Preparation of 2-substituted 4-methyltetrahydropyrans from 2-substituted 4-hydroxy-4-methyltetrahydropyrans as starting materials

Description

BACKGROUND OF THE INVENTION

[0001] The present invention relates to a process for the production of 2-substituted 4-methyltetrahydropyrans from 2-substituted 4-hydroxy-4-methyl-tetrahydropyrans as starting materials. STATE OF THE ART

[0002] Alkyl-substituted tetrahydropyrans are widely used as flavorings and aroma compounds. A well-known representative of this class is 2-isobutyl-4-methyltetrahydropyran (Dihydrorosan oxide or Dihydrorosan®), which has a floral, green fragrance.

[0003] The first synthesis of dihydrorose oxide was described by M. Julia and B. Jacquet in Bulletin de la Société Chimique de France 1963, 8-9, 1983. Starting from but-2-ene-1-al, a cyclic acetal was obtained by a Diels-Alder reaction with ethyl vinyl ether followed by hydrogenation. After elimination of ethanol, hydrobromination of the resulting double bond, and a final Grignard reaction with isopropylmagnesium bromide, a racemic mixture of cis- and trans-dihydrorose oxide was obtained.

[0004] Liu et al. describe in J. Heterocyclic Chem., 21, 129-132 (1984) the preparation of cis-dihydrorose oxide by hydrogenation of 2-isobutyl-4-methyl-5,6-dihydro-4H-pyran with PtO 2 in acetic acid.

[0005] In Perfume & Flavorist, Vol. 11, 29-30 (1986), Schindler and Vogel schematically describe the preparation of dihydrorose oxide from 3-methylbut-3-en-1-ol and 3-methylbutanal as starting materials, yielding a cis / trans mixture in a 70:30 ratio. Neither the reaction pathway nor the conditions to be observed are described in detail.

[0006] EP 0 770 670 B1 describes a perfume composition containing 2-substituted (4R)-cis-4-methyl-tetrahydro-2H-pyrans. The application describes the odor properties of the isomers of rose oxide and dihydrorose oxide. The synthesis of the dihydrorose oxide isomers is achieved by hydrogenation of the corresponding rose oxide isomers.

[0007] WO 2014 / 060345 describes a process for the preparation of 2-substituted 4-hydroxy-4-methyltetrahydropyrans and 2-substituted 4-methyltetrahydropyrans by reacting isoprenol (3-methylbut-3-enol) with an aldehyde. In the first step, isoprenol is reacted in the presence of a suitable aldehyde, yielding a mixture of 2-substituted 4-hydroxy-4-methyltetrahydropyrans, 6-substituted 4-methyl-3,6-dihydro-2H-pyrans, 2-substituted 4-methylenetetrahydropyrans, 2-substituted 4-methyl-3,6-dihydro-2H-pyrans, and 2-substituted 4,4-dimethyl-1,3-dioxanes. The alcohol compound is separated. The remaining compounds are subjected to hydrogenation to obtain 2-substituted 4-methyltetrahydropyrans and dioxane compounds.

[0008] WO 2015 / 158584 describes a process for the preparation of 2-substituted 4-hydroxy-4-methyltetrahydropyrans. 2-Substituted 4,4-dimethyl-1,3-dioxanes are reacted with a strong acid, yielding a product mixture of 6-substituted 4-methyl-3,6-dihydro-2H-pyrans, 2-substituted 4-methylenetetrahydropyrans, and 2-substituted 4-methyl-3,6-dihydro-2H-pyrans. The product mixture is then subjected to hydrogenation.

[0009] Both US 2009 / 0263336 and EP 2 112 144 describe the synthesis of 2-alkyl-4-methyltetrahydropyranol compounds. The resulting pyranol can be further dehydrogenated to yield a mixture of 4-methylene-2-alkyl-tetrahydropyran, 4-methyl-2-alkyl-5,6-dihydropyran, and 4-methyl-2-alkyl-3,6-dihydropyran. Optionally, the resulting mixture can be hydrogenated to obtain the corresponding 4-methyl-2-alkyl-tetrahydropyrans. Firstly, the procedures described in these documents were not a one-pot synthesis. Each intermediate compound had to be isolated for the subsequent step. Secondly, the synthesis of the 2-alkyl-4-methyl-tetrahydropyran derivatives in these documents is carried out from a mixture of the aforementioned compounds by hydrogenation. An acid catalyst is not mentioned. The acid mentioned in these documents is only used in the production of pyranol.

[0010] There remains a great need for effective methods for the synthesis of 2-substituted 4-methyltetrahydropyrans from readily available starting materials. In addition to synthesis from pure substances, the utilization of byproducts from other synthetic processes that have not yet been used is of particular interest.

[0011] The present invention is based on the objective of providing an improved process for the production of 2-substituted 4-methyltetrahydropyrans.

