Patent Description:
Homofarnesol is an important intermediate for the production of (-)-Ambrox (3a,<NUM>,<NUM>,9a-tetramethyldodecahydronaphtho[<NUM>,<NUM>-b]furan), a sought-after fragrance ingredient. The literature describes various processes for the preparation of homofarnesol. For example, it may be prepared by a lengthy process starting from Nerolidol (<NUM>,<NUM>,<NUM>-trimethyldodeca-<NUM>,<NUM>,<NUM>-trien-<NUM>-ol), via homofarnesylic acid amide (<NPL>). Alternatively, homofarnesol may be prepared by carbonylation of Nerolidol in the presence of a polar solvent and a palladium halide catalyst (<CIT>). Another way for the production of homofarnesol has been described by <NPL>), starting from dihydrofuran via five steps via homogeraniol. Also the synthesis of homofarnesol from geranylacetone via Wittig olefination, followed by cyclopropane ring opening and formyloxylation has been described in the literature (<CIT>). Those methods are relatively long and intensive in costs.

A useful intermediate for the preparation of homofarnesol is farnesyl chloride. Routes via this compound have not been studied in detail so far, in particular not with a focus on the double bond configuration.

It is therefore desirable to provide new or improved methods for making homofarnesol while controlling the double bond configuration.

In accordance with a first aspect of the present invention there is provided a method for preparing homofarnesol (<NUM>)
<CHM>
the method comprising the steps of:.

Certain embodiments of any aspect of the present invention may provide one or more of the following advantages:.

The details, examples and preferences provided in relation to any particular one or more of the stated aspects of the present invention will be further described herein and apply equally to all aspects of the present invention.

The present invention is based on the surprising finding that homofarnesol (<NUM>) can be obtain from farnesyl chloride (<NUM>) under conditions allowing to preserve the configuration of the double bonds. Homofarnesol (<NUM>) is obtained without E/Z isomerization in good yields.

There is therefore provided herein a method for preparing homofarnesol (<NUM>)
<CHM>
the method comprising the steps of:.

By this method homofarnesol (<NUM>) can be obtained in good yields without isomerization of the double bonds, in particular without isomerization of the C3 double bound which is close to the reaction site of the compound.

If no double bond configuration is indicated for a given compound, then the configuration is either not specified or refers to a mixture of isomers. For a certain configuration of a compound, the prefixes E- and Z- are used, for example (E,E)-<NUM> or (<NUM>E,<NUM>E)-<NUM>.

If farnesyl chloride (<NUM>) is provided with a certain double bond configuration, said configuration will be maintained in the resulting homofarnesol (<NUM>). If farnesyl chloride (<NUM>) is provided as a mixture of double bond isomers, the resulting homofarnesol (<NUM>) will be obtained as a mixture of double bond isomers with a corresponding ratio. The described method is suitable to obtain homofarnesol (<NUM>) with a desired double bond configuration, as the configuration of the double bonds is preserved during the entire reaction sequence from the starting material to the final product. The method is suitable to provide homofarnesol (<NUM>) with any double bond configuration, in particular it is suitable to provide (<NUM>E,<NUM>E)-<NUM>. For the preparation of (<NUM>E,<NUM>E)-<NUM>, the starting material and the intermediate compounds possess also E,E configuration of the respective two double bonds, that is (E,E)-farnesyl chloride ((E,E)-<NUM>) and (E,E)-homofarnesate ((E,E)-<NUM>).

Farnesyl chloride (<NUM>) can be prepared for example in two steps from farnesene (<NUM>) via farnesyl amine (<NUM>), as described in <CIT>.

Step b) of the method for preparing homofarnesol (<NUM>), the reaction of farnesyl chloride (<NUM>) to homofarnesate (<NUM>), can be achieved by alkoxycarbonylation. The reaction is carried out in the presence of palladium on carbon as catalyst in aq. ethanolic solution under CO atmosphere. The double bond configuration of the substrate is preserved.

