Process for preparation of 2, 2, 6, 6, 7, 8, 8-heptamethyl-3, 6, 7, 8-tetrahydro-2h-indeno [4, 5-b] furan and uses thereof

Abstract

The present disclosure relates to a process involving the use of 1, 1, 2, 3, 3-pentamethyl-5-(2-methylallyl)-1, 2, 3, 5, 6, 7-hexahydro-4H-inden-4-one (methylallylindomuscone) and / or 5-(2-hydroxy-2-methylpropyl)-1, 1, 2, 3, 3-pentamethyl-1, 2, 3, 5, 6, 7-hexahydro-4H-inden-4-one (hydroxyisobutylindomuscone) as starting materials to prepare 2, 2, 6, 6, 7, 8-heptamethyl-3, 6, 7, 8, 8-pentamethyl-3, 6, 7, 8-tetramethyl-3, 6, 7, 8-tetramethyl-3, 6, 7, 8-tetramethyl-3, 6, 7, 8-tetramethyl-3, 6, the present invention relates to 1, 2, 3, 4, 5-tetrahydro-2H-indeno [4, 5-b] furan (an aromatic cyclized compound). The present disclosure also relates to an anaerobic process involving the use of methylallylindomuscone and / or hydroxyisobutylindomuscone as a starting material to prepare one or more intermediate compounds that can be used to prepare an aromatic cyclized compound or a 2, 2, 6, 6, 7, 8, 8-heptamethyldecahydro-2H-indeno [4, 4-b] indole-3-ketone compound, which can be used in the preparation of 2, 2, 6, 6, 7, 8, 8-heptamethyldecahydro-2H-indeno [4, 4-b] indole-3-ketone. The invention relates to 2-(2, 5-b) furan (musk indeno furan) The present disclosure also relates to a process for preparing musk indenofurans by using an aromatic cyclized compound as an intermediate. The present disclosure also relates to a one-pot process for the preparation of musk indenofurans by using hydroxyisobutylindomuscone as a starting material. The present disclosure also relates to a phosphine derivative compound having the structural formula (X), wherein R is selected from the group consisting of alkyl, cycloalkyl, phenyl, substituted phenyl, and perfluoroalkyl, and a method for preparing the same. # imgabs0 #

Description

Background Art Technical Field

[0001] The present disclosure relates to a catalytic method for preparing 2,2,6,6,7,8,8-heptamethyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan (aromatic cyclized compound), which can be used as an intermediate to prepare 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan (musk indenofuran). The present disclosure also relates to anaerobic methods for preparing various intermediate compounds, which can be used to prepare aromatic cyclized compounds or musk indenofuran. The present disclosure also relates to phosphine derivatives and methods for preparing them from aromatic cyclized compounds.

[0002] Related technical description

[0003] IFF Amber Xtreme TM The fragrance is a popular and rich amber wood fragrance ingredient that can provide extraordinary performance for many fragrance types. It can be prepared using indole musk ketone (1,1,2,3,3-pentamethyloctahydro-4H-inden-4-one) as a starting material. However, the method uses five steps. Therefore, there is still a need to optimize the manufacturing method. Summary of the invention

[0004] The present disclosure provides a method for preparing an aromatic cyclized compound. The method includes: cyclizing a starting material in a reaction zone in the presence of oxygen, an acid catalyst and a solvent to form 2,2,6,6,7,8,8-heptamethyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan (aromatic cyclized compound), wherein the acid catalyst is a homogeneous acid catalyst and / or a heterogeneous acid catalyst having a pKa not exceeding zero, and the starting material is 1,1,2,3,3-pentamethyl-5-(2-methylallyl)-1,2,3,5,6,7-hexahydro-4H-indene-4-one (methylallyl indole musk ketone) and / or 5-(2-hydroxy-2-methylpropyl)-1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-indene-4-one (hydroxyisobutyl indole musk ketone).

