Method for producing a MUSK fragrance intermediate using heterogeneous catalysts

Abstract

Disclosed is a method for producing a musk fragrance intermediate by reacting an alcohol with an epoxide in the presence of zeolite as catalyst.

Description

METHOD FOR PRODUCING A MUSK FRAGRANCE INTERMEDIATE USING HETEROGENEOUS CATALYSTSBackground

[0001] In the fragrance industry there is a constant demand for compounds having pleasing odor properties. Such compounds extend a perfumer's palette and result in greater product diversity for consumers. In particular, there is demand for compounds that have musk odor characteristics. Such compounds are highly esteemed in perfumery and are perhaps some of the most versatile and common compounds found in fragrance compositions. Exemplary musk fragrances include, e.g., Helvetolide (Firmenich), Romandolide (Firmenich), Serenolide (Givaudan), and Appelide (International Flavors & Fragrances Inc.) and derivatives thereof. These, and other musk fragrances are described in, e.g., WO 2002 / 096852 A1 to Givaudan SA; WO 2004 / 050595 A1 to Givaudan SA; WO 2004 / 050602 A1 to Givaudan SA; WO 2005 / 108534 A1 to Givaudan SA; WO 2011 / 29895 A2 to Givaudan SA; US 5,166,412 A to Firmenich SA; WO 2000 / 014051 A1 to Firmenich SA; WO 2009 / 034510 A2 to Firmenich SA; US 6,384,269 B1 to Firmenich SA; WO 2005 / 01222 2 A1 and EP 1492759 B1 to Symrise AG; US 2004 / 053811 A1 to International Flavors & Fragrances Inc.; and WO 2019 / 124533 A1 to Takasago International Corp.

[0002] Epoxides are versatile intermediates in organic transformations to products of interest, due to their availability and their capability to react with a large amount of nucleophiles such as water, alcohols, amines, hydrides or halides. In particular, the O- alkylation of alcohols with epoxides through ring opening reactions is a common route for the production of / / -alkoxyalcohols, which are compounds of interest to the pharmaceutical, solvents and fragrance industry.

[0003] The main challenges for these reactions are, on the one hand, the tendency of epoxides, especially terminal epoxides, to polymerize, which will directly affect overall selectivity to the O-alkylation product. Thus, it is required to work under mild conditions. On the other hand, the higher reactivity of the reaction product towards a second O- alkylation with epoxides results in low performance (low selectivity) reactions.

[0004] In order to overcome these inherent limitations of the O-alkylation of alcohols, one can use a selective homogeneous catalyst, in which the mentioned limitation is solved homogeneously with reactants in the reaction media, or use a heterogenous catalyst, which includes solid active materials in which reaction takes place between molecules absorbed and activated on its surface-active sites. A catalyst, in general, allows activating molecules and decreasing energy barriers (activation energy), favoringthe formation of intermediate compound precursors of the desired product against intermediate compound precursors leading to the formation of side products. Thus, a catalyst accelerates reaction rates towards desired compounds vs undesired ones, allowing reactions to be performed faster, under milder conditions and with better selectivity.

[0005] Different heterogeneous catalysts, containing both Bronsted and Lewis acid sites, have been described as catalysts for the O-alkylation of alcohols with epoxides with a limited success in terms of performance or catalyst stability. For instance, polymer resin supported cobalt-salen [Feng et al., Chem. Cat. Chem.2013, 5, 3636] or metal containing zeolites [Deshpand et al., J. Catal. 2019, 370, 46], [Manjunathan et al., Sci Rep, 2021 , 11 , 15718], Thus, according to the literature known to the inventors, Lewis and / or Bronsted acids are active for the ring opening reaction of epoxides with alcohols under mild conditions. However, the catalytic performance is highly dependent on the type of organic substrates, nature of active sites and the textural properties of the material.

[0006] Nowadays, most common industrial methods to produce this type of compounds via O-alkylation reaction makes use of homogeneous catalytic system, such as SnCh, which is used often in equal stoichiometric amounts as the main reactant. In addition, current industrial alcohol O-alkylation processes operate at low conversion in diluted systems. The combination of both allows smoothing the selectivity loss by formation of an intermediate adduct of the metal salt and the desired product. Then, the final product is recovered by means of downstream work-up steps involving washing with strong acid, typically HCI, requiring the use of glass-line reactor, separation of organic and aqueous streams and, finally, neutralization or organic stream with caustic. Therefore, current alcohol o-alkylation processes are typically low efficient and produce substantial amounts of organic (solvent) and aqueous waste due to required downstream workups.

[0007] In view of these problems and given the value of these musk fragrances, there remains a need for a cost effective, high yield and, specially, more environmentally friendly method for producing said compounds.Summary of the Invention

[0008] According to one aspect, the invention relates to a method for producing a musk fragrance intermediate {e.g., a musk fragrance intermediate of Formula (I), in particular demol) comprises reacting an alcohol {e.g., an alcohol of Formula (II), inparticular cyclademol) with an epoxide (e.g., an epoxide of Formula (III), in particular isobutylene oxide) in the presence of a large pore zeolite with a faujasite structure (code FAU by international Zeolite association) containing Silicon (Si) and aluminum (Al) in a Si to Al mol ratio in the range of 2.5 to 250, preferably in the range of 10 to 150, more preferably in the range of 50-85, and at least one of tin (Sn), Zinc (Zn), Iron (Fe), zirconium (Zr), cobalt (Co), or Copper (Cu), or combinations thereof which functions as a solid zeolite-based catalyst thereby producing the musk fragrance intermediate.

[0009] As described in “The Atlas of Zeolite Framework Types” (C. Baerlocher, WM Merier, DH Olson, Sixth revised edition ed.; Elsevier, BV: 2007), “the faujasite framework consists of sodalite cages which are connected through hexagonal prisms. The pore, which is formed by a 12-membered ring, has a relatively large diameter of 7.4 A. The inner cavity has a diameter of 12 A and is surrounded by 10 sodalite cages. The FAU framework has the following properties: the unit cell is cubic; Pearson symbol cF576, symmetry Fd3m, No. 227 and a lattice constant 24.7 A.

[0010] According to a first aspect of the invention, a method for producing a musk fragrance intermediate is provided. Said method comprising reacting an alcohol with an epoxide in the presence of a zeolite-based catalyst thereby producing a musk fragrance intermediate.

[0011] As shown in the Example section, a zeolite-based catalyst according to the disclosure, for example a partially dealuminated Si / AI-based zeolite, optionally comprising a further metal, can be operated as a “true” catalyst so that it can be recovered and regenerated employing a simple procedure, so it can be reused with no activity loss; and it prevents side reactions. Further, it enables operation at higher temperature with higher activity and higher mass selectivity.

[0012] Musk fragrance intermediate.In one example, the musk fragrance intermediate has the structure of Formula (I):wherein n represents 1 or 0,each R1, independently from each other, represents a hydrogen atom or a methyl or ethyl group, or the two R1taken together represent a (CH2)mgroup, wherein m represents 3, 4, or 5; each R2, independently from each other, represents a hydrogen atom or a methyl or ethyl group, or the two R2taken together represent a (CH2)mgroup, wherein m represents 3, 4, or 5; andR3represents a phenyl group optionally substituted, a saturated or unsaturated Cs- Ce cyclic hydrocarbon moiety optionally substituted, a CH(R4)2 moiety, or R4CH=CR4moiety, wherein R4represents a Ci-Ce alkyl or alkenyl group optionally substituted.

[0013] In some examples, R3may be substituted by at least one C1-C3 alkyl group. In some examples, R3may be substituted by 1 , 2 or 3 C1-C3 alkyl groups. In some examples, R3can be substituted by 2 C1-C3 alkyl groups. The C1-C3 alkyl groups may be a methyl, an ethyl or a propyl group.

[0014] In some examples, R3may be substituted by 2 methyl groups.

