Process for the preparation of 4-hydroxy-2-methylene-butanaldehyde, 4-hydroxy-2-methyl-butan-2-enaldehyde and their esters

Abstract

The present invention relates to a process for the preparation of 4-hydroxy-2-methylene-butyraldehyde, 4-hydroxy-2-methyl-butyl-2-enal and their esters of formulae (I.a) and (I.b), # imgabs0 wherein R1 is as defined in the claims and the description, by subjecting isoprenols or esters thereof to photooxidation in the presence of a photosensitizer and an acylating agent. Furthermore, the invention relates to certain hydroperoxides of such compounds (I.a) or (I.b) and to their use as intermediates in the synthesis of compounds (I.a) and (I.b) or in the synthesis of retinol, stereoisomers and derivatives thereof.

Description

[0001] The present invention relates to a process for preparing 4-hydroxy-2-methylene-butyraldehyde, 4-hydroxy-2-methyl-but-2-enal and / or their esters of formula Ia and Ib as defined below, by subjecting an isoprenol of formula II.a as defined below or its ester to photooxidation in the presence of a photosensitizer and an acylating agent. In addition, the present invention relates to the use of certain compounds of formula Ia or Ib as defined below as intermediates in the synthesis of retinol, its stereoisomers and derivatives, in particular esters; to certain hydroperoxides of formula III.a, III.b or III.c as defined below; and to their use as intermediates in the synthesis of compounds Ia and Ib or in the synthesis of retinol, its stereoisomers and derivatives, in particular esters. Background Art

[0002] 4-Acetoxy-2-methylbut-2-enal (its E isomer is also called C5 acetate), the acetate ester of the above-mentioned 4-hydroxy-2-methyl-but-2-enal, is an important building block in the industrial synthesis of retinol, its stereoisomers and derivatives. Acetoxy-2-methylbut-2-enal, for example 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 subsequent steps are described, for example, in DE 10117065 and the references cited therein.

[0003] However, the economic availability of VGDA depends on the unaltered continuation of the industrial processes from which it originates. Given that the lifespan of such processes is increasingly unpredictable, whether due to increasing raw material and energy costs, increasing ecological demands, or increasingly unreliable supply chains, it is desirable to have alternative pathways to C5 acetates, their isomers and derivatives on hand. Furthermore, the limited amount of VGDA available through the processes makes alternative pathways desirable.

[0004] Other known synthetic routes to C5 acetates are the oxidation of prenyl acetate with selenium dioxide as described, for example, in CN 108997112, the oxidation of benzyl isoprene ether as described, for example, in S. Inoue et al., Chemistry Lett. 1986, 2035-2038, the oxidation of isoprene chloride with oxygen as described, for example, in CN 108707076, the oxidation of isoprene as described, for example, in PA Wehrli et al., Synthesis, 1977, 649-650, the acetylation of prenyl alcohol and the oxidation of the resulting prenyl alcohol acetate with peroxide under irradiation in the presence of a photosensitizer as described in CN 110981724 A and the oxidation of prenyl alcohol acetate in an electrochemical process as described in CN 111270261 A. However, these routes are not suitable for application on an industrial scale.

[0005] 4-Acetoxy-2-methylbut-2-enal, basic alcohol 4-hydroxy-2-methyl-but-2-enal and other esters thereof can be obtained by known methods, for example via Pd-catalyzed C-C double bond isomerization as described, for example, in US 4,124,619 or CN 103467287, from the corresponding 2-methylene double bond isomers (i.e. from 3-formylbut-3-enyl acetate, 4-hydroxy-2-methylene-butyraldehyde or other esters thereof).

[0006] It is desirable to find an alternative route to 4-hydroxy-2-methyl-but-2-enal or 4-hydroxy-2-methylene-butyraldehyde and the 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, in particular should also operate with very small amounts of solvent; ideally pure, i.e. in the absence of solvent.

[0007] Isoprenol (3-methylbut-3-en-1-ol) is a bulk chemical readily available from isobutylene and formaldehyde. Isomerization of its double bond yields isoprenol (3-methylbut-2-en-1-ol). Its esters are available via standard esterification processes.

[0008] The photooxidation of olefins with singlet oxygen to allylic hydroperoxides (Schenckene reaction) followed by dehydration to α-enones has been described in the art.

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

[0010] H.-J. Liu et al. describe the synthesis of (+)-artemisinin in Tetrahedron Lett. 1993, 34 (28), 4435-4438. The synthesis covers in particular a step in which a tricyclic olefinically unsaturated carbocycle is converted into the corresponding α-enone by irradiation of a reaction mixture containing the unsaturated ring, acetic anhydride, pyridine, DMAP and TPP in methylene chloride through which oxygen is passed.

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

[0012] P. Bayer et al., Green Chem., DOI: 10.1039 / d0gc00436g, describe the photooxidation of olefins to hydroperoxides with singlet oxygen in a solvent-free continuous flow reaction apparatus. The further conversion of unstable hydroperoxides to, for example, α-ene ketones is schematically described as the reaction of hydroperoxides with acetic anhydride and pyridine in dichloromethane.

[0013] EL Clennan et al. describe the photooxidation of various allylic alcohols with singlet oxygen in Photochemistry and Photobiology, 2006, 82, 1226-1232. In particular, isoprenol 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-dioxolane-3-ol in the presence of TPP in CDCl3. Summary of the invention

[0014] The present inventors have found that 4-hydroxy-2-methyl-but-2-enal, 4-hydroxy-2-methylene-butyraldehyde and esters of these alcohols can be obtained by subjecting isoprenol or its ester to photooxidation in the presence of a photosensitizer and an acylating agent, or by subjecting isoprenol or its ester to photooxidation in the presence of a photosensitizer and subsequently reacting the hydroperoxide formed in the photooxidation with an acylating agent.

[0015] Therefore, the present invention relates to a process for preparing a compound of formula Ia or Ib, or a stereoisomer of compound Ia or Ib, or a mixture of different stereoisomers of compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib.

[0016]

[0017] in

[0018] R 1 is hydrogen or -C(=O)R 2 ;and

[0019] R 2 It is C1-C 20 -alkyl;

[0020] The method includes

[0021] (i) providing a reaction mixture comprising a compound of formula II.a, a photosensitizer and optionally an acylating agent:

[0022]

[0023] Where R 1 As defined above;

[0024] (ii) passing an oxygen-containing gas through the reaction mixture provided in step (i) while irradiating the reaction mixture with light;

[0025] (iii) adding an acylating agent to the reaction mixture obtained in step (ii) if the acylating agent has not been provided in step (i);

[0026] (iv.1) if desired, after the reaction is complete (to the desired extent), isolating the one or more compounds (Ia) or (Ib) obtained in step (ii) or (iii); and

[0027] (v.1) If desired, hydrolyzing one or more compounds Ia or Ib isolated in step (iv.1) to form compounds Ia or Ib wherein R 1 It is hydrogen;

[0028] or

[0029] (iv.2) if desired, hydrolyzing the reaction mixture obtained in step (ii) or (iii); and

[0030] (v.2) If desired, isolating the compound or compounds Ia or Ib obtained in step (iv.2).

[0031] Furthermore, the present invention relates to the use of a compound of formula Ia or Ib other than (E)-4-acetoxy-2-methylbut-2-enal as defined above, or a stereoisomer of compound Ia or Ib other than (E)-4-acetoxy-2-methylbut-2-enal, or a mixture of different stereoisomers of compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib, as an intermediate in the synthesis of retinol, its stereoisomers, its derivatives (wherein the derivatives are in particular its esters) or stereoisomers of its derivatives (wherein the derivatives are in particular its esters).

[0032] The present invention also 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

[0033]

[0034] in

[0035] In compound III.a, R 1 is hydrogen or -C(=O)R 2 ; and R 2 It is C1-C 20 -alkyl;

[0036] In compound III.b, R 1 Yes-C(=O)R 2 ; and R 2 It is C1-C 20 -alkyl; and

[0037] In compound III.c, R 1 is hydrogen or -C(=O)R 2 ; and R 2 It is C1-C 20 -alkyl;

[0038] Preferably it is a hydroperoxide compound of the formula III.a or III.b, or a stereoisomer of a compound of the 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

[0039]

[0040] and relates to the use of 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, wherein R 1 It can also be hydrogen, preferably the use of a hydroperoxide of the formula III.a or III.b as defined above, or a stereoisomer of a compound of the 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, wherein, however, in compound III.b R 1 It can also be hydrogen, which is used as an intermediate in the synthesis of a compound of formula Ia or Ib as defined above, 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, or as an intermediate in the synthesis of retinol, its stereoisomers, its derivatives (wherein the derivatives are preferably its esters (i.e. retinol esters), retinal or retinoic acid, and in particular its esters) or stereoisomers of its derivatives (wherein the derivatives are preferably its esters (i.e. retinol esters), retinal or retinoic acid, and in particular its esters). DETAILED DESCRIPTION

[0041] definition

[0042] "Alkyl" is used in the usual sense. The term "alkyl" refers to a group having 1 or 2 carbon atoms ("C1-C2-alkyl"), 1 to 4 carbon atoms ("C1-C4-alkyl"), or 1 to 20 carbon atoms ("C1-C 20C1-C2-alkyl means a saturated straight-chain or branched aliphatic acyclic hydrocarbon radical having 1 or 2 carbon atoms. Examples are methyl and ethyl. C1-C4-alkyl means a saturated straight-chain or branched aliphatic acyclic hydrocarbon radical having 1 to 4 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. C1-C 20 -Alkyl represents a saturated straight-chain or branched aliphatic acyclic 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-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 their (other) structural isomers. 15 -Alkyl is CH3(CH2) 14 -.

[0043] Chlorinated C1-C2-alkanes are methane or ethane in which some or all of the hydrogen atoms are replaced by chlorine atoms. Examples are 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.

[0044] 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 more than one stereogenic center in a 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:

[0045]

[0046] If the free radical R1 Yes-C(=O)R 2 And R 2 It is a C4-C with one or more stereogenic centers. 20 -alkyl group, such as sec-butyl, then optical isomers of compound Ib exist.

[0047] Similarly, the stereoisomers of compound III.b are mainly E isomer (E)-III.b and Z isomer (Z)-III.b:

[0048]

[0049] If the free radical R 1 Yes-C(=O)R 2 And R 2 It is a C4-C with one or more stereogenic centers. 20 -alkyl group, such as sec-butyl, then the optical isomers of compound III.b exist.

[0050] Similarly, if the free radical R 1 Yes-C(=O)R 2 And R 2 It is a C4-C with one or more stereogenic centers. 20 -alkyl group, such as sec-butyl, then the optical isomers of compound Ia exist; and if the free radical R 1 Yes-C(=O)R 2 And R 2 It is a C4-C with one or more stereogenic centers. 20 -alkyl group, such as sec-butyl, then the optical isomers of compounds III.a and III.c exist.

[0051] The mixture of different stereoisomers of Compound Ib is mainly a mixture of E-isomers and Z-isomers, but may also be a mixture of enantiomers or diastereomers of Compound Ib, wherein R 1 Yes-C(=O)R 2 And R 2 It is a C4-C with one or more stereogenic centers. 20 -alkyl group. Similarly, a mixture of different stereoisomers of compound III.b is primarily a mixture of E-isomers and Z-isomers, but may also be a mixture of enantiomers or diastereomers of compound III.b, wherein R 1 Yes-C(=O)R 2 And R 2 It is a C4-C with one or more stereogenic centers. 20-alkyl group. A mixture of different stereoisomers of compound Ia is a mixture of enantiomers or diastereomers of compound Ia, wherein R 1 Yes-C(=O)R 2 And R 2 It is a C4-C with one or more stereogenic centers. 20 -alkyl group. Similarly, a mixture of different stereoisomers of compound III.a is a mixture of enantiomers or diastereomers of compound III.a, wherein R 1 Yes-C(=O)R 2 And R 2 It is a C4-C with one or more stereogenic centers. 20 -alkyl group. Similarly, a mixture of different stereoisomers of compound III.c is a mixture of enantiomers or diastereomers of compound III.c, wherein R 1 Yes-C(=O)R 2 And R 2 It is a C4-C with one or more stereogenic centers. 20 -alkyl group.