[0012] Surprisingly, it has now been found that by hydrogenation of 2-substituted 4-hydroxy-4-methyl-tetrahydropyrans in the presence of a hydrogenation catalyst under acidic conditions, 2-substituted 4-methyl-tetrahydropyrans, specifically dihydrorose oxide, can be rapidly converted. SUMMARY THE INVENTION

[0013] The invention relates to a method for producing compounds of the general formula (I) where R 1< is selected under straight-chain or branched C1-C12 alkyl, wherein the alkyl is unsubstituted or has at least one substituent selected from aryl, C1-C12 alkoxy and C1-C12 alkylcarbonyl, unsubstituted or with 1, 2, 3 or 4 substituents selected from C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkyl, C1-C12 alkoxy, phenyl and benzyl, cycloalkyl having a total of 3 to 20 carbon atoms, comprising the steps of: a) providing at least one compound of general formula (II) where R 1< has the meaning given above, b) hydrogenation of compound (II) in the presence of a hydrogenation catalyst under acidic conditions, wherein it is a one-pot synthesis.

[0014] Another object of the invention is a method for producing compounds of the general formula (I) where R 1< is selected under straight-chain or branched C1-C12 alkyl, wherein the alkyl is unsubstituted or has at least one substituent selected from aryl, C1-C12 alkoxy and C1-C12 alkylcarbonyl, unsubstituted or with 1, 2, 3 or 4 substituents selected from C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkyl, C1-C12 alkoxy, phenyl and benzyl, cycloalkyl having a total of 3 to 20 carbon atoms, comprising the steps of: a) providing at least one compound of general formula (II) where R 1< has the meaning given above, b) hydrogenation of compound (II) in the presence of a hydrogenation catalyst under acidic conditions. DESCRIPTION OF THE INVENTION

[0015] The method according to the invention has the following advantages: The reaction provided according to the invention provides access to 2-substituted 4-methyltetrahydropyrans and specifically to Dihydrorosan oxide / Dihydrorosan ®< enables a synthesis requiring only one reaction step (one-pot synthesis). The preparation of the 2-substituted 4-methyltetrahydropyrans, especially dihydrorose oxide, does not require the use of other expensive and / or potentially hazardous reagents, such as Grignard reagents or complex hydrides like lithium aluminum hydride.

[0016] One-pot synthesis according to the invention describes a synthesis that requires only one reaction step. Isolation of intermediate compounds does not take place. The reaction according to the invention occurs in situ. In other words, all substances required for the process according to the invention in steps a) and b) are already present in the reaction vessel from the beginning or are added during the course of the reaction without, however, stopping the reaction. As soon as the reaction is complete, the desired product is obtained. The product can optionally be purified by conventional purification methods known to those skilled in the art, such as filtration, distillation, extraction, or a combination thereof. Unless otherwise specified below, the terms

[0017] "2-substituted 4-methyltetrahydropyran", "2-(2-methylpropyl)-4-methyltetrahydropyran", "2-isobutyl-4-methyltetrahydropyran" (= "Dihydrorosan oxide" or "Dihydrorosan ®< "), "2-substituted 4-hydroxy-4-methyltetrahydropyran", "2-(2-methylpropyl)-4-hydroxy-4-methyl-tetrahydropyran", "2-isobutyl-4-methyl-tetrahydropyran-4-ol" within the scope of the invention, cis / trans mixtures of any composition as well as the pure conformational isomers. The aforementioned terms also refer to all enantiomers in pure form as well as racemic and optically active mixtures of the enantiomers of these compounds.

[0018] Where cis and trans diastereomers of compounds (I) or (II) are mentioned below, only one of the enantiomeric forms is shown. For illustrative purposes only, the isomers of 2-(2-methylpropyl)-4-methyltetrahydropyran (I) (dihydrorosan oxide / dihydrorosan ®< ) are shown below:

[0019] Within the scope of the present invention, the term straight-chain or branched alkyl preferably refers to C1-C6 alkyl and particularly preferably to C1-C4 alkyl. Alkyl specifically refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl (2-methylpropyl), sec-butyl (1-methylpropyl), tert-butyl (1,1-dimethylethyl), n-pentyl, or n-hexyl. Specifically, alkyl refers to methyl, ethyl, n-propyl, isopropyl, or isobutyl.

[0020] Within the scope of the present invention, the term "aryl-substituted alkyl" preferably refers to aryl-substituted C1-C6 alkyl and particularly preferably to aryl-substituted C1-C4 alkyl. "aryl-substituted alkyl" particularly refers to benzyl, 1-phenethyl, or 2-phenethyl.

[0021] Within the scope of the present invention, the term straight-chain or branched alkoxy preferably refers to C1-C6 alkoxy and particularly preferably to C1-C4 alkoxy. Alkoxy specifically refers to methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, or n-hexyloxy. More specifically, alkoxy refers to methoxy, ethoxy, n-propyloxy, isopropyloxy, or isobutyloxy.

