Title of Invention	A PROCESS FOR THE CATALYTIC ISOMERIZATION OF Z-ISOMERS OF VITAMIN A COMPOUNDS TO A MIXTURE OF ALL-E AND 13-Z ISOMERS OF THE CORRESPONDING VITAMIN A COMPOUNDS
Abstract	The invention relates to a process for the catalytic isomerization of Z-isomers of Vitamin A compounds to a mixture of all-E- and 13-Z-isomers of the corresponding Vitamin A compounds. 1he said process comprises using nitrogen monoxide or a gas mixture containing nitrogen monoxide as the isomerization catalyst. Moreover, the isomerization process is conveniently effected in a polar or apolar organic solvent at temperatures up to about 200 C and in such a manner that the catalytic contact with nitrogen monoxide is effected by introducing nitrogen monoxide or a 9as mixture containin9 nitrogen monoxide e.g. With nitrogen, into the (optionally dissolved) vitamin A compound to be isomerized and dispersing the nitrogen monoxide or the gas mixture containing nitrogen monoxide at atmospheric pressure or under slight over -_pressure, e.g. up to 10 bar. Vitamin A acetate or vitamin A acid is prefereably used as the vitamin A compound. The thus -_produced all-E vitamin A and its alkanoyl esters have of all isomers by far the highest biological activity and are accordingly almost exclusively used in human and animal nutrition. The 13-Z-vitamin A compounds in turn play an important role as Pharmaceutically active Substances.

Title of Invention

A PROCESS FOR THE CATALYTIC ISOMERIZATION OF Z-ISOMERS OF VITAMIN A COMPOUNDS TO A MIXTURE OF ALL-E AND 13-Z ISOMERS OF THE CORRESPONDING VITAMIN A COMPOUNDS

Abstract

The invention relates to a process for the catalytic isomerization of Z-isomers of Vitamin A compounds to a mixture of all-E- and 13-Z-isomers of the corresponding Vitamin A compounds. 1he said process comprises using nitrogen monoxide or a gas mixture containing nitrogen monoxide as the isomerization catalyst. Moreover, the isomerization process is conveniently effected in a polar or apolar organic solvent at temperatures up to about 200 C and in such a manner that the catalytic contact with nitrogen monoxide is effected by introducing nitrogen monoxide or a 9as mixture containin9 nitrogen monoxide e.g. With nitrogen, into the (optionally dissolved) vitamin A compound to be isomerized and dispersing the nitrogen monoxide or the gas mixture containing nitrogen monoxide at atmospheric pressure or under slight over -_pressure, e.g. up to 10 bar. Vitamin A acetate or vitamin A acid is prefereably used as the vitamin A compound. The thus -_produced all-E vitamin A and its alkanoyl esters have of all isomers by far the highest biological activity and are accordingly almost exclusively used in human and animal nutrition. The 13-Z-vitamin A compounds in turn play an important role as Pharmaceutically active Substances.