[0052] The mixture of compounds Ia or Ib may be a mixture of two or more different compounds Ia, wherein the free radicals R 1 different; a mixture of two or more different compounds Ib, wherein the free radical R 1 Different; a mixture of compound Ia and compound Ib, wherein the free radical R in compound Ia and Ib 1 has the same meaning; a mixture of compound Ia and compound Ib, wherein the free radical R in compounds Ia and Ib 1 has different meanings; a mixture of compound Ia with two or more different compounds Ib; a mixture of compound Ib with two or more different compounds Ia; or a mixture of two or more different compounds Ia with two or more different compounds Ia. However, primarily, a mixture of compounds Ia or Ib refers to a mixture of compounds Ia and compounds Ib, wherein the free radical R in compounds Ia and Ib is 1 Compound Ib in the mixture defined above may be present as a pure E isomer, a pure Z isomer or a mixture of E and Z isomers.

[0053] A similar definition applies to mixtures of compounds III.a, III.b or III.c.

[0054] For the purposes of the present invention, a photosensitizer is an organic molecule (usually a dye) which can convert triplet oxygen into singlet oxygen when subjected to irradiation (usually electromagnetic radiation in the UV, visible or near IR region): after irradiation, the sensitizer forms the corresponding excited singlet state. Intersystem crossing provides an excited triplet state of the sensitizer, thus transferring energy to triplet oxygen to form singlet oxygen.

[0055] "Light" in the correct sense is electromagnetic radiation with a wavelength (range) in the visible spectrum (380nm to 780nm). However, for the purposes of the present invention, unless otherwise specified, the term "light" also encompasses the directly adjacent wavelength spectrum, i.e. near IR (>780nm to 1μm) and near UV (315nm to <380nm).

[0056] Retinol is (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)non-2,4,6,8-tetraen-1-ol (all trans). For the purposes of the present invention, stereoisomers of retinol relate to retinol, however, wherein one, two, three or all four double bonds in the 2-, 4-, 6- and 8-positions have a Z geometry. Specific examples of such stereoisomers are:

[0057] (2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraen-1-ol;

[0058] (2E,4Z,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraen-1-ol;

[0059] (2Z,4Z,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraen-1-ol;

[0060] or (2Z,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraen-1-ol (also known as (13Z) retinol according to the carotenoid nomenclature).

[0061] For the purposes of the present invention, retinol derivatives are preferably retinol esters, ie retinol in which the -OH group is esterified to a group -OC(=O)R, wherein R is an organic moiety and is preferably R 2 However, retinol derivatives are also oxidized forms of retinol, such as retinal (-CH2OH group oxidized to -CHO) or retinoic acid (-CH2OH group oxidized to -C(=O)OH).

[0062] Stereoisomers of retinol derivatives are retinol derivatives as defined above, however, wherein one, two, three or all four of the double bonds in the 2-, 4-, 6- and 8-positions have Z geometry.

[0063] Embodiments of the present invention (Ex)

[0064] Typical and preferred embodiments Ex are summarized in the following non-exhaustive list. Other preferred embodiments will become apparent from the paragraphs following this list.

[0065] E.1. A method for preparing a compound of formula Ia or formula Ib or a mixture thereof, or a stereoisomer of said compound Ia or Ib, or a mixture of different stereoisomers of said compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib

[0066]

[0067] in

[0068] R 1 is hydrogen or -C(=O)R 2 ;and

[0069] R 2 It is C1-C 20 -alkyl;

[0070] The method comprises

[0071] (i) providing a reaction mixture comprising a compound of formula II.a, a photosensitizer and optionally an acylating agent:

[0072]

[0073] Where R 1 As defined above;

[0074] (ii) passing an oxygen-containing gas through the reaction mixture provided in step (i) while irradiating the reaction mixture with light;

[0075] (iii) adding an acylating agent to the reaction mixture obtained in step (ii) if the acylating agent has not been provided in step (i);

[0076] (iv.1) if desired, after completion of the reaction, isolating the one or more compounds (Ia) or (Ib) obtained in step (ii) or (iii); and

[0077] (v.1) if desired, hydrolyzing the one or more compounds (Ia) or (Ib) isolated in step (iv.1) to form compounds (Ia) or (Ib) wherein R 1 It is hydrogen;

[0078] or

[0079] (iv.2) if desired, hydrolyzing the reaction mixture obtained in step (ii) or (iii); and

[0080] (v.2) if desired, isolating the one or more compounds (Ia) or (Ib) obtained in step (iv.2).

[0081] E.2. The method according to embodiment E.1, wherein R 2 is C1-C4-alkyl or n-C 15 -alkyl.

[0082] E.3. The method according to embodiment E.2, wherein R 2 It is C1-C4-alkyl.

[0083] E.4. The method according to embodiment E.3, wherein R 2 It's methyl.

[0084] E.5. A method according to any one of the preceding embodiments, wherein in the compound II.a R 1 Yes-C(=O)R 2 .

[0085] E.6. A method according to any one of the preceding embodiments, wherein the acylating agent used in step (i) or (iii) is selected from the group consisting of: a carboxylic acid halide R 2a -C(=O)-X, carboxylic anhydride R 2a -C(=O)-OC(=O)-R 2a and enone R 2a -C(H)=C=O, where R 2a Independently having any one of embodiments E.1 to E.4 for R 2 one of the meanings given, and X is Cl, Br or I.

[0086] E.7. The method according to embodiment E.6, wherein the acylating agent used in step (i) or (iii) is a carboxylic anhydride R 2a -C(=O)-OC(=O)-R 2a , where R 2a It is C1-C4-alkyl.

[0087] E.8. The method according to embodiment E.7, wherein the acylating agent used in step (i) or (iii) is a carboxylic anhydride R 2a -C(=O)-OC(=O)-R 2a , where R 2a is methyl (thus, the acylating agent is acetic anhydride).

[0088] E.9. A method according to any one of the preceding embodiments, wherein if R 1 Yes-C(=O)R 2 , then the molar ratio of the compound of formula II.a to the acylating agent is 20:1 to 1:5, and if R 1 For hydrogen, the ratio is 10:1 to 1:5.

[0089] E.10. A method according to embodiment E.9, wherein if R 1 Yes-C(=O)R 2 , then the molar ratio of the compound of formula II.a to the acylating agent is 5:1 to 1:5, and if R 1 For hydrogen, the ratio is 1:1 to 1:5.

[0090] E.11. A method according to embodiment E.10, wherein if R 1 Yes-C(=O)R 2 , then the molar ratio of the compound of formula II.a to the acylating agent is 3:1 to 1:2, and if R 1 For hydrogen, the ratio is 1:1.1 to 1:3.

[0091] E.12. A method according to embodiment E.11, wherein if R 1 Yes-C(=O)R 2 , then the molar ratio of the compound of formula II.a to the acylating agent is 3:1 to 1:1, and if R 1 For hydrogen, the ratio is 1:1.5 to 1:3.

[0092] E.13. A method according to any one of the preceding embodiments, wherein the photosensitizer is selected from the group consisting of: fluorescein, eosin, rose bengal, erythrosine, tetraphenylporphyrin, tetraphenylporphyrin cobalt, tetraphenylporphyrin zinc, hematoporphyrin, rhodamine B, Besickel's brilliant red, methyl violet, methylene blue, fullerene C 60 , Fullerene C 70 , graphene, carbon nanotubes, Ru(bpy)3 2+ Salt, Ru(phen)3 2+ Salts, cercosporin, hypocrellin-A and mixtures thereof.

[0093] E.14. A method according to embodiment E.13, wherein the photosensitizer is selected from the group consisting of:

[0094] Tetraphenylporphyrin, Tetraphenylporphyrin Cobalt, Tetraphenylporphyrin Zinc, Methylene Blue, Ru(bpy)3 2+ Salt and Ru(phen)3 2+ Salt.

[0095] E.15. A method according to embodiment E.14, wherein the photosensitizer is selected from the group consisting of:

[0096] Tetraphenylporphyrin, tetraphenylporphyrin zinc and Ru(bpy)3 2+ Salt.

[0097] E.16. The method according to any of the preceding embodiments, wherein in step (ii), further photosensitizer is added if this photosensitizer is consumed during irradiation.

[0098] E.17. The method according to any of the preceding embodiments, wherein the photosensitizer is used in a total amount of 0.00001 mol-% to 1 mol-% relative to 1 mol of the compound of formula II.a.

[0099] E.18. The method according to embodiment E.17, wherein the photosensitizer is used in a total amount of 0.0001 mol-% to 0.5 mol-% relative to 1 mol of the compound of formula II.a.

[0100] E.19. The method according to any one of embodiments E.1 to E.16, wherein the photosensitizer is used in a total amount of 0.000005 mol to 0.01 mol per mol of the compound of formula II.a.

[0101] E.20. The method according to embodiment E.19, wherein the photosensitizer is used in a total amount of 0.00001 mol to 0.005 mol per mol of the compound of formula II.a.

[0102] E.21. The method according to embodiment E.20, wherein the photosensitizer is used in a total amount of 0.0001 mol to 0.005 mol per mol of the compound of formula II.a.

[0103] E.22. The method according to any of the preceding embodiments, wherein in step (ii), the reaction mixture is irradiated with light having a wavelength in the range of 350 nm to 800 nm.

[0104] E.23. A method according to embodiment E.22, wherein in step (ii), the reaction mixture is irradiated with light having a wavelength in the range of 350 nm to 680 nm.

[0105] E.24. A method according to embodiment E.23, wherein in step (ii), the reaction mixture is irradiated with light having a wavelength in the range of 400 nm to 650 nm.

[0106] E.25. A method according to embodiment E.24, wherein in step (ii), the reaction mixture is irradiated with light having a wavelength in the range of 400 nm to 580 nm.

[0107] E.26. A method according to embodiment E.25, wherein in step (ii), the reaction mixture is irradiated with light having a wavelength in the range of 400 nm to 500 nm.

[0108] E.27. A method according to any one of embodiments E.14 to E.26, wherein the photosensitizer is tetraphenylporphyrin, tetraphenylporphyrin cobalt or tetraphenylporphyrin zinc, and in step (ii), the reaction mixture is irradiated with light having a wavelength in the range of 400 nm to 430 nm, preferably 400 nm to 420 nm, for example 400 nm to 410 nm; or the photosensitizer is methylene blue, and in step (ii), the reaction mixture is irradiated with light having a wavelength in the range of 600 nm to 620 nm, or the photosensitizer is Ru(bpy)3 2+ Salt or Ru(phen)3 2+ salt, and in step (ii), irradiating the reaction mixture with light having a wavelength in the range of 450 nm to 480 nm, preferably 460 nm to 475 nm.

[0109] E.28. The method according to any one of the preceding embodiments, wherein in step (ii), the reaction mixture is irradiated with monochromatic light.

[0110] E.29. A method according to 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, wherein at least 90% of the light emitted by the monochromatic light source is within the wavelength range of 350nm to 800nm.

[0111] E.30. A method according to embodiment E.29, wherein the irradiation in step (ii) is performed using a monochromatic light source, preferably an electroluminescent lighting device that emits monochromatic light, wherein at least 90% of the light emitted by the monochromatic light source is within the wavelength range of 350 nm to 680 nm.

[0112] E.31. A method according to embodiment E.30, wherein the irradiation in step (ii) is performed using a monochromatic light source, preferably an electroluminescent lighting device that emits monochromatic light, wherein at least 90% of the light emitted by the monochromatic light source is within the wavelength range of 400 nm to 650 nm.

