WO2004096790A1

WO2004096790A1 - Process for the manufacture of tocyl and tocopheryl acylates

Info

Publication number: WO2004096790A1
Application number: PCT/EP2004/004144
Authority: WO
Inventors: Werner Bonrath; Alois Haas; Simone Hoppmann; Thomas Netscher; Horst Pauling
Original assignee: Dsm Ip Assets B.V.
Priority date: 2003-04-28
Filing date: 2004-04-19
Publication date: 2004-11-11

Abstract

A process for the manufacture of a tocyl acylate or a tocopheryl acylate comprises reacting tocol or a tocopherol with an acylating agent in the presence of a catalyst of the general formula HC1R2R3, wherein R1, R2 and R3 each signify the sulpho group, or R1, R2 and R3 each signify a perfluoroalkylsulphonyl group whereby at least two of R1, R2 and R3 are identical such perfluoroalkyl-sulphonyl groups, or R1 signifies the pentafluorophenyl-sulphonyl group and R2 and R3 each signify an identical perfluoroalkylsulphonyl group. The main commercial form of vitamin E, being (all-rac)-α-tocapheryl acetate, can be manufactured by acylation of (all-rac)-α-tocopherol according to this process.

Description

Process for the Manufacture of Tocyl and Tocopheryl Acylates

The present invention is concerned with a novel process for the manufacture of acylates of tocol and of tocopherol.

The term "tocopherol" as used herein is to be understood to refer to any compound derived from the basic structure of tocol [2-methyl-2-(4,8,12-trimethyltridecyl)-6- chromanol] and having vitamin E character, viz. any tocopherol having the saturated side chain 4,8,12-trimethyltridecyl, such as α-, β-, γ-, δ-, ζ₂- or η -tocopherol, and also any tocotrienol having three double bonds in the side chain [4,8,12-trimethyltridec-3,7,ll- trienyl], such as ε- or ζi- tocopherol. Of these various tocopherols (all-rac)-α-tocopherol, generally referred to as vitamin E, is of primary interest, being the most active and industrially most important member of the vitamin E group.

The present invention is preferably concerned with a novel process for the manufacture of acylates of tocopherols (tocopheryl acylates), more particularly tocopheryl acetates. The main commercial form of vitamin E being (all-rac)-α-tocopheryl acetate, the invention, in a more preferred aspect, is concerned with a process for the manufacture of (all-rac)-α-tocopheryl acetate. However, tocol itself and the other tocopherols such as those mentioned above can be readily acylated by the process of the present invention. In general, tocol and each of the tocopherols can be acylated in the form of its racemate or of any individual stereoisomer.

The synthesis of α-tocopheryl acetate by esterification of -tocopherol with excess acetic anhydride in the absence of a catalyst is described and exemplified by J. D. Surmatis et al. in U. S. Patent Specification (USP) 2,723,278. The product (dl)-α-tocopherol acetate was formed under reflux conditions for 5 hours; the yield is not given. This reaction can also be carried out with pyridine as the catalyst to afford, after three days reaction at room temperature, α-tocopheryl acetate in 96% yield, as reported by N. Cohen et al. on page 1172 of Helv. Chim. Acta 64, 1158-1172(1981).

The novel process according to the present invention provides excellent yields, avoids corrosion problems and can be carried in the absence of an additional solvent, thus avoiding the need to recycle solvents, and can be carried out in a continuous or batchwise mode.

According to the present invention there is provided a process for the manufacture of an acylate of tocol or a tocopherol (tocyl acylate or a tocopheryl acylate) which comprises reacting tocol or a tocopherol with an acylating agent in the presence of a catalyst of the general formula HCR R R , wherein R , R and R each signify the sulpho group (-SO₃H), or R , R² and R each signify a perfluoroalkylsulphonyl group of the formula -SO₂R⁴ , wherein R⁴ signifies a group of the formula C_nF _{n +} 1 and n is an integer from 1 to 10, and whereby at least two of R¹, R² and R³ are identical such perfluoroalkyl- sulphonyl groups, or R¹ signifies the pentafluorophenylsulphonyl group (-SO₂C₆F₅) and R² and R³ each signify an identical perfluoroalkylsulphonyl group of the above formula -SO₂R⁴.

