Process for the manufacture of macrocyclic musk compounds

Abstract

The present invention relates to a new process for the manufacture of macrocyclic musk compounds, which makes use of renewable starting materials and practical reaction conditions that are easy to scale up. The present invention also relates to novel macrocyclic musk ketones with unique organoleptic properties that can be obtained by the new process.

Description

Technical Field

[0001] This invention relates to a novel method for producing macrocyclic musk compounds, utilizing renewable raw materials and readily scalable reaction conditions. The invention also relates to novel macrocyclic musk ketones with unique sensory properties obtainable through this novel method. Background of the Invention Since these compounds have been widely used as musk scenting agents in the perfume industry, extensive research has been conducted on the efficient synthesis of saturated or unsaturated macrocyclic ketones (rings with 14 to 18 carbon atoms). For example, fully saturated 15-membered macrocyclic ketones—cyclopentadecanone and muscone—were the first macrocyclic musks discovered by Ruzica et al. in the first half of the last century (Helv. Chim. Acta, 9, (1926), 230). Several macrocyclic musks possess double bonds and exhibit cis-trans stereoisomerism, resulting in mixtures of diastereomers and / or regioisomers; for example, (Z)-4-cyclopentadecane-1-one reported by G. Ohloff et al. (Helv. Chim. Acta 50 (1967) 705), Ambretone (cyclohexadecade-5-en-1-one) reported by T. Kato et al. ("Bull. Chem. Soc. Jpn.," Vol. 53, p. 2958 (1980)), 3-methylcyclopentadecane-5-en-1-one disclosed by E. Demole et al. (US Patent No. 5,354,735), and cycloheptadecade-9-en-1-one (civetone) reported by Ruzica et al. (Helv. Chim. Acta, 9, (1926), 230). These unsaturated macrocyclic compounds with mixtures of isomers possess excellent odor properties.

[0003] The main products from unsaturated musks, Exaltenone®, Muscenone®, and Ambretone® or Velvione®, have been reported to be synthesized from cyclododecanone. Cyclododecanone is industrially obtained via the trimerization of 1,3-butadiene to cyclodecanetriene, which is then converted to cyclododecanone in two steps. Cyclododecanone is an important intermediate in the synthesis of dodecanoic acid and laurolactam, which are widely used in the industrial synthesis of polymers. Exaltenone® and Muscenone® are synthesized from cyclododecanone by expanding the ring with three carbon atoms to provide a 15-membered carbon ring.

[0004] Scheme 1 shows the synthesis of muscenone from cyclododecanone.

[0005] Option 1: Synthesis of Muscenone (γ+δ) from cyclododecanone On the other hand, Ambretone® or Velvione® (5-cyclohexadecene-1-one) is synthesized as shown in Scheme 2. As originally patented in JPS-524787B1, cyclododecone is chlorinated with gaseous chlorine or CuCl2-DMF to give 2-chlorocyclododecone, which is then reacted with 2 equivalents of vinyl magnesium chloride to obtain 1,2-divinylcyclododecyl alcohol. This alcohol is subjected to a thermal oxa-Cope rearrangement at 180-250°C to obtain 5-cyclohexadecene-1-one.

[0006] Option 2: Synthesis of 5-cyclohexadecene-1-one from cyclododecanone Cyclododecanoyl ketone is limited in availability, and more importantly, 1,3-butadiene is a petroleum product. Many reported synthetic macrocyclic musks utilize cyclododecanoyl ketone as a starting material. However, there is an urgent need to develop methods utilizing renewable raw materials in the field of macrocyclic musks.

[0007] EP1264594B1 describes the use of macrocyclic compounds to inhibit melanin synthesis. The synthesis of the novel macrocyclic diene mentioned in EP1264594, as well as other macrocyclic compounds, was originally described in US6200254B1. However, the raw materials used in US6200254B1 are also derived from petroleum products. Furthermore, the use of Grignard reagents as listed in all claims requires anhydrous conditions in the reaction medium. The Claisen condensation employed in both inventions ensures that the double bond in the final macrocyclic ketone is always at position 4 or 5 of the carbonyl carbon. This is another limitation of this method. On the other hand, the methods disclosed in this invention are very broad and can synthesize macrocyclic diene ketones with double bonds at any position from the 4th to the 8th carbon of the carbonyl group.

[0008] US8642814B1 describes the anticipated synthesis of macrocyclic compounds from a mixture of palmitic acid (C16:1) and oleic acid (C18:1). For example, an ω-7-rich oil is subjected to transesterification and distillation to obtain an ω-7-rich ester fraction. This fraction is then subjected to metathesis and subsequent Dieckmann cyclization to finally obtain civetone. The main limitation of this method is that only 17-membered macrocycles are produced by this approach.

[0009] Common and practical synthetic routes that facilitate the synthesis of various unsaturated and substituted macrocyclic ketones with different double bond and methyl positions using different starting materials would be a welcome addition to the existing library of macrocyclic ketone synthetic methods.

[0010] Surprisingly, the inventors were able to design and optimize such promising methods. The reaction sequences claimed herein are novel, and the addition of renewable starting materials in the synthesis of various macrocyclic ketones represents a significant feature of this invention. Invention Overview This invention relates to a novel method for preparing unsaturated macrocycles of formula (I) using a series of common organic reactions. This reaction sequence utilizes low-cost reagents. More importantly, the key raw materials used in this invention are renewable resources.

[0012] The first objective of this invention is to prepare unsaturated macrocyclic ketones of the following formula (I): Methods involving mixtures of its regional isomers and / or stereoisomers; Where m is an integer selected from 0, 1, 2, 3, and 4. R1, R2, R3, R4, R5, R6, and R7 represent hydrogen atoms or methyl groups, and The dashed lines represent alternating positions of double bonds, where the double bond is between carbon atoms 4 and 5, or 5 and 6, or 6 and 7, or 7 and 8, or 8 and 9.

[0013] A second objective of the present invention is to provide a novel unsaturated macrocyclic ketone of formula (I).

[0014] A third object of the present invention is to provide a novel mixture of regioisomers and / or stereoisomers of an unsaturated macrocyclic ketone of formula (I).

[0015] A fourth object of the present invention is to provide an aromatic composition comprising a compound represented by general formula (I). Invention Details You can use Ru / C with Al 11.6 PO 23.7 The catalyst converts biomass-derived furfural to cyclopentanone in aqueous medium with a yield of 84% (Shen, T. et al.). RSC Adv. 2018, 8, 37993). Naturally occurring anethole can be converted to cyclohexanone using bromide-modified Pd / C in H2O / CH2Cl2 [Meng, Q. et al., 2018, 8, 37993]. Nature Communications , 8, Article number: 14190 (2017)]. 3-Methylcyclohexanone can be obtained from peppermint ( ). Mentha pulegium ), a flowering plant.

[0017] Similarly, many long-chain ω-enyl alcohols, such as 10-undecen-1-ol and 9-decen-1-ol, are commercially produced from feedstocks available from natural resources.

[0018] As shown in the experimental section, our method uses the renewable starting materials detailed above.

[0019] The first embodiment of the present invention is method-1, as given below.

[0020] The first step involves a radical coupling reaction between the substituted cyclic ketone 2 and the ω-alkenylalkyl carboxylic acid ester 1. The resulting substituted ketone 3 is converted to a lactone 4 in step-2. In step-3, the lactone is hydrolyzed to the corresponding hydroxylated 1,ω-dicarboxylic acid ester 5, which is subsequently dehydrated in step-4 to the corresponding unsaturated 1,ω-dicarboxylic acid ester 6. In step-5, the intramolecular Dickmann reaction of diester 6 and subsequent hydrolytic decarboxylation provide a mixture of macrocyclic ketones of the desired general formula (I).

[0021] The conversion of the lactone to the corresponding hydroxylated 1,ω-dicarboxylic acid ester is not illustrated in any literature. This hydroxyl derivative is then dehydrated to the corresponding unsaturated 1,ω-dicarboxylic acid ester. In summary, steps 3 and 4 are crucial for introducing unsaturation into this invention.

[0022] Another embodiment of the present invention is the following method-2.

[0023] In Method-2, the first step involves a radical coupling reaction between the substituted cyclic ketone 2 and the ω-alkenylalkyl carboxylic acid ester 1. The resulting substituted ketone 3 is converted to a lactone 4 in Step-2. In Step-3, the lactone is heated with thionyl chloride to convert it to the corresponding chlorinated 1,ω-dicarboxylic acid ester 5. In Method-A, compound 5 is subsequently dehydrochlorinated in Step-4 to the corresponding unsaturated 1,ω-dicarboxylic acid ester 6. In Step-5, the intramolecular Dickmann reaction of diester 6 and subsequent hydrolytic decarboxylation provide a mixture of macrocyclic ketones of the desired general formula (I).

[0024] As shown in Method-B, compounds of general formula (I) are prepared by the following method: intramolecular Dickmann reaction of compound 5 followed by hydrolysis and decarboxylation to obtain compound 6-B, which yields the desired macrocyclic ketone of general formula (I) by base-mediated elimination.

[0025] The conversion of the lactone to the corresponding chlorinated 1,ω-dicarboxylic acid ester is not illustrated in any literature. This chlorinated derivative is then dehydrochlorinated to the corresponding unsaturated 1,ω-dicarboxylic acid ester. In summary, steps 3 and 4 are crucial for introducing unsaturation into this invention.

[0026] Another embodiment of the present invention is the following method-3.

[0027] In method-3, the first step involves a radical coupling reaction between the substituted cyclic ketone 2 and the ω-alkenylalkyl carboxylic acid ester 1. The resulting substituted ketone 3 is converted to a lactone 4 in step-2. In step-3, the lactone is hydrolyzed to the corresponding hydroxylated 1,ω-dicarboxylic acid ester 5, which is subsequently dehydrated in step-4 to the corresponding unsaturated 1,ω-dicarboxylic acid ester 6. In steps-5 / 6, the coupling condensation of diester 6 yields an α-hydroxy ester 7, which, upon dehydroxylation (e.g., by using zinc / acetic acid / concentrated HCl), gives a mixture of macrocyclic ketones of the desired general formula (I).

[0028] The conversion of the lactone to the corresponding hydroxylated 1,ω-dicarboxylic acid ester is not illustrated in any literature. This hydroxyl derivative is then dehydrated to the corresponding unsaturated 1,ω-dicarboxylic acid ester. In summary, steps 3 and 4 are crucial for introducing unsaturation into this invention.

[0029] Another embodiment of the present invention is the following method-4.

[0030] In method 4, the first step involves a radical coupling reaction between the substituted cyclic ketone 1 and the ω-alkenylalkyl carboxylic acid ester 2. The resulting substituted ketone 3 is converted to a lactone 4 in step 2. In step 3, the lactone is heated with thionyl chloride to convert it to the corresponding chlorinated 1,ω-dicarboxylic acid ester 5, which is subsequently dehydrochlorinated in step 4 to the corresponding unsaturated 1,ω-dicarboxylic acid ester 6. In steps 5 / 6, the coupling condensation of diester 6 yields an α-hydroxy ester 7, which, upon dehydroxylation (e.g., by using zinc / acetic acid / concentrated HCl), gives a mixture of macrocyclic ketones of the desired general formula (I).

[0031] The conversion of the lactone to the corresponding chlorinated 1,ω-dicarboxylic acid ester is not illustrated in any literature. This chlorinated derivative is then dehydrochlorinated to the corresponding unsaturated 1,ω-dicarboxylic acid ester. In summary, steps 3 and 4 are crucial for introducing unsaturation into this invention.

[0032] As previously described, there are many notable features of this invention: the use of renewable starting materials to form a single novel compound or mixture of unsaturated macrocyclic ketones; a general synthetic route employing a novel reaction sequence that acts as a divergent synthetic pathway, allowing the same unsaturated 1,ω-dicarboxylic acid ester 6 to be converted into macrocyclic ketones of different sizes by employing intramolecular Dickmann reaction or inco-condensation.

[0033] A very significant feature of this invention is that the synthetic route described herein enables the synthesis of new macrocyclic ketones in a crowded field of research where many macrocyclic ketones have already been reported.

[0034] In one embodiment, compounds of general formula (I) or mixtures of their regioisomers and / or stereoisomers can be advantageously prepared by the claimed method: Where m is an integer / natural number selected from 0, 1, 2, 3, and 4. R1, R2, R3, R4, R5, R6, and R7 represent hydrogen atoms or methyl groups. The dashed lines indicate alternating positions of double bonds, which can be between carbon atoms 4 and 5, 5 and 6, 6 and 7, 7 and 8, or 8 and 9.

[0035] In a preferred embodiment, the compounds of general formula (I) are selected from: (i) Z )-4-methylcyclopentadecan-5-en-1-one, (ii) E )-4-methylcyclopentadecan-5-en-1-one, (iii) Z )-5-methylcyclohexadec-6-en-1-one, (iv) E )-5-methylcyclohexadec-6-en-1-one, (v) (Z)-4-methylcyclohexadecyl-6-en-1-one, (vi) E )-4-methylcyclohexadec-6-en-1-one, (vii) Z )-3-methylcycloheptadecane-5-en-1-one, (viii) E )-3-methylcycloheptadecane-5-en-1-one, (ix) Z )-3-methylcycloheptadecane-6-en-1-one, (x) E )-3-methylcycloheptadecane-6-en-1-one, (xi) Z )-5-methylcyclohexadecane-5-en-1-one, (xii) E )-5-methylcyclohexadecane-5-en-1-one, (xiii) Z )-5-methylcyclohexadecane-6-en-1-one, (xiv) E )-5-methylcyclohexadecane-6-en-1-one, (xv)( Z )-4-methylcycloheptadecane-5-en-1-one, (xvi) E )-4-methylcycloheptadecane-5-en-1-one, (xvii) Z )-4-methylcycloheptadecane-6-en-1-one, (xviii) E )-4-methylcycloheptadecane-6-en-1-one, (xix) Z )-Cyclooctadecyl-6-en-1-one, (xx) ( E )-Cyclooctadecyl-6-en-1-one, (xxi) Z )-Cyclooctadecyl-7-en-1-one, or (xxii) E )-Cyclooctadecyl-7-en-1-one, Or a mixture of its regional isomers and / or stereoisomers.