[0022] Within the scope of the invention, cycloalkyl denotes a cycloaliphatic residue with preferably 3 to 10, particularly preferably 5 to 8, carbon atoms. Examples of cycloalkyl groups are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. Specifically, cycloalkyl refers to cyclohexyl.

[0023] Substituted cycloalkyl groups can have one or more (e.g., 1, 2, 3, 4, or 5) substituents, depending on the ring size. These are preferably selected independently of one another from C1-C6 alkyl, C1-C6 alkoxy, phenyl, and benzyl, with C1-C6 alkyl and C1-C6 alkoxy being particularly preferred. In the case of substitution, the cycloalkyl groups preferably bear one or more, for example, one, two, three, four, or five, C1-C6 alkyl groups. Examples of substituted cycloalkyl groups include, in particular, 2- and 3-methylcyclopentyl, 2- and 3-ethylcyclopentyl, 2-, 3- and 4-methylcyclohexyl, 2-, 3- and 4-ethylcyclohexyl, 2-, 3- and 4-propylcyclohexyl, 2-, 3- and 4-isopropylcyclohexyl, 2-, 3- and 4-butylcyclohexyl and 2-, 3- and 4-isobutylcyclohexyl.

[0024] Within the scope of the invention, the term alkyl-carbonyl preferably refers to (C 1 -C 6 -alkyl)carbonyl, wherein alkyl, as defined above, is bonded to the rest of the molecule via a carbonyl group.

[0025] Within the scope of the present invention, the term "aryl" encompasses mono- or polynuclear aromatic hydrocarbon residues typically having 6 to 18, preferably 6 to 14, and particularly preferably 6 to 10 carbon atoms. Examples of aryl include, in particular, phenyl, naphthyl, indenyl, fluorenyl, anthracenyl, phenanthrenyl, naphthacenyl, chrysenyl, pyrenyl, etc., and specifically phenyl or naphthyl.

[0026] Substituted aryls can have one or more (e.g., 1, 2, 3, 4, or 5) substituents, depending on the number and size of their ring systems. These are preferably selected independently of one another from among C1-C6 alkyl and C1-C6 alkoxy. Examples of substituted aryl groups are 2-, 3- and 4-methylphenyl, 2,4-, 2,5-, 3,5- and 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 2-, 3- and 4-ethylphenyl, 2,4-, 2,5-, 3,5- and 2,6-diethylphenyl, 2,4,6-triethylphenyl, 2-, 3- and 4-propylphenyl, 2,4-, 2,5-, 3,5- and 2,6-dipropylphenyl, 2,4,6-tripropylphenyl, 2-, 3- and 4-isopropylphenyl, 2,4-, 2,5-, 3,5- and 2,6-diisopropylphenyl, 2,4,6-triisopropylphenyl, 2-, 3- and 4-butylphenyl, 2,4-, 2,5-, 3,5- and 2,6-Dibutylphenyl, 2,4,6-Tributylphenyl, 2-, 3- and 4-Isobutylphenyl, 2,4-, 2,5-, 3,5- and 2,6-Diisobutylphenyl, 2,4,6-Triisobutylphenyl, 2-, 3- and 4-sec-Butylphenyl, 2,4-, 2,5-, 3,5- and 2,6-Di-sec-butylphenyl, 2,4,6-Tri-sec-butylphenyl, 2-, 3- and 4-tert.-Butylphenyl, 2,4-, 2,5-, 3,5- and 2,6-di-tert-butylphenyl, 2,4,6-tri-tert-butylphenyl, 1-methyl-2-naphthyl, 3-methyl-2-naphthyl, 1,3-dimethyl-2-naphthyl, 5,6,7,8-tetramethyl-2-naphthyl, 5-Methyl-2-naphthyl, 6-Methyl-2-naphthyl, 7-Methyl-2-naphthyl, 8-Methyl-2-naphthyl.

[0027] Preferably, R< in the compounds of formulas (I) and (II) represents straight-chain or branched C1-C12 alkyl, wherein the alkyl is unsubstituted or substituted with aryl. Particularly preferably, R< in the compounds of formulas (I) and (II) represents straight-chain or branched C1-C6 alkyl, wherein the alkyl is unsubstituted or has at least one substituent selected from phenyl and C1-C6 alkoxy.

[0028] Preferred meanings for the residue R 1< according to the invention are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl or n-heptyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and most preferably isobutyl (2-methylpropyl).

