Process

Abstract

Described herein is a method for making intermediates in the production of fragrance components starting from β-farnesene via a mixture comprising an epoxide represented by formula (III) as defined herein and an epoxide represented by formula (IV). In particular, methods for making acetylmethyl farnesol and hydroxyfarnesyl acetone and their homologues are described.

Description

Technical Field

[0001] Technical Field The present invention relates to a method for preparing intermediates in the production of fragrances such as amber ketal and amber ketal homologs starting from β-farnesene. In particular, the present invention relates to the production of acetylmethyl farnesol and hydroxyfarnesyl acetone and their homologs. The present invention further relates to a method for producing the intermediate.

Background Art

[0002] Background Amber ketal provides a strong and persistent amber and woody fragrance and is useful in fragrance compositions either alone or in combination with other woody or amber components. Amber ketal has traditionally been produced from ambergris through numerous chemical conversions. However, the supply of natural ambergris is limited. Therefore, it is desirable to provide a new efficient and cost-effective synthetic route for obtaining amber ketal and amber ketal homologs.

[0003] A synthetic route to an amber ketal homolog (Formula A) involving contacting a compound represented by Formula B (wherein R 1 is H, methyl or ethyl) with a squalene-hopene cyclase (SHC) enzyme or enzyme variant is disclosed in WO2021 / 209482.

Chemical Formula

[0004] Therefore, it is desirable to provide a new efficient access to the compound represented by Formula B that can be used in the production of amber ketal and amber ketal homologs.

Summary of the Invention

[0005] Summary According to a first aspect of the present invention, a compound represented by formula (V)

Chemical formula

Chemical formula

[0006] In a second aspect of the present invention, a compound represented by formula (V) is provided, wherein R 1 is selected from the group consisting of C1-C6 alkyl (such as ethyl, propyl, isopropyl, etc.), and Z is selected from Cl, I, and Br.

[0007] In a third aspect of the present invention, a compound represented by formula (VI)

Chemical formula

[0008] An embodiment of any aspect of the present invention has the following advantages: · Avoiding expensive and low-sustainability catalysts and ligands · Controlling the selectivity for one isomer, if desired · A continuous one-pot synthesis (telescope method) without directly isolating unreacted starting materials and / or intermediates One or more of which may be provided.

[0009] The details, examples and preferences provided with respect to one or more specific aspects of the present invention are further described herein and will be equally applicable to all aspects of the present invention. Combinations in all variations of any of the embodiments, examples and preferences described herein are encompassed by the present invention unless otherwise indicated herein or clearly contradicted by the context.

Problems to be Solved by the Invention

[0010] Detailed Description The present invention provides a novel and selective method for producing a compound represented by formula (I) via a mixture containing an epoxide of formula (III) and an epoxide of formula (IV). The compound represented by formula (I) may be used, for example, in the production of amber ketals and amber ketal homologs as described in WO2021 / 209482.

Means for Solving the Problems

[0011] In particular, the present invention is based on the surprising discovery that the conversion of epoxides (e.g., the epoxide of formula (III) and the epoxide of formula (IV) as defined herein) can be carried out at least in part without using an organometallic catalyst of a homogeneous transition metal catalyst (such as palladium, nickel, platinum, tungsten, iron, cobalt, copper, molybdenum, ruthenium, rhodium, iridium, etc.) which would be necessary for the Tsuji-Trost alkylation of 1,3-ketoesters by allyl epoxides and vinyl epoxides such as the epoxides of formula (IV) and formula (III).

[0012] The inventors have discovered that the conversion of epoxides is carried out in the presence of an acyl halide as an activator.

[0013] Thus, in a first aspect of the present invention, a compound represented by formula (V) [Chemical formula] is provided, wherein the method comprises a) contacting a mixture comprising a compound represented by formula (III) and a compound represented by formula (IV) [Chemical formula] with an acyl halide R 1 C(O)X (for example, acetyl chloride) optionally in the presence of a halide salt (AY), wherein R 1 is selected from the group consisting of C1-C6 alkyl (such as ethyl, propyl, isopropyl, etc.), X, Y, and Z are selected from Cl, I, and Br, and A is selected from Na, K, Li, and quaternary ammonium salts.

[0014] The epoxide of formula (III) and the epoxide of formula (IV) are generally obtained as a mixture from, for example, β-farnesene (7,11-dimethyl-3-methylene-1,6,10-dodecatriene) as described in International Patent Application WO2022 / 268840.

[0015] The inventors have surprisingly discovered that the ring-opening of the epoxide occurs for both epoxides or only for one of the epoxides by using an acyl halide optionally in the presence of a halide salt (i.e., in the presence or absence of a halide salt). This allows for the chemical separation of the epoxide of formula (III) and the epoxide of formula (IV), as will be described in more detail below if desired.

[0016] When a halide salt is not added in step a), 1,4-haloacylation is mainly observed with the exo-epoxide (the compound represented by formula (IV)) to form the compound represented by formula (V). Surprisingly, it has been found that the 1,2-epoxide (the compound represented by formula (III)) is slowly converted by the compound represented by formula (X) and its positional isomer (X').

Chemical formula

[0017] The same is also observed when a halide salt in which the halide is not iodine is added in step a), that is, mainly 1,4-haloacylation of the exo-epoxide and slower conversion of the 1,2-epoxide are carried out.

[0018] When a mixture containing the compound represented by formula (III) and the compound represented by formula (IV) is contacted with an acyl halide R1C(O)X in which X is Cl or Br in the absence of a halide salt or in the presence of a halide salt AY, where the halide Y is not iodine (for example, Y is Cl or Br), the (Z) isomer of the compound represented by formula (V), that is, the compound represented by formula (V')[[]]

Chemical formula

[0019] Therefore, in one specific embodiment of the first aspect of the present invention, a method for preparing a compound represented by formula (V') is provided, the method comprising: a) a mixture comprising a compound represented by formula (III) and a compound represented by formula (IV) is

Chemical formula

[0020] Without wishing to be bound by theory, the halide salt AY (as an example, Y is selected from Cl and Br) - may react with the acyl halide R 1 C(O)X to form a new acyl halide R 1 C(O)Y, and / or - may react in combination with the acyl halide R 1 C(O)X and open the epoxide. It is believed that.

[0021] When step a) is carried out with an acyl halide R 1 C(O)X in the presence of an iodine salt (AY, Y = I), either the 1,2-epoxide or the exo-epoxide is converted to the compound represented by formula (V) and the compound represented by formula (VI) at a similar rate, thus a mixture comprising the compound represented by formula (V) and the compound represented by formula (VI) [Chemical formula] In the formula, Z is iodine, and R 1 is selected from the group consisting of C1-C6 alkyl (such as ethyl, propyl, isopropyl, etc.), and it was observed that it can be obtained.

[0022] The same thing was also observed when step a) was carried out with acyl iodide (i.e., R 1 C(O)X, where X = I).

[0023] Therefore, in a further aspect of the first aspect of the present invention, a method for preparing a composition containing a compound represented by formula (V) and a compound represented by formula (VI) [Chemical formula] is provided, The method comprises a) contacting a mixture containing a compound represented by formula (III) and a compound represented by formula (IV) [Chemical formula] with acyl iodide R1C(O)I or acyl halide R1C(O)X (X is selected from Cl and Br) in the presence of iodine salt AI, where A is selected from Na, K, Li, and quaternary ammonium salts, and where R 1 is selected from the group consisting of C1-C6 alkyl (such as ethyl, propyl, isopropyl, etc.), and Z is iodine.

[0024] The ratio of the compound represented by formula (V) to the compound represented by formula (VI) is the same as the ratio of the starting materials, that is, it is maintained at the ratio of the epoxides. For example, if the epoxides (III) and (IV) are present in a ratio of about 1:1, the compounds represented by formula (V) and formula (VI) will also be in a ratio of about 1:1.

[0025] ​The acyl halide R present in step a) 1 C(O)X, in one specific embodiment, is selected from acyl chlorides of the formula R 1 C(O)Cl, wherein R 1 is selected from the group consisting of C1-C6 alkyl (such as ethyl, propyl, isopropyl, etc.).

