Process

Abstract

Described herein are processes for preparing intermediates in the production of perfume ingredients starting from beta-farnesene via a mixture comprising an epoxide of formula (III) and an epoxide of formula (IV) as defined herein. In particular, methods are described for the preparation of acetylmethyl farnesyl alcohol and hydroxy-farnesyl acetone and homologues thereof.

Description

Technical Field

[0001] The present invention relates to a process for preparing intermediates in the production of fragrances such as succinic ketals and succinic ketal homologues starting from β-farnesene. In particular, the present invention relates to the production of acetylmethylfarnesol and hydroxy-farnesylacetone and their homologues. The present invention further relates to a process for the production of intermediates thereof.

[0002] background

[0003] Succinyl ketal provides strong and lasting amber and woody smells, which can be used in perfume compositions alone or in combination with other woody or ambery ingredients. Succinyl ketal is traditionally prepared from manool via many chemical transformations. However, the supply of natural manool is limited. Therefore, it is desirable to provide new, efficient and economical synthetic routes to obtain succinyl ketal and succinyl ketal homologues.

[0004] WO2021 / 209482 discloses a synthetic route for succinyl ketal homologues (Formula A) comprising: preparing a compound of Formula B (wherein R 1 is H, methyl or ethyl) is contacted with a squalene-hopene cyclase (SHC) enzyme or enzyme variant.

[0005]

[0006] It would therefore be desirable to provide new and efficient routes to obtain compounds of formula B, which can then be used in the production of succinates and succinate homologues.

[0007] Overview

[0008] According to a first aspect of the present invention, there is provided a method for preparing a compound of formula (V)

[0009]

[0010] The method comprises the following steps

[0011] a) reacting a mixture comprising a compound of formula (III) and a compound of formula (IV) with an acyl halide R 1 C(O)X (e.g. acetyl chloride) optionally in the presence of a halide salt (AY) is contacted

[0012]

[0013] Where R 1 is selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl), X, Y and Z are selected from Cl, I and Br, and A is selected from Na, K, Li and quaternary ammonium salts.

[0014] In a second aspect of the present invention, there is provided a compound of formula (V), wherein R 1 is selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl), and Z is selected from Cl, I and Br.

[0015] In a third aspect of the present invention, there is provided a compound of formula (VI)

[0016]

[0017] Where R 1 is selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl), and Z is selected from Cl, I and Br.

[0018] Certain embodiments of any aspect of the invention may provide one or more of the following advantages:

[0019] Avoid expensive and less sustainable catalysts and ligands;

[0020] • If desired, control the selectivity towards one isomer.

[0021] • Sequential one-pot synthesis without direct isolation of unreacted starting materials and / or intermediates (shortened procedure).

[0022] The details, embodiments and preferences provided about any specific one or more described aspects of the present invention will be further described herein and are equally applicable to all aspects of the present invention. Unless otherwise specified in this article, or clearly contradictory with context, any combination of the embodiments, embodiments and preferences described in all possible variations thereof is included in the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention provides a novel and selective method for producing a compound of formula (I) via a mixture comprising an epoxide of formula (III) and an epoxide of formula (IV). The compound of formula (I) can be used in the production of succinyl ketal and succinyl ketal homologues, as described in, for example, WO2021 / 209482.

[0025] In particular, the present invention is based, at least in part, on the surprising discovery that the conversion of epoxides (e.g., epoxides of formula (III), epoxides of formula (IV) as defined herein) can be carried out avoiding the use of organometallic catalysts, such as homogeneous transition metal catalysts (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-keto-esters with allyl and vinyl epoxides (such as epoxides of formula (IV) and formula (III)).

[0026] The inventors have found that the conversion of epoxides proceeds in the presence of acyl halides as activating agents.

[0027] Therefore, in a first aspect of the present invention, there is provided a process for preparing a compound of formula (V)

[0028]

[0029] The method comprises the following steps

[0030] a) reacting a mixture comprising a compound of formula (III) and a compound of formula (IV) with an acyl halide R 1 C(O)X (e.g. acetyl chloride) optionally in the presence of a halide salt (AY) is contacted

[0031]

[0032] Where R 1 is selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl), X, Y and Z are selected from Cl, I and Br, and A is selected from Na, K, Li and quaternary ammonium salts.

[0033] The epoxides of the formula (III) and the epoxides of the formula (IV) are generally obtained as a mixture from β-farnesene (7,11-dimethyl-3-methylene-1,6,10-dodecatriene), for example as described in the international patent application WO 2022 / 268840.

[0034] The inventors have surprisingly found that by using an acyl halide, optionally in the presence of a halide salt (i.e., in the presence or absence of a halide salt), the ring opening of the epoxide occurs for both epoxides or only for one of the epoxides. This allows, if desired, the chemical separation of the epoxide of formula (III) and the epoxide of formula (IV), as described in more detail herein below.

[0035] If no halide salt is added to step a), 1,4-halo-acylation of the exo-epoxide (compound of formula (IV)) to form the compound of formula (V) is mainly observed. Surprisingly, it was found that the 1,2-epoxide (compound of formula (III)) is converted more slowly to the compound of formula (X) and its regioisomer (X')

[0036]

[0037] Where R 1 is selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl), Z is selected from Cl and Br,

[0038] Both are formed via 1,2 addition of the acyl halide rather than 1,4 addition, which would be observed for the exo-epoxide.

[0039] The same situation is observed when a halide salt (wherein the halide is not iodide) is added to step a), ie predominantly 1,4 halo-acylation for the exo-epoxide and a slower conversion of the 1,2-epoxide.

[0040] When a mixture comprising a compound of formula (III) and a compound of formula (IV) is contacted with an acyl halide R1C(O)X (wherein X is Cl or Br) in the absence of a halide salt or in the presence of a halide salt AY (wherein halide Y is not iodine (e.g. Y is Cl or Br)), almost exclusively the (Z)-isomer of the compound of formula (V), i.e. the compound of formula (V'), is formed.

[0041]

[0042] Where R 1 Selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl), Z is Cl or Br.

[0043] Therefore, in a specific embodiment of the first aspect of the present invention, there is provided a method for preparing a compound of formula (V'), comprising the following steps:

[0044] a) making a mixture comprising a compound of formula (III) and a compound of formula (IV)

[0045]

[0046] i) in the absence of a halide salt, with an acyl halide R 1 C(O)X contact, or

[0047] ii) in the presence of a halide salt AY (wherein Y is not iodine (eg Y is selected from Cl and Br)) and an acyl halide R 1C(O)X Contact

[0048] Where R 1 is selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl), 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.

