Process for preparing 4-hydroxy-2-methylene-butanal, 4-hydroxy-2-methyl-but-2-enal and their esters

Abstract

The present invention provides a method for producing isoprenol or an ester thereof by photooxidation in the presence of a photosensitizer and, optionally, a transition metal catalyst, wherein the photooxidation is carried out in the absence of a transition metal catalyst, and the reaction mixture obtained from the photooxidation is then contacted with a transition metal catalyst. 1 The present invention further relates to specific hydroperoxides of compounds (Ia) or (Ib) and their use as intermediates in the synthesis of compounds (Ia) and (Ib) or in the synthesis of retinol, its stereoisomers and derivatives. [Formula 1] TIFF2025526983000028.tif35170

Description

[Technical Field]

[0001] The present invention relates to a method for preparing 4-hydroxy-2-methylene-butanal, 4-hydroxy-2-methyl-but-2-enal, and / or esters thereof of formulae Ia and Ib as defined below by subjecting isoprenol or an ester thereof of formula II.a as defined below to photooxidation in the presence of a photosensitizer and, optionally, a transition metal catalyst, where the photooxidation is carried out in the absence of a transition metal catalyst and then contacting the reaction mixture obtained in the photooxidation with the transition metal catalyst. The present invention further relates to the use of specific compounds of formula Ia or Ib as defined below as intermediates in the synthesis of retinol, its stereoisomers and derivatives, particularly esters thereof; specific hydroperoxides of formulae III.a, III.b, or III.c as defined below; and their use as intermediates in the synthesis of compounds Ia and Ib or as intermediates in the synthesis of retinol, its stereoisomers and derivatives, particularly esters thereof. [Background technology]

[0002] 4-Acetoxy-2-methylbut-2-enal (its E isomer is also called C5 acetate), i.e., the acetate ester of the above-mentioned 4-hydroxy-2-methylbut-2-enal, is an important building block in the industrial synthesis of retinol, its stereoisomers and derivatives. For example, acetoxy-2-methylbut-2-enal in the form of its E isomer C5 acetate is currently obtained on an industrial scale from vinyl glycol-1,2-diacetate (VGDA), a by-product of industrial processes, via hydroformylation and deacetoxylation. The latter step is described, for example, in German Patent Application Publication No. 10117065 and the references cited therein.

[0003] However, the economic viability of VGDA depends on the continued unaltered industrial processes from which it is derived. Given that the lifespan of such processes is becoming unpredictable, whether due to rising raw material and energy costs, ecological requirements, or an increasingly unreliable supply chain, it would be desirable to have alternative routes to C5 acetate, its isomers, and derivatives at hand. Furthermore, the limited amount of VGDA available from such processes makes alternative routes desirable.

[0004] Other known synthetic routes to C5 acetates include the oxidation of prenyl acetate with selenium dioxide, as described in, for example, Chinese Patent No. 108997112; the oxidation of benzyl prenyl ether, as described in, for example, S. Inoue et al., Chemistry Lett. 1986, pp. 2035-2038; the oxidation of prenyl chloride with oxygen, as described in, for example, Chinese Patent No. 108707076; the oxidation of isoprene, as described in, for example, PA Wehrli et al., Synthesis, 1977, pp. 649-650; the acetylation of prenol by irradiation in the presence of a photosensitizer and oxidation of the resulting prenol acetate with peroxide, as described in, for example, Chinese Patent No. 110981724A; and the oxidation of prenol acetate in an electrochemical process, as described in, for example, Chinese Patent No. 111270261A. However, these routes are not suitable for industrial-scale applications.

[0005] 4-Acetoxy-2-methyl-but-2-enal, the basic alcohol 4-hydroxy-2-methyl-but-2-enal and other esters thereof can be obtained from the corresponding 2-methylene double bond isomers (i.e., from 3-formylbut-3-enyl acetate, 4-hydroxy-2-methylene-butanal or other esters) by known methods, for example, via Pd-catalyzed C-C double bond isomerization as described in U.S. Pat. No. 4,124,619 or Chinese Patent No. 103467287.

[0006] It is desirable to find an alternative route to 4-hydroxy-2-methyl-but-2-enal or 4-hydroxy-2-methylene-butanal and esters of these alcohols; ideally, this route should be suitable for industrial scale. For environmental and economic reasons, this route, at least its essential steps, should operate in very small amounts of solvent; ideally, neat, i.e., in the absence of solvent.

[0007] Isoprenol (3-methylbut-3-en-1-ol) is a readily available bulk chemical from isobutene and formaldehyde. Its double bond isomerization gives prenol (3-methylbut-2-en-1-ol). Its esters can be obtained by standard esterification processes.

[0008] The photooxidation of alkenes by singlet oxygen to allylic hydroperoxides (Schenck ene reaction) and subsequent dehydration to α-enones has been described in the art.

[0009] ED Mihelich et al., J. Org. Chem. 1983, 48, 4135-4137, describe the preparation of α-enones by the reaction of cycloalkenes, methyl oleate, and other olefinically unsaturated hydrocarbons with singlet oxygen. To this end, oxygen is passed through a reaction mixture containing the olefinically unsaturated hydrocarbon, acetic anhydride, pyridine, N,N-dimethylaminopyridine (DMAP), and tetraphenylporphyrin (TPP) as a photosensitizer in methylene chloride, and the reaction is simultaneously irradiated with a sodium vapor lamp.

[0010] H.-J. Liu et al., Tetrahedron Lett. 1993, 34(28), 4435-4438, describe the synthesis of (+)-Qinghaosu. This synthesis involves, inter alia, the conversion of a tricyclic olefinically unsaturated carbocycle to the corresponding α-enone by irradiation of a reaction mixture containing the unsaturated ring, acetic anhydride, pyridine, DMAP, and TPP in methylene chloride through oxygen.

[0011] K. You et al., Journal of Photochemistry and Photobiology A: Chemistry, 2011, 217, 321-325, describe the photosensitized oxidation of α-pinene, β-pinene and limonene, particularly to α-enones, using sodium tetrachloroiodofluorescein as a sensitizer in methanol or DMF as a solvent in the presence or absence of lutidine and / or acetic anhydride.

[0012] P. Bayer et al., Green Chem., DOI:10.1039 / d0gc00436g, describe the photooxygenation of alkenes to hydroperoxides using singlet oxygen in a solvent-free continuous-flow reaction setup. Further conversion of unstable hydroperoxides to α-enones, etc., is described schematically as the reaction of the hydroperoxides with acetic anhydride and pyridine in dichloromethane.

[0013] ELClennan et al., in Photochemistry and Photobiology, 2006, 82, 1226-1232, describe the photooxidation of various allylic alcohols using singlet oxygen. In particular, prenol is converted to 3-methyl-but-2-enal, 3,3-dimethyloxirane-2-carbaldehyde, 2-hydroperoxy-3-methyl-but-3-en-1-ol, and 5,5-dimethyl-1,2-dioxolan-3-ol in CDCl3 in the presence of TPP.

[0014] The conversion of acyclic geminal disubstituted α-olefins to aldehydes by transition metal catalyzed photooxidation and dehydration has not yet been described in the prior art. Summary of the Invention

[0015] The present inventors have found that 4-hydroxy-2-methyl-but-2-enal, 4-hydroxy-2-methylene-butanal, and esters of these alcohols can be obtained by photooxidizing isoprenol or an ester thereof in the presence of a photosensitizer and a transition metal catalyst, or by photooxidizing isoprenol or an ester thereof in the presence of a photosensitizer and subsequently contacting the hydroperoxide formed by the photooxidation with a transition metal catalyst.

[0016] The present invention therefore relates to a process for the preparation of a compound of formula Ia or formula Ib, or a mixture thereof, or a stereoisomer of compound Ia or Ib, or a mixture of different stereoisomers of compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib. [ka] [In the formula, R 1 is hydrogen or -C(=O)R 2 and; R 2 is C1~C 20 -alkyl] The method comprises: (i) a compound of formula II.a [ka] (In the formula, R 1 is as defined above), providing a reaction mixture comprising a photosensitizer and optionally a transition metal catalyst; (ii) passing an oxygen-containing gas through the reaction mixture provided in step (i) while simultaneously irradiating the reaction mixture with light; (iii) if no transition metal catalyst was provided in step (i), contacting the reaction mixture of or resulting from step (ii) with an acylating agent; (iv.1) if desired, after completion of the reaction, isolating one or more compounds (Ia) or (Ib) obtained in step (ii) or (iii); (v.1) If desired, one or more of the compounds (Ia) or (Ib) isolated in step (iv.1) may be hydrolyzed to form R 1 is hydrogen to compound (Ia) or (Ib); Or, (iv.2) if desired, hydrolyzing the reaction mixture obtained in step (ii) or (iii); (v.2) if desired, isolating one or more compounds (Ia) or (Ib) obtained in step (iv.2); The present invention relates to a method comprising:

[0017] The present invention further relates to the use of a compound of formula Ia or Ib other than (E)-4-acetoxy-2-methylbut-2-enal, or a stereoisomer of compound Ia or Ib other than (E)-4-acetoxy-2-methylbut-2-enal, or a mixture of different stereoisomers of formula Ia and / or Ib, or a mixture of different compounds Ia and / or Ib as defined above, as an intermediate in the synthesis of retinol, a stereoisomer thereof, a derivative thereof (in particular when the derivative is an ester thereof), or a stereoisomer of a derivative thereof (in particular when the derivative is an ester thereof).

[0018] The present invention relates to a hydroperoxide compound of formula III.a, III.b or III.c, or a stereoisomer of a compound of formula III.a, III.b or III.c, or a mixture of different stereoisomers of compounds III.a, III.b and / or III.c, or a mixture of different compounds III.a, III.b and / or III.c. [ka] [In the formula, In compound III.a, R 1 is hydrogen or -C(=O)R 2 and;R 2 is C1~C 20 - is alkyl; In compound III.b, R 1is -C(=O)R 2 and;R 2 is C1~C 20 - is alkyl; In compound III.c, R 1 is hydrogen or -C(=O)R 2 and;R 2 is C1~C 20 -alkyl], Preferably, a hydroperoxide compound of formula III.a or III.b, or a stereoisomer of a compound of formula III.a or III.b, or a mixture of different stereoisomers of compounds III.a and / or III.b, or a mixture of different compounds III.a and / or III.b. [ka] and; Said hydroperoxides of formula III.a, III.b or III.c, or stereoisomers of compounds of formula III.a, III.b or III.c, or mixtures of different stereoisomers of compounds III.a and / or III.b and / or III.c, or mixtures of different compounds III.a, III.b and / or III.c as defined above (provided that in compound III.b R 1 may also be hydrogen), preferably said hydroperoxides of formula III.a or III.b, or stereoisomers of compounds of formula III.a or III.b, or mixtures of different stereoisomers of compounds III.a and / or III.b, or mixtures of different compounds III.a and / or III.b as defined above (provided that in compound III.b R 1can also be hydrogen) as an intermediate in the synthesis of a compound of formula Ia or Ib, or a stereoisomer of compound Ia or Ib, or a mixture of different stereoisomers of compound Ia and / or Ib, or a mixture of different compounds of formula Ia and / or Ib as defined above, or as an intermediate in the synthesis of retinol, a stereoisomer thereof, a derivative thereof, which derivative is preferably an ester thereof (i.e. a retinol ester), retinal or retinoic acid, in particular an ester thereof, or a stereoisomer of a derivative thereof, which derivative is preferably an ester thereof (i.e. a retinol ester), retinal or retinoic acid, in particular an ester thereof. DETAILED DESCRIPTION OF THE INVENTION

[0019] definition "Alkyl" is used in its conventional sense. The term "alkyl" refers to 1 or 2 alkyl groups ("C1-C2 alkyl"), 1 to 4 alkyl groups ("C1-C4 alkyl"), or 1 to 20 alkyl groups ("C1-C 20 C1-C2 alkyl refers to a saturated linear or branched hydrocarbon group having 1 to 2 carbon atoms. Examples include methyl and ethyl. C1-C4 alkyl refers to a saturated linear or branched aliphatic acyl hydrocarbon group having 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. C1-C 20-Alkyl denotes a saturated linear or branched aliphatic acyl hydrocarbon radical having 1 to 20 carbon atoms. Examples, in addition to those mentioned for C1-C4-alkyl, are n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, 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 n-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, n-octyl, 2-ethylhexyl, n-nonyl, n-decyl, 2-propylheptyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl and other structural isomers thereof. 15 -Alkyl is CH3(CH2) 14- is.

