WO2002014253A1 - Cyclohexyl ethers as fragrance compounds - Google Patents

Cyclohexyl ethers as fragrance compounds Download PDF

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Publication number
WO2002014253A1
WO2002014253A1 PCT/GB2001/003616 GB0103616W WO0214253A1 WO 2002014253 A1 WO2002014253 A1 WO 2002014253A1 GB 0103616 W GB0103616 W GB 0103616W WO 0214253 A1 WO0214253 A1 WO 0214253A1
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Prior art keywords
methylpropyl
methyl
methoxy
ether
methylcyclohexanol
Prior art date
Application number
PCT/GB2001/003616
Other languages
French (fr)
Inventor
Simon Ellwood
Jan Thomas Haines
Christopher Paul Newman
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Quest International B.V.
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Publication date
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Publication of WO2002014253A1 publication Critical patent/WO2002014253A1/en

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Classifications

    • CCHEMISTRY; METALLURGY
    • C11ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11BPRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B9/00Essential oils; Perfumes
    • C11B9/0026Essential oils; Perfumes compounds containing an alicyclic ring not condensed with another ring
    • C11B9/0034Essential oils; Perfumes compounds containing an alicyclic ring not condensed with another ring the ring containing six carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C07C1/20Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/09Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
    • C07C29/10Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/02Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic
    • C07C35/08Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a six-membered rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00Ethers; Compounds having groups, groups or groups
    • C07C43/02Ethers
    • C07C43/18Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C43/184Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring to a carbon atom of a non-condensed ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07Optical isomers
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/12Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14The ring being saturated

