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

Abstract

The present invention provides compounds of formula (Ia) and (Ib) (R 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] TIFF2025528382000031.tif31170

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 their esters of formulae Ia and Ib, as defined below, by subjecting isoprenol or its esters of formula II.a, as defined below, to photooxidation in the presence of a photosensitizer and an acylating agent. 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 its esters; specific hydroperoxides of formula 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 its esters. [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., without the use 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. Summary of the Invention

[0014] 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 an acylating agent, or by photooxidizing isoprenol or an ester thereof in the presence of a photosensitizer and subsequently reacting the hydroperoxide formed by the photooxidation with an acylating agent.

[0015] The present invention therefore relates to a process for the preparation of a compound of formula Ia or formula 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, which comprises [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 an acylating agent; (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 acylating agent was provided in step (i), adding an acylating agent 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 (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 give 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:

[0016] 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 formula Ia and / or Ib, or the use of a mixture of different compounds Ia and / or Ib as defined above as intermediates in the synthesis of retinol, its stereoisomers, derivatives thereof (especially when the derivatives are esters thereof), or stereoisomers of its derivatives (especially when the derivatives are esters thereof).

[0017] 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 1 is -C(=O)R 2and;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; The 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 described 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

[0018] 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 -It is.

[0019] Chlorinated C1-C2-alkanes are methane or ethane in which some or all of the hydrogen atoms have been replaced by 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.

[0020] 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]

[0021] 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.

[0022] Similarly, the stereoisomers of compound III.b are mainly the E isomer (E)-III.b and the Z isomer (Z)-III.b. [ka]

[0023] 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.

[0024] 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 base -C(=O)R 2 and R 2C4-C with one or more stereocenters such as sec-butyl 20 - alkyl group.

[0025] 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.

[0026] A mixture of compounds Ia or Ib is a mixture of two or more different compounds Ia (compound Ia is R 1a mixture of two or more different compounds Ib (wherein R 1 a mixture of compounds Ia and Ib (where the groups R 1 have the same meaning); a mixture of compound Ia and compound Ib (in compounds Ia and Ib, R 1 The group R has a different meaning; 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.

[0027] The same definition applies to mixtures of compounds III.a, III.b or III.c.

[0028] 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.

[0029] "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).

[0030] 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).

[0031] 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).

[0032] 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.

[0033] 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.