Full Text	The present invention is concerned with a process for the catalytic isomerization of Z isomers of Vitamin A compounds to the all-E and 13-Z isomers of the corresponding Vitamin A compounds using nitrogen monoxide as the isomerization catalyst. In particular, the invention is concerned with the isomerization of undesired isomers of Vitamin A compounds, e.g.the 9-Z-, 11-Z-, 9,13-di-Z- and 11,13-di-Z-vitamin A compounds individually or as a mixture of these isomers, into a corresponding mixture of the useful all-E- and 13-Z compounds, which are by necessity present in equilibrium. In natural vitamin A, as is contained in many fish liver oils, e.g. shark, cod, halibut and californian Jew fish liver oil, the total content of vitamin A consists of about 65% of all-E vitamin A and about 35% of 13-Z- vitamin A. The all-E-vitamin A and its alkanoyl esters have of all isomers by far the highest biological activity and are accordingly almost exclusively used in human and animal nutrition. On the other hand, the 13-Z-vitamin A compounds also play an important role, namely as pharmaceutically active substances. The vitamin A preparations commercialized at present are almost exclusively produced synthetically. Since the previously known and used processes for the production of a vitamin A compound do not yield pure all-E compound, but only mixtures of various isomers having more or less large amounts of the all-E isomer, there has hitherto always been the problem of the isomerization of the various undesired isomers to the all-E isomer. The problem is firstly to achieve yields of all-E compounds which are as high as possible and also- since the total Z—► E conversion is not possible- to obtain mixtures from which the all-E isomer can be isolated in a manner which is as simple as possible. The method most used previously was the isomerization with iodine in the presence of pyridine [see, for example, German Auslegeschrift (DAS) 1 468 798]. The addition of pyridine is necessary in order to keep the formation of the 9-Z isomer as low as possible. However, this method has the disadvantage that the iodine must be removed as completely as possible from the reaction mixture after the isomerization and prior to the isolation of the all-E compound. This is usually carried out by the addition of an iodine reducing agent, such as, for example, sodium thiosulphate, sodium bisulphite or sodium borohydride, the excess of which is subsequently removed by washing, filtration or other suitable methods. The photochemical isomerization using sensitizers is also known (see, for example, DAS 2 210 800). However, this method is encumbered with the disadvantage that the sensitizer must be removed after completion of the isomerization. Moreover, the photochemical isomerization (not only with, but also without sensitizers) requires complex and expensive special apparatuses, which can lead to considerable difficulties especially when working on an industrial scale. The object of the present invention is, starting from the pure isomers or also any isomer mixtures, even in the presence of impurities, to obtain a mixture having a content of the corresponding all-E-vitamin A compound which is as high as possible and from which the all-fi isomer and the 13-Z isomer which is unavoidably present with this isomer in equilibrium can be isolated readily and without great expense in a form which is as pure as possible. It has now surprisingly been found that this object can be achieved by catalysis with gaseous nitrogen monoKide (NO), especially at atmospheric pressure or under a slight over-pressure. The isomerization catalyst NO is removed by replacing the NO atmosphere or simply by de-pressurizing the reaction mixture. The isolation of the all-E and of the 13-Z isomer can then be effected according to methods known per se, e.g. cooling crystallization or evaporation crystallization. A very stable product is produced using this isomerization process. No special apparatuses are required. The object of the present invention is accordingly a process for the catalytic isomerization of Z-isomers of Vitamin A compounds such as herein described to a mixture of all-E and 13-Z isomers of the corresponding vitamin A compounds under conditions which, apart from the nature and use of the catalyst itself, are known per se, which process comprises using as the isomerisation catalyst nitrogen monoxide or a gaseous mixture containing nitrogen monoxide, and, if desired, subsequently separating the produced all-E and 13-Z isomers from the reaction mixture by methods known per se. Under the term "vitamin A compounds" there are to be understood in the scope of the present invention vitamin A itself (retinol), vitamin A aldehyde (retinal) and vitamin A acid and their derivatives, e.g. esters, acetals and amides. The term embraces especially the following compounds of general formula I in which no indication of the stereoisomerism is given: wherein R represents the group -CHO, -CH2OH, -COOH, -CH(R1)2,' -CH2OR2, -COOR3, -CONHR4 or -CON(R4)2, in which both Rl's each independently signify lower alkoxy or two residues R1 together signify lower alkylenedioxy, R2 signifies alkanoyl or aroyl, R3 signifies alkyl, aryl or aralkyl and R4 or both R4's each independently signify hydrogen, alkyl, aryl or aralkyl. In the scope of the above definition the term "lower alkoxy" signifies especially an alkoxy group with 1 to 6 carbon atoms, such as, for example, methoxy, ethoxy or propoxy. "Lower alkylenedioxy" signifies such a group which likewise contains 1 to 6 carbon atoms, e.g. methylenedioxy or ethylenedioxy. In both cases the alkyl or alkylene part can be straight-chain or branched depending on the number of carbon atoms. The term "alkanoyl" embraces not