Definitions

  • This invention concerns novel fragrance compounds, their method of production, and their use in perfumes and perfumed products and as intermediates in production of other materials, particularly other fragrance compounds.
  • the invention provides an ether having the structure
  • the ether of the invention occurs in a number of different isomeric forms and the invention includes within its scope each individual isomer and also mixtures of two or more of the isomers.
  • the ethers of the invention individually and collectively, exhibit interesting fragrance properties or odour characteristics, generally herbal, floral or buttery in nature, and so may be used as such to impart, strengthen or improve the odour of a wide variety of products, or it may be used as a component of a perfume (or fragrance composition) to contribute its odour character to the overall odour of such perfume.
  • a perfume is intended to mean a mixture of fragrance materials, if desired mixed with or dissolved in a suitable solvent or mixed with a solid substrate, which is used to impart a desired odour to the skin and/or any product for which an agreeable odour is indispensable or desirable.
  • Such products are: fabric washing powders, washing liquids, washing tablets, fabric softeners and other fabric care products; detergents and household cleaning, scouring and disinfection products; air fresheners, room sprays and pomanders; soaps, bath and shower gels, shampoos, hair conditioners and other personal cleansing products; cosmetics such as creams, ointments, toilet waters, preshave, aftershave, skin and other lotions, talcum powders, body deodorants and antiperspirants, etc.
  • fragrance materials which can be advantageously combined with an ether according to the invention in a perfume are, for example, natural products such as extracts, essential oils, absolutes, resinoids, resins, concretes etc., but also synthetic materials such as hydrocarbons, alcohols, aldehydes, ketones, ethers, acids, esters, acetals, ketals, nitriles, etc., including saturated and unsaturated compounds, aliphatic, carbocyclic and heterocyclic compounds.
  • fragrance materials are mentioned, for example, in S. Arctander, Perfume and Flavor Chemicals (Montclair, N.J., 1969), in S. Arctander, Perfume and Flavor Materials of Natural Origin (Elizabeth, N.J., 1960) and in "Flavor and Fragrance Materials - 1991", Allured Publishing Co. Wheaton, 111. USA.
  • fragrance materials which can be used in combination with an ether according to the invention are: geraniol, geranyl acetate, linalol, linalyl acetate, tetrahydrolinalol, citronellol, citronellyl acetate, dihydromyrcenol, dihydromyrcenyl acetate, tetrahydro- myrcenol, terpineol, te ⁇ inyl acetate, nopol, nopyl acetate, 2-phenylethanol, 2-phenylethyl acetate, benzyl alcohol, benzyl acetate, benzyl salicylate, styrallyl acetate, benzyl benzoate, amyl salicylate, dimethylbenzylcarbinol, trichloromethylphenylcarbinyl acetate, p-tert-butyl- cyclohexyl acetate, isononon
  • Solvents which can be used for perfumes which contain an ether according to the invention are, for example: ethanol, isopropanol, diethyleneglycol monoethyl ether, dipropylene glycol, diethyl phthalate, triethyl citrate, isopropyl myristate, etc.
  • an ether according to the invention can be used in perfumes or in products to be perfumed may vary within wide limits and depend, inter alia, on the nature of the product, on the nature and the quantity of the other components of the perfume in which the ether is used and on the olfactive effect desired. It is therefore only possible to specify wide limits, which, however, provide sufficient information for the specialist in the art to be able to use the ether according to the invention for his specific purpose.
  • an amount of 0.01% by weight or more of the ether according to the invention will generally have a perceptible olfactive effect.
  • the amount of the ether according to the invention in a perfume is from 0.01% to 25% by weight, preferably from 1% to 5% by weight.
  • the amount of the ether according to the invention present in products will generally be from 1 to 10,000 ppm by weight, preferably from 10 to 1000 ppm, depending on the product to be perfumed.
  • the invention thus provides a perfume comprising an ether of the invention in an olfactively effective amount.
  • the invention also covers a perfumed product comprising an ether of the invention.
  • the ethers of the invention are also useful as intermediates in the preparation of other compounds, particularly other fragrance compounds.
  • the ethers find particular application in the production of 3-(2-methylpropyl)-l-methylcyclohexanol (also known as l-methyl-3- (2-methylpropyl)cyclohexan-l-ol) (as described in WO 98/47842), which is a very useful fragrance material, e.g. by a two stage process comprising as the first stage an elimination reaction performed on one or more of the ethers preferably together with one or more 4-(2- methylpropyl)-2-methyl-cyclohexanols (known alcohols as disclosed in WO 99/55811), e.g.
  • the invention also includes within its scope reaction products (direct or indirect) made from an ether of the invention, particularly 3-(2-methylpropyl)-l-methylcyclohexanol (1-methyl- 3-(2-methylpropyl)cyclohexan-l-ol).
  • the invention includes within its scope a method of making an alkene comprising performing an elimination reaction on an ether of the invention to produce one or more alkenes, and preferably hydrating said one or more alkenes to produce one or more cycloalkanols typically having the following structure:
  • Ri represents a methyl or ethyl group
  • R 2 represents hydrogen
  • R 3 represents an ethyl, propyl, butyl, isobutyl or isoamyl group
  • Rj represents hydrogen and R .
  • R . represents hydrogen, or a methyl, ethyl, propyl, isobutyl or isoamyl group.
  • the cycloalkanol is 3-(2-methylpropyl)- 1 -methylcyclohexanol.
  • the invention also includes within its scope a cycloalkanol, preferably 3-(2- methylpropyl)-l -methylcyclohexanol, produced by the above described method.
  • the ethers of the invention may be prepared by catalytic hydrogenation in typically a one pot conversion of l-(4-methoxy-3-methylphenyl)-2-methyl-l-propanone to give 4-(2- methylpropyl)-l-methoxy-2-methylbenzene and then a mixture of the ethers together with 4- (2-methylpropyl)-2-methyl-cyclohexanols. If required, the ethers may be separated from the alcohol product using known techniques such as fractional distillation.
