Manufacture of trimethylhydroquinone diacylates

This application is the National Stage of International Application No. PCT/EP02/13890, filed Dec. 7, 2002.

The present invention is concerned with a process for the manufacture of 2,3,5-trimethylhydroquinone diacylates by reacting ketoisophorone with an acylating agent in the presence of a so-called NH- or CH-acidic catalyst. The products of the process are useful as reactants for the manufacture of 2,3,5-trimethylhydroquinone, itself a known valuable reactant for the manufacture of (all-rac)-α-tocopherol, the most active member of the vitamin E group.

2,3,5-Trimethylhydroquinone diacylates are known to be producible by reacting ketoisophorone with an acylating agent in the presence of a strongly acidic catalyst. Many such catalysts have been proposed in the past for this purpose, in particular protonic acids, e.g. such inorganic acids as sulphuric acid; such organic acids as p-toluenesulphonic acid; strongly acidic ion exchange resins; and such Lewis acids as zinc chloride, boron trifluoride, antimony pentafluoride and titanium tetrachloride: see inter alia German Offenlegungsschrift 2149159 and European Patent Publications EP 0916642 A1 and EP 1028103 A1. In accordance with the present invention it has been found that the conversion of ketoisophorone to 2,3,5-trimethylhydroquinone diacylates can be advantageously accomplished by the use of NH-acidic or CH-acidic catalysts, especially those which have been found to be useful catalysts for the condensation of 2,3,5-trimethylhydroquinone with isophytol to yield α-tocopherol, as described in PCT Publication WO 98/21197 and European Patent Publications EP 1180517 A1 and EP 1134218 A1. Advantages of such catalysts used in the process in accordance with the present invention are the avoidance of corrosion, the avoidance of waste water contamination with heavy metal ions and the high selectivity.

Accordingly, the present invention provides a process for the manufacture of a 2,3,5-trimethylhydroquinone diacylate, which process comprises reacting ketoisophorone with an acylating agent in the presence of a NH-acidic catalyst, especially one of the general formula

[(R 1 SO 2 ) 2 N] x R 2   (I)

or a CH-acidic catalyst, especially one of the general formula

[(R 3 SO 2 ) 3 C] x R 2   (II)

wherein each of R 1 , independently, signifies a perfluoroalkyl group C n F 2n+1 or pentafluorophenyl, or both symbols R 1 together signify a poly-difluoromethylene group —(CF 2 ) m —,

R 2 signifies a proton or a metal cation selected from the group consisting of boron, magnesium, aluminium, silicon, scandium, titanium, vanadium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, rhodium, palladium, silver, tin, lanthanum, cerium, praseodymium, neodymium, europium, dysprosium, thulium, ytterbium, hafnium, platinum and gold cations, each of R 3 , independently, signifies a perfluoroalkyl group C n F 2n+1 or pentafluorophenyl, m signifies an integer from 2 to 4, n signifies an integer from 1 to 10 and x signifies an integer from 1 to 5 corresponding to the valency of the proton (1) or the metal cation (1, 2, 3, 4 or 5) signified by R 2 .

Examples of the cations signified by R 2 in both formulae above, using their chemical symbols, are B 3+ , Mg 2+ , Al 3+ , Si 4+ , Sc 3+ , Ti 4+ , V 3+ , V 3+ , Mn 2+ , Mn 4+ , Fe 2+ , Fe 3+ , Co 2+ , Ni 2+ , Cu + , Cu 2+ , Zn 2+ , Y 3+ , Zr 4+ , Rh 3+ , Pd 2+ , Ag + , Sn 4+ , La 3+ , Ce 3+ , Pr 3+ , Nd 3+ , Eu 2+ , Dy 3+ , Tm 3+ , Yb 3+ , Hf 4+ , Pt 2+ and Au 3+ .

