Isomerization of polyunsaturated non-aromatic compounds

Abstract

The present invention relates to an improved method for isomerizing polyunsaturated non-aromatic compounds, including acyclic conjugated polyenes and alicyclic conjugated polyenes. In particular, it relates to an improved and safe method for producing 11-E retinoid compounds in high yields with as little energy consumption as possible and by maximally avoiding by-products and product mixtures. This is achieved by feeding at least one retinoid compound of Formulas 2-5, or at least one retinoid compound of Formulas 2-5 and a retinoid compound of Formula 1, an organic solvent, and a photosensitizer into a reactor, and irradiating the resulting reaction mixture with visible monochromatic light, wherein at least 90% and up to 100% of the power of the monochromatic light is emitted in the range of 460 nm to 580 nm.

Description

Technical Field

[0001] The present invention relates to an improved method for isomerizing polyunsaturated non-aromatic compounds containing acyclic conjugated polyenes and alicyclic conjugated polyenes. In particular, it relates to an improved and safe method for producing all-E retinoid compounds in high yield by minimizing energy consumption and avoiding as much as possible any possible by-products or product mixtures.

Background Art

[0002] DE 25 48 883 describes a method for photo-isomerizing vitamin A compounds of different conformations to the all-E form using a 150 W xenon gas discharge lamp or a xenon arc lamp (see Examples 1 and 2). Such a xenon arc lamp results in an emission spectrum or output profile as shown in FIG. 1. It is observed that a large peak or mountain extends from 240 nm to 1000 nm, that is, extensive emission also occurs in the range of 240 nm to 400 nm. Such emission (UV light) can cause all kinds of isomerizations and can even cause undesirable compounds such as 9Z-retinoids (DE 25 48 883, page 5) which are difficult to convert to all-E retinoid compounds (synonymous with all-trans retinoid compounds) by further irradiation. In all embodiments, regardless of the composition of the starting material, a mixture of isomers (for example, 60-90% all-E, 10-30% 9Z, and 5% 13Z retinol acetate) is obtained. This means that a starting material already containing an excess of all-E retinoid compound reduces said excess all-E upon photo-irradiation with a xenon arc lamp. Furthermore, most of the high-energy irradiation in the UV range is suitable for irreversibly bleaching or destroying polyene compounds such as vitamin A. Another drawback of UV light is dimer formation and solvolysis (see DE 2 210 800, from line 66 of column 1 to line 4 of column 2).

[0003] DE 25 48 883 specifically claims that the irradiation occurs between 240 nm and 450 nm, thereby accepting the above-mentioned disadvantages. Protective measures such as photosensitizers, which would at least partially prevent the loss of vitamin A compounds caused by light of this wavelength, are expressly excluded (see claim 1). Similarly, filtering measures are proposed only to prevent the transmission of light below 240 nm into the reaction chamber (see page 7, paragraph 3). Thus, high-energy UV light starting from 240 nm that penetrates further inside the reactor may intentionally interact with and damage the vitamin A compounds.

[0004] According to the output profile in Fig. 1, xenon gas discharge lamps or xenon arc lamps show a spectrum with strong emission almost covering the entire range from far ultraviolet light to infrared light. In fact, a large amount of energy consumed by xenon gas discharge tubes or xenon gas discharge lamps is released in the form of heat (about 64%), thus making them a not very environmentally friendly light source. Furthermore, a large amount of electrical energy applied to produce light irradiation by xenon gas discharge is dissipated at wavelengths that do not affect the isomerization of cis-vitamin A compounds. Utilizing only a small part of the light spectrum emitted by xenon arc lamps or xenon gas discharge lamps would mean not only a large waste of valuable electrical energy, especially when used on an industrial scale, but also providing an expensive means to release excess heat, i.e., infrared light emitted by the lamp.

[0005] A further disadvantage of using a xenon gas discharge lamp is its high price. During operation, high temperature, temperature gradient and high pressure occur inside the lamp, making it not easy to handle and having low safety. Such operating conditions are likely to cause severe burns upon contact or make it easy to get cut by an explosion caused by mechanical shock to which the lamp may be exposed during operation. As a result, such lamps can only be used by specially trained staff and require the use of protective clothing. Most xenon discharge lamps require a cooling device and an explosion-proof housing to operate safely. This is cumbersome to handle and expensive.

[0006] Still another disadvantage of document DE 25 48 883 is the use of a base, namely tripropylamine, in the photo-isomerization process. The use of a base together with a poly-unsaturated compound may lead to further reactions, especially under the photo-irradiation conditions described in this publication. This base has to be removed.

[0007] EP 0 742 204 A1 discloses a method for converting 11-cis, 13-cis retinoic acid to 13-cis retinoic acid by irradiating at a wavelength of 400 to 700 nm from an 8W Hitachi lamp F875 / CW in a solvent mixture containing 7 parts of acetonitrile having a triple bond and 3 parts of methylene chloride. The formation of all-trans retinoic acid is not disclosed.

[0008] In V. Raj Gopal et al., J. Photochem. Photobiol. A: Chem. 74 (1993), 81-84, retinol and retinol acetate solutions were suspended with semiconductors CdS and CdSe and irradiated with a 450W medium-pressure mercury lamp. NaNO2- and K2CrO7-CuSO4 were used as filtering means to remove wavelengths below 500 nm and below 400 nm. This configuration is sensitive to oxygen, which acts as an effective quencher. The photoisomerization process is selectively restricted to the trisubstituted double bonds of retinoids (13-cis and 9-cis). The amount of the all-trans isomer decreases over time (see Figures 1 and 2), favoring the formation of the 13-cis isomer. No method for increasing the amount of all-trans retinoid was described.

[0009] DE 22 10 800 teaches the isomerization of a mixture of vitamin A isomers by a high-pressure mercury lamp doped with thallium iodide in the presence of a photosensitizer (see in particular Example 1). The harmful short-wave light is partially filtered out by a potassium chromate solution acting as a filtering means (see Example 1). However, the chromate solution still shows a strong transmission between 290 nm and 360 nm, as can be seen in FIG. 2. This means that only UV light below 290 nm is successfully filtered out by the filtering means, while the UV light part above 290 nm remains and reacts by irradiating the sample (see Table A in 1 below, especially the radiant flux generated by a high-pressure mercury lamp doped with thallium iodide of the TQ 150 Z2 type at wavelengths of 313, 322, 334, 352 and 366 nm).

[0010] Working with thallium iodide-doped high-pressure mercury lamps under the conditions described in Example 1 of DE 22 10 800 already makes it possible to eliminate to some extent the harmful high-energy light and to avoid side reactions more efficiently than in DE 25 48 883. However, the use of high-pressure mercury lamps still has the following disadvantages, making industrial processes expensive and complicated and producing highly toxic wastes when the high-pressure mercury lamps break down or are taken out of service:

[0011] 1. A mercury lamp emits light energy scattered in a number of lines in the Hg spectrum. The spectrum spreads from approximately 230 to 600 nm. A typical signal of a high-pressure mercury lamp doped with thallium iodide of type TQ 150 Z2 is shown in Table A below:

[0012]

Table A

[0013] 2. The light yield (light output / electric power input) in a commercially available doped mercury lamp (e.g., TQ 150 Z2) is only in the range of 5 - 10% based on the radiant flux applied for the photoreaction. 90 - 95% of the power is converted into heat and emitted to the bright side of the lamp, and an advanced cooling system is essential. The loss of electrical energy is quite large.

[0014] 3. Even with a properly doped mercury lamp, an optical filter must be applied to prevent the decomposition of vitamin A compounds, especially retinyl esters, by the UV light (less than 400 nm) still emitted. The state-of-the-art solution is a potassium chromate filter having the drawbacks shown above. Potassium chromate is a toxic, environmentally burdensome, mutagenic and carcinogenic salt.

[0015] 4. The isomerization of 11Z vitamin A compounds (e.g., retinyl esters) to all-E vitamin A compounds (e.g., retinyl esters) via a high-pressure mercury lamp involves the formation of various other Z isomers, such as 9Z retinyl ester, 13Z retinyl ester, and 9Z,11Z retinyl ester, all of which are unwanted and consequently reduce the overall yield of the all-E retinoid compound.

[0016] 5. So far, in most industrial photochemical processes, 5 - 60 kW mercury lamps have been applied. However, due to environmental protection reasons and to prevent lamp manufacturers from being exposed to more dangerous working conditions, the UN mercury regulations (Minamata Convention on Mercury, EuP Directive 2005 / 32 / EC) have triggered, and the production of mercury lamps may soon cease. Also, for this reason, it is necessary to improve the isomerization reaction conditions of vitamin A compounds.