[0029] The present invention thus relates, in a preferred embodiment, to a process for the preparation and isolation of 2-(2-methylpropyl)-4-methyltetrahydropyran of formula (1a) (Dihydrorosan oxide / Dihydrorosan ®< ). Step a)

[0030] Suitable starting materials for use in step a) may include at least one compound of formula (II) be, where R 1< is selected under straight-chain or branched C1-C12 alkyl, wherein the alkyl is unsubstituted or has at least one substituent selected from aryl, C1-C12 alkoxy and C1-C12 alkylcarbonyl, unsubstituted or with 1, 2, 3 or 4 substituents selected from C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkyl, C1-C12 alkoxy, phenyl and benzyl, cycloalkyl having a total of 3 to 20 carbon atoms.

[0031] Preferably, R 1< is selected from a straight-chain or branched C 1 -C 6 alkyl, wherein the alkyl is unsubstituted or has at least one substituent selected from phenyl and C 1 -C 6 alkoxy.

[0032] R 1< is particularly preferred selected from Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, n-Pentyl, n-Hexyl and Phenyl.

[0033] R 1< is particularly preferred selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and n-hexyl.

[0034] In a special embodiment, R 1< stands for isobutyl (2-methylpropyl).

[0035] The synthesis route for the preparation of the compound of formula (II) is described in WO 2010 / 133473, WO 2015 / 158454 and WO 2014 / 060345. Step b)

[0036] According to the invention, the compound of formula (II) is subjected to an elimination followed by a hydrogenation in the presence of a hydrogenation catalyst under acidic conditions. By the elimination and hydrogenation in step b), the compound of formula (II) is converted to the corresponding compound of formula (I).

[0037] The elimination followed by hydrogenation preferably takes place in one reaction step (one-pot synthesis), i.e. without isolation of intermediate compounds.

[0038] In the context of the invention, the term "under acidic conditions" means that the reaction takes place in the presence of an acid. An acid is understood to be any substance that exhibits Brønsted or Lewis acidity.

[0039] Preferably, such substances are selected from proton donors, electron acceptors and mixtures thereof.

[0040] Proton donors are preferably selected from molecular protic acids, ion exchangers and mixtures thereof.

[0041] Electron acceptors are preferably selected from acidic molecular element compounds, oxidic acidic solids and mixtures thereof.

[0042] Suitable molecular protic acids include, for example, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, trifluoromethylsulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and mixtures thereof.

[0043] Suitable acidic molecular element compounds include, for example, aluminium chloride, boron trifluoride, zinc chloride, phosphorus pentafluoride, arsenic trifluoride, tin tetrachloride, titanium tetrachloride, antimony pentafluoride and mixtures thereof.

[0044] Suitable oxide acidic solids include, for example, zeolites, silicates, aluminates, aluminosilicates, clays and mixtures thereof. Suitable ion exchangers are acidic cationic ion exchangers.

[0045] Within the scope of the present invention, the term "acidic cation exchanger" refers to cation exchangers in the H+< form that contain acidic groups, generally sulfonic acid groups, whose matrix may be gel-like or macroporous. Accordingly, a preferred embodiment of the process according to the invention is characterized by the use of an acidic cation exchanger containing or comprising sulfonic acid groups.

[0046] Acidic cation exchangers are primarily ion exchange resins in the H+< form. Examples include: Acidic ion exchangers (such as Amberlyst, Amberlite, Dowex, Lewatit, Purolite, Serdolit), which are based on polystyrene and contain copolymers of styrene and divinylbenzene as a support matrix with sulfonic acid groups in H+<-form, with sulfonic acid groups (-SO3H) functionalized ion exchanger groups.

[0047] Ion exchange resins differ in the structure of their polymer backbones, and a distinction is made between gel-like and macroporous resins. Acidic ion exchange resins are generally regenerated with hydrochloric acid and / or sulfuric acid.

[0048] Nafion® is DuPont's brand name for perfluorinated polymeric ion exchange resins. These are perfluorinated ion exchange materials consisting of fluorocarbon base chains and perfluorinated side chains containing sulfonic acid groups. The resins are produced by copolymerizing perfluorinated, terminally unsaturated ethoxylates functionalized with sulfonyl fluoride with perfluoroethene. Nafion® is classified as a gel-like ion exchange resin. Nafion® NR-50 is an example of such a perfluorinated polymeric ion exchange resin.

[0049] Acidic cation exchangers are generally used in the H+< form, where the ion exchanger contains a polymer backbone with sulfonic acid groups and is either gel-like or contains macroporous resins.

[0050] A particularly preferred embodiment of the method according to the invention is characterized in that the ion exchanger is based on a polystyrene framework with sulfonic acid groups or on a perfluorinated ion exchange resin with sulfonic acid groups.