[0113] E.32. A method according to 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, wherein at least 90% of the light emitted by the monochromatic light source is within the wavelength range of 400nm to 580nm.

[0114] E.33. A method according to 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, wherein at least 90% of the light emitted by the monochromatic light source is within the wavelength range of 400nm to 500nm.

[0115] E.34. A method according to any one of embodiments E.28 to E.33, wherein the irradiation in step (ii) is performed using an electroluminescent lighting device that emits monochromatic light, wherein the electroluminescent lighting device consists of at least one LED.

[0116] E.35. A method according to any of the preceding embodiments, wherein the oxygen-containing gas used in step (ii) is selected from the group consisting of: oxygen, air, and a mixture of oxygen and nitrogen, wherein the mixture contains oxygen in a range of 1 wt. % to 99 wt. % relative to the total weight of the mixture (i.e., the mixture of oxygen and nitrogen).

[0117] E.36. A method according to embodiment E.35, wherein the oxygen-containing gas used in step (ii) is oxygen, air, and a mixture of oxygen and nitrogen, and the mixture contains oxygen in a range of 20 wt% to 99 wt% relative to the total weight of the mixture.

[0118] E.37. A method according to embodiment E.36, wherein the oxygen-containing gas used in step (ii) is oxygen.

[0119] E.38. A method according to any one of the preceding embodiments, wherein step (ii) is performed neat. E.39. A method according to any one of embodiments E.1 to E.37, wherein step (ii) is performed in the presence of a chlorinated C1-

[0120] C2-alkane in the presence of, wherein the compound (II.a) provided in step (i) and the chlorinated

[0121] The molar ratio of the C1-C2-alkanes is from 30:1 to 1:1.5, preferably from 10:1 to 1:1.5.

[0122] E.40. The method according to embodiment E.39, wherein the compound (II.a) provided in step (i)

[0123] The molar ratio to the chlorinated C1-C2-alkane is 5:1 to 1:1.

[0124] E.41. The method according to any one of embodiments E.39 and E.40, wherein the chlorinated C1-C2-alkane is trichloromethane or tetrachloromethane.

[0125] E.42. A method according to any one of the preceding embodiments, wherein an acylating agent is provided in step (i) and the acylating agent is a carboxylic acid halide R 2a -C(=O)-X or carboxylic anhydride R 2a -C(=O)-OC(=O)-R 2a In the case where step (ii) is carried out in the presence of a base, and in the case where an acylating agent has not been provided in step (i), if the acylating agent added in step (iii) is a carboxylic acid halide R 2a -C(=O)-X or carboxylic anhydride R 2a -C(=O)-OC(=O)-R 2a , then in step (iii) a base is also added to the reaction mixture obtained in step (ii).

[0126] E.43. The method according to embodiment E.42, wherein the base is an organic base.

[0127] E.44. A method according to embodiment E.43, wherein the base is selected from tertiary amines, basic 3- to 10-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycles containing 1, 2, 3 or 4 nitrogen atoms as ring members, guanidines and amidines.

[0128] E.45. The method according to embodiment E.44, wherein the base is selected from the group consisting of:

[0129] -Formula N(R 3 )3 tertiary amine, wherein each R 3 are independently C1-C4-alkyl;

[0130] - a 3- to 8-membered saturated monocyclic or bridged heterocyclic ring containing 1 or 2 nitrogen atoms or 1 nitrogen atom and one oxygen atom as ring members; in particular, of the formula NR 31 (R 32 )2, wherein R 31are hydrogen or C1-C4-alkyl, and both R 32 Together they form a bridging group -(CH2) n -, where n is 2,

[0131] 3, 4 or 5, or together form a bridging group -(CH2)2-N(R 33 )-(CH2)2- or -(CH2)2-O-

[0132] (CH2)2-, where R 33 is hydrogen or C1-C4-alkyl; or DABCO;

[0133] - a 5- to 10-membered monocyclic or bicyclic heteroaromatic ring containing 1 or 2 nitrogen ring atoms as ring members; in particular chosen from the group consisting of imidazole, pyridine, pyrazine, pyridazine, pyrimidine, quinolone and isoquinoline; wherein the monocyclic or bicyclic heteroaromatic ring is unsubstituted or carries 1, 2 or 3 C1-C4-alkyl substituents;

[0134] -Formula (R 3 )2N-C(=NR 3 )-N(R 3 )2 guanidine, wherein each R 3 are independently C1-C4-alkyl, or the two R are bound to the same nitrogen atom or to different nitrogen atoms 3 Together to form a bridging group

[0135] -(CH2) n -, where n is 2, 3, 4 or 5; and

[0136] - Bicyclic amidine DBN or DBU.

[0137] E.46. A method according to embodiment E.45, wherein in case an acylating agent is provided in step (i), step (ii) is carried out in the presence of a base selected from a 5- to 10-membered monocyclic or bicyclic heteroaromatic ring containing 1 or 2 nitrogen ring atoms as ring members.

[0138] E.47. A method according to embodiment E.6, wherein the base is selected from the group consisting of: imidazole, pyridine, pyrazine, pyridazine, pyrimidine, quinolone and isoquinoline; wherein the monocyclic or bicyclic heteroaromatic ring is unsubstituted or carries 1, 2 or 3 C1-C4-alkyl substituents; and in particular is pyridine which is unsubstituted or carries 1, 2 or 3 C1-C4-alkyl substituents.

[0139] E.48. A method according to embodiment E.47, wherein the base is selected from pyridine, picoline, dimethylpyridine, trimethylpyridine and mixtures thereof.

[0140] E.49. A method according to embodiment E.48, wherein the base is pyridine.

[0141] E.50. The method according to 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.

[0142] E.51. The method according to embodiment E.50, wherein the molar ratio of the compound of formula II.a to the base is 3:1 to 1:3.

[0143] E.52. The method according to embodiment E.51, wherein the molar ratio of the compound of formula II.a to the base is 2:1 to 1:2.

[0144] E.53. The method according to embodiment E.52, wherein the molar ratio of the compound of formula II.a to the base is 1.5:1 to 1:2, such as 1.5:1 to 1:1.5.

[0145] E.54. A method according to any one of the preceding embodiments, wherein, in case an acylating agent is provided in step (i), step (ii) is carried out in the presence of an acylating catalyst, and in case an acylating agent is not provided in step (i), an acylating catalyst is also added to the reaction mixture obtained in step (ii) in step (iii).

[0146] E.55. A method according to embodiment E.54, wherein the acylation catalyst is selected from the group consisting of 4-dimethylaminopyridine (DMAP), 4-pyrrolidinylpyridine (PPY), 1,6-dibenzyl

[0147] -2,3,5,6-tetrahydro-1H,4H-1,3a,6,8-tetraazaphenazone (Super DMAP) and the following acylation catalyst

[0148]

[0149] Each R 4 is independently methyl or ethyl.

[0150] E.56. A method according to embodiment E.55, wherein the acylation catalyst is 4-dimethylaminopyridine (DMAP).

[0151] E.57. The process according to 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.

[0152] E.58. The method according to embodiment E.57, wherein the molar ratio of the compound of formula II.a to the acylation catalyst is from 200:1 to 5:1.

[0153] E.59. The method according to embodiment E.58, wherein the molar ratio of the compound of formula II.a to the acylation catalyst is from 150:1 to 10:1.

[0154] E.60. The method according to any of the preceding embodiments, wherein step (ii) is carried out at a temperature of -20°C to 150°C.

[0155] E.61. A method according to embodiment E.60, wherein step (ii) is carried out at a temperature of 0°C to 70°C, for example 0°C to 60°C or 5°C to 50°C.

[0156] E.62. A method according to any of the preceding embodiments, wherein step (ii) is carried out at a pressure of from atmospheric pressure to 100 bar (10 MPa).

[0157] E.63. A method according to embodiment E.62, wherein step (ii) is carried out at >1 bar to 10 bar (>0.1 MPa to 1 MPa).

[0158] E.64. A method according to embodiment E.63, wherein step (ii) is carried out at 1.5 bar to 8 bar (0.15 MPa to 0.8 MPa).

[0159] E.65. A method according to embodiment E.64, wherein step (ii) is carried out at 5 bar to 20 bar (0.5 MPa to 2 MPa).

[0160] E.66. A method according to embodiment E.65, wherein step (ii) is carried out at 10 bar to 15 bar (1 MPa to 1.5 MPa).

[0161] E.67. A method according to embodiment E.66, wherein step (ii) is carried out at atmospheric pressure.

[0162] E.68. A method according to any of the preceding embodiments, wherein in step (ii), the entire reaction mixture is irradiated or only different parts of the reaction mixture are irradiated.

[0163] E.69. A method according to any of the preceding embodiments, wherein step (ii) is carried out in a side loop flow photoreactor, a continuous flow photoreactor or a submersible photoreactor.

[0164] E.70. A process according to any of the preceding embodiments, wherein an acylating agent, a base and optionally an acylation catalyst are provided in step (i) (and step (iii) is not performed).

[0165] E.71. A method according to embodiment E.70, wherein an acylating agent, an acylation catalyst and a base are provided in step (i) (and step (iii) is not performed).

[0166] 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 compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib according to any one of embodiments E.1 to E.5, as an intermediate in the synthesis of retinol, its stereoisomers, its derivatives (preferably its esters) or stereoisomers of its derivatives (preferably stereoisomers of its esters).

[0167] E.73. A hydroperoxide compound of formula III.a, III.b or III.c, or a stereoisomer of said compound of formula III.a, III.b or III.c, or a mixture of different stereoisomers of said compound III.a, III.b and / or III.c, or a mixture of different compounds III.a, III.b and / or III.c

[0168]

[0169] in

[0170] In compound III.a, R 1 is hydrogen or -C(=O)R 2 ; and R 2 It is C1-C 20 -alkyl;

[0171] In compound III.b, R 1 Yes-C(=O)R 2 ; and R 2 It is C1-C 20 -alkyl; and

[0172] In compound III.c, R 1 is hydrogen or -C(=O)R 2 ; and R 2 It is C1-C 20 -alkyl.

[0173] E.74. A hydroperoxide compound according to embodiment E.73, wherein R 2 It is C1-C4-alkyl.

[0174] E.75. A hydroperoxide compound according to embodiment E.74, wherein R 2 It's methyl.

[0175] E.76. A hydroperoxide compound according to any one of embodiments E.73 to E.75, wherein the hydroperoxide compound is a 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.

[0176] E.77. A hydroperoxide compound according to any one of embodiments E.73 to E.75, wherein the hydroperoxide compound is a compound of formula III.a or III.c, or a stereoisomer of the compound of formula III.a or III.c, or a mixture of different stereoisomers of the compound III.a and / or III.c, or a mixture of different compounds III.a and / or III.c.

[0177] E.78. A hydroperoxide compound according to any one of embodiments E.73 to E.75, wherein the hydroperoxide compound is a compound of formula III.a, or a stereoisomer of the compound of formula III.a, or a mixture of different stereoisomers of the compound III.a, or a mixture of different compounds III.a.

[0178] E.79. Use of 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, according to any one of embodiments E.73 to E.75, wherein R 1It can also be hydrogen, which is used as an intermediate in the synthesis of a compound of formula Ia or Ib according to any one of Embodiments E.1 to E.5, or a stereoisomer of the compound Ia or Ib, or a mixture of different stereoisomers of the compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib, or as an intermediate in the synthesis of retinol, its stereoisomers, its derivatives (preferably its esters) or stereoisomers of its derivatives (preferably stereoisomers of its esters).

[0179] E.80. The use according to embodiment E.79, wherein the use is the use of the hydroperoxide compound of formula III.a or III.b, or the 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.

[0180] E.81. The use according to embodiment E.79, which is the use of the hydroperoxide compound of formula III.a, or the stereoisomer of the compound of formula III.a, or a mixture of different stereoisomers of the compound III.a, or a mixture of different compounds III.a.