only straight-chain, but also branched alkanoyl groups with 1-18 carbon atoms, such as, for example, formyl, acetyl, propionyl, butyryl, stearoyl and palmitoyl. The term "aroyl" is derived from aromatic carboxylic acids with 7 and 11 carbon atoms and accordingly signifies benzoyl or naphthoyl, respectively. The term "alkyl" signifies a straight-chain or branched alkyl group with 1 to 18 carbon atoms, e.g. methyl, ethyl, propyl, butyl, decyl, dodecyl, hexadecyl or octadecyl. The term "aryl" as such or as part of "aralkyl" signifies especially phenyl or naphthyl. Finally, the term "aralkyl" embraces such groups with 1 to 4 carbon atoms in the aliphatic part, e.g. benzyl and phenylpropyl. Vitamin A acetate or vitamin A acid is preferably used as the vitamin A compound. A Z isomer of a vitamin A compound to be isomerized, e.g. the 9-Z, the 11-Z, the 9,13-di-Z or the 11,13-di-Z isomer, can be isomerized individually or as a component of a mixture of several of such Z isomers, whereby in a mixture already to some extent the all-E isomer and the 13-Z isomer which by necessity is present in equilibrium with this all-E isomer and/or impurities can also be present. Furthermore, several vitamin A compounds can be present as isomers in a mixture to be isomerized. A typical example of such a mixture results from the multi-stage production of a vitamin A compound, e.g. vitamin A acetate: after several stages there is obtained by-crystallization and filtration a crystallizate cantaining an all E-vitamin A compound and a mother liquor. In addition to impurities this mother liquor contains not only the all-E isomer, but also Z isomers of the desired vitamin A compound, whereby the amount of isomerizable Z isomers may be considerable. This mixture, or the mother liquour remaining after removal of most of the impurities, can be subjected to the isomerization process in accordance with the invention. After carryir.g out the isomerization process in accordance with the invention and removiig the all-E isomer there is obtained a mixture which is rich in the 13-Z isomer, from which, if desired, the 13-Z isomer can likewise be removed. The catalyzed isomerization in accordance with the invention is conveniently effected in an inert solvent, even when the isomer or isomer mixture to be isomerized is liquid at the proc sss temperature. As solvents there come into consideration not only polar organic solvents, e.g. acetonitrile and dimethylformamide (aprotic polar solvents), but also apolar organic solvents, such as aliphatic and aromatic hydrocarbons, e.g. pentane, hexane, heptane, benzene, toluene, xylene and petroleum ether; and halogenated aliphatic and aromatic hydrocarbons, e.g. methylene chloride, ethylene chloride, chloroform, carbon tetrachloride and chlorobenzene. Other polar organic solvents which come into consideration are lower aliphatic alcohols, e.g. methanol, ethanol and propanol (protic polar solvents) and lower aliphatic esters, e.g. methyl acetate and ethyl acetate (aprotic polar solvents). Solvent mixtures, even in combination with small amounts of water, can also be used. Tie aliphatic hydrocarbons, especially hexane, and the lower aliphatic al:ohols, especially ethanol, are especially preferred solvents. Insofar as a substance to be isomerizec is present in liquid form, the isomerization can also be carried out in the absence of a solvent. However, the use of a solvent is preferred having regarci to a subsequent crystallization. Convenient solutions used in the isomerization are those having a concentration up to 90 wt.% (weight of educt to total weight), especially about * 5 wt.% to about 80 wt.%. About 50 wt.% to 7C wt.% solutions are especially preferred, since these represent the best con( [itions for the subsequent crystallization of the all-E isomer. The catalytic contact with NO is conve liently effected by introducing NO or a gas mixture containing NO into the [optionally dissolved) vitamin A compound to be isomerized and dispersing the NO or the gas mixture containing NO, e.g. by rotating the gas stream, at atmospheric pressure or under a slight over-pressure. Pressures up to 10 bar (1 MPa) over-pressure, especially pressures of 0.1 bar (10 kPa) over-pressure to 3 bar (300 kPa) over¬pressure, are preferred. When gas mixtures containing NO are used for the catalysis, these conveniently contain 1 to about 90 wt.% NO (weight of NO to weight of mixture). Gas mixtures with 10 to 30 wt.% NO, especially with 10 to 60 wt.% NO, are preferably used. Inert giises, such as, for example, nitrogen, helium, argon, carbon dioxide, dinitrogen monoxide, methane and ethane, are suitable for the production of the NO gas mixture. Nitrogen, which is simultaneously employed for the intsrtization of the reaction mixture, is preferably used. The isomerization process in accordance with the invention can conveniently be carried out at temperatures i;p to about 200^0. The process is preferably effected at temperatures up to about 150^0, especially up to about 100°C. It is especially preferred to carry out the process at temperatures in the range of about SO^C to about 80°C. The isomerization can also be effected at room temperature and thereunder. Conveniently, in the isomerization the concentration and temperature are chosen such that the all-E isomer formed is separated continuously; this can be effected in a manner known per se. The isomerization period is generally between about 1 minute and about 50 hours, especially between about 10 minutes and about 30 hours, preferably between about 30 minutes and about 20 hours. The isomerization period is largely dependent on the chosen temperature and the set NO pressure. In the case of long isomerization periods low temperatures and low NO pressures have the