[0034] E.1. Method for preparing compounds of formula Ia or 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 an acylating agent; (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 acylating agent was provided in step (i), adding an acylating agent 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 (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.a, R 1 -C(=O)R 2 The method of any one of embodiments E.1 to E.4, wherein E.6. The acylating agent used in step (i) or (iii) is a carboxylic acid halide R 2a -C(=O)-X, carboxylic acid anhydride R 2a -C(=O)-OC(=O)-R 2a , and ketene R 2a -C(H)=C=O(in the formula, R 2a may independently be R in any of embodiments E.1 to E.4. 2 and X is Cl, Br, or I. E.7. The acylating agent used in step (i) or (iii) is a carboxylic acid anhydride R 2a -C(=O)-OC(=O)-R 2a (In the formula, R 2a is C1-C4-alkyl. E.8. The acylating agent used in step (i) or (iii) is a carboxylic acid anhydride R 2a -C(=O)-OC(=O)-R 2a [In the formula, R 2ais methyl (and thus the acylating agent is acetic anhydride)]. E.9. The molar ratio of the compound of Formula II.a to the acylating agent is R 1 -C(=O)R 2 In the case of 1 The method of any one of embodiments E.1 to E.8, wherein when is hydrogen, it is 10:1 to 1:5. E.10. The molar ratio of the compound of Formula II.a to the acylating agent is R 1 -C(=O)R 2 In this case, the ratio is 5:1 to 1:5, and R 1 10. The method of embodiment 9, wherein when is hydrogen, it is 1:1 to 1:5. E.11. The molar ratio of the compound of Formula II.a to the acylating agent is R 1 -C(=O)R 2 In the case of 1 The method of embodiment E.10, wherein when is hydrogen, it is 1:1.1 to 1:3. E.12. The molar ratio of the compound of Formula II.a to the acylating agent is R 1 -C(=O)R 2 In the case of 1 The method of embodiment E.11, wherein when is hydrogen, it is 1:1.5 to 1:3. E.13. 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 according to any of embodiments E.1 to E.12, wherein the compound is selected from the group consisting of a salt, cercosporin, hypocrellin-A, and mixtures thereof. E.14. 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.13, wherein the compound is selected from the group consisting of salts. E.15. Photosensitizers include tetraphenylporphyrin, zinc-tetraphenylporphyrin, and Ru(bpy)3. 2+ The method of embodiment E.14, wherein the compound is selected from the group consisting of salts. E.16. The method of any of embodiments E.1-E.15, wherein in step (ii), additional photosensitizer is added if depleted during irradiation. E.17. The method of any of embodiments E.1 to E.16, 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.18. The method of embodiment E.17, 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.19. The method of any of embodiments E.1 to E.16, 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.20. The method of embodiment E.19, 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.21. The method of embodiment E.20, wherein the photosensitizer is used in a total amount of 0.0001 to 0.005 mol per mol of the compound of formula II.a. E.22. The method of any one of embodiments E.1 to E.21, wherein in step (ii), the reaction mixture is irradiated with light in the wavelength range of 350 to 800 nm. E.23. The method of embodiment E.22, wherein in step (ii), the reaction mixture is irradiated with light in the wavelength range of 350 to 680 nm. E.24. The method of embodiment E.23, wherein in step (ii), the reaction mixture is irradiated with light in the wavelength range of 400 to 650 nm. E.25. The method of embodiment E.24, wherein in step (ii), the reaction mixture is irradiated with light in the wavelength range of 400 to 580 nm. E.26. The method of embodiment E.25, wherein in step (ii), the reaction mixture is irradiated with light in the wavelength range of 400 to 500 nm. E.27. 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.14 to E.26, 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.28. The method of any one of embodiments E.1-E.27, wherein in step (ii), the reaction mixture is irradiated with monochromatic light. E.29. The method of embodiment E.28, 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.30. The method of embodiment E.29, 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 680 nm. E.31. The method of embodiment E.30, 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 400 to 650 nm. E.32. The method of embodiment E.31, 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 400 to 580 nm. E.33. The method of embodiment E.32, 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 400 to 500 nm. E.34. The method of any one of embodiments E.28 to E.33, wherein the irradiating in step (ii) is performed using an electroluminescent lighting device that emits monochromatic light, the electroluminescent lighting device consisting of at least one LED. E.35. The method of any of embodiments E.1 to E.34, wherein the oxygen-containing gas used in step (ii) is selected from the group consisting of oxygen, air, and a mixture (i.e., oxygen and nitrogen) containing oxygen in the range of 1 to 99% by weight, based on the total weight of the mixture of oxygen and nitrogen. E.36. The method of embodiment E.35, wherein the oxygen-containing gas used in step (ii) is oxygen, air, or a mixture containing oxygen in the range of 20 to 99 wt. % based on the total weight of the mixture of oxygen and nitrogen. E.37. The method of embodiment 36, wherein the oxygen-containing gas used in step (ii) is oxygen. E.38. The method of any one of embodiments E.1-E.37, wherein step (ii) is performed neat. E.39. The method of any of embodiments E.1 to E.37, wherein step (ii) is 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 30:1 to 1:1.5, preferably from 10:1 to 1:1.5. E.40. The method of embodiment E.39, wherein the molar ratio of compound (II.a) provided in step (i) to chlorinated C1-C2-alkane is from 5:1 to 1:1. E.41. The method of embodiment E.39 or E.40, wherein the chlorinated C1-C2-alkane is trichloromethane or tetrachloromethane. E.42. In step (i), an acylating agent is provided, and the acylating agent is converted to a carboxylic acid halide R 2a -C(=O)-X or carboxylic acid anhydride R 2a -C(=O)-OC(=O)-R 2a where step (ii) is carried out in the presence of a base, and if no acylating agent is provided in step (i), the acylating agent added in step (iii) is a carboxylic acid halide R 2a -C(=O)-X or carboxylic acid anhydride R 2a -C(=O)-OC(=O)-R 2a The method of any one of embodiments E.1 to E.41, wherein a base is also added to the reaction mixture obtained in step (ii). E.43. The method of embodiment E.42, wherein the base is an organic base. E.44. The method of embodiment E.43, wherein the base is selected from tertiary amines, basic 3- to 10-membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic heterocycles containing 1, 2, 3, or 4 nitrogen atoms as ring members, guanidines, and amidines. E.45. Bases are - Formula N(R 3 ) 3 tertiary amines (wherein each R 3 are independently C1-C4 alkyl; - 3-8 membered saturated monocyclic or bridged heterocyclic rings containing one or two nitrogen atoms or one nitrogen atom and one oxygen atom as ring members; in particular those of the formula NR 31 (R 32 )2, a compound of formula (wherein R 31 is hydrogen or C1-C4-alkyl, and two R 32 together form the bridging group -(CH2) n - (where n is 2, 3, 4 or 5), or together form a bridging group -(CH2)2-N(R 33 )-(CH2)2- or -(CH2)2-O-(CH2)2- (wherein R 33is hydrogen or C1-C4-alkyl); or DABCO; - 5-10-membered monocyclic or bicyclic heteroaromatic rings containing 1 or 2 nitrogen ring atoms as ring members; in particular selected from the group consisting of imidazole, pyridine, pyrazine, pyridazine, pyrimidine, quinolone and isoquinoline; the monocyclic or bicyclic heteroaromatic rings are unsubstituted or carry 1, 2 or 3 C1-C4-alkyl substituents; - Formula (R 3 )2N-C(=NR 3 )-N(R 3 )2 guanidines, wherein each R 3 are independently C1-C4 alkyl or two R's attached to the same nitrogen atom or to different nitrogen atoms; 3 are taken together to form the bridging group -(CH2) n guanidine, wherein n is 2, 3, 4, or 5; and - bicyclic amidine DBN or DBU The method of embodiment E.44, wherein the compound is selected from the group consisting of: E.46. The method of embodiment E.45, wherein if an acylating agent is provided in step (i), step (ii) is carried out in the presence of a base selected from 5-10 membered monocyclic or bicyclic heteroaromatic rings containing 1 or 2 nitrogen ring atoms as ring members. E.47. The method of embodiment E.6, wherein the base is selected from the group consisting of imidazole, pyridine, pyrazine, pyridazine, pyrimidine, quinolone and isoquinoline; the monocyclic or bicyclic heteroaromatic ring is unsubstituted or has 1, 2 or 3 C1-C4-alkyl substituents; in particular pyridine which is unsubstituted or has 1, 2 or 3 C1-C4-alkyl substituents. E.48. The method of embodiment E.47, wherein the base is selected from pyridine, picoline, lutidine, collidine, and mixtures thereof. E.49. The method of embodiment E.48, wherein the base is pyridine. E.50. The method of any one of embodiments E.42 to E.49, wherein the molar ratio of the compound of Formula II.a to the base is 5:1 to 1:5. E.51. The method of embodiment E.50, wherein the molar ratio of the compound of Formula II.a to the base is 3:1 to 1:3. E.52. The method of embodiment E.51, wherein the molar ratio of the compound of Formula II.a to the base is 2:1 to 1:2. E.53. The method of embodiment E.52, wherein the molar ratio of the compound of Formula II.a to the base is 1.5:1 to 1:2, for example, 1.5:1 to 1:1.5. E.54. The method of any of embodiments E.1 to E.53, wherein if an acylating agent is provided in step (i), step (ii) is carried out in the presence of an acylation catalyst, and if no acylating agent is provided in step (i), then in step (iii) an acylation catalyst is also added to the reaction mixture obtained in step (ii). E.55. Acylation catalysts include 4-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine (PPY), 1,6-dibenzyl-2,3,5,6-tetrahydro-1H,4H-1,3a,6,8-tetraazaphenalene (Super DMAP), and acylation catalysts of the following general formula: [ka] (In the formula, each R 4 is independently selected from the group consisting of methyl or ethyl. E.56. The method of embodiment E.55, wherein the acylation catalyst is 4-dimethylaminopyridine (DMAP). E.57. The method of any one of embodiments E.52 to E.56, wherein the molar ratio of the compound of Formula II.a to the acylation catalyst is from 200:1 to 1:1. E.58. The method of embodiment E.57, wherein the molar ratio of the compound of Formula II.a to the acylation catalyst is 200:1 to 5:1. E.59. The method of embodiment E.58, wherein the molar ratio of the compound of Formula II.a to the acylation catalyst is 150:1 to 10:1. E.60. The method of any one of embodiments E.1 to E.59, wherein step (ii) is carried out at a temperature of -20 to 150°C. E.61. The method of embodiment E.60, wherein step (ii) is carried out at 0 to 70°C, for example, 0 to 60°C or 5 to 50°C. E.62. The method of any one of embodiments E.1-E.61, wherein step (ii) is carried out at a pressure from atmospheric to 100 bar (10 MPa). E.63. The method of embodiment E.62, wherein step (ii) is carried out at >1 to 10 bar (>0.1 to 1 MPa). E.64. The method of embodiment E.63, wherein step (ii) is carried out at 1.5 to 8 bar (0.15 to 0.8 MPa). E.65. The method of embodiment E.64, wherein step (ii) is carried out at 5 to 20 bar (0.5 to 2 MPa). E.66. The method of embodiment E.65, wherein step (ii) is carried out at 10 to 15 bar (1 to 1.5 MPa). E.67. The method of embodiment E.66, wherein step (ii) is carried out at atmospheric pressure. E.68. The method of any one of embodiments E.1 to E.67, wherein in step (ii), the complete reaction mixture or only a distinct portion of the reaction mixture is irradiated. E.69. The method of any one of embodiments E.1 to E.68, wherein step (ii) is carried out in a side loop photoreactor, a continuous flow photoreactor, or a submerged photoreactor. E.70. The method of any one of embodiments E.1 to E.69, wherein in step (i), an acylating agent, a base, and optionally an acylation catalyst are provided [step (iii) is not performed]. E.71. The method of embodiment E.70, wherein in step (i), an acylating agent, an acylation catalyst, and optionally a base are provided [step (iii) is not performed]. E.72. 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.73. 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.74.R 2 The hydroperoxide compound according to embodiment E.73, wherein is C1-C4-alkyl. E.75.R 2 The hydroperoxide compound according to embodiment E.74, wherein is methyl. E.76. The hydroperoxide compound according to any of embodiments E.73 to E.75, 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.77. The hydroperoxide compound according to any of embodiments E.73 to E.75, 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 III.c. E.78. The hydroperoxide compound according to any of embodiments E.73 to E.75, 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.79. 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 as defined in any of embodiments E.73 to E.75 (but 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 of formula Ia and / or Ib as defined in 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.80. Use 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, according to embodiment E.79. E.81. 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, according to embodiment E.79.