[0036] In another embodiment, a mixture of regioisomers and / or stereoisomers of the compound of formula (I) can be advantageously prepared by the claimed method; said mixture can be advantageously characterized by a weight ratio between the regioisomers and / or stereoisomers of 95:5 to 5:95.

[0037] In one embodiment, a fragrance agent composed of compounds or mixtures as defined above is provided.

[0038] In one embodiment, a fragrance, flavoring, and / or deodorizing / masking composition comprising compounds or mixtures as defined above is provided.

[0039] The invention will now be further described with reference to the following non-limiting embodiments. These embodiments are for illustrative purposes only, and it should be understood that changes and modifications can be made by those skilled in the art. Example

[0040] Example 1: ( E & Z )-cyclopentadecan-4-en-1-one and ( E & Z Preparation of a mixture of isomers of cyclopentadecano-5-en-1-one Step 1: Methyl 11-(2-oxocyclopentyl)undecanoate: A 500 mL round-bottom three-necked flask equipped with a magnetic stirrer, a feeding funnel, and a reflux condenser was loaded with di-tert-butyl peroxide (0.66 g, 0.004 mol) and cyclopentanone (212 g, 2.52 mol). The solution was slowly heated to 110–120 °C, and then a solution of methyl 10-undecenoate (50 g, 0.252 mol) and di-tert-butyl peroxide (5.3 g, 0.034 mol) was carefully added over a 20-minute period via the feeding funnel. The reaction mixture was refluxed at 120 °C for 4 hours. After cooling to room temperature, water (50 mL) was added and the layers were separated. The organic layer was washed with saturated aqueous sodium carbonate solution (50 mL), 5% aqueous acetic acid solution (50 mL), and saturated brine (50 mL). The organic layer was concentrated under reduced pressure to remove excess cyclopentanone. The obtained material was purified by fractional distillation to obtain methyl 11-(2-oxocyclopentyl)undecanoate as a colorless liquid (57 g, 80% yield).

[0041] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 3.63 (s, 3H), 2.32-2.28 (m, 1H), 2.8-2.23 (t, J = 7.2 Hz, 2H), 2.2-1.994 (m, 6H), 1.787-1.741 (m, 2H), 1.61-1.53(m, 2H), 1.26 (s, 14H). 13 C-NMR (100.6 MHz, CDCl3) δ (ppm): 221.4, 174.8, 51.2, 48.9, 37.9,33.9, 29.5, 29.4, 29.3, 29.2, 29.02, 28.9, 27.3, 24.7, 20.5 GCMS: 282.2 (M + ), 251.2, 222.2, 198.2, 167.1, 149.1, 129.1, 111.1, 84.1, 55.1 IR (pure sample): 2925, 2854, 1735 (s) cm -1 .

[0042] Step 2: Methyl 11-(6-oxotetrahydro-2H-pyran-2-yl)undecanoate: Methyl 11-(2-oxocyclopentyl)undecanoate (57 g, 0.20 mol) and sodium carbonate (23 g, 0.21 mol) were charged into a three-necked 500 mL round-bottom flask equipped with a top stirrer, feeding funnel, and reflux condenser under a nitrogen atmosphere and cooled to 0 °C in an ice bath. Peracetic acid (17 g, 0.27 mol) was added to the reaction mixture after 1 hour. The solution was then heated to room temperature and stirred for 8 hours. The reaction was quenched with ice water (200 mL) and ethyl acetate (200 mL) was added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with an aqueous solution of FeSO4 and hot water, and then dried over anhydrous Na2SO4. The organic layers were concentrated to obtain a white solid (58 g, 90% yield), which was used as is in the next step.

[0043] 1 H-NMR (400 MHz, CDCI3) δ (ppm): 4.30-4.24 (m, 1H), 3.66 (s, 3H), 2.62-2.46 (m, 2H), 2.44-2.42 (t, J= 7.2 Hz, 2H), 1.93-1.81 (m, 4H), 1.69-1.47(m, 4H), 1.26(s, 14H) 13 C-NMR (100.6 MHz, CDCl3) δ (ppm): 174.35, 172.02, 80.60, 51.4,35.8, 34.1, 29.4, 29.4, 29.2, 29.1, 27.8, 24.9, 18.5 GCMS: 299.1 (M + ), 280.1, 249.1, 227.2, 207.2, 185.2, 151.1, 123.1, 99.0, 74.1, 55.1 IR (pure sample): 2919, 1720 cm -1 .

[0044] Step 3: Dimethyl 5-chlorohexadecanoate: A three-necked 500 mL round-bottom flask equipped with a magnetic stirrer, a feeding funnel, and a reflux condenser was placed under a nitrogen atmosphere and successively charged with methylcyclohexane (100 mL), methyl 11-(6-oxotetrahydro-2H-pyran-2-yl)undecanoate (58 g, 0.19 mol), and 0.526 g of zinc chloride (0.003 mol). The reaction mixture was then cooled to 0 °C, and thionyl chloride (45.8 g, 0.39 mol) was added dropwise over 1.5 hours via the feeding funnel. The reaction mixture was then heated to room temperature and refluxed at 80 °C for 5 hours. The dark-colored reaction mixture was cooled to 0 °C and quenched with methanol (100 mL) added slowly to the reaction mixture. The reaction mixture was stirred for 1 hour. The methanol was then evaporated, and the dark crude product was quenched with a saturated aqueous sodium carbonate solution (100 mL) and extracted with ethyl acetate (2 x 200 mL), followed by separation of the organic layer. The organic layer was finally washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated to obtain a crude product (65 g). The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain dimethyl 5-chlorohexadecanoate as a pale yellow liquid (40.9 g, 60% yield), which was used in the next step.

[0045] 1 H-NMR (400 MHz, CDCI3) δ (ppm): 3.92-3.85 (m, 1H), 3.68-3.667 (2s,6H), 2.35-2.29 (m, 4H), 1.93-1.59 (m, 8H), 1.55-1.39 (m, 2H), 1.275 (m,12H) 13 C-NMR (100.6 MHz, CDCl3) δ (ppm): 174.2-173.6, 63.3, 51.3, 38.3,37.6, 33.9, 33.3, 29.3, 29.1, 28.9, 26.3, 24.8, 21.8. GCMS: 349.2 (M + ), 313.2 281.2, 249.2 , 207.2 , 165.1 , 123.1 , 98.1 ,98.1 , 74.1 , 41.1 IR (pure sample): 2927, 1737 cm -1 .

[0046] Step 4: ( E & Z)-Hexadecyl-4-enic acid dimethyl ester and ( E & Z Dimethyl hexadecanoate: Dimethyl 5-chlorohexadecanoate (40.9 g, 0.12 mol) was added to a three-necked 250 mL round-bottom flask equipped with a magnetic stirrer and a reflux condenser and cooled to 10 °C. Using a feeding funnel, 1,8-diazabicyclo(5.4.0)undec-7-ene (35.3 g, 0.23 mol) was added very slowly over 1 hour to control the exothermic reaction. The reaction mixture was slowly heated to 125 °C and maintained at this temperature for 6 hours. The dark reaction mixture was then cooled to room temperature and quenched with 6N HCl until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with a saturated aqueous sodium carbonate solution (100 mL) and subsequently with saturated brine (100 mL). The organic layers were then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude product (30 g). The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain a pale yellow liquid. E & Z )-Hexadecyl-4-enic acid dimethyl ester and ( E & Z A mixture of hexadecyl-5-enedioic acid dimethyl ester (21.7 g, 60% yield) was used for the next step.

[0047] 1 H-NMR (400 MHz, CDCI3) δ (ppm): 5.46-5.35 (m, 2H), 3.66 (s,6H), 2.36-2.28 (t, 2H J=7.6Hz), 2.02-1.95 (m, 4H), 1.70-1.67 (m,2H), 1.634-1.634(m, 2H) , 1.28-1.26 (m, 14H) 13 C-NMR (100.6 MHz, CDCl3) δ (ppm): 174.1-173.5, 131.7, 128.7-127.7,51.3, 33.9, 33.2, 32.3, 31.8, 29.3, 29.1, 28.9, 27.6, 24.8 GCMS: 312.2 (M + ), 280.1, 248.2, 220.2, 178.2, 150.1 IR (pure sample): 2925, 1738 cm-1 Step 5: ( E & Z methyl 2-oxocyclopentadecan-5-ene-1-carboxylate, ( E & Z methyl 2-oxocyclopentadecan-6-ene-1-carboxylate, ( E & Z methyl 1,5-oxocyclopentadecan-3-ene-1-carboxylate and ( E & Z A mixture of methyl 1,5-oxocyclopentadecan-4-ene-1-carboxylate: Under a nitrogen atmosphere ( E & Z )-Hexadecyl-4-enic acid dimethyl ester and ( E & Z A solution of dimethyl hexadecyl 5-enidine (10 g, 0.03 mol) in THF (600 mL) was slowly added to a reflux mixture of LiHMDS (hexamethyldisiloxane-lithium) (192 mL, 1 M in THF, 0.19 mol) and THF (350 mL). After the addition was complete, the mixture was further stirred under reflux for 15 min. The mixture was then cooled to room temperature, treated with 1 N HCl (pH = 4–5), and then extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude liquid was purified by column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain a pale yellow oil. E & Z methyl 2-oxocyclopentadecan-5-ene-1-carboxylate, ( E & Z methyl 2-oxocyclopentadecan-6-ene-1-carboxylate, ( E & Z methyl 1,5-oxocyclopentadecan-3-ene-1-carboxylate and ( E & Z A mixture of methyl 1-15-oxocyclopentadecan-4-ene-1-carboxylate (4.5 g, 55% yield).

[0048] 1 H-NMR (400 MHz, CDCI3) δ (ppm): 5.33-5.17 (m, 2H), 3.63-3.49 (m,4H), 2.51-2.39 (m, 4H), 1.94-1.56 (m, 4H), 1.31-1.07 (m,14H) 13 C-NMR (100.6 MHz, CDCl3) δ (ppm): 205.8, 170.2-169.7, 133.8, 133.1,132.4, , 131.9, 129.9, 128.9, 126.2, 58.1, 57.7, 56.9, 56.6, 52.2, 42.7,42.5, 41.8, 40.4, 31.4, 31.2, 31.0, 30.8, 30.2, 29.55, 29.2, 28.5, 28.1,27.9, 27.4, 27.1, 26.9 GCMS: 280.1 (M + ), 248.1, 220.1, 179.1, 135.1, 95.1, 55.1 IR (pure sample): 2926, 1746, 1714, 1645 cm⁻¹ -1 .

[0049] Step 6: Cyclopentadecano-4-en-1-one and cyclopentadecano-5-en-1-one E & Z Mixtures of isomers: A solution of the mixture of compounds from step-5 (4 g, 0.01 mol) in MeOH (20 mL) was treated with an aqueous solution of NaOH (1.68 g, 0.04 mol in 10 mL of water), and the resulting mixture was heated to reflux for 1.5 h. The resulting mixture was then cooled to room temperature and acidified to pH 1 by dropwise addition of 10% H₂SO₄, followed by heating to reflux for 30 min. The reaction mixture was then cooled to room temperature and the MeOH was evaporated. The crude solution was extracted with MTBE (2 x 30 mL), and the combined organic layers were washed with water (100 mL) and saturated brine (100 mL). The organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain cyclopentadecan-4-en-1-one and cyclopentadecan-5-en-1-one as colorless liquids. E & Z A mixture of isomers (2.5 g, 0.011 mol, 80% yield).

[0050] 1H-NMR (400 MHz, CDCI3) δ (ppm): 5.42-5.26 (m,2H), 2.50-2.41 (m, 4H), 2.39-2.32 (m, 2H), 2.06-2.00 (m, 2H), 1.67-1.60 (m, 2H), 1.38-1.19 (m, 14H) 13 C-NMR (100.6 MHz, CDCl3) δ (ppm): 212.75-211.51, 132.25-128.09,42.49, 42.35, 41.65, 41.26, 31.38, 31.01, 30.62, 27.93, 27.31, 27.18, 27.00,26.90, 26.74, 26.31, 26.15, 26.08, 25.79 GCMS: 222.2 (M + ), 207.2, 193.2 IR (pure sample): 2925, 1712, 1645 cm -1 Scent: Creamy, musky, and animalic.