The acylation can be carried out in principle using any acylating agent conventionally used for the acylation of a phenolic hydroxyl group as is present in tocol and tocopherols. Especially suitable types of such acylating agents are acid anhydrides and acyl halides. The acyl groups in such acylating agent may be derived from aliphatic carboxylic acids, e.g. from straight or branched chain alkanoic acids, in particular C_1-7- alkanoic acids such as acetic acid, propionic acid, butyric acid and pivalic acid, or from higher alkanoic acids (fatty acids) with up to 20 carbon atoms such as palmitic acid; or from aromatic carboxylic acids, particularly benzoic acid, so that in each case the appropriate acylate, being an alkanoate, or e.g. the benzoate, respectively, of tocol or the tocopherol is produced in the acylation process. Examples of aliphatic acyl halides are straight or branched chain alkanoyl chlorides such as acetyl, propionyl and butyryl chloride, and, of aromatic acyl halides, benzoyl chloride. The preferred acylating agent is acetic anhydride or acetyl chloride, most preferably acetic anhydride.

The catalysts of the general formula HCR^R³ for use in the process of the present invention are of the following types: Methane trisulphonate of the formula HC(SO₃H)₃; tris(perfluoroalkylsulphonyl)methanes of the formula HC(SO₂C_πF_{2π +} i)₃ in which all three perfluoroalkylsulphonyl groups -SO₂C_nF_{2n + 1} are identical; tris(perfluoroalkylsulphonyl)mefhanes of the formula HC(SO C_πF_{2n + 1})₃ in which two of the three perfluoroalkylsulphonyl groups are identical, examples being the tris(perfluoroalkylsulphonyl)methanes of the formulae HC(SO₂C F₉)₂(SO₂CF₃) and HC(SO₂C₈F₁₇)₂(SO₂CF₃); and bis(perfluoroalkylsulphonyl)monopentafluorophenylsulphonylmethanes of the formula HC(SO₂C_nF_{2n +} i)₂(SO₂C₆F₅) in which the two perfluoroalkylsulphonyl groups are identical, examples being the bis(perfluoroalkylsulphonyl)monopentafluorophenyl- sulphonylmethane of the formula HC(SO₂C F₉)₂(SO₂C₆F₅).

The perfluoroalkyl groups in the tris(perfluoroalkylsulphonyl)methanes and the bis(perfluoroalkylsulphonyl)monopentafluorophenylsulphonylmethanes, when containing three or more carbon atoms, may be straight chain or branched. They preferably contain 1 to 8 carbon atoms (n of C_nF _{n + 1} being 1 to 8).

Each catalyst may be used in such molecular form, or it may be used for example as a hydrate or other such equivalent functional form which may exist, particularly in a form readily available commercially. For example, methane trisulphonate is conveniently used in the readily available trihydrate form [HC(SO₃H)₃-3H₂O] .

In one embodiment of the invention, the catalyst is used in solid form, i.e. it is introduced into the vessel or reactor in which the reaction is to take place undiluted, particularly since many of the catalysts are beset with solubility problems and cannot readily or necessarily be added in solution.

The acylation in accordance with the process of the present invention may by carried out in the presence or in the absence of an added solvent, but preferably one of the reactants, i.e. the tocol or tocopherol or the acylating agent, is used in excess and no added solvent used. Preferably, the acylating agent is used in excess, preferably in a one- to about a threefold molar amount, more preferably in a 1.5- to 2.5-fold molar amount, and most preferably in a 1.75- to 2.25-fold molar amount, relative to the molar amount of tocol or tocopherol present in the initial reaction mixture. If an additional solvent is used, however, this is suitably a polar or non-polar aprotic organic solvent, particularly an aliphatic, preferably C to C₁₀ aliphatic, hydrocarbon, e.g. pentane, hexane, heptane or decane; an alicyclic, preferably C₄ to C₇ alicyclic, hydrocarbon, e.g. cyclohexane; or an aromatic, particularly C₆ to o aromatic, hydrocarbon, e.g. benzene, toluene, an xylene or naphthalene.

The amount of the catalyst of the general formula HCR¹R²R³ used is based on the molar amount of the reactant, i.e. the tocol or tocopherol or the acylating agent, usually the former, which is used in the lesser molar amount and is suitably in the range from about 0.02 to about 0.2 mol %, preferably from about 0.03 to about 0.1 mol %, based on said lesser molar amount, when the process is effected in a batchwise operational mode. For the alternative continuous operational mode, the relative amount of catalyst will be adjusted to the size of the reactor and the flow of the reactants. In this case it will be appreciated that the determination of the appropriate relative amount based on the figures for the batchwise operational mode is within the normal skill of the production chemist.

The acylation process in accordance with the present invention is convenientiy carried out at temperatures from about 80°C to about 120°C, preferably from about 90°C to about 110°C.

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

The progress of the reaction is suitably monitored by analytical means, such as gas chromatography or mass spectrometry of samples taken from the reaction mixture at various time intervals during the reaction.

After completion of the acylation the produced tocyl or tocopheryl acylate can be isolated by distilling off, preferably under reduced pressure, the remaining (unreacted) tocol or tocopherol or acylating agent, whichever has been used in excess, and the secondary product formed in the acylation, e.g. acetic acid when acetic anhydride is used as the acylating agent, followed by further distillation, also preferably under reduced pressure, to collect as pure a fraction of the desired acylation product as required.

Methane trisulphonate, of the formula HC(SO₃H)₃ and one of the possible catalysts used in the process of the present invention, is a known compound and can be produced from acetone or acetanilide in oleum, as described in e.g. J. Prakt. Chem. 336, 373-374 (1994). The acidity of this and further alkane polysulphonates is discussed in Z. Naturforsch. 51b, 1691-1700 (1996): see compound 24 in Table II therein.

Some of the catalysts of the general formula HCR^R³, wherein all three of R¹, R² and R³ signify identical perfluoroalkylsulphonyl groups, are also known compounds. Thus in Inorg. Chem. 27, 2135-2137 (1988) K. Seppelt and L. Turowsky describe for the first time the preparation of inter alia tris(trifluoromethylsulphonyl)methane, HC(SO₂CF₃)₃. The preparation of this compound is also described by F. J. Waller et al. in J. Org. Chem. 64, 2910-2913 (1999). Other tris(perfluoroalkylsulphonyl)methanes and metal salts thereof, i.e. certain methides, including ones with two of the three perfluoroalkylsulphonyl groups being identical, and their preparation are described by J. Nishikido et al. in Synlett 1999, No. 12, 1990-1992, by A. G. M. Barrett et al. in Tetrahedron 58, 3835-3840 (2002) and Synlett 2002, No. 10, 1653-1656, and in USP 5,273,840 and/or USP 5,554,664. The former USP includes a general description of how to prepare bis(trifluoromethyl- sulphonyl)monopentafluorophenylsulphonylmethane, i.e. a representative member of the above-mentioned type of catalysts of the general formula HCR^XR²R³ featuring two identical perfluoroalkylsuphonyl groups and the pentafluorophenylsulphonyl group, i.e. of the bis(perfluoroalkylsulphonyl)monopentafluorophenylsulphonylmethanes. Further literature concerning the preparation of tris(perfluoroalkylsulphonyl/pentafiuoro- phenylsulphonyl)methanes may be found in the many references mentioned in these aforementioned publications. In the case of the trisubstituted methanes which may still not be known methods analogous to the ones for producing the known such compounds may be used.

As an example of a new compound bis(nonafluorobutylsulphonyl)mono- pentafluorophenylsulphonylmethane, of the formula HC(SO₂C F₉)₂(SO₂C₆F₅), and its synthesis have not been described so far. This particular compound can be obtained as described in the final Example presented later in this specification; this is a typical synthetic method for producing those catalysts of the general formula HCR¹R²R³ wherein two of R¹, R² and R³ are identical groups. Such a method, applicable both to the preparation of the tris(perfluoroalkylsulphonyl)methanes with two identical perfluoroalkylsulphonyl groups and to the preparation of the bis(perfluoroalkyl- sulphonyl)monopentafluorophenylsulphonylmethanes, is generally effected by reacting the appropriate bis(perfluoroalkylsulphonyl)methane at a relatively low temperature and under as anhydrous and oxygen-free conditions as possible with the Grignard reagent methyl or ethyl magnesium halide (chloride, bromide or iodide, of which the chloride is preferred) in an aliphatic or cyclic ether, and then adding pentafluorophenylsulphonyl chloride or a perfluoroalkylsulphonyl chloride featuring a different perfluoroalkylsulphonyl group to those in the bis(perfluoroalkylsulphonyl)methane, also under relatively low temperature conditions, and allowing the mixture to react further to the desired product. The aliphatic or cyclic ether used as the solvent is suitably a dialkyl ether with a total of up to 10 carbon atoms, preferably 4 to 10 carbon atoms, e.g. diethyl ether, diisopropyl ether, dibutyl ether, methyl tert. butyl ether or methyl amyl ether, or tetrahydrofuran or dioxan, respectively. The amount of Grignard reagent relative to the amount of bis(perfluoroalkylsulphonyl)methane is suitably in a ratio of about 2-4 : 1, expressed in equivalents, and the amount of subsequently added pentafluorophenylsulphonyl chloride or perfluoroalkylsulphonyl chloride relative to the amount of starting bis(perfluoroalkyl-sulphonyl)methane is suitably in a ratio of about 1-4 :1, preferably about 2-2.5 : 1, also expressed in equivalents. The temperatures at which both stages of the reaction are suitably effected depends on the boiling point of the ethereal solvent used and are generally in the range from about 0°C to about 110°C. More particularly, each reaction stage is performed at temperatures from about 10 to about 50°C, preferably from about 15 to about 30°C. The progress of the reaction in each stage is suitably monitored by analysis, such as by gas chromatography or mass spectrometry, of samples taken from the reaction mixture at various time intervals during the reaction. After completion of the second stage of the reaction the mixture is suitably freed of solvent by evaporation and the residue dissolved in water, acidified with a mineral acid, preferably hydrochloric acid, and extracted into a water-immiscible organic solvent such as methylene chloride. Evaporation of the organic extract(s) affords the product, which after optional acidification with a mineral acid, e.g. sulphuric acid, can if desired be purified and collected by sublimation under reduced pressure.

The acylation process in accordance with the present invention is illustrated by the following Examples.

Example 1

51.09 g (0.116 mol) of (all-rac)-α-tocopherol were dissolved in 24.7 g (0.242 mol) of acetic anhydride in the presence of 15.6 mg (0.0503 mmol, 0.0433 mol %) of methane trisulphonate trihydrate in a 200 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser with an argon inlet. The mixture was stirred at 400 rpm and heated at 100°C (internal temperature) for 1 hour. The mixture was then cooled to 45°C and evaporated under reduced pressure [10 mbar (1 kPa), 60°C]. 57.45 g of (all- rac)- -tocopheryl acetate as a brownish oil were obtained with a purity of 94.4% according to analysis by gas chromatography (GC; internal standard). The yield was 98.9% based on the starting (all-rac)-α-tocopherol.

Example 2

8.68 g (20 mmol) of (all-rac)-α-tocopherol were dissolved in 4.28 g (42 mmol) of acetic anhydride in the presence of 22.9 mg (0.1 mol%, 0.0206 mmol) of the catalyst of the formula HC(SO₂C₈F₁₇)₂(SO₂CF₃) in a 50 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser with an argon inlet. The mixture was stirred at 400 rpm and heated at 100°C (internal temperature) for 4 hours. The mixture was then evaporated under reduced pressure [10 mbar (1 kPa), 60°C]. 9.99 g of (all-rac)-α- tocopheryl acetate as a brownish oil were obtained with a purity of 90.2% according to analysis by GC. The crude product was further purified by bulb-to-bulb distillation at 206°C/0.014 mbar (1.4 Pa). 9.1 g of the pure product tocopheryl acetate was isolated as a colourless to light yellowish oil in 92.2% purity [GC, based on the starting (all-rac)-α- tocopherol] .

Example 3

In analogy to Example 2 but using the catalyst of the formula HC(SO₂C₄F₉)₂(SO₂CF₃) (all-rac)-α-tocopheryl acetate was obtained in a yield of 97.6%, based on the starting (all-rac)-α-tocopherol.

Example 4

25.57 g (0.058mol) of (all-rac)-γ-tocopherol were dissolved in 13.2 g (0.128 mol) of acetic anhydride in the presence of 50.6 mg (0.1 mol %) of the catalyst of the formula HC(SO₂C₄F₉)₃ in a 200 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser with an argon inlet. The mixture was stirred at 400 rpm and heated at 100°C (internal temperature) for 1 hour. The mixture was then cooled to 45°C and evaporated under reduced pressure [10 mbar (1 kPa), 50°C]. 29.05 g of (all-rac)-γ- tocopheryl acetate as a brownish oil were obtained with a purity of 90.8% according to analysis GC (internal standard), representing a yield 98.9 % based on the starting (all-rac)- γ- tocopherol. 28.47 g of the crude product were further purified by bulb-to-bulb distillation at 210°C/0.03 mbar (3 Pa). The pure product was isolated as colourless to light yellowish oil in 93.2% purity (GC, internal standard). 27.23 g of (all-rac)-γ-tocopheryl acetate were obtained, representing a yield of 96.9 % based on the starting (all-rac)-γ- tocopherol.

Example 5

In analogy to Example 2 but using the catalyst of the formula HC(SO₂C₄F₉)₂(SO₂C₆F₅) (all-rac)-α-tocopheryl acetate was obtained in a yield of 97.6% based on the starting (all-rac)-α-tocopherol.

The compound HC(SO₂C₄F₉)₂(SO₂C₆F₅) used as the catalyst in this Example was prepared as follows:

2.25 g (3.8 mmol) of bis(nonafluoroburyl sulphonyl)methane in 15 ml of dry tetrahydrofuran were introduced into a dried 250 ml three-necked flask fitted with reflux condenser, an argon inlet, a dip tube and a mechanical stirrer. The solution was cooled to 0°C in an ice-water bath. Under strictly anhydrous and oxygen-free conditions methyl magnesium chloride (2.6 ml of a 3M solution in tetrahydrofuran) was slowly added to the rapidly stirred solution. After stirring at 23°C for 1 hour pentafluorophenylsulphonyl chloride (3.10 g, 11.6 mmol) was added under ice water bath)cooling and stirred for 4 hours at 0°C and for an additional 3 days at 23°C. Thereafter the solvent was evaporated off, the residue was dissolved in 10 ml of distilled water and the solution was acidified with aqueous hydrochloric acid. The solution was extracted three times with methylene chloride, the combined extracts evaporated to dryness and the solid residue acidified with a few grams of concentrated sulphuric acid. Sublimation in vacuo at 50°C afforded 1.59 g (51% yield) of the compound of bis(nonafluorobutylsulphonyl)mono(pentafluorophenyl- sulphonyl)methane, of the formula

as colourless, hygroscopic crystals of melting point 60°C. Analysis:

IR (KBr): 2998 (m), 2956 (m), 2929 (m), 1508 (s), 1395 (vs), 1351 (vs), 1293 (s), 1243 (vs), 1214 (vs),1196 (vs), 1174 (vs), 1143 (vs), 1112 (s), 1027 (m), 718 (s) and 692 (s);