[0181] Without wishing to be bound by theory, it is assumed that in the process according to the invention, the conversion of the compound of the formula II.a into the compound Ia and / or Ib proceeds via a Schenckene reaction (= "ene" reaction in which the singlet oxygen is the enophile) and simultaneously (if step (iii) is not carried out) or subsequently (if step (iii) is carried out) a Kornblum-DeLaMare rearrangement (which is actually an elimination reaction; here a dehydrogenative acylation).

[0182] In the method of the present invention, if an acylating agent is provided in step (i), the conversion of the compound of formula II.a into compound Ia and / or Ib can be carried out in one step (e.g. as a one-pot reaction). In this case, step (iii) is of course not carried out. Without wishing to be bound by theory, it is assumed that during step (ii), the compound of formula II.a is converted into allyl hydroperoxide, which is acylated in situ by an acylating agent. Then, the acylated hydroperoxide is dehydrated in situ, more precisely, dehydrogenated acylation, to obtain compound Ia and / or Ib. It is assumed that compound Ib is the result of double bond isomerization, which can occur during the formation of hydroperoxides and can produce hydroperoxide intermediates III.b as described above or below.

[0183] Alternatively, in the process according to the invention, if an acylating agent is provided in step (i), the conversion of the compound of formula II.a into compound Ia and / or Ib can be carried out in two steps. In this case, step (iii) is mandatory. During step (ii), a hydroperoxide is formed, which after the addition of an acylating agent in step (iii) is acylated and further reacted into compound Ia and / or Ib, as explained above.

[0184] In view of the safety risks associated with the formation of hydroperoxides and longer storage times, and also for simpler handling, the first alternative is preferred, i.e. converting the compound of formula II.a into compound Ia and / or Ib in one step by providing a reaction mixture comprising an acylating agent in step (i).

[0185] Therefore, in a preferred embodiment, the present invention relates to a process 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.

[0186]

[0187] in

[0188] R 1 is hydrogen or -C(=O)R 2 ;and

[0189] R 2 It is C1-C 20 -alkyl;

[0190] The method includes

[0191] (i) providing a reaction mixture comprising a compound of formula II.a, a photosensitizer and an acylating agent:

[0192]

[0193] Where R 1 As defined above;

[0194] (ii) passing an oxygen-containing gas through the reaction mixture provided in step (i) while irradiating the reaction mixture with light;

[0195] (iv.1) if desired, after the reaction is complete (to the desired extent), isolating the one or more compounds (Ia) or (Ib) obtained in step (ii); and

[0196] (v.1) If desired, hydrolyzing the one or more compounds (Ia) or (Ib) isolated in step (iv.1) to form compounds (Ia) or (Ib) wherein R 1 It is hydrogen;

[0197] or

[0198] (iv.2) if desired, hydrolyzing the reaction mixture obtained in step (ii); and

[0199] (v.2) If desired, isolating the compound or compounds (Ia) or (Ib) obtained in step (iv.2).

[0200] In compounds Ia, Ib and II.a, R 2 Preferably it is C1-C4-alkyl or n-C 15 -alkyl, more preferably C1-C4-alkyl, even more preferably C1-C2-alkyl and in particular methyl.

[0201] R 1 Preferably -C(=O)R 2 , especially in compound II.a.

[0202] The acylating agent used in step (i) or (iii) can be essentially any substance that can acylate the hydroperoxide formed in the reaction of compound II.a with oxygen. Typical acylating agents are carboxylic acids, carboxylic acid active esters, carboxylic acid halides, carboxylic acid anhydrides and enones. Preferably, the acylating agent is selected from the group consisting of: carboxylic acid halides R 2a -C(=O)-X, carboxylic anhydride R 2a -C(=O)-OC(=O)-R 2a and enone R 2a -C(H)=C=O, where R 2a Independently have the above for R 2 and X is Cl, Br or I. More preferably, the acylating agent used in step (i) or (iii) is a carboxylic anhydride R 2a -C(=O)-OC(=O)-R 2a , even more preferably the carboxylic anhydride R 2a -C(=O)-OC(=O)-R 2a , where R 2a is C1-C4-alkyl and in particular is a carboxylic anhydride R 2a -C(=O)-OC(=O)-R 2a , where R 2a is a methyl group, so the carboxylic anhydride is acetic anhydride.

[0203] The acylating agent is provided in an amount such that at least a portion of the hydroperoxide groups formed are acylated. 1 is hydrogen, then the alcohol group OR 1 Acylation of the =OH groups competes with acylation of the hydroperoxide groups. It is therefore advantageous in this case to use an amount of the acylating agent which is sufficiently large to allow at least a portion of the hydroperoxide groups to be acylated.

[0204] Preferably, the acylating agent is provided in an amount such that if R 1 Yes-C(=O)R 2 , then the molar ratio of the compound of formula II.a to the acylating agent is 20:1 to 1:5, and if R 1 is hydrogen, then 10:1 to 1:5. More preferably, if R 1 Yes-C(=O)R 2 , then the molar ratio of the compound of formula II.a to the acylating agent is 5:1 to 1:5, and if R 1 is hydrogen, then the ratio is 1:1 to 1:5. Even more preferably, if R 1 Yes-C(=O)R 2 , then the molar ratio of the compound of formula II.a to the acylating agent is 3:1 to 1:2, and if R 1 is hydrogen, then the ratio is 1:1.1 to 1:3. In particular, if R 1 Yes-C(=O)R 2 , then the molar ratio of the compound of formula II.a to the acylating agent is 3:1 to 1:1, and if R 1 For hydrogen, the ratio is 1:1.5 to 1:3.

[0205] The above ratios relate to the amount of compound II.a provided in step (i) and also take into account the preferred embodiments described above or below, according to which the reaction is carried out such that only a portion of compound II.a is converted.

[0206] As explained above, the photosensitizer used in the method of the invention is a compound that can convert triplet oxygen into singlet oxygen when subjected to irradiation (usually electromagnetic radiation in the UV, visible or near IR region): after irradiation, the sensitizer forms the corresponding excited singlet state. Intersystem crossing provides the excited triplet state of the sensitizer, thus transferring energy to triplet oxygen to form singlet oxygen. Singlet oxygen is the substance that oxidizes compound II.a to the corresponding hydroperoxide (or its double bond isomer).

[0207] Preferably, the photosensitizer can convert triplet oxygen into singlet oxygen when subjected 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.

[0208] Preferably, the photosensitizer is selected from the group consisting of: fluorescein, eosin, rose bengal (RB), erythrosine, tetraphenylporphyrin (more specifically, 5,10,15,20-tetraphenyl-21H,23H-porphyrin; 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, Besickel's 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, usually in the form of hexahydrate), Ru(phen)3 2+ salt (phen = 1,10-phenanthroline) (e.g. dichlorotri(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+ A salt (particularly tris(2,2'-bipyridyl)ruthenium(II) hexafluorophosphate, tris(2,2'-bipyridyl)ruthenium(II) chloride or a hexahydrate thereof) and Ru(phen)3 2+ salt (particularly dichlorotris(1,10-phenanthroline)ruthenium(II) chloride), and in particular selected from the group consisting of tetraphenylporphyrin, tetraphenylporphyrin zinc and Ru(bpy)3 2+ Salt (particularly tris(2,2'-bipyridyl)ruthenium(II) hexafluorophosphate, tris(2,2'-bipyridyl)ruthenium(II) chloride or a hexahydrate thereof).

[0209] The photosensitizer can be provided in step (i) in very small amounts. However, during the irradiation, part of the photosensitizer may degrade, resulting in less and less singlet oxygen generation and thus slowing down the conversion of compound II.a into the corresponding hydroperoxide and ultimately into the desired compound Ia and / or Ib. Therefore, a larger amount of photosensitizer is provided in step (i), or, during step (ii), if this photosensitizer is depleted during the irradiation, further photosensitizer is added. The degree of depletion / degradation of the photosensitizer can be monitored during step (ii), for example by UV / Vis spectroscopy, which can also be performed in coordination.

[0210] The photosensitizer is preferably used in a total amount of 0.00001 mol-% to 1 mol-% relative to 1 mol of the compound of formula II.a. The total amount means the total amount of the photosensitizer provided in step (i) and added during step (ii) (if applicable). More preferably, the photosensitizer is used in a total amount of 0.0001 mol-% to 0.5 mol-% relative to 1 mol of the compound of formula II.a.

[0211] Alternatively, the photosensitizer is preferably used in a total amount of 0.0000001 mol to 0.01 mol, more preferably 0.000001 mol to 0.01 mol or 0.000001 mol to 0.005 mol, even more preferably 0.000005 mol to 0.01 mol, particularly preferably 0.00001 mol to 0.005 mol, specifically 0.0001 mol to 0.005 mol, per 1 mol of the compound of formula II.a.

[0212] Typical photosensitizers are dyes and can therefore be excited by 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 and in particular in the visible range.

[0213] Preferably, in step (ii), the reaction mixture is irradiated with light having a wavelength in the range of 350 nm to 800 nm, more preferably 350 nm to 680 nm, even more preferably in the range of 400 nm to 650 nm, even more preferably 400 nm to 580 nm and in particular 400 nm to 500 nm. The optimal wavelength range generally depends on the photosensitizer used and, if it is not known anyway to the person skilled in the art, can be determined, for example, by short-term tests, or can be selected by UV spectroscopy.

[0214] For example, if the photosensitizer is tetraphenylporphyrin, tetraphenylporphyrin cobalt or tetraphenylporphyrin zinc, in step (ii), the reaction mixture may be irradiated, for example, with light having a wavelength in the range of 400 nm to 430 nm, preferably 400 nm to 420 nm, for example 400 nm to 410 nm; if the photosensitizer is methylene blue, in step (ii), the reaction mixture may be irradiated, for example, with light having a wavelength in the range of 600 nm to 620 nm, or if the photosensitizer is Ru(bpy)3 2+ Salt or Ru(phen)3 2+ If a salt is present, then in step (ii), the reaction mixture may be irradiated, for example, with light having a wavelength in the range of 450 nm to 480 nm, preferably 460 nm to 475 nm.

[0215] In step (ii), the reaction mixture is preferably irradiated with monochromatic light.

[0216] In theory, monochromatic light is light with a single constant frequency / light with a single vacuum wavelength range. However, in practice, there is no radiation that can be completely monochromatic. Therefore, in practice, "monochromatic" light - even from a laser or a spectral line - always consists of components with a certain non-zero width frequency range. For the purposes of the present invention, monochromatic light is understood to be light produced by a monochromatic light source of the prior art, such as a monochromator, a filter, an Hg vapor lamp (high-pressure, medium-pressure or low-pressure lamp) (usually in combination with a filter), a doped Hg vapor lamp (if necessary, in combination with a filter), a Na vapor lamp (high-pressure or low-pressure lamp), a laser or in particular a monochromatic LED.

[0217] 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 the monochromatic light source is within the wavelength range of 350nm to 800nm, preferably 350nm to 680nm, more preferably 400nm to 650nm, even more preferably 400nm to 580nm, in particular 400nm to 500nm.

[0218] Preferably, the irradiation in step (ii) is performed using an electroluminescent lighting device emitting monochromatic light, wherein the electroluminescent lighting device consists of at least one LED.

[0219] 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, the mixture containing, relative to the gross weight of the mixture, a range of 1 wt % to 99 wt % oxygen. 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, the mixture containing a range of 20 wt % to 99 wt % oxygen, and in particular oxygen.

[0220] "Passing an oxygen-containing gas through the reaction mixture provided in step (i)" is not limited to bubbling an oxygen-containing gas through the mixture, thereby allowing most of the oxygen-containing gas to escape, but also encompasses inserting and maintaining the oxygen-containing gas in the reaction mixture, for example by using a closed, usually pressurized reaction vessel.

[0221] In case an acylating agent is provided in step (i), step (ii) is preferably carried out in the presence of a base, in particular if the acylating agent is a carboxylic acid halide or a carboxylic anhydride. In this case, the base is used in particular to neutralize the acid (HX or R 2aCOOH). 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.