[0035] 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] Kornblum-DeLaMare rearrangement (which is actually an elimination reaction; here it is a dehydroacylation).

[0036] 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 the acylating agent is provided in step (i). Naturally, in this case, step (iii) is not performed. Without wishing to be bound by theory, it is assumed that in step (ii), the compound of formula II.a is converted to an allylic hydroperoxide that is acylated in situ with the acylating agent. The acylated hydroperoxide is then dehydrated in situ, or more precisely, dehydroacylated, to give compounds Ia and / or Ib. It is assumed 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.

[0037] 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 an acylating agent is not provided in step (i). In this case, step (iii) is mandatory. During step (ii), a hydroperoxide is formed, which is acylated in step (iii) by the addition of an acylating agent and further reacts to give compounds Ia and / or Ib as described above.

[0038] Considering the safety risks associated with the formation of hydroperoxides and longer storage times, as well as simpler handling, the first option, i.e., converting the compound of formula II.a to compounds Ia and / or Ib in one step by providing a reaction mixture comprising an acylating agent in step (i), is preferred.

[0039] Therefore, 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 Ib, or a mixture of different stereoisomers of compound 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 an acylating agent; (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:

[0040] 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.

[0041] R 1 is preferably —C(═O)R, especially in compounds II.a. 2 is.

[0042] The acylating agent used in step (i) or (iii) can be essentially any substance capable of acylating the hydroperoxide formed in the reaction of compound II.a with oxygen. Typical acylating agents are carboxylic acids, carboxylic acid activated esters, carboxylic acid halides, carboxylic acid anhydrides and ketenes. Preferably, the acylating agent is a carboxylic acid halide R 2a -C(=O)-X, carboxylic acid anhydride R 2a -C(=O)-OC(=O)-R 2a , and ketene R 2a -C(H)=C=O, wherein R 2a are independently 2and X is Cl, Br, or I. More preferably, the acylating agent used in step (i) or (iii) is a carboxylic acid anhydride. R 2a -C(=O)-OC(=O)-R 2a , and even more preferably carboxylic acid anhydrides R 2a -C(=O)-OC(=O)-R 2a (In the formula, R 2a is C1-C4-alkyl), in particular carboxylic acid anhydrides R 2a -C(=O)-OC(=O)-R 2a (In the formula, R 2a is methyl), and therefore the carboxylic acid anhydride is acetic anhydride.

[0043] The acylating agent is provided in an amount such that at least a portion of the hydroperoxide groups formed are acylated. 1 is hydrogen, the alcohol group OR 1 Acylation of the =OH groups competes with acylation of the hydroperoxide groups, so in this case it is advantageous to use the acylating agent in an amount large enough to allow acylation of at least a portion of the hydroperoxide groups.

[0044] Preferably, the acylating agent is selected from the group consisting of a compound of formula II.a and a hydroxy group, the molar ratio of which to the acylating agent is R 1 -C(=O)R 2 In the case of 1 is hydrogen, it is provided in an amount such that it is 10:1 to 1:5. More preferably, the molar ratio of the compound of formula II.a to the acylating agent is 1 -C(=O)R 2 In the case of 1 is hydrogen, it is 1:1 to 1:5. Even more preferably, the molar ratio of compound of formula II.a to acylating agent is 1 -C(=O)R 2 In the case of 1In particular, the molar ratio of the compound of formula II.a to the acylating agent is 1:1.1 to 1:3 when R is hydrogen. 1 -C(=O)R 2 In the case of 1 When is hydrogen, the ratio is 1:1.5 to 1:3.

[0045] The above ratios relate to the amount of compound II.a provided in step (i), taking into account the preferred embodiments described above or below in which the reaction is carried out so that only a portion of compound II.a is converted.

[0046] 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 assumes 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).

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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. By total amount is meant 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 % relative to 1 mol of the compound of formula II.a.

[0051] 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 0.000005 to 0.01 mol, particularly preferably 0.00001 to 0.005 mol, and in particular 0.0001 to 0.005 mol, per 1 mol of compound of formula II.a.

[0052] 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.

[0053] 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, be determined by short-term trials if not known to the skilled person or can be selected by UV spectroscopy.

[0054] 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.

[0055] In step (ii), the reaction mixture is preferably irradiated with monochromatic light.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] "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.

[0061] If an acylating agent is provided in step (i), step (ii) is preferably carried out in the presence of a base, especially when the acylating agent is a carboxylic acid halide or anhydride. The base in this case is particularly suitable for cleaving the formed acid (HX or R 2a COOH). The base is preferably an organic base. In this case, step (i) preferably comprises providing a reaction mixture comprising a compound of formula II.a, a photosensitizer, an acylating agent and a base, preferably an organic base.

[0062] If no acylating agent was provided in step (i), then in step (iii), a base, preferably an organic base, is also added to the reaction mixture obtained in step (ii), particularly when the acylating agent is a carboxylic acid halide or a carboxylic acid anhydride. In this case, step (iii) preferably comprises adding the acylating agent and a base, preferably an organic base, to the reaction mixture obtained in step (ii).

[0063] The organic base preferably added in step (i) or (iii) is preferably selected from tertiary amines, basic 3-10 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocycles containing 1, 2, 3 or 4 nitrogen atoms as ring members, guanidines and amidines.

[0064] More preferably, the base is: - Formula N(R 3 )3(in the formula, each R 3 are independently C1-C4 alkyl); - 3-8 membered saturated monocyclic or bridged heterocyclic rings containing one or two nitrogen atoms or one nitrogen atom and one oxygen atom as ring members; in particular, rings of the formula NR 31 (R 32 )2, a compound of formula (wherein R 31 is hydrogen or C1-C4-alkyl, and two R 32 are taken together to form the bridging group -(CH2) n - (where n is 2, 3, 4 or 5), or together form a bridging group -(CH)-N(R 33 )-(CH2)2- or -(CH2)2-O-(CH2)2- (wherein R 33 is hydrogen or C1-C4-alkyl); or DABCO; - 5-10-membered monocyclic or bicyclic heteroaromatic rings containing 1 or 2 nitrogen ring atoms as ring members; in particular selected from the group consisting of imidazole, pyridine, pyrazine, pyridazine, pyrimidine, quinolone and isoquinoline; the monocyclic or bicyclic heteroaromatic rings are unsubstituted or carry 1, 2 or 3 C1-C4-alkyl substituents; - Formula (R 3 )2N-C(=NR 3 )-N(R 3 )2 guanidines, wherein each R 3 are independently C1-C4 alkyl or two R's attached to the same nitrogen atom or to different nitrogen atoms; 3 are taken together to form the bridging group -(CH2) nguanidine, wherein n is 2, 3, 4, or 5; and bicyclic amidines selected from the group consisting of DBN or DBU;

[0065] Each R 3 are independently C1-C4-alkyl; 3 Examples of tertiary amines include trimethylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine (Hunig's base), and the like.

