thiol.

[0066] According to a preferred embodiment of the present invention, a process as defined above is preferred, wherein in step (d) 0.5 to 2 equivalents, preferably 0.75 to 1.5 equivalents, most preferably 1.2 equivalents of the betaine and / or betaine monohydrate are added, based on the total amount of alcohol or, respectively, thiol according to formula (III) in step (a).

[0067] Advantageously, the process as defined above results in particularly good yields of the thio)ethers when performed with the equivalents as defined above.

[0068] A further preferred embodiment of the present invention is a process as defined above, wherein in step (b) 0.2 to 2 equivalents, preferably 0.8 to 1.2 equivalents, most preferably 1 equivalent of the base are mixed with the alcohol or thiol according to formula (IV) provided in step (a), based on the total amount of alcohol or, respectively, thiol. A preferred embodiment of the present invention is a process as defined above, wherein in step (d) 0.5 to 2 equivalents, preferably 0.75 to 1.5 equivalents, most preferably 1.2 equivalents of the betaine and / or betaine monohydrate are added, based on the total amount of alcohol or, respectively, thiol according to formula (IV) in step (a).

[0069] Preferred is a process according to the invention as defined above, wherein in step (b) the base is selected from the group consisting of alkali bases, preferably Li, Na or K alkali bases, most preferably potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, potassium acetate, or calcium dihydroxide, in particular potassium hydroxide or sodium hydroxide.

[0070] During research, it was found that the process according to the invention as defined herein is particularly advantageous when the bases are used as described herein.

[0071] A preferred embodiment of the present invention is a process as defined above, wherein in step (a) the solvent(s), if present, is / are selected from the group consisting of alkylated aromatic compounds and / or aromatic ethers and / or aliphatic ethers and / or water, preferably anisol, biphenyl, methoxyanisol, decan, xylol, polyethylenglycol.

[0072] During research, it was found that the process according to the invention as defined herein is particularly advantageous when the solvents (if present) are used as described herein.

[0073] Preferred is a process according to the invention as defined above, wherein in step (c) reacting the mixture obtained in step (b) is performed for a period of 1 to 120 min, preferably for a period of 5 to 60 min, most preferably for a period of 10 to 30 min.

[0074] The process according to the invention as defined herein is particularly advantageous when conducted at the reaction times as defined herein.

[0075] According to a preferred embodiment of the present invention, a process as defined above is preferred, wherein after step (e) one more or all of the following further steps are performed:

[0076] (f) cooling of the mixture obtained in step (e) to a temperature below 100 °C,

[0077] (g) adding water and an organic solvent, preferably ethyl acetate and / or methyl-tert-butylether, to the mixture obtained in step (f), if present, or step (e), to obtain an aqueous and an organic layer, (h) separating the organic layer obtained from step (g), if present, from the aqueous layer and washing the organic layer with aqueous sulphuric acid and / or aqueous sodium hydroxide and / or water,

[0078] (i) drying the organic layer obtained from step (h), if present, with a drying agent,

[0079] (j) removing the solvent(s), if used in step (a) and / or step (g) and / or step (h), and

[0080] (k) purifying the obtained methylether or methyltioether by distillation and / or column chromatography.

[0081] A further preferred embodiment of the present invention is a process as defined above, preferably as described above as preferred, wherein the prepared methylether is

[0082]

[0083] The process according to the invention as defined herein is particularly advantageous for the manufacturing of Thymolmethylether.

[0084] The invention will now be described in more detail hereinafter with references to selected examples. Further aspects of the present invention are disclosed in the accompanying claims.

[0085] Examples

[0086] Example 1: Process development and optimization for the methylation of thymol to thymolmethylether

[0087] General synthesis procedure

[0088] 1.00 eq. alcohol / thiol was heated to 50 °C and 0.25 - 2 eq. base were added. During addition of the base, the temperature of the reaction mixture was raised to ~60 °C. The mixture was stirred for 10 min at 50-60 °C. 0.5 - 2 eq. betaine were added, before the reaction mixture was heated and stirred at 105-160 °C for 2 h - 16 h. After cooling to <100 °C, water and methyl-tert-butylether were added and the organic layer was washed with aq. H2SO4- solution (10%), three times with aq. KOH-solution (5%) and once with water. The organic layer was dried over Na2SO4and the solvent was removed under reduced pressure to obtain the raw product.