  • the ethers may alternatively be made by other routes, such as catalytic hydrogenation of 1- (4-methoxy-3-methylphenyl)-2-methyl-l-propanone to give 4-(2-methylpropyl)-l-methoxy- 2-methylbenzene which is separated from the reaction mixture and purified before a further catalytic hydrogenation reaction is carried out to give 4-(2-methylpropyl)-l-methoxy-2- methylcyclohexane, together with a small amount of 4-(2-methylpropyl)-2-methyl- cyclohexanol.
  • the alcohol product may be removed from the ethers by the addition of boric acid to this hydrogenation reaction mixture, prior to purification of the ethers using known distillation techniques.
  • the resulting isomeric mixture may be used as such, either as a fragrance material or as an intermediate in preparation of other compounds.
  • the isomers may be separated, eg using known separation techniques such as chromatographic or distillation techniques. Isomers (other than enantiomers) may also be separated by derivatisation and crystallisation.
  • Example 1 on a manufacturing plant scale, describes a 2 stage process for production of a mixture of ethers in accordance with the invention, mixed with 4-(2-methylpropyl)-2- methyl-cyclohexanols, followed by a two stage conversion to 3-(2-methylpropyl)-l- methylcyclohexanol.
  • Example 2 describes an alternative route for production of the ethers of the invention on a laboratory scale.
  • the crude material (381.4 kg, 1.86 kmol) was purified by distillation under reduced pressure through a 5 theoretical plate packed column.
  • the product, l-(4-methoxy-3- methylphenyl)-2-methyl-l-propanone (345.5 kg, purity 97.7% rpa, 1.76 kmol) was collected at 137-140°C at 8mBar and crystallised on standing with a melting point of 22 °C.
  • the overall yield of distilled product was 84.1 % based on l-methoxy-2- methylbenzene.
  • the stirring mixture was placed under a hydrogen atmosphere of 20 bar and taken to a temperature of 100°C over a period of 1 hr, maintaining the pressure of 20 bar gauge with the addition of more hydrogen gas. This temperature and pressure was maintained for a further hour until hydrogen addition effectively ceased ( ⁇ 15 g/hr).
  • the pressure was raised to 48 bar gauge before heating to 140°C-150°C. This temperature and pressure was maintained for about 6-10 hours (with the reaction time depending on the quality of both the catalyst and feedstock) until hydrogen addition effectively ceased. After cooling to room temperature the pressure was released and, after nitrogen purging, the mixture was filtered to remove the hydrogenation catalyst.
  • the aqueous layer was separated from the crude product (55.4 kg).
  • Detailed GLC analysis of the crude product showed an isomeric mixture of 4-(2- methylpropyl)- 1 -methoxy-2-methylcyclohexanes and 4-(2-methylpropyl)-2- methylcyclohexanols constituting 93.3 % ⁇ a of the product.
  • these desired products totalled 0.29 kmol, which corresponded to a 92.8% theoretical yield based on l-(4-methoxy-3-methylphenyl)-2-methyl-l-propanone.
  • the cyclohexane/ water/methanol azeotrope was removed in the Dean & Stark, with the upper cyclohexane layer being returned to the flask.
  • the quantity of cyclohexane was adjusted to maintain the flask temperature at 150°C-155°C. These conditions were maintained for 8 hours.
  • the crude product (80.4 kg) from two such reactions, containing 64.5 % ⁇ a pure by GC (0.34 kmol) of the desired alkenes was purified by careful fractional distillation under reduced pressure through a 30 theoretical plate packed column at a 20:1 reflux ratio.
  • the mixture of 3-(2-methylpropyl)-l-methyl-l-cyclohexene and 5-(2-methylpropyl)-l-methyl-l- cyclohexene was collected in the range 88-93 °C/32-40mBar.
  • the purified product (61 kg) contained 81.5 % rpa of the desired alkenes corresponding to a distillation yield of 96 %.
  • the product is a liquid at normal temperatures.
  • the stirred mixture was cooled to -5°C and sulphuric acid, 76% w/w (20.4 kg, 0.158 kmol) was added slowly over 5 hours, maintaining the temperature in the range -6°C to -3°C.
  • the stirred mixture was held at this temperature range for a further hour after the acid addition.
  • the mixture was slowly added to water (80.0 kg, 4.4 kmol) in a well-stirred quench vessel maintaining the temperature below 25 °C, before separating the lower aqueous phase.
  • the organic layer was washed with water (11.0 kg) while still maintaining the temperature below 25 °C.
  • the residual acid catalyst was neutralised by washing the reaction mixture with 5% sodium hydroxide solution (10.0 kg), maintaining a temperature below 30°C.
  • the crude product (30.8 kg, 0.095 kmol) was purified by fractional distillation under reduced pressure through a packed column of about 15 theoretical plates.
  • the product (3- (2-methylpro ⁇ yl)-l-methylcyclohexanol (15.28 kg, 98.7 % by GC ⁇ a, 0.089 kmol) was collected at 98-100°C, 15 mBar. This gave an overall yield of 55.1 %w/w of Perfumery Quality material based on 3-(2-methylpropyl)-l-methyl-l-cyclohexene/5-(2-methylpropyl)- 1 -methyl- 1-cyclohexene.
  • the product, 3-(2-methylpropyl)-l-methylcyclohexanol was a mixture of approximately 35-45% cis, and about 55-65% trans isomers.
  • the product may solidify on standing with a melting point of 20-25°C.
  • l-(4-methoxy-3-methylphenyl)-2-methyl-l-propanone 50.0g, 0.255mol was charged to a high pressure 100ml reactor fitted with a stirrer and hydrogen supply.
  • Distilled water (lO.Og, 0.556mol), lactic acid co-catalyst, 85% aq. solution (2.0g, 18.9mmol) and hydrogenation catalyst ([5% palladium supported on carbon wet (40% w/w)]; l.Og) were then charged to the reactor.
  • the stirring mixture was placed under a hydrogen atmosphere of 20 bar and taken to a temperature of 100°C, maintaining the pressure of 20 bar gauge with the addition of more hydrogen gas.
  • the crude intermediate (4-(2-methylpropyl)-l-methoxy-2-methylbenzene) was separated from light heads and residues by simple distillation up a short, packed column.
  • the pure material i.e. (4-(2-methylpropyl)-l-methoxy-2-methylbenzene), lO.Og, 0.05 mol
  • Fresh hydrogenation catalyst [essentially dry 5% rhodium supported on carbon]; 0.2g)
  • the stirring mixture was placed under a hydrogen atmosphere of 50 bar and taken to a temperature of 50°C, maintaining the pressure of 50 bar gauge with the addition of more hydrogen gas. This temperature and pressure were maintained until no more hydrogen addition was observed.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
  • Wood Science & Technology (AREA)
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Abstract