[0051] The commercially available acidic cation exchangers are known under the trade names Lewatit ®< (Lanxess), Purolite ®< (The Purolite Company), Dowex ®< (Dow Chemical Company), Amberlite ®< (Rohm and Haas Company), Amberlyst ™< (Rohm and Haas Company). Examples of acidic cation exchangers preferred according to the invention are: Lewatit® < K 1221, Lewatit® < K 1461, Lewatit® < K 2431, Lewatit® < K 2620, Lewatit® < K 2621, Lewatit® < K 2629, Lewatit® < K 2649, Amberlite® < IR 120, Amberlyst™ < 131, Amberlyst™ < 15, Amberlyst™ < 31, Amberlyst™ < 35, Amberlyst™ < 36, Amberlyst™ < 39, Amberlyst™ < 46, Amberlyst™ < 70, Purolite® < SGC650, Purolite® < C100H, Purolite ®< C150H, Dowex ®< 50X8, Dowex ®< 88, Serdolit ®< red and Nation ®< NR-50.

[0052] In a preferred embodiment, the reaction of compound (II) according to the invention is carried out in the presence of at least one acidic cation exchanger selected from the group of cation exchangers comprising Lewatit ®< K 1221, Lewatit ®< K 2629, Amberlyst ™< 131, Amberlyst ™< 35, Purolite ®< SGC650, Purolite ®< C100H, Purolite ®< C15OH, Amberlite ®< IR 120, Dowex ®< 88, and Dowex ®< 50X8.

[0053] According to the invention, particularly preferred acidic cation exchangers are the cation exchangers Amberlyst™< 35, Dowex®< 88, and / or Amberlite®< IR 120.

[0054] One particularly preferred acidic cation exchanger according to the invention is Amberlyst™< 35, which, like the other cation exchangers mentioned, is commercially available.

[0055] The acidic ion exchange resins are usually regenerated with hydrochloric acid and / or sulfuric acid.

[0056] The hydrogenation in step b) can be carried out in a conventional manner using a prior art hydrogenation catalyst. The hydrogenation can be catalytically performed in either the gas or liquid phase. Preferably, the hydrogenation in step b) is carried out in the liquid phase in the presence of a heterogenous hydrogenation catalyst and a hydrogen-containing gas.

[0057] In principle, all homogeneous and heterogeneous catalysts suitable for the hydrogenation of unsaturated organic compounds can be considered as hydrogenation catalysts. These include, for example, metals, metal oxides, various metal compounds, or mixtures thereof. Suitable hydrogenation catalysts preferably contain at least one transition metal, preferably from groups I and VI to VIII of the periodic table. These preferably include Pd, Pt, Ni, Rh, Ru, Co, Fe, Zn, Cu, Re, or mixtures thereof.

[0058] The hydrogenation catalyst may contain at least one additional metal / element that differs from the metals described above. This additional metal / element is preferably selected from alkali metals, alkaline earth metals, aluminum, silicon, lanthanides, and mixtures thereof.

[0059] The proportion of the additional metal / element is preferably in the range of 0.1 to 10 wt.% based on the total weight of the active part of the hydrogenation catalyst (excluding the support).

[0060] The catalysts can consist solely of the active components, or the active components can be applied to supports. Suitable support materials include, for example, zirconium dioxide, barium oxide, zinc oxide, magnesium oxide, titanium oxide, aluminum oxide, TiO₂-Al₂O₃, ZrO₂-Al₂O₃, zeolites, hydrotalcite, silicon carbide, tungsten carbide, silicon dioxide, carbon, especially activated carbon or sulfated carbon, diatomaceous earth, alumina, barium sulfate, calcium carbonate, and mixtures thereof.

[0061] In one embodiment, the carrier materials simultaneously comprise or consist of an acid used according to the invention.

[0062] To increase catalytic activity, Ni, Cu or Co, also in the form of Raney catalysts, Pd, Pt, Rh, Ru, Co, Fe, Zn, Cu, or mixtures thereof can be used as a metal sponge with a very large surface area.

[0063] For the hydrogenation in step b) of the process according to the invention, palladium on carbon, palladium on Al₂O₃, palladium on SiO₂, or platinum on carbon is preferably used. Palladium on carbon is particularly advantageous.

[0064] Other suitable catalysts contain, for example, 80 to 100 wt% nickel and / or cobalt and up to 20 wt% activating metals such as copper and / or chromium. Such catalysts are particularly advantageous when used as supported catalysts.

[0065] The content of catalytically active metals in such supported catalysts, where the support material is carbon, is typically 0.05 to 10 wt.%, based on the sum of catalytically active metals and support.

[0066] The content of catalytically active metals in such supported catalysts, where the support material is an oxide, e.g. Al 2 O 3 or SiO 2, is typically 0.01 to 1 wt.%, based on the sum of catalytically active metals and support.

[0067] The catalysts can be used in hydrogenation in step b) as shaped bodies. Examples include catalyst extrudates such as strands, ribbed strands and other extrudate forms, shell catalysts, tablets, rings, spheres, chips, etc.

[0068] Preferably, the hydrogenation in step b) is carried out at a temperature of 60 to 200 °C, preferably 120 to 150 °C, particularly 135 to 145 °C.