[0049] Without wishing to be bound by theory, it is believed that the halide salt AY (eg, Y is selected from Cl and Br)

[0050] - may react with acyl halides R 1 C(O)X reacts to form a new acyl halide R 1 C(O)Y; and / or

[0051] - may react with acyl halides R 1 C(O)X reacts combinatorially to open the epoxide ring.

[0052] If step a) is carried out with an acyl halide R in the presence of an iodine salt (AY, wherein Y=I) 1 C(O)X is carried out, it is observed that the two epoxides 1,2-epoxide and the exoepoxide are converted into the compound of formula (V) and the compound of formula (VI) respectively at similar rates, thereby obtaining a mixture comprising the compound of formula (V) and the compound of formula (VI)

[0053]

[0054] in

[0055] Z is iodine, and R 1 Selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl).

[0056] When step a) uses an acyl iodide (i.e. R 1 The same situation was observed when C(O)X, where X=I) was performed.

[0057] Therefore, in a further embodiment of the first aspect of the present invention, there is provided a method for preparing a composition comprising a compound of formula (V) and a compound of formula (VI)

[0058]

[0059] It includes the following steps

[0060] a) making a mixture comprising a compound of formula (III) and a compound of formula (IV)

[0061]

[0062] with an acyl iodide R1C(O)I, or an acyl halide R1C(O)X (wherein X is selected from Cl and Br) in the presence of an iodide salt AI (wherein A is selected from Na, K, Li and a quaternary ammonium salt), and wherein R 1 is selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl), and Z is iodine.

[0063] The ratio of the compound of formula (V) to the compound of formula (VI) is maintained at the same ratio as the starting materials, i.e., the ratio of the epoxides. For example, if epoxides (III) and (IV) are present in a ratio of about 1:1, then the compounds of formula (V) and formula (VI) will also be present in a ratio of about 1:1.

[0064] In one embodiment, the acyl halide R present in step a) 1 C(O)X is selected from the formula R 1 C(O)Cl chloride, where R 1 Selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl).

[0065] In some embodiments, the acyl halide R present in step a) is 1 C(O)X is selected from acetyl chloride and acetyl bromide.

[0066] In some embodiments, the acyl halide R present in step a) is 1 C(O)X is added in an amount of about 0.9 to about 1.5 mol equivalents (eg, about 1 to about 1.2 mol equivalents) relative to the total amount of epoxides (compounds of formula (IV) and compounds of formula (III)).

[0067] In some embodiments, the acyl halide R present in step a) is 1 C(O)X is added in an amount of about 0.9 to about 1.5 mol equivalents (eg, about 1 to about 1.2 mol equivalents) relative to the amount of the compound of formula (IV).

[0068] Unless otherwise stated, the halide salt in step a) (if present) is a compound AY, wherein A is selected from Na, K, Li and quaternary ammonium salts (eg, tetraalkylammonium such as tetra-n-butylammonium), and Y is selected from Cl, I and Br.

[0069] In some examples, the halide salt present in step a) is selected from NaCl, NaI, NaBr, LiI, LiBr, KI and KBr.

[0070] In some embodiments, the halide salt present in step a) is tetra-C1-C 15 Alkylammonium (eg, tetra-n-butylammonium, n-methyl-tri-n-octylammonium).

[0071] In some examples, the halide salt in step a) (if present) is added in an amount of about 0.01 to about 1.2 mol equivalents, such as about 0.05 to about 1.1 mol equivalents, such as about 0.1 to about 1 mol equivalents, such as about 0.2 to about 0.9 mol equivalents, such as about 0.3 to about 0.8 mol equivalents, such as about 0.4 to about 0.7 mol equivalents, such as about 0.5 to about 0.6 mol equivalents, relative to the total amount of the epoxide (compound of formula (IV) and compound of formula (III)).

[0072] In some examples, the halide salt in step a) (if present) is added in an amount of about 0.01 to about 1.2 mol equivalents, such as about 0.05 to about 1.1 mol equivalents, such as about 0.1 to about 1 mol equivalents, such as about 0.2 to about 0.9 mol equivalents, such as about 0.3 to about 0.8 mol equivalents, such as about 0.4 to about 0.7 mol equivalents, such as about 0.5 to about 0.6 mol equivalents, relative to the amount of the compound of formula (IV).

[0073] In some examples, the method described above is performed at room temperature or lower (eg, about 0°C to room temperature, or about 5°C to room temperature, including 10°C). Room temperature may be a temperature of about 20°C to about 25°C.

[0074] In some examples, the methods described above are performed at room temperature (about 20°C to about 25°C) or higher temperatures (e.g., about room temperature up to 120°C (e.g., up to 100°C or up to 70°C), including temperatures from about 25°C to about 65°C (e.g., about 50°C)).

[0075] In some examples, the methods described above are carried out at a temperature that is the reflux temperature of the corresponding solvent used.

[0076] In some embodiments, the methods described above are performed in the presence of a solvent. In some examples, the solvent is a) an ether solvent such as dibutyl ether, methyl-tetrahydrofuran (Me-THF) and tetrahydrofuran (THF), or b) toluene, cyclohexane, or acetonitrile (MeCN).

[0077] In some examples, the method of preparing the compound of formula (V'), the compound of formula (X), and the compound of formula (X'), or a mixture thereof comprises reacting a mixture comprising a compound of formula (IV) and a compound of formula (III)

[0078] a) in the absence of a halide salt, with an acyl halide R 1 C(O)X, wherein X is Cl or Br, or

[0079] b) reacting an acyl halide R 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) 1 C(O)X contact, wherein X is Cl or Br,

[0080] For about 0.5 h to about 24 h, for example, about 1 h to about 18 h, for example, about 1.5 h to about 12 h, for example, about 2 h to about 8 h, for example, about 3 h to about 4 h.

[0081] The extended reaction time can lead to the formation of higher amounts of compounds of formula (X) and (X'). Therefore, the reaction time should be as short as possible. Good selectivity is obtained in favor of compounds of formula (V'), for example, for about 0.5h to 5h, for example, about 2h to about 4h.

[0082] In some examples, the compound of formula (III) and the compound of formula (IV) are E-formula (III) and (IV).

[0083]

[0084] In some examples, the compound of formula (III) is farnesene 1,2-epoxide, which is a compound having CAS number [83637-40-5].