[0020] Chlorinated C1-C2-alkanes are methane or ethane in which some or all of the hydrogen atoms have been replaced with chlorine atoms. Examples include dichloromethane (methylene chloride), trichloromethane (chloroform), tetrachloromethane (carbon tetrachloride), 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, and pentachloroethane.

[0021] C2-C8-carboxylates are the anions or salts of C2-C8-carboxylic acids. The anion is RC(=O)O - where R is a C1-C7 alkyl. Examples include acetate, propionate, and butyrate.

[0022] The term "stereoisomer" as used in the context of the present invention relates to optical isomers such as enantiomers or diastereomers, the latter existing due to the presence of two or more stereocenters in the molecule, but in particular to Z / E isomers (due to the presence of correspondingly substituted double bonds or ring systems). Thus, the stereoisomers of compound Ib are mainly the E isomer (E)-Ib and the Z isomer (Z)-Ib. [ka]

[0023] The optical isomer of compound Ib is R 1 The group is -C(=O)R 2 and R 2 C4-C with one or more stereocenters such as sec-butyl 20 - alkyl group.

[0024] Similarly, the stereoisomers of compound III.b are mainly the E isomer (E)-III.b and the Z isomer (Z)-III.b. [ka]

[0025] The optical isomer of compound III.b is R 1 The group is -C(=O)R 2 and R 2 C4-C with one or more stereoisomeric centers, such as sec-butyl 20 - alkyl group.

[0026] Similarly, the optical isomer of compound Ia is R 1 The group is -C(=O)R 2 and R 2 C4-C with one or more stereocenters, such as sec-butyl 20 -alkyl group; the optical isomers of compounds III.a and III.c are 1 The group is -C(=O)R 2 and R 2C4-C with one or more stereoisomeric centers, such as sec-butyl 20 - alkyl group.

[0027] The mixture of different stereoisomers of compound Ib is primarily a mixture of E- and Z-isomers, but the R 1 -C(=O)R 2 and R 2 C4-C with one or more stereocenters 20 Similarly, a mixture of different stereoisomers of compound III.b may be a mixture of mainly E- and Z-isomers, but also a mixture of enantiomers or diastereomers of compound Ib where R is an alkyl group. 1 -C(=O)R 2 and R 2 C4-C with one or more stereocenters 20 The compound Ia may also be a mixture of enantiomers or diastereomers of the compound III.b, where R is an alkyl group. 1 -C(=O)R 2 and R 2 C4-C with one or more stereocenters 20 -alkyl groups. Similarly, a mixture of different stereoisomers of compound III.a is a mixture of enantiomers or diastereomers of compound Ia where R 1 -C(=O)R 2 and R 2 C4-C with one or more stereocenters 20 -alkyl groups. Similarly, a mixture of different stereoisomers of compound III.c is a mixture of different enantiomers or diastereomers of compound III.a where R 1 -C(=O)R 2 and R 2 C4-C with one or more stereocenters 20 -alkyl groups of compounds III.c.

[0028] A mixture of compounds Ia or Ib is a mixture of two or more different compounds Ia (compound Ia is R1 a mixture of two or more different compounds Ib (wherein R 1 a mixture of compounds Ia and Ib (where R 1 groups have the same meaning); a mixture of compounds Ia and Ib (in compounds Ia and Ib, R 1 The groups have different meanings; a mixture of compound Ia and two or more different compounds Ib; a mixture of compound Ib and two or more different compounds Ia; or a mixture of two or more different compounds Ia and two or more different compounds Ia. However, primarily, a mixture of compounds Ia or Ib refers to a mixture of compounds Ia and Ib, and in compounds Ia and Ib, R 1 The groups have the same meaning. Compound Ib in the mixture defined above can be present as the pure E isomer, the pure Z isomer or as a mixture of E and Z isomers.

[0029] The same definition applies to mixtures of compounds III.a, III.b or III.c.

[0030] Photosensitizers, in the context of the present invention, are organic molecules (generally dyes) that, upon irradiation (generally electromagnetic radiation in the UV, visible, or near-IR range), are capable of converting triplet oxygen into singlet oxygen: upon irradiation, the sensitizer forms the corresponding excited singlet state. Intersystem crossing renders the sensitizer's excited triplet state, thereby transferring energy to triplet oxygen to form singlet oxygen.

[0031] "Light" properly means electromagnetic radiation having a wavelength (range) in the visible spectrum (380-780 nm). However, in the context of the present invention, unless otherwise specified, the term "light" also encompasses the immediately adjacent wavelength spectrum, namely near IR (above 780 nm to 1 μm) and near UV (315-<380 nm).

[0032] Retinol is (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexyl-1-enyl)nona-2,4,6,8-tetraen-1-ol (all-trans). A stereoisomer of retinol in the context of the present invention relates to a retinol in which one, two, three or all four of the double bonds at positions 2, 4, 6 and 8 have the Z configuration. Specific examples of such stereoisomers include: (2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraen-1-ol; (2E,4Z,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraen-1-ol; (2Z,4Z,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraen-1-ol; or (2Z,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraen-1-ol (also known as (13Z)-retinol in carotenoid nomenclature).

[0033] Retinol derivatives in the context of the present invention are preferably retinol esters, i.e., the -OH group is replaced by an -OC(=O)R group, where R is an organic moiety, preferably R 2 However, retinol derivatives can also be oxidized forms of retinol, such as retinal (where the -CHOH group is oxidized to -CHO) or retinoic acid (where the -CHOH group is oxidized to -C(=O)OH).

[0034] Stereoisomers of retinol derivatives are retinol derivatives as defined above, except that one, two, three or all four of the double bonds at positions 2, 4, 6 and 8 have the Z configuration.

[0035] Embodiment (Ex) of the present invention Typical and preferred embodiments Ex are summarized in the following non-exhaustive list: Further preferred embodiments will become apparent from the paragraphs following this list.

