WO2004033401A1 - Procede pour la production d'alpha-bisabolol a partir de nerolidol - Google Patents

Procede pour la production d'alpha-bisabolol a partir de nerolidol Download PDF

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Publication number
WO2004033401A1
WO2004033401A1 PCT/EP2003/010991 EP0310991W WO2004033401A1 WO 2004033401 A1 WO2004033401 A1 WO 2004033401A1 EP 0310991 W EP0310991 W EP 0310991W WO 2004033401 A1 WO2004033401 A1 WO 2004033401A1
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WO
WIPO (PCT)
Prior art keywords
bisabolol
alpha
nerolidol
butyl
propyl
Prior art date
Application number
PCT/EP2003/010991
Other languages
German (de)
English (en)
Inventor
Dietmar Schatkowski
Wilhelm Pickenhagen
Original Assignee
Symrise Gmbh & Co. Kg
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 Symrise Gmbh & Co. Kg filed Critical Symrise Gmbh & Co. Kg
Priority to EP03779800A priority Critical patent/EP1549596A1/fr
Priority to AU2003287957A priority patent/AU2003287957A1/en
Publication of WO2004033401A1 publication Critical patent/WO2004033401A1/fr

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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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/56—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by isomerisation
    • 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

  • Chamomile oil is the essential oil from the flower heads of real chamomile, Chamomilla recutita (L) Rauschert. It is listed as "Oleum chamomillae” in the supplement to the German Pharmacopoeia.
  • the real chamomile is one of the most common medicinal plants.
  • the composition of the chamomile oil depends on the provenance or the type of drug used. It is also influenced by the distillation conditions of steam distillation.
  • Chamomile oil itself contains a large number of mono- and sesquiterpenes, the therapeutically relevant sesquiterpenes quantitatively dominating.
  • the most important components of the essential oil are chamazulen, which gives it its deep blue color, (-) - alpha-bisabolol, bisabololoxide A, bisaboloxide B, Bisabolonoxide A, eis- and trans-spiroether and Famesen.
  • Chamomile flowers of different origins also show clear differences in their composition. While chamomile of the bisabolol type is limited in its natural occurrence to northeastern Spain, the
  • the rarer bisabolon oxide A type is known from Bulgaria and Turkey.
  • the (-) - alpha-bisabolol occupies a dominant position in the assessment of the therapeutic efficacy of chamomile extract preparations because its antiphlogistic effects are clearly superior to the (+) - alpha-bisabolol, the synthetic bisabolol racemate and the bisabolol oxides A and B. is.
  • alpha-bisabolol usually represents a diastereomeric racemate of equal proportions (+/-) - alpha-bisabolol and (+/-) - epi-alpha-bisabolol. All four enantiomers were found in nature.
  • (-) - (4S, 8R) -alpha-epi-bisabolol is a natural component of Citrus bergamia RISSO essential oil [(Ohloff, G .; Giersch, W .; Naf, R .; Delay, F .; Helv. Chim Acta 1986, 69, 698)] and its enantiomer (+) - (4R, 8S) -alpha-epi- bisabolol was isolated from various Abies and Picea Specien [O Donnel, GW; Sutherland, MD; Aust.J.Chem.
  • (+) - (4R, 8R) alpha-bisabolol part of Atalantia monophylla Corren oils [O 'Donnel, GW; Sutherland, MD Aust. J. Chem. 1989, 42, 2021 Babin.D .; Fourneron, JD; Julia, M .; Tetrahedron 1981, 37 (suppl.]
  • enantiomer (-) - (4S, 8S) -alpha-bisabolol is one of the main components of the German chamomile [Jellinek, JS; Parf. Cosm.Aromes 1984, 57, 55]
  • (-) - (4S, 8S) -aipha-Bisabolol is manufactured on a large industrial scale for numerous applications in the cosmetics and fragrance sector, for example for use in protective creams, lotions, deodorants etc., in particular because of its anti-inflammatory, bactereostatic and antimycocitic properties [CR; Fleischhauer, J .; Beyer, J .; Reinhard, E .; Planta Med. 1990, 56, 456].
  • serpentine lines each independently represent an S or R configuration on the associated C atom.
  • Gutsche reports on the acid-catalyzed cyclization of farnesol and nerolidol. Starting from farnesol or nerolidol, the corresponding formates were first obtained by reaction with formic acid, which were then saponified to give the alcohols in a second step.
  • K. Uneyama reports on an electrochemical display method [K.Uneyama, Y. Masatsugu, T.Ueda, S.Torii, Chem. Lett. , 1984, 529]; the production of DL bisabolol from DL nerolidol is also reported.
