Preparation method of 6-isopropenyl-3-methyl-9-decenyl acetate and intermediates thereof

Abstract

The present invention provides a method for preparing 6-isopropenyl-3-methyl-9-decenyl acetate (5), wherein Ac represents an acetyl group, and the method comprises the following steps: subjecting a 2-methyl-2,6-heptadiene compound (1) having a leaving group X at position 1 to a nucleophilic substitution reaction with a 3-methylpentyl nucleophile (2) having a protected hydroxyl group at position 5 to form a 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1; subjecting the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1 to a deprotection reaction to form 6-isopropenyl-3-methyl-9-decenol (4); and acetylation of the 6-isopropenyl-3-methyl-9-decenol (4) to form 6-isopropenyl-3-methyl-9-decenyl acetate (5).

Description

Technical Field

[0001] The present invention relates to a method for preparing 6-isopropenyl-3-methyl-9-decenyl acetate, which is a sex pheromone substance of citrus pest California red scale (scientific name: Aonidiella aurantii (red scale)), and intermediates thereof. Background Art

[0002] Insect sex pheromones are biologically active substances usually carried by female insects to attract male insects, and they show high attractant activity even in small amounts. Sex pheromones are widely used as a means of predicting pest outbreaks and confirming geographical spread (invasion of a specific area), and are also used as a means of controlling pests. Widely used pest control methods include: mass trapping methods, lure and kill or attract and kill methods, lure and infect or attract and infect methods, and mating disruption methods. Naturally occurring sex pheromones can only be extracted in trace amounts from individual insects. Therefore, it is difficult to use naturally occurring sex pheromones to interfere with mating methods. Before the actual use of sex pheromones, it is necessary to artificially produce sufficient amounts of sex pheromones for basic research and application.

[0003] California red scale is a pest that is widely spread around the world and attacks citrus. (3S,6R)-6-isopropenyl-3-methyl-9-decenyl acetate is reported to be the sex pheromone of California red scale (Non-Patent Document 1 below). 6-Isopropenyl-3-methyl-9-decenyl acetate includes four isomers: (3R,6R)-6-isopropenyl-3-methyl-9-decenyl acetate, (3R,6S)-6-isopropenyl-3-methyl-9-decenyl acetate, (3S,6R)-6-isopropenyl-3-methyl-9-decenyl acetate and (3S,6S)-6-isopropenyl-3-methyl-9-decenyl acetate. California red scale is also reported to be attracted to a mixture of these four isomers (Non-Patent Document 1 below).

[0004] A method for preparing 6-isopropenyl-3-methyl-9-decenyl acetate is reported. For example, in the following non-patent document 2, the method includes using selenium dioxide and tert-butyl hydroperoxide to oxidize the trisubstituted double bond part of citronellol acetate, chlorinating the introduced hydroxyl group with triphenylphosphine and carbon tetrachloride, and subjecting the product to a nucleophilic substitution reaction to form (3S, 6RS)-6-isopropenyl-3-methyl-9-decenyl acetate. In the following non-patent document 3, the method includes preparing a sulfide compound from citronellol acetate, subjecting the sulfide compound to a 1,2-Stevens rearrangement reaction with meta-chloroperbenzoic acid in the presence of a strong base, oxidizing the product with meta-chloroperbenzoic acid to prepare a sulfone compound, and then performing trialkylation of the sulfone compound and reduction elimination of the sulfone to form 6-isopropenyl-3-methyl-9-decenyl acetate.

[0005] In addition, a method for preparing (3S,6R)-6-isopropenyl-3-methyl-9-decenyl acetate is also reported in the following non-patent document 4, wherein the method includes the first eight steps, including converting (-)-dihydrocarvone into a silyl enol ether compound, ozone oxidation, reduction with sodium borohydride, and methylation of carboxylic acid with diazomethane to synthesize (2S,5R)-5-isopropenyl-2-methyl-8-nonenyl iodide; followed by four steps including preparing a nitrile compound with sodium cyanide.

[0006] Reference list

[0007] [Non-patent literature]

[0008] [Non-patent document 1] MJ GIESELMANN et al., J. Insect. Physiol. 26, 179 (1980)

[0009] [Non-patent document 2] Panagiotis Kefalas et al., Synthesis. 644 (1995)

[0010] [Non-patent document 3] VA Dragan et al., Russ. Chem. Bull. 38, 1038 (1989)

[0011] [Non-patent document 4] R. Boudduy et al., Tetrahedron. 44, 471 (1988)

[0012] Problems to be solved by the present invention

[0013] In the method described in Non-Patent Document 2, selenium dioxide and tert-butyl hydroperoxide used for the oxidation reaction of citronellol acetate produce wastes that are toxic and highly harmful to the environment and are not conducive to environmental protection. The oxidation reaction may cause an explosion, and therefore, it is not very feasible in industry. In addition, the oxidation reaction yield is as low as 52%.

[0014] In the method described in Non-Patent Document 3, the meta-chloroperbenzoic acid used to oxidize the sulfide compound may cause an explosion. Highly toxic hexamethylphosphoric triamide is used as a solvent in the alkylation reaction. These make the method less feasible industrially. The method consists of eight steps and the yield is as low as 12.3%.

[0015] In the method described in non-patent literature 4, the synthesis of intermediate (2S, 5R)-5-isopropenyl-2-methyl-8-nonenyl iodide requires eight steps, including ozone oxidation, which is not industrially feasible, and using diazomethane, which is explosive and highly toxic. Therefore, this method is industrially disadvantageous. In addition, it takes a total of four steps to form (3S, 6R)-6-isopropenyl-3-methyl-9-decenyl acetate from (2S, 5R)-5-isopropenyl-2-methyl-8-nonenyl iodide. Highly toxic sodium cyanide is used. These make this method industrially unfeasible.

[0016] Therefore, it seems difficult to industrially prepare 6-isopropenyl-3-methyl-9-decenyl acetate in a sufficient amount by the above-mentioned known methods. Summary of the invention

[0017] The present invention has been accomplished under these circumstances, and its object is to provide a method for efficiently and industrially preparing 6-isopropenyl-3-methyl-9-decenyl acetate without causing an oxidation reaction, in an amount sufficient for biological or agricultural activity tests and / or practical applications.

[0018] To solve these problems, the present inventors conducted intensive research and found a 2-methyl-2,6-heptadiene compound; the compound can be used for industrial preparation of 6-isopropenyl-3-methyl-9-decenyl acetate; and the 2-methyl-2,6-heptadiene compound is a useful intermediate for preparing 6-isopropenyl-3-methyl-9-decenyl acetate. Therefore, the present invention was invented.

[0019] One aspect of the present invention provides a method for preparing 6-isopropenyl-3-methyl-9-decenyl acetate of the following formula (5):

[0020]

[0021] Wherein Ac represents an acetyl group,

[0022] The method comprises the following steps:

[0023] A 2-methyl-2,6-heptadiene compound of the following general formula (1) having a leaving group X at position 1:

[0024]

[0025] wherein X represents an acyloxy group having 1 to 10 carbon atoms including the carbon atom of the carbonyl group, an alkanesulfonyloxy group having 1 to 10 carbon atoms, an arylsulfonyloxy group having 6 to 20 carbon atoms, or a halogen atom,

[0026] A nucleophilic substitution reaction is carried out with a 3-methylpentyl nucleophile of the following general formula (2) having a protected hydroxyl group at the 5-position:

[0027]

[0028] Where M represents Li, Mg, Z 1 、ZnZ 1 ,Cu,CuZ 1 or CuLiZ 1 , where Z 1 Represents a halogen atom or CH 2 CH 2 CH(CH 3 )CH 2 CH 2 OR group, and R represents a protecting group for a hydroxyl group,

[0029] To form a 6-isopropenyl-3-methyl-9-decene compound of the following general formula (3) having a protected hydroxyl group at position 1:

[0030]

[0031] wherein R is as defined above;

[0032] The 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at the 1-position is subjected to a deprotection reaction to form 6-isopropenyl-3-methyl-9-decenol of the following formula (4):

[0033]

[0034] 6-Isopropenyl-3-methyl-9-decenol (4) is acetylated to form 6-isopropenyl-3-methyl-9-decenyl acetate (5).

[0035] Another aspect of the present invention provides a method for preparing 6-isopropenyl-3-methyl-9-decenyl acetate of the following general formula (5):

[0036]

[0037] Wherein Ac represents an acetyl group,

[0038] The method comprises the following steps:

[0039] A 2-methyl-2,6-heptadiene compound of the following general formula (1) having a leaving group X at position 1:

[0040]

[0041] wherein X represents an acyloxy group having 1 to 10 carbon atoms including the carbon atom of the carbonyl group, an alkanesulfonyloxy group having 1 to 10 carbon atoms, an arylsulfonyloxy group having 6 to 20 carbon atoms, or a halogen atom,

[0042] A nucleophilic substitution reaction is carried out with a 3-methylpentyl nucleophile of the following general formula (2) having a protected hydroxyl group at the 5-position:

[0043]

[0044] Where M represents Li, Mg, Z 1 、ZnZ 1 ,Cu,CuZ 1 or CuLiZ 1 , where Z 1 Represents a halogen atom or CH 2 CH 2 CH(CH 3 )CH 2 CH 2 OR group, and R represents a protecting group for a hydroxyl group,

[0045] To form a 6-isopropenyl-3-methyl-9-decene compound of the following general formula (3) having a protected hydroxyl group at position 1:

[0046]

[0047] wherein R is as defined above; and

[0048] The 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at the 1-position is subjected to acetylation to form 6-isopropenyl-3-methyl-9-decenyl acetate (5).

[0049] Another aspect of the present invention provides a method for preparing 6-isopropenyl-3-methyl-9-decenyl acetate (5), the method further comprising the following steps:

[0050] The hydroxyl group of 2-methyl-2,6-heptadienol of the following formula (6):

[0051]

[0052] Converted to X to form a 2-methyl-2,6-heptadiene compound (1) having a leaving group X at position 1, wherein X is as defined above.

[0053] Another aspect of the present invention provides a 2-methyl-2,6-heptadiene compound of the following general formula (1') having X' at position 1:

[0054]

[0055] wherein X' represents an acyloxy group having 1 to 10 carbon atoms including the carbon atom of the carbonyl group.

[0056] Another aspect of the present invention provides a 2-methyl-2,6-heptadiene compound of the following general formula (1") having X" at position 1:

[0057]

[0058] wherein X" represents an alkanesulfonyloxy group having 1 to 10 carbon atoms or an arylsulfonyloxy group having 6 to 20 carbon atoms.

[0059] The present invention provides a method for efficiently and industrially preparing 6-isopropenyl-3-methyl-9-decenyl acetate without using an oxidation reaction which is industrially disadvantageous in view of safety, economy and environmental burden. The present invention also provides a 2-methyl-2,6-heptadiene compound (1') and a 2-methyl-2,6-heptadiene compound (1') which are useful intermediates for preparing 6-isopropenyl-3-methyl-9-decenyl acetate. DETAILED DESCRIPTION

[0060] Embodiments of the present invention will be described in detail below. It should be understood that the present invention is not limited to or by the embodiments. In the intermediates, reagents and target compounds represented by chemical formulas in this specification, some stereoisomers, such as enantiomers or diastereomers, may exist. Unless otherwise indicated, each chemical formula should be interpreted as representing all these isomers. Isomers can be single or in combination.

[0061] The present inventors considered a synthesis scheme of 6-isopropenyl-3-methyl-9-decenyl acetate (5) as described below.

[0062]

[0063] In the reaction formula of the retrosynthetic analysis shown above, the open arrows represent the transformation in the retrosynthetic analysis. Ac represents an acetyl group; R represents a protecting group for a hydroxyl group; X represents an acyloxy group having 1 to 10 carbon atoms including the carbon atom of a carbonyl group, an alkanesulfonyloxy group having 1 to 10 carbon atoms, an arylsulfonyloxy group having 6 to 20 carbon atoms, or a halogen atom; M represents Li, Mg, Z 1 、ZnZ 1 ,Cu,CuZ 1 or CuLiZ 1 , where Z 1 Represents a halogen atom or CH 2 CH 2CH(CH 3 )CH 2 CH 2 OR group; and R represents a protecting group for a hydroxyl group.

[0064] Step D'

[0065] The target compound of the present invention, 6-isopropenyl-3-methyl-9-decenyl acetate (5), is considered to be synthesized by acetylation of 6-isopropenyl-3-methyl-9-decenol (4).

[0066] Formula (5) represents (3R, 6R)-6-isopropenyl-3-methyl-9-decenyl acetate of the following formula (5a), (3R, 6S)-6-isopropenyl-3-methyl-9-decenyl acetate of the following formula (5b), (3S, 6R)-6-isopropenyl-3-methyl-9-decenyl acetate of the following formula (5c), or (3S, 6S)-6-isopropenyl-3-methyl-9-decenyl acetate of the following formula (5d), or a combination thereof.

[0067]

[0068] Formula (4) represents (3R, 6R)-6-isopropenyl-3-methyl-9-decenol of the following formula (4a), (3R, 6S)-6-isopropenyl-3-methyl-9-decenol of the following formula (4b), (3S, 6R)-6-isopropenyl-3-methyl-9-decenol of the following formula (4c), or (3S, 6S)-6-isopropenyl-3-methyl-9-decenol of the following formula (4d), or a combination thereof.

[0069]

[0070] Step C'

[0071] The target compound 6-isopropenyl-3-methyl-9-decanol (4) is considered to be synthesized by deprotecting a 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at the 1-position.

[0072] The general formula (3) represents a (3R,6R)-6-isopropenyl-3-methyl-9-decene compound of the following general formula (3a) having a protected hydroxyl group at position 1, a (3R,6S)-6-isopropenyl-3-methyl-9-decene compound of the following general formula (3b) having a protected hydroxyl group at position 1, a (3S,6R)-6-isopropenyl-3-methyl-9-decene compound of the following general formula (3c) having a protected hydroxyl group at position 1, or a (3S,6S)-6-isopropenyl-3-methyl-9-decene compound of the following general formula (3d) having a protected hydroxyl group at position 1, or a combination thereof.

[0073]

[0074] Step B'

[0075] The target compound, a 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at the 1-position, is believed to be synthesized by a regioselective reaction between a 3-methylpentyl nucleophile (2) having a protected hydroxyl group at the 5-position and a carbon atom at the 3-position of a 2-methyl-2,6-heptadiene compound (1) having a leaving group X at the 1-position.

[0076] The general formula (2) represents a (R)-3-methylpentyl nucleophile of the following general formula (2a) having a protected hydroxyl group at position 5, or a (S)-3-methylpentyl nucleophile of the following general formula (2b) having a protected hydroxyl group at position 5, or a combination thereof. In the nomenclature of the nucleophiles of the general formulas (2a) and (2b), M has a higher priority than O in the R / S system.

[0077]

[0078] The general formula (1) represents a (Z)-2-methyl-2,6-heptadiene compound of the following general formula (1a) having a leaving group X at the 1-position or a (E)-2-methyl-2,6-heptadiene compound of the following general formula (1b) having a leaving group X at the 1-position, or a combination thereof.

[0079]

[0080] Step A'

[0081] The target compound, 2-methyl-2,6-heptadiene compound (1) having a leaving group X at position 1, is considered to be synthesized by conversion of the hydroxyl group of 2-methyl-2,6-heptadiene (6).

[0082] Formula (6) represents (Z)-2-methyl-2,6-heptadienol of the following formula (6a), or (E)-2-methyl-2,6-heptadienol of the following formula (6b), or a combination thereof.

[0083]

[0084] With the foregoing retrosynthetic analysis in mind, embodiments of the present invention may be described by the following chemical reaction schemes.

[0085]

[0086] Therefore, the chemical reaction scheme includes step A, wherein a 2-methyl-2,6-heptadiene compound (1) having a leaving group X at position 1 is synthesized by conversion of the hydroxyl group of 2-methyl-2,6-heptadienol (6); step B, wherein a 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1 is synthesized by a regioselective nucleophilic substitution reaction between a 3-methylpentyl nucleophile (2) having a protected hydroxyl group at position 5 and the carbon atom at position 3 of the 2-methyl-2,6-heptadiene compound (1) having a leaving group X at position 1; step C, wherein the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1 is deprotected; and finally step D, wherein the target compound of the present invention, 6-isopropenyl-3-methyl-9-decenyl acetate (5), is synthesized by acetylation of 6-isopropenyl-3-methyl-9-decenol (4).

[0087] Steps A to D as embodiments of the present invention will be described in detail below. These will be explained in the order of steps B, C, D, and A. In the explanation of step B, useful intermediates, 2-methyl-2,6-heptadiene compound (1') and 2-methyl-2,6-heptadiene compound (1") are also described.