[0069] If the reaction is carried out in the gas phase, the pressure is preferably in the range of 0.9 to 50 bar, particularly preferably 1 to 20 bar.

[0070] If the reaction is carried out in the liquid phase, the pressure is preferably in the range of 0.9 to 200 bar, in particular from 40 to 80 bar.

[0071] The hydrogenation in step b) can be carried out in one reactor or in several reactors connected in series. The hydrogenation can be batch or continuous. For batch hydrogenation, a pressure vessel can be used, for example. Suitable pressure vessels include autoclaves equipped with a device for heating and stirring the reactor contents. Preferably, the hydrogenation takes place in the liquid phase over a fixed bed, preferably in a sump or trickle flow system, or as a suspension catalysis. The fixed-bed system can be implemented, for example, in a sump or trickle flow system. The catalysts are preferably used as shaped bodies, e.g., in the form of pressed cylinders, tablets, lozenges, wheels, rings, stars, or extruded products such as solid strands, polylobar strands, hollow strands, honeycomb structures, etc.

[0072] Heterogeneous catalysts are also used in suspension processes. These heterogeneous catalysts are usually used in a finely dispersed state and are suspended in the reaction medium.

[0073] In fixed-bed hydrogenation, a reactor is used in which a fixed bed is arranged inside, through which the reaction medium flows. The fixed bed can consist of a single or multiple packed beds. Each packed bed can have one or more zones, with at least one of the zones containing a material active as a hydrogenation catalyst. Each zone can contain one or more different catalytically active materials and / or one or more different inert materials.

[0074] Different zones can have the same or different compositions. It is also possible to provide several catalytically active zones, separated from each other, for example, by inert packings. The individual zones can also have different catalytic activities. For this purpose, different catalytically active materials can be used and / or an inert material can be added to at least one of the zones. According to the invention, the reaction medium flowing through the fixed bed contains at least one liquid phase. The reaction medium can also additionally contain a gaseous phase.

[0075] The reactors used for hydrogenation in suspension include, in particular, loop reactors such as jet loops or propeller loops, stirred tank reactors, which can also be designed as stirred tank cascades, bubble columns or air-lift reactors.

[0076] Preferably, the hydrogenation in step b) takes place in suspension mode.

[0077] The hydrogenation can be carried out with or without the addition of a solvent. Suitable solvents include alcohols, ethers, and hydrocarbons such as methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, n-pentane, hexane, cyclohexane, toluene, etc. Preferably, the hydrogenation in step b) is carried out without the addition of a solvent.

[0078] For the hydrogenation in step b), the compound of formula (II) obtained in step a) can be contacted with a hydrogen-containing gas and a hydrogenation catalyst. Suitable hydrogen-containing gases are selected from hydrogen and mixtures of hydrogen with at least one inert gas. Suitable inert gases are, for example, nitrogen or argon. Preferably, undiluted hydrogen, usually with a purity of about 99.9 vol.%, is used for the hydrogenation in step b).

[0079] The hydrogenation in step b) converts the compounds of formula (II) into 2-substituted 4-methyltetrahydropyrans (I). Preferably, the starting material used for the hydrogenation contains compounds of formula (II), wherein the substituent R< has the meanings mentioned above. R< preferably represents isobutyl.

[0080] In a particular embodiment, the hydrogenation in step b) converts the compounds (II) into 2-isobutyl-4-methyl-tetrahydropyran (1a) (dihydrorose oxide).

[0081] The compound of formula (I) obtained in step b) preferably has a diastereomeric ratio of the cis-diastereomer to the trans-diastereomer in a range of 10 : 90 to 90 : 10, particularly preferably from 65 : 35 to 90 : 10.

[0082] The compound of formula (I) obtained in step b) can be converted into a form suitable for commercial use by simple purification steps.

[0083] If desired, the compound of formula (I) obtained in step b) can be subjected to further processing. For this purpose, the compound (I) obtained in step b) can be subjected to standard purification processes known to those skilled in the art. These include, for example, filtration, neutralization, distillation, extraction, or a combination thereof.

[0084] Preferably, a fraction enriched in 2-substituted 4-methyltetrahydropyrans (I) and a fraction depleted in 2-substituted 4-methyltetrahydropyrans (I) is isolated from the hydrogenation product obtained in step b).

[0085] Preferably, the compound (I) obtained in step b) is subjected to distillative separation. Suitable apparatus for distillative separation includes distillation columns, such as tray columns, which may be equipped with bells, sieve plates, sieve trays, packings, fills, valves, side draw-offs, etc., evaporators, such as thin-film evaporators, falling-film evaporators, forced-circulation evaporators, Sambay evaporators, etc., and combinations thereof.

[0086] Preferably, the compound (I) obtained in step b) is subjected in step c) to a distillative separation in at least one distillation column which is equipped with separating internals.