[0015] In some examples, R3may be a saturated or unsaturated Cs-Ce cyclic hydrocarbon moiety, for example a Ce cyclic hydrocarbon moiety, substituted by 2 methyl groups.

[0016] In some examples, R4may be substituted by at least one C1-C3 alkyl group. In some examples, R4may be substituted by 1 , 2 or 3 C1-C3 alkyl groups. In some examples, R4can be substituted by two C1-C3 alkyl groups. The C1-C3 alkyl groups may be a methyl, an ethyl or a propyl group.

[0017] Alcohol. In one example, the alcohol has the structure of Formula (II):Wherein each R2, independently from each other, represents a hydrogen atom or a methyl or ethyl group, or the two R2taken together represent a (CH2)mgroup, wherein m represents 3, 4, or 5; and R3represents a phenyl group optionally substituted, a saturated or unsaturated Cs-Ce cyclic hydrocarbon moiety optionally substituted, a CH(R4)2 moiety, or R4CH=CR4moiety, wherein R4represents a Ci-Ce alkyl or alkenyl group optionally substituted.

[0018] In some examples, R3may be substituted by at least one C1-C3 alkyl group. In some examples, R3may be substituted by 1 , 2 or 3 C1-C3 alkyl groups. In someexamples, R3can be substituted by two C1-C3 alkyl groups. The C1-C3 alkyl groups may be a methyl, an ethyl or a propyl group.

[0019] In some examples, R3may be substituted by 2 methyl groups.

[0020] In some examples, R3may be a saturated or unsaturated Cs-Ce cyclic hydrocarbon moiety, for example a Ce cyclic hydrocarbon moiety, substituted by 2 methyl groups.In some examples, R4may be substituted by at least one C1-C3 alkyl group. In some examples, R4may be substituted by 1 , 2 or 3 C1-C3 alkyl groups. In some examples, R4can be substituted by 2 C1-C3 alkyl groups. The C1-C3 alkyl groups may be a methyl, an ethyl or a propyl group.

[0021] Epoxide. In one example, the epoxide has the structure of Formula (III):wherein each R1, independently from each other, represents a hydrogen atom or a methyl or ethyl group, or the two R1taken together represent a (CH2)mgroup, wherein m represents 3, 4, or 5.

[0022] The following describes examples of the musk fragrance intermediate, alcohol, epoxide and a zeolite-based catalyst.

[0023] In one example, the musk fragrance intermediate is 2-[1-(3,3- dimethylcyclohexyl)ethoxy]-2-methylpropan-1-ol) (Demol).

[0024] In one example, the alcohol is (1-(3,3-dimethylcyclohexyl)ethanol)(Cyclademol).

[0025] In one example, the epoxide is isobutylene oxide.

[0026] In one example, the zeolite-based catalyst comprises a large pore zeolite with a FAU structure comprising silicon (Si) and aluminum (Al) in a Si / AI mol ratio in the range of 2.5 to 250, preferably in the range of 10 to 150, more preferably in the range of 50-85, and at least one of tin (Sn), iron (Fe), cobalt (Co), copper (Cu), zinc (Zn) or zirconium (Zr) or combinations thereof.

[0027] The at least one metal selected from tin (Sn), iron (Fe), cobalt (Co), copper (Cu), zinc (Zn), or zirconium (Zr) or combinations thereof, can be incorporated into the FAU structure by any of the procedures well-known in the state of the art, such as direct synthesis, ion exchange, incipient wetness impregnation, wet impregnation or grafting, among others.

[0028] The metal may be incorporated in framework positions.

[0029] In a preferred example, the zeolite-based catalyst is a Sn-FAll.

[0030] In one example, the Sn content is ranging from 0.01 to 5.00 wt%, such as 0.05 to 3.00 wt% or 0.05 to 2.00 wt%

[0031] In one example, the method is carried out at a reaction temperature between 20 and 150°C, preferably in the range of 35 to 120 °C, more preferably in the range of 50-70 °C.

[0032] In one example, the method is carried out at a pressure between 1 and 30 bar, preferably in the range of 500 mbar to 10 bar, and more preferably under atmospheric pressure.

[0033] In one example, the method is carried out at a pressure between 100 mbar and 30 bar, preferably in the range of 500 mbar to 10 bar, and more preferably under atmospheric pressure.

[0034] In a specific example, the method comprises the following steps;

[0035] a) adding the alcohol to a reactor comprising the zeolite-based catalyst, where the zeolite-based catalyst comprises a large pore FAU zeolite with a Lewis acid function.

[0036] b) adding the epoxide to the reactor comprising the zeolite-based catalyst and the alcohol by means of a controlled continuous flow, thereby creating a reaction mixture;

[0037] c) producing the musk fragrance intermediate within the reactor by performing an O-alkylation of the alcohol by the epoxide, catalyzed by the zeolite-based catalyst

[0038] d) separating the zeolite-based catalyst from the reaction mixture, regenerating the zeolite-based catalyst and reusing the zeolite-based catalysts as described in steps a) to c).

[0039] In a specific example, the method comprises the following steps;

[0040] a) adding the alcohol to a reactor comprising the zeolite-based catalyst, where the zeolite-based catalyst comprises a large pore FAU zeolite with a Lewis acid function.

[0041] b) adding the epoxide to the reactor comprising the zeolite-based catalyst and the alcohol by means of a controlled continuous flow, thereby creating a reaction mixture;

[0042] c) producing the musk fragrance intermediate within the reactor by performing an O-alkylation of the alcohol by the epoxide, catalyzed by the zeolite-based catalyst

[0043] d) obtaining directly the desired product from the zeolite-based catalyst, with no need of performing any additional steps comprising neutralization, hydrolysis and extraction;

[0044] e) separating the zeolite-based catalyst from the reaction mixture, regenerating the zeolite-based catalyst and reusing the zeolite-based catalysts as described in steps a) to c) with no performance loss.Brief Description of Figures

[0045] The above objects and other advantages of the invention will become more readily apparent upon reading the following description and drawings, in which:

[0046] FIG. 1 shows a DRUV-VIS spectra of acid Sn-doped HLISY catalysts.

[0047] FIG. 2 shows a DRUV-VIS spectra of Dealuminated Sn-doped USY catalysts.Detailed Description of the Invention

[0048] The examples provided in the detailed description are merely examples and should not be used to limit the scope of the claims in any claim construction or interpretation.

[0049] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having” or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Further, unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0050] Also, use of “a” or “an” are used to describe elements and components described herein. This is done merely for convenience and to give a general sense of the scope of the invention. This description should be read to include one or at least one and the singular also includes the plural unless it is obvious that it is meant otherwise.

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of examples of the present invention, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0052] When an amount, concentration, or other value or parameter is given as either a range, preferred range or a list of upper preferable values and / or lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. Where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range. For example, when a range of “1 to 10” is recited, the recited range should be construed as including ranges “1 to 8,” “3 to 10,” “2 to 7,” “1.5 to 6,” “3.4 to 7.8,” “1 to 2 and 7-10,” “2 to 4 and 6 to 9,” “1 to 3.6 and 7.2 to 8.9,” “1-5 and 10,” “2 and 8 to 10,” “1.5-4 and 8,” and the like.

[0053] The present specification illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations that are not specifically disclosed herein. While compositions and methods are described herein in terms of “comprising” various components or steps, the compositions and methods also can “consist essentially of” or “consist of’ the various components or steps, unless stated otherwise.

[0054] A person of ordinary skill in the art appreciates that some chemical compounds in this specification have chiral center, carbon-carbon double bond, and / or cyclic structure. Unless explicitly indicated, a chemical compound in this specification includes its stereoisomers, such as enantiomers and diastereomers.