Step c) of the method for preparing homofarnesol (<NUM>), the reaction of homofarnesate (<NUM>) to homofarnesol (<NUM>), can be achieved by reduction with NaAlH<NUM>(OCH<NUM>CH<NUM>OCH<NUM>)<NUM> (<NPL>, known under the trade names Red-Al or Vitride). Also, reduction with LAH is possible. Both organometallic reagents are used in stoichiometric or sub-stoichiometric amount. Alternatively, the conversion can be a hydrogenation in the presence of a homogenous catalyst. Also in this step, the double bond configuration of the substrate is preserved.

In one embodiment of the invention, there is provided a method for preparing homofarnesol (<NUM>) as described above, wherein the alkoxycarbonylation of farnesyl chloride (<NUM>) is carried out in the presence of a phase transfer catalyst. By the addition of a phase transfer catalyst, the formation of side products like ethers is lowered, and the alkoxycarbonylation rate is enhanced. Furthermore, the use of a phase transfer catalyst can reduce the amount of inorganic base, e.g. K<NUM>CO<NUM> from <NUM> to <NUM> mol equivalents or lower, for example <NUM> mol equivalent or lower.

For example, the phase transfer catalyst can be selected from the group consisting of tetraalkylammonium salts, for example tetrabutylammonium halides as TBA-Cl, TBA-Br or TBA-I, or TBA-HSO<NUM>.

In one embodiment of the reaction, the phase transfer catalyst is TBA-Br.

For example, the phase transfer catalyst is used in <NUM>-<NUM> mol% of farnesyl chloride (<NUM>), preferably in <NUM>-<NUM> mol%, more preferably <NUM> mol%.

In one embodiment of the invention, there is provided a method for preparing homofarnesol (<NUM>) as described above, wherein farnesyl chloride (<NUM>) is provided in a mixture with a carbamate (<NUM>)
<CHM>.

Preferably, the two R" residues of the carbamate (<NUM>) are same alkyl groups selected from Et and n-propyl.

As mentioned above, farnesyl chloride (<NUM>) can be obtained in two steps from farnesene (<NUM>) via farnesyl amine (<NUM>). The amine is treated with an alkyl chloroformate ClCO<NUM>R', resulting in a mixture of farnesyl chloride (<NUM>) and the byproduct carbamate (<NUM>), wherein R' is an alkyl group selected from Me, Et, n-Pr, optionally substituted, and the two R" residues are same or different alkyl groups selected from Me, Et, n-propyl, i-propyl, n-butyl, i-butyl etc, or the two R" residues form together a ring system, such as morpholine, pyrrolidine, which is optionally substituted. Preferably, the two R" residues of the carbamate (<NUM>) are same alkyl groups selected from Et and n-propyl.

The carbamate (<NUM>) is usually removed before further conversion of farnesyl chloride (<NUM>) to avoid side reactions, for example by distillation. However, farnesyl chloride (<NUM>) is unstable; and as distillation is causing its partial decomposition, it is disadvantageous at this stage. Surprisingly, it was found, that the alkoxycarbonylation of farnesyl chloride (<NUM>) is possible in the presence of carbamate (<NUM>) without undesired side reactions. This allows the preparation of farnesyl chloride (<NUM>) with ClCO<NUM>R' from farnesyl amine (<NUM>), alkoxycarbonylation of the crude mixture without distillative removal of the carbamate (<NUM>) from the unstable farnesyl chloride (<NUM>), and easy separation of the more stable homofarnesate (<NUM>) from carbamate (<NUM>) by distillation.

So in one embodiment of the invention, there is provided a method for preparing homofarnesol (<NUM>) as described above, wherein farnesyl chloride (<NUM>) is provided as a mixture with carbamate (<NUM>), obtained from farnesyl amine (<NUM>) by treatment with an alkyl chloroformate ClCO<NUM>R'.

In one embodiment of the reaction, there is provided a method for preparing homofarnesol (<NUM>) as described above, further comprising the preparation of farnesyl chloride (<NUM>) from β-farnesene (<NUM>)), by the following additional steps:.

For the preparation of (E,E)-farnesyl chloride ((E,E)-<NUM>), the starting material is (E,β)-farnesene ((E,β)-<NUM>).

Step ii) in the method described above is a nucleophilic addition of a dialkylamine R"<NUM>NH to farnesene (<NUM>) in order to obtain farnesyl amine (<NUM>). The two R" residues are same or different alkyl groups selected from Me, Et, n-propyl, i-propyl, n-butyl, i-butyl etc, or the two R" residues form together a ring system, such as morpholine, pyrrolidine, which is optionally substituted. Preferably, the two R" residues are same alkyl groups selected from Et and n-propyl.