[0026] In some examples, the acyl halide R present in step a) 1 C(O)X is selected from acetyl chloride and acetyl bromide.

[0027] In some examples, the acyl halide R present in step a) 1 C(O)X is added in an amount of about 0.9 to about 1.5 molar equivalents (e.g., about 1 to about 1.2 molar equivalents) relative to the total amount of the epoxides (the compound represented by formula (IV) and the compound represented by formula (III)).

[0028] In some examples, the acyl halide R present in step a) 1 C(O)X is added in an amount of about 0.9 to about 1.5 molar equivalents (e.g., about 1 to about 1.2 molar equivalents) relative to the amount of the compound represented by formula (IV).

[0029] When present in step a), the halide salt is the compound AY, wherein A is selected from Na, K, Li, and quaternary ammonium salts (e.g., tetraalkylammonium, such as tetra-n-butylammonium), and Y is selected from Cl, I, and Br, unless otherwise indicated.

[0030] In some examples, the halide salt present in step a) is selected from NaCl, NaI, NaBr, LiI, LiBr, KI, and KBr.

[0031] In some examples, the halide salt present in step a) is tetra C1-C 15It is an alkylammonium (for example, tetra-n-butylammonium, n-methyl-tri-n-octylammonium).

[0032] In some examples, when present in step a), the halide salt is present in an amount of about 0.01 to about 1.2 molar equivalents, such as about 0.05 to about 1.1 molar equivalents, such as about 0.1 to about 1 molar equivalent, such as about 0.2 to about 0.9 molar equivalent, such as about 0.3 to about 0.8 molar equivalent, such as about 0.4 to about 0.7 molar equivalent, such as about 0.5 to about 0.6 molar equivalent, relative to the total amount of the epoxides (the compounds represented by formula (IV) and the compounds represented by formula (III)).

[0033] In some examples, when present in step a), the halide salt is added in an amount of about 0.01 to about 1.2 molar equivalents, such as about 0.05 to about 1.1 molar equivalents, such as about 0.1 to about 1 molar equivalent, such as about 0.2 to about 0.9 molar equivalent, such as about 0.3 to about 0.8 molar equivalent, such as about 0.4 to about 0.7 molar equivalent, such as about 0.5 to about 0.6 molar equivalent, relative to the amount of the compound represented by formula (IV).

[0034] In some examples, the method described herein is carried out at room temperature or a temperature below it, such as from about 0 °C to room temperature, or from about 5 °C to room temperature, which includes 10 °C. Room temperature may be a temperature of about 20 °C to about 25 °C.

[0035] In some examples, the method described herein is carried out at room temperature (about 20 °C to about 25 °C) or above it, such as from about room temperature to 120 °C (by way of example, up to 100 °C or up to 70 °C), which includes a temperature of about 25 °C to about 65 °C (by way of example, about 50 °C).

[0036] In some examples, the method described herein is carried out at a temperature that is the reflux temperature of each solvent used.

[0037] In some examples, the methods described herein are carried out in the presence of a solvent. In some examples, the solvent is either a) an ether solvent such as dibutyl ether, methyltetrahydrofuran (Me-THF), tetrahydrofuran (THF), or b) toluene, cyclohexane, or acetonitrile (MeCN).

[0038] In some examples, a method for making a compound represented by formula (V’), a compound represented by formula (X), and a compound represented by formula (X’), or a mixture thereof, comprises contacting a mixture comprising a compound represented by formula (IV) and a compound represented by formula (III) with a) an acyl halide R 1 C(O)X, wherein X is Cl or Br and no halide salt is present, or b) an acyl halide R 1 C(O)X, wherein X is Cl or Br, in the presence of a halide salt AY, wherein Y is Cl or Br and A is selected from Na, K, Li, and quaternary ammonium salts, for about 0.5 hour to about 24 hours, for example, about 1 hour to about 18 hours, for example, about 1.5 hours to about 12 hours, for example, about 2 hours to about 8 hours, for example about 3 hours to about 4 hours.

[0039] A longer reaction time may result in the formation of a higher amount of the compounds represented by formulas (X) and (X’). Thus, the reaction time should be as short as possible. Good selectivity for the compound represented by formula (V’) is obtained, for example, in about 0.5 hour to 5 hours, for example, about 2 hours to about 4 hours.

[0040] In some examples, the compounds represented by formula (III) and the compounds represented by formula (IV) are the E-forms of (III) and (IV).

Chemical formula

[0041] In some examples, the compound represented by formula (III) is farnesene 1,2-epoxide, a compound having the CAS number [83637-40-5].

[0042] In some examples, the compound represented by formula (IV) is farnesene exoepoxide, a compound represented by the CAS number [1404220-65-0].

[0043] Thus, the composition of the first aspect of the present invention containing the compound represented by formula (V) (covering the compound represented by formula (V’)) is the compound represented by formula (VII)

Chemical formula

Chemical formula

Chemical formula

[0044] As described herein, mainly whether the compound represented by formula (V) (covering the compound represented by formula (V’)) is obtained, a mixture containing the compound represented by formula (V) and the compound represented by formula (VI) is obtained, or a mixture containing the compound represented by formula (V’) and the compounds represented by formula (X) and (X’) is obtained depends on the additive added in step a) and the subsequent purification method.

[0045] Thus, in a further aspect of the present invention, a compound represented by formula (I)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0046] As already described above, a) in the presence of an acyl halide R1C(O)X, wherein X is selected from Cl and Br, and in the absence of a halide salt, or b) in the presence of an acyl halide R1C(O)X, wherein X is selected from Cl and Br, and in the presence of a chloride salt or a bromide salt (AY, wherein Y is selected from Cl and Br, and A has the meaning provided above in the present specification) the (Z) isomer of the compound represented by formula (V), i.e., the compound represented by formula (V'), is formed almost exclusively, and thus, in step b), the (Z) isomer of the compound represented by formula (VIII) (i.e., the compound represented by formula (VIII'))

Chemical formula

Chemical formula

[0047] This method can selectively prepare the compound of formula (I’) from β-farnesene via the epoxide of formula (IV), which has the advantage of allowing easier isolation of the said compound. This method also allows easier separation from the unreacted compound of formula (III) or its derivative, which is any of the compound represented by formula (V’), the compound represented by formula (VIII’), or the compound represented by formula (I’). As a result, the overall yield is increased.

[0048] In a further aspect of the present invention, a compound represented by formula (I) and a compound represented by formula (II)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0049] In certain embodiments, the method comprising steps a) to c) should be understood as performing a continuous one-pot synthesis (telescoping procedure) without directly separating unreacted starting materials and intermediates.

[0050] In another specific embodiment, a method comprising steps a) to c) is provided, wherein the product obtained in step a) (the compound represented by formula (V) and the compound represented by formula (VI)) is first purified, and the method comprising steps b) and c) follows as a continuous one-pot synthesis.

[0051] In another specific embodiment, a method comprising steps a) to c) is provided, wherein the product obtained in step a) (the compound represented by formula (V')) is first purified, and then the method comprising steps b) and c) is performed as a continuous one-pot synthesis.

[0052] The compound represented by formula (I) exists in the form of four different stereoisomers, for example, as the compound represented by formula (I) having an E,E- or E,Z-configuration. The stereochemistry of the double bond between C-8 and C-9 remains unchanged during the process of preparing the compound represented by formula (I), the compound represented by formula (II), or a mixture thereof. In other words, when the compound represented by formula (IV) in which the double bond is in the E-configuration is used as the starting material, the double bond between C-8 and C-9 of the compound represented by formula (I) remains in the E-configuration. When the compound represented by formula (IV) in which the double bond is in the Z-configuration is used as the starting material, the double bond between C-8 and C-9 of the compound represented by formula (I) remains in the Z-configuration.

[0053] The same applies to the compound represented by formula (II). In other words, when the compound represented by formula (III) in which the double bond is in the E-configuration is used as the starting material, the double bond between C-8 and C-9 of the compound represented by formula (II) remains in the E-configuration. When the compound represented by formula (III) in which the double bond is in the Z-configuration is used as the starting material, the double bond between C-8 and C-9 of the compound represented by formula (II) remains in the Z-configuration.

