ISOMERIZATION OF POLYUNSATURATED NON-AROMATIC COMPOUNDS

Abstract

The invention relates to an improved process for isomerizing polyunsaturated non-aromatic compounds including acyclic conjugated polyenes and alicyclic conjugated polyenes. In particular it relates to an improved and safe process for forming a 11-E retinoid compounds in high yield by expending as few energy as possible and with avoiding at most possible side products or product mixtures. This is achieved by feeding at least one of retinoid compounds of formula 2 to 5, or at least one of retinoid compounds of formula 2 to 5 and retinoid compound of formula 1, an organic solvent and a photosensitizer into a reaction device and irradiating the thus obtained reaction mixture with visible monochromatic light, at least 90% of the power of said monochromatic light and at most 100% of said power being emitted in the range from 460 nm to 580 nm.

Claims

1.-15. (canceled)

16. Process for obtaining an all-E retinoid compound or a mixture of all-E retinoid compounds of formula 1 ##STR00036## with R being selected from the group of moieties consisting of CH.sub.2—OH, CHO, CH.sub.2—OR.sup.2, COOH, COOR.sup.3; with R.sup.2 being (C═O)-alkyl; with R.sup.3 being alkyl; with alkyl being selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 2-butyl, sec-butyl, isobutyl, tert.-butyl; comprising the reaction steps: feeding a retinoid compound of formula 2 ##STR00037## or a retinoid compound of formula 3 ##STR00038## or a retinoid compound of formula 4 ##STR00039## or a retinoid compound of formula 5 ##STR00040## 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 and retinoid compound of formula 1, an organic solvent and a photosensitizer into a reaction device, irradiating the thus obtained reaction mixture by means of a filter-free, electroluminescent lighting device emitting monochromatic light, at least 90% of the power of said monochromatic light and at most 100% of said power being emitted in the range from 460 nm to 580 nm.

17. Process according to claim 16, wherein at least 90% of the power of said monochromatic light and at most 100% of said power being emitted in the range from 501 nm to 550 nm.

18. Process according to claim 16, wherein the monochromatic light is selected such that the electric energy consumed by said lighting device for obtaining 1 kg of retinoid compound of formula 1 does not exceed 800 Wh.

19. The process according to claim 16, wherein R is CH.sub.2—O—(C═O)-alkyl with alkyl being selected from the group of methyl, ethyl.

20. The process according to claim 16, wherein the weight portion of the sum of retinoid compound of formula 1 and formula 2 prior to irradiation amounts to at least 80 w % of the retinoid compounds present in the reaction mixture, said retinoid compounds being selected from the group of retinoid compound of formula 1, retinoid compound of formula 2, retinoid compound of formula 3, retinoid compound of formula 4 and retinoid compound of formula 5.

21. The process according to claim 16, wherein the organic solvent is a mixture of at least one representative of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon.

22. The process according to claim 21, wherein the mixture of at least one representative of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon is selected such that it forms a uniform phase.

23. The process according to claim 21, wherein the mixture of at least one representative of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon comprises between 0.1 and 12 w % of a hydrocarbon.

24. The process according to claim 21, wherein the mixture of at least one representative of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon comprises between 1 and 12 w % of a heptane including 10 w %.

25. The process according to claim 21, wherein the mixture of at least one representative of the group of C1-C6-alcohols and at least one C5-C10 hydrocarbon comprises between 1 and 5 w % of a heptane.

26. The process according to claim 16, wherein the photosensitizer is selected from at least one compound of the group consisting of fluorescein, eosin, rose bengal, erythrosine, cobalt-tetraphenylporphyrin, zinc-tetraphenylporphyrin, rhodamine B, basacryl brilliant red, iodine.

27. The process according to claim 16, wherein the lighting device comprises a semiconductor material.

28. The process according to claim 16, wherein the lighting device comprises at least one light emitting diode (LED).

29. The process according to claim 16, wherein only a distinct portion of the reaction mixture is irradiated.

30. The process according to claim 16, wherein at least one of the retinoid compounds of claim 16 in an organic solvent supplemented with a photosensitizer is irradiated at a temperature ranging from −20° C. to 30° C. with lowering the reaction temperature during the course of the reaction, in particular during the course of and/or after irradiation.

31. The process according to claim 16, wherein at least one of the retinoid compounds 1 to 5 is fed in the reaction device such that the overall concentration of at least one of the retinoid compounds 1 to 5 ranges from 5 to 50 w % with respect to the reaction mixture.

32. The process according to claim 16, wherein at least one of the retinoid compounds 1 to 5 is fed in the reaction device such that the overall concentration of at least one of the retinoid compounds 1 to 5 ranges from 5 to 50 w % with respect to the reaction mixture, wherein at least one of the retinoid compounds 1 to 5 consisting of isomers of retinol acetate is placed in the reaction vessel such that the overall concentration of at least one of the retinoid compounds 1 to 5 ranges from 5 to 50 w % with respect to the reaction mixture.

