Process for the preparation of 2-exo-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane

Abstract

The present invention relates to a process for the preparation of (±)‑2‑exo‑(2‑methylbenzyloxy)‑1‑methyl‑4‑isopropyl‑7‑oxabicyclo[2.2.1]heptane of formula (I), any of its individual enantiomers or any non-racemic mixture thereof, comprising the steps of: (a) reacting (±)‑2‑exo‑hydroxy‑1‑methyl‑4‑isopropyl‑7‑oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers or any non-racemic mixture thereof, with a 2-methylbenzyl compound of formula (III), wherein X is a leaving group, in the presence of at least one base capable of forming water or a C1-C4 alkyl alcohol under the reaction conditions and at least one inert organic solvent, and (b) simultaneously removing water, C1-C4 alkyl alcohol or any mixture thereof from the reaction mixture.

Description

[0001] The present invention relates to a method for preparing (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (I), any of its enantiomers or any non-racemic mixtures thereof, by reacting (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its enantiomers or any non-racemic mixtures thereof, with a 2-methylbenzyl compound of formula (III) in the presence of a base and an organic solvent.

[0002]

[0003] The racemic mixture (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane is a known herbicide compound that has been developed for use in rice. It is described in The Pesticide Manual, 14th edition, edited by CDSTomlin, British Crop Production Council, 2006, item 157, pp. 195-196, and its common name is Cinmethylin, with the IUPAC name (1RS,2SR,4SR)-1,4-epoxy-p- -2-yl-2-methylbenzyl ether, whose chemical abstract name is exo-(±)-1-methyl-4-(1-methylethyl)-2-[(2-methylphenyl)methoxy]-7-oxabicyclo[2.2.1]heptane.

[0004] The racemic mixture (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane (also referred to herein as the “ex-(±)-isomer”, CAS RN 87818-31-3) comprises equal parts of two enantiomers: (+)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane (also referred herein as the “ex-(+)-isomer”, CAS RN 87818-61-9) and (-)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane (also referred herein as the “ex-(-)-isomer”, CAS RN 87819-60-1).

[0005]

[0006] EP 0 081 893 A2 describes the preparation of (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane and its ex-(+)- and ex-(-)- isomers (see Examples 29, 34, 35 and 62) by reacting (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane with 2-methylbenzyl chloride in the presence of sodium hydride as a base and dimethylformamide as an organic solvent.

[0007] The preparation of (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane by reacting (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane with 2-methylbenzyl chloride is also described in US 4,487,945 (see Embodiment 48), US 4,542,244 (see Embodiment 219) and US 4,670,041 (see Embodiment 219). Furthermore, in any of the foregoing references, the preparation of the exo-(-)-isomer by reacting (-)-2-exo-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane with 2-methylbenzyl chloride was carried out in the presence of sodium hydride as a base and N,N-dimethylacetamide as an organic solvent (see US 4,487,945, Example 46; US 4,542,244, Example 218 and US 4,670,041, Example 218).

[0008] CN 101602770 A describes a three-step synthesis for the preparation of cycloheptafluphenone. In steps 1 and 2, terpinene-4-ol is converted to the corresponding 1,2-epoxide, which is then isomerized to give the 1,2-epoxide isomerized product. In the final step 3, cycloheptafluphenone is obtained by condensation of the 1,2-epoxide isomerized product in the presence of various combinations of bases and organic solvents (see Examples 1, 2, 3, 8 and 9: sodium hydroxide / ethyl acetate; Examples 4 and 5: sodium amide / dichloromethane; Example 6: sodium hydride / benzene and Example 7: sodium hydride / toluene).

[0009] However, alkali metal hydrides such as sodium hydride or amides such as sodium amide are hazardously reactive in the presence of small amounts of oxygen or moisture. Such reactions may result in the formation of hazardous gases such as hydrogen (H2) or ammonia (NH3). Therefore, appropriate care and precautions should be taken during the handling and storage of these substances, as well as during the preparation of (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxadicyclo[2.2.1]heptane as described above. Specific safety measures are therefore required during the reaction process, such as an inert gas atmosphere (e.g., nitrogen), proper cooling, removal of gases such as H2 or NH3, and dilution.

[0010] Furthermore, alkali metal hydroxides such as sodium hydroxide are known bases in the saponification of esters. Therefore, the combined use of sodium hydroxide and ethyl acetate (see Examples 1, 2, 3, 8, and 9 of CN101602770A) in the synthesis of (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane can lead to the hydrolysis of the solvent ethyl acetate. This implies the formation of relatively large amounts of undesirable byproducts, low yields, and the loss of valuable solvent that cannot be recycled.

[0011] Philip W. Lee et al., Journal of Agricultural and Food Chemistry, Vol. 34, No. 2, 1986, pp. 162-170, disclose the preparation of the mentioned cycloheptafluphene metabolite, namely ex-2-[[2-(chloromethyl)phenyl]methoxy]-1-methyl-4-(1-methylethyl)-7-oxabicyclo[2.2.1]heptane, by reflux of a solution of ex-1-methyl-4-(1-methylethyl)-7-oxabicyclo[2.2.1]heptane in toluene and powdered sodium hydroxide under a Starkey-Dean water separator until water can no longer be removed. The resulting solution is then reacted with α,α-dichloro-o-xylene to give a mixture of mono- and disubstituted products in approximately 50:50 ratios, along with unreacted dichloroxylene. Purification of the reaction mixture yielded exo-2-[[2-(chloromethyl)phenyl]methoxy]-1-methyl-4-(1-methylethyl)-7-oxabicyclo[2.2.1]heptane in a low yield of 30%.

[0012] The aforementioned drawbacks make existing technological methods unsuitable for industrial-scale production and have gone largely unnoticed due to economic, environmental, and occupational health reasons.

[0013] In view of the above-mentioned drawbacks, there is still a need for improved methods for preparing (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (I), any of its individual enantiomers or any non-racemic mixtures thereof, which not only make the synthesis safe and environmentally friendly, but also simple and cost-effective for commercial applications.

[0014] Therefore, one object of the present invention is to overcome or improve at least one of the above-mentioned disadvantages, and thereby provide an improved and more economical and commercially viable method for preparing (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxadicyclo[2.2.1]heptane of formula (I), any of its individual enantiomers or any non-racemic mixture thereof.

[0015] Another objective is to provide an industrially simple method for preparing (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxadicyclo[2.2.1]heptane of formula (I), any of its individual enantiomers or any non-racemic mixtures thereof, the method yielding the desired final product in good yield.

[0016] Another objective is to provide a more environmentally friendly method for preparing (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (I), any of its individual enantiomers or any non-racemic mixtures thereof, by reducing adverse environmental impacts.

[0017] Another object of the present invention is to provide an industrially feasible method for preparing (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxadicyclo[2.2.1]heptane of formula (I), any of its individual enantiomers or any non-racemic mixtures thereof, said method reducing safety concerns and the presence of hazardous conditions.

[0018] Another objective is to provide a method for preparing (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (I), any of its individual enantiomers or any non-racemic mixtures thereof, said method reducing the formation of undesirable byproducts.

[0019] Surprisingly, these and other objectives have been achieved, in part or in whole, by a process for preparing (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (I), any of its individual enantiomers or any non-racemic mixture thereof.

[0020]

[0021] The method includes the following steps:

[0022] (a) Reaction of (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers or any non-racemic mixture thereof, with 2-methylbenzyl compound of formula (III) in the presence of at least one base capable of forming water or C1-C4 alkyl alcohol under the reaction conditions and at least one inert organic solvent:

[0023]

[0024] Where X is a leaving group, and

[0025] (b) Remove water, C1-C4 alkyl alcohols or any mixture thereof from the reaction mixture simultaneously.

[0026] Therefore, the preparation method of (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of the above formula (I), any of its individual enantiomers or any non-racemic mixture thereof is a subject of this invention.

[0027] The method of the present invention has a series of advantages and overcomes the shortcomings of existing technical methods.

[0028] The method of the present invention does not use hazardous substances such as alkali metal hydrides (e.g., sodium hydride) or amides (e.g., sodium amino), thereby minimizing the presence of hazardous reaction conditions and the need for safety measures and equipment, while maintaining efficiency and ease of operation.