[0089] According to table 1, the use of 0.25 eq. of KOH led to the desired product in about 20% (entry 4). Consequently, the use of 1.0 eq KOH or NaOH at 130 °C and a reaction time of 7 h led to the desired product in more than 90% (entries 5-6). Longer reaction time gave similar results, also for bigger scale (entries 7-8). Higher amounts of KOH and / or betaine led surprisingly to worse yield of the methylation product, which is maybe a consequence of the higher viscosity of the reaction mixture (entries 9-11). Surprisingly, first trials with K2CO3, KOAc or Ca(OH)2as base resulted in less significant conversion of the starting material in comparison to the bases shown below.

[0090] Table 1: Process development and optimization for the methylation of thymol.

[0091] Entry Thymol [g] Betaine [eq.] Base Base [eq.] Tempera-ture [°C] Time [h] GC-Conversion [%] 1 10.0 0.50 KOH 0.25 150 3.0 21 2 10.0 1.20 KOH 1.0 130 7.0 92 3 10.0 1.20 NaOH 1.0 130 7.0 91 4 10.0 1.20 KOH 1.0 130 12.0 96 5 50.0 1.20 KOH 1.0 130 12.0 98 6 10.0 1.20 KOH 2.0 130 7.0 69 7 10.0 2.00 KOH 2.0 130 7.0 62 8 10.0 2.00 KOH 1.0 130 7.0 84

[0092] Example 2: Experimental procedures

[0093] 2.1) 1-lsopropyl-2-methoxy-4-methyl-benzene

[0094] Betaine 140 °C, 14 h

[0095] 200 g nat. Thymol (1.00 eq, 1.33 mol) were melted at 50 °C. 86.9 g KOH (85%, 1.00 eq,

[0096]

[0097] 1.33 mol) were added while the temperature of the reaction mixture increased to 80 °C.

[0098] 187.2 g Betaine (1.20 eq, 1.60 mol) were added and the reaction mixture was stirred for 14 h at 140 °C. After cooling to <100 °C, 800 mL water and 200 mL Methyl-tert-butylether were added and the organic layer was washed with 200 mL aq. H2SO4-solution (10%), three times with 100 mL aq. KOH-solution (5%) and once with 200 mL water. The organic layer was dried over Na2SO4and the solvent was removed under reduced pressure to obtain 182 g of the raw product (GC-purity: 88%). The raw material was combined with a second trial (crude product: 355 g) and purified by distillation (1.0 mbar, 80-95 °C) to obtain 285 g 1-isopropyl-2-methoxy-4-methyl-benzene (1.73 mol, GC-purity: >99%) as colorless liquid.

[0099]

[0100] NMR (400 MHz, CDCl₃) 6 = 7.08 (d, J = 7.6 Hz, 1 H), 6.74 (dq, J = 7.6, 1.0 Hz, 1 H), 6.66 (d, J = 1.6 Hz, 1H), 3.80 (s, 3H), 3.27 (hept, J = 6.9 Hz, 1H), 2.32 (s, 3H), 1.19 (d, J = 7.0 Hz, 6H) ppm.

[0101] GC-MS: [M]+ = [C₁₁H₁₆O]+- = 164 m / z.

[0102] 2.2) 5-lsopropyl-2-methyl-phenol

[0103] OH

[0104] Betaine

[0105] 130 °C, 6 h

[0106]

[0107] 4.39 g KOH (85%, 1.00 eq, 66.6 mmol) were added to 10 g Carvacrol (1.00 eq, 66.6 mmol) and the mixture was stirred for 10 min at 60 °C. 10.8 g Betaine monohydrate (1.20 eq, 79.9 mmol) were added and the reaction mixture was stirred for 6 h at 130 °C. After cooling to 90 °C, 80 mL water and 80 mL Methyl-tert-butylether were added and the organic layer was washed with 30 mL aq. H2SG4-solution (10%), three times with 50 mL aq. KOH-solution (5%) and once with 50 mL water. The organic layer was dried over Na2SO4and the solvent was removed under reduced pressure to obtain 7.6 g of the raw product (GC-purity: 83%). 2.5 g of the raw material were purified by column chromatography on silica (EtOAc / Cyclohexane) to obtain 1.8 g 5-isopropyl-2-methyl-phenol (11.0 mmol, GC-puritiy: >99%) as colorless oil.

