Mono-saponifaction of diesters of trimethylhydroquinone and its use in the process of manufacturing esterified alpha-tocopherol

Abstract

The present invention relates to the mono-saponification of diesters of 2,3,5-trimethylhydroquinone by a base allowing an advantageous synthesis of esterified alpha-tocopherol. The mono-saponification has been demonstrated to occur very selectively at very high yield.

Description

[0001] MONO-SAPONIFACTION OF DIESTERS OF TRIMETHYLHYDROQUINONE AND ITS USE IN THE PROCESS OF MANUFACTURING ESTERIFIED ALPHATOCOPHEROL

[0002] Technical Field

[0003] The present invention relates to the field of synthesis a-tocopherol or its esters.

[0004] Background of the invention a-Tocopherol is a key product in the field of vitamins. It is normally manufactured from isophytol and 2,3,5-trimethylhydroquinone (TMHQ).

[0005] An interesting route for the manufacturing of TMHQ is based on isophorone, which is a naturally occurring and readily accessible starting material. In this route, necessarily, a diester of TMHQ is formed which then is saponified to form TMHQ.

[0006] For increasing its stability, however, a-tocopherol is commercialized as its acetate, which is produced by esterification of a-tocopherol by an additional chemical step.

[0007] In other words, based on an isophorone-based synthetic route, first the TMHQ diester needs to be saponified and the end a-tocopherol is to be esterified again. This is very inefficient and an improvement if this process would be highly appreciated.

[0008] CS 239 442 B1 discloses the synthesis of TMHQ monoacetate from TMHQ diacetate in the presence of a sodium bisulfite or sodium dithionite as reducing agent. The reaction is exemplified in aqueous MeOH having 5 to 25 % of water at a temperature of between 35 and 40°C.

[0009] The use of reducing agent makes the process rather difficult to handle. Furthermore, such a reducing agent is an additional ingredient to be used in the process, which consequently makes the process more expensive . Furthermore, it leads additionally to the problem that said reduction agent leads to subsequent reaction products which need to be separated. Said separation operation is rather challenging and cost intensive. Summary of the invention

[0010] Therefore, the problem to be solved by the present invention is to offer an improved process for manufacturing esters of a-tocopherol based on diesters of TMHQ as starting material.

[0011] Surprisingly, it has been found that the process according to claim 1 offers a solution to this problem.

[0012] It has been shown that the diester of TMHQ can be efficiently monosaponified and reacted with phytol or isophytol to form directly esterified a-tocopherol. This process is very advantageous as the esterification step of a-tocopherol can be eliminated and less waste material is produced offering a more sustainable route for esters of a-tocopherol can be offered.

[0013] It has been shown particularly that the use of a reducing agent is not needed for the monosaponification of TMHQ diester.

[0014] It has been shown that mono-saponification of the diester leads to the desired monoester of TMHQ at high selectivity and yield. Even at very low reaction temperature these high yields and selectivities can be obtained.

[0015] Further aspects of the invention are subject of further independent claims. Particularly preferred embodiments are subject of dependent claims.

[0016] Detailed description of the invention

[0017] In a first aspect the present invention relates to a process of manufacturing of the compound of the formula (I) from the compound of the formula (II) by a mono-saponification step using a base in the absence of any reducing agent; wherein R is an C1-8 alkyl or a phenyl group, preferably a methyl group.

[0018] The compound of the formula (I) is the monoester of the 2, 3, 5-trimethyl- hydroquinone (TMHQ), i.e. 4-hydroxy-2,3,6-trimethylphenyl acylate (or 2,3,5- trimethylhydroquinone-4-monoacylate), named in this document also “TMHQ monoacylate” (=TMHQ-MAc”). In the preferred embodiment (R=methyl), this monoester, i.e. 4-hydroxy-2,3,6-trimethylphenyl acetate (or 2,3,5-trimethylhydro- quinone-4-monoacetate), is named in this document “TMHQ-monoacetate” (-’TMHQ-MA”).

[0019] The compound of the formula (II) is the diester of the 2,3,5-trimethylhydro- quinone (TMHQ), named in this document also TMHQ diacylate (=TMHQ-DAc). In the preferred embodiment (R=methyl), this diester is named in this document TMHQ-diacetate (=TMHQ-DA).