The novel isomeric ethers having the structure (I) exhibit interesting odour characteristics, generally herbal, floral or buttery nature, and so find use in perfumes and in perfumed products. The ethers are also useful as intermediates in the preparation of other compounds, particularly other fragrance compounds, such as 1-methyl-3-(2-methylpropyl)cyclohexan-1-ol.

Description

CYCLOHEXYL ETHERS AS FRAGRANCE COMPOUNDS
Field of the Invention
This invention concerns novel fragrance compounds, their method of production, and their use in perfumes and perfumed products and as intermediates in production of other materials, particularly other fragrance compounds.
Summary of the Invention
In one aspect the invention provides an ether having the structure
Figure imgf000002_0001
For brevity and simplicity, such materials are referred to herein as the "ether" or "ethers", the "novel ether" or "novel ethers" or the "ether of the invention" or "ethers of the invention".
The ether of the invention occurs in a number of different isomeric forms and the invention includes within its scope each individual isomer and also mixtures of two or more of the isomers.
The different isomers are as follows:
Figure imgf000003_0001
(la) (1S,2R,4R) 4-(2-methylpropyl)-l- (lb) (1R,2S,4S) 4-(2-methylpropyl)-l- methoxy-2-methylcyclohexane methoxy-2-methylcyclohexane
Figure imgf000003_0002
(2a) (1S,2S,4R) 4-(2-methylpropyl)-l- (2b) (1R,2R,4S) 4-(2-methylpropyl)-l- methoxy-2-methylcyclohexane methoxy-2-methylcyclohexane
Figure imgf000003_0003
(3a) (1R.2S.4R) 4 2-methylpropyl)-l- (3b) (1S.2R.4S) 4-(2-methylpropyl)-l- methoxy-2-methylcyclohexane methoxy-2-methylcyclohexane
Figure imgf000004_0001
(4a) (1R,2R,4R) 4-(2-methylpropyl)-l- (4b) (1S.2S.4S) 4-(2-methylpropyl)-l- methoxy-2-methylcycIohexane - methoxy-2-methylcyclohexane
The ethers of the invention, individually and collectively, exhibit interesting fragrance properties or odour characteristics, generally herbal, floral or buttery in nature, and so may be used as such to impart, strengthen or improve the odour of a wide variety of products, or it may be used as a component of a perfume (or fragrance composition) to contribute its odour character to the overall odour of such perfume. For the purposes of this invention a perfume is intended to mean a mixture of fragrance materials, if desired mixed with or dissolved in a suitable solvent or mixed with a solid substrate, which is used to impart a desired odour to the skin and/or any product for which an agreeable odour is indispensable or desirable. Examples of such products are: fabric washing powders, washing liquids, washing tablets, fabric softeners and other fabric care products; detergents and household cleaning, scouring and disinfection products; air fresheners, room sprays and pomanders; soaps, bath and shower gels, shampoos, hair conditioners and other personal cleansing products; cosmetics such as creams, ointments, toilet waters, preshave, aftershave, skin and other lotions, talcum powders, body deodorants and antiperspirants, etc.
Other fragrance materials which can be advantageously combined with an ether according to the invention in a perfume are, for example, natural products such as extracts, essential oils, absolutes, resinoids, resins, concretes etc., but also synthetic materials such as hydrocarbons, alcohols, aldehydes, ketones, ethers, acids, esters, acetals, ketals, nitriles, etc., including saturated and unsaturated compounds, aliphatic, carbocyclic and heterocyclic compounds.
Such fragrance materials are mentioned, for example, in S. Arctander, Perfume and Flavor Chemicals (Montclair, N.J., 1969), in S. Arctander, Perfume and Flavor Materials of Natural Origin (Elizabeth, N.J., 1960) and in "Flavor and Fragrance Materials - 1991", Allured Publishing Co. Wheaton, 111. USA.
Examples of fragrance materials which can be used in combination with an ether according to the invention are: geraniol, geranyl acetate, linalol, linalyl acetate, tetrahydrolinalol, citronellol, citronellyl acetate, dihydromyrcenol, dihydromyrcenyl acetate, tetrahydro- myrcenol, terpineol, teφinyl acetate, nopol, nopyl acetate, 2-phenylethanol, 2-phenylethyl acetate, benzyl alcohol, benzyl acetate, benzyl salicylate, styrallyl acetate, benzyl benzoate, amyl salicylate, dimethylbenzylcarbinol, trichloromethylphenylcarbinyl acetate, p-tert-butyl- cyclohexyl acetate, isononyl acetate, vetiveryl acetate, vetiverol, -hexylcinnamaldehyde, 2-methyl-3-(p-tert-butylphenyl)propanal, 2-methyl-3-(p-isopropylphenyl)propanal,
3 -(p-tert-butylphenyl)-propanal, 2,4-dimethylcyclohex-3 -enyl-carboxaldehyde, tricyclodecenyl acetate, tricyclodecenyl propionate, 4-(4-hydroxy-4-methylpentyl)- 3-cyclohexenecarboxaldehyde, 4-(4-methyl-3-pentenyl)-3-cyclohexenecarboxaldehyde,
4-acetoxy-3-pentyl-tetrahydropyran, 3-carboxymethyl-2-pentylcyclopentane, 2-n-heptyl- cyclopentanone, 3-methyl-2-pentyl-2-cyclopentenone, n-decanal, n-dodecanal, 9-decen-l-ol, phenoxyethyl isobutyrate, phenylacetaldehyde dimethyl acetal, phenylacetaldehyde diethyl acetal, geranyl nitrile, citronellyl nitrile, cedryl acetate, 3-isocamphylcyclohexanol, cedryl methyl ether, isolongifolanone, aubepine nitrile, aubepine, heliotropin, coumarin, eugenol, vanillin, diphenyl oxide, hydroxycitronellal, ionones, methylionones, isomethylionones, irones, cis-3-hexenol and esters thereof, indan musks, tetralin musks, isochroman musks, macrocyclic ketones, macrolactone musks, ethylene brassylate.
Solvents which can be used for perfumes which contain an ether according to the invention are, for example: ethanol, isopropanol, diethyleneglycol monoethyl ether, dipropylene glycol, diethyl phthalate, triethyl citrate, isopropyl myristate, etc.