[0005] The present disclosure also provides a method for preparing one or more intermediate compounds, which can be used to prepare aromatic cyclized compounds or musk indenofuran. The method comprises: in a reaction zone, in the presence of an acid catalyst and a solvent, converting a starting material into an intermediate compound, wherein the intermediate compound is selected from the group consisting of: 1,1,2,3,3-pentamethyl-5-(2-methylallyl)-2,3-dihydro-1H-inden-4-ol (methylallylphenol compound), 2,2,6,6,7,8,8-heptamethyl-3,4,5,6,7,8-hexahydro-2H-indeno[4,5-b]furan (endocyclic diene I), 2,2,6,6,7,8,8-heptamethyl-3,3a,4,6,7,8-hexahydro-2H-indeno[4,5 -b] furan (endocyclic diene II) and mixtures thereof, wherein the conversion process is carried out in the substantial absence of oxygen, the acid catalyst is a homogeneous acid catalyst and / or a heterogeneous acid catalyst having a pKa of no more than zero, and the starting material is 1,1,2,3,3-pentamethyl-5-(2-methylallyl)-1,2,3,5,6,7-hexahydro-4H-indene-4-one (methylallylindolemusk ketone) and / or 5-(2-hydroxy-2-methylpropyl)-1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-indene-4-one (hydroxyisobutylindolemusk ketone).

[0006] The present disclosure also provides a method for preparing musk indenofuran, which comprises: (a) alkylating indoles musk ketone with methallyl chloride under conditions effective to produce methallyl indoles musk ketone, (b) cyclizing methallyl indoles musk ketone under conditions effective to produce aromatic cyclized compounds, and (c) hydrogenating aromatic cyclized compounds under conditions effective to produce musk indenofuran.

[0007] The present disclosure also provides a method for preparing musk indenofuran, which comprises: (a) alkylating indoles musk ketone with isobutylene oxide under conditions effective to produce hydroxyisobutyl indoles musk ketone, (b) cyclizing hydroxyisobutyl indoles musk ketone under conditions effective to produce aromatic cyclized compounds, and (c) hydrogenating aromatic cyclized compounds under conditions effective to produce musk indenofuran.

[0008] The present disclosure also provides a method for preparing musk indenofuran. The method comprises: contacting hydroxyisobutylindole musk ketone with a hydrogenation catalyst in the presence of a solvent and hydrogen (H2) in a reaction zone to produce a product mixture containing musk indenofuran.

[0009] The present disclosure also provides a phosphine derivative compound having a structural formula (X):

[0010]

[0011] wherein R is selected from the group consisting of alkyl, cycloalkyl, phenyl, substituted phenyl, and perfluoroalkyl.

[0012] The present disclosure further provides a method for preparing a phosphine derivative compound having a structural formula (X). The method comprises: (a) brominating an aromatic cyclized compound in the presence of a brominating agent and a solvent to form 5-bromo-2,2,6,6,7,8,8-heptamethyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan (aromatic bromide compound), (b) contacting the aromatic bromide compound with a lithiating agent in the presence of a solvent in a reaction zone to form a reaction mixture, and (c) adding a chlorinated phosphine compound having a formula R2PCl to the reaction mixture to form a phosphine derivative compound having a structural formula (X), wherein R is selected from the group consisting of an alkyl group, a cycloalkyl group, a phenyl group, a substituted phenyl group, and a perfluoroalkyl group. DETAILED DESCRIPTION

[0013] The foregoing general description and the following detailed description are exemplary and explanatory only and do not limit the invention as defined in the appended claims.Other features and benefits of any one or more embodiments will be apparent from the following detailed description and from the claims.

[0014] 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 includes 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. In addition, 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 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).

[0015] Moreover, "a / an" is used to describe the elements and components described herein. This is done only for convenience and to give a general sense of the scope of the invention. The description should be interpreted as including one / kind or at least one / kind, and the singular also includes the plural unless it is obvious that it is otherwise intended.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present invention belongs. In the event of a conflict, this specification (including definitions) shall prevail. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, suitable methods and materials are described below. In addition, materials, methods and examples are only illustrative and are not intended to be restrictive.

[0017] When amount, concentration or other values ​​or parameters are given with scope, preferred range or a series of upper preferred values ​​and / or lower preferred values, this should be understood as particularly disclosing all scopes formed by any pairing of any upper range limit or preferred value and any lower range limit or preferred value, and no matter whether these scopes are disclosed separately.When numerical range is enumerated herein, unless otherwise indicated, the scope is intended to include its endpoints, and all integers and fractions in the scope.For example, when enumerating the scope of "1 to 10", the enumerated scope should be interpreted as including scopes 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".

[0018] The present disclosure illustratively described herein may suitably be practiced without any element or elements, limitation or limitations not specifically disclosed herein. Although compositions and methods are described herein as "comprising" various components or steps, unless otherwise indicated, these compositions and methods may also "consist essentially of" or "consist of" the various components or steps.