[0222] In case an acylating agent has not been provided in step (i), a base, preferably an organic base, is also added to the reaction mixture obtained in step (ii) in step (iii), especially if the acylating agent is a carboxylic acid halide or a carboxylic acid anhydride. In this case, step (iii) preferably comprises: adding an acylating agent and a base, preferably an organic base, to the reaction mixture obtained in step (ii).

[0223] The organic base preferably added in step (i) or (iii) is preferably selected from tertiary amines, basic 3- to 10-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycles containing 1, 2, 3 or 4 nitrogen atoms as ring members, guanidines and amidines.

[0224] More preferably, the base is selected from the group consisting of:

[0225] -Formula N(R 3 )3 tertiary amine, wherein each R 3 are independently C1-C4-alkyl;

[0226] - a 3- to 8-membered saturated monocyclic or bridged heterocyclic ring containing 1 or 2 nitrogen atoms or 1 nitrogen atom and one oxygen atom as ring members; in particular, of the formula NR 31 (R 32 )2, wherein R 31 are hydrogen or C1-C4-alkyl, and both R 32 Together they form a bridging group -(CH2) n -, wherein 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-, where R 33 is hydrogen or C1-C4-alkyl; or DABCO;

[0227] - a 5- to 10-membered monocyclic or bicyclic heteroaromatic ring 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;

[0228] wherein the monocyclic or bicyclic heteroaromatic ring is unsubstituted or carries 1, 2 or 3 C1-C4-alkyl substituents;

[0229] -Formula (R 3 )2N-C(=NR 3 )-N(R 3)2 guanidine, wherein each R 3 are independently C1-C4-alkyl, or the two R are bound to the same nitrogen atom or to different nitrogen atoms 3 Together they form a bridging group -(CH2) n -, where n is 2, 3, 4 or 5; and

[0230] - Bicyclic amidine DBN or DBU.

[0231] Each R 3 are independently C1-C4-alkyl groups of the formula N(R 3 Examples of the tertiary amine of )3 are trimethylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine (Hünig's base), and the like.

[0232] Examples of 3- to 8-membered saturated monocyclic or bridged heterocyclic rings containing 1 or 2 nitrogen atoms or 1 nitrogen atom and one oxygen atom as ring members are piperidine, 1-methylpiperidine, 1-ethylpiperidine, piperazine, morpholine, 1,4-diazabicyclo-[2.2.2]-octane (DABCO), and the like.

[0233] Examples of 5- to 10-membered mono- or bicyclic heteroaromatic rings which contain 1 or 2 nitrogen ring atoms and unsubstituted or substituted 1, 2 or 3 C1-C4-alkyl substituents as ring members are imidazole, pyridine, picoline, lutidine, pyrazine, pyridazine, pyrimidine, quinolone and isoquinoline.

[0234] When step (ii) is carried out in the presence of a base, the latter is advantageously selected from a 5- to 10-membered monocyclic or bicyclic heteroaromatic ring containing 1 or 2 nitrogen ring atoms as ring members (thus, conveniently, if step (ii) is carried out in the presence of a base, the reaction mixture provided in step (i) advantageously comprises a base selected from a 5- to 10-membered monocyclic or bicyclic heteroaromatic ring containing 1 or 2 nitrogen ring atoms as ring members), because some of the other bases, especially bases of the formula N(R 3)3, which may interfere negatively in the photooxidation reaction. More preferably, the base is selected from the group consisting of imidazole, pyridine, pyrazine, pyridazine, pyrimidine, quinolone and isoquinoline; wherein the monocyclic or bicyclic heteroaromatic ring is unsubstituted or carries 1, 2 or 3 C1-C4-alkyl substituents; and particularly preferably is unsubstituted or carries 1, 2 or 3 C1-C4-alkyl substituents pyridine. In particular, the base is selected from pyridine, picoline (i.e. 2-picoline, 3-picoline, 4-picoline or mixtures thereof), lutidine (i.e. 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine or mixtures thereof), collidine (i.e. 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, 3,4,5-collidine and mixtures thereof) and mixtures thereof, and even more particularly pyridine.

[0235] If an acylating agent has not been provided in step (i) and step (iii) is carried out, the base added in step (iii) may preferably be any of the above-mentioned organic bases, since there is no possibility of negative interference in the photooxidation reaction in this device. However, it is preferably the same base as those mentioned above for the base added in step (i).

[0236] The amount of base used is preferably such that the molar ratio of compound of formula II.a to base is 5:1 to 1:5, more preferably 3:1 to 1:3, even more preferably 2:1 to 1:2 and in particular 1.5:1 to 1:2 or 1.5:1 to 1:1.5.

[0237] In case an acylating agent has been 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).

[0238] In case an acylating agent has not been provided in step (i), in step (iii) an acylating 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 acylating catalyst and optionally a base, preferably an organic base (different from the acylating catalyst; see below) to the reaction mixture obtained in step (ii). More preferably, step (iii) comprises: adding an acylating agent, an acylating catalyst and a base, preferably an organic base (different from the acylating catalyst; see below) to the reaction mixture obtained in step (ii).

[0239] Preferably, the acylation catalyst is selected from the group consisting of 4-dimethylaminopyridine (DMAP), 4-pyrrolidinylpyridine (PPY), 1,6-dibenzyl-2,3,5,6-tetrahydro-1H,4H-1,3a,6,8-tetraazaphenazone (Super DMAP) and an acylation catalyst of the following general formula

[0240]

[0241] Each R 4 are independently methyl or ethyl;

[0242] More preferably, the acylation catalyst is 4-dimethylaminopyridine (DMAP).

[0243] The amount of acylation catalyst used is preferably such that the molar ratio of compound of the formula II.a to acylation catalyst is preferably from 200:1 to 1:1, more preferably from 200:1 to 5:1 and in particular from 150:1 to 10:1.

[0244] Preferably, step (ii) is carried out neat (i.e. substantially). "Clean" or "substantially" means that there is no additional solvent. The description "additional" takes into account the fact that the starting compound II.a and the hydroperoxide or optional base formed intermediately can act as a solvent or dispersant for the photosensitizer, acylating agent (if present), optionally present acylation catalyst and optionally present base (if the latter does not itself act as a solvent). In order 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 any additional solvent, or by mixing the starting materials in the presence of an additional solvent and then removing it before carrying out step (ii).

[0245] In an alternatively preferred embodiment, step (ii) is carried out in the presence of a chlorinated C1-C2-alkane. To achieve this, 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.

[0246] However, more preferably, step (ii) is performed neat.

[0247] In a preferred embodiment of the method of the present invention, compound II.a, an acylating agent, a photosensitizer, a base and an acylation catalyst, which are optionally present, are provided in step (i) (and step (iii) is not carried out), and step (ii) is carried out neat. More preferably, compound II.a, a photosensitizer, an acylating agent, a base and an acylation catalyst are provided in step (i) (and step (iii) is not carried out), and step (ii) is carried out neat. In a particular embodiment, compound II.a, a photosensitizer (particularly TPP, Zn-TPP or Ru(bpy)3) are provided in step (i). 2+ A salt (for example tris(2,2'-bipyridyl)ruthenium(II) hexafluorophosphate or tris(2,2'-bipyridyl)ruthenium(II) chloride)), acetic anhydride, pyridine or pyridine carrying 1, 2 or 3 methyl groups and optionally DMAP (and without carrying out step (iii)), and carrying out step (ii) neat. More particularly, in step (i), compound II.a, a photosensitizer (especially TPP, Zn-TPP or Ru(bpy)3 are provided. 2+ A salt (for example tris(2,2'-bipyridyl)ruthenium(II) hexafluorophosphate or tris(2,2'-bipyridyl)ruthenium(II) chloride)), acetic anhydride, pyridine or pyridine carrying 1, 2 or 3 methyl groups and DMAP (and step (iii) is not carried out), and step (ii) is carried out neat. Even more particularly, in step (i), compound II.a, a photosensitizer (especially TPP, Zn-TPP or Ru(bpy)3 are provided. 2+ salt (eg tris(2,2'-bipyridyl)ruthenium(II) hexafluorophosphate or tris(2,2'-bipyridyl)ruthenium(II) chloride)), acetic anhydride, pyridine and DMAP (and without carrying out step (iii)), and carrying out step (ii) neat.

[0248] Step (ii) is preferably carried out at a temperature of -20 to 150°C, more preferably 0 to 70°C, such as 0 to 60°C or 5 to 50°C.

[0249] Step (ii) is preferably carried out under the pressure of atmospheric pressure to 100 bar (10MPa). Atmospheric pressure means local environmental pressure, and is therefore roughly 1013.25hPa ± 200hPa. In a more preferred embodiment, step (ii) is carried out under the pressure of> 1 bar to 10 bar (> 0.1MPa to 1MPa), especially 1.5 bar to 8 bar (0.15MPa to 0.8MPa). In another more preferred embodiment, step (ii) is carried out under the pressure of 5 bar to 20 bar (0.5MPa to 2MPa) and especially 10 bar to 15 bar (1MPa to 1.5MPa). In another more preferred embodiment, step (ii) is carried out under atmospheric pressure.

[0250] In step (ii) the entire reaction mixture may be irradiated or only different parts of the reaction mixture may be irradiated. For example, the latter may occur if only a portion of the reaction mixture (e.g. only 20% to 90% by weight, or 30% to 80% by weight, or 50% to 80% by weight of the reaction mixture) is passed through the irradiation source.

[0251] Step (ii) can be carried out in any reactor known in the art to be suitable for photooxidation. Suitable reactors contain at least means for introducing an oxygen-containing gas and a radiation source. In addition, the reactor conveniently contains a stirrer and means for cooling or heating.

[0252] Examples of suitable reactors are side loop flow photoreactors, continuous flow photoreactors or submersible photoreactors.

[0253] In a specific embodiment, 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 serve as a solvent for other substances present in the reaction mixture. Preferably, at least 20%, more preferably at least 50% of the initial charge of compound II.a remains unreacted in step (ii). After post-treatment, separation and purification (as desired), 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 sample collection and analysis or coordinated analysis of the composition of the reaction mixture, or by passing oxygen through the reaction mixture in a predetermined substoichiometric amount. The reaction in step (ii) is interrupted, for example, by stopping the oxygen feed and / or by stopping the irradiation.

[0254] If no acylating agent is added in step (i) and step (iii) is therefore carried out, the acylating agent, optionally an acylating catalyst and optionally a base are added to the reaction mixture obtained in step (ii) after the reaction in step (ii) has been completed to the desired extent. For safety reasons, conveniently, the hydroperoxides formed in step (ii) are not isolated before being subjected to the acylation / dehydroacylation step (iii), but the reaction mixture is used directly in step (iii).

[0255] Step (iii) can be carried out neat (= essentially) or in the presence of a solvent. Generally speaking, the most common solvents can be used. Suitable solvents are, for example, aliphatic hydrocarbons such as pentane, hexane or heptane; alicyclic 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), chloroform (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-alkane Alcohols such as methanol, ethanol, n-propanol, isopropanol and butanol; C2-C3-alkanediols (diols) such as ethylene glycol or propylene glycol; open chain ethers such as diethyl ether, di-n-propyl ether or methyl tert-butyl ether; cyclic ethers such as tetrahydrofuran or 1,4-dioxane; ketones such as acetone or ethyl ketone; C1-C3-alkyl esters of C2-C3-carboxylic acids such as methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate or propyl propionate; nitrile such as acetonitrile; amides such as N,N,-dimethylformamide, N,N,-diethylformamide, N,N,-dimethylacetamide or N,N,-diethylacetamide; sulfoxides such as dimethyl sulfoxide; or CS2. Among them, preferred are chlorinated C1-C2-alkanes, chloro-fluoro-C1-C2-alkanes and CS2, and more preferred are chlorinated C1-C2-alkanes. However, it is preferred that step (iii) is carried out neat. "Neatly" or "substantially" means that no additional solvent is present. With regard to the specification "additional", reference is made to the comments made above in the context of step (i).