[0088] [1] Step B

[0089] Step B for obtaining a 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1 will be described below. As shown in the following chemical reaction formula, a 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1 is synthesized by a nucleophilic substitution reaction between a 2-methyl-2,6-heptadiene compound (1) having a leaving group X at position 1 and a 3-methylpentyl nucleophile (2) having a protected hydroxyl group at position 5.

[0090]

[0091] First, a 2-methyl-2,6-heptadiene compound of the following general formula (1) having a leaving group X at the 1-position will be described.

[0092]

[0093] X in the general formula (1) represents a leaving group.

[0094] The 2-methyl-2,6-heptadiene compound (1) having a leaving group X at position 1 may be a (Z)-2-methyl-2,6-heptadiene compound of the following general formula (1a) having a leaving group X at position 1, or a (E)-2-methyl-2,6-heptadiene compound of the following general formula (1b) having a leaving group X at position 1. The 2-methyl-2,6-heptadiene compound (1) having a leaving group X at position 1 may be an isomer or a mixture of isomers.

[0095]

[0096] The leaving group X represents an acyloxy group having 1 to 10 carbon atoms including the carbon atom of the carbonyl group, an alkanesulfonyloxy group having 1 to 10 carbon atoms, an arylsulfonyloxy group having 6 to 20 carbon atoms or a halogen atom, and may be appropriately selected from these groups in view of reactivity, reaction selectivity, availability of raw materials, ease of synthesis, storage stability, toxicity and / or price.

[0097] Examples of acyloxy groups having 1 to 10 carbon atoms including the carbon atom of the carbonyl group include straight-chain aliphatic acyloxy groups, such as formyloxy groups, acetyloxy groups, propionyloxy groups, butyryloxy groups, pentanoyloxy groups, hexanoyloxy groups, heptanoyloxy groups, octanoyloxy groups, nonanoyloxy groups, decanoyloxy groups, and crotonyloxy groups; branched aliphatic acyloxy groups, such as 2-methylpropionyloxy groups, pivaloyloxy groups, 2-methylbutyryloxy groups, 3-methyl-2-butenoyloxy groups, and 3-methyl-3-butenoyloxy groups; halogenated acyloxy groups, such as trichloroacetoxy groups and trifluoroacetoxy groups; aromatic acyloxy groups, such as benzoyloxy groups; and isomers thereof. A portion of the hydrogen atoms in the acyloxy group may be substituted by, for example, a methyl group, an ethyl group, or a halogen atom. Examples of halogen atoms include chlorine atoms, bromine atoms, and iodine atoms.

[0098] Among the acyloxy groups, a formyloxy group, an acetoxy group, a propionyloxy group, a pivaloyloxy group, a 2-methylpropionyloxy group and a benzoyloxy group are preferred in view of availability.

[0099] The example of the alkanesulfonyloxy group with 1 to 10 carbon atoms includes a methylsulfonyloxy group, an ethylsulfonyloxy group, a 1-butylsulfonyloxy group, a 1-pentanesulfonyloxy group, a 1-hexylsulfonyloxy group, a 1-heptylsulfonyloxy group, a 1-octanesulfonyloxy group, a 1-nonanesulfonyloxy group, a 1-decanesulfonyloxy group, an allylsulfonyloxy group, a 10-camphorsulfonyloxy group, a trifluoromethanesulfonyloxy group, an α-benzylsulfonyloxy group and an isomer thereof. A part of the hydrogen atoms in the alkanesulfonyloxy group can be replaced by, for example, a methyl group, an ethyl group or a halogen atom. The example of a halogen atom includes a chlorine atom, a bromine atom and an iodine atom.

[0100] Among the alkanesulfonyloxy groups, a methanesulfonyloxy group and an ethanesulfonyloxy group are preferred in view of availability.

[0101] Examples of the arylsulfonyloxy group having 6 to 20 carbon atoms include a benzenesulfonyloxy group, a 4-chlorobenzenesulfonyloxy group, a 4-methoxybenzenesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, a 2,4,6-trimethylbenzenesulfonyloxy group, a p-toluenesulfonyloxy group, a 1-naphthalenesulfonyloxy group, a 2-naphthalenesulfonyloxy group and isomers thereof. A portion of the hydrogen atoms in the arylsulfonyloxy group may be substituted by, for example, a methyl group, an ethyl group or a halogen atom. Examples of the halogen atom include a chlorine atom, a bromine atom and an iodine atom.

[0102] Among the arylsulfonyloxy groups, a benzenesulfonyloxy group and a p-toluenesulfonyloxy group are preferred in view of availability.

[0103] Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0104] Among the halogen atoms, a chlorine atom and a bromine atom are preferred in view of availability.

[0105] In view of reactivity and / or economical properties, the 2-methyl-2,6-heptadiene compound (1) having a leaving group X at position 1 is particularly preferably a 2-methyl-2,6-heptadiene compound of the following general formula (1′):

[0106]

[0107] X' in the general formula (1') represents an acyloxy group having 1 to 10 carbon atoms including the carbon atom of the carbonyl group.

[0108] Specific examples of the acyloxy group having 1 to 10 carbon atoms including the carbon atom of the carbonyl group are the same as those mentioned for the acyloxy group as the leaving group X.

[0109] In addition to the 2-methyl-2,6-heptadiene compound (1'), the 2-methyl-2,6-heptadiene compound of the following general formula (1") is preferred in view of the availability of raw materials:

[0110]

[0111] X" in the general formula (1") represents an alkanesulfonyloxy group having 1 to 10 carbon atoms or an arylsulfonyloxy group having 6 to 20 carbon atoms.

[0112] Specific examples of the alkanesulfonyloxy group having 1 to 10 carbon atoms and the arylsulfonyloxy group having 6 to 20 carbon atoms are those mentioned for 3) the CH leaving group X.

[0113] The leaving group X is located at the allylic position of the 2-methyl-2,6-heptadiene compound (1) having the leaving group X at the 1-position. Therefore, the 3-methylpentyl nucleophile (2) having a protected hydroxyl group at the 5-position can attack the carbon atom at the 1-position to which the leaving group X is attached and the carbon atom at the 3-position of the 2-methyl-2,6-heptadiene compound (1) having the leaving group X at the 1-position.

[0114] When a 3-methylpentyl nucleophile (2) having a protected hydroxyl group at the 5-position attacks a carbon atom at the 3-position of a 2-methyl-2,6-heptadiene compound (1) having a leaving group X at the 1-position (so-called S N 2' mechanism), nucleophilic substitution and allylic rearrangement occur simultaneously to generate 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1.

[0115] At the same time, when the 3-methylpentyl nucleophile (2) having a protected hydroxyl group at the 5-position attacks the carbon atom at the 1-position of the 2-methyl-2,6-heptadiene compound (1) having a leaving group X at the 1-position (so-called S N 2 mechanism), a 3,7-dimethyl-7,11-dodecadiene compound of the following general formula (3') having a protected hydroxyl group at the 1-position is generated.

[0116]

[0117] That is, in step B, the production of the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1 may compete with the production of the 3,7-dimethyl-7,11-dodecadiene compound (3'). Among the nucleophilic substitution reaction conditions described below, optimal conditions may be employed to reduce the production of the by-product, the 3,7-dimethyl-7,11-dodecadiene compound (3') having a protected hydroxyl group at position 1, and to increase the yield of the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1. Examples of optimal conditions include the use of a 2-methyl-2,6-heptadiene compound (1') (wherein the leaving group X in the 2-methyl-2,6-heptadiene compound (1) having a leaving group X at position 1 is an acyloxy group having 1 to 10 carbon atoms including the carbon atom of the carbonyl group), the use of a 5-(1-ethoxyethyloxy)-3-methylpentylmagnesium halide nucleophile (wherein the protecting group is a 1-ethoxyethyl group), and the use of a copper halide including copper and cuprous and a lithium salt combination catalyst in a nucleophilic substitution reaction. The catalyst combination is believed to suppress the formation of by-products and improve the yield of the target compound (for example, see Examples 6 and 7 below).

[0118] The 3-methylpentyl nucleophile (2) having a protected hydroxyl group at the 5-position may be a (R)-3-methylpentyl nucleophile of the following general formula (2a) having a protected hydroxyl group at the 5-position, or a (S)-3-methylpentyl nucleophile of the following general formula (2b) having a protected hydroxyl group at the 5-position, wherein in the R / S system, M has a higher priority than O. The 3-methylpentyl nucleophile (2) may be an isomer or a combination of isomers, but preferably comprises a compound (2a) having the same backbone as the naturally occurring sex pheromone carried by female California red scale insects.

[0119]

[0120] The 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at the 1-position may be a (3R,6R)-6-isopropenyl-3-methyl-9-decene compound of the following general formula (3a) having a protected hydroxyl group at the 1-position, a (3R,6S)-6-isopropenyl-3-methyl-9-decene compound of the following general formula (3b) having a protected hydroxyl group at the 1-position, a (3S,6R)-6-isopropenyl-3-methyl-9-decene compound of the following general formula (3c) having a protected hydroxyl group at the 1-position, or a (3S,6S)-6-isopropenyl-3-methyl-9-decene compound of the following general formula (3d) having a protected hydroxyl group at the 1-position. The 6-isopropenyl-3-methyl-9-decene compound (3) may be an isomer or a mixture of isomers, but preferably comprises a compound (3c) having the same main chain as the naturally occurring sex pheromone carried by female California red scale insects.

[0121]

[0122] The by-product in the nucleophilic substitution reaction, the 3,7-dimethyl-7,11-dodecadiene compound (3') having a protected hydroxyl group at position 1 may be a (R,Z)-3,7-dimethyl-7,11-dodecene compound of the following general formula (3'a) having a protected hydroxyl group at position 1, a (R,E)-3,7-dimethyl-7,11-dodecene compound of the following general formula (3'b) having a protected hydroxyl group at position 1, a (S,Z)-3,7-dimethyl-7,11-dodecene compound of the following general formula (3'c) having a protected hydroxyl group at position 1, a (S,E)-3,7-dimethyl-7,11-dodecene compound of the following general formula (3'd) having a protected hydroxyl group at position 1, or a mixture thereof.

[0123]

[0124] R in the 3-methylpentyl nucleophile (2) having a protected hydroxyl group at the 5-position represents a protecting group for the hydroxyl group. The protecting group may be appropriately selected from known protecting groups for hydroxyl groups, which are stable and easily deprotected during reaction, post-treatment and storage. Examples of suitable protecting groups R include oxyalkyl groups, such as methoxymethyl groups, 2-methoxyethoxymethyl groups, benzyloxymethyl groups, p-methoxybenzyloxymethyl groups, 2,2,2-trichloroethoxymethyl groups, 1-ethoxyethyl groups and tetrahydropyranyl groups and isomers thereof. A portion of the hydrogen atoms in the protecting group may be substituted by, for example, a methyl group or an ethyl group. Examples of other protecting groups include trialkylsilyl groups, such as trimethylsilyl groups, triethylsilyl groups, triisopropylsilyl groups and tert-butyldimethylsilyl groups; monoalkyldiarylsilyl groups, such as tert-butyldiphenylsilyl groups and isomers thereof. A portion of the hydrogen atoms in the silyl group may be substituted by, for example, a methyl group, an ethyl group or a halogen atom. Examples of the halogen atom include a chlorine atom, a bromine atom and an iodine atom.

[0125] In view of reactivity and / or economy, the protecting group R is preferably a tetrahydropyranyl group or a 1-ethoxyethyl group.

[0126] In the 3-methylpentyl nucleophile (2) having a protected hydroxyl group at the 5-position, M represents Li, Mg, Z 1 、ZnZ 1 ,Cu,CuZ 1 or CuLiZ 1 , where Z 1 Represents a halogen atom or CH 2 CH 2 CH(CH 3 )CH 2 CH 2 OR group, and R represents a protecting group for a hydroxyl group.

[0127] In view of reactivity, selectivity and / or ease of preparation, the 3-methylpentyl nucleophilic reagent (2) having a protected hydroxyl group at position 5 is preferably an organolithium reagent such as a 3-methylpentyl lithium halide compound having a protected hydroxyl group at position 5, or an organomagnesium reagent such as a 3-methylpentyl magnesium halide compound (Grignard reagent) having a protected hydroxyl group at position 5. In particular, a 3-methylpentyl magnesium halide compound (Grignard reagent) is preferred.

[0128] Specific examples of the 3-methylpentylmagnesium halide compound having a protected hydroxyl group at the 5-position include a 3-methylpentylmagnesium chloride compound having a protected hydroxyl group at the 5-position, a 3-methylpentylmagnesium bromide compound having a protected hydroxyl group at the 5-position, and a 3-methylpentylmagnesium iodide compound having a protected hydroxyl group at the 5-position.

[0129] The 3-methylpentyl nucleophile (2) having a protected hydroxyl group at the 5-position can be prepared by a conventional method, for example, from its corresponding halide, 3-methylpentyl halide having a protected hydroxyl group at the 5-position. Examples of the 3-methylpentyl halide having a protected hydroxyl group at the 5-position include a 3-methylpentyl chloride compound having a protected hydroxyl group at the 5-position, a 3-methylpentyl bromide compound having a protected hydroxyl group at the 5-position, and a 3-methylpentyl iodide compound having a protected hydroxyl group at the 5-position. In view of the ease of preparation and / or stability of the 3-methylpentyl nucleophile (2) having a protected hydroxyl group at the 5-position, 3-methyl-pentyl chloride compounds having a protected hydroxyl group at the 5-position and 3-methyl-pentyl bromide compounds having a protected hydroxyl group at the 5-position are preferred.

[0130] The 3-methylpentyl nucleophile (2) having a protected hydroxyl group at the 5-position can be prepared by subjecting an organolithium reagent or an organomagnesium reagent to a metal exchange reaction with a stoichiometric amount (1 mol) of a transition metal compound, or can be formed in situ by reacting an organolithium reagent or a Grignard reagent with an extremely small amount (e.g., 0.0001 or more) of a transition metal compound.

[0131] Examples of transition metal compounds include those containing copper, iron, nickel, palladium, zinc, titanium or silver. Preferred are cuprous halides such as cuprous chloride (I), cuprous bromide (I) and cuprous iodide (I); cupric halides such as cuprous chloride (II), cupric bromide (II) and cupric iodide (II); copper cyanides such as cuprous cyanide (I) and cupric cyanide (II); copper oxides such as cuprous oxide (I) and cupric oxide (II); and copper compounds such as dilithium tetrachlorocuprate (Li 2 CuCl 4 ). In view of reactivity, cuprous halide is particularly preferred.

[0132] The amount of the transition metal compound may be a very small amount, such as 0.0001 to 1 times the stoichiometric amount relative to the amount of the 2-isopropenyl-5-hexenyl compound containing a metal element of Group I or II, or even a 100-fold excess. An amount of 0.0001 to 10 mol is preferred.

[0133] R in the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1 is as defined in the general formula (2).

[0134] In the nucleophilic substitution reaction between the 2-methyl-2,6-heptadiene compound (1) having a leaving group X at the 1-position and the 3-methylpentyl nucleophile (2) having a protected hydroxyl group at the 5-position, an organometallic reagent containing a metal element of Group I or II or a transition metal element is generally used.

[0135] When a transition metal compound is used for a nucleophilic substitution reaction, a phosphorus compound may also be used in view of enhancing the solubility of the transition metal compound in a solvent.

[0136] Examples of the phosphorus compound include trialkyl phosphites such as triethyl phosphite; and triaryl phosphines such as triphenyl phosphine.

[0137] If necessary, the phosphorus compound may be used alone or in combination. The phosphorus compound may be a commercially available product.

[0138] The phosphorus compound is used in an amount of 0.001 to 1000 parts per 100 parts of the transition metal compound to improve the solubility of the transition metal compound in the solvent.

[0139] In the nucleophilic substitution reaction, 0.001 to 1000 mol of a lithium salt such as lithium chloride, lithium bromide or lithium iodide can be used as a catalyst for the reaction per mol of the 2-methyl-2,6-heptadiene compound (1) having a leaving group X at the 1-position.

[0140] In the nucleophilic substitution reaction, a combination of a cuprous halide and a lithium salt is particularly preferred in view of reactivity (including the formation ratio of the target compound to the by-product) (see Examples 6 and 7 below).

[0141] The amount of the 3-methylpentyl nucleophile having a protected hydroxyl group at the 5-position (2) can be arbitrarily set in consideration of reagents, reaction conditions, reaction yield, economics (e.g., price of intermediates) and / or easiness of purification of the target compound from the reaction mixture, and is preferably 0.2 to 100 mol, more preferably 0.5 to 20 mol, even more preferably 0.8 to 5 mol per mol of the 2-methyl-2,6-heptadiene compound (1).