[0036] E.1. Process for preparing compounds of formula Ia or formula Ib, or mixtures thereof, or stereoisomers of compounds Ia or Ib, or mixtures of different stereoisomers of compounds Ia and / or Ib, or mixtures of different compounds Ia and / or Ib [ka] [In the formula, R 1 is hydrogen or -C(=O)R 2 and; R 2 is C1~C 20 -alkyl] The method comprises: (i) a compound of formula II.a [ka] (In the formula, R 1 is as defined above), providing a reaction mixture comprising a photosensitizer and optionally a transition metal catalyst; (ii) passing an oxygen-containing gas through the reaction mixture provided in step (i) while simultaneously irradiating the reaction mixture with light; (iii) if no transition metal catalyst was provided in step (i), contacting the reaction mixture of or resulting from step (ii) with a transition metal catalyst; (iv.1) if desired, after completion of the reaction, isolating one or more compounds (Ia) or (Ib) obtained in step (ii) or (iii); (v.1) If desired, one or more of the compounds (Ia) or (Ib) isolated in step (iv.1) may be hydrolyzed to form R 1 is hydrogen to compound (Ia) or (Ib); Or, (iv.2) if desired, hydrolyzing the reaction mixture obtained in step (ii) or (iii); (v.2) if desired, isolating one or more compounds (Ia) or (Ib) obtained in step (iv.2); A method comprising: E.2.R 2 is C1-C4 alkyl or nC 15 The method of embodiment E.1, wherein -alkyl. E.3.R 2 The method of embodiment E.2, wherein is C1-C4-alkyl. E.4.R 2 The method of embodiment E.3, wherein is methyl. E.5. In Compound II., R 1 -C(=O)R 2 The method of any one of embodiments E.1 to E.4, wherein E.6. The method of any one of embodiments E.1-E.5, wherein the transition metal catalyst comprises a transition metal from Groups 4 to 12 of the Periodic Table of the Elements in elemental or oxidized form. E.7. The method of embodiment E.6, wherein the transition metal catalyst comprises a row 4 transition metal from groups 4 to 12 of the periodic table of the elements in elemental or oxidized form. E.8. The method of any one of embodiments E.1-E.7, wherein the transition metal catalyst used in step (i) or (iii) is a heterogeneous catalyst. E.9. The method of embodiment E.7, wherein the heterogeneous transition metal catalyst is a supported catalyst. E.10. The method of embodiment E.8, wherein the heterogeneous transition metal catalyst comprises at least one salt or oxide of a transition metal from Groups 4 to 12 of the Periodic Table of the Elements supported on a support material. E.11. The method of embodiment E.10, wherein the transition metal salt or oxide is a C2 to C8-carboxylate, halide, nitrate, phosphate, chlorate, perchlorate, or oxide, or a chromate, chlorochromate, dichromate, or permanganate, of a transition metal from row 4 of groups 4 to 12 of the periodic table of the elements. E.12. The method of embodiment E.11, wherein the transition metal salt or oxide is a C2-C8-carboxylate, halide, nitrate, phosphate, sulfate, chlorate, perchlorate, or oxide, or a chromate or dichromate of Cu, Cr, Fe, or Ni. E.13. The method of embodiment E.12, wherein the chromate or dichromate is an alkali metal, Zn, or Fe chromate or dichromate. E.14. The method of embodiment E.12 or E.13, wherein the transition metal salt or oxide is selected from the group consisting of Cu(II) acetate, Cu(ClO4)2, CuCl2, CuO, Co(II) acetate, CrO3, and alkali metal dichromates. E.15. The method of embodiment E.14, wherein the alkali metal dichromate is K2Cr2O7. E.16. The method of embodiment E.14, wherein the transition metal salt or oxide is Cr(VI) oxide (CrO3). E.17. The method of any one of embodiments E.9-E.16, wherein the support material is selected from the group consisting of carbon, e.g., activated carbon, alumina, silica, silicon carbide, alumosilicates, e.g., zeolites, titanium dioxide, zirconium dioxide, and organic polymers. E.18. The method of embodiment E.17, wherein the support material is an organic polymer. E.19. The method of embodiment E.18, wherein the support material is an organic polymer selected from the group consisting of vinylpyridine homo- and copolymers, N-vinylpyrrolidine homo- and copolymers, styrene homo- and copolymers, polyurethanes, acrylate homo- and copolymers, and methacrylate homo- and copolymers. E.20. The method of embodiment E.19, wherein the organic polymer is selected from the group consisting of 2-vinylpyridine homo- and copolymers, 4-vinylpyridine homo- and copolymers, and N-vinylpyrrolidine homo- and copolymers. E.21. The method of embodiment E.20, wherein the organic polymer is selected from the group consisting of poly(2-vinylpyridine), poly(4-vinylpyridine), copolymers, preferably block copolymers, of 2-vinylpyridine and methyl methacrylate; and poly(N-vinylpyrrolidine). E.22. The method of embodiment E.21, wherein the organic polymer is selected from the group consisting of polyvinylpyridines, preferably poly(2-vinylpyridine) and poly(4-vinylpyridine). E.23. The method of embodiment E.22, wherein the organic polymer is selected from the group consisting of poly(4-vinylpyridine). E.24. Photosensitizers include fluorescein, eosin, rose bengal, erythrosine, tetraphenylporphyrin, cobalt-tetraphenylporphyrin, zinc-tetraphenylporphyrin, hematoporphyrin, rhodamine B, basacryl brilliant red, methyl violet, methylene blue, and fullerene C. 60 , fullerene C 70 , graphene, carbon nanotubes, Ru(bpy)3 2+ Salt, Ru(phen)3 2+ The method of any of embodiments E.1-E.23, wherein the compound is selected from the group consisting of a salt, cercosporin, hypocrellin-A, and mixtures thereof. E.25. Photosensitizers include tetraphenylporphyrin, cobalt-tetraphenylporphyrin, zinc-tetraphenylporphyrin, methylene blue, and Ru(bpy)3. 2+ salt, and Ru(phen)3 2+ The method of embodiment E.24, wherein the compound is selected from the group consisting of salts. E.26. Photosensitizers include tetraphenylporphyrin, zinc-tetraphenylporphyrin, and Ru(bpy)3. 2+ The method of embodiment E.25, wherein the compound is selected from the group consisting of salts. E.27. The method of embodiment E.26, wherein the photosensitizer is a tetraphenylporphyrin. E.28. The method of any of embodiments E.1-E.27, wherein in step (ii), additional photosensitizer is added if depleted during irradiation. E.29. The method of any of embodiments E.1 to E.28, wherein the photosensitizer is used in a total amount of 0.00001 to 1 mol % relative to 1 mol of the compound of formula II.a. E.30. The method of embodiment E.29, wherein the photosensitizer is used in a total amount of 0.0001 to 0.5 mol % relative to 1 mol of the compound of formula II.a. E.31. The method of any of embodiments E.1 to E.28, wherein the photosensitizer is used in a total amount of 0.000005 to 0.01 mol per mol of the compound of formula II.a. E.32. The method of embodiment E.31, wherein the photosensitizer is used in a total amount of 0.00001 to 0.005 mol per mol of the compound of formula II.a. E.33. The method of embodiment E.32, wherein the photosensitizer is used in a total amount of 0.00001 to 0.001 mol per mol of the compound of formula II.a. E.34. The method of any one of embodiments E.1 to E.33, wherein in step (ii), the reaction mixture is irradiated with light in the wavelength range of 350 to 800 nm. E.35. The method of embodiment E.34, wherein in step (ii), the reaction mixture is irradiated with light in the wavelength range of 350 to 680 nm. E.36. The method of embodiment E.35, wherein in step (ii), the reaction mixture is irradiated with light in the wavelength range of 400 to 650 nm. E.37. The method of embodiment E.36, wherein in step (ii), the reaction mixture is irradiated with light in the wavelength range of 400 to 580 nm. E.38. The method of embodiment E.37, wherein in step (ii), the reaction mixture is irradiated with light in the wavelength range of 400 to 500 nm. E.39. The method of any one of embodiments E.1 to E.38, wherein in step (ii), the reaction mixture is irradiated with monochromatic light. E.40. The method of embodiment E.39, wherein the irradiation in step (ii) is carried out using a monochromatic light source, preferably an electroluminescent lighting device that emits monochromatic light, and at least 90% of the light emitted by the monochromatic light source is in the wavelength range of 350 to 800 nm. E.41. The method of embodiment E.40, wherein at least 90% of the light emitted by the monochromatic light source is in the wavelength range of 350 to 680 nm. E.42. The method of embodiment E.41, wherein at least 90% of the light emitted by the monochromatic light source is in the wavelength range of 400 to 650 nm. E.43. The method of embodiment E.42, wherein at least 90% of the light emitted by the monochromatic light source is in the wavelength range of 400 to 580 nm. E.44. The method of embodiment E.43, wherein at least 90% of the light emitted by the monochromatic light source is in the wavelength range of 400 to 500 nm. E.45. The photosensitizer is tetraphenylporphyrin, cobalt-tetraphenylporphyrin, or zinc-tetraphenylporphyrin, and in step (ii), the reaction mixture is irradiated with light in the wavelength range of 400 to 430 nm, preferably 400 to 420 nm, for example, 400 to 410 nm; or the photosensitizer is methylene blue, and in step (ii), the reaction mixture is irradiated with light in the wavelength range of 600 to 620 nm, or the photosensitizer is Ru(bpy)3 2+ Salt or Ru(phen)3 2+ The method of any one of embodiments E.25 to E.43, wherein the salt is a salt, and in step (ii), the reaction mixture is irradiated with light in the wavelength range of 450 to 480 nm, preferably 460 to 475 nm. E.46. The method of any one of embodiments E.39 to E.45, wherein the irradiating in step (ii) is carried out using an electroluminescent lighting device that emits monochromatic light, and the electroluminescent lighting device consists of at least one LED. E.47. The method of any of embodiments E.1 to E.46, wherein the oxygen-containing gas used in step (ii) is selected from the group consisting of oxygen, air, and mixtures containing oxygen in the range of 1 to 99% by weight, based on the total weight of the mixture of oxygen and nitrogen. E.48. The method of embodiment 47, wherein the oxygen-containing gas used in step (ii) is oxygen. E.49. The method of any one of embodiments E.1 to E.48, wherein steps (ii) and (iii) are performed neat. E.50. The method of any of embodiments E.1 to E.48, wherein steps (ii) and (iii) are carried out in the presence of a chlorinated C1-C2-alkane, and the molar ratio of compound (II.a) provided in step (i) to the chlorinated C1-C2-alkane is from 50:1 to 1:1.5. E.51. The method of any of embodiments E.50, wherein the molar ratio of compound (II.a) provided in step (i) to chlorinated C1-C2-alkane is 30:1 to 1:1, preferably 20:1 to 1:1. E.52. The method of embodiment E.51, wherein the molar ratio of compound (II.a) provided in step (i) to chlorinated C1-C2-alkane is 15:1 to 2:1. E.53. The method of any one of embodiments E.50-E.52, wherein the chlorinated C1-C2-alkane is trichloromethane or tetrachloromethane. E.54. The method of any one of embodiments E.1 to E.53, wherein step (ii) is carried out at a temperature of -20 to 150°C. E.55. The method of embodiment E.54, wherein step (ii) is carried out at a temperature of 0 to 70°C, preferably 10 to 60°C. E.56. The method of embodiment E.55, wherein step (ii) is carried out at a temperature of 20 to 50°C. E.57. The method of any one of embodiments E.1 to E.56, wherein step (ii) is carried out at a pressure from atmospheric to 100 bar (10 MPa). E.58. The method of embodiment E.57, wherein step (ii) is carried out at a pressure from atmospheric pressure to 10 bar (1 MPa). E.59. The method of any one of embodiments E.1 to E.58, wherein in step (ii), the complete reaction mixture or only a distinct portion of the reaction mixture is irradiated. E.60. The method of any one of embodiments E.1 to E.59, wherein step (ii) is carried out in a side loop photoreactor, a continuous flow photoreactor, or a submerged photoreactor. E.61. The method of any one of embodiments E.1-E.60, wherein step (ii) is carried out in a reactor comprising a reaction zone for photooxidation and a reaction zone containing a transition metal catalyst. E.62. The method of any one of embodiments E.1 to E.61, (i) providing a reaction mixture comprising a compound of Formula II.a, a photosensitizer, and a transition metal catalyst; (ii) passing an oxygen-containing gas through the reaction mixture provided in step (i) while simultaneously irradiating the reaction mixture with light; (iv.1) if desired, after completion of the reaction, isolating one or more compounds (Ia) or (Ib) obtained in step (ii); (v.1) If desired, one or more of the compounds (Ia) or (Ib) isolated in step (iv.1) may be hydrolyzed to form R 1 is hydrogen to compound (Ia) or (Ib); Or, (iv.2) if desired, hydrolyzing the reaction mixture obtained in step (ii); (v.2) if desired, isolating one or more compounds (Ia) or (Ib) obtained in step (iv.2); A method comprising: E.63. The method of any of embodiments E.1-E.61, comprising: (i) providing a reaction mixture comprising a compound of Formula II.a and a photosensitizer; (ii) passing an oxygen-containing gas through the reaction mixture provided in step (i) while simultaneously irradiating the reaction mixture with light; (iii) adding a transition metal catalyst to the reaction mixture obtained in step (ii); (iv.1) if desired, after completion of the reaction, isolating one or more compounds (Ia) or (Ib) obtained in step (iii); (v.1) If desired, one or more of the compounds (Ia) or (Ib) isolated in step (iv.1) may be hydrolyzed to form R 1 is hydrogen to compound (Ia) or (Ib); Or, (iv.2) if desired, hydrolyzing the reaction mixture obtained in step (iii); (v.2) if desired, isolating one or more compounds (Ia) or (Ib) obtained in step (iv.2); A method comprising: E.64. The method of any one of embodiments E.1 to E.61, (i) providing a reaction mixture comprising a compound of Formula II.a and a photosensitizer; (ii) passing an oxygen-containing gas through the reaction mixture provided in step (i) while simultaneously irradiating the reaction mixture with light in the first reaction zone; (iii) passing the reaction mixture obtained in step (ii) through a second reaction zone containing a transition metal catalyst; If desired, recycling the reaction mixture obtained in step (iii) through the first and second reaction zones one or more times; (iv.1) if desired, after completion of the reaction, isolating one or more compounds (Ia) or (Ib) obtained in step (ii); (v.1) If desired, one or more of the compounds (Ia) or (Ib) isolated in step (iv.1) may be hydrolyzed to form R 1 is hydrogen to compound (Ia) or (Ib); Or, (iv.2) if desired, hydrolyzing the reaction mixture obtained in step (iii); (v.2) if desired, isolating one or more compounds (Ia) or (Ib) obtained in step (iv.2); A method comprising: E.65. Use of a compound of formula Ia or Ib other than (E)-4-acetoxy-2-methylbut-2-enal, or a stereoisomer of compound Ia or Ib other than (E)-4-acetoxy-2-methylbut-2-enal, or a mixture of different stereoisomers of formula Ia and / or Ib, or a mixture of different compounds Ia and / or Ib as defined in any of embodiments E.1 to E.5, as an intermediate in the synthesis of retinol, a stereoisomer thereof, a derivative thereof (preferably an ester thereof), or a stereoisomer of a derivative thereof (preferably a stereoisomer of an ester thereof). E.66. Hydroperoxide compounds of formula III.a, III.b or III.c, or stereoisomers of compounds of formula III.a, III.b or III.c, or mixtures of different stereoisomers of compounds III.a, III.b and / or III.c, or mixtures of different compounds III.a, III.b and / or III.c. [ka] [In the formula, In compound III.a, R 1 is hydrogen or -C(=O)R 2 and;R 2 is C1~C 20 - is alkyl; In compound III.b, R 1 is -C(=O)R 2 and;R 2 is C1~C 20 - is alkyl; In compound III.c, R 1 is hydrogen or -C(=O)R 2 and;R 2 is C1~C 20 -alkyl] E.67.R 2 The hydroperoxide compound according to embodiment E.66, wherein is C1-C4-alkyl. E.68.R 2 The hydroperoxide compound according to embodiment E.67, wherein is methyl. E.69. The hydroperoxide compound according to any of embodiments E.66 to E.68, which is a compound of formula III.a or III.b, or a stereoisomer of a compound of formula III.a or III.b, or a mixture of different stereoisomers of compound III.a and / or III.b, or a mixture of different compounds III.a and / or III.b. E.70. The hydroperoxide compound according to any of embodiments E.66 to E.68, which is a compound of formula III.a or III.c, or a stereoisomer of a compound of formula III.a or III.c, or a mixture of different stereoisomers of compound III.a and / or III.c, or a mixture of different compounds III.a and / or IIIc. E.71. The hydroperoxide compound according to any of embodiments E.66 to E.68, which is a compound of formula III.a, or a stereoisomer of a compound of formula III.a, or a mixture of different stereoisomers of compound III.a, or a mixture of different compounds III.a. E.72. A hydroperoxide compound of formula III.a, III.b or III.c, or a stereoisomer of a compound of formula III.a, III.b or III.c, or a mixture of different stereoisomers of compounds III.a, III.b and / or III.c, or a mixture of different compounds III.a, III.b and / or III.c as defined in any of embodiments E.66 to E.71, except that in compound III.b R 1 can also be hydrogen), as an intermediate in the synthesis of a compound of formula Ia or Ib, or a stereoisomer of compound Ia or Ib, or a mixture of different stereoisomers of compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib as defined in any of embodiments E.1 to E.5, or as an intermediate in the synthesis of retinol, a stereoisomer thereof, a derivative thereof (preferably an ester thereof), or a stereoisomer of a derivative thereof (preferably a stereoisomer of an ester thereof). E.73. Use according to embodiment E.72 of a hydroperoxide compound of formula III.a or III.b, or a stereoisomer of a compound of formula III.a or III.b, or a mixture of different stereoisomers of compounds III.a and / or III.b, or a mixture of different compounds III.a and / or III.b. E.74. Use of a hydroperoxide compound of Formula III.a, or a stereoisomer of a compound of Formula III.a, or a mixture of different stereoisomers of compound III.a, or a mixture of different compounds III.a, as according to embodiment E.72.