The quantities in which an ether according to the invention can be used in perfumes or in products to be perfumed may vary within wide limits and depend, inter alia, on the nature of the product, on the nature and the quantity of the other components of the perfume in which the ether is used and on the olfactive effect desired. It is therefore only possible to specify wide limits, which, however, provide sufficient information for the specialist in the art to be able to use the ether according to the invention for his specific purpose. In perfumes an amount of 0.01% by weight or more of the ether according to the invention will generally have a perceptible olfactive effect. Typically, the amount of the ether according to the invention in a perfume is from 0.01% to 25% by weight, preferably from 1% to 5% by weight. The amount of the ether according to the invention present in products will generally be from 1 to 10,000 ppm by weight, preferably from 10 to 1000 ppm, depending on the product to be perfumed.
In a further aspect the invention thus provides a perfume comprising an ether of the invention in an olfactively effective amount.
The invention also covers a perfumed product comprising an ether of the invention.
The ethers of the invention are also useful as intermediates in the preparation of other compounds, particularly other fragrance compounds. The ethers find particular application in the production of 3-(2-methylpropyl)-l-methylcyclohexanol (also known as l-methyl-3- (2-methylpropyl)cyclohexan-l-ol) (as described in WO 98/47842), which is a very useful fragrance material, e.g. by a two stage process comprising as the first stage an elimination reaction performed on one or more of the ethers preferably together with one or more 4-(2- methylpropyl)-2-methyl-cyclohexanols (known alcohols as disclosed in WO 99/55811), e.g. using 4-methylbenzenesulphonic acid (pTSA) catalyst and cyclohexane solvent. This reaction results in production of a mixture of the three isomeric alkenes, 5-(2-methylpropyl)- 1 -methyl- 1-cyclohexene, l-methylidene-3-(2-methylpropyl) cyclohexane and 3-(2- methylpropyl)-l-methyl-cyclohexene, as disclosed in our co-pending application under the reference C 81.02/Q. In the second stage, this mixture of alkenes is hydrated to produce 3- (2-methylpropyl)-l-methylcyclohexanol (l-methyl-3-(2-methylpropyl)cyclohexan-l-ol). The invention also includes within its scope reaction products (direct or indirect) made from an ether of the invention, particularly 3-(2-methylpropyl)-l-methylcyclohexanol (1-methyl- 3-(2-methylpropyl)cyclohexan-l-ol).
This, in a further aspect, the invention includes within its scope a method of making an alkene comprising performing an elimination reaction on an ether of the invention to produce one or more alkenes, and preferably hydrating said one or more alkenes to produce one or more cycloalkanols typically having the following structure:
Figure imgf000007_0001
where Ri represents a methyl or ethyl group, R2 represents hydrogen, R3 represents an ethyl, propyl, butyl, isobutyl or isoamyl group, Rj represents hydrogen and R. represents hydrogen, or a methyl, ethyl, propyl, isobutyl or isoamyl group. Preferably the cycloalkanol is 3-(2-methylpropyl)- 1 -methylcyclohexanol.
Accordingly, the invention also includes within its scope a cycloalkanol, preferably 3-(2- methylpropyl)-l -methylcyclohexanol, produced by the above described method.
The ethers of the invention may be prepared by catalytic hydrogenation in typically a one pot conversion of l-(4-methoxy-3-methylphenyl)-2-methyl-l-propanone to give 4-(2- methylpropyl)-l-methoxy-2-methylbenzene and then a mixture of the ethers together with 4- (2-methylpropyl)-2-methyl-cyclohexanols. If required, the ethers may be separated from the alcohol product using known techniques such as fractional distillation.
The ethers may alternatively be made by other routes, such as catalytic hydrogenation of 1- (4-methoxy-3-methylphenyl)-2-methyl-l-propanone to give 4-(2-methylpropyl)-l-methoxy- 2-methylbenzene which is separated from the reaction mixture and purified before a further catalytic hydrogenation reaction is carried out to give 4-(2-methylpropyl)-l-methoxy-2- methylcyclohexane, together with a small amount of 4-(2-methylpropyl)-2-methyl- cyclohexanol. The alcohol product may be removed from the ethers by the addition of boric acid to this hydrogenation reaction mixture, prior to purification of the ethers using known distillation techniques. The resulting isomeric mixture may be used as such, either as a fragrance material or as an intermediate in preparation of other compounds. Alternatively the isomers may be separated, eg using known separation techniques such as chromatographic or distillation techniques. Isomers (other than enantiomers) may also be separated by derivatisation and crystallisation.
The invention will be further described, by way of illustration, in the following Examples. Example 1, on a manufacturing plant scale, describes a 2 stage process for production of a mixture of ethers in accordance with the invention, mixed with 4-(2-methylpropyl)-2- methyl-cyclohexanols, followed by a two stage conversion to 3-(2-methylpropyl)-l- methylcyclohexanol. Example 2 describes an alternative route for production of the ethers of the invention on a laboratory scale.
Example 1
GC/GLC conditions utilised for analyses in the following Example:
GC: Hewlett Packard HP 6890 Gas Chromatograph
Column: HP-5 (SE54) 30m x 0.32mm (internal diameter) x 0.25μm df supplied by Hewlett Packard Carrier Gas: Hydrogen
Solvent/Injection Volume: Acetone, 0.2μl Injector: 220 °C, split 60:1
Detector: FID, 280°C
Temperature Prog.: 70 °C (initial oven temperature), hold for 3 minutes, ramp at
10°C/min to 100°C, then ramp at 25°C/min to 280°C and hold for 4 minutes.
Stage 1. Friedel Crafts Acylation.