[0054] In a specific embodiment, the compound represented by formula (I) is obtained in a state enriched with the isomer of formula (I) in which the double bond between C-4 and C-5 is in the Z-configuration. Enrichment means that the amount of the compound represented by formula (I) (formula (I')) in which the double bond between C-4 and C-5 is in the Z-configuration is higher than 50% with respect to the compound represented by formula (I) in which the double bond between C-4 and C-5 is in the E-configuration (for example, the ratio of the Z-configuration compound to the E-configuration compound of formula (I) is equal to or greater than 51:49). For example, the weight ratio of the Z-configuration compound of formula (I) to the E-configuration compound of formula (I) is equal to or greater than 2:1 (for example, 3:1 or greater, 4:1 or greater, 5:1 or greater, 6:1 or greater, 7:1 or greater, 8:1 or greater, 9:1 or greater, 10:1 or greater).

[0055] In a specific example, R 1 is methyl. When R 1 is methyl, the compound represented by formula (I) may be referred to as hydroxyl-farnesylacetone (6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one), E,Z-hydroxylfarnesylacetone (CAS 173198-97-5, that is, the compound represented by formula (I) in which the double bond between C-4 and C-5 is in the Z configuration and the double bond between C-8 and C-9 is in the E configuration), E,E-hydroxylfarnesylacetone, Z,Z-hydroxylfarnesylacetone, and Z,E-hydroxylfarnesylacetone are covered.

[0056] R 1 When is methyl, the compound represented by formula (II) may be referred to as acetylmethyl farnesol.

[0057] The compound represented by formula (V) (including the compound represented by formula (V')) has not been described in the literature, and therefore it is novel per se.

[0058] Therefore, in a second aspect of the present invention, the compound represented by formula (V)

Chemical formula

[0059] The compound represented by formula (VI) has not been described in the literature and is therefore novel per se.

[0060] Therefore, in a third aspect of the present invention, the compound represented by formula (VI)

Chemical formula

[0061] The compound represented by formula (VII) is an oxoalkanoic acid, an oxoalkanoic acid ester, malonic acid or a malonic acid ester. The compound represented by formula (VII) may be an oxoalkanoic acid ester or a malonic acid ester.

Chemical formula

[0062] In some examples, R is selected from the group consisting of hydrogen and C1-C6 alkyl groups. In some examples, R is selected from the group consisting of hydrogen, methyl, ethyl, propyl and isopropyl. In some examples, R is selected from the group consisting of hydrogen, methyl and ethyl. In some examples, R is methyl.

[0063] In some examples, R' is selected from the group consisting of C1-C6 alkyl groups and OR groups. In some examples, R' is selected from the group consisting of C1-C6 alkyl groups, hydroxyl groups, and C1-C6 alkoxy groups. In some examples, R' is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, hydroxyl, methoxy, ethoxy, propoxy and isopropoxy. In some examples, R' is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl. In some examples, R' is a hydroxyl or methyl group. In some examples, R' is a methyl group.

[0064] In some examples, the compound represented by formula (VII) is the compound represented by formula (VIIa).

Chemical formula

[0065] In some examples, the sodium salt of the compound represented by formula (VII) (including the compound represented by formula (VIIa)) is used. Said salts are commercially available or can be prepared according to procedures well known to those skilled in the art.

[0066] In some examples, step b) of the methods described herein is carried out in the presence of a base, in particular a non-nucleophilic base such as potassium carbonate (K2CO3).

[0067] The examples described herein are illustrative of the disclosure and are not intended to be limiting thereof. Various aspects of the disclosure have been described in accordance with the disclosure. Many modifications and variations can be made to the techniques described and illustrated herein without departing from the spirit and scope of the invention. Thus, it should be understood that the examples are for illustration only and do not limit the scope of the disclosure.

Examples

[0068] Example The following illustrate examples of the methods and other aspects described herein. Thus, these examples should not be considered as limitations of the disclosure, but are only there to teach how to make examples of the disclosure.

[0069] Example 1: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one A mixture of beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)) and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (100 g; beta-farnesene / E-formula (IV) / E-formula (III) = 1:0.7:0.5; 118 mmol E-formula (IV)) in Me-THF (100 ml) was treated dropwise with acetyl chloride (10.2 ml, 142 mmol) at 5 °C. The resulting mixture was stirred at 60 °C for 7 hours, at 50 °C for 16 hours, and at 60 °C for 6 hours. After evaporating the solvent under reduced pressure, a crude mixture containing (2Z,5E)-2-(2-chloroethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate (E-formula (V’), Z = Cl) was isolated. The mixture was cooled to 5 °C and successively treated with Me-THF (65 ml), methyl acetoacetate (formula (VII), R = Me, R’ = Me; 28.3 ml, 260 mmol), aliquot 336 (0.48 g, 1.18 mmol) and potassium carbonate (36.6 g, 260 mmol). The resulting mixture was stirred at 70 °C for 17 hours, cooled to room temperature, and successively treated with water (60 ml) and, dropwise (while maintaining the internal temperature at 10 °C), with 8 M aqueous NaOH solution (59 ml). The resulting biphasic mixture was vigorously stirred at room temperature for 3 hours and refluxed for 12 hours with the successive addition of 8 M aqueous NaOH solution (50 ml) after 3 hours.

[0070] The resulting mixture was cooled to room temperature and diluted with MTBE (30 ml) and water (75 ml). The aqueous phase was extracted with MTBE (3 x 40 ml). The combined organic phases were washed with saturated aqueous NH4Cl solution (500 ml) and water (2 x 500 ml), dried over MgSO4, filtered, and concentrated under reduced pressure to afford a crude orange oil containing beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)), (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)), and (5Z,9E)-6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,Z-formula (I), R’ = Me) (105.8 g; beta-farnesene / E-formula (IV) / E-formula (III) / E,Z-formula (I) = 1:0.1:0.5:0.5).

[0071] (5Z,9E)-6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one: 1 H NMR (400 MHz, CDCl3) δ ppm 5.17 (t, J = 7.6, 1H), 5.13 - 5.05 (m, 2H), 4.14 (s, 2H), 3.00 - 2.55 (br. s, OH), 2.55 (t, J = 6.7, 2H), 2.35 (dt, J = 6.9, 7.1, 2H), 2.13 (s, 3H, MeCO), 2.17 - 2.01 (m, 6H), 2.00 - 1.92 (m, 2H), 1.67 (br. s, 3H), 1.60 (br. s, 3H), 1.59 (br. s, 3H). 1313C NMR (100 MHz, CDCl3) δ ppm 209.02 (s, 1 C, C=O), 139.79 (s, 1 C), 135.30 (s, 1 C), 131.27 (s, 1 C), 126.65 (d, 1 C), 124.26 (d, 1 C), 123.85 (d, 1 C), 60.20 (t, 1 C), 43.19 (t, 1 C), 39.66 (t, 1 C), 35.60 (t, 1 C), 30.15 (q, 1 C), 26.74 (t, 1 C), 26.69 (t, 1 C), 25.66 (q, 1 C), 21.73 (t, 1 C), 17.65 (q, 1 C), 16.01 (q, 1 C). GC-MS (EI): 278 (1), 260 (1, [M-H2O] + ), 245 (1), 217 (3), 202 (1), 178 (5), 159 (4), 141 (5), 137 (4), 133 (19), 123 (13),105 (11), 95 (16), 93 (16), 81 (34), 79 (15), 69 (100), 67 (19), 55 (15), 43 (87), 41 (62), 31 (1).

[0072] Example 2: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one A mixture of beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)) and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (100 g; beta-farnesene / E-formula (IV) / E-formula (III) = 1:0.65:0.45; 110 mmol E-formula (IV)) in Me-THF (90 ml) was treated dropwise with acetyl chloride (9.5 ml, 132 mmol) at 5 °C. The resulting mixture was stirred at 65 °C for 7 hours, at 50 °C for 15 hours, and at 60 °C for 5 hours. The resulting solution was cooled to 5 °C and treated successively with methyl acetoacetate (formula (VII), R = Me, R' = Me, 26.4 ml, 243 mmol), Aliquat 336 (0.45 g, 1.1 mmol) and potassium carbonate (34.2 g, 243 mmol). The resulting mixture was stirred at 70 °C for 15 hours, cooled to room temperature, treated successively with water (60 ml) and then dropwise with 50% aqueous NaOH solution (44 g) while maintaining the internal temperature at 10 °C. The resulting biphasic mixture was stirred vigorously at room temperature for 1 hour and then refluxed continuously for 8 hours with the addition of 50% NaOH solution (23 ml) after 3 hours.

[0073] The reaction mixture was cooled to room temperature and diluted with MTBE (30 ml) and water (75 ml). The aqueous phase was extracted with MTBE (3 x 40 ml). The combined organic phases were washed with saturated aqueous NH4Cl (500 ml) and water (2 x 500 ml), dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude orange oil containing beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)), (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)), and (5Z,9E)-6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,Z-formula (I), R’=Me) (105.8 g; beta-farnesene / E-formula (IV) / E-formula (III) / E,Z-formula (I) = 1:0.04:0.45:0.41).

[0074] Example 3: (2Z,5E)-2-(2-Chloroethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate A mixture of beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)) and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (100 g; beta-farnesene / E-formula (IV) / E-formula (III) = 1:0.9:0.6; 136 mmol E-formula (IV)) in Me-THF (90 ml) was treated dropwise with acetyl chloride (12.1 ml, 170 mmol) at 10 °C. The resulting mixture was stirred at 60 °C for 18 hours. After evaporating the solvent under reduced pressure, a crude mixture containing (2Z,5E)-2-(2-chloroethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate (E-formula (V’), Z = Cl) was isolated. The mixture was placed in a distillation apparatus and polymer amine (0.5 g) was added as a stabilizer. The mixture was short-path distilled at 0.03 mbar to obtain a mixture of beta-farnesene and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (58.1 g, beta-farnesene / E-formula (III) = 1:0.4) with a boiling point range of 88 - 93 °C and (2Z,5E)-2-(2-chloroethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate (33.0 g, purity 75%, yield 59% / E-formula (V’), Z = Cl) with a boiling point of 142 °C.

[0075] (2Z,5E)-2-(2-chloroethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate: 1 H NMR (400 MHz, CDCl3) δ ppm 5.65 (br. t, J = 8.1, 1 H), 5.15 - 5.05 (m, 2H), 4.64 (s, 2H), 4.16 (d, J = 8.1, 2H), 2.06 (s, 3H), 2.25 - 1.95 (m, 8H), 1.68 (br. s, 3H), 1.61 (s, 6H). 1313C NMR (100 MHz, CDCl3) δ ppm 170.74 (s, 1 C), 139.54 (s, 1 C), 136.03 (s, 1 C), 131.36 (s, 1 C), 125.68 (d, 1 C), 124.21 (d, 1 C), 122.94 (d, 1 C), 61.18 (t, 1 C), 39.63 (t, 2 C), 35.10 (t, 1 C), 26.65 (t, 1 C), 26.16 (t, 1 C), 25.66 (q, 1 C), 20.88 (q, 1 C), 17.66 (q, 1 C), 16.04 (q, 1 C). GC-MS (EI): 298 (1), 262 (1), 239 (1), 223 (1), 203 (2), 195 (3), 159 (2), 137 (6), 133 (10), 123 (7), 105 (13), 93 (17), 91 (18), 81 (28), 69 (100), 79 (13), 67 (16), 55 (10), 53 (10), 43 (41), 41 (47).

[0076] Example 4: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (2Z,5E)-2-(2-Chloroethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate, Aliquat 336 (0.34 g, 0.83 mmol) (solution of E-form (V’), Z = Cl; 40.0 g, 100 mmol prepared according to Example 3) and methyl acetoacetate (formula (VII), R = Me, R’ = Me; 19 ml, 180 mmol) in Me-THF (40 ml) were cooled to 10 °C and treated with potassium carbonate (25 g, 180 mmol). The resulting mixture was stirred at 70 °C for 3 h, cooled to room temperature and treated successively with water (20 ml) and 32% aqueous NaOH solution (32 ml). The resulting mixture was stirred at reflux temperature for 4 h with subsequent addition of 32% aqueous NaOH solution (21 ml) after 3 h.

[0077] The resulting mixture was cooled to room temperature and diluted with water (80 ml). The aqueous phase was extracted with MTBE (100 ml). The combined organic phases were washed with saturated aqueous NH4Cl (200 ml), water (200 ml) and saturated aqueous NaCl (200 ml), dried over MgSO4, filtered and concentrated under reduced pressure to give (5Z,9E)-6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,Z-formula (I), R’ = Me) (37.1 g, purity 55%, yield 73%).

[0078] Example 5: (2Z,5E)-2-(2-Iodoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate and (2E,5E)-2-(2-Iodoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate At 5 °C, a solution of (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)) (0.30 g, 1.36 mmol) and NaI (0.21 g, 1.36 mmol) in MeCN (1 ml) was treated dropwise with acetyl chloride (0.1 ml, 1.43 mmol). The resulting mixture was stirred at 5 °C for 30 min and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (3 times). The combined organic phases were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure to afford a crude yellow oil containing (2Z,5E)-2-(2-iodoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate (E,Z-formula (V), Z = I) and (2E,5E)-2-(2-iodoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate (E,E-formula (V), Z = I) (0.46 g; E,Z-formula (V) / E,E-formula (V) = 3.5:1).

[0079] 1 H-NMR (400 MHz, CDCl3) δ ppm selected signals (E,Z-Formula (V)) 5.74 (br. t, J = 8.9, 1H), 5.18 - 5.03 (m, 2H), 4.63 (s, 2H, CH2O), 3.96 (d, J = 8.9, 2H, CH2I), 2.08 (s, 3H, Ac), 1.67 (s, 3H), 1.59 (s, 6H). 13 13C NMR (101 MHz, CDCl3) δ ppm signals for (E,Z-Formula (V)) 170.83 (s, 1 C), 138.30 (s, 1 C), 135.88 (s, 1 C), 131.23 (s, 1 C), 127.34 (d, 1 C), 124.18 (d, 1 C), 122.86 (d, 1 C), 60.67 (t, 1 C), 39.56 (t, 1 C), 35.20 (t, 1 C), 26.57 (t, 1 C), 26.00 (t, 1 C), 25.61 (q, 1 C), 20.79 (q, 1 C), 17.62 (q, 1 C), 15.99 (q, 1 C), 0.19 (t, 1 C, CH2I). 10 - 20% minor E,E-Formula (V).

[0080] Example 6: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,Z-form (I), R’ = Me), (5E,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,E-form (I), R’ = Me), (5Z,8E)-5-(2-Hydroxyethylidene)-9,13-dimethyltetradeca-8,12-dien-2-one (E,Z-form (II), R’ = Me), and (5E,8E)-5-(2-Hydroxyethylidene)-9,13-dimethyltetradeca-8,12-dien-2-one (E,E-form (II), R’ = Me) A solution of a mixture of β-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-Formula (IV)) and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-Formula (III)) (0.5 g; β-farnesene / E-Formula (IV) / E-Formula (III) = 1:0.9:0.7; 1.18 mmol E-Formula (IV)) and NaI (0.18 g; 1.18 mmol) in MeCN (4 ml) was treated dropwise with acetyl chloride (0.09 ml, 1.24 mmol) and stirred at 5 °C for 2 h. The resulting solution was successively treated with methyl acetoacetate (Formula (VII), R = Me, R’ = Me; 0.26 ml, 2.36 mmol) and potassium carbonate (0.33 g, 2.36 mmol). The resulting mixture was stirred at 60 °C for 4 h, cooled to room temperature and diluted with MTBE and water. The aqueous phase was extracted with MTBE (3 times). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure to give β-farnesene, (E,Z-Formula (VIII), R = R 1 =R’ = Me), (E,E-Formula (VIII), R = R 1=R’=Me), (E,Z-formula (IX), R = R 1 =R’=Me), and (E,E-formula (IX), R = R 1 gave a crude dark yellow oil containing a mixture (0.66 g) of =R’=Me).

[0081] A mixture of the above crude mixture and water (0.45 ml) was treated by dropwise addition with a 32% aqueous solution of NaOH solution (0.45 ml). The resulting biphasic mixture was stirred under reflux for 1 hour. The reaction mixture was cooled to room temperature and diluted with MTBE and water. The aqueous phase was extracted with MTBE (3). The combined organic phases were washed with saturated aqueous NH4Cl and saturated aqueous NaCl (twice), dried over MgSO4, filtered, and concentrated under reduced pressure to give 54% beta-farnesene, 11% (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)), and 35% of a mixture of (5Z,9E)-6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,Z-formula (I), R’ = Me), (5E,9E)-6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,E-formula (I), R’ = Me), (5Z,8E)-5-(2-hydroxyethylidene)-9,13-dimethyltetradeca-8,12-dien-2-one (E,Z-formula (II), R’ = Me), and (5E,8E)-5-(2-hydroxyethylidene)-9,13-dimethyltetradeca-8,12-dien-2-one (E,E-formula (II), R’ = Me) in a ratio of E,Z-formula (I) / E,E-formula (I) / E,Z-formula (II) / E,E-formula (II) = 5.5:1.0:3.3:1.9, yielding 0.39 g of a crude orange oil.

[0082] (5Z,9E)-6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one: For analytical data, see Example 1

[0083] (5E,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one: 1 H NMR (400 MHz, CDCl3) δ ppm 5.33 (t, J = 7.2, 1H), 5.13 - 5.01 (m, 2H), 3.98 (br. s, 2H), 2.46 (t, J = 7.3, 2H), 2.29 (dt, J = 7.1, 7.3, 2H), 2.22 - 2.05 (br. s, OH), 2.10 (s, 3H, MeCO), 2.13 - 1.98 (m, 6H), 1.97 - 1.90 (m, 2H), 1.64 (br. s, 3H), 1.56 (br. s, 6H). 13 C NMR (100 MHz, CDCl3) δ ppm 208.37 (s, 1 C), 139.91 (s, 1 C), 135.46 (s, 1 C), 131.19 (s, 1 C), 124.42 (d, 1 C), 124.11 (d, 1 C), 123.60 (d, 1 C), 66.54 (t, 1 C), 43.40 (t, 1 C), 39.57 (t, 1 C), 29.75 (q, 1 C), 27.96 (t, 1 C), 26.75 (t, 1 C), 26.51 (t, 1 C), 25.52 (q, 1 C), 21.68 (t, 1 C), 17.51 (q, 1 C), 15.84 (q, 1 C).

[0084] (5Z,8E)-5-(2-Hydroxyethylidene)-9,13-dimethyltetradeca-8,12-dien-2-one: 11H NMR (400 MHz, CDCl3) δ ppm 5.45 (t, J = 7.2, 1H), 5.10 - 5.02 (m, 2H), 4.11 (d, J = 7.1, 2H), 2.53 (t, J = 7.4, 2H), 2.32 (t, J = 7.4, 2H), 2.11 (s, 3H, MeCO), 2.10 - 1.90 (m, 8H), 1.65 (br. s, 3H), 1.57 (s, 6H). 13 13C NMR (100 MHz, CDCl3) δ ppm 208.47 (s, 1 C), 141.50 (s, 1 C), 135.45 (s, 1 C), 131.19 (s, 1 C), 124.81 (d, 1 C), 124.15 (d, 1 C), 123.42 (d, 1 C), 58.50 (t, 1 C), 41.89 (t, 1 C), 39.56 (t, 1 C), 36.14 (t, 1 C), 29.96 (q, 1 C), 26.57 (t, 1 C), 26.34 (t, 1 C), 25.56 (q, 1 C), 23.96 (t, 1 C), 17.55 (q, 1 C) 15.92 (q, 1 C).

[0085] (5E,8E)-5-(2-Hydroxyethylidene)-9,13-dimethyltetradeca-8,12-dien-2-one: 1H NMR (400 MHz, CDCl3) δ ppm 5.35 (br. t, J = 6.9, 1H), 5.10 - 5.02 (m, 2H), 4.10 (d, J = 6.9, 2H), 2.57 - 2.52 (m, 2H), 2.28 (t, J = 7.1, 2H), 2.13 (s, 3H, MeCO), 2.10 - 1.90 (m, 8H), 1.65 (br. s, 3H), 1.57 (s, 6H). 1313C NMR (100 MHz, CDCl3) δ ppm 208.23 (s, 1 C), 141.48 (s, 1 C), 135.92 (s, 1 C), 131.28 (s, 1 C), 124.27 (d, 1 C), 124.08 (d, 1 C), 123.25 (d, 1 C), 58.77 (t, 1 C), 41.93 (t, 1 C), 39.56 (t, 1 C), 30.64 (t, 1 C), 30.16 (t, 1 C), 29.80 (q, 1 C), 26.81 (t, 1 C), 26.52 (t, 1 C), 25.56 (q, 1 C), 17.55 (q, 1 C), 15.89 (q, 1 C).

[0086] Example 7: (E)-2-Chloro-7,11-dimethyl-3-methylenedeca-6,10-dien-1-yl acetate and (E)-1-Chloro-7,11-dimethyl-3-methylenedeca-6,10-dien-2-yl acetate A solution of (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (0.50 g, 2.1 mmol) in MeCN (3 ml) was treated dropwise with acetyl chloride (0.16 ml, 2.2 mmol) at 5 °C. The resulting mixture was stirred at 5 °C for 3 hours and at room temperature for 24 hours and then diluted with MTBE and water. The aqueous phase was extracted with MTBE (3 times). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure to give 0.62 g of a crude orange oil containing a mixture of (E)-2-chloro-7,11-dimethyl-3-methylenedeca-6,10-dien-1-yl acetate (E-formula (X), Z = Cl) and (E)-1-chloro-7,11-dimethyl-3-methylenedeca-6,10-dien-2-yl acetate (E-formula (X’), Z = Cl) (E-formula (X) / E-formula (X’) = 5.5:1) and unconfirmed by-products.

[0087] (E)-2-chloro-7,11-dimethyl-3-methylenedeca-6,10-dien-1-yl acetate: 1H-NMR (500 MHz, CDCl3) δ ppm 5.19 (br. s, 1H), 5.15 - 5.06 (m, 2H), 5.05 (br. m, 1H), 4.55 (br. t, J = 6.9, 1H, CHCl), 4.30 (d, J = 6.8, 2H, CH2O), 2.23 - 1.94 (m, 8H), 2.07 (s, 3H), 1.67 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H). 3 C NMR (125 MHz, CDCl3) δ ppm 170.39 (s, 1 C), 144.91 (s, 1 C), 135.83 (s, 1 C), 131.24 (s, 1 C), 124.16 (d, 1 C), 123.16 (d, 1 C), 114.73 (t, 1 C), 65.86 (t, 1 C), 61.24 (d, 1 C), 39.57 (t, 1 C), 31.36 (t, 1 C), 26.55 (t, 1 C), 26.07 (t, 1 C), 25.60 (q, 1 C), 20.64 (q, 1 C), 17.59 (q, 1 C), 15.98 (q, 1 C). GC-MS (EI): 298 (1), 283 (1), 238 (1), 223 (1), 203 (2), 137 (3), 133 (12), 123 (7), 105 (12), 93 (16), 91 (15), 81 (21), 69 (100), 79 (11), 67 (12), 55 (9), 53 (9), 43 (50), 41 (45).

[0088] (E)-1-chloro-7,11-dimethyl-3-methylidenedeca-6,10-dien-2-yl acetate: 11H-NMR (500 MHz, CDCl3) δ ppm 5.21 (broad singlet, 1H), 5.15 - 5.06 (multiplet, 2H), 5.01 (broad multiplet, 1H), 4.47 (doublet of doublets, J = 5.5, 7.3, 1H, CHCl), 3.82 (doublet of doublets, J = 5.3, 11.9, 1H, CH2O), 3.78 (doublet of doublets, J = 7.5, 11.9, 1H, CH2O), 2.28 - 1.94 (multiplet, 8H), 2.07 (singlet, 3H), 1.67 (singlet, 3H), 1.61 (singlet, 3H), 1.59 (singlet, 3H). 13 13C NMR (125 MHz, CDCl3) δ ppm (selected signals) 175.49 (singlet, 1C), 114.60 (triplet, 1C) 66.34 (doublet, 1C) 65.42 (triplet, 1C).

[0089] Example 8: (2Z,5E)-2-(2-Bromoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate A mixture of beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)) and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (1.0 g; beta-farnesene / E-formula (IV) / E-formula (III) = 1:0.65:0.45; 1.1 mmol E-formula (IV)) in MeCN (4 ml) was treated dropwise with acetyl bromide (0.1 ml, 1.3 mmol) at 5 °C. The resulting mixture was stirred at 5 °C for 4 h and diluted with MTBE and saturated aqueous NH4Cl. The aqueous phase was extracted with MTBE (3 times). The combined organic phases were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude yellow oil containing beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)), (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) and (2Z,5E)-2-(2-bromoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate (E-formula (V’), Z = Br) (1.07 g, beta-farnesene / E-formula (IV) / E-formula (III) / E-formula (V’) = 1:0.06:0.31:0.21).

[0090] (2Z,5E)-2-(2-bromoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate: 1 H-NMR (400 MHz, CDCl3) δ ppm 5.74 (br. t, J = 8.6, 1 H), 5.15 - 5.05 (m, 2 H), 4.67 (s, 2 H, CH2O), 4.06 (d, J = 8.6, 2 H, CH2Br), 2.09 (s, Ac), 2.25 - 1.95 (m, 8 H), 1.69 (br. s, Me), 1.61 (s, 2 Me). 1313C-NMR (100 MHz, CDCl3) δ ppm 170.76 (s, 1 C), 139.93 (s, 1 C), 136.03 (s, 1 C), 131.36 (s, 1 C), 125.84 (d, 1 C), 124.23 (d, 1 C), 122.91 (d, 1 C), 60.95 (t, 1 C), 39.67 (t, 2 C), 35.20 (t, 1 C), 26.68 (t, 1 C), 26.14 (t, 1 C), 25.66 (q, 1 C), 20.87 (q, 1 C), 17.66 (q, 1 C), 16.05 (q, 1 C). GC-MS (EI) m / z 291 (1), 249 (1), 224 (1), 203 (5), 177 (1), 161 (2), 147 (7), 137 (11), 133 (12), 123 (10), 119 (10), 105 (13), 93 (24), 91 (17), 81 (31), 79 (13), 69 (100), 67 (19), 55 (8), 53 (9), 43 (34), 41 (37), 28 (2).

[0091] Example 9: (E)-2-Bromo-7,11-dimethyl-3-methylenedeca-6,10-dien-1-yl acetate and (2Z,5E)-2-(2-Bromoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate A mixture of beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)) and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (1.0 g; beta-farnesene / E-formula (IV) / E-formula (III) = 1:0.65:0.45; 1.9 mmol of E-formula (IV) and E-formula (III)) in MeCN (4 ml) was treated by dropwise addition of acetyl bromide (0.15 ml, 1.9 mmol) at 5 °C. The resulting mixture was stirred at 5 °C for 2 hours and diluted with MTBE and saturated aqueous NH4Cl solution. The aqueous phase was extracted with MTBE (3 times). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain a crude yellow oil containing beta-farnesene, (E)-2-bromo-7,11-dimethyl-3-methylenedeca-6,10-dien-1-yl acetate (E-formula (X), Z = Br) and (2Z,5E)-2-(2-bromoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate (E-formula (V’), Z = Br)) (1.07 g; beta-farnesene / E-formula (X) / E-formula (V’) = 1:0.27:0.28).

[0092] (E)-2-bromo-7,11-dimethyl-3-methylenedeca-6,10-dien-1-yl acetate: 1 H-NMR (500 MHz, CDCl3) δ ppm selected signals 5.21 (br. s, 1 H), 5.15 - 5.05 (m, 2 H), 5.04 (br. m, 1 H), 4.65 (br. t, J = 7.3, 1 H, CHBr), 4.42 (dd, J = 7.3, 11.8, 1 H, CH2O), 4.34 (dd, J = 7.3, 11.8, 1 H, CH2O), 2.05 (s, Ac), 1.67 (s, Me), 1.61 (s, Me), 1.58 (s, Me). 1313C-NMR (125 MHz, CDCl3) δ ppm 170.24 (s, 1 C), 145.32 (s, 1 C), 135.80 (s, 1 C), 131.23 (s, 1 C), 124.15 (d, 1 C), 123.22 (d, 1 C), 123.15 (s, 1 C), 114.66 (t, 1 C), 65.61 (t, 1 C), 52.55 (d, 1 C), 39.55 (t, 1 C), 31.61 (t, 1 C), 26.54 (t, 1 C), 25.59 (q, 1 C), 20.61 (q, 1 C), 17.58 (q, 1 C), 15.98 (q, 1 C). GC-MS (EI) m / z 282 (1), 203 (10), 161 (3), 147 (6), 135 (7), 133 (16), 123 (5), 119 (11), 107 (15), 105 (15), 95 (9), 93 (26), 91 (17), 81 (20), 79 (14), 69 (100), 67 (14), 55 (11), 53 (10), 43 (51), 41 (49), 29 (4).

[0093] Example 10: (E)-2-Bromo-7,11-dimethyl-3-methylenedeca-6,10-dien-1-yl acetate, (E)-2-chloro-7,11-dimethyl-3-methylenedeca-6,10-dien-1-yl acetate and (E)-1-bromo-7,11-dimethyl-3-methylenedeca-6,10-dien-2-yl acetate At 5 °C, a solution of (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (0.50 g, 2.1 mmol) and NaBr (0.22 g, 2.1 mmol) in MeCN (3 ml) was treated dropwise with acetyl chloride (0.16 ml, 2.2 mmol). The resulting mixture was stirred at 5 °C for 24 h and at room temperature for 24 h and subsequently diluted with MTBE and water. The aqueous phase was extracted with MTBE (3 times). The combined organic phases were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to give 0.74 g of a crude orange oil containing a mixture of (E)-2-bromo-7,11-dimethyl-3-methylenedeca-6,10-dien-1-yl acetate (E-formula (X), Z = Br), (E)-2-chloro-7,11-dimethyl-3-methylenedeca-6,10-dien-1-yl acetate (E-formula (X), Z = Cl) and (E)-1-bromo-7,11-dimethyl-3-methylenedeca-6,10-dien-2-yl acetate (E-formula (X), Z = Br) (E-formula (X), Z = Br / E-formula (X), Z = Cl / E-formula (X') = 9:3.8:1). (E)-1-bromo-7,11-dimethyl-3-methylenedeca-6,10-dien-2-yl acetate: 1 H-NMR (400 MHz, CDCl3) δ ppm, selected signals: 5.25 - 4.95 (m, 4 H), 4.61 (br. dd, J = 6.0, 7.0, 1 H, CHBr), 3.88 (dd, J = 7.3, 11.9, 1 H, CH2O), 3.84 (dd, J = 6.1, 11.9, 1 H, CH2O).

[0094] Example 11: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one A mixture of beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)) and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (1.0 g; beta-farnesene / E-formula (IV) / E-formula (III) = 1:0.65:0.45; 1.9 mmol of E-formula (IV) and E-formula (III)) in MeCN (4 ml) was treated by dropwise addition of acetyl bromide (0.15 ml, 2.0 mmol) at 5 °C. The resulting mixture was stirred at 5 °C for 2 h. After evaporation of the solvent under reduced pressure, the remaining crude mixture was cooled to 5 °C and treated with THF (4 ml), methyl acetoacetate (formula (VII), R = Me, R' = Me; 0.45 ml, 4.1 mmol) and potassium carbonate (0.58 g, 4.1 mmol). The resulting mixture was stirred at 70 °C for 3 h, cooled to room temperature, and successively treated with water (1 ml) and 8M aqueous NaOH solution (1.4 ml) dropwise (while maintaining the internal temperature at 10 °C). The resulting biphasic mixture was vigorously stirred at 75 °C for 3 h.

[0095] The resulting mixture was cooled to room temperature and diluted with MTBE and water. The aqueous phase was extracted with MTBE (3 times). The combined organic phases were washed with saturated NH4Cl solution and water (2 times), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain a crude orange oil containing beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)), (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) and (5Z,9E)-6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,Z-formula (I), R' = Me) (1.07 g; beta-farnesene / E-formula (IV) / E-formula (III) / E,Z-formula (I) = 1:0.1:0.3:0.45).

[0096] Example 12: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one A mixture of beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)) and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (1.0 g; beta-farnesene / E-formula (IV) / E-formula (III) = 1:0.65:0.45; 1.1 mmol E-formula (IV)) in MeCN (4 ml) was treated dropwise with acetyl bromide (0.11 ml, 1.4 mmol) at 5 °C. The resulting mixture was stirred at 5 °C for 5 h and kept at this temperature overnight. After evaporation of the solvent under reduced pressure, the remaining crude mixture was cooled to 5 °C and treated with THF (4 ml), methyl acetoacetate (formula (VII), R = Me, R' = Me; 0.26 ml, 2.4 mmol) and potassium carbonate (0.34 g, 2.4 mmol). The resulting mixture was stirred at 70 °C for 3 h, cooled to room temperature, treated successively with water (0.4 ml) and, while maintaining the internal temperature at 10 °C, dropwise with 8M NaOH solution (0.8 ml). The resulting two-phase mixture was vigorously stirred at 75 °C for 3 h.

[0097] The resulting mixture was cooled to room temperature and diluted with MTBE and water. The aqueous phase was extracted with MTBE (3 times). The combined organic phases were washed with saturated aqueous NH4Cl and water (2 times), dried over MgSO4, filtered and concentrated under reduced pressure to give a crude orange oil containing beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)), (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) and (5Z,9E)-6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,Z-formula (I), R' = Me) (1.07 g; beta-farnesene / E-formula (IV) / E-formula (III) / E,Z-formula (I) = 1:0.05:0.5:0.5).

[0098] Example 13: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one A mixture of beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)) and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (1.0 g; beta-farnesene / E-formula (IV) / E-formula (III) = 1:0.8:0.7; 2.3 mmol of E-formula (IV) & E-formula (III)) and NaBr (0.24 g; 2.3 mmol) in MeCN (6 ml) was treated by dropwise addition of acetyl bromide (0.17 ml, 2.4 mmol) at 5 °C. The resulting mixture was stirred at 5 °C for 3.5 h and then diluted with MTBE and water. The aqueous phase was extracted with MTBE (3 times). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 1.24 g of a crude orange oil containing beta-farnesene, (E)-2-bromo-7,11-dimethyl-3-methylenedeca-6,10-dien-1-yl acetate (E-formula (X), Z = Br), (E)-1-bromo-7,11-dimethyl-3-methylenedeca-6,10-dien-2-yl acetate (E-formula (X’), Z = Br) and (2Z,5E)-2-(2-bromoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate (E-formula (V’), Z = Br) (beta-farnesene / E-formula (X) / E-formula (X’) / E-formula (V’) = 1:0.26:0.05:0.27).

[0099] A solution of the above mixture in THF (6 ml) was successively treated with methyl acetoacetate (formula (VII), R = Me, R’ = Me; 0.36 ml, 3.3 mmol) and potassium carbonate (0.46 g, 3.3 mmol). The resulting mixture was stirred at 70 °C for 4 h, cooled first to room temperature and successively treated at 5 °C with water (6 ml) and, dropwise, with 32% NaOH solution (4 ml). The resulting biphasic mixture was stirred vigorously at 75 °C for 5 h and at room temperature overnight. The resulting mixture was diluted with MTBE and water. The aqueous phase was extracted with MTBE (3 times). The combined organic phases were washed with saturated NH4Cl solution and saturated aqueous NaCl solution (2 times), dried over MgSO4, filtered and concentrated under reduced pressure to give a crude orange oil containing beta-farnesene, (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) and (5Z,9E)-6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,Z-formula (I), R’ = Me) (0.99 g; beta-farnesene / E-formula (III) / E,Z-formula (I) = 3.3:1:1.5).

[0100] Example 14: (2Z,6E)-3-(Iodomethyl)-7,11-dimethyldodeca-2,6,10-trien-1-yl acetate and (2E,6E)-3-(Iodomethyl)-7,11-dimethyldodeca-2,6,10-trien-1-yl acetate At 5 °C, a mixture of (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (0.2 g, 0.84 mmol), NaI (0.13 g, 0.84 mmol) and MeCN (1 ml) was added dropwise with acetyl chloride (0.064 ml, 0.89 mmol), stirred at 5 °C for 1 h, diluted with EtOAc and poured into water. The aqueous phase was extracted with EtOAc (3 times), the combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 0.31 g of a crude yellow oil containing (2Z,6E)-3-(iodomethyl)-7,11-dimethyldodeca-2,6,10-trien-1-yl acetate (ZE-formula (VI), Z = I) and (2E,6E)-3-(iodomethyl)-7,11-dimethyldodeca-2,6,10-trien-1-yl acetate (EE-formula (VI), Z = I) (ZE-formula (VI) / EE-formula (VI) = ca. 1:1).

[0101] (6E)-3-(Iodomethyl)-7,11-dimethyldodeca-2,6,10-trien-1-yl acetate: 1 H NMR (400 MHz, CDCl3) δ ppm, selected signals 5.79 (t, J = 6.9, 1H), 5.51 (br. tt, J = 7.0, 1.2, 1H), 5.18 - 5.03 (m, 2 x 2H), 4.58 (d, J = 7.0, 2 H, CH2O), 4.55 (d, J = 7.0, 2H, CH2O), 3.95 (br. s, 2H, CH2I), 3.94 (br. s, 2H, CH2I), 2.35 - 1.95 (m), 2.07 (s, 3H), 2.06 (s, 3H), 1.68 (s, 2 x 3H), 1.60 (s, 2 x 3H). 13 C NMR (100 MHz, CDCl3) δ ppm 170.86 (s, 1 C), 170.81 (s, 1 C), 142.32 (s, 1 C), 142.16 (s, 1 C), 136.46 (s, 1 C), 136.06 (s, 1 C), 131.43 (s, 1 C), 131.35 (s, 1 C), 124.16 (d, 1 C), 124.10 (d, 1 C), 123.31 (d, 1 C), 122.89 (d, 1 C), 122.64 (d, 1 C), 122.40 (d, 1 C), 60.93 (t, 1 C), 60.23 (t, 1 C), 39.61 (t, 2 C), 35.47 (t, 1 C), 29.29 (t, 1 C), 26.63 (t, 1 C), 26.61 (t, 1 C), 26.54 (t, 1 C), 26.09 (t, 1 C), 25.66 (q, 2 C), 20.87 (q, 1 C), 20.85 (q, 1 C), 17.66 (q, 2 C), 16.07 (q, 1 C), 16.05 (q, 1 C) 11.47 (t, 1 C, CH2I) 2.60 (t, 1 C, CH2I).