[0017] According to the teachings of the prior art, the light for isomerizing vitamin A always includes the UV light part. To properly achieve the isomerization of vitamin A compounds, UV light up to 400 nm is essential, and it even gives the impression that the harmful effects of that UV light on vitamin A compounds must be tolerated. SUMMARY OF THE INVENTION

[0018] The object of the present invention is to devise an improved method for obtaining all-E polyunsaturated non-aromatic compounds, particularly all-E retinoid compounds of formula 1, which overcome the various drawbacks described above. The method should, to the extent possible, in a highly preferred manner, completely avoid the loss of polyunsaturated compounds caused by UV irradiation. It should be inexpensive, rapid, provide high selectivity for all-E polyunsaturated non-aromatic compounds, particularly all-E retinoid compounds of formula 1, and provide a high yield thereof. Sophisticated cooling, shielding, and explosion-proof means should be avoided for the new process and should be safe and simple. Filtering means in both solution and solid forms should be avoided. Complex reaction mixtures and their elaborate post-treatment should be reduced to the greatest extent possible. Also, the object of the method of the present invention compared to the prior art is to save energy with respect to the amount of all-E polyunsaturated non-aromatic compounds produced, particularly all-E retinoid compounds of formula 1. The amount of energy required to obtain such all-E polyunsaturated species, particularly such all-E retinoid compounds of formula 1, should be adjustable with respect to the reaction conditions. A simple scale-up and scale-down of the method of the present invention should be possible without significantly changing the reaction setup.

[0019] The object of the present invention is an all-E retinoid compound of formula 1 or a mixture of all-E retinoid compounds

[0020] [Chemical formula] [wherein, R is selected from the group of groups consisting of CH2-OH, CHO, CH2-OR 2 , COOH, COOR 3 , and R R 2 is (C=O)-alkyl, R 3 is alkyl, alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 2-butyl, sec-butyl, isobutyl, tert-butyl) A method for obtaining, comprising the following reaction steps: - A retinoid compound of formula 2

[0021]

Chem.

[0022]

Chem.

[0023]

Chem.

[0024]

Chem.

[0025] Surprisingly, high yields of acyclic conjugated all-E polyenes and alicyclic conjugated all-E polyenes, in particular all-E retinoid compounds of formula 1, were observed by using visible light almost exclusively or exclusively within the scope claimed in the claims. This is in contrast to the prior art, which assumes that UV light is essential for the realization of Z-E isomerization in individual retinoid compounds (the retinoid compounds are not bound to any support means, such as a protein, for example). The high yields can be obtained by consuming only half of the electrical energy used with a high-pressure mercury lamp. Despite the low electrical energy consumption, the selectivity for all-E polyunsaturated non-aromatic compounds, in particular all-E retinoid compounds of formula 1, is high compared to the use of high-pressure mercury lamps in the prior art. No bleaching or spoiling of the polyunsaturated compounds was observed in either the starting materials or the products. The raw material mixture immediately after irradiation is considerably simpler compared to that obtained by prior art methods. The novel method of the present invention does not require enzymatic or biochemical reaction steps. The risk of skin and visual impairment for individuals implementing the method of the present invention is significantly reduced by using almost exclusively or only visible light, and in some embodiments, is further completely avoided with a low energy impact.\n

Embodiments for Carrying Out the Invention

[0026] The all-E retinoid compounds of the present invention are any compound of Formula 1, wherein R is CH2-OH, CHO, CH2-OC(=O)-CH3, CH2-OC(=O)-CH2-CH3, CH2-OC(=O)-CH2-CH2-CH3, CH2-OC(=O)-CH-(CH3), CH2-OC(=O)-CH2-CH2-CH2-CH3, CH2-OC(=O)-CH-(CH3)2, CH2-OC(=O)-CH2-CH2-CH2-CH3, CH2-OC(=O)-CH-(CH3 )-CH2-CH3, CH2-OC(=O)-CH2-CH(CH3)2, CH2-OC(=O)-C(CH3)3, COOH, COOCH3, COO-CH2-CH3, COO-CH 2-CH2-CH3, COO-CH-(CH3)2, COO-CH2-CH2-CH2-CH3, COO-CH-(CH3)-CH2-CH3, COO-CH2-CH(CH3)2, CO O-C(CH3)3, i.e., All-E Retinol, All-E Retinal, All-E Retinyl Acetate, All-E Retinyl Propionate, All-E Retinyl Butyrate, All-E Retinyl Isobutyrate, All-E Retinyl Pentanoate, All-E Retinyl Sec-Pentanoate, All-E Retinyl Isopentanoate, All-E Retinyl Tert-Pentanoate, All-E Retinoic Acid, All-E Retinoic Acid Methyl Ester, All-E Retinoic Acid Ethyl Ester, All-E Retinoic Acid Propyl Ester, All-E Retinoic Acid Isopropyl Ester, All-E Retinoic Acid Butyl Ester, All-E Retinoic Acid 2-Butyl Ester, All-E Retinoic Acid Sec-Butyl Ester, All-E Retinoic Acid Isobutyl Ester, All-E Retinoic Acid tert-Butyl Ester.

[0027] The cis retinoid compounds of formulas 2, 3, 4, and 5 have the same molecular formula and molecular weight as the respective compounds of formula 1. However, their stereochemistry differs from that of formula 1. Retinoid compound 2 has an 11Z structure, retinoid compound 3 has a 13Z structure, retinoid compound 4 has a 9Z structure, and retinoid compound 5 has an 11,13Z structure.

[0028] In one embodiment of the present invention, at least one of the retinoid compounds of formula 2, formula 3, formula 4 or formula 5 is used as raw material or starting material. In a further embodiment, at least one of the retinoid compounds of formula 2, formula 3, formula 4 or formula 5 is used in combination with an all-E retinoid compound of formula 1 as raw material or starting material. This means that instead of using only the distinct cis-isomers of formulas 2-5 or mixtures thereof as raw material, a mixture comprising at least one of the retinoid compounds of formulas 2-5 as well as the product of formula 1 is also used. The process of the present invention is therefore adapted to be used with pure raw material as well as with mixtures comprising, inter alia, raw material and product of formula 1.

[0029] An important feature of the method of the present invention is an organic solvent that solubilizes at least one or a mixture of the aforementioned retinoid compounds 2 to 5. It is conceivable that photoisomerization can occur without the use of such a solvent, but post-treatment at the end of photoisomerization would be more tedious.

[0030] The organic solvent according to the present invention is any solvent that does not interfere with the reaction pathway of the method of the present invention, i.e. does not interact with the applied light and the retinoid compounds of formulae 1 to 5. In particular, the organic solvent is any solvent selected from the group consisting of C1-C6 alcohols, C5-C10 hydrocarbons, retinoid compounds of formulae C x H m Cl n (wherein x represents the number of carbon atoms, m represents the number of hydrogen atoms, and n represents the number of chlorine atoms, where m+n=2x+2), y H m Cl nC2-C4 hydrocarbons of the formula L1-COO-L2, where y represents the number of carbon atoms, m represents the number of hydrogen atoms, and n represents the number of chlorine atoms, with m+n=2y; carboxylic acid esters of the formula L1-COO-L2, where L1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and L2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, 2-butyl, sec-butyl, tert-butyl; ethers of the formula L2-O-L2, where L2 has the meaning as defined above; tetrahydrofurans of the formula L2-O-L2, where L2 has the meaning as defined above; It is understood that the ketone L3-(C=O)-L3 (wherein L3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, 2-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, sec-pentyl, 3-pentyl or amyl, 2-methylbutyl) is at least one compound selected from the group consisting of toluene, dioxane, ketones of formula L3-(C=O)-L3 (wherein L3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, 2-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, sec-pentyl, 3-pentyl or amyl, 2-methylbutyl), dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, benzene, toluene, xylene, chlorobenzene.

[0031] The group of C1 to C6 alcohols consists of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, n-pentanol, 2-pentanol, 3-pentanol, 3-methyl-butan-1-ol or isopentanol, tert-pentanol or 2-methyl-butan-2-ol, cyclohexanol.

