EP1999094A1 - Procede pour produire de l'alpha-bisabolol a partir de farnesol - Google Patents

Procede pour produire de l'alpha-bisabolol a partir de farnesol

Info

Publication number
EP1999094A1
EP1999094A1 EP06819156A EP06819156A EP1999094A1 EP 1999094 A1 EP1999094 A1 EP 1999094A1 EP 06819156 A EP06819156 A EP 06819156A EP 06819156 A EP06819156 A EP 06819156A EP 1999094 A1 EP1999094 A1 EP 1999094A1
Authority
EP
European Patent Office
Prior art keywords
acid
farnesol
bisabolol
formula
ketone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06819156A
Other languages
German (de)
English (en)
Inventor
Klemens Massonne
Klaus-Peter Pfaff
Jürgen Schubert
Günther GOTTWALD
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF SE
Original Assignee
BASF SE
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BASF SE filed Critical BASF SE
Publication of EP1999094A1 publication Critical patent/EP1999094A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to a process for the production of ⁇ -bisabolol from farnesol.
  • ⁇ -Bisabolol is one of the most important components of camphor oil, which is valuable from a cosmetic and pharmaceutical point of view.
  • alpha-bisabolol is usually a diastereomeric racemate of equal proportions (+/-) - ⁇ -bisabolol and (+/-) - epi- ⁇ -bisabolol. All four enantiomers were found in nature.
  • meandered lines each independently represent an S or R configuration on the associated C atom.
  • Gutsche et al. in Tetrahedron 24, 8591 (1968) described the acid-catalyzed cyclization of farnesol and nerolidol. Starting from farnesol or nerolidol were Initially obtained by reacting with formic acid, the corresponding formates, which were then saponified in a second step to the alcohols.
  • JP 60120828 relates to the use of a nonpolar solvent having a dielectric constant of up to 3.0, especially hexane, in the context of the abovementioned reaction for improving the workup process and the yield.
  • WO 2004/03301 discloses a process for the preparation of ⁇ -bisabolol comprising the reaction of nerolidol with a mixture of a ketone, a sulfonic acid and perchloric acid. The process is limited to the starting material nerolidol and provides for the use of perchloric acid.
  • the object of the present invention was to provide a process for the single-stage preparation of ⁇ -bisabolol starting from the cheap and easily accessible on an industrial scale farnesol.
  • the process should be economically advantageous and procedurally simple manner feasible.
  • the object has been achieved in a surprising manner by providing a process for the preparation of ⁇ -bisabolol comprising the reaction of farnesol in the presence of a ketone, a sulfonic acid and another strong acid.
  • the present invention relates to processes for the preparation of ⁇ -bisabolol comprising, as an essential step, the reaction of farnesol in the presence of a mixture of a ketone, a sulfonic acid and another strong acid.
  • the reaction according to the invention of farnesol is carried out in a mixture of a ketone, a sulfonic acid and another strong acid.
  • the starting material for carrying out the process according to the invention is farnesol of the formula (IV)
  • bisabolol of the formula (III) is obtained in the form of racemic mixtures of ⁇ -bisabolol of the formula (IIIa)
  • the process according to the invention is characterized in that the reaction of farnesol is carried out in the presence of a ketone, a sulfonic acid and another strong acid.
  • ketones in the process according to the invention are those of the formula (I)
  • radicals R 1 and R 2 may be identical or different and represent a straight-chain or branched C 1 - to C 4 -alkyl radical such as, for example, methyl, ethyl, n- Propyl, n-butyl, iso-propyl, sec-butyl or tert-butyl or together are a cyclic alkylene radical having 3 to 5 carbon atoms.
  • Particularly preferred ketones according to the invention are: acetone, methyl ethyl ketone, diethyl ketone and cyclohexanone.
  • Preferred sulfonic acids according to the invention are those of the formula (II)
  • radical R 3 may be straight-chain or branched C 1 - to C 12 -alkyl, C 6 - to Cio-aryl, C 2 - to C 12 -alkylaryl or C 2 - to C 12 -arylalkyl, where the radicals mentioned are each one or more , usually from 1 to about 6, may have identical or different substituents which are selected from the group of the substituents fluorine, chlorine, -OR 4 and -C (O) OR 5 , where R 4 and R 5 are independently of one another Can mean hydrogen or C 1 to C 4 -AlkVl.
  • R 3 C 1 - to C 12 -alkyl as mentioned above for C 1 - to C 4 -alkyl and furthermore n-pentyl, n-hexyl, cyclohexyl, octyl, decyl, dodecyl, trifluoromethyl 1,1,1-trifluoroethyl, fluoromethyl and difluoromethyl .
  • C ⁇ to Cio-aryl such as phenyl or naphthyl
  • C 1 to C 12 alkylaryl such as para-tolyl, ortho-tolyl, para-tert-butylphenyl
  • C 7 - to C 12 -arylalkyl such as benzyl, phenylethyl.
  • sulfonic acids of the formula (II) may be mentioned: methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphtholsulphonic acid.
  • the molar ratio of ketone to the farnesol to be reacted can be varied within wide ranges, but is preferably in the range of 0.1: 1 to 30: 1. Molar ratios in the range of about 1: 1 to about 15: 1, more preferably about 5 to 1 to about 10 to 1 have proven particularly useful.