[0256] In a preferred embodiment of the method of the present invention, compound II.a, an acylating agent, a photosensitizer, a base and an acylation catalyst, which are optionally present, are provided in step (i) (and step (iii) is not carried out), and step (ii) is carried out neat. More preferably, compound II.a, a photosensitizer, an acylating agent, a base and an acylation catalyst are provided in step (i) (and step (iii) is not carried out), and step (ii) is carried out neat. In a particular embodiment, compound II.a, a photosensitizer (particularly TPP, Zn-TPP or Ru(bpy)3) are provided in step (i). 2+ A salt (for example tris(2,2'-bipyridyl)ruthenium(II) hexafluorophosphate or tris(2,2'-bipyridyl)ruthenium(II) chloride)), acetic anhydride, pyridine or pyridine carrying 1, 2 or 3 methyl groups and optionally DMAP (and without carrying out step (iii)), and carrying out step (ii) neat. More particularly, in step (i), compound II.a, a photosensitizer (particularly TPP, Zn-TPP or Ru(bpy)3 2+ A salt (for example tris(2,2'-bipyridyl)ruthenium(II) hexafluorophosphate or tris(2,2'-bipyridyl)ruthenium(II) chloride)), acetic anhydride, pyridine or pyridine carrying 1, 2 or 3 methyl groups and DMAP (and step (iii) is not carried out), and step (ii) is carried out neat. Even more particularly, in step (i), compound II.a, a photosensitizer (especially TPP, Zn-TPP or Ru(bpy)3 are provided. 2+ salt (eg tris(2,2'-bipyridyl)ruthenium(II) hexafluorophosphate or tris(2,2'-bipyridyl)ruthenium(II) chloride)), acetic anhydride, pyridine and DMAP (and without carrying out step (iii)), and carrying out step (ii) neat.

[0257] After the reaction is complete, step (ii) (if step (iii) is not carried out) or the reaction mixture obtained in step (iii) is usually treated. In this context, "completion" of the reaction does not necessarily mean the maximum conversion of the starting material, but rather the conversion to the desired degree. As explained above, the starting compound II.a usually serves as a solvent, especially if step (ii) is carried out neat. In this case, the reaction is conveniently stopped significantly before the maximum conversion of II.a.

[0258] Step (ii) (if step (iii) is not carried out) or the workup of the reaction mixture obtained in step (iii) can be carried out by conventional means, such as neutralization (if necessary or desired) and separation of the desired reaction products Ia and / or Ib (step (iv.1)), by separation from other 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 each other. The separation can be carried out by conventional means, such as extraction, distillation or chromatography.

[0259] If compounds Ia or Ib are formed as different stereoisomers, these can be separated from one another if desired.

[0260] In order to obtain compounds Ia and / or Ib, wherein R 1 is hydrogen, the compound Ia and / or Ib isolated according to step (iv.1) or from step (ii) (if step (iii) is not carried out) or the reaction mixture obtained from step (iii) is hydrolyzed, for example by reaction with an acid or with a base. If in compound II.a (and therefore also in the obtained compound Ia and / or Ib) R 1 Yes-C(O)R 2 , then hydrolysis is of course necessary (to obtain compounds Ia and / or Ib, wherein R 1 is hydrogen), but if in compound II.a R 1 It may also be necessary if the acylating agent is hydrogen, since a portion of the hydroxyl groups may be acylated by the acylating agent, especially if the acylating agent is used in excess.

[0261] If the reaction mixture obtained from step (ii) (if step (iii) is not carried out) or from step (iii) is hydrolyzed (step (v.1)), the reaction mixture obtained can be worked up and the desired reaction products Ia and / or Ib (step (iv.1)) can be separated from the other components of the reaction mixture and also from each other by customary means, such as extraction, distillation or chromatography.

[0262] The method of the present invention provides a simple method for preparing compounds Ia and / or Ib starting from readily available bulk chemicals prenyl alcohol and prenyl alcohol ester II.a. Compounds Ia and Ib can serve as retinol, its stereoisomers, derivatives thereof (preferably esters thereof; in particular, wherein the OH group of retinol is esterified to -OC(O)R 2 esters of) or stereoisomers of their derivatives (preferably stereoisomers of their esters; in particular, wherein the OH group of retinol is esterified to -OC(O)R 2Compound Ia can be converted into compound Ib by known Pd-catalyzed double bond isomerization reactions, as described, for example, in US 4,124,619 or CN 103467287.

[0263] Furthermore, the present invention relates to the use of a compound of formula Ia or Ib other than (E)-4-acetoxy-2-methylbut-2-enal, or a stereoisomer of compound Ia or Ib other than (E)-4-acetoxy-2-methylbut-2-enal, or a mixture of different stereoisomers of compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib as defined above, as retinol, its stereoisomers, its derivatives (preferably its esters; in particular wherein the OH group of retinol is esterified to -OC(O)R 2 esters of) or stereoisomers of their derivatives (preferably stereoisomers of their esters; in particular, wherein the OH group of retinol is esterified to -OC(O)R 2 As explained above, compound Ia can be easily converted to Ib. The latter can be reacted with β-ionideneethyltriphenylphosphonium salt to retinol in a Wittig reaction (if R in Ib is 1 =H, this directly produces), its stereoisomers, its esters (if in Ib R 1 =-C(O)R 2 , where the OH group of retinol is esterified to -OC(O)R 2 The ester is directly produced) or a stereoisomer of its ester, as described, for example, by J. Paust et al. in Carotenoids, 1996, Vol. 2, pp. 258-292, in US 5,087,762, in H. Ernst, Pure Appl. Chem. 2002, 74, 2213 or in GL Parker et al., Tetrahedron 2016, 72, 1645-1652. Other retinol derivatives are obtainable by conventional means; for example, by using different R 2 -C(O)OH or an acid or acid derivative thereof; 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 a retinol ester (or its stereoisomer). These transformations are well known in the art.

[0264] Furthermore, the present invention relates to a hydroperoxide compound of the formula III.a, III.b or III.c, or a stereoisomer of a compound of the formula III.a, III.b or III.c, or a mixture of different stereoisomers of the compound III.a and / or III.b and / or III.c, or a mixture of different compounds III.a, III.b and / or III.c

[0265]

[0266] in

[0267] In compound III.a, R 1 is hydrogen or -C(=O)R 2 ; and R 2 It is C1-C 20 -alkyl;

[0268] In compound III.b, R 1 Yes-C(=O)R 2 ; and R 2 It is C1-C 20 -alkyl; and

[0269] In compound III.c, R 1 is hydrogen or -C(=O)R 2 ; and R 2 It is C1-C 20 -alkyl.

[0270] The hydroperoxides III.a, III.b and III.c are formed in step (ii) of the process according to the 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 also isolated, since their further reaction / decomposition in the absence of an acylating agent is rather slow.

[0271] The present invention preferably relates to a hydroperoxide compound of the formula III.a or III.b, or a stereoisomer of a compound of the 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.

[0272] The present invention alternatively preferably relates to one hydroperoxide 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 compounds III.a and / or III.c, or a mixture of different compounds III.a and / or III.c.

[0273] The present invention particularly relates to a hydroperoxide compound of the formula III.a, or a stereoisomer of a compound of the formula III.a, or a mixture of different stereoisomers of a compound III.a, or a mixture of different compounds III.a.

[0274] Furthermore, the present invention relates to the use of a hydroperoxide compound of the formula III.a, III.b or III.c as defined above, or a stereoisomer of a compound of the 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, wherein, however, in compound III.b R 1 It may also be hydrogen, which is used as an intermediate in the synthesis of a compound of formula Ia or Ib as defined above, 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, or as retinol, its stereoisomers, its derivatives (preferably its esters; in particular wherein the OH group of retinol is esterified to -OC(O)R 2 esters of) or stereoisomers of their derivatives (preferably stereoisomers of their esters; in particular, wherein the OH group of retinol is esterified to -OC(O)R 2 esters) in the synthesis of intermediates.

[0275] The conversion of compound III.a and / or III.b into compound Ia and / or Ib is carried out by subjecting compound III.a and / or III.b to step (iii) and optionally steps (iv) and (v) of the method of the present invention described above. Compound Ia and / or Ib can be converted into retinol, its stereoisomers, its derivatives or stereoisomers of its derivatives as described above.

[0276] The present invention preferably relates to the use of a hydroperoxide compound of formula III.a or III.b as defined above, 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, wherein, however, in compound III.b R 1It may also be hydrogen, which is used as an intermediate in the synthesis of a compound of formula Ia or Ib as defined above, 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, or as retinol, its stereoisomers, its derivatives (preferably its esters; in particular wherein the OH group of retinol is esterified to -OC(O)R 2 esters of) or stereoisomers of their derivatives (preferably stereoisomers of their esters; in particular, wherein the OH group of retinol is esterified to -OC(O)R 2 esters) in the synthesis of intermediates.

[0277] The present invention particularly relates to the use of a hydroperoxide compound of formula III.a, or a stereoisomer of a compound of formula III.a, or a mixture of different stereoisomers of compound III.a, or a mixture of different compounds III.a, as an intermediate in the synthesis of a compound of formula Ia or Ib, or a stereoisomer of compound Ia or Ib, or a mixture of different stereoisomers of compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib as defined above, or as retinol, its stereoisomers, its derivatives (preferably its esters; in particular wherein the OH group of retinol is esterified to -OC(O)R 2 esters of) or stereoisomers of their derivatives (preferably stereoisomers of their esters; in particular, wherein the OH group of retinol is esterified to -OC(O)R 2 esters) in the synthesis of intermediates.

[0278] The following examples are used to further illustrate the present invention.

[0279] Example

[0280] Compounds by 1 H-NMR and also partially through 13 The signals are characterized by C-NMR. NMR analysis was performed on Bruker 400 MHz, 500 MHz and 700 MHz spectrometers in CDCl3. The signals are characterized by the chemical shift (ppm) relative to tetramethylsilane, their multiplicity and their integration (relative number of given hydrogen atoms). The following abbreviations are used to characterize the multiplicity of the signals: m = multiplet, q = quartet, t = triplet, d = doublet and s = singlet.

[0281] 1. Photooxidation and simultaneous Kornblum-DeLaMare rearrangement of isoprene acetate in a double-jacketed reactor

[0282] Example 1 to Example 4

[0283] Equipment: Double-jacketed vessel, cylindrical with tempered outer jacket, inner diameter 45 mm, total volume 150 mL (reaction volume approximately 24 mL, corresponding to approximately 18 mm filling height), illuminated from below by 24 LEDs with a wavelength of 405 nm and a total radiant power of 27 W, impeller stirrer.

[0284] In a 50 mL glass vial, 12.46 g (97.2 mmol, 1 equivalent) of isoprene acetate (IPA; Compound II.a, wherein R 1 =-C(O)CH3), 6.15g (77.7mmol, 0.8 equivalent) pyridine and 3.96g (38.8mmol, 0.4 equivalent) acetic anhydride mixture, and as NMR internal standard 0.68g (3.5mmol, 0.036 equivalent) dimethyl phthalate, 0.21g (1.75mmol, 0.018 equivalent) N, N-dimethylaminopyridine (DMAP) (Example 4: 0.009 equivalent DMAP) and 4.4μmol (0.000045 equivalent) photosensitizer (Examples 1, 2 and 4: tetraphenylporphyrin (TPP), Example 3: tetraphenylporphyrin zinc (Zn-TPP), Example 4: 0.000067 equivalent TPP) were dissolved in the mixture. The reaction mixture was poured into a temperature-controlled double-jacketed container and stirred at 1000rpm. At the temperature indicated in the table below, the solution was irradiated from below for a period of 6 hours while 2 L / h of oxygen was introduced into the solution. During the reaction, up to 34 μmol of photosensitizer were added in batches. The reaction was clearly terminated before the complete conversion of isoprene acetate (the conversion rates for each experiment are listed in Table 1). At the end of the experiment, the reaction mixture was analyzed without further post-treatment. No hydroperoxides were detected. The results are summarized in Table 1.