[0032] C5-C10 hydrocarbons are understood to be hydrocarbons having at least 5 and at most 10 carbon atoms, bonded only to hydrogen atoms. These are selected from the group of n-pentane, isopentane and all other pentane isomers, n-hexane and all other hexane isomers, n-heptane and all other heptane isomers, n-octane and all other octane isomers, 2-methylpentane, 2,2,3-trimethylpentane or isooctane, cyclopentane, cyclohexane, cyclooctane, petroleum ether, white spirit, methylcyclohexane, all isomers of nonane, all isomers of decane.

[0033] An important aspect of the method of the present invention is the use of a photosensitizer. The photosensitizer is understood to absorb at least partially radiation in the range of 460 - 580 nm and convert it into energy capable of exciting electrons in the cis-double bonds of the retinoid compounds 2 - 5. Once excited, the cis double bond can dissociate and rearrange into the trans or E orientation. In the prior art, the isomerization has always been achieved by means of combining UV light of less than 400 nm, optionally visible light and finally thermal radiation. However, to date, no method or apparatus has been proposed that uses exclusively or predominantly visible light, in particular monochromatic light as defined below, to isomerize at least one of the retinoid compounds 2 - 5 to obtain the retinoid compound of formula 1 in high yield.

[0034] In the method of the present invention, the term reaction mixture is understood to comprise at least one of the retinoid compounds 2 - 5, optionally the retinoid compound of formula 1, a defined organic solvent and at least one photosensitizer.

[0035] Monochromatic light as understood in the present disclosure is all radiation having at least 90% of its power and up to 100% of its power emitted in the range of 460 nm to 580 nm. The power of minor components of monochromatic light outside the given wavelength range may total up to 10% depending on the nature and amount of the non-filtered electroluminescent lighting device, photosensitizer and organic solvent used. However, most embodiments of monochromatic light contain only a small portion of light from above 460 nm to 580 nm. In one embodiment, monochromatic light is understood to be at least 95% of the power of said monochromatic light and up to 100% of said power emitted in the range of 460 nm to 580 nm. In yet another embodiment, monochromatic light means that at least 98% of the power of said monochromatic light, more preferably at least 99% and up to 100% of said power is emitted in the range of 460 nm to 580 nm. The amount of monochromatic light is expressed in power, because doing so does not encourage the otherwise defined amount of light permitted above or below the claimed wavelength range in lumens lm or Wh or candela cd. Said amount, if not expressed in power, varies as a function of the wavelength considered. In further specific embodiments, monochromatic light as understood within the present disclosure is any radiation that emits at least 90% of its power, and up to 100% of its power, in the range of 460 nm to 580 nm, and whose monomodal emission spectrum exhibits a half-width of + / - 10 to + / - 30 nm relative to the wavelength of the emission maximum. Said defined half-width results in a highly structured photoirradiation signal, which results in an improved yield of the retinoid compound of formula 1.

[0036] The filterless electroluminescent lighting device in the present disclosure is any electroluminescent device that emits light and can operate for an intentionally selected time only by being turned on and off, and does not include filtering means. The filtering means may be a layer, compound or product applied on the lighting device. The filtering means may also be a compound that is immersed or solubilized in a solvent that circulates, is pumped, or floats around the lighting device and absorbs light within a clearly distinguishable range, but is adapted not to transfer the energy emerging from the absorbed light to one of retinoid compounds 1 to 5. The electroluminescent lighting device does not need to be operated by any kind of chemically induced light irradiation such as gas ionization or by heating means. The filterless electroluminescent lighting device is preferably understood to emit electromagnetic radiation in the form of visible light, resulting in light (photons) from electrons that fill holes or gaps in the electron-deficient material. The filterless electroluminescent lighting device is selected from the group consisting of a light-emitting electrochemical cell, an electroluminescent wire, a magnetic field-induced electroluminescent polymer, a light-emitting diode, an organic light-emitting diode, a polymer light-emitting diode, an active matrix organic light-emitting diode (AMOLED), particularly an electroluminescent film based on an inorganic phosphor, a semiconductor laser, a diode laser, a chemical laser, a dye laser, a free electron laser, a gas dynamic laser, a gas laser, an ion laser, a laser flashlight, a metal vapor laser, a monolithic optical quantum well laser, a ruby laser, a solid-state laser. Preferably, the filterless electroluminescent lighting device is selected from the group consisting of a light-emitting electrochemical cell, an electroluminescent wire, a magnetic field-induced electroluminescent polymer, a light-emitting diode, an organic light-emitting diode, a polymer light-emitting diode, an active matrix organic light-emitting diode (AMOLED), particularly an electroluminescent film based on an inorganic phosphor.

[0037] In a more sophisticated embodiment of the method of the present invention, at least 90% of the power of the monochromatic light and up to 100% of the power is emitted in the range of 501 nm to 550 nm. This relatively narrow wavelength range of operation results in good conversion and high yields of all-E polyunsaturated non-aromatic compounds, including acyclic and alicyclic conjugated all-E polyenes, especially all-E retinoid compounds of formula 1, but with a narrower wavelength spectrum, less power and energy is consumed. Side reactions, such as isomerization to undesirable compounds, are further suppressed or preferably completely avoided in this wavelength range. Narrowing the wavelength range in a non-filtered electroluminescent lighting device is achieved by selectively controlling separate electronic components in the device.

[0038] Another important feature of the method of the invention is to carefully control the amount of energy introduced into the reaction mixture. This is achieved by choosing a monochromatic light so that the electrical energy consumed by the lighting device to obtain 1 kg of the retinoid compound of formula 1 does not exceed 800 Wh. When doing this, the loss of the compound in the reaction mixture is greatly reduced, and preferably even completely avoided. The same is true for the formation of undesirable isomers of the retinoid compound of formula 1. This is important because the longer the process of the method of the invention proceeds, the more difficult it becomes to reverse the formation of the particularly undesirable retinoid compound 4. After a certain reaction time, it is no longer possible to remove the retinoid compounds 3 and 4 formed during the course of the reaction. In other words, the reaction conditions must be selected such that the amount of retinoid compounds 3 and 4 (if present in the reaction mixture) is already reduced at the start of the method of the invention and no new formation thereof occurs. One parameter to be considered in this regard is the amount of energy put into the reaction mixture.

[0039] The control of this energy is hardly possible or only approximately possible when using any kind of mercury lamp or xenon arc lamp, each xenon gas discharge lamp. These lamps have a wide emission spectrum showing a number of peaks of different energies. Furthermore, the overall intensity of the peaks changes with their usage time. The energy supply decreases with the usage time and it has to be determined or estimated regularly to adjust the amount of energy supplied. This is cumbersome, time-consuming and not suitable for an economical industrial process.

[0040] The method of the present invention produces all-E polyunsaturated compounds in various yields depending on the residue R selected in all-E polyunsaturated non-aromatic compounds containing acyclic conjugated all-E polyenes and alicyclic conjugated all-E polyenes. In particular, this applies to retinoid compounds 1 to 5. When the residue R is CH2-O-(C=O)-alkyl and the alkyl is selected from the group of methyl and ethyl, a high-yield all-E retinoid compound of formula 1 in a clearly well-structured or crystallized form is obtained. No complex reaction mixture that is difficult to separate is produced. This may be due, at least in part, to the clearly distinguishable solubility and precipitation or crystallization ability of each cis-retinoid ester 2 to 5, compared to each all-E retinoid ester or all-trans retinoid ester where R is as described above, where R is as described above. The all-E retinoid esters where R is CH2-O-(C-O)-CH3 or CH2-O-(C-O)-CH2-CH3 in various solvents or solvent mixtures tend to precipitate, but the corresponding cis-isomers of formulas 2 to 5 do not have that tendency.

[0041] Previously, it has already been stated that it is possible but difficult to isomerize the retinoid compounds of Formulas 3 and 4 to the corresponding all-E retinoid compounds of Formula 1. Presumably, this also applies to cis polyunsaturated non-aromatic compounds containing acyclic conjugated cis polyenes and alicyclic conjugated cis polyenes (these cis-polyunsaturated compounds have at least one cis-double bond). An extended version of the method of the present invention addresses this problem, and the total parts by weight of the retinoid compounds of Formulas 1 and 2 before irradiation account for at least 80 w% of the retinoid compounds present in the reaction mixture, and the said retinoid compounds are defined as being selected from the group consisting of the retinoid compound of Formula 1, the retinoid compound of Formula 2, the retinoid compound of Formula 3, the retinoid compound of Formula 4, and the retinoid compound of Formula 5. Preferably, the total parts by weight of the retinoid compounds of Formulas 1 and 2 before irradiation account for at least 82 w%, more preferably at least 85 w%, still more preferably at least 90 w%, and most preferably at least 92 w% of the retinoid compounds present in the reaction mixture, and the said retinoid compounds are selected from the group consisting of the retinoid compound of Formula 1, the retinoid compound of Formula 2, the retinoid compound of Formula 3, the retinoid compound of Formula 4, and the retinoid compound of Formula 5. When using a mixture of retinoid compounds 1-5 in the amounts shown above, the method of the present invention is rather simple. Complicated mixtures that are difficult to separate are avoided, as well as large amounts of the undesirable retinoid compound of Formula 4. Crystallization of the retinoid compound of Formula 1 occurs immediately with the selection of a solvent and is difficult otherwise.