[0055] Musk fragrance intermediate. Within the disclosure, the expression “musk fragrance intermediate” intends to refer to a compound usable in the synthesis of a musk fragrance according to the method as disclosed herein. In some examples and comprising a hydroxy alkyl ether-based structure, R-O-R'-OH, where R is -(CR2R2)n-R3and R’ is -(CH2-CR1R1)-, with R1, R2, and R3being as defined herein.

[0056] Alcohol. Within the disclosure, the term “alcohol” intends to refer to organic compounds characterized by the presence of at least one hydroxyl (-OH) functional groups attached to a carbon atom, and being of general formula R-OH, where R represents an alkyl group. Herein, alcohol intends to refer to primary, secondary and tertiary alcohols. In some examples, “Alkyl” intends to refer to linear, branched, saturated or unsaturated, optionally substituted with a saturated or unsaturated cyclic alkyl group, and comprising from 6 to 16 carbon atoms.

[0057] Epoxide. Within the disclosure, the term “epoxide” intends to refer to a threemembered ring structure consisting of two carbon atoms and one oxygen atom, each of the carbon atom being, independently of the other, substituted by H, a linear or branched,saturated or unsaturated Ci-Ce alkyl group, or being part of a saturated or unsaturated C4- C7 cyclic alkyl.

[0058] Zeolite-based catalyst. Within the disclosure, the expression “zeolite-based catalyst” intends to refer to catalyst comprising a three-dimensional, microporous, crystalline, aluminosilicate-based structure.

[0059] Partially dealuminated. Within the disclosure, the expression “partially dealuminated” used in connection with “zeolite-based catalyst” intends to refer to a zeolite modified via post-synthesis methods as to obtain a Si / AI ratio higher than that of zeolite as synthetized. The dealumination ranges of a given zeolite may be influenced by different factors. Those factors are well-known to a skilled person and may inclide the zeolite topology, the Si / AI ratio of the framework (as synthetized), the crystal size, or the number of Bronsted acid sites interacting with the framework or the number of defect sites. Dealuminization may be carried out by means of a controlled process to remove a portion of the aluminum atoms from its aluminosilicate framework. Dealumination, typically involves treatments such as acid leaching, steaming, or chemical extraction with or without subsequent washing to remove extra-framework aluminium species (EFAI) depending on the desired properties. The zeolite framework of a partially dealuminated zeolite has a higher Si / AI ratio compared with the initial, “non-dealuminated”, zeolite, due to the partial removal of aluminum atoms. A partially dealuminated zeolite may have an increase of the Si / AI ratio of about 2 to about 20-fold compared with the initial “nondealuminated” zeolite, for example of about 4 to about 18-fold, or about 8 to about 16- fold, or about 10 to about 14-fold. A partially dealuminated zeolite may have a Si / AI ratio equal to or above 25, preferably equal to or above 40, most preferably equal to or above 70.

[0060] Demol. Demol is (2-[1-(3,3-dimethylcyclohexyl)ethoxy]-2-methylpropan-1-ol).

[0061] The musk fragrance Helvimor is produced via a 2-step process from cyclademol (1-(3,3-dimethylcyclohexyl)ethanol) (Scheme 1). The key intermediate in this process is Demol (2-[1-(3,3-dimethylcyclohexyl)ethoxy]-2-methylpropan-1-ol), which has been synthesized from cyclademol using BF3 (see EP 2200963 B1) or stoichiometric amounts of SnCh as catalysts. Due to the use of high amounts of SnCh (26 wt%), the yield per pass is very low (approximately 28 wt%). The present specification provides a simple, commercially feasible method for producing Demol using a large pore zeolite with a FAU structure containing silicon (Si) and aluminium (Al) in a Si to Al mol ratio in the range of 2.5 to 250, preferably in the range of 10 to 150, more preferably in the range of 50-85, and at least one of tin (Sn), iron (Fe), zinc (Zn), cobalt (Co), copper (Cu) orzirconium (Zr) or combinations thereof as the catalyst. This catalyst provides an increase in the selectivity to Demol as compared to the use of SnCh. Moreover, there is a significant reduction in the amount of solvent used. Most importantly, the zeolite-based catalyst enables a simplified process whereby the desired product is obtained directly in one step from the reactants, preventing the need of intensive downstream workup in (chloride) acidic media. This means a regular stainless-steel reactor can be used while product distillation requirements are substantially reduced, which simplifies production and saves manufacturing costs. Also, a significant reduction of waste-water produced is achieved.

[0062] Accordingly, this present specification provides a method for producing a musk fragrance intermediate by reacting a suitable alcohol with an alkylating agent, in particular an epoxide, in the presence of a catalyst comprising a large pore zeolite with a FAU structure comprising silicon (Si) and aluminum (Al) in a Si to Al mol ratio in the range of 2.5 to 250, preferably in the range of 10 to 150, more preferably in the range of 50-85, and and at least one of tin (Sn) iron (Fe), cobalt (Co), copper (Cu), zinc (Zn), or zirconium (Zr), or combinations thereof, thereby selectively achieving O-alkylation of the alcohol and producing the musk fragrance intermediate.

[0063] The large pore zeolite has a microporous type FAU structure according to IUPAC nomenclature. More information related to this structure can be found e.g. in The Atlas of Zeolite Framework Types (C. Baerlocher, WM Merier, DH Olson, Sixth revised edition ed.; Elsevier, BV: 2007), the disclosure of which is incorporated by reference herein.

[0064] Example of a musk fragrance intermediate. In particular aspects, this specification provides for the production of a musk fragrance intermediate of Formula (I):wherein n represents 1 or 0, each R1, independently from each other, represents a hydrogen atom or a methyl or ethyl group, or the two R1taken together represent a (CH2)mgroup, m representing 3,4, or 5;each R2, independently from each other, represents a hydrogen atom or a methyl or ethyl group, or the two R2taken together represent a (CH2)mgroup, m representing 3, 4, or 5; andR3represents a phenyl group optionally substituted, a saturated or unsaturated Cs- Ce cyclic hydrocarbon moiety optionally substituted, or a CH(R4)2, or R4CH=CR4moiety, R4representing a Ci-Ce alkyl or alkenyl group optionally substituted.

[0065] According to particular aspects of the teachings of this specification, the compound of Formula (I) is one in which n is 1 , each R1is independently a hydrogen atom or methyl group, each R2is independently a hydrogen atom or methyl group, and R3represents a phenyl group optionally substituted, a saturated or unsaturated Cs-Ce cyclic hydrocarbon moiety optionally substituted, or a CH(R4)2, or R4CH=CR4moiety, R4representing a Ci-Ce alkyl or alkenyl group optionally substituted.

[0066] In some examples, R3may be substituted by at least one C1-C3 alkyl group. In some examples, R3may be substituted by 1 , 2 or 3 C1-C3 alkyl groups. In some examples, R3can be substituted by two C1-C3 alkyl groups. The C1-C3 alkyl groups may be a methyl, an ethyl or a propyl group.

[0067] In some examples, R3may be substituted by 2 methyl groups.

[0068] In some examples, R3may be a saturated or unsaturated Cs-Ce cyclic hydrocarbon moiety, for example a Ce cyclic hydrocarbon moiety, substituted by 2 methyl groups.

[0069] In some examples, R4may be substituted by at least one C1-C3 alkyl group. In some examples, R4may be substituted by 1 , 2 or 3 C1-C3 alkyl groups. In some examples, R4can be substituted by two C1-C3 alkyl groups. The C1-C3 alkyl groups may be a methyl, an ethyl or a propyl group.

[0070] In some aspects, optional substituents of R3are one, two or three C1-C3 alkyl groups, C1-C3 alkenyl groups, or C1-C3 alkoxy groups. In particular, optional substituents of R3are one, two or three methyl or ethyl groups. Non-limiting typical examples of R3groups include 3,3-dimethyl-cyclohexyl, 3,3-dimethylcyclohex-1-en-1-yl, 4-methyl-pent- 2-en-2-yl, 5-methyl-cyclohex-3-en-1-yl, and 2-methyl-cyclohexyl. In particular aspects, the musk fragrance intermediate of Formula (I) is demol (2-[1-(3,3- dimethylcyclohexyl)ethoxy]-2-methylpropan-1-ol).