[0142] The nucleophilic substitution reaction is carried out in the presence of a solvent, with heating or cooling if necessary.

[0143] Examples of solvents used in nucleophilic substitution reactions include ethers, such as diethyl ether, n-butyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane; hydrocarbons, such as hexane, heptane, benzene, toluene, xylene and isopropylbenzene; and aprotic polar solvents, such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N,N-dimethylpropionamide, 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO) and hexamethylphosphoric triamide (HMPA). Ethers are preferred in view of reactivity. The solvent may be a single ether, or, if necessary, a combination of an ether and one or more of the above solvents other than an ether. The solvent may be a commercially available product.

[0144] The amount of the solvent used is not particularly limited, and is preferably 10 to 1,000,000 g, more preferably 100 to 100,000 g, even more preferably 150 to 10,000 g per mol of the 3-methylpentyl nucleophile (2) having a protected hydroxyl group at the 5-position.

[0145] The reaction temperature of the nucleophilic substitution reaction is preferably from -78°C to the boiling point of the solvent, more preferably from -78 to 100°C.

[0146] The reaction time of the nucleophilic substitution reaction can be set arbitrarily and can be optimized by monitoring the reaction process by gas chromatography (GC) or thin layer chromatography (TLC). The reaction time is usually and preferably 5 minutes to 240 hours.

[0147] When the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1 obtained in the nucleophilic substitution reaction has sufficient purity, the 6-isopropenyl-3-methyl-9-decene compound (3) can be used as such in the subsequent step. Alternatively, the crude product can be purified by any purification method used in conventional organic synthesis, such as distillation or various chromatography methods. In view of industrial economic efficiency, distillation is particularly preferred.

[0148] [2] Step C

[0149] Step C for obtaining 6-isopropenyl-3-methyl-9-decenol (4) will be described below. As shown in the following chemical reaction formula, 6-isopropenyl-3-methyl-9-decenol (4) is synthesized by subjecting the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at the 1-position obtained in Step B to a deprotection reaction.

[0150]

[0151] In the deprotection reaction, an isomer may be generated as a by-product, and the isopropenyl group in the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at the 1-position is converted into a 1-methylethylene group in the isomer of the following formula (4'), and the double bond converted at the 4-position is derived from the double bond in the above-mentioned isopropenyl group. Among the conditions for the deprotection reaction described below, optimal conditions may be adopted to reduce the formation of the by-product isomer (4') and enhance the formation of 6-isopropenyl-3-methyl-9-decenol (4). Examples of the optimal conditions include using a 6-isopropenyl-3-methyl-9-decene compound (3) in which R is a 1-ethoxyethyl group, introducing acetic acid and water in the deprotection reaction, and a reaction temperature of 120° C. or less.

[0152]

[0153] The 6-isopropenyl-3-methyl-9-decene compound (4) may be (3R,6R)-6-isopropenyl-3-methyl-9-decenol of the following formula (4a), (3R,6S)-6-isopropenyl-3-methyl-9-decenol of the following formula (4b), (3S,6R)-6-isopropenyl-3-methyl-9-decenol of the following formula (4c), or (3S,6S)-6-isopropenyl-3-methyl-9-decenol of the following formula (4d). The 6-isopropenyl-3-methyl-9-decene compound (4) may be an isomer or a mixture of isomers, but preferably contains a compound (4c) having the same main chain as the naturally occurring sex pheromone carried by female California red scale insects.

[0154]

[0155] The isomer (4') represents an (R)-isomer (4') of the following general formula (4'a), an (S)-isomer (4') of the following general formula (4'b), or a combination thereof.

[0156]

[0157] The deprotection reaction conditions can be appropriately selected according to the type of the protecting group in the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1. For example, when the protecting group is an oxyalkyl group (e.g., a methoxymethyl group), the deprotection reaction is carried out by the solvolysis of an acid. When the protecting group is a silyl group (e.g., a tert-butyldimethylsilyl group), in addition to the deprotection reaction by the solvolysis of an acid, the deprotection reaction can be carried out using fluoride ions.

[0158] For the deprotection reaction using an acid, 6-isopropenyl-3-methyl-9-decenol (4) is obtained by adding an acid and, if necessary, water or a solvent to a 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at the 1-position, followed by cooling or heating.

[0159] Examples of the acid used in the deprotection reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, or salts thereof; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (p-TsOH) and naphthalenesulfonic acid, or salts thereof; Lewis acids such as lithium tetrafluoroborate, boron trifluoride, boron trichloride, boron tribromide, aluminum trichloride, zinc chloride, zinc bromide, zinc iodide, tin tetrachloride, tin tetrabromide, tin dichloride, titanium tetrachloride, titanium tetrabromide and trimethylsilyl iodide; oxides such as aluminum oxide, silica gel and titanium dioxide; and minerals such as montmorillonite.

[0160] The acid used in the deprotection reaction is preferably acetic acid in view of economy, reactivity and / or suppression of the formation of the by-product isomer (4').

[0161] If necessary, the acid may be used alone or in combination. The acid may be a commercially available product.

[0162] The amount of the acid is preferably smaller in view of economical efficiency and can be arbitrarily set as long as a practically sufficient reaction rate is achieved. The amount of the acid is preferably 0.00001 to 10,000 mol, more preferably 0.0001 to 1,000 mol, even more preferably 0.001 to 100 mol per mol of the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1.

[0163] When water is additionally used in the deprotection reaction using an acid, the amount of water is preferably 1 to 10,000 mol, more preferably 1 to 1,000 mol, even more preferably 1 to 500 mol per mol of the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1.

[0164] Examples of the solvent used in the deprotection reaction using an acid include ethers such as diethyl ether, dibutyl ether, tetrahydrofuran and 1,4-dioxane; hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene; chlorinated solvents such as dichloromethane, chloroform and trichloroethylene; ketones such as acetone and methyl ethyl ketone; aprotic polar solvents such as N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO) and hexamethylphosphoric triamide (HMPA); nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and n-butyl acetate; and alcohols such as methanol, ethanol and tert-butanol.

[0165] If necessary, the solvents may be used alone or in combination. The solvent may be a commercially available product.

[0166] When water or alcohol is used as a solvent in the deprotection, the compound having an alcohol may form a by-product adduct with the double bond of 6-isopropenyl-3-methyl-9-decanediol (4) and / or isomer (4'). This side reaction can be suppressed by adopting appropriate conditions, such as acid and / or reaction temperature. Examples of appropriate conditions include the use of acetic acid and / or a reaction temperature of 120° C. or less.

[0167] The amount of the solvent used in the deprotection reaction with an acid is preferably 10 g to 10,000 g per mol of the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at the 1-position.

[0168] The reaction temperature of the deprotection reaction with an acid varies depending on the reaction conditions, and is preferably -78°C to 160°C, more preferably -50°C to 140°C, even more preferably -30°C to 120°C.

[0169] The reaction time of the deprotection reaction using an acid can be set arbitrarily. Considering the yield, it is desirable to monitor the reaction with gas chromatography (GC) or thin layer chromatography (TLC) to complete the reaction. The reaction time is generally about 0.5 to 24 hours.

[0170] When the protecting group is a silyl group and the deprotection reaction is carried out using fluoride ions, 6-isopropenyl-3-methyl-9-decenol (4) can be obtained by adding a reagent that can be used as a fluoride ion source and, if necessary, a solvent to a 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1, and cooling or heating the same. The deprotection reaction can also be carried out in combination with an acid as described above for the deprotection reaction using an acid.

[0171] Examples of reagents that can be used as fluoride ion sources include inorganic acids such as hydrofluoric acid; amine complexes such as pyridine-nHF and triethylamine-nHF; inorganic salts such as cesium fluoride, potassium fluoride, lithium fluoride (LiBF 4 ) and ammonium fluoride; and organic salts such as tetrabutylammonium fluoride (TBAF).

[0172] If necessary, the reagents that can be used as a fluoride ion source can be used alone or in combination. The reagents that can be used as a fluoride ion source can be commercially available.

[0173] The amount of the reagent in the deprotection reaction using fluoride ion is preferably 0.1 to 500 mol, more preferably 0.1 to 50 mol per mol of the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at the 1-position.

[0174] The solvent, amount of the solvent, reaction time and reaction temperature in the deprotection reaction using fluoride ion are the same as those mentioned for the deprotection reaction of the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at the 1-position using an acid.

[0175] The alcohol compound may be generated as a by-product in the deprotection reaction. For example, when the 1-ethoxyethoxy group is a protecting group and is removed, ethanol is generated as a by-product. When the alcohol compound is generated as a by-product, the deprotection reaction may be carried out while removing the alcohol compound generated as a by-product from the reaction system, for example, by distillation.

[0176] When the 6-isopropenyl-3-methyl-9-decenol (4) obtained from the deprotection reaction has sufficient purity, it can be used in the subsequent steps. Alternatively, the crude product can be purified in any purification method used in conventional organic synthesis, such as distillation or various chromatography methods. In view of industrial economics, distillation is particularly preferred.

[0177] [3] Step D

[0178] Step D for obtaining 6-isopropenyl-3-methyl-9-decenyl acetate (5) will be described below. As shown in the following chemical reaction formula, 6-isopropenyl-3-methyl-9-decenyl acetate (5) is obtained by acetylation of 6-isopropenyl-3-methyl-9-decenol (4) obtained in step C.

[0179]

[0180] 6-isopropenyl-3-methyl-9-decenyl acetate (5) may be (3R,6R)-6-isopropenyl-3-methyl-9-decenyl acetate of the following formula (5a), (3R,6S)-6-isopropenyl-3-methyl-9-decenyl acetate of the following formula (5b), (3S,6R)-6-isopropenyl-3-methyl-9-decenyl acetate of the following formula (5c), or (3S,6S)-6-isopropenyl-3-methyl-9-decenyl acetate of the following formula (5d). 6-isopropenyl-3-methyl-9-decenyl acetate (5) may be an isomer or a combination of isomers, but preferably comprises a compound (5c) having the same main chain as the naturally occurring sex pheromone carried by female California red scale insects.

[0181]

[0182] Acetylation can be carried out by any known method for preparing acetate esters, for example, (i) reaction with an acetylating agent, (ii) dehydration reaction with acetic acid, (iii) transesterification reaction with acetate ester and (iv) converting 6-isopropenyl-3-methyl-9-decenol (4) into an alkylating agent followed by acetoxylation with acetic acid and the like.

[0183] (i) Reaction with acetylating agent

[0184] The reaction with the acetylating agent can be carried out by a method in which 2-methyl-2,6-heptadienol (6) is reacted with an acylating agent and a base in this order, in the reverse order or simultaneously in a single solvent or a mixed solvent, or by a method in which 6-isopropenyl-3-methyl-9-decenol (4) is reacted with an acetylating agent in the presence of a catalyst in a single solvent or a mixed solvent.

[0185] Examples of the acetylating agent include acetyl chloride, acetyl bromide and acetic anhydride.

[0186] In view of economy, the amount of the acetylating agent to be used is preferably 1 mol to 500 mol, more preferably 1 mol to 50 mol, even more preferably 1 mol to 5 mol, per mol of 6-isopropenyl-3-methyl-9-decenol (4).

[0187] Examples of the base used in the reaction with the acetylating agent include amines such as triethylamine, pyridine, N,N-dimethylaminopyridine and N,N-dimethylaniline; organic lithium compounds such as n-butyllithium, methyllithium and phenyllithium; metal hydroxides such as sodium hydroxide, potassium hydroxide; and metal carbonates such as potassium carbonate, sodium carbonate and sodium bicarbonate.

[0188] The amount of the base to be used is preferably 1 to 500 mol per mol of 6-isopropenyl-3-methyl-9-decenol (4).

[0189] When the acetylating agent is acetic anhydride, a catalyst may be used. Examples of the catalyst include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; organic acids such as trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; Lewis acids such as aluminum chloride, aluminum ethoxide, aluminum isopropoxide, aluminum oxide, boron trifluoride, boron trichloride, boron tribromide, magnesium chloride, magnesium bromide, magnesium iodide, zinc chloride, zinc bromide, zinc iodide, tin tetrachloride, tin tetrabromide, dibutyltin dichloride, dibutyltin dimethanolate, dibutyltin oxide, titanium tetrachloride, titanium tetrabromide, titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) isopropoxide and titanium (IV) oxide; metal acetates such as sodium acetate and potassium acetate.

[0190] The amount of the catalyst used in the reaction with the acetylating agent is preferably 0.0001 to 100 mol per mol of 6-isopropenyl-3-methyl-9-decenol (4).

[0191] Examples of the solvent used in the reaction with the acetylating agent include halogenated solvents such as dichloromethane and chloroform; hydrocarbon solvents such as hexane, heptane, benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; nitrile solvents such as acetonitrile; ketone solvents such as acetone, methyl ethyl ketone and diisobutyl ketone; ester solvents such as ethyl acetate and butyl acetate; and aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and hexamethylphosphoric triamide.

[0192] If necessary, the solvent may be used alone or in combination. Depending on the acetylating agent to be used, the reaction may be carried out without a solvent. The solvent may be a commercially available product.

[0193] In view of economic efficiency, the amount of the solvent to be used is preferably 0 to 2000 g, more preferably 0 to 500 g per mol of 6-isopropenyl-3-methyl-9-decenol (4).

[0194] The reaction temperature of the reaction with the acetylating agent is preferably from -50°C to the boiling point of the solvent, more preferably from -30°C to 80°C, in terms of reactivity and yield.

[0195] The reaction time of the reaction with the acetylating agent can be set arbitrarily and can be optimized by monitoring the reaction process by gas chromatography (GC) or thin layer chromatography (TLC). The reaction time is usually and preferably 5 minutes to 240 hours.

[0196] (ii) Dehydration reaction with acetic acid

[0197] The dehydration reaction of 6-isopropenyl-3-methyl-9-decenol (4) with acetic acid can usually be carried out in the presence of an acid or a Lewis acid catalyst.

[0198] Examples of the catalyst used in the dehydration reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; organic acids such as trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and Lewis acids such as aluminum trichloride, aluminum ethoxide, aluminum isopropoxide, aluminum oxide, boron trifluoride, boron trichloride, boron tribromide, magnesium chloride, magnesium bromide, magnesium iodide, zinc chloride, zinc bromide, zinc iodide, tin tetrachloride, tin tetrabromide, dibutyltin dichloride, dibutyltin dimethanolate, dibutyltin oxide, titanium tetrachloride, titanium tetrabromide, titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) isopropoxide and titanium (IV) oxide.

[0199] If necessary, the acid may be used alone or in combination. The acid may be a commercially available product.

[0200] In view of economy and reactivity, the amount of the catalyst used in the dehydration reaction is preferably 0.001 to 1 mol, more preferably 0.01 mol to 0.1 mol per mol of 6-isopropenyl-3-methyl-9-decenol (4).

[0201] The dehydration reaction with acetic acid can be carried out while removing water produced as a by-product in the reaction, for example, by azeotropically distilling off the solvent and water under normal pressure or reduced pressure, or by adding a dehydrating agent such as anhydrous magnesium sulfate, molecular sieves, or dicyclohexylcarbodiimide to the reaction system.

[0202] Examples of the solvent used in the dehydration reaction include halogenated solvents such as dichloromethane and chloroform; hydrocarbon solvents such as hexane, heptane, benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; nitrile solvents such as acetonitrile; ketone solvents such as acetone, methyl ethyl ketone and diisobutyl ketone; and ester solvents such as ethyl acetate and butyl acetate.

[0203] If necessary, solvents may be used alone or in combination. Depending on the reaction conditions to be used, the dehydration reaction may be carried out without a solvent. The solvent may be a commercially available product.

[0204] In view of economic efficiency, the amount of the solvent used in the dehydration reaction is preferably 0 to 2000 g, more preferably 0 to 500 g per mol of 6-isopropenyl-3-methyl-9-decenol (4).

[0205] The reaction temperature of the dehydration reaction can be appropriately selected according to the catalyst to be used. Usually, in view of reactivity and yield, the reaction temperature is preferably -50°C to 200°C, more preferably -20°C to 100°C. When the water produced as a by-product in the reaction is removed by azeotropic distillation of water and solvent, the reaction temperature is preferably the azeotropic boiling point or higher under normal pressure or reduced pressure.

[0206] The reaction time of the dehydration reaction can be set arbitrarily and can be optimized by monitoring the reaction process by gas chromatography (GC) or thin layer chromatography (TLC). The reaction time is usually and preferably 5 minutes to 240 hours.

[0207] (iii) Transesterification with acetate

[0208] The transesterification reaction with the acetate is usually carried out in the presence of a catalyst and can be promoted by removing the alcohol formed from the acetate under normal or reduced pressure.