same effect as hijjh temperatures and correspondingly shorter isomerization periods. Since, as is known, vitamin A compounds are relatively unstable compounds, the reaction conditions are conveniently chosen such that the reaction m ixture need not be heated to high temperatures for a long period. The isomerlzation is conveniently effected with the exclusion of air, i.e. under an inert gas, e.g. nitrogen or argon. Moreover, the Isonerization oan be carried out not only discontlnuously, but also continuously. After completion of the isonerization process the isolation of the desired all-E- or 13-Z-vitanin A compound can be carried out according to methods known per se, such as, for example, cooling crystallization or evaporation crystallization. Thereby, for a separation which is as complete as possible the clear differences in solubility behaviour between the isomers to be isolated and the remaining isomers (including impurities) are of significance. The isomerization process in accordance with the invention is illustrated by the following Examples; in the Examples all analyses given have been carried by high pressure liquid chromatography (HPLC). ExftPple 1 49 g of a mixture containing 23X all-E-vitamin A acetiite, 39X 13-Z-vitamin A acetate, 18X 11-Z-vitamin A acetate, 5X llilS-di-Z-vitamin A acetate and 3X 9-Z- and/or 9,13-di-Z-vitamii\| A acetate (remainder impurities) are dissolved in 35 ml of mel\|hyl acetate under argon in a sulphonatlon flask. Pure NO gas is ihen conducted into this solution while stirring for 10 minut'es. Subsequently, the reaction apparatus is completely closed and the solution is stirred intensively at room temperature for 5 hours. Subsequently, the NO atmosphere is replaced by inert gas. A mixture containing 435K all-E-. 26% 13-Z-, 12% ll-Z, 4% U,13-di-Z- and 3% 9-Z and/or 9,13-di-Z-vitamin A acetate is obtained. Exanplo Z 200 g of a mixture containing 23% all-E-, 40% 13-Z, 17% 11-Z-. 5% 11,13-di-Z- and 3% 9-Z- and/or 9,13-di-Z-vit«mln A acetate, the balance being non-reaotable impurities are dissolved in 140 ml of hexane under nitrogen in a pressure-tight apparatus. After flushing the apparatus with nitrogen at atmospheric pressure HO gas is introduced at room temperature while stirring to an over-pressure of 0.5 bar (50 kPa) and the apparatus is closed. The solution is heated to 40°C while stirring and stirred intensively for 5 hours. Subsequently, the apparatus is, de-pressurized and cooled to room temperature. A mixture containing 48% all-E-, 24% 13-Z-, 4% 11-Z-, 4 % 11,13-di-Z- and 3% 9-Z- and/or 9,13-di-Z-vitamin A acetate is obtained. Example 3 100 g of a mixture containing 23% all-E-, 32% 13-Z-, 15% 11-Z-, 6% 11,13-di-Z- and 3% 9-Z- and/or 9,13-di-Z-vitamin A acetate are placed without solvent under nitrogen in a pressure-tight apparatus. After flushing the apparatus with nitrogen at atmospheric pressure NO gas is introduced at room temperature while stirring to an over-pressure of 0.5 bar (50 kPa) and the apparatus is closed. The liquid is heated to 40°C while stirring and stirred intensively for 5 hours. Subsequently, the apparatus is de-pressurized and cooled to room temperature. A mixture containing 48% all-E-, 21% 13-Z-, 2% 11-Z-, 5 % 11,13-di-Z- and 3% 9-Z- and/or 9,13-di-Z-vitamin A acetate is obtained. Example 4 19 g of a mixture containing 94% all-E-vitamin A acetate and 3% 13-Z-vitamin A acetate are dissolved in 38 g oj" ethanol under nitrogen in a pressure-tight apparatus. After flushing the apparatus with nitrogen at atmospheric pressure NO gas is introduced at room temperature while stirring to an over-pressure of 0.5 bar (50 kPa) and the apparatus is closed. The solution is heated to 40^0 while stirring and stirred intensively for 5 hours. Subsequently, the apparatus is depressurized and cooled to room temperature. A mixture containing 67% all-E-vitamin A acetate and 28% 13-Z-vitamin A acetate is obtained. The content of the other isomers (11-Z-, 11,13-di-Z- and 9-Z- and/or 9,13-di-Z-vitamin A acetate) is significantly below 1%. WE CLAIM : 1. A process for the catalytic isomerization of Z-isomers of Vitamin A compounds such as herein described to a mixture of all-E_ and 13-Z isomers of the corresponding vitamin A compounds under conditions which, apart from the nature and use of the catalyst itself, are known per se, which process comprises using as the isomerisation catalyst nitrogen monoxide or a gaseous mixture containing nitrogen monoxide, and, if desired, subsequently separating the produced all-E and 13-Z isomers from the reaction mixture by methods known per se. 2. The process according to claim 1, wherein the vitamin A compound is vitamin A, vitamin A aldehyde, vitamin A acid or a wherein R represents the group -CHO, -CH2OH, -COOH, -CH(R )2/ CHjOR^, -COOR^, -CONHR^ or -C0N(R^)2, in which both R""' s each independently signify lower alkoxy or two residues R together 2 3 signify lower alkylenedioxy, R signifies alkanoyl or aroyl, R 4 4 signifies alkyl, aryl or aralkyl and R or both R s each independently signify hydrogen, alkyl, aryl or aralkyl. 3. The process according to claims 1 or 2, wherein the Z isomer to be isomerized is the 9-Z, the 11-Z, the 9,13-di-Z or the 11,13-di-Z isomer or a mixture thereof. 4. The process according to any one of claims 1 to 3, wherein the isomerization is effected in a polar or apolar organic solvent. 5. The process according to claim 4, wherein the solvent is an aliphatic hydrocarbon or a lower aliphatic alcohol. 6. The process according to claim 5, wherein the solvent is hexane or ethangl. 1?. A prorpss for the catalytic isomerization of 2 isomers of vitamin A cmpounds to a mixture of all-E and 13-Z isomers of the corresponding vitamin A compounds substantially as herein before described.