[0071] In one example, the alcohol used as the starting compound is an alcohol of Formula (II):wherein each R2, independently from each other, represents a hydrogen atom or a methyl or ethyl group, or the two R2taken together represent a (CH2)mgroup, m representing 3, 4, or 5; andR3represents a phenyl group optionally substituted, a saturated or unsaturated Cs- Ce cyclic hydrocarbon moiety optionally substituted, or a CH(R4)2, or R4CH=CR4moiety, R4representing a Ci-Ce alkyl or alkenyl group optionally substituted. In particular aspects, the alcohol of Formula (II) is cyclademol (1-(3,3-dimethylcyclohexyl)ethanol).

[0072] In some examples, R3may be substituted by at least one C1-C3 alkyl group. In some examples, R3may be substituted by 1 , 2 or 3 C1-C3 alkyl groups. In some examples, R3can be substituted by two C1-C3 alkyl groups. The C1-C3 alkyl groups may be a methyl, an ethyl or a propyl group.

[0073] In some examples, R3may be substituted by 2 methyl groups.

[0074] In some examples, R3may be a saturated or unsaturated Cs-Ce cyclic hydrocarbon moiety, for example a Ce cyclic hydrocarbon moiety, substituted by 2 methyl groups.

[0075] In some examples, R4may be substituted by at least one C1-C3 alkyl group. In some examples, R4may be substituted by 1 , 2 or 3 C1-C3 alkyl groups. In some examples, R4can be substituted by two C1-C3 alkyl groups. The C1-C3 alkyl groups may be a methyl, an ethyl or a propyl group.

[0076] In some aspects, optional substituents of R3are one, two or three C1-C3 alkyl groups, C1-C3 alkenyl groups, or C1-C3 alkoxy groups. In particular, optional substituents of R3are one, two or three methyl or ethyl groups. Non-limiting typical examples of R3groups include 3,3-dimethyl-cyclohexyl, 3,3-dimethylcyclohex-1-en-1-yl, 4-methyl-pent- 2-en-2-yl, 5-methyl-cyclohex-3-en-1-yl, and 2-methyl-cyclohexyl.

[0077] Exemplary epoxides. Epoxides are cyclic ethers with three-membered cyclic rings composed of an oxygen atom attached to two adjacent carbon atoms. Epoxides of use in the method of this invention may have from 3 to 25 carbon atoms and one epoxy group. Exemplary epoxides include ethylene oxide, propylene oxide (1 ,2-propene oxide), butylene oxide (1 ,2-butene oxide), pentylene oxide (also known as 1 ,2-epoxypentane), hexylene oxide (also known as 1 ,2-epoxyhexane), octylene oxide (also known as 1 ,2- epoxyoctane), nonylene oxide (also known as 1 ,2-epoxynonane), decylene oxide (alsoknown as 1 ,2-epoxydecane), isobutylene oxide, 4-methyl-1 -pentylene oxide, and styrene oxide. In certain aspects, the epoxide used in the method of this invention is an epoxide of Formula (III):wherein each R1, independently from each other, represents a hydrogen atom or a methyl or ethyl group, or the two R1taken together represent a (CH2)mgroup, m representing 3, 4, or 5. In particular aspects, the epoxide used in the process of the invention is isobutylene oxide.

[0078] Zeolite-based catalysts / USY. In one example, the method of the invention is carried out in the presence of a zeolite-based catalyst, and the zeolite-based catalyst comprises a large pore zeolite comprising silicon (Si), aluminium (Al), tin (Sn), on (Fe), zinc (Zn), cobalt (Co), copper (Cu), or zirconium (Zr) or combinations thereof. In another example, a zeolite-based catalyst consists of a USY zeolite with a FAU structure comprising silicon (Si) and aluminum (Al) in a Si to Al mol ratio in the range of 2.5 to 250, preferably in the range of 10 to 150, more preferably in the range of 50-85, or in the range of 65 to 75, or may be 70. In another example, a zeolite-based catalyst consists of a USY zeolite with a FAU structure comprising silicon (Si) and aluminum (Al), and at least one of tin (Sn), iron (Fe), zinc (Zn), cobalt (Co), copper (Cu), zirconium (Zr) or aluminum (Al) or combinations thereof. In another example, a zeolite-based catalyst consists of a USY zeolite with a FAU structure comprising silicon (Si) and aluminum (Al) in a Si to Al mol ratio in the range of 2.5 to 250, preferably in the range of 10 to 150, more preferably in the range of 50-85, and at least one of tin (Sn), iron (Fe), zinc (Zn), cobalt (Co), copper (Cu), zirconium (Zr) or aluminum (Al) or combinations thereof. As known in the art, a standard zeolite is usually formed by silicon (Si) and aluminum (Al) and does not include a metal such as tin (Sn), iron (Fe), zinc (Zn), cobalt (Co), copper (Cu) or zirconium (Zr).

[0079] In some examples, the metal is incorporated in framework positions.

[0080] In a specific example, the zeolite contains tin, i.e., a Sn-zeolite. In some examples, the Sn content is ranging from 0.01 to 5.00 wt%, such as 0.05 to 3.00 wt% or 0.05 to 2.00 wt%. In some examples, the Sn content is ranging from 0.2 to 3.0 wt%. In some examples, the Sn content is about 0.5 wt%, 1.5 wt% or 3.0 wt%.

[0081] In some examples, the zeolite is a Zr-zeolite. In some examples, the Zr content is ranging from 0.05 to 5.00 wt%, such as 0.1 to 3.00 wt% or 0.5 to 2.00 wt%.

[0082] In some examples, the zeolite is a Fe-zeolite. In some examples, the Fe content is ranging from 0.05 to 5.00 wt%, such as 0.1 to 3.00 wt% or 0.5 to 2.00 wt%.

[0083] In another specific example, the zeolite is of type Y, i.e., a Y zeolite. The aluminum component in zeolite Y can be partly removed by acid-treatment and / or steamtreatment, and the resulting faujasite is called USY (Ultrastable zeolite Y). In a specific example, the zeolite is an ultrastable Y (USY) zeolite.

[0084] A partial dealumination of the zeolite can be achieved by means of thermal treatments at temperatures above 500 °C, by hydrothermal treatments combined with acid treatments, or by a combination of the preceding methods. These modification procedures are well known to a person skilled in the art (see for instance Introduction to Zeolite Science and Practice, Stud. Surf. Sci. Catal. Vol. 137, by Herman van Bekkum, pp. 267-268, the disclosure of which is incorporated herein by reference). In some examples, the zeolite is a partially dealuminated zeolite.

[0085] Exemplary Zeolite in a zeolite-based catalyst. In a preferred example, the zeolite is of ultrastable Y type and contains tin, i.e. a Sn-USY zeolite. Sn-USY is an ultrastable Y zeolite containing Sn. In a preferred example, Sn is incorporated into the zeolite framework, which forms the crystalline structure of the zeolite composed originally by Si and Al atoms, and occupies very specific, tetrahedral, positions.

[0086] Reaction Temperature. The reaction temperature at which a musk fragrance intermediate of Formula (I) is prepared, that is, the reaction temperature in the methods of this specification, is ideally between 20°C and 150°C, or more preferably in the range of between 30°C and 55°C, such as 50°C. In some examples, the temperature may vary in the range of 35 to 120 °C, more preferably in the range of 50-70 °C. In some examples, the reaction temperature in the methods of this specification, is ideally between 20°C and 150°C. In some examples, the temperature may vary in the range of 30 to 90 °C.