[0037] Without wishing to be bound by theory, it is hypothesized that in the process of the present invention, the conversion of compounds of formula II.a to compounds Ia and / or Ib proceeds via a Schenck ene reaction (= an "ene" reaction in which singlet oxygen is the enophile) and a simultaneous [if step (iii) is not performed] or subsequent [if step (iii) is performed] transition metal-catalyzed dehydration (of the hydroperoxide formed by photooxidation in the Schenck ene reaction).

[0038] In the method of the present invention, the conversion of the compound of formula II.a to compounds Ia and / or Ib can be carried out in one step, for example as a one-pot reaction, if a transition metal catalyst is provided in step (i). Naturally, in this case, step (iii) is not performed. Without wishing to be bound by theory, it is hypothesized that during step (ii), the compound of formula II.a is converted to an allylic hydroperoxide, which is subsequently catalytically dehydrated to give compounds Ia and / or Ib. It is hypothesized that compound Ib is the result of double bond isomerization that may occur during the formation of the hydroperoxide, resulting in the hydroperoxide intermediate III.b depicted above or below.

[0039] Alternatively, in the process of the present invention, the conversion of the compound of formula II.a to compounds Ia and / or Ib can be carried out in two steps if a transition metal catalyst is not provided in step (i). In this case, step (iii) is mandatory. During step (ii), hydroperoxides are formed which, upon contact with the transition metal catalyst, are dehydrated to compounds Ia and / or Ib as explained above.

[0040] Steps (ii) and (iii) can be repeated several times until the desired conversion is achieved. For example, to this end, the reaction mixture containing the compound of formula II.a and the photosensitizer can be circulated in a reactor comprising a first reaction zone in which photooxidation occurs and a second reaction zone containing a transition metal catalyst in which dehydration of the hydroperoxide formed in the first reaction zone occurs. This reaction regime can, of course, also be carried out continuously or semi-continuously by continuously or irregularly adding II.a and / or the photosensitizer to replace depleted starting materials and continuously or irregularly removing the reaction mixture containing the desired products Ia and / or Ib.

[0041] In a preferred embodiment, the present invention relates to a method for preparing a compound of formula Ia or formula Ib, or a mixture thereof, or a stereoisomer of compound Ia or Ib, or a mixture of different stereoisomers of compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib. [ka] [In the formula, R 1 is hydrogen or -C(=O)R 2 and; R 2 is C1~C 20 -alkyl] The method comprises: (i) a compound of formula II.a [ka] (In the formula, R 1is as defined above), providing a reaction mixture comprising a photosensitizer and a transition metal catalyst; (ii) passing an oxygen-containing gas through the reaction mixture provided in step (i) while simultaneously irradiating the reaction mixture with light; (iv.1) if desired, after completion of the reaction (to the desired extent), isolating one or more compounds (Ia) or (Ib) obtained in step (ii); (v.1) If desired, one or more of the compounds (Ia) or (Ib) isolated in step (iv.1) may be hydrolyzed to form R 1 is hydrogen to compound (Ia) or (Ib); Or, (iv.2) if desired, hydrolyzing the reaction mixture obtained in step (ii); (v.2) if desired, isolating one or more compounds (Ia) or (Ib) obtained in step (iv.2); The present invention relates to a method comprising:

[0042] In another preferred embodiment, the present invention relates to a method for preparing a compound of formula Ia or formula Ib, or a mixture thereof, or a stereoisomer of compound Ia or Ib, or a mixture of different stereoisomers of compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib. [ka] [In the formula, R 1 is hydrogen or -C(=O)R 2 and; R 2 is C1~C 20 -alkyl] The method comprises: (i) a compound of formula II.a [ka] (In the formula, R 1 is as defined above) providing a reaction mixture comprising a photosensitizer; (ii) passing an oxygen-containing gas through the reaction mixture provided in step (i) while simultaneously irradiating the reaction mixture with light; (iii) adding a transition metal catalyst to the reaction mixture obtained in step (ii); (iv.1) if desired, after completion of the reaction (to the desired extent), isolating one or more compounds (Ia) or (Ib) obtained in step (iii); (v.1) If desired, one or more of the compounds (Ia) or (Ib) isolated in step (iv.1) may be hydrolyzed to form R 1 is hydrogen to compound (Ia) or (Ib); Or, (iv.2) if desired, hydrolyzing the reaction mixture obtained in step (iii); (v.2) if desired, isolating one or more compounds (Ia) or (Ib) obtained in step (iv.2); The present invention relates to a method comprising:

[0043] In yet another preferred embodiment, the present invention relates to a method for preparing a compound of formula Ia or formula Ib, or a mixture thereof, or a stereoisomer of compound Ia or Ib, or a mixture of different stereoisomers of compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib. [ka] [In the formula, R 1 is hydrogen or -C(=O)R 2 and; R 2 is C1~C 20 -alkyl] The method comprises: (i) a compound of formula II.a [ka] (In the formula, R 1 is as defined above) providing a reaction mixture comprising a photosensitizer; (ii) passing an oxygen-containing gas through the reaction mixture provided in step (i) while simultaneously irradiating the reaction mixture with light in the first reaction zone; (iii) passing the reaction mixture obtained in step (ii) through a second reaction zone containing a transition metal catalyst; If desired, recycling the reaction mixture obtained in step (iii) through the first reaction zone and then through the second reaction zone one or more times; (iv.1) if desired, after completion of the reaction (to the desired extent), isolating one or more compounds (Ia) or (Ib) obtained in step (ii); (v.1) If desired, one or more of the compounds (Ia) or (Ib) isolated in step (iv.1) may be hydrolyzed to form R 1 is hydrogen to compound (Ia) or (Ib); Or, (iv.2) if desired, hydrolyzing the reaction mixture obtained in step (iii); (v.2) if desired, isolating one or more compounds (Ia) or (Ib) obtained in step (iv.2); The present invention relates to a method comprising:

[0044] In compounds Ia, Ib and II.a, R 2 is preferably C1-C4-alkyl or nC 15 -alkyl, more preferably C1-C4-alkyl, even more preferably C1-C2-alkyl, in particular methyl.

[0045] R 1 is preferably —C(═O)R, especially in compounds II.a. 2 is.

[0046] The transition metal catalyst used in step (i) or (iii) may be a homogeneous or heterogeneous catalyst. In homogeneous catalysis, the catalyst is in the same phase as the reactants or products, whereas in heterogeneous catalysis, the catalyst is in a different phase from the reactants or products. Thus, a heterogeneous catalyst in the sense of the present invention is a catalyst that is not soluble in the reaction medium.

[0047] The transition metal catalyst used in step (i) or (iii) is preferably a heterogeneous catalyst.

[0048] Heterogeneous catalysts are generally either full catalysts or supported catalysts. Full catalysts are catalysts in which the active metal in its elemental or oxidized form constitutes the majority of the catalyst in active form, i.e., more than 50% by weight, in particular at least 80% by weight. Supported catalysts are catalysts in which the active metal is supported on a support material.

[0049] Preferably, the heterogeneous transition metal catalyst is a supported catalyst.

[0050] In metal salts, the catalytically active metal is either part of the cation moiety or part of the anion.

[0051] Metal compounds in this context are, for example, metal oxides (not generally appreciated among metal salts) and metal complexes (coordination compounds).

[0052] The active metal of the metal catalyst is a transition metal. "Active" metal means that this metal is the catalytically active site. Transition metal catalysts may contain other metals, for example, for charge balancing, when, for example, the active metal is part of an anion that is not necessarily a transition metal (such as in permanganate, chromate, dichromate, etc.).

[0053] Preferably, the transition metal catalyst comprises a transition metal from Groups 4 to 12 of the Periodic Table of the Elements in elemental or oxidized form, more preferably, the transition metal catalyst comprises a transition metal from Groups 4 to 12 of the Periodic Table of the Elements in oxidized form.

[0054] The group numbers are based on the IUPAC nomenclature of 1985. Thus, groups 4 to 12 are the groups of Ti, V, Cr, Mn, Fe, Co, Ni, Cu, and Zn.

[0055] Preferably, the transition metal catalyst comprises a fourth row transition metal from groups 4 to 12 of the periodic table of the elements (i.e., Ti, V, Cr, Mn, Fe, CO, Ni, Cu, Zn) in elemental or oxidized form. More preferably, the transition metal catalyst comprises a fourth row transition metal from groups 4 to 12 of the periodic table of the elements (i.e., Ti, V, Cr, Mn, Fe, CO, Ni, Cu, Zn) in oxidized form.

[0056] Preferably, the transition metal catalyst comprises a transition metal salt or transition metal oxide, more preferably a salt or oxide of a metal from Groups 4 to 12 of the Periodic Table of the Elements, and even more preferably a salt or oxide of a metal from Groups 4 to 12 of the Periodic Table of the Elements, Period 4.

[0057] The metal salts or oxides are preferably C2-C8-carboxylates of transition metals [RC(=O)O, where R is C1-C7-alkyl]. - , for example acetate, propionate, butyrate, etc.], a halide (for example fluoride, chloride, bromide, iodide), nitrate, phosphate, sulfate, chlorate, perchlorate or oxide, more preferably a C2 to C8-carboxylate, halide, nitrate, phosphate, sulfate, chlorate, perchlorate or oxide of a transition metal of groups 4 to 12 of the periodic table of the elements, even more preferably a C2 to C8-carboxylate, halide, nitrate, phosphate, sulfate, chlorate, perchlorate or oxide of a transition metal of groups 4 to 12 of the periodic table of the elements, row 4; or a chromate, chlorochromate, dichromate or permanganate.

[0058] More preferably, the transition metal salt or oxide is a C2-C8 carboxylate, halide, nitrate, phosphate, sulfate, chlorate, perchlorate or oxide of Cu, Cr, Fe or Ni, or a chromate or dichromate, which is preferably an alkali metal, Zn or Fe chromate or dichromate.

[0059] Even more preferably, the transition metal salt or oxide is selected from the group consisting of Cu(II) acetate, Cu(ClO4), CuCl2, CuO, Co(II) acetate, CrO3 and alkali metal dichromates (the latter preferably being K2Cr2O7).

[0060] In particular, the transition metal catalyst comprises Cr(VI) oxide (CrO3).

[0061] As previously mentioned, the transition metal catalyst is preferably a supported catalyst.

[0062] Suitable support materials are known in the art, for example carbon such as activated carbon, alumina, silica, silicon carbide, aluminosilicates such as zeolites, titanium dioxide, zirconium dioxide, or organic polymers.

[0063] Suitable organic polymers are vinylpyridine homo- and copolymers, N-vinylpyrrolidine homo- and copolymers, styrene homo- and copolymers, polyurethanes, acrylate homo- and copolymers and methacrylate homo- and copolymers.

[0064] Preferably, the support material is an organic polymer, preferably selected from vinylpyridine homo- and copolymers, N-vinylpyrrolidine homo- and copolymers, styrene homo- and copolymers, polyurethanes, acrylate homo- and copolymers, and methacrylate homo- and copolymers, more preferably 2-vinylpyridine homo- and copolymers, 4-vinylpyridine homo- and copolymers, and N-vinylpyrrolidine homo- and copolymers, even more preferably poly(2-vinylpyridine), poly(4-vinylpyridine), copolymers, preferably block copolymers, of 2-vinylpyridine and methyl methacrylate; and poly(N-vinylpyrrolidine), especially polyvinylpyridine, particularly poly(2-vinylpyridine) or poly(4-vinylpyridine), very particularly poly(4-vinylpyridine).

[0065] The molecular weight of the polymer can vary over a wide range. For example, the polymer may have a number average molecular weight (M) of 500 to 1,000,000, e.g., 2,000 to 500,000 or 10,000 to 300,000. n ) and a weight average molecular weight (M) of 700 to 2,000,000, for example, 5,000 to 1,000,000 or 15,000 to 500,000. w ) can be included.

[0066] The polymer can be further crosslinked to enhance stability and / or loading capacity.