[0085] In some examples, the compound of formula (IV) is a farnesene exo-epoxide, which is a compound having CAS number [1404220-65-0].

[0086] The composition of the first aspect of the present invention comprising a compound of formula (V) (which encompasses a compound of formula (V')) thus obtained may be further contacted with a compound of formula (VII) (step b)

[0087]

[0088] To obtain a compound of formula (VIII)

[0089]

[0090] Optionally, the compound of formula (VIII) is subsequently hydrolyzed and decarboxylated to obtain the compound of formula (I)

[0091]

[0092] Where R 1 is selected from the group consisting of C1 to C6 alkyl groups such as ethyl, propyl, isopropyl, R' is selected from the group consisting of C1-C6 alkyl groups and OR groups, and R is selected from the group consisting of hydrogen and C1 to C6 alkyl groups.

[0093] As described herein above, this depends on whether the additives added to step a) and the subsequent purification process predominantly result in obtaining compounds of formula (V) (which encompass compounds of formula (V')) or a mixture comprising compounds of formula (V) and compounds of formula (VI) or a mixture comprising compounds of formula (V') and compounds of formula (X) and (X').

[0094] Therefore, in another embodiment of the present invention, there is provided a method for preparing a compound of formula (I)

[0095]

[0096] The method comprises the following steps

[0097] a) making a mixture comprising a compound of formula (III) and a compound of formula (IV)

[0098]

[0099] i) contacting with an acyl halide R1C(O)X, wherein X is selected from Cl, I and Br, in the absence of a halide salt, or

[0100] ii) contacting with an acyl halide R1C(O)X, wherein X is selected from Cl, I and Br, in the presence of a halide salt AY, wherein Y is not iodine (e.g. Y is selected from Cl and Br, and A is selected from Na, K, Li and quaternary ammonium salts,

[0101] To obtain a compound of formula (V)

[0102]

[0103] Where R 1 is selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl), and Z is selected from Cl, I and Br,

[0104] a) contacting a compound of formula (V) with a compound of formula (VII)

[0105]

[0106] To obtain a compound of formula (VIII)

[0107]

[0108] Where R 1 is selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl), R' is selected from the group consisting of C1-C6 alkyl and OR groups, and R is selected from the group consisting of hydrogen and C1 to C6 alkyl,

[0109] b) The compound of formula (VIII) is subsequently hydrolyzed and decarboxylated.

[0110] As already mentioned above,

[0111] 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

[0112] 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 as provided herein above)

[0113] Almost exclusively the (Z)-isomer of the compound of formula (V), ie the compound of formula (V'), is formed, and thus in step b) almost exclusively the (Z)-isomer of the compound of formula (VIII), ie the compound of formula (VIII'), is formed.

[0114]

[0115] After hydrolysis and decarboxylation of the compound of formula (VIII'), a compound of formula (I') is obtained (step c)

[0116]

[0117] Where R 1 is selected from the group consisting of C1 to C6 alkyl groups such as ethyl, propyl, isopropyl, R' is selected from the group consisting of C1-C6 alkyl groups and OR groups, and R is selected from the group consisting of hydrogen and C1 to C6 alkyl groups.

[0118] The method has the advantage that the compound of formula (I') can be selectively prepared from β-farnesene via the epoxide of formula (IV), which allows the compound to be more easily separated. The method also allows the compound of formula (V'), the compound of formula (VIII') or the compound of formula (I') to be more easily separated from the unreacted compound of formula (III) or its derivatives. Therefore, a higher overall yield is obtained.

[0119] In another aspect of the present invention, there is provided a method for preparing a mixture comprising a compound of formula (I) and a compound of formula (II)

[0120]

[0121] The method comprises the following steps

[0122] a) making a mixture comprising a compound of formula (III) and a compound of formula (IV)

[0123]

[0124] a) in the presence of a halide salt AY, with an acyl halide R 1 C(O)X, wherein X is selected from Cl, I and Br, wherein Y is iodine and A is selected from Na, K, Li and quaternary ammonium salts, or

[0125] b) in the absence of a halide salt, with an acyl iodide (R 1 C(O)X, wherein X is I) contact

[0126] To obtain a mixture comprising a compound of formula (V) and a compound of formula (VI)

[0127]

[0128] in

[0129] Z is iodine, and R 1 Selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl);

[0130] b) contacting the compound of formula (V), the compound of formula (VI) or a mixture thereof with the compound of formula (VII) to obtain the compound of formula (VIII), the compound of formula (IX) or a mixture thereof

[0131]

[0132] in

[0133] R 1 is selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl), R' is selected from the group consisting of C1-C6 alkyl and OR groups, and R is selected from the group consisting of hydrogen and C1 to C6 alkyl;

[0134] c) subsequently hydrolyzing and decarboxylating the compound of formula (VIII), the compound of formula (IX) or a mixture thereof, respectively.

[0135] In a specific embodiment, the process comprising steps a) to c) is to be understood as a sequential one-pot synthesis without direct isolation of unreacted starting materials and / or intermediates (shortened procedure).

[0136] In another specific embodiment, a method comprising steps a) to c) is provided, characterized in that the obtained product of step a) (compound of formula (V) and compound of formula (VI)) is first purified, followed by the method comprising steps b) and c) as a sequential one-pot synthesis.

[0137] In another specific embodiment, a method comprising steps a) to c) is provided, characterized in that the obtained product of step a) (compound of formula (V')) is first purified, followed by the method comprising steps b) and c) as a sequential one-pot synthesis.

[0138] The compound of formula (I) exists in the form of four different stereoisomers, for example as a compound of formula (I) with E, E- or E, Z- configuration. During the method for preparing the compound of formula (I), the compound of formula (II) or its mixture, the stereochemistry of the double bond between C-8 and C-9 remains unchanged. In other words, if the compound of formula (IV) (wherein the double bond is in E- configuration) is used as starting material, the double bond between C-8 and C-9 of the compound of formula (I) remains in E- configuration. If the compound of formula (IV) (wherein the double bond is in Z- configuration) is used as starting material, the double bond between C-8 and C-9 of the compound of formula (I) remains in Z- configuration.

[0139] This also applies to compounds of formula (II). In other words, if a compound of formula (III) (wherein the double bond is in the E-configuration) is used as a starting material, the double bond between C-8 and C-9 of the compound of formula (II) remains in the E-configuration. If a compound of formula (III) (wherein the double bond is in the Z-configuration) is used as a starting material, the double bond between C-8 and C-9 of the compound of formula (II) remains in the Z-configuration.