[0209] Examples of the acetate used in the transesterification reaction include acetates such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and phenyl acetate. Among these acetates, methyl acetate and ethyl acetate are preferred in view of economy, reactivity and ease of removing alcohol formed from the acetate.

[0210] The amount of the acetate used in the transesterification reaction is preferably 1 to 50 mol, more preferably 1 to 5 mol, per mol of 6-isopropenyl-3-methyl-9-decenol (4).

[0211] Examples of the catalyst used in the transesterification reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid; organic acids such as oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; bases such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and 4-dimethylaminopyridine; salts such as sodium cyanide, potassium cyanide, sodium acetate, potassium acetate, calcium acetate, tin acetate, aluminum acetate, aluminum acetoacetate and alumina (aluminum oxide); and Lewis acids such as aluminum trichloride, aluminum ethoxide, aluminum isopropoxide, aluminum oxide, boron trifluoride, boron trichloride, boron tribromide, magnesium chloride, magnesium bromide, magnesium iodide, zinc chloride, zinc bromide, zinc iodide, tin tetrachloride, tin tetrabromide, dibutyltin dichloride, dibutyltin dimethoxide, dibutyltin oxide, titanium tetrachloride, titanium tetrabromide, titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) isopropoxide and titanium (IV) oxide.

[0212] If necessary, the catalyst may be used alone or in combination. The catalyst may be a commercially available product.

[0213] The amount of the catalyst used in the transesterification reaction is preferably 0.001 mol to 1 mol, more preferably 0.01 to 0.05 mol per mol of 6-isopropenyl-3-methyl-9-decenol (4).

[0214] Examples of the solvent used in the transesterification reaction include halogenated solvents such as dichloromethane and chloroform; hydrocarbon solvents such as hexane, heptane, benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; nitrile solvents such as acetonitrile; ketone solvents such as acetone, methyl ethyl ketone and diisobutyl ketone; and ester solvents such as ethyl acetate and butyl acetate.

[0215] If necessary, the solvent may be used alone or in combination. Depending on the reaction conditions in the transesterification reaction, the transesterification reaction may be carried out without any solvent other than the acetate and the catalyst, and only with the alcohol compound generated as a by-product in the transesterification reaction. The solvent may be a commercially available product.

[0216] In view of economic efficiency, the amount of the solvent used in the transesterification reaction is preferably 0 to 2000 g, more preferably 0 to 500 g per mol of 6-isopropenyl-3-methyl-9-decenol (4).

[0217] The reaction temperature of the transesterification reaction can be appropriately selected according to the acetate and catalyst used. Generally, the reaction temperature is preferably 0° C. to 200° C., more preferably 50° C. to 160° C. When the transesterification reaction is promoted by removing the alcohol formed from the acetate, the reaction temperature is preferably the boiling point of the alcohol to be removed under normal pressure or reduced pressure or higher.

[0218] The reaction time of the transesterification reaction can be set arbitrarily and can be optimized by monitoring the reaction process by gas chromatography (GC) or thin layer chromatography (TLC). The reaction time is usually and preferably 5 minutes to 240 hours.

[0219] (iv) converting 6-isopropenyl-3-methyl-9-decenol (4) into an alkylating agent, followed by acetoxylation with acetic acid or the like

[0220] Generally, the conversion of 6-isopropenyl-3-methyl-9-decenol (4) into an alkylating agent and the subsequent acetoxylation with acetic acid or the like can be carried out by converting 6-isopropenyl-3-methyl-9-decenol (4) into its corresponding alkylating agent, for example, a halide such as chloride, bromide or iodide, or a sulfonate such as methanesulfonate, benzenesulfonate or p-toluenesulfonate, and reacting the resulting alkylating agent with acetic acid in the presence of a base. The reaction can also be carried out in the absence of a base and using a readily available metal acetate (e.g., sodium acetate or potassium acetate) instead of acetic acid.

[0221] After the conversion of 6-isopropenyl-3-methyl-9-decenol (4) into its corresponding alkylating agent, the one-step acetoxylation may be carried out immediately. Alternatively, after the conversion of 6-isopropenyl-3-methyl-9-decenol (4) into its corresponding alkylating agent, the organic phase is washed, the solvent is removed, the alkylating agent is purified as necessary, and then the acetoxylation is carried out.

[0222] The conversion of 6-isopropenyl-3-methyl-9-decenol (4) into its corresponding alkylating agent can be accomplished in a manner in which 6-isopropenyl-3-methyl-9-decenol (4) is converted into a chloride, bromide or iodide using a halogenating agent. 6-isopropenyl-3-methyl-9-decenol (4) is converted into a sulfonate using a sulfonylating agent.

[0223] Examples of the halogenating agent include chlorinating agents such as hydrochloric acid, phosphorus trichloride, thionyl chloride, carbon tetrachloride, methanesulfonyl chloride and p-toluenesulfonyl chloride; brominating agents such as hydrobromic acid, phosphorus tribromide, thionyl bromide and carbon tetrabromide; and iodinating agents such as hydroiodic acid, potassium iodide and phosphorus triiodide.

[0224] Examples of the sulfonylating agent include methanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride.

[0225] In view of economic efficiency, the amount of the halogenating agent or sulfonylating agent used in converting 6-isopropenyl-3-methyl-9-decenol (4) into the alkylating agent is preferably 1 to 50 mol, more preferably 1 to 10 mol, per mol of 6-isopropenyl-3-methyl-9-decenol (4).

[0226] Examples of the solvent used in converting 6-isopropenyl-3-methyl-9-decenol (4) into an alkylating agent include halogenated solvents such as dichloromethane and chloroform; hydrocarbon solvents such as hexane, heptane, benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; nitrile solvents such as acetonitrile; ketone solvents such as acetone, methyl ethyl ketone and diisobutyl ketone; ester solvents such as ethyl acetate and butyl acetate; and aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and hexamethylphosphoric triamide.

[0227] If necessary, solvents may be used alone or in combination. The conversion may be performed without a solvent. The solvent may be a commercially available product.

[0228] In view of economic efficiency, the amount of the solvent used in converting 6-isopropenyl-3-methyl-9-decenol (4) into the alkylating agent is preferably 0 to 2000 g, more preferably 0 to 500 g per mol of 6-isopropenyl-3-methyl-9-decenol (4).

[0229] The reaction temperature for converting 6-isopropenyl-3-methyl-9-decenol (4) into an alkylating agent is preferably -30°C to 250°C, more preferably 0°C to 180°C, in view of reactivity and yield.

[0230] In view of economic efficiency, the amount of acetic acid or metal acetate used in the acetoxylation reaction of the obtained alkylating agent is preferably 1 mol to 50 mol, more preferably 1 to 10 mol per mol of the alkylating agent.

[0231] Examples of the base used in the acetoxylation reaction of the resulting alkylating agent include amines such as triethylamine, pyridine, N,N-dimethylaminopyridine and dimethylaniline; organic lithium compounds such as n-butyllithium, methyllithium and phenyllithium; metal hydroxides such as sodium hydroxide, potassium hydroxide; metal carbonates such as potassium carbonate, sodium carbonate and sodium bicarbonate; metal hydrides such as sodium hydride and potassium hydride.

[0232] The amount of the base used in the acetoxylation reaction of the obtained alkylating agent is preferably 1 mol to 50 mol, more preferably 1 to 10 mol, per mol of the alkylating agent, in view of economic efficiency.

[0233] Examples of the solvent used in the acetoxylation reaction of the obtained alkylating agent include halogenated solvents such as dichloromethane and chloroform; hydrocarbon solvents such as hexane, heptane, benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; nitrile solvents such as acetonitrile; ketone solvents such as acetone, methyl ethyl ketone and diisobutyl ketone; ester solvents such as ethyl acetate and butyl acetate; and aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and hexamethylphosphoric triamide.

[0234] If necessary, the solvents may be used alone or in combination. Depending on the alkylating agent to be used, the acetoxylation reaction may be carried out without a solvent.

[0235] In view of economic efficiency, the amount of the solvent used in the acetoxylation reaction of the obtained alkylating agent is preferably 0 to 2000 g, more preferably 0 to 500 g per mol of the alkylating agent.

[0236] The reaction temperature of the acetoxylation reaction of the resulting alkylating agent is preferably -30°C to 250°C, more preferably 25°C to 180°C, in view of reactivity and yield.

[0237] The reaction time of the acetoxylation can be set arbitrarily and can be optimized by monitoring the progress of the reaction by gas chromatography (GC) or thin layer chromatography (TLC). The reaction time is usually and preferably from 5 minutes to 240 hours.

[0238] The crude product 6-isopropenyl-3-methyl-9-decenyl acetate (5) obtained by acetoxylation can be purified by any purification method used in ordinary organic synthesis, such as distillation or various chromatography methods. Distillation is particularly preferred in view of industrial economics.

[0239] [4] Step A

[0240] Step A for obtaining 2-methyl-2,6-heptadiene compound (1) is described below. As shown in the following chemical reaction formula, 2-methyl-2,6-heptadiene compound (1) is synthesized by converting the hydroxyl group of 2-methyl-2,6-heptadienol (6).

[0241]

[0242] 2-Methyl-2,6-heptadienol (6) may be (Z)-2-methyl-2,6-heptadienol of the following formula (6a) or (E)-2-methyl-2,6-heptadienol of the following formula (6b). 2-Methyl-2,6-heptadienol (6) may be an isomer or a combination of isomers.

[0243]

[0244] The method for preparing 2-methyl-2,6-heptadienol (6) is not particularly limited. For example, 2-methyl-2,6-heptadienol (6) can be synthesized by reducing 2-methyl-2,6-heptadienoic acid ester with a reducing agent.

[0245] When the leaving group X is an acyloxy group, the conversion of the hydroxyl group of 2-methyl-2,6-heptadienol (6) is an esterification reaction. The esterification reaction may be any known ester-forming method, for example, (i) reaction with an acylating agent, (ii) reaction with a carboxylic acid, (iii) transesterification, and (iv) conversion of the hydroxyl group of 2-methyl-2,6-heptadienol (6) into a leaving group followed by reaction with a carboxylic acid.

[0246] (i) Reaction with acylating agent

[0247] The reaction with the acylating agent can be carried out by reacting 2-methyl-2,6-heptadienol (6) with the acylating agent and the base in this order, in the reverse order or simultaneously in a single solvent or a mixed solvent.

[0248] Examples of the acylating agent include acid halides such as acid chlorides and acid bromides; carboxylic acid mixed anhydrides such as carboxylic acid anhydride, carboxylic acid / trifluoroacetic acid mixed anhydride, carboxylic acid / methanesulfonic acid mixed anhydride, carboxylic acid / trifluoromethanesulfonic acid mixed anhydride, carboxylic acid / benzenesulfonic acid mixed anhydride and carboxylic acid / p-toluenesulfonic acid mixed anhydride; and p-nitrophenyl carboxylate.

[0249] Specific examples of the acid chloride include acetyl chloride, propionyl chloride, crotonyl chloride and benzoyl chloride. Examples of the carboxylic anhydride include acetic anhydride and propionic anhydride.

[0250] The amount of the acylating agent to be used is preferably 1 to 500 mol, more preferably 1 to 50 mol, per mol of 2-methyl-2,6-heptadienol (6).

[0251] Examples of the base used in the reaction with the acylating agent include N,N-diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, pyridine, 2-ethylpyridine and 4-dimethylaminopyridine.

[0252] The amount of the base used is 1 to 500 mol per mol of 2-methyl-2,6-heptadienol (6).

[0253] The solvent used in the reaction with the acylating agent may be the above-mentioned base itself. Examples of the solvent include chlorinated solvents such as dichloromethane, chloroform and trichloroethylene; hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene; ethers such as diethyl ether, dibutyl ether, diethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran and 1,4-dioxane; nitriles such as acetonitrile; ketones such as acetone and 2-butanone; esters such as ethyl acetate and n-butyl acetate; and aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide and hexamethylphosphoric triamide.

[0254] If necessary, the solvents may be used alone or in combination. The solvent may be a commercially available product.

[0255] The amount of the solvent used is preferably 10 to 1,000,000 g per mol of 2-methyl-2,6-heptadienol (6).

[0256] The reaction with an acylating agent such as carboxylic acid anhydride, carboxylic acid mixed anhydride and p-nitrophenyl carboxylate can be carried out in the presence of an acid catalyst instead of a base.

[0257] Examples of the acid catalyst include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid; organic acids such as oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and Lewis acids such as aluminum trichloride, aluminum ethoxide, aluminum isopropoxide, aluminum oxide, boron trifluoride, boron trichloride, boron tribromide, magnesium chloride, magnesium bromide, magnesium iodide, zinc chloride, zinc bromide, zinc iodide, tin tetrachloride, tin tetrabromide, dibutyltin dichloride, dibutyltin dimethanolate, dibutyltin oxide, titanium tetrachloride, titanium tetrabromide, titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) isopropoxide and titanium (IV) oxide.

[0258] If necessary, an acid catalyst may be used alone or in combination. The acid catalyst may be a commercially available product.

[0259] The amount of the acid catalyst used in the reaction with the acylating agent (such as carboxylic acid anhydride, carboxylic acid mixed anhydride or p-nitrophenylcarboxylate) is preferably 0.0001 to 100 mol.

[0260] The reaction temperature of the reaction with the acylating agent can be appropriately selected according to the acylating agent and / or the reaction conditions. Generally, the reaction temperature is preferably -50°C to the boiling point of the solvent, more preferably -20°C to room temperature (5°C to 35°C, the same below).

[0261] The reaction time for the reaction with the acylating agent can be set arbitrarily and can be optimized by monitoring the reaction process by gas chromatography (GC) or thin layer chromatography (TLC). The reaction time is usually and preferably 5 minutes to 240 hours.

[0262] (ii) Reaction with carboxylic acid

[0263] The reaction with carboxylic acid is a dehydration reaction between 2-methyl-2,6-heptadienol (6) and carboxylic acid, and is usually carried out in the presence of an acid catalyst.

[0264] Specific examples of the carboxylic acid used in the reaction between 2-methyl-2,6-heptadienol (6) and the carboxylic acid include straight-chain saturated carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid and hexanoic acid; branched-chain saturated carboxylic acids such as isobutyric acid, isovaleric acid, 4-methylvaleric acid, 2-methylbutyric acid and pivalic acid; straight-chain unsaturated carboxylic acids such as acrylic acid, crotonic acid and 3-butenoic acid; branched-chain unsaturated carboxylic acids such as methacrylic acid, senecioic acid, tiglic acid, angelic acid, 3-methyl-4-pentenoic acid and 4-methyl-4-pentenoic acid; and aromatic carboxylic acids such as benzoic acid.

[0265] The amount of the carboxylic acid to be used is preferably 1 to 500 mol, more preferably 1 to 50 mol, even more preferably 1 to 5 mol, per mol of 2-methyl-2,6-heptadienol (6).

[0266] In the reaction between 2-methyl-2,6-heptadienol (6) and carboxylic acid, an acid catalyst may be used. The acid catalyst is those mentioned for the reaction with the acylating agent.

[0267] The amount of the acid catalyst to be used is preferably 0.0001 to 100 mol, more preferably 0.001 to 1 mol, even more preferably 0.01 to 0.05 mol per mol of 2-methyl-2,6-heptadienol (6).

[0268] The solvent and the amount thereof used in the reaction between 2-methyl-2,6-heptadienol (6) and carboxylic acid are the same as those mentioned for the reaction of the acylating agent.

[0269] The reaction temperature of the reaction between 2-methyl-2,6-heptadienol (6) and carboxylic acid can be appropriately selected depending on the reaction conditions. Generally, the reaction temperature is preferably from -50°C to the boiling point of the solvent, more preferably from room temperature to the boiling point of the solvent.

[0270] The reaction can be carried out in a solvent comprising hydrocarbons (e.g., hexane, heptane, benzene, toluene, xylene and cumene), while removing the water formed from the reaction system by azeotropic distillation. Alternatively, water can be removed by reflux distillation at the boiling point of the solvent under normal pressure conditions, or by distillation at a lower temperature below the boiling point of the solvent under reduced pressure conditions.

[0271] The reaction time for the reaction with the carboxylic acid can be set arbitrarily and can be optimized by monitoring the reaction process by gas chromatography (GC) or thin layer chromatography (TLC). The reaction time is usually and preferably 5 minutes to 240 hours.

[0272] (iii) Transesterification

[0273] The transesterification reaction is carried out by reacting 2-methyl-2,6-heptadienol (6) with an alkyl carboxylic acid ester in the presence of a catalyst and removing the alcohol formed.