[0067] A typical crosslinking material for polyvinylpyridine is, for example, divinylbenzene. The degree of crosslinking depends on the desired stiffness of the material and can range from 1 to 40%, preferably 2 to 30%, more preferably 10 to 30%, and especially 20 to 30%. The degree of crosslinking is the quotient of the number of moles of crosslinker and the total number of moles of building blocks present in the crosslinked polymer network, expressed here as a percentage (e.g., polyvinylpyridine crosslinked with 1% divinylbenzene means 99 moles of vinylpyridine crosslinked with 1 mole of divinylbenzene). The degree of crosslinking is generally determined analytically, for example, rheologically.

[0068] Depending on the nature of the catalytic metal species and the support material, the bond between the catalytic metal species and the support material can be, for example, by adsorption, electrostatic interaction, coordinate bond, or covalent bond. By way of example only, when the nitrogen atom of the pyridine ring is quaternized, such as by protonation or alkylation, the polyvinylpyridine support material preferably used can electrostatically interact with negatively charged metal species (i.e., when the metal is part of an anion such as permanganate, chromate, or dichromate). In the case of metal species in a metal oxide or metal salt in which the metal is a cation or part of a complex cation, or the metal is part of an anion and the counter cation is one to which the pyridine nitrogen atom can coordinate (e.g., Ag, Fe, or Zn chromate or dichromate), the polyvinylpyridine support material generally interacts coordinately with the nitrogen atom of the pyridine ring, which acts as a ligand.

[0069] The catalyst loading of active metal (i.e., for example, a transition metal from Groups 4 to 12), i.e., the amount of active metal in the supported catalyst, is preferably in the range of 1 to 20 wt. %, more preferably 1 to 15 wt. %, even more preferably 1 to 10 wt. %, and especially 2 to 10 wt. %, based on the total (dry) weight of the supported catalyst. The percentage refers to the active metal only, not the salt or oxide or other form in which the metal is actually present (e.g., if Cr is present as CrO or chromate or dichromate, etc., the percentage refers to Cr only). The loading can be determined analytically, for example, by atomic absorption spectroscopy, or can be calculated from the preparation method.

[0070] Alternatively, the catalyst loading of the active metal salt, oxide, or complex (i.e., the salt, oxide, or complex of a transition metal, e.g., a Group 4 to Group 12 transition metal)—i.e., the amount of the active metal present in the supported catalyst—is preferably in the range of 2 to 40 wt. %, more preferably 3 to 35 wt. %, even more preferably 5 to 30 wt. %, and especially 5 to 20 wt. %, based on the total (dry) weight of the supported catalyst. The percentage refers to the weight of the active metal present, i.e., the salt, oxide, or other form in which the metal is actually present (e.g., if Cr is present as CrO or chromate or dichromate, the percentage refers to CrO or chromate or dichromate). The loading can be determined analytically, for example, by atomic absorption spectrometry, or can be calculated from the preparation method.

[0071] Supported transition metal catalysts suitable for the process according to the invention are commercially available or can be obtained by methods known in the art, for example by bringing the metal species or a precursor thereof and the support material or a precursor thereof into intimate contact with each other, optionally in the presence of a solvent which can then be removed; optionally or conveniently under heating. If necessary, the metal species or a precursor of the support material is first treated to convert it into a form capable of interacting with its counterpart. By way of example only, if the support material is polyvinylpyridine, which interacts electrostatically with negatively charged metal species, the polyvinylpyridine is first quaternized, for example, by contacting the polyvinylpyridine with a Bronsted acid to protonate (some of) the nitrogen atoms of the pyridine ring, or by contacting it with an alkylating agent (e.g., an alkyl bromide or alkyl iodide or alkyl sulfate, e.g., butyl bromide) to alkylate the nitrogen atoms of the pyridine ring, and then the resulting support material with the quaternized nitrogen atoms of the pyridine ring is contacted with a salt of the negatively charged metal species to exchange anions and thus bind the metal species to the support material via ionic interactions.

[0072] The catalyst (calculated based on the active metal content) is preferably used in an amount of 0.0001 to 15 mol %, more preferably 0.001 to 10 mol %, even more preferably 0.01 to 5 mol %, in particular 0.1 to 5 mol %, particularly 1 to 5 mol %, and even more particularly 1 to 3 mol %, relative to 1 mol of compound II.a.

[0073] Support materials are commercially available (for example from Acros Chemicals, Merck or Vertellus). Polymeric support materials are often commercially available as ion exchange resins.

[0074] Heterogeneous catalysts can be used in bulk loose form or can be immobilized, for example in a fixed bed.

[0075] As explained above, the photosensitizers used in the methods of the present invention are compounds that, upon irradiation (typically electromagnetic radiation in the UV, visible, or near-IR range), are capable of converting triplet oxygen to singlet oxygen: upon irradiation, the sensitizer forms the corresponding excited singlet state. Intersystem crossing renders the excited triplet state of the sensitizer, thereby transferring energy to triplet oxygen to form singlet oxygen. Singlet oxygen is the species that oxidizes compound II.a to the corresponding hydroperoxide (or its double-bond isomer).

[0076] Preferably, the photosensitizer is capable of converting triplet oxygen to singlet oxygen when exposed to electromagnetic radiation in the near UV, visible or near IR region, more preferably in the visible or near IR region, especially in the visible region.

[0077] Preferably, the photosensitizer is fluorescein, eosin, rose bengal (RB), erythrosine, tetraphenylporphyrin (more precisely 5,10,15,20-tetraphenyl-21H,23H-porphine; TPP; 2HTPP), cobalt-tetraphenylporphyrin (Co-TPP; i.e., a cobalt complex of TPP and Co(II)), zinc-tetraphenylporphyrin (Zn-TPP; i.e., a zinc complex of TPP and Zn(II)), hematoporphyrin, rhodamine B, basacryl brilliant red, methyl violet, methylene blue, fullerene C 60 , fullerene C 70 , graphene, carbon nanotubes, Ru(bpy)3 2+ salts (bpy = 2,2'-bipyridine) [e.g., tris(2,2'-bipyridine)ruthenium(II) hexafluorophosphate, tris(2,2'-bipyridine)ruthenium(II) chloride, often hexahydrate], Ru(phen)3 2+ salts (phen=1,10-phenanthroline) [e.g., dichlorotris(1,10-phenanthroline)ruthenium(II) chloride], cercosporin, hypocrellin-A, and mixtures thereof. More preferably, the photosensitizer is selected from the group consisting of tetraphenylporphyrin, cobalt-tetraphenylporphyrin, zinc-tetraphenylporphyrin, methylene blue, Ru(bpy)3 2+ salts [especially tris(2,2'-bipyridine)ruthenium(II) hexafluorophosphate, tris(2,2'-bipyridine)ruthenium(II) chloride, or their hexahydrates], and Ru(phen)3 2+ Salts [especially dichlorotris(1,10-phenanthroline)ruthenium(II) chloride], especially tetraphenylporphyrin, zinc-tetraphenylporphyrin, and Ru(bpy)3 2+ salts, particularly tris(2,2'-bipyridine)ruthenium(II) hexafluorophosphate, tris(2,2'-bipyridine)ruthenium(II) chloride, or the hexahydrates thereof; and in particular tetraphenylporphyrin.

[0078] The photosensitizer can be provided in very small amounts in step (i). However, during irradiation, some of the photosensitizer decomposes, reducing the production of singlet oxygen and potentially slowing the conversion of compound II.a to the corresponding hydroperoxide and ultimately to the desired compounds Ia and / or Ib. Therefore, a larger amount of photosensitizer can be provided in step (i), or additional photosensitizer can be added during step (ii) if the photosensitizer is depleted during irradiation. The degree of depletion / decomposition of the photosensitizer can be monitored during step (ii), for example, by UV / Vis spectroscopy, which can also be performed inline.

[0079] The photosensitizer is preferably used in a total amount of 0.00001 to 1 mol % relative to 1 mol of the compound of formula II.a. The total amount refers to the total amount of photosensitizer provided in step (i) and, if applicable, added during step (ii). More preferably, the photosensitizer is used in a total amount of 0.0001 to 0.5 mol %, even more preferably 0.0001 to 0.2 mol %, for example 0.0005 to 0.2 mol % or 0.001 to 0.1 mol %, relative to 1 mol of the compound of formula II.a.

[0080] Alternatively, the photosensitizer is preferably used in a total amount of 0.0000001 to 0.01 mol, more preferably 0.000001 to 0.01 mol, or 0.000001 to 0.005 mol, even more preferably 0.000001 to 0.002 mol or 0.000005 to 0.01 mol, particularly preferably 0.00001 to 0.001 mol, in particular 0.00001 to 0.005 mol or 0.00001 to 0.001 mol, for example 0.00001 to 0.0005 mol, per 1 mol of the compound of formula II.a.

[0081] Typical photosensitizers are dyes and therefore excitable with electromagnetic radiation in the near-UV, visible, or near-infrared (near-IR; NIR) electromagnetic spectrum. Thus, preferably, in step (ii), the reaction mixture is irradiated with light in the near-UV, visible, or near-IR range. More preferably, in step (ii), the reaction mixture is irradiated with light in the visible or near-IR range, especially the visible range.

[0082] Preferably, in step (ii), the reaction mixture is irradiated with light in the wavelength range of 350 to 800 nm, more preferably 350 to 680 nm, even more preferably 400 to 650 nm, even more preferably 400 to 580 nm, and especially 400 to 500 nm. The optimal wavelength range depends, inter alia, on the photosensitizer used and can, for example, if not known to the skilled person, be determined by short trials or selected by UV spectroscopy.

[0083] For example, when the photosensitizer is tetraphenylporphyrin, cobalt-tetraphenylporphyrin, or zinc-tetraphenylporphyrin, in step (ii), the reaction mixture may be irradiated with light in the wavelength range of, for example, 400 to 430 nm, preferably 400 to 420 nm, for example, 400 to 410 nm; when the photosensitizer is methylene blue, in step (ii), the reaction mixture may be irradiated with light in the wavelength range of, for example, 600 to 620 nm, and the photosensitizer is Ru(bpy)3 2+ Salt or Ru(phen)3 2+ In the case of a salt, in step (ii), the reaction mixture may be irradiated with light in the wavelength range of, for example, 450 to 480 nm, preferably 460 to 475 nm.

[0084] In step (ii), the reaction mixture is preferably irradiated with monochromatic light.

[0085] In theory, monochromatic light is light with a single constant frequency / light in a single vacuum wavelength range. However, in practice, no radiation can be completely monochromatic. Therefore, in practice, "monochromatic" light, whether from a laser or a spectral line, always consists of components with a frequency range of a non-zero width. In the context of the present invention, monochromatic light is understood to be light generated by monochromatic light sources of the prior art, such as monochromators, optical filters, Hg vapor lamps (high, medium or low pressure lamps) generally combined with optical filters, doped Hg vapor lamps, Na vapor lamps (high or low pressure lamps) optionally combined with optical filters, lasers, or, in particular, monochromatic LEDs.

[0086] Preferably, the irradiation in step (ii) is carried out using a monochromatic light source, preferably an electroluminescent lighting device emitting monochromatic light, wherein at least 90% of the light emitted by said monochromatic light source is in the wavelength range of 350 to 800 nm, preferably 350 to 680 nm, more preferably 400 to 650 nm, even more preferably 400 to 580 nm, especially 400 to 500 nm.

[0087] Preferably, the irradiation in step (ii) is carried out using an electroluminescent lighting device that emits monochromatic light, the electroluminescent lighting device consisting of at least one LED.

[0088] The oxygen-containing gas used in step (ii) is preferably selected from the group consisting of oxygen, air, and a mixture of oxygen and nitrogen containing 1 to 99% by weight of oxygen based on the total weight of the mixture. More preferably, the oxygen-containing gas used in step (ii) is selected from the group consisting of oxygen, air, and a mixture of oxygen and nitrogen containing 20 to 99% by weight of oxygen, in particular oxygen.

[0089] "Passing an oxygen-containing gas through the reaction mixture provided in step (i)" is not limited to bubbling the oxygen-containing gas through said mixture, thereby allowing a substantial portion of the oxygen-containing gas to escape, but also includes inserting and maintaining the oxygen-containing gas in the reaction mixture, for example, by using a sealed, typically pressurized, reaction vessel.

