Method for continuously acylating chromanol ester derivatives

Details Method for continuously acylating chromanol ester derivatives Method for continuously acylating chromanol ester derivatives

2003-05-12

2004-08-31

Desai, Rita (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S410000, C549S412000

Reexamination Certificate

active

06784303

ABSTRACT:

The present invention relates to a process for continuously preparing chromanol ester derivatives, in particular for continuously preparing carboxylic esters of tocopherols and tocotrienols by continuous acylation with carboxylic acids or carboxylic anhydrides.
Compounds having vitamin E activity, such as the naturally occurring chromanol derivatives of the tocopherol and tocotrienol group, are important fat-soluble antioxidants. A vitamin E deficiency in humans and animals leads to pathophysiological conditions. Vitamin E compounds therefore have a high economic value as additives in the food and feed sectors, in pharmaceutical formulations and in cosmetics applications. The compounds having vitamin E activity, in particular &agr;-tocopherol, are used for this principally in the form of their acetate esters. An economic process for preparing chromanol ester derivatives is therefore of high importance.
It is known to react tocopherol derivatives batchwise with acetic anhydride to give the corresponding acetate esters.
EP 850 937 describes in the examples a batchwise process for preparing &agr;-tocopherol acetate by heating under reflux &agr;-tocopherol with acetic anhydride in a stirred flask having an attached reflux condenser. The reaction discharge is then worked up by distillation.
DE 19 603 142 describes a process for preparing d1-&agr;-tocopherol acetate by acid-catalyzed reaction of 2,3,5-trimethylhydroquinone (TMH) with phytol or isophytol (IP) in a solvent at elevated temperature and subsequent acetylation of the resultant tocopherol. The tocopherol is acetylated by acid-catalyzed reaction with excess acetic anhydride. The reaction discharge is worked up by fractional distillation under reduced pressure. For the continuous reaction of 2,3,5-trimethylhydroquinone with phytol, a reaction column is proposed into which a mixture of cyclic carbonate, the catalyst, TMH and IP are fed in laterally. The hydrocarbon and the water formed are removed at the top of the column and hot cyclic carbonate and vitamin E are taken off from the bottom. No description is given of the process design of the subsequent acylation. An example mentions that the tocopherol isolated after phase separation was esterified with acetic anhydride.
A process for preparing d1-&agr;-tocopherol or d1-&agr;-tocopherol acetate by acid-catalyzed reaction of 2,3,5-trimethylhydroquinone (TMH) with phytol or isophytol (IP) in the presence of a mixture of orthoboric acid and certain aliphatic di- or tricarboxylic acids with or without subsequent esterification with acetic anhydride is described in DE 42 08 477. According to DE 42 08 477, the tocopherol prepared is converted in a similar manner to DE 19 603 142 into tocopherol acetate batchwise with excess acetic anhydride under acid catalysis and purified by fractional distillation under a greatly reduced pressure. The initial molar ratio of acetic anhydride/tocopherol was greater than 1.3 mol/mol and the acid concentration was approximately 0.055 mol % based on tocopherol.
EP 0 784 042 claimed hydrogen bis(oxalato)borate as protic acid catalyst for the Friedel-Crafts condensation of trimethylhydroquinone with isophytol and the acylation of phenols, for example tocopherol. In an example the acylation of tocopherol is described. For this, tocopherol was charged into a flask together with acetic anhydride and hydrogen bis(oxalato)borate and the reaction mixture was heated to reflux for one hour under an argon atmosphere. The initial molar ratio of acetic anhydride/tocopherol was greater than 1.1 mol/mol and the borate concentration was approximately 0.5 mol %, based on tocopherol. After concentration on a rotary evaporator, tocopherol acetate was obtained in a purity of 87% at a yield of 92%. This batch process has the disadvantage that both yield and purity are still not satisfactorily high. In addition, carrying out the reaction in an argon atmosphere is associated with high costs for industrial production.
JP 49 055 633 describes the batchwise preparation of tocopherol acetate by acylation of tocopherol with acetic anhydride in the presence of inorganic solid acids which are insoluble in the reaction mixture. In the process, tocopherol and acetic anhydride in the solvent toluene are heated in the presence of the catalyst for about 4 hours under reflux, a product purity of about 91% being achieved. As an example of the catalyst, SiO
2
/Al
2
O
3
is mentioned. Disadvantages of the process are the low space-time yields and the low product purities.
The acylation of tocopherol with acetic anhydride in the presence of a mixture of hydrochloric acid and zinc or zinc chloride is described in JP 56 073 081. According to this process, tocopherol is heated with acetic anhydride and the catalyst mixture at from 10 to 30° C. for from 0.5 to 2 hours. The catalyst is then removed and the reaction mixture is washed with water. Hydrochloric acid is used at a concentration of from 0.02 to 0.06 mol % based on tocopherol, the zinc is used at a concentration of from 0.01 to 0.2 mol % based on tocopherol and the zinc chloride is used at a concentration of from 0.001 to 0.1 mol % based on tocopherol. Acetic anhydride is used at a from 1.2 to 1.5 times molar excess. The process gives tocopherol acetate at a yield of 92.5% based on tocopherol. The complex workup, the batchwise reaction procedure and the solids handling cause a low space-time yield in this process, despite the short reaction time.
DE 2 208 795 describes the reaction of trimethylhydroquinone with isophytol in the presence of a mixture of a Lewis acid and a protic acid in an inert solvent. The catalyst system which can be used is, for example, a mixture of zinc chloride with NaHSO
4
, H
2
SO
4
or p-toluenesulfonic acid. Optionally, the reaction discharge can be reacted with acetic anhydride without further workup. For this acetic anhydride is added to the reaction mixture and heated under reflux for about 6 hours. A disadvantage of this process is the low space-time yield for the acylation.
A continuous process for reacting trimethylhydroquinone with isophytol, phytol or phytadienes in the presence of acid condensation catalysts in a packed column is described in U.S. Pat. No. 3,444,213. In this process the reactants, optionally premixed or dissolved in an inert solvent, are applied to the top of a heated column and the resultant reaction water is evaporated via the top of the column. The column, however, is only a heated tubular reactor without evaporator, and not a reactive distillation column. The product arising at the bottom of the column is reacted in the course of one hour batchwise with acetic anhydride in the solvent pyridine. A disadvantage of this process is the low space-time yield of the acylation and the use of a solvent.
A further continuous process for reacting trimethylhydroquinone with isophytol is described in CS 205 951. In this patent also, the acylation is performed batchwise using acetic anhydride.
All known processes of the prior art for acetylating tocopherol derivatives have the disadvantage of high residence times and thus low space-time yields and high capital costs. In all cases the tocopherol derivative, in the absence or presence of a catalyst, is reacted batchwise with acetic anhydride and the reaction mixture is worked up by distillation. In this case, firstly the acetic acid and the acetic anhydride are removed at low vacuum and the acetate of the tocopherol derivative is then purified by distillation under a high vacuum.
Furthermore, the yields of these processes, at about from 92 to 95%, are insufficiently satisfactory. The acetic anhydride is always used in a relatively high excess of at least 1.2 mol per mole of tocopherol derivative, in order to achieve a sufficient conversion rate at an acceptable reaction time. As implied by EP 0 784 042, reduction in the excess of acetic anhydride is only possible if the acid concentration is considerably increased. However, this leads to an increased formation of byproducts and thus to decreased yields and product purity.
It is an object of th

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