[0102] Example 15: (2Z,5E)-2-(2-Iodoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate, (2E,5E)-2-(2-Iodoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate, (2Z,6E)-3-(Iodomethyl)-7,11-dimethyldodeca-2,6,10-trien-1-yl acetate and (2E,6E)-3-(Iodomethyl)-7,11-dimethyldodeca-2,6,10-trien-1-yl acetate At 5 °C, protected from daylight, a solution of a mixture of beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)) and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (1.0 g; beta-farnesene / E-formula (IV) / E-formula (III) = 1:0.65:0.45; 1.9 mmol E-formula (IV) & E-formula (III)) and MeCN (4 ml) was added dropwise with acetyl iodide (0.16 ml, 2.0 mmol), and the mixture was stirred at 5 °C for 0.5 h. The resulting solution was diluted with MTBE and saturated aqueous NH4Cl. The aqueous phase was extracted with MTBE (3 times), the combined organic phases were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give a crude dark orange oil (1.40 g) containing beta-farnesene, (2Z,5E)-2-(2-iodoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate (ZE-formula (V), Z = I) and (2E,5E)-2-(2-iodoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate (EE-formula (V), Z = I) (ZE-formula (V) / EE-formula (V) = 4:1), and (2Z,6E)-3-(iodomethyl)-7,11-dimethyldodeca-2,6,10-trien-1-yl acetate (ZE-formula (VI), Z = I), (2E,6E)-3-(iodomethyl)-7,11-dimethyldodeca-2,6,10-trien-1-yl acetate (EE-formula (VI), Z = I) (ZE-formula (VI) / EE-formula (VI) = 1:1) in a ratio of beta-farnesene / E-formula (V) / E-formula (VI) = 1:0.39:0.44.

[0103] Example 16: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,Z-form (I), R’ = Me), (5E,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,E-form (I), R’ = Me), (5Z,8E)-5-(2-Hydroxyethylidene)-9,13-dimethyltetradeca-8,12-dien-2-one (E,Z-form (II), R’ = Me), and (5E,8E)-5-(2-Hydroxyethylidene)-9,13-dimethyltetradeca-8,12-dien-2-one (E,E-form (II), R’ = Me) At 5 °C, protected from daylight, a solution of a mixture of beta-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyloxirane (E-formula (IV)) and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (1.0 g; beta-farnesene / E-formula (IV) / E-formula (III) = 1:0.65:0.45; 1.9 mmol E-formula (IV) & E-formula (III)) and MeCN (4 ml) was added dropwise with acetyl iodide (0.16 ml, 2.0 mmol) and stirred at 5 °C for 0.5 h. The resulting solution was concentrated under reduced pressure, and the remaining crude mixture was cooled to 5 °C, dissolved in THF (4 ml), and successively treated with methyl acetoacetate (formula (VII), R = Me, R' = Me; 0.45 ml, 4.1 mmol) and potassium carbonate (0.58 g, 4.1 mmol). The resulting mixture was stirred at 66 °C for 6 h and at room temperature overnight. The reaction mixture was cooled to 5 °C and treated by dropwise addition of a 32% aqueous solution. NaOH solution (1.4 ml, 15 mmol) and water (0.7 ml) were added, and the resulting biphasic mixture was stirred under reflux for 3 h. The reaction mixture was cooled to room temperature and diluted with MTBE and water.The aqueous phase was extracted with MTBE (3 times), and the combined organic phases were washed with saturated aqueous NH4Cl and water (2 times), dried over MgSO4, filtered, and concentrated under reduced pressure to give 0.993 g of a crude orange oil containing 40% of a mixture of 50% beta-farnesene and (5Z,9E)-6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,Z-form (I), R’ = Me), (5E,9E)-6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one (E,E-form (I), R’ = Me), (5Z,8E)-5-(2-hydroxyethylidene)-9,13-dimethyltetradeca-8,12-dien-2-one (E,Z-form (II), R’ = Me) and (5E,8E)-5-(2-hydroxyethylidene)-9,13-dimethyltetradeca-8,12-dien-2-one (E,E-form (II), R’ = Me) in a ratio of E,Z-form (I) / E,E-form (I) / E,Z-form (II) / E,E-form (II) = 5.5:1.2:3.3:1.6.

Claims

1. A method for preparing a compound represented by formula (V), 【Chemical 1】 wherein the method comprises wherein the method is a) a compound represented by formula (III) and a compound represented by formula (IV) [Chemical Formula 2] A mixture containing is optionally contacted, in the presence of a halide salt (AY), with an acyl halide R １ C(O)X, comprising the step of In the formula, R １ is selected from the group consisting of C １ to C ６ alkyl, X, Y, and Z are selected from Cl, I, and Br, and A is selected from Na, K, Li, and quaternary ammonium salts. The method as described above.

2. The method for preparing a compound represented by formula (V) according to claim 1, wherein the compound represented by formula (V) is a compound represented by formula (V'), 【Chemical Formula 3】 wherein the method comprises wherein the method is a) contacting a mixture comprising a compound represented by formula (III) and a compound represented by formula (IV) i) In the absence of a halide salt, an acyl halide R １ C(O)X, or ii) acyl halide R in the presence of halide salt AY １ C(O)X, where Y is not iodine, and comprising a step of contacting, Wherein, R １ is selected from the group consisting of C １ to C ６ alkyl, X is selected from Cl and Br, A is selected from Na, K, Li, and quaternary ammonium salts, and Z is selected from Cl and Br The method as described above.

3. The method according to claim 2 for preparing a compound represented by formula (V') and a compound represented by formula (X) and / or its regioisomer (X'), 【Chemical 4】 The method as described above. In the formula, R １ is selected from the group consisting of C １ to C ６ alkyl, and Z is selected from Cl and Br The method as described above.

4. The method according to claim 1 for preparing a compound represented by formula (V) and a compound represented by formula (VI), 【Chemical Formula 5】 wherein the method is wherein, in the formula, X is selected from Cl and Br, and in the formula, A is selected from Na, K, Li, and quaternary ammonium salts, a) A mixture comprising a compound represented by formula (III) and a compound represented by formula (IV) is contacted with an acyl iodide (R １ C(O)I) or an acyl halide R １ C(O)X in the presence of an iodine salt AI, comprising the step of The method as described above. R １ is selected from the group consisting of C １ to C ６ alkyl, and Z is iodine The method as described above.

5. The method according to any one of claims 1 to 4, wherein the compound represented by formula (III) and the compound represented by formula (IV) are E-form (III) and (IV). [Chemical Formula 6] The method as described above.

6. The method according to any one of claims 1 to 5, wherein step b) the compound represented by formula (V) is contacted with a compound represented by formula (VII) 【Chemical Formula 7】 to obtain a compound represented by formula (VIII), 【Chemical 8】 The method as described above. In the formula, R １ is selected from the group consisting of C １ to C ６ alkyl, R' is selected from the group consisting of C １ to C ６ alkyl and OR groups, R is selected from the group consisting of hydrogen and C １ to C ６ alkyl groups, and Z is selected from Cl, I, and Br The method as described above.

7. The method according to claim 6, wherein step c) the compound represented by formula (VIII) is hydrolyzed and decarboxylated to obtain a compound of formula (I). 【Chemical Formula 9】 The method as described above. 【Chemical 10】 The method as described above. In the formula, R １ is selected from the group consisting of C １ to C ６ alkyl, R' is selected from the group consisting of C １ to C ６ alkyl and OR groups, and R is selected from the group consisting of hydrogen and C １ to C ６ alkyl groups. The method as described above.

8. The method according to claim 7, wherein steps a) to c) are understood as a continuous one-pot synthesis.

9. The method according to claim 8, wherein steps a) to c) are understood as a continuous one-pot synthesis without isolation of unreacted starting materials.

10. The method according to claim 8 or 9, wherein steps a) to c) are understood as a continuous one-pot synthesis without isolation of intermediates.

11. The method according to claim 7, wherein the compound represented by formula (V) obtained in step a) is first purified, and a method comprising steps b) and c) as a continuous one-pot synthesis follows.

12. The compound represented by formula (V) is a compound represented by formula (V'), 【Chemical Formula 11】 wherein In the formula, R １ is selected from the group consisting of C １ -C ６ alkyl, and Z is selected from Cl and Br The method according to claim 11.

13. R １ The method according to any one of claims 1 to 12, wherein R is methyl.

14. The compound represented by formula (V) 【Chemical Formula 12】 wherein wherein R １ is selected from the group consisting of C １ -C ６ alkyl, and Z is selected from Cl, I, and Br said compound

15. The compound represented by formula (VI) 【Chemical Formula 13】 wherein In the formula, R １ is selected from the group consisting of C １ -C ６ alkyl, and Z is selected from Cl, I, and Br said compound

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