[0020] For sake of clarity, some terms used in the present document are defined as follows:

[0021] In the present document, a “Cx-y-alkyl” group is an alkyl group comprising x to y carbon atoms, i.e. , for example, a Ci-3-alkyl group is an alkyl group comprising 1 to 3 carbon atoms. The alkyl group can be linear or branched. For example -CH(CH3)-CH2-CH3 is considered as a C4-alkyl group.

[0022] In case identical labels for symbols or groups are present in several formulae, in the present document, the definition of said group or symbol made in the context of one specific formula applies also to other formulae which comprises the same said label. ln the present document, any wavy line in any formula represents independently from each other a carbon-carbon bond which is either in the (Z) or in the (E)-configuration. It is preferred that the configuration is in the (E)- configuration, i.e. that the (E)-stereoisomer is preferred. If there are several such wavy lines in a specific formula, it is preferred that all double bonds are in the (E)- configuration.

[0023] The term “independently from each other” in this document means, in the context of substituents, moieties, or groups, that identically designated substituents, moieties, or groups can occur simultaneously with a different meaning in the same molecule.

[0024] The compound of the formula (II) is typically produced by the reaction ii) as shown in figure 1 of 2,6,6-trimethylcyclohex-2-ene-1 ,4-dione (=keto-isopho- rone, KIP) (compound of the formula (IV)) which itself is prepared from 3,5,5- trimethylcyclohex-3-en-1-one (= p-isophorone) (compound of the formula (V)) in reaction step i).

[0025] P-lsophorone (V) is typically oxidized by air or oxygen in the presence of a catalyst in step i) to keto-isophorone (IV).

[0026] Keto-isophorone (IV) is converted to TMHQ-DAc (II), by treatment of KIP by the respective anhydride of the formula R(CO)O-(OC)R in the presence of an acid.

[0027] It is, therefore, preferred that the compound of the formula (II) is prepared by the reaction of 2,6,6-trimethylcyclohex-2-ene-1 ,4-dione of the formula (IV) with the anhydride of the formula R(CO)-O-(OC)R in the presence of a Bronsted acid.

[0028] Preferably, the anhydride is acetic anhydride. In the above process the TMHQ-DAc is mono-saponified to TMHQ-MAc by a base.

[0029] It has been observed that when the diester of TMHA (TMHQ-DAc), particularly the TMHQ diacetate (TMHQ-DA), is saponified under acidic conditions, the desired product, i.e. the TMHQ monoacylate (TMHQ-MAc), particularly the TMHQ monoacetate (TMHQ-MA) cannot be obtained in high amounts.

[0030] It is important to note that the mono-saponification is performed in the absence of any reducing agents. Particularly, it is performed in the absence of a reducing agent of the groups consisting of alkali hydrogensulfites, sulfites and dithionites. Even in the absence of such reducing agents no brown residues have been observed and particularly also high yields and selectivities in the desired TMHQ monoacylate have been obtained.

[0031] Furthermore, no inert atmosphere was required for the performance of the monosaponification.

[0032] Due to the absence of any reducing agent and inert atmosphere the reaction was very easy and with standard equipment to perform. This of course is a very high advantage for the production of TMHQ monoacylate.

[0033] In a first embodiment, said base is a hydroxide or an alcoholate of an alkali metal or of an alkaline earth metal. Hydroxides or an alcoholates of an alkali metal, particularly sodium, are preferred. Most preferred is sodium hydroxide.

[0034] In a second embodiment, said base is a carbonate or a hydrogen carbonate of an alkali metal or of an alkaline earth metal.

[0035] Preferred bases of this embodiment are NaHCOs, Na2CO3, most preferred NaHCO3.

[0036] In a third embodiment, said base is an organic base, particularly an organic amine.

[0037] Preferred organic amines are selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, morpholine, piperidine, pyrazole, picolines and collidines. In a fourth embodiment, said base is a basic ion exchange resin.

[0038] Preferred basic ion exchange resins are basic ion exchange resins based on porous copolymers, preferably based on copolymers of styrene and divinyl benzene. Particularly suitable basic ion exchange resin are the products as commercialized as AMBERLYST™ A-26 OH, AMBERLYST™ A-25 OH, AMBERLITE™ IRA-26, AMBERLITE™ IRA-96 or AMBERLITE™ IRA-958

[0039] Particularly preferred basic ion exchange resin is as AMBERLYST™ A-26 OH.