[0140] In a specific embodiment, a compound of formula (I) enriched in the isomer of formula (I) in which the double bond between C-4 and C-5 is in the Z-configuration is obtained. By enriched, we mean that the amount of the compound of formula (I) in which the double bond between C-4 and C-5 is in the Z-configuration (formula (I')) is greater than 50% relative to the compound of formula (I) in which the double bond between C-4 and C-5 is in the E-configuration (e.g., the ratio between the Z-configuration and the E-configuration of the 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 (e.g., 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).

[0141] In one embodiment, R 1 is a methyl group. 1When it is methyl, the compound of formula (I) can be referred to as hydroxy-farnesyl acetone (6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one), covering E,Z-hydroxyfarnesyl acetone (CAS173198-97-5, i.e., a compound of formula (I) wherein 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-hydroxyfarnesyl acetone, Z,Z-hydroxyfarnesyl acetone and Z,E-hydroxyfarnesyl acetone.

[0142] When R 1 When is methyl, the compound of formula (II) may be referred to as acetylmethylfarnesol.

[0143] The compounds of formula (V), which encompass compounds of formula (V′), have not been described in the literature and are therefore novel per se.

[0144] Therefore, in a second aspect of the present invention, there is provided a compound of formula (V)

[0145]

[0146] Where R 1 is selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl), and Z is selected from Cl, I and Br.

[0147] The compounds of formula (VI) have not been described in the literature and are therefore novel per se.

[0148] Therefore, in a third aspect of the present invention, there is provided a compound of formula (VI)

[0149]

[0150] Where R 1 is selected from the group consisting of C1 to C6 alkyl (such as ethyl, propyl, isopropyl), and Z is selected from Cl, I and Br.

[0151] The compound of formula (VII) is an oxoalkanoic acid, an oxoalkanoate, a malonic acid or a malonic ester. The compound of formula (VII) may be an oxoalkanoate or a malonic ester.

[0152]

[0153] In some instances, R is selected from the group consisting of hydrogen and C1 to C6 alkyl. In some instances, R is selected from the group consisting of hydrogen, methyl, ethyl, propyl and isopropyl. In some instances, R is selected from the group consisting of hydrogen, methyl and ethyl. In some instances, R is methyl.

[0154] In some instances, R' is selected from the group consisting of C1 to C6 alkyl and OR groups. In some instances, R' is selected from the group consisting of C1 to C6 alkyl, hydroxyl and C1 to C6 alkoxy. In some instances, R' is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, hydroxyl, methoxy, ethoxy, propoxy and isopropoxy. In some instances, R' is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl. In some instances, R' is hydroxyl or methyl. In some instances, R' is methyl.

[0155] In some examples, the compound of formula (VII) is a compound of formula (VIIa).

[0156]

[0157] In some examples, sodium salts of compounds of formula (VII) (which encompass compounds of formula (VIIa)) are used. Such salts are commercially available, or they can be prepared according to procedures well known to those skilled in the art.

[0158] In some examples, step b) of the methods described herein is performed in the presence of a base, particularly a non-nucleophilic base, such as potassium carbonate (K2CO3).

[0159] The embodiments described herein are illustrative embodiments of the present disclosure and are not intended to be limited thereto. Different embodiments of the present disclosure have been described according to the present disclosure. Without departing from the spirit and scope of the present disclosure, many modifications and changes may be made to the technology described and illustrated herein. Therefore, it should be understood that the embodiments are only illustrative and do not limit the scope of the present disclosure. Example

[0160] The following are examples of the methods and other aspects described herein. Therefore, these examples should not be considered as limitations of the present disclosure, but are only used to teach how to make examples of the present disclosure.

[0161] Example 1: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one

[0162] 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-dimethylundec-1,5,9-trien-2-yl)oxirane (E-formula (III)) (100 g; β-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 h, at 50° C. for 16 h and at 60° C. for 6 h. After evaporation of the solvent under reduced pressure, the crude mixture containing (2Z,5E)-2-(2-chloroethylidene)-6,10-dimethylundec-5,9-dien-1-yl acetate (E-formula (V'), Z=Cl) was isolated. The mixture was cooled to 5°C and treated successively with Me-THF (65 ml), methyl acetoacetate (formula (VII), R=Me, R'=Me; 28.3 ml, 260 mmol), Aliquat 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 h, cooled to room temperature and treated successively with water (60 ml) and dropwise with 8M aqueous NaOH solution (59 ml) (maintaining the internal temperature at 10°C). The resulting biphasic mixture was stirred vigorously at room temperature for 3 h and at reflux for 12 h, followed by the addition of 8M aqueous NaOH solution (50 ml) after 3 h.

[0163] 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 (2×500 ml), dried over MgSO4, filtered and concentrated under reduced pressure to give a crude orange oil containing β-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; β-farnesene / E-Formula (IV) / E-Formula (III) / E,Z-Formula (I)=1:0.1:0.5:0.5).

[0164] (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one:

[0165] 1 H NMR(400MHz,CDCl3)δppm 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)。

[0166] 13 C NMR(100MHz,CDCl3)δppm 209.02(s,1C,C=O),139.79(s,1C),135.30(s,1C),131.27(s,1C),126.65(d,1C),124.26(d,1C),123.85(d,1C),60.20(t,1C),43.19(t,1C),39.66(t,1C),35.60(t,1C),30.15(q,1C),26.74(t,1C),26.69(t,1C),25.66(q,1C),21.73(t,1C),17.65(q,1C),16.01(q,1C)。

[0167] 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)。

[0168] Example 2: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one

[0169] 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-dimethylundec-1,5,9-trien-2-yl)oxirane (E-formula (III)) (100 g; β-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 h, at 50° C. for 15 h and at 60° C. for 5 h. 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 h, cooled to room temperature and treated successively with water (60 ml) and dropwise with 50% aqueous NaOH solution (44 g) (maintaining the internal temperature at 10°C). The resulting biphasic mixture was stirred vigorously at room temperature for 1 h and at reflux for 8 h, followed by the addition of 50% aqueous NaOH solution (23 ml) after 3 h.

[0170] 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 solution (500 ml) and water (2×500 ml), dried over MgSO4, filtered and concentrated under reduced pressure to give a crude orange oil containing β-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) (101.8 g; β-farnesene / E-Formula (IV) / E-Formula (III) / E,Z-Formula (I)=1:0.04:0.45:0.41).

