WO2006070383A1 - Procede de synthese de l'oxyde de nerol - Google Patents

Procede de synthese de l'oxyde de nerol Download PDF

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Publication number
WO2006070383A1
WO2006070383A1 PCT/IN2004/000415 IN2004000415W WO2006070383A1 WO 2006070383 A1 WO2006070383 A1 WO 2006070383A1 IN 2004000415 W IN2004000415 W IN 2004000415W WO 2006070383 A1 WO2006070383 A1 WO 2006070383A1
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WO
WIPO (PCT)
Prior art keywords
formula
nerol
solvent
group
dehydrohalogenation
Prior art date
Application number
PCT/IN2004/000415
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English (en)
Inventor
Vijay Kumar Sethi
Samar Singh Andotra
Subhash Chandra Taneja
Pankaj Gupta
Ghulam Nabi Qazi
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Council Of Scientific And Industrial Research
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.)
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Application filed by Council Of Scientific And Industrial Research filed Critical Council Of Scientific And Industrial Research
Priority to PCT/IN2004/000415 priority Critical patent/WO2006070383A1/fr
Publication of WO2006070383A1 publication Critical patent/WO2006070383A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/18—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member containing only hydrogen and carbon atoms in addition to the ring hetero atom

Definitions

  • the present invention relates to a process for the synthesis of racemic nerol oxide i.e.3,6-dihydro-4-methyl-2-[2-methyl-l-propenyl)-2H-pyran from monoterpene alcohol nerol i.e.cw-3,7-dimethylocta-2,6-diene-l-ol.
  • the present invention particularly relates to a process for the preparation of racemic nerol oxide of formula 1 from nerol of formula 2 comprising addition of a halogenating agent to monoterpene nerol of formula 2 in an anhydrous alcoholic solvent to produce 7-alkoxy-3,7-dimethyl-6-halo-2-octenol of formula 3
  • R represents the alkyl group such as methyl, ethyl, n-propyl and n-butyl and the like
  • X represents a halogen such as chloro, bromo-, iodo, thereafter dehydrohalogenation of the compound of formula 3 with a strong base or an alkali furnishing 7-alkoxy-3,7-dimethyl-octa-2,5-dien-l-ol derivative of formula 4 and finally converting the octadienol of formula 4 to produce racemic nerol oxide of formula 1 using dilute mineral acid, Lewis acid or an acidic resin.
  • Nerol oxide is a valuable base material in perfumery and occur naturally as an ingredient of Bulgarian rose oil (0.038%) and grape juice. It exists naturally as a racemic mixture of (R and S) isomers of 3,6-dihydro-4-methyl-2-(2-methyl-l-propenyl)-2H pyran.
  • the olfactory properties of racemic nerol oxide are comparable to those of diastereoisomeric rose oxides as regards totality and strength and is dominated by a powerful greenish-spicy note of the geranium type corresponding to the odour of (-)-c/s-rose oxide.
  • Nerol and geraniol are the monoterpenic constituents of Cymbopogon spp.
  • nerol was first subjected to epoxidation at C 6 -C 7 double bond and the epoxy derivative so obtained was heated in dimethyl amine at 150° to give 3,7- dimethyl-6-dimethyl amino-2-octen-l,7-diol which on oxidation with hydrogen peroxide and pyrolysis at 18O 0 C gave a diol intermediate that on acid catalysed cyclisation led to the formation of nerol oxide [G. Ohloff & B. Lienhard HeIv. Chim. Acta. 48, 182, 1965].
  • Another objective of the invention is to develop a process from commercially available monoterpene alcohol nerol utilizing the cheap and recoverable reagents in the process that may be capable of facile up scaling.
  • the present invention provides a process for the preparation of racemic nerol oxide of formula 1 from monoterpene nerol of formula 2, the process comprising:
  • R is selected from the group consisting of methyl, ethyl, n-propyl and n-butyl.
  • X is selected from the group consisting of chloro, bromo- and iodo.
  • the dehydrohalogenation of compound of formula 3 is carried out with a strong base or an alkali.
  • the compound of formula 4 is converted into racemic nerol of formula 1 using dilute mineral acid, lewis acid or an acidic resin.
  • the halogenating agent is selected from the group consisting of N-halogenated compounds selected in turn from the group consisting of
  • DDH dimethylhydantoin
  • the solvent used in haloalkoxylation reaction is an alcoholic solvent selected from the group consisting of methanol, ethanol and propanol, or water or any mixture thereof.
  • the haloalkoxylation reaction is effected at a temperature in the range of 0-50 0 C.
  • the base used for dehydrohalogenation is an inorganic base selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide and barium hydroxide.
  • the base used for dehydrohalogenation is an organic base selected from the group consisting of diethyl amine, triethyl amine, 1,8-diaza [5,4,0] undec-7-en (DBU), pyridine and collidine.