[0029] A particular advantage of this invention is that the removal of water and / or C1-C4 alkyl alcohols during the reaction avoids the agglomeration and heavy deposition (also referred to herein as “fouling”) of salts on the reactor walls and various other components (such as baffles or agitators), which would otherwise reduce conversion rates and cause significant large-scale difficulties. For example, severe agglomeration of salts on the reactor walls and other components can hinder proper heat transfer, deheating, and agitation within the reactor. Surprisingly, such reactor fouling is virtually nonexistent in the method of this invention because the salts formed during the reaction are suspended as fine particles in the reaction medium.

[0030] Therefore, in another aspect, the present invention relates to a method for preventing or reducing the formation of deposits inside a reactor, wherein the preparation of (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (I), any of its individual enantiomers or any non-racemic mixture thereof is carried out by reacting (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers or any non-racemic mixture thereof with a 2-methylbenzyl compound of formula (III):

[0031]

[0032]

[0033] Where X is a leaving group.

[0034] The method includes the following steps:

[0035] (a) The reaction of (±)-2-exo-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any one of its enantiomers or any non-racemic mixtures thereof, with a 2-methylbenzyl compound of formula (III) is carried out in the presence of at least one base capable of forming water or a C1-C4 alkyl alcohol under the reaction conditions and at least one inert organic solvent.

[0036] (b) Remove water, C1-C4 alkyl alcohols or any mixture thereof from the reaction mixture simultaneously.

[0037] As used herein, the term "reactor interior" refers to various internal components of the reactor, such as the reactor wall, agitator, and baffles. In a preferred embodiment, the reactor interior includes the reactor wall, agitator, baffles, and any combination thereof, more preferably the reactor wall, agitator, or any combination thereof.

[0038] The reactants used in the above-described method of the present invention, namely the compounds of formulas (II) and (III) mentioned above, the base, the inert organic solvent, and the reaction conditions and their preferred embodiments, are the same as those described herein in the method of the present invention.

[0039] Furthermore, the inert organic solvents used in this invention can be easily recovered and recycled, resulting in an economical and sustainable method.

[0040] Another advantage is the removal of water and / or C1-C4 alkyl alcohols during the reaction to avoid the formation of byproducts and to provide the desired formula (I) (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane, any of its individual enantiomers or any non-racemic mixture thereof in high yield.

[0041] Therefore, the process of the present invention allows the preparation of (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (I), any of its individual enantiomers or any non-racemic mixtures thereof, to be carried out in a smooth and controlled manner, which is very safe, industrially simple, economical, environmentally friendly and commercially feasible.

[0042] Other embodiments of the invention will become apparent from the claims, description, and examples. It should be understood that individual features of the subject matter of the invention described herein can be applied not only to the combinations given in each particular case, but also to other combinations, without departing from the scope of the invention.

[0043] The raw materials of this invention are commercially available or known compounds that can be prepared in a known manner.

[0044] For example, (±)-2-exo-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers or any non-racemic mixture thereof may be prepared by any of the methods described in EP 0 081 893 A2 (see Example 15), US 4,487,945 (see Embodiments 1 and 45), US 4,542,244 (see Embodiments 1 and 217) and US 4,670,041 (see Embodiments 1 and 217) or in a similar manner.

[0045] In the 2-methylbenzyl compound of formula (III), substituent X is a leaving group. As used herein, the term "leaving group" means any group that leaves a pair of electrons from the molecule in heterolytic bond cleavage so that the molecule can participate in nucleophilic substitution reactions with (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane (II), any of its individual enantiomers or any non-racemic mixtures thereof.

[0046] The preferred leaving group X is selected from halogens, oxygen-linked leaving groups, and ammonium groups of formula (IV).

[0047] -N(R1)(R2)(R3) + Y - (IV)

[0048] R1, R2, and R3 are each independently selected from C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups.10 cycloalkyl and C6-C 20 Aryl, Y - Selected from halide ions, hydroxide ions, C1-C4 alkyl sulfonate ions and C6-C 20 Arylsulfonate ion.

[0049] In some variables (i.e., R) 1 R 2 and R 3 The definition of ) mentions the organic structural part, sulfonate (i.e., C1-C4 alkyl sulfonate, C1-C4-haloalkyl sulfonate, C6-C 20 Arylsulfonate and C3-C 10 Cycloalkyl sulfonates) and phase transfer catalysts (i.e., tetra-C1-C4 alkylammonium chloride, tetra-C1-C4 alkylammonium bromide, tetra-C1-C4 alkylammonium iodide or tetra-C1-C4 alkylammonium hydroxide, tetra-C1-C8 alkylammonium chloride, tetra-C1-C8 alkylammonium bromide, tetra-C1-C8 alkylammonium iodide or tetra-C1-C8 alkylammonium hydroxide and tetra-C1-C4 alkylammonium hydroxide) 12 Alkyl ammonium chloride, tetra-C1-C 12 Alkyl ammonium bromide, tetra-C1-C 12 Alkyl ammonium iodide or tetra-C1-C 12 Alkyl ammonium hydroxide, like the term halogen, is a collective term that lists independent members. The term "halogen" in each case refers to fluorine, chlorine, bromine, or iodine. All hydrocarbon chains, such as alkyl chains, can be straight or branched, prefixed with C. n -C m In each case, this indicates the possible number of carbon atoms in the group. Examples of this meaning are:

[0050] -C1-C4 alkyl groups: for example, methyl, ethyl, n-propyl, isopropyl (-CH(CH3)2), n-butyl, sec-butyl (-CH(CH3)-C2H5), isobutyl (-CH2-CH(CH3)2) or tert-butyl (-C(CH3)3);

[0051] -C1-C6 alkyl: C1-C4 alkyl as described above, and for example, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl;

[0052] -C1-C8 alkyl: C1-C6 alkyl as described above, and for example, n-heptyl, n-octyl or 2-ethylhexyl;

[0053] -C1-C 12 Alkyl groups: C1-C8 alkyl groups as described above, and for example, n-nonyl, isononyl, n-decyl, n-undecyl, or n-dodecyl;

[0054] -C1-C4 haloalkyl: C1-C4 alkyl groups as described above that are partially or completely substituted with fluorine, chlorine, bromine and / or iodine, such as monochloromethyl, dichloromethyl, trichloromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichloromonofluoromethyl, monochlorodifluoromethyl, bromomethyl, iodomethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoro propyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1-(fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, nonafluorobutyl, 1,1,2,2-tetrafluoroethyl or 1-trifluoromethyl-1,2,2,2-tetrafluoroethyl; and

[0055] -C3-C 10 Cycloalkyl groups: such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl.

[0056] The term "C6-C" is used in this article. 20 "Aryl" refers to an unsaturated aromatic carbocyclic group having 6-20 carbon atoms, which has a monocyclic (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl or dihydrophenanthrene). C6-C 20 Examples of aryl groups include phenyl, p-tolyl, 1-naphthyl, 2-naphthyl, anthracel, indene, or phenanthryl. Phenyl is a preferred aryl group.

[0057] The term "halogen ion" as used in this article refers to, for example, fluoride ions, chloride ions, bromide ions, or iodide ions.

[0058] The preferred oxygen-linked leaving group is selected from C1-C4 alkyl sulfonates, C1-C4 haloalkyl sulfonates, and C6-C4 alkyl sulfonates. 20 Aryl sulfonates, C3-C10 Cycloalkyl sulfonates and imidazolium sulfonates (imidazylates), more preferably C1-C4 alkyl sulfonates, C1-C4 haloalkyl sulfonates and C6-C 20 Aryl sulfonates, and even more preferably C1-C4 alkyl sulfonates and C6-C4 alkyl sulfonates. 20 Aryl sulfonates.

[0059] Examples of C1-C4 alkyl sulfonates include, but are not limited to, methanesulfonates, ethanesulfonates, n-propyl sulfonates, isopropyl sulfonates, n-butyl sulfonates, isobutyl sulfonates, sec-butyl sulfonates, and tert-butyl sulfonates.

[0060] Examples of C1-C4 haloalkyl sulfonates include, but are not limited to, trifluoromethane sulfonates (trifluoromethane sulfonates) and chloroform sulfonates.