Full Text

The present invention is concerned with a process for the catalytic isomerization of Z isomers of Vitamin A compounds to the all-E and 13-Z isomers of the corresponding Vitamin A compounds using nitrogen monoxide as the isomerization catalyst. In particular, the invention is concerned with the isomerization of undesired isomers of Vitamin A compounds, e.g.the 9-Z-, 11-Z-, 9,13-di-Z- and 11,13-di-Z-vitamin A compounds individually or as a mixture of these isomers, into a corresponding mixture of the useful all-E- and 13-Z compounds, which are by necessity present in equilibrium.
In natural vitamin A, as is contained in many fish liver oils, e.g. shark, cod, halibut and californian Jew fish liver oil, the total content of vitamin A consists of about 65% of all-E vitamin A and about 35% of 13-Z- vitamin A. The all-E-vitamin A and its alkanoyl esters have of all isomers by far the highest biological activity and are accordingly almost exclusively used in human and animal nutrition. On the other hand, the 13-Z-vitamin A compounds also play an important role, namely as pharmaceutically active substances.
The vitamin A preparations commercialized at present are almost exclusively produced synthetically. Since the previously known and used processes for the production of a vitamin A compound do not yield pure all-E compound, but only mixtures of various isomers having more or less large amounts of the all-E isomer, there has hitherto always been the problem of the isomerization of the various undesired isomers to the all-E isomer. The problem is firstly to achieve yields of all-E compounds which are as high as possible and also- since the total Z—► E conversion is not possible- to obtain mixtures from which the all-E isomer can be isolated in a manner which is as simple

as possible. The method most used previously was the isomerization with iodine in the presence of pyridine [see, for example, German Auslegeschrift (DAS) 1 468 798]. The addition of pyridine is necessary in order to keep the formation of the 9-Z isomer as low as possible. However, this method has the disadvantage that the iodine must be removed as completely as possible from the reaction mixture after the isomerization and prior to the isolation of the all-E compound. This is usually carried out by the addition of an iodine reducing agent, such as, for example, sodium thiosulphate, sodium bisulphite or sodium borohydride, the excess of which is subsequently removed by washing, filtration or other suitable methods.
The photochemical isomerization using sensitizers is also known (see, for example, DAS 2 210 800). However, this method is encumbered with the disadvantage that the sensitizer must be removed after completion of the isomerization. Moreover, the photochemical isomerization (not only with, but also without sensitizers) requires complex and expensive special apparatuses, which can lead to considerable difficulties especially when working on an industrial scale.
The object of the present invention is, starting from the pure isomers or also any isomer mixtures, even in the presence of impurities, to obtain a mixture having a content of the corresponding all-E-vitamin A compound which is as high as possible and from which the all-fi isomer and the 13-Z isomer which is unavoidably present with this isomer in equilibrium can be isolated readily and without great expense in a form which is as pure as possible. It has now surprisingly been found that this object can be achieved by catalysis with gaseous nitrogen

monoKide (NO), especially at atmospheric pressure or under a slight over-pressure. The isomerization catalyst NO is removed by replacing the NO atmosphere or simply by de-pressurizing the reaction mixture. The isolation of the all-E and of the 13-Z isomer can then be effected according to methods known per se, e.g. cooling crystallization or evaporation crystallization. A very stable product is produced using this isomerization process. No special apparatuses are required.
The object of the present invention is accordingly a process for the catalytic isomerization of Z-isomers of Vitamin A compounds such as herein described to a mixture of all-E and 13-Z isomers of the corresponding vitamin A compounds under conditions which, apart from the nature and use of the catalyst itself, are known per se, which process comprises using as the isomerisation catalyst nitrogen monoxide or a gaseous mixture containing nitrogen monoxide, and, if desired, subsequently separating the produced all-E and 13-Z isomers from the reaction mixture by methods known per se.
Under the term "vitamin A compounds" there are to be understood in the scope of the present invention vitamin A itself (retinol), vitamin A aldehyde (retinal) and vitamin A acid and their derivatives, e.g. esters, acetals and amides. The term embraces especially the following compounds of general formula I in which no indication of the stereoisomerism is given:

wherein R represents the group -CHO, -CH2OH, -COOH, -CH(R1)2,' -CH2OR2, -COOR3, -CONHR4 or -CON(R4)2, in which both Rl's each independently signify lower alkoxy or two residues R1 together signify lower alkylenedioxy, R2 signifies alkanoyl or aroyl, R3 signifies alkyl, aryl or aralkyl and R4 or both R4's each independently signify hydrogen, alkyl, aryl or aralkyl.
In the scope of the above definition the term "lower alkoxy" signifies especially an alkoxy group with 1 to 6 carbon atoms, such as, for example, methoxy, ethoxy or propoxy. "Lower alkylenedioxy" signifies such a group which likewise contains 1 to 6 carbon atoms, e.g. methylenedioxy or ethylenedioxy. In both cases the alkyl or alkylene part can be straight-chain or branched depending on the number of carbon atoms. The term "alkanoyl" embraces not only straight-chain, but also branched alkanoyl groups with 1-18 carbon atoms, such as, for example, formyl, acetyl, propionyl, butyryl, stearoyl and palmitoyl. The term "aroyl" is derived from aromatic carboxylic acids with 7 and 11 carbon atoms and accordingly signifies benzoyl or naphthoyl, respectively. The term "alkyl" signifies a straight-chain or branched alkyl group with 1 to 18 carbon atoms, e.g. methyl, ethyl, propyl, butyl, decyl, dodecyl, hexadecyl or octadecyl. The term "aryl" as such or as part of "aralkyl" signifies especially phenyl or naphthyl. Finally, the term "aralkyl" embraces such groups with 1 to 4 carbon atoms in the aliphatic part, e.g. benzyl and phenylpropyl.
Vitamin A acetate or vitamin A acid is preferably used as the vitamin A compound.
A Z isomer of a vitamin A compound to be isomerized, e.g. the 9-Z, the 11-Z, the 9,13-di-Z or the 11,13-di-Z isomer, can be isomerized individually or as a component of a mixture of several of such Z isomers, whereby in a mixture already to some extent the all-E isomer and the 13-Z isomer which by necessity is present in equilibrium with this all-E isomer and/or

impurities can also be present. Furthermore, several vitamin A compounds can be present as isomers in a mixture to be isomerized. A typical example of such a mixture results from the multi-stage production of a vitamin A compound, e.g. vitamin A acetate: after several stages there is obtained by-crystallization and filtration a crystallizate cantaining an all E-vitamin A compound and a mother liquor. In addition to impurities this mother liquor contains not only the all-E isomer, but also Z isomers of the desired vitamin A compound, whereby the amount of isomerizable Z isomers may be considerable. This mixture, or the mother liquour remaining after removal of most of the impurities, can be subjected to the isomerization process in accordance with the invention. After carryir.g out the isomerization process in accordance with the invention and removiig the all-E isomer there is obtained a mixture which is rich in the 13-Z isomer, from which, if desired, the 13-Z isomer can likewise be removed.
The catalyzed isomerization in accordance with the invention is conveniently effected in an inert solvent, even when the isomer or isomer mixture to be isomerized is liquid at the proc sss temperature. As solvents there come into consideration not only polar organic solvents, e.g. acetonitrile and dimethylformamide (aprotic polar solvents), but also apolar organic solvents, such as aliphatic and aromatic hydrocarbons, e.g. pentane, hexane, heptane, benzene, toluene, xylene and petroleum ether; and halogenated aliphatic and aromatic hydrocarbons, e.g. methylene chloride, ethylene chloride, chloroform, carbon tetrachloride and chlorobenzene. Other polar organic solvents which come into consideration are lower aliphatic alcohols, e.g. methanol, ethanol and propanol (protic polar solvents) and lower aliphatic esters, e.g. methyl acetate and ethyl acetate (aprotic polar solvents). Solvent mixtures, even in combination with small amounts of water, can also be used. Tie aliphatic hydrocarbons, especially hexane, and the lower aliphatic al:ohols, especially ethanol, are especially preferred solvents.
Insofar as a substance to be isomerizec is present in liquid form, the isomerization can also be carried out in the absence of a solvent. However, the use of a solvent is preferred having regarci to a subsequent crystallization.
Convenient solutions used in the isomerization are those having a concentration up to 90 wt.% (weight of educt to total weight), especially about