[0042] Another subject of the present invention is to speed up the method of the present invention, thereby saving costs and avoiding elaborate work-up essential for complex reaction mixtures, which is to work in a suitable organic solvent. The suitable organic solvent should have the ability to at least partially distinguish, on the one hand, all E-retinoid compounds of formula 1 and, on the other hand, retinoid compounds of formulas 2 to 5 and photosensitizers, for example with reference to different solubility or redistribution behavior in said solvent. Such an object is achieved by a further embodiment of the present invention, wherein the organic solvent is selected from at least one representative example of the group of C1-C6 alcohols, preferably methanol and ethanol or mixtures thereof. Such C1-C6 alcohols, in particular methanol and ethanol, each dissolve the retinoid compounds of formulas 2 to 5 more readily and hardly dissolve or do not dissolve the retinoid compounds of formula 1 at all. The term C1-C6-alcohol has the meaning as indicated above in the present disclosure.

[0043] The aforementioned embodiment avoids highly complex reaction mixtures, but generally requires longer reaction times, thereby increasing the risk of the formation of retinoid compounds 2-5. This may also at least partially lead to the oiling-out of the retinoid compound of formula 1, instead of crystallization. The oiling-out compound 1 may be partially associated with at least one of the oiling-out compounds of formulas 2-5. This is avoided in a further extension of the method of the invention when using a mixture of at least one representative of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon as organic solvent. C1-C6-alcohols and C5-C10 hydrocarbons have the meanings as indicated above. C1-C6-alcohols themselves contain water to a more or less well-defined extent. This can result in interphases between the alcohol and the water, i.e. a separation that is not really precise, affecting the redistribution of the various components of the reaction mixture. Adding C5-C10 hydrocarbon to the C1-C6-alcohol from the start makes the alcohol phase more hydrophobic, thus leading to better separation of the all-E retinoid compound of formula 1 from the retinoid compounds 2-5 and / or photosensitizer. This strategy can reduce the oil-out of retinoid compounds 1-5, making the isolation of compound 1 quicker and easier.

[0044] C1-C6 alcohols and C5-C10 hydrocarbons, when mixed in equal amounts, result in two separate phases. In this state, the method of the present invention can be successfully realized by vigorously stirring the reaction mixture. This embodiment has the advantage that different types of compounds in the reaction mixture can be separated according to their overall polarity simply by stopping the stirring means. However, this advantage makes the crystallization of all-E retinoid compounds of formula 1 more sophisticated because while the reaction mixture is being stirred, all the compounds in the reaction mixture are continuously mixed and, once stirring stops, they distribute into each phase according to their respective polarities. When dealing with a high-concentration reaction mixture, instead of the crystallization of the retinoid compound of formula 1, a significantly reduced but very small amount of oil-out may occur. This simplifies the isolation of compound 1 from the reaction mixture.

[0045] However, surprisingly, in a further developed embodiment of the present invention, when a mixture of at least one representative example from the group of C1-C6 alcohols and at least one C5-C10 hydrocarbon is selected to form a homogeneous phase, a better crystallization pattern of all-E retinoid compounds of formula 1 is observed with high yield and short reaction time. A homogeneous phase means that two solvents mix with each other in such a way that they cannot be identified as two separate entities. That is, the amount of C5-C10 hydrocarbon in the organic solvent is trace and is not allowed to exceed a specific threshold. No oil-out of all-E retinoid compounds of formula 1 was observed. Instead, crystallization occurs during irradiation, the amount of dissolved all-E retinoid compounds of formula 1 decreases, and new dissolved all-E retinoid compounds of formula 1 are formed by being formed from the irradiation process. The new all-E retinoid compounds of formula 1 also crystallize, etc. once they become saturated in the solution. This feature strongly promotes the rapid formation of all-E retinoid compounds of formula 1.

[0046] In further tests, when a mixture of at least one representative example of the group of C1-C6 alcohols and at least one C5-C10 hydrocarbon contains 0.1-12 w% hydrocarbon, more preferably 1-12 w% (including 10 w%) heptane, and most preferably 1-5 w% heptane, it has been shown that timely optimized crystallization of the highly uniform crystals of all-E retinoid compounds of formula 1 can be obtained. The formation of an interphase and partial oil-out of all-E retinoid compounds of formula 1 were not observed. By timely crystallization, a long reaction time can be avoided, and thus the formation of the undesirable retinoid compounds of formula 4 can be completely prevented.

[0047] One of the beneficial features of the present invention is to avoid UV irradiation in the method of the present invention. Even when only visible light is used as the radiation for the photochemical reaction of the method of the present invention, a significant increase in the reaction rate was observed when at least one specific photosensitizer was used. Therefore, a further embodiment of the present invention discloses a photosensitizer of the present invention selected from at least one compound of the group consisting of fluorescein, eosin, rose bengal, erythrosin, cobalt-tetraphenylporphyrin, zinc-tetraphenylporphyrin, rhodamine B, basacryl brilliant red, iodine.

[0048] A further important embodiment of the method of the present invention discloses a filterless electroluminescent lighting device containing a semiconductor material. The semiconductor material meets several objectives of the present invention. It provides radiation of a selected wavelength or wavelength range outside the UV range. Thus, it can significantly reduce, and preferably even completely avoid, the loss of polyunsaturated non-aromatic compounds, particularly retinoid compounds of formulas 1-5, including acyclic conjugated all-E polyenes and alicyclic conjugated all-E polyenes. Therefore, it does not require the shielding or filtering of dangerous or harmful light not within the desired wavelength range. Similarly, a lighting device containing a semiconductor does not tend to explode or emit a large amount of heat, so it does not require sophisticated cooling or explosion protection. The semiconductor material generally consumes only an equivalent small amount of electrical energy, and its ability to emit light can be easily controlled or adjusted by adjusting the current and voltage or by changing the amount of semiconductor material used. The time for which the reaction mixture is exposed to the light emitted from the semiconductor material can be easily and repeatedly controlled by simply switching the current passing through the material of the electroluminescent lighting device on and off. This procedure is not possible with xenon arc lamps or high-pressure mercury lamps because it takes time to switch them on and repeated switching dramatically reduces their lifespan. The amount of energy wasted in generating radiation unrelated to photochemistry is significantly reduced because the emission spectrum of the semiconductor material preferably has only a defined bandwidth adapted to the radiation necessary to cause the isomerization process of the present invention. The semiconductor material is silicon, diamond, germanium, α-tin, α-sulfur, selenium, tellurium, BN, BP, Bas, B 12 As2, AlN, AlP, AlAs, AlGaN, AlGaP, Al x Ga 1-x As, AlGaAsN, AlGaAsP, AlGaInP, Al x In 1-x As, AlInAsP, AlSb, Al x In 1-xSb, GaN, GaAsN, GaP, GaAs, GaAsP, GaAsSb, GaAsSbN, GaAsSbN, GaInAsSbP, GaMnAs, GaSb, GaSe, InAlAsN, InN, InP, InAs, InAsSb, InAsSbP, InGaN, In x Ga 1-x P, In x Ga 1-x As, InGaAsN, InGaAsP, InGaAsSb, InGaSb, InMnAs, InSb, TlBr, CdSe, CdS, Cd3P2, Cd3As2, Cd3Sb2, CdTe, CdMnTe, CdZnTe, ZnO, ZnSe, ZnS, ZnTe, Zn3P2, ZnSiP2, Zn3As2, Zn3Sb2, TiO2, SrTiO3, BaTiO3, VO2, LiNbO3, CrBr3, MoS2, FeO, FeS2, NiO, Cu2O, CuO, CuCl, Cu2S, CulnSe2, Cu(In,Ga)Se2, Cu2ZnSnS4, Cu 1.18 Zn 0.40 Sb 1.90 S 7.2 , Cu2SnS3, Ag2S, AgGaS2, Si 1-x Ge x , Si 1-x Ge x , Si 1-x Sn x , PbI2, PbSe, PbS, PbTe, PbMnTe, Pb 1-x Sn x Te, SnO2, SnS, SnS2, SnTe, PbSnTe, Pb 1-x Sn x Te, Tl2SnTe5, Tl2GeTe5, As2S3, As4S4, Bi2O3, Bi2O3, Bi2S3, Bi2Te3, BiI3, and is selected from at least one compound of the group consisting thereof. Preferably, the semiconductor material is selected from the group consisting of InGaN (indium gallium nitride) / GaN (gallium nitride), GaP (gallium phosphide), AlGaInP (aluminum gallium indium phosphide), AlGaP (aluminum gallium phosphide), ZnO (zinc oxide).