[0019] Those of ordinary skill in the art understand that some compounds in the present disclosure have chiral centers, carbon-carbon double bonds, and / or cyclic structures. Unless explicitly stated, compounds in the present disclosure include stereoisomers thereof, such as enantiomers and diastereomers.

[0020] Before presenting details of the following embodiments, some terms are defined or clarified.

[0021] As used herein, the term "indole musk ketone" is a compound named 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one and represented by the following structural formula (I):

[0022]

[0023] As used herein, the term "methallylindolemusk ketone" is a compound named 1,1,2,3,3-pentamethyl-5-(2-methylallyl)-1,2,3,5,6,7-hexahydro-4H-inden-4-one and represented by the following structural formula (II):

[0024]

[0025] As used herein, the term "aromatic cyclized compound" is a compound named 2,2,6,6,7,8,8-heptamethyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan and represented by the following structural formula (III):

[0026]

[0027] As used herein, the term "musk indenofuran" is a compound named 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan and represented by the following structural formula (IV):

[0028]

[0029] As used herein, the term "hydroxyisobutylindole musk ketone" is a compound named 5-(2-hydroxy-2-methylpropyl)-1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one and represented by the following structural formula (V):

[0030]

[0031] As used herein, the term "methallylphenol compound" is a compound named 1,1,2,3,3-pentamethyl-5-(2-methylallyl)-2,3-dihydro-1H-inden-4-ol and represented by the following structural formula (VI):

[0032]

[0033] As used herein, the term "endocyclic diene I" is a compound named 2,2,6,6,7,8,8-heptamethyl-3,4,5,6,7,8-hexahydro-2H-indeno[4,5-b]furan and represented by the following structural formula (VII):

[0034]

[0035] As used herein, the term "endocyclic diene II" is a compound named 2,2,6,6,7,8,8-heptamethyl-3,3a,4,6,7,8-hexahydro-2H-indeno[4,5-b]furan and represented by the following structural formula (VIII):

[0036]

[0037] As used herein, the term "aromatic bromide compound" is a compound named 5-bromo-2,2,6,6,7,8,8-heptamethyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan and represented by the following structural formula (IX):

[0038]

[0039] As used herein, the term "heterogeneous acid catalyst" or "solid acid catalyst" means a solid catalyst comprising Bronsted acid (or proton) sites. Bronsted acid sites are sites with ionizable hydrogen atoms. The terms "heterogeneous acid catalyst" and "solid acid catalyst" can be used interchangeably in this disclosure.

[0040] The present disclosure provides a method for preparing 2,2,6,6,7,8,8-heptamethyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan (aromatic cyclization compound). The method includes cyclizing a starting material in the presence of oxygen, an acid catalyst and a solvent in a reaction zone to form an aromatic cyclization compound, wherein the acid catalyst is a homogeneous acid catalyst and / or a heterogeneous acid catalyst having a pKa not exceeding zero, and the starting material is 1,1,2,3,3-pentamethyl-5-(2-methylallyl)-1,2,3,5,6,7-hexahydro-4H-indene-4-one (methylallyl indole musk ketone) and / or 5-(2-hydroxy-2-methylpropyl)-1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-indene-4-one (hydroxyisobutyl indole musk ketone).

[0041] Alternatively, the present disclosure provides a method for preparing an intermediate compound of an aromatic cyclized compound. The method comprises converting a starting material into an intermediate compound in the presence of an acid catalyst and a solvent in a reaction zone, the intermediate compound being selected from the group consisting of: 1,1,2,3,3-pentamethyl-5-(2-methylallyl)-2,3-dihydro-1H-inden-4-ol (methylallylphenol compound), 2,2,6,6,7,8,8-heptamethyl-3,4,5,6,7,8-hexahydro-2H-indeno[4,5-b]furan (endocyclic diene I), 2,2,6,6,7,8,8-heptamethyl-3,3a,4,6,7,8-hexahydro-2H-indeno[4,5 -b] furan (endocyclic diene II) and mixtures thereof, wherein the conversion process is carried out in the substantial absence of oxygen, the acid catalyst is a homogeneous acid catalyst and / or a heterogeneous acid catalyst having a pKa of no more than zero, and the starting material is 1,1,2,3,3-pentamethyl-5-(2-methylallyl)-1,2,3,5,6,7-hexahydro-4H-indene-4-one (methylallylindolemusk ketone) and / or 5-(2-hydroxy-2-methylpropyl)-1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-indene-4-one (hydroxyisobutylindolemusk ketone).