[0087] In a particular aspect, demol is prepared by reacting cyclademol with isobutylene oxide in the presence of Sn-Y zeolite at a reaction temperature in the range of 20 and 150°C, or of 20°C and 100°C, or more preferably in the range of between 30°C and 55°C, such as 50°C. The method is carried out at a pressure between 100 mbar and 30 bar, preferably in the range of 500 mbar to 10 bar, and more preferably under atmospheric pressure. The O-alkylation reaction is carried out at a pressure ranging from 1 to 30 bar. Ideally, the reaction is carried out at atmospheric pressure in batch or semibatch, or continuous mode. However, in some cases, a person of ordinary skill in the art can readily modify the pressure conditions in the reaction so that the reaction may be carried out under reduced pressures conditions, e.g., between 0.5 and 100 mbar.

[0088] Mole ratio. In some aspects, the mole ratio (also expressed herein as equiv. or Eq.) of zeolite-based catalysts to alcohol {e.g., cyclademol) is in a range below 1 :1 , for example of 0.001 :1 to 0.5:1 , or in the range of 0.005:1 to 0.3:1 , or in the range of 0.01 to 0.2, or in the range of 0.02 to 0.15, or in the range of 0.05 to 0.1. In some aspects, the mole ratio (also expressed herein as equiv. or Eq.) of metal to alcohol {e.g., cyclademol) is in the range of 0.001 to 0.5, or more preferably in the range of 0.005 to 0.30, or most preferably in the range of 0.005 to 0.2. In other aspects, the mole ratio of epoxide e.g., isobutylene oxide) to alcohol {e.g., cyclademol) is in the range of 0.5 to 2.0, more preferably 0.8 to 1.4, or most preferably 1.0 to 1.2. In some aspects, the alcohol {e.g., cyclademol) and the catalyst are fed into a reaction zone, followed by the addition of epoxide {e.g., isobutylene oxide) into the reaction zone at the reaction temperature continuously or in portions {e.g., in two or more portions). In other aspects, the amount of catalyst (metal + FAU support) is less than 20 wt% of the reaction mixture before adding the epoxide, less than 18 wt% of the reaction mixture, less than 15 wt% of the reaction mixture, less than 10 wt% of the reaction mixture, or less than 8 wt% of the reaction mixture. Preferably, the amount of catalyst is about 5 wt% of the reaction mixture.

[0089] The present method provides the advantage of overall improvements in yield and process productivity, including a decrease in the amount of catalyst, decrease in the reaction time, and increase in the percent conversion as compared to using SnCh. Moreover, in some aspects, the reaction does not require the use of a solvent. Most importantly, as compared to previous production procedures, the present invention discloses the finding and use of a true catalyst, therefore employed in a catalytic amount and, most importantly, allowing to directly obtain the desired product with high selectivity without the need to apply the typical downstream workup steps (acid quenching and basic hydrolysis) required when using a homogenous catalyst. As such, the present reaction provides for reduced organic and water waste streams production and manufacturing costs associated with the preparation of musk fragrance intermediates as compared to using SnCh.Example 1 : Conventional Process for Synthesizing Helvimor from Cyclademol using SnCh (Scheme 1) (Prior Art)SCHEME 1

[0090] In general, cyclademol, catalyst and other reagents (solvent, internal standard, etc.) are loaded in the reactor. When the desired temperature is reached, isobutylene oxide addition starts. Samples are taken, analyzed by gas chromatography and when the reaction is finished, the crude product is directly quenched with acid hydrolysis using diluted hydrochloric acid. The product is washed with water and neutralized with diluted sodium hydroxide. The organic crude product is distilled with a fractional column in order to recover unreacted Cyclademol and Demol.

[0091] Demol and sodium hydroxide (0.11 wt%) as catalyst are loaded into a reactor. At 110°C, propionic anhydride (1.3 eq) addition begins. When addition is finished, the temperature is increased to 130°C. The reaction is finished when Demol < 1% by gas chromatography. The crude product is directly quenched with sodium hydroxide solution (1.5 eq NaOH). The product is washed with water and hexane is used to facilitate the separation between the aqueous and organic phase. The final organic phase is distilled to obtain Helvimor.Example 2: Preparation of Sn-USY catalysts, examples of zeolite-based catalysts

[0092] Various zeolite-based catalysts were tested for their ability to catalyze the conversion of cyclademol and isobutylene oxide to demol.

[0093] Commercially supplied USY zeolite was used as the parent material for the preparation of this set of catalysts.

[0094] HUSY. An example of commercially available USY is CBV720 supplied by Zeolyst International in its protonic form and with a Si / AI molar ratio of 15 (HUSY). HUSY zeolite was used as supplied and after applying a dealumination treatment for reducingits aluminum content. HLISY zeolite is the acid form of the ultra-stable Y zeolite (commercial catalyst). Different Sn contents were then incorporated either in the parent or in the dealuminated USY by different procedures as detailed below.

[0095] The parent HLISY zeolite was mixed with concentrated nitric acid (HNO3, 69%) in a liquid to solid ratio of 25 mL / g and stirred under reflux at 100°C for 21 h. The recovered suspension was cooled down to room temperature and diluted with distilled water. The solids were recovered by filtration, washed extensively with distilled water until neutral pH and finally dried overnight at 100°C.

[0096] DHUSY. The dealuminated zeolite is named as DHLISY and has a Si / AI molar ratio in the range of 65 to 75, preferably 70.

[0097] Preparation by IWI. Sn / LISY catalysts with Sn contents in the range of 0.2 to 3.0 wt% were prepared by incipient wetness impregnation (IWI). Typically, for 1 g of zeolite (HLISY or DHUSY), the required amount of tin(ll) acetate was dissolved in 2.3 mL of toluene. Then the solution was added dropwise to the solid while carefully mixing with a spatula. The samples were dried for 2 h at 100°C to remove the toluene. The dried solids were then treated in N2 flow (100 mL / min) at 550°C for 3 h, and finally calcined in air flow (100 mL / min) at 550°C for 3 h.Example 3: Preparation of Zr-USY catalysts, examples of a zeolite-based catalysts

[0098] Zr / USY with 1 .6 wt% Zr has been prepared by IWI. Typically, for 1 g of zeolite DHUSY, the Zr precursor, ZrOCl2'8H2O, was dissolved in 2.2 mL of mili-Q water and added dropwise to the solid while carefully mixing with a spatula. After drying at 100 °C overnight, the sample was calcined in a muffle oven at 600 °C for 8 h with a heating rate of 2 °C / min.Example 4: Preparation of Cu-USY catalysts, examples of zeolite-based catalysts

[0099] Cu / USY with 1 .5 wt% Cu has been prepared by IWI. For 1g of zeolite DHUSY, 53.23 mg of Cu(NO3)2'2.5H2O were dissolved in 2.2 mL of mili-Q water and added dropwise to the solid while carefully mixing with a spatula. After drying at 100°C overnight, the sample was calcined under 100 mL / min flow of air at 550 °C for 3 h with a heating ramp of 2 °C / min.Example 5: Preparation of Zn-USY catalysts, examples of zeolite-based catalysts

[0100] Zn / USY with 0.5, 1.5 and 3.0 wt% Zn have been prepared by IWI. For 1g of zeolite DHUSY, the required amount, e.g., 22.75, 68.25 and 140.5 mg of of the Znprecursor, Zn(NO3)2'6H2O, were dissolved in 2.2 mL of mili-Q water and added dropwise to the solid while carefully mixing with a spatula. After drying at 100°C overnight, the samples were calcined under 100 mL / min flow of air at 550 °C for 3 h with a heating ramp of 2 °C / min.Example 6: Preparation of Fe-USY catalysts, examples of zeolite-based catalysts