Experimental l-methoxy-2-methylbenzene (methyl anisole) (261 kg, 98.6% pure, 2.109 kmol) and trifluoromethanesulphonic acid (triflic acid) (326g, 2.17 mol) (catalyst) were charged to a 1360 litre general purpose glass-lined reactor. The mixture was heated under nitrogen with stirring to a temperature of 150°C. Once at temperature, 1-methylpropanoic anhydride (365 kg, 2.31 kmol) was charged gradually to the reactor over a period of two hours while maintaining the reaction temperature at 150°C. The mixture was stirred for a further one and a half hours at this temperature. After cooling to 40 °C the catalyst was neutralised with solid sodium carbonate (230 g, 2.16 mol) and the 2-methylpropanoic acid by-product was distilled off under reduced pressure (30 mBar) up to a pot temperature of 120°C. The resultant material was washed twice with a 5% w/w sodium carbonate solution (60 kg) to leave the crude product, l-(4-methoxy-3-methylphenyl)-2-methyl-l-propanone, 93.9% pure by GC rpa. (385 kg, 1.88 kmol, 89.2% theoretical yield by analysis based on 1- methoxy-2-methylbenzene) .
Distillation
The crude material (381.4 kg, 1.86 kmol) was purified by distillation under reduced pressure through a 5 theoretical plate packed column. The product, l-(4-methoxy-3- methylphenyl)-2-methyl-l-propanone (345.5 kg, purity 97.7% rpa, 1.76 kmol) was collected at 137-140°C at 8mBar and crystallised on standing with a melting point of 22 °C. Thus, the overall yield of distilled product was 84.1 % based on l-methoxy-2- methylbenzene.
Figure imgf000010_0001
l-methoxy-2- l-methylpropanoic l-(4-methoxy-3-methylphenyl)- 2-methylpropanoic acid methylbenzene anhydride 2-methyl-l-propanone
Stage 2. Hydrogenation
Experimental
l-(4-methoxy-3-methylρhenyl)-2-methyl-l-propanone (60.0 kg, 97.3% pure by GC, 0.304 kmol) made as described above was charged to a high-pressure 100 litre reactor fitted with a stirrer and hydrogen supply. Distilled water (25.0 kg, 1.389 kmol), lactic acid co- catalyst, 85% aq. solution (2.0 kg, 18.9 mol) and hydrogenation catalyst (5% palladium on charcoal Type 87L paste ex Johnson Matthey, 1.2 kg) were charged to the reactor. After purging with nitrogen and hydrogen, for the first stage of hydrogenation, the stirring mixture was placed under a hydrogen atmosphere of 20 bar and taken to a temperature of 100°C over a period of 1 hr, maintaining the pressure of 20 bar gauge with the addition of more hydrogen gas. This temperature and pressure was maintained for a further hour until hydrogen addition effectively ceased (< 15 g/hr). For the second stage of hydrogenation, the pressure was raised to 48 bar gauge before heating to 140°C-150°C. This temperature and pressure was maintained for about 6-10 hours (with the reaction time depending on the quality of both the catalyst and feedstock) until hydrogen addition effectively ceased. After cooling to room temperature the pressure was released and, after nitrogen purging, the mixture was filtered to remove the hydrogenation catalyst. The aqueous layer was separated from the crude product (55.4 kg). Detailed GLC analysis of the crude product showed an isomeric mixture of 4-(2- methylpropyl)- 1 -methoxy-2-methylcyclohexanes and 4-(2-methylpropyl)-2- methylcyclohexanols constituting 93.3 % φa of the product. According to this analysis, these desired products totalled 0.29 kmol, which corresponded to a 92.8% theoretical yield based on l-(4-methoxy-3-methylphenyl)-2-methyl-l-propanone.
Distillation
Distillation is not essential, but usefully the product ethers and alcohols are together separated from water, light heads and residues by a simple distillation up a short, packed column of about 5 theoretical plates: Typically, crude 4-(2-methylpropyl)-l-methoxy-2- methylcyclohexane/4-(2-methylpropyl)-2-methylcyclohexanol (55.4 kg, 93.3 % φa pure by GC, 0.29 kmol) yielded an isomeric mixture of 4-(2-methylpropyl)-l-methoxy-2- methylcyclohexanes and 4-(2-methylpropyl)-2-methylcyclohexanols (52.4 kg, 96.0 % φa pure by GC, 0.28 kmol) having a boiling range of 98-116°C/30 mBar.
Figure imgf000011_0001
l-(4-ι_ιethoxy-3- 4-(2-methylpropyl)-l- 4-(2-ι_ιethylpropyl)- 4-(2-methylpropyl)- methylphenyl)-2- methoxy-2-me hylbenzene l-methoxy-2- 2-methylcyclohexanol methyl-l-propanone methylcyclohexane
The ethers occur in a number of different isomeric forms as follows:
Figure imgf000012_0001
(la) (1S.2R.4R) 4-(2-methylpropyl)-l- (lb) (1R.2S.4S) 4-(2-methylp_opyl)-l- methoxy-2-methylcyclohexane methoxy-2-methylcyclohexane
Figure imgf000012_0002
(2a) (1S.2S.4R) 4-(2-methylpropyl)-l- (2b) (1R.2R.4S) 4-(2-methylpropyl)-l- methoxy-2-methylcyclohexane methoxy-2-methylcyclohexane
Figure imgf000012_0003
(3a) (1R.2S.4R) 4-(2-methylpropyl)-l- (3b) (1S.2R.4S) 4-(2-methylpropyl)-l- meth oxy-2-methylcyclohexane meώoxy-2-methylcyclohexane
Figure imgf000013_0001
(4a) (1R.2R.4R) 4-(2-methylpropyl)-l- (4b) (1S.2S.4S) 4-(2-methylpropyl)-l- methoxy-2-methylcyclohexane methoxy-2-methylcyclohexane
The alcohols occur in a number of corresponding isomeric forms as follows:
Figure imgf000013_0002
(5a) (1S.2R.4R) 4-(2-methylpropyl)-2- (5b) (1R.2S.4S) 4-(2-methylpropyl)-2- methylcyclohexanol methylcyclohexanol
(6a) (1S.2S.4R) 4-(2-methylpropyl)-2- (6b) (1R.2R.4S) 4-(2-methylpropyl)-2- methylcyclohexanol methylcyclohexanol
Figure imgf000014_0001
(7a) (1R.2S.4R) 4-(2-methylpropyl)-2- (7b) (1S.2R.4S) 4-(2-mefhylpropyl)-2- methylcyclohexanol methylcyclohexanol
Figure imgf000014_0002
(8a) (1R.2R.4R) 4-(2-methylpropyl)-2- (8b) (1S.2S.4S) 4-(2-methylpropyl)-2- methylcyclohexanol methylcyclohexanol
Stage 3. Elimination
Experimental
An isomeric mixture of 4-(2-methylpropyl)-l-methoxy-2-methylcyclohexanes and 4-(2- methylpropyl)-2-methylcyclohexanols (46.3 kg, 92.6 % φa pure by GC, -0.24 kmol) made as described above, 4-methylbenzenesulphonic acid monohydrate (pTSA catalyst) (1.4 kg, 7.4 mol) and cyclohexane (10.0 kg) were charged to a 100 litre glass-lined general puφose reactor. The stirred mixture was heated to a temperature of 150° C under a nitrogen atmosphere. The cyclohexane/ water/methanol azeotrope was removed in the Dean & Stark, with the upper cyclohexane layer being returned to the flask. The quantity of cyclohexane was adjusted to maintain the flask temperature at 150°C-155°C. These conditions were maintained for 8 hours. After cooling to 40 °C the mixture was washed twice with a 5% w/w sodium carbonate solution (9.0 kg) and dehydrated to leave the crude product 3-(2-methylpropyl)-l-methyl-l-cyclohexene/5-(2-methylpropyl)-l-methyl-l- cyclohexene (typically in the ratio 1:2), 40.4 kg, 66.9 % φa pure by GC (27.0 kg, 0.18 kmol) with trace amounts of l-methylidene-3-(2-methylpropyl)cyclohexane, and unreacted starting materials 9.6 % φa by GC (3.9 kg, 0.02 kmol). Thus, the chemical yield of this reaction was 75 % and the selectivity was 82 % .