[0061] C6-C 20 Examples of aryl sulfonates include, but are not limited to, toluenesulfonates (p-toluenesulfonates), benzenesulfonates, and 2-naphthylsulfonates.

[0062] C3-C 10 Examples of cycloalkyl sulfonates include, but are not limited to, cyclohexyl sulfonates.

[0063] Preferably, the oxygen-linked leaving group is selected from methanesulfonate, ethanesulfonate, n-propylsulfonate, isopropylsulfonate, n-butylsulfonate, isobutylsulfonate, sec-butylsulfonate, tert-butylsulfonate, trifluoromethanesulfonate, chloroform sulfonate, toluenesulfonate (p-toluenesulfonate), benzenesulfonate, 2-naphthylsulfonate, cyclohexylsulfonate, and imidazolesulfonate (imidazolesulfonate), more preferably methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, toluenesulfonate, and benzenesulfonate, and even more preferably methanesulfonate and toluenesulfonate.

[0064] In another preferred embodiment, the leaving group X is selected from halogens, C1-C4 alkyl sulfonates, C6-C4 alkyl sulfonates, and C6-C4 alkyl sulfonates. 20 Aryl sulfonates and ammonium groups of formula (IV)

[0065] -N(R1)(R2)(R3) + Y - (IV)

[0066] R1, R2, and R3 are each independently selected from C1-C6 alkyl groups, Y -Selected from halide ions, hydroxide ions, C1-C4 alkyl sulfonate ions and C6-C 20 Arylsulfonate ion.

[0067] More preferably, the leaving group X is selected from halogens, C1-C4 alkyl sulfonates, C6-C4 alkyl sulfonates, and C6-C4 alkyl sulfonates. 20 Aryl sulfonates and ammonium groups of formula (IV) (where R1, R2, and R3 are each independently selected from C1-C6 alkyl groups, Y - Selected from halide ions, hydroxide ions, methanesulfonate ions, and toluenesulfonate ions.

[0068] Even more preferably, the leaving group X is selected from halogens, C1-C4 alkyl sulfonates, C6-C4 alkyl sulfonates, and C6-C4 alkyl sulfonates. 20 Aryl sulfonates and ammonium groups of formula (IV) (where R1, R2, and R3 are each independently selected from C1-C6 alkyl groups, Y - Selected from halide ions (preferably chloride ions)).

[0069] More preferably, the leaving group X is selected from chlorine, bromine, iodine, methanesulfonate, toluenesulfonate, and trimethylammonium chloride group of formula (IVa).

[0070] -N(CH3)3 + Cl - (IVa)

[0071] Triethylammonium chloride group of formula (IVb)

[0072] -N(CH2CH3)3 + Cl - (IVb).

[0073] More preferably, the leaving group X is selected from chlorine, bromine, iodine, methanesulfonate, toluenesulfonate and trimethylammonium chloride group of formula (IVa).

[0074] Even more preferably, the leaving group X is selected from chlorine, methanesulfonate, toluenesulfonate and trimethylammonium chloride group of formula (IVa).

[0075] In another preferred embodiment, the leaving group X is selected from halogens, particularly chlorine, bromine, and iodine. Most preferably, the leaving group X is chlorine.

[0076] In another embodiment, the 2-methylbenzyl compound of formula (III) is selected from the group consisting of: - 2-methylbenzyl chloride of formula (IIIa) (1-(chloromethyl)-2-methylbenzene)

[0077]

[0078] 2-Methylbenzyl bromide of formula (IIIb) (1-(bromomethyl)-2-methylbenzene)

[0079]

[0080] 2-Methylbenzyl iodide of formula (IIIc) (1-(iodomethyl)-2-methylbenzene)

[0081]

[0082] 2-Methylbenzyl methanesulfonate of formula (IIId) ((2-methylphenyl)methyl methanesulfonate)

[0083]

[0084] 2-Methylbenzyltoluenesulfonate of formula (IIIe) ((2-methylphenyl)methyl4-methylbenzenesulfonate)

[0085]

[0086] Trimethyl(o-tolylmethyl)ammonium chloride of formula (IIIf)

[0087] and

[0088] Triethyl(o-tolylmethyl)ammonium chloride of formula (IIIg)

[0089]

[0090] Most preferably, the 2-methylbenzyl compound of formula (III) is 2-methylbenzyl chloride (1-(chloromethyl)-2-methylbenzene) of formula (IIIa).

[0091] The 2-methylbenzyl compound of formula (III) used as a raw material in the method of the present invention is commercially available or can be prepared by methods known in the art or in a similar manner.

[0092] For example, 2-methylbenzyl compounds of formula (III) in which X is a halogen (e.g., 2-methylbenzyl chloride of formula (IIIa)) can be prepared by the methods described in Synthetic Communications, Vol. 33, No. 7, pp. 1103-1107, 2003 or similarly.

[0093] For example, where X is a C1-C4 alkyl sulfonate or a C6-C4 alkyl sulfonate. 202-methylbenzyl compounds of formula (III) aryl sulfonates (e.g., 2-methylbenzyl methanesulfonate of formula (IIId) or 2-methylbenzyl toluenesulfonate of formula (IIIe)) can be prepared by the methods described in Energy & Fuels, 21(3), pp. 1695-1698, 2007 or Phosphorus, Sulphur and Silicon and the Related Elements, 184(5), pp. 1161-1174, 2009.

[0094] 2-methylbenzyl compounds of formula (III) in which X is an ammonium group of formula (IV) (e.g., trimethyl(o-tolylmethyl)ammonium chloride of formula (IIIf) or triethyl(o-tolylmethyl)ammonium chloride of formula (IIIg)) can be prepared by methods similar to those described in Organic Syntheses, Coll., Vol. 4, p. 98 (1963); Vol. 38, p. 5 (1958). For example, X is selected from halogens (preferably chlorine, bromine, or iodine, more preferably chlorine), C1-C4 alkyl sulfonates (preferably methanesulfonates), or C6-C4 alkyl sulfonates. 20 The 2-methylbenzyl compound of formula (III) of aryl sulfonates (preferably toluenesulfonates) wherein R1, R2, and R3 have the same meaning as in formula (IV) (preferably wherein R1, R2, and R3 are each independently selected from C1-C6 alkyl and C6-C...). 20 Tertiary amines of the formula NR1R2R3 (aryl, more preferably C1-C6 alkyl, even more preferably methyl or ethyl, most preferably methyl) are reacted in a suitable solvent (e.g., anhydrous ethanol).

[0095] Where X is an ammonium group of formula (IV), a 2-methylbenzyl compound of formula (III) (e.g., trimethyl(o-tolylmethyl)ammonium chloride of formula (IIIf) or triethyl(o-tolylmethyl)ammonium chloride of formula (IIIg)) can be added to the reaction mixture alone (i.e. as a separate substance or in a solution in any suitable solvent) or formed in situ in the reaction mixture.

[0096] When it is necessary to form in situ a 2-methylbenzyl compound of formula (III) in which X is an ammonium group of formula (IV) (e.g., trimethyl(o-tolylmethyl)ammonium chloride of formula (IIIf) or triethyl(o-tolyl)ammonium chloride of formula (IIIg)), the method of the present invention uses at least one tertiary amine of formula NR1R2R3 (wherein R1, R2 and R3 have the same meaning as in formula (IV) (preferably wherein R1, R2 and R3 are each independently selected from C1-C6 alkyl and C6-C6 alkyl groups) 20 The process is carried out in the presence of aryl, more preferably C1-C6 alkyl, even more preferably methyl or ethyl, with methyl being the most preferred.

[0097] Examples of suitable tertiary amines of the formula NR1R2R3 are tri(C1-C6)alkylamines such as trimethylamine, triethylamine, tributylamine and N,N-diisopropylethylamine; and di(C1-C6)alkylphenylamines such as N,N-dimethylaniline and N,N-diethylaniline.

[0098] The tertiary amine of the formula NR1R2R3 is preferred, wherein R1, R2 and R3 are each C1-C6 alkyl, more preferably C1-C4 alkyl, especially methyl or ethyl, and most preferably methyl.

[0099] Therefore, in a particularly preferred embodiment, the tertiary amine of formula NR1R2R3 is selected from trimethylamine, triethylamine, or a combination thereof. The most preferred tertiary amine of formula NR1R2R3 is trimethylamine.