[0090] Preferably, steps (ii) and (iii) are carried out neat (i.e., reagents only). "Neat" or "reagents only" means that no additional solvent is present. "Additional" in this context takes into account the fact that the starting compound II.a and, furthermore, the hydroperoxide formed as an intermediate, can function as a solvent or dispersant for the photosensitizer and transition metal catalyst. To carry out step (ii) neat, the reaction mixture provided in step (i) is prepared, for example, by mixing the starting materials (compound II.a, photosensitizer, transition metal catalyst if the reaction is carried out in one step) in the absence of additional solvent, or by mixing the starting materials in the presence of additional solvent, which is then removed before carrying out step (ii).

[0091] In an alternatively preferred embodiment, steps (ii) and (iii) are carried out in the presence of a chlorinated C1-C2-alkane. To this end, said chlorinated C1-C2-alkane is conveniently provided in the reaction mixture of step (i). The molar ratio of compound (II.a) to chlorinated C1-C2-alkane provided in step (i) is 50:1 to 1:1.5, more preferably 30:1 to 1:1, even more preferably 20:1 to 1:1, in particular 15:1 to 2:1. The chlorinated C1-C2-alkane is preferably trichloromethane or tetrachloromethane.

[0092] More preferably, however, steps (ii) and (iii) are carried out neat.

[0093] Step (c) is preferably carried out at a temperature of -20 to 150°C, more preferably 0 to 70°C, for example 0 to 60°C, 5 to 50°C, or 20 to 50°C.

[0094] Step (ii) is preferably carried out at a pressure of from atmospheric pressure to 100 bar (10 MPa). Atmospheric pressure means the local ambient pressure and is therefore approximately 1013.25 hPa ± 200 hPa. In a more preferred embodiment, step (ii) is carried out at a pressure of from atmospheric pressure to 10 bar (> 0.1 - 1 mPa).

[0095] In step (ii), the complete reaction mixture or only a defined portion of the reaction mixture is irradiated, for example, when only a portion of the reaction mixture (e.g., only 20-90 wt. %, or 30-80 wt. %, or 50-80 wt. % of the reaction mixture) passes through the irradiation source.

[0096] In certain embodiments, step (ii) is carried out so that a portion of the starting compound II.a remains unreacted. This ensures that compound II.a can still function as a solvent for other substances present in the reaction mixture. Preferably, at least 20%, more preferably at least 50%, of the initially charged amount of compound II.a remains unreacted in step (ii). After workup, isolation, and optional purification, compound II.a can be reused in step (i). The degree of conversion of compound II.a can be determined by conventional means, for example, by periodic or continuous sampling and analysis or in-line analysis of the composition of the reaction mixture, or by passing oxygen through the reaction mixture in a predetermined amount by substoichiometric methods. The reaction in step (ii) is interrupted, for example, by stopping the oxygen supply and / or by stopping the irradiation.

[0097] Steps (ii) and (iii) can be carried out in any reactor known in the art as suitable for photooxidation. Suitable reactors contain at least a means for introducing an oxygen-containing gas and a radiation source. Furthermore, the reactor conveniently contains an agitator and a means for cooling or heating.

[0098] Examples of suitable reactors include a side loop photoreactor, a continuous flow photoreactor, or a submerged photoreactor.

[0099] To circulate the reaction mixture containing the compound of Formula II.a and the photosensitizer in a reactor comprising a first reaction zone in which photooxidation takes place and a second reaction zone containing a transition metal catalyst in which dehydration of the hydroperoxide formed in the first reaction zone takes place, a suitable reactor conveniently comprises pumps and lines for circulating the reaction mixture, i.e., from one zone to the other. For example, the photoreactor can be connected to a reactor containing the transition metal catalyst, and the reaction mixture can be circulated between the photoreactor and the reactor containing the transition metal catalyst.

[0100] After completion of the reaction, step (ii) [if step (iii) is not performed] or the reaction mixture obtained in step (iii) is generally worked up. In this context, "completion" of the reaction does not necessarily mean maximum conversion of the starting material, but rather conversion to the desired extent. As explained above, starting compound II.a generally functions as a solvent, especially when step (ii) is performed neat. In this case, it is advantageous to explicitly stop the reaction before maximum conversion of II.a.

[0101]

[0044] Work-up of step (ii) [if step (iii) is not performed] or of the reaction mixture obtained in step (iii) can be carried out by conventional means, for example by separating the transition metal catalyst, if necessary, and isolating the desired reaction products Ia and / or Ib [(step (iv.1)] from further components of the reaction mixture, such as unreacted compound II.a, photosensitizer, or undesired by-products, and, if desired, from each other. Separation can be carried out by conventional means, such as extraction, distillation or chromatographic methods.

[0102] If compounds Ia or Ib are formed as different stereoisomers, these can be separated from one another if desired.

[0103] R 1 is hydrogen, either the compounds Ia and / or Ib isolated according to step (iv.1), or the reaction mixture obtained from step (ii) [if step (iii) is not performed] or step (iii), are hydrolyzed, for example by reaction with an acid or a base. Hydrolysis results in a cleavage of R in compound II.a (and therefore in the resulting compounds Ia and / or Ib). 1 -C(O)R 2 Of course, if (R 1 is hydrogen) but in compound II.a R 1 is hydrogen, this may be necessary since some of the hydroxyl groups may be acylated by the acylating agent, especially if this is used in excess.

[0104] In the case of step (ii) [if step (iii) is not carried out] or of the reaction mixture resulting from step (iii) being hydrolyzed [step (v.1)], the reaction mixture obtained is worked up and the desired reaction products Ia and / or Ib [(step (iv.1)]] can be separated from the further components of the reaction mixture and from each other by conventional means such as extraction, distillation or chromatographic methods.

[0105] The process of the present invention provides a simple method for the preparation of compounds Ia and / or Ib starting from the readily available bulk chemicals isoprenol and isoprenol ester II.a. Compounds Ia and Ib are derived from retinol, its stereoisomers, its derivatives [preferably its esters; particularly those in which the OH group of retinol is -OC(O)R]. 2 or a stereoisomer of a derivative thereof [preferably a stereoisomer of the ester; in particular, a stereoisomer in which the OH group of retinol is esterified to -OC(O)R 2 Compound Ia can serve as an intermediate in the preparation of an ester esterified to [the ester of the ...

[0106] The present invention further relates to a compound of formula Ia or Ib other than (E)-4-acetoxy-2-methylbut-2-enal, or a stereoisomer of compound Ia or Ib other than (E)-4-acetoxy-2-methylbut-2-enal, or a mixture of different stereoisomers of compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib as defined above, or to retinol, its stereoisomers, its derivatives [preferably esters; in particular, when the OH group of retinol is -OC(O)R 2 or a stereoisomer of a derivative thereof [preferably a stereoisomer of the ester; in particular, a stereoisomer of a compound in which the OH group of retinol is esterified to -OC(O)R 2As explained above, compound Ia can be easily converted to Ib. The latter can be reacted with β-ionylideneethyltriphenylphosphonium salt in a Wittig reaction to give retinol (which is esterified to R in Ib), as described, for example, in J. Paust et al., Carotenoids, Birkhaeuser, 1996, vol. 2, pp. 258-292, U.S. Pat. No. 5,087,762, or H. Ernst, Pure Appl. Chem. 2002, 74, 2213, or G.L. Parker et al., Tetrahedron 2016, 72, 1645-1652. 1 =H), its stereoisomers, its esters [OH group of retinol is -OC(O)R 2 The ester esterified to R 1 =-C(O)R 2 or its ester stereoisomers. Other retinol derivatives can be prepared by conventional means; for example, by reacting retinol (or a stereoisomer thereof) with R 2 It can be obtained by esterification with an acid or acid derivative different from -C(O)OH or its derivative; or by oxidation of retinol (or its stereoisomer) to retinal (or its stereoisomer) or retinoic acid (or its stereoisomer). Retinol (or its stereoisomer) can be obtained by saponification (ester cleavage) of retinol ester (or its stereoisomer). These conversions are well known in the art.

[0107] The present invention further relates to a hydroperoxide compound of formula III.a, III.b or III.c, or a stereoisomer of a compound of formula III.a, III.b or III.c, or a mixture of different stereoisomers of compounds III.a and / or III.b and / or III.c, or a mixture of different compounds III.a, III.b and / or III.c. [ka] [In the formula, In compound III.a, R 1 is hydrogen or -C(=O)R 2 and;R 2 is C1~C 20 - is alkyl; In compound III.b, R 1 is -C(=O)R 2 and;R 2 is C1~C 20 - is alkyl; In compound III.c, R 1 is hydrogen or -C(=O)R 2 and;R 2 is C1~C 20 -alkyl].

[0108] The hydroperoxides III.a, III.b and III.c are formed in step (ii) of the process of the present invention. If the reaction mixture provided in step (i) does not contain an acylating agent, the hydroperoxides formed in step (ii) can be detected and further isolated, since their further reaction / decomposition is rather slow in the absence of an acylating agent.

[0109] The present invention preferably relates to hydroperoxide compounds of the formula III.a or III.b, or to stereoisomers of compounds of the formula III.a or III.b, or to mixtures of different stereoisomers of compounds III.a and / or III.b, or to mixtures of different compounds III.a and / or III.b.

[0110] Alternatively, the invention relates to a hydroperoxide compound of formula III.a or III.c, or to a stereoisomer of a compound of formula III.a or III.c, or to a mixture of different stereoisomers of compounds III.a and / or III.c, or to a mixture of different compounds III.a and / or III.c.

[0111] The invention particularly relates to hydroperoxide compounds of formula III.a, or to stereoisomers of compounds of formula III.a, or to mixtures of different stereoisomers of compounds III.a, or to mixtures of different compounds III.a.

[0112] The present invention further relates to a hydroperoxide compound of formula III.a, III.b or III.c, or a stereoisomer of a compound of formula III.a, III.b or III.c, or a mixture of different stereoisomers of compounds III.a, III.b and / or III.c, or a mixture of different compounds III.a, III.b and / or III.c as defined above (but in compound III.b R 1 may also be hydrogen), or as intermediates in the synthesis of compounds of formula Ia or Ib, or stereoisomers of compounds Ia or Ib, or mixtures of different stereoisomers of compounds Ia and / or Ib, or mixtures of different compounds Ia and / or Ib as defined above, or as intermediates in the synthesis of retinol, its stereoisomers, derivatives thereof [preferably esters thereof; in particular those in which the OH group of retinol is -OC(O)R 2 or a stereoisomer of a derivative thereof [preferably a stereoisomer of the ester; in particular, a stereoisomer in which the OH group of retinol is esterified to -OC(O)R 2 The present invention relates to the use of the compound as an intermediate in the synthesis of an ester of methyl ester of methyl ester.

[0113] The conversion of compounds III.a and / or III.b to compounds Ia and / or Ib is carried out by subjecting compounds III.a and / or III.b to step (iii) and optionally steps (iv) and (v) of the method of the present invention described above. Compounds Ia and / or Ib can be converted to retinol, a stereoisomer thereof, a derivative thereof or a stereoisomer of a derivative thereof, as described above.

[0114] The present invention preferably relates to a hydroperoxide compound of formula III.a or III.b, or a stereoisomer of a compound of formula III.a or III.b, or a mixture of different stereoisomers of compounds III.a and / or III.b, or a mixture of different compounds III.a and / or III.b as defined above (provided that in compound III.b R 1 may also be hydrogen), or as intermediates in the synthesis of compounds of formula Ia or Ib, or stereoisomers of compounds Ia or Ib, or mixtures of different stereoisomers of compounds Ia and / or Ib, or mixtures of different compounds Ia and / or Ib as defined above, or as intermediates in the synthesis of retinol, its stereoisomers, derivatives thereof [preferably esters thereof; in particular those in which the OH group of retinol is -OC(O)R 2 or a stereoisomer of a derivative thereof [preferably a stereoisomer of the ester; in particular, a stereoisomer in which the OH group of retinol is esterified to -OC(O)R 2 The present invention relates to the use of the compound as an intermediate in the synthesis of an ester of methyl ester of methyl ester.