[0108] NMR (400 MHz, CDCl₃) 6 = 7.04 (dd, J = 7.6, 0.9, 1 H), 6.73 (dd, J = 7.6, 1.7, 1 H), 6.70 (d, J = 1.6, 1H), 3.82 (s, 3H), 2.87 (hept, J = 6.9, 1H), 2.18 (s, 3H), 1.25 (d, J = 7.0, 6H) ppm.

[0109] GC-MS: [M]+= [C₁₁H₁₆O]+- = 164 m / z.

[0110] 2.3) 1,2-Dimethoxybenzene Betaine

[0111] 130 °C, 4 h

[0112]

[0113] 5.32 g KOH (85%, 1.00 eq, 80.6 mmol) were added to 10 g Guajakol (1.00 eq, 80.6 mmol) and the mixture was stirred for 10 min at 60 °C. 13.1 g Betaine monohydrate (1.20 eq, 96.7 mmol) were added and the reaction mixture was stirred for 4 h at 130 °C. After cooling to 90 °C, 80 mL water and 80 mL Methyl-tert-butylether were added and the organic layer was washed with 30 mL aq. H2SG4-solution (10%), three times with 50 mL aq. KOH-solution (5%) and once with 50 mL water. The organic layer was dried over Na2SO4and the solvent was removed under reduced pressure to obtain 4.3 g of the raw product (GC-purity: 99%). The raw material was purified by bulb-to-bulb distillation to obtain 3.8 g 1,2-Dimethoxybenzene (27.5 mmol, GC-purity: 98%) as colorless oil.

[0114]

[0115] NMR (400 MHz, CDCl₃) 6 = 6.90 (m, 4H), 3.88 (s, 6H) ppm.

[0116] GC-MS: [M]+= [C8H10O2]+- = 138 m / z.

[0117] 2.4) 1 -Methoxyhexane

[0118] Betaine

[0119]

[0120] 122 °C, 5 h

[0121] 3.23 g KOH (85%, 1.00 eq, 48.9 mmol) were added to 10 g Hexanol (2.00 eq, 97.9 mmol) and the mixture was stirred for 10 min at 60 °C. 6.88 g Betaine (1.20 eq, 58.7 mmol) were added and the reaction mixture was stirred for 5 h at 122 °C. After cooling to 90 °C, 100 mL water were added, and the organic layer was separated and washed with additional 100 mL water. The organic layer was dried over Na2SO4and the solvent was removed under reduced pressure to obtain 7.0 g of the raw product (GC-purity: 37.8%). 5.0 g of the raw material were purified by column chromatography on silica (EtOAc / Cyclohexane) to obtain 2.0 g 1 -Methoxyhexane (17.2 mmol, GC-purity. >99%) as colorless liquid.

[0122]

[0123] NMR (400 MHz, CDCl₃) 6 = 3.37 (t, J = 6.7 Hz, 2H), 3.33 (s, 3H), 1.56 (m, 2H), 1.31 (m, 6H), 0.89 (m, 3H) ppm.

[0124] GC-MS: [M]+ = [C7Hi6O]+- = 116 m / z. 2.5) (1 S,2R,4R)-1 -lsopropyl-2-methoxy-4-methyl-cyclohexane

[0125] Betaine

[0126] 122 °C, 5 h

[0127]

[0128] 10 g L-Menthol (1.00 eq, 64.0 mmol) were melted at 50 °C. 4.18 g KOH (86%, 1.00 eq, 64.0 mmol) were added and the reaction mixture was stirred for 60 °C for 10 min. 9.00 g Betaine (1.20 eq, 76.8 mmol) were added and the reaction mixture was stirred for 12 h at 140 °C. After cooling to 90 °C, 100 mL water and 100 mL Methyl-tert-butylether were added and the organic layer was washed with 100 mL water, dried over Na2SO4and the solvent was removed under reduced pressure to obtain the raw product (GC-purity: 47%).