[0051] Example 2: Preparation of a mixture of isomers of 3-methylcyclopentadecano-5-en-1-one, 3-methylcyclopentadecano-6-en-1-one, 5-methylcyclopentadecano-5-en-1-one and 5-methylcyclopentadecano-6-en-1-one Step 1: Methyl 10-(4-methyl-2-oxocyclohexyl)decanoate and methyl 10-(2-methyl-6-oxocyclohexyl)decanoate: A 500 mL round-bottom three-necked flask equipped with a magnetic stirrer, a feeding funnel, and a reflux condenser was loaded with di-tert-butyl peroxide (0.674 g, 0.004 mol) and 3-methylcyclohexane-1-one (147 g, 1.31 mol). The solution was slowly heated to 110–120 °C, and then a solution of methyl decanoate (50 g, 0.27 mol) and di-tert-butyl peroxide (6.67 g, 0.04 mol) was carefully added over a 20-minute period via the feeding funnel. The reaction mixture was refluxed at 120 °C for 16 hours. After cooling to room temperature, water (50 mL) was added and the layers were separated. The organic layer was washed with saturated aqueous sodium carbonate solution (50 mL), 5% aqueous acetic acid solution (50 mL), and saturated brine (50 mL). The organic layer was concentrated under reduced pressure to remove excess cyclohexane. The material was purified by fractional distillation to obtain methyl 10-(4-methyl-2-oxocyclohexyl)decanoate and methyl 10-(2-methyl-6-oxocyclohexyl)decanoate as colorless liquids (70 g, 87% yield).

[0052] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 3.63 (s, 3H), 2.34-2.28 (m, 4H), 2.25 -1.56 (m, 8H), 1.32 -1.27 (m, 14H), 0.99-0.97 (m, 3H).

[0053] Step 2: Methyl 10-(5-methyl-7-oxoxetane-2-yl)decanoate and methyl 10-(3-methyl-7-oxoxetane-2-yl)decanoate: In a nitrogen atmosphere, methyl 10-(4-methyl-2-oxocyclohexyl)decanoate and methyl 10-(2-methyl-6-oxocyclohexyl)decanoate (45 g, 0.15 mol), sodium carbonate (16.05 g, 0.15 mol), were charged into a three-necked 500 mL round-bottom flask equipped with a top stirrer, feeding funnel, and reflux condenser, and cooled to 0 °C in an ice bath. Peracetic acid (115 g, 0.30 mol) was added to the reaction mixture after 1 hour. The solution was then heated to room temperature and stirred for 8 h. The reaction was quenched with ice water (200 mL) and ethyl acetate (200 mL) was added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with an aqueous FeSO4 solution and hot water, and then dried over anhydrous Na2SO4. The organic layers were concentrated to obtain a thick liquid (40 g, 84% yield), which was used as is in the next step.

[0054] 1H-NMR (400 MHz, CDCl3) δ (ppm): 4.22 – 4.05 (m, 1H), 3.59 (s, 3H), 2.54 -2.37 (m, 4H), 2.25-2.21 (m, 2H), 1.82 – 1.39 (m, 7H), 1.38 -1.20 (m,12H), 0.98 – 0.96 (m, 3H).

[0055] Step 3: Dimethyl 6-chloro-3-methylhexadecanoate and dimethyl 6-chloro-5-methylhexadecanoate: A three-necked 250 mL round-bottom flask equipped with a magnetic stirrer, a feeding funnel, and a reflux condenser was placed under a nitrogen atmosphere and successively charged with methyl 10-(5-methyl-7-oxoxetane-2-yl)decanoate and methyl 10-(3-methyl-7-oxoxetane-2-yl)decanoate (60 g, 0.18 mol) and 0.52 mg of zinc chloride (0.004 mol). The reaction mixture was then cooled to 0 °C, and thionyl chloride (45.7 g, 0.38 mol) was added dropwise through the feeding funnel over a period of 1.5 hours. The reaction mixture was then heated to room temperature and refluxed at 80 °C for 5 hours. The dark-colored reaction mixture was cooled to 0 °C and quenched with methanol (100 mL) added slowly to the reaction mixture. The reaction mixture was stirred for 1 hour. The methanol was then evaporated, and the dark crude product was quenched with a saturated aqueous sodium carbonate solution (100 mL) and extracted with ethyl acetate (2 x 200 mL), followed by separation of the organic layer. The pH of the organic layer was maintained at 7-8. The organic layer was finally washed with brine (200 mL), dried over anhydrous Na₂SO₄, and concentrated to obtain a crude product (60 g). The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain dimethyl 6-chloro-3-methylhexadecanoate and dimethyl 6-chloro-5-methylhexadecanoate as a pale yellow liquid (16.5 g, 24% yield), which were used in the following steps.

[0056] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 3.85-3.850 (m, 1H), 3.68-3.667 (2s,6H), 2.35-2.29 (m, 4H), 1.93-1.59 (m, 8H), 1.55-1.39 (m, 2H), 1.275 (m,12H).

[0057] Step 4: ( E &Z) 3-Methylhexadecyl-5-enic acid dimethyl ester, ( E&Z) 3-Methylhexadecyl-6-enic acid dimethyl ester, ( E &Z) 5-methylhexadecyl-5-enic acid dimethyl ester and ( E Dimethyl hexadecanoate (&Z) 5-methylhexadecyl-6-enic acid dimethyl ester: Dimethyl 6-chloro-3-methylhexadecanoate and dimethyl 6-chloro-5-methylhexadecanoate (40.0 g, 0.11 mol) were charged into a three-necked 250 mL round-bottom flask equipped with a magnetic stirrer and a reflux condenser and cooled to 10 °C. Using a feeding funnel, 1,8-diazabicyclo(5.4.0)undec-7-ene (33.5 g, 0.22 mol) was added very slowly over 1 hour to control the exothermic reaction. The reaction mixture was slowly heated to 125 °C and maintained at this temperature for 6 hours. The dark reaction mixture was then cooled to room temperature and quenched with 6N HCl until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with a saturated aqueous sodium carbonate solution (100 mL), followed by a saturated brine solution (100 mL). The organic layers were then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude product (30 g). The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain a pale yellow liquid. E Dimethyl 3-methylhexadecyl-5-enic acid dimethyl ester, (Z) E Dimethyl 3-methylhexadecyl-6-enedioic acid dimethyl ester, (Z) E (Z) Dimethyl 5-methylhexadecyl-5-enic acid and ( E A mixture of (Z)5-methylhexadecyl-6-enedimethyl ester (14.4 g, 40% yield) was used for the next step.

[0058] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 5.40-5.29 (m, 2H), 3.64 (s, 6H), 2.29-2.25 (m, 4H), 1.98-1.91 (m, 3H), 1.61-1.55 (m, 4H), 1.32 -1.24 (m, 12H), 0.93-0.89 (m, 3H).

[0059] Step 5: ( E & Z methyl 4-methyl-2-oxocyclopentadecan-5-ene-1-carboxylate, ( E & Z methyl 4-methyl-15-oxocyclopentadecan-3-ene-1-carboxylate, ( E &Z methyl 4-methyl-2-oxocyclopentadecan-6-ene-1-carboxylate and ( E & Z A mixture of methyl 4-methyl-15-oxocyclopentadecan-4-ene-1-carboxylate: Under a nitrogen atmosphere ( E & Z )-3-methylhexadecyl-5-enic acid dimethyl ester, ( E & Z )-3-methylhexadecyl-6-enedioic acid dimethyl ester, ( E & Z )-5-methylhexadecyl-5-enic acid dimethyl ester and ( E & Z A solution of 5-methylhexadecyl-6-enedimethyl ester (10 g, 0.03 mol) in THF (600 mL) was slowly added to a reflux mixture of LiHMDS (hexamethyldisiloxane-lithium nitride) (180 mL, 1 M in THF, 0.18 mol) and THF (350 mL). After the addition was complete, the mixture was further stirred under reflux for 15 min. The mixture was then cooled to room temperature, treated with 1N HCl (pH = 4–5), and subsequently extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude liquid was purified by column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain a pale yellow oil. E & Z methyl 4-methyl-2-oxocyclopentadecan-5-ene-1-carboxylate, ( E & Z methyl 4-methyl-15-oxocyclopentadecan-3-ene-1-carboxylate, ( E & Z methyl 4-methyl-2-oxocyclopentadecan-6-ene-1-carboxylate and ( E & Z A mixture of methyl 4-methyl-15-oxocyclopentadecan-4-ene-1-carboxylate (3.78 g, 42% yield).

[0060] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 5.39-5.30 (m, 2H), 3.70-3.67 (m,3H), 3.55-3.42 (m, 1H), 2.45-1.99 (m, 6H), 1.39-1.18 (m, 15 H), 0.99-0.88(m,3H) IR (pure sample): 2926, 2855, 1748, 1713, 1644 cm -1 Step 6: 3-Methylcyclopentadecano-5-en-1-one, 3-methylcyclopentadecano-6-en-1-one, 5-methylcyclopentadecano-5-en-1-one and 5-methylcyclopentadecano-6-en-1-one E & Z Mixtures of isomers: A solution of the mixture of compounds from step-5 (4 g, 0.01 mol) in MeOH (20 mL) was treated with an aqueous solution of NaOH (1.68 g, 0.04 mol in 10 mL of water), and the resulting mixture was heated to reflux for 1.5 h. The resulting mixture was then cooled to room temperature and acidified to pH 1 by dropwise addition of 10% H₂SO₄, followed by heating to reflux for 30 min. The reaction mixture was then cooled to room temperature and the MeOH was evaporated. The crude solution was extracted with MTBE (2 x 30 mL), and the combined organic layers were washed with water (100 mL) and saturated brine (100 mL). The organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain 3-methylcyclopentadecane-5-en-1-one, 3-methylcyclopentadecane-6-en-1-one, 5-methylcyclopentadecane-5-en-1-one, and 5-methylcyclopentadecane-6-en-1-one as colorless liquids. E & Z A mixture of isomers (1.9 g, 0.008 mol, 60% yield).

[0061] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 5.40-5.32 (m, 2H), 2.70-2.62 (m,1H), 2.43-2.25 (m, 2H), 2.18-2.03 (m, 4H), 1.72-1.55 (m, 4H), 1.37-1.19 (m,12H), 0.96 – 0.90 (m, 3H). IR (pure sample): 2925 (s), 2854, 1709 (s) cm⁻¹ -1 Scent: Animalic, powdery, and musky.

[0062] Example 3: Preparation of a mixture of isomers of cyclohexadec-5-en-1-one and cyclohexadec-6-en-1-one Step 1: Methyl 11-(2-oxocyclohexyl)undecanoate: A 100 mL round-bottom three-necked flask equipped with a magnetic stirrer, a feeding funnel, and a reflux condenser was filled with di-tert-butyl peroxide (0.125 g, 0.85 mmol) and cyclohexanone (47.8 g, 0.48 mol). The solution was slowly heated to 110–120 °C, and then, over a period of 20 minutes, a solution of methyl 10-undecenoate (10 g, 0.05 mol) and di-tert-butyl peroxide (1.12 g, 0.007 mol) was carefully added via the feeding funnel. The reaction mixture was refluxed at 120 °C for 4 hours. After cooling to room temperature, water (30 mL) was added and the layers were separated. The organic layer was washed with a saturated aqueous sodium carbonate solution (30 mL), a 5% aqueous acetic acid solution (20 mL), and a saturated brine solution (20 mL). The organic layer was concentrated under reduced pressure to remove excess cyclohexanone. The material was purified by fractional distillation to obtain methyl 11-(2-oxocyclohexyl)undecanoate as a colorless liquid (7.3 g, 49% yield).

[0063] 1 H NMR (400 MHz, CDCl3) δ (ppm): 3.64 (s, 3H), 2.39-2.33 (m, 1H), 2.30-2.19 (m, 2H), 2.2-1.99 (m, 8H), 1.78-1.71 (m, 2H), 1.61-1.53 ​​(m, 2H),1.23-0.85 (m, 14H) GCMS: 296.45 (M) + ), 265.2, 236.2, 198.2, 168.1, 149.1, 121.1, 98.1, 74.1, 55.1 IR (pure sample): 2925, 2854, 1739, 1709, 1248 cm⁻¹ -1 .

[0064] Step 2: Methyl 11-(7-oxoxetane-2-yl)undecanoate: Methyl 11-(2-oxocyclohexyl)undecanoate (55 g, 0.18 mol) and sodium carbonate (19.6 g, 0.18 mol) were charged into a three-necked 500 mL round-bottom flask equipped with a top stirrer, feeding funnel, and reflux condenser under a nitrogen atmosphere and cooled to 0 °C in an ice bath. Peracetic acid (212 g, 0.55 mol) was added to the reaction mixture after 1 hour. The solution was then heated to room temperature and stirred for 8 h. The reaction was quenched with ice water (200 mL) and ethyl acetate (200 mL) was added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with an aqueous solution of FeSO4 and hot water, and then dried over anhydrous Na2SO4. The organic layers were concentrated to obtain a white solid (45 g, 81% yield), which was used as is in the next step.

[0065] 1 H NMR (400 MHz, CDCl3) δ (ppm): 4.30-4.23 (m, 1H), 3.66 (s, 3H), 2.619-2.45 (m, 2H), 2.43-2.41 (m, 2H), 1.93-1.81 (m, 6H), 1.69-1.47 (m, 4H),1.26-0.85 (m, 14H) GCMS: 312.45 (M) + ), 294.2, 263.1, 200.2, 143.1, 113.1, 84.1, 55.1 IR (pure sample): 2925, 2855, 1731, 1251, 1172 cm⁻¹ -1 Step 3: Dimethyl 6-chloroheptadecanoate: A three-necked 250 mL round-bottom flask equipped with a magnetic stirrer, a feeding funnel, and a reflux condenser was placed under a nitrogen atmosphere and successively charged with methylcyclohexane (100 mL), methyl 11-(7-oxoxetane-2-yl)undecanoate (50 g, 0.16 mol), and 0.43 g of zinc chloride (0.003 mol). The reaction mixture was then cooled to 0 °C, and thionyl chloride (38 g, 0.32 mol) was added dropwise through the feeding funnel over 1.5 hours. The reaction mixture was then heated to room temperature and refluxed at 80 °C for 5 hours. The dark-colored reaction mixture was cooled to 0 °C and quenched with methanol (100 mL) added slowly to the reaction mixture. The reaction mixture was stirred for 1 hour. The methanol was then evaporated, and the dark crude product was quenched with a saturated aqueous sodium carbonate solution (100 mL) and extracted with ethyl acetate (2 x 200 mL), followed by separation of the organic layer. The pH of the organic layer was maintained at 7–8. The organic layer was finally washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated to obtain a crude product (55 g). The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain dimethyl 6-chloroheptadecanoate as a pale yellow liquid (18 g, 31% yield), which was used in the following steps.

