Synthesis of 14-methyl-16-oxabicyclo[10.3.1]hexadec-12-ene

Abstract

Disclosed is a scalable process for preparing 14-methyl-16-oxabicyclo[10.3.1]hexadec-12-ene (BCE), a key intermediate for preparing the flavor ingredient 3-methylcyclopentadecanone and analogs, by reacting 3-methyl-1,5-cyclopentadecanedione (MCPD) and analogs with metal or metalloid alkoxides in high yield and purity.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. application serial number 62 / 793,569, filed on January 17, 2019, the contents of which are incorporated by reference in their entirety. Field of the Invention

[0003] The present invention relates to the field of fragrance compounds and to their synthesis on a commercial scale. Background of the Invention

[0005] 14-Methyl-16-oxabicyclo[10.3.1]hexadec-12-ene (BCE) and its isomers are used to prepare the flavor ingredient dehydrated musk ketone And useful intermediates of musk ketone.

[0006] US 4,480,107A describes the cyclodehydrogenation-dehydration of 3-methyl-1,5-cyclopentadecanediol (DIOL) by gradual addition of DIOL to a Raney copper catalyst maintained at 160-165°C / 20 Torr. The yield of BCE was 78.9% and the purity was 90%. See Scheme I, below.

[0007]

[0008] WO 2017 / 089327A1 describes cyclodehydrogenation-dehydration of DIOL by heating in the presence of a Raney copper catalyst suspended in 1-hexadecanol, wherein the vapor pressure is between DIOL and BCE. The produced BCE is continuously distilled from the reaction mixture as it is formed, thereby minimizing the formation of the hydrogenation byproduct 14-methyl-16-oxabicyclo[10.3.1]hexadecane. The yield of BCE is 80% and the purity is 92-93.7%. The process can be run continuously. DIOL is prepared by hydrogenating 3-methyl-1,5-cyclopentadecanedione (MCPD) in the presence of Raney nickel.

[0009] According to WO 2017 / 050713A1, DIOL can also be prepared in two steps by ozonolysis of 14-methylbicyclo[10.3.0][1(12)]pentadecadecene to give 14-methyl-16,17,18-trioxatricyclo[10.3.2.11,12]octadecane, which is hydrogenolyzed in the presence of molybdenum-doped Raney nickel using hydrogen in 80% yield. The main disadvantage of the preparation of DIOL disclosed in WO 2017 / 050713A1 is the use of ozonolysis, which is considered to be hazardous and unsuitable for use on a commercial scale. In addition, the intermediate ozonide (14-methyl-16,17,18-trioxatricyclo[10.3.2.11,12]octadecane) can be explosive and its subsequent hydrogenolysis requires the use of an expensive molybdenum-doped Raney nickel catalyst. See Scheme II.

[0010]

[0011] The main disadvantage of both US 4480107A and WO 2017 / 089327A1 is that MCPD must be converted into BCE in two steps through the intermediate DIOL. The dehydrogenation-dehydration of DIOL to BCE requires the use of expensive Raney copper catalysts and extended reaction times. In addition, dehydrogenation produces hydrogen, which reduces a large amount of BCE to useless by-product 14-methyl-16-oxabicyclo[10.3.1]hexadecane (saturated BCE). See Scheme III.

[0012]

[0013] WO 2017 / 089327A1 teaches that in order to minimize the formation of 14-methyl-16-oxabicyclo[10.3.1]hexadecane, 1-hexadecanol is added as a solvent, and BCE must be distilled off when it is formed. Subsequently, 1-hexadecanol is recovered, which is a complex process due to its very high boiling point (344°C / 760 mmHg).

[0014] WO 2018 / 011386A1 describes a method in which MCPD is partially reduced by sodium borohydride to give a mixture of BCE, 5-hydroxy-3-methylcyclopentadecanone (KETOL), DIOL and unreacted MCPD. See Scheme IV.

[0015]

[0016] At 60% MCPD conversion, the selectivity to BCE and KETOL was 79.8%. After treating the reaction mixture with 80% phosphoric acid in toluene under reflux, the yield of 3-methylcyclopentadecenone was 32% based on MCPD. If the unreacted MCPD is recovered and reused, the yield can be increased to 50%. This yield is not cost effective.

[0017] Therefore, there is a need for a new and simple economical process that converts MCPD directly and in high yield to BCE without these disadvantages. SUMMARY OF THE INVENTION

[0019] It has now been found that the above disadvantages are overcome by converting MCPD directly to BCE in a single step in an inert solvent in the presence of a metal or metalloid alkoxide (as shown in Scheme V below). BCE is the major product, along with trace amounts of iso-BCE (a BCE isomer). Both BCE and iso-BCE can be readily converted to dehydromuscone after treatment with an acid.

[0020]

[0021] One aspect of the present invention relates to a method for preparing 14-methyl-16-oxabicyclo[10.3.1]hexadec-12-ene (BCE), comprising the steps of: a) reacting 3-methyl-1,5-cyclopentadecanedione (MCPD) with a C1-C4 alkoxide of a metal or metalloid in an inert organic solvent and at a temperature above 80° C. to form a reaction mixture, wherein an alcohol is generated as a by-product; and b) treating the reaction mixture with an aqueous mineral acid solution. The method may also include isolating the product BCE by extraction and / or distillation.

[0022] In a particular embodiment, the present invention is directed to a process for preparing BCE comprising the steps of: a) reacting MCPD with aluminum sec-butoxide in toluene at a temperature of 80° C. to 110° C. to form a reaction mixture, b) treating the reaction mixture with hydrochloric acid; and c) isolating the product BCE by extraction and distillation.

[0023] In another aspect, the present invention provides a method for preparing an oxabicycloolefin compound of formula (II) and / or (III) (especially (II)):

[0024]

[0025] The method comprises the steps of: a) reacting a cycloalkane-1,5-dione compound of formula (I) with an alkoxide of a metal or metalloid in an inert organic solvent at elevated temperature to form a reaction mixture, the metal or metalloid being selected from the group consisting of sodium, magnesium, aluminum, boron, tin, zirconium and lanthanides; and b) treating the reaction mixture with an acidic aqueous solution;

[0026] Where R is C1-C 10 Alkyl, preferably C1-C6 alkyl, more preferably C1-C4 alkyl, and most preferably methyl or ethyl; and

[0027] n is an integer selected from 4 to 10, preferably 4 to 8, more preferably 4 to 7 and most preferably 7.

[0028] The process may also comprise isolating the product of formula (II) and / or (III), in particular the product of formula (II), by extraction and / or distillation.

[0029] In the methods disclosed herein, preferably, there is more than one molar equivalent of a metal or metalloid alkoxide relative to MCPD or the cycloalkane-1,5-dione compound of formula (I). The molar equivalent of the metal or metalloid alkoxide may range from 1 to 3 equivalents. Preferably, the molar equivalent of the metal or metalloid alkoxide ranges from 1.5 to 1.8. More preferably, there are 1.67 molar equivalents of a metal or metalloid alkoxide. The metal alkoxide of the method is preferably an aluminum alkoxide. The aluminum alkoxide is preferably aluminum sec-butoxide.

[0030] The process is preferably carried out at a temperature of 80° C. to 110° C. The inert organic solvent of the process is preferably toluene. The aqueous mineral acid solution of the process is preferably aqueous hydrochloric acid, preferably with a concentration of 20-23%. DETAILED DESCRIPTION OF THE INVENTION

[0032] It has now been found that the disadvantages of the literature methods are overcome by converting MCPD directly to BCE in a single step in an inert solvent in the presence of a metal or metalloid alkoxide (as shown in Scheme V above). The major product is 14-methyl-16-oxabicyclo[10.3.1]hexadecane (BCE), along with trace amounts of its isomer 14-methyl-16-oxabicyclo[10.3.1]hexadec-1-ene (isoBCE). Both BCE and isoBCE are readily converted to dehydromuscone by acid treatment

[0033] A large number of commercially available metal or metalloid alkoxides can be used in the method. Available metal or metalloid alkoxides include, but are not limited to, methoxides, ethoxides, propoxides, isopropoxides, butoxides, isobutoxides, sec-butoxides and tert-butoxides of metals (such as sodium, magnesium, aluminum, boron, tin, lanthanides and zirconium). Preferred alkoxides include ethoxides, isopropoxides and sec-butoxides. Preferably, the metal or metalloid alkoxide is dissolved in an inert solvent selected for the reaction. As shown in Scheme VII below, excellent results were obtained using aluminum alkoxides. MCPD is reacted by heating it in an inert organic solvent at an elevated temperature in the presence of an excess of aluminum alkoxide, thereby fully converting MCPD into BCE with high selectivity.

[0034]

[0035] The aluminum alkoxide is used in excess of the stoichiometric amount relative to the MCPD. The preferred molar range of the aluminum alkoxide is 1 to 3 molar equivalents. A particularly preferred range is 1.5 to 1.8 molar equivalents. More particularly, 1.67 molar equivalents of aluminum alkoxide is preferred.

[0036] The aluminum alkoxide may be selected from aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, aluminum butoxide, aluminum sec-butoxide and aluminum tert-butoxide. Preferably, it is aluminum isopropoxide and aluminum sec-butoxide. Aluminum sec-butoxide is particularly preferred because it is liquid at room temperature and is easy to handle.

[0037] The inert solvent may be selected from aliphatic and aromatic hydrocarbons, and aliphatic and aromatic halogenated hydrocarbons. Typical commercially available inert solvents include, but are not limited to, hexane, heptane, isooctane, toluene, xylene, dichloroethane, chlorobenzene, and 1,2-dichlorobenzene. Toluene is preferred.

[0038] For any of the above reactions, the preferred temperature range is 80° C. to 110° C. at atmospheric pressure. A particularly preferred range is 90° C. to 95° C. For example, when aluminum isopropoxide is used as the metal alkoxide, isopropanol is produced.

[0039] The reaction mixture is post-treated by adding thereto an aqueous mineral acid solution such as hydrochloric acid (HCl), sulfuric acid and phosphoric acid. A preferred mineral acid is an aqueous HCl solution having a concentration of 15% to 25%. A particularly preferred HCl concentration is 20% to 23%, which allows a clear phase separation.

[0040] KETOL is first formed in the work-up step and then converted to BCE under acidic conditions with iso-BCE as a byproduct:

[0041]

[0042] In summary, one aspect of the present invention relates to a method for preparing BCE, comprising the steps of: a) reacting MCPD with a C1-C4 alkoxide of a metal or metalloid in an inert organic solvent at a temperature above 80°C, above 85°C or above 90°C to form a reaction mixture, wherein the metal or metalloid is selected from the group consisting of sodium, magnesium, aluminum, boron, tin, zirconium and lanthanide; and b) hydrolyzing the reaction mixture with an aqueous mineral acid solution. The method may also include isolating the product BCE.

[0043] In the method, preferably, there is more than one molar equivalent of a metal or metalloid alkoxide. The molar equivalent of the metal or metalloid alkoxide may range from 1 to 3 equivalents, or from 1 to 2.5 equivalents, or from 1 to 2 equivalents, or from 1.5 to 2 equivalents relative to MCPD or the cycloalkane-1,5-dione compound of formula (I). Preferably, the molar equivalent of the metal or metalloid alkoxide ranges from 1.5 to 1.8. More preferably, there are 1.67 molar equivalents of the metal or metalloid alkoxide. The metal alkoxide of the method is preferably an aluminum alkoxide. The aluminum alkoxide is preferably aluminum sec-butoxide or aluminum isopropoxide.

