Method for producing musk perfume intermediate by using AlCl3 as catalyst

Abstract

Disclosed is a process for producing a musk perfume intermediate by reacting an alcohol with an epoxide in the presence of AlCl3 as a catalyst.

Description

Background Technology

[0001] In the fragrance industry, there is a continuous need for compounds with pleasant odor properties. Such compounds expand the perfumer's palette and bring greater product diversity to consumers. In particular, there is a need for compounds with musky odor characteristics. These compounds are highly valued in perfumes and are among the most common and versatile compounds found in fragrance compositions. Exemplary musky fragrances include, for example, Helvetolide. ® Firmenich, Romandolide ® Firmenich, Serenolide, and Appelide, and their derivatives. These and other musk fragrances are described in, for example, Givaudan SA's WO 2002 / 096852 A1; Givaudan SA's WO 2004 / 050595 A1; Givaudan SA's WO 2004 / 050602 A1; Givaudan SA's WO 2005 / 108534 A1; Givaudan SA's WO 2011 / 29895 A2; Firmenich SA's US 5,166,412 A; Firmenich SA's WO 2000 / 014051 A1; Firmenich SA's WO 2009 / 034510 A2; Firmenich SA's US 6,384,269 B1; Symrise AG's WO 2005 / 01222 2 A1 and EP 1492759. B1; US ​​2004 / 053811 A1, Flavors & Fragrances Inc.; and WO2019 / 124533 A1, Takasago International Corp.

[0002] Given the value of these musk fragrances, there is a need in the art for a cost-effective, high-yield method for producing said compounds. This invention addresses this need in the art. Summary of the Invention

[0003] This invention provides a method for producing musk fragrance intermediates (e.g., musk fragrance intermediates of formula (I), particularly demol) by reacting an alcohol (e.g., an alcohol of formula (II), particularly cyclademol) with an epoxide (e.g., an epoxide of formula (III), particularly isobutane epoxide) in the presence of AlCl3 as a catalyst, thereby producing the musk fragrance intermediate. In some aspects, the method is carried out at a reaction temperature in the range of 30°C–35°C and / or at atmospheric pressure. Detailed Implementation

[0004] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” or any other variation thereof are intended to cover non-exclusive inclusion. For example, a process, method, article of manufacture, or apparatus that includes a list of elements is not necessarily limited to those elements, but may include other elements not expressly listed or inherent to such process, method, article of manufacture, or apparatus. Furthermore, unless expressly stated to the contrary, “or” refers to inclusive or, not exclusive or. For example, condition A or B is satisfied by any of the following: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); and both A and B are true (or exist).

[0005] Furthermore, the use of "a / an" is intended to describe the elements and components described herein. This is done solely for convenience and to give a general meaning to the scope of the invention. This description should be interpreted as including one / an or at least one / an, and the singular form includes the plural form, unless it clearly indicates otherwise.

[0006] 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 pertains. In case of conflict, this specification (including the definitions) shall prevail. Although similar or equivalent methods and materials described herein may be used in the practice or testing of embodiments of the invention, suitable methods and materials are described below. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0007] When a quantity, concentration, or other value or parameter is given as a range, preferred range, or a series of upper and / or lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any upper or preferred value with any lower or preferred value, regardless of whether such ranges are disclosed individually. When numerical ranges are listed herein, unless otherwise stated, the range is intended to include its endpoints, as well as all integers and fractions within that range. For example, when a range of “1 to 10” is listed, the listed range should be interpreted as including ranges such as “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”, etc.

[0008] The disclosure described illustratively herein may be practiced without any one or more elements or limitations not specifically disclosed herein. Although compositions and methods are described herein as “comprising” various components or steps, unless otherwise stated, these compositions and methods may also be “substantially composed of various components or steps” or “consisting of various components or steps”.

[0009] Those skilled in the art will understand that some of the compounds in this disclosure have chiral centers, carbon-carbon double bonds, and / or cyclic structures. Unless explicitly stated otherwise, the compounds in this disclosure include their stereoisomers, such as enantiomers and diastereomers.

