Title of Invention

A PROCESS FORTHE MANUFACTURE OF D, 1-TOCOPHEROL

Abstract

1. A process for the manufacture of d,1~α-tocopherol by condensing trimethylhydroquinone with isophytol, which process comprises carrying out the condensation in the presence of a polyperfluoroalkylenesulphonic acid and in a solvent and recovering d,1-α-tocopherol by known means. 2. The process according to claim 1, wherein the condensation is carried out at temperature between 80°C and 140°C, preferably between 85°C and 120°C.

Full Text

The present invention is concerned with a novel process for the manufacture of d,1-a-tocopherol by condensing trimethyl-hydroquinone with isophytoi. d,l-a-Tocopherol is a diastereomer mixture of a derivative of the vitamin E group. Various processes for the manufacture of d,l-a-tocopherol by condensing trimethyihydroquinone with isophytoi have already been described. Thus, for example, according to Chem. Abstracts (C.A.) 103, 104799 (1985), C.A. 103, 123731 (1 985) and C.A. 110, 39221 (1989) the condensation is carried out in the presence of zinc and zinc chloride (ZnClz) and a protonic acid such as a hydrohalic acid, e.g. hydrochloric acid (HCI), trichloroacetic acid, acetic acid and the like, especially ZnClz/HCI, as the catalyst. The manufacture of d,l-a-tocopherol by reacting trimethyi¬hydroquinone with phytyl chloride or isophytoi in the presence of boron trifluoride (BF3) or its etherate (BF3 ■ EtzO) as the catalyst is described in German Offenlegungsschriften 960720 and 1015446 as well as in US Patent 4,634,781. The condensation of trimethyihydroquinone with isophytoi or phytol, which has been treated with ammonia or amines, in the presence of ZnClz/HCI or a Lewis acid/HCI, such as e.g. BF3 or aluminium trichloride (AICI3), as the catalyst is described in US Patent 4,634,781. According to US Patent 3,789,086 the condensation is carried out in the presence of a FeClz/Fe/HCI catalyst, while according to EP-A 1 2824 the condensation is effected using trifluoroacetic acid. All of these previously known processes have serious disadvantages: thus, corrosion problems occur in all processes, when boron trifluoride is used there are additionally toxicity problems with the boron trifluoride adducts and when iron or zinc is used there is contamination of the waste water with iron of zinc ions which today is no longer acceptable. The use of ion exchangers, e.g. Amberlyst 15 , as the catalyst is described in US Patent 3 459 773. However, according to this process the d,1-α-tocophero1 could not be obtained in the requisite purity. The object of the present invention is to provide a process for the manufacture of d,1 -«C-tocopherol by condensing trimethy1hydroquinone with isophytol in the presence of a catalyst which does not have the disadvantages of the previously known procedures. For this purpose, it is necessary that the catalyst employed does not have a corrosive action, is non-toxic, does not contaminate the environment and catalyzes the desired reaction as selectively as possible and in high yields. Furthermore, the catalyst should display its activity in truly only catalytic amounts and should be readily separable and re¬usable several times. In the scope of the present invention this object is achieved by carrying out the condensation of trimethy1hydroquinone with isophytol in the presence of a pdlyperf1uoroalkylenesulphonic acid and in a solvent. ; *' The condensation is conveniently effected at temperatures between about 80"c and 140°C, preferably between about 85°c and 120°c. Moreover, about equimolar amounts of trimethyIhydroquinone and isophytol are conveniently used. Aprotic solvents, especially aliphatic and cyclic ketones, e.g. isobutyl methyl ketone and diethyl ketone and, cyclopentanone and isophorone; aliphatic and cyclic esters, ethyl acetate, isopropyl acetate and, butyrolactone; and aromatic hydrocarbons, e.g. toluene and xylene, can be named as suitable solvents in the scope of the present invention. Polar aprotic solvents, e.g. diethyl ketone, ethyl acetate, isopropyl acetate and y-butyrolactone, are preferred. The condensation takes place according to the following Reaction Scheme: Trimethylhydroquinone Isophytol Catalyst d,l a-Tocopherol Those polyperfluoroalkylenesulphonic acids which are available under the proprietary names Nafion® are preferably used as the acidic condensation catalysts in the process in accordance with the invention. Nafion NR 50® and Nafion 117® are especially preferred. Conveniently, 1-20 wt.%, preferably 1-10 wt.