[0274] The alkyl carboxylate is preferably a primary alkyl ester of a carboxylic acid. In view of price and / or easiness of reaction, methyl carboxylate, ethyl carboxylate and n-propyl carboxylate are preferred.

[0275] Examples of the carboxylic acid may be those used for the esterification reaction with the carboxylic acid.

[0276] The amount of the alkyl carboxylic acid ester to be used is preferably 1 to 500 mol, more preferably 1 to 50 mol, even more preferably 1 to 5 mol, per mol of 2-methyl-2,6-heptadienol (6).

[0277] Examples of the catalyst used in the transesterification reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid; organic acids such as oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; bases such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and 4-dimethylaminopyridine; salts such as sodium cyanide, potassium cyanide, sodium acetate, potassium acetate, calcium acetate, tin acetate, aluminum acetate, aluminum acetoacetate and alumina (aluminum oxide); Lewis acids such as aluminum trichloride, aluminum ethoxide, aluminum isopropoxide, aluminum oxide, boron trifluoride, boron trichloride, boron tribromide, magnesium chloride, magnesium bromide, magnesium iodide, zinc chloride, zinc bromide, zinc iodide, tin tetrachloride, tin tetrabromide, dibutyltin dichloride, dibutyltin dimethoxide, dibutyltin oxide, titanium tetrachloride, titanium tetrabromide, titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) isopropoxide and titanium (IV) oxide.

[0278] If necessary, the catalyst may be used alone or in combination. The catalyst may be a commercially available product.

[0279] The amount of the catalyst to be used is preferably 0.0001 to 100 mol, more preferably 0.001 to 1 mol, even more preferably 0.01 to 0.05 mol per mol of 2-methyl-2,6-heptadienol (6).

[0280] The transesterification can be carried out in the alkyl carboxylic acid ester as solvent, without any additional solvent, or with the use of an auxiliary solvent. It is preferred not to use any additional solvent, since this does not require additional operations such as concentration or solvent recovery.

[0281] Examples of the solvent used in the transesterification reaction include hydrocarbons such as hexane, heptane, benzene, toluene, xylene, and cumene; and ethers such as diethyl ether, dibutyl ether, diethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, and 1,4-dioxane.

[0282] If necessary, the solvents may be used alone or in combination. The solvent may be a commercially available product.

[0283] The amount of the solvent used is preferably 10 to 1,000,000 g per mol of 2-methyl-2,6-heptadienol (6).

[0284] The reaction temperature of the transesterification reaction can be appropriately selected according to the alkyl carboxylate and / or the reaction conditions. The transesterification reaction is usually carried out under heating conditions. Considering the ease of the reaction, the transesterification reaction is preferably carried out in the low C 1-3 The alcohol (i.e., methanol, ethanol or 1-propanol) is distilled off at a temperature below the boiling point under reduced pressure.

[0285] The transesterification reaction time can be set arbitrarily and can be optimized by monitoring the reaction process by gas chromatography (GC) or thin layer chromatography (TLC). The reaction time is usually and preferably 5 minutes to 240 hours.

[0286] (iv) Converting the hydroxyl group of 2-methyl-2,6-heptadienol (6) into a leaving group, followed by reaction with a carboxylic acid

[0287] The conversion of the hydroxyl group of 2-methyl-2,6-heptadienol (6) into a leaving group and the subsequent reaction with a carboxylic acid can be carried out as follows: for example, the hydroxyl group of 2-methyl-2,6-heptadienol (6) is converted into a leaving group such as a halogen atom, for example, a chlorine atom, a bromine atom or an iodine atom; or an alkanesulfonyloxy group, for example, a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group; or an arylsulfonyloxy group, for example, a benzenesulfonyloxy group or a p-toluenesulfonyloxy group, and the resulting compound is reacted with a carboxylic acid in the presence of a base. The conversion can also be carried out in the absence of a base, and a readily available metal carboxylate (for example, sodium carboxylate or potassium carboxylate) is used instead of a carboxylic acid.

[0288] Examples of the carboxylic acid may be those used for the reaction with the carboxylic acid.

[0289] The amount of the carboxylic acid to be used is preferably 1 to 500 mol, more preferably 1 to 50 mol, even more preferably 1 to 5 mol, per mol of 2-methyl-2,6-heptadienol (6).

[0290] Examples of the base include amines such as triethylamine, pyridine, N,N-dimethylaminopyridine and dimethylaniline; organic lithium compounds such as n-butyllithium, methyllithium and phenyllithium; metal hydroxides such as sodium hydroxide, potassium hydroxide; metal carbonates such as potassium carbonate, sodium carbonate and sodium bicarbonate; metal hydrides such as sodium hydride and potassium hydride.

[0291] In view of economy, the amount of the base to be used is preferably 1 to 50 mol, more preferably 1 to 10 mol, per mol of the alkylating agent.

[0292] The solvent, amount of the solvent, reaction time and reaction temperature in the conversion of the hydroxyl group of 2-methyl-2,6-heptadienol (6) into a leaving group and the reaction with the carboxylic acid are the same as those mentioned for the reaction between 2-methyl-2,6-heptadienol (6) and the acylating agent.

[0293] A carboxylate salt (e.g., sodium carboxylate, lithium carboxylate, potassium carboxylate, or ammonium carboxylate) may be used in combination with a base instead of a carboxylic acid. The amount of the carboxylate salt is the same as the amount of the carboxylic acid in the carboxylation reaction.

[0294] When the leaving group X is an alkanesulfonyloxy group, the hydroxyl group of 2-methyl-2,6-heptadienol (6) is converted using an alkanesulfonylating agent. The reaction with the alkanesulfonylating agent can be carried out by reacting 2-methyl-2,6-heptadienol (6) with an alkanesulfonylating agent and a base in this order, in the reverse order or simultaneously in a single solvent or a mixed solvent.

[0295] Examples of the alkanesulfonylating agent include alkanesulfonic anhydrides which may be substituted, such as methanesulfonic anhydride, ethanesulfonic anhydride and trifluoromethanesulfonic anhydride; and alkanesulfonyl halides which may be substituted, such as methanesulfonyl chloride, ethanesulfonyl chloride and trifluoromethanesulfonyl chloride.

[0296] The amount of the alkanesulfonylating agent to be used is preferably 1 to 500 mol, more preferably 1 to 50 mol, even more preferably 1 to 5 mol, per mol of 2-methyl-2,6-heptadienol (6).

[0297] Examples of the base used in the reaction with the alkanesulfonylating agent include organic bases, including amines such as diethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, diazabicyclononene (DBN), diazabicycloundecene (DBU), N-methylmorpholine and N,N-dimethylaniline; pyridines such as pyridine, methylethylpyridine, lutidine and N,N-dimethyl-4-aminopyridine; imidazoles; and pyrazoles; and inorganic bases including alkali metal or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and barium hydroxide; alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate and barium carbonate; metal alkoxides such as sodium ethoxide; alkali metal amides such as sodium amide and lithium amide; and alkali metal hydrides such as sodium hydride and lithium hydride. Preferred examples include pyridine and triethylamine.

[0298] The amount of the base to be used is preferably 1 to 500 mol per mol of 2-methyl-2,6-heptadienol (6).

[0299] The solvent used in the reaction with the alkanesulfonylating agent may be the above-mentioned base itself. Examples of the solvent include chlorinated solvents such as dichloromethane, chloroform and trichloroethylene; hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene; ethers such as diethyl ether, dibutyl ether, diethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran and 1,4-dioxane; nitriles such as acetonitrile; ketones such as acetone and 2-butanone; esters such as ethyl acetate and n-butyl acetate; and aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide and hexamethylphosphoric triamide.

[0300] If necessary, the solvent may be used alone or in combination. The solvent may be a commercially available product.

[0301] The amount of the solvent used is preferably 10 to 1,000,000 g per mol of 2-methyl-2,6-heptadienol (6).

[0302] The reaction temperature of the reaction with the alkanesulfonylating agent can be appropriately selected according to the alkanesulfonylating agent to be used and / or the reaction conditions. Generally, the reaction temperature is preferably -50°C to the boiling point of the solvent. More preferably, -20°C to room temperature (5°C to 35°C).

[0303] The reaction time of the reaction with the alkanesulfonylating agent can be set arbitrarily and can be optimized by monitoring the reaction process by gas chromatography (GC) or thin layer chromatography (TLC). The reaction time is usually and preferably 5 minutes to 240 hours.

[0304] When the leaving group X is an arylsulfonyloxy group, the hydroxyl group of 2-methyl-2,6-heptadienol (6) is converted using an arylsulfonylating agent. This reaction with the arylsulfonylating agent can be carried out by reacting 2-methyl-2,6-heptadienol (6) with an arylsulfonylating agent and a base in this order, in the reverse order or simultaneously in a single solvent or a mixed solvent.

[0305] Examples of the aromatic sulfonylating agent include aromatic sulfonic anhydrides such as benzenesulfonic anhydride and p-toluenesulfonic anhydride; and aromatic sulfonyl halides such as benzenesulfonyl chloride and p-toluenesulfonyl chloride.

[0306] The amount of the aromatic sulfonylating agent is preferably 1 to 500 mol, more preferably 1 to 50 mol, even more preferably 1 to 5 mol, per mol of 2-methyl-2,6-heptadienol (6).

[0307] The base, the amount of the base, the solvent, the amount of the solvent, the reaction time and the reaction temperature in the reaction with the arylsulfonylating agent are the same as those used for the reaction between 2-methyl-2,6-heptadienol (6) and the alkanesulfonylating agent.

[0308] When the leaving group X is a halogen atom, the hydroxyl group of 2-methyl-2,6-heptadienol (6) is converted using a halogenating agent. This reaction with the halogen atom can be carried out by reacting 2-methyl-2,6-heptadienol (6) with a halogenating agent and a base in this order, in the reverse order or simultaneously in a single solvent or a mixed solvent.

[0309] Examples of the halogenating agent include thionyl halides such as thionyl chloride and thionyl bromide; phosphorus halide compounds such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride and phosphorus pentabromide; phosphorus halides such as phosphoryl chloride and phosphoryl bromide; and aromatic phosphorus halide compounds such as dichlorotriphenylphosphane and dibromotriphenylphosphane.

[0310] When a sulfonyl halide such as methanesulfonyl chloride, ethanesulfonyl chloride or trifluoromethanesulfonyl chloride is used instead of the halogenating agent, the hydroxyl group of 2-methyl-2,6-heptadienol (6) is sulfonylated and then substituted with a halogen atom corresponding to the sulfonyl halide by heating if necessary.

[0311] When a hydroxy group is sulfonylated with a sulfonylating agent other than a sulfonyl halide or halogenated with a halogenating agent, the resulting compound can be converted into the corresponding halide using a halogenating agent such as a metal halide or a quaternary onium salt.

[0312] Examples of the metal halide include lithium bromide, sodium bromide, potassium bromide, lithium iodide, sodium iodide, and potassium iodide.

[0313] Examples of the quaternary onium salt include tetraethylammonium bromide, tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetraethylammonium iodide, tetrabutylammonium iodide, and tetrabutylphosphonium iodide.

[0314] The amount of the halogenating agent to be used is preferably 1 to 500 mol, more preferably 1 to 50 mol, even more preferably 1 to 5 mol, per mol of 2-methyl-2,6-heptadienol (6).

[0315] The base, the amount of the base, the solvent, the amount of the solvent, the reaction time and the reaction temperature in the reaction with the halogenating agent are the same as those used for the reaction between 2-methyl-2,6-heptadienol (6) and the alkanesulfonylating agent.

[0316] When the 2-methyl-2,6-heptadiene compound (1) having a leaving group X at position 1 obtained by the conversion of the hydroxyl group has sufficient purity, the 2-methyl-2,6-heptadiene compound (1) can be used as such in the subsequent step. Alternatively, the crude product can be purified by any purification method used in conventional organic synthesis, such as distillation or various chromatography methods. Distillation is particularly preferred in view of industrial economics.

[0317] In an embodiment of the present invention including steps A to D, a 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1 is deprotected in step C to form 6-isopropenyl-3-methyl-9-decenol (4), and then 6-isopropenyl-3-methyl-9-decenol (4) is acetylated in step D to form the target compound, 6-isopropenyl-3-methyl-9-decenyl acetate (5). The present inventors have also found that 6-isopropenyl-3-methyl-9-decenyl acetate (5) can be obtained using an acetylating agent under deprotection conditions instead of steps C and D, as shown in the following chemical reaction formula. In other words, it is believed that in the case where an acetylating agent is used under deprotection conditions, an acetylation reaction occurs after the deprotection reaction, and thus 6-isopropenyl-3-methyl-9-decenyl acetate (5) is obtained in a single step. Whether or not the acetylation reaction occurs after the deprotection reaction depends on, for example, the protecting group in the 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1. Examples of such protecting groups include those that can be deprotected with an acid, specifically, oxyalkyl groups such as a 1-ethoxyethyl group. For example, an acetylating agent such as acetic anhydride can promote acetylation after the deprotection reaction in a single step in the presence of an acid catalyst. Examples of acid catalysts include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; organic acids such as trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; Lewis acids such as aluminum chloride, aluminum ethoxide, aluminum isopropoxide, aluminum oxide, boron trifluoride, boron trichloride, boron tribromide, magnesium chloride, magnesium bromide, magnesium iodide, zinc chloride, zinc bromide, zinc iodide, tin tetrachloride, tin tetrabromide, dibutyltin dichloride, dibutyltin dimethanolate, dibutyltin oxide, titanium tetrachloride, titanium tetrabromide, titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) isopropoxide and titanium (IV) oxide; and metal acetates such as sodium acetate and potassium acetate. Preferably, when the acetylating agent is acetic anhydride and the acid catalyst is p-toluenesulfonic acid, the acetylation reaction occurs after the deprotection reaction, so that the deprotection reaction and the acetylation reaction occur in the same step (see Example 19 below).

[0318] Therefore, an efficient and industrially viable method for preparing 6-isopropenyl-3-methyl-9-decenyl acetate (5), as well as 2-methyl-2,6-heptadiene compounds (1') and 2-methyl-2,6-heptadiene compounds (1"), both of which are useful intermediate materials for the above-mentioned method, is provided.

[0319] Example

[0320] The present invention will be further described with reference to the following examples. It should be understood that the present invention is not limited to or by the following examples.

[0321] Unless otherwise specified, the term "purity" used herein refers to the area percentage obtained by gas chromatography (GC). The term "production ratio" refers to the ratio of the area percentages obtained by GC. The term "yield" is calculated from the area percentages obtained by GC.

[0322] In some cases, samples for measuring spectra were obtained by purification of crude products.

[0323] In the examples, the monitoring of the reaction and the calculation of the yield were carried out under the following GC conditions.

[0324] GC conditions: GC: capillary gas chromatograph GC-2014 (Shimadzu Corporation); column: DB-5, 0.25 μm×0.25 mmφ×30 m; carrier gas: He (1.55 mL / min), detector: FID; column temperature: 100°C, increasing at a rate of 10°C / min to a maximum of 230°C.

[0325] In the examples, some reactions were monitored by thin layer chromatography (TLC). In the TLC data, the solvents shown in brackets represent the elution solvents or developing solvents used, and the ratios are expressed as volume ratios.

[0326] Taking into account the purity (%GC) of the starting material and the product, the yield was calculated according to the following equation.

[0327] Yield (%) = {[(weight of product obtained by reaction × %GC) / molecular weight of product] ÷ [(weight of starting material in reaction × %GC) / molecular weight of starting material]} × 100

[0328] The term "crude yield" refers to the yield of a crude product obtained without purification.

[0329] Example 1: Preparation of 2-methyl-2,6-heptadienyl acetate (1':X'=OAc)

[0330]

[0331] 2-Methyl-2,6-heptadienol (6) (3.00 g: 0.021 mol), pyridine (5.81 g: 0.73 mol), acetic anhydride (Ac 2O) (3.59 g: 0.029 mol) and acetonitrile (MeCN) (10 ml), and stirred at room temperature for 14 hours and 40 minutes. Then, pure water (20 g) and hexane (20 g) were added, stirred for 30 minutes, and the organic phase was separated. The separated organic phase was post-treated, i.e., washed, dried and concentrated in the usual way to obtain a crude product, 2-methyl-2,6-heptadienyl acetate (1': X'=OAc) (3.60 g), with a crude yield of 90.45%.

[0332] The following are the spectral data of 2-methyl-2,6-heptadienyl acetate (1':X'=OAc) thus obtained.

[0333] IR(D-ATR): ν=3078,2975,2922,1741,1641,1440,1367,1233,1023,984,957,913,634,607,560cm -1 .