[0066] Examples of 3- to 8-membered saturated monocyclic or bridged heterocyclic rings containing one or two nitrogen atoms, or one nitrogen atom and one oxygen atom as ring members, include piperidine, 1-methylpiperidine, 1-ethylpiperidine, piperazine, morpholine, 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.

[0067] Examples of 5-10 membered monocyclic or bicyclic heteroaromatic rings containing one or two nitrogen ring atoms as ring members and one, two or three unsubstituted or substituted C1-C4 alkyl substituents include imidazole, pyridine, picoline, lutidine, pyrazine, pyridazine, pyrimidine, quinolone and isoquinoline.

[0068] When step (ii) is carried out in the presence of a base, the latter is advantageously chosen from 5-10 membered mono- or bicyclic heteroaromatic rings containing 1 or 2 nitrogen ring atoms as ring members (thus, conveniently, when step (ii) is carried out in the presence of a base, the reaction mixture provided in step (i) advantageously contains a base chosen from 5-10 membered mono- or bicyclic heteroaromatic rings containing 1 or 2 nitrogen ring atoms as ring members), although this may be in addition to some other bases, in particular compounds of formula N(R 3) 3 because the tertiary amine may negatively interfere in the photooxidation reaction. More preferably, the base is selected from the group consisting of imidazole, pyridine, pyrazine, pyridazine, pyrimidine, quinolone and isoquinoline; the monocyclic or bicyclic heteroaromatic ring is unsubstituted or has 1, 2 or 3 C1-C4 alkyl substituents; particularly preferred is pyridine, which is unsubstituted or has 1, 2 or 3 C1-C4 alkyl substituents. In particular, the base is selected from pyridine, picoline (i.e., 2-methylpyridine, 3-methylpyridine, 4-methylpyridine or mixtures thereof), lutidine (i.e., 2,3-dimethylpyridine, 2,4-dimethylpyridine, 2,5-dimethylpyridine, 2,6-dimethylpyridine, 3,4-dimethylpyridine, 3,5-dimethylpyridine or mixtures thereof), collidine (i.e., 2,3,3-trimethylpyridine, 2,3,5-trimethylpyridine, 2,3,6-trimethylpyridine, 2,4,5-trimethylpyridine, 2,4,6-trimethylpyridine, 3,4,5-trimethylpyridine and mixtures thereof) and mixtures thereof, and even more particularly is pyridine.

[0069] If no acylating agent is provided in step (i) and step (iii) is carried out, preferably the base added in step (iii) may be any of the organic bases mentioned above, since negative interference in the photooxidation reaction may occur in this setup, however, the same bases as those mentioned above for the base added in step (i) are nevertheless preferred.

[0070] The base is preferably used in an amount such that the molar ratio of compound of formula II.a to base is preferably 5:1 to 1:5, more preferably 3:1 to 1:3, even more preferably 2:1 to 1:2, in particular 1.5:1 to 1:2 or 1.5:1 to 1:1.5.

[0071] If an acylating agent is provided in step (i), step (ii) is preferably carried out in the presence of an acylation catalyst. In this case, step (i) preferably comprises providing a reaction mixture comprising a compound of formula II.a, a photosensitizer, an acylating agent, an acylation catalyst, and optionally a base, preferably an organic base (different from the acylation catalyst; see below). More preferably, step (i) comprises providing a reaction mixture comprising a compound of formula II.a, a photosensitizer, an acylating agent, an acylation catalyst, and a base, preferably an organic base (different from the acylation catalyst; see below).

[0072] If no acylating agent is provided in step (i), then in step (iii), an acylation catalyst is preferably also added to the reaction mixture obtained in step (ii). In this case, step (iii) preferably comprises adding an acylating agent, an acylation catalyst, and optionally a base, preferably an organic base (different from the acylation catalyst; see below), to the reaction mixture obtained in step (ii). More preferably, step (iii) comprises adding an acylating agent, an acylation catalyst, and a base, preferably an organic base (different from the acylation catalyst; see below), to the reaction mixture obtained in step (ii).

[0073] Preferably, the acylation catalyst is 4-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine (PPY), 1,6-dibenzyl-2,3,5,6-tetrahydro-1H,4H-1,3a,6,8-tetraazaphenalene (Super DMAP), and an acylation catalyst of the general formula: [ka] (In the formula, each R 4 is independently methyl or ethyl).

[0074] More preferably, the acylation catalyst is 4-dimethylaminopyridine (DMAP).

[0075] The acylation catalyst is preferably used in an amount such that the molar ratio of compound of formula II.a to acylation catalyst is preferably from 200:1 to 1:1, more preferably from 200:1 to 5:1, in particular from 150:1 to 10:1.

[0076] Preferably, step (ii) is 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 further the hydroperoxide or optional base formed as an intermediate can function as a solvent or dispersant for the photosensitizer, acylating agent, if present, the optionally present acylation catalyst, and the optionally present base (if the latter does not act as a solvent). 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, acylating agent if the reaction is carried out in one step, optionally acylation catalyst, optionally base) 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).

[0077] In an alternatively preferred embodiment, step (ii) is carried out in the presence of a chlorinated C1-C2-alkane. To this end, the chlorinated C1-C2-alkane is conveniently provided in the reaction mixture of step (i). The molar ratio of compound (II.a) to the chlorinated C1-C2-alkane provided in step (i) is 30:1 to 1:1.5, preferably 10:1 to 1:1.5, more preferably 5:1 to 1:1. The chlorinated C1-C2-alkane is preferably trichloromethane or tetrachloromethane.

[0078] More preferably, however, step (ii) is carried out neat.