  • the molar ratio of sulfonic acid to be reacted Farnesol can be varied within a wide range. However, preferred are molar ratios in the range of 0.001 to 1 and 10 to 1, with particularly good results were achieved with molar ratios in the range of 0.01 to 1 to 0.5 to 1.
  • the reaction of farnesol according to the invention into bisabolol is carried out in addition to the said ketone and the sulfonic acid mentioned in the presence of at least one further strong acid, ie either in the presence of a strong acid or a mixture of different strong acids.
  • strong acid is preferably to be understood as meaning an acid which has a pKs value of up to about 2, preferably from about -3 to about 2 and more preferably from about -3 to about 0.
  • Particularly preferred strong acids according to the invention are: sulfuric acid, perchloric acid, tetrafluoroboric acid, trifluoromethanesulfonic acid trichloroacetic acid, trifluoroacetic acid, nitric acid, phosphoric acid, pyrophosphoric acid and hexafluorophosphoric acid, very particularly preferably tetrafluoroboric acid (HBF 4 ), perchloric acid and sulfuric acid and particularly preferably tetrafluoroboric acid and sulfuric acid.
  • HPF 4 tetrafluoroboric acid
  • the further strong acid to be used according to the invention is preferably used in amounts of from about 0.1 to about 100 mol%, more preferably from about 2 to about 40 mol%, and most preferably in an amount from about 10 to about 30 mol% on the amount of farnesol to be reacted.
  • the reaction according to the invention can be carried out in the presence of water, the amount of water present being tolerable within wide limits. In some cases, the presence of water has even proved to be advantageous, and the molar ratio between water and farnesol should be about 0.001 to 1 to about 10 to 1, preferably about 0.01 to 1 to about 1 to 1.
  • the inventive reaction is conveniently carried out at temperatures of about -10 0 C to about 50 ° C, preferably at about 10 ° C to about 30 ° C.
  • the reaction according to the invention is substantially complete after reaction times of about 2 hours to about 3 days, often after about 24 hours, depending on the chosen reaction conditions.
  • the workup of the product mixtures obtained according to the invention can be carried out by methods known to those skilled in the art.
  • the reaction mixture is first neutralized and then worked up by extraction. For further purification or separation of the components contained in the crude product, further purification processes, for example distillations, can be carried out.
  • reaction mechanism of the reaction according to the invention is currently unknown, but appears to differ from the reaction mechanism cited in WO 2004/03301, in which farnesol is formed as a by-product in the context of the conversion of nerolidol to bisabolol.
  • the process according to the invention advantageously leads directly from farnesol to the desired bisabolol of the formula (III) in one step, and thus represents a substantial improvement in comparison with the known multistage processes. Moreover, it allows me to proceed in a technically straightforward manner at unproblematic reaction temperatures or print.
  • the method according to the invention is also distinguished by the fact that it leads to a particularly pure bisabolol. It is possible by the inventive method to keep the content of unreacted farnesol in the product mixture below 2 wt .-%, which is a significant advantage in terms of further purification or recovery of the bisabolol obtained according to the invention.
  • the process according to the invention starting from farnesol, leads in one stage to a product mixture which contains ⁇ -bisabolol in a particularly high proportion and, in addition, only small amounts of unreacted farnesol. It thus represents a significant improvement to the known two-stage process for the preparation of ⁇ -bisabolol starting from farnesol. Distillative removal of the remaining amount of farnesol therefore does not take a long time, which ultimately leads to bisabolol when using the process according to the invention can be produced in good space / time yields, in high purity and with a sensorially advantageous quality.
  • the present invention also relates to the use of sulfonic acids as catalysts or reactants or reagents for the production of ⁇ -bisabolol starting from farnesol.
  • the resulting mixture was admixed with 300 ml of water, brought to pH 7 with sodium bicarbonate and extracted with 300 ml of ether. After distillative removal of the ether, 121 g of a product mixture were obtained, which was analyzed by gas chromatography and (in addition to unidentified by-products) had the following constituents (proportions in GC area%): bisabolene: 31, 6%, nerolidol: 4 %, Bisabolol: 37.5%, farnesol 1.2%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé pour produire de l'a-bisabolol qui consiste à mettre en réaction du farnésol en présence d'une cétone, d'un acide sulfonique et d'un autre acide fort.
EP06819156A 2005-11-07 2006-10-26 Procede pour produire de l'alpha-bisabolol a partir de farnesol Withdrawn EP1999094A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005053329A DE102005053329A1 (de) 2005-11-07 2005-11-07 Verfahren zur Herstellung von α-Bisabolol aus Farnesol
PCT/EP2006/067815 WO2007051757A1 (fr) 2005-11-07 2006-10-26 PROCEDE POUR PRODUIRE DE L'α-BISABOLOL A PARTIR DE FARNESOL