  • organic base selected from the group consisting of diethyl amine, triethyl amine, 1,8-diaza [5,4,0] undec-7-en (DBU), pyridine and collidine.
  • dehydrohalogenation in step (ii) is carried out in the presence of a solvent selected from non-polar and polar solvents.
  • the solvent is selected from the group consisting of hexane, toluene, dioxane, dimethoxy ethane, methanol, ethanol, dimethyl formamide, water and any mixture thereof.
  • dehydrohalogenation is effected at ambient to reflux temperature of the solvent used.
  • cyclisation of the intermediate octadienol of formula 4 to produce racemic nerol oxide is effected in the presence of an organic solvent, an aqueous solvent or an aqueous alcoholic solvent.
  • the hydrohalogenation is effected at a temperature in the range of 0-20 0 C.
  • the mineral acid is dilute sulphuric acid.
  • step (iii) is carried out at a temperature in the range of 0-50 0 C preferably 0-15 0 C.
  • the present invention provides a novel process for the preparation of racemic nerol oxide of formula (1) above from a monoterpene nerol of formula (2) above.
  • the process comprises addition of halogenating reagent in presence of an alcohol to the monoterpene nerol of formula 2 to produce 7-alkoxy-3,7-dimethy-6-halo-2-octenol of formula 3 where R represents an alkyl group and X represents a halogen.
  • the halogenated product is subsequently dehydrohalogenated using a strong base or an alkali to give 7-alkoxy-3,7- dimethyl-octa-2,5-dien-l-ol of formula 4.
  • the compound of the formula 4 is easily cyclised when stirred with an acid or an acidic resin or Lewis acid to produce racemic nerol oxide of formula 1.
  • the halo alkoxylation reaction of monoterpenic alcohol nerol of the formula 2 is preferably effected by N- halogenated succinimide selected from N-chlorosuccinimide, N- bromosuccinimide, N-iodosuccinimide or N, N-dihalogenated dimethyl hydantoin such as l,3-dibromo-5,5-dimethyl hydantoin (DDH) or a halogen or halogenated salts such as bromine, iodine, iodine monochloride, potassium iodate and the like but more preferably 1,3- dibromo-5,5-dimethyl hydantoin (DDH) in a polar anhydrous alcoholic solvent such as methanol, ethanol, propanol and
  • the cohalogenation is effected at a temperature at 0-50 0 C, more preferably at 0-20 0 C.
  • the base used for dehydrohalogenation of the halogenated product of formula 3 is preferably selected from inorganic bases such as sodium hydroxide, potassium hydroxide or barium hydroxide, sodium carbonate and the like or it may be selected from the organic bases such as diethyl amine, triethyl amine, 1,8-diazabicyclo [5,4,0]-undec-7-en (DBU), pyridine, collidine and the like but more preferably an inorganic base to produce 7-alkoxy-3,7-dimethyl-octa-2,5-dien-l- ol of formula 4.
  • inorganic bases such as sodium hydroxide, potassium hydroxide or barium hydroxide, sodium carbonate and the like or it may be selected from the organic bases such as diethyl amine, triethyl amine, 1,8-diazabicy
  • Dehydrohalogenation reaction is effected in a polar or medium polar solvents such as water, ethanol, methanol, dioxane, dimethoxy ethane and the like or the mixture thereof at ambient to reflux temperature of the solvent.
  • Cyclisation of compound of formula 4 is effected using acidic reagents such as an acidic resin or dilute mineral acid and the like or a Lewis acid, more preferably a dilute mineral acid such as sulphuric acid in an organic solvent or aqueous or aqueous alcoholic solution at a temperature 0-50 0 C preferably 0-15 0 C.
  • nerol 0.0g, 0.324 mol, 95% purity
  • anhydrous methanol 150 mL
  • a thermometer a dropping funnel
  • a nitrogen inlet a nitrogen inlet
  • 1,3- Dibromo-5,5-dimethylhydantoin (DDH) 50.0 g, 0.174 mol
  • DDH 1,3- Dibromo-5,5-dimethylhydantoin
  • the temperature during the addition of DDH is maintained between 10-15 0 C.
  • the reaction mixture is further stirred for one hr.
  • the mixture is poured in cold water in a separating funnel and extracted with ethyl acetate (3 x 50 mL).
  • chloroform layer is dried over anhydrous sodium sulphate and concentrated under reduced pressure to produce a pale yellow oily substance which is identified as 3,7-dimethyl-7-methoxy-octa-2,5-dien-l-ol of formula 4 (43.69 g, 89.56%) from its spectral data.
  • N-bromosuccinimide (60.0 g, 0.337 mol) dissolved in anhydrous ethanol (150 mL) is placed in a flask fitted with a thermometer, a dropping funnel and a nitrogen inlet.
  • Commercial nerol (50.0g, 0.324 mol, 95% purirty) is taken in the dropping funnel and added slowly with vigorous stirring at a temperature of 5-20 0 C in nitrogen atmosphere . The temperature during the addition of nerol is maintained between 10-20 0 C.
  • the reaction mixture is poured in cold water in a separating funnel and extracted with n-hexane (3 x 100 mL).
  • the process is high yielding and yield in each step is between 80-90%.
  • the reagents used are commercially available, cheap and after recovery may be reutilized after reconversion to the corresponding halo derivatives. 5.
  • the process can be easily up scaled for commercial production.