%, of catalyst is used based on the weight of the trimethyl¬hydroquinone or isophytol used. In accordance with the invention isophytol can be added dropwise to a suspension of trimethylhydroquinone and catalyst in a suitable solvent. The rate at which the isophytol is added is not critical. Conveniently, isophytol is added dropwise over a period of 1-4 hours. After completion of the isophytol addition and an appropriate subsequent reaction period the working up is effected by procedures conventionally used in organic chemistry. Conveniently, the reaction solution is separated from the hetero¬geneous catalyst by filtration or by decantation and the solvent is evaporated off. The process of the invention enables the catalyst to be separated readily and to be re-used several times. Accordingly the present invention therefore provides a process for the manufacture of d,1-α -tocopherol by condensing trimethylhydroquinone with isophytol, which process comprises carrying out the condensation in the presence of a polyperfluoroalkylenesulphonic acid and in a solvent and recovering d,1-α -tocopherol by known means. The following Examples for the manufacture of d,l- oc-tocopherol by condensing trimethyIhydroquinone with isophytol illustrate advantageous embodiments of the process in accordance with the invention, but they are not intended to be limiting in any manner. All temperatures are given in degrees Celsius. Example 1 Condensat ion of trimethylhydroquinone with isophytol in toluene 31.4 g (200 mmol) of trimethyIhydroquinone and 8.5 g of the polyperfluoroalkylenesulphonic acid catalyst (Nafion NR 50 ) were suspended in 50 ml of toluene in a 500 ml four-necked flask at room temperature. The suspension was heated to 107°. 73 ml (200 mmol) of isophytol were added dropwise within 2 hours. The reaction mixture was heated to reflux for 30 minutes. After cooling to room temperature the catalyst was filtered off and the filtrate was concentrated on a rotary evaporator. The crude product obtained was analyzed by gas chromatography according to known procedures. Yield : 75.33% of theory of d,1-α -tocopherol. Example 2 Condensat ion of trimethylhydroquinone wi th isophytol in ethyl acetate 31.4 g (200 mmo1) of trimethylhydroquinone and 8.5 g of the polyperfluoroaIky 1enesulphonic acid catalyst (Nafion NR 50 ) were suspended in 100 ml of ethyl acetate in a 500 ml four-necked flask at room temperature. The suspension was heated to 85°. 73 ml (200 mmol) of isophytol were added dropwise within 4 hours. The solvent was subsequently distilled off. Yield: 83.55% of theory of d,l-a-tocopherol. In a variant, 9.8 ml of Nafion 11 7® were used in place of Nafion NR 50®. Yield: 63.49% of theory of d,l-α -tocopherol. Example 3 Condensation of trimethvlhvdroquinone with isophvtol in diethyl ketone 31.4 g (200 mmol) of trimethylhydroquinone and 1 5 g of the polyperfluoroalkylenesulphonic acid catalyst (Nafion NR 50®) were suspended in 50 ml of diethyl ketone in a 500 ml four-necked flask at room temperature. The suspension was heated to 109°. 73 ml (200 mmol) of isophytol were added dropwise within 2 hours. The reaction mixture was heated to reflux for 30 minutes. After cooling to room temperature the catalyst was filtered off and the filtrate was concentrated on a rotary evaporator. Yield: 84.69% of theory of d,l-a-tocopherol. Example 4 Condensation of trimethvlhvdroquinone with isophvtol In y-butvrolactone 31.4 g (200 mmol) of trimethylhydroquinone and 8.5 g of the polyperfluoroalkylenesulphonic acid catalyst (Nafion NR 50®) were suspended in 50 ml of y-butyrolactone in a 500 ml four-necked flask at room temperature. The suspension was heated to 117°. 73 ml (200 mmol) of isophytol were added dropwise within 2 hours. The reaction mixture was heated to reflux for 30 minutes. After cooling to room temperature the catalyst was filtered off and the filtrate was concentrated on a rotary evaporator. Yield: 84.5% of theory of d,l-α -tocopherol. WE CLAIM : 1. A process for the manufacture of d,1~α-tocopherol by condensing trimethylhydroquinone with isophytol, which process comprises carrying out the condensation in the presence of a polyperfluoroalkylenesulphonic acid and in a solvent and recovering d,1-α-tocopherol by known means. 2. The process according to claim 1, wherein the condensation is carried out at temperature between 80°C and 140°C, preferably between 85°C and 120°C. 3. The process according to claims 1 or 2, wherein the condensation is carried out in an aprotic solvent. 4. The process according to claim 3, wherein isobutyl methyl ketone, diethyl ketone, cyclopentanohe, isophorone, ethyl acetate, isopropyl acetate, α-butyrolactone, toluene or xylene is used as the solvent. 5. The process according to claim 4, wherein toluene is used as the solvent. 6. The process according to claim 3, wherein the condensation is carried out in the presence of a polar aprotic solvent. 7. The process according to claim 6, wherein diethyl ketone, ethyl acetate, isopropyl acetate or α-butyrolactone is used as the solvent, 8. The process according to any one of claims I to 7, wherein 1-20 wt % preferably 1-10 wt % of polyperfluoroalkylene¬sulphonic acid is based on the wt% of the trimethylhydroquinone or isophytol used. 9. A process for the manufacture of d,l- α-tocopherol i substantially as herein described and exemplified.

Documents:

2231-mas-1996 claims.pdf

2231-mas-1996 correspondence-others.pdf

2231-mas-1996 correspondence-po.pdf

2231-mas-1996 description(complete).pdf

2231-mas-1996 form-1.pdf

2231-mas-1996 form-26.pdf

2231-mas-1996 form-4.pdf

2231-mas-1996 others.pdf

2231-mas-1996 petition.pdf