* 5 wt.% to about 80 wt.%. About 50 wt.% to 7C wt.% solutions are especially preferred, since these represent the best con( [itions for the subsequent crystallization of the all-E isomer.
The catalytic contact with NO is conve liently effected by introducing NO or a gas mixture containing NO into the [optionally dissolved) vitamin A compound to be isomerized and dispersing the NO or the gas mixture containing NO, e.g. by rotating the gas stream, at atmospheric pressure or under a slight over-pressure. Pressures up to 10 bar (1 MPa) over-pressure, especially pressures of 0.1 bar (10 kPa) over-pressure to 3 bar (300 kPa) over¬pressure, are preferred. When gas mixtures containing NO are used for the catalysis, these conveniently contain 1 to about 90 wt.% NO (weight of NO to weight of mixture). Gas mixtures with 10 to 30 wt.% NO, especially with 10 to 60 wt.% NO, are preferably used. Inert giises, such as, for example, nitrogen, helium, argon, carbon dioxide, dinitrogen monoxide, methane and ethane, are suitable for the production of the NO gas mixture. Nitrogen, which is simultaneously employed for the intsrtization of the reaction mixture, is preferably used.
The isomerization process in accordance with the invention can conveniently be carried out at temperatures i;p to about 200^0. The process is preferably effected at temperatures up to about 150^0, especially up to about 100°C. It is especially preferred to carry out the process at temperatures in the range of about SO^C to about 80°C. The isomerization can also be effected at room temperature and thereunder. Conveniently, in the isomerization the concentration and temperature are chosen such that the all-E isomer formed is separated continuously; this can be effected in a manner known per se.
The isomerization period is generally between about 1 minute and about 50 hours, especially between about 10 minutes and about 30 hours, preferably between about 30 minutes and about 20 hours. The isomerization period is largely dependent on the chosen temperature and the set NO pressure. In the case of long isomerization periods low temperatures and low NO pressures have the same effect as hijjh temperatures and correspondingly shorter isomerization periods. Since, as is known, vitamin A compounds are relatively unstable compounds, the reaction conditions are conveniently chosen such that the reaction m ixture need not be heated to high temperatures for a long period.

The isomerlzation is conveniently effected with the exclusion of air, i.e. under an inert gas, e.g. nitrogen or argon. Moreover, the Isonerization oan be carried out not only discontlnuously, but also continuously.
After completion of the isonerization process the isolation of the desired all-E- or 13-Z-vitanin A compound can be carried out according to methods known per se, such as, for example, cooling crystallization or evaporation crystallization. Thereby, for a separation which is as complete as possible the clear differences in solubility behaviour between the isomers to be isolated and the remaining isomers (including impurities) are of significance.
The isomerization process in accordance with the invention is illustrated by the following Examples; in the Examples all analyses given have been carried by high pressure liquid chromatography (HPLC).
ExftPple 1
49 g of a mixture containing 23X all-E-vitamin A acetiite, 39X 13-Z-vitamin A acetate, 18X 11-Z-vitamin A acetate, 5X llilS-di-Z-vitamin A acetate and 3X 9-Z- and/or 9,13-di-Z-vitamii| A acetate (remainder impurities) are dissolved in 35 ml of mel|hyl acetate under argon in a sulphonatlon flask. Pure NO gas is ihen conducted into this solution while stirring for 10 minut'es. Subsequently, the reaction apparatus is completely closed and the solution is stirred intensively at room temperature for 5 hours. Subsequently, the NO atmosphere is replaced by inert gas. A mixture containing 435K all-E-. 26% 13-Z-, 12% ll-Z, 4% U,13-di-Z- and 3% 9-Z and/or 9,13-di-Z-vitamin A acetate is obtained.
Exanplo Z 200 g of a mixture containing 23% all-E-, 40% 13-Z, 17% 11-Z-. 5% 11,13-di-Z- and 3% 9-Z- and/or 9,13-di-Z-vit«mln A acetate, the balance being non-reaotable impurities are dissolved in 140 ml of hexane under nitrogen in a pressure-tight apparatus. After flushing the apparatus with nitrogen at atmospheric pressure HO gas is introduced at room temperature while stirring to an over-pressure of 0.5 bar (50 kPa) and the apparatus is closed. The solution is heated to 40°C while