[0334] 1 H-NMR (500MHz, CDCl 3 ): δ=1.74(3H,s-like),2.06(3H,s),2.07-2.19(4H,m),4.57(2H,s),4.94-5.03(2H,m),5.39(1H,t,J=7.6Hz),5.75-5.83(1H,m)ppm.

[0335] 13 C-NMR (125MHz, CDCl 3 ): δ=20.90,21.37,27.09,33.75,63.12,113.89,129.98,130.15,137.93,171.08ppm.

[0336] GC-MS (EI, 70eV): 27, 43, 55, 67, 79, 93, 108, 126, 140, 153, 168.

[0337] Example 2: Preparation of 2-methyl-2,6-heptadienyl isobutyrate (1': X'=OC(=O)CH(CH 3 ) 2 )

[0338]

[0339] 2-Methyl-2,6-heptadienol (6) (3.00 g: 0.017 mol), pyridine (6.64 g: 0.84 mol), isobutyric anhydride (5.32 g: 0.034 mol) and acetonitrile (MeCN) (10 ml) were placed in a reactor under a nitrogen atmosphere and stirred at room temperature for 7 hours. Then, pure water (20 g) and hexane (20 g) were added and stirred for 30 minutes, and the organic phase was separated. The separated organic phase was post-treated, i.e., washed, dried and concentrated to obtain a crude product, 2-methyl-2,6-heptadienyl isobutyrate (1': X'=OC(=O)CH(CH 3 ) 2 )(4.62 g), crude yield was 100%.

[0340] The following is the 2-methyl-2,6-heptadienyl isobutyrate (1': X'=OC(=O)CH(CH 3 ) 2 )’s spectral data.

[0341] IR(D-ATR): ν=3078,2975,2938,2879,1814,1736,1641,1471,1388,1354,1252,1190,1154,1117,1068,1021,965,913,756,642cm -1 .

[0342] 1 H-NMR (500MHz, CDCl 3 ): δ=1.16(6H,d,J=7.3Hz),1.73(3H,s-like),2.06-2.20(4H,m),2.51-2.59(1H, m), 4.57 (2H, s), 4.94-5.03 (2H, m), 5.39 (1H, t, J = 7.5Hz), 5.75-5.83 (1H, m) ppm.

[0343] 13 C-NMR (125MHz, CDCl 3 ): δ=18.24,18.97,21.30,27.09,33.79,34.02,62.96,114.86,129.66,130.41,137.98,177.10ppm.

[0344] GC-MS (EI, 70eV): 27, 43, 55, 71, 81, 93, 108, 126, 142, 155, 168, 181, 196.

[0345] Example 3: Preparation of 2-methyl-2,6-heptadienyl bromide (1: X=Br)

[0346]

[0347] Triphenylphosphine (PPh 3 ) (7.73 g: 0.029 mol) and acetonitrile (MeCN) (16.8 g), and the mixture was cooled to an internal temperature of -5°C to 5°C. Then, bromine (Br 2 ) (4.50 g: 0.028 mol) was added dropwise to the reactor and stirred at an internal temperature of -5°C to 10°C for 3 hours. Then, 2-methyl-2,6-heptadienol (6) (3.00 g: 0.021 mol) and triethylamine (Et 3 A liquid mixture of 2-methyl-2,6-heptadienyl bromide (1: X=Br) (3.33 g) was added dropwise to the reactor and stirred at an internal temperature of -5°C to 10°C for 1 hour. Then, the mixture was stirred at room temperature for 14 hours. Pure water (20 g) and hexane (20 g) were added to the reactor and stirred for 30 minutes, and the organic phase was separated. The separated organic phase was post-treated, i.e., washed, dried and concentrated to obtain a crude product, 2-methyl-2,6-heptadienyl bromide (1: X=Br) (3.33 g), with a crude yield of 71.43%.

[0348] The following are the spectrum data of 2-methyl-2,6-heptadienyl bromide (1: X=Br) thus obtained.

[0349] IR(D-ATR): ν=3078,3028,2975,2919,2856,2735,1830,1739,1641,1438,1379,1205,1119,1065,992,913,847,811,769,721,696,636,542cm -1 .

[0350] 1 H-NMR (500MHz, CDCl 3 ): δ=1.84(3H,s-like),2.07-2.19(4H,m),3.98(2H,s),4.97-5.03(2H,m),5.39(1H,t-like,J=6.8Hz),5.75-5.85(1H,m)ppm.

[0351] 13 C-NMR (125MHz, CDCl 3): δ=21.84,27.39,32.24,33.24,115.06,130.79,131.92,137.83ppm.

[0352] GC-MS (EI, 70eV): 27, 41, 55, 67, 79, 93, 109, 119, 133, 147, 162, 175, 188.

[0353] Example 4: Preparation of 2-methyl-2,6-heptadienyl chloride (1: X=Cl)

[0354]

[0355] 2-Methyl-2,6-heptadienol (6) (8.00 g: 0.056 mol), pyridine (7.97 g: 0.101 mol) and dimethylformamide (DMF) (10 ml) were placed in a reactor under a nitrogen atmosphere, and the mixture was cooled to an internal temperature of -5°C to 5°C and stirred for 15 minutes. Then, methanesulfonyl chloride (MsCl) (8.98 g: 0.078 mol) was added dropwise to the reactor within 10 minutes while the internal temperature was maintained at -5°C to 5°C. After the addition was completed, the mixture was stirred at an internal temperature of -5°C to 5°C for 1 hour and further stirred at room temperature for 12 hours. Pure water (20 g) and hexane (20 g) were then added to the reactor and stirred for 30 minutes, and the organic phase was separated. The separated organic phase was post-treated, ie, washed, dried and concentrated to obtain a crude product, 2-methyl-2,6-heptadienyl chloride (1: X=Cl) (4.36 g), with a crude yield of 48.21%.

[0356] The following are the spectrum data of 2-methyl-2,6-heptadienyl chloride (1: X=Cl) thus obtained.

[0357] IR(D-ATR): ν=3078,2975,2934,2921,2854,2735,1831,1728,1641,1443,1380,1257,1119,1077,992,913,850,815,700,641cm -1 .

[0358] 1 H-NMR (500MHz, CDCl 3 ): δ=1.83(3H,s-like),2.07-2.21(4H,m),4.06(2H,s),4.97-5.03(2H,m),5.39(1H,t-like,J=7.2Hz),5.75-5.85(1H,m)ppm.

[0359] 13 C-NMR (125MHz, CDCl 3 ): δ = 21.84, 27.25, 32.24, 33.55, 115.04, 130.39, 131.71, 137.84ppm.

[0360] GC-MS (EI, 70eV): 27, 41, 53, 67, 75, 87, 95, 103, 116, 129, 144.

[0361] Example 5: Preparation of 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2:M=MgZ 1 , Z 1 =Cl, R = 2-tetrahydropyranyl group (THP)) and tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H pyran (3: R = THP)

[0362]

[0363] Magnesium (0.19 g: 0.0078 mol) and tetrahydrofuran (THF) (0.7 g) were placed in a reactor under a nitrogen atmosphere, heated to 60° C., and stirred for 15 minutes. Then, a mixed solution of tetrahydro-2-(5-chloro-3-methylpentyloxy)-2H-pyran (1.7 g: 0.007 mol) and tetrahydrofuran (THF) (1.5 g) was added dropwise to the reactor over 30 minutes. After the addition was completed, the mixture was stirred at an internal temperature of 50° C. to 60° C. for 3 hours to obtain 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2: M=MgZ 1 , Z 1 =Cl, R = THP). Then, the thus obtained 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2: M = MgZ 1 , Z 1 =Cl, R=THP) was cooled to room temperature.

[0364] In another reactor under nitrogen atmosphere, copper (I) iodide (CuI) (0.002 g), triethyl phosphite (P(OEt) 3 ) (0.003 g), tetrahydrofuran (THF) (4 ml) and 2-methyl-2,6-heptadienyl bromide (1: X = Br) (0.80 g: 0.004 mol) obtained according to Example 3. The mixture was stirred and cooled to -78°C to -50°C. The entire amount of 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2: M = MgZ) prepared above was added at -50°C or lower within 30 minutes. 1 , Z 1=Cl, R = THP) is added dropwise to the other reactor. After completion of the dropwise addition, the mixture is stirred for 3 hours. An aqueous solution of pure water (10g) and ammonium chloride (1g) is added dropwise to the other reactor and stirred for 30 minutes, and then the organic phase is separated. The separated organic phase is post-processed, i.e., washed, dried and concentrated to obtain a crude product tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyrans (3: R = THP) (1.24g: 0.04mol), and the crude yield is 10.00%. The yield ratio of tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyrans (3: R = THP) to tetrahydro-2-(3,7-dimethyl-7,11-dodecadienyloxy)-2H-pyrans is 72: 28.

[0365] The following are the spectrum data of the crude product tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3: R = THP) thus obtained.

[0366] IR(D-ATR): ν=3072,2928,2870,1642,1453,1441,1376,1353,1323,1260,1201,1184,1136,1122,1078,1035,991,970,908,888,870,815cm -1 .

[0367] 1 H-NMR (500MHz, CDCl 3 ): δ=0.86-0.89(3H,m),1.00-1.08(1H,m),1.16-2.10(20H,m),3.34-3.43(1H,m),3.47-3.53(1H,m),3.72-3.80(1H,m) ,3.83-3.89(1H,m),4.55-4.57(1H,m),4.63-4.65(1H,m),4.72-4.73(1H,m),4.90-5.02(2H,m),5.75-5.83(1H,m)ppm.

[0368] 13 C-NMR (125MHz, CDCl 3): δ=17.68,17.70,17.79,19.49,19.62,19.64,19.73,19.80,19.92,25.42,25.48,29. 83,30.03,30.11,30.53,30.56,30.63,30.66,30.77,31.66,32.56,32.71,34.70,34.75 ,34.78,34.88,36.38,36.47,36.82,36.86,46.95,47.00,47.07,47.10,62.28,65.82,6 5.86,65.98,94.61,98.73,98.91,111.64,111.73,114.13,139.08,147.20,147.32ppm.

[0369] GC-MS (EI, 70eV): 27, 41, 55, 69, 85, 109, 123, 149, 163, 182, 196, 210, 224, 240, 261, 276, 294.

[0370] Example 6: Preparation of 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2:M=MgZ 1 , Z 1 =Cl, R = THP) and tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3: R = THP)

[0371]

[0372] Magnesium (0.26 g: 0.011 mol) and tetrahydrofuran (THF) (1 g) were placed in a reactor under a nitrogen atmosphere, heated to 60° C., and stirred for 10 minutes. Then, a mixed solution of tetrahydro-2-(5-chloro-3-methylpentyloxy)-2H-pyran (2.21 g: 0.01 mol) and tetrahydrofuran (THF) (2 g) was added dropwise to the reactor over 10 minutes. After the addition was completed, the mixture was stirred at an internal temperature of 50° C. to 60° C. for 3 hours to obtain 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2: M=MgZ 1 , Z 1 =Cl, R = THP). Then, the thus obtained 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2: M = MgZ 1 , Z 1 =Cl, R=THP) was cooled to -5°C to 0°C.

[0373] A mixed solution of copper (I) cyanide (CuCN) (0.90 g), lithium bromide (LiBr) (1.74 g) and tetrahydrofuran (THF) (10 ml) was added dropwise to the reactor within 10 minutes, and then cooled to -78°C to -50°C. Then, a mixed solution of 2-methyl-2,6-heptadienyl chloride (1: X = Cl) (0.50 g: 0.002 mol) and THF (10 ml) obtained according to Example 4 was added dropwise to the reactor within 20 minutes. After the addition was completed, the mixture was stirred at -78°C to -50°C for 1 hour. A mixture of pure water (20 g) and ammonium chloride (2 g) was added to the reactor and stirred for 30 minutes, and then the organic phase was separated. The separated organic phase was post-treated, i.e., washed, dried and concentrated to obtain a crude product of tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3: R = THP) (1.86 g: 0.003 mol), with a crude yield of 100%. The yield ratio of tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3: R = THP):tetrahydro-2-(3,7-dimethyl-7,11-dodecadienyloxy)-2H-pyran was 99:1.

[0374] The spectral data of tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3:R=THP) thus obtained were the same as those obtained in Example 5.

[0375] Example 7: Preparation of 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2:M=MgZ 1 , Z 1 =Cl, R = THP) and tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3: R = THP)

[0376]

[0377] Magnesium (0.26 g: 0.01 mol) and tetrahydrofuran (THF) (1 g) were placed in a reactor under a nitrogen atmosphere, heated to 60° C., and stirred for 15 minutes. A mixed solution of tetrahydro-2-(5-chloro-3-methylpentyloxy)-2H-pyran (2.21 g: 0.01 mol) and tetrahydrofuran (THF) (2 g) was then added dropwise to the reactor over 30 minutes. After the addition was completed, the mixture was stirred at an internal temperature of 50° C. to 60° C. for 3 hours to obtain 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2: M=MgZ 1 , Z 1 =Cl, R = THP). Then, the thus obtained 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2: M = MgZ1 , Z 1 =Cl, R=THP) was cooled to room temperature.

[0378] In another reactor under nitrogen atmosphere, copper (I) bromide (CuBr) (1.29 g), lithium bromide (LiBr) (1.56 g), tetrahydrofuran (THF) (10 ml) and 2-methyl-2,6-heptadienyl chloride (1: X = Cl) (0.50 g: 0.003 mol) obtained according to Example 4 were placed. The mixture was stirred and cooled to -78°C to -50°C. Then, the whole amount of 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2: M = MgZ) prepared above was added at a temperature of -50°C or lower within 50 minutes. 1 , Z 1 =Cl, R = THP) is added dropwise to the other reactor. After the addition is completed, the mixture is stirred for 3 hours. A mixture of pure water (20g) and ammonium chloride (2g) is added to the other reactor and further stirred for 30 minutes, and then the organic phase is separated. The separated organic phase is post-processed, i.e., washed, dried and concentrated to obtain a crude product tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyrans (3: R = THP) (2.13g: 0.004mol), and the crude yield is 100%. Tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyrans) (3: R = THP): The yield ratio of tetrahydro-2-(3,7-dimethyl-7,11-dodecadienyloxy)-2H-pyrans is 99: 1.

[0379] The spectral data of tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3:R=THP) thus obtained were the same as those obtained in Example 5.

[0380] Example 8: Preparation of 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2:M=MgZ 1 , Z 1 =Cl, R = THP) and tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3: R = THP)

[0381]

[0382] Magnesium (0.26 g: 0.01 mol) and tetrahydrofuran (THF) (1 g) were placed in a reactor under a nitrogen atmosphere, heated to 60° C., and stirred for 10 minutes. Then, a mixed solution of tetrahydro-2-(5-chloro-3-methylpentyloxy)-2H-pyran (2.21 g: 0.01 mol) and tetrahydrofuran (THF) (2 g) was added dropwise to the reactor over 5 minutes. After the addition was completed, the mixture was stirred at an internal temperature of 50° C. to 60° C. for 3 hours to obtain 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2: M=MgZ 1 , Z 1 =Cl, R = THP). Then, the thus obtained 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2: M = MgZ 1 ,Z 1 =Cl, R = THP) was cooled to room temperature.

[0383] Titanium tetraisopropoxide (Ti(OiPr) 4 ) (2.89g) and tetrahydrofuran (THF) (10ml) and cooled to -10°C to -5°C. Then, the whole amount of 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2) prepared above was added dropwise to the other reactor at a temperature of -5°C or lower within 15 minutes. After the addition was completed, a mixed solution of cuprous iodide (I) (CuI) (0.10g), lithium bromide (LiBr) (0.09g) and THF (10ml) was added dropwise to the other reactor at a temperature of -5°C or lower within 2 minutes. After the addition was completed, 2-methyl-2,6-heptadienyl chloride (1:X=Cl) (1.45g:0.009mol) obtained according to Example 4 was added dropwise at a temperature of -5°C or lower within 20 minutes. After the addition was completed, the mixture was stirred at -10°C to -5°C for 2 hours, and further stirred at room temperature for 24 hours. The aqueous solution of pure water (20g) and ammonium chloride (2g) was added to the other reactor and stirred for 30 minutes, and then the organic phase was separated. The separated organic phase was post-processed, i.e., washed, dried and concentrated to obtain a crude product tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyrans (3: R = THP) (2.13g: 0.004mol), with a crude yield of 50.0%. The yield ratio of tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyrans (3: R = THP): tetrahydro-2-(3,7-dimethyl-7,11-dodecadienyloxy)-2H-pyrans was 94:6.

[0384] The spectral data of tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3:R=THP) thus obtained were the same as those obtained in Example 5.