Distillation
The crude product (80.4 kg) from two such reactions, containing 64.5 % φa pure by GC (0.34 kmol) of the desired alkenes was purified by careful fractional distillation under reduced pressure through a 30 theoretical plate packed column at a 20:1 reflux ratio. The mixture of 3-(2-methylpropyl)-l-methyl-l-cyclohexene and 5-(2-methylpropyl)-l-methyl-l- cyclohexene was collected in the range 88-93 °C/32-40mBar. The purified product (61 kg) contained 81.5 % rpa of the desired alkenes corresponding to a distillation yield of 96 %. The product is a liquid at normal temperatures.
The unreacted starting materials remained in the distillation residues.
+_nethanol +H20
Figure imgf000015_0001
4-(2-ι_ιethy_propyl)- 5-(2-methylpιopyl)- 3-(2-methylprapyl)- l-methoxy-2- 1-methyl-l- 1-methyl-l- methylcyclohexane cyclohexene cyclohexene
4-(2-methylpropyl)- l-methylidene-3- 2-methylcyclohexanol (2-methylpropyl) cyclohexane Stage 4. Hydration
Experimental
A mixture of 3-(2-methylpropyl)-l-methyl-l-cyclohexene and 5-(2-methylpropyl)-l- methyl-1-cyclohexene (30.1 kg, "purity" 82.1% φa, 0.16 kmol) together with a small amount of l-methylidene-3-(2-methylpropyl)cyclohexane, made as described above was charged to a 100 litre glass-lined general puφose reactor. 3-(2-methylpropyl)-l- methylcyclohexanol (0.3 kg, 1.76 mol) was added (this small amount of the desired end product acts as a phase transfer agent and helps the reaction initiate). The stirred mixture was cooled to -5°C and sulphuric acid, 76% w/w (20.4 kg, 0.158 kmol) was added slowly over 5 hours, maintaining the temperature in the range -6°C to -3°C. The stirred mixture was held at this temperature range for a further hour after the acid addition. The mixture was slowly added to water (80.0 kg, 4.4 kmol) in a well-stirred quench vessel maintaining the temperature below 25 °C, before separating the lower aqueous phase. The organic layer was washed with water (11.0 kg) while still maintaining the temperature below 25 °C. The residual acid catalyst was neutralised by washing the reaction mixture with 5% sodium hydroxide solution (10.0 kg), maintaining a temperature below 30°C. The resultant product was washed twice with water (10.0 kg) at 50 °C - 55° C to leave the crude product (3-(2-methylpropyl)-l -methylcyclohexanol) (30.8 kg). GLC analysis showed that this crude product contained 52.55% φa (0.095 kmol) of pure 3-(2-methylpropyl)-l- methylcyclohexanol, in the form of a mixture of trans and cis isomers. This corresponds to a chemical yield of 59.1 % based on 3-(2-methylpropyl)-l-methyl-l-cyclohexene/5-(2- methylpropyl)- 1 -methyl- 1 -cyclohexene .
Distillation
The crude product (30.8 kg, 0.095 kmol) was purified by fractional distillation under reduced pressure through a packed column of about 15 theoretical plates. The product (3- (2-methylproρyl)-l-methylcyclohexanol (15.28 kg, 98.7 % by GC φa, 0.089 kmol) was collected at 98-100°C, 15 mBar. This gave an overall yield of 55.1 %w/w of Perfumery Quality material based on 3-(2-methylpropyl)-l-methyl-l-cyclohexene/5-(2-methylpropyl)- 1 -methyl- 1-cyclohexene. The product, 3-(2-methylpropyl)-l-methylcyclohexanol was a mixture of approximately 35-45% cis, and about 55-65% trans isomers. The product may solidify on standing with a melting point of 20-25°C.
Figure imgf000017_0001
5-(2-methylpropyl)- 3-(2-methylpropyl)- 3-(2-methylpropyl)-
1-methyl-l- 1-methyl-l- 1 -methylcyclohexanol cyclohexene cyclohexene
Example 2
Stage 1. Friedel-Crafts Acylation
l-(4-methoxy-3-methylphenyl)-2-methyl-l-propanone was prepared as outlined in Example 1.
Stage 2. Hydrogenation
Experimental
l-(4-methoxy-3-methylphenyl)-2-methyl-l-propanone (50.0g, 0.255mol) was charged to a high pressure 100ml reactor fitted with a stirrer and hydrogen supply. Distilled water (lO.Og, 0.556mol), lactic acid co-catalyst, 85% aq. solution (2.0g, 18.9mmol) and hydrogenation catalyst ([5% palladium supported on carbon wet (40% w/w)]; l.Og) were then charged to the reactor. After purging with nitrogen and hydrogen, the stirring mixture was placed under a hydrogen atmosphere of 20 bar and taken to a temperature of 100°C, maintaining the pressure of 20 bar gauge with the addition of more hydrogen gas. This temperature and pressure were maintained until no more hydrogen addition was observed. After cooling to room temperature the pressure was released and, after nitrogen purging, the mixture was filtered to remove the hydrogenation catalyst. The aqueous layer was separated from the crude intermediate 4-(2-methylpropyl)-l-methoxy-2-methylbenzene).
The crude intermediate (4-(2-methylpropyl)-l-methoxy-2-methylbenzene) was separated from light heads and residues by simple distillation up a short, packed column.
The pure material (i.e. (4-(2-methylpropyl)-l-methoxy-2-methylbenzene), lO.Og, 0.05 mol) was returned to the high-pressure reactor. Fresh hydrogenation catalyst ([essentially dry 5% rhodium supported on carbon]; 0.2g), was then added to the reactor. After purging with nitrogen and hydrogen, the stirring mixture was placed under a hydrogen atmosphere of 50 bar and taken to a temperature of 50°C, maintaining the pressure of 50 bar gauge with the addition of more hydrogen gas. This temperature and pressure were maintained until no more hydrogen addition was observed. After cooling to room temperature the pressure was released and, after nitrogen purging, the mixture was filtered to remove the hydrogenation catalyst from the crude product (4-(2-methylpropyl)-l-methoxy-2-methylcyclohexane), which also contained small amounts of 4-(2-methylpropyl)-2-methylcyclohexanol.
Distillation
Boric acid was added to the crude product prior to distillation to remove any alcohols. The product ethers were then separated from light heads and residues by simple distillation up a short, packed column.