[0042] In some embodiments, the starting material is methyl allyl indole musk ketone. In some embodiments, the starting material is hydroxyisobutyl indole musk ketone. In some embodiments, there is no noble metal catalyst, such as palladium (Pd) catalyst, in the reaction zone.

[0043] pKa is a concept well known in the art. It is the negative logarithm of the acid dissociation constant Ka with base 10, i.e. pKa = -log 10 Ka. In the present disclosure, pKa means the pKa value of the corresponding acid in aqueous solution at 25°C. In some embodiments, the acid catalyst is a homogeneous acid catalyst having a pKa of no more than 0, or no more than -1, or no more than -2. In some embodiments, the homogeneous acid catalyst is selected from the group consisting of: p-toluenesulfonic acid (pTsOH), methanesulfonic acid (MSA), sulfuric acid, trifluoromethanesulfonic acid (triflicacid) (trifluoromethanesulfonic acid, TfOH), trifluoromethanesulfonimide ((CF3SO2)2NH), trifluoromethanesulfonamide (CF3SO2NH2), and mixtures thereof. In some embodiments, the homogeneous acid catalyst is selected from the group consisting of: p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), and mixtures thereof.

[0044] In some embodiments, the heterogeneous acid catalyst is selected from the group consisting of: alumina, silica-alumina, zeolite, silicoaluminophosphate, aluminophosphate, sulfated zirconia, zirconium oxide (zirconium dioxide), sulfonic acid resin, and mixtures thereof. In some embodiments, the silica-alumina catalyst is amorphous. In some embodiments, the heterogeneous acid catalyst has a porous structure. In some embodiments, the heterogeneous acid catalyst is selected from the group consisting of: zeolite, sulfonic acid resin, and mixtures thereof. As used herein, the term "sulfonic acid resin" means a resin functionalized with p-toluenesulfonic acid end groups (such as polystyrene resin). Examples of sulfonic acid resins include Amberlyst acidic cation exchange resins, Amberlyst 15 resins, Amberlyst 16 resins, and Amberlyst 20 resins. In some embodiments, the heterogeneous acid catalyst is a zeolite. In the present disclosure, the zeolite contains Bronsted acid (or proton) sites. Examples of suitable zeolites include H-Beta zeolite and H-USY zeolite.

[0045] In some embodiments, the acid catalyst is a homogeneous acid catalyst, and the amount of the homogeneous acid catalyst is at least 0.01 mol%, or at least 0.1 mol%, or at least 0.5 mol%, or at least 1 mol%, or at least 5 mol%, or at least 10 mol%, or at least 15 mol% based on the molar amount of the starting material. In some embodiments, the amount of the homogeneous acid catalyst is no more than 10 times, or 5 times, or 2 times, or 1 times the molar amount of the starting material.

[0046] In some embodiments, the acid catalyst is a heterogeneous acid catalyst, and the amount of the heterogeneous acid catalyst is at least 1 wt%, or at least 5 wt%, or at least 10 wt%, or at least 20 wt%, or at least 30 wt%, or at least 40 wt%, or at least 50 wt% based on the weight of the starting material. In some embodiments, the amount of the heterogeneous acid catalyst is no more than 50 times, or 10 times, or 5 times, or 2 times the weight of the starting material.

[0047] Examples of solvents include toluene, xylene, alcohols, ethers, and combinations thereof. Examples of alcohols include methanol, ethanol, 1-propanol, isopropanol, butanol and isomers thereof, amyl alcohol and isomers thereof, and combinations thereof. Examples of ethers include THF, dioxane, anisole, and combinations thereof. In some embodiments, the solvent is substantially free of acetonitrile. In some embodiments, the solvent is substantially free of water. In some embodiments, the solvent comprises acetonitrile of no more than 20wt%, or no more than 10wt%, or no more than 5wt%, or no more than 2wt%, or no more than 1wt%, based on the total weight of the solvent. In some embodiments, the solvent comprises water of no more than 10wt%, or no more than 5wt%, or no more than 2wt%, or no more than 1wt%, based on the total weight of the solvent.

[0048] In some embodiments, the concentration of the starting material in the solvent is from about 0.05 M (mol / L) to about 5 M, or from about 0.1 M to about 3 M, or from about 0.2 M to about 2 M. In some embodiments, the concentration of the starting material in the solvent is at least 0.01 M, or at least 0.02 M, or at least 0.05 M, or at least 0.1 M, or at least 0.2 M, or at least 0.3 M, or at least 0.4 M, or at least 0.5 M. In some embodiments, the concentration of the starting material in the solvent is no more than 10 M, or no more than 5 M, or no more than 4 M, or no more than 3 M, or no more than 2 M, or no more than 1 M.