33. The process according to claim 16, wherein it is realized in a side-loop photoreactor, in a continuous flow-photoreactor or in a submersible photoreactor.

Description

[0188] The invention and its advantageous features will now be further explained in the specific description including the examples and making reference to the figures.

[0189] FIG. 1 Output profile of a xenon arc lamp

[0190] FIG. 2 Transmittancy of a K.sub.2CrO.sub.4-solution

[0191] FIG. 3 Emission spectrum of the light emitting diode within the lighting device used

[0192] Some of the advantageous features of the inventive process are:

[0193] 1. The yield of all-E retinoid compound of formula 1, viz. all-E retinol acetate is higher when using light emitting diodes (LED's) compared to experiments with conventional high pressure mercury vapour lamps in combination with a chromate filter.

[0194] 2. There are considerable savings of electric energy for the same amount of all-E retinoid compound of formula 1, in particular of all-E retinol acetate produced.

[0195] 3. There is a remarkable increase in selectivity. In course of the reaction a considerably reduced amount of retinoid compounds of formula 2 to 5, in particular of 11,13Z-retinol acetate, of 9Z-retinol acetate, and 13Z-retinol acetate are formed with the inventive filter-free, electroluminescent lighting device compared to the high pressure mercury vapor lamp.

[0196] FIG. 3 discloses the emission spectrum of the type of light emitting diode (LED) as used in the examples, which are embodiments of the inventive process. One realizes that 90% or more of the emitted light has a wavelength ranging from 460 nm to 580 nm. The power in μW/nm reaching the reaction mixture is adapted to be narrowed further either by changing the angle and/or distance of incident light, i.e. the angle/distance between the light emitting diode and the reaction mixture or by adjusting the voltage/courant applied onto the light emitting diode, or by adjusting the time, the reaction is exposed to light from the electroluminescent lighting device. In a further embodiment power is adjusted or narrowed by the number of light emitting diodes (LED's) used. The electric power consumption per light emitting diode is 2.8 W. Part or all of these adjusting measures can also be combined.

EXAMPLES 1 TO 3 AND COMPARATIVE EXAMPLE C4

[0197] In a 2.5| reaction vessel, equipped with a side-loop photoreactor with either a LED-lamp as electroluminescent lighting device emitting monochromatic light, said LED-lamp comprising a number of light emitting diodes (LED's) as specified in table 1 below, or with a high pressure mercury vapor lamp TQ 150 Z2, are placed 1.049 g of crude vitamin A (containing 941 g 11,13Z-, 9Z-, 13Z-,11Z- and all-E retinol acetate isomers), 1.159 g of methanol, 52 g of heptane and 72 mg erythrosine. At 15° C. the reaction mixture is pumped through the side loop photoreactor and irradiated for 4 h. Samples were taken frequently and subjected to quantitative HPLC. After irradiation, the suspension formed is cooled down to −10° C. and filtered. The filter cake is washed with 500 ml of methanol and dried in a current of nitrogen. The apparatus is rinsed with acetone to collect remaining product. The filter cake, the mother liquor and the acetone rinse are subjected to quantitative HPLC. The sum of amounts of all-E retinol acetate formed in course of the reaction are calculated based on the weight of the filter cakes, mother liquors and acetone rinses, each having a respective all-E retinoid amount as determined by HPLC w %. The yields are calculated based on the total amount of retinol acetate isomers subjected into the reaction.

[0198] Table 1: Total amount of all-E retinol acetate and yield obtained in examples 1-3 and comparative example C4. All experiments were performed with the same starting material and the same photoreactor.

TABLE-US-00002 TABLE 1 Total mass of all E retionol acetate in Number of LEDs/ Total mass of Exam- crude vitamin A prior mercury lamp all-E retinol Yield ple to irradiaton [g] applied acetate [g] [%] 1 533.7 48 722.5 76.8 2 533.7 36 699.8 74.4 3 533.7 24 710.2 75.5 C4 533.7 TQ 150 Z2 + filter 681.3 72.4

[0199] From Table 1, two things can be noticed. The yield when working with light emitting diodes (LED's) in each of examples 1 to 3 is higher than in comparative example C4 using the high pressure mercury vapor lamp. The highest yield of all-E retinol acetate can be obtained with the highest amount of light emitting diodes (LED's) used. However, also with a reduced amount of light emitting diodes (cf. example 3) increased yields can be obtained.