[0115] The invention relates in particular to hydroperoxide compounds of formula III.a, or stereoisomers of compounds of formula III.a, or mixtures of different stereoisomers of compound III.a, or mixtures of different compounds III.a, to compounds of formula Ia or Ib, or stereoisomers of compounds Ia or Ib, or mixtures of different stereoisomers of compounds Ia and / or Ib, or mixtures of different stereoisomers of compounds Ia and / or Ib as defined above, as intermediates in the synthesis of retinol, its stereoisomers, derivatives thereof [preferably its esters; in particular those in which the OH group of retinol is -OC(O)R 2 or a stereoisomer thereof [preferably a stereoisomer thereof; in particular, an ester in which the OH group of retinol is esterified to -OC(O)R 2 The present invention relates to the use of the compound as an intermediate in the synthesis of an ester of methyl ester of methyl ester.

[0116] The following examples further illustrate the present invention. [Example]

[0117] The properties of the compound 1 H-NMR, part 13 The signals were also identified by C-NMR. NMR analysis was performed on a Bruker 400 MHz and 500 MHz Spectrometer in CDCl3. Signals are identified by their chemical shift (ppm) relative to tetramethylsilane, their multiplicity, and their integral (relative number of a given hydrogen atom). The following abbreviations are used to identify the signal multiplicity: m = multiplet, q = quartet, t = triplet, d = doublet, and s = singlet.

[0118] A. Preparation of the metal catalyst CrO3-PVPy [CrO3 on poly-(4-vinylpyridine)] Device: Four-neck reaction flask, stirrer, thermometer, dropping funnel, nitrogen blanket.

[0119] Basic steps: In a 1 L reaction flask under nitrogen, 200 g of poly(4-vinylpyridine, 25%) crosslinked with divinylbenzene (Acros Chemicals, sieved to a particle size of 0.85–1.0 mm) was placed in 400 mL of water. At room temperature, with slight cooling, a solution of 20.0 g (0.2 mmol) of chromium(VI) oxide and 60 mL of water was added dropwise. The orange reaction mixture was stirred overnight at room temperature at 150 rpm and then filtered through a glass suction filter. The spherical residue was washed twice with 500 mL of water each time and then dried in a vacuum drying oven at 50 °C and 30 mbar for at least 12 h. The chromium content was analyzed by atomic absorption spectrometry. CrO3-PVPy catalysts containing higher or lower amounts of CrO3 can be obtained by using correspondingly adapted amounts of CrO3 and / or polymer.

[0120] B. Photooxidation 1. Photooxidation of isoprenyl acetate in a G1 Corning photoreactor and rearrangement / dehydration using CrO3-PVPy Examples 1 to 3 Device: G1-Corning photoreactor (five reinforced G1 plates, layer thickness approximately 1 mm, illuminated on each side with LEDs, a total of 200 LEDs with a wavelength of 405 nm, total radiant power 195 W); a 100 mL mini-plant reactor with an impeller agitator as the feeding vessel; Overflow valve 8bar; a glass column (d = 2.5 cm) packed with CrO3-PVPy; Two FLOM double-stroke piston pumps in parallel with a maximum flow rate of 99.9 mL / min each

[0121] experiment: 266.4 g (2078.6 mmol, 1 eq) of isoprenyl acetate (IPA) was placed in a glass vial, 11.71 g (60.3 mmol, 0.029 eq) of dimethyl phthalate was added as an internal NMR standard, and 43.2 mg (70.27 μmol, 0.000034 eq) of the photosensitizer tetraphenylporphyrin (TPP) was dissolved in the mixture. The reaction mixture was transferred to a Corning photoreactor via a 100 mL mini-plant reactor, stirred at 100 rpm, and circulated through the system by pumping the solution downstream of the Corning photoreactor through a discharge valve that only opened at 8 bar to increase oxygen solubility. Downstream of the valve, the reaction mixture was passed, without pressure, through a glass column containing 38 g of CrO3-PVPy (loaded with approximately 15 wt% CrO3 based on the total weight of the supported catalyst). The hydroperoxides formed in the Corning photoreactor were then eluted with R. 1 =C(O)CH3 to compounds Ia and Ib. From there, the reaction mixture was pumped back into the miniplant reactor. The solution was circulated between the miniplant reactor, Corning photoreactor, and CrO3-PVPy glass column at the temperatures shown in Table 1 and irradiated for 6 hours while introducing 1.5 L / h of oxygen into the Corning photoreactor. During the reaction, TPP was gradually replenished up to 69 mg (112 μmol). At the end of the experiment, the reaction mixture was analyzed without further workup. The results are summarized in Table 1.

[0122] [Table 1]

[0123] Ia # : 1 H-NMR (400MHz, CDCl3): δ=9.56(1H),6.11(1H),6.36(1H),4.19(2H),2.61(2H),2.03(3H) Ib ## : 1 H-NMR (400MHz, CDCl3): δ=9.56(1H),6.10(1H),4.60(2H),2.03(3H),1.84(3H)

[0124] 2. Photooxidation of isoprenyl acetate in a ring gap reactor and simultaneous rearrangement / dehydration using CrO3-PVPy Example 4 Device: Temperature-controlled annular gap reactor, approximately 500 mL volume, 40 mm diameter, 20 mm displacer, 10 mm bed thickness; irradiated from outside in; LED lamp (two half shells with a total of 256 LEDs with a wavelength of 420 nm, total radiant power of 86 W at 4.2 A), a Harvard syringe pump for refilling the photosensitizer (dissolved in the reaction medium); A glass column (d = 3.5 cm) packed with CrO3-PVPy. Ismatec® gear pump, pump head max. 540mL / min.

[0125] experiment: 403.8 g (3151 mmol, 1 eq) of isoprenyl acetate (IPA) was placed in a glass bottle, 17.75 g (91.4 mmol, 0.029 eq) of dimethyl phthalate was added as an internal NMR standard, and 4.0 mg (6.5 μmol, 0.0000021 eq) of the photosensitizer tetraphenylporphyrin (TPP) was dissolved in the mixture. The reaction mixture was then introduced into the apparatus via a dropping funnel and circulated between the irradiated annular gap reactor and a glass column containing 73 g of CrO3-PVPy (approximately 14 wt% CrO3 based on the total weight of the supported catalyst). The formed hydroperoxide was then oxidized by R. 1 =C(O)CH3 to compounds Ia and Ib. The solution was irradiated at 420 nm for 5 h at 40 °C, during which 2 L / h of oxygen was admitted to the annular gap reactor from below through a frit. During the reaction, 24 mg (39 μmol) of tetraphenylporphyrin dissolved in the reaction medium was continuously added by syringe pump depending on the transmittance. At the end of the experiment, the reaction mixture was analyzed without further workup. The results are summarized in Table 2.

[0126] [Table 2]

[0127] 3. Photooxidation of isoprenyl acetate and simultaneous rearrangement / dehydration using CrO3-PVPy in a double-jacket reactor Examples 5 and 6 Device: Cylindrical double-jacketed vessel with a reinforced outer jacket, inner diameter 45 mm, total volume 150 mL (corresponding to a reaction volume of approximately 24 mL and a fill height of approximately 18 mm), illuminated from below by 24 LEDs with a wavelength of 405 nm, total radiant power 27 W, impeller agitator.

[0128] experiment: 26.3 g (205.27 mmol, 1 eq) of isoprenyl acetate (IPA) was placed in a glass bottle, 1.22 g (6.28 mmol, 0.031 eq) of dimethyl phthalate was added as an internal NMR standard, and 9.8 mg (15.9 mL, 0.000078 eq) of the photosensitizer tetraphenylporphyrin (TPP) was dissolved in the mixture. The reaction mixture was poured into a temperature-controlled double-jacketed vessel along with 5 g of CrO3-PVPy (containing approximately 12.5% CrO3 by weight based on the total weight of the supported catalyst) and stirred at 800 rpm. The solution was irradiated from below for 4 hours at 30 °C while introducing oxygen into the solution at 2 L / h (Example 7) or 1.5 L / h (Example 8). At the end of the experiment, the reaction mixture was analyzed without further workup. The results are summarized in Table 3.

[0129] [Table 3]

[0130] Example 7 Device: Cylindrical double-jacketed vessel with a reinforced outer jacket, inner diameter 45 mm, total volume 150 mL (corresponding to a reaction volume of approximately 24 mL and a fill height of approximately 18 mm), illuminated from below by 24 LEDs with a wavelength of 405 nm, total radiant power 27 W, impeller agitator.

[0131] experiment: 23.7 g (184.8 mmol, 1 eq) of isoprenyl acetate (IPA) was placed in a glass vial, 1.22 g (6.28 mmol, 0.034 eq) of dimethyl phthalate was added as an internal NMR standard, and 10.0 mg (16.3 mL, 0.000088 eq) of the photosensitizer tetraphenylporphyrin (TPP) was dissolved in the mixture. Additionally, 2.62 g (17.0 mmol, 0.09 eq) of carbon tetrachloride was added. The reaction mixture, along with 3.7 g of CrO3-PVPy (approximately 12.5% CrO3 by weight based on the total weight of the supported catalyst), was poured into a temperature-controlled double-jacketed vessel and stirred at 800 rpm. The solution was irradiated from below at 30 °C for 4 h while introducing oxygen at 1.5 L / h. At the end of the experiment, the reaction mixture was analyzed without further workup. The results are summarized in Table 4.

[0132] [Table 4]

[0133] The yields given above are relative to the amount of starting compound (IPA) used in the reaction. Because the reaction is conducted so that only a fairly small amount of the starting compound reacts (and the remainder can further function as a dispersion medium), only yields based on the amount of reacted starting material reflect the effectiveness of the reaction. These can be calculated by relating the yields of Ia and Ib to the amount of IPA conversion (not shown in the table above).

[0134] 4. Photooxidation of isoprenyl acetate to isoprenyl acetate hydroperoxide Example 8 Equipment: Corning® G1 photoreactor (five reinforced G1 plates, layer thickness approximately 1 mm, illuminated on each side with LEDs, a total of 200 LEDs with a wavelength of 405 nm, total radiation power 195 W), 100 mL mini-plant reactor, impeller agitator, gear pump.

[0135] experiment: A mixture of 135.0 g (1053.3 mmol, 1 eq) of isoprenyl acetate (IPA) and 6.22 g (32.0 mmol, 0.03 eq) of dimethyl phthalate as an internal NMR standard was prepared in a 100 mL miniplant reactor. 15 mg (24.7 μmol, 0.000023 eq) of tetraphenylporphyrin as a photosensitizer was dissolved in the mixture. The reaction solution was stirred at 100 rpm and pumped in a circuit to the Corning® reactor. The solution was irradiated for 6 h at the temperature shown in Table 5 while introducing 3 L / h of oxygen at 1.7-2.4 bar into the Corning® reactor. The reaction was stopped explicitly before complete conversion of isoprenyl acetate (the conversion rate of the experiment is listed in Table 5). At the end of the experiment, the reaction mixture was analyzed without further workup. The results are summarized in Table 5.

[0136] [Table 5]

[0137] III.a + : 1 H-NMR (500MHz, CDCl3): δ=5.19(1H),5.10(1H),4.47(2H),4.26(2H),2.47(2H),2.06(3H) 13 C-NMR (125MHz, CDCl3): δ=171.19(s),140.75(s),116.58(t),79.82(t),62.69(t),32.36(t),22.34(q)

[0138] Furthermore, R 1 =-C(O)CH3, was identified, which is presumed to be the result of further photooxidation of compound III.b in competition with the conversion of III.b to Ib, or the direct result of the (double) photooxidation of II.a: III.c + : 1 H-NMR (700MHz, CDCl3): δ=5.45(1H),5.41(1H),4.71(1H),4.55(2H),4.39(2H),2.09(3H) 13 C-NMR (175MHz, CDCl3): δ=170.6(s),139.8(s),120.2(t),83.3(d),77.8(t),62.7(t),21.1(q)

[0139] 5. Photooxidation of isoprenol to isoprenol hydroperoxide Example 9 Equipment: Corning® G1 photoreactor (five reinforced G1 plates, layer thickness approximately 1 mm, illuminated on each side with LEDs, a total of 200 LEDs with a wavelength of 610 nm, total radiant power 83 W), 100 mL mini-plant reactor, impeller agitator, gear pump.