Claims

Claims
1. An ether having the structure
Figure imgf000019_0001
2. An ether according to claim 1, comprising an individual isomer.
3. An ether according to claim 1, comprising a mixture of two or more of the isomers.
4. An ether according to claim 1, 2 or 3, made by catalytic hydrogenation of l-(4-methoxy- 3 -methylphenyl)-2-methyl- 1 -propanone.
5. A perfume comprising an ether in accordance with any one of the preceding claims in an olfactively effective amount.
6. A perfumed product comprising an ether according to any one of claims 1 to 4 or a perfume according to claim 5.
7. A method of making an alkene, comprising performing an elimination reaction on an ether in accordance with any one of claims 1 to 4 to produce one or more alkenes.
8. A method according to claim 7, wherein the method further comprises hydrating the one or more alkenes to produce one or more cycloalkanols.
9. A method according to claim 8, wherein the one or more cycloalkanols have the following structure:
Figure imgf000020_0001
where Ri represents a methyl or ethyl group, R2 represents hydrogen, R3 represents an ethyl, propyl, butyl, isobutyl or isoamyl group, R represents hydrogen and R5 represents hydrogen, or a methyl, ethyl, propyl, isobutyl or isoamyl group.
10. A method according to claim 9, wherein the cycloalkanol is 3-(2-methylpropyl)-l- methylcyclohexanol.
11. A cycloalkanol, preferably 3-(2-methylpropyl)-l-methylcyclohexanol, produced by the method of any one of claims 7 to 10.
PCT/GB2001/003616 2000-08-14 2001-08-10 Cyclohexyl ethers as fragrance compounds WO2002014253A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102548943A (en) * 2009-09-18 2012-07-04 三菱瓦斯化学株式会社 Method for producing cyclohexyl alkyl ketones
WO2018233804A1 (en) * 2017-06-19 2018-12-27 Symrise Ag Novel ambergris and/or indole-like compositions of odoriferous substances

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EP0005196A1 (en) * 1978-05-05 1979-11-14 BASF Aktiengesellschaft Octylcyclohexane derivatives, their preparation and their use as perfuming agents
EP0262388A2 (en) * 1986-08-30 1988-04-06 BASF Aktiengesellschaft Derivatives of 2-tert.-butyl-4-methyl-cyclohexanol, their preparation and use as fragrance compounds
WO1998047842A1 (en) * 1997-04-23 1998-10-29 Quest International B.V. Perfumes comprising 3-alkylcycloalkanols
WO1999055811A1 (en) * 1998-04-24 1999-11-04 Quest International B.V. Perfumes comprising 4-isobutylcyclohexanols

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* Cited by examiner, † Cited by third party
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EP0005196A1 (en) * 1978-05-05 1979-11-14 BASF Aktiengesellschaft Octylcyclohexane derivatives, their preparation and their use as perfuming agents
EP0262388A2 (en) * 1986-08-30 1988-04-06 BASF Aktiengesellschaft Derivatives of 2-tert.-butyl-4-methyl-cyclohexanol, their preparation and use as fragrance compounds
WO1998047842A1 (en) * 1997-04-23 1998-10-29 Quest International B.V. Perfumes comprising 3-alkylcycloalkanols
WO1999055811A1 (en) * 1998-04-24 1999-11-04 Quest International B.V. Perfumes comprising 4-isobutylcyclohexanols

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102548943A (en) * 2009-09-18 2012-07-04 三菱瓦斯化学株式会社 Method for producing cyclohexyl alkyl ketones
CN102548943B (en) * 2009-09-18 2014-07-02 三菱瓦斯化学株式会社 Method for producing cyclohexyl alkyl ketones
WO2018233804A1 (en) * 2017-06-19 2018-12-27 Symrise Ag Novel ambergris and/or indole-like compositions of odoriferous substances
CN110809622A (en) * 2017-06-19 2020-02-18 西姆莱斯有限公司 Novel ambergris and/or indole aromatic composition
US10920169B2 (en) 2017-06-19 2021-02-16 Symrise Ag Ambergris and/or indole-like compositions of odoriferous substances
CN110809622B (en) * 2017-06-19 2024-05-24 西姆莱斯有限公司 Novel ambergris and/or indole fragrance compositions

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