The dialkylamines R"<NUM>NH differ in boiling points and they can therefore affect the reaction conditions and handling. Their selection can also have an impact on the yield and E/Z ratio of the farnesyl amine (<NUM>). Best results are obtained with diethylamine and dipropylamine.

In one embodiment of the invention, the E/Z ratio of the double bond at C3 of homofarnesol (<NUM>) is greater than <NUM>:<NUM>, more particularly greater than <NUM>:<NUM>, still more particularly greater than <NUM>:<NUM>.

In one embodiment of the invention, the E,E-homofarnesol ((E,E)-<NUM>) is present in <NUM> percent or more percent in the isomeric mixture, more particularly in <NUM> percent, more particularly in <NUM> percent or more, still more particularly in <NUM> percent or more.

In one embodiment of the invention, the alkoxycarbonylation reaction takes place under elevated pressure. For example, the reaction takes place under pressure of at least <NUM> bar or of at least <NUM> bar, or of at least <NUM> bar, or of at least <NUM> bar, or of at least <NUM> bar or more.

E,E-homofarnesol ((<NUM>E,<NUM>E)-<NUM>,<NUM>,<NUM>-Trimethyltrideca-<NUM>,<NUM>,<NUM>-trien-<NUM>-ol, (E,E)-<NUM>, disclosed for example in <CIT> or by <NPL>) is of particular interest, because the specific configuration provides, after cyclization under conditions known in the art, the very valuable fragrance ingredient known as Ambrox with a high content of the desired olfactorily active 3aR,5aS,9aS,9bR-enantiomer or the corresponding racemate (3aRS,5aSR,9aSR,9bRS) depending on reagents and conditions. For example, the cyclization can be carried out by biocatalytical means using Squalene Hopene Cyclase (SHC).

Therefore, in one embodiment of the invention, there is provided a method of preparing Ambrox, comprising the method for preparing (E,E)-homofarnesol ((E,E)-<NUM>) according to the methods described above, followed by cyclisation of (E,E)-homofarnesol ((E,E)-<NUM>)
<CHM>
preferably by using the bacterial enzyme squalene hopene cyclase (SHC).

The invention is now further illustrated by the following non-limiting examples.

GCMS: <NUM> / <NUM>, <NUM> / min <NUM>, <NUM> / min <NUM>. Agilent 5975C MSD with HP 7890A Series GC system. Non-polar column: BPX5 from SGE, <NUM>% phenyl <NUM>% dimethylpolysiloxan <NUM> x <NUM> x <NUM>. Carrier gas: helium. Injector temperature: <NUM>. Split <NUM>:<NUM>. Flow: <NUM>/min. Transfer line: <NUM>. MS-quadrupol: <NUM>. MS-source: <NUM>. Injection vol. Ionization mode Electron Impact (EI) at <NUM> eV.

GC: <NUM> / <NUM>, <NUM> / min <NUM>, <NUM> / <NUM>. Thermo Focus GC. Non-polar column: Agilent Technologies J&W Scientific DB-<NUM> ((<NUM> % Phenyl)-methylpolysiloxane) <NUM> x <NUM> x <NUM>. Carrier gas: helium. FID-Detector, Detector temp. Injector temperature: <NUM>. Split <NUM>:<NUM>. Pressure <NUM> kPa.

<NUM>H- and <NUM>C-NMR: Bruker-DPX-<NUM> spectrometer; spectra were recorded at <NUM> (<NUM>H) and <NUM> (<NUM>C) respectively in CDCl<NUM>; δ in ppm rel. to SiMe<NUM>; coupling constants J in Hz. The <NUM>,<NUM>-EZ ratios of homofarnesol <NUM>, farnesyl chloride <NUM>, homofarnesate <NUM> and farnesyl amine <NUM> were determined by integration of the corresponding NMR peaks.