[0285] Table 1

[0286]

[0287] 1 Yield relative to the amount of IPA used in the reaction (here 97.2 mmol)

[0288] *Zn-TPP instead of TPP

[0289] **0.009 equivalent DMPA; 0.000067 equivalent TPP

[0290] # Compound Ia, wherein R 1 =C(O)CH3

[0291] ## A mixture of E isomers and Z isomers of compound Ib, wherein R1 =C(O)CH3

[0292] 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)

[0293] Ib ## : 1 H-NMR (400MHz, CDCl3): δ = 9.56 (1H), 6.10 (1H), 4.60 (2H), 2.03 (3H), 1.84 (3H)

[0294] Example 5

[0295] Equipment: Same as in Examples 1 to 4, however illuminated from below by 24 LEDs with a wavelength of 465 nm and a total radiant power of 31 W.

[0296] In a 50 mL glass bottle, a mixture of 12.57 g (98 mmol, 1 equivalent) of isoprene acetate (IPA), 6.21 g (78.5 mmol, 0.8 equivalent) of pyridine and 4.0 g (39.2 mmol, 0.4 equivalent) of acetic anhydride was prepared, and 0.68 g (3.5 mmol, 0.036 equivalent) of dimethyl phthalate, 0.1 g (0.87 mmol, 0.009 equivalent) of N,N-dimethylaminopyridine (DMAP) as an NMR internal standard and 6.7 mg (7.8 μmol, 0.00008 equivalent) 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 container and stirred at 1000 rpm. The solution was irradiated from below for a period of 6 hours at 12°C while 2 L / h of oxygen was introduced into the solution. During the reaction, another 3.9 mg (4.5 μmol, 0.000046 eq.) of photosensitizer was added. The reaction was apparently terminated before the complete conversion of isoprene acetate (the conversion rates of the experiment are listed in Table 2). At the end of the experiment, the reaction mixture was analyzed without further post-treatment. No hydroperoxides were detected. The results are summarized in Table 2.

[0297] Table 2

[0298]

[0299] 1 Yield relative to the amount of IPA used in the reaction (here 98 mmol)

[0300] Example 6

[0301] Equipment: Same as in Example 1 to Example 4

[0302] In a 50 mL glass vial, a mixture of 7.1 g (55.4 mmol, 1 eq) of isoprene 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, and 0.69 g (3.55 mmol, 0.064 eq) of dimethyl phthalate, 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 as a photosensitizer were dissolved in the mixture. The reaction solution was poured into a temperature-controlled double-jacketed container and stirred at 1000 rpm. The solution was irradiated from below at 32°C for a period of 6 hours while 1.5 L / h of oxygen was introduced into the solution. During the reaction, a further 32.8 mg (53.4 μmol, 0.00096 eq.) of photosensitizer was added in batches. The reaction was apparently terminated before the complete conversion of isoprene acetate (the conversion rates of the experiment are listed in Table 3). At the end of the experiment, the reaction mixture was analyzed without further post-treatment. No hydroperoxides were detected. The results are summarized in Table 3.

[0303] Table 3

[0304]

[0305] 1 Yield relative to the amount of IPA used in the reaction (here 55.4 mmol)

[0306] 2. Photooxidation of isoprene acetate in a G1 photoreactor and simultaneous Kornblum-DeLaMare Rearrange

[0307] equipment: G1 reactor (5 tempered G1 plates, layer thickness approximately 1 mm, each illuminated on both sides by LEDs, a total of 200 LEDs with a wavelength of 405 nm and a total radiant power of 195 W), 100 mL small device reactor as feed container, impeller stirrer, gear pump.

[0308] Example 7 to Example 9

[0309] In a 100 mL mini-unit reactor, a mixture of 83.0 g (647.5 mmol, 1 eq) of isoprene 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, and 4.55 g (23.3 mmol, 0.036 eq) of dimethyl phthalate as an NMR internal 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 loop to The solution was irradiated at the temperature and pressure indicated in Table 6 for a period of 6 hours while 3 L / h of oxygen (Example 8: air; Example 9: a mixture of oxygen:nitrogen = 1:1) was introduced into the reactor. The reaction mixture was stirred for 2 hours at room temperature for 1 000 rpm. ...

[0310] Table 4

[0311]

[0312] 1 Yield relative to the amount of IPA used in the reaction (here 647.5 mmol)

[0313] *Air instead of oxygen

[0314] ** A mixture of oxygen and nitrogen with a mixing ratio of 1:1

[0315] Example 10

[0316] In a 100 mL mini-unit reactor, a mixture of 56.5 g (440.8 mmol, 1 eq) of isoprene 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, and 4.55 g (23.4 mmol, 0.053 eq) of dimethyl phthalate as an NMR internal standard, 26.5 g (222 mmol, 0.5 eq) of chloroform, 2.86 g (23.41 mmol, 0.053 eq) of N,N-dimethylaminopyridine 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 loop to The solution was irradiated at 30°C for a period of 6 hours while 3 L / h of oxygen was introduced at 1.9 bar to 2.4 bar. The reaction mixture was stirred for 2 hours at room temperature for 1 000 rpm and then stirred for 2 hours at room temperature. The reaction mixture was stirred for 2 hours at room temperature for 1 000 rpm ...

[0317] Table 5

[0318]

[0319] 1 Yield relative to the amount of IPA used in the reaction (here 440.8 mmol)

[0320] Embodiment 11

[0321] In a 100 mL small-scale reactor, a mixture of 43.25 g (337.4 mmol, 1 eq) of isoprene 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, and 4.55 g (23.4 mmol, 0.069 eq) of dimethyl phthalate as an NMR internal 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 as a photosensitizer were dissolved in the mixture. The reaction solution was stirred at 100 rpm and pumped in a loop to The solution was irradiated at 50°C for a period of 6 hours while 3 L / h of oxygen was introduced at 1.9 bar to 2.3 bar. The reaction mixture was stirred for 2 hours at room temperature for 1 000 rpm. ...

[0322] Table 6

[0323]

[0324] 1 Yield relative to the amount of IPA used in the reaction (here 337.4 mmol)

[0325] 3. Photooxidation of isoprene acetate in a G3 photoreactor and simultaneous Kornblum-DeLaMare Rearrange

[0326] equipment: G3 reactor (tempered G3 plates, layer thickness approximately 1 mm, each illuminated on both sides by LEDs, a total of 384 LEDs with a wavelength of 470 nm and a total radiant power of 576 W), feed container, gear pump.

[0327] Example 12

[0328] In a 500 mL glass vial, a mixture of 155 g (1209 mmol, 1 equivalent) of isoprene acetate (IPA), 76.6 g (0.8 equivalent) of pyridine and 49.4 g (0.4 equivalent) of acetic anhydride was prepared, and 8.22 g (0.035 equivalent) of dimethyl phthalate as an NMR internal standard, 1.33 g (0.009 equivalent) of N,N-dimethylaminopyridine and 79 mg (0.000076 equivalent) of tris-(2,2'-bipyridyl)-ruthenium bis-(hexafluorophosphate) as a photosensitizer were dissolved in the mixture. The reaction solution was poured into a feed container and then pumped to The solution was irradiated at 18°C ​​for a period of 6 hours while 3 L / h of oxygen was introduced into the reactor at 5 bar. The reaction was terminated before the complete conversion of isoprene acetate (the conversions of the experiment 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.

[0329] Table 7

[0330]

[0331] 1 Yield relative to the amount of IPA used in the reaction (here 1209 mmol)

[0332] Example 13

[0333] In a 500 mL glass vial, a mixture of 103.0 g (803.6 mmol, 1 eq) of isoprene 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, and 5.48 g (28.2 mmol, 0.035 eq) of dimethyl phthalate as an NMR internal 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 container and then pumped to The solution was irradiated at 18°C ​​for a period of 6 hours while 3 L / h of oxygen was introduced into the reactor at 5 bar. The reaction was terminated before the complete conversion of isoprene acetate (the conversions of the experiment 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.

[0334] Table 8

[0335]

[0336] 1 Yield relative to the amount of IPA used in the reaction (here 803.6 mmol)

[0337] 4. Photooxidation of isoprene acetate to isoprene acetate hydroperoxide

[0338] Embodiment 14

[0339] equipment: G1 photoreactor (5 tempered G1 plates, layer thickness approximately 1 mm, each illuminated by LEDs on both sides, a total of 200 LEDs with a wavelength of 405 nm and a total radiant power of 195 W), 100 mL small device reactor, impeller stirrer, gear pump.

[0340] In a 100 mL mini-unit reactor, a mixture of 135.0 g (1053.3 mmol, 1 eq) of isoprene acetate (IPA) and 6.22 g (32.0 mmol, 0.03 eq) of dimethyl phthalate as an NMR internal standard was prepared, and 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 loop to The solution was irradiated at the temperature indicated in Table 9 for a period of 6 hours while 3 L / h of oxygen was introduced at 1.7 bar to 2.4 bar. The reaction was terminated before the complete conversion of isoprene acetate (the conversions of the experiment are 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.

[0341] Table 9

[0342]

[0343] 1 Yield relative to the amount of IPA used in the reaction (here 1053.3 mmol)

[0344] + Compound III.a, wherein R 1 =-C(O)CH3

[0345] 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)

[0346] 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)

[0347] In addition, compound III.c was identified, where R 1 =-C(O)CH3, which is assumed to be the result of further photooxidation of compound III.b competing with the conversion of III.b to Ib, or directly the result of (double) photooxidation of II.a:

[0348] III.c + : 1H-NMR (700MHz, CDCl3): δ=5.45(1H),5.41(1H),4.71(1H),4.55(2H),4.39(2H),2.09(3H)

[0349] 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)

[0350] 5. Photooxidation of isoprenol to isoprenol hydroperoxide

[0351] Embodiment 15

[0352] equipment: G1 photoreactor (5 tempered G1 plates, layer thickness approximately 1 mm, each illuminated by LEDs on both sides, a total of 200 LEDs with a wavelength of 610 nm and a total radiant power of 83 W), 100 mL small device reactor, impeller stirrer, gear pump.

[0353] In a 100 mL small-scale reactor, 135.0 g (1567.4 mmol, 1 equivalent) of isoprenol (IP; Compound II.a, wherein R 1 The reaction solution was stirred at 300 rpm and pumped to a reactor at 100 mL / min in a loop. The solution was irradiated for a period of 4 hours at 30°C while 3 L / h of oxygen was introduced into the reactor at 5 bar. The reaction mixture was stirred for 2 h at room temperature for 1 h. The reaction mixture was stirred for 2 h at room temperature for 1 h. The reaction mixture was stirred for 2 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 2 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 2 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 2 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 2 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 4 ...2 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 2 h.

[0354] Table 10

[0355]

[0356] 1 Yield relative to the amount of IP used in the reaction (here 1567.4 mmol)

[0357] ++ Compound III.a, wherein R1 =H

[0358] ### Compound Ia, wherein R 1 =H

[0359] III.a ++ : 1 H-NMR (400MHz, CDCl3): δ=5.24(1H),5.16(1H),4.47(2H),3.86(2H),2.41(2H)

[0360] Example 16

[0361] Equipment: Double-jacketed vessel, cylindrical with tempered outer jacket, inner diameter 45 mm, total volume 150 mL (reaction volume approximately 38 mL, corresponding to approximately 24 mm filling height), illuminated from below by 24 LEDs with a wavelength of 405 nm and a total radiant power of 27 W, impeller stirrer.