[0087] Preferably in step c) a fraction enriched with 2-substituted 4-methyltetrahydropyrans (I) is isolated from the compound (I) obtained in step b), wherein the diastereomeric ratio of the cis-diastereomer to the trans-diastereomer is in a range of 10 : 90 to 90 : 10, preferably from 65 : 35 to 90 : 10.

[0088] To remove further water-soluble impurities, the fraction obtained in step c) enriched with 2-substituted 4-methyltetrahydropyrans (I) can be subjected to at least one washing step with water. Alternatively or additionally, the fraction obtained in step c) enriched with 2-substituted 4-methyltetrahydropyrans (I) can be subjected to further distillation purification.

[0089] The following examples serve to illustrate the invention. EXAMPLES

[0090] Gas chromatographic analyses were performed using the following method: Column: DB WAX 30 m x 0.32 mm; FD 0.25 µm; Injector temperature: 200 °C; Detector temperature: 280 °C; Temperature program: Initial temp.: 50 °C, at 3 °C / min to 170 °C, at 20 °C / min to 230 °C, 7 min isothermal; Retention times: 2-Isobutyl-4-methyl-tetrahydropyran-4-ol tR = 28.9 min and 30.4 min; cis-Dihydrorose oxide tR = 8.77 min; trans-Dihydrorose oxide tR = 10.09 min

[0091] Concentrations of the crude products obtained (wt%) were determined by GC analysis using an internal standard. 1. Preparation of 2-isobutyl-4-methyl-tetrahydropyran starting from 2-isobutyl-4-methyl-tetrahydropyran-4-ol in methanol

[0092] 12 g of 2-isobutyl-4-methyltetrahydropyran-4-ol (isomer ratio 24:76), 28 g of methanol, 0.2 g of catalyst Pd / C (10% Pd on C), and 0.2 g of Amberlyst 35 dry are weighed into an autoclave. The autoclave is sealed and purged once with nitrogen and once with hydrogen. Hydrogen is then forced in at 30 bar, the autoclave is heated to 140 °C, and after reaching the reaction temperature, the pressure is adjusted to 50 bar. The mixture is stirred under these conditions for 12 hours, with hydrogen being added after 1 h, 3 h, and 5 h to maintain the pressure at 50 bar. The autoclave is then depressurized and cooled. The catalyst and ion exchanger are filtered off; the resulting solution is colorless and clear.

[0093] With a 2-isobutyl-4-methyl-tetrahydropyran-4-ol conversion of >99%, 2-isobutyl-4-methyl-tetrahydropyran-4-ol was formed with a selectivity of 86%. The cis / trans ratio was 5.33:1. 2. Solvent-free synthesis of 2-isobutyl-4-methyl-tetrahydropyran starting from 2-isobutyl-4-methyl-tetrahydropyran-4-ol

[0094] 36 g of 2-isobutyl-4-methyl-tetrahydropyran-4-ol (isomer ratio 24:76), 0.4 g of catalyst Pd / C (10% Pd on C), and 0.4 g of Amberlyst 35 dry are weighed into an autoclave. The autoclave is sealed and purged once with nitrogen and once with hydrogen. Hydrogen is then forced in at 30 bar, the autoclave is heated to 140 °C, and once the reaction temperature is reached, the pressure is adjusted to 50 bar. The mixture is stirred under these conditions for 12 hours, with hydrogen being added after 1 h, 3 h, and 5 h to maintain the pressure at 50 bar. The autoclave is then depressurized and cooled. The catalyst and ion exchanger are filtered off; the resulting solution is colorless and clear.

[0095] With a 2-isobutyl-4-methyl-tetrahydropyran-4-ol conversion of 60%, 2-isobutyl-4-methyl-tetrahydropyran was formed with a selectivity of 50% for 2-isobutyl-4-methyl-tetrahydropyran-4-ol. The cis / trans ratio is 6.1:1. 3. Preparation of 2-isobutyl-4-methyl-tetrahydropyran starting from 2-isobutyl-4-methyl-tetrahydropyran-4-ol in methanol

[0096] 12 g of 2-isobutyl-4-methyltetrahydropyran-4-ol (isomer ratio 24:76), 28 g of methanol, 0.4 g of catalyst Pd / C (5% Pd on C), and 0.4 g of Amberlyst 35 dry are weighed into an autoclave. The autoclave is sealed and purged once with nitrogen and once with hydrogen. Hydrogen is then forced in at 30 bar, the autoclave is heated to 140 °C, and after reaching the reaction temperature, the pressure is adjusted to 50 bar. The mixture is stirred under these conditions for 12 hours, with hydrogen being added after 1 h, 3 h, and 5 h to maintain the pressure at 50 bar. The autoclave is then depressurized and cooled. The catalyst and ion exchanger are filtered off; the resulting solution is colorless and clear.