[0066] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 3.92-3.84 (m, 1H), 3.67-3.66 (s,6H), 2.34-2.28 (m, 4H), 1.93-1.59 (m, 8H), 1.54-1.39 (m, 2H), 1.27-0.86 (m,15H) IR (pure sample): 2925, 2855, 1731, 1251, 1172 cm⁻¹ -1 Method A: Step 4: ( E & Z )-Heptadecyl-5-enedioxycarboxylic acid dimethyl ester and ( E & Z Dimethyl heptadecanoate: Dimethyl 6-chloroheptadecanoate (45 g, 0.14 mol) was charged into a three-necked 250 mL round-bottom flask equipped with a magnetic stirrer and a reflux condenser and cooled to 10 °C. Using a feeding funnel, 1,8-diazabicyclo(5.4.0)undec-7-ene (42.6 g, 0.28 mol) was added very slowly over 1 hour to control the exothermic reaction. The reaction mixture was slowly heated to 125 °C and maintained at this temperature for 6 hours. The dark reaction mixture was then cooled to room temperature and quenched with 6N HCl until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with a saturated aqueous sodium carbonate solution (100 mL) and subsequently with saturated brine (100 mL). The organic layers were then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product (25 g). The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain a pale yellow liquid. E & Z )-Heptadecyl-5-enedioxycarboxylic acid dimethyl ester and ( E & Z A mixture of 18 g (44% yield) of heptadecanoic acid dimethyl ester was used in the next step.

[0067] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 5.45-5.34 (m, 2H), 3.66 (s, 6H), 2.32-2.28 (m, 4H), 2.02-1.95 (m, 4H), 1.70-1.66 (m, 2H), 1.63-1.63 (m, 2H) ,1.28-1.25 (s, 14H) GCMS: 326.2 (M + ), 294.2, 262.2, 234.2, 192.2, 150.1, 121.1, 81.1, 55.1 IR (pure sample): 2925, 2854, 1738, 1195, 1167 cm⁻¹ -1 .

[0068] Method A: Step 5: ( E & Z methyl 2-oxocyclopentadecan-5-ene-1-carboxylate, ( E & Z methyl 2-oxocyclopentadecan-6-ene-1-carboxylate, ( E & Zmethyl 1,5-oxocyclopentadecan-3-ene-1-carboxylate and ( E & Z A mixture of methyl 1,5-oxocyclopentadecan-4-ene-1-carboxylate: Under a nitrogen atmosphere ( E & Z )-Heptadecyl-5-enedioxycarboxylic acid dimethyl ester and ( E & Z A solution of dimethyl heptadecanoate (10 g, 0.03 mol) in THF (600 mL) was slowly added to a reflux mixture of LiHMDS (hexamethyldisiloxane-lithium) (183 mL, 1 M in THF, 0.18 mol) and THF (350 mL). After the addition was complete, the mixture was further stirred under reflux for 15 min. The mixture was then cooled to room temperature, treated with 1 N HCl (pH = 4–5), and subsequently extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude liquid was purified by column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain a pale yellow oil. E & Z methyl 2-oxocyclopentadecan-5-ene-1-carboxylate, ( E & Z methyl 2-oxocyclopentadecan-6-ene-1-carboxylate, ( E & Z methyl 1,5-oxocyclopentadecan-3-ene-1-carboxylate and ( E & Z A mixture of methyl 1-15-oxocyclopentadecan-4-ene-1-carboxylate (3.5 g, 39% yield).

[0069] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 5.32 - 5.17 (m, 2H), 3.63-3.57 (s,3H), 3.55-3.49 (m, 1H), 2.51-2.38 (m, 2H), 1.94-1.56 (m, 4H), 1.30-1.07 (s,18H) GCMS: 294.2(M+), 262.2, 234.2, 192.2, 150.1, 121.1, 81.1, 55.1 IR (pure sample): 2925, 2854, 1747, 1714, 1646, 1437, 1235 cm -1 Step 6: ( E & Z A mixture of cyclohexadec-5-en-1-one and cyclohexadec-6-en-1-one: Method A A solution of the mixture of compounds from step-5 (4.0 g, 0.014 mol) in MeOH (20 mL) was treated with an aqueous solution of NaOH (1.68 g, 0.04 mol in 10 mL of water), and the resulting mixture was heated to reflux for 1.5 h. The resulting mixture was then cooled to room temperature and acidified to pH 1 by dropwise addition of 10% H₂SO₄, followed by heating to reflux for 30 min. The reaction mixture was then cooled to room temperature and the MeOH was evaporated. The crude solution was extracted with MTBE (2 x 30 mL), and the combined organic layers were washed with water (100 mL) and saturated brine (100 mL). The organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain cyclopentadecan-4-en-1-one and cyclopentadecan-5-en-1-one as colorless liquids. E & Z A mixture of isomers (2.2 g, 66% yield).

[0070] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 5.41-5.25 (m, 2H), 2.45-2.30 (m,4H), 2.09-2.01 (m, 4H), 1.70-1.64 (m, 2H), 1.39-1.20 (m, 16 H) GCMS: 236.2 (M) + ), 218.2, 193.2, 175.2, 152.1, 133.1, 109.1, 81.1, 55.1 IR (pure sample): 2925, 2854, 1711, 1459, 967 cm⁻¹ -1 Scent: Musky, creamy, powdery.

[0071] Method B: Step 4: Methyl 13-chloro-2-oxocyclohexadecane-1-carboxylate and methyl 7-chloro-2-oxocyclohexadecane-1-carboxylate: A solution of dimethyl 6-chloroheptadecanoate (5.0 g, 0.014 mol) in THF (300 mL) was slowly added under a nitrogen atmosphere to a reflux mixture of LiHMDS (hexamethyldisiloxane-lithium nitrogen) (85 mL, 1 M in THF, 0.084 mol) and THF (300 mL). After the addition was complete, the mixture was further stirred under reflux for 15 min. The mixture was then cooled to room temperature, treated with 1N HCl (pH = 4–5), and subsequently extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude liquid was purified by column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain a mixture of methyl 13-chloro-2-oxocyclohexadecane-1-carboxylate and methyl 7-chloro-2-oxocyclohexadecane-1-carboxylate as a pale yellow oil (2.5 g, 55% yield).

[0072] 1 H NMR (400 MHz, CDCl3) δ 4.09 – 3.87 (m, 1H), 3.70 (s, 3H), 3.58 – 3.41 (m, 1H), 2.61 – 2.54 (m,1H), 2.05 – 1.94 (m, 1H), 1.88 – 1.61 (m, 7H),1.40 – 1.18 (m, 17H).

[0073] GCMS: 330.2 (M + ), 295.2, 263.2, 234.2, 202.2, 165.1, 132.0 IR (pure sample): 2928, 2858, 1744, 1713 cm -1 Step 5: Synthesis of 6-chlorocyclohexadeca-1-one: A solution of the mixture of compounds from step-4 (4.5 g, 0.014 mol) in MeOH (30 mL) was treated with an aqueous solution of NaOH (1.63 g, 0.04 mol in 30 mL water), and the resulting mixture was heated to reflux for 1.5 h. The resulting mixture was then cooled to room temperature and acidified to pH 1 by dropwise addition of 10% H₂SO₄, followed by heating to reflux for 30 min. The reaction mixture was then cooled to room temperature and the MeOH was evaporated. The crude solution was extracted with MTBE (2 x 30 mL), and the combined organic layers were washed with water (100 mL) and saturated brine (100 mL). The organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain 6-chlorocyclohexadeca-1-one (1.7 g, 46% yield) as a colorless liquid.

[0074] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 3.99 -3.96 (m, 1H), 2.52 - 2.31 (m,4H), 1.81 - 1.55 (m, 10 H), 1.45 -1.39 (m, 3H), 1.32 - 1.23 (m, 11H).

[0075] GCMS: 272.2(M+), 236.2, 207.2, 178.2 IR (pure sample): 2927, 2857, 1709, 1458 cm⁻¹ -1 Step 6: ( E & Z A mixture of cyclohexadec-5-en-1-one and cyclohexadec-6-en-1-one: 6-Chloroheptadecanoate (1.5 g, 0.006 mol) was added to a three-necked 50 mL round-bottom flask equipped with a magnetic stirrer and a reflux condenser and cooled to 10 °C. Then, 1,8-diazabicyclo(5.4.0)undec-7-ene (1.67 g, 0.011 mol) was added very slowly over 10 minutes to control the exothermic reaction. The reaction mixture was slowly heated to 125 °C and maintained at this temperature for 6 hours. The dark reaction mixture was then cooled to room temperature and quenched with 6N HCl until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with a saturated aqueous sodium carbonate solution (10 mL) and subsequently with saturated brine (10 mL). The organic layers were then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product (1.7 g). The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain cyclopentadecano-4-en-1-one and cyclopentadecano-5-en-1-one as colorless liquids. E & Z A mixture of isomers (0.5 g, 38% yield).

[0076] 1 H-NMR (400 MHz, CDCl3) δ (ppm): δ 5.41 – 5.22 (m, 2H), 2.46 – 2.30 (m, 4H), 2.08 – 1.98 (m, 4H), 1.70 – 1.52 (m, 2H), 1.28 – 0.57 (m, 16H).

[0077] GCMS: 236.2 (M+), 221.2, 195.1, 179.2 IR (pure sample): 2925, 2854, 1710, 1440 cm⁻¹ -1 Scent: Musky, creamy, powdery.

[0078] Example 4: Preparation of a mixture of isomers of 3-methylcyclohexadec-5-en-1-one, 3-methylcyclohexadec-6-en-1-one, 5-methylcyclohexadec-5-en-1-one and 5-methylcyclohexadec-6-en-1-one Step 1: Methyl 11-(4-methyl-2-oxocyclohexyl)undecanoate and methyl 11-(2-methyl-6-oxocyclohexyl)undecanoate: A 500 mL round-bottom three-necked flask equipped with a magnetic stirrer, a feeding funnel, and a reflux condenser was loaded with di-tert-butyl peroxide (0.62 g, 0.004 mol) and 3-methylcyclohexane-1-one (156 g, 1.38 mol). The solution was slowly heated to 110–120 °C, and then, over a period of 20 minutes, a solution of methyl 10-undecenoate (50 g, 0.25 mol) and di-tert-butyl peroxide (5.63 g, 0.038 mol) was carefully added via the feeding funnel. The reaction mixture was refluxed at 120 °C for 16 hours. After cooling to room temperature, water (50 mL) was added and the layers were separated. The organic layer was washed with saturated aqueous sodium carbonate solution (50 mL), 5% aqueous acetic acid solution (50 mL), and saturated brine (50 mL). The organic layer was concentrated under reduced pressure to remove excess cyclohexane. The material was purified by fractional distillation to obtain methyl 11-(4-methyl-2-oxocyclohexyl)undecanoate and methyl 11-(2-methyl-6-oxocyclohexyl)undecanoate as colorless liquids (40.5 g, 58% yield).

[0079] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 3.63 (s, 3 H), 2.32-2.09 (m, 4 H), 2.08-2.01 (m, 2 H), 1.86-1.55 (m, 4 H), 1.63-1.53 ​​(m, 2 H), 1.54-1.44 (m, 1H), 1.22-1.03 (m, 15 H). 1.02-0.91 (m, 3 H).

[0080] GCMS: 310.3 (M + ), 279.2, 263.2, 237.2, 219.2, 198.2, 176.1 IR (pure sample): 2926, 2856, 1739, 1710 cm⁻¹ -1 Step 2: Methyl 11-(5-methyl-7-oxoxetane-2-yl)undecanoate and methyl 11-(3-methyl-7-oxoxetane-2-yl)undecanoate: In a nitrogen atmosphere, methyl 11-(4-methyl-2-oxocyclohexyl)undecanoate and methyl 11-(2-methyl-6-oxocyclohexyl)undecanoate (50 g, 0.16 mol), sodium carbonate (17.05 g, 0.16 mol), were charged into a three-necked 500 mL round-bottom flask equipped with a top stirrer, a feeding funnel, and a reflux condenser, and cooled to 0 °C in an ice bath. Peracetic acid (110 g, 0.29 mol) was added to the reaction mixture after 1 hour. The solution was then heated to room temperature and stirred for 8 h. The reaction was quenched with ice water (200 mL) and ethyl acetate (200 mL) was added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with an aqueous FeSO4 solution and hot water, and then dried over anhydrous Na2SO4. The organic layers were concentrated to obtain a thick liquid (47.5 g, 90% yield), which was used as is in the next step.

[0081] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 4.22- 4.15 (m, 1H), 3.66 (s, 3H), 2.92-2.83 (dd, J = 13.2, 2.8 Hz, 1H), 2.59-2.46 (m, 1H), 2.30-2.06 (t, J = 7.2Hz, 2H), 1.87-1.65 (m, 5H), 1.61-1.43 (m, 4H), 1.25-1.04 (s, 14H). 1.02-0.90 (m, 3H).