[0101] Fe / LISY with 1.5 wt% Fe has been prepared by IWI. For 1g of zeolite DHLISY, 109.17 mg of Fe(NO3)3'9H2O were dissolved in 2.2 mL of mili-Q water and added dropwise to the solid while carefully mixing with a spatula. After drying at 100°C overnight, the sample was calcined under 100 mL / min flow of air at 550 °C for 3 h with a heating ramp of 2 °C / min.Example 7: Preparation of Co-USY catalysts, examples of zeolite-based catalysts

[0102] Co / USY with 1 .5 wt% Co has been prepared by IWI. For 1g of zeolite DHUSY, 74.07 mg of Co(NO3)3'6H2O were dissolved in 2.2 mL of mili-Q water and added dropwise to the solid while carefully mixing with a spatula. After drying at 100°C overnight, the sample was calcined under 100 mL / min flow of air at 550 °C for 3 h with a heating ramp of 2 °C / min.Example 8: Preparation of Sn-MCM-41 catalysts, examples of metal containing structured material-based catalysts

[0103] The following relates to materials which are not zeolitic materials. Two Sn- MCM-41 which are well-known mesoporous structured materials of SiO2, with 0.5 and 1.0 wt% Sn have been prepared by one-pot synthesis by means of the following procedure: an aqueous solution of hexadecyltrimethylammonium hydroxide / bromide (CieTAOH / Br) was mixed with a tetramethylammonium hydroxide solution (25%, Aldrich) and an aqueous solution of SnC SFW (98%, Aldrich). After homogenization, silica (Aerosil, Degussa) was added under continuous stirring. The final composition was the following: 1SiO2: (0.16 - 4x), Ci6TABr : 4x CI6TAQH:0.26 TMAOH : x SnCI4: 24.3 H2O, where x was varied between 0.04 and 0.01. CieTABr was partially exchanged to compensate for the OH- depletion produced by the incorporation of SnCL into the synthesis gel. The homogeneous gel was sealed in Teflon lined stainless steel autoclaves and heated at 135°C under static conditions for 24 h. The resulting solid product was recovered by filtration, washed with water and dried at 60°C for 24 h. Theoccluded organic was removed by heating the solid at 540 °C for 1 h in a flow of N2, followed by 6 h in air.Example 9: Preparation of Sn-Beta catalysts, examples of zeolite-based catalysts

[0104] Commercially supplied beta zeolite was used as the parent material for the preparation of this catalyst. An example of commercially available beta is CP814E supplied by Zeolyst International in its ammonic form and with a Si / AI molar ratio of 9 (NH4-BEA). The commercial beta was converted to its acid form HBEA by calcination in air at 500°C for 3 hours where “H” refers to the acid form and BEA refers to the topology of the zeolite (zeolite Beta).

[0105] The beta zeolite was dealuminated by adding concentrated nitric acid (PanReac AppliChem, 69%) to 9BEAH in a liquid to solid ratio of 25 mL / g and stirred under reflux for 16 h at 80°C. The recovered solution was cooled down to room temperature and diluted with distilled water. The solids were recovered by filtration, washed extensively with distilled water until neutral pH and finally dried overnight at 100°C

[0106] Sn was introduced in the dealuminated beta zeolite (DHBEA) by a postsynthetic grafting method as follows. 1 g of DHBEA was placed into a three-neck roundbottom flask with a septum stopper on two of the openings and a seal valve connected to the third mouth. The sample was dried overnight at 130°C under vacuum. Then, 100 mL of dichloromethane (DCM) anhydrous (from a Schlenk line) and 2.5 mL of a previously prepared anhydrous DCM solution of tin chloride (SnCU from Merck, 99 % in a sealed anhydrous bottle) containing 0.166 mmol Sn / gr zeolite was added to the roundbottom flask via syringe in two steps. Finally, the system is connected to the reflux under N2 flow and heated to 60°C for 7 h under reflux in nitrogen. Finally, the solids were recovered by filtration, washed thoroughly with isopropanol and dried overnight at 100°C.Example 10: Catalytic tests of materials in the selective O-alkylation of CDML with IBO to produce Demol (DML)

[0107] The O-alkylation reaction between cyclademol and isobutylene oxide to produce demol was performed under reflux conditions in a three necked round bottom flask connected to a reflux condenser, stirred magnetically 500 r.pm, respectively, and operated under IX^ / Argon flow by using a gas bubbler to maintain a dry atmosphere. In a typical experiment, the reflux condenser and the flask containing 300 mg of the catalystwere purged with a high flow of N2 for around 10 minutes until stable temperature of 14 °C in condenser was achieved and no water condensation was observed.Loading of cyclademol (CDML). Then, 4097.6 mg, 26 mmol of dry cyclademol (CDML), was mixed with 60 mg of n-dodecane (internal standard) and introduced into the round bottom flask by means of a pipet. Next, the flask was sealed using a rubber stopper and the temperature was increased under N2 flow to maintain a dry atmosphere until the mixture reached the desired temperature.

[0108] IBP addition. Finally, the required amount of isobutylene oxide (IBP) was added using a perfusion pump by means of a 5- or 10-mL Hamilton syringe using a cannula directly immersed in the reaction mixture as to avoid evaporation of the epoxide.

[0109] Experimental conditions: Reaction temperature was varied in the range of 30 to 90°C. IBP addition rate was varied in the range of 2.6 to 150 mmol / h.25 pL samples were taken at regular intervals using a gas-tight 250 pL Hamilton syringe and diluted with 1 mL of Toluene. The diluted samples were analyzed by gas chromatography in an Agilent 8860 using a SupraWAX-280 Capillary Column (15 m x 0.25 mm x 0.50 pm) using a flame ionization detector (FID) to determine the amounts of demol and side products produced at each reaction stage as well as the amount of unreacted cyclademol and isobutylene oxide.Example 11 : Sn / HUSY: Influence of Sn loading on O-alkylation of CDML with IBO

[0110] A set of Sn-loaded HUSY catalysts has been prepared following the IWI procedure described in Example 2, with theoretical Sn contents in the range of 0.5 to 3.4 wt% (see Table 1). According to the diffuse Reflectance UV-vis (DRUV-VIS) spectra performed and shown in Figure 1 , Sn is present in all cases as a tetrahedrally coordinated framework Snlv. The content of the metal (wt% of metal in the sample, gram of metal per gram of sample on a percentual basis), is determined experimentally by inductively coupled plasma atomic emission spectroscopy (ICP-AES) measurements, is enclosed in Table 1.Table 1. Chemical composition of Sn / HUSY and Sn / DHUSY samples prepared by IWI following Example 2Sn (wt%)Catalyst — Si:AI[b]AI:Sn[blTheoretical Experimental0.4Sn / HUSY 0.5 0.4 13.2 28.91.0Sn / HUSY 1.0 1.0 13.5 12.71.5Sn / HUSY 1.7 1.5 13.2 8.82.9Sn / HUSY 3.4 2.9 13.2 4.50.05Sn / DHUSY 0.05 0.05 71 49.20.1Sn / DHUSY 0.1 0.1 72 24.90.2SnDHUSY 0.2 0.2 72 12.50.7Sn / DHUSY 0.5 0.7 70 3.91.4Sn / DHUSY 1.7 1.4 73 1.82.9Sn / DHUSY 3.4 2.9 74 0.8[a] wt% Sn and [b] Si / AI molar ratio calculated experimentally by ICP-AES data.