[0079] In a preferred embodiment of the method of the present invention, in step (i), compound II.a, an acylating agent, a photosensitizer, a base, and optionally an acylation catalyst are provided (step (iii) is not performed), and step (ii) is performed neat. More preferably, in step (i), compound II.a, a photosensitizer, an acylating agent, a base, and an acylation catalyst are provided (step (iii) is not performed), and step (ii) is performed neat. In a particular embodiment, in step (i), compound II.a, a photosensitizer {particularly TPP, Zn-TPP, or Ru(bpy)3 2+ In step (i), compound II.a, a photosensitizer {e.g., tris(2,2'-bipyridine)ruthenium(II) hexafluorophosphate or tris(2,2'-bipyridine)ruthenium(II) chloride}, acetic anhydride, pyridine or a pyridine having one, two, or three methyl groups, and optionally DMAP are provided (step (iii) is not performed), and step (ii) is performed neat. More specifically, in step (i), compound II.a, a photosensitizer {e.g., TPP, Zn-TPP, or Ru(bpy)3 2+ In step (i), compound II.a, a photosensitizer {e.g., TPP, Zn-TPP, or Ru(bpy)3}, a salt [e.g., tris(2,2'-bipyridine)ruthenium(II) hexafluorophosphate or tris(2,2'-bipyridine)ruthenium(II) chloride], acetic anhydride, pyridine or a pyridine having one, two, or three methyl groups, and DMAP are provided (step (iii) is not performed), and step (ii) is performed neat. Even more particularly, in step (i), compound II.a, a photosensitizer {e.g., TPP, Zn-TPP, or Ru(bpy)3}, 2+ A salt [e.g., tris(2,2'-bipyridine)ruthenium(II) hexafluorophosphate or tris(2,2'-bipyridine)ruthenium(II) chloride], acetic anhydride, pyridine, and DMAP are provided [step (iii) is not performed], and step (ii) is performed neat.

[0080] Step (ii) is preferably carried out at a temperature of -20 to 150°C, more preferably 0 to 70°C, for example 0 to 60°C or 5 to 50°C.

[0081] 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 > 1 to 10 bar (> 0.1 to 1 mPa), in particular 1.5 to 8 bar (0.15 to 0.8 MPa). In another even more preferred embodiment, step (ii) is carried out at a pressure of 5 to 20 bar (0.5 to 2 MPa), in particular 10 to 15 bar (1 to 1.5 MPa). In yet another even more preferred embodiment, step (ii) is carried out at atmospheric pressure.

[0082] In step (ii), the entire reaction mixture or only a distinct portion of the reaction mixture is irradiated, which occurs, 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.

[0083] Step (ii) 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.

[0084] Examples of suitable reactors include a side loop photoreactor, a continuous flow photoreactor, or a submerged photoreactor.

[0085] 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, such as 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.

[0086] If no acylating agent is added in step (i) and step (iii) is therefore carried out, after the reaction of step (ii) has reached the desired degree of completion, an acylating agent, optionally an acylation catalyst and optionally a base are added to the reaction mixture obtained in step (ii). For safety reasons, it is advantageous to use the reaction mixture directly in step (iii) rather than isolating the hydroperoxide produced in step (ii) before subjecting it to the acylation / dehydroacylation step (iii).

[0087] Step (iii) can be carried out neat (= reagents only) or in the presence of a solvent. In general, most common solvents can be used. Suitable solvents are, for example, aliphatic hydrocarbons, such as pentane, hexane or heptane; cycloaliphatic hydrocarbons, such as cyclohexane, cycloheptane or cyclooctane; aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated aliphatic hydrocarbons, such as chlorinated C1-C2-alkanes, for example 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; or chloro-fluoro-C1-C2-alkanes, for example fluorotrichloromethane; aromatic hydrocarbons, such as chlorobenzene, dichlorobenzene or hexafluorobenzene; C1-C4-alkanols, for example methanoic acid, methyl ... open-chain ethers, for example diethyl ether, di-n-propyl ether or methyl tert-butyl ether; cyclic ethers, for example tetrahydrofuran or 1,4-dioxane; ketones, for example acetone or ethyl methyl ketone; C1-C3-alkyl esters of C2-C3-carboxylic acids, for example methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate or propyl propionate; nitriles, for example acetonitrile; carboxamides, for example N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide or N,N-diethylacetamide; sulfoxides, for example dimethyl sulfoxide; or CS2. Among these, chlorinated C1-C2-alkanes, chloro-fluoro-C1-C2-alkanes and CS2 are preferred, with chlorinated C1-C2-alkanes being more preferred. Preferably, however, step (iii) is carried out neat. By "neat" or "reagents only" is meant that no additional solvent is present.With respect to "additional" in the specification, please refer to the comment above in relation to step (i).

[0088] In a preferred embodiment of the method of the present invention, in step (i), compound II.a, an acylating agent, a photosensitizer, a base, and optionally an acylation catalyst are provided (step (iii) is not performed), and step (ii) is performed neat. More preferably, in step (i), compound II.a, a photosensitizer, an acylating agent, a base, and an acylation catalyst are provided (step (iii) is not performed), and step (ii) is performed neat. In a particular embodiment, in step (i), compound II.a, a photosensitizer {particularly TPP, Zn-TPP, or Ru(bpy)3 2+ In step (i), compound II.a, a photosensitizer {e.g., tris(2,2'-bipyridine)ruthenium(II) hexafluorophosphate or tris(2,2'-bipyridine)ruthenium(II) chloride}, acetic anhydride, pyridine or a pyridine having one, two, or three methyl groups, and optionally DMAP are provided (step (iii) is not performed), and step (ii) is performed neat. More specifically, in step (i), compound II.a, a photosensitizer {e.g., TPP, Zn-TPP, or Ru(bpy)3 2+ In step (i), compound II.a, a photosensitizer {e.g., TPP, Zn-TPP, or Ru(bpy)3}, a salt [e.g., tris(2,2'-bipyridine)ruthenium(II) hexafluorophosphate or tris(2,2'-bipyridine)ruthenium(II) chloride], acetic anhydride, pyridine or a pyridine having one, two, or three methyl groups, and DMAP are provided (step (iii) is not performed), and step (ii) is performed neat. Even more particularly, in step (i), compound II.a, a photosensitizer {e.g., TPP, Zn-TPP, or Ru(bpy)3}, 2+ A salt [e.g., tris(2,2'-bipyridine)ruthenium(II) hexafluorophosphate or tris(2,2'-bipyridine)ruthenium(II) chloride], acetic anhydride, pyridine, and DMAP are provided [step (iii) is not performed], and step (ii) is performed neat.

[0089] 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 carried out neat. In this case, it is advantageous to explicitly stop the reaction before maximum conversion of II.a.

[0090]

[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, e.g., by neutralization, if necessary or desired, and isolation of the desired reaction products Ia and / or Ib [(step (iv.1)]] from further components of the reaction mixture, such as unreacted compound II.a, acylating agent, base and acylation catalyst or undesired by-products, and, if desired, from one another. Separation can be carried out by conventional means, such as extraction, distillation or chromatographic methods.

[0091] If compounds Ia or Ib are formed as different stereoisomers, these can be separated from one another if desired.

[0092] 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 1is 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.

[0093] 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.

[0094] 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 ...

[0095] 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 to retinol, its stereoisomers, derivatives thereof [preferably esters thereof; in particular, a compound in which the OH group of retinol is -OC(O)R 2or 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 2 This invention relates to the use of a mixture of different compounds Ia and / or Ib as defined above as intermediates in the synthesis of Ib, which is an ester esterified to Ia. As 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, in H. Ernst, U.S. Pat. No. 5,087,762, in Pure Appl. Chem. 2002, 74, 2213, or in 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 Other retinol derivatives, which can be made into the stereoisomers of the esters thereof, 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 oxidizing 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.