[0100] In particular, 2-methylbenzyl compounds of formula (III) in which X is an ammonium group of formula (IV) (e.g., trimethyl(o-tolylmethyl)ammonium chloride of formula (IIIf) or triethyl(o-tolylmethyl)ammonium chloride of formula (IIIg)) can be modified by selecting X from halogens, C1-C4 alkyl sulfonates or C6-C4 alkyl sulfonates. 20 A 2-methylbenzyl compound of formula (III) of aryl sulfonates (preferably halogens, more preferably chlorine, bromine, or iodine, even more preferably chlorine) wherein R1, R2, and R3 have the same meaning as in formula (IV) (preferably wherein R1, R2, and R3 are each independently selected from C1-C6 alkyl and C6-C...). 20 A tertiary amine of formula NR1R2R3 (aryl, more preferably C1-C6 alkyl, even more preferably methyl or ethyl, most preferably methyl) is formed in situ by reacting it in a reaction mixture comprising (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers or any non-racemic mixtures thereof, a base as defined herein, and an inert organic solvent as defined herein.

[0101] More specifically, the in-situ formation of a 2-methylbenzyl compound of formula (III) wherein X is an ammonium group of formula (IV) (e.g., trimethyl(o-tolylmethyl)ammonium chloride of formula (IIIf) or triethyl(o-tolylmethyl)ammonium chloride of formula (IIIg)) can be carried out by: placing (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers or any non-racemic mixture thereof, a base as defined herein, an inert organic solvent as defined herein, and a tertiary amine of formula NR1R2R3 as defined herein in a reactor to obtain a first mixture, heating the first mixture, and placing a 2-methylbenzyl compound of formula (III) wherein X is selected from halogens, C1-C4 alkyl sulfonates or C6-C 20A 2-methylbenzyl compound of formula (III) of an aryl sulfonate (preferably halogen, more preferably chlorine, bromine or iodine, even more preferably chlorine) is metered into the first mixture to obtain the reaction mixture and simultaneously remove water, C1-C4 alkyl alcohol or any mixture thereof from the reaction mixture.

[0102] Imagine a tertiary amine NR1R2R3 replacing X, where X is selected from halogens, C1-C4 alkyl sulfonates, or C6-C4 alkyl sulfonates. 20 The leaving group X of a 2-methylbenzyl compound of formula (III) of aryl sulfonates (preferably halogens, more preferably chlorine, bromine, or iodine, even more preferably chlorine) is removed to form the corresponding ammonium salt, i.e., a 2-methylbenzyl compound of formula (III) of formula (IV) where X is an ammonium group (e.g., trimethyl(o-tolylmethyl)ammonium chloride of formula (IIIf) or triethyl(o-tolylmethyl)ammonium chloride of formula (IIIg)). The ammonium salt formed in situ reacts immediately with a salt of (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers, or any non-racemic mixture thereof, present in the reaction mixture. During this benzylation, the tertiary amine is released again and can thus be used to restart the reaction where X is selected from halogens, C1-C4 alkyl sulfonates, or C6-C4 alkyl sulfonates. 20 Nucleophilic substitution of 2-methylbenzyl compounds of formula (III) of aryl sulfonates (preferably halogens, more preferably chlorine, bromine or iodine, even more preferably chlorine).

[0103] The in-situ formation of the above-mentioned 2-methylbenzyl compound of formula (III), wherein X is an ammonium group of formula (IV), is further illustrated in the reaction scheme below.

[0104]

[0105] X = halogen, C1-C4 alkyl sulfonate, or C6-C 20 Aryl sulfonates

[0106]

[0107] Therefore, this variation of the method of the present invention is particularly advantageous because it is relative to the fact that X is selected from halogens, C1-C4 alkyl sulfonates or C6-C4 alkyl sulfonates. 20 2-methylbenzyl compounds of formula (III) containing aryl sulfonates (preferably halogens, more preferably chlorine, bromine, or iodine, even more preferably chlorine) require only a stoichiometric or even catalytic amount of the tertiary amine NR1R2R3 without interrupting the benzylation reaction. Furthermore, compared to the direct use of halogens, where X is selected from halogens, C1-C4 alkyl sulfonates, or C6-C4 alkyl sulfonates... 20Compared to aryl sulfonates of formula (III), 2-methylbenzyl compounds exhibit accelerated reactions due to the higher electrophilicity of the ionic nature of the 2-methylbenzyl compound of formula (III) in which X is an ammonium group of formula (IV). Furthermore, the amphiphilic nature of the 2-methylbenzyl compound of formula (III) in which X is an ammonium group of formula (IV) is also advantageous because the reaction medium forms a heterogeneous mixture comprising both liquid and solid phases.

[0108] The molar ratio of the 2-methylbenzyl compound of formula (III) (especially the 2-methylbenzyl chloride of formula (IIIa)) to (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers or any non-racemic mixture thereof, especially (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II) can vary widely and depends on the nature of the 2-methylbenzyl compound (III) used and the reaction conditions used, but is generally from 3:1 to 0.9:1, preferably from 2:1 to 0.9:1, more preferably from 1.5:1 to 0.9:1, and even more preferably from 1.1:1 to 0.9:1.

[0109] The method of the present invention is carried out in the presence of at least one base capable of forming water or C1-C4 alkyl alcohols under reaction conditions.

[0110] Examples of C1-C4 alkyl alcohols include methanol, ethanol, n-propanol, isopropanol (prop-2-ol), n-butanol, sec-butanol (but-2-ol), isobutanol (2-methyl-1-propanol) or tert-butanol (2-methyl-2-propanol), preferably methanol, ethanol, isopropanol or tert-butanol, more preferably methanol.

[0111] In a preferred embodiment, the method of the present invention is carried out in the presence of at least one base capable of forming water, methanol, ethanol, isopropanol or tert-butanol (more preferably water or methanol, most preferably water) under reaction conditions.

[0112] In particular, the alkali used in this invention is selected from alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal carbonates, alkali metal and alkaline earth metal bicarbonates, alkali metal and alkaline earth metal oxides, alkali metal and alkaline earth metal C1-C4 alkoxides and any combination thereof, more preferably alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal carbonates, alkali metal and alkaline earth metal C1-C4 alkoxides and any combination thereof, even more preferably alkali metal hydroxides, alkali metal carbonates, alkali metal C1-C4 alkoxides and any combination thereof, more preferably alkali metal hydroxides, alkali metal C1-C4 alkoxides and any combination thereof, and even more preferably alkali metal hydroxides.

[0113] The term "alkali metals" as used in this article includes, for example, lithium, sodium, and potassium.

[0114] The term "alkaline earth metals" as used in this article includes, for example, calcium, magnesium, and barium.

[0115] Lithium hydroxide, sodium hydroxide, and potassium hydroxide can be used as alkali metal hydroxides.

[0116] As alkaline earth metal hydroxides, calcium hydroxide, magnesium hydroxide, or barium hydroxide can be used.

[0117] Lithium carbonate, sodium carbonate, or potassium carbonate can be used as alkali metal carbonates.

[0118] As alkaline earth metal carbonates, calcium carbonate, magnesium carbonate, or barium carbonate can be used.

[0119] Lithium bicarbonate, sodium bicarbonate, or potassium bicarbonate can be used as alkali metal bicarbonates.

[0120] As alkaline earth metal bicarbonates, calcium bicarbonate, magnesium bicarbonate, or barium bicarbonate can be used.

[0121] Lithium oxide, sodium oxide, or potassium oxide can be used as alkali metal oxides.

[0122] Calcium oxide, magnesium oxide, or barium oxide can be used as alkaline earth metal oxides.

[0123] As alkali metal C1-C4 alkoxides, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium n-propoxide, sodium n-propoxide, potassium n-propoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium n-butoxide, sodium n-butoxide, potassium n-butoxide, lithium tert-butoxide, sodium tert-butoxide, or potassium tert-butoxide can be used.

[0124] As alkaline earth metal C1-C4 alkoxides, magnesium dimethoxide, calcium dimethoxide, barium dimethoxide, magnesium diethanoloxide, calcium diethanoloxide, barium diethanoloxide, magnesium di-n-propoxide, calcium di-n-propoxide, barium di-n-propoxide, magnesium diisopropoxide, calcium diisopropoxide, barium diisopropoxide, magnesium di-n-butoxide, calcium di-n-butoxide, barium di-n-butoxide, magnesium di-tert-butoxide, calcium di-tert-butoxide, or barium di-tert-butoxide can be used.