Not only some of the above-defined NH-acidic catalysts of the formula I wherein R 2 signifies a proton [all being bis(perfluorinated hydrocarbyl sulphonyl)imides] but also some of their metal salts amongst the catalysts of formula I are known compounds. Those catalysts of formula I which may still not be known can be produced by methods analogous to the published methods for producing bis(trifluoromethylsulphonyl)imide and its metal salts and the higher members of these sulphonimides and their metal salts: see, for example, EP 364340/U.S. Pat. No. 5,256,821, Japanese Patent Publications (Kokai) 246338/1995, 064238/1996 (with the US counterpart U.S. Pat. No. 5,650,244), 057110/1997, 169690/1997, 176063/1997, 176171/1997, 241184/1997, 230166/1998, 330314/1998 and 209338/1999, DOS 4217366/U.S. Pat. No. 5,502,251, DOS 19533711/U.S. Pat. No. 5,723,664, Chemiker Zeitung 96, 582–583 (1972), Chem. Lett. 1995, 307–308, Synlett 1996, 171–172, 265–266 and 839–841, Inorg. Chem. 35(7), 1918–1925 (1996), J. Power Sources 68, 307–310 (1997) and Cat. Today 36(1), 81–84 (1997) as well as the further literature references mentioned in this state of the art. For example, many of the salts can be produced from the appropriate bis(perfluorinated hydrocarbyl sulphonyl)imide of formula I in which R 2 signifies a proton and the metal acetate, oxide, hydroxide or alcoholate featuring the desired metal cation. In the case of the aluminium, zinc and various other metal salts these can also be produced using the corresponding alkylmetal or dialkylmetal hydride, e.g. diethylzinc or triethylaluminium or, respectively, diisobutylaluminium hydride.

In some cases the metal salts can be present in monomeric or polymeric form and, accordingly, formula I is intended to embrace all such forms. Further, these catalysts can be used in isolated form or produced in situ.

Examples of a catalyst of formula I in which the symbols R 1 together signify a poly-difluoromethylene group —(CF 2 ) m — are 4,4,5,5,6,6-hexafluoro-(1,3,2)dithiazinane-1,3-dioxide and its silver salt.

Some of the CH-acidic catalysts of the formula II wherein R 2 signifies a proton and their metal salts are known compounds. Thus in Inorg. Chem. 27, 2135–2137 (1988) K. Seppelt and L. Turowsky describe for the first time the preparation of tris(trifluoromethanesulphonyl)methane, (CF 3 SO 2 ) 3 CH, and of four salts thereof, viz. the potassium, rubidium, silver and cesium salts. The lithium and further metal salts of (CF 3 SO 2 ) 3 CH and other tris(perfluoroalkanesulphonyl)methides and their preparation are described in U.S. Pat. No. 5,273,840. Also developing the original work of Seppelt and Turowsky, F. J. Waller et al. describe in J. Org. Chem. 64, 2910–2913 (1999) the further preparation of (CF 3 SO 2 ) 3 CH and its cesium salt, and also the preparation of the corresponding scandium and ytterbium salts. In Synlett 1999, No. 12, 1990–1992, J. Nishikido et al. describe the preparation of scandium, yttrium and, in general, lanthanide (III) tris(perfluorobutanesulphonyl)methide complexes. Further literature concerning the preparation of these and further metal tris(perfluoroalkanesulphonyl)methides includes U.S. Pat. No. 5,554,664 and the many references mentioned in this and in other aforementioned publications.

The tris(perfluoroalkanesulphonyl or pentafluorobenzenesulphonyl)methanes or metal salts thereof embraced by the formula II hereinbefore and used as the catalysts in the process of the present invention can be produced according to such published methods or, in the case of those methanes or metal salts thereof which may still not be known, according to analogous methods.

Preferred NH- and CH-acidic catalysts for use in the process of the present invention are those NH-acidic catalysts of the formula I wherein each of R 1 signifies trifluoromethyl or pentafluoroethyl, or both symbols R 1 together signify perfluoro-1,3-propylene, especially those wherein in addition R 2 signifies a proton; and those CH-acidic catalysts of the formula II wherein each of R 3 signifies trifluoromethyl, especially those wherein in addition R 2 signifies a proton or a divalent nickel cation.