[0049] In a further specific embodiment of the method of the present invention, the filterless electroluminescent lighting device comprises, preferably consists of, at least one light-emitting diode (LED). The light-emitting diode is a light source that is inexpensive to manufacture, generates a specific emission spectrum, emits little to almost no waste heat, and can be used very versatilely in the method of the present invention. The illumination energy applied to the reaction mixture can be easily adjusted simply by connecting in series the number of light-emitting diodes required for the specified energy input. Further options for adjusting the energy input to the reaction mixture are possible with the light-emitting diodes. By changing the current and / or voltage applied to the light-emitting diode, the brightness of the diode, i.e., the light beam entering the reaction mixture, and thus the energy, is changed. Yet another method of adjusting the energy input to the reaction mixture is to control the irradiation time. The light-emitting diode has a considerably longer operating or service life compared to a mercury lamp or a xenon arc lamp, i.e., a xenon discharge lamp. Thus, since the light-emitting diode is not troubled by the performance loss accumulated during operation, the light-emitting diode greatly reduces the cost for carrying out the method of the present invention.

[0050] In a preferred embodiment of the method of the present invention, the lighting device comprises, preferably consists of, at least one light-emitting diode (LED), and the light-emitting diode contains, as an electroluminescent material, a compound selected from at least one compound of the group consisting of Si (silicon), SiO2, SiC, hydrogenated amorphous silicon, Ge, arsenic, a mixture of selenium and tellurium, AlBGaN, AlN, AlGaN, AlGaN / AlN, AlGaP, AlGaAs, AlGaAsP, AlInGaP, AlGaInP, GaN, GaAs, GaP, GaAsP, GaInN, GaInP, InN, InP, InGaN, InGaN / AlGaN, ZnO, ZnS (doped with Mn), ZnS (doped with Cu), ZnSe.

[0051] In yet another embodiment adapted to wavelengths in the middle of the visible spectrum, the writing device includes, preferably consists of, at least one light-emitting diode (LED), and the light-emitting diode includes at least one compound selected from the group consisting of AlGaP, AlGaAsP, AlGaInP, GaN, GaP, GaInP, InGaN, and ZnO as an electroluminescent material. The electroluminescent material exhibits strong emission in the middle of the visible spectrum, that is, emits light from cyan to green to yellow. The energy of this light is still sufficient to obtain the all-E retinoid compound of Formula 1.

[0052] In many embodiments of the method of the present invention, the reaction mixture before irradiation is in the form of a homogeneous phase, a supersaturated homogeneous phase, or an emulsion or a supersaturated emulsion. In the present disclosure, supersaturation means that a compound is diluted in a solvent or a solvent mixture to such an extent that it is close to or already exceeds its solubility product (colloidal solution) and yet no precipitation has occurred. During irradiation, the amount of the retinoid compound of Formula 1 increases until the point at which the retinoid compound of Formula 1 begins to precipitate in crystalline form. On the one hand, the formation of the crystals is desirable. However, together with these crystals, some mother liquor is also separated from the reaction mixture to some extent and can no longer be irradiated uniformly. In one embodiment of the method of the present invention, to avoid this, only a distinct portion of the reaction mixture is irradiated. By this operation, a part of the reaction mixture remains as it was before irradiation, while another part precipitates crystals and turns into a suspension.

[0053] Irradiation of only the clearly distinguishable part of the reaction mixture can be achieved in two ways. In one embodiment, only one section of the reaction mixture, i.e., the upper, lower, left, or right part, is exposed to monochromatic light from a filterless electroluminescent lighting device by arranging a filterless electroluminescent lighting device that emits monochromatic light so as to irradiate only the clearly distinguishable part of the reaction mixture. In an embodiment particularly adapted to a large amount of reaction mixture, the reaction mixture is led into a circuit, and only one area of the circuit is exposed to monochromatic light from a filterless electroluminescent lighting device to irradiate only the clearly distinguishable part of the reaction mixture. The circuit is understood to be any arrangement of pipes, tubes, and / or vessels through which the reaction mixture circulates.

[0054] In another embodiment of the method of the present invention for obtaining all-E retinoid compounds or a mixture of all-E retinoid compounds of formula 1, at least one of the retinoid compounds of formulas 2-5, or at least one of the retinoid compounds of formulas 2-5 mixed with a compound of formula 1, an organic solvent, and a photosensitizer are fed into a reactor, and the reaction mixture thus obtained is irradiated at a temperature in the range of -20°C to 30°C by a filterless electroluminescent lighting device that emits monochromatic light, where at least 90% and at most 100% of the power of the monochromatic light is emitted in the range of 460 nm to 580 nm. The predetermined low or moderate temperature reduces or prevents the decomposition or loss of the retinoid compounds of formulas 1-5.

[0055] In the method of the present invention for obtaining all-E retinoid compounds of formula 1 or mixtures of all-E retinoid compounds, the decomposition or loss of the retinoid compounds of formulas 1 to 5 can be further reduced by supplying at least one of the retinoid compounds of formulas 2 to 5 or at least one of the retinoid compounds of formulas 2 to 5 mixed with the compound of formula 1, an organic solvent, and a photosensitizer to a reaction apparatus, and irradiating the reaction mixture thus obtained with a filterless electroluminescent lighting device that emits monochromatic light at a temperature in the range of -10°C to 20°C, where at least 90% of the power of the monochromatic light and up to 100% of the power are emitted in the range of 460 nm to 580 nm.

[0056] The increase in temperature during a chemical reaction accelerates the reaction rate, and as a result, the amount of product formed in a given time also increases. However, this was not observed in the method of the present invention. In contrast, the reaction rate and the product yield increased with a decrease in temperature during the course of the method of the present invention. A decrease in the reaction temperature during supply and / or irradiation and / or after irradiation was observed to accelerate the formation of the product. Accordingly, embodiments of the method of the present invention aimed at achieving a very high product yield are determined such that at least one of the retinoid compounds of formulas 1 to 5 in an organic solvent with added photosensitizer is irradiated at a temperature in the range of -20°C to 30°C with a decrease in the reaction temperature during the course of the reaction, particularly during and / or after irradiation.

[0057] When referring to the method of the present invention, the term "reaction" is understood to include at least a supply step and an irradiation step. In the foregoing embodiment, this includes a supply step, an irradiation step, and an incubation step following the irradiation step. The incubation step is understood to be the period after irradiation during which the reaction mixture is maintained without irradiation or cooled without irradiation.

[0058] At low reaction temperatures, e.g., below 10°C, this tends to make the reaction mixture more viscous, thus preventing good mixing of the reaction mixture. To meet and address this, in a further embodiment, an all-E retinoid compound or mixture of all-E retinoid compounds of Formula 1 is used.

[0059] [ka] (Wherein, R is CH2-OH, CHO, CH2-OR 2 , COOH, COOR 3 is selected from the group of groups consisting of R 2 is (C=O)-alkyl, R 3 is alkyl, alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 2-butyl, sec-butyl, isobutyl, and tert-butyl; The method of the present invention for obtaining - a retinoid compound of formula 2

[0060] [ka] or a retinoid compound of formula 3

[0061] [ka] or a retinoid compound of formula 4

[0062] [ka] or a retinoid compound of formula 5

[0063] [ka] or a mixture of at least two of retinoid compounds 2 to 5; a mixture of at least one of retinoid compounds 2 to 5 and the retinoid compound of formula 1, a step of supplying an organic solvent and a photosensitizer to a reaction apparatus, - a step of irradiating the reaction mixture thus obtained with a filterless electroluminescent lighting device that emits monochromatic light, wherein at least 90% and at most 100% of the power of the monochromatic light is emitted in the range of 460 nm to 580 nm, A method comprising is defined in that at least one of the reaction steps is carried out under pressure.