[0125] In a preferred embodiment, the alkali used in this invention is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, barium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, barium bicarbonate, lithium oxide, sodium oxide, potassium oxide, calcium oxide, magnesium oxide, barium oxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium n-propoxide, sodium n-propoxide, potassium n-propoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium n-butoxide, sodium n-butoxide, potassium n-butoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium dimethoxide, calcium dimethoxide, barium dimethoxide, magnesium diethanoloxide, calcium diethanoloxide, barium diethanoloxide, magnesium di-n-propoxide, calcium di-n-propoxide, barium di-n-propoxy, magnesium diisopropoxide, and diisopropanol. The alkali used in this invention is preferably calcium, barium diisopropoxide, magnesium di-n-butoxide, calcium di-n-butoxide, barium di-n-butoxide, magnesium di-tert-butoxide, calcium di-tert-butoxide, barium di-tert-butoxide, or any combination thereof. More preferably, it is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, barium carbonate, lithium methoxide, sodium methoxide, potassium methoxide, magnesium dimethoxide, calcium dimethoxide, barium dimethoxide, or any combination thereof. Even more preferably, it is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium methoxide, sodium methoxide, potassium methoxide, or any combination thereof. Most preferably, the alkali used in this invention is sodium hydroxide.

[0126] The molar ratio of the base to (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers or any non-racemic mixture thereof, especially (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), can vary widely and depends on the reaction conditions used, but is generally 1:1 to 5:1, preferably 1:1 to 3:1, more preferably 1:1 to 2:1, and even more preferably 1:1 to 1.5:1.

[0127] The base used in this invention can be added to the reaction mixture in solid form, as an aqueous solution, or in combination thereof.

[0128] As used herein, the term "solid form" includes, but is not limited to, powders, tablets, pills, flakes, granules, or microbeads.

[0129] The concentration of alkali in the aqueous solution can vary and depends on the nature of the alkali and the reaction conditions used, but is generally based on 5-50% by weight of the aqueous solution, preferably 10-50% by weight, and more preferably 30-50% by weight of the alkali.

[0130] The alkali selected from alkali metal hydroxides (preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, and any combination thereof, more preferably sodium hydroxide, potassium hydroxide, and combinations thereof, and most preferably sodium hydroxide) is preferably added to the reaction mixture in solid form. As a solid form of alkali metal hydroxide, pellets, tablets, granules, or microbeads can be used, preferably microbeads. The aforementioned solid forms of alkali metal hydroxides are commercially available from various suppliers. In a preferred embodiment, the method of the present invention is carried out in the presence of sodium hydroxide microbeads as the alkali. Therefore, the alkali used in the present invention preferably comprises sodium hydroxide microbeads, more preferably consists of sodium hydroxide microbeads.

[0131] In another embodiment, an aqueous solution of an alkali selected from alkali metal hydroxides (preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, and any combination thereof, more preferably sodium hydroxide, potassium hydroxide, and combinations thereof, and most preferably sodium hydroxide) may be added to the reaction mixture. Preferably, the aqueous solution of the alkali metal hydroxide (preferably sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide) contains 10-50% by weight, more preferably 25-50% by weight, and even more preferably 35-50% by weight of the alkali metal hydroxide (preferably sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide) based on the weight of the aqueous solution. The aqueous solution of the alkali metal hydroxide (preferably sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide) can be provided by known methods, but can also be obtained commercially from various concentrations.

[0132] The method of the present invention is carried out in the presence of at least one inert organic solvent.

[0133] "Inert organic solvent" refers to an organic solvent that does not react significantly with the reactants or products under the reaction conditions of the method of this invention.

[0134] The inert organic solvent used in the method of the present invention can be selected from various solvents depending on the reaction conditions used.

[0135] Suitable inert organic solvents can be selected from hydrocarbons, amides, ethers, ketones, nitriles and any combination thereof.

[0136] In this invention, the hydrocarbon used as an inert organic solvent may be selected from aliphatic hydrocarbons, cyclic aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, and any combination thereof.

[0137] Preferably, the inert organic solvent may be selected from aliphatic hydrocarbons, cyclic aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, amides, ethers, ketones, nitriles, and any combination thereof.

[0138] The term "aliphatic hydrocarbons" includes both straight-chain and branched-chain aliphatic hydrocarbons.

[0139] The straight-chain aliphatic hydrocarbons that can be used in this invention are those having 5-15 carbon atoms, preferably 5-10 carbon atoms. Examples of straight-chain aliphatic hydrocarbons include n-pentane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, or any combination thereof, preferably n-heptane, n-octane, n-nonane, n-decane, or any combination thereof.

[0140] The branched aliphatic hydrocarbons applicable to this invention are those having 4-15 carbon atoms, preferably 5-12 carbon atoms, more preferably 7-12 carbon atoms, and even more preferably 8-11 carbon atoms. Examples of suitable branched aliphatic hydrocarbons include 2-methylpropane, 2-methylbutane, 2,3-dimethylbutane, 2-methylpentane, 3-methylpentane, 2,2-dimethylpentane, 2,3-dimethylpentane, 2,4-dimethylpentane, 2,2,4-trimethylpentane, 2-methylhexane, 3-methylhexane, 2,4-dimethylhexane, 2,5-dimethylhexane, 2,2,4-trimethylhexane, 2,3,4-trimethylhexane, 3,3,4-trimethylhexane, 2-methylheptane, 3-methylheptane, 2,3-dimethylheptane, 3,4-dimethylpentane, 2-ethyloctane, 2,3-dimethyloctane, 2-methylnonane, 3,4-dimethylnonane, 3-methyldecane, 2-methylundecane, 2-methyldodecane, 2,2,4-trimethyldodecane, and any combination thereof.

[0141] Particularly suitable are mixtures of branched aliphatic hydrocarbons having 5-12 carbon atoms, preferably 7-12 carbon atoms, and more preferably 8-11 carbon atoms, such as those produced by ExxonMobil Chemical under the trade name... Commercial mixtures of isoparaffins for sale, such as E. Isoopar E is a mixture of isoparaffins with a distillation range of 113-139℃.

[0142] Examples of suitable cycloaliphatic hydrocarbons include saturated or unsaturated cycloaliphatic hydrocarbons, such as cyclopentane, cyclohexane, cyclohexene, cycloheptane, cyclooctane, cyclooctene, 1,5-cyclooctadiene, etc. Saturated cycloaliphatic hydrocarbons having 5-10 carbon atoms are preferred. Cyclohexane is particularly preferred.

[0143] Examples of suitable aromatic hydrocarbons include toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 2-propylbenzene (isopropylbenzene), 2-isopropyltoluene (o-cymol), 3-isopropyltoluene (m-cymol), 4-isopropyltoluene (p-cymol), 1,3,5-trimethylbenzene (mesotrimethylbenzene), etc. Toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (mesotrimethylbenzene), and any combination thereof are preferred. Among aromatic hydrocarbons, toluene, o-xylene, m-xylene, p-xylene, 1,3,5-trimethylbenzene (mesotrimethylbenzene), and any combination thereof are particularly preferred, with toluene being the most preferred.

[0144] Examples of suitable haloalliparaffins include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, etc. Dichloromethane and 1,2-dichloroethane, and any combination thereof are preferred.

[0145] Suitable examples of halogenated aromatic hydrocarbons include chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, α,α,α-trifluorotoluene (benzotrifluoride), etc.

[0146] Examples of suitable amides include N,N-dimethylformamide, dimethylacetamide, diethylacetamide, etc.

[0147] Examples of suitable ethers include acyclic, cyclic, or aromatic ethers, such as diethyl ether, diisopropyl ether, n-butyl methyl ether, isobutyl methyl ether, sec-butyl methyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-diethyl ether, etc. Alkane, anisole, etc.

[0148] Examples of suitable ketones include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclopropyl methyl ketone, etc.

[0149] Suitable examples of nitrile include acetonitrile, benzyl nitrile, etc.