[0171] Example 3: (2Z,5E)-2-(2-chloroethylidene)-6,10-dimethylundec-5,9-dien-1-yl acetate

[0172] 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-dimethylundec-1,5,9-trien-2-yl)oxirane (E-formula (III)) (100 g; β-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 h. After evaporation of the solvent under reduced pressure, the crude mixture containing (2Z,5E)-2-(2-chloroethylidene)-6,10-dimethylundec-5,9-dien-1-yl acetate (E-formula (V'), Z=Cl) was isolated. The mixture was placed in a distillation apparatus and polymeric amine (0.5 g) was added as a stabilizer. The mixture was short-path distilled at 0.03 mbar to give a mixture of β-farnesene and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) at a boiling point range of 88°C-93°C (58.1 g; β-farnesene / E-formula (III)=1:0.4), 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) having a boiling point of 142°C.

[0173] (2Z,5E)-2-(2-chloroethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate:

[0174] 1 H NMR (400MHz, CDCl3) δppm 5.65(br.t,J=8.1,1H),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).

[0175] 13C NMR(100MHz,CDCl3)δppm 170.74(s,1C),139.54(s,1C),136.03(s,1C),131.36(s,1C),125.68(d,1C),124.21(d,1C),122.94(d,1C),61.18(t, 1C),39.63(t,2C),35.10(t,1C),26.65(t,1C),26.16(t,1C),25.66(q,1C),20.88(q,1C),17.66(q,1C),16.04(q,1C).

[0176] 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).

[0177] Example 4: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one

[0178] A solution of (2Z,5E)-2-(2-chloroethylidene)-6,10-dimethylundec-5,9-dien-1-yl acetate (E-formula (V'), Z = Cl, prepared according to Example 3; 40.0 g, 100 mmol), Aliquat336 (0.34 g, 0.83 mmol) and methyl acetoacetate (formula (VII), R = Me, R' = Me; 19 ml, 180 mmol) in Me-THF (40 ml) was 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 with 32% aqueous NaOH solution (32 ml). The resulting mixture was stirred at reflux for 4 h, then 32% aqueous NaOH solution (21 ml) was added after 3 h.

[0179] 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 phase was washed with saturated NH4Cl aqueous solution (200 ml), water (200 ml) and saturated NaCl aqueous solution (200 ml), dried over MgSO4, filtered and concentrated under reduced pressure to give (5Z, 9E)-6-(hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-triene-2-one (E, Z-formula (I), R'=Me) (37.1 g, purity 55%, yield 73%).

[0180] 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

[0181] 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) at 5°C. The resulting mixture was stirred at 5°C for 30 min, diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (3×). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure to give a crude yellow oil containing (2Z,5E)-2-(2-iodoethylidene)-6,10-dimethylundec-5,9-dien-1-yl acetate (E,Z-Formula (V), Z=I) and (2E,5E)-2-(2-iodoethylidene)-6,10-dimethylundec-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).

[0182] 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).

[0183] 13 C NMR (101 MHz, CDCl3) δ ppm for signal of (E,Z-Formula (V)) 170.83 (s, 1C), 138.30 (s, 1C), 135.88 (s, 1C), 131.23 (s, 1C), 127.34 (d, 1C), 124.18 (d, 1C), 122.86 (d, 1C), 60.67 (t, 1C), 39.56 (t, 1C), 35.20 (t, 1C), 26.57 (t, 1C), 26.00 (t, 1C), 25.61 (q, 1C), 20.79 (q, 1C), 17.62 (q, 1C), 15.99 (q, 1C), 0.19 (t, 1C, CH2I). 10%-20% minor E,E-Formula (V).

[0184] Example 6: (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-triene-2-one (E,E-formula (I), R'=Me), (5Z,8E)-5-(2-hydroxyethylidene)-9,13-dimethyltetradec-8,12-dien-2-one (E,Z-formula (II), R'=Me) and (5E,8E)-5-(2-hydroxyethylidene)-9,13-dimethyltetradec-8,12-dien-2-one (E,E- Formula (II), R'=Me)

[0185] At 5°C, 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 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) in sequence. 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×). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure to obtain a product containing 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 =R'=Me) as a crude dark yellow oil (0.66 g).

[0186] A mixture of the crude mixture from above and water (0.45 ml) was treated dropwise with 32% aqueous NaOH (0.45 ml), and the resulting biphasic mixture was stirred at reflux for 1 h. 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 (2×), dried over MgSO4, filtered and concentrated under reduced pressure to give 0.39 g of a 3-hydroxy-1,4-dimethyl-6-(2-undecyl)-1,5,9-trien-2-yl)oxirane (E-formula (III)) containing 54% β-farnesene, 11% (E)-2-(6,10-dimethylundecyl-1,5,9-trien-2-yl)oxirane (E-formula (III)) and 35% (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,Z-formula (I), R′=Me), A crude orange oil of a mixture of 5,9,13-trien-2-one (E,E-Formula (I), R'=Me), (5Z,8E)-5-(2-hydroxyethylidene)-9,13-dimethyltetradec-8,12-dien-2-one (E,Z-Formula (II), R'=Me) and (5E,8E)-5-(2-hydroxyethylidene)-9,13-dimethyltetradec-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.

[0187] (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one:

[0188] For analytical data, see Example 1

[0189] (5E,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one:

[0190] 1 H NMR (400MHz, CDCl3) δppm 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).

[0191] 13C NMR(100MHz,CDCl3)δppm 208.37(s,1C),139.91(s,1C),135.46(s,1C),131.19(s,1C),124.42(d,1C),124.11(d,1C),123.60(d,1C),66.54(t,1C),43.40(t, 1C),39.57(t,1C),29.75(q,1C),27.96(t,1C),26.75(t,1C),26.51(t,1C),25.52(q,1C),21.68(t,1C),17.51(q,1C),15.84(q,1C).

[0192] (5Z,8E)-5-(2-Hydroxyethylidene)-9,13-dimethyltetradec-8,12-dien-2-one:

[0193] 1 H NMR (400MHz, CDCl3) δppm 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),2.3 2(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).

[0194] 13 C NMR(100MHz,CDCl3)δppm 208.47(s,1C),141.50(s,1C),135.45(s,1C),131.19(s,1C),124.81(d,1C),124.15(d,1C),123.42(d,1C),58.50(t,1C),41.89(t, 1C),39.56(t,1C),36.14(t,1C),29.96(q,1C),26.57(t,1C),26.34(t,1C),25.56(q,1C),23.96(t,1C),17.55(q,1C)15.92(q,1C).