[0064] all-E retinoid compound of formula 1 or a mixture of all-E retinoid compounds

[0065]

Chemical formula

[0066]

Chemical formula

[0067]

Chemical formula

[0068]

Chemical formula

[0069]

Chemical formula

[0070] The pressure as understood in the present disclosure means a value in the range from ambient pressure to 100 bar (ambient pressure means, on average, 1 bar depending on climate and altitude conditions without applying a device suitable for increasing or decreasing pressure).

[0071] Each of the two aforementioned embodiments in a further extended version includes a pressure in the range from ambient pressure to 100 bar (ambient pressure means, on average, 1 bar depending on climate and altitude conditions without applying any device suitable for increasing or decreasing pressure).

[0072] On the other hand, the viscosity tends to decrease at high temperatures. Further, for example, in order to obtain a supersaturated reaction mixture, it may be desirable to vary the amount of the organic solvent during the progress of the method of the present invention.

[0073] This need is met by the all-E retinoid compound or mixture of all-E retinoid compounds of formula 1.

[0074] [ka] (Wherein, R is CH2-OH, CHO, CH2-OR 2 , COOH, COOR 3 is selected from the group of groups consisting of R 2 is (C=O)-alkyl, R 3 is alkyl, alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 2-butyl, sec-butyl, isobutyl, and tert-butyl; The method of the present invention for obtaining - a retinoid compound of formula 2

[0075] [ka] or a retinoid compound of formula 3

[0076] [ka] or a retinoid compound of formula 4

[0077] [ka] or a retinoid compound of formula 5

[0078] [ka] or a mixture of at least two of retinoid compounds 2 to 5; or a mixture of at least one of retinoid compounds 2 to 5 with a retinoid compound of formula 1; providing an organic solvent and a photosensitizer to a reactor; - illuminating the reaction mixture thus obtained with a filter-free electroluminescent lighting device that emits monochromatic light, at least 90% of the power of the monochromatic light and up to 100% of the power is emitted in the range of 460 nm to 580 nm; wherein at least one of the reaction steps is achieved under vacuum.

[0079] This previously described embodiment can be further improved and a higher yield obtained when incorporating this additional feature as follows:

[0080] All-E retinoid compound or mixture of all-E retinoid compounds of formula 1

[0081] [ka] (Wherein, R is CH2-OH, CHO, CH2-OR 2 , COOH, COOR 3 is selected from the group of groups consisting of R 2 is (C=O)-alkyl, R 3 is alkyl, alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 2-butyl, sec-butyl, isobutyl, and tert-butyl; The method for obtaining the compound of formula (I) comprises the steps of: - a retinoid compound of formula 2

[0082] [ka] or a retinoid compound of formula 3

[0083] [ka] or a retinoid compound of formula 4

[0084] [Chemical formula] or a retinoid compound of formula 5

[0085] [Chemical formula] or a mixture of at least two of retinoid compounds 2 - 5, or a mixture of at least one of retinoid compounds 2 - 5 and a retinoid compound of formula 1, a step of supplying an organic solvent and a photosensitizer to a reaction apparatus, - the reaction mixture thus obtained, during the course of the reaction, particularly during and / or after irradiation, the reaction temperature is decreased to a temperature in the range of -20°C to 30°C, a step of irradiating with a filterless electroluminescent lighting device that emits monochromatic light, wherein at least 90% and at most 100% of the power of the monochromatic light is emitted in the range of 460 nm to 580 nm, comprising, and at least one of the reaction steps is realized under vacuum, a method.

[0086] As used herein, the vacuum disclosed herein means a range from 50 mbar to ambient pressure at most (ambient pressure, as described above, means 1 bar on average).

[0087] In a further extended version, each of the last two embodiments described above defines the vacuum as a range from 50 mbar to 1 bar.

[0088] 1) To provide an inexpensive and rapid process that results in high selectivity and high yield of all-E polyunsaturated non-aromatic compounds, particularly all-E retinoid compounds of formula 1, 2) To contribute to the purpose of avoiding or reducing complex reaction mixtures and their cumbersome post-treatment, and 3) To ensure easy scale-up and scale-down of the method of the present invention without extensive changes to the reaction setup, a further embodiment of the present invention determines the following: At least one of retinoid compounds 1 to 5 is supplied to a reaction apparatus such that the total concentration of at least one of retinoid compounds 1 to 5 is in the range of 5 to 50 w% with respect to the reaction mixture. Preferably, at least one of retinoid compounds 1 to 5 consisting of isomers of retinol acetate is placed in a reaction vessel such that the total concentration of at least one of retinoid compounds 1 to 5 is in the range of 5 to 50 w% with respect to the reaction mixture. The term "at least one of retinoid compounds 1 to 5" is understood to include one of retinoid compounds 1 to 5, or a permutation of two compounds selected from retinoid compounds 1 to 5 (e.g., 1 and 4; 2 and 3), or a permutation of three compounds selected from retinoid compounds 1 to 5 (e.g., 1, 2, and 4; 3, 4, and 5), or a permutation of four compounds selected from retinoid compounds 1 to 5, or all five retinoid compounds 1 to 5. When using the concentrations of retinoid compounds within the ranges disclosed above, particularly preferably the concentration of retinol acetate, the reaction mixture remains homogeneous. Precipitation or formation of a complex reaction mixture prior to irradiation, as can occur in the case of a high-concentration reaction mixture, does not occur. A reaction mixture containing less than 5 w% of retinoid compounds 1 to 5 is thought to mean operating a large amount of organic solvent, and thus the processing cost will increase significantly.

[0089] Yet another embodiment defines that the method of the present invention is implemented in a side-loop photoreactor, a continuous flow-photoreactor, or a submersible photoreactor.

[0090] A side-loop photoreactor is a reactor that is introduced into a part of a reaction circuit or attached to a part of a reaction circuit. The reaction circuit is a device or mounting through which a reaction mixture circulates. The side-loop photoreactor can be easily attached to or incorporated into an existing reaction vessel or reaction plant. During operation, the reaction mixture circulates from this reaction vessel or reaction plant through the side-loop photoreactor. By doing this, only a part of the reaction mixture comes into contact with the radiation emitted from a filter-free electroluminescent lighting device (located in the side-loop photoreactor) for a specified period of time. The said part then enters the reaction plant or reaction vessel and moves through the side-loop photoreactor again. This intermittent contact between the reaction mixture and the radiation from the said lighting device promotes the reaction process and at the same time further reduces the amount of damaged or undesirable retinoid compounds of Formulas 2 - 4.

[0091] When using a continuous-flow photoreactor, the reaction mixture passes through the electroluminescent lighting device only once. This type of reactor is advantageous when using a reaction mixture highly filled with a retinoid compound or when the power sent from the electroluminescent lighting device is 800 Wh or near it (near means more than 500 Wh).

[0092] When it is desired to operate under pressure or under vacuum, an underwater photoreactor is particularly useful and is easily achieved when the photoreactor is completely immersed in the reaction mixture.

[0093] The step in the present disclosure of "irradiating the reaction mixture thus obtained with a filter-free electroluminescent lighting device that emits monochromatic light, wherein at least 90% and at most 100% of the power of the monochromatic light is emitted in the range of 460 nm to 580 nm" is also called the photo-isomerization step.

[0094] After the photo-isomerization step in one embodiment, crystallization of the all-E retinoid compound of formula 1 follows, particularly crystallization of the all-E retinoid compound of formula 1 where R is CH2-O-(C=O)-alkyl and alkyl is selected from the group of methyl and ethyl. The subsequent crystallization step is caused, for example, by evaporation of a certain amount of organic solvent.

[0095] In a further embodiment, the photo-isomerization step and the crystallization of the all-E retinoid compound of formula 1, particularly crystallization of the all-E retinoid compound of formula 1 where R is CH2-O-(C=O)-alkyl and alkyl is selected from the group of methyl and ethyl, can be carried out simultaneously. This embodiment is preferred. This embodiment is carried out when the reaction mixture before irradiation is a supersaturated solution / dispersion and / or when a mixture of at least one representative example from the group of C1-C6-alcohols and at least one C5-C10-hydrocarbon is selected to form a homogeneous phase. In the preferred embodiment expected above, the reaction conditions for obtaining the all-E retinoid compound of formula 1 or a mixture of all-E retinoid compounds are as follows: a retinoid compound of formula 2, 3, 4 or 5, or a mixture of at least two of retinoid compounds 2-5, or a mixture of at least one of retinoid compounds 2-5 and a retinoid compound of formula 1, an organic solvent and a photosensitizer are fed (preferably in a dispersed form) into a reaction apparatus, and the reaction mixture thus obtained is irradiated at 15 °C with an electroluminescent lighting device without a filter that emits monochromatic light, where at least 90% of the power of the monochromatic light and at most 100% of the power are emitted in the range of 460 nm to 580 nm, and then the reaction mixture is cooled to a temperature in the range of -10 °C to -15 °C, filtered, and the filter cake is washed.