[0040] It is important to mention that we have found that in the above second, third and fourth embodiments, particularly the second, and third embodiments, the mono-saponification is particularly performed in the presence of an alcohol, particularly an alcohol having 1 to 6 carbon atoms, preferably ethanol or methanol, more preferably methanol, for assuring the reaction to occur smoothly and to obtain the desired product, i.e. the TMHQ monoacylate (TMHQ-MAc), or TMHQ monoacetate (TMHQ-MA), respectively.

[0041] For the first embodiment, the presence of said alcohol is not that much needed, but is still preferred.

[0042] It is particularly preferred that the mono-saponification step is performed in the presence of a mixture of water and an alcohol, particularly an alcohol having 1 to 6 carbon atoms, preferably ethanol or methanol, more preferably methanol.

[0043] In a further embodiment, mixtures of an alcohol and / or water as mentioned above, with organic solvents are used for the mono-saponification step.

[0044] If the mono-saponification step is performed in the presence of a mixture of water it is preferred that the volume ratio of water to alcohol is 1 .1 or less, preferably between 1 .0 and 0.1 .

[0045] It has been particularly found that for volume ratios of water to alcohol of between 1.1 and 0.5, more preferably of between 1.1. and 0.9, most preferably of 1 , very high yields and selectivities can be obtained. For the mono-saponification it is preferred that the molar ratio of base to the compound of the formula (II) is less than 1 , preferable less than 0.50, more preferably less than 0.30, even more preferred less than 0.10.

[0046] It is preferred that the mono-saponification is performed at a temperature of between -10 °C and 70°C, preferably between -5°C and 65 °C.

[0047] It has been shown that when the mono-saponification is performed using a basic ion exchange resin, the preferred temperatures of mono-saponification is between 20°C and 70°C, particularly at temperatures between 55 °C and 65°C.

[0048] It has been shown that when the mono-saponification is performed using a hydroxide or an alcoholate of an alkali metal or of an alkaline earth metal, the preferred temperature of mono-saponification is between 0°C and 40°C, particularly at a temperature of between 20 °C and 30°C, more preferably at a temperature of 20 to 25°C.

[0049] The mono-saponification can be performed not only batch-wise but is also possible to be performed as a continuous process.

[0050] In one of the embodiments the process is a continuous process, preferably performed in a tubular reactor.

[0051] In a continuous process, the residence time (T) of the reaction mixture in the reactor is typically between 10 minutes and 5 hours, preferably between 20 minutes and 2 hours, more preferably between 20 minutes and 40 minutes. In the continuous process the reaction is performed preferably at a temperature between 0°C and 40°C, particularly at a temperature of between 20 °C and 30°C.

[0052] It is preferred that the compound of the formula (I) is purified after the mono-saponification step by precipitation with water or by crystallisation.

[0053] We have found that the mono-saponification of the TMHQ-diester can be obtained with very high yield and selectivity. The manufacturing of the TMHQ monoacylate, or TMHQ monoacetate, respectively, allows to prepare very efficiently an ester of a-tocopherol.

[0054] Therefore, another aspect of the present invention is a process of a) preparing a compound of the formula (I) by a process as discussed above in great detail b) reacting the compound of the formula (I) with the compound of the formula (lll-A) or (lll-B) in the presence of a Lewis acid or a Bronsted wherein R is an C1-8 alkyl group, preferably a methyl group; and any wavy line independently from each other represents a carboncarbon bond which is either in the Z- or in the E-configuration. This reaction, as well the above mentioned reactions to form the TMHQ diester (II), are illustrated in figure 1 .

[0055] For the reaction of the TMHQ monoester, particularly of THMQ monoacetate, with phytol (lll-B) or isophytol (lll-A), particularly with isophytol, in reaction step b) a Lewis acid or a Bronsted acid is needed.

[0056] Particularly useful as Lewis acid or a Bronsted acid are transition metal triflates, sulfonic acids, such triflic acid or p-toluenesulfonic acid or methanesulfonic acid, or heteropoly acids, particularly 12-tungstophosphoric acid or 12-tungstosilicic acid.