[0044] The process is preferably carried out at the reflux temperature of the azeotropic solvent mixture. The process is preferably carried out at a temperature of 80°C to 110°C, or 85°C to 100°C, or 90°C to 95°C, or 90°C to 110°C, or 85°C to 105°C. The inert organic solvent is preferably toluene. The aqueous mineral acid solution is preferably aqueous hydrochloric acid solution, preferably with a concentration of 20% to 23% hydrochloric acid.

[0045] In one embodiment, the present invention is directed to a process for preparing BCE comprising the steps of: a) reacting MCPD with aluminum sec-butoxide in toluene at a temperature of 80°C to 110°C, or 85°C to 100°C, or 90°C to 95°C, or 90°C to 110°C, or 85°C to 105°C to form a reaction mixture, and b) hydrolyzing the reaction mixture with 20% to 23% aqueous hydrochloric acid.

[0046] The method may further comprise isolating the product BCE by extraction and / or distillation. In the method, preferably, more than one molar equivalent of aluminum sec-butoxide is present. The molar equivalent of aluminum sec-butoxide ranges from 1 to 3 equivalents, or 1 to 2.5 equivalents, or 1 to 2 equivalents, or 1.5 to 2 equivalents relative to MCPD or the cycloalkane-1,5-dione compound of formula (I); preferably 1.5 to 1.8 equivalents. More preferably, 1.67 molar equivalents of aluminum sec-butoxide are present.

[0047] In another aspect, the present invention provides a method for preparing an oxabicycloolefin compound of general formula (II) or (III) (especially (II)), the method comprising the steps of: a) reacting a cycloalkane-1,5-dione compound of formula (I) with a metal or metalloid alkoxide in an inert organic solvent at elevated temperature to form a reaction mixture, the metal or metalloid being selected from the group consisting of sodium, magnesium, aluminum, boron, tin, zirconium and lanthanide; and b) treating the reaction mixture with an acidic aqueous solution:

[0048]

[0049] Where R is C1-C 10 Alkyl, preferably C1-C6 alkyl, more preferably C1-C4 alkyl, and most preferably methyl or ethyl;

[0050] n is an integer selected from 4 to 10, preferably 4 to 8, more preferably 4 to 7 and most preferably 7.

[0051] The metal alkoxide used in the method is preferably an aluminum alkoxide. The aluminum alkoxide is preferably aluminum sec-butoxide or aluminum isopropoxide.

[0052] The process may also comprise isolating the product of formula (II) and / or (III), in particular the product of formula (II), by extraction and / or distillation.

[0053] In yet another aspect, the present invention provides a method for preparing an oxabicycloolefin compound of formula (V) and / or (VI) (especially (V)) from a compound of formula (IV):

[0054]

[0055] The method comprises the steps of: a) reacting a cycloalkanedione compound of formula (IV) with an alkoxide of a metal or metalloid in an inert organic solvent at elevated temperature to form a reaction mixture, the metal or metalloid being selected from the group consisting of sodium, magnesium, aluminum, boron, tin, zirconium and lanthanides; and b) treating the reaction mixture with an acidic aqueous solution;

[0056] wherein each of R1 to R8 individually and directly attached to the ring of the compounds of formula (IV), (V) and (VI) is H or C1-C 10 Alkyl, preferably C1-C6 alkyl, more preferably C1-C4 alkyl, and most preferably methyl or ethyl;

[0057] m is an integer selected from 4 to 10, preferably 4 to 8, more preferably 4 to 7 and most preferably 7; and

[0058] k is 1, 2, 3 or 4.

[0059] Each of R1 to R8 may be attached to any carbon atom on either of the two rings of the compounds of formula (IV), (V) and (VI).

[0060] The process may also comprise isolating the product of formula (V) and / or (VI), in particular the product of formula (V), by extraction and / or distillation.

[0061] Exemplary compounds of formula (V) are shown below:

[0062]

[0063] Exemplary compounds of formula (VI) are shown below:

[0064]

[0065] Other conditions and procedures described above and / or in the following examples are applicable and / or suitable for the preparation methods herein. Example

[0066] The following examples are intended to illustrate the present invention but are not intended to limit the present invention in any way.

[0067] Example 1. 14-Methyl-16-oxabicyclo[10.3.1]hexadec-12-ene (BCE) was prepared using aluminum isopropoxide.

[0068] Aluminum isopropoxide (136 g), MCPD (100 g) and toluene (200 g) were loaded into a reactor equipped with a mechanical stirrer, a reflux condenser and a thermometer. Under continuous stirring, the mixture was heated to 93 ° C under gentle reflux. Heating was continued for 6 to 7 hours. At this stage, the reaction mixture contained <0.5% MCPD, iso-BCE <2.5% and BCE>85%. The reaction mixture was cooled to 50 ° C. At 50 ° C, toluene (400 g) was added, followed by the slow addition of 350 g of 23% HCl aqueous solution. The mixture was stirred at 40 ° C for 30 minutes. The HCl aqueous phase was removed. At 45 ° C, the organic phase was washed with 200 g of 5% NaOH aqueous solution. The NaOH aqueous phase was removed. Then at 50 ° C, the organic phase was washed with 200 g of 20% phosphoric acid aqueous solution and 9% NaCl aqueous solution for 1 hour. After removal of the acidic aqueous phase, the organic phase was washed again with 180 g of 2.4% aqueous NaCl solution (pH>6).

[0069] The organic phase was distilled at atmospheric pressure to remove water (temperature about 93°C). The residue was flashed at 160°C to 185°C and 1 mmHg vacuum to give 85 g of BCE with a purity of 93%. Yield 89-93%. IR: 1668.7 cm -1. UV: 203nm; MS: M+=236, (58). m / e:221(36),207(7),194(21),178(23),165(5),149(14),135(16),121(22),109(44),95(71),81(55),69(100),55(47),41(29). NMR δ ppm (CDCl3): 0.95 (3H, d, J = 7); 1.2-1.5 (18H, m); 1.9-2.4 (5H, m); 3.8-3.9 (1H, m); 4.3-4.4 (1H, d).

[0070] Example 2. 14-Methyl-16-oxabicyclo[10.3.1]hexadec-12-ene (BCE) was prepared using aluminum sec-butoxide.

[0071] Aluminum sec-butoxide (974.9 g), MCPD (600 g) and toluene (2000 g) were charged into a reactor equipped with a mechanical stirrer, reflux condenser, thermometer and Dean-Stark trap. The mixture was stirred and the temperature was raised to 90-95° C. until a gentle reflux was maintained while methyl ethyl ketone, sec-butanol and toluene were distilled off (head temperature 52-58° C.). Heating was continued for 3-4 hours. The reaction was judged to be complete when the reaction mixture contained <0.5% MCPD, 92.4% BCE and 4.3% iso-BCE. The reaction mixture was cooled to 30° C. to be treated with 23% aqueous HCl at 50° C. for 60 minutes. The organic phase was collected by removing the aqueous phase. This water wash step was repeated three times using the following aqueous solutions: (1) 5% NaOH, 45° C., 45 minutes; (2) 20% phosphoric acid, 50° C., 1 hour; and (3) 10% sodium sulfate, 50° C., 1 hour. Subsequently, toluene was removed from the organic phase by distillation. The residue was flashed at 170-180°C / 1 mmHg to give 526 g of BCE (93% yield).

[0072] Example 3 . Preparation of KETOL using aluminum sec-butoxide.

[0073] Aluminum sec-butoxide (140 g), MCPD (76.5 g) and toluene (154 g) were charged into a reactor equipped with a mechanical stirrer, a reflux condenser and a thermometer. The mixture was heated to 93 ° C and kept at a gentle reflux for 3 hours while forming 2-butanone and sec-butanol. The reaction mixture was then cooled to room temperature and subsequently 5% sodium hydroxide solution (220 mL) and toluene (200 mL) were added. The organic phase was separated and concentrated to give KETOL. When KETOL was treated with a hydrochloric acid solution according to Example 2, BCE was formed in a yield of 92%.