[0195] (5E,8E)-5-(2-Hydroxyethylidene)-9,13-dimethyltetradec-8,12-dien-2-one:

[0196] 1H NMR (400MHz, CDCl3) δppm 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).

[0197] 13 C NMR(100MHz,CDCl3)δppm 208.23(s,1C),141.48(s,1C),135.92(s,1C),131.28(s,1C),124.27(d,1C),124.08(d,1C),123.25(d,1C),58.77(t,1C),41.93(t, 1C),39.56(t,1C),30.64(t,1C),30.16(t,1C),29.80(q,1C),26.81(t,1C),26.52(t,1C),25.56(q,1C),17.55(q,1C),15.89(q,1C).

[0198] Example 7: (E)-2-chloro-7,11-dimethyl-3-methylene dodeca-6,10-dien-1-yl acetate and (E)-1-Chloro-7,11-dimethyl-3-methylenedodeca-6,10-dien-2-yl acetate

[0199] A solution of (E)-2-(6,10-dimethylundec-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 h and at room temperature for 24 h, and then diluted with MTBE and water. The aqueous phase was extracted with MTBE (3×). 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-methylene dodeca-6,10-dien-1-yl acetate (E-formula (X), Z = Cl) and (E)-1-chloro-7,11-dimethyl-3-methylene dodeca-6,10-dien-2-yl acetate (E-formula (X'), Z = Cl) (E-formula (X) / E-formula (X') = 5.5:1) and unidentified by-products.

[0200] (E)-2-Chloro-7,11-dimethyl-3-methylenedodeca-6,10-dien-1-yl acetate:

[0201] 1H-NMR(500MHz,CDCl3)δppm 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).

[0202] 13 C NMR (125MHz, CDCl3) δppm 170.39(s,1C),144.91(s,1C),135.83(s,1C),131.24(s,1C),124.16(d,1C),123.16(d,1C),114.73(t,1C),65.86(t,1C),61 .24(d,1C),39.57(t,1C),31.36(t,1C),26.55(t,1C),26.07(t,1C),25.60(q,1C),20.64(q,1C),17.59(q,1C),15.98(q,1C).

[0203] GC-MS(EI):298(1),283(1),238(1),223(1),203(2),137(3),133(12),123(7),105(1 2),93(16),91(15),81(21),69(100),79(11),67(12),55(9),53(9),43(50),41(45).

[0204] (E)-1-Chloro-7,11-dimethyl-3-methylene dodeca-6,10-dien-2-yl acetate:

[0205] 1 H-NMR(500MHz,CDCl3)δppm 5.21(br.s,1H),5.15-5.06(m,2H),5.01(br.m,1H),4.47(dd,J=5.5,7.3,1H,CHCl),3.82(dd,J=5.3,11.9,1H, CH2O), 3.78 (dd, J = 7.5, 11.9, 1H, CH2O), 2.28-1.94 (m, 8H), 2.07 (s, 3H), 1.67 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H).

[0206] 13C NMR (125 MHz, CDCl3) δ ppm (selected signal) 175.49 (s, 1C), 114.60 (t, 1C) 66.34 (d, 1C) 65.42 (t, 1C).

[0207] Example 8: (2Z,5E)-2-(2-bromoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate

[0208] 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-dimethylundec-1,5,9-trien-2-yl)oxirane (E-formula (III)) (1.0 g; β-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×). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure to give a crude yellow oil (1.07 g; β-farnesene / E-Formula (IV) / E-Formula (III) / E-Formula (V') = 1:0.06:0.31:0.21) containing β-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).

[0209] (2Z,5E)-2-(2-Bromoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate:

[0210] 1 H-NMR(400MHz,CDCl3)δppm 5.74(br.t,J=8.6,1H),5.15-5.05(m,2H),4.67(s,2H,CH2O),4.06(d,J=8.6 ,2H,CH2Br),2.09(s,Ac),2.25-1.95(m,8H),1.69(br.s,Me),1.61(s,2Me).

[0211] 13C-NMR(100MHz,CDCl3)δppm 170.76(s,1C),139.93(s,1C),136.03(s,1C),131.36(s,1C),125.84(d,1C),124.23(d,1C),122.91(d,1C),60.95(t, 1C),39.67(t,2C),35.20(t,1C),26.68(t,1C),26.14(t,1C),25.66(q,1C),20.87(q,1C),17.66(q,1C),16.05(q,1C).

[0212] 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),1 05(13),93(24),91(17),81(31),79(13),69(100),67(19),55(8),53(9),43(34),41(37),28(2).

[0213] Example 9: (E)-2-bromo-7,11-dimethyl-3-methylene dodeca-6,10-dien-1-yl acetate and (2Z,5E)-2-(2-Bromoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetate

[0214] 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-dimethylundec-1,5,9-trien-2-yl)oxirane (E-formula (III)) (1.0 g; β-farnesene / E-formula (IV) / E-formula (III) = 1:0.65:0.45; 1.9 mmol E-formula (IV) & ​​E-formula (III)) in MeCN (4 ml) was treated dropwise with acetyl bromide (0.15 ml, 1.9 mmol) at 5°C. The resulting mixture was stirred at 5°C for 2 h, diluted with MTBE and saturated aqueous NH4Cl solution. The aqueous phase was extracted with MTBE (3×). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure to give a crude yellow oil (1.07 g; β-farnesene / E-formula (X) / E-formula (V') = 1:0.27:0.28) containing β-farnesene, (E)-2-bromo-7,11-dimethyl-3-methylenedodeca-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).

[0215] (E)-2-Bromo-7,11-dimethyl-3-methylenedodeca-6,10-dien-1-yl acetate:

[0216] 1 H-NMR (500 MHz, CDCl3) δppm selected signals 5.21 (br.s, 1H), 5.15-5.05 (m, 2H), 5.04 (br.m, 1H), 4.65 (br.t, J=7.3, 1H, CHBr), 4.42 (dd, J=7.3, 11.8, 1H, CH2O), 4.34 (dd, J=7.3, 11.8, 1H, CH2O), 2.05 (s, Ac), 1.67 (s, Me), 1.61 (s, Me), 1.58 (s, Me).