[0057] The reaction step b) is found to occur in very high yields. Even in case, the mono-saponification is not completely selective, the reaction would form next to the desired TMHQ-monoester (I) TMHQ small amounts of TMHQ (XIX). When reacted such a mixture without further purification small amounts a-tocopherol (XX) would be formed in the desired ester of a-tocopherol (X). Small amounts of a-tocopherol (XX), however, are not very critical in view of the stability of ester of a-tocopherol (X). Remainder of non-reacted TMHQ diacylate (TMHQ-DAc) in the mono-saponification reaction - beside reducing the overall yield in the desired ester of a-tocopherol - do not harm as TMHQ diacylate (TMHQ-DAc) does not react in the reaction step b). It is evident that it is preferred to have a selectivity in the TMHQ monoester as high as possible in the mono-saponification process to reduce the amounts of TMHQ as much as possible.

[0058] The present invention has the big advantage that it is very efficient and has less steps than to first produce a-tocopherol and then to esterify a-tocopherol.

[0059] This is advantage is shown in figure 2.

[0060] On the right side of figure 2, the inventive process is shown in which the diester of TMHQ (II) is mono-saponified to yield in step a) the monoester of TMHQ (I), i.e. 1 carboxyl group is removed. The TMHQ monoester (I) is then reacted in step b) with isophytol (lll-A) or phytol (lll-B) to yield directly the ester of a- tocopherol (X). In summary, the inventive process allows to produce the ester of a-tocopherol (X) from the TMHQ diester (II) in only two steps. On the left side of figure 2, however, the reaction scheme based on the traditional way is shown. Here the diester of TMHQ (II) is completely saponified, i.e. 2 carboxyl groups are removed to yield TMHQ (XIX) in a first step a). TMHQ is then reacted in a second step ) with isophytol (lll-A) or phytol (lll-B) to yield a- tocopherol (XX). a-Tocopherol (XX). is finally in a third reaction step y) esterified to yield the ester of a-tocopherol (X), i.e. one carboxyl group is added again. In summary, the traditional approach uses three steps to produce the ester of a-tocopherol (X) from the TMHQ diester (II). In this reaction scheme, first 2 carboxyl group are needed to be removed and at the end 1 carboxyl group needs to be added again. It is obvious that each reaction relating to a removal and addition of a carboxyl group is not running perfectly, so that the residual material is lost in form of waste. Therefore, the three-step process of preparing the ester of a-tocopherol (X) according to the reaction scheme on the left side of figure 2 is much disadvan- tageous over the two-step process of the invention shown on the right side of figure 2.

[0061] Examples

[0062] The following examples are provided to further illustrate the compositions and effects of the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way.

[0063] Mono-saponification of TMHQ-diacetate using basic ion exchange resin

[0064] 5 g 2,3,5-Trimethylhydroguinone diacetate in 10 ml methanol were treated with 20 % by weight of basic ion exchange resin as given in table 1 and stirred at 60°C during the time indicated in table 1 . Table 1 shows the obtained amounts.

[0065] Table 1 . Mono-saponification of TMHQ diacetate using different basic ion exchange resins. determined as area % by GC.

[0066] The results of table 1 show that all basic ion exchange resins principally work for the process in guestion. It also shows that AMBERLYST™ A-26 OH by far shows the highest selectivity and shows, even at short contact time, the highest amounts in TMHQ-MA.

[0067] In a further series of experiments, 5 g 2,3,5-trimethylhydroguinone diacetate in an amount of methanol as given in table 2 were treated with the amount % by weight of AMBERLYST™ A-26 OH as given in table 2 and stirred at the temperature and time indicated in table 2. Table 2 shows the obtained amounts.

[0068] Table 2. Mono-saponification of TMHQ diacetate using AMBERLYST™ A-26 OH with different conditions, determined as area % by GC.

[0069] The results of table 2 show that is preferred to perform the mono-saponifi- cation at elevated temperatures and at high amounts of basic ion exchange resin.

[0070] Mono-saponification of TMHQ-diacetate using sodium hydroxide 5 g 2,3,5-Trimethylhydroquinone diacetate in the amount of solvent as given in table 3 were treated with the amount of sodium hydroxide and stirred at 25°C during the time as indicated in table 3. At the end of reaction HCI was added.

[0071] Table 3 shows the obtained amounts.

[0072] Table 3. Mono-saponification of TMHQ diacetate using sodium hydroxide using different conditions.

[0073] 1determined as area % by GC.

[0074] The results of table 3 show that is preferred to perform the mono-saponifi- cation with a mixture of water and an alcohol. Mono-saponification of TMHQ-diacetate in a continuous process 2,3,5-Trimethylhydroquinone diacetate was dissolved in the respective solvent according to Table 4 yielding a concentration of 10 g / L and introduced to a tubular reactor together with a solution of the base according to table 4. After a given residence time (T) of 30 minutes at 25°C, the reaction mixture was quenched with acetic acid (1 mol / L in MeOH) and the solution was analysed by qGC.

[0075] Table 4. Mono-saponification of TMHQ diacetate in a continuous process. The results of table 4 show that very high selectivity, conversion and yields can be obtained by the mono-saponification process in a continuous process.

[0076] Mono-saponification of TMHQ-diacetate using sodium hydroxide and workup

[0077] The experiments 8 to 11 were repeated and subsequent workup as indicated in table 5 was used. Table 5 shows the selectivity, conversion and yield of TMHQ-MA obtained for the overall process.

[0078] Table 5. Mono-saponification of TMHQ diacetate using sodium hydroxide using different conditions.

[0079] 1adding 250 ml water to reaction mixture at 25°C / stimng 2 h

[0080] 2adding reaction mixture to 60 ml water at 25°C / stimng 4 h

[0081] 3adding dropwise 60ml ml of water at 25°C, slow removing 10 ml of MeOH by vacuum distillation during 1.5 hours

[0082] 4adding dropwise 50ml water to reaction mixture at 0°C, further stirring 16 h at 0°C.

[0083] The results of table 5 show that very high conversion and yields can be obtained by the mono-saponification process as described in this document.

Claims

Claims1 . A process of manufacturing of the compound of the formula (I) from the compound of the formula (II)by a mono-saponification step using a base in the absence of any reducing agent; wherein R is an C1-8 alkyl or a phenyl group, preferably a methyl group.

2. The process according to claim 1 , characterized in that the base is a hydroxide or an alcoholate of an alkali metal or of an alkaline earth metal.

3. The process according to claim 1 or 2, characterized in that in the monosaponification step is performed in the presence of an alcohol having 1 to 6 carbon atoms, preferably ethanol or methanol, more preferably methanol.

4. The process according to claim 3, characterized in that in the monosaponification step is performed in the presence of a mixture of water and an alcohol having 1 to 6 carbon atoms, preferably ethanol or methanol, more preferably methanol.

5. The process according to claim 4, characterized in that the volume ratio of water to alcohol is 1 .1 and 0.5, more preferably of between 1.

1. and 0.9, most preferably of 1 .

6. The process according to claim 3 or 4 or 5, characterized in that the base is a carbonate or a hydrogen carbonate of an alkali metal or of an alkaline earth metal.

7. The process according to claim 3 or 4 or 5, characterized in that the base is an organic base, particularly an organic amine.

8. The process according to claim 3 or 4 or 5, characterized in that the base is a basic ion exchange resin.

9. The process according to any of the preceding claims 1 to 7, characterized in that the molar ratio of base to the compound of the formula (II) is less than 1 , preferable less than 0.50, more preferably less than 0.30, even more preferred less than 0.10.

10. The process according to any of the preceding claims characterized in that the mono-saponification is performed at a temperature of between -10 °C and 70°C, preferably between -5°C and 65°C.11 . The process according to claim 6, characterized in that the temperature of mono-saponification is between 0°C and 40°C, particularly at a temperature of between 20 °C and 30°C, more preferably at a temperature of 20 to 25°C.

12. The process according to any of the preceding claims characterized in that the compound of the formula (II) is prepared by the reaction of 2,6,6- trimethylcyclohex-2-ene-1 ,4-dione of the formula (IV) with the anhydride of the formula R(CO)-O-(OC)R in the presence of a Bronsted acid13. The process according to any of the preceding claims characterized in that the compound of the formula (I) is purified after the mono-saponification step by precipitation with water or by crystallisation.

14. The process according to any of the preceding claims, characterized in that the process is a continuous process, preferably performed in a tubular reactor.a) preparing a compound of the formula (I) by a process according to any of the preceding claims 1-14b) reacting the compound of the formula (I) with the compound of the ula (lll-A) or (lll-B) in the presence of a Lewis acid or a Bronstedwherein R is an C1-8 alkyl group, preferably a methyl group; and any wavy line independently from each other represents a carboncarbon bond which is either in the Z- or in the E-configuration.