[0074] Example 4. Preparation of 15-oxabicyclo[10.2.1]pentadeca-1-ene and 4-hydroxy-cyclotetradecanone.

[0075]

[0076] 15-Oxabicyclo[10.2.1]pentadeca-1-ene was obtained from 1,4-cyclotetradecanedione according to the procedure described in Example 1. Alkaline hydrolysis of the reaction mixture gave 4-hydroxy-cyclotetradecanone. See J. Am. Chem. Soc. 105, 5709-5710 (1983).

[0077]

[0078] Example 5. Preparation of 17-oxabicyclo[10.4.1]heptadeca-12-ene and 6-hydroxycyclohexadecane-1-one.

[0079]

[0080] Treatment of 1,6-cyclohexadecanedione with aluminum isopropoxide according to Example 1 gave 17-oxabicyclo[10.4.1]heptadeca-12-ene. Basic hydrolysis of the reaction mixture according to Example 3 gave 6-hydroxycyclohexadecan-1-one.

[0081]

[0082] Example 6. Preparation of 14-methyl-17-oxabicyclo[10.4.1]heptadeca-12-ene and 15-methyl-17-oxabicyclo[10.4.1]heptadeca-12-ene.

[0083]

[0084] 3-Methylcyclohexadecane-1,6-dione was reacted with aluminum sec-butoxide according to Example 2 to obtain an isomeric mixture of 14-methyl-17-oxabicyclo[10.4.1]-heptadeca-12-ene and 15-methyl-17-oxabicyclo[10.4.1]heptadeca-12-ene.

[0085] The reaction mixture was treated with 5% aqueous NaOH according to Example 3 to obtain a mixture of 6-hydroxy-3-methylcyclohexadecane-1-one and 6-hydroxy-4-methylcyclohexadecane-1-one.

[0086]

[0087] Example 7. Preparation of 14,15-dimethyl-17-oxabicyclo[10.4.1]heptadeca-12-ene.

[0088]

[0089] 3,4-dimethylcyclohexadecane-1,6-dione was reacted with aluminum isopropoxide according to Example 1 to give 14,15-dimethyl-17-oxabicyclo[10.4.1]heptadeca-12-ene. The reaction mixture was post-treated with 5% aqueous NaOH according to Example 3 to give 6-hydroxy-3,4-dimethylcyclohexadecane-1-one.

[0090]

[0091] Comparative example.

[0092] Comparative Example 1 Preparation of BCE by ruthenium-catalyzed hypochlorite oxidation of 3-methyl-1,5-cyclopentadecanediol (DIOL).

[0093] DIOL (50 g, 100%) was dissolved in 500 g of toluene. Trichlororuthenium hydrate (0.4 g) was added and the mixture was stirred at room temperature. 6 wt % sodium hypochlorite solution (640 g) was added dropwise over 2.5 hours at a rate maintaining the temperature at 25° C. to 33° C. When the addition was complete, stirring was stopped to allow phase separation. The lower aqueous phase was removed.

[0094] To the organic phase was added 33% aqueous HCl (120 mL). The temperature was raised to 80°C and stirred for 30 minutes. The organic phase was separated from the aqueous phase and washed three times with water (400 mL each time).

[0095] The wet organic phase was then distilled at atmospheric pressure using a Dean-Stark separator, during which the intermediate KETOL was converted to BCE. The toluene phase contained 72-75% BCE, 7-10% MCPD and 1% DIOL. The yield of BCE was 75-84%.

[0096] Comparative Example 2 .Preparation of BCE using Ru / Al(O)OH.

[0097] The Ru / Al(O)OH catalyst was prepared according to the procedure described by Won-Hee Kim, In Soo Park and Jaiwook Park, Organic Letters, 8(12), 2543 (2006).

[0098] DIOL (0.25 g), Ru / Al(O)OH (0.25 g) and toluene (10 mL) were charged into a reaction vessel equipped with magnetic stirring. The stirred mixture was heated to 90° C. for 10 hours and then cooled to room temperature. According to GC analysis, the reaction mixture contained 59.6% BCE, 3.7% MCPD, 1.8% KETOL and 25% unchanged DIOL.

[0099] Comparative Example 3. BCE was prepared using Shvo's catalyst.

[0100] DIOL (1 g), Shvo catalyst (0.25 g, 5 mol%) and toluene (10 mL) were charged into a reaction vessel equipped with magnetic stirring. The reaction mixture was stirred at 110° C. for 4 hours to obtain 69.3% BCE (2 isomers, ratio of 4.6:1) and 16.6% MCPD.

[0101] As disclosed herein, many numerical ranges are provided.It should be understood that, unless the context clearly states otherwise, each intermediate value (one tenth of the unit of the lower limit) between the upper and lower limits of the scope is also specifically disclosed.Each smaller range between the value or intermediate value of any record in the range of the record and the value or intermediate value of any other record in the range of the record is included in the present invention.The upper and lower limits of these smaller ranges can be independently included in the range or excluded from the range, and any one, both or both of them are included in each range in the smaller range are included in the present invention, subject to the limit clearly excluded in the recorded range.In the case where the recorded range includes one or two limits, the scope not including any one or two of the limits included is also included in the present invention.

[0102] The values ​​and dimensions disclosed herein are not to be understood as being strictly limited to the exact numerical values ​​recited. Rather, unless otherwise specified, each such value is intended to mean both the recited value and a functionally equivalent range around that value. For example, a value disclosed as "50%" is intended to mean "about 50%," which typically includes up to ±10% of the indicated numerical value of 50%.

[0103] Unless otherwise specified, all parts, percentages and ratios referred to herein and in the claims are by weight.

[0104] The terms "including," "comprising," and "containing" are intended to be non-limiting.

[0105] As used herein, the term "metalloid" refers to a chemical element that exhibits some properties of metals and some properties of non-metals, such as boron.

[0106] As used herein, the term "alkyl" means a straight or branched chain saturated hydrocarbon group containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, sometimes more preferably 1 to 6 carbon atoms ("lower alkyl") and sometimes more preferably 1 to 4 carbon atoms, which is connected to the rest of the molecular moiety by one or more single bonds. Representative examples of alkyl include, but are not limited to, methyl ("Me"), methylene (i.e., a divalent methyl group), ethyl ("Et"), ethylene, n-propyl, n-propylene, isopropyl, isopropylidene, n-butyl, sec-butyl, isobutyl, tert-butyl, n-butylidene, sec-butylidene, isobutylidene, tert-butylidene, and the like.

[0107] The term "halo" or "halogen" refers to F, Cl, Br and I, preferably Cl, Br and I.

[0108] The singular forms "a," "an," and "the" include plural referents and vice versa unless the context clearly dictates otherwise.

[0109] All publications cited herein are incorporated by reference in their entirety for all purposes.

[0110] It should be understood that the embodiments described herein should be considered to be illustrative only and not limiting the scope of the invention. Descriptions of features or aspects within each embodiment should typically be considered as available for other similar features or aspects in other embodiments.

[0111] Although several embodiments have been described in the foregoing examples, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present disclosure as defined by the following claims.

Claims

1. A method for preparing 14-methyl-16-oxabicyclo[10.3.1]hexadec-12-ene, the method comprising: reacting 3-methyl-1,5-cyclopentadecanedione with an alkoxide of a metal selected from the group consisting of sodium, magnesium, and aluminum in an inert organic solvent at a temperature above 80° C. to form a reaction mixture; and The reaction mixture is treated with an aqueous mineral acid to obtain 14-methyl-16-oxabicyclo[10.3.1]hexadec-12-ene as a product, The amount of the metal alkoxide is one molar equivalent or more than one molar equivalent relative to 3-methyl-1,5-cyclopentadecanedione.