[0150] In a preferred embodiment, the inert organic solvent is selected from hydrocarbons, acyclic ethers, cyclic ethers, aromatic ethers, and any combination thereof, more preferably aliphatic hydrocarbons, cyclic aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, acyclic ethers, cyclic ethers, aromatic ethers, and any combination thereof, even more preferably aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, and any combination thereof, more preferably aliphatic hydrocarbons, aromatic hydrocarbons, and any combination thereof, and even more preferably aromatic hydrocarbons.

[0151] In another preferred embodiment, the inert organic solvent is selected from hydrocarbons.

[0152] In a more preferred embodiment, the inert organic solvent is selected from n-heptane, n-octane, n-nonane, n-decane, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (trimethylbenzene), dichloromethane, chlorobenzene, and any combination thereof.

[0153] In one or even a more preferred embodiment, the inert organic solvent is selected from n-heptane, n-octane, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (trimethylbenzene), chlorobenzene, and any combination thereof.

[0154] More preferably, the inert organic solvent is selected from n-heptane, toluene, o-xylene, m-xylene, p-xylene, and any combination thereof.

[0155] Particularly preferred inert organic solvents are alkylbenzenes substituted with alkyl mono-, di-, or trialkyl groups each containing 1-3 carbon atoms, particularly those selected from toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, 1,3,5-trimethylbenzene (mesenthalpy trimethylbenzene), and any combination thereof, more preferably selected from toluene, o-xylene, m-xylene, p-xylene, and any combination thereof. Most preferably, the inert organic solvent is toluene.

[0156] In another embodiment, the inert organic solvent is capable of forming an azeotrope with water, C1-C4 alkyl alcohols, or any mixture thereof.

[0157] Preferably, the inert organic solvent is capable of forming an azeotrope with water.

[0158] In another embodiment, the inert organic solvent is capable of forming an azeotrope with C1-C4 alkyl alcohols (preferably methanol, ethanol, isopropanol or tert-butanol, more preferably methanol).

[0159] In another embodiment, the inert organic solvent is capable of forming an azeotrope with water, methanol, ethanol, isopropanol or tert-butanol, preferably water, methanol, ethanol or tert-butanol, more preferably water or methanol, and most preferably water.

[0160] In another embodiment, the inert organic solvent has a boiling point of 35-200°C, preferably 90-165°C, and more preferably 100-150°C at ambient pressure (1 bar).

[0161] The molar ratio of the inert organic solvent to (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers or any non-racemic mixture thereof, especially (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), can vary widely and depends on the reaction conditions used, but is generally 30:1 to 1:1, preferably 15:1 to 1:1, more preferably 10:1 to 1:1, and even more preferably 5:1 to 1:1.

[0162] In another embodiment, the molar ratio of toluene to (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers or any non-racemic mixture thereof, especially (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), is from 10:1 to 1:1, preferably from 5:1 to 2:1, more preferably from 4:1 to 3:1.

[0163] The method of the present invention can optionally be carried out in the presence of at least one phase transfer catalyst.

[0164] Phase transfer catalysts suitable for the method of the present invention are those well known in the art, such as quaternary ammonium salts. Examples of suitable phase transfer catalysts are trimethyl(phenyl)ammonium chloride, trimethyl(phenyl)ammonium bromide, trimethyl(phenyl)ammonium iodide, or trimethyl(phenyl)ammonium hydroxide, such as tetra-n-C1-C14. 12 Alkyl ammonium chloride, tetra-C1-C 12 Alkyl ammonium bromide, tetra-C1-C 12 Alkyl ammonium iodide or tetra-C1-C 12Alkyl ammonium hydroxide, preferably tetra-C1-C8 alkyl ammonium chloride, tetra-C1-C8 alkyl ammonium bromide, tetra-C1-C8 alkyl ammonium iodide, or tetra-C1-C8 alkyl ammonium hydroxide, such as tetramethyl ammonium chloride, tetramethyl ammonium bromide, tetramethyl ammonium iodide, or tetramethyl ammonium hydroxide; tetraethyl ammonium chloride, tetraethyl ammonium bromide, tetraethyl ammonium iodide, or tetraethyl ammonium hydroxide; tetra-n-propyl ammonium chloride, tetra-n-propyl ammonium bromide, tetra-n-propyl ammonium iodide, or tetra-n-propyl ammonium hydroxide; tetra-n-butyl ammonium chloride, tetra-n-butyl ammonium bromide, tetra-n-butyl ammonium iodide, or tetra-n-butyl ammonium hydroxide; tetra-n-pentyl ammonium chloride, tetra-n-pentyl ammonium bromide, tetra-n-pentyl ammonium iodide, or tetra-n-pentyl ammonium hydroxide; tetra-n-hexyl ammonium chloride, tetra-n-hexyl ammonium bromide, tetra-n-hexyl ammonium iodide, or tetra-n-hexyl ammonium hydroxide; tetra-n-heptyl ammonium chloride, tetra-n-propyl ammonium bromide, tetra-n-propyl ammonium iodide, or tetra-n-propyl ammonium hydroxide; tetra-n-butyl ammonium chloride, tetra-n-butyl ammonium bromide, tetra-n-hexyl ammonium iodide, or tetra-n-hexyl ammonium hydroxide; tetra-n-heptyl ammonium hydroxide, etc. Ammonium chloride, tetrahedralammonium bromide, tetrahedralammonium iodide or tetrahedralammonium hydroxide, tetrahedralammonium chloride, tetrahedralammonium bromide, tetrahedralammonium iodide or tetrahedralammonium hydroxide, methyltri-n-butylammonium chloride, methyltri-n-butylammonium bromide, methyltri-n-butylammonium iodide or methyltri-n-butylammonium hydroxide, ethyltrimethylammonium chloride, ethyltrimethylammonium bromide, ethyltrimethylammonium iodide or ethyltrimethylammonium hydroxide, n-propyltrimethylammonium chloride, n-propyltrimethylammonium bromide, n-propyltrimethylammonium iodide or n-propyltrimethylammonium hydroxide, methyltriethylammonium chloride, methyltriethylammonium bromide, methyltriethylammonium iodide or methyltriethylammonium hydroxide, and n-butyltriethylammonium chloride, n-butyltriethylammonium bromide, n-butyltriethylammonium iodide or n-butyltriethylammonium hydroxide. Tetra-C1-C4 alkylammonium chloride, tetra-C1-C4 alkylammonium bromide, tetra-C1-C4 alkylammonium iodide, or tetra-C1-C4 alkylammonium hydroxide are particularly preferred, especially tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, or tetra-n-butylammonium hydroxide, and methyltri-n-butylammonium chloride, methyltri-n-butylammonium bromide, methyltri-n-butylammonium iodide, or methyltri-n-butylammonium hydroxide. Phase transfer catalysts, typically in pure solid form, can be used as is, or preferably in dissolved form. The effective amount of phase transfer catalyst relative to (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane(II), any of its individual enantiomers or any non-racemic mixtures thereof, especially (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane(II), can be 0.001-0.5 molar equivalents, preferably 0.001-0.2 molar equivalents.

[0165] The method of the present invention can be carried out under ambient pressure or under slightly increased or decreased pressure. Typically, atmospheric pressure is used. In another embodiment, the method of the present invention is carried out at a reduced pressure, preferably 0.01-10 bar, more preferably 0.1-6 bar.

[0166] The temperature used in the method of the present invention can vary widely and depends on a variety of factors, such as the inert organic solvent and the pressure used. At atmospheric pressure (1 bar), the temperature is typically 35-200°C, preferably 70-170°C, more preferably 80-150°C, and even more preferably 110-135°C.

[0167] The reaction time can vary over a wide range and depends on a variety of factors, such as temperature, pressure, or the reagents and auxiliary substances used. Typical reaction times are 10-50 hours, preferably 12-30 hours, and more preferably 15-25 hours.

[0168] In another embodiment, step (a) includes the following steps:

[0169] (a1.1) Provides a reaction mixture comprising (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers or any non-racemic mixtures thereof (preferably (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), a 2-methylbenzyl compound of formula (III), a base and an inert organic solvent, and

[0170] (a1.2) Heat the reaction mixture to reflux.

[0171] In yet another implementation, step (a) includes the following steps:

[0172] (a2.1) Provides a first mixture comprising (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers or any non-racemic mixtures thereof (preferably (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), a base, and an inert organic solvent.

