Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
2002-03-29
2004-02-17
Lilling, Herbert J (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S195000, C435S198000, C435S280000, C549S356000
Reexamination Certificate
active
06692944
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the systhesis of optically enriched dextro- and laevo-rotatory isomers of rose oxide from racemic citronellol. The invention particularly relates to the preparation of optically enriched (−)-(2 S, 4 R)-rose oxide and its isomer (+)-(2 R, 4 S)-rose oxide from racemic citronellol.
BACKGROUND OF THE INVENTION
Natural rose oxide, a minor though essential olfactive, organoleptic constituent of Bulgarian rose and Geranium bourbon oils consists of mainly (−)-(2 S, 4 R)-2-(2-methyl-1-propenyl)-4-methyl tetrahydropyran. Natural rose oxide is a mixture of both cis- and trans-rose oxides wherein the cis-isomer is the major component. Rose oxides were first isolated from rose oil [Seidel and Stoll, Helv. Chem. Acta. 42, 1830, (1959)]. It was later found to be also an essential constituent of oil of Geranium bourbon [Seidel et al, Helv. Chem. Acta. 44, 598 (1961)].
Rose oxide is normally manufactured from citronellol which occurs in
Java citronella
oil.
Java citronella
is abundantly available raw material and its oil has significant industrial application in perfumery. Synthetically racemic citronellol is made from nerol/geraniol or citral by their hydrogenation. These monoterpenes are abundantly available from the natural sources. An elegant and economically feasible synthesis of racemic citronellol starts from dihydromyrcene (3,7-dimethyl-octa-1,6-diene) which can be obtained from the readily available &agr;-or &bgr;-pinenes via hydrogenation and subsequent pyrolysis.
Although there are numerous ways to synthesize rose oxides, most of the presently known routes involve acid-catalysed cyclisation of (E)-3,7-dimethyl-5-octen-1,7-diol produced in various ways from citronellol [Ohloff G and Lienhard, Helv. Chem. Acta. 48, 182 (1962)]. Ohloff prepared (E)-3,7-dimethyl-5-octen-1,7-diol by the photosensitized air oxidation of citronellol to give alkyl hydroperoxide which on reduction and subsequent cyclisation with an acid gave a mixture of cis- and trans-rose oxide. Eschinasi prepared [Eschinasi E. H., J. Org. Chem. 35, 1097 (1970)] rose oxide mixture by the acid-catalysed cyclisation of (E)-8-acetoxy-2,6-dimethyl-1,3-octadiene obtained from the pyrolysis of 2,6-dimethyl-2,3,8-triacetoxy octane.
In 1984, a total synthesis of cis-rich (2S, 4 R)-rose oxide was carried out by P. Audin, et.al using chiral catalysts which is more of an academic interest [Audin, P; Douthean, A; Gore, J; Bull. Soc. Chem. Fr. 1984, 7, D-297-II 306].
No prior art is available in the literature concerning the preparation of optically enriched dextro- and laevo-rotatory isomers of rose oxides from racemic citronellol using biocatalytic methods.
OBJECTS OF THE INVENTION
The main object of the present invention, therefore, is to provide a novel synthetic process for the preparation of optically enriched (−)-(2S, 4R) and (+)-(2 R, 4 S)-rose oxides making use of a biocatalyst or a micro organism during the intermediate stage of synthesis.
Another object of the present invention is to develop a novel, economical and environment friendly process for the preparation of optically enriched rose oxide using biocatalyst or an enzyme, from racemic citronellol which is an abundantly available raw material.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of optically enriched (−)-(2 S, 4 R)-rose oxide and its isomer (+)-(2 R, 4 S)-rose oxide from racemic citronellol, said process comprising cohalogenating racemic citronellol with a halogenation reagent in anhydrous alcohol to obtain an alkoxy halide, dehydrohalogenating the alkoxy halide to obtain the corresponding 3-octenol derivative, acylating the alcoholic function of the 3-octanol derivative with an acylating agent in presence of a base to give the corresponding acylate, subjecting the acylate so obtained to kinetic resolution using a biocatalyst or an enzyme, separating the mixture of reaction products comprising of optically enriched hydrolysed alcohol and unhydrolysed acylate derivatives, hydrolysing the optically enriched acylate with a base to furnish optically enriched primary alcohol and cyclised the alcohol so obtained with an acid catalyst to produce dextrorotatory (2R, 4S)-rose oxide, the optically enriched hydrolysed alcohol being directly cyclised with an acid catalyst to produce laevorotatory (2R, 4S)-rose oxide.