[0217] 13 C-NMR(125MHz,CDCl3)δppm 170.24(s,1C),145.32(s,1C),135.80(s,1C),131.23(s,1C),124.15(d,1C),123.22(d,1C),123.15(s,1C),114.66(t,1C),65 .61(t,1C),52.55(d,1C),39.55(t,1C),31.61(t,1C),26.54(t,1C),25.59(q,1C),20.61(q,1C),17.58(q,1C),15.98(q,1C).

[0218] 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).

[0219] Example 10: (E)-2-bromo-7,11-dimethyl-3-methylene dodeca-6,10-dien-1-yl acetate, (E)-2-chloro-7,11-dimethyl-3-methylene dodeca-6,10-dien-1-yl acetate and (E)-1-bromo-7,11-dimethyl 3-Methylene Dodeca-6,10-Dien-2-yl Acetate

[0220] A solution of (E)-2-(6,10-dimethylundec-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) at 5°C. The resulting mixture was stirred at 5°C for 24 h and at room temperature for 24 h, and then diluted with MTBE and water. The aqueous phase was extracted with MTBE (3×). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure to give 0.74 g of a mixture containing (E)-2-bromo-7,11-dimethyl-3-methylenedodec-6,10-dien-1-yl acetate (E-formula (X), Z=Br), (E)-2-chloro-7,11-dimethyl-3-methylenedodec-6,10-dien-1-yl acetate (E-formula (X), Z=Cl) and (E)-1-bromo-7,11-dimethyl-3-methylenedodec-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) of a crude orange oil.

[0221] (E)-1-Bromo-7,11-dimethyl-3-methylenedodeca-6,10-dien-2-yl acetate:

[0222] 1 H-NMR (400 MHz, CDCl3) δ ppm, selected signals: 5.25-4.95 (m, 4H), 4.61 (br.dd, J = 6.0, 7.0, 1H, CHBr), 3.88 (dd, J = 7.3, 11.9, 1H, CH2O), 3.84 (dd, J = 6.1, 11.9, 1H, CH2O).

[0223] Example 11: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one

[0224] 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)) (1.0 g; β-farnesene / E-formula (IV) / E-formula (III) = 1:0.65:0.45; 1.9 mmol E-formula (IV) & ​​E-formula (III)) in MeCN (4 ml) was treated dropwise with 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 residual crude mixture was cooled to 5°C and treated successively 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 treated successively with water (1 ml) and 8M aqueous NaOH solution (1.4 ml) dropwise (maintaining the internal temperature at 10°C). The resulting biphasic mixture was vigorously stirred at 75°C for 3 h.

[0225] The resulting mixture was cooled to room temperature and diluted with MTBE and water. The aqueous phase was extracted with MTBE (3x). The combined organic phases were washed with saturated aqueous NH4Cl and water (2×), dried over MgSO4, filtered and concentrated under reduced pressure to give a crude orange oil containing β-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; β-farnesene / E-Formula (IV) / E-Formula (III) / E,Z-Formula (I)=1:0.1:0.3:0.45).

[0226] Example 12: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one

[0227] 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-dimethylundec-1,5,9-trien-2-yl)oxirane (E-formula (III)) (1.0 g; β-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 that temperature overnight. After evaporation of the solvent under reduced pressure, the residual crude mixture was cooled to 5°C and treated successively 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 and treated successively with water (0.4 ml) and 8M aqueous NaOH solution (0.8 ml) dropwise (maintaining the internal temperature at 10°C). The resulting biphasic mixture was vigorously stirred at 75°C for 3 h.

[0228] The resulting mixture was cooled to room temperature and diluted with MTBE and water. The aqueous phase was extracted with MTBE (3x). The combined organic phases were washed with saturated aqueous NH4Cl and water (2×), dried over MgSO4, filtered and concentrated under reduced pressure to give a crude orange oil containing β-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) (1.02 g; β-farnesene / E-Formula (IV) / E-Formula (III) / E,Z-Formula (I)=1:0.05:0.5:0.5).

[0229] Example 13: (5Z,9E)-6-(Hydroxymethyl)-10,14-dimethylpentadeca-5,9,13-trien-2-one

[0230] At 5°C, a mixture of β-farnesene, (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-vinyl oxirane (E-formula (IV)) and (E)-2-(6,10-dimethylundeca-1,5,9-trien-2-yl)oxirane (E-formula (III)) (1.0 g; β-farnesene / E-formula (IV) / E-formula (III) = 1:0.8:0.7; 2.3 mmol) was added. A solution of E-formula (IV) & ​​E-formula (III)) and NaBr (0.24 g; 2.3 mmol) in MeCN (6 ml) was treated dropwise with acetyl chloride (0.17 ml, 2.4 mmol). 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×). The combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure to give 1.24 g of (E)-2-bromo-7,11-dimethyl-3-methylene Crude orange oil of dodeca-6,10-dien-1-yl acetate (E-formula (X), Z=Br), (E)-1-bromo-7,11-dimethyl-3-methylenedodec-6,10-dien-2-yl acetate (E-formula (X'), Z=Br) and (2Z,5E)-2-(2-bromoethylidene)-6,10-dimethylundec-5,9-dien-1-yl acetate (E-formula (V'), Z=Br) (β-farnesene / E-formula (X) / E-formula (X') / E-formula (V')=1:0.26:0.05:0.27).

[0231] A solution of the above mixture in THF (6 ml) was 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) in sequence. The resulting mixture was stirred at 70 ° C for 4 h, first cooled to room temperature, and then treated dropwise with water (6 ml) and 32% NaOH aqueous solution (4 ml) at 5 ° C. The resulting biphasic mixture was vigorously stirred at 75 ° C for 5 h and stirred at room temperature overnight. The resulting mixture was 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 (2×), dried over MgSO4, filtered and concentrated under reduced pressure to give a crude orange oil (0.99 g; β-farnesene / E-formula (III) / E,Z-formula (I) = 3.3:1:1.5) containing β-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).

[0232] 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

[0233] 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 treated dropwise with acetyl chloride (0.064 ml, 0.89 mmol) at 5 °C, stirred at 5 °C for 1 h, diluted with EtOAc and poured into water. The aqueous phase was extracted with EtOAc (3×), and 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)=~1:1).

[0234] (6E)-3-(Iodomethyl)-7,11-dimethyldodeca-2,6,10-trien-1-yl acetate:

[0235] 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, 2x 2H), 4.58 (d, J = 7.0, 2H, 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, 2x 3H), 1.60 (s, 2x 3H).