Dipropylamine (<NUM>, <NUM> mol), (E,β)-farnesene ((E,β)-<NUM>, <NUM>, <NUM> mol) and lithium (<NUM>, <NUM> mol) are heated for <NUM> to <NUM> under nitrogen and stirring. The mixture is cooled to <NUM>, and methanol (<NUM>) is added to quench traces of remaining lithium. The mixture is filtered and the filter cake rinsed with methanol (<NUM>). Methanol and dipropylamine are removed from the filtrate at <NUM> / <NUM> bar and the residue washed with water (<NUM>) and brine (<NUM>). After drying over magnesium sulfate the crude product is distilled at <NUM> / <NUM> mbar giving <NUM> of N,N'-Dipropyl E,E-farnesylamine (E,E)-5a of <NUM>% yield and <NUM>% GC-purity.

<NUM>H-NMR (<NUM>, CDCl<NUM>): δ (ppm) = <NUM> (m, <NUM>), <NUM> - <NUM> (<NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> - <NUM> (<NUM>), <NUM> - <NUM> (<NUM>), <NUM> (<NUM>, <NUM>), <NUM> (<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, <NUM>).

<NUM>C-NMR (<NUM>, CDCl<NUM>): δ (ppm) = <NUM> (s), <NUM> (s), <NUM> (s), <NUM> (d), <NUM> (d), <NUM> (d), <NUM> (t, <NUM> C), <NUM> (t), <NUM> (t), <NUM> (t), <NUM> (t), <NUM> (t), <NUM> (q), <NUM> (t, <NUM> C), <NUM> (q), <NUM> (q), <NUM> (q), <NUM> (q, <NUM> C).

GCMS: m/z = <NUM> [M]+ (<NUM> %), <NUM> [M-<NUM>]+ (<NUM> %), <NUM> (<NUM>%), <NUM> (<NUM>%), <NUM> (<NUM> %), <NUM> (<NUM>%), <NUM> (<NUM> %), <NUM> (<NUM> %), <NUM> (<NUM> %), <NUM> (<NUM> %), <NUM> (<NUM>%), <NUM> (<NUM> %), <NUM> (<NUM> %), <NUM> (<NUM>%), <NUM> (<NUM> %).

For the synthesis of E,E-farnesyl chloride see <CIT>).

Following general conditions described by <NPL>) a reaction flask with Na<NUM>PdCl<NUM> (<NUM>, <NUM> mmol, <NUM> mol%) and bis(diphenyl-phosphino)ethane (<NUM>, <NUM> mmol) is evacuated and refilled <NUM> times with carbon monoxide. A solution of E,E-Farnesyl chloride ((E,E)-<NUM>, <NUM>, <NUM> mmol, <NUM>,<NUM>-EZ <NUM>:<NUM>) in ethanol (<NUM>) is added and the pink solution heated under <NUM> bar carbon monoxide to <NUM>.

At this temperature a mixture of sodium ethylate (<NUM>, <NUM> mmol) <NUM>% in ethanol and ethanol (<NUM>) are added dropwise within <NUM>. After <NUM> complete conversion is detected by GC and the reaction mixture cooled to <NUM>. The carbon monoxide atmosphere is replaced by argon and the suspension poured onto water (<NUM>), followed by extraction with methyl tert-butyl ether. The combined organic phase is washed with water and brine and is dried over MgSO<NUM>. Filtration and evaporation of the solvents under reduced pressure gives <NUM> of crude product which is purified by flash chromatography through silicagel giving farnesene (<NUM>), O-Ethyl nerolidol and E,E-farnesyl ethers (<NUM>), E,Z-homofarnesate (<NUM>, <NUM>% yield) and E,E-ethyl homofarnesate 3a (<NUM>, <NUM>% yield) with an <NUM>,<NUM>-EZ ratio of <NUM>:<NUM>. The analytical data of the thus-obtained ethyl homofarnesate (E,E)-3a are identical to the ones obtained in a <NUM>,<NUM>-EZ <NUM>:<NUM> mixture by <NPL>.

This experiment shows that under the conditions of Kiji relatively low yield of Ethyl farnesate and byproducts are obtained.

An autoclave charged with E,E-Farnesyl chloride ((E,E)-<NUM>, <NUM>, <NUM> mmol, <NUM>,<NUM>-EZ ratio <NUM>:<NUM>), potassium carbonate (<NUM>, <NUM> mol) and palladium on carbon (<NUM>, <NUM> mmol) in water (<NUM>) and ethanol (<NUM>) is stirred under <NUM> bar carbon monoxide for <NUM>. After filtration of the reaction mass and removal of the ethanol under reduced pressure the two-phase mixture is extracted with methyl tert-butyl ether. The combined organic phase is washed with aqueous NaHCO<NUM> and brine, dried over MgSO<NUM> and filtered. Removal of the solvent under reduced pressure gives <NUM> 3a (<NUM>% yield based on E,E-isomers) of crude ethyl homofarnesate with purity of <NUM>% (EZ) and an <NUM>,<NUM>-EZ ratio of <NUM>:<NUM>. The analytical data of the product are within the frame of the slightly different <NUM>,<NUM>-EZ-ratios identical to the ones obtained in example <NUM>.

Methyl chloroformate (<NUM>, <NUM> mol) is added slowly over <NUM> to N,N-Dipropyl-E,E-farnesylamine ((E,E)-5a, <NUM>, <NUM> mol) maintaining a reaction temperature of < <NUM>. After another <NUM> at <NUM> the mixture is transferred to a <NUM> autoclave. Tetrabutylammonium bromide (<NUM>, <NUM> mmol), Pd <NUM>% on carbon (<NUM>, <NUM> mmol), ethanol (<NUM>) and K<NUM>CO<NUM> (<NUM>, <NUM> mol) in water (<NUM>) are added. The autoclave is sealed, purged with carbon monoxide and pressurized to <NUM> bar. After <NUM> stirring at <NUM> the pressure is released. Ethanol (<NUM>) and water (<NUM>) are added and the reaction mixture is filtered over Celite, followed by evaporation of the ethanol at <NUM> / <NUM> mbar. After extraction with methyl tert-butyl ether the combined organic phase is washed with saturated NaHCO<NUM> and brine until pH = <NUM>, dried over MgSO<NUM> and filtered. The solvents are removed under reduced pressure. The crude product 3a is flash-distilled giving a product which is fractionally distilled at <NUM> / <NUM> mbar head temperature giving <NUM> (<NUM>% yield) of Ethyl homofarnesate 3a with a <NUM>,<NUM>-EZ ratio of <NUM>:<NUM>.

The analytical data of the product 3a are within the frame of the slightly different <NUM>,<NUM>-EZ-ratios identical to the ones obtained in example <NUM>.

Ethyl E,E-Homofarnesate ((E,E)-3a, <NUM>, <NUM> mol, <NUM>,<NUM>-EZ > <NUM>:<NUM>) is added dropwise to Vitride <NUM>% in toluene (<NUM>, <NUM> mol) at <NUM> - <NUM> under nitrogen and stirring. One hour after completed addition the reaction mass is cooled to ambient temperature and poured slowly onto <NUM>% NaOH (<NUM> Itr) under stirring. After <NUM> stirring the phases are separated. The aqueous phase is washed with toluene. The combined organic phase is washed with water, brine, dried over MgSO<NUM> and filtered. The solvent is removed under reduced pressure giving <NUM> of crude product, which is flash distilled and then fractionally distilled at <NUM> / <NUM> mbar giving <NUM> (<NUM>% yield) of E,E-Homofarnesol <NUM> with <NUM>% purity (GC rpa, based on the E,E-isomer) and a <NUM>,<NUM>-EZ ratio of <NUM>:<NUM>. The analytical data of E,E-Homofarnesol <NUM> are consistent with the ones in the literature, see for example <NPL>).

Claim 1:
A method for preparing homofarnesol (<NUM>)
<CHM>
the method comprising the steps of:
a) providing farnesyl chloride (<NUM>)
<CHM>
b) reacting farnesyl chloride (<NUM>) to homofarnesate (<NUM>) by alkoxycarbonylation
<CHM>
and
c) reacting homofarnesate (<NUM>) to homofarnesol (<NUM>),
wherein R is a C<NUM>-C<NUM> alkyl group, for example Me, Et, n-propyl, i-propyl, n-butyl, i-butyl etc, including ring systems, optionally substituted; and
wherein the configuration of the double bonds in the compounds <NUM>, <NUM> and <NUM> is preserved.