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

Abstract

La présente invention décrit un procédé de synthèse de l'oxyde de nérol racémique, c'est-à-dire du 3,6-dihydro-4-méthyl-2-[2-méthyl-1-propényl)-2H-pyrane, à partir du nérol, c'est-à-dire du cis-3,7-diméthylocta-2,6-diène-1-ol, un alcool monoterpénique.
PCT/IN2004/000415 2004-12-27 2004-12-27 Procede de synthese de l'oxyde de nerol WO2006070383A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2004/000415 WO2006070383A1 (fr) 2004-12-27 2004-12-27 Procede de synthese de l'oxyde de nerol

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2004/000415 WO2006070383A1 (fr) 2004-12-27 2004-12-27 Procede de synthese de l'oxyde de nerol

Publications (1)

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WO2006070383A1 true WO2006070383A1 (fr) 2006-07-06

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PCT/IN2004/000415 WO2006070383A1 (fr) 2004-12-27 2004-12-27 Procede de synthese de l'oxyde de nerol

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5555126A (en) * 1978-10-20 1980-04-22 T Hasegawa Co Ltd Preparation of nerol oxide, its novel intermediate, and its utilization
US4312717A (en) * 1979-06-19 1982-01-26 Sumitomo Chemical Company, Limited Process for producing 2-(2'-methyl-1'-propenyl)-4-methyltetrahydropyran
EP0761628A1 (fr) * 1995-08-29 1997-03-12 Takasago International Corporation Procédé pour la préparation de 3,7-diméthyle-5,7-octadién-1-ol ou d'oxyde de rose
US5892059A (en) * 1996-11-08 1999-04-06 Dragoco Gerberding & Co. Aktiengesellschaft Process for producing a rose oxide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5555126A (en) * 1978-10-20 1980-04-22 T Hasegawa Co Ltd Preparation of nerol oxide, its novel intermediate, and its utilization
US4312717A (en) * 1979-06-19 1982-01-26 Sumitomo Chemical Company, Limited Process for producing 2-(2'-methyl-1'-propenyl)-4-methyltetrahydropyran
EP0761628A1 (fr) * 1995-08-29 1997-03-12 Takasago International Corporation Procédé pour la préparation de 3,7-diméthyle-5,7-octadién-1-ol ou d'oxyde de rose
US5892059A (en) * 1996-11-08 1999-04-06 Dragoco Gerberding & Co. Aktiengesellschaft Process for producing a rose oxide

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
ESCHINASI E H: "A NEW SYNTHESIS OF ROSOXIDES CIS- AND TRANS-2-(2-METHYL-1-PROPEN-1-YL)-4-METHYLTETRAHYDROPYRAN", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 35, no. 4, 1 April 1970 (1970-04-01), pages 1097 - 1100, XP000608609, ISSN: 0022-3263 *
G. BERGSTRÖM AND AL: "Species-specific, two-component, volatile signals in two sympatric ant-lion species: syclysis baetica and acanthalisis occitanica", JOURNAL OF CHEMICAL ECOLOGY, vol. 18, no. 7, 1992, pages 1177 - 1188, XP009053354 *
M. WÜST AND AL: "Structure elucidation, enantioselective analysis, and biogenesis of nerol oxide in pelargonium species", J. AGRIC. FOOD CHEM., vol. 47, 1999, pages 3145 - 3150, XP002344503 *
OHLOFF G: "ODOROUS PROPERTIES OF ENANTIOMERIC COMPOUNDS", OLFACTION AND TASTE, vol. 4, 1972, pages 156 - 160, XP000609977 *
PATEL J S ET AL: "SYNTHETIC STUDIES ON ROSEOXIDE", INDIAN JOURNAL OF CHEMISTRY, SECTION B: ORGANIC, INCL. MEDICINAL, PUBLICATIONS & INFORMATIONS DIRECTORATE, NEW DELHI, IN, vol. 16B, no. 3, March 1978 (1978-03-01), pages 188 - 190, XP002053576, ISSN: 0019-5103 *
PATENT ABSTRACTS OF JAPAN vol. 004, no. 093 (C - 017) 5 July 1980 (1980-07-05) *
S.C. TANEJA AND AL: "N-iodosuccinimide for the synthesis of rose oxide", J. ORG. CHEM., vol. 43, no. 5, 1978, pages 997 - 998, XP002344504 *
T. KITAHARA AND AL: "Structure and the synthesis of novel constituents of yudzu peel oil and their conversion to related monoterpenes", AGRICUL. BIOL. CHEM., vol. 44, no. 4, 1980, pages 897 - 901, XP009053452 *
YAMAMOTO T ET AL: "Synthesis and odor of optically active rose oxide", TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 43, no. 50, 9 December 2002 (2002-12-09), pages 9077 - 9080, XP004391905, ISSN: 0040-4039 *

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