[0111] The catalysts were tested in the O-alkylation of cyclademol (CDML) with isobutylene oxide (IBO) at 50°C and with an IBO addition rate of 3.6pL / min, following the procedure described in Example 10. The results obtained are compared in Table 2 with those obtained with the Sn-free reference catalyst HLISY (commercial ultrastable Y zeolite in acidic form).Table 2. Influence of Sn loading on the O-alkylation of cyclademol with IBO catalyzed by Sn / HUSY and Sn / DHUSY at 50°C. XCDML: Cyclademol conversion, SDMLIBOI : Mass selectivity at the given XCDML.T=50°CCatalystXCDML (%) SDMLIBOI (wt %)HUSY 0 0DHUSY 0 00.4Sn / HUSY 55 701.0Sn / HUSY 54 721.5Sn / HUSY 50 902.9Sn / HUSY 58 600.7Sn / DHUSY* 53 1051.4Sn / DHUSY 40 1022.9Sn / DHUSY 45 100

[0112] Under these conditions, the highest mass selectivity to the primary O- alkylation product, DMLIBO1 (90 wt%), is obtained with catalyst 1.5Sn / HUSY at 50% CDML conversion (see Table 2).Example 12: Sn / DHUSY: Influence of Sn loading on O-alkylation of CDML with IBO

[0113] A set of Sn-loaded DHUSY catalysts has been prepared following the IWI procedure described in Example 2, with theoretical Sn contents in the range of 0.05 to 3.4 wt% (see Table 1). According to the DRUV-VIS spectra shown in Figure 2, Sn is present in all cases as a tetrahedrally coordinated framework Snlv. The content of the metal (wt% of metal in the sample, gram of metal per gram of sample on a percentual basis), as determined experimentally by inductively coupled plasma atomic emission spectroscopy (ICP-AES), is given in Table 1.

[0114] The catalysts were tested in the O-alkylation of CDML with IBO at 50°C and with an IBO addition rate of 15.3 pL / min, following the procedure described in Example 10. The results obtained are compared in Table 2 with those obtained with the reference Sn-free catalyst, DHUSY.

[0115] Under these conditions, the highest cyclademol conversion after 6 hours is obtained with catalyst 0.7Sn / DHUSY, with a mass selectivity to the primary O-alkylation product, Demol (DMLIBO1), of 105 wt%, at 53% CDML conversion. Comparing these results with those obtained with the Sn / HUSY catalysts, it can be concluded that decreasing the aluminum content of the USY zeolite has a positive influence on the mass selectivity to the desired primary O-alkylation product, DMLIBO1.Example 13: 1.5Sn / HUSY and 0.7Sn / DHUSY: Influence of reaction temperature on O-alkylation of CDML with IBO

[0116] Catalysts 1.5Sn / HUSY and 0.7Sn / DHUSY, prepared following the IWI procedure described in Example 2 with a theoretical Sn content of 0.5 wt% (see Table 1) have been tested in the O-alkylation of CDML with IBO following the procedure described in Example 10, using an IBO addition rate of 15.3 pL / min, and at reaction temperatures of 30, 50, 70 and 90°C. The results obtained are compared in Table 3. Comparing the results obtained for the two catalysts it can be concluded that decreasing the aluminum content of the USY zeolite enables operation at higher temperature with higher activity and higher mass selectivity as compared to 1.5Sn / HUSY. Sn metal oxide catalysts, SnO and SnO2, and metal-free USY zeolites, HUSY and DHUSY, have been also evaluated under the same conditions for comparison purposes. The resultsobtained, enclosed in Table 3, show unambiguously that the Sn oxides, alone, are not active at all in the O-alkylation reaction of cyclademol with I BO and that Sn species others than those incorporated in the Y zeolite framework do not present catalytic activity. Moreover, USY zeolites, alone, do not present any activity in the O-alkylation reaction of cyclademol with I BO and the presence of Sn species in the USY framework are necessary to perform the catalytic reaction.Table 3. Influence of temperature on the O-alkylation of cyclademol with IBO catalyzed by 1.5Sn / HUSY and 0.7Sn / DHUSY. XCDML is Cyclademol conversion, SDMLIBOI is Mass selectivity towards Demol at the given XCDML.Example 14: 0.7 Sn / DHUSY: Influence of IBO addition rate

[0117] Catalyst 0.7Sn / DHUSY, prepared following the IWI procedure described in Example 2 with a theoretical Sn content of 0.5 wt% (see Table 1) has been tested in the O-alkylation of CDML with IBO at 50°C and with an IBO addition rate ranging from 3.6 to 350 pL / min, following the procedure described in Example 10. The results obtained are compared in Table 4.Table 4. Influence of IBO addition rate on the O-alkylation of cyclademol with IBO catalyzed by 0.7Sn / DHUSY at T=50°C. XCDML: Cyclademol conversion, SDMLIBOI : Mass selectivity towards demol at the given XCDMLQIBO (pL / min) XCDML (%) SDMLIBOI (wt %)15.3 53 105153 (*) 42 125* Total catalyst deactivation after 1 hour of reaction.Example 15: Influence of the Lewis acid function added to DHUSY, an example of a comparison of zeolite-based catalyst with different Lewis acid functions vs Sn and of different Sn-containing structured material-based catalyst

[0118] In this example, DHUSY-based catalysts with different Lewis acid functions have been compared with a zeolitic and non-zeolitic structured material-based catalysts such as Sn / DHBEA and Sn / MCM41 , respectively. Thus, 0.7Sn / DHUSY, 1.7Zr / DHUSY, 1.5CU / DHUSY, 1.5Zn / DHUSY, 1.5Fe / DHUSY and 1.5Co / DHUSY, prepared following the procedures described in Examples 2 to 7, respectively, have been tested as catalyst for the O-alkylation of CDML with IBO at 50°C and with an IBO addition rate of 15.3 L / min, following the procedure described in Example 10. The results are compared in Table 5, with the DHUSY zeolite-based catalysts significantly outperforming others with different topology such as Sn / DHBEA, or with an ordered mesoporous structure such as Sn / MCM41. This table shows that a structured material, zeolitic or non-zeolitic, in which Sn is incorporated is not sufficient condition as to obtain high catalytic activity. Moreover, from the different metals compared, providing the Lewis acid function to the DHUSY- based catalysts, Sn is the best performing. Thus, only the combination of the right zeolite topology and Si / AI molar ratio in combination with the proper metal provides the desired catalyst with high activity and optimum selectivity.Table 5. Influence of Lewis acid function incorporated to a DHUSY-based catalyst and of different Sn-containing structured material-based catalyst on the O-alkylation of cyclademol with IBO at 50°C. XCDML: Cyclademol conversion, SDMLIBOI : Mass selectivity at the given XCDMLT=50°CCatalystXCDML (%) SDMLIBOI (wt %)0.7Sn / DHUSY* 53 1051.7Zr / DHUSY 50 901.5Cu / DHUSY 23 1281.5Zn / DHUSY 30 1301.5Fe / DHUSY 50 821.5CO / DHUSY <10 135Sn / DHBEA <3 146Sn / MCM41 14 105Example 16: Regeneration of spent catalyst and re-use

[0119] Catalyst 0.7Sn / DHUSY, prepared following the procedure described in Example 2 and tested as catalyst in the O-alkylation of CDML with I BO at 50°C and with an I BO addition rate of 15.3 pL / min, following the procedure described in Example 10, has been recovered after 6 hours of reaction, separated from the reaction mixture by filtration, washed with toluene and dried over-night. This spent (S) catalyst, S- 0.7Sn / DHUSY, has been regenerated by washing with methyl-tert-butyl ether (W-S- 0.7Sn / DHUSY), by thermal treatment at 200°C (2°C / min) for 12 h under a 100 mL / min flow of an inert gas (LT-S-0.7Sn / DHUSY) and by thermal treatment at 500°C (2°C / min) for 3h under 100 ml / min flow of air (HT-S-0.7Sn / DHUSY). The regenerated catalysts have been tested under the same conditions as the fresh catalyst and the results are compared in Table 6. The results show that the catalytic behavior of the fresh 0.7Sn / DHUSY catalyst is completely recovered. The term “fresh” with reference to a catalyst means a catalyst that is being used for the first time after catalyst preparation in a given reaction / transformation. When a catalyst is recovered and reused, it is referred to as a “spent catalyst.”Table 6. Influence of the regeneration procedure applied to 0.7Sn / DHUSY-based catalyst for the O-alkylation of cyclademol with I BO at 50°C. XCDML: Cyclademol conversion, SDMLIBOI : Mass selectivity at the given XCDMLT=50°CCatalystXCDML (%) SDMLIBOI (wt %)0.7Sn / DHUSY FRESH 53 105W-S-0.7Sn / DHUSY 50 110LT-S-0.7Sn / DHUSY 50 106HT-S-0.7Sn / DHUSY 51 105Example 17: O-alkylation of cyclademol with IBO with homogeneous SnCh catalyst

[0120] Catalyst SnCh, has been tested in the O-alkylation of CDML with IBO, at optimum process conditions. CDML and SnCh (29 wt%) was introduced into a reactor. The reactor was set at 25°C and isobutylene oxide (IBO) was subsequently added to the reactor. After a short induction period (0.03 hours), the reaction started and the processtemperature was adjusted to 35°C. All operations were carried out at atmospheric pressure. Samples were taken, quenched, and analyzed by gas chromatography during the reaction. When the reaction was finished (after 18 hours), crude product was directly quenched via acid hydrolysis with diluted hydrochloric acid (10 wt%) by adding the crude reaction to the acid solution. The product was washed with water and neutralized with diluted sodium hydroxide (10 wt%). The organic crude product was distilled with a fractional column in order to recover unreacted cyclademol and Demol.

[0121] The results are compared in Table 7. Comparing the results obtained for an exemplary heterogeneous metal-zeolite catalyst of this invention with the conventional SnCI2 homogeneous catalyst, it can be concluded that heterogeneous catalytic system outperforms previous known homogeneous system in terms of performance and, specially, regarding associated waste generation. The high selectivity value obtained at much higher CDML conversion values is surprising and unexpected given the nature of the main side reaction known for alcohol O-alkylation. These results suggest that the exemplary heterogeneous catalyst described in the invention (1) operates as a “true” catalyst in that it is employed in sub stoichiometric amounts, i.e. the catalyst is used in an amount lower than the reactant, for example, not in a 1 :1 ratio as the reactant; it is a catalyst that can be recovered and regenerated employing a simple procedure so it can be reused with no activity loss; and (2) prevents side reactions of the CDML O-alkylation by means of very specific and selective Sn-active sites in combination with zeolite shape selective effect.Table 7.Comparison of conventional homogeneous SnCh catalytic system with 0.7Sn / DHUSY- based catalyst for the O-alkylation of cyclademol with I BO. XCDML: Cyclademol conversion, SDMLIBOI : Mass selectivity towards demol at the given XCDML . . . Catalystv.... . . .. , Aqueous waste kg per Cataiystwto / oXCDML ( / o) SDMLIBOI (wt / o) Kg of product)SnCI2(homogeneous 29.0 28 82 12-14 catalyst)0.7Sn / DHUSY 2 50 H0 0

[0122] The examples above are on a smaller scale than a commercial manufacturing situation. However, a person skilled in the art would be able to scale up the manufacturing processes described herein and thus easily arrive at a large-scale commercial manufacturing with the benefits already described, inter alia, a process enabling the desired product to be obtained directly in one step from the reactants, preventing the need of intensive downstream workup in (chloride) acidic media. Thus, a large-scale commercial process can easily be derived based on the teachings of the specification herein, simplifying production, saving manufacturing costs and significantly reducing wastewater produced.

[0123] The range of recited numerical values disclosed in the specification includes values, e.g., + / — 5-10% of the recited value, that a person of ordinary skill in the art would consider equivalent to the recited value, e.g., having the same function or result.

[0124] The claims are not limited by the preferred embodiments and examples but will cover many modifications and equivalents consistent with the written description as a whole.

Claims

What is claimed is:

1. A method for producing a musk fragrance intermediate comprising reacting an alcohol with an epoxide in the presence of a zeolite-based catalyst, thereby producing a musk fragrance intermediate.

2. The method of claim 1 , wherein the musk fragrance intermediate has the structure of Formula (I):wherein n represents 1 or 0, each R1, independently from each other, represents a hydrogen atom or a methyl or ethyl group, or the two R1taken together represent a (CH2)mgroup, wherein m represents 3, 4, or 5; each R2, independently from each other, represents a hydrogen atom or a methyl or ethyl group, or the two R2taken together represent a (CH2)mgroup, wherein m represents 3, 4, or 5; andR3represents a phenyl group optionally substituted, a saturated or unsaturated Cs- Ce cyclic hydrocarbon moiety optionally substituted, a CH(R4)2 moiety, or R4CH=CR4moiety, wherein R4represents a Ci-Ce alkyl or alkenyl group optionally substituted.

3. The method of any one of claims 1-2, wherein the alcohol has the structure of Formula (II):wherein each R2, independently from each other, represents a hydrogen atom or a methyl or ethyl group, or the two R2taken together represent a (CH2)mgroup, wherein m represents 3, 4, or 5; andR3represents a phenyl group optionally substituted, a saturated or unsaturated Cs- Ce cyclic hydrocarbon moiety optionally substituted, a CH(R4)2 moiety, or R4CH=CR4moiety, wherein R4represents a Ci-Ce alkyl or alkenyl group optionally substituted.

4. The method of any one of claims 1-3, wherein the epoxide has the structure of Formula (III):wherein each R1, independently from each other, represents a hydrogen atom or a methyl or ethyl group, or the two R1taken together represent a (CH2)mgroup, wherein m represents 3, 4, or 5.

5. The method of any one of claims 1-4, wherein the musk fragrance intermediate is (2-[1-(3,3-dimethylcyclohexyl)ethoxy]-2-methylpropan-1-ol).

6. The method of any one of claims claim 1-5, wherein the alcohol is (1-(3,3- dimethylcyclohexyl)ethanol).

7. The method of any one of claims 1-6, wherein the epoxide is isobutylene oxide.

8. The method of any one of claims 1-7, wherein the zeolite-based catalyst is a large pore zeolite with a FAU structure comprising silicon (Si) and aluminum (Al) in a Si to Al mol ratio in the range of 2.5 to 250, preferably in the range of 10 to 150, more preferably in the range of 50-85, and at least one of tin (Sn), iron (Fe), zinc (Zn), cobalt (Co), copper (Cu), or zirconium (Zr) or combinations thereof.

9. The method according to claim 8, wherein the metal is incorporated in framework positions.

10. The method according to any one of claims 1-9, wherein the zeolite-based catalyst is a Sn-FAll.

11. The method according to claim 10, wherein the Sn content is ranging from 0.01 to 5.00 wt%, such as 0.05 to 3.00 wt% or 0.05 to 2.00 wt%.

12. The method of any one of claims 1-7, wherein said method is carried out at a reaction temperature between 20 and 150°C, preferably in the range of 35 to 120 °C, more preferably in the range of 50-70 °C.

13. The method of any one of claims 1-8, wherein said method is carried out at a pressure between 100 mbar and 30 bar, preferably in the range of 500 mbar to 10 bar, and more preferably under atmospheric pressure.

14. The method of any one of claims 1-13, wherein the method comprises the following steps; a) adding the alcohol to a reactor comprising the zeolite-based catalyst, where the zeolite-based catalyst comprises a large pore FAU zeolite with a Lewis acid function; b) adding the epoxide to the reactor comprising the zeolite-based catalyst and the alcohol by means of a controlled continuous flow, thereby creating a reaction mixture; c) producing the musk fragrance intermediate within the reactor by performing an O- alkylation of the alcohol by the epoxide, catalyzed by the zeolite-based catalyst; d) obtaining directly the desired product from the zeolite-based catalyst, with no need of performing any additional steps comprising neutralization, hydrolysis and extraction; e) separating the zeolite-based catalyst from the reaction mixture, regenerating the zeolite-based catalyst and reusing the zeolite-based catalyst as described in steps a) to c) with no performance loss.

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