[0010] Musk and spices Helvimor ® Cycademol (1-(3,3-dimethylcyclohexyl)ethanol) is produced via a two-step process (Scheme 1). The key intermediate in this process is Demol (2-[1-(3,3-dimethylcyclohexyl)ethoxy]-2-methylprop-1-ol), which is synthesized from cyclademol using BF3 (see EP 2200963 B1) or a stoichiometric amount of SnCl2 as a catalyst. Due to the use of a large amount of SnCl2 (26 wt%), the yield per pass is very low (approximately 28 wt%). This disclosure provides a simple, commercially viable method for producing Demol using AlCl3 as a catalyst. Besides being inexpensive, this catalyst improves the selectivity of Demol compared to using SnCl2. Furthermore, the amount of solvent used and the amount of wastewater generated are significantly reduced.

[0011] Therefore, this disclosure provides a method for producing musk fragrance intermediates by reacting a suitable alcohol with an alkylating agent, particularly an epoxide, in the presence of AlCl3 as a catalyst, thereby selectively achieving o-alkylation of the alcohol and producing musk fragrance intermediates.

[0012] In a specific aspect, this disclosure provides the production of the musk flavor intermediate of formula (I):

[0013] (I)

[0014] in

[0015] n represents 1 or 0,

[0016] Each R 1 Each can independently represent a hydrogen atom or a methyl or ethyl atom, or two R atoms. 1 Together they represent (CH2) m Group, m represents 3, 4, or 5;

[0017] Each R 2 Each can independently represent a hydrogen atom or a methyl or ethyl atom, or two R atoms. 2 Together they represent (CH2) m Group, m represents 3, 4, or 5; and

[0018] R 3 This indicates an optionally substituted phenyl group, an optionally substituted saturated or unsaturated C5-C6 cyclic hydrocarbon moiety, or CH(R) 4 )2, or R 4 CH=CR 4 Partial, R 4 This indicates an optional substituted C1-C6 alkyl or alkenyl group.

[0019] According to a specific aspect of this disclosure, the compound of formula (I) is a compound in which n is 1, and each R 1 Independently, each R is a hydrogen atom or a methyl group. 2 It is independently a hydrogen atom or a methyl group, and R 3 This indicates an optionally substituted phenyl group, an optionally substituted saturated or unsaturated C5-C6 cyclic hydrocarbon moiety, or CH(R) 4 )2, or R 4 CH=CR 4 Partial, R 4 Indicates optional substituted C1-C6 alkyl or alkenyl groups.

[0020] In some respects, R 3 The optional substituents are one, two, or three C1-C3 alkyl, C1-C3 alkenyl, or C1-C3 alkoxy groups. Specifically, R... 3The optional substituents are one, two, or three methyl or ethyl groups. R 3 Non-limiting typical examples of the group 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 a specific aspect, the musk fragrance intermediate of formula (I) is demol (2-[1-(3,3-dimethylcyclohexyl)ethoxy]-2-methylprop-1-ol).

[0021] In some respects, the alcohol used as the starting compound is an alcohol of formula (II):

[0022] (II)

[0023] Each R 2 Each can independently represent a hydrogen atom or a methyl or ethyl atom, or two R atoms. 2 Together they represent (CH2) m Group, m represents 3, 4, or 5; and

[0024] R 3 This indicates an optionally substituted phenyl group, an optionally substituted saturated or unsaturated C5-C6 cyclic hydrocarbon moiety, or CH(R) 4 )2, or R 4 CH=CR 4 Partial, R 4 The C1-C6 alkyl or alkenyl groups are optionally substituted. In a specific instance, the alcohol of formula (II) is cyclademol (1-(3,3-dimethylcyclohexyl)ethanol).

[0025] Epoxides are cyclic ethers having a three-membered ring consisting of oxygen atoms attached to two adjacent carbon atoms. The epoxides used in the methods of this invention can have 3 to 25 carbon atoms and an epoxy group. Exemplary epoxides include ethylene oxide, propylene oxide (1,2-epoxypropane), butane oxide (1,2-epoxybutane), pentane oxide (also known as 1,2-epoxypentane), hexane oxide (also known as 1,2-epoxyhexane), octane oxide (also known as 1,2-epoxyoctane), nonane oxide (also known as 1,2-epoxynonane), decane oxide (also known as 1,2-epoxydecane), isobutane oxide, 4-methyl-1-epoxypentane, and styrene oxide. In some aspects, the epoxides used in the methods of this invention are epoxides of formula (III):

[0026] (III)

[0027] Each R 1 Each can independently represent a hydrogen atom or a methyl or ethyl atom, or two R atoms.1 Together they represent (CH2) m The group m represents 3, 4, or 5. In a specific aspect, the epoxide used in the method of the present invention is isobutane epoxide.