[0129] 3.5 g of the raw material were purified by column chromatography on silica (EtOAc / Cyclo-hexane) to obtain 1.5 g (1S,2R,4R)-1-lsopropyl-2-methoxy-4-methyl-cyclohexane (8.8 mmol, GC-purity: >99%) as colorless liquid.

[0130] NMR (400 MHz, CDCl₃) 6 = 3.34 (s, 3H), 2.93 (td, J = 10.5, 4.1, 1 H), 2.19 (qd, J = 7.0, 2.8, 1H), 2.13 (dtd, J = 12.2, 3.9, 2.1, 1H), 1.63 (m, 2H), 1.35 (m, 1H), 1.19 (ddt, J = 12.2, 10.3, 3.1, 1H), 0.99 (m, 1H), 0.92 (d, J = 6.6, 3H), 0.89 (d, J = 7.1, 3H), 0.83 (m, 2H), 0.78 (d, J = 6.9, 3H) ppm.

[0131] GC-MS: [M-CH3]+= [C10H19O]+= 155 m / z.

[0132] 2.6) (2E)-1 -Methoxy-3,7-dimethyl-octa-2,6-diene

[0133] OH Betaine

[0134]

[0135] 122 °C, 5 h

[0136] 4.23 g KOH (86%, 1.00 eq, 64.8 mmol) were added to 10 g Geraniol (1.00 eq, 64.8 mmol) and the mixture was stirred for 10 min at 60 °C. 9.11 g Betaine (1.20 eq, 77.8 mmol) were added and the reaction mixture was stirred for 8 h at 130 °C. After cooling to 90 °C, 100 mL water and 100 mL Methyl-tert-butylether were added and the organic layer was washed two times with 50 mL aq. H2SG4-solution (10%), two times with 50 mL aq. KOH-solution (5%) and once with 50 mL water. The organic layer was dried over Na2SO4and the solvent was removed under reduced pressure to obtain 7.3 g of the raw product (GC-purity: 73%). 2.5 g of the raw material were purified by column chromatography on silica (EtOAc / Cyclo-hexane) to obtain 1.1 g (2E)-1-Methoxy-3,7-dimethyl-octa-2,6-diene (6.5 mmol, GC-purity: 98%) as colorless liquid.

[0137] NMR (400 MHz, CDCl₃) 6 = 5.35 (tq, J = 6.8, 1.3, 1 H), 5.10 (ddp, J = 6.9, 5.7, 1.4, 1 H), 3.94 (d, J = 6.6, 2H), 3.32 (s, 3H), 2.11 (m, 2H), 2.04 (m, 2H), 1.68 (m, 6 H), 1.60 (s, 3H) ppm.

[0138] GC-MS: [M]+= [C11H20O]+- = 168 m / z.

[0139] 2.7) 2-Methyl-3-methylsulfanyl-furan

[0140] Betaine

[0141] 105 °C, 5 h

[0142]

[0143] 4.39 g KOH (86%, 1.00 eq, 66.6 mmol) were added to 8.00 g 2-Methylfuran-3-thiol (1.00 eq, 66.6 mmol) and the mixture was stirred for 15 min at 60 °C. 9.36 g Betaine (1.20 eq, 79.9 mmol) and 3 mL water were added, and the mixture was stirred for 5 h at 105 °C. After cooling to 90 °C, 100 mL water and 100 mL Methyl-tert-butylether were added and the organic layer was washed three times with 50 mL aq. KOH solution (5%) and once with water. The solvent was removed under reduced pressure to obtain 3.0 g 2-Methyl-3-methylsulfa-nyl-furan (GC-purity: 92%). The raw material was purified by bulb-to-bulb distillation to obtain 1.2 g 2-Methyl-3-methylsulfanyl-furan (9.4 mmol, GC-purity: >99%) as colorless liquid.