The acylating agent used in the process of the present invention may be any acylating agent that is conventionally used in the conversion of ketoisophorone to 2,3,5-trimethylhydroquinone acylates, particularly acid anhydrides, acyl halides, and enol esters. Examples of acid anhydrides are straight or branched chain alkanoic acid anhydrides such as acetic, propionic and butyric anhydride. Examples of acyl halides are straight or branched chain alkanoyl chlorides such as acetyl, propionyl and butyryl chloride. Finally, examples of enol esters are isopropenyl acetate and butyrate. The preferred acylating agent is acetic anhydride or acetyl chloride, especially acetic anhydride.

The process of the present invention can be carried out in the presence or in the absence of a solvent. As a solvent, any inert polar or non-polar organic solvent or any mixture of two or more of such solvents can be used. Suitable classes of polar organic solvents include aliphatic and cyclic ketones, e.g. diethyl ketone and isobutyl methyl ketone and, respectively, cyclopentanone and isophorone; and aliphatic and cyclic esters, e.g. ethyl acetate and isopropyl acetate, and, respectively, γ-butyrolactone, ethylene carbonate and propylene carbonate. As suitable classes of non-polar organic solvents there may be mentioned aliphatic hydrocarbons, e.g. hexane, heptane and octane, and aromatic hydrocarbons, e.g. benzene, toluene and the xylenes. The reaction can be effected in a single solvent phase, e.g. in toluene alone as the solvent, or in a biphasic solvent system, e.g. in ethylene or propylene carbonate and heptane.

While the ratio of acylating agent to ketoisophorone is not narrowly critical the ratio of acylating agent (equivalents) to ketoisophorone (moles) is suitably from about 1:1 to about 5:1, preferably from about 2:1 to about 3:1, and is most preferably about 3:1.

The amount of catalyst of formula I or II used is suitably about 0.1 to about 2.0 mole %, preferably about 0.5 to about 1.5 mole %, and most preferably about 0.8 to about 1.2 mole %, based on the moles of ketoisophorone present.

The process is conveniently carried out at temperatures from about 20° C. to about 60° C., preferably from about 30° C. to about 50° C.

Moreover, the process is conveniently carried out under an inert gas atmosphere, preferably under gaseous nitrogen or argon.

The progress of the reaction is suitably monitored by gas chromatography and mass spectrometry of samples taken from the reaction mixture at various time intervals during the reaction.

The produced 2,3,5-trimethylhydroquinone diacylate can be isolated after distilling off the remaining acylating agent and the secondary product formed in the acylation, e.g. acetic acid when acetic anhydride is used as the acylating agent, by extraction of the crude product mixture with a suitable organic solvent, e.g. toluene. For instance, in effecting this procedure using acetic anhydride as the acylating agent 2,3,5-trimethylhydroquinone diacetate was obtained as colourless crystals after evaporating off the toluene used as the extracting solvent. Another isolation procedure is the crystallization of the 2,3,5-trimethylhydroquinone diacylate from the mixture at the termination of the reaction by cooling, and, optionally, adding water, to the mixture to promote the crystallization.

The catalyst can be recovered by extraction with water or acid-water and concentration of the extract. Alternatively, the catalyst can be recovered by adding a biphasic solvent system, e.g. a carbonate (particularly ethylene carbonate or propylene carbonate) and an aliphatic hydrocarbon (particularly heptane or octane), and isolating it from the polar (carbonate) phase

The 2,3,5-trimethylhydroquinone diacylate obtained by the process of the present invention can be converted into 2,3,5-trimethylhydroquinone by transesterification, i.e. by treatment with an alcohol, e.g. an aliphatic alcohol such as isopropanol or n-butanol. Depending on the amounts of alcohol and catalyst and on the temperature in the reaction mixture, the transesterification yields the unesterified 2,3,5-trimethylhydroquinone and the ester formed as the further product. The former product can be converted into (all-rac)-α-tocopherol by reaction with isophytol, preferably in a biphasic solvent system, e.g. in a solvent system comprising a polar solvent such as ethylene or propylene carbonate, and an non-polar solvent, particularly an aliphatic hydrocarbon such as heptane.

The invention is illustrated by the following Examples.