Macrocyclic MUSK compounds and a process for the production of macrocyclic MUSK compounds

Abstract

The present invention is concerned with a new process for the production of macrocyclic musk compounds of formula (I), utilizing renewable starting materials and practical reaction conditions that allow easy scale up.

Description

[0001] PROCESS FOR THE PRODUCTION OF MACROCYCLIC MUSK COMPOUNDS FIELD OF THE INVENTION

[0002] The present invention is concerned with a new process for the production of macrocyclic musk lactones utilizing renewable starting materials and practical reaction conditions that allow easy scale up. The invention is concerned with mixtures of macrocyclic musk lactones having unique organoleptic properties. The invention is also concerned with novel macrocyclic musk lactones having unique organoleptic properties. BACKGROUND OF THE INVENTION

[0003] The efficient synthesis of saturated or unsaturated macrocyclic lactones (ring sizes of 14 to 18 carbon atoms) has been explored a lot since these compounds are used quite extensively as musk odorants in the field of perfumery. For example, fully saturated 16- membered macrocyclic lactone oxacyclohexadecan-2-one (Exaltolide®) is a naturally occurring musk lactone that was discovered in the first half of 20thcentury. Many saturated lactones containing 14-18 membered rings are known. Corresponding unsaturated lactones with C=C bond in varied positions in the ring have been synthesized. Similarly, various saturated as well as unsaturated lactones with one methyl group at varied positions in the ring have also been reported. Muscolide (16-membered), Ambrettolide (17-membered) and Habanolide ® (16-membered) are examples of unsaturated macrocyclic lactones that are widely used.

[0004] Oxacyclohexadecan-2-one is synthesized by epoxidation of cyclopentadecanone, a 15- membered macrocyclic ketone. Another route is a polymerization-depolymerization approach starting with 15-hydroxypentadecanic acid.

[0005] Scheme 1 :

[0006] 15-hydroxypentadecanoic acid oxacyclohexadecan-2-one cyclopentadecanone

[0007] Scheme 2 details synthesis of Habanolide ® from cyclododecanone. Allylation of cyclododecanone is achieved by heating with allyl alcohol in presence of di-tertiary butyl peroxide at 100 °C (DE19853862). As reported in EP0424787, the resulting 2-(3- hydroxypropyl)cyclododecan-l-one is cyclized under acidic conditions and then treated with hydrogen peroxide to afford a hydroperoxide that is subjected to ring expansion in presence of Cu(OAc)2-FeSO4 to afford a mixture of 4 lactones (43% of trans-pentadec-11- en-15-olide; 26% of trans-pentadec-12-en-l 5-olide, 18% of cis-pentadec-l l-en-15-olide and 5% of cis-pentadec-12-en-l 5-olide).

[0008] Scheme 2:

[0009] Mixture of 4 lactones Cyclododecanone is industrially accessed via trimerization of 1,3-butadiene to cyclodecatriene which is then converted into cyclododecanone in 2 steps. Cyclododecanone is an important intermediate for the synthesis of dodecanedioic acid and laurolactam which in turn are extensively used in industrial synthesis of polymers.

[0010] Availability of cyclododecanone is limited and more importantly 1,3-butadiene is a petroleum product. Many reported syntheses of macrocyclic musk compounds utilize cyclododecanone as the starting material. However, there is an urgent need in the field of macrocyclic musk compounds for the development of a process that utilizes renewable starting materials. Ring-closing metathesis (RCM) is another key reaction that has been reported in synthesis of macrocyclic musk compounds. As shown in Scheme 3, a 14-membered unsaturated lactone has been synthesized using RCM. However, requirement of high dilution conditions required in RCM severely limits easy scale up of this protocol. Scheme 3:

[0011] Choon Woo Lee and Robert H. Grubbs

[0012] Org. Lett. 2000, 2, 14, 2145-2147

[0013] A common and practical synthetic route that easily enables synthesis of various unsaturated and substituted macrocyclic lactones, by enabling variation in the position of the double bond and methyl group, by use of different starting materials, will be a welcome addition to the existing arsenal of synthetic methods of macrocyclic lactones.

[0014] Surprisingly, the inventors were able to design and optimize such awaited process. The sequence of reactions claimed here is novel and additionally uses renewable starting materials in synthesis of multiple macrocyclic lactones which represents a salient feature of this invention.

[0015] SUMMARY OF THE INVENTION

[0016] The invention relates to a novel process that allows preparation of unsaturated macrocycles of formula (I) by using a sequence of common organic reactions. The sequence of reactions utilizes low cost reagents. More importantly, the key starting materials used in the present invention are renewable raw materials.

[0017] A first object of the present invention is a process for the preparation of the following unsaturated macrocycle lactones of formula (I) or the mixture of its regioisomers that differ in the position of the double bond and / or stereoisomers thereof; wherein m is an integer selected from 0, 1, 2, 3, 4, 5 and 6.

[0018] Ri, R2 R3, R4, Rs, Re and R7 represent a hydrogen atom or a methyl group, and the dotted lines represent at least one double bond and wherein the potential position(s) of said double bond(s) is(are) between carbon atoms 4 and 5, and / or 5 and 6, and / or 6 and 7, and / or 7 and 8, and / or 8 and 9. In an embodiment, there is only one double bond amongst the dotted lines.

[0019] A second object of the invention is to provide a novel unsaturated macrocycle lactone of formula (I).

[0020] A third object of the invention is to provide a novel mixture of regioisomers that differ in the position of the double bond and / or of the stereoisomers of the unsaturated macrocyclic lactone of formula (I).

[0021] A fourth object of the invention is to provide a novel mixture of regioisomers that differ in the position of the double bond and of the stereoisomers of the unsaturated macrocyclic lactone of formula (I).

[0022] A fifth object of the present invention is to provide an odorant consisting of any of the compounds represented by general formula (I), preferably a mixture of regioisomers that differ in the position of the double bond and of the stereoisomers of the unsaturated macrocyclic lactone of formula (I).

[0023] A sixth object of the present invention is to provide fragrance, flavor and / or deodorizing / masking compositions comprising the compounds represented by general formula (I), preferably a mixture of regioisomers that differ in the position of the double bond and of the stereoisomers of the unsaturated macrocyclic lactone of formula (I). DETAILED DESCRIPTION OF THE EMBODIMENTS

[0024] Furfural which can be obtained from biomass can be converted into cyclopentanone using Ru / C with AI11.6PO23.7 catalyst in 84% yield in aqueous medium (Shen, T. et a., RSC Adv. 2018, 8, 37993). Anisole which is available naturally can be converted into cyclohexanone using bromide salt-modified Pd / C in H2O / CH2Q2 [Meng, Q. et al., Nature Communications, 8, Article number: 14190 (2017)]. 3 -Methylcyclohexanone can be obtained from Mentha pulegium, a flowering plant.

[0025] Similarly, many long chain co-alkenyl alcohols such as 10-undecen-l-ol and 9- Decen-l-ol are produced commercially from raw materials that are available from natural resources.

[0026] As exemplified in the experimental section, our processes use renewable starting materials detailed above.

[0027] The first embodiment of this invention is Process- 1 which is given below.

[0028] Process-1

[0029] The first step involves free radical coupling reaction between an co-alkenyl acetate 1 and a substituted cyclic ketone 2. The resulting substituted ketone 3 is converted into a lactone 4 in step-2. In step-3, the lactone 4 is heated first with thionyl chloride in presence of catalytic zinc chloride followed by quenching with methanol to convert it into the corresponding chloro-substituted co-hydroxy carboxylate 5. In step 4, the compound 5 is then dehydrochlorinated to the corresponding unsaturated co-hydroxycarboxylate 6. Intramolecular esterification is effected in presence of titanium tetraisopropoxide to furnish desired mixtures of macrocyclic lactones of general formula (I). Conversion of a lactone to the corresponding chloro-substituted co-hydroxycarboxylate has not been exemplified in any literature. This chloro derivative is then dehydrochlorinated to the corresponding unsaturated co-hydroxycarboxylate. Taken together, steps 3 and 4 are key to our invention for the introduction of unsaturation.

[0030] Another embodiment of this invention is Process-2 as outlined below.

[0031] Process-2

[0032] In Process-2, step-3 involves refluxing the lactone 4 with HBr in acetic acid followed by refluxing in methanol to open the lactone and form the bromo-substituted co- hydroxycarboxylate 7. In step 4, the compound 7 is then dehydrobrominated to the corresponding unsaturated co-hydroxycarboxylate 6. Intramolecular esterification is effected in presence of titanium tetraisopropoxide to furnish desired mixtures of macrocyclic lactones of general formula (I).

[0033] Conversion of lactone to a corresponding bromo-substituted co-hydroxycarboxylate has not been exemplified in any literature. This bromo derivative is then dehydrochlorinated to the corresponding unsaturated co-hydroxycarboxylate. Taken together, steps 3 and 4 are key to our invention for the introduction of unsaturation.

[0034] Alternatively, as shown in Process-3, step-5 macrolactonization can be performed by polymerization-depolymerization sequence that is well reported in literature. Thus, unsaturated co-hydroxycarboxylate 6 is hydrolyzed to afford the corresponding unsaturated co-hydroxy carboxylic acid 8 that is polymerized in presence of pata toluene sulfonic acid in cumene to afford a polyester 9 of chain length between 3-8 monomers. The polyester is then depolymerized at high temperature and desired macrocyclic lactone of formula (I) is obtained upon reactive distillation. Process-3 p-TSA, Cumene polymerization n

[0035] Polyester

[0036] As described before, there are many salient features of this invention: use of renewable starting materials, formation of single novel compounds or mixtures of unsaturated macrocyclic lactones, a common synthetic pathway with a novel sequence of reactions that enables installation of methyl groups as well as C=C bond at varied positions in the ring, and synthesis of different sized macrocyclic lactones by subsequent macrolactonization.

[0037] It is a very salient feature of this invention that the synthetic pathways described in this invention allow one to synthesize novel macrocyclic lactones in a crowded research area where lot of macrocyclic lactones are already reported.

[0038] Illustrative examples of unsaturated macrocycle lactones of formula (I) which can be prepared are

[0039] • (Z)-oxacyclohexadec-5-en-2-one

[0040] • (E)-oxacyclohexadec-5-en-2-one • (Z)-oxacyclohexadec-6-en-2-one

[0041] • (E)-oxacyclohexadec-6-en-2-one

[0042] • (Z)-oxacycloheptadec-5-en-2-one

[0043] • (E)-oxacycloheptadec-5-en-2-one

[0044] • (Z)-oxacycloheptadec-6-en-2-one • (£)-oxacycloheptadec-6-en-2-one

[0045] • (Z)-oxacycloheptadec-7-en-2-one

[0046] • (£)-oxacycloheptadec-7-en-2-one

[0047] • (Z)-oxacyclooctadec-6-en-2-one

[0048] • (£)-oxacyclooctadec-6-en-2-one

[0049] • (Z)-oxacyclooctadec-7-en-2-one

[0050] • (£)-oxacyclooctadec-7-en-2-one

[0051] • (Z)-4-methyloxacycloheptadec-6-en-2-one

[0052] • (£)-4-methyloxacycloheptadec-6-en-2-one

[0053] • (Z)-4-methyloxacycloheptadec-7-en-2-one

[0054] • (£)-4-methyloxacycloheptadec-7-en-2-one

[0055] • (Z)-4-methyloxacyclooctadec-6-en-2-one

[0056] • (£)-4-methyloxacyclooctadec-6-en-2-one

[0057] • (Z)-4-methyloxacyclooctadec-7-en-2-one

[0058] • (£)-4-methyloxacyclooctadec-7-en-2-one

[0059] • (Z)-5-methyloxacycloheptadec-6-en-2-one

[0060] • (£)-5-methyloxacycloheptadec-6-en-2-one

[0061] • (Z)-5-methyloxacycloheptadec-7-en-2-one

[0062] • (£)-5-methyloxacycloheptadec-7-en-2-one

[0063] • (Z)-5-methyloxacyclooctadec-6-en-2-one

[0064] • (£)-5-methyloxacyclooctadec-6-en-2-one

[0065] • (Z)-5-methyloxacyclooctadec-7-en-2-one

[0066] • (£)-5-methyloxacyclooctadec-7-en-2-one

[0067] • (Z)-oxacyclooctadec-8-en-2-one

[0068] • (£)-oxacyclooctadec-8-en-2-one

[0069] • (Z)-oxacyclononadec-7-en-2-one

[0070] • (£)-oxacyclononadec-7-en-2-one

[0071] • (Z)-oxacyclononadec-8-en-2-one

[0072] • (£)-oxacyclononadec-8-en-2-one

[0073] • (Z)-oxacyclononadec-9-en-2-one

[0074] • (£)-oxacyclononadec-9-en-2-one • (Z)-oxacycloicos-8-en-2-one

[0075] • (£)-oxacycloicos-8-en-2-one

[0076] • (Z)-oxacycloicos-9-en-2-one

[0077] • (£)-oxacycloicos-9-en-2-one

[0078] The invention is now further described with reference to the following non-limiting examples. These examples are for the purpose of illustration only and it is understood that variations and modifications can be made by one skilled in the art.

[0079] Example 1 : Preparation of a mixture of isomers of oxacycloheptadec-5-en -2-one and oxacycloheptadec-6-en-2-one

[0080] Step 1 : Synthesis of l l-(2-oxocyclopentyl)undecyl acetate

[0081] A 3 -neck 2000 mL round bottom flask equipped with a magnetic stirer, addition funnel and reflux condenser was charged with di- / c / 7-butyl peroxide (1.3 g, 9.4 mmol), and cyclopentanone (356 g, 4233 mmol). The solution was slowly heated to 110-120 °C and then carefully charged with a solution of undec- 10-en-l-yl acetate (100 g, 470 mmol) and di-tert- butyl peroxide (12.3 g, 84.6 mmol) via addition funnel over a period of 20 min. The reaction mixture was refluxed at 120 °C for 16 hr. After cooling to room temperature, water (200 mL) was added and the layers were separated. The organic layer was washed with aqueous saturated sodium carbonate (200 mL), 5% aqueous acetic acid (200 mL) and saturated brine (200 mL). The organic layer was concentrated under reduced pressure and excess cyclopentanone was removed. The resulting material was purified by fractional distillation to give 1 l-(2-oxocyclopentyl)undecyl acetate (120 g, 75% yield) as a colorless liquid.

[0082] ’H NMR (400 MHz, CDCh) 8 4.01 (t, J = 6.8 Hz, 2H), 2.12 - 2.03 (m, 1H), 2.01 (s, 3H), 1.98 - 1.92 (m, 1H), 1.80 - 1.66 (m, 2H), 1.61 - 1.42 (m, 4H), 1.37 - 1.14 (m, 20H).

[0083] 13C NMR (101 MHz, CDCh) 6 221.75, 171.23, 64.62, 49.14, 38.16, 29.63, 29.55, 29.51, 29.48, 29.44, 29.42, 29.20, 28.55, 27.52, 25.86, 20.98, 20.73.

[0084] GCMS: 296.2 (M+), 254.2, 207.2, 152.1, 133.1, 111.1, 84.1, 55.1

[0085] IR (Neat) in cm’1: 2925, 2855, 1737

[0086] Step 2: Synthesis of l l-(6-oxotetrahydro-2H-pyran-2-yl)undecyl acetate: A 3-neck 500 mL round bottom flask, equipped with an overhead stirrer, addition funnel and reflux condenser was charged with 1 l-(2-oxocyclopentyl)undecyl acetate (77 g, 259 mmol), sodium carbonate (27.5 g, 259 mmol) under nitrogen atmosphere and cooled to 0 °C in an ice bath. To this reaction mixture, peracetic acid (127 g, 17%, 285 mmol) was added over a period of 1 h. The solution was then allowed to warm to room temperature and stirred for 32 h. The reaction was quenched with ice water (3 x 100 mL) and to it was added MTBE (250 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with aqueous FeSCL, hot water and then dried over anhydrous Na2SO4. The organic layer was concentrated to afford a white solid (60 g, 74% yield) which was used as such for the next step.

[0087] 1H NMR (400 MHz, CDC13) 5 4.22 (m, 1H), 3.98 (t, J = 6.8 Hz, 2H), 2.56 - 2.48 (m, 1H), 2.42 - 2.32 (m, 1H), 1.98 (s, 3H), 1.90 - 1.76 (m, 2H), 1.59 - 1.46 (m, 4H), 1.30 - 1.15 (m, 14H).

[0088] 13C NMR (101 MHz, CDCh) 8 172.05, 171.26, 80.59, 64.62, 35.78, 29.44, 29.41, 29.34, 29.17, 28.53, 27.74, 25.84, 24.86, 20.96, 18.44.

[0089] GCMS: 312.2 (M+), 294.2, 252.2, 213.1, 192.2, 168.1, 138.1, 99.1, 79.1, 55.1

[0090] IR (Neat) in cm'1: 1735

[0091] Step 3: Synthesis of methyl 5-chl oro-16-hydroxyhexadecanoate:

[0092] A 3-neck 500 mL round bottom flask equipped with a magnetic stirrer, addition funnel and reflux condenser was placed under nitrogen atmosphere and charged successively with methyl cyclohexane (100 mL), methyl 1 l-(6-oxotetrahydro-2H-pyran-2-yl)undecanoate (58 g, 190 mmol) and 0.526 g of zinc chloride (3 mmol). The reaction mixture was then cooled to 0 °C and then dropwise addition of thionyl chloride (45.8 g, 390 mmol) via addition funnel was done over 1.5 h. The reaction mixture was then warmed up to room temperature and then refluxed at 80 °C for 5 hours. The dark reaction mixture was cooled to 0 °C and quenched by slow addition of methanol (100 mL). The reaction mixture was allowed to stir for Ih. Then methanol was evaporated and the dark crude residue was quenched with aqueous saturated sodium carbonate (100 mL) and extracted with ethyl acetate (2 X 200 mL) and then organic layers were separated. The organic layer was finally washed with brine (200 mL) and dried over anhydrous Na2SO4 and concentrated to afford crude product (65 g). The crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane, to afford dimethyl 5-chlorohexadecanedioate (40.9 g, 60% yield), as a pale yellow liquid which was used in the following step.

[0093] ‘HNMR (400 MHz, CDCh) 8 3.86 (m, 1H), 3.65 (s, 3H), 3.60 (t, J = 6.7 Hz, 2H), 2.32 (t, J = 6.7 Hz, 2H), 1.90 - 1.80 (m, 1H), 1.78 - 1.64 (m, 6H), 1.57 - 1.45 (m, 3H), 1.26-1.21 (m, 15H).

[0094] 13C NMR (101 MHz, CDCh) 6 173.72, 64.55, 63.49, 63.46, 62.99, 51.53, 38.41, 38.39, 37.67, 37.65, 33.68, 33.40, 32.75, 29.52, 29.47, 29.42, 29.41, 29.36, 29.19, 29.09, 29.07, 28.59, 26.40, 26.38, 25.88, 25.69, 21.92, 21.87.

[0095] GCMS: 321.2 (M+), 275.2, 252.2 , 222.2 , 192.2, 171.1, 150.1 , 123.1 , 96.1 , 55.1

[0096] IR (Neat) in cm’1: 3382, 1737

[0097] Step 4: Synthesis of mixtures of methyl (E & Z)-16-hydroxyhexadec-4-enoate and methyl (E & Z) -16-hydroxyhexadec-5 -enoate

[0098] A 3 -neck 250 mL round bottom flask equipped with a magnetic stirrer and reflux condenser was charged with methyl 5-chloro-16-hydroxyhexadecanoate (9 g, 26.4 mmol) and cooled to 5 °C. Using addition funnel, l,8-Diazabicyclo(5.4.0)undec-7-ene (12.1 g, 79 mmol) was added very slowly over a period of 1 h to control the exotherm generated. The reaction mixture was slowly heated to 125 °C and maintained at that temperature until starting material was completely consumed. The dark colored reaction mixture was then cooled to room temperature and quenched with 6N HC1 until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with aqueous saturated sodium carbonate (100 mL) followed by saturated brine (100 mL). The organic layer was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product. The crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to give a mixtures of methyl (E & Z)-16-hydroxyhexadec-4-enoate and methyl (E & Z)-16-hydroxyhexadec-5 -enoate (6.4 g, 60% yield), as a pale yellow liquid which was used in the next step. ’H NMR (400 MHz, CDCh) 6 5.49 - 5.30 (m, 2H), 4.07 - 4.01 (m, 1H), 3.71 - 3.57 (m, 4H), 2.40 - 2.24 (m, 3H), 2.08 - 1.91 (m, 3H), 1.72 - 1.64 (m, 2H), 1.60 - 1.51 (m, 2H), 1.37 - 1.21 (m, 14H).

[0099] 13C NMR (101 MHz, CDCh) 6 174.25, 173.74, 131.91, 131.68, 128.80, 127.81, 63.05, 51.46, 51.44, 34.18, 33.37, 32.79, 32.52, 32.47, 31.89, 29.56, 29.54, 29.50, 29.45, 29.40, 29.10, 29.08, 27.89, 25.71, 24.73.

[0100] GCMS: 284.2 (M+), 252.2, 234.1, 210.1, 192.2, 150.1, 123.1, 96.1, 67.1, 47.1

[0101] IR (Neat) cm’1: 3440, 1738

[0102] Step 5: Synthesis of mixture of (E & Z)-oxacycloheptadec-5-en -2-one and (E & Z)- oxacycloheptadec-6-en-2-one:

[0103] A 3 -neck 250 mL round bottom flask equipped with a magnetic stirrer and reflux condenser was charged was charged with titanium(IV) propan-2-olate (0.879 g, 3.00 mmol) and anhydrous toluene (190 ml) and the mixture was refluxed under nitrogen atmosphere for 15 minutes. Then methyl (E & Z)-16-hydroxyhexadec-4-enoate and methyl (E & Z)-16- hydroxyhexadec-5 -enoate (2 g, 6.00 mmol) was added under refluxing condition over 3h. After complete addition, the reaction mixture was allowed to reflux at 110 °C for Ih. After cooling to ambient temperature, the reaction mixture was quenched by addition of water. The solution was diluted with ethyl acetate, and layers were separated and washed with saturated brine. The organic layer was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product. Crude was purified by column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to give 500 mg (33% yield) of a mixture of (E & Z) -oxacycloheptadec-5-en -2-one and (E & Z) - oxacycloheptadec-6-en-2-one'

[0104] IH NMR (400 MHz, CDC13) 5 5.46 - 5.42 (m, IH), 5.38 - 5.33 (m, IH), 4.15 - 4.08 (m, 2H), 2.42 - 2.35 (m, IH), 2.34 - 2.28 (m, 2H), 2.07 - 1.96 (m, 3H), 1.75 - 1.67 (m, IH), 1.64 - 1.56 (m, 3H), 1.35 - 1.26 (m, 14H).

[0105] 13C-NMR (101 MHz, CDCh) 8 (ppm): 173.45, 132.03, 131.72, 129.73, 128.60, 64.10, 34.52, 33.24, 31.62, 31.36, 31.27, 28.31, 28.24, 28.12, 27.98, 27.78, 27.73, 27.64, 27.54, 27.36, 27.30, 27.26, 27.22, 26.69, 26.45, 25.73, 24.76, 24.69.

[0106] GCMS: 252.2 (M+), 234.2, 210.2, 192.2, 163.1, 135.1, 109.1, 82.1, 55.1 IR (Neat) in cm'1: 1735

[0107] Odour: Strong musky powdery animalic

[0108] Example 2: Preparation of mixture of isomers of oxacyclohexdec-5-en-2-one and oxacyclohexdec-6-en-2-one

[0109] Step 1 : Synthesis of 10-(2-oxocyclopentyl)decyl acetate

[0110] Procedure and workup were identical to those describe as mentioned in step 1 for Example 1. Instead of undec- 10-en-l-yl acetate, dec-9-en-l-yl acetate was used and reacted with excess cyclopentanone. The product exhibits the following spectral characteristics

[0111] ’H NMR (400 MHz, CDCh) 8 4.02 (t, J = 6.8 Hz, 2H), 2.40 - 2.10 (m, 2H), 2.02 (s, 3H), 2.13 - 1.91 (m, 2H), 1.81 - 1.66 (m, 1H), 1.64 - 1.42 (m, 2H), 1.25 (m, 18H).

[0112] 13C NMR (101 MHz, CDCh) 6 221.87, 171.27, 64.62, 49.13, 38.15, 32.74, 29.59, 29.45, 29.42, 29.39, 29.17, 29.14, 28.51, 27.49, 25.83, 20.96, 20.70.

[0113] GCMS: 282.2 (M+), 252.2, 234.2, 209.2, 185.1, 150.1, 123.1, 96.1, 67.1, 41.1

[0114] IR (Neat) in cm'1: 1736

[0115] Step 2: Synthesis of 10-(6-oxotetrahydro-2H-pyran-2-yl)decyl acetate

[0116] Procedure and workup were identical to those describe as mentioned in step 2 for Example 1. Instead of l l-(2-oxocyclopentyl)undecyl acetate, 10-(2-oxocyclopentyl)decyl acetate acetate was used as reactant. The product exhibits the following spectral characteristics

[0117] ’H NMR (400 MHz, CDCh) 6 4.21 (m, 1H), 4.04 (q, J= 7.2 Hz, 1H), 3.97 (t, J = 6.8 Hz, 2H), 2.51 (m, 1H), 2.42 - 2.24 (m, 1H), 1.97 (d, J= 0.9 Hz, 4H), 1.89 - 1.74 (m, 2H), 1.65 - 1.41 (m, 6H), 1.32 - 1.11 (m, 14H).

[0118] 13C NMR (101 MHz, CDCh) 6 172.01, 171.00, 80.45, 71.10, 64.44, 60.20, 35.60, 29.24, 29.16, 28.99, 28.35, 27.57, 25.67, 24.69, 20.81, 18.25, 13.97.

[0119] GCMS: 298.2 (M+), 294.2, 280.2, 258.2, 238.2, 201.2, 178.2, 151.2, 124.1, 99.0, 79.1, 55.0 IR (Neat) in cm'1: 1734

[0120] Step 3: Synthesis of methyl 5-chl oro-15-hydroxypentadecanoate Procedure and workup were identical to those describe as mentioned in step 3 for Example 1. 10-(6-oxotetrahydro-2H-pyran-2-yl)decyl acetate was used as reactant. The product exhibits the following spectral characteristics

[0121] ‘HNMR (400 MHz, CDCh) 3.66 (s, 3H), 3.61 (t, J= 6.6 Hz, 2H), 2.32 (t, J= 6.8 Hz, 2H), 1.91 - 1.83 (m, 1H), 1.79 - 1.60 (m, 7H), 1.58 - 1.48 (m, 3H), 1.28 (d, J= 12.4 Hz, 14H).

[0122] 13C NMR (101 MHz, CDCh) 8 173.75, 63.46, 62.94, 51.54, 38.36, 37.62, 33.38, 32.71, 29.48, 29.36 (d, J= 5.4 Hz), 29.05, 26.36, 25.67, 21.90.

[0123] GCMS: 306.2 (M+), 294.2, 252.2 , 229.2 , 201.2, 165.1, 140.2, 113.1 , 94.1 , 55.1

[0124] IR (Neat) in cm'1: 1733

[0125] Step 4: Synthesis of mixtures of methyl (E & Z)- 15 -hydroxypentadec-5 -enoate and methyl (E & Z)-16-hydroxyhexadec-4-enoate

[0126] Procedure and workup were identical to those describe as mentioned in step 4 for Example 1. Methyl 5-chloro-15-hydroxypentadecanoate was used as reactant. The product exhibits the following spectral characteristics

[0127] ‘HNMR (400 MHz, CDCh) 5 5.51 - 5.28 (m, 2H), 3.65 (d, J= 0.9 Hz, 3H), 3.62 (t, J= 6.6 Hz, 2H), 2.38 - 2.25 (m, 4H), 2.03 - 1.92 (m, 2H), 1.67 (td, J= 7.4, 2.2 Hz, 1H), 1.59 - 1.50 (m, 2H), 1.33 - 1.22 (m, 14H).

[0128] 13C NMR (101 MHz, CDCh) 6 173.41, 128.29, 127.20, 63.02, 51.52, 34.16, 33.35, 32.75, 32.45, 31.87, 29.51, 29.36, 29.08, 29.05, 28.61, 27.87, 25.69.

[0129] GCMS: 270.2 (M+), 248.2, 224.2, 210.1, 193.1, 165.1, 137.1, 115.1, 95.1, 73.1, 55.1

[0130] IR (Neat) in cm'1: 3441, 1737

[0131] Step 5: Synthesis of mixture of (E & Z)- oxacyclohexadec-5-en-2-one and (E & Z)- oxacyclohexadec-6-en-2-one:

[0132] Procedure and workup were identical to those describe as mentioned in step 5 for Example 1. Mixtures of methyl (E & Z)- 15 -hydroxypentadec-5 -enoate and methyl (E & Z)-16- hydroxyhexadec- -enoate was used as reactant. The product exhibits the following spectral characteristics

[0133] ‘H NMR (400 MHz, CDCh) 6 5.41 (q, J = 4.8 Hz, 1H), 5.33 (q, J = 5.8 Hz, 1H), 4.12 (m, 2H), 2.35 (m, , 3H), 2.03 (m, 3H), 1.76 - 1.58 (m, 5H), 1.46 - 1.19 (m, 15H).

[0134] 13C NMR (101 MHZ, CDCh) 6 173.37, 132.25, 131.44, 129.50, 128.78, 64.47, 63.54, 34.51, 32.06, 30.78, 28.27, 27.83, 27.44, 27.29, 26.88, 26.75, 26.05, 25.85, 24.16, 23.48. GCMS: 238.2 (M+), 252.2, 234.2, 209.2, 185.1, 123.1, 96.1, 67.1, 41.1

[0135] IR (Neat) in cm'1: 1737

[0136] Odour: Musky animalic powdery

[0137] Example 3: Preparation of mixture of isomers of oxacycloheptadec-6-en-2-one and oxacycloheptadec-7-en-2-one

[0138] Step 1 : Synthesis of 10-(2-oxocyclohexyl)decyl acetate

[0139] A 3 -neck 2000 mL round bottom flask equipped with a overhead stirer, addition funnel and reflux condenser was charged with di- / c / 7-butyl peroxide (1.45 g, 10 mmol), and cyclohexanone (445 g, 4538 mmol). The solution was slowly heated to 110-120 °C and then carefully charged with a solution of dec-9-en-l-yl acetate (100 g, 504 mmol) and di-Zc / V- butyl peroxide (13.2 g, 90 mmol) via additional funnel over a period of 20 min. The reaction mixture was refluxed at 120 °C for 24 hr. After cooling to room temperature, water (200 mL) was added and the layers were separated. The organic layer was washed with aqueous saturated sodium carbonate (200 mL), 5% aqueous acetic acid (200 mL) and saturated brine (200 mL). The organic layer was concentrated under reduced pressure and excess cyclopentanone was removed. The resulting material was purified by fractional distillation to give l l-(2-oxocyclopentyl)undecyl acetate (135 g, 74% GC purity, 67% yield) as a colorless liquid. 5 g crude was purified by column chromatography to get 3 g of pure 10-(2- oxocyclohexyl)decyl acetate. The product exhibits the following spectral characteristics

[0140] ’H NMR (400 MHz, CDCh) 8 4.03 (t, J= 6.8 Hz, 2H), 2.39 - 2.23 (m, 1H), 2.16 - 2.08 (m, 2H), 2.03 (s, 3H), 2.00 - 1.95 (m, 4H), 1.90 - 1.79 (m, 2H), 1.76 - 1.67 (m, 2H), 1.64 - 1.55 (m, 2H), 1.39 - 1.19 (m, 14H).

[0141] 13C NMR (101 MHz, CDCh) 6 212.90, 171.24, 64.63, 50.56, 49.91, 49.78, 47.58, 38.24, 35.68, 34.06, 33.61, 32.88, 30.33, 29.96, 29.78, 29.69, 29.55, 29.46, 29.20, 29.19, 28.88, 28.55, 27.36, 27.20, 27.17, 27.07, 25.86, 25.36, 22.35, 20.99, 20.76, 20.48.

[0142] IR (Neat) in cm : 1738, 1709

[0143] Step 2: Synthesis of 10-(7-oxooxepan-2-yl)decyl acetate:

[0144] A 3 -neck 1000 mL round bottom flask equipped with an overhead stirrer, addition funnel and reflux condenser was charged with l l-(2-oxocyclopentyl)undecyl acetate (135 g, 74% GC purity, 332 mmol), sodium carbonate (35.2 g, 332 mmol) under nitrogen atmosphere and cooled to 0 °C in an ice bath. To this reaction mixture, peracetic acid (185 g, 15%, 366 mmol) was added over a period of 1 h. The solution was then allowed to warm to room temperature and stirred for 32 h and monitered using TLC. Once the Starting material was consumed the reaction was taken for workup. The reaction was quenched with ice water (3X100 mL) and to it was added MTBE (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3X100 mL). The combined organic layer was washed with aqueous FeSO4, hot water and then dried over anhydrous Na2SO4. The organic layer was concentrated to afford a colorless liquid (125 g, 72% GC purity, 87% yield) which was used as such for the next step. 5 g crude was purified by column chromatography to get 3.2 g of pure 10-(7-oxooxepan-2-yl)decyl acetate. The product exhibits the following spectral characteristics

[0145] 'H NMR (400 MHz, CDCh) 5 4.11 - 4.03 (m, 1H), 4.00 (t, J= 6.7 Hz, 2H), 2.66 - 2.54 (t, 2H), 2.00 (s, 3H), 1.93 - 1.82 (m, 2H), 1.69 - 1.44 (m, 8H), 1.35 - 1.16 (m, 14H).

[0146] 13C NMR (101 MHz, CDCh) 8 175.82, 171.16, 80.47, 64.52, 60.27, 36.29, 34.81, 29.32, 29.30, 29.25, 29.08, 28.45, 28.19, 25.75, 25.26, 22.93, 20.90, 20.88, 14.06.

[0147] GCMS: 312.2 (M+), 294.2, 252.2, 213.1, 192.2, 168.1, 138.1, 99.1, 79.1, 55.1

[0148] IR (Neat) in cm’1: 1733

[0149] Step 3: Synthesis of methyl 6-chl oro-16-hydroxyhexadecanoate:

[0150] A 3-neck 500 mL round bottom flask equipped with a magnetic stirrer, addition funnel and reflux condenser was placed under nitrogen atmosphere and charged successively methyl cyclohexane (100 mL), 10-(7-oxooxepan-2-yl)decyl acetate (67 g, 163 mmol) and 0.444 g of zinc chloride (3.26 mmol). The reaction mixture was then cooled to 0 °C and then dropwise addition of thionyl chloride (38.8 g, 326 mmol) via addition funnel was done over a period of 1.5 h. The reaction mixture was then warmed up to room temperature and then refluxed at 80 °C for 5 hours. The dark reaction mixture was cooled to 0 °C and quenched with methanol (100 mL) which was slowly added to the reaction mixture. The reaction mixture was allowed to stir for Ih. Then methanol was evaporated and the dark crude was quenched with aqueous saturated sodium carbonate (100 mL) and extracted with ethyl acetate (2 X 200 mL) and then organic layers were separated. The organic layer was finally washed with brine (200 mL) and dried over anhydrous Na2SO4 and concentrated to afford crude product (65 g). The crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane, to afford methyl 6-chloro-16- hydroxyhexadecanoate (22 g, 42% yield), as a pale yellow liquid which was used in the following step. The product exhibits the following spectral characteristics

[0151] 'H NMR (400 MHz, CDCh) 8 3.89 - 3.82 (m, 1H), 3.64 (s, 3H), 3.60 (t, J = 6.7 Hz, 2H), 2.30 (t, J= 7.4, 5.5 Hz, 2H), 2.03 (m, 2H), 1.51-1.27 (m, 23H).

[0152] 13C NMR (101 MHz, CDCh) 6 173.99, 173.66, 64.45, 63.81, 62.91, 51.47, 38.43, 38.02, 34.12, 33.83, 32.66, 29.47, 29.38, 29.32, 29.15, 29.05, 28.54, 26.39, 25.96, 25.84, 25.65, 24.45, 24.38.

[0153] GCMS: 321.1 (M+), 275.2, 252.1 , 222.2 , 192.2, 171.1, 150.2 , 123.2 , 96.1 , 55.1

[0154] IR (Neat) in cm’1: 3439, 1737

[0155] Step 4: Synthesis of mixtures of methyl (E & Z)-16-hydroxyhexadec-6-enoate and methyl (E & Z)-16-hydroxyhexadec-7-enoate

[0156] A 3 -neck 250 mL round bottom flask equipped with a magnetic stirrer and reflux condenser was charged with methyl 5-chloro-16-hydroxyhexadecanoate (21 g, 65 mmol) and cooled to

[0157] 5 °C. Using addition funnel, l,8-Diazabicyclo(5.4.0)undec-7-ene (30 g, 196 mmol) was added very slowly over a period of 1 h to control the exotherm generated. The reaction mixture was slowly heated to 125 °C and maintained at that temperature until starting material is completely consumed. The dark colored reaction mixture was then cooled to room temperature and quenched with 6N HC1 until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and layers were separated. The aqueous layer was extracted with ethyl acetate (3 X 100 mL). The combined organic layer was washed with aqueous saturated sodium carbonate (200 mL) followed by saturated brine (200 mL). The organic layer was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product. The crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to give a mixtures of methyl (E

[0158] 6 Z)-16-hydroxyhexadec-6-enoate and methyl (E & Z)-16-hydroxyhexadec-7-enoate (6.5 g, 35% yield), as a pale yellow liquid which was used in the next step. The product exhibits the following spectral characteristics

[0159] XH NMR (400 MHz, CDCh) 6 5.37 (dq, J= 11.4, 6.2 Hz, 2H), 3.64 (s, 3H), 3.60 (t, J = 6.7 Hz, 2H), 2.32 - 2.27 (t, 2H), 1.99 - 1.94 (m, 4H), 1.67-1.55 (m, 4H),1.35 - 1.24 (m, 15H).13C NMR (101 MHz, CDCh) 6 174.25, 131.66, 131.60, 130.89, 129.54, 128.85, 128.78, 64.41, 63.01, 51.44, 33.93, 33.35, 32.76, 32.52, 32.13, 31.88, 29.54, 29.52, 29.49, 29.43, 29.38, 29.22, 29.09, 29.03, 28.61, 25.89, 25.70, 24.70, 24.38.

[0160] GCMS: 284.2 (M+), 252.2, 234.1, 210.1, 192.2, 150.1, 123.1, 96.1, 67.1, 47.1 IR (Neat) cm’1: 3432, 1737

[0161] Step 5: Synthesis of mixture of (E & Z)-oxacycloheptadec-6-en-2-one and (E & Z)- oxacycloheptadec-7-en-2-one:

[0162] A 3 -neck 250 mL round bottom flask equipped with a magnetic stirrer and reflux condenser was charged was charged with titanium(IV) isopropoxide (0.943 g, 3.32 mmol) and anhydrous toluene (200 ml) and the mixture was refluxed under nitrogen atmosphere for 15 minutes. Then methyl (E & Z)-16-hydroxyhexadec-6-enoate and methyl (E & Z)-16- hydroxyhexadec-7 -enoate obtained in previous step (2 g, 6.63 mmol) was added under refluxing condition over a period of 3h. After complete addition, the reaction mixture was allowed to reflux at 110 °C for Ih and then analyzed using TLC & GC. After cooling to ambient temperature, the reaction mixture was quenched by addition of water. The solution was diluted with ethyl acetate, and layers were separated and washed with saturated brine. The organic layer was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product. Crude was purified by column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to give 0.580 g (2.23 mmol, 34% yield) mixtures of (E & Z)-oxacy cl oheptadec-5-en -2-one and (E & Z)-oxacycloheptadec-6-en-2- one as pure product with GC purity of 97%. The product exhibits the following spectral characteristics

[0163] ‘HNMR (400 MHz, CDCh) 5 5.44 - 5.24 (m, 2H), 4.11 (t, J = 5.3 Hz, 2H), 2.37 - 2.23 (m, 2H), 2.11 - 1.95 (m, 4H), 1.66 - 1.58 (m, 4H), 1.44 - 1.24 (m, 14H).

[0164] 13C NMR (101 MHz, CDCh) 8 174.02, 173.92, 132.03, 131.37, 130.14, 129.73, 64.70, 64.36, 35.32, 33.24, 31.90, 31.74, 31.63, 31.27, 28.94, 28.86, 28.75, 28.46, 28.24, 28.19, 28.12, 27.83, 27.78, 27.73, 27.64, 27.26, 27.12, 26.59, 25.73, 24.76, 24.71.

[0165] GCMS: 252.2 (M+), 234.2, 210.2, 192.2, 163.1, 135.1, 109.1, 82.1, 55.1

[0166] IR (Neat) in cm’1: 1733

[0167] Odour: Sweet musky vanilla like Example 4: Preparation of mixture of isomers of 3-methyloxacycloheptadec-6-en-2-one, 3- methyloxacycloheptadec-7-en-2-one, 5-methyloxacycloheptadec-6-en-2-one and 5- methyloxacycloheptadec-7-en-2-one

[0168] Step 1 : Synthesis of 10-(4-methyl-2-oxocyclohexyl)decyl acetate

[0169] Procedure and workup were identical to those describe as mentioned in step 1 for Example 3. Instead of cyclohexanone, 3 -methyl cyclohexanone was used and reacted with dec-9-en- 1-yl acetate. The product exhibits the following spectral characteristics

[0170] ’H NMR (400 MHz, CDCh) 8 4.03 (t, J= 6.8 Hz, 2H), 2.39 - 2.30 (m, 2H), 2.29 - 2.22 (m, 1H), 2.20 - 2.08 (m, 2H), 2.03 (s, 3H), 1.89 - 1.81 (m, 2H), 1.63 - 1.56 (m, 3H), 1.36 - 1.22 (m, 16H), 0.98 (d, 3H).

[0171] 13C NMR (101 MHz, CDCh) 6 214.56, 212.90, 171.24, 64.62, 57.40, 50.54, 49.94, 49.90, 49.77, 47.57, 41.36, 41.08, 38.23, 35.67, 34.15, 34.04, 33.60, 33.25, 32.87, 32.84, 30.32, 29.95, 29.77, 29.72, 29.67, 29.65, 29.54, 29.46, 29.45, 29.42, 29.40, 29.19, 28.87, 28.54, 27.35, 27.19, 27.15, 27.05, 25.85, 25.35, 25.26, 22.34, 22.03, 20.98, 20.75, 20.47.

[0172] IR (Neat) in cm'1: 1738, 1709

[0173] Step 2: Synthesis of mixture of 10-(3-methyl-7-oxooxepan-2-yl)decyl acetate and 10-(5- methyl-7-oxooxepan-2-yl)decyl acetate

[0174] Procedure and workup were identical to those describe as mentioned in step 2 for Example 3. Instead of 10-(2-oxocyclohexyl)decyl acetate, 10-(4-methyl-2-oxocyclohexyl)decyl acetate was used as reactant. The product exhibits the following spectral characteristics

[0175] ‘HNMR (400 MHz, CDCh) 6 4.24 - 4.12 (m, 1H), 4.01 (t, J= 6.8 Hz, 2H), 2.66 - 2.39 (m, 2H), 2.21 - 2.09 (m, 2H), 2.01 (s, 3H), 1.94 - 1.77 (m, 2H), 1.75 - 1.65 (m, 2H), 1.65 - 1.53 (m, 2H), 1.51 - 1.42 (m, 1H), 1.46 - 1.13 (m, 14H), 1.05 - 0.86 (m, 3H).

[0176] 13C NMR (101 MHz, CDCh) 6 174.95, 174.41, 171.21, 80.49, 80.37, 64.55, 42.54, 40.72, 37.29, 36.30, 36.19, 34.13, 34.02, 30.15, 29.83, 29.42, 29.39, 29.35, 29.33, 29.26, 29.11, 28.47, 26.44, 25.78, 25.33, 25.24, 23.87, 20.92, 17.38.

[0177] IR (Neat) in cm'1: 1734

[0178] Step 3: Synthesis of mixture of methyl 6-chloro-16-hydroxy-3 -methylhexadecanoate and methyl 6-chloro-16-hydroxy-5 -methylhexadecanoate Procedure and workup were identical to those describe as mentioned in step 3 for Example 3. Mixture of 10-(3-methyl-7-oxooxepan-2-yl)decyl acetate and 10-(5-methyl-7-oxooxepan- 2-yl)decyl acetate was used as reactant. The product exhibits the following spectral characteristics

[0179] ’H NMR (400 MHz, CDCh) 8 3.90 - 3.80 (m, 1H), 3.65 (s, 3H), 3.62 (t, J = 6.7 Hz, 2H), 2.30 (ddd, J = 14.9, 6.1, 4.7 Hz, 2H), 2.13 (m, J = 14.8, 10.2, 8.0 Hz, 1H), 2.00 - 1.89 (m, 1H), 1.70 - 1.64 (m, 4H), 1.59 - 1.50 (m, 4H), 1.34 - 1.25 (m, 14H), 0.94 (dd, J = 6.6, 4.5 Hz, 3H).

[0180] 13C NMR (101 MHz, CDCh) 6 173.49, 64.20, 62.97, 51.40, 41.58, 41.29, 38.51, 38.32, 35.83, 33.33, 33.30, 32.72, 30.06, 29.95, 29.49, 29.41, 29.34, 29.08, 26.42, 26.38, 25.68, 19.81, 19.49.

[0181] IR (Neat) in cm’1: 3396, 1736

[0182] Step 4: Synthesis of mixtures of methyl (E & Z)-16-hydroxy-3-methylhexadec-6-enoate, (E & Z)-16-hydroxy-3-methylhexadec-7-enoate, (E & Z)-16-hydroxy-5-methylhexadec-6- enoate and (E & Z)-16-hydroxy-5-methylhexadec-6-enoate

[0183] Procedure and workup were identical to those describe as mentioned in step 4 for Example 3. Mixture of methyl 6-chloro-16-hydroxy-3 -methylhexadecanoate and methyl 6-chloro-16- hydroxy-5 -methylhexadecanoate was used as reactant. The product exhibits the following spectral characteristics

[0184] ’H NMR (400 MHz, CDCh) 6 5.46 - 5.28 (m, 2H), 4.05 (td, J= 6.8, 2.9 Hz, 1H), 3.65 (s, 3H), 3.63 (t, J= 6.6 Hz, 2H), 2.31 (d, J= 5.0 Hz, 2H), 1.98 - 1.93 (m, 4H), 1.60 - 1.53 (m, 3H), 1.30 - 1.24 (m, 14H), 0.93 (d, 3H).

[0185] 13C NMR (101 MHz, CDCh) 6 173.72, 132.88, 130.69, 130.67, 129.68, 127.45, 63.02, 51.34, 41.53, 40.85, 39.72, 36.54, 32.76, 32.55, 32.53, 30.55, 29.93, 29.82, 29.54, 29.51, 29.42, 29.38, 29.09, 25.70, 19.58, 19.54.

[0186] IR (Neat) in cm’1: 3442, 1737

[0187] Step 5: Synthesis of mixture of (E & Z)-3-methyloxacycloheptadec-6-en-2-one, (E & Z)-3- methyloxacycloheptadec-7-en-2-one, (E & Z)-5-methyloxacycloheptadec-6-en-2-one and (E & Z)-5-methyloxacycloheptadec-6-en-2-one Procedure and workup were identical to those describe as mentioned in step 5 for Example 3. Mixtures of methyl (E & Z)-16-hydroxy-3-methylhexadec-6-enoate, (E & Z)-16-hydroxy- 3-methylhexadec-7-enoate, (E & Z)-16-hydroxy-5-methylhexadec-6-enoate and (E & Z)-16- hydroxy-5-methylhexadec-6-enoate was used as reactant. The product exhibits the following spectral characteristics

[0188] ‘HNMR (400 MHz, CDCh) 8 5.46 - 5.28 (m, 2H), 4.12 (m, 2H), 2.52 - 2.36 (m, 2H), 2.36 - 2.13 (m, 2H), 2.12 - 1.94 (m, 3H), 1.68 - 1.58 (m, 2H), 1.52 - 1.13 (m, 14H), 0.97 (m, 3H).

[0189] 13C NMR (101 MHz, CDCh) 6 173.33, 132.71, 131.04, 130.15, 128.66, 64.59, 64.21, 43.06, 40.44, 39.45, 36.08, 31.58, 31.50, 30.88, 29.43, 29.26, 28.88, 28.58, 28.41, 28.22, 28.06, 27.94, 27.77, 27.62, 27.53, 27.49, 27.34, 27.14, 27.02, 26.56, 25.41, 20.41, 18.93.

[0190] IR (Neat) in cm'1: 1733

[0191] Odour: Musky woody dry mossy

[0192] Example 5: Preparation of mixture of isomers of 5-methyloxacycloheptadec-6-en-2-one and 5-methyloxacycloheptadec-7-en-2-one

[0193] Step 1 : Synthesis of 10-(5-methyl-2-oxocyclohexyl)decyl acetate

[0194] Procedure and workup were identical to those describe as mentioned in step 1 for Example 3. Instead of 3-methyl cyclohexanone, 4-methyl cyclohexanone was used and reacted with dec-9-en-l-yl acetate. The product exhibits the following spectral characteristics

[0195] ‘HNMR (400 MHz, CDCh) 6 3.98 (t, J= 1.2 Hz, 2H), 2.37 - 2.24 (m, 2H), 2.23 - 2.17 (m, 1H), 2.16 - 2.00 (m, 2H), 1.98 (s, 3H), 1.95 - 1.89 (m, 1H), 1.83 - 1.76 (m, 2H), 1.54 (m, , 2H), 1.29 - 1.13 (m, 16H), 0.94 (d, 3H).

[0196] 13C NMR (101 MHz, CDCh) 6 214.54, 212.88, 171.23, 64.62, 57.40, 50.54, 49.90, 49.77, 47.57, 41.36, 38.23, 35.67, 34.04, 33.60, 32.87, 32.84, 30.32, 29.95, 29.77, 29.67, 29.54, 29.46, 29.45, 29.43, 29.40, 29.36, 29.19, 28.87, 28.54, 27.35, 27.19, 27.15, 27.05, 25.85, 25.35, 22.34, 20.98, 20.75, 20.47.

[0197] IR (Neat) in cm'1: 1738, 1709

[0198] Step 2: Synthesis of 10-(4-methyl-7-oxooxepan-2-yl)decyl acetate Procedure and workup were identical to those describe as mentioned in step 2 for Example 3. 10-(5-methyl-2-oxocyclohexyl)decyl acetate was used as reactant. The product exhibits the following spectral characteristics

[0199] ’H NMR (400 MHz, CDCh) 8 4.09 - 4.03 (m, 1H), 3.99 (t, J= 6.8 Hz, 2H), 2.60 - 2.54 (m, 2H), 1.98 (s, 3H), 1.87 - 1.74 (m, 2H), 1.68 - 1.46 (m, 4H), 1.47 - 1.41 (m, 1H), 1.39 - 1.11 (m, 16H), 0.95 (dd, J= 29.0, 6.7 Hz, 3H).

[0200] 13C NMR (101 MHz, CDCh) 6 175.64, 171.08, 79.48, 79.46, 64.47, 64.46, 60.22, 42.83, 36.32, 36.30, 35.16, 35.14, 33.86, 31.09, 29.31, 29.28, 29.22, 29.06, 29.04, 28.43, 28.41, 25.74, 25.71, 25.19, 25.17, 22.50, 20.85, 20.84, 14.04, 14.02.

[0201] IR (Neat) in cm'1: 1734

[0202] Step 3: Synthesis of methyl 6-chl oro-16-hydroxy-4-methylhexadecanoate

[0203] Procedure and workup were identical to those describe as mentioned in step 3 for Example 3. 10-(4-methyl-7-oxooxepan-2-yl)decyl acetate was used as reactant. The product exhibits the following spectral characteristics

[0204] ’H NMR (400 MHz, CDCh) 6 4.08 - 4.01 (m, 1H), 3.97 (tt, J= 8.3, 5.2 Hz, 1H), 3.66 (s, 3H), 3.63 (t, J= 6.6 Hz, 2H), 2.37 - 2.27 (m, 2H), 1.65 - 1.54 (m, 5H), 1.34 - 1.25 (m, 18H), 0.91 (d, .7= 6.5 Hz, 3H).

[0205] 13C NMR (101 MHz, CDCh) 6 174.25, 63.01, 61.76, 51.56, 45.83, 38.56, 32.73, 31.54, 30.56, 29.72, 29.50, 29.42, 29.35, 29.12, 26.30, 25.68, 19.57.

[0206] IR (Neat) in cm'1: 3341, 1737

[0207] Step 4: Synthesis of mixtures of methyl (E & Z)-16-hydroxy-4-methylhexadec-5-enoate and methyl (E & Z)-16-hydroxy-4-methylhexadec-6-enoate

[0208] Procedure and workup were identical to those describe as mentioned in step 4 for Example 3. Methyl 6-chloro-16-hydroxy-4-methylhexadecanoate was used as reactant. The product exhibits the following spectral characteristics

[0209] 3H NMR (400 MHz, CDCh) 6 5.36 (d, J= 3.6 Hz, 1H), 5.19 (q, 1H), 4.07 (d, J= 3.5 Hz, 2H), 3.64 (s, 3H), 2.40 - 2.22 (m, 2H), 2.10 - 1.89 (m, 3H), 1.83 (dt, J= 13.5, 6.6 Hz, 1H), 1.72 - 1.51 (m, 4H), 1.39 - 1.15 (m, 14H), 0.91 (dd, J= 44.9, 6.6 Hz, 3H).

[0210] 13C NMR (101 MHz, CDCh) 6 174.49, 174.16, 134.90, 134.83, 132.19, 129.91, 129.84, 128.03, 127.99, 64.41, 63.04, 51.48, 51.44, 39.70, 39.68, 36.52, 32.77, 32.75, 32.59, 32.50, 32.38, 32.18, 32.10, 31.98, 31.90, 31.44, 31.37, 29.55, 29.53, 29.51, 29.43, 29.39, 29.24, 29.10, 28.62, 25.91, 25.71, 20.85, 19.05, 14.22.

[0211] IR (Neat) in cm’1: 3367, 1737

[0212] Step 5: Synthesis of mixture of (E & Z)- 5-methyloxacycloheptadec-6-en-2-one and (E & Z)-5-methyloxacycloheptadec-7-en-2-one

[0213] Procedure and workup were identical to those describe as mentioned in step 5 for Example 3. Mixtures of methyl (E & Z)-16-hydroxy-4-methylhexadec-5 -enoate and methyl (E & Z)- 16-hydroxy-4-methylhexadec-6-enoate was used as reactant. The product exhibits the following spectral characteristics

[0214] ‘HNMR (400 MHz, CDCh) 8 5.42 - 5.30 (q, 1H), 5.29 - 5.02 (t, 1H), 4.10 (t, J= 3.5 Hz, 2H), 2.30 (t, .7= 2.9 Hz, 2H), 2.17 - 1.93 (m, 3H), 1.77 - 1.57 (m, 4H), 1.46 - 1.18 (m, 14H), 0.94 (d, 3H).

[0215] 13C NMR (101 MHz, CDCh) 6 174.24, 174.09, 135.96, 132.13, 130.05, 128.54, 64.66, 64.37, 39.84, 36.47, 32.97, 32.77, 32.28, 32.07, 31.72, 31.66, 30.91, 28.85, 28.75, 28.61, 28.28, 28.19, 28.11, 27.93, 27.64, 27.61, 27.56, 27.54, 27.47, 27.03, 26.48, 25.53, 20.76, 19.62.

[0216] IR (Neat) in cm'1: 1734

[0217] Odour: Musky woody balsamic powdery

[0218] Following table gives an overview of the starting materials and the corresponding mixture of lactones that were synthesized.

Claims

CLAIMS1. Process for the preparation of an unsaturated macrocycle lactone of formula (I) or a mixture of the regioisomers that differ in the position of the double bond and / or of the stereoisomers thereofwherein m is an integer selected from 0, 1, 2, 3, 4, 5 and 6;Ri, R2, R3, R4, Rs, Rs and R7 represent a hydrogen atom or a methyl group, and the dotted lines represent at least one double bond and wherein the potential position(s) of said double bond(s) is(are) between carbon atoms 4 and 5, and / or 5 and 6, and / or 6 and 7, and / or 7 and 8, and / or 8 and 9, comprising the following steps:R | )n n = 0-3 reacting a substituted cyclic ketone 0with an co-alkenyl acetate n = 0-3to prepare a substituted ketone0wherein R = H or methyl and n is 0, 1, 2 or 3, and reacting the substituted ketone 3 with an acid selected from peracetic acid, perbenzoic acid or 3-Chloroperbenoic acid to prepare lactone 4,wherein R = H or methyl and n is 0, 1, 2 or 3, and either (A) converting the lactone 4 to form the chloro-substituted co- hydroxycarboxylate 5and dehydrochlorinating chloro-substituted co-hydroxycarboxylate 5 to form unsaturated co-hydroxycarboxylate 6wherein R = H or methyl and n is 0, 1, 2 or 3, or (B) converting the lactone 4 to form the bromo-substituted co- hydroxycarboxylate 7and dehydrobrominating the bromo-substituted co-hydroxycarboxylate 7 to form unsaturated co-hydroxycarboxylate 6wherein R = H or methyl and n is 0, 1, 2 or 3, and subjecting the unsaturated l,co-dicarboxylate 6 to intramolecular macrolactonization in presence of titanium(IV) propan-2-olate (Titanium isopropoxide) to form the unsaturatedmacrocycle lactone of formula (I) or the mixture of the regioisomers that differ in the position of the double bond and / or of the stereoisomers thereof:m = 0,1 , 2, 3, 4, 5, 6(I)2. Process for the preparation of an unsaturated macrocycle lactone of formula (I) or a mixture of the regioisomers that differ in the position of the double bond and / or of the stereoisomers thereofwherein m is an integer selected from 0, 1, 2, 3, 4, 5 and 6;Ri, R.

2. R3, R4, Rs, Rs and R7 represent a hydrogen atom or a methyl group, and the dotted lines represent at least one double bond and wherein the potential position(s) of said double bond(s) is(are) between carbon atoms 4 and 5, and / or 5 and 6, and / or 6 and 7, and / or 7 and 8, and / or 8 and 9, comprising the following steps:R Cl )n n = 0-3 reacting a substituted cyclic ketone 0with an co-alkenyl acetateto prepare a substituted ketone0wherein R = H or methyl and n is 0, 1, 2 or 3, and reacting the substituted ketone 3 with an acid selected from peracetic acid, perbenzoic acid or 3-Chloroperbenoic acid to prepare lactone 4,wherein R = H or methyl and n is 0, 1, 2 or 3, and either (A) converting the lactone 4 to form the chloro-substituted co- hydroxycarboxylate 5and dehydrochlorinating chloro-substituted co-hydroxycarboxylate 5 to form unsaturated co-hydroxycarboxylate 6wherein R = H or methyl and n is 0, 1, 2 or 3, or (B) converting the lactone 4 to form the bromo-substituted co- hydroxycarboxylate 7dehydrobrominating the bromo-substituted co-hydroxycarboxylate 7 to form unsaturated co-hydroxycarboxylate 6wherein R = H or methyl and n is 0, 1, 2 or 3, and hydrolysis of unsaturated co-hydroxycarboxylate 6to afford the corresponding unsaturated co-hydroxy carboxylic acid 8R = H, Me and subjecting the unsaturated co-hydroxy carboxylic acid 8 to polymerization in presence of acidic conditions in a solvent (for example, para-toluene sulfonic acid incumene) to afford a polyester Polyester of chain length of 3-8 monomers and depolymerization and reactive distillation of polyester 8 in presence of glycerine to form the unsaturated macrocycle lactone of formula (I) or the mixture of the regioisomers that differ in the position of the double bond and / or of the stereoisomers thereof:

3. Mixture of regioisomers that differ in the position of the double bond and of stereoisomers of compounds of general formula (I)wherein m is an integer / whole number selected from 0, 1, 2, 3, 4, 5 and 6,Ri, R2, R3, R4, Rs, Re and R7 represent a hydrogen atom or a methyl group, and the dotted lines represent at least one double bond and wherein the potential position(s) of said double bond(s) is(are) between carbon atoms 4 and 5, and / or 5 and 6, and / or 6 and 7, and / or 7 and 8, and / or 8 and 9.

4. Compound of formula (I) or a mixture of the regioisomers that differ in the position of the double bond and / or of the stereoisomers thereofwherein m is an integer selected from 0, 1, 2, 3, 4, 5 and 6;Rl, R2, R3, R4, R5, R6 and R7 represent a hydrogen atom or a methyl group, and the dotted lines represent at least one double bond and wherein the potential position(s) of said double bond(s) is(are) between carbon atoms 4 and 5, and / or 5 and 6, and / or 6 and 7, and / or 7 and 8, and / or 8 and 9, and which are selected from• (Z)-oxacyclooctadec-6-en-2-one• (£)-oxacyclooctadec-6-en-2-one• (Z)-oxacyclooctadec-7-en-2-one• (£)-oxacyclooctadec-7-en-2-one• (Z)-4-methyloxacycloheptadec-6-en-2-one• (£)-4-methyloxacycloheptadec-6-en-2-one• (Z)-4-methyloxacycloheptadec-7-en-2-one• (£)-4-methyloxacycloheptadec-7-en-2-one• (Z)-4-methyloxacyclooctadec-6-en-2-one• (£)-4-methyloxacyclooctadec-6-en-2-one• (Z)-4-methyloxacyclooctadec-7-en-2-one• (£)-4-methyloxacyclooctadec-7-en-2-one• (Z)-5-methyloxacycloheptadec-6-en-2-one• (£)-5-methyloxacycloheptadec-6-en-2-one• (Z)-5-methyloxacycloheptadec-7-en-2-one• (£)-5-methyloxacycloheptadec-7-en-2-one• (Z)-5-methyloxacyclooctadec-6-en-2-one• (£)-5-methyloxacyclooctadec-6-en-2-one• (Z)-5-methyloxacyclooctadec-7-en-2-one• (£)-5-methyloxacyclooctadec-7-en-2-one• (£)-oxacyclooctadec-8-en-2-one• (Z)-oxacyclononadec-7-en-2-one• (Z)-oxacyclononadec-8-en-2-one• (£)-oxacyclononadec-8-en-2-one• (£)-oxacycloicos-9-en-2-one5. Mixture of regioisomers that differ in the position of the double bond and / or of stereoisomers of compounds according to claim 4.

6. Mixture of regioisomers that differ in the position of the double bond and of stereoisomers of compounds according to claim 4.

7. Mixture according to any one of the claims 3, 5 or 6 wherein the weight ratio between regioisomers that differ in the position of the double bond and / or of the stereoisomers is between 95:5 and 5:95.

8. Odorant consisting of a compound or mixture according to any one of the claims 3 to 7.

9. Odorant consisting of a mixture according to any one of the claims 3, 5, 6, or 7.

10. Fragrance, flavor and / or deodorizing / masking compositions comprising a compound or a mixture according to any one of the claims 3 to 7.

11. Fragrance, flavor and / or deodorizing / masking compositions comprising a mixture according to any one of the claims 3, 5, 6 or 7.

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