stirring and stirred intensively for 5 hours. Subsequently, the apparatus is, de-pressurized and cooled to room temperature. A mixture containing 48% all-E-, 24% 13-Z-, 4% 11-Z-, 4 % 11,13-di-Z- and 3% 9-Z- and/or 9,13-di-Z-vitamin A acetate is obtained.
Example 3
100 g of a mixture containing 23% all-E-, 32% 13-Z-, 15% 11-Z-, 6% 11,13-di-Z- and 3% 9-Z- and/or 9,13-di-Z-vitamin A acetate are placed without solvent under nitrogen in a pressure-tight apparatus. After flushing the apparatus with nitrogen at atmospheric pressure NO gas is introduced at room temperature while stirring to an over-pressure of 0.5 bar (50 kPa) and the apparatus is closed. The liquid is heated to 40°C while stirring and stirred intensively for 5 hours. Subsequently, the apparatus is de-pressurized and cooled to room temperature. A mixture containing 48% all-E-, 21% 13-Z-, 2% 11-Z-, 5 % 11,13-di-Z- and 3% 9-Z- and/or 9,13-di-Z-vitamin A acetate is obtained.
Example 4
19 g of a mixture containing 94% all-E-vitamin A acetate and 3% 13-Z-vitamin A acetate are dissolved in 38 g oj" ethanol under nitrogen in a pressure-tight apparatus. After flushing the apparatus with nitrogen at atmospheric pressure NO gas is introduced at room temperature while stirring to an over-pressure of 0.5 bar (50 kPa) and the apparatus is closed. The solution is heated to 40^0 while stirring and stirred intensively for 5 hours. Subsequently, the apparatus is depressurized and cooled to room temperature. A mixture containing 67% all-E-vitamin A acetate and 28% 13-Z-vitamin A acetate is obtained. The content of the other isomers (11-Z-, 11,13-di-Z- and 9-Z- and/or 9,13-di-Z-vitamin A acetate) is significantly below 1%.

WE CLAIM :
1. A process for the catalytic isomerization of Z-isomers
of Vitamin A compounds such as herein described to a mixture of
all-E_ and 13-Z isomers of the corresponding vitamin A compounds
under conditions which, apart from the nature and use of the
catalyst itself, are known per se, which process comprises using
as the isomerisation catalyst nitrogen monoxide or a gaseous
mixture containing nitrogen monoxide, and, if desired,
subsequently separating the produced all-E and 13-Z isomers from
the reaction mixture by methods known per se.
2. The process according to claim 1, wherein the vitamin A
compound is vitamin A, vitamin A aldehyde, vitamin A acid or a

wherein R represents the group -CHO, -CH2OH, -COOH, -CH(R )2/ CHjOR^, -COOR^, -CONHR^ or -C0N(R^)2, in which both R"*"' s each
independently signify lower alkoxy or two residues R together
2 3
signify lower alkylenedioxy, R signifies alkanoyl or aroyl, R
4 4
signifies alkyl, aryl or aralkyl and R or both R s each
independently signify hydrogen, alkyl, aryl or aralkyl.
3. The process according to claims 1 or 2, wherein the Z
isomer to be isomerized is the 9-Z, the 11-Z, the 9,13-di-Z or
the 11,13-di-Z isomer or a mixture thereof.
4. The process according to any one of claims 1 to 3,
wherein the isomerization is effected in a polar or apolar
organic solvent.
5. The process according to claim 4, wherein the solvent
* is an aliphatic hydrocarbon or a lower aliphatic alcohol.
6. The process according to claim 5, wherein the solvent
is hexane or ethangl.

1?. A prorpss for the catalytic isomerization of 2
isomers of vitamin A cmpounds to a mixture of all-E and 13-Z isomers of the corresponding vitamin A compounds substantially as herein before described.

Documents:

126-mas-98 abstract.pdf

126-mas-98 claims.pdf

126-mas-98 correspondence (others).pdf

126-mas-98 description (complete).pdf

126-mas-98 form-1.pdf

126-mas-98 form-26.pdf

126-mas-98 form-4.pdf

126-mas-98 form-6.pdf

126-mas-98 petition.pdf

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Patent Number

184150

Indian Patent Application Number

126/MAS/1998

PG Journal Number

30/2009

Publication Date

24-Jul-2009

Grant Date

08-Jan-2001

Date of Filing

20-Jan-1998

Name of Patentee

M/S. HOFFMANN LA ROCHE AG

Applicant Address

124 GRENZACHERSTRASSE, CH 4070 BASLE

Inventors:

#	Inventor's Name	Inventor's Address
1	ANGELA WILDERMANN	13 ROT-KREUZ-STRASSE, D 79713 BAD SACKINGEN

PCT International Classification Number

C07C 175/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA