Process for esterifying farnesol in a mixture with alpha-bisabolol and process for producing a product comprising alpha-bisabolol

Abstract

A process for the esterification of farnesol in a starting mixture comprising alpha-bisabolol, farnesol and optionally further components, comprising the following steps: (a) providing or preparing the starting mixture, (b) adding (i) a transesterification catalyst and (ii) one or more compounds of the formula B, where in each case: R1 denotes an alkyl radical having 1 to 12 C atoms; R2 denotes hydrogen, an alkyl radical having 1 to 20 C atoms, a cycloalkyl radical having 5 to 20 C atoms, an aryl radical having 6 to 20 C atoms or a heteroaryl radical having 5 to 20 C atoms; and Y denotes CH2, CH(Me), CH(Et), C(Me)2, CH2-CH(Me), CH(Me)-CH2 or CH2-CH(Me)-CH2 and n denotes an integer from 0 to 6; or R2 represents a group CO2R3, where R3 represents an alkyl radical having 1 to 12 C atoms;orY represents an optionally substituted phenyl or naphthyl ring having a total of not more than four substituents on the ring, where n = 1 and where the transesterification catalyst is a titanium alcoholate of the formula Ti(ORi)4 or a zirconium alcoholate of the formula Zr(ORi)4, where in each case: Ri is a branched- or straight-chain alkyl radical having 1 to 12 carbon atoms.;

Description

[0001] The present invention relates to methods for reducing the proportion of farnesol in mixtures containing farnesol and alpha-bisabolol. Chamomile oil is the essential oil from the flower heads of the true chamomile, Chamomilla recutita (L) Rauschert. It is listed as "Oleum chamomillae" in the supplementary book to the German Pharmacopoeia. True chamomile is one of the most commonly used medicinal plants. The composition of chamomile oil depends on the provenance or drug type of the drug material used. It is also influenced by the distillation conditions of the steam distillation. Chamomile oil itself contains a large number of mono- and sesquiterpenes, with the therapeutically relevant sesquiterpenes quantitatively dominating. The main components of the essential oil are chamazulene, which gives it its deep blue color, (-)-alpha-bisabolol, bisabolol oxide A, bisabolol oxide B, bisabolone oxide A, cis- and trans-spiroethers and farnesene.Chamomile flowers from different origins also exhibit significant differences in their composition. While bisabolol-type chamomile is naturally limited to northeastern Spain, the bisabolol oxide A type is widespread throughout Central, Southern, and Eastern Europe, as well as Egypt. The rarer bisabolone oxide A type is known from Albania and Turkey.

[0002] In the assessment of the therapeutic efficacy of chamomile extract preparations, (-)-alpha-bisabolol occupies a dominant position, as its anti-inflammatory effect is clearly superior to (+)-alpha-bisabolol, the synthetic bisabolol racemate and the bisabolol oxides A and B.

[0003] While the systematic cultivation of medicinal and aromatic plants continues to gain importance due to an increased demand for “renewable raw materials,” the limited natural resources have simultaneously led to the search for and development of processes for the production of synthetic products.

[0004] Synthetic “alpha-bisabolol” is usually a diastereomeric racemate of equal parts of (+ / -)-alpha-bisabolol and (+ / -)-epi-alpha-bisabolol. All four enantiomers have been found in nature. (-)-(4S,8R)-alpha-epi-bisabolol is a natural constituent of Citrus bergamia RISSO essential oil [Helv. Chim. Acta 1986, 69, 698] and its enantiomer (+)-(4R,8S)-alpha-epi-bisabolol has been isolated from various Abies and Picea species [Aust. J. Chem. 1989, 42, 2021], while (+)-(4R,8R)-alpha-bisabolol is a constituent of Atalantia monophylla corren oil [Aust. J. Chem. 1989, 42, 2021; Tetrahedron 1981, 37 (suppl.) and its enantiomer (-)-(4S,8S)-alpha-bisabolol is one of the main components of German chamomile [Parf. Cosm. Aromes 1984, 57, 55]. (-)-(4S,8S)-alpha-bisabolol is produced on a large industrial scale for numerous applications in the cosmetic and fragrance sectors, e.g. for use in protective creams, lotions, deodorants, etc., particularly because of its anti-inflammatory, bactereostatic and antifungal properties [Planta Med. 1990, 56, 456].

[0005] For a long time, the absolute configuration of the individual enantiomers of alpha-bisabolol was not clearly determined. However, J. Org. Chem. 1993, 58, 5528 finally describes a process for the preparation of the individual isomers by enantioselective hydrolysis starting from (4S,8RS)- and (4R,8RS)-8,9-epoxy-p-menth-1-ene.

[0006] Due to its described effects, there is a constant demand for (+), (-), and (+ / -)-alpha-bisabolol, and / or (+)-epi, (-)-epi, and (+ / -)-epi-alpha-bisabolol, i.e., compounds of formula A, in which the wavy lines each independently represent an S or R configuration at the corresponding C atom. Thus, a variety of methods and processes for the production of bisabolol starting from nerolidol have been described in the past.

[0007] The first catalytic cyclization of farnesol was reported in 1913, when it was observed that, in addition to the expected hydrocarbons, some mono- and bicyclic compounds were also found when the reaction was carried out in the presence of potassium hydrogen sulfate [Chem. Ber. 46, 4024 (1913)]. Later studies identified these cyclic compounds as bisabolene and cadalene compounds.

[0008] In 1925, a thorough investigation was conducted for the first time, in which products such as farnesene, bisabolene, and bisabolol were obtained from nerolidol by acid catalysis [Helv. Chim. Acta 8, 259 (1925)]. In particular, it was shown that nerolidol, upon addition of acetic anhydride, subsequent reaction with acetic acid / sulfuric acid or formic acid at room temperature, and subsequent saponification, yields a mixture comprising bisabolol and farnesol.

[0009] In 1968, Gutsche [Tetrahedron 24, 859] reported on the acid-catalyzed cyclization of farnesol and nerolidol. Starting with farnesol or nerolidol, the corresponding formates were initially obtained by treatment with formic acid, which were then saponified to the alcohols in a second step. However, this procedure produces mixtures containing farnesols in addition to bisabolol. Subsequent distillative purification to obtain highly enriched bisabolol proves difficult, particularly because alpha-bisabolol and cis,cis-farnesol have almost identical boiling points, and the mixtures obtained by the described procedure contain up to 10% cis,cis-farnesol.

[0010] Further syntheses of bisabolol were described by Ruzicka et al. [Helv. Chim. Acta 15, 3, (1932)] and by Manjarrez et al. [J. Org. Chem. 31, 348, (1966)]. Acid-catalyzed cyclization in the presence of formic acid in pentane or AlCl3 in ether [Tetrahedron Lett. 1972, 2455], KHSO4 [J. Org. Chem. 34, 3789, (1969)], and BF3 etherate in methylene chloride [Chem. Lett. 1972, 263] has also been described.

[0011] Uneyama et al. reported an electrochemical preparation method [Chem. Lett. 1984, 529], including the preparation of DL-bisabolol from DL-nerolidol. While the previously presented processes starting from nerolidol rarely resulted in bisabolol yields above 30%, yields of up to 52% were achieved using electrochemical methods.

[0012] WO 2004 / 033401 describes a process for the production of alpha-bisabolol, in which nerolidol is reacted in one step with a mixture consisting of a ketone, a sulfonic acid, and perchloric acid. This process is characterized, among other things, by the fact that it results in a particularly pure alpha-bisabolol and, in particular, the (+), (-), or (+ / -)-farnesol, which is formed as a byproduct in the previously described processes with a yield of up to 40%, is formed only in comparatively low concentrations.

[0013] Common to the processes known from the prior art for the production of bisabolol is that farnesols are regularly produced in varying quantities. However, the presence of farnesol in product mixtures alongside bisabolol is undesirable because farnesols are believed to have allergenic potential, which makes their use in cosmetic products particularly problematic. When developing cosmetic products, not only the cosmetic properties are of interest; the safety of the substances they contain for humans and the environment must also be given the utmost consideration. Improved toxicological, ecotoxicological, and dermatological properties contribute in particular to the value of a new product. From a dermatological perspective, a cosmetic product should not exhibit any skin-irritating, sensitizing, and / or photosensitizing properties.In this respect, the presence of farnesol in cosmetic products is increasingly perceived as problematic. The IFRA (International Fragrance Association) has classified farnesol and several other mono- and sesquiterpenes into Subcategory 2, which includes products whose allergenic potential, although less frequently observed, is still observed in a significantly high number of test subjects. The permissible use concentrations of the compounds contained in Subcategory 2 have been limited in various product categories.

[0014] It has already been mentioned above that the distillative separation of alpha-bisabolol and farnesol is particularly difficult because alpha-bisabolol and cis,cis-farnesol have almost identical boiling points. If product mixtures containing a significant proportion of farnesols in addition to the desired alpha-bisabolol are to be separated by distillation, achieving at least a certain degree of success requires such a long thermal exposure that a high degree of side reactions occurs, particularly the decomposition of the previously synthesized compounds.

[0015] It was therefore the object of the present invention to provide a process which enables or facilitates the separation of alpha-bisabolol and farnesol(s) so that overall a product or product mixture can be obtained which is largely or substantially free of farnesol(s).

[0016] Preferably, a product mixture prepared by the process should contain a proportion of at least 90 wt.% bisabolol and a proportion of farnesol of less than 0.5 wt.%.

[0017] This object is achieved according to the invention by a process for the esterification of farnesol by means of transesterification in a starting mixture comprising alpha-bisabolol, farnesol and optionally further components, with the following steps: 1. Providing or preparing the starting mixture (i.e. comprising alpha-bisabolol, farnesol and, if applicable, other components), 2. Adding (i) a transesterification catalyst and (ii) one or more compounds of formula Bwherein: R 1 means an alkyl radical having 1 to 12 C atoms; R 2means hydrogen, an alkyl radical having 1 to 20 C atoms, a cycloalkyl radical having 5 to 20 C atoms, an aryl radical having 6 to 20 C atoms or a heteroaryl radical having 5 to 20 C atoms; and Y represents CH2, CH(Me), CH(Et), C(Me)2, CH2-CH(Me), CH(Me)-CH2 or CH2-CH(Me)-CH2 and n represents an integer from 0 to 6; or R 2 means a group CO2R 3 , where R 3 an alkyl radical having 1 to 12 C atoms; and Y is CH2, CH(Me), CH(Et), C(Me)2, CH2-CH(Me), CH(Me)-CH2 or CH2-CH(Me)-CH2 and n is an integer from 0 to 8, or

[0018] Y represents an optionally substituted phenyl or naphthyl ring having a maximum of four substituents on the ring, where n = 1; and where the transesterification catalyst is a titanium alcoholate of the formula Ti(OR i )4 or a zirconium alcoholate of the formula Zr(OR i )4, where R iis a branched or straight-chain alkyl radical having 1 to 12 C atoms, preferably 1 to 4 C atoms.

[0019] The abbreviations Me and Et have the usual meaning: Me = Methyl and Et = Ethyl.

[0020] The respective alkyl radicals can be branched or straight-chain.

[0021] The mixture used (starting mixture) comprising bisabolol, farnesol, and optionally other components is preferably prepared by one of the processes discussed above, preferably by the process according to WO 2004 / 033401. Alternative processes for the production of alpha-bisabolol, in particular those starting from nerolidol as the starting material, can also be used to produce starting mixtures comprising bisabolol, farnesol, and optionally other components.

[0022] For the purposes of this text, the term "alpha-bisabolol" includes (+)-alpha-bisabolol, (-)-alpha-bisabolol, (+)-epi-alpha-bisabolol, and (-)-epi-alpha-bisabolol, as well as mixtures of two, three, or all of the aforementioned isomers of alpha-bisabolol. In particular, the term "alpha-bisabolol" includes racemic mixtures of (+ / -)-alpha-bisabolol and / or (+ / -)-epi-alpha-bisabolol.

[0023] The invention is based on the surprising finding that the farnesol present in the mixture (comprising alpha-bisabolol, farnesol and optionally further components) is converted into a farnesyl ester in the presence of one of the transesterification catalysts to be used according to the invention and one or more compounds of formula B, while the alpha-bisabolol present simultaneously in the mixture is not esterified at all or at most to an insignificant extent.

[0024] The compound(s) of formula B have surprisingly proven to be extremely selective transesterification or esterification reagents which, when added to a mixture of alpha-bisabolol and farnesol, esterify the farnesols highly selectively, while the alpha-bisabolol is esterified to a small extent or not at all.

[0025] In the process according to the invention, the amount of one or more compounds of formula B (as specified above) used is preferably sufficient to esterify the amount of farnesol present in the mixture. It should be noted that, in addition to alpha-bisabolol and farnesol, other alcohols may be present in the mixture, for example, starting material from bisabolol synthesis, in particular nerolidol. Nerolidol also remains essentially unaffected by the transesterification reaction.

[0026] Particularly when the proportion of other alcohols (besides alpha-bisabolol and farnesol) is only small, the molar ratio of farnesol to the total amount of the compound(s) of formula B is preferably in the range from 1:1 to 1:10, preferably in the range from 1:1.1 to 1:5. With such molar ratios, the farnesol present in the mixture (comprising alpha-bisabolol, farnesol and optionally other components) can usually be completely esterified with high selectivity.

[0027] The reaction of a mixture comprising alpha-bisabolol and farnesol is shown in simplified form in Scheme 1 below. The isomers of alpha-bisabolol and farnesol shown are merely examples.

[0028] Depending on the manufacturing process, the starting mixtures to be treated contain, in addition to bisabolol and farnesol, one or more of the following substances: nerolidol; elimination products of bisabolol (bisabolene); elimination products of farnesol (farnesene); etherification products of farnesol (difarnesyl ether); rearrangement products of bisabolol and / or farnesol and / or nerolidol; sesquiterpenes and sesquiterpene alcohols such as khusiol, germacradienol, elemol or eudesmol.

[0029] In the process according to the invention, monocarboxylic acid alkyl esters or dicarboxylic acid dialkyl esters of formula B are used. The amount of the compound(s) of formula B used is preferably selected such that at least 1 molar equivalent of compound(s) of formula B is used for the molar amount of farnesol present in the starting mixture (comprising alpha-bisabolol, farnesol and optionally further constituents). The greater the molar excess of compound(s) of formula B, the faster the transesterification reaction with farnesol proceeds and the lower the farnesol content in the alpha-bisabolol (after purification operations such as distillation). For process economic reasons, the molar ratio of farnesol to the total amount of the compound(s) of formula B is particularly preferably in the range from 1:1.2 to 1:3.5.

[0030] Preferably, R 1an alkyl radical having 1 to 4 C atoms, particularly preferably methyl, ethyl, n-propyl or iso-propyl.

[0031] In case compound B is a monocarboxylic acid alkyl ester, R 2 preferably hydrogen, an alkyl radical having 3 to 8 C atoms or an aryl radical having 6 to 10 C atoms, particularly preferably an aryl radical having 6 to 8 C atoms; and / or

[0032] Y denotes CH2, CH(Me), CH2-CH(Me), CH(Me)-CH2 or CH2-CH(Me)-CH2 and n denotes an integer from 0 to 6, wherein again the monocarboxylic acid moiety of the monocarboxylic acid alkyl ester of formula B preferably has a total number of C atoms of at least 5 and at most 12, preferably of at least 6 and at most 10.

[0033] Particularly preferred monocarboxylic acid alkyl esters of formula B are: C1-C4 benzoate, in particular methyl benzoate and ethyl benzoate.

[0034] In case compound B is a dicarboxylic acid dialkyl ester, R 2 prefers a group CO2R 3 , where R 3 an alkyl radical having 1 to 4 C atoms, in particular methyl, ethyl, n-propyl or isopropyl, and more preferably has the same meaning as R 1 has; and / or

[0035] Y is CH2 and n is an integer from 0 to 6, preferably an integer from 2 to 5, or

[0036] Y is CH2-CH(Me), CH(Me)-CH2 or CH2-CH(Me)-CH2 and n = 0, 1 or 2; or

[0037] Y represents a phenyl or naphthyl ring, where n = 1.

[0038] In the case of the alkyldicarboxylic acid dialkyl esters of the formula B, preference is given to those in which the alkyldicarboxylic acid part of the dicarboxylic acid dialkyl ester of the formula B has a total number of C atoms of at least 3 and at most 12, preferably of at least 4 and at most 10.

[0039] Particularly preferred alkyldicarboxylic acid dialkyl esters of the formula B are: C1-C4 succinate, in particular ethyl succinate, isopropyl succinate, C1-C4 adipic acid, in particular ethyl adipic acid, isopropyl adipic acid, C1-C4 glutarate, in particular ethyl glutarate, isopropyl glutarate, C1-C4 glutarate, in particular ethyl glutarate, isopropyl glutarate, C1-C4 3-methylglutarate, in particular ethyl 3-methylglutarate, isopropyl 3-methylglutarate, C1-C4 suberic acid, C1-C4 azelaic acid.

[0040] In the case of the aryldicarboxylic acid dialkyl esters of formula B, preference is given to those in which the aryldicarboxylic acid moiety of the dicarboxylic acid dialkyl ester of formula B has a total number of C atoms of at least 8 and at most 12.

[0041] Particularly preferred aryldicarboxylic acid dialkyl esters of formula B are: diethyl phthalate, diisopropyl phthalate, dibutyl phthalate, diethyl terephthalate, diethyl 2,6-naphthalenedicarboxylate, di-2-ethylhexyl 2,6-naphthalenedicarboxylate.

[0042] Preferably, the compound(s) of formula B to be used according to the invention does / do not have (almost) the same boiling point as alpha-bisabolol (approx. 287°C at 1013 mbar).

[0043] In a preferred embodiment of the present invention, the compound(s) of formula B has or have a boiling point of at most 275°C, preferably at most 260°C, each at 1013 mbar. This enables an economically advantageous isolation of the purified alpha-bisabolol. After the transesterification reaction has ended, any remaining excess amount of compound(s) of formula B can be distilled off, followed by alpha-bisabolol, leaving the esterified farnesol and other esterified alcohols originating from the original mixture in the bottoms.

[0044] The amount of transesterification catalyst used is preferably selected such that, based on the molar amount of farnesol present in the starting mixture (comprising alpha-bisabolol, farnesol and optionally further components), 0.001 to 0.5 molar equivalents of transesterification catalyst are used, preferably 0.01 to 0.1 molar equivalents.

[0045] Suitable transesterification catalysts are titanium alcoholates Ti(OR i )4 and zirconium alcoholates Zr(OR i )4, where the remainder R i is a branched or straight-chain alkyl radical having 1 to 12 C atoms. Particularly preferred transesterification catalysts are Ti(OR i )4 and Zr(OR i )4, where R i is a branched or straight-chain alkyl radical having 1 to 4 C atoms. Preferred zirconium alcoholates are Zr(OR i )4, since particularly good results were achieved with these transesterification catalysts.

[0046] Various transesterification catalysts are known from the literature, including those based on titanium and zirconium, for example from DE 199 42 541, Tetrahedron. Lett. 1998, 39, 4223 and Synthesis 1982, 138. Such transesterification catalysts can optionally be used in the process according to the invention.

[0047] In a particularly preferred embodiment of the process according to the invention, the starting mixture comprising bisabolol, farnesol, and optionally other components is reacted with diisopropyl adipic acid and zirconium tetra-n-propylate. Excellent results can be achieved with this combination.

[0048] The transesterification or esterification reaction is regularly carried out at a temperature in the range of 100 - 250 °C, preferably in the range of 150 - 200 °C.

[0049] It is also advantageous to conduct the reaction under a weak vacuum, preferably at a pressure in the range of 500 - 10 mbar. Typically, the alcohol R formed during the transesterification is 1 -OH from the compound(s) of formula B and optionally other low-boiling components (e.g. alcohols resulting from the transesterification catalyst) are distilled off.

[0050] Finally, the desired product, alpha-bisabolol, is distilled overhead, preferably at a pressure in the range of 0.5 - 5 mbar. The higher-boiling products remain in the bottoms, depending on the type and amount of the compound(s) of formula B used, in particular monocarboxylic acid farnesyl ester or dicarboxylic acid difarnesyl ester / dicarboxylic acid alkylfarnesyl ester, as well as any unreacted amounts of compound(s) of formula B.

[0051] According to a further aspect, the invention also relates to a process for producing a product comprising alpha-bisabolol, which comprises the following steps: - Conversion of nerolidol into a product mixture comprising alpha-bisabolol and farnesol, - esterifying the farnesol in the product mixture by a process according to the invention.

[0052] With regard to the preferred embodiment of the process for the esterification of farnesol, the above applies accordingly.

[0053] The processes according to the invention (i) for esterifying farnesol in a mixture comprising alpha-bisabolol, farnesol, and optionally other components, or (ii) for producing a product comprising alpha-bisabolol, are preferably completed by a workup / purification operation. During the workup / purification operation, the alpha-bisabolol and the ester formed by reacting the farnesol with the compound of formula B are preferably separated from one another.

[0054] A particularly preferred processing / cleaning operation includes the following steps: - Distillative separation of alpha-bisabolol from the reaction mixture from the transesterification reaction.

[0055] After separation of alpha-bisabolol from the monocarboxylic acid farnesyl ester or dicarboxylic acid difarnesyl ester / dicarboxylic acid alkylfarnesyl ester formed by reacting farnesol with the compound of formula B, the resulting product does not contain the said ester(s) and has a farnesol content of less than 0.5% by weight. Typically, for example, after fractional distillation, alpha-bisabolol is present in a highly pure form, as desired by the cosmetic industry.

[0056] The invention is explained in more detail below using exemplary embodiments. Example 1: Preparation of alpha-bisabolol (not according to the invention)

[0057] In a standard apparatus consisting of a 2000 ml three-necked flask equipped with a reflux condenser, dropping funnel, and thermometer, 266 g (1.2 mol) (+ / -) nerolidol and 528 g (9.1 mol) of acetone were placed. A solution of 22 g (0.192 mol) of methanesulfonic acid and 10.8 g (67 mmol) of 60% perchloric acid was then added dropwise at 10 °C over a period of 30 minutes. The reaction mixture was then stirred for 24 hours at 15 °C and processed after GC monitoring.

[0058] The reaction mixture was worked up by adding 500 g of water and 200 g of diethyl ether, and then separating the organic phase. The organic phase was then washed neutral with sodium carbonate solution and water. After distilling off the solvent, 268 g of crude product remained. GC: alpha-bisabolol 47.2%; Farnesol (Sum of the 4 isomers cis / cis; cis / trans; trans / cis; trans / trans): 2.4%

[0059] The crude product also contained significant amounts of unreacted nerolidol and farnesene as well as other sesquiterpene hydrocarbons. Example 2: Preparation of alpha-bisabolol (not according to the invention)

[0060] 264 g (1.2 mol) of (+ / -)-nerolidol and 528 g (9.1 mol) of acetone were placed in a 2000 ml three-neck flask equipped with a reflux condenser, dropping funnel, and thermometer. Then, 10.8 g (67.2 mmol) of 60% perchloric acid were added dropwise at 15 °C over a period of 40 minutes. The reaction mixture was then stirred for 24 hours at 20 °C and processed after GC monitoring.

[0061] The reaction mixture was worked up by adding 500 g of water and 200 g of diethyl ether, and then separating the organic phase. The organic phase was then washed neutral with sodium carbonate solution and water. After distilling off the solvent, 272 g of crude product remained. GC: alpha - Bisabolol: 23.4% Farnesol (sum of the 4 isomers cis / cis;cis / trans;trans / cis;trans / trans): 17.4% Bisabolene (due to elimination from bisabolol): 55.4% Example 3.1: Preparation of bisabolol formate (not according to the invention)

[0062] 264 g (1.2 mol) of (+ / -)-nerolidol and 100 g of hexane were placed in a 2000 ml three-neck flask equipped with a reflux condenser and thermometer. A total of 92 g (2 mol) of formic acid was then added dropwise at 10-15 °C over a period of 60 minutes. The reaction mixture was then stirred for 20 hours at 10-15 °C and processed after GC monitoring.

[0063] The reaction mixture was worked up by adding 500 g of water. The organic phase was then separated and washed with sodium carbonate solution and water until neutral. After distilling off the solvent, 300 g of crude product remained. GC: alpha-bisabolyl formate: 38.9%; Farnesyl formate (sum of the 4 isomers cis / cis;cis / trans;trans / cis;trans / trans): 29.7% Example 3.2: Preparation of alpha-bisabolol (not according to the invention)

[0064] In a 2000 ml three-neck flask equipped with a reflux condenser, dropping funnel, and thermometer, 300 g (0.8 mol) of the crude mixture from Example 3.1 and 400 g of methanol were placed. 480 g of 10% sodium hydroxide solution were then added over a period of 15 minutes at a temperature of 20-40 °C. The mixture was then stirred for 2 hours at 30-40 °C and processed after GC control.

[0065] The reaction mixture was worked up by adding 400 g of water and 200 g of diethyl ether, and then separating the organic phase. The organic phase was then washed with water until neutral. After distilling off the solvent, 259.2 g of crude product remained. GC: alpha - Bisabolol: 37.3% Farnesol (sum of the 4 isomers cis / cis;cis / trans;trans / cis;trans / trans): 28.9%

[0066] By rectification on a 40-tray column, the bisabolol content was increased to 86% and the farnesol content (c / c) was reduced to 7%. Example 4: Preparation of farnesol-depleted alpha-bisabolol (according to the invention)

[0067] A 1000 ml three-neck flask equipped with a distillation bridge and thermometer was charged with 500 g of a bisabolol / farnesol mixture (86% bisabolol, 7% farnesol, corresponding to 0.16 mol farnesol), 50 g of isopropyl adipate (0.22 mol), and 5 g of zirconium tetrapropylate (70% in propanol, corresponding to 0.01 mol). The mixture was heated for 2 hours at a temperature of 160-165 °C and a pressure of 30 mbar. 11 g of low-boiling components (propanol and isopropanol) distilled over. The reaction mixture was then distilled on a 60 cm column with VA-BX packing at a vacuum of 1 mbar.

[0068] At a head temperature of 110 - 121 °C, a total of 26 g of foreshots are transferred.

[0069] At a head temperature of 121–122 °C, 413 g of the main fraction pass over (GC: alpha-bisabolol 95.3%; <0.1% farnesol), corresponding to a yield of 92% of theory. 86 g of distillation residue remained in the reactor, containing mainly difarnesyl adipate and isopropylfarnesyl adipate. Example 5: Preparation of farnesol-depleted alpha-bisabolol (according to the invention)

[0070] In a 1000 ml three-neck flask fitted with a 30 cm packed column with V4A spirals, distillation bridge, and thermometer, 500 g of a bisabolol / farnesol mixture (86% bisabolol, 7% farnesol, corresponding to 0.16 mol farnesol), 50 g of methyl benzoate (0.37 mol), and 5 g of zirconium tetrapropylate (70% in propanol, corresponding to 0.01 mol) were placed. The mixture was heated at 160-165 °C and a pressure of 30 mbar for 2 hours. 10 g of low-boiling components (methanol and isopropanol) distilled over. The reaction mixture was then distilled at 3 mbar.

[0071] At a head temperature of 110 - 126 °C, 25 g of foreshots pass over.

[0072] At a head temperature of 126–135 °C, 432 g of the main fraction (GC: alpha-bisabolol 94.8%; 0.1% farnesol) pass over, corresponding to a yield of 95% of theory. 80 g of distillation residue remain in the reactor, which mainly contained difarnesyl adipate and isopropylfarnesyl adipate.