[0096] When represented in the terms of the claims, this embodiment is as follows: an all-E retinoid compound of formula 1 or a mixture of all-E retinoid compounds

[0097]

Chemical formula

[0098]

Chemical formula

[0099]

Chemical formula

[0100]

Chemical formula

[0101]

Chemical formula

[0102] The reaction steps referred to in the above embodiment of "providing at least one retinoid compound of formulas 1-5, an organic solvent and a photosensitizer," "irradiating the reaction mixture thus obtained," and the resulting "crystallization of the all-E retinoid compound of formula 1" can be carried out in a batch reactor, in which the irradiation source is preferably immersed in the reaction mixture or placed in a side loop of the reactor through which the reaction mixture circulates. Alternatively, the reaction steps can be carried out semi-continuously, for example in a series reaction vessel, or continuously, for example in a flow reactor.

[0103] Further elaborated embodiments allow for further increases in the reaction rate and / or yield of the methods of the present invention. Said embodiments comprise an all-E retinoid compound or a mixture of all-E retinoid compounds of Formula 1.

[0104] [ka] (Wherein, R is CH2-OH, CHO, CH2-OR 2 , COOH, COOR 3 is selected from the group of groups consisting of R 2 is (C=O)-alkyl, R 3 is alkyl, alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 2-butyl, sec-butyl, isobutyl, and tert-butyl; The method for obtaining the compound of formula (I) comprises the steps of: - a retinoid compound of formula 2

[0105] [Chemical formula] or a retinoid compound of formula 3

[0106] [Chemical formula] or a retinoid compound of formula 4

[0107] [Chemical formula] or a retinoid compound of formula 5

[0108] [Chemical formula] or a mixture of at least two of retinoid compounds 2 - 5, or a mixture of at least one of retinoid compounds 2 - 5 and a retinoid compound of formula 1, a step of supplying an organic solvent and a photosensitizer to a reaction apparatus, - a step of irradiating the reaction mixture thus obtained with a filterless electroluminescent lighting device that emits monochromatic light, wherein at least 90% and at most 100% of the power of the monochromatic light is emitted in the range of 460 nm to 580 nm, - a step of supplying the reaction mixture together with at least one seed crystal of compound 1 before or during irradiation The method comprises the steps.

[0109] The above - mentioned more sophisticated embodiment is further improved when the organic solvent used is a mixture of at least one representative example of the group of C1 - C6 - alcohols and at least one C5 - C10 hydrocarbon.

[0110] A further alternative development of this more sophisticated embodiment is achieved when the organic solvent used is a mixture of at least one representative example of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon and when the mixture of at least one representative example of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon is selected to form a homogeneous phase.

[0111] When the organic solvent used is a mixture of at least one representative example of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon, the mixture of at least one representative example of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon is selected to form a homogeneous phase, and the mixture of at least one representative example of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon contains methanol or ethanol as the C1-C6-alcohol and 0.1-12 w% of hydrocarbon, this more sophisticated embodiment provides a very high yield in a short reaction time.

[0112] When the organic solvent used is a mixture of at least one representative example of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon, the mixture of at least one representative example of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon is selected to form a homogeneous phase, and the mixture of at least one representative example of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon contains methanol as the C1-C6-alcohol and 0.1-12 w% of hydrocarbon, this more sophisticated embodiment provides an even improved yield in a short reaction time.

[0113] The very high yields at short reaction times are further improved by this more elaborate embodiment, if the organic solvent used is a mixture of at least one representative from the group of C1-C6 alcohols and at least one C5-C10 hydrocarbon, selected so that said mixture of at least one representative from the group of C1-C6 alcohols and at least one C5-C10 hydrocarbon forms a homogeneous phase, and if said mixture of at least one representative from the group of C1-C6 alcohols and at least one C5-C10 hydrocarbon comprises methanol as C1-C6 alcohol and 1-12 wt. % heptane (including 10 wt. %), most preferably 1-5 wt. % heptane.

[0114] Yet another embodiment of the present invention is the use of the process of the present invention as disclosed in any one of the previous embodiments for isomerizing polyunsaturated compounds, in particular for isomerizing polyunsaturated non-aromatic compounds.

[0115] The invention and its advantageous features will now be further explained in a specific description including examples and with reference to the drawings. [Brief description of the drawings]

[0116] [Figure 1] Xenon Arc Lamp Output Profile [Diagram 2] Transmittance of K2CrO4 solution [Diagram 3] Emission spectrum of light-emitting diodes in used lighting devices

[0117] Some advantageous features of the method of the present invention are as follows:

[0118] 1. The yield of the all-E retinoid compound of Formula 1, i.e., all-E retinol acetate, is higher when using light-emitting diodes (LEDs) compared to experiments using conventional high-pressure mercury lamps in combination with chromate filters.

[0119] 2. Considerable savings in electrical energy are achieved for the same amount of all-E retinoid compounds of formula 1, especially for the industrially produced all-E retinol acetate.

[0120] 3. The selectivity is significantly increased. During the course of the reaction, the amounts of retinoid compounds of formulas 2 to 5, especially 11,13Z-retinol acetate, 9Z-retinol acetate, and 13Z-retinol acetate, formed using the filterless electroluminescent lighting device of the present invention are considerably reduced compared to a high-pressure mercury lamp.

[0121] Figure 3 discloses the emission spectrum of a light-emitting diode (LED) of the type used in the examples, which is an embodiment of the method of the present invention. More than 90% of the emitted light has wavelengths in the range of 460 nm to 580 nm. The power (μW / nm) reaching the reaction mixture is adapted to be further narrowed by varying the angle and / or distance of the incident light, i.e., the angle / distance between the light-emitting diode and the reaction mixture, or by adjusting the voltage / current applied to the light-emitting diode, or by adjusting the time, and the reaction is exposed to light from the electroluminescent lighting device. In a further embodiment, the power is adjusted or narrowed by the number of light-emitting diodes (LEDs) used. The power consumption per light-emitting diode is 2.8 W. It is also possible to combine some or all of these adjustment means.

Examples

[0122] [Examples 1 to 3 and Comparative Example C4] An LED lamp as an electroluminescent lighting device that emits monochromatic light (the LED lamp includes the number of light-emitting diodes (LEDs) specified in Table 1 below) or a 2.5 L reaction vessel equipped with a side-loop photoreactor having a high-pressure mercury lamp TQ 150 Z2 contains 1.049 g of crude vitamin A (including 941 g of 11,13Z-, 9Z-, 13Z-, 11Z- and all-E retinol acetate isomers), 1.159 g of methanol, 52 g of heptane and 72 mg of erythrosine. At 15 °C, the reaction mixture is pumped into the side-loop photoreactor and irradiated for 4 hours. Samples are taken frequently and subjected to quantitative HPLC. After irradiation, the formed suspension is cooled to -10 °C and filtered. The filter cake is washed with 500 ml of methanol and dried in a nitrogen stream. The apparatus is rinsed with acetone and the residual product is collected. The filter cake, mother liquor and acetone rinse are subjected to quantitative HPLC. The total amount of all-E retinol acetate formed during the course of the reaction is calculated based on the weights of the filter cake, mother liquor and acetone rinse (each having the amount of all-E retinoid determined by HPLC w%). The yield is calculated based on the total amount of retinol acetate isomers subjected to the reaction.

[0123] Table 1: Total amount of all-E retinol acetate and yields obtained in Examples 1-3 and Comparative Example C4. All experiments were carried out using the same starting materials and the same photoreactor.

[0124]

Table 1

[0125] From Table 1, two points can be noted. The yield when each of the light-emitting diodes (LEDs) in Examples 1-3 was operated is higher than that of Comparative Example C4 using a high-pressure mercury lamp. The highest yield of all-E retinol acetate can be obtained when the amount of the light-emitting diodes (LEDs) used is the largest. However, even if the amount of the light-emitting diodes is reduced (see Example 3), an increase in the yield can be brought about.