[0096] The present invention further relates to hydroperoxide compounds of formula III.a, III.b or III.c, or to stereoisomers of compounds of formula III.a, III.b or III.c, or to mixtures of different stereoisomers of compounds III.a and / or III.b and / or III.c, or to 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]

[0097] 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.

[0098] 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.

[0099] 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, and / or to a mixture of different compounds III.a and / or III.c.

[0100] 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.

[0101] 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 of formula 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.

[0102] 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.

[0103] 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 of formula 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.

[0104] 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.

[0105] The following examples further illustrate the present invention. [Example]

[0106] 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, 500 MHz, and 700 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.

[0107] 1. Simultaneous Photooxidation of Isoprenyl Acetate and Kornblum-DeLaMare Rearrangement in a Double-Jacketed Reactor Examples 1 to 4 Apparatus: double-jacketed vessel, cylindrical 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.

[0108] In a 50 mL glass vial, add isoprenyl acetate [IPA; 1 A mixture of 12.46 g (97.2 mmol, 1 eq) of compound II.a (=-C(O)CH), 6.15 g (77.7 mmol, 0.8 eq) of pyridine, and 3.96 g (38.8 mmol, 0.4 eq) of acetic anhydride was prepared. 0.68 g (3.5 mmol, 0.036 eq) of dimethyl phthalate (internal NMR standard), 0.21 g (1.75 mmol, 0.018 eq) of N,N-dimethylaminopyridine (DMAP) (Example 4: 0.009 eq of DMAP), and 4.4 μmol (0.000045 eq) of a photosensitizer (tetraphenylporphyrin (TPP) in Examples 1, 2, and 4, zinc tetraphenylporphyrin (Zn-TPP) in Example 3, and 0.000067 eq of TPP in Example 4) were dissolved in the mixture. The reaction mixture was poured into a temperature-controlled double-jacket vessel and stirred at 1000 rpm. The solution was irradiated from below for 6 hours while introducing 2 L / h of oxygen into the solution at the temperature shown in the table below. Up to 34 μmol of photosensitizer was added in small increments during the reaction. The reaction was stopped explicitly before the complete conversion of isoprenyl acetate (the conversion rate for each experiment is shown in Table 1). At the end of the experiment, the reaction mixture was analyzed without further workup. No hydroperoxides were detected. The results are summarized in Table 1.

[0109] [Table 1]

[0110] 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)

[0111] Example 5 Apparatus: As in Examples 1 to 4, but illuminated from below by 24 LEDs with a wavelength of 465 nm, with a total radiant power of 31 W.

[0112] A mixture of 12.57 g (98 mmol, 1 eq) of isoprenyl acetate (IPA), 6.21 g (78.5 mmol, 0.8 eq) of pyridine, and 4.0 g (39.2 mmol, 0.4 eq) of acetic anhydride was prepared in a 50 mL glass bottle. 0.68 g (3.5 mmol, 0.036 eq) of dimethyl phthalate as an internal NMR standard, 0.1 g (0.87 mmol, 0.009 eq) of N,N-dimethylaminopyridine (DMAP), and 6.7 mg (7.8 μmol, 0.00008 eq) of tris-(2,2'-bipyridine)-ruthenium bis-(hexafluorophosphate) as a photosensitizer were dissolved in the mixture. The reaction solution was poured into a temperature-controlled double-jacketed vessel and stirred at 1000 rpm. The solution was irradiated from below at 12 °C for 6 h while introducing oxygen at 2 L / h. During the reaction, an additional 3.9 mg (4.5 μmol, 0.000046 eq) of photosensitizer was added. The reaction was stopped explicitly before the complete conversion of isoprenyl acetate (experimental conversions are shown in Table 2). At the end of the experiment, the reaction mixture was analyzed without further workup. No hydroperoxides were detected. The results are summarized in Table 2.

[0113] [Table 2]

[0114] Example 6 Apparatus: Same as in Examples 1 to 4.

[0115] A mixture of 7.1 g (55.4 mmol, 1 eq) of isoprenyl acetate (IPA), 6.11 g (77.2 mmol, 1.4 eq) of pyridine, and 3.94 g (38.6 mmol, 0.7 eq) of acetic anhydride was prepared in a 50 mL glass vial. 0.69 g (3.55 mmol, 0.064 eq) of dimethyl phthalate (internal NMR standard), 8.42 g (54.7 mmol, 0.99 eq) of carbon tetrachloride, 0.11 g (0.89 mmol, 0.016 eq) of N,N-dimethylaminopyridine, and 13.3 mg (21.6 μmol, 0.00039 eq) of tetraphenylporphyrin (photosensitizer) were dissolved in the mixture. The reaction solution was poured into a temperature-controlled double-jacketed vessel and stirred at 1000 rpm. The solution was irradiated from below for 6 hours at 32 °C while oxygen was introduced into the solution at 1.5 L / h. During the reaction, an additional 32.8 mg (53.4 μmol, 0.00096 eq) of photosensitizer was added portionwise. The reaction was stopped clearly before the complete conversion of isoprenyl acetate (the conversion of the experiment is shown in Table 3). At the end of the experiment, the reaction mixture was analyzed without further workup. No hydroperoxide was detected. The results are summarized in Table 3.

[0116] [Table 3]

[0117] 2. Simultaneous Photooxidation of Isoprenyl Acetate and Kornblum-DeLaMare Rearrangement in a Corning® G1 Reactor Equipment: Corning® G1 reactor (5 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), 100 mL mini-plant reactor as feed vessel, impeller agitator, gear pump.

[0118] Examples 7 to 9 A mixture of 83.0 g (647.5 mmol, 1 eq) of isoprenyl acetate (IPA), 40.73 g (515 mmol, 0.8 eq) of pyridine, and 26.28 g (259 mmol, 0.4 eq) of acetic anhydride was prepared in a 100 mL mini-plant reactor. 4.55 g (23.3 mmol, 0.036 eq) of dimethyl phthalate as an internal NMR standard, 2.86 g (11.66 mmol, 0.018 eq) of N,N-dimethylaminopyridine (DMAP), and 18 mg (29.1 μmol, 0.000045 eq) of tetraphenylporphyrin as a photosensitizer were dissolved in the mixture. The reaction solution was stirred at 100 rpm and pumped in a circuit to a Corning® reactor. The solution was irradiated for 6 hours while introducing 3 L / h of oxygen (Example 8: air; Example 9: 1:1 oxygen:nitrogen mixture) into the Corning® reactor at the temperature and pressure shown in Table 6. Up to 74 mg (120 μmol) of additional tetraphenylporphyrin was added in small increments during the reaction. The reaction was stopped explicitly before the complete conversion of isoprenyl acetate (the conversion rate for each experiment is shown in Table 4). At the end of the experiment, the reaction mixture was analyzed without further workup. No hydroperoxides were detected. The results are summarized in Table 4.