[0173] (a2.2) Heat the first mixture to reflux, and

[0174] (a2.3) The 2-methylbenzyl compound of formula (III) is added to the first mixture under stirring to form a reaction mixture.

[0175] In the case where X is an ammonium group of formula (IV) and a 2-methylbenzyl compound of formula (III) (e.g., trimethyl(o-tolylmethyl)ammonium chloride of formula (IIIf) or triethyl(o-tolylmethyl)ammonium chloride of formula (IIIg)) is formed in situ as described herein, step (a) comprises the following steps:

[0176] (a3.1) Provides (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any of its individual enantiomers or any non-racemic mixtures thereof (preferably (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), a base, an inert organic solvent, and wherein R1, R2 and R3 have the same meaning as in formula (IV) (preferably wherein R1, R2 and R3 are each independently selected from C1-C6 alkyl and C6-C6 alkyl groups). 20 A first mixture of tertiary amines of the formula NR1R2R3 (aryl, more preferably C1-C6 alkyl, even more preferably methyl or ethyl, most preferably methyl)

[0177] (a3.2) Heat the first mixture to reflux, and

[0178] (a3.3) Under stirring, X is selected from halogens, C1-C4 alkyl sulfonates, or C6-C 20 A 2-methylbenzyl compound of formula (III) of aryl sulfonate (preferably halogen, more preferably chlorine, bromine or iodine, even more preferably chlorine) is added to the first mixture to form a reaction mixture.

[0179] A tertiary amine of the formula NR1R2R3 (especially trimethylamine, triethylamine, or combinations thereof, more preferably trimethylamine) and wherein X is selected from halogens, C1-C4 alkyl sulfonates, or C6-C 20 The molar ratio of 2-methylbenzyl compounds of formula (III) of aryl sulfonates (preferably halogens, more preferably chlorine, bromine or iodine, even more preferably chlorine) can be 1:1-0.1:1, preferably 0.5:1-0.1:1, more preferably 0.25:1-0.1:1, even more preferably 0.15:1-0.1:1, and even more preferably 0.1:1-0.01:1.

[0180] In step (a), more specifically, in any of steps (a1.1), (a2.1) and (a3.1) as defined above, the base (in solid form, as an aqueous solution or as a combination thereof) may be added in batches or metered continuously (in one or more separate portions, preferably in one portion), wherein batch addition is preferred.

[0181] In step (a), more specifically, in any of steps (a1.1), (a2.3) and (a3.3) as defined above, the 2-methylbenzyl compound of formula (III) may be added in batches or in continuous metering (in one or more separate portions), wherein continuous metering is preferred.

[0182] In step (b), water, C1-C4 alkyl alcohols, or any mixture thereof (preferably water) are simultaneously removed from the reaction mixture. Preferably, water, C1-C4 alkyl alcohols, or any mixture thereof (preferably water) are removed from the reaction mixture simultaneously and continuously or simultaneously and intermittently (more preferably simultaneously and continuously) during the reaction.

[0183] The removal of water, C1-C4 alkyl alcohols, or any mixture thereof (preferably water) according to step (b) can be achieved by various methods known in the art, such as chemical or physicochemical methods. As a chemical method, the addition of chemical scavengers or drying agents (e.g., sodium sulfate, magnesium sulfate, molecular sieves, zeolites, or calcium oxide) can be used. Physicochemical methods include, but are not limited to, membrane separation methods (e.g., nanofiltration) or azeotropic distillation. In a preferred embodiment, water, C1-C4 alkyl alcohols, or any mixture thereof (preferably water) are removed from the reaction mixture by azeotropic distillation. Specifically, water, C1-C4 alkyl alcohols, or any mixture thereof (preferably water) are removed from the reaction mixture as an azeotrope formed by an inert organic solvent and water, C1-C4 alkyl alcohols, or any mixture thereof.

[0184] To offset the potential loss of inert organic solvent removed by azeotropic distillation in the reaction mixture, fresh inert organic solvent, recycled inert organic solvent, or a mixture containing inert organic solvent and having a lower concentration of water, C1-C4 alkyl alcohols, or any mixture thereof, can be added to the reaction mixture during the reaction. Therefore, in a preferred embodiment, step (b) includes step...

[0185] (b1.1) As an azeotrope formed by an inert organic solvent and water, C1-C4 alkyl alcohols or any mixture thereof, water, C1-C4 alkyl alcohols or any mixture thereof are simultaneously (preferably simultaneously and continuously) removed from the reaction mixture, and

[0186] (b1.2) During the reaction, an inert organic solvent or a mixture comprising an inert organic solvent and water, C1-C4 alkyl alcohol or any mixture thereof having a lower concentration than the azeotrope is added to the reaction mixture.

[0187] In step (b.12) above, an inert organic solvent (fresh inert organic solvent, recycled inert organic solvent or a combination thereof) or a mixture containing an inert organic solvent and having a lower concentration of water, C1-C4 alkyl alcohol or any mixture thereof, may be continuously or periodically (preferably continuously) added to the reaction mixture during the reaction.

[0188] Preferably, an inert organic solvent (fresh, recycled, or a combination thereof) or a mixture containing an inert organic solvent and having a lower concentration of water, C1-C4 alkyl alcohols, or any mixture thereof, may be added to the reaction mixture in an amount such that the initial volume of the reaction mixture is maintained or reduced to a volume less than the initial volume of the reaction mixture during the reaction (e.g., ≤90%, ≤80%, ≤70%, ≤60%, ≤50%, ≤40%, or ≤30% of the initial volume of the reaction mixture). Alternatively, an inert organic solvent (fresh, recycled, or a combination thereof) or a mixture containing an inert organic solvent and having a lower concentration of water, C1-C4 alkyl alcohols, or any mixture thereof, may be added in an amount such that the resulting volume is higher than the initial volume of the reaction mixture.

[0189] In a preferred embodiment, step (b) includes the following steps:

[0190] (b2.1) Distillation of azeotropes formed by inert organic solvents and water.

[0191] (b2.2) The azeotrope is continuously condensed and separated into an organic solvent phase and an aqueous phase.

[0192] (b2.3) Recycle the organic solvent phase into the reaction mixture, and

[0193] (b2.4) Remove the aqueous phase from the method.

[0194] In a particularly preferred embodiment, step (b) includes the following steps:

[0195] (b3.1) The azeotrope formed by the inert organic solvent and water is removed from the reaction mixture as a vapor fraction.

[0196] (b3.2) The vapor fraction is condensed to form a two-phase condensate, and the two-phase condensate is passed through a phase separator to form an organic solvent phase and an aqueous phase.

[0197] (b3.3) Transfer the inert organic solvent phase (preferably via overflow) to the reaction mixture, and

[0198] (b3.4) Remove the aqueous phase from the method.

[0199] The (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (I), any of its individual enantiomers or any non-racemic mixture thereof (preferably the (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (I)) is preferably separated from the final reaction mixture obtained in step (b) by conventional methods (e.g. by extraction, particularly extraction with an alkaline or neutral aqueous medium, distillation, etc.).

[0200] After the reaction is complete, the reaction mixture is preferably extracted with water, followed by concentration and removal of the inert organic solvent. For further purification, thin-film evaporation and distillation can be applied.

[0201] The present invention is illustrated by the following examples, but is not intended to limit or restrict the invention thereon.

[0202] Example 1: Preparation of (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxadicyclo[2.2.1]heptane by removing water via azeotropic distillation (base: solid sodium hydroxide, solvent: toluene, 1 molar equivalent of 1-(chloromethyl)-2-methylbenzene)

[0203] (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane (120.7 g, 0.705 mol) and solid sodium hydroxide (37.4 g, 0.916 mol) were suspended in toluene (227.5 g, 2.469 mol). The reaction mixture was heated to reflux (internal temperature 116 °C). At this temperature, 1-(chloromethyl)-2-methylbenzene (101.7 g, 0.705 mol) was added to the mixture over 7 hours. The reaction mixture was maintained under reflux for 24 hours (with the internal temperature rising to 130 °C during the reaction) and water was continuously removed from the reaction mixture during this period by azeotropic distillation (Dean-Starck conditions). After cooling the reaction mixture to 25 °C, water (235.1 g) was added, and the reaction mixture was extracted. After phase separation, water (214.7 g) was added again. The mixture was extracted and the phases were separated. The product solution was distilled using Dean-Starck conditions. The product solution (413.5 g) was analyzed by quantitative gas chromatography (GC) (GC with internal standard) and showed a concentration of 41.9% for (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane. This corresponds to a yield of 89.5% for (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane. Based on the recovered feedstock ((±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane), the yield corresponds to 93.6%.

[0204] In the experiment of Example 1 (with water removed), no scaling, i.e., salt agglomeration and heavy deposition on the reactor walls, was observed after reaction times of 4.5 hours or even 22.75 hours. Instead, the salt particles formed during the reaction remained suspended in the reaction medium.

[0205] Comparative Example 1: Preparation of (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane without removing water (base: solid sodium hydroxide, solvent: toluene, 1 molar equivalent of 1-(chloromethyl)-2-methylbenzene, not of this invention)

[0206] (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane (125.9 g, 0.736 mol) and solid sodium hydroxide (39.0 g, 0.956 mol) were suspended in toluene (237.3 g, 2.575 mol). The reaction mixture was heated to reflux (internal temperature 116 °C). At this temperature, 1-(chloromethyl)-2-methylbenzene (106.1 g, 0.736 mol) was added to the mixture over 7 hours. The reaction mixture was maintained under reflux for 24 hours (with the internal temperature rising to 130 °C during the reaction). After cooling the reaction mixture to 25 °C, water (200 g) was added, and the reaction mixture was extracted. After phase separation, water (201 g) was added again. The mixture was extracted and the phases were separated. The product solution was distilled using Dean-Stark conditions. The product solution (279.2 g) was analyzed by quantitative gas chromatography (GC) (GC with internal standard) and showed a concentration of 47.9% for (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane. This corresponds to a yield of 66.2% for (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane. The yield based on the recovered feedstock ((±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane) corresponds to 88.3%.

[0207] In the experiment of Comparative Example 1 (without removing water), severe fouling, namely the agglomeration and heavy deposition of salts on the reactor wall, was observed after a reaction time of 4.5 hours.

[0208] Example 2: Preparation of (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxadicyclo[2.2.1]heptane by removing water via azeotropic distillation (base: solid sodium hydroxide, solvent: toluene, 2 molar equivalents of 1-(chloromethyl)-2-methylbenzene)

[0209] (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane (80.0 g, 0.459 mol), solid sodium hydroxide (24.1 g, 0.596 mol), and 1-(chloromethyl)-2-methylbenzene (129.0 g, 0.917 mol) were mixed in toluene (380.3 g, 4.127 mol). The reaction mixture was heated to reflux (jacket temperature 130 °C), and water was continuously removed from the reaction mixture by azeotropic distillation (Dean-Stark conditions) over the reaction time. After 15 hours, the mixture was cooled to 28 °C, water (120 g) was added, the reaction mixture was extracted, and the phases were separated. The product solution was concentrated. The product solution (192.7 g) was analyzed by quantitative high performance liquid chromatography (HPLC) and showed a concentration of 62.4% for (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane. This corresponds to a yield of 95.5% for (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane.

[0210] Example 3: Preparation of (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxadicyclo[2.2.1]heptane by removing water via azeotropic distillation (base: solid sodium hydroxide, solvent: toluene, 1 molar equivalent of 1-(chloromethyl)-2-methylbenzene)

[0211] (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane (80.0 g, 0.459 mol), solid sodium hydroxide (24.1 g, 0.596 mol), and 1-(chloromethyl)-2-methylbenzene (64.5 g, 0.459 mol) were mixed in toluene (380.3 g, 4.127 mol). The reaction mixture was heated to reflux (jacket temperature 130 °C), and water was continuously removed from the reaction mixture by azeotropic distillation (Dean-Stark conditions) over the reaction time. After 15 hours, the mixture was cooled to 28 °C, water (112 g) was added, the reaction mixture was extracted, and the phases were separated. A sodium chloride solution (15%) (100.0 g) was added. After extraction, the organic phase was separated and concentrated. The product solution (134.2 g) was analyzed by quantitative high performance liquid chromatography (HPLC) and showed a concentration of 79.8% for (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane. This corresponds to a yield of 85.1% for (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane.

[0212] Example 4: Preparation of (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxadicyclo[2.2.1]heptane by removing water via azeotropic distillation (base: solid potassium hydroxide, solvent: toluene, 1 molar equivalent of 1-(chloromethyl)-2-methylbenzene)

[0213] (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane (180.0 g, 1.032 mol), solid potassium hydroxide (70.8 g, 1.136 mol), and 1-(chloromethyl)-2-methylbenzene (145.1 g, 1.032 mol) were mixed in toluene (855.7 g, 9.287 mol). The reaction mixture was heated to reflux (jacket temperature 130 °C), and water was continuously removed from the reaction mixture during this period by azeotropic distillation (Dean-Stark conditions). After 15 hours, the mixture was cooled to 25 °C, water (402.1 g) was added, and the reaction mixture was extracted. After phase separation, a sodium chloride solution (15%) (387.8 g) was added. After extraction, the organic phase was separated and concentrated. The product solution (299.3 g) was analyzed by quantitative high-performance liquid chromatography (HPLC), showing a concentration of 85.4% for (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane. This corresponds to a yield of 90.2% for (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane. Based on the recovered starting material ((±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane), the yield corresponds to 99.9%.

[0214] Comparative Example 2: Preparation of (±)-2-exo-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane according to Example 3 on pages 19-20 of CN101602770A.

[0215] (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane (99.5%) (36.3 g, 0.21 mol) was dissolved in ethyl acetate (73.5 g, 0.83 mol) and sodium hydroxide (10.2 g, 0.25 mol) was added. 1-(chloromethyl)-2-methylbenzene (38.6 g, 0.27 mol) was added dropwise over 1 hour at ambient temperature. The mixture was then heated to 50 °C and stirred for 5 hours. The mixture was cooled to 25 °C and water (100 g) was added. After phase separation, the organic phase was analyzed. Analysis showed less than 0.1% of the desired product (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane, but significant amounts of the acetylated product (16 area %), (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane (26 area %), 1-(chloromethyl)-2-methylbenzene (56 area %), and ethanol obtained by acylation were identified by gas chromatography and GC-MS.

[0216]

Claims

1. A method for preparing (±)-2-ex-(2-methylbenzyloxy)-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (I), any one of its enantiomeric forms or any non-racemic mixture thereof, The method includes the following steps: (a) Reaction of (±)-2-ex-hydroxy-1-methyl-4-isopropyl-7-oxabicyclo[2.2.1]heptane of formula (II), any one of its enantiomeric forms or any non-racemic mixture thereof, with 2-methylbenzyl compound of formula (III) in the presence of at least one base capable of forming water under the reaction conditions and at least one inert organic solvent. Where X is a leaving group, and (b) Remove water from the reaction mixture simultaneously and continuously. The 2-methylbenzyl compound of formula (III) is 2-methylbenzyl chloride of formula (IIIa): The base is selected from alkali metal hydroxides. Inert organic solvents that can form azeotropes with water and are selected from hydrocarbons, and In step (b), water is removed from the reaction mixture by azeotropic distillation.

2. The method of claim 1, wherein step (b) comprises the following steps: (b1.1) Water is simultaneously and continuously removed from the reaction mixture as an azeotrope formed by an inert organic solvent and water, and (b1.2) During the reaction, an inert organic solvent or a mixture containing the inert organic solvent and having a lower concentration of water than the azeotrope is added to the reaction mixture.

3. The method according to claim 1 or 2, wherein the base is selected from sodium hydroxide and potassium hydroxide and combinations thereof.

4. The method according to any one of claims 1-3, wherein the base is sodium hydroxide.

5. The method according to any one of claims 1-4, wherein the base is added to the reaction mixture in solid form.

6. The method according to any one of claims 1-5, wherein the inert organic solvent is selected from aliphatic hydrocarbons, cyclic aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, and any combination thereof.

7. The method according to any one of claims 1-6, wherein the inert organic solvent is selected from aromatic hydrocarbons.

8. The method according to any one of claims 1-7, wherein the inert organic solvent is toluene.

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