[0126] [Examples 1 to 3 and Comparative Example C4 (Energy Consumption)] Table 2 discloses the electrical energy consumed to produce 1 kg of all-E retinol acetate in Examples 1 to 3 and Comparative Example C4. The power consumption per light-emitting diode (LED) is 2.8 W, and that of a mercury lamp TQ 150 Z2 is 150 W.

[0127]

Table 2

[0128] The amount of electrical energy used (Wh) is calculated as follows: number of light-emitting diodes × power per light-emitting diode × exposure time. For example, for Example 1, this is 48 × 2.8 W × 4 h = 537.6 Wh. The amount of electrical energy in the sixth column of Table 2 relates to 1 kg of all-E retinol acetate produced.

[0129] In Table 2, it is observed that a high-pressure mercury lamp requires more electrical energy than the light-emitting diodes (LEDs) used to produce 1 kg of all-E retinol acetate. The electrical energy consumption by the light-emitting diodes (LEDs) increases with the number of LEDs used.

[0130] [Examples 1 to 3 and Comparative Example C4 (Formation of Unwanted Retinol Acetate Isomers)] Table 3 discloses the concentration of the 11,13Z,9Z,13Z isomer of unwanted retinol acetate in the reaction mixtures formed during the course of the reactions in Examples 1 to 3 and Comparative Example C4 before irradiation. Further, it discloses the total concentration of Z-isomers of retinol acetate present in the reaction mixtures formed before irradiation and after 4 hours of irradiation in Examples 1 to 3 and Comparative Example C4.

[0131]

Table 3

[0132] From Table 3, it can be confirmed that the amount of the unwanted, so-called Z-isomer of retinol acetate is the largest before irradiation. This decreases during the course of irradiation and is always maximum when using a high-pressure mercury lamp. When using 24 LEDs (Example 3), 36 LEDs (Example 2), and 48 LEDs (Example 1), the amount of the unwanted isomer is always less than that obtained with a high-pressure mercury lamp. The amount of the unwanted isomer obtained is the least when using 48 LEDs for 3 to 4 hours (see Example 1).

[0133] From the present disclosure, an improved process for isomerizing polyunsaturated non-aromatic compounds including acyclic conjugated polyenes and alicyclic conjugated polyenes can be learned. In particular, this is an improved and safe process for forming all-E retinoid compounds in high yields by minimizing energy consumption and avoiding possible by-products or product mixtures to the maximum extent. This is achieved by supplying at least one of the retinoid compounds of Formulas 2 to 5, or at least one of the retinoid compounds of Formulas 2 to 5 and the retinoid compound of Formula 1, an organic solvent, and a photosensitizer to a reaction apparatus, and irradiating the thus-obtained reaction mixture with visible monochromatic light, where at least 90% and at most 100% of the power of the monochromatic light is emitted in the range of 460 nm to 580 nm. Good results are obtained when the reaction mixture contains an organic solvent and is a mixture of at least two solvents, and the electroluminescent lighting device used is a semiconductor material. Using the method of the present invention for isomerizing polyunsaturated compounds, particularly polyunsaturated non-aromatic compounds, is another important subject of the present invention. The present invention includes, for example, the following embodiments. [Item 1] The all-E retinoid compound of Formula 1 or a mixture of all-E retinoid compounds [Chemical formula] (wherein R is CH2-OH, CHO, CH2-OR 2 , COOH, COOR 3Selected from the group of groups consisting of R 2 is (C=O)-alkyl, R 3 is alkyl, Alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 2-butyl, sec-butyl, isobutyl, tert-butyl) A method for obtaining - A retinoid compound of formula 2

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

1. An all-E retinoid compound of formula 1 or a mixture of all-E retinoid compounds 【Chemical 1】 (wherein R is selected from the group consisting of CH 2 -OH, CHO, CH 2 -OR 2 , COOH, COOR 3 ;) R 2 is (C=O)-alkyl and R 3 is alkyl, Alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 2-butyl, sec-butyl, isobutyl, tert-butyl) A method for obtaining, comprising the following reaction steps: - A retinoid compound of formula 2 【Chemical 2】 Or a retinoid compound of formula 3 【Chemical Formula 3】 Or a retinoid compound of formula 4 【Chemical Formula 4】 Or a retinoid compound of formula 5 【Chemical Formula 5】 Or a mixture of at least two of retinoid compounds 2-5 Or a mixture of at least one of retinoid compounds 2-5 and a retinoid compound of formula 1, an organic solvent and a photosensitizer are fed into a reactor; - Irradiating the reaction mixture thus obtained with an electroluminescent lighting device without a filter that emits monochromatic light, wherein at least 90% of the power of the monochromatic light and at most 100% of the power are emitted in the range of 460 nm to 580 nm; A method comprising.

2. The method according to claim 1, wherein at least 90% of the power of the monochromatic light and at most 100% of the power are emitted in the range of 501 nm to 550 nm.

3. The method according to claim 1 or 2, wherein the monochromatic light is selected such that the electrical energy consumed by the lighting device to obtain 1 kg of the retinoid compound of formula 1 does not exceed 800 Wh.

4. R is CH 2 The method according to any one of claims 1 to 3, wherein -O-(C=O)-alkyl, and the alkyl is selected from the group consisting of methyl and ethyl.

5. The total weight parts of the retinoid compounds of formula 1 and formula 2 before irradiation account for at least 80 w% of the retinoid compounds present in the reaction mixture, and the retinoid compounds are selected from the group consisting of the retinoid compound of formula 1, the retinoid compound of formula 2, the retinoid compound of formula 3, the retinoid compound of formula 4, and the retinoid compound of formula 5. The method according to any one of claims 1 to 4.

6. The method according to any one of claims 1 to 5, wherein the organic solvent is a mixture of at least one representative example of the group of C1-C6 alcohols and at least one C5-C10 hydrocarbon.

7. The method according to claim 6, wherein the mixture of at least one representative example of the group of C1-C6 alcohols and at least one C5-C10 hydrocarbon is selected to form a homogeneous phase.

8. The method according to claim 6 or 7, wherein a mixture of at least one representative example of the group of C1-C6 alcohols and at least one C5-C10 hydrocarbon contains 0.1-12 w% of hydrocarbon.

9. The method according to claim 6 or 7, wherein a mixture of at least one representative example of the group of C1-C6 alcohols and at least one C5-C10 hydrocarbon contains 1-12 w% of heptane.

10. The method according to claim 6 or 7, wherein a mixture of at least one representative example of the group of C1-C6 alcohols and at least one C5-C10 hydrocarbon contains 1-5 w% of heptane.

11. The method according to any one of claims 1 to 10, wherein the photosensitizer is selected from at least one compound of the group consisting of fluorescein, eosin, rose bengal, erythrosin, cobalt-tetraphenylporphyrin, zinc-tetraphenylporphyrin, rhodamine B, basakryl brilliant red, iodine.

12. The method according to any one of claims 1 to 11, wherein the writing device contains a semiconductor material.

13. The method according to any one of claims 1 to 12, wherein the writing device includes at least one light-emitting diode (LED) or consists of at least one light-emitting diode (LED).

14. The reaction mixture is introduced into a circuit, and only one area of the circuit is exposed to monochromatic light from a filterless electroluminescent writing device, so that only a clearly distinguishable portion of the reaction mixture is irradiated, where the circuit is any arrangement of pipes, tubes, and / or containers through which the reaction mixture circulates. The method according to any one of claims 1 to 13.

15. The method according to any one of claims 1 to 14, wherein at least one of the retinoid compounds according to claim 1 in an organic solvent added with a photosensitizer is irradiated at a temperature in the range of -20°C to 30°C by reducing the reaction temperature during the progress of the reaction.

16. The method according to any one of claims 1 to 14, wherein at least one of the retinoid compounds according to claim 1 in an organic solvent added with a photosensitizer is irradiated at a temperature in the range of -20°C to 30°C by reducing the reaction temperature during and / or after irradiation.

17. The method according to any one of claims 1 to 16, wherein at least one of retinoid compounds 1 to 5 is supplied into a reaction apparatus such that the total concentration of at least one of retinoid compounds 1 to 5 is in the range of 5 to 50 w% with respect to the reaction mixture.

18. The method according to any one of claims 1 to 16, wherein at least one of retinoid compounds 1 to 5 consisting of isomers of retinol acetate is placed in a reaction vessel such that the total concentration of at least one of retinoid compounds 1 to 5 is in the range of 5 to 50 w% with respect to the reaction mixture.

19. The method according to any one of claims 1 to 18, which is carried out in a side-loop photoreactor, a continuous-flow photoreactor or an underwater photoreactor.

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