[0097] With a 2-isobutyl-4-methyl-tetrahydropyran-4-ol conversion of >81.2%, 2-isobutyl-4-methyl-tetrahydropyran was formed with a selectivity of 65.6% for 2-isobutyl-4-methyl-tetrahydropyran-4-ol. The cis / trans ratio is 6.06 : 1. 4. Preparation of 2-isobutyl-4-methyl-tetrahydropyran starting from 2-isobutyl-4-methyl-tetrahydropyran-4-ol in methanol

[0098] 12 g of 2-isobutyl-4-methyltetrahydropyran-4-ol (isomer ratio 24:76), 28 g of methanol, 0.7 g of catalyst Pd / C (5% Pd on C), and 0.7 g of Amberlyst 35 dry are weighed into an autoclave. The autoclave is sealed and purged once with nitrogen and once with hydrogen. Hydrogen is then forced in at 30 bar, after which the autoclave is heated to 120 °C. Once the reaction temperature is reached, the pressure is adjusted to 80 bar. The mixture is stirred under these conditions for 12 hours. After 1 h, 3 h, and 5 h, more hydrogen is forced in to maintain a pressure of 50 bar. The autoclave is then depressurized and cooled. The catalyst and ion exchanger are filtered off; the resulting solution is colorless and clear.

[0099] With a 2-isobutyl-4-methyl-tetrahydropyran-4-ol conversion of 56.7%, 2-isobutyl-4-methyl-tetrahydropyran was formed with a selectivity of 62% for 2-isobutyl-4-methyl-tetrahydropyran-4-ol. The cis / trans ratio was 5.17:1.

Claims

1. A method for preparing compounds of the general formula (I) where R1 is selected from straight-chain or branched C1-C12-alkyl, where alkyl is unsubstituted or has at least one substituent selected from aryl, C1-C12-alkoxy and C1-C12-alkylcarbonyl, cycloalkyl having a total of 3 to 20 carbon atoms that is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from C1-C12-alkyl, C1-C12-alkoxy, C1-C12-alkyl, C1-C12-alkoxy, phenyl and benzyl, comprising the steps of: a) providing at least one compound of the general formula (II) where R1 is as defined above, b) hydrogenating the compound (II) in the presence of a hydrogenation catalyst under acidic conditions, wherein it is a one-pot synthesis.

2. The method according to claim 1, wherein R1 is a straight-chain or branched C1-C6-alkyl, where alkyl is unsubstituted or has at least one substituent selected from phenyl and C1-C6-alkoxy.

3. The method according to either of the preceding claims, wherein R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl or phenyl, preferably isobutyl.

4. The method according to any of the preceding claims, wherein the isomeric ratio of cis : trans of compound (I) is in the range from 10 : 90 to 90 : 10, preferably in the range from 65 : 35 to 90 : 10.

5. The method according to any of the preceding claims, wherein the hydrogenation in step b) is carried out in the presence of an acid selected from at least one protic acid, at least one Lewis acid, at least one acidic ion exchanger, at least one oxidic acidic solid, at least one acidic molecular element compound and mixtures thereof.

6. The method according to any of claims 1 to 5, wherein the hydrogenation in step b) is carried out in the presence of an acid which is selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, trifluoromethylsulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, aluminum chloride, boron trifluoride, zinc chloride, phosphorus pentafluoride, arsenic trifluoride, tin tetrachloride, titanium tetrachloride, antimony pentafluoride and mixtures thereof.

7. The method according to any of claims 1 to 5, wherein the hydrogenation in step b) is carried out in the presence of an acidic cation exchanger.

8. The method according to any of claims 1 to 5, wherein the hydrogenation in step b) is carried out in the presence of an oxidic acidic solid which is selected from zeolites, silicates, aluminates, aluminosilicates and clays.

9. The method according to any of the preceding claims, wherein the catalyst comprises at least one transition metal selected from Pd, Pt, Ni, Rh, Ru, Co, Fe, Zn, Cu, Re or mixtures thereof.

10. The method according to any of the preceding claims, wherein the hydrogenation catalyst is a supported catalyst.

11. The method according to any of the preceding claims, wherein the catalyst support is selected from zirconium dioxide, zinc oxide, magnesium oxide, titanium oxide, aluminum oxide, barium oxide, TiO2-Al2O3, ZrO2-Al2O3, zeolites, hydrotalcite, silicon carbide, tungsten carbide, silicon dioxide, carbon, especially activated carbon or sulfated carbon, diatomaceous earth, clay, barium sulfate, calcium carbonate and mixtures thereof.

12. The method according to any of the preceding claims, wherein the temperature in step b) is in the range from 60 to 200°C, preferably in the range from 120 to 150°C.

13. The method according to any of the preceding claims, wherein the pressure in step b) is in a range from 900 mbar to 200 bar, preferably 40 to 80 bar.