[0028] In some aspects, the methods of this disclosure are carried out in the presence of a catalyst, and the catalyst comprises, is substantially composed of, or is composed of AlCl3. In some aspects, the AlCl3 catalyst may be dry (e.g., in anhydrous form) or hydrated. In some aspects, the AlCl3 catalyst is not supported on a catalyst support (e.g., zeolite or activated carbon). In some aspects, the methods of this disclosure are carried out in a reaction zone, and the AlCl3 catalyst fed into the reaction zone is not in the form of a complex with a ligand. In some aspects, the catalyst is AlCl3.

[0029] In some respects, the reaction is carried out in the presence of a reduced amount of solvent (e.g., water and / or organic solvents). Thus, in some respects, the musk fragrance intermediate of formula (I) is prepared by reacting an alcohol of formula (II) with an epoxide of formula (III) in the presence of a solvent not exceeding about 20 wt%, 25 wt%, 30 wt%, 33 wt%, or 35 wt% of the reaction mixture (containing starting materials, products, byproducts, and catalyst). In other respects, demol is prepared by reacting cyclademol with isobutane epoxide in the presence of AlCl3 in the presence of a solvent not exceeding about 20 wt%, 25 wt%, 30 wt%, 33 wt%, or 35 wt% of the reaction mixture.

[0030] The reaction temperature for preparing the musk fragrance intermediate of formula (I), i.e., the reaction temperature in the method of this disclosure, is ideally between 20°C and 40°C, or more preferably between 30°C and 35°C. Specifically, demol is prepared by reacting cyclademol with isobutane oxide in the presence of AlCl3 at a reaction temperature between 20°C and 40°C, or more preferably between 30°C and 35°C. Ideally, the reaction is carried out at atmospheric pressure in a batch or semi-batch mode. However, in some cases, the reaction may be carried out under reduced pressure conditions (e.g., between 0.5 and 100 mbar) in a batch or semi-batch mode.

[0031] In some aspects, the molar ratio of the catalyst to the alcohol (e.g., cyclademol) (also expressed herein as equivalents) is in the range of 0.1 to 0.4, or more preferably in the range of 0.2 to 0.3. In other aspects, the molar ratio of the epoxide (e.g., isobutane epoxide) to the alcohol (e.g., cyclademol) is in the range of 0.5 to 2.0, or more preferably in the range of 0.6 to 1.0. In other aspects, the amount of catalyst is less than 20 wt%, less than 18 wt%, less than 15 wt%, less than 10 wt%, or less than 8 wt% of the reaction mixture.

[0032] Compared to SnCl2, the method of the present invention offers the advantage of an overall improvement in process productivity, including reduced reaction time and increased molar selectivity. Furthermore, in some respects, this reaction uses less solvent than comparable reactions using SnCl2. Therefore, the reaction of the present invention provides reduced wastewater generation and manufacturing costs associated with the preparation of musk fragrance intermediates.

[0033] Example 1: A standard method for synthesizing Helvimor from Cyclademol using SnCl2 (Scheme 1)

[0034] Option 1

[0035] Typically, cyclademol, catalyst, and other reagents (solvents, internal standards, etc.) are loaded into the reactor. When the desired temperature is reached, isobutane oxide is added. Samples are taken and analyzed by gas chromatography, and when the reaction is complete, the crude product is directly quenched by acid hydrolysis with dilute hydrochloric acid. The product is washed with water and neutralized with dilute sodium hydroxide. The crude organic product is then distilled using a fractionating column to recover unreacted cyclademol and demol.

[0036] Demol and sodium hydroxide (0.11 wt%) as a catalyst were loaded into the reactor. Propionic anhydride (1.3 equivalents) was added at 110°C. When the addition was complete, the temperature was raised to 130°C. The reaction was considered complete when the Demol concentration by gas chromatography was <1%. The crude product was directly quenched with a sodium hydroxide solution (1.5 equivalents NaOH). The product was washed with water, and hexane was used to facilitate the separation of the aqueous and organic phases. The final organic phase was distilled to obtain Helvimor. ® .