[0119] [Table 4]

[0120] Example 10 A mixture of 56.5 g (440.8 mmol, 1 eq) of isoprenyl acetate (IPA), 40.73 g (515 mmol, 1.16 eq) of pyridine, and 26.28 g (257 mmol, 0.58 eq) of acetic anhydride was prepared in a 100 mL mini-plant reactor. 4.55 g (23.4 mmol, 0.053 eq) of dimethyl phthalate as an internal NMR standard, 26.5 g (222 mmol, 0.5 eq) of chloroform, 2.86 g (23.41 mmol, 0.053 eq) of N,N-dimethylaminopyridine (DMAP), and 18.2 mg (29.6 μmol, 0.000067 eq) of tetraphenylporphyrin as a photosensitizer were dissolved in the mixture. The reaction solution was stirred at 100 rpm and pumped in a circuit to a Corning® reactor. The solution was irradiated for 6 hours at 30°C while 3 L / h of oxygen was introduced into the Corning® reactor at 1.9-2.4 bar. During the reaction, an additional 26.2 mg (42.8 μmol) of tetraphenylporphyrin was added portionwise. The reaction was stopped explicitly before complete conversion of isoprenyl acetate (experimental conversions are listed in Table 5). At the end of the experiment, the reaction mixture was analyzed without further workup. No hydroperoxides were detected. The results are summarized in Table 5.

[0121] [Table 5]

[0122] Example 11 A mixture of 43.25 g (337.4 mmol, 1 eq) of isoprenyl acetate (IPA), 40.73 g (515 mmol, 1.52 eq) of pyridine, and 26.29 g (257.5 mmol, 0.76 eq) of acetic anhydride was prepared in a 100 mL mini-plant reactor. 4.55 g (23.4 mmol, 0.069 eq) of dimethyl phthalate (internal NMR standard), 39.74 g (332.9 mmol, 0.99 eq) of chloroform, 2.86 g (23.41 mmol, 0.069 eq) of N,N-dimethylaminopyridine, and 18.2 mg (29.6 μmol, 0.000088 eq) of tetraphenylporphyrin (photosensitizer) were dissolved in the mixture. The reaction solution was stirred at 100 rpm and pumped into a Corning® reactor in a circuit. The solution was irradiated for 6 hours at 50°C while 3 L / h of oxygen was introduced into the Corning® reactor at 1.9-2.3 bar. During the reaction, an additional 20.3 mg (33.0 μmol) of tetraphenylporphyrin was added portionwise. The reaction was stopped explicitly before complete conversion of isoprenyl acetate (experimental conversions are listed in Table 6). At the end of the experiment, the reaction mixture was analyzed without further workup. No hydroperoxides were detected. The results are summarized in Table 6.

[0123] [Table 6]

[0124] 3. Simultaneous Photooxidation of Isoprenyl Acetate and Kornblum-DeLaMare Rearrangement in a Corning® G3 Reactor Equipment: Corning® G3 reactor (reinforced G3 plate, layer thickness approx. 1 mm, illuminated with LEDs on each side, total of 384 LEDs with wavelength 470 nm, total radiant power 576 W), feed vessel, gear pump.

[0125] Example 12 A mixture of 155 g (1209 mmol, 1 eq) of isoprenyl acetate (IPa), 76.6 g (0.8 eq) of pyridine, and 49.4 g (0.4 eq) of acetic anhydride was prepared in a 500 mL glass vial. 8.22 g (0.035 eq) of dimethyl phthalate as an internal NMR standard, 1.33 g (0.009 eq) of N,N-dimethylaminopyridine, and 79 mg (0.000076 eq) of tris-(2,2'-bipyridine)-ruthenium bis-(hexafluorophosphate) as a photosensitizer were dissolved in the mixture. The reaction solution was poured into a feed vessel and then pumped into a Corning® reactor, circulating at 1980 mL / min. The solution was irradiated at 18 °C for 6 h while introducing 3 L / h of oxygen at 5 bar into the Corning® reactor. The reaction was stopped explicitly before complete conversion of isoprenyl acetate (experimental conversions are listed in Table 7). At the end of the experiment, the reaction mixture was analyzed without further workup. No hydroperoxides were detected. The results are summarized in Table 7.

[0126] [Table 7]

[0127] Example 13 A mixture of 103.0 g (803.6 mmol, 1 eq) of isoprenyl acetate (IPA), 50.8 g (642.9 mmol, 0.8 eq) of pyridine, and 32.8 g (32.1 mmol, 0.4 eq) of acetic anhydride was prepared in a 500 mL glass vial. 5.48 g (28.2 mmol, 0.035 eq) of dimethyl phthalate as an internal NMR standard, 0.88 g (7.24 mmol, 0.009 eq) of N,N-dimethylaminopyridine, and 105.1 mg (122.3 μmol, 0.00015 eq) of tris-(2,2'-bipyridine)-ruthenium bis-(hexafluorophosphate) as a photosensitizer were dissolved in the mixture. The reaction solution was poured into a feed vessel and then pumped into a Corning® reactor, circulating at 1760 mL / min. The solution was irradiated at 18°C ​​for 6 hours while 3 L / h of oxygen at 5 bar was introduced into the Corning® reactor. The reaction was stopped explicitly before complete conversion of isoprenyl acetate (experimental conversions are listed in Table 8). At the end of the experiment, the reaction mixture was analyzed without further workup. No hydroperoxides were detected. The results are summarized in Table 8.

[0128] [Table 8]

[0129] 4. Photooxidation of isoprenyl acetate to isoprenyl acetate hydroperoxide Example 14 Equipment: Corning® G1 photoreactor (five reinforced G1 plates, layer thickness approximately 1 mm, illuminated on each side with LEDs, total of 200 LEDs with a wavelength of 405 nm, total radiant power 195 W), 100 mL mini-plant reactor, impeller agitator, gear pump.

[0130] 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 while introducing 3 L / h of oxygen at 1.7-2.4 bar into the Corning® reactor at the temperature shown in Table 9. The reaction was stopped explicitly before complete conversion of isoprenyl acetate (the conversion rate of the experiment is listed in Table 9). At the end of the experiment, the reaction mixture was analyzed without further workup. The results are summarized in Table 9.

[0131] [Table 9]

[0132] 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)

[0133] 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)

[0134] 5. Photooxidation of isoprenol to isoprenol hydroperoxide Example 15 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.

[0135] 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 isoprenyl acetate (the conversions of the experiment are listed in Table 10). At the end of the experiment, the reaction mixture was analyzed without further workup. The results are summarized in Table 10.

[0136] [Table 10]

[0137] III.a ++ : 1 H-NMR (400MHz, CDCl3): δ=5.24(1H),5.16(1H),4.47(2H),3.86(2H),2.41(2H)

[0138] Example 16 Apparatus: double-jacketed vessel, cylindrical 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.

[0139] 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 rates for the experiment are listed in Table 11). At the end of the experiment, the reaction mixture was analyzed without further workup. The results are summarized in Table 11.

[0140] [Table 11]

[0141] 6.R 1 Kornblum-DeLaMare rearrangement of III.a hydroperoxides with ═H Example 17 Apparatus: 0.25 l miniplant reactor equipped with impeller agitator, 4-fold baffle, ministat, dropping funnel.