MS (El): 682 (M⁺-2 SO₂, 1 %), 430 (C₄F₉CSC₆F₅ ⁺, 8 %), 398 (C₄F₉CC₆F₅ ⁺, 34 %), 231 (C₆F₅SO₂ ⁺, 36 %), 219 (C₄F₉ ⁺, 100 %), 199 (C₆F₅S⁺, 84 %), 167 (C₆F₅ ⁺, 29 %), 131 (C₃F₅ ⁺, 85 %), 117 (C₅F₃ ⁺, 27 %), 100 (C₂F₄ ⁺, 18 %), 69 (CF₃ ⁺, 100 %);

1H-NMR (tetrahydrofuran-d₈): δ = 7,18 (br);

¹⁹F-NMR (tetrahydrofuran-d₈, trifluoroacetic acid): δ(C₄F₉): -4,52 (6F), -31,37 (2F), -32,98(2F), -44,13 (4F), -49,05 (4F); δ(C₆F₅): -59,16 (2F), -65,81 (IF), -82,61 (2F).

Claims

1. A process for the manufacture of a tocyl acylate or a tocopheryl acylate which comprises reacting tocol or a tocopherol with an acylating agent in the presence of a catalyst of the general formula HCR R R , wherein R , R and R each signify the sulpho group (-SO₃H), or R¹, R² and R³ each signify a perfluoroalkylsulphonyl group of the formula -SO₂R⁴ , wherein R signifies a group of the formula C_nF_{2n + \} and n is an integer from 1 to 10, and whereby at least two of R¹, R² and R³ are identical such perfluoroalkylsulphonyl groups, or R¹ signifies the pentafluorophenylsulphonyl group (-SO₂C₆F₅) and R² and R³ each signify an identical perfluoroalkylsulphonyl group of the above formula -SO₂R⁴.

2. A process according to claim 1 wherein the acylating agent is an acid anhydride or an acyl halide.

3. A process according to claim 2 wherein the acyl group in the acylating agent is derived from an aliphatic carboxylic acid, preferably from a straight or branched chain C_1- -alkanoic acid or a higher alkanoic acid with up to 20 carbon atoms, or from an aromatic carboxylic acid.

4. A process according to claim 3 wherein the acyl group in the acylating agent is derived from acetic acid, propionic acid, butyric acid, pivalic acid or benzoic acid.

5. A process according to claim 4 wherein the acylating agent is acetic anhydride or acetyl chloride.

6. A process according to any one of claims 1 to 5 wherein the catalyst is one of those of the formulae HC(SO₃H)₃, HC(SO₂C₄F₉)₂(SO₂CF₃), HC( SO₂C₈Fι₇)₂(SO₂CF₃) and HC(SO₂C₄F₉)₂(SO₂C₆F₅).

7. A process according to any one of claims 1 to 6 wherein the reaction is carried out with one of the reactants, i.e. the tocol or tocopherol or the acylating agent, in excess and in the absence of an added solvent.

8. A process according to claim 7 wherein the acylating agent is used in excess, preferably in a one- to about a threefold molar amount, more preferably in a 1.5- to 2.5- fold molar amount, and most preferably in a 1.75- to 2.25-fold molar amount, relative to the molar amount of tocol or tocopherol present in the initial reaction mixture.

9. A process according to any one of claims 1 to 8, wherein the reaction is effected in a batchwise operational mode and the amount of the catalyst of the general formula HCR¹R²R³ used based on the molar amount of the reactant, i.e. the tocol or tocopherol or - li the acylating agent, which is used in the lesser molar amount is in the range from about 0.02 to about 0.2 mol %, preferably from about 0.03 to about 0.1 mol %, based on said lesser molar amount.

10. A process according to any one of claims 1 to 9, wherein the reaction is carried out at temperatures from about 80°C to about 120°C, preferably from about 90°C to about 110°C.

11. A process according to any one of claims 1 to 10, wherein (all-rac)-α-tocopherol or (all-rac)-γ- tocopherol is acylated to (all-rac)-α-tocopheryl acetate or (all-rac)-γ- tocopheryl acetate, respectively.