[0144]

[0145] NMR (600 MHz, CDCl₃) 6 = 7.27 (d, J = 1.9 Hz, 1 H), 6.36 (d, J = 1.9 Hz, 1 H), 2.33 (s, 3H), 2.27 (s, 3H) ppm.

[0146] GC-MS:[M]+= [C6H8OS]+- = 128 m / z.

Claims

Claims1. Process for the preparation of an aliphatic or aromatic methylether or methylthi- oether, preferably according to formula (I)1H3CXR1(I)wherein X is O or S and R1is selected from the group consisting of primary, secondary or tertiary aliphatic or aromatic residues, preferably is selected from the group consisting of linear, substituted or cyclic Ci - CM alkyl residues, linear, substituted or cyclic Ci - CM heteroalkyl residues, C6 - C14 aromatic residues, or C4 - C14 heteroaro- matic residues,more preferably is selected from the group consisting ofcomprising or consisting of the following steps:(a) providing an aliphatic or aromatic primary, secondary or tertiary alcohol or thiol, preferably according to formula (III),(HI),wherein X is O or S and R1is selected from the group consisting ofandoptionally adding (a) solvent / sand / oroptionally melting the provided alcohol or thiol,(b) mixing a base with the alcohol or thiol provided in step (a),(c) reacting the mixture obtained in step (b) at a temperature in a range of from 30 - 100 °C, preferably in a range of from 40 - 70 °C, most preferably in a range of from 50 - 60 °C,(d) adding betaine and / or betaine monohydrate to the mixture obtained in step (c),(e) reacting the mixture obtained in step (d) at a temperature in a range of from 90 - 160 °C, preferably in a range of from 120 - 150 °C, most preferably in a range of from 130 - 140 °C, preferably for a period of 120 to 1440 min.

2. Process according to claim 1, wherein the prepared methylether or methylthioether is selected from the group consisting of3. Process according to claim 1 or 2, wherein in step (b) 0.2 to 2 equivalents, preferably 0.8 to 1.2 equivalents, most preferably 1 equivalent of the base are mixed with the alcohol or thiol according to formula (III) provided in step (a), based on the total amount of alcohol or, respectively, thiol.

4. Process according to any of the preceding claims, wherein in step (d) 0.5 to 2 equivalents, preferably 0.75 to 1.5 equivalents, most preferably 1.2 equivalents of the betaine and / or betaine monohydrate are added, based on the total amount of alcohol or, respectively, thiol according to formula (III) in step (a).

5. Process according to any of the preceding claims, wherein in step (b) the base is selected from the group consisting of alkali bases, preferably Li, Na or K alkali bases, most preferably potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, potassium acetate, or calcium dihydroxide.

6. Process according to any of the preceding claims, wherein in step (a) the solvent(s), if present, is / are selected from the group consisting of alkylated aromatic compounds and / or aromatic ethers and / or aliphatic ethers and / or water, preferably anisol, biphenyl, methoxyanisol, decan, xylol, polyethylenglycol.

7. Process according to any of the preceding claims, wherein in step (c) reacting the mixture obtained in step (b) is performed for a period of 1 to 120 min, preferably for a period of 5 to 60 min, most preferably for a period of 10 to 30 min.

8. Process according to any of the preceding claims, wherein after step (e) one more or all of the following further steps are performed:(f) cooling of the mixture obtained in step (e) to a temperature below 100 °C,(g) adding water and an organic solvent, preferably ethyl acetate and / or methyl-tert-butylether, to the mixture obtained in step (f), if present, or step (e), to obtain an aqueous and an organic layer,(h) separating the organic layer obtained from step (g), if present, from the aqueous layer and washing the organic layer with aqueous sulphuric acid and / or aqueous sodium hydroxide and / or water,(i) drying the organic layer obtained from step (h), if present, with a drying agent,(j) removing the solvent(s), if used in step (a) and / or step (h), and(k) purifying the obtained methylether or methyltioether by distillation and / or column chromatography.

9. Process according to any of the preceding claims, wherein the prepared methylether

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