[0049] In some embodiments, the acid catalyst is a homogeneous acid catalyst, and the cyclization or conversion (conversion to an intermediate compound) reaction is carried out at a temperature (reaction temperature, or temperature in the reaction zone) of about 20°C to about 120°C, or about 30°C to about 110°C, or about 40°C to about 100°C, or about 50°C to about 90°C. In some embodiments, the reaction temperature is at least 10°C, or at least 20°C, or at least 30°C, or at least 40°C, or at least 50°C, or at least 60°C. In some embodiments, the reaction temperature is no more than 150°C, or no more than 140°C, or no more than 130°C, or no more than 120°C, or no more than 110°C, or no more than 100°C, or no more than 90°C, or no more than 80°C.

[0050] In some embodiments, the acid catalyst is a heterogeneous acid catalyst, and the cyclization or conversion (conversion to intermediate compounds) reaction is carried out at a temperature (reaction temperature, or temperature in the reaction zone) of about 70°C to about 150°C, or about 80°C to about 140°C, or about 90°C to about 130°C, or about 100°C to about 120°C. In some embodiments, the reaction temperature is at least 50°C, or at least 60°C, or at least 70°C, or at least 80°C, or at least 90°C, or at least 100°C. In some embodiments, the reaction temperature is no more than 200°C, or no more than 180°C, or no more than 170°C, or no more than 160°C, or no more than 150°C, or no more than 140°C, or no more than 130°C, or no more than 120°C.

[0051] The reaction zone pressure is not critical for the cyclization or conversion reaction. The cyclization or conversion reaction can be carried out at atmospheric pressure or at a pressure less than or greater than atmospheric pressure. In some embodiments, the cyclization reaction is carried out under ambient atmosphere (i.e., air).

[0052] The cyclization or conversion process time (cyclization or conversion reaction time) can be in the range of about 1 hr (hour) to about 72 hr (hour), or about 6 hr to about 48 hr, or about 8 hr to about 36 hr. In some embodiments, the cyclization or conversion reaction time is at least 1 hr, or at least 2 hr, or at least 4 hr, or at least 6 hr, or at least 8 hr, or at least 10 hr, or at least 12 hr, or at least 14 hr, or at least 16 hr, or at least 18 hr, or at least 20 hr, or at least 22 hr, or at least 24 hr. In some embodiments, the cyclization or conversion reaction time is no more than 7 days, or no more than 6 days, or no more than 5 days, or no more than 4 days, or no more than 72 hr, or no more than 60 hr, or no more than 54 hr, or no more than 48 hr, or no more than 42 hr, or no more than 36 hr, or no more than 30 hr, or no more than 24 hr.

[0053] The cyclization reaction is carried out in the presence of oxygen. The oxygen can be in the form of pure oxygen, oxygen mixed with an inert gas such as nitrogen, or oxygen present in the air. In some embodiments, the cyclization reaction can first be carried out under nitrogen (i.e., in the absence of oxygen) and then exposed to oxygen.

[0054] The desired product aromatic cyclized compound can be separated and recovered by methods known in the art such as distillation and chromatography. In some embodiments, the yield of the aromatic cyclized compound is at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%.

[0055] The conversion reaction is carried out in the substantial absence of oxygen. "Substantially absent oxygen" means that the amount of oxygen present in or fed into the reaction zone is no more than 40 mol%, or no more than 30 mol%, or no more than 20 mol%, or no more than 10 mol%, or no more than 5 mol% based on the molar amount of the starting material. In some embodiments, the conversion reaction can be carried out under an inert gas such as nitrogen.

[0056] In certain embodiments, one or more intermediate compounds can be further converted into aromatic cyclized compounds.Methallylphenol compounds can be converted into aromatic cyclized compounds in the presence of an acid catalyst and a solvent in the reaction zone.In certain embodiments, acid catalysts and / or solvents are identical to those used in the reaction of conversion (conversion into intermediate compounds).Internal ring dienes (internal ring diene I and / or internal ring diene II) can be converted into aromatic cyclized compounds in the presence of oxygen and a solvent in the reaction zone.In certain embodiments, solvent is identical to the solvent used in the reaction of conversion (conversion into intermediate compounds).

