Method of manufacturing an organic compound

Abstract

The present invention provides a process for preparing homofarnesol (1), said process comprising the steps of: a) providing farnesyl chloride (2), b) reacting farnesyl chloride (2) to homofarnesyl ester (3) by alkyloxycarbonylation; and c) reacting homofarnesyl ester (3) to homofarnesol (1), wherein the configuration of the double bonds in compounds 1, 2 and 3 is maintained.

Description

[0001] This invention relates to a novel method for preparing high-farnesol, particularly (3E,7E)-high-farnesol. The invention further relates to the use of said high-farnesol as an intermediate in the preparation of fragrance and flavor components.

[0002] background

[0003] Kafarniol is an important intermediate in the production of the popular fragrance ingredient (-)-ambroxan (3a,6,6,9a-tetramethyldodecano[2,1-b]furan). Various methods for its preparation have been described in the literature. For example, it can be prepared via a lengthy process of nerolidinyl (3,7,11-trimethyldodecano-1,6,10-trien-3-ol) via a kafarniol amide (AF Barrero et al., J. Org. Chem. 1996, 61, 2215). Alternatively, kafarniol can be prepared by carbonylating nerolidinyl in the presence of a polar solvent and a palladium halide catalyst (WO92 / 06063). P. Kociensiki et al. (J. Org. Chem. 1989, 54, 1215) describe another method for producing kafarniol, which begins with dihydrofuran and proceeds via kafarniol in five steps. The literature (WO2013 / 156398) also describes the synthesis of high farnesol from geranylacetone via vitiformation, followed by cyclopropane ring-opening and formicooxylation. Those methods are relatively lengthy and costly.

[0004] A useful intermediate for the preparation of high farnesol is farnesyl chloride. To date, the routes via this compound have not been studied in detail, particularly regarding the double bond configuration.

[0005] Therefore, there is a need to provide new or improved methods for preparing highfarnesol while controlling the double bond configuration.

[0006] Overview

[0007] According to a first aspect of the present invention, a method for preparing high farnesol (1) is provided.

[0008]

[0009] The method includes the following steps:

[0010] a) Provide farnesyl chloride (2)

[0011]

[0012] b) React farnesyl chloride (2) into high farnesyl ester (3) via alkoxycarbonylation.

[0013]

[0014] c) React perfarnesate (3) to perfarnesol (1);

[0015] Where R is C1-C 10 Alkyl groups, such as Me, Et, n-propyl, isopropyl, n-butyl, isobutyl, etc., including cyclic systems, which may optionally be substituted; and

[0016] The configuration of the double bonds in compounds 1, 2 and 3 is preserved.

[0017] Certain embodiments of any aspect of the present invention may provide one or more of the following advantages:

[0018] ● Retention of double bond configuration;

[0019] ●High-efficiency conversion;

[0020] ● Mild reaction conditions;

[0021] ● Simple and cost-effective reagents;

[0022] ●Avoid waste that is difficult to handle;

[0023] ● Avoid difficult post-processing and purification; and

[0024] ● Avoid using toxic reagents that are difficult to handle.

[0025] Details, embodiments, and preferences relating to any particular aspect or one of the described aspects of the invention will be further described herein and are equally applicable to all aspects of the invention. Unless otherwise stated herein or obviously contradicted by the context, any combination of all possible variations of the embodiments, embodiments, and preferences described herein is included in the invention.

[0026] Detailed description

[0027] This invention is based on the surprising discovery that high-farnesol (1) can be obtained from farnesyl chloride (2) under conditions that allow the configuration of the double bonds to be preserved. High-farnesol (1) is obtained in good yield without E / Z isomerization.

[0028] Therefore, the present invention provides a method for preparing high farnesol (1),

[0029]

[0030] The method includes the following steps:

[0031] a) Provide farnesyl chloride (2)

[0032]

[0033] b) React farnesyl chloride (2) into high farnesyl ester (3) via alkoxycarbonylation.

[0034] and

[0035] c) React perfarnesate (3) to perfarnesol (1);

[0036] Where R is C1-C 10 Alkyl groups, such as Me, Et, n-propyl, isopropyl, n-butyl, isobutyl, etc., including cyclic systems, which may optionally be substituted; and

[0037] The configuration of the double bonds in compounds 1, 2 and 3 is preserved.

[0038] By this method, high farnesol (1) can be obtained in good yields without isomerization of the double bond, especially without isomerization of the double bond at C3 near the reaction site of the compound.

[0039] If the configuration of the double bond is not specified for a given compound, then the configuration is either unspecified or refers to a mixture of isomers. For a certain configuration of a compound, the prefixes E- and Z- are used, such as (E,E)-1 or (3E,7E)-1.

[0040] If farnesyl chloride (2) has a certain double bond configuration, the configuration will be retained in the resulting homofarnesol (1). If farnesyl chloride (2) is provided as a mixture of double bond isomers, the resulting homofarnesol (1) will be obtained as a mixture of double bond isomers in the appropriate ratio. The method is suitable for obtaining homofarnesol (1) with the desired double bond configuration because the configuration of the double bonds is maintained throughout the entire reaction sequence from the starting material to the final product. The method is suitable for providing homofarnesol (1) with any double bond configuration, especially for providing (3E,7E)-1. For the preparation of (3E,7E)-1, the starting material and intermediate compound also have their respective two double bonds in the E,E configuration, namely (E,E)-farnesyl chloride (2) ((E,E)-2) and (E,E)-hofarnesol ester ((E,E)-3).

[0041] As described in WO2019237005, farnesyl chloride (2) can be prepared, for example, in two steps from farnesene (4) via farnesylamine (5).

[0042] Step b) of the method for preparing perfarnesol (1), namely the reaction of farnesyl chloride (2) to perfarnesol ester (3), can be achieved by alkoxycarbonylation. This reaction is carried out in an aqueous ethanol solution under a CO atmosphere in the presence of palladium on carbon as a catalyst. The double bond configuration of the substrate is preserved.

[0043] Step c) of the method for preparing perfarnesol (1), namely the reaction of perfarnesol ester (3) to perfarnesol (1), can be achieved by reduction with NaAlH2(OCH2CH2OCH3)2 (CAS No. 22722-98-1, trade name Red-Al or Vitride). Alternatively, reduction with LAH is also possible. Both organometallic reagents are used in stoichiometric or substoichiometric amounts. Alternatively, the conversion can be hydrogenation in the presence of a homogeneous catalyst. Also in this step, the double bond configuration of the substrate is preserved.

[0044] In one embodiment of the invention, a method for preparing the above-mentioned high-farnesol (1) is provided, wherein the alkoxycarbonylation of the farnesyl chloride (2) is carried out in the presence of a phase transfer catalyst. By adding a phase transfer catalyst, the formation of byproducts such as ethers is reduced, and the alkoxycarbonylation rate is increased. Furthermore, using a phase transfer catalyst can reduce the amount of inorganic base (e.g., K₂CO₃) from 3 mol equivalents to 2 mol equivalents or less, for example, 1 mol equivalent or less.

[0045] For example, the phase transfer catalyst may be selected from tetraalkylammonium salts, such as tetrabutylammonium halide, such as TBA-Cl, TBA-Br, TBA-I, or TBA-HSO4.

[0046] In one embodiment of the reaction, the phase transfer catalyst is TBA-Br.

[0047] For example, the amount of the phase transfer catalyst is 1-10 mol% of farnesyl chloride (2), preferably 3-8 mol%, more preferably 5 mol%.

[0048] In one embodiment of the invention, a method for preparing the above-mentioned high farnesol (1) is provided, wherein farnesyl chloride (2) is provided as a mixture with carbamate (6).

[0049]

[0050] Wherein R' is an alkyl group selected from Me, Et, n-Pr, which may optionally be substituted, and

[0051] The two R” residues are the same or different alkyl groups selected from Me, Et, n-propyl, isopropyl, n-butyl, isobutyl, etc., or the two R” residues together form a cyclic system, such as morpholine, pyrrolidine, which may optionally be substituted.

[0052] Preferably, the two R” residues of the carbamate (6) are the same alkyl group selected from Et and n-propyl.

[0053] As described above, farnesyl chloride (2) can be obtained from farnesene (4) via farnesylamine (5) in two steps. The amine is treated with an alkyl chloroformate ClCO2R' to obtain a mixture of farnesyl chloride (2) and a byproduct carbamate (6), wherein R' is an alkyl group selected from Me, Et, n-Pr, optionally substituted, and the two R'" residues are the same or different alkyl groups selected from Me, Et, n-propyl, isopropyl, n-butyl, isobutyl, etc., or the two R'" residues together form a cyclic system, such as morpholine, pyrrolidine, optionally substituted. Preferably, the two R'" residues of the carbamate (6) are the same alkyl group selected from Et and n-propyl.

[0054] Normally, carbamate (6) is removed from farnesyl chloride (2) before further conversion to avoid side reactions, for example by distillation. However, farnesyl chloride (2) is unstable; and this stage is unfavorable because distillation leads to its partial decomposition. Surprisingly, it was found that alkoxycarbonylation of farnesyl chloride (2) is possible in the presence of carbamate (6) without undesirable side reactions. This allows for the preparation of farnesyl chloride (2) from farnesylamine (5) using ClCO2R', alkoxycarbonylation of the crude mixture without removing carbamate (6) from the unstable farnesyl chloride (2) by distillation, and easy separation of the more stable high farnesyl ester (3) from carbamate (6) by distillation.

[0055] Therefore, in one embodiment of the present invention, a method for preparing the above-mentioned high farnesol (1) is provided, wherein farnesyl chloride (2) is provided in the form of a mixture with urethane (6), which is obtained by treating farnesylamine (5) with alkyl chloroformate ClCO2R'.

[0056] In one embodiment of the reaction, a method for preparing the above-mentioned high farnesol (1) is provided, the method further comprising preparing farnesyl chloride (2) from β-farnesene (4) by the following additional step:

[0057] i) Provide farnesene (4)

[0058]

[0059] ii) React farnesene (4) to farnesylamine (5).

[0060] and

[0061] iii) React farnesylamine (5) to farnesyl chloride (2).

[0062]

[0063] For the preparation of (E,E)-farnesyl chloride ((E,E)-2), the starting material is (E,β)-farnesene ((E,β)-4).

[0064] Step ii) in the above method is the nucleophilic addition of dialkylamine R”2NH to farnesene (4) to obtain farnesylamine (5). The two R” residues are the same or different alkyl groups selected from Me, Et, n-propyl, isopropyl, n-butyl, isobutyl, etc., or the two R” residues together form a cyclic system, such as morpholine, pyrrolidine, which may optionally be substituted. Preferably, the two R” residues are the same alkyl group selected from Et and n-propyl.

[0065] Dialkylamines R”2NH have different boiling points, thus affecting reaction conditions and operation. Their selection also affects the yield of farnesylamine (5) and the E / Z ratio. The best results were obtained with diethylamine and dipropylamine.

[0066] In one embodiment of the invention, the E / Z ratio of the double bond at C3 of the high farnesol (1) is greater than 80:20, more particularly greater than 85:15, and still more particularly greater than 90:10.

[0067] In one embodiment of the invention, E,E-hofarnesol ((E,E)-1) is present in the isomer mixture at a percentage of 50% or higher, more particularly at 75%, more particularly at 85% or higher, and still more particularly at 90% or higher.

[0068] In one embodiment of the invention, the alkoxycarbonylation reaction is carried out under elevated pressure. For example, the reaction is carried out at a pressure of at least 2 bar or at least 10 bar, or at least 20 bar, or at least 25 bar or at least 50 bar or higher.

[0069] E,E-hofarnesol ((3E,7E)-4,8,12-trimethyldecadec-3,7,11-trien-1-ol, (E,E)-1, disclosed, for example, in US2013 / 0273619A1 or by Kocienski et al., J. Org. Chem. 54(5), 1215-1217, 1989) is of particular interest because, upon cyclization under conditions known in the art, depending on the cyclizing agent and conditions, specific configurations provide highly valuable fragrance components known as ambroxol, having high concentrations of the desired olfactory activity of the 3aR,5aS,9aS,9bR-enantiomers or the corresponding racemic mixtures (3aRS,5aSR,9aSR,9bRS). For example, the cyclization can be carried out by a biocatalytic method using squalene-hopaene cyclase (SHC).

[0070]

[0071] Therefore, in one embodiment of the present invention, a method for preparing ambroxan is provided, the method comprising preparing (E,E)-hofarnesol ((E,E)-1) according to the above method, and then cyclizing (E,E)-hofarnesol ((E,E)-1), the cyclization preferably being carried out by using the bacterial enzyme squalene-hopaene cyclase (SHC).

[0072]

[0073] The invention will now be further illustrated by the following non-limiting embodiments. Example

[0074] General:

[0075] GCMS: 50℃ / 2min, 20℃ / min 240℃, 35℃ / min 270℃. Agilent 5975C MSD with HP7890A series GC system. Nonpolar column: BPX5 from SGE, 5% phenyl 95% dimethyl polysiloxane, 0.2mm x 0.25μm x 12m. Carrier gas: Helium. Injector temperature: 230℃. Split ratio 1:50. Flow rate: 1.0ml / min. Transfer line: 250℃. MS-quadrupole: 160℃. MS-source: 230℃. Injection volume 1μL. Ionization mode electron collision (EI) at 70eV.

[0076] GC: 100℃ / 2min, 15℃ / min, 240℃, 240℃ / 5min. Thermal focusing GC. Non-polar column: Agilent Technologies J&W Scientific DB-5 ((5% phenyl)-methylpolysiloxane) 0.32mm x 0.25μm x 30m. Carrier gas: Helium. FID detector, detector temperature 270℃. Injector temperature: 240℃. Split ratio 1:42.3. Pressure 70kPa.

[0077] 1 H- and 13 C-NMR: Bruker-DPX-400MHz spectrometer; in CDCl3, at 400MHz ( 1 H) and 100MHz 13 C) Recorded spectra; δ, in ppm, relative to SiMe4; coupling constant J, in Hz. The 3,4-EZ ratios of perfarnesol 1, perfarnesyl chloride 2, perfarnesyl ester 3, and perfarnesylamine 5 were determined by integrating the corresponding NMR peaks.

[0078] abbreviation

[0079] dppe bis(diphenylphosphine)ethane

[0080] Et Ethyl

[0081] FC rapid chromatography

[0082] GC gas chromatography

[0083] See GC and MS for GCMS.

[0084] Hz Hertz

[0085] M molecular weight

[0086] Me methyl

[0087] MS mass spectrometry, molecular sieve

[0088] MHz

[0089] NMR (Nuclear Magnetic Resonance)

[0090] Pr n-propyl

[0091] quantification

[0092] rpa Total peak area (GC)

[0093] Ru-MACHO-BH Carbonyl Hydrogen (Tetrahydroboron) [Bis(2-Diphenylphosphinoethyl)-Amino]Ruthenium(II) (CAS 1295649-41-0)

[0094] TEBAB Tetrabutylammonium Bromide

[0095] Example 1: N,N'-DipropylE,E-Farnesylamine (E,E)-5a

[0096] Dipropylamine (844 g, 8.34 mol), (E,β)-farnesene ((E,β)-4, 1 kg, 4.8 mol), and lithium (3.5 g, 0.5 mol) were heated to 60 °C for 2 h under nitrogen and stirring. The mixture was cooled to 25 °C, and methanol (20 ml) was added to quench any remaining trace amounts of lithium. The mixture was filtered, and the filter cake was washed with methanol (220 ml). Methanol and dipropylamine were removed from the filtrate at 40 °C / 1 bar, and the residue was washed with water (1 L) and brine (300 ml). After drying with magnesium sulfate, the crude product was distilled at 130 °C / 1 mbar to give 1245 g of N,N'-dipropylE,E-farnesene (E,E)-5a, yield 76%, GC purity 90%.

[0097] 1H-NMR (400MHz, CDCl3): δ (ppm) = 5.3 (m, 1H), 5.1-5.2 (2H), 3.1 (m, 2H), 2.35 (m, 4H), 1.9-2.2 (8H), 1.95-2 .2(8H),1.65(2s,6H),1.55(2s,6H),1.73(s,3H),1.65(s,3H),1.6(s,6H),1.4-1.5(m,4H),0.85(t,6H).

[0098] 13 C-NMR (100MHz, CDCl3): δ (ppm) = 137.4 (s), 135.0 (s), 131.2 (s), 124.35 (d), 124.1 (d), 122.0 (d), 56.0 (t, 2C), 5 1.6(t),39.8(t),39.7(t),26.75(t),26.4(t),25.6(q),20.3(t,2C),17.6(q),16.3(q),15.95(q),12.0(q,2C).

[0099] GCMS: m / z = 305 [M] + (6%), 290 [M-15] + (3%), 276(28%), 236(58%), 168(12%), 154(100%), 137(10%), 114(21%), 100(12%), 81(41%), 72(71%), 69(67%), 55(13%), 43(18%), 41(36%).

[0100] Comparative Example 2: Preparation of E,E-perfarnesic ethyl ester ((E,E)-3a) from E,E-farnesyl chloride ((E,E)-2) under Kiji conditions

[0101] For the synthesis of E,E-farnesyl chloride, please refer to WO2019237005 (Amyris).

[0102] Following the general conditions described by Kiji et al. (Chemistry Letters 1873-1876, 1989), a reaction flask containing Na₂PdCl₄ (24 mg, 0.083 mmol, 0.65 mol%) and bis(diphenyl-phosphine)ethane (33 mg, 0.083 mmol) was evacuated and refilled three times with carbon monoxide. A solution of E,E-farnesyl chloride ((E,E)-2,3 g, 12.5 mmol, 2,3-EZ 98:2) in ethanol (5 mL) was added, and the pink solution was heated to 50 °C at 1 bar of carbon monoxide. At this temperature, a mixture of sodium ethoxide (4 g, 12.5 mmol) and ethanol (10 mL) in 21% ethanol was added dropwise over 2.5 h. After 1 h, complete conversion was detected by GC, and the reaction mixture was cooled to 25 °C. The carbon monoxide atmosphere was replaced with argon and the suspension was poured onto water (50 ml), followed by extraction with methyl tert-butyl ether. The combined organic phases were washed with water and brine and dried over MgSO4. The mixture was filtered and the solvent was evaporated under reduced pressure to give 3.1 g of crude product, which was purified by silica gel chromatography to give farnesene (0.9 g), O-ethyl nerolidol and E,E-farnesyl ether (0.5 g), E,Z-perfarnesate (70 mg, 2% yield) and E,E-perfarnesate ethyl 3a (0.99 g, 28% yield), with a 3,4-EZ ratio of 93:7. The analytical data for perfarnesate ethyl (E,E)-3a obtained therefrom were the same as those obtained by C. Chapuis et al. in Helv. Chim. Acta 102(7), 2019 in a 3,4-EZ 76:24 mixture.

[0103] This experiment shows that under Kiji's conditions, the yield of ethyl farnesate is relatively low, and byproducts are obtained.

[0104] Example 3: Preparation of E,E-perfarnesic ethyl ester ((E,E)-3a) from E,E-farnesyl chloride ((E,E)-2).

[0105] For the synthesis of E,E-farnesyl chloride, please refer to WO2019237005 (Amyris).

[0106] An autoclave containing E,E-farnesyl chloride ((E,E)-2, 100 g, 332 mmol, 3,4-EZ ratio 90:10) in water (128 ml) and ethanol (300 ml), potassium carbonate (143 g, 1.03 mol), and palladium on carbon (7.1 g, 3.3 mmol) was stirred at 25 bar for 24 h under carbon monoxide. The reaction mixture was filtered, and after removing ethanol under reduced pressure, the two-phase mixture was extracted with methyl tert-butyl ether. The combined organic phases were washed with an aqueous solution of NaHCO3 and brine, dried over MgSO4, and filtered. Solvent removal under reduced pressure yielded 92.5 g of crude ethyl farnesate (3a) (71% yield based on the E,E- isomer), with a purity of 80% (EZ) and a 3,4-EZ ratio of 89:11. The analytical data of the product, within slightly different 3,4-EZ ratios, were consistent with those obtained in Example 2.

[0107] Example 4: Preparation of E,E-perfarnesyl ethyl ester ((E,E)-3a) from N,N-dipropylE,E-farnesylamine ((E,E)-5a) via E,E-farnesyl chloride ((E,E)-2).

[0108] Methyl chloroformate (111 g, 1.17 mol) was slowly added to N,N-dipropyl-E,E-farnesylamine ((E,E)-5a, 351 g, 1.03 mol) over 3 h, maintaining a reaction temperature <25 °C. After another 30 h at 25 °C, the mixture was transferred to a 5 L autoclave. Tetrabutylammonium bromide (17 g, 53 mmol), Pd / carbon 5% (22 g, 10 mmol), ethanol (1 L), and K₂CO₃ (430 g, 3 mol) in water (385 g) were added. The autoclave was sealed, purged with carbon monoxide, and pressurized to 25 bar. After stirring at 25 °C for 24 h, the pressure was released. Ethanol (250 mL) and water (250 mL) were added, the reaction mixture was filtered through diatomaceous earth, and then the ethanol was evaporated at 40 °C / 100 mbar. After extraction with methyl tert-butyl ether, the combined organic phases were washed with saturated NaHCO3 and brine until pH = 7, dried over MgSO4, and filtered. The solvent was removed under reduced pressure. The crude product 3a was rapidly distilled to obtain the product, which was then fractionated at a column top temperature of 137 °C / 1 mbar to give 176 g (49% yield) of ethyl perfarnesate 3a, with a 3,4-EZ ratio of 91:9.

[0109] The analytical data for product 3a, within a slightly different range of 3,4-EZ ratios, are the same as those obtained in Example 2.

[0110] Example 5: Preparation of E,E-perfarnesol ((E,E)-1) from E,E-perfarnesol ((E,E)-3a) by reduction with red aluminum.

[0111] Ethyl E,E-perfarnesate ((E,E)-3a, 645 g, 1.9 mol, 3,4-EZ > 90:1) was added dropwise to a 65% aluminum red toluene solution (769 g, 2.5 mol) at 65-75 °C under nitrogen and stirring. One hour after the addition, the reactants were cooled to ambient temperature and slowly poured into 1 L of 20% NaOH with stirring. After stirring for 30 minutes, the phases were separated. The aqueous phase was washed with toluene. The combined organic phases were washed with water and brine, dried over MgSO4, and filtered. The solvent was removed under reduced pressure to obtain 634 g of crude product, which was rapidly distilled and then fractionated at 128 °C / 1 mbar to give 351 g (69% yield) of E,E-perfarnesol 1 with a purity of 87% (GC rpa, based on the E,E-isomer) and a 3,4-EZ ratio of 92:8. The analytical data for E,E-hofarnesol 1 are consistent with those in the literature, see, for example, P. Kocienski, S. Wadman J. Org. Chem. 54, 1215 (1989).

[0112] Example 6: Preparation of E,E-perfarnesol ((E,E)-1) from E,E-perfarnesol ((E,E)-3a) by homcat hydrogenation

[0113] Ethyl E,E-perfarnesate ((E,E)-3a, 1 g, 3.6 mmol) and Ru-Macho-BH (10.5 mg, 0.018 mmol) in tetrahydrofuran (10 ml) were hydrogenated in an autoclave at 100 °C under 50 bar of hydrogen. After 18 h, complete conversion to homoallyl alcohol was detected by GC. The mixture was filtered through a silica gel pad and THF was removed under reduced pressure to give 0.83 g (97% yield) of E,E-perfarnesol 1 as a clear yellow liquid with a 3,4-EZ ratio of 98:2. The analytical data of E,E-perfarnesol 1 were consistent with those of the same compound synthesized in Example 5.

Claims

1. A method for preparing high farnesol (1), (1), The method includes the following steps: a) Provide farnesyl chloride (2) (2)； b) React farnesyl chloride (2) into high farnesyl ester (3) via alkoxycarbonylation. (3); and c) React perfarnesate (3) to perfarnesol (1), Where R is C1-C 10 Alkyl groups, including cyclic systems, which may optionally be substituted; and The configurations of the double bonds in compounds 1, 2, and 3 are preserved. Furthermore, the alkoxy carbonylation is carried out in an aqueous ethanol solution under a CO atmosphere in the presence of palladium on carbon as a catalyst.

2. The method according to claim 1, wherein farnesyl chloride (2) is provided in the form of a mixture with urethane (6), (6), R' is an alkyl group selected from Me, Et, n-Pr, which may optionally be substituted, and the two R'' residues are the same or different alkyl groups selected from Me, Et, n-propyl, isopropyl, n-butyl, isobutyl, or the two R'' residues together form a cyclic system, which may optionally be substituted.

3. The method according to claim 2, wherein the two R'' residues of the carbamate (6) are the same alkyl group selected from Et and n-propyl.

4. The method according to claim 1 or 2, wherein the E / Z ratio of the double bond at C3 of the high farnesol (1) is greater than 80:

20.

5. The method according to claim 1 or 2, wherein R is Me or Et.

6. The method according to claim 1 or 2 above, wherein the reaction of perfarnesate (3) to perfarnesol (1) is a reduction.

7. The method according to claim 1 or 2, wherein the alkoxy carbonylation is carried out in the presence of a phase transfer catalyst.

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