  • the essential step of the process according to the invention for the production of alpha-bisabolol comprises: reacting nerolidol with a mixture of a ketone, a sulfonic acid and perchloric acid.
  • sulfonic acid as a catalyst / reactant in the conversion of nerolidol to alpha-bisabolol is an essential aspect of the present invention.
  • alpha-bisabolol in this context includes (+) - alpha-bisabolol, (-) - alpha-bisabolol, (+) - epi-alpha-bisabolol and (-) - epi-alpha-bisabolol as well as mixtures of 'two, three or all of the isomers of alpha-bisabolol.
  • alpha-bisabolol encompasses racemic mixtures of (+/-) - alpha-bisabolol and / or (+/-) - epi-alpha-bisabolol.
  • nerolidol encompasses S-nerolidol, R-nerolidol and mixtures of S- and R-nerolidol, in particular racemic mixtures.
  • the sulfonic acid used in the process according to the invention preferably has the following formula C.
  • R2 alkyl, aryl or alkaryl, each branched or unbranched, substituted or unsubstituted.
  • R2 alkyl, aryl or alkaryl, each branched or unbranched, substituted or unsubstituted.
  • ketones for use in the process according to the invention are ketones of the formula B below
  • R Me, Et, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl
  • R1 Me, Et, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl
  • the molar ratio of ketone to nerolidol can be varied within a wide range, but is preferably in the range between 0.1: 1 and 30: 1. Molar ratios in the range between 1: 1 and 10: 1 have proven particularly useful.
  • the molar ratio of sulfonic acid to nerolidol can also be varied within a wide range. However, molar ratios between 0.001: 1 and 10: 1 are preferred, with particularly good results having molar ratios in the range between 0.01: 1 and 0.5: 1 being achieved.
  • the presence of water in the process according to the invention is tolerable within wide limits.
  • the presence of water has even proven to be advantageous, the molar ratio between water and nerolidol should be in the range between 0.001: 1 and 10: 1. Molar ratios in the range between 0.01: 1 and 1: 1 are preferred.
  • the cyclization to the bisabolyl skeleton can be interpreted via a concerted mechanism.
  • a hemiacetal is formed from the nerolidol and the ketone of the compound B under acid catalysis, which is then esterified with the acid of the formula C.
  • ester groups are good leaving groups [K.Peter; C.Vollhardt; N. E. Schore Organic. Chemistry 2nd edition p. 194 ISBN 3-527-29097-45], and apparently they favor a concerted cyclization to the 6-membered ring compared to an ionic intermediate which leads to the famesyl type (cf. "Farnesol reaction path", Fig. 2) ,
  • the process according to the invention advantageously leads in one step directly from nerolidol to the desired bisabolol of the formula A, so that a detour over several stages does not have to be carried out, as described for other processes. No special equipment is required to carry out the process.
  • the process according to the invention is also distinguished by the fact that it leads to a particularly pure bisabolol and in particular the (+), (-) or (+ /) which is produced as a by-product in the processes from the prior art in a yield of up to 40%. -) -Famesol, only in concentrations of less than 2 wt .-% arises.
  • Product mixtures which, in addition to the desired alpha-bisabolol, also comprise a significant proportion of farnesols, are subject to prolonged thermal stress during the subsequent distillative removal of the farnesols, which can lead to side reactions and in particular to the decomposition of the products formed.
  • the process according to the invention leads to a product mixture which contains a particularly high proportion of alpha-bisabolol and, in addition, only small amounts of farnesol.
  • the distillative removal of the farnesol therefore does not take a long time, which ultimately leads to bisabolol being used when the process according to the invention can be produced in good space / time yields, in high purity and with an optimal sensor quality.
  • the workup was carried out in such a way that 100 g of water and 100 diethyl ether were added to the reaction mixture and then the org. Phase was separated. The org. Phase was then with soda solution. and water washed neutral. After the solvent had been distilled off, 43 g of crude product remained. The subsequent distillation was carried out on a 1 m rotating column.