[0082] GCMS: 326.7 (M + ), 308.2, 277.2, 235.2, 200.2, 157.1, 127.1, 98.169.1, 41.0 IR (pure sample): 2926, 2856, 1730 cm⁻¹ -1 Step 3: Dimethyl 6-chloro-3-methylheptadecanoate and dimethyl 6-chloro-5-methylheptadecanoate: A three-necked 250 mL round-bottom flask equipped with a magnetic stirrer, a feeding funnel, and a reflux condenser was placed under a nitrogen atmosphere and successively charged with methylcyclohexane (100 mL), methyl 11-(5-methyl-7-oxooxetane-2-yl)undecanoate and methyl 11-(3-methyl-7-oxooxetane-2-yl)undecanoate (50 g, 0.15 mol), and 0.42 g of zinc chloride (0.003 mol). The reaction mixture was then cooled to 0 °C, and thionyl chloride (36 g, 0.31 mol) was added dropwise through the feeding funnel over a period of 1.5 hours. The reaction mixture was then heated to room temperature and refluxed at 80 °C for 5 hours. The dark-colored reaction mixture was cooled to 0 °C and quenched with methanol (100 mL) slowly added to the reaction mixture. The reaction mixture was stirred for 1 hour. The methanol was then evaporated, and the dark crude product was quenched with a saturated aqueous sodium carbonate solution (100 mL) and extracted with ethyl acetate (2 x 200 mL), followed by separation of the organic layer. The pH of the organic layer was maintained at 7–8. The organic layer was finally washed with brine (200 mL), dried over anhydrous Na₂SO₄, and concentrated to obtain the crude product (52 g). The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain dimethyl 6-chloro-3-methylheptadecanoate and dimethyl 6-chloro-5-methylheptadecanoate (20 g, 35% yield) as a pale yellow liquid, which were used in the following steps.

[0083] 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.86-3.82 (m, 1H), 3.64 (s, 6H), 2.35-2.23 (m, 4H), 2.16-2.08 (m, 1H), 1.72-1.55 (m, 7H), 1.25 (bs, 15H), 0.92(t, J = 6.8 Hz, 3H) GCMS: 377.2 (M+), 308.1, 276.2, 235.3, 193.2, 146.1, 98.0 IR (pure sample): 2926, 2855, 1737 cm -1 .

[0084] Step 4: ( E & Z )-3-methylheptadecanoic acid dimethyl ester and ( E & Z Dimethyl 3-methylheptadecanoate: Dimethyl 6-chloro-3-methylheptadecanoate and dimethyl 6-chloro-5-methylheptadecanoate (40 g, 0.11 mol) were charged into a three-necked 250 mL round-bottom flask equipped with a magnetic stirrer and a reflux condenser and cooled to 10 °C. Using a feeding funnel, 1,8-diazabicyclo(5.4.0)undec-7-ene (30.4 g, 0.22 mol) was added very slowly over 1 hour to control the exothermic reaction. The reaction mixture was slowly heated to 125 °C and maintained at this temperature for 6 hours. The dark reaction mixture was then cooled to room temperature and quenched with 6N HCl until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with a saturated aqueous sodium carbonate solution (100 mL) and subsequently with saturated brine (100 mL). The organic layers were then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product (34 g). The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain a pale yellow liquid. E & Z )-3-methylheptadecanoic acid dimethyl ester and ( E & Z A mixture of 3-methylheptadecanoic acid dimethyl ester (12.3 g, 34% yield) was used for the next step.

[0085] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 5.43-5.30 (m, 2H), 3.65 (s, 6H), 3.35-3.23 (m, 4H), 2.01-1.89 (m, 4H), 1.63-1.56 (m, 3H), 1.29 (bs, 14H).0.95-0.86 (m, 3H).

[0086] GCMS: 340.2 (M + ), 308.2, 290.2, 276.2, 262.1, 248.2, 234.2 IR (pure sample): 3521, 2925, 2854, 1736 cm⁻¹ -1 .

[0087] Step 5: ( E & Z 4-Methyl-2-oxocyclohexadecyl-6-ene-1-carboxylate, ( E & Z 4-Methyl-2-oxocyclohexadecyl-7-ene-1-carboxylate, ( E &Z 4-Methyl-2-oxocyclohexadecyl-7-ene-1-carboxylate and ( E & Z A mixture of methyl 6-methyl-2-oxocyclohexadecyl-7-ene-1-carboxylate: Under a nitrogen atmosphere ( E & Z ) 3-Methylheptadecanoic acid dimethyl ester and ( E & Z A solution of dimethyl 3-methylheptadecanoate (9 g, 0.026 mol) in THF (600 mL) was slowly added to a reflux mixture of LiHMDS (hexamethyldisiloxane-lithium) (162 mL, 1M in THF, 0.16 mol) and THF (350 mL). After the addition was complete, the mixture was further stirred under reflux for 15 min. The mixture was then cooled to room temperature, treated with 1N HCl (pH = 4–5), and then extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude liquid was purified by column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain a pale yellow oil. E & Z 4-Methyl-2-oxocyclohexadecyl-6-ene-1-carboxylate, ( E & Z 4-Methyl-2-oxocyclohexadecyl-7-ene-1-carboxylate, ( E & Z 4-Methyl-2-oxocyclohexadecyl-7-ene-1-carboxylate and ( E & Z A mixture of methyl 6-methyl-2-oxocyclohexadecyl-7-ene-1-carboxylate (3.0 g, 37% yield).

[0088] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 5.34-5.28 (m, 1H), 3.74-3.66 (m, 3H), 3.53-3.46 (m, 1H), 2.01-1.84 (m, 9 H), 1.29 (bs, 15H). 0.97-0.86 (m, 3H).

[0089] GCMS: 308.0 (M + ), 275.3, 231.2, 179.1, 135.1, 95.1, 55.1 IR (pure sample): 2926, 2855, 1746, 1713 cm -1 .

[0090] Step 6: ( E & Z) 3-Methylcyclohexadec-5-en-1-one, ( E & Z) 3-Methylcyclohexadec-6-en-1-one, ( E & Z) 5-Methylcyclohexadec-5-en-1-one and ( E & Z) A mixture of 5-methylcyclohexadec-6-en-1-one: A solution of the mixture of compounds from step-5 (3.0 g, 0.01 mol) in MeOH (20 mL) was treated with an aqueous solution of NaOH (1.2 g, 0.04 mol in 10 mL of water) and the resulting mixture was heated to reflux for 1.5 h. The resulting mixture was then cooled to room temperature, acidified to pH 1 by dropwise addition of 10% H₂SO₄, and then heated to reflux for 30 min. The reaction mixture was then cooled to room temperature and the MeOH was evaporated. The crude solution was extracted with MTBE (2 x 30 mL), and the combined organic layers were washed with water (100 mL) and saturated brine (100 mL). The organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain a colorless liquid (…). E & Z) 3-Methylcyclohexadec-5-en-1-one, ( E & Z) 3-Methylcyclohexadec-6-en-1-one, ( E & Z) 5-Methylcyclohexadec-5-en-1-one and ( E & Z) A mixture of 5-methylcyclohexadec-6-en-1-one (1.8 g, 74% yield).

[0091] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 5.38-5.34 (m, 1H), 2.40-2.29 (m, 3H), 2.11-1.97 (m, 5H), 1.69-1.54 (m, 4H), 1.29 (bs, 14H), 0.95-0.86 (m, 3H).

[0092] GCMS: 250.2 (M +), 221.2, 192.2, 165.1, 135.1, 109.1, 81.1 IR (pure sample): 2924, 2854, 1710 cm⁻¹ -1 Scent: Creamy, powdery, musky, highly sillage Example 5: Preparation of a mixture of isomers of 4-methylcyclohexadec-5-en-1-one and 4-methylcyclohexadec-6-en-1-one Step 1: Methyl 11-(5-methyl-2-oxocyclohexyl)undecanoate: A 500 mL round-bottom three-necked flask equipped with a magnetic stirrer, a feeding funnel, and a reflux condenser was loaded with di-tert-butyl peroxide (0.69 g, 4.7 mmol) and 4-methylcyclohexane-1-one (198 g, 1.77 mol). The solution was slowly heated to 110–120 °C, and then, over a period of 20 min, a solution of methyl 10-undecenoate (50 g, 0.252 mol) and di-tert-butyl peroxide (6.23 g, 0.042 mol) was carefully added via the feeding funnel. The reaction mixture was refluxed at 120 °C for 16 h. After cooling to room temperature, water (50 mL) was added and the layers were separated. The organic layer was washed with saturated aqueous sodium carbonate solution (50 mL), 5% aqueous acetic acid solution (50 mL), and saturated brine (50 mL). The organic layer was concentrated under reduced pressure to remove excess cyclohexane. The material was purified by fractional distillation to obtain methyl 11-(5-methyl-2-oxocyclohexyl)undecanoate as a colorless liquid (64.5 g, 82% yield).

[0093] 1H NMR (400 MHz, CDCl3): δ 3.67 (s, 3H), 2.52 – 2.22 (m, 5H), 2.16 –1.86 (m, 3H), 1.81 – 1.54 (m, 5H), 1.25 (s, 15H), 1.01 (dd, J = 20.5, 6.6 Hz, 3H).

[0094] 13C (400MHz, CDCl3): 215.2, 213.4, 174.2, 51.3, 49.5, 48.5, 42.2,41.6, 39.6, 37.8, 35.9, 34.5, 34.0, 32.0, 31.0, 29.7, 29.54, 29.4, 29.4,29.3, 29.3, 29.1, 29.0, 29.0, 27.2, 27.0, 26.4, 25.0, 21.2, 20.3 IR (pure sample): 2926, 2856, 1738, 1711 cm -1 Step 2: Methyl 11-(4-methyl-7-oxoxetane-2-yl)undecanoate: Methyl 11-(5-methyl-2-oxocyclohexyl)undecanoate (50 g, 0.16 mol) and sodium carbonate (60 g, 0.19 mol) were charged into a three-necked 500 mL round-bottom flask equipped with a top stirrer, feeding funnel, and reflux condenser under a nitrogen atmosphere and cooled to 0 °C in an ice bath. Peracetic acid (136 g, 0.30 mol) was added to the reaction mixture after 1 hour. The solution was then heated to room temperature and stirred for 8 h. The reaction was quenched with ice water (200 mL) and ethyl acetate (200 mL) was added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with an aqueous FeSO4 solution and hot water, followed by drying with anhydrous Na2SO4. The organic layers were concentrated to obtain a liquid (70 g, 91% yield), which was used as is in the next step.

[0095] 1H NMR (400 MHz, CDCl3) δ 4.46 – 4.34 (m, 1H), 3.66 (s, 3H), 2.30 (t,J = 7.5 Hz, 2H), 2.13 – 1.97 (m, 1H), 1.93 – 1.77 (m, 2H), 1.74 – 1.54 (m,4H), 1.27 (s, 16H), 1.01 (dd, J = 29.7, 6.7 Hz, 3H).

[0096] 13C (400MHz, CDCl3): 175.3, 174.0, 79.3, 75.4, 51.12, 43.0, 41.0,36.2, 36.0, 35.1, 34.0, 31.0, 30.1, 29.2, 29.1, 29.0, 28.1, 28.0, 25.2, 24.7,22.4 IR (pure sample): 2925, 2855, 1731 cm -1 Step 3: Dimethyl 6-chloro-4-methylheptadecanoate: A three-necked 250 mL round-bottom flask equipped with a magnetic stirrer, a feeding funnel, and a reflux condenser was placed under a nitrogen atmosphere and successively charged with methyl 11-(4-methyl-7-oxoxetane-2-yl)undecanoate (67 g, 0.20 mol) and 0.56 g of zinc chloride (0.004 mol). The reaction mixture was then cooled to 0 °C, and thionyl chloride (61 g, 0.51 mol) was added dropwise via the feeding funnel over a period of 1.5 h. The reaction mixture was then heated to room temperature and refluxed at 80 °C for 5 h. The dark-colored reaction mixture was cooled to 0 °C and quenched with methanol (100 mL) added slowly to the reaction mixture. The reaction mixture was stirred for 1 h. The methanol was then evaporated, and the dark crude product was quenched with a saturated aqueous sodium carbonate solution (100 mL) and extracted with ethyl acetate (2 x 200 mL), followed by separation of the organic layer. The pH of the organic layer was maintained at 7–8. The organic layer was finally washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated to obtain a crude product (70 g). The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain dimethyl 6-chloro-4-methylheptadecanoate as a pale yellow liquid (33 g, 43% yield), which was used in the following steps.

[0097] 1H NMR (400 MHz, CDCl3) δ 4.06 – 3.88 (m, 1H), 3.73 – 3.59 (m, 6H), 2.46 – 2.23 (m, 4H), 1.83 – 1.45 (m, 9H), 1.28 (s, 14H), 0.91 (t, J = 6.7 Hz, 3H).