[0385] Example 9: Preparation of 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2:M=MgZ 1 , Z 1 =Cl, R = THP) and tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3: R = THP)

[0386]

[0387] Magnesium (0.087 g: 0.0035 mol) and tetrahydrofuran (THF) (0.3 g) were placed in a reactor under a nitrogen atmosphere, heated to 60° C., and stirred for 5 minutes. Then, a mixed solution of tetrahydro-2-(5-chloro-3-methylpentyloxy)-2H-pyran (0.74 g: 0.003 mol) and tetrahydrofuran (THF) (0.7 g) was added dropwise to the reactor over 15 minutes. After the addition was completed, the mixture was stirred at an internal temperature of 50° C. to 60° C. for 3 hours to obtain 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride (2: M=MgZ 1 , Z 1 =Cl, R=THP). Then, the 3-methyl-5-(tetrahydropyran-2-yloxy)pentylmagnesium chloride thus obtained was cooled to -5°C to 5°C.

[0388] Zinc chloride (ZnCl 2 )(0.08 g), copper(II) chloride (CuCl 2 ) (0.08g) and lithium chloride (LiCl) (0.05g) were added to the reactor, and then a mixed solution of 2-methyl-2,6-heptadienyl chloride (1: X=Cl) (0.50g:0.003mol) and THF (10ml) obtained according to Example 4 was added dropwise within 10 minutes. After the addition was completed, the mixture was stirred at -5°C to 5°C for 5 hours. An aqueous solution of pure water (20g) and ammonium chloride (2g) was added to the reactor and stirred for 30 minutes, and then the organic phase was separated. The separated organic phase was post-treated, i.e., washed, dried and concentrated to obtain a crude product, tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3: R=THP) (1.86g:0.003mol), with a crude yield of 50.0%. The yield ratio of tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3:R=THP):tetrahydro-2-(3,7-dimethyl-7,11-dodecadienyloxy)-2H-pyran is 78:22.

[0389] The spectral data of tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3:R=THP) thus obtained were the same as those obtained in Example 5.

[0390] Example 10: Preparation of 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2:M=MgZ 1 , Z 1 =Cl, R = ethoxyethyl group (EE)) and tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3: R = EE)

[0391]

[0392] Magnesium (31.84 g: 1.31 mol) and tetrahydrofuran (THF) (126 g) were placed in a reactor under a nitrogen atmosphere, heated to 60° C., and stirred for 40 minutes. Then, a mixed solution (252 g) of 5-chloro-1-(1-ethoxyethoxy)-3-methylpentane (262.83 g: 1.26 mol) and tetrahydrofuran (THF) (252 g) was added to the reactor over 5 hours. After the dropwise addition was completed, the mixture was stirred at an internal temperature of 60° C. to 70° C. for 3 hours to obtain 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2: M=MgZ 1 , Z 1 =Cl, R = EE). Then, the 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2: M = MgZ 1 , Z 1 =Cl, R=EE) was cooled to room temperature.

[0393] In another reactor under nitrogen atmosphere, copper (I) bromide (CuBr) (72.30 g), lithium chloride (LiCl) (42.73 g) and tetrahydrofuran (THF) (756 g) were placed, stirred at room temperature for 15 minutes, and cooled to 0°C to 10°C. Then, 2-methyl-2,6-heptadienyl acetate (1':X'=OAc) (144.32 g:0.84 mol) obtained according to Example 1 was added to the other reactor, stirred, and cooled to -5°C to 5°C. Then, the whole amount of 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2:M=MgZ prepared above) prepared above was added to the reactor at -5°C to 5°C for 11 hours and 35 minutes. 1 , Z 1=Cl, R = EE) is added dropwise to the other reactor. After the addition is completed, the mixture is stirred at 10 ° C to 15 ° C for 2 hours, and further stirred at room temperature for 12 hours. A mixture of pure water (630g), ammonium chloride (63g) and 20% by weight of hydrogen chloride aqueous solution (126g) is added to the other reactor, and then n-hexane (500ml) is added and stirred for 30 minutes. The organic phase is then separated. The separated organic phase is post-processed, i.e., washed, dried and concentrated to obtain a crude product 1- (1-ethoxyethoxy) -6-isopropenyl -3-methyl -9-decene (3: R = EE) (320.21g: 0.623mol), and the crude yield is 74.17%. The yield ratio of 1-(1-ethoxyethoxy)-6-isopropenyl-3-methyl-9-decene (3:R=EE):1-(1-ethoxyethoxy)-3,7-dimethyl-7,11-dodecadiene (3':R=EE) is 96:4.

[0394] The following are the spectrum data of 1-(1-ethoxyethoxy)-6-isopropenyl-3-methyl-9-decene (3:R=EE) thus obtained.

[0395] IR(D-ATR): ν=3074,2975,2928,2872,1643,1453,1377,1339,1134,1101,1087,1062,992,932,909,889,845,640,554cm -1 .

[0396] 1 H-NMR (500MHz, CDCl 3 ): δ=0.86-0.88(3H,m),0.98-1.08(1H,m),1.16-1.69(17H,m),1.89-2.07(3H,m),3.38-3.50(2H,m) ,3.51-3.73(2H,m),4.64-4.69(2H,m),4.72-4.74(1H,m),4.90-5.00(2H,m),5.75-5.83(1H,m)ppm.

[0397] 13 C-NMR (125MHz, CDCl 3): δ=15.30,17.69,17.80,19.47,19.52,19.76,19.80,19.85,29.75,29.80, 29.94,29.97,30.52,30.65,31.66,32.58,32.73,34.68,34.73,34.81,34.86 ,36.62,36.86,36.98,37.00,46.99,47.02,47.11,47.13,60.58,60.59,63.4 0,99.46,99.50,99.52,111.65,111.74,114.15,139.06,147.19,147.31ppm.

[0398] GC-MS (EI, 70eV): 29, 45, 59, 73, 95, 109, 123, 149, 163, 177, 194, 208, 237, 267, 282.

[0399] Example 11: Preparation of 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2:M=MgZ 1 , Z 1 =Cl, R = EE) and tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyrrolidone (3: R = EE)

[0400]

[0401] Magnesium (3.49 g: 0.14 mol) and tetrahydrofuran (THF) (13.8 g) were placed in a reactor under a nitrogen atmosphere, heated to 60° C., and stirred for 5 minutes. Then, a mixed solution of 5-chloro-1-(1-ethoxyethoxy)-3-methylpentane (30.82 g: 0.14 mol) and tetrahydrofuran (THF) (27.6 g) was added dropwise to the reactor over 100 minutes. After the addition was completed, the mixture was stirred at an internal temperature of 60° C. to 70° C. for 6 hours to obtain 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2: M=MgZ 1 , Z 1 =Cl, R = EE). Then, the 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2: M = MgZ 1 , Z 1 =Cl, R=EE) was cooled to room temperature.

[0402] In another reactor under nitrogen atmosphere, copper (I) bromide (CuBr) (7.92 g), lithium chloride (LiCl) (4.68 g) and tetrahydrofuran (THF) (82.80 g) were placed, stirred at room temperature for 100 minutes, and cooled to 10° C. to 15° C. Then, 2-methyl-2,6-heptadienyl isobutyrate (1: X = isobutyryloxy) (20.00 g: 0.09 mol) obtained according to Example 2 was added to the other reactor and stirred. Then, the whole amount of 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2: M = MgZ prepared above) prepared above was added to the reactor over 4 hours at 10° C. to 15° C. 1 , Z 1 =Cl, R = EE) was added dropwise to the other reactor. After the addition was completed, the mixture was stirred at 10°C to 15°C for 18 hours. A mixture of pure water (41g), ammonium chloride (4.1g) and 20% by weight aqueous hydrogen chloride solution (13.8g) was then added to the other reactor. n-Hexane (138g) was added, stirred for 30 minutes, and then the organic phase was separated. The separated organic phase was post-treated, i.e., washed, dried and concentrated to obtain a crude product 1-(1-ethoxyethoxy)-6-isopropenyl-3-methyl-9-decene (3) (36.04g), with a crude yield of 54.44%. 1-(1-ethoxyethoxy)-6-isopropenyl-3-methyl-9-decene (2: M = MgZ 1 , Z 1 =Cl, R=EE): the yield ratio of 1-(1-ethoxyethoxy)-3,7-dimethyl-7,11-dodecadiene is 65:35.

[0403] Example 12: Preparation of 2-methyl-2,6-heptadienyl methanesulfonate (1":X"=OMs), 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2:M=MgZ 1 , Z 1 =Cl, R = EE) and tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3: R = EE)

[0404]

[0405] 2-methyl-2,6-heptadienol (10.00 g: 0.074 mol), triethylamine (11.23 g: 0.111 mol) and toluene (65 g) were placed in a reactor under a nitrogen atmosphere, and the mixture was cooled to an internal temperature of -5°C to 5°C and stirred for 20 minutes. Then, a mixed solution of methanesulfonyl chloride (MsCl) (12.71 g: 0.111 mol) and toluene (80 g) was added dropwise to the reactor within 90 minutes while maintaining an internal temperature of -5°C to 5°C. After the addition was completed, the mixture was stirred at an internal temperature of -5°C to 5°C for 8 hours. Then, pure water (130 g) was added to the reactor and stirred for 30 minutes, and then the organic phase was separated. The separated organic phase was post-treated, i.e., washed, dried and concentrated to obtain a toluene solution (190.97 g) containing a crude product 2-methyl-2,6-heptadienyl methanesulfonate (1": X" = OMs).

[0406] The following are the Rf value in thin layer chromatography and spectrum data of the crude product 2-methyl-2,6-heptadienyl methanesulfonate (1":X"=OMs) thus obtained.

[0407] Thin layer chromatography (TLC): Rf=0.19 (hexane:ethyl acetate=10:1).

[0408] 1 H-NMR (500MHz, CDCl 3 ): δ=1.83(3H,s-like),2.11-2.25(4H,m),3.00(3H,s),4.75(2H,s),4.98-5.09(2H,m),5.54(1H,t-like,J=7.3Hz),5.75-5.84(1H,m)ppm.

[0409] GC-MS (EI, 70eV): 27, 41, 55, 67, 79, 93, 108, 121, 135, 150, 163, 176, 204.

[0410] Magnesium (2.96 g: 0.12 mol) and tetrahydrofuran (THF) (11.7 g) were placed in a reactor under a nitrogen atmosphere, heated to 60° C., and stirred for 10 minutes. Then, a mixed solution of 5-chloro-1-(1-ethoxyethoxy)-3-methylpentane (26.13 g: 0.12 mol) and tetrahydrofuran (THF) (23.4 g) was added dropwise to the reactor over 115 minutes. After the addition was completed, the mixture was stirred at an internal temperature of 60° C. to 70° C. for 2 hours to obtain 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2: M=MgZ 1 , Z 1=Cl, R = EE). Then, the 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2: M = MgZ 1 , Z 1 =Cl, R=EE) was cooled to room temperature.

[0411] In another reactor under nitrogen atmosphere, copper (I) bromide (CuBr) (5.59 g), lithium chloride (LiCl) (3.31 g) and tetrahydrofuran (THF) (35.10 g) were placed, stirred at room temperature for 90 minutes, and then cooled to 10° C. to 15° C. Then, a toluene solution (100.00 g) containing the obtained crude product 2-methyl-2,6-heptadienyl methanesulfonate (1:X=OMs) was added to the other reactor and stirred. Then, the whole amount of 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2:M=MgZ prepared above) was added to the reactor at -5° C. to 5° C. within 3 hours. 1 , Z 1 =Cl, R = EE) is added dropwise to the other reactor. After the addition is completed, the mixture is stirred at 10 ° C to 15 ° C for 14 hours. A mixture of pure water (100g), ammonium chloride (4g) and 20% by weight of aqueous hydrogen chloride solution (4g) is added to the other reactor. Then, n-hexane (100g) is added and stirred for 30 minutes to separate the organic phase. The separated organic phase is post-processed, i.e., washed, dried and concentrated to obtain a crude product 1- (1-ethoxyethoxy) -6-isopropenyl -3-methyl -9-decene (3: R = EE) (21.55g). The crude yield based on 2-methyl-2,6-heptadienol is 30.77%. The yield ratio of 1-(1-ethoxyethoxy)-6-isopropenyl-3-methyl-9-decene (3:R=EE):1-(1-ethoxyethoxy)-3,7-dimethyl-7,11-dodecadiene is 63:37.

[0412] Example 13: Preparation of 2-methyl-2,6-heptadienyl p-toluenesulfonate (1":X"=p-toluenesulfonyloxy group (OTs)), 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2:M=MgZ 1 , Z 1 =Cl, R = EE) and tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3: R = EE)

[0413]

[0414] 2-methyl-2,6-heptadienol (10.00g: 0.074mol), triethylamine (11.23g: 0.111mol) and toluene (65g) were placed in a reactor under a nitrogen atmosphere, cooled to an internal temperature of -5°C to 5°C, and stirred for 50 minutes. Then, a mixed solution of p-toluenesulfonyl chloride (TsCl) (21.16g: 0.111mol) and toluene (80g) was added dropwise to the reactor within 90 minutes while the internal temperature was maintained at -5°C to 5°C. After the addition was completed, the mixture was stirred at an internal temperature of -5°C to 5°C for 7 hours. Then, pure water (130g) was added to the reactor and stirred for 30 minutes, and the organic phase was separated. The separated organic phase was post-treated, i.e., washed, dried and concentrated to obtain a toluene solution (185.69g) containing a crude product 2-methyl-2,6-heptadienyl p-toluenesulfonate (1": X" = OTs).

[0415] The following are the Rf value in thin layer chromatography and spectrum data of 2-methyl-2,6-heptadienyl p-toluenesulfonate (1":X"=OTs) thus obtained.

[0416] Thin layer chromatography (TLC): Rf=0.21 (hexane:ethyl acetate=10:1).

[0417] 1 H-NMR (500MHz, CDCl 3 ): δ=1.70(3H,s-like),2.00-2.08(4H,m),2.46(3H,s),4.55(2H,s),4.96-5.01(2H,m) ,5.41-5.44(1H,m),5.69-5.78(1H,m),7.35(2H,d,J=8.0Hz),7.82(2H,d,J=8.4Hz)ppm.

[0418] Magnesium (3.03 g: 0.12 mol) and tetrahydrofuran (THF) (12.0 g) were placed in a reactor under a nitrogen atmosphere, heated to 60° C., and stirred for 10 minutes. Then, a mixed solution of 5-chloro-1-(1-ethoxyethoxy)-3-methylpentane (26.80 g: 0.12 mol) and tetrahydrofuran (THF) (24.0 g) was added dropwise to the reactor over 120 minutes. After the addition was completed, the mixture was stirred at an internal temperature of 60° C. to 70° C. for 2 hours to obtain 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2: M=MgZ 1 , Z 1 =Cl, R = EE). Then, the 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2: M = MgZ 1 , Z 1=Cl, R=EE) was cooled to room temperature.

[0419] In another reactor under nitrogen atmosphere, copper (I) bromide (CuBr) (5.74 g), lithium chloride (LiCl) (3.39 g) and tetrahydrofuran (THF) (36.00 g) were placed, stirred at room temperature for 120 minutes, and then cooled to 10° C. to 15° C. Then, a toluene solution (100.00 g) containing the obtained crude product 2-methyl-2,6-heptadienyl p-toluenesulfonate (1”:X”=OTs) was added to the other reactor and stirred. Then, the whole amount of 5-(1-ethoxyethoxy)-3-methylpentylmagnesium chloride (2:M=MgZ prepared above) was added to the reactor at -5° C. to 5° C. within 3 hours. 1 , Z 1 =Cl, R = EE) is added dropwise to the other reactor. After the addition is completed, the mixture is stirred at 10 ° C to 15 ° C for 14 hours. Then a mixture of pure water (100g), ammonium chloride (4g) and 20% by weight of aqueous hydrogen chloride solution (4g) is added to the other reactor. Add n-hexane (100g) and stir for 30 minutes, and then separate the organic phase. The separated organic phase is post-processed, i.e., washed, dried and concentrated to obtain a crude product 1- (1-ethoxyethoxy) -6-isopropenyl -3-methyl -9-decene (3: R = EE) (25.55g). The crude yield based on 2-methyl-2,6-heptadienol is 43.30%. The yield ratio of 1-(1-ethoxyethoxy)-6-isopropenyl-3-methyl-9-decene (3:R=EE):1-(1-ethoxyethoxy)-3,7-dimethyl-7,11-dodecadiene is 59:41.

[0420] The spectral data of 1-(1-ethoxyethoxy)-6-isopropenyl-3-methyl-9-decene (3:R=EE) thus obtained were the same as those obtained in Example 10.