Claims

[1] Process for the esterification of farnesol in a starting mixture comprising alpha-bisabolol, farnesol and optionally further components, comprising the following steps: (a) Providing or preparing the starting mixture, (b) Add (i) a transesterification catalyst and (ii) one or more compounds of formula Bwherein: R1 represents an alkyl radical having 1 to 12 C atoms; R2 represents hydrogen, an alkyl radical having 1 to 20 C atoms, a cycloalkyl radical having 5 to 20 C atoms, an aryl radical having 6 to 20 C atoms or a heteroaryl radical having 5 to 20 C atoms; and Y is CH2, CH(Me), CH(Et), C(Me)2, CH2-CH(Me), CH(Me)-CH2 or CH2-CH(Me)-CH2 and n is an integer from 0 to 6; or R 2 means a group CO2R 3 , where R 3 an alkyl radical having 1 to 12 C atoms; or Y represents an optionally substituted phenyl or naphthyl ring having a maximum of four substituents on the ring, where n = 1 and where the transesterification catalyst is a titanium alcoholate of the formula Ti(OR i )4 or a zirconium alcoholate of the formula Zr(OR i )4, where Ri is a branched or straight-chain alkyl radical having 1 to 12 carbon atoms. [2] Process according to claim 1, wherein the amount of the one or more compounds of formula B used is sufficient to esterify the amount of farnesol present in the mixture. [3] A process according to any one of the preceding claims, wherein the molar ratio of farnesol to the total amount of the compound(s) of formula B is in the range from 1:1 to 1:

10. [4] A process according to any one of the preceding claims, wherein the mixture contains one or more further components selected from the group consisting of: nerolidol, elimination products of alpha-bisabolol, elimination products of farnesol, elimination products of nerolidol, etherification products of farnesol, sesquiterpenes and sesquiterpene alcohols. [5] A process according to any one of the preceding claims, wherein in formula BR 1 , represents an alkyl radical having 1 to 4 C atoms. [6] A process according to any one of the preceding claims, wherein the compound of formula B is a monocarboxylic acid alkyl ester, and R 2 hydrogen, an alkyl radical having 3 to 8 C atoms or an aryl radical having 6 to 10 C atoms; and / or Y is CH2, CH(Me), CH2-CH(Me), CH(Me)-CH2 or CH2-CH(Me)-CH2 and n is an integer from 0 to 6. [7] A process according to any one of the preceding claims, wherein the compound of formula B is selected from the group consisting of benzoic acid C1-C4 esters. [8] A process according to any one of claims 1-5, wherein compound B is a dicarboxylic acid dialkyl ester, R 2 a group CO2R 3 means, where R 3 represents an alkyl radical having 1 to 4 C atoms, and / or Y represents CH2 and n represents an integer from 0 to 6, or Y represents CH2-CH(Me), CH(Me)-CH2 or CH2-CH(Me)-CH2 and n represents 0, 1 or 2; or Y represents a phenyl or naphthyl ring, where n represents 1. [9] A process according to any one of claims 1-5, wherein the compound according to formula B is selected from: Succinic acid C1-C4 ester, Isopropyl succinate, Adipic acid C1-C4 esters, Isopropyl adipic acid, Glutaric acid C1-C4 ester, Glutaric acid isopropyl ester, 3-Methylglutaric acid-C1-C a-esters, 3-methylglutaric acid isopropyl ester, Suberic acid C1-C4 esters, Azelaic acid C1-C4 ester. [10] A process according to any one of claims 1-5, wherein the compound according to formula B is selected from the group consisting of Phthalic acid diethyl ester, Phthalic acid diisopropyl ester, Phthalic acid dibutyl ester, Diethyl terephthalate, 2,6-Naphthalenedicarboxylic acid diethyl ester, 2,6-Naphthalenedicarboxylic acid di-2-ethylhexyl ester. [11] A process for the preparation of a product comprising alpha-bisabolol, comprising the following steps: - Conversion of nerolidol into a product mixture comprising alpha-bisabolol and farnesol, - esterifying the farnesol in the product mixture by a process according to any one of claims 1 to 10. [12] A process according to any one of the preceding claims, wherein the alpha-bisabolol and the ester formed by reacting the farnesol with the compound of formula B are separated from each other. [13] Method according to one of the preceding claims 1 to 12, further comprising the following step: - Distillative separation of alpha-bisabolol from the reaction mixture.