[0057] In some embodiments, one or more intermediate compounds are further converted to aromatic cyclized compounds in the presence of oxygen. In some embodiments, after the starting materials are converted to intermediate compounds in the presence of an acid catalyst and a solvent in a reaction zone, oxygen (e.g., an oxygen-containing gas such as air) is introduced into the reaction zone, and the intermediate compounds are further converted in situ to aromatic cyclized compounds in the presence of oxygen, an acid catalyst, and a solvent, without isolating or purifying the intermediate compounds from the reaction mixture and without removing the acid catalyst and solvent from the reaction zone.

[0058] The reaction temperature for the further conversion (from the intermediate compound to the aromatic cyclized compound) may be in the same range as the reaction temperature for the cyclization or conversion (to the intermediate compound) described in the present disclosure.

[0059] In some embodiments, the intermediate compound produced during the conversion process includes an endocyclic diene compound (endocyclic diene I and / or endocyclic diene II), and the endocyclic diene compound can be hydrogenated under effective conditions in the presence of a hydrogenation catalyst, a solvent, and hydrogen to form 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan (musk indenofuran). In some embodiments, the conversion process is carried out in the presence of a zeolite catalyst and a solvent in a reaction zone, the solvent being selected from the group consisting of an alcohol, an ether, and a mixture thereof. After the conversion process, a hydrogenation catalyst is fed into the reaction zone, and the hydrogenation process can be carried out in situ without isolating or purifying the endocyclic diene compound from the reaction mixture and without removing the zeolite catalyst and solvent from the reaction zone. Alternatively, the conversion process is carried out with a heterogeneous acid catalyst, and after the conversion process, the heterogeneous acid catalyst is removed from the reaction mixture (e.g., by filtration), a hydrogenation catalyst is fed into the reaction zone, and the hydrogenation process can be carried out in situ without separating the endocyclic diene compound and the solvent from the reaction mixture.

[0060] Methallyl indole musk ketone can be synthesized by alkylating indole musk ketone with methallyl chloride (CH2=C(CH3)CH2Cl). In some embodiments, the method includes alkylating indole musk ketone with methallyl chloride in the presence of a strong base and a solvent in a reaction zone to produce a product mixture containing methallyl indole musk ketone. Examples of strong bases include sodium amide (NaNH2), lithium diisopropylamide (LiN(CH(CH3)2)2), and combinations thereof. Examples of solvents include toluene, THF, and combinations thereof. In some embodiments, the molar ratio of indole musk ketone fed to the reaction zone to methallyl chloride is about 1:1 to about 1:5, or about 1:1 to about 1:1.5. In some embodiments, the molar ratio of indole musk ketone fed to the reaction zone to the strong base is about 1:1 to about 1:5, or about 1:1 to about 1:1.5. The reaction temperature can be in the range of about 25°C to about 150°C, or about 40°C to about 130°C, or about 40°C to about 80°C, or about 90°C to about 130°C. The reaction time can be in the range of about 1hr to about 36hr, or about 4hr to about 30hr, or about 6hr to about 18hr, or about 12hr to about 30hr. In some embodiments, the yield of methyl allyl indole musk ketone is at least 50%, or at least 55%, or at least 60%.

[0061] Hydroxyisobutyl indole musk ketone can be synthesized by alkylating indole musk ketone with isobutylene oxide. In certain embodiments, the method includes alkylating indole musk ketone with isobutylene oxide in the presence of a strong base and a solvent in a reaction zone to produce a product mixture comprising hydroxyisobutyl indole musk ketone. Examples of strong bases include sodium amide (NaNH2), lithium diisopropylamide (LiN(CH(CH3)2)2), and combinations thereof. Examples of solvents include toluene, THF, and combinations thereof. In certain embodiments, the molar ratio of indole musk ketone to isobutylene oxide fed into the reaction zone is about 1:1 to about 1:5 or about 1:1 to about 1:1.5. In certain embodiments, the molar ratio of indole musk ketone to a strong base fed into the reaction zone is about 1:1 to about 1:5 or about 1:1 to about 1:1.5. The reaction temperature can be in the range of about 25°C to about 150°C, or about 25°C to about 120°C, or about 25°C to about 100°C, or about 25°C to about 80°C, or about 40°C to about 80°C, or about 50°C to about 70°C, or about 35°C to about 70°C. The reaction time can be in the range of about 1 hr to about 24 hr, or about 2 hr to about 20 hr, or about 3 hr to about 16 hr, or about 6 hr to about 20 hr, or about 8 hr to about 16 hr. In some embodiments, the yield of hydroxyisobutylindole musk ketone is at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%.

[0