[0362] In a 50 mL glass vial, a mixture of 30.0 g (348.3 mmol, 1 eq.) isoprenol (IP), 1.39 g (7.2 mmol, 0.021 eq.) dimethyl phthalate and 1.5 g (12.5 mmol, 0.036 eq.) chloroform as an NMR internal standard was prepared, and 4.6 mg (7.5 μmol, 0.000021 eq.) tetraphenylporphyrin as a photosensitizer was dissolved in the mixture. The reaction solution was poured into a temperature-controlled double-jacketed container and stirred at 800 rpm. The solution was irradiated at 10° C. for a period of 5 hours while 2 L / h of oxygen was introduced into the solution. During the reaction, another 8.2 mg (13.3 μmol) of photosensitizer was added in batches. The reaction was clearly terminated before the complete conversion of isoprenol (the conversion rates of the experiments are listed in Table 11). At the end of the experiment, the reaction mixture was analyzed without further post-treatment. The results are summarized in Table 11.

[0363] Table 11

[0364]

[0365] 1 Yield relative to the amount of IP used in the reaction (here 348.3 mmol)

[0366] 6. Kornblum-DeLaMare rearrangement of hydroperoxide III.a, where R 1 =H

[0367] Embodiment 17

[0368] Equipment: 0.25 l small-scale reactor with impeller stirrer, 4-fold baffle, ministat, dropping funnel.

[0369] 1.81 g (15.32 mmol) of prenol hydroperoxide (Compound III.a, wherein R 1 =H) in isoprenol was placed in a 250 mL small-scale reactor, 133 g of dichloromethane was added, and then 33.48 g (423.26 mmol) of pyridine was added dropwise at 17°C within 10 min. After cooling to 3°C, 17.28 g (169.26 mmol) of acetic anhydride was added within 20 min. The reaction mixture was stirred at 0°C for 17.25 h, and then 50 g of water was added within 30 min. 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 a saturated NaHCO3 solution, and once with water. The red-brown organic phase was then concentrated on a rotary evaporator at 40°C / 30 mbar. 1.68 g (11.8 mmol, 77%) of R was obtained. 1 It is a solution of 8.98 g of compound Ia in prenyl acetate.

[0370] The yields given above are relative to the amount of the starting compound (IPA or IP) used in the reaction. Since the reaction is carried out so that only a relatively small portion of the starting compound reacts (and the remaining portion can further serve as a dispersion medium), the yield based only on the amount of starting material reacted reflects the effectiveness of the reaction. These yields can be calculated by correlating the yields of Ia and Ib with the amount of conversion of IPA or IP (not shown in the above table).

Claims

1. A method for preparing a compound of formula Ia or formula Ib or a mixture thereof, or a stereoisomer of said compound Ia or Ib, or a mixture of different stereoisomers of said compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib in R 1 is hydrogen or -C(=O)R 2 ;and R 2 It is C1-C 20 -alkyl; The method comprises (i) providing a reaction mixture comprising a compound of formula II.a, a photosensitizer and optionally an acylating agent: Where R 1 As defined above; (ii) passing an oxygen-containing gas through the reaction mixture provided in step (i) while irradiating the reaction mixture with light; (iii) adding an acylating agent to the reaction mixture obtained in step (ii) if the acylating agent has not been provided in step (i); (iv.1) if desired, after completion of the reaction, isolating the one or more compounds (Ia) or (Ib) obtained in step (ii) or (iii); and (v.1) if desired, hydrolyzing the one or more compounds (Ia) or (Ib) isolated in step (iv.1) to form compounds (Ia) or (Ib) wherein R 1 It is hydrogen; or (iv.2) if desired, hydrolyzing the reaction mixture obtained in step (ii) or (iii); and (v.2) if desired, isolating the one or more compounds (Ia) or (Ib) obtained in step (iv.2).

2. The method according to claim 1, wherein R 2 is C1-C4-alkyl or n-C 15 -alkyl.

3. The method according to claim 2, wherein R 2 is C1-C4-alkyl, preferably methyl.

4. The process according to any one of the preceding claims, wherein the acylating agent used in step (i) or (iii) is selected from the group consisting of: a carboxylic acid halide R 2a -C(=O)-X, carboxylic anhydride R 2a -C(=O)-OC(=O)-R 2a and enone R 2a -C(H)=C=O, where R 2a Independently having any one of claims 1 to 3 for R 2 one of the meanings given, and X is Cl, Br or I.

5. The process according to claim 4, wherein the acylating agent used in step (i) or (iii) is a carboxylic anhydride R 2a -C(=O)-OC(=O)-R 2a , where R 2a It is C1-C4-alkyl, preferably methyl.

6. The method according to any one of the preceding claims, wherein the photosensitizer is selected from the group consisting of: fluorescein, eosin, rose bengal, erythrosine, tetraphenylporphyrin, tetraphenylporphyrin cobalt, tetraphenylporphyrin zinc, hematoporphyrin, rhodamine B, Besickel's brilliant red, methyl violet, methylene blue, fullerene C 60 , Fullerene C 70 , graphene, carbon nanotubes, Ru(bpy)3 2+ Salt, Ru(phen)3 2+ Salts, cercosporin, hypocrellin-A and mixtures thereof.

7. The method according to claim 6, wherein the photosensitizer is selected from the group consisting of tetraphenylporphyrin, cobalt tetraphenylporphyrin, zinc tetraphenylporphyrin, methylene blue, Ru(bpy)3 2+ Salt and Ru(phen)3 2+ salt, and is preferably selected from tetraphenylporphyrin, tetraphenylporphyrin zinc and Ru(bpy)3 2+ Salt.

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

9. The method according to any one of claims 7 or 8, wherein the photosensitizer is tetraphenylporphyrin, tetraphenylporphyrin cobalt or tetraphenylporphyrin zinc, and in step (ii), the reaction mixture is irradiated with light having a wavelength in the range of 400 nm to 430 nm, preferably 400 nm to 420 nm, preferably monochromatic light; or the photosensitizer is methylene blue, and in step (ii), the reaction mixture is irradiated with light having a wavelength in the range of 600 nm to 620 nm, preferably monochromatic light, or the photosensitizer is Ru(bpy)3 2+ Salt or Ru(phen)3 2+ salt, and in step (ii), irradiating the reaction mixture with light, preferably monochromatic light, having a wavelength in the range of 450 nm to 480 nm, preferably 460 nm to 475 nm.

10. A method according to any one of the preceding claims, wherein the oxygen-containing gas used in step (ii) is selected from the group consisting of oxygen, air and a mixture of oxygen and nitrogen, the mixture containing oxygen in a range of 1 wt % to 99 wt % relative to the gross weight of the mixture, wherein the oxygen-containing gas used in step (ii) is preferably oxygen.

11. The process according to any one of the preceding claims, wherein step (ii) is performed neat.

12. The process according to any one of claims 1 to 10, wherein step (ii) is carried out in the presence of a chlorinated C1-C2-alkane, wherein the molar ratio of the compound (II.a) provided in step (i) to the chlorinated C1-C2-alkane is 10:1 to 1:1.5, preferably 5:1 to 1:

1.

13. The process according to any one of the preceding claims, wherein in case an acylating agent has been provided in step (i), step (ii) is carried out in the presence of a base, preferably an organic base, and in case an acylating agent has not been provided in step (i), a base, preferably an organic base, is also added in step (iii) to the reaction mixture obtained in step (ii), wherein the base is preferably selected from tertiary amines, basic 3- to 10-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycles containing 1, 2, 3 or 4 nitrogen atoms as ring members, guanidines and amidines, wherein the base is more preferably selected from the group consisting of: -Formula N(R 3 )3 tertiary amine, wherein each R 3 are independently C1-C4-alkyl; - a 3- to 8-membered saturated monocyclic or bridged heterocyclic ring containing 1 or 2 nitrogen atoms or 1 nitrogen atom and one oxygen atom as ring members; in particular, of the formula NR 31 (R 32 )2, wherein R 31 are hydrogen or C1-C4-alkyl, and both R 32 Together they form a bridging group -(CH2) n -, wherein 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-, where R 33 is hydrogen or C1-C4-alkyl; or DABCO; - a 5- to 10-membered monocyclic or bicyclic heteroaromatic ring containing 1 or 2 nitrogen ring atoms as ring members; in particular chosen from the group consisting of imidazole, pyridine, pyrazine, pyridazine, pyrimidine, quinolone and isoquinoline; wherein the monocyclic or bicyclic heteroaromatic ring is unsubstituted or carries 1, 2 or 3 C1-C4-alkyl substituents; -Formula (R 3 )2N-C(=NR 3 )-N(R 3 )2 guanidine, wherein each R 3 are independently C1-C4-alkyl, or the two R are bound to the same nitrogen atom or to different nitrogen atoms 3 Together they form a bridging group -(CH2) n -, where n is 2, 3, 4 or 5; and - Bicyclic amidine DBN or DBU.

14. The process according to claim 13, wherein in case an acylating agent is provided in step (i), step (ii) is carried out in the presence of a base selected from a 5- to 10-membered monocyclic or bicyclic heteroaromatic ring containing 1 or 2 nitrogen ring atoms as ring members; wherein the base is preferably selected from the group consisting of imidazole, pyridine, pyrazine, pyridazine, pyrimidine, quinolone and isoquinoline; wherein the mono- or bicyclic heteroaromatic ring is unsubstituted or carries 1, 2 or 3 C1-C4-alkyl substituents.

15. The process according to claim 14, wherein the base is a pyridine which is unsubstituted or carries 1, 2 or 3 C1-C4-alkyl substituents, The base is preferably selected from pyridine, picoline and lutidine, and is particularly pyridine.

16. The process according to any one of the preceding claims, wherein in case an acylating agent has been provided in step (i), step (ii) is carried out in the presence of an acylating catalyst, and in case an acylating agent has not been provided in step (i), an acylating catalyst is also added in step (iii) to the reaction mixture obtained in step (ii); The acylation catalyst is preferably selected from the group consisting of 4-dimethylaminopyridine DMAP, 4-pyrrolidinylpyridine 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 Each R 4 is independently methyl or ethyl.

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

18. A process according to any one of the preceding claims, wherein in step (i) an acylating agent, a base and optionally an acylation catalyst are provided (and step (iii) is not carried out), wherein preferably in step (i) an acylating agent, an acylation catalyst and a base are provided.

19. A hydroperoxide compound of formula III.a, III.b or III.c, or a stereoisomer of said compound of formula III.a, III.b or III.c, or a mixture of different stereoisomers of said compound III.a, III.b and / or III.c, or a mixture of different compounds III.a, III.b and / or III.c in In compound III.a, R 1 is hydrogen or -C(=O)R 2 ; and R 2 It is C1-C 20 -alkyl; In compound III.b, R 1 Yes-C(=O)R 2 ; and R 2 It is C1-C 20 -alkyl; and In compound III.c, R 1 is hydrogen or -C(=O)R 2 ; and R 2 It is C1-C 20 -alkyl; Preference is given to one hydroperoxide compound of the formula III.a or III.b, or a stereoisomer of said compound of the formula III.a or III.b, or a mixture of different stereoisomers of said compounds III.a and / or III.b, or a mixture of different compounds III.a and / or III.b.

20. Use of 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 and / or III.b and / or III.c, according to claim 19, wherein R 1 It can also be hydrogen, preferably the use of a hydroperoxide compound of formula III.a or III.b according to claim 19, or a stereoisomer of a 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, wherein, however, in compound III.b R 1 It may also be hydrogen; it is used as an intermediate in the synthesis of a compound of formula Ia or Ib according to any one of claims 1 to 3, or a stereoisomer of the compound Ia or Ib, or a mixture of different stereoisomers of the compound Ia and / or Ib, or a mixture of different compounds Ia and / or Ib, or as an intermediate in the synthesis of retinol, its stereoisomers, its derivatives, or stereoisomers of its derivatives, wherein the derivative of retinol is preferably selected from the group consisting of: retinol esters, retinal and retinoic acid.

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