In on embodiment of the invention, the alkyl group in the alkoxy halide is selected from the group consisting of methyl, ethyl, n-propyl and n-butyl.
In another embodiment of the invention, the halide is selected from the group consisting of chloro-, bromo-, iodo-.
In another embodiment of the invention, the 3-octanol formed is 2-alkoxy-3-halo-2,6-dimethyl-8-octanol.
In another embodiment of the invention, dehydrohalogenation of the alkoxy halide is done using a strong base or an alkali to provide (E)-2-alkoxy-2,6-dimethyl-3-octen-8-ol.
In a further embodiment of the invention, (E)-2-alkoxy-2,6-dimethyl-3-octen-8-ol is acylated to obtain (E)-8-acyloxy-2-alkoxy-2,6-dimethyl-3-octene.
In another embodiment of the invention, cohalogenation of racemic citronellol is carried out using an N-halogenated succinimide selected from the group consisting of N-chlorosucccinimide, N-bromosuccinimide and N-iodosuccinimide.
In another embodiment of the invention, cohalogenation of the racemic citronellol is done using a halogen selected from bromine and iodine, or a halogenated salt selected from iodine mono chloride and potassium iodate.
In another embodiment of the invention, the cohalogenation of the racemic citronellol is carried out in a polar anhydrous alcoholic solvent selected from the group consisting of methanol, ethanol and propanol.
In a further embodiment of the invention, the cohalogenation of the racemic citronellol is effected at a temperature at 0-50° C., more preferably at 10-20° C.
In another embodiment of the invention, the base used dehydrohalogenation of the alkoxy halide is an inorganic base selected from the group comprising sodium hydroxide, potassium hydroxide and barium hydroxide.
In yet another embodiment of the invention, the base used for dehydrohalogenation of the alkoxy halide is an organic base selected from the group consisting of dimethyl amine, triethyl amine, 1,8-diazabicyclo [5,4,0] undec-7-ene and pyridine.
In yet another embodiment of the invention, the acylating agent is selected from an acid anhydride and an acylchloride.
In a further embodiment of the invention, the acid anhydride is selected from the group consisting of acetic anhydride, propanoic anhydride and butanoic anhydride.
In a further embodiment of the invention, the acylchloride is selected from acetyl chloride and propanoyl chloride.
In yet another embodiment of the invention, the acylation is carried out in the presence of an organic base selected from the group consisting of pyridine, 4-dimethyl amino pyridine and piperidine, preferably pyridine.
In yet another embodiment of the invention, the enzyme catalyst is selected from a hydolase and lipase selected from Pseudomonas sp lipase (PSL) and
Candide cylinderacae
lipase (CCL).
In another embodiment of the invention the acylation is carried out in an aqueous or phosphate buffer, with the pH of the aqueous medium being maintained at pH 5-9, more preferably at 7.
In another embodiment of the invention, the temperature of the enzymatic reaction is maintained at a range of 10-45° C., preferably at a range of 15-20° C.
In yet another embodiment of the invention, separation of optically enriched unhydrolysed acylate and hydrolysed primary alcohol is effected by column chromatography or fractional distillation.
In yet another embodiment of the invention, the deacetylation of the optically enriched acylate to produce optically enriched alcohol is carried out using an alcoholic or aqueous solution of a base selected from the group consisting of sodium carbonate, sodium hydroxide, potassium hydroxide and b
Andotra Samar Singh
Koul Surrinder
Qazi Ghulam Nabi
Sethi Vijay Kumar
Taneja Shubash Chandra
Lilling Herbert J
Sughrue & Mion, PLLC
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