[0421] Example 14: Preparation of 5-(tert-butyldimethylsilyloxy)-3-methylpentylmagnesium chloride (2:M=MgZ 1 , Z 1 =Cl, R = tert-butyldimethylsilyl (TBS)) and 1-(tert-butyldimethylsilyloxy)-6-isopropenyl-3-methyl-9-decene (3: R = TBS)

[0422]

[0423] Magnesium (1.07 g: 0.044 mol) and tetrahydrofuran (THF) (4.2 g) were placed in a reactor under a nitrogen atmosphere, heated to 60° C., and stirred for 50 minutes. Then, a mixed solution of 5-chloro-1-(tert-butyldimethylsilyloxy)-3-methylpentane (10.80 g: 0.042 mol) and tetrahydrofuran (THF) (8.4 g) was added dropwise to the reactor over 40 minutes. After the addition was completed, the mixture was stirred at an internal temperature of 60° C. to 70° C. for 4 hours to obtain 5-(tert-butyldimethylsilyloxy)-3-methylpentylmagnesium chloride (2: M=MgZ). 1 , Z 1 =Cl, R = TBS). Then, the 5-(tert-butyldimethylsilyloxy)-3-methylpentylmagnesium chloride (2: M = MgZ 1 , Z 1 =Cl, R = TBS) was cooled to room temperature.

[0424] In another reactor, copper (I) bromide (CuBr) (2.32 g), lithium chloride (LiCl) (1.37 g) and tetrahydrofuran (THF) (24.4 g) were placed under a nitrogen atmosphere, stirred at room temperature for 10 minutes, and then cooled to 0°C to 10°C. Then, 2-methyl-2,6-heptadienyl acetate (1':X'=OAc) (4.66 g:0.027 mol) was added to the other reactor, stirred, and cooled to 0°C to 5°C. Then, the entire amount of 5-(tert-butyldimethylsilyloxy)-3-methylpentylmagnesium chloride (2) prepared above was added dropwise to the other reactor at -5°C to 5°C over 3 hours. After the addition was completed, the mixture was stirred at 10°C to 15°C for 15 hours. A mixture of pure water (13.5 g), ammonium chloride (1.35 g) and a 20 wt% aqueous solution of hydrogen chloride (4.59 g) was added to the other reactor. Toluene (10 g) was added and stirred for 30 minutes, and then the organic phase was separated. The separated organic phase was post-processed, i.e., washed, dried and concentrated to obtain a crude product of 1-(tert-butyldimethylsilyloxy)-6-isopropenyl-3-methyl-9-decene (3: R = TBS) (11.89 g), with a crude yield of 55.56%. The yield ratio of 1-(tert-butyldimethylsilyloxy)-6-isopropenyl-3-methyl-9-decene (3: R = TBS):1-(tert-butyldimethylsilyloxy)-3,7-dimethyl-7,11-dodecadiene was 75:25.

[0425] The following are the spectrum data of 1-(tert-butyldimethylsilyloxy)-6-isopropenyl-3-methyl-9-decene (3:R=TBS) thus obtained.

[0426] IR(D-ATR): ν=3074,2955,2928,2857,1643,1472,1462,1376,1361,1255,1097,1005,992,939,909,890,836,811,775,731,662cm -1 .

[0427] 1 H-NMR (500MHz, CDCl 3 ): δ=0.05(6H,s),0.84-0.87(3H,m),0.89(9H,s),0.98-1.09(1H,m),1.15-1.1.43(6H,m),1.46-1.61(5H,m),1.8 8-2.04(3H,m),3.58-3.68(2H,m),4.66(1H,s-like),4.73-4.75(1H,m),4.91-5.01(2H,m),5.76-5.84(1H,m)ppm.

[0428] 13 C-NMR (125MHz, CDCl 3 ): δ=-5.29,17.72,17.81,18.33,19.58,19.89,25.97,29.42,29.54,30.61,30.69,31.70,32.61,32.75,34 .78,34.86,39.72,40.12,47.02,47.11,61.45,61.47,111.65,111.73,114.14,139.11,147.25,147.36ppm.

[0429] GC-MS (EI, 70eV): 29,55,75,95,113,129,157,173,191,213,233,249,267.

[0430] Example 15: Preparation of 6-isopropenyl-3-methyl-9-decenol (4)

[0431]

[0432] Tetrahydro-2-(6-isopropenyl-3-methyl-9-decenyloxy)-2H-pyran (3: R = THP) (27.47 g: 0.69 mol), p-toluenesulfonic acid (5.36 g) and methanol (93 g) were placed in a reactor under a nitrogen atmosphere and stirred at an internal temperature of 50°C to 60°C for 4 hours. After the stirring was completed, the solvent was removed by concentration. Methanol (93 g) was then added to the reactor and stirred at room temperature for 12 hours. The mixture was then stirred at an internal temperature of 50°C to 60°C for 2 hours and the solvent was removed by concentration. Then, pure water (150 g) and n-hexane (100 g) were added to the reactor and stirred for 30 minutes, and then the organic phase was separated. The separated organic phase was post-processed, i.e., washed, dried and concentrated to obtain a crude product 6-isopropenyl-3-methyl-9-decenol (4) (18.46 g) with a crude yield of 72.46%.

[0433] The following are the spectrum data of 6-isopropenyl-3-methyl-9-decenol (4) thus obtained.

[0434] IR(D-ATR): ν=3332,3074,2928,2871,1642,1452,1376,1058,994,909,889,641cm -1 .

[0435] 1 H-NMR (500MHz, CDCl 3 ): δ=0.87-0.90(3H,m),1.00-1.09(1H,m),1.17-1.69(12H,m),1.87-2.08(3H,m),3.60-3. 70(2H,m),4.66(1H,s-like),4.74(1H,s-like),4.90-5.02(2H,m),5.75-5.84(1H,m)ppm.

[0436] 13 C-NMR (125MHz, CDCl 3 ): δ=17.63,17.79,18.52,19.77,29.29,29.61,30.46,30.64,30.65,32.56,32.74,34.62,34.88,39. 63,40.04,46.91,47.10,61.11,61.14,111.70,111.81,114.17,139.04,139.06,147.21,147.28ppm.

[0437] GC-MS (EI, 70eV): 29, 41, 55, 69, 81, 95, 109, 123, 135, 149, 167, 182, 195, 210.

[0438] Example 16: Preparation of 6-isopropenyl-3-methyl-9-decenol (4)

[0439]

[0440] 1-(1-ethoxyethoxy)-6-isopropenyl-3-methyl-9-decene (3: R = EE) (273.79 g: 0.59 mol), acetic acid (35.52 g), tetrahydrofuran (THF) (250 g) and pure water (266.4 g) were placed in a reactor under a nitrogen atmosphere and stirred at an internal temperature of 70°C to 80°C for 7 hours. Then, the contents of the reactor were cooled to room temperature, pure water (500 g) and toluene (200 g) were added and stirred for 30 minutes. The organic phase was then separated. The separated organic phase was post-treated, i.e., washed, dried and concentrated to obtain a crude product 6-isopropenyl-3-methyl-9-decenol (4) (216.33 g) with a crude yield of 100%.

[0441] The spectral data of 6-isopropenyl-3-methyl-9-decenol (4) thus obtained were the same as those obtained in Example 15.

[0442] Example 17: Preparation of 6-isopropenyl-3-methyl-9-decenol (4)

[0443]

[0444] 1-(tert-butyldimethylsilyloxy)-6-isopropenyl-3-methyl-9-decene (3: R=TBS) (2.00 g: 0.003 mol) and tetrahydrofuran (THF) (30 g) obtained according to Example 14 were placed in a reactor under a nitrogen atmosphere and stirred at room temperature for 5 minutes. Then, a THF solution of tetrabutylammonium fluoride (5.4 mL: 0.005 mol) was added dropwise to the reactor within 10 minutes. After the addition was complete, the mixture was stirred at room temperature for 5 hours. Then pure water (30 g), sodium chloride (3 g) and n-hexane (30 g) were added to the reactor and stirred for 30 minutes, and the organic phase was separated. The separated organic phase was post-processed, i.e., washed, dried and concentrated to obtain a crude product 6-isopropenyl-3-methyl-9-decenol (4) (1.99 g), with a crude yield of 100%.

[0445] The spectral data of 6-isopropenyl-3-methyl-9-decenol (4) thus obtained were the same as those obtained in Example 15.

[0446] Example 18: Preparation of 6-isopropenyl-3-methyl-9-decenyl acetate (5)

[0447]

[0448] 6-isopropenyl-3-methyl-9-decenol (4) (215.33 g: 0.77 mol), pyridine (213.45 g), acetic anhydride (131.78 g) and acetonitrile (220 g) obtained according to Example 16 were placed in a reactor under a nitrogen atmosphere and stirred at room temperature for 4 hours and 45 minutes. Then, pure water (600 g) and n-hexane (300 g) were added to the reactor and stirred for 30 minutes, and the organic phase was separated. The separated organic phase was post-treated, i.e., washed, dried and concentrated to obtain a crude product, 6-isopropenyl-3-methyl-9-decenyl acetate (5) (245.31 g). The crude product was distilled under reduced pressure to obtain the target compound 6-isopropenyl-3-methyl-9-decenyl acetate (5) (142.32 g: 0.55 mol). The yield of all fractions including the first fraction was 83.27%.

[0449] The following are the spectrum data of 6-isopropenyl-3-methyl-9-decenyl acetate (5) thus obtained.

[0450] IR (D-ATR): ν=3073,2928,2871,1742,1642,1454,1367,1239,1037,995,909,889,636,606cm -1 .

[0451] 1 H-NMR (500MHz, CDCl 3 ): δ=0.87-0.90(3H,m),1.01-1.09(1H,m),1.18-1.54(7H,m),1.56-1.58(3H,m),1.59-1.68(1H,m),1.89-2.01(3H, m),2.02(3H,s),4.01-4.12(2H,m),4.65(1H,s-like),4.74(1H,s-like),4.91-5.01(2H,m),5.74-5.83(1H,m)ppm.

[0452] 13 C-NMR (125MHz, CDCl 3): δ=17.63,17.77,19.32,19.63,20.99,29.68,29.96,30.43,30.56,31.62,31.65,32.56,32.72,34.49,34. 64,35.19,35.64,46.89,47.04,62.98,63.02,111.77,111.86,114.19,138.99,147.03,147.15,171.16ppm.

[0453] GC-MS (EI, 70eV): 29, 43, 55, 67, 81, 95, 109, 123, 135, 149, 163, 177, 192, 209, 223, 237, 252.

[0454] Example 19: Preparation of 6-isopropenyl-3-methyl-9-decenyl acetate (5)

[0455]

[0456] Under nitrogen atmosphere, acetic anhydride (24.50 g) and p-toluenesulfonic acid (0.05 g) were placed in a reactor and stirred at room temperature for 5 minutes. Then, 1-(1-ethoxyethoxy)-6-isopropenyl-3-methyl-9-decene (3: R=EE) (10.00 g: 0.023 mol) obtained according to Example 10 was added dropwise to the reactor within 1 minute, and the mixture was stirred at an internal temperature of 90° C. for 6 hours. Then, pure water (10 g) and n-hexane (50 g) were added to the reactor and stirred for 30 minutes. After stirring, the organic phase was separated. The separated organic phase was post-processed, i.e., washed, dried and concentrated to obtain a crude product, 6-isopropenyl-3-methyl-9-decenyl acetate (5) (9.50 g), with a crude yield of 100%.

[0457] The spectral data of 6-isopropenyl-3-methyl-9-decenyl acetate (5) thus obtained were the same as those obtained in Example 18.

Claims

1. A method for preparing 6-isopropenyl-3-methyl-9-decenyl acetate of formula (5): Wherein Ac represents an acetyl group, The method comprises the following steps: A 2-methyl-2,6-heptadiene compound of the following general formula (1) having a leaving group X at position 1: wherein X represents an acyloxy group having 1 to 10 carbon atoms including the carbon atom of the carbonyl group, an alkanesulfonyloxy group having 1 to 10 carbon atoms, an arylsulfonyloxy group having 6 to 20 carbon atoms, or a halogen atom, A nucleophilic substitution reaction is carried out with a 3-methylpentyl nucleophile of the following general formula (2) having a protected hydroxyl group at the 5-position: Where M represents MgZ 1 、ZnZ 1 ,Cu,CuZ 1 or CuLiZ 1 , where Z 1 represents a halogen atom or a CH2CH2CH(CH3)CH2CH2OR group, and R represents a protecting group for a hydroxyl group, To form a 6-isopropenyl-3-methyl-9-decene compound of the following general formula (3) having a protected hydroxyl group at position 1: wherein R is as defined above; The 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1 is subjected to a deprotection reaction to form 6-isopropenyl-3-methyl-9-decenol of the following formula (4): and 6-Isopropenyl-3-methyl-9-decenol (4) is acetylated to form 6-isopropenyl-3-methyl-9-decenyl acetate (5).

2. The method for preparing 6-isopropenyl-3-methyl-9-decenyl acetate of formula (5) according to claim 1, further comprising the following steps: The hydroxyl group of 2-methyl-2,6-heptadienol of the following formula (6): Converted to X to form a 2-methyl-2,6-heptadiene compound (1) having a leaving group X at position 1, wherein X is as defined above.

3. A method for preparing 6-isopropenyl-3-methyl-9-decenyl acetate of formula (5): Wherein Ac represents an acetyl group, The method comprises the following steps: A 2-methyl-2,6-heptadiene compound of the following general formula (1) having a leaving group X at position 1: wherein X represents an acyloxy group having 1 to 10 carbon atoms including the carbon atom of the carbonyl group, an alkanesulfonyloxy group having 1 to 10 carbon atoms, an arylsulfonyloxy group having 6 to 20 carbon atoms, or a halogen atom, A nucleophilic substitution reaction is carried out with a 3-methylpentyl nucleophile of the following general formula (2) having a protected hydroxyl group at the 5-position: Where M represents MgZ 1 、ZnZ 1 ,Cu,CuZ 1 or CuLiZ 1 , where Z 1 represents a halogen atom or a CH2CH2CH(CH3)CH2CH2OR group, and R represents a protecting group for a hydroxyl group, To form a 6-isopropenyl-3-methyl-9-decene compound of the following general formula (3) having a protected hydroxyl group at position 1: wherein R is as defined above; and The 6-isopropenyl-3-methyl-9-decene compound (3) having a protected hydroxyl group at position 1 is subjected to acetylation to form 6-isopropenyl-3-methyl-9-decenyl acetate (5).

4. The method for preparing 6-isopropenyl-3-methyl-9-decenyl acetate of formula (5) according to claim 3, further comprising the following steps: The hydroxyl group of 2-methyl-2,6-heptadienol of the following formula (6): Converted to X to form a 2-methyl-2,6-heptadiene compound (1) having a leaving group X at position 1, wherein X is as defined above.

5. A 2-methyl-2,6-heptadiene compound of the general formula (1') having X' at position 1: wherein X' represents an acyloxy group having 1 to 10 carbon atoms including the carbon atom of the carbonyl group, wherein the acyloxy group is selected from the group consisting of a straight chain aliphatic acyloxy group; a branched chain aliphatic acyloxy group; a trichloroacetoxy group or a trifluoroacetoxy group as a halogenated acyloxy group; and an aromatic acyloxy group.

6. The 2-methyl-2,6-heptadiene compound of the general formula (1') having X' at position 1 according to claim 5, wherein the acyloxy group is selected from the group consisting of a linear aliphatic acyloxy group.

7. The 2-methyl-2,6-heptadiene compound of the general formula (1') having X' at position 1 according to claim 5, wherein the acyloxy group is selected from the group consisting of a branched aliphatic acyloxy group.

8. The 2-methyl-2,6-heptadiene compound of the general formula (1') having X' at position 1 according to claim 5, wherein the acyloxy group is selected from the group consisting of a trichloroacetoxy group or a trifluoroacetoxy group as a halogenated acyloxy group.

9. The 2-methyl-2,6-heptadiene compound of the general formula (1') having X' at position 1 according to claim 5, wherein the acyloxy group is selected from the group consisting of an aromatic acyloxy group.

10. The 2-methyl-2,6-heptadiene compound of the general formula (1') having X' at position 1 according to claim 5, wherein the acyloxy group is selected from the group consisting of a formyloxy group, an acetoxy group, a propionyloxy group, a pivaloyloxy group, a 2-methylpropionyloxy group, and a benzoyloxy group.

11. A 2-methyl-2,6-heptadiene compound of the following general formula (1") having X" at position 1: wherein X" represents an alkanesulfonyloxy group having 1 to 10 carbon atoms or an arylsulfonyloxy group having 6 to 20 carbon atoms.

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