Abstract

L'invention concerne un procédé servant à produire de l'alpha-bisabolol et comprenant l'étape suivante : réaction de nérolidol avec un mélange constitué d'une cétone, d'un acide sulfonique et d'acide perchlorique.
PCT/EP2003/010991 2002-10-02 2003-10-02 Procede pour la production d'alpha-bisabolol a partir de nerolidol WO2004033401A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP03779800A EP1549596A1 (fr) 2002-10-02 2003-10-02 Procede pour la production d'alpha-bisabolol a partir de nerolidol
AU2003287957A AU2003287957A1 (en) 2002-10-02 2003-10-02 Method for the production of alpha-bisabolol from nerolidol

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10246038.8 2002-10-02
DE10246038A DE10246038B3 (de) 2002-10-02 2002-10-02 Verfahren zur Herstellung von alpha-Bisabolol aus Nerolidol

Publications (1)

Publication Number Publication Date
WO2004033401A1 true WO2004033401A1 (fr) 2004-04-22

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Application Number Title Priority Date Filing Date
PCT/EP2003/010991 WO2004033401A1 (fr) 2002-10-02 2003-10-02 Procede pour la production d'alpha-bisabolol a partir de nerolidol

Country Status (4)

Country Link
EP (1) EP1549596A1 (fr)
AU (1) AU2003287957A1 (fr)
DE (1) DE10246038B3 (fr)
WO (1) WO2004033401A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007051757A1 (fr) * 2005-11-07 2007-05-10 Basf Se PROCEDE POUR PRODUIRE DE L'α-BISABOLOL A PARTIR DE FARNESOL
WO2007051758A1 (fr) * 2005-11-07 2007-05-10 Basf Se PROCEDE POUR PRODUIRE DE L'α-BISABOLOL A PARTIR DE FARNESOL OU DE NEROLIDOL
EP2657216A1 (fr) 2012-04-27 2013-10-30 Symrise AG Procédé de basculement du farnésol au nérolidol en présence d'alpha-bisabolol

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102005026768B4 (de) * 2005-06-10 2007-05-03 Symrise Gmbh & Co. Kg Verfahren zum Entfernen von Farnesol aus Mischungen mit alpha-Bisabolol
WO2007082847A1 (fr) * 2006-01-16 2007-07-26 Basf Se Procédé de production de bisabolol exempt de farnesol ou pauvre en farnesol

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0007076A1 (fr) * 1978-07-14 1980-01-23 BASF Aktiengesellschaft Dihydrobisabolènes et dihydrobisabolol, leur préparation et utilisation comme agents odoriférants

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0007076A1 (fr) * 1978-07-14 1980-01-23 BASF Aktiengesellschaft Dihydrobisabolènes et dihydrobisabolol, leur préparation et utilisation comme agents odoriférants

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KENJI UNEYAMA ET AL.: "An electrochemical method specifically directed to the preparation of DL-Bisabolol from DL-Nerolidol", CHEMISTRY LETTERS, 1984, pages 529 - 530, XP009027259 *
L.RUZICKA AND E.CAPATO: "Höhere Terpenverbindungen", HELVETICA CHIMICA ACTA, vol. 8, 1925, pages 259 - 274, XP009026973 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007051757A1 (fr) * 2005-11-07 2007-05-10 Basf Se PROCEDE POUR PRODUIRE DE L'α-BISABOLOL A PARTIR DE FARNESOL
WO2007051758A1 (fr) * 2005-11-07 2007-05-10 Basf Se PROCEDE POUR PRODUIRE DE L'α-BISABOLOL A PARTIR DE FARNESOL OU DE NEROLIDOL
US7622617B2 (en) 2005-11-07 2009-11-24 Basf Se Method for producing α-bisabolol from farnesol
EP2657216A1 (fr) 2012-04-27 2013-10-30 Symrise AG Procédé de basculement du farnésol au nérolidol en présence d'alpha-bisabolol
US9199900B2 (en) 2012-04-27 2015-12-01 Symrise Ag Method for converting farnesol to nerolidol in the presence of alpha-bisabolol

Also Published As

Publication number Publication date
DE10246038B3 (de) 2004-04-15
EP1549596A1 (fr) 2005-07-06
AU2003287957A1 (en) 2004-05-04

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