[0098] 13C (400MHz, CDCl3): 174.1, 61.7, 51.2, 45.7, 45.2, 39.1, 38.4, 33.8,32.1, 30.4, 29.6, 29.3, 29.2, 29.1, 28.9, 26.3, 24.8, 19.4, 18.1 IR (pure sample): 2926, 2855, 1737 cm -1 Step 4: ( E & Z )-4-methylheptadecanoic acid dimethyl ester and ( E & Z 4-Methylheptadecyl-6-enediol dimethyl ester: Dimethyl 6-chloro-4-methylheptadecanoate (30 g, 95% GC purity, 0.08 mol) was charged into a three-necked 250 mL round-bottom flask equipped with a magnetic stirrer and a reflux condenser and cooled to 10 °C. Using a feeding funnel, 1,8-diazabicyclo(5.4.0)undec-7-ene (46 g, 0.32 mol) was added very slowly over 1 h to control the exothermic reaction. The reaction mixture was slowly heated to 125 °C and maintained at this temperature for 6 h. The dark reaction mixture was then cooled to room temperature and quenched with 6N HCl until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with a saturated aqueous sodium carbonate solution (100 mL) and subsequently with saturated brine (100 mL). The organic layers were then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product (30 g). The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain a pale yellow liquid. E & Z )-4-methylheptadecanoic acid dimethyl ester and ( E & Z A mixture of 4-methylheptadecanoic acid dimethyl ester (15 g, 58% yield) was used for the next step.

[0099] 1H NMR (400 MHz, CDCl3) δ 5.45 – 5.10 (m, 2H), 3.63 (s, 6H), 2.27 (t,J = 7.6 Hz, 4H), 2.05 – 1.73 (m, 4H), 1.69 – 1.35 (m, 5H), 1.23 (s, 14H),0.89 (dd, J = 45.0, 6.6 Hz, 3H).

[0100] 13 C (400MHz, CDCl3): 174.3, 134.6, 132.1, 129.8, 127.9, 51.3, 39.6,36.4, 34.0, 32.6, 32.5, 32.4, 32.0, 31.8, 31.3, 29.4, 29.3, 29.2, 29.1, 24.9,20.8, 19.0 IR (pure sample): 2925, 2854, 1738 cm -1 Step 5: ( E & Z methyl 3-methyl-16-oxocyclohexadecyl-4-ene-1-carboxylate, ( E & Z methyl 3-methyl-16-oxocyclohexadecyl-5-ene-1-carboxylate, ( E & Z methyl 5-methyl-2-oxocyclohexadecyl-6-ene-1-carboxylate and ( E & Z A mixture of methyl 5-methyl-2-oxocyclohexadecyl-7-ene-1-carboxylate: Under a nitrogen atmosphere ( E & Z )-4-methylheptadecanoic acid dimethyl ester and ( E & Z A solution of dimethyl 4-methylheptadecanoate (5 g, 0.014 mol) in THF (88 mL) was slowly added to a reflux mixture of LiHMDS (hexamethyldisiloxane-lithium) (58 mL, 1 M in THF, 0.058 mol) and THF (176 mL). After the addition was complete, the mixture was further stirred under reflux for 15 min. The mixture was then cooled to room temperature, treated with 1N HCl (pH = 4–5), and subsequently extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain a colorless liquid ( ). E & Z methyl 3-methyl-16-oxocyclohexadecyl-4-ene-1-carboxylate, ( E & Z methyl 3-methyl-16-oxocyclohexadecyl-5-ene-1-carboxylate, ( E & Zmethyl 5-methyl-2-oxocyclohexadecyl-6-ene-1-carboxylate and ( E & Z A mixture of methyl 5-methyl-2-oxocyclohexadecyl-7-ene-1-carboxylate (2.5 g, 55% yield).

[0101] 1 H NMR (400 MHz, CDCl3): 5.4-5.0 (m,2H), 3.7-3.4 (m,3H), 2.6-2.4(m,2H), 2.1-2.0 (m,5H), 1.7-1.3(m,14H), 0.9-0.95 (m,3H) 13 C (400MHz, CDCl3): 206.6, 205.8, 170.4, 135.7, 134.9, 133.1, 132.4,131.2, 130.4, 128.9, 127.9, 71.8, 57.79, 57.2, 55.4, 52.4, 41.4, 40.7, 40.0,39.5, 37.0, 36.5, 36.0, 35.1, 34.9, 33.8, 32.2, 30.9, 30.3, ,29.3, 28.5,28.0, 27.5, 27.1, 26.9, 26.6, 26.4, 25.9, 25.7, 25.6, 25.3, 24.9, 23.4, 21.7, 20.0, 19.1 IR (pure sample): 2926, 2855, 1746, 1714 cm -1 Step 6: ( E & Z A mixture of isomers of 4-methylcyclohexadec-5-en-1-one and 4-methylcyclohexadec-6-en-1-one: A solution of the mixture of compounds from step-5 (2.1 g, 0.006 mol) in MeOH (20 mL) was treated with an aqueous solution of KOH (1.1 g, 0.02 mol in 10 mL of water), and the resulting mixture was heated to reflux for 1.5 h. The resulting mixture was then cooled to room temperature and acidified to pH 1 by dropwise addition of 10% H₂SO₄, followed by heating to reflux for 30 min. The reaction mixture was then cooled to room temperature and the MeOH was evaporated. The crude solution was extracted with MTBE (2 x 30 mL), and the combined organic layers were washed with water (100 mL) and saturated brine (100 mL). The organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (eluting with a gradient of ethyl acetate in hexane) to obtain a colorless liquid ( ). E & Z) 3-Methylcyclohexadec-5-en-1-one, ( E & Z) 3-Methylcyclohexadec-6-en-1-one, ( E & Z) 5-Methylcyclohexadec-5-en-1-one and ( E & Z) A mixture of 5-methylcyclohexadec-6-en-1-one (1.2 g, 70% yield).

[0102] 1 H NMR (400 MHz, CDCl3): 5.3-5.1 (m,2H), 2.5-2.3 (m,4H), 2.1-1.7 (m,6H), 1.3(s,12H), 1.0-0.9 (dd, 3H) 13 C (400MHz, CDCl3): 212.6, 136.0, 132.3, 130.1, 128.8, 42.1, 41.0,40.3, 36.8, 32.7, 32.2, 32.1, 30.3, 30.1, 28.6, 28.5, 27.7, 27.5, 27.2, 27.0,26.8, 26.7, 26.6, 26.3, 25.7, 25.5 GCMS: 250.2 (M + ), 221.2, 192.2, 165.1, 135.1, 109.1, 81.1 IR (pure sample): 2924, 2854, 1711 cm -1 Scent: A very elegant and superior musk. Example 6: ( E & Z Preparation of a mixture of isomers of cyclotetradecane-4-en-1-one and (Z)-cyclotetradecane-5-en-1-one Step 1: Methyl 10-(2-oxocyclopentyl)decanoate: Methyl 10-(2-oxocyclopentyl)decanoate was synthesized using cyclopentanone and methyl 9-decenoate following the procedure in step 1 of Example 1.

[0103] 1 H (400 MHz, CDCl3) δ (ppm): 3.63 (s, 3H), 2.32-2.28 (m, 1H), 2.8-2.23 (m, 2H), 2.21-1.99 (m, 4H), 1.787-1.741 (m, 2H), 1.61-1.53 (m, 2H),1.26 (s, 14H).

[0104] 13 C (100.6 MHz, CDCl3) δ (ppm): 221.4(s), 174.8, 51.2, 48.9, 37.9,33.9, 29.5, 29.4, 29.3, 29.2, 29.0, 28.9, 27.3, 24.7, 20.6.

[0105] GCMS: 268.2 (M + ), 251.2, 222.2, 203.1, 184.1 IR (cm -1 ): 2926, 2855, 1735 Step 2: Methyl 10-(6-oxotetrahydro-2H-pyran-2-yl)decanoate Methyl 10-(2-oxocyclopentyl)decanoate was converted to methyl 10-(6-oxotetrahydro-2H-pyran-2-yl)decanoate following the procedure mentioned in step 2 of Example 1.

[0106] 1 H (400 MHz, CDCl3) δ (ppm): 4.30-4.24 (m, 1H), 3.66 (s, 3H), 2.62-2.45 (m, 2H), 2.44-2.42 (m, 2H), 1.93-1.81 (m, 4H), 1.69-1.47 (m, 2H), 1.26(s, 14H).

[0107] 13C (100.6 MHz, CDCl3) δ (ppm): 174.3, 172.1, 80.6, 51.4, 35.8, 34.1,29.4, 29.4, 29.2, 29.1, 27.8, 24.9, 18.5.

[0108] GCMS: 284.1 (M + ), 266.1, 235.2, 193.2 IR (cm -1 ): 2926, 2855, 1733 Step 3: Dimethyl 5-chloropentadecanedioate Dimethyl 5-chloropentadecanedioate was synthesized using methyl 10-(6-oxotetrahydro-2H-pyran-2-yl)decanoate following the protocol in step 3 of Example 1.

[0109] 1 H (400 MHz, CDCl3) δ (ppm): 3.92-3.85 (m, 1H), 3.68-3.67 (s, 6H), 2.35-2.29 (m, 4H), 1.93-1.59 (m, 8H), 1.549-1.397 (m, 2H), 1.275 (s,10H) 13 C (100.6 MHz, CDCl3) δ (ppm): 174.2,173.6, 63.3, 51.3, 38.3, 37.5,33.9, 33.2, 29.3, 29.1, 28.9, 26.3, 24.8, 21.8 GCMS: 334.1 (M + ), 299.2, 267.2, 235.2, 193.2 IR (cm - ): 2928, 2855, 1736 Step 4: ( E & Z )-Pentadecyl-4-enedioxycarboxylic acid dimethyl ester and ( E & Z Dimethyl 5-pentadecanedioic acid Following the protocol in step 4 of Example 1, dimethyl 5-chloropentadecanedioate was used to synthesize ( E & Z )-Pentadecyl-4-enedioxycarboxylic acid dimethyl ester and ( E & Z A mixture of 5-pentadecanedioic acid dimethyl ester.

[0110] 1 H (400 MHz, CDCl3) δ (ppm): 5.46-5.35 (m, 2H), 3.66 (s,6H), 2.32-2.28 (m, 2H), 2.02-1.95 (m, 4H), 1.70-1.67 (m,2H), 1.63 (m, 2H), 1.28-1.26(s, 12H) 13 C (100.6 MHz, CDCl3) δ (ppm): 174.1,173.5, 131.7, 128.6,127.7,51.2, 33.9, 33.2, 32.3, 31.8, 29.3, 29.1, 28.9, 27.8, 24.8 GCMS: 298.2 (M + ), 266.1, 234.2, 193.2 IR (cm -1 ): 2926, 2854, 1737 Step 5: ( E & Z methyl 2-oxocyclotetradecyl-6-ene-1-carboxylate, ( E & Z methyl 2-oxocyclotetradecyl-5-ene-1-carboxylate, ( E & Z methyl 1,4-oxocyclotetradecyl-3-ene-1-carboxylate and ( E & Z A mixture of methyl 1,4-oxocyclotetradecane-4-ene-1-carboxylate Following the scheme mentioned in step 5 of Example 1, ( E & Z )-Pentadecyl-4-enedioxycarboxylic acid dimethyl ester and ( E & Z A mixture of )-pentadecanedioic acid dimethyl esters is converted into ( E & Z methyl 2-oxocyclotetradecyl-6-ene-1-carboxylate, ( E & Z methyl 2-oxocyclotetradecyl-5-ene-1-carboxylate, ( E & Z methyl 1,4-oxocyclotetradecyl-3-ene-1-carboxylate and ( E & Z A mixture of methyl 1,4-oxocyclotetradecyl-4-ene-1-carboxylate.

[0111] 1 H (400 MHz, CDCl3) δ (ppm): 5.33 - 5.17 (m, 2H), 3.63-3.57 (s, 3H), 3.56-3.49 (m, 1H), 2.51-2.39 (m, 4H), 1.94-1.56 (m, 6H), 1.31-1.07 (s,14H) 13 C (100.6 MHz, CDCl3) δ (ppm): 205.80 (d), 170.15-169.68 (d), 133.80, 133.10, 132.36, , 131.95, 129.90, 128.93, 126.22, 58.13, 57.67,56.93, 56.65, 52.19, 42.66, 42.50, 41.82, 40.41, 31.40, 31.24, 31.05, 30.76,30.19, 29.55, 29.20, 28.46, 28.06, 27.88, 27.41, 27.10, 26.96 GCMS: 266.2 (M+) IR (cm -1 ): 2927, 2854, 1738 Step 6: ( E & Z )-cyclotetradecano-4-en-1-one and ( E & Z ) - A mixture of cyclotetradecano-5-en-1-ones: Use the scheme in step 6 of Example 1 ( E & Z methyl 2-oxocyclotetradecyl-6-ene-1-carboxylate, ( E & Z methyl 2-oxocyclotetradecyl-5-ene-1-carboxylate, ( E & Z methyl 1,4-oxocyclotetradecyl-3-ene-1-carboxylate and ( E & Z Synthesis of a mixture of methyl 1-14-oxocyclotetradecane-4-ene-1-carboxylate ( E & Z )-cyclotetradecano-4-en-1-one and ( E & Z ) - A mixture of cyclotetradecano-5-en-1-one.

[0112] 1 H (400 MHz, CDCl3) δ (ppm): 5.42-5.26 (m, 2H), 2.50-2.41 (m, 4H), 2.39-2.32 (m, 2H), 2.06-2.00 (m, 2H), 1.672-1.604 (m, 2H), 1.38-1.19 (m,12H) 13 C (100.6 MHz, CDCl3) δ (ppm): 212.75-211.5, 132.3-128.1, 42.5,42.4, 41.7, 41.3, 31.38, 31.0, 30.6, 27.9, 27.3, 27.2, 27.0, 26.9, 26.7,26.3, 26.2, 26.1, 25.8 GCMS: 208.2 (M + ) IR (cm -1 ): 2927, 2854, 1708 Scent: Musky, smoky, leathery Example 7: Preparation following method 3 ( E & Z A mixture of isomers of cyclohexadec-4-en-1-one and cyclohexadec-5-en-1-one: Anhydrous toluene (44.8 ml) was added to a 250 mL three-necked RBF container equipped with a magnetic stirrer and a reflux condenser under a nitrogen atmosphere. The RBF was then heated to reflux to remove residual water from the solvent. The temperature was then raised to approximately 70–80 °C, and freshly chopped, bright sodium flakes were added to the reaction mixture one at a time. The temperature was increased to 110 °C until the sodium metal turned into shiny gray beads. Then, under reflux conditions, the solution dissolved in toluene (44.8 ml) was added dropwise over 3 h using a feeding funnel. E & Z )-Hexadecyl-4-enic acid dimethyl ester and ( E & ZDimethyl hexadecanoate (Example 1, intermediate of step 4) (10 g, 32.0 mmol). After addition, RM was refluxed for 1 h. The reaction mixture was cooled to room temperature and then to -5 °C. A 1:1 mixture of glacial acetic acid and toluene (30 ml) was then added dropwise while maintaining the temperature below 5 °C. The reaction mixture was diluted with ethyl acetate (100 ml), and the binary layer was stirred for 1 h until sodium was completely quenched. The layers were separated, the aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with water and then with brine. The organic layer was concentrated to obtain 9 g of crude residue. The compound was purified by column chromatography to obtain 3.6 g ( E & Z )-2-hydroxycyclohexadec-4-en-1-one and ( E & Z A mixture of 2-hydroxycyclohexadec-5-en-1-one, which is used in the next step.

[0113] 1 H NMR (400 MHz, CDCl3): d 5.36-5.32 (m, 2H), 4.26-4.03 (m, 1H), 3.64-3.46 (bs, 1H), 2.55-2.26 (m, 2H), 2.11-1.94 (m, 4H), 1.831.74 (m, 2H), 1.65-1.49 (m, 4H), 1.34-1.17 (m, 16H), 0.99-0.87 (m, 2H). 13 C NMR (100 MHz, CDCl3): d 212.8, 136.0, 135.3, 132.0, 130.4, 128.6, 75.9, 39.7, 37.3, 36.3, 35.5, 33.5, 32.1, 31.4, 30.7, 28.8, 27.9, 27.0, 26.8, 22.6, 22.0, 20.2.

[0114] IR ν (pure sample, cm) -1 ): 3483, 1709 The product of the above reaction (0.5 g, 1.981 mmol) and 10 mL of acetic acid were charged into a 50 mL two-necked RBF container equipped with a magnetic stirrer and a reflux condenser. Sievened zinc powder was then added to the reaction mixture under vigorous stirring, followed by dropwise addition of concentrated HCl. The mixture was heated to 120 °C, with additional hydrochloric acid added twice at 30-minute intervals. The reaction mixture was then poured off to remove the zinc from the container. It was cooled to 25 °C and 50 mL of water was added. The organic layer was extracted twice with diethyl ether. The combined organic layers were washed with saturated sodium carbonate aqueous solution (50 mL) followed by saturated brine (50 mL). The organic layers were then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel to obtain 0.2 g (yield 43%) of ( E & Z A mixture of cyclohexadec-4-en-1-one and cyclohexadec-5-en-1-one.

[0115] 1 H NMR (400 MHz, CDCl3): d 5.39-5.27 (m, 2H), 2.45-2.30 (m, 4H), 2.20-2.03 (bs, 4H), 1.65-1.61 (m, 4H), 1.36-1.28 (m, 14H) 13 C NMR (100 MHz, CDCl3): d 212.6, 212.3, 132.1, 131.7, 130.8, 129.8, 43.0, 42.1, 41.0, 40.5, 32.1, 31.9, 31.1, 28.4, 27.9, 27.5, 27.1, 26.9, 26.8, 26.7, 26.6, 25.8, 25.6, 24.0, 23.2 IR ν (pure sample, cm) -1 ): 1712 Scent: Fresh, with a hint of white musk.

[0116] Example 8: ( E & Z Preparation of a mixture of isomers of cyclohexadeca-5-en-1-one and cyclohexadeca-6-en-1-one: The reaction was carried out in two steps following the reaction protocol mentioned in Example 7, using a mixture of (E / Z)-heptadecanoic acid dimethyl ester and (E / Z)-heptadecanoic acid dimethyl ester (the intermediate from step 4 in Example 3) to prepare ( E & ZA mixture of isomers of cyclohexadecano-5-en-1-one and cyclohexadecano-6-en-1-one.

[0117] 1 H NMR (400 MHz, CDCl3): d 5.37-5.35 (m, 2H), 2.42-2.38 (m, 4H), 2.04-2.02 (bs, 4H), 1.88-1.58 (m, 4H), 1.37-1.30 (m, 16H) 13 C NMR (100 MHz, CDCl3): d 212.8, 211.9, 131.1, 130.4, 42.9, 42.2, 32.1, 32.0, 31.8, 31.8, 31.8, 31.4, 29.4, 28.9, 28.7, 28.6, 28.5, 28.3, 28.2, 28.1, 28.1, 28.0, 27.9, 27.8, 27.7, 27.6, 27.5, 27.4, 27.3, 27.2, 27.2 IR ν (pure sample, cm) -1 ): 2923, 2853, 1711 Scent: Musky, powdery, highly sillage Example 9: ( E & Z )-3-methylcycloheptadecyl-5-en-1-one, ( E & Z )-3-methylcycloheptadecyl-6-en-1-one, ( E & Z )-5-methylcyclohexadecane-5-en-1-one and ( E & Z Preparation of a mixture of isomers of 5-methylcycloheptadecane-6-en-1-one The method described in Example 7 is followed via inbreeding condensation. E & Z )-3-methylheptadecanoic acid dimethyl ester and ( E & Z A mixture of 3-methylheptadecanoic acid dimethyl ester (Example 4, intermediate of step 4) was used to synthesize ( E & Z )-3-methylcycloheptadecyl-5-en-1-one, ( E & Z )-3-methylcycloheptadecyl-6-en-1-one, ( E &Z )-5-methylcyclohexadecane-5-en-1-one and ( E & Z A mixture of isomers of 5-methylcyclohexadecane-6-en-1-one.

[0118] 1 H NMR (400 MHz, CDCl3): d 5.38-5.33 (m, 2H), 2.43-2.35 (m, 4H), 2.08-1.97 (m, 4H), 1.70-1.58 (m, 4H), 1.56-1.33 (m, 14H), 1.00-0.80 (m, 4H) 13 C NMR (100 MHz, CDCl3): d 212.9, 212.2, 132.6, 132.0, 130.8, 128.6, 51.0, 48.7, 42.8, 41.9, 40.9, 39.8, 36.6, 33.0, 31.9, 30.3, 29.7, 29.2, 28.6, 27.9, 27.5, 27.2, 27.0, 26.3, 23.7, 23.3. IR (pure sample, cm) -1 ): 2924, 2855, 1712 Scent: Musky, powdery.

[0119] Alternative synthetic scheme for a mixture of isomers of 3-methylcyclohexadec-5-en-1-one, 3-methylcyclohexadec-6-en-1-one, 5-methylcyclohexadec-5-en-1-one and 5-methylcyclohexadec-6-en-1-one (Example 4) The method described in Example 7 is followed via inbreeding condensation. E &Z) 3-Methylhexadecyl-5-enic acid dimethyl ester, ( E &Z) 3-Methylhexadecyl-6-enic acid dimethyl ester, ( E &Z) 5-methylhexadecyl-5-enic acid dimethyl ester and ( E &Z) 5-methylhexadecyl-6-enic acid dimethyl ester (Example 2, intermediate of step 4) to synthesize ( E / Z 3-Methylcyclohexadec-5-en-1-one, ( E / Z 3-Methylcyclohexadec-6-en-1-one, ( E / Z 5-Methylcyclohexadec-5-en-1-one and ( E / ZA mixture of isomers of 5-methylcyclohexadec-6-en-1-one. Spectrochemical data are consistent with those of Example 4.

[0120] composition evaluation example: In the following invention, as shown in Table 1, compositions (C) containing compounds from Example-1 were compared with compositions of commercially available materials such as 3,7-dimethyloct-6-en-1-ylethyl oxalate (citronellol ethoxylate, composition G), ethylene glycol brassinate (composition B), and exaltolide (composition I). (Composition A = blank sample), DPG = dipropylene glycol.

[0121] Table 1: Example-1 in shampoo: .

[0122] When Example-1 was added to a shampoo at a 10% w / w concentration, Composition C provided a strong and pronounced musky character. Compared to other compositions B, G, and I, which respectively contain the commercially available compounds ethylene glycol brassinate, 3,7-dimethyloctyl-6-en-1-ylethyl oxalate (citronellol ethoxylate), and cyclopentadecanolactone, Composition C exhibited a richer, fuller, and more comprehensive character. On scent strips, the compounds from Example-1 were found to be significantly more concentrated and persistent than ethylene glycol brassinate, citronellol ethoxylate, and cyclopentadecanolactone.

[0123] In the following invention, as shown in Table-2, a composition (A) containing the compound from Example-5 was compared with a commercially available composition of cyclopentadecanolactone (composition B), wherein composition C served as a blank sample (isopropyl myristate IPM).

[0124] Table 2: Example 5 in shampoo: .

[0125] In the above-mentioned floral, fruity, and musky fragrances, a comparison between composition A containing Example-5 and composition B containing the commercially available compound cyclopentadecanolide shows that, compared to cyclopentadecanolide, the addition of Example-1 provides a more natural volume and imparts a significant richness and creaminess to this fragrance.

[0126] The detailed description of the prior invention is merely illustrative and not intended to be limiting. Since modifications to the disclosed embodiments will be apparent to those skilled in the art in combination with the spirit and essence of the invention, the invention should be construed as including all contents within the scope of this disclosure. Claims (as amended under Article 19 of the Treaty) 1. A method for preparing unsaturated macrocyclic ketones of formula (I) or mixtures of their regioisomers and / or stereoisomers: Where m is an integer selected from 0, 1, 2, 3, and 4. R1, R2, R3, R4, R5, R6, and R7 represent hydrogen atoms or methyl groups, and The dashed lines represent alternating positions of double bonds, where the double bonds are between carbon atoms 4 and 5, or 5 and 6, or 6 and 7, or 7 and 8, or 8 and 9. The method includes the following steps: Substituted cyclic ketones Reaction with ω-alkenylalkylcarboxylic esters To prepare substituted ketone 3 Where R = H or methyl, and n is 0, 1, 2 or 3, and The substituted ketone 3 is reacted with an acid selected from peracetic acid, perbenzoic acid, or 3-chloroperbenzoic acid to prepare lactone 4. Where R = H or methyl, and n is 0, 1, 2 or 3, and - (A) Hydrolyzing lactone 4 to form a hydroxylated 1,ω-dicarboxylic acid ester. The hydroxyl-substituted 1,ω-dicarboxylic acid ester 5 is then dehydrated to form an unsaturated 1,ω-dicarboxylic acid ester 6. Where R = H or methyl, and n is 0, 1, 2 or 3. - or (B) converting said lactone 4 to form a chlorinated 1,ω-dicarboxylic acid ester. and The chlorinated 1,ω-dicarboxylic acid ester 5 is dehydrochlorinated to form an unsaturated 1,ω-dicarboxylic acid ester 6. Where R = H or methyl, and n is 0, 1, 2 or 3. or The intramolecular Dickmann condensation of compound 5 followed by hydrolysis and decarboxylation yields compound 6B, where R = H or methyl, and n is 0, 1, 2, or 3. and - (C) Elimination of compound 6B to form an unsaturated macrocyclic ketone of formula (I) or a mixture of its regioisomers and / or stereoisomers; or - (D) The unsaturated 1,ω-dicarboxylic acid ester 6 is subjected to an intramolecular Dickmann reaction and subsequently hydrolyzed and decarboxylated to form an unsaturated macrocyclic ketone of formula (I) or a mixture of its regioisomers and / or stereoisomers. - or (E) subject the unsaturated 1,ω-dicarboxylic acid ester 6 to an inco-condensation to form an α-hydroxy ester 7. - and dehydroxylate the α-hydroxy ester 7 to form an unsaturated macrocyclic ketone of formula (I) or a mixture of its regioisomers and / or stereoisomers. 2. The method for preparing unsaturated macrocyclic ketones of general formula (I) according to claim 1. Includes the following steps: The lactone 4 is hydrolyzed to the corresponding hydroxylated 1,ω-dicarboxylic acid ester 5. Where R = H or Me, and n is 0, 1, 2 or 3; The hydroxyl-substituted 1,ω-dicarboxylic acid ester 5 is dehydrated to an unsaturated 1,ω-dicarboxylic acid ester 6. Where R = H or Me, and n is 0, 1, 2, or 3. The unsaturated 1,ω-dicarboxylic acid ester 6 is subjected to an intramolecular Dickmann reaction followed by hydrolysis and decarboxylation to obtain a macrocyclic ketone of general formula (I) or a mixture of its regioisomers and / or stereoisomers. . 3. The method for preparing unsaturated macrocyclic ketones of general formula (I) according to claim 1 Includes the following steps: The lactone 4 is converted into the corresponding chlorinated 1,ω-dicarboxylic acid ester 5. Where R = H or Me, and n is 0, 1, 2 or 3; The chlorine-substituted 1,ω-dicarboxylic acid ester 5 is dehydrochlorinated to form an unsaturated 1,ω-dicarboxylic acid ester 6. Where R = H or methyl, and n is 0, 1, 2 or 3. The unsaturated 1,ω-dicarboxylic acid ester 6 is subjected to an intramolecular Dickmann reaction followed by hydrolysis and decarboxylation to obtain a macrocyclic ketone of general formula (I) or a mixture of its regioisomers and / or stereoisomers. . 4. The method for preparing unsaturated macrocyclic ketones of general formula (I) according to claim 1 Includes the following steps: The lactone 4 is converted into the corresponding chlorinated 1,ω-dicarboxylic acid ester 5. Where R = H or Me, and n is 0, 1, 2 or 3; The chlorinated 1,ω-dicarboxylic acid ester 5 was subjected to Dickmann condensation followed by hydrolysis and decarboxylation to obtain an unsaturated macrocycle 6-B. The unsaturated macrocycle 6-B is subjected to base-mediated dehydrochlorination to obtain a macrocyclic ketone of general formula (I) or a mixture of its regioisomers and / or stereoisomers. . 5. The method for preparing unsaturated macrocyclic ketones of general formula (I) according to claim 1. Includes the following steps: The lactone 4 is hydrolyzed to the corresponding hydroxylated 1,ω-dicarboxylic acid ester 5. Where R = H or Me, and n is 0, 1, 2 or 3; The hydroxyl-substituted 1,ω-dicarboxylic acid ester 5 is dehydrated to an unsaturated 1,ω-dicarboxylic acid ester 6. Where R = H or methyl, and n is 0, 1, 2 or 3. The unsaturated 1,ω-dicarboxylic acid ester 6 is subjected to an inco-infusion condensation to obtain the α-hydroxy ester 7. Finally, the α-hydroxy ester 7 is dehydroxylated to obtain a macrocyclic ketone of general formula (I) or a mixture of its regio isomers and / or stereoisomers. . 6. The method for preparing unsaturated macrocyclic ketones of general formula (I) according to claim 1 Includes the following steps: The lactone 4 is converted into the corresponding chlorinated 1,ω-dicarboxylic acid ester 5. Where R = H or Me, and n is 0, 1, 2 or 3; The chlorine-substituted 1,ω-dicarboxylic acid ester 5 is dehydrochlorinated to form an unsaturated 1,ω-dicarboxylic acid ester 6. Where R = H or Me, and n is 0, 1, 2, or 3. The unsaturated 1,ω-dicarboxylic acid ester 6 is subjected to an inco-infusion condensation to obtain the α-hydroxy ester 7. Finally, the α-hydroxy ester 7 is dehydroxylated to obtain a macrocyclic ketone of general formula (I) or a mixture of its regio isomers and / or stereoisomers. . 7. Compounds of general formula (I) Where m is an integer / natural number selected from 0, 1, 2, 3, and 4. R1, R2, R3, R4, R5, R6, and R7 represent hydrogen atoms or methyl groups. The dashed lines indicate alternating positions of double bonds, which can be between carbon atoms 4 and 5, 5 and 6, 6 and 7, 7 and 8, or 8 and 9. And selected from: (i) Z 5-Methylcyclohexadec-6-en-1-one (ii) E 5-Methylcyclohexadec-6-en-1-one (iii) Z )-4-methylcyclohexadec-6-en-1-one (iv) E )-4-methylcyclohexadec-6-en-1-one (v) (Z)-3-methylcycloheptadecyl-5-en-1-one (vi) E )-3-methylcyclohexadecane-5-en-1-one (vii) Z )-3-methylcyclohexadecane-6-en-1-one (viii) E )-3-methylcyclohexadecane-6-en-1-one (ix) Z 5-Methylcyclohexadecane-5-en-1-one (x) E 5-Methylcyclohexadecane-5-en-1-one (xi) Z 5-Methylcyclohexadecane-6-en-1-one (xii)E 5-Methylcyclohexadecane-6-en-1-one (xiii) Z )-4-methylcyclohexadecane-5-en-1-one (xiv) E )-4-methylcyclohexadecane-5-en-1-one (xv)( Z )-4-Methylcycloheptadecyl-6-en-1-one (xvi) E )-4-Methylcycloheptadecyl-6-en-1-one (xvii) Z )-Cyclooctadecyl-6-en-1-one (xviii) E )-Cyclooctadecyl-6-en-1-one (xix) Z )-Cyclooctadecyl-7-en-1-one, or (xx) ( E )-Cyclooctadecyl-7-en-1-one, Or a mixture of its regional isomers and / or stereoisomers. 8. A mixture of regioisomers and / or stereoisomers of the compound according to claim 7. 9. The mixture according to claim 8, wherein the weight ratio between the regioisomers and / or stereoisomers is 95:5 to 5:95. 10. A flavoring agent consisting of a compound or mixture according to any one of claims 7 to 9. 11. A fragrance, flavoring and / or deodorizing / masking composition comprising a compound or mixture according to any one of claims 7 to 9.

Claims

1. A method for preparing unsaturated macrocyclic ketones of formula (I) or mixtures of their regioisomers and / or stereoisomers: Where m is an integer selected from 0, 1, 2, 3, and 4. R1, R2, R3, R4, R5, R6, and R7 represent hydrogen atoms or methyl groups, and The dashed lines represent alternating positions of double bonds, where the double bonds are between carbon atoms 4 and 5, or 5 and 6, or 6 and 7, or 7 and 8, or 8 and 9. The method includes the following steps: Substituted cyclic ketones Reaction with ω-alkenylalkylcarboxylic esters To prepare substituted ketone 3 Where R = H or methyl, and n is 0, 1, 2 or 3, and The substituted ketone 3 is reacted with an acid selected from peracetic acid, perbenzoic acid, or 3-chloroperbenzoic acid to prepare lactone 4. Where R = H or methyl, and n is 0, 1, 2 or 3, and - (A) Hydrolyzing lactone 4 to form a hydroxylated 1,ω-dicarboxylic acid ester. The hydroxyl-substituted 1,ω-dicarboxylic acid ester 5 is then dehydrated to form an unsaturated 1,ω-dicarboxylic acid ester 6. Where R = H or methyl, and n is 0, 1, 2 or 3. - or (B) converting said lactone 4 to form a chlorinated 1,ω-dicarboxylic acid ester. and The chlorinated 1,ω-dicarboxylic acid ester 5 is dehydrochlorinated to form an unsaturated 1,ω-dicarboxylic acid ester 6. Where R = H or methyl, and n is 0, 1, 2 or 3. or The intramolecular Dickmann condensation of compound 5 followed by hydrolysis and decarboxylation yields compound 6B, where R = H or methyl, and n is 0, 1, 2, or 3. and - (C) Elimination of compound 6B to form an unsaturated macrocyclic ketone of formula (I) or a mixture of its regioisomers and / or stereoisomers; or - (D) The unsaturated 1,ω-dicarboxylic acid ester 6 is subjected to an intramolecular Dickmann reaction and subsequently hydrolyzed and decarboxylated to form an unsaturated macrocyclic ketone of formula (I) or a mixture of its regioisomers and / or stereoisomers. - or (E) subject the unsaturated 1,ω-dicarboxylic acid ester 6 to an inco-condensation to form an α-hydroxy ester 7. - and dehydroxylate the α-hydroxy ester 7 to form an unsaturated macrocyclic ketone of formula (I) or a mixture of its regioisomers and / or stereoisomers.

2. The method for preparing unsaturated macrocyclic ketones of general formula (I) according to claim 1. Includes the following steps: The lactone 4 is hydrolyzed to the corresponding hydroxylated 1,ω-dicarboxylic acid ester 5. Where R = H or Me, and n is 0, 1, 2 or 3; The hydroxyl-substituted 1,ω-dicarboxylic acid ester 5 is dehydrated to an unsaturated 1,ω-dicarboxylic acid ester 6. Where R = H or Me, and n is 0, 1, 2, or 3. The unsaturated 1,ω-dicarboxylic acid ester 6 is subjected to an intramolecular Dickmann reaction followed by hydrolysis and decarboxylation to obtain a macrocyclic ketone of general formula (I) or a mixture of its regioisomers and / or stereoisomers. 。 3. The method for preparing unsaturated macrocyclic ketones of general formula (I) according to claim 1 Includes the following steps: The lactone 4 is converted into the corresponding chlorinated 1,ω-dicarboxylic acid ester 5. Where R = H or Me, and n is 0, 1, 2 or 3; The chlorine-substituted 1,ω-dicarboxylic acid ester 5 is dehydrochlorinated to form an unsaturated 1,ω-dicarboxylic acid ester 6. Where R = H or methyl, and n is 0, 1, 2 or 3. The unsaturated 1,ω-dicarboxylic acid ester 6 is subjected to an intramolecular Dickmann reaction followed by hydrolysis and decarboxylation to obtain a macrocyclic ketone of general formula (I) or a mixture of its regioisomers and / or stereoisomers. 。 4. The method for preparing unsaturated macrocyclic ketones of general formula (I) according to claim 1 Includes the following steps: The lactone 4 is converted into the corresponding chlorinated 1,ω-dicarboxylic acid ester 5. Where R = H or Me, and n is 0, 1, 2 or 3; The chlorinated 1,ω-dicarboxylic acid ester 5 was subjected to Dickmann condensation followed by hydrolysis and decarboxylation to obtain an unsaturated macrocycle 6-B. The unsaturated macrocycle 6-B is subjected to base-mediated dehydrochlorination to obtain a macrocyclic ketone of general formula (I) or a mixture of its regioisomers and / or stereoisomers. 。 5. The method for preparing unsaturated macrocyclic ketones of general formula (I) according to claim 1. Includes the following steps: The lactone 4 is hydrolyzed to the corresponding hydroxylated 1,ω-dicarboxylic acid ester 5. Where R = H or Me, and n is 0, 1, 2 or 3; The hydroxyl-substituted 1,ω-dicarboxylic acid ester 5 is dehydrated to an unsaturated 1,ω-dicarboxylic acid ester 6. Where R = H or methyl, and n is 0, 1, 2 or 3. The unsaturated 1,ω-dicarboxylic acid ester 6 is subjected to an inco-infusion condensation to obtain the α-hydroxy ester 7. Finally, the α-hydroxy ester 7 is dehydroxylated to obtain a macrocyclic ketone of general formula (I) or a mixture of its regio isomers and / or stereoisomers. 。 6. The method for preparing unsaturated macrocyclic ketones of general formula (I) according to claim 1 Includes the following steps: The lactone 4 is converted into the corresponding chlorinated 1,ω-dicarboxylic acid ester 5. Where R = H or Me, and n is 0, 1, 2 or 3; The chlorine-substituted 1,ω-dicarboxylic acid ester 5 is dehydrochlorinated to form an unsaturated 1,ω-dicarboxylic acid ester 6. Where R = H or Me, and n is 0, 1, 2, or 3. The unsaturated 1,ω-dicarboxylic acid ester 6 is subjected to an inco-infusion condensation to obtain the α-hydroxy ester 7. Finally, the α-hydroxy ester 7 is dehydroxylated to obtain a macrocyclic ketone of general formula (I) or a mixture of its regio isomers and / or stereoisomers. 。 7. Compounds of general formula (I) Where m is an integer / natural number selected from 0, 1, 2, 3, and 4. R1, R2, R3, R4, R5, R6, and R7 represent hydrogen atoms or methyl groups. The dashed lines indicate alternating positions of double bonds, which can be between carbon atoms 4 and 5, 5 and 6, 6 and 7, 7 and 8, or 8 and 9. And selected from: (i) Z )-4-Methylcyclopentadecan-5-en-1-one (ii) E )-4-Methylcyclopentadecan-5-en-1-one (iii) Z 5-Methylcyclohexadec-6-en-1-one (iv) E 5-Methylcyclohexadec-6-en-1-one (v) (Z)-4-methylcyclohexadecyl-6-en-1-one (vi) E )-4-methylcyclohexadec-6-en-1-one (vii) Z )-3-methylcyclohexadecane-5-en-1-one (viii) E )-3-methylcyclohexadecane-5-en-1-one (ix) Z )-3-methylcyclohexadecane-6-en-1-one (x) E )-3-methylcyclohexadecane-6-en-1-one (xi) Z 5-Methylcyclohexadecane-5-en-1-one (xii) E 5-Methylcyclohexadecane-5-en-1-one (xiii) Z 5-Methylcyclohexadecane-6-en-1-one (xiv) E 5-Methylcyclohexadecane-6-en-1-one (xv)( Z )-4-methylcyclohexadecane-5-en-1-one (xvi) E )-4-methylcyclohexadecane-5-en-1-one (xvii) Z )-4-Methylcycloheptadecyl-6-en-1-one (xviii) E )-4-Methylcycloheptadecyl-6-en-1-one (xix) Z )-Cyclooctadecyl-6-en-1-one (xx) ( E )-Cyclooctadecyl-6-en-1-one (xxi) Z )-Cyclooctadecyl-7-en-1-one, or (xxii) E )-Cyclooctadecyl-7-en-1-one, Or a mixture of its regional isomers and / or stereoisomers.

8. A mixture of regioisomers and / or stereoisomers of the compound according to claim 7.

9. The mixture according to claim 8, wherein the weight ratio between the regioisomers and / or stereoisomers is 95:5 to 5:

95.

10. A flavoring agent consisting of a compound or mixture according to any one of claims 7 to 9.

11. A fragrance, flavoring and / or deodorizing / masking composition comprising a compound or mixture according to any one of claims 7 to 9.

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