[0142] Isoprenol hydroperoxide (R 110 g of a solution of 1.81 g (15.32 mmol) of compound III.a) in ═H in isoprenol was placed in a 250 ml mini-plant reactor, 133 g of dichloromethane was added, and then 33.48 g (423.26 mmol) of pyridine was added dropwise at 17°C over 10 minutes. After cooling to 3°C, 17.28 g (169.26 mmol) of acetic anhydride was added over 20 minutes. The reaction mixture was stirred at 0°C for 17.25 hours, and then 50 g of water was added over 30 minutes. The yellow-brown emulsion was heated to 22°C, the phases were separated, and the organic phase was extracted once with 10% HCl, once with saturated NaHCO3 solution, and once with water. The red-brown organic phase was then concentrated on a rotary evaporator at 40°C / 30 mbar. The R in isoprenyl acetate was obtained. 1 8.98 g of a solution of 1.68 g (11.8 mmol, 77%) of compound Ia, where is H, was obtained.

[0143] The yields given above are relative to the amount of starting compound (IPA or IP) 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 or IP conversion (not shown in the table above).

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 an acylating agent; (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 acylating agent was provided in step (i), adding an acylating agent to the reaction mixture obtained in step (ii); (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).

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. The acylating agent used in step (i) or (iii) is a carboxylic acid halide R ２ａ -C(=O)-X, carboxylic acid anhydride R ２ａ -C(=O)-O-C(=O)-R ２ａ , and ketene R ２ａ -C(H)=C=O (in the formula, R ２ａ are independently selected from R in any one of claims 1 to 3. ２ and X is Cl, Br or I.

5. The acylating agent used in step (i) or (iii) is a carboxylic acid anhydride R ２ａ -C(=O)-O-C(=O)-R ２ａ (In the formula, R ２ａ is C １ ~C ４ - alkyl, preferably methyl).

6. 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＋ The method of any one of claims 1 to 5, wherein the compound is selected from the group consisting of a salt, cercosporin, hypocrellin-A, and mixtures thereof.

7. The photosensitizers include tetraphenylporphyrin, cobalt-tetraphenylporphyrin, zinc-tetraphenylporphyrin, methylene blue, Ru(bpy), ３ ２＋ salt, and Ru(phen) ３ ２＋ Salts, preferably tetraphenylporphyrin, zinc-tetraphenylporphyrin, and Ru(bpy) ３ ２＋ 7. The method of claim 6, wherein the compound is selected from the group consisting of salts.

8. 8. The method according to any one of claims 1 to 7, 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.

9. 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＋ 9. The method according to claim 7 or 8, 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.

10. 10. The method according to any one of claims 1 to 9, 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 the oxygen-containing gas used in step (ii) is preferably oxygen.

11. 11. The method of any one of claims 1 to 10, wherein step (ii) is carried out neat.

12. Step (ii) is the chlorination of C １ ~C ２ - a reaction of said compound (II.a) provided in step (i) with said chlorinated C １ ~C ２ 11. The process according to any one of claims 1 to 10, wherein the molar ratio of alkane to olefin is between 10:1 and 1:1.5, preferably between 5:1 and 1:

1.

13. if an acylating agent is provided in step (i), step (ii) is carried out in the presence of a base, preferably an organic base, and if no acylating agent is provided in step (i), also in step (iii) a base, preferably an organic base, is added to the reaction mixture obtained in step (ii), the base is preferably selected from tertiary amines, basic 3-10 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocycles containing 1, 2, 3 or 4 nitrogen atoms as ring members, guanidines and amidines; The base is more preferably - Formula N(R ３ ) ３ (In the formula, each R ３ are independently １ ~C ４ -alkyl); - 3-8 membered saturated monocyclic or bridged heterocyclic rings containing one or two nitrogen atoms or one nitrogen atom and one oxygen atom as ring members; in particular rings of the formula NR ３１ (R ３２ ) ２ wherein R ３１ is hydrogen or C １ ~C ４ -alkyl, and two R ３２ together form the bridging group -(CH ２ ) ｎ - (wherein n is 2, 3, 4 or 5), or together form a bridging group -(CH ２ ) ２ -N(R ３３ )-(CH ２ ) ２ - or - (CH ２ ) ２ -O-(CH ２ ) ２ - (wherein, R ３３ is hydrogen or C １ ~C ４ -alkyl); or DABCO; - 5-10 membered monocyclic or bicyclic heteroaromatic rings containing 1 or 2 nitrogen ring atoms as ring members; in particular selected from the group consisting of imidazole, pyridine, pyrazine, pyridazine, pyrimidine, quinolone and isoquinoline; said monocyclic or bicyclic heteroaromatic rings are unsubstituted or contain 1, 2 or 3 C １ ~C ４ - those with alkyl substituents; - Formula (R ３ ) ２ N-C (=NR ３ )-N(R ３ ) ２ wherein each R ３ are independently １ ~C ４ - alkyl or two R attached to the same nitrogen atom or to different nitrogen atoms ３ are taken together to form the bridging group -(CH ２ ) ｎ -, where n is 2, 3, 4, or 5; and bicyclic amidines DBN or DBU The method of any one of claims 1 to 12, selected from the group consisting of:

14. When an acylating agent is provided in step (i), step (ii) is carried out in the presence of a base selected from 5-10 membered monocyclic or bicyclic heteroaromatic rings containing 1 or 2 nitrogen ring atoms as ring members; The base is preferably selected from the group consisting of imidazole, pyridine, pyrazine, pyridazine, pyrimidine, quinolone and isoquinoline; the monocyclic or bicyclic heteroaromatic ring is unsubstituted or contains 1, 2 or 3 C １ ~C ４ The method of claim 13, wherein the hydroxyl group has an alkyl substituent.

15. The bases are unsubstituted or contain 1, 2 or 3 C １ ~C ４ - a pyridine having an alkyl substituent, 15. The method according to claim 14, wherein the base is preferably selected from pyridine, picoline and lutidine, in particular pyridine.

16. if an acylating agent is provided in step (i), step (ii) is carried out in the presence of an acylation catalyst, and if no acylating agent is provided in step (i), then also in step (iii) an acylation catalyst is added to the reaction mixture obtained in step (ii), The acylation catalyst is preferably 4-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine (PPY), 1,6-dibenzyl-2,3,5,6-tetrahydro-1H,4H-1,3a,6,8-tetraazaphenalene (Super DMAP), and an acylation catalyst of the following general formula: 【Chemistry 3】 (In the formula, each R ４ are independently methyl or ethyl. The method of any one of claims 1 to 15, selected from the group consisting of:

17. 17. The method of claim 16, wherein the acylation catalyst is 4-dimethylaminopyridine (DMAP).

18. 18. The method of any one of claims 1 to 17, wherein in step (i) an acylating agent, a base and optionally an acylation catalyst are provided [step (iii) is not performed], preferably in step (i) an acylating agent, an acylation catalyst and a base are provided.

19. 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 4】 [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 -alkyl] 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.

20. 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 and / or III.b and / or III.c, or mixtures of different compounds III.a and / or III.b and / or III.c as defined in claim 19 (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 compounds III.a and / or III.b, or a mixture of different compounds III.a and / or III.b as defined in claim 19 (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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