Publications (1)

Publication Number Publication Date
EP1999094A1 true EP1999094A1 (fr) 2008-12-10

Family

ID=37694090

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06819156A Withdrawn EP1999094A1 (fr) 2005-11-07 2006-10-26 Procede pour produire de l'alpha-bisabolol a partir de farnesol

Country Status (9)

Country Link
US (1) US7622617B2 (fr)
EP (1) EP1999094A1 (fr)
JP (1) JP2009514831A (fr)
CN (1) CN101300217A (fr)
BR (1) BRPI0618257A2 (fr)
CA (1) CA2626458A1 (fr)
DE (1) DE102005053329A1 (fr)
RU (1) RU2008122536A (fr)
WO (1) WO2007051757A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102144994B (zh) * 2010-02-04 2014-08-13 天士力制药集团股份有限公司 一种从降香中提取的化合物的抗血小板聚集作用
EP2657216B1 (fr) 2012-04-27 2014-06-25 Symrise AG Procédé de basculement du farnésol au nérolidol en présence d'alpha-bisabolol

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60120828A (ja) 1983-12-01 1985-06-28 Kuraray Co Ltd ビサボロ−ルの製造方法
KR20050031072A (ko) 2002-07-01 2005-04-01 컴팩션 테크놀로지 (소일) 리미티드 낙하 질량체에 의한 토양 다짐
DE10246038B3 (de) 2002-10-02 2004-04-15 Symrise Gmbh & Co. Kg Verfahren zur Herstellung von alpha-Bisabolol aus Nerolidol

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007051757A1 *

Also Published As

Publication number Publication date
BRPI0618257A2 (pt) 2016-11-16
CA2626458A1 (fr) 2007-05-10
RU2008122536A (ru) 2009-12-20
US20080269530A1 (en) 2008-10-30
WO2007051757A1 (fr) 2007-05-10
CN101300217A (zh) 2008-11-05
JP2009514831A (ja) 2009-04-09
US7622617B2 (en) 2009-11-24
DE102005053329A1 (de) 2007-05-10

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