2. The method according to claim 1, further comprising isolating the product 14-methyl-16-oxabicyclo[10.3.1]hexadec-12-ene by extraction, distillation or both.

3. The method according to claim 1, wherein the amount of the metal alkoxide is in the range of 1 to 3 molar equivalents.

4. The method according to claim 1, wherein the amount of the metal alkoxide is in the range of 1.5 to 1.8 molar equivalents.

5. The method according to claim 1, wherein the amount of the metal alkoxide is 1.67 molar equivalents. The method according to claim 1 , wherein the metal alkoxide is an aluminum alkoxide.

7. The method of claim 1, wherein the metal alkoxide is aluminum sec-butoxide.

8. The method of claim 1, wherein the inert organic solvent is selected from the group consisting of hexane, heptane, isooctane, toluene, xylene, ethylene dichloride, chlorobenzene, and 1,2-dichlorobenzene.

9. The process of claim 1, wherein the inert organic solvent is toluene.

10. The method of claim 1, wherein the temperature above 80°C is 80°C to 110°C.

11. The method according to claim 1, wherein the aqueous mineral acid solution is an aqueous hydrochloric acid solution.

12. The method according to claim 1, wherein the aqueous mineral acid solution is hydrochloric acid with a concentration of 20-23%.

13. A method for preparing 14-methyl-16-oxabicyclo[10.3.1]hexadec-12-ene, the method comprising: reacting 3-methyl-1,5-cyclopentadecanedione with aluminum sec-butoxide in toluene at a temperature of 80° C. to 110° C. to form a reaction mixture, and The reaction mixture was treated with hydrochloric acid to obtain 14-methyl-16-oxabicyclo[10.3.1]hexadec-12-ene as a product, Wherein more than one molar equivalent of aluminum sec-butoxide is present relative to 3-methyl-1,5-cyclopentadecanedione.

14. The method according to claim 13, further comprising isolating the product 14-methyl-16-oxabicyclo[10.3.1]hexadec-12-ene by extraction and / or distillation.

15. The method according to claim 13, wherein the molar range of aluminum sec-butoxide is 1 to 3 equivalents relative to 3-methyl-1,5-cyclopentadecanedione.

16. The method according to claim 13, wherein the molar range of aluminum sec-butoxide is 1.5 to 1.8 equivalents.

17. The process of claim 13 wherein 1.67 molar equivalents of aluminum sec-butoxide are present.

18. A method for preparing a compound of formula (II) and / or (III), the method comprising: reacting a compound of formula (I) with an alkoxide of a metal selected from the group consisting of sodium, magnesium and aluminum in an inert organic solvent and at a temperature above 80° C. to form a reaction mixture; treating the reaction mixture with an aqueous mineral acid solution; and separating the compounds of formula (II) and (III), Where R is C1-C 10 Alkyl; and n is an integer selected from 4 to 10, wherein more than one molar equivalent of the metal alkoxide is present relative to the compound of formula (I).

19. The method of claim 18, wherein R is a C1-C6 alkyl group.

20. The method of claim 18, wherein R is methyl or ethyl.

21. The method according to claim 18, wherein n is an integer selected from 3 to 8.

22. The method of claim 21, wherein n is 5, 6 or 7.

23. The method of claim 18, wherein the metal alkoxide is an aluminum alkoxide.

24. The method of claim 18, wherein the metal alkoxide is aluminum sec-butoxide or aluminum isopropoxide.

25. The method of claim 18, wherein the inert organic solvent is selected from the group consisting of hexane, heptane, isooctane, toluene, xylene, ethylene dichloride, chlorobenzene, and 1,2-dichlorobenzene.

26. The method of claim 18, wherein the inert organic solvent is toluene.

27. The method of claim 18, wherein the temperature above 80°C is 80°C to 110°C.

28. The method of claim 18, wherein the inorganic acid is hydrochloric acid.

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