EXAMPLE 1 TO 3 AND COMPARATIVE EXAMPLE C4 (ENERGY CONSUMPTION)

[0200] Table 2 discloses the electric energy spent for making 1 kg of all-E retinol acetate of example 1-3 and of comparative example C4. The electric power consumption per light emitting diode (LED) amounts to 2.8 W and for the mercury lamp TQ 150 Z2 it amounts to 150 W.

TABLE-US-00003 TABLE 2 Total mass of Total mass Electric all E retionol Number of (all-E energy/all-E acetate prior LEDs/ retinol Electric retinol Exam- to irradiaton mercury lamp acetate) energy acetate ple [g] applied [g] [Wh] [Wh/kg] 1 533.7 48 722.5 537.6 744.1 2 533.7 36 699.8 403.2 576.2 3 533.7 24 710.2 268.8 378.5 C4 533.7 TQ 150 Z2 + 681.3 600.0 880.7 filter

[0201] The amount of electric energy (Wh) employed is calculated as follows: Number of light emitting diodes x power per light emitting diode x time of exposure. Regarding for instance example 1, this is 48×2.8 W×4 h=537.6 Wh. Said amount of electric energy in column 6 of table 2 is related to 1 kg of all-E retinol acetate produced.

[0202] One observes in table 2, that the high pressure mercury vapor lamp requires more electric energy for producing 1 kg of all-E retinol acetate than the light emitting diodes (LED's) used. The consumption of electric energy by the light emitting diodes (LED's) increases with the number of LED's used.

EXAMPLE 1 TO 3 AND COMPARATIVE EXAMPLE C4 (FORMATION OF UNDESIRED ISOMERS OF RETINOL ACETATE)

[0203] Table 3 discloses the concentration of undesired 11,13Z-, 9Z-, 13Z-isomers of retinol acetate in the reaction mixture prior to irradiation and formed in course of the reaction in examples 1-3 and comparative example C4. It further discloses in examples 1-3 and comparative example C4 the concentration of the sum of Z-isomers of retinol acetate present in the reaction mixture prior to irradiation and formed after four hours of irradiation.

TABLE-US-00004 TABLE 3 Example 1 2 3 C4 Sum Sum of Sum Sum of Sum Sum of Sum Sum of (11, 13Z-, Z-iso- (11, 13Z-, Z-iso- (11, 13Z-, Z-iso- (11, 13Z-, Z-iso- 9Z-, mers in 9Z-, mers in 9Z-, mers in 9Z-, mers in 13Z-ret- crude 13Z-ret- crude 13Z-ret- crude 13Z-ret- crude inol ace- vitamin inol ace- vitamin inol ace- vitamin inol ace- vitamin Reaction tate) A tate) A tate) A tate) A time (h) (w %) (w %) (w %) (w %) (w %) (w %) (w %) (w %) 0.00 13.49 38.8 13.49 38.8 13.49 38.8 13.49 38.8 0.50 14.63 — 14.47 — 14.79 — 16.40 — 1.00 15.55 — 15.08 — 15.97 — 16.72 — 2.00 15.14 — 15.09 — 15.83 — 16.94 — 3.00 14.14 — 14.54 — 15.23 — 16.37 — 4.00 13.96 16.2 14.04 17.5 15.46 18.5 16.00 19.6

[0204] From table 3, it can be seen that the amount of undesired so-called Z-isomers of retinol acetate is the highest prior to irradiation. It decreases during the course of irradiation and it is always the highest, when using the high pressure mercury vapor lamp. With 24 LED's (example 3), 36 LED's (example 2) and 48 LED's (example 1) the amount of undesired isomers is always inferior to this one obtained with the high pressure mercury vapor lamp. The lowest amount of undesired isomers is obtained when one uses 48 LED's during a time of 3 to 4 h (cf. example 1).

[0205] One learns from this disclosure about an improved process for isomerizing polyunsaturated non-aromatic compounds including acyclic conjugated polyenes and alicyclic conjugated polyenes. In particular it is an improved and safe process for forming all-E retinoid compounds in high yield by expending as few energy as possible and with avoiding at most possible side products or product mixtures. This is achieved by feeding at least one of retinoid compounds of formula 2 to 5, or at least one of retinoid compounds of formula 2 to 5 and retinoid compound of formula 1, an organic solvent and a photosensitizer into a reaction device and irradiating the thus obtained reaction mixture with visible monochromatic light, at least 90% of the power of said monochromatic light and at most 100% of said power being emitted in the range from 460 nm to 580 nm. Good results are obtained, when the reaction mixture comprises an organic solvent, being a mixture of at least two solvents and the electroluminescent lighting device used is a semiconductor material. Using the inventive process for isomerizing polyunsaturated compounds, in particular for isomerizing polyunsaturated non-aromatic compounds is another crucial topic of the invention.