[0140] experiment: In a 100 mL miniplant reactor, isoprenol (IP;R 1 135.0 g (1567.4 mmol, 1 eq) of compound II.a) where H and 9.13 g (47.0 mmol, 0.03 eq) of dimethyl phthalate as an internal NMR standard were prepared, and 28.3 mg (84 μmol, 0.000054 eq) of methylene blue monohydrate as a photosensitizer was dissolved in the mixture. The reaction solution was stirred at 300 rpm and pumped into a Corning® reactor at 100 mL / min in a circuit. The solution was irradiated for 4 hours at 30 °C while introducing 3 L / h of oxygen at 5 bar into the Corning® reactor. During the reaction, an additional 63.5 mg (188 μmol) of photosensitizer was added in small portions. The reaction was stopped explicitly before the complete conversion of isoprenol (the conversion rate of the experiment is listed in Table 6). At the end of the experiment, the reaction mixture was analyzed without further workup. The results are summarized in Table 6.

[0141] [Table 6]

[0142] III.a ++ : 1 H-NMR (400MHz, CDCl3): δ=5.24(1H),5.16(1H),4.47(2H),3.86(2H),2.41(2H)

[0143] Example 10 Apparatus: Cylindrical double-jacketed vessel with a reinforced outer jacket, inner diameter 45 mm, total volume 150 mL (corresponding to a reaction volume of approximately 38 mL and a fill height of approximately 24 mm), illuminated from below by 24 LEDs with a wavelength of 405 nm, total radiant power 27 W, impeller agitator.

[0144] experiment: A mixture of 30.0 g (348.3 mmol, 1 eq) of isoprenol (IP), 1.39 g (7.2 mmol, 0.021 eq) of dimethyl phthalate as an internal NMR standard, and 1.5 g (12.5 mmol, 0.036 eq) of chloroform was prepared in a 50 mL glass vial. 4.6 mg (7.5 μmol, 0.000021 eq) of tetraphenylporphyrin as a photosensitizer was dissolved in the mixture. The reaction solution was poured into a temperature-controlled double-jacketed vessel and stirred at 800 rpm. The solution was irradiated for 5 h at 10 °C while introducing oxygen at 2 L / h. During the reaction, an additional 8.2 mg (13.3 μmol) of photosensitizer was added in small portions. The reaction was stopped explicitly before complete conversion of isoprenol (the conversion rate for the experiment is listed in Table 7). At the end of the experiment, the reaction mixture was analyzed without further workup. The results are summarized in Table 7.

[0145] [Table 7]

Claims

1. Process for the preparation of a compound of formula I.a or formula I.b, or a mixture thereof, or a stereoisomer of said compound I.a or I.b, or a mixture of different stereoisomers of said compound I.a and / or I.b, or a mixture of different compounds I.a and / or I.b 【Chemical 1】 [In the formula, R １ is hydrogen or -C(=O)R ２ and R ２ is C １ ~C ２０ -alkyl] The method comprises: (i) a compound of formula II.a 【Chemistry 2】 (In the formula, R １ is as defined above), providing a reaction mixture comprising a photosensitizer and optionally a transition metal catalyst; (ii) passing an oxygen-containing gas through the reaction mixture provided in step (i) while simultaneously irradiating the reaction mixture with light; (iii) if no transition metal catalyst was provided in step (i), contacting the reaction mixture of or resulting from step (ii) with a transition metal catalyst; (iv.1) if desired, after completion of the reaction, isolating said one or more compounds (I.a) or (I.b) obtained in step (ii) or (iii); (v.1) If desired, the one or more compounds (I.a) or (I.b) isolated in step (iv.1) may be hydrolyzed to give R １ is hydrogen; Or, (iv.2) if desired, hydrolyzing the reaction mixture obtained in step (ii) or (iii); (v.2) if desired, isolating said one or more compounds (I.a) or (I.b) obtained in step (iv.2); A method comprising:

2. R ２ is C １ ~C ４ -alkyl or n-C １５ The method of claim 1, wherein the aryl group is -alkyl.

3. R ２ is C １ ~C ４ 3. The method of claim 2, wherein the aryl group is - alkyl, preferably methyl.

4. 4. The process according to any one of claims 1 to 3, wherein the transition metal catalyst used in step (i) or (iii) is a heterogeneous catalyst, preferably a supported heterogeneous catalyst, and the support material is preferably selected from the group consisting of carbon, alumina, silica, zeolites and organic polymers.

5. the heterogeneous transition metal catalyst comprises at least one salt or oxide of a transition metal from groups 4 to 12 of the periodic table of the elements; 5. The method of claim 4, wherein the heterogeneous transition metal catalyst is preferably a supported catalyst comprising at least one salt or oxide of a transition metal from groups 4 to 12 of the periodic table of the elements supported on a support material, the support material preferably being selected from the group consisting of carbon, alumina, silica, zeolite and organic polymers.

6. The salt or oxide of the transition metal is a C transition metal of the fourth period of the 4th to 12th groups of the periodic table of elements. ２ ~C ８ - carboxylate, halide, nitrate, phosphate, sulfate, chlorate, perchlorate or oxide, or chromate, chlorochromate, dichromate or permanganate; The salt or oxide of the transition metal is preferably Cu, Cr, Fe or Ni. ２ ~C ８ - carboxylate, halide, nitrate, phosphate, sulfate, chlorate, perchlorate or oxide, or a chromate or dichromate, preferably an alkali metal, Zn or Fe chromate or dichromate, The salt or oxide of the transition metal is more preferably Cu(II) acetate, Cu(ClO ４ ) ２ , CuCl ２ , CuO, Co(II) acetate, CrO ３ and alkali metal dichromates, preferably K ２ Cr ２ O ７ 6. The method of claim 5, wherein the compound is selected from the group consisting of:

7. The transition metal salt or oxide is Cr(VI) oxide (CrO ３ 7. The method of claim 6, wherein

8. the transition metal catalyst used in step (i) or (iii) is a supported heterogeneous catalyst, the support material is an organic polymer, the organic polymer being selected from the group consisting of vinylpyridine homo- and copolymers, N-vinylpyrrolidine homo- and copolymers, styrene homo- and copolymers, polyurethanes, acrylate homo- and copolymers, and methacrylate homo- and copolymers; The method according to any one of claims 1 to 7, wherein the organic polymer is preferably selected from the group consisting of vinylpyridine homopolymers and copolymers.

9. the organic polymer is selected from the group consisting of 2-vinylpyridine homo- and copolymers, 4-vinylpyridine homo- and copolymers, and N-vinylpyrrolidine homo- and copolymers; 9. The method of claim 8, wherein the organic polymer is preferably selected from the group consisting of poly(2-vinylpyridine), poly(4-vinylpyridine), copolymers, preferably block copolymers, of 2-vinylpyridine and methyl methacrylate; and poly(N-vinylpyrrolidine), more preferably polyvinylpyridine, especially poly(4-vinylpyridine).

10. The transition metal is Cr(VI) oxide (CrO) on polyvinylpyridine, preferably poly(4-vinylpyridine). ３ The method according to any one of claims 1 to 9, wherein

11. The photosensitizer may be fluorescein, eosin, rose bengal, erythrosine, tetraphenylporphyrin, cobalt-tetraphenylporphyrin, zinc-tetraphenylporphyrin, hematoporphyrin, rhodamine B, basacryl brilliant red, methyl violet, methylene blue, or fullerene C. ６０ , fullerene C ７０ , graphene, carbon nanotubes, Ru(bpy) ３ ２＋ Salt, Ru(phen) ３ ２＋ selected from the group consisting of salts, cercosporin, hypocrellin-A, and mixtures thereof; The photosensitizer is preferably tetraphenylporphyrin, cobalt-tetraphenylporphyrin, zinc-tetraphenylporphyrin, methylene blue, Ru(bpy), ３ ２＋ salt, and Ru(phen) ３ ２＋ The method of any one of claims 1 to 10, wherein the compound is selected from the group consisting of salts.

12. The photosensitizers include tetraphenylporphyrin, zinc-tetraphenylporphyrin, and Ru(bpy). ３ ２＋ 12. The method of claim 11, wherein the compound is selected from the group consisting of salts of tetraphenylporphyrin.

13. 13. The method according to any one of claims 1 to 12, wherein in step (ii) the reaction mixture is irradiated with light, preferably monochromatic light, in the wavelength range of 350 to 800 nm, preferably in the wavelength range of 350 to 680 nm, more preferably in the wavelength range of 400 to 650 nm, even more preferably in the wavelength range of 400 to 580 nm, in particular in the wavelength range of 400 to 500 nm.

14. The photosensitizer is tetraphenylporphyrin, cobalt-tetraphenylporphyrin or zinc-tetraphenylporphyrin, and in step (ii) the reaction mixture is irradiated with light in the wavelength range of 400 to 430 nm, preferably 400 to 420 nm, preferably monochromatic light; or the photosensitizer is methylene blue, and in step (ii) the reaction mixture is irradiated with light in the wavelength range of 600 to 620 nm, preferably monochromatic light, or the photosensitizer is Ru(bpy) ３ ２＋ Salt or Ru(phen) ３ ２＋ 14. The method according to any one of claims 11 to 13, wherein in step (ii) the reaction mixture is irradiated with light in the wavelength range of 450 to 480 nm, preferably 460 to 475 nm, preferably monochromatic light.

15. 15. The method according to any one of claims 1 to 14, wherein the oxygen-containing gas used in step (ii) is selected from the group consisting of oxygen, air, and mixtures of oxygen and nitrogen containing oxygen in the range of 1 to 99% by weight based on the total weight of the mixture, and wherein the oxygen-containing gas used in step (ii) is preferably oxygen.

16. Steps (ii) and (iii) are carried out neat; Or, Steps (ii) and (iii) are chlorinated C １ ~C ２ - a reaction of the compound (II.a) provided in step (i) with the chlorinated C １ ~C ２ 16. The process according to any one of claims 1 to 15, wherein the molar ratio of alkane to olefin is between 50:1 and 1:1.5, preferably between 20:1 and 1:1, more preferably between 15:1 and 2:

1.

17. Hydroperoxide compounds of formula III.a, III.b or III.c, or stereoisomers of said compounds of formula III.a, III.b or III.c, or mixtures of different stereoisomers of said compounds III.a, III.b and / or III.c, or mixtures of different compounds III.a, III.b and / or III.c. 【Chemistry 3】 [In the formula, In compound III.a, R １ is hydrogen or -C(=O)R ２ and R ２ is C １ ~C ２０ - alkyl; In compound III.b, R １ is -C(=O)R ２ and R ２ is C １ ~C ２０ - alkyl; In compound III.c, R １ is hydrogen or -C(=O)R ２ and R ２ is C １ ~C ２０ -alkylalkyl]; Preferably, the hydroperoxide compound of formula III.a or III.b, or a stereoisomer of the compound of formula III.a or III.b, or a mixture of different stereoisomers of the compound III.a and / or III.b, or a mixture of different compounds III.a and / or III.b.

18. The hydroperoxide compounds of formula III.a, III.b or III.c, or stereoisomers of the compounds of formula III.a, III.b or III.c, or mixtures of different stereoisomers of compounds III.a, III.b and / or III.c, or mixtures of different compounds III.a, III.b and / or III.c as defined in claim 17 (provided that in compound III.b R １ may also be hydrogen), preferably a hydroperoxide compound of said formula III.a or III.b, or a stereoisomer of a compound of said formula III.a or III.b, or a mixture of different stereoisomers of said compounds III.a and / or III.b, or a mixture of different compounds III.a and / or III.b as defined in claim 17 (provided that in compound III.b R １ can also be hydrogen), as an intermediate in the synthesis of a compound of formula I.a or I.b, or a stereoisomer of compound I.a or I.b, or a mixture of different stereoisomers of compound I.a and / or I.b, or a mixture of different compounds I.a and / or I.b as defined in any one of claims 1 to 3, or as an intermediate in the synthesis of retinol, a stereoisomer thereof, a derivative thereof, or a stereoisomer of a derivative thereof, the derivative of retinol being preferably selected from the group consisting of retinol esters, retinal and retinoic acid.

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