[0037] Example 2: Catalyst Screening

[0038] The ability of various catalysts to catalyze the conversion of cyclademol and isobutane oxide to demol was tested. For these reactions, cyclademol, catalyst, and other reagents (solvent, internal standard, etc.) were loaded into the reactor (Table 1). Isobutane oxide was added when the desired temperature was reached (Table 2). Samples were taken periodically and analyzed by gas chromatography. When the reaction was complete, the crude product was directly quenched by acid hydrolysis with dilute hydrochloric acid. The product was washed with water and neutralized with dilute sodium hydroxide. In these tests, the temperature and addition time of isobutane oxide (Table 2), reaction time and temperature (Table 2), catalyst (Table 1), and the amount of isobutane oxide (relative to cyclademol) (Table 2) and solvent (Table 1) were adjusted as needed. In particular, based on percentage conversion, selectivity, and yield (Table 3) and ease of use, AlCl3 is a suitable substitute for SnCl2 in the synthesis of demol.

[0039] Table 1

[0040]

[0041] Ti(Oct)4, titanium tetraoctanoate; X, zeolite X.

[0042] 1 Equivalent catalyst, relative to the catalyst equivalent of cyclademol (i.e., the molar ratio of catalyst to cyclademol).

[0043] 2 wt.%, relative to the solvent wt% of the mixture of cyclademol + solvent.

[0044] DCM, dichloromethane. EB, ethylbenzene.

[0045] Table 2

[0046]

[0047] "T (°C) addition" is the temperature at which isobutane oxide is added to the reaction. "Addition time (h)" is the duration of IBO addition. "Reaction T (°C)" is the temperature at which the reaction is allowed to proceed after the addition of isobutane oxide. "Reaction time (h)" is the time the reaction takes to proceed, including the time for IBO addition. RT, room temperature.

[0048] 1 IBO equivalent, relative to the cyclademol of isobutane equivalent (i.e., the molar ratio of isobutane to cyclademol).

[0049] Table 3

[0050]

[0051] Ti(Oct)4, titanium tetraoctanoate; X, zeolite X.

Claims

1. A method for producing a musk fragrance intermediate, the method comprising reacting an alcohol with an epoxide in the presence of AlCl3 as a catalyst to produce the musk fragrance intermediate.

2. The method as described in claim 1, wherein, The musk flavoring intermediate has the structure of formula (I): (I) in n represents 1 or 0, Each R 1 Each can independently represent a hydrogen atom or a methyl or ethyl atom, or two R atoms. 1 Together they represent (CH2) m Group, where m represents 3, 4, or 5; Each R 2 Each can independently represent a hydrogen atom or a methyl or ethyl atom, or two R atoms. 2 Together they represent (CH2) m Group, where m represents 3, 4, or 5; and R 3 This indicates an optionally substituted phenyl group, an optionally substituted saturated or unsaturated C5-C6 cyclic hydrocarbon moiety, or CH(R) 4 Part 2, or R 4 CH=CR 4 Part, of which R 4 This indicates an optional substituted C1-C6 alkyl or alkenyl group.

3. The method according to any one of claims 1-2, wherein, The alcohol has the structure of formula (II): (II) in Each R 2 Each can independently represent a hydrogen atom or a methyl or ethyl atom, or two R atoms. 2 Together they represent (CH2) m Group, where m represents 3, 4, or 5; and R 3 This indicates an optionally substituted phenyl group, an optionally substituted saturated or unsaturated C5-C6 cyclic hydrocarbon moiety, or CH(R) 4 Part 2, or R 4 CH=CR 4 Part, of which R 4 This indicates an optional substituted C1-C6 alkyl or alkenyl group.

4. The method according to any one of claims 1-3, wherein, The epoxide has the structure of formula (III): (III) in Each R 1 Each can independently represent a hydrogen atom or a methyl or ethyl atom, or two R atoms. 1 Together they represent (CH2) m Group, where m represents 3, 4, or 5.

5. The method according to any one of claims 1-4, wherein, The musk fragrance intermediate is demol.

6. The method according to any one of claims 1-5, wherein, The alcohol is cyclademol.

7. The method according to any one of claims 1-6, wherein, The epoxide is epoxide isobutane.

8. The method according to any one of claims 1-7, wherein, The method is carried out at a reaction temperature in the range of 30°C to 35°C.

9. The method according to any one of claims 1-8, wherein, The method is performed at atmospheric pressure.

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