[0236] 13C NMR(100MHz,CDCl3)δppm 170.86(s,1C),170.81(s,1C),142.32(s,1C),142.16(s,1C),136.46(s,1C),136.06(s,1C),131.43(s,1C),131.35(s,1C),124.16(d,1C),124.10(d,1C),123.31(d,1C),122.89(d,1C),122.64(d,1C),122.40(d,1C),60.93(t,1C),60.23(t,1C),39.61(t,2C),35.47(t,1C),29.29(t,1C),26.63(t,1C),26.61(t,1C),26.54(t,1C),26.09(t,1C),25.66(q,2C),20.87(q,1C),20.85(q,1C),17.66(q,2C),16.07(q,1C),16.05(q,1C)11.47(t,1C,CH2I)2.60(t,1C,CH2I)。

[0237] Example 15: (2Z,5E)-2-(2-iodoethylidene)-6,10-dimethylundeca-5,9-dien-1-yl acetic acid Ester, (2E,5E)-2-(2-iodoethylidene)-6,10-dimethylundec-5,9-dien-1-yl acetate, (2Z,6E)-3-(iodoethyl methyl)-7,11-dimethyldodeca-2,6,10-trien-1-yl acetate and (2E,6E)-3-(iodomethyl)-7,11-dimethyl 2,6,10-trien-1-yl acetate

[0238] 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)) (1.0 g; β-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 treated dropwise with acetyl iodide (0.16 ml, 2.0 mmol) at 5° C. and protected from sunlight, and stirred for 0.5 h at 5° C. The resulting solution was diluted with MTBE and saturated aqueous NH4Cl. The aqueous phase was extracted with MTBE (3×), and the combined organic phases were washed with brine, dried (MgSO ), filtered and concentrated under reduced pressure to give a mixture containing β-farnesene, (2Z,5E)-2-(2-iodoethylidene)-6,10-dimethylundec-5,9-dien-1-yl acetate (ZE-Formula (V), Z=I) and (2E,5E)-2-(2-iodoethylidene)-6,10-dimethylundec-5,9-dien-1-yl acetate in a ratio of β-farnesene / E-Formula (V) / E-Formula (VI)=1:0.39:0.44. The crude dark orange oil (1.40 g) of (2Z,6E)-3-(iodomethyl)-7,11-dimethyldodeca-2,6,10-trien-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) 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)=1:1).

[0239] Example 16: (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-dimethyltetradec-8,12-dien-2-one (E,Z- Formula (II), R'=Me) and (5E,8E)-5-(2-hydroxyethylidene)-9,13-dimethyltetradec-8,12-dien-2-one (E, E-formula (II), R'=Me)

[0240] At 5°C and protected from sunlight, a solution 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)) (1.0 g; β-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 treated 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, the residue was cooled to 5°C, dissolved in THF (4 ml) and treated sequentially 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 dropwise with 32% aqueous NaOH solution (1.4 ml, 15 mmol) and water (0.7 ml), and the resulting biphasic mixture was stirred at 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×), and the combined organic phases were washed with saturated aqueous NH4Cl and water (2×), dried over MgSO4, filtered and concentrated under reduced pressure to give 0.993 g 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), The invention discloses a crude orange oil of a mixture of (5Z,8E)-5-(2-hydroxyethylidene)-9,13-dimethyltetradec-8,12-dien-2-one (E,Z-formula (II), R'=Me) and (5E,8E)-5-(2-hydroxyethylidene)-9,13-dimethyltetradec-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)=5.5:1.2:3.3:1.6.

Claims

1. A method for preparing a compound of formula (V) The method comprises the following steps a) reacting a mixture comprising a compound of formula (III) and a compound of formula (IV) with an acyl halide R 1 C(O)X is contacted with, optionally in the presence of, a halide salt (AY) Where R 1 is selected from the group consisting of C1 to C6 alkyl, X, Y and Z are selected from Cl, I and Br, and A is selected from Na, K, Li and quaternary ammonium salts.

2. The method according to claim 1, for preparing a compound of formula (V), wherein the compound of formula (V) is a compound of formula (V') The method comprises the following steps a) making a mixture comprising a compound of formula (III) and a compound of formula (IV) i) in the absence of a halide salt, with an acyl halide R 1 C(O)X contact, or ii) in the presence of a halide salt AY in which Y is not iodine, with an acyl halide R 1 C(O)X contact, Where R 1 is selected from the group consisting of C1 to C6 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.

3. The method according to claim 2, for preparing a compound of formula (V') and a compound of formula (X) and / or its regioisomer (X') Where R 1 is selected from the group consisting of C1 to C6 alkyl, and Z is selected from Cl and Br.

4. The method according to claim 1, for preparing a compound of formula (V) and a compound of formula (VI) The method comprises the following steps a) contacting a mixture comprising a compound of formula (III) and a compound of formula (IV) with an acyl iodide (R1C(O)I), or an acyl halide R1C(O)X wherein X is selected from Cl and Br in the presence of an iodide salt AI wherein A is selected from Na, K, Li and a quaternary ammonium salt, R 1 is selected from the group consisting of C1 to C6 alkyl, and Z is iodine.

5. The method according to any one of claims 1 to 4, wherein the compound of formula (III) and the compound of formula (IV) are E-formula (III) and (IV) 6. The method according to any one of claims 1 to 5, which is followed by Step b) contacting a compound of formula (V) with a compound of formula (VII) To obtain a compound of formula (VIII) Where R 1 is selected from the group consisting of C1 to C6 alkyl, R' is selected from the group consisting of C1-C6 alkyl and OR group, R is selected from the group consisting of hydrogen and C1 to C6 alkyl, and Z is selected from Cl, I and Br.

7. The method according to claim 6, which is followed by Step c) hydrolyzing and decarboxylating the compound of formula (VIII) To obtain a compound of formula (I) Where R 1 is selected from the group consisting of C1 to C6 alkyl, R' is selected from the group consisting of C1-C6 alkyl and OR group, and R is selected from the group consisting of hydrogen and C1 to C6 alkyl.

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

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

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

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

12. The method according to claim 11, wherein the compound of formula (V) is a compound of formula (V') in R 1 is selected from the group consisting of C1 to C6 alkyl, and Z is selected from Cl and Br.

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

14. A compound of formula (V) in R 1 is selected from the group consisting of C1 to C6 alkyl, and Z is selected from Cl, I and Br.

15. A compound of formula (VI) in R 1 is selected from the group consisting of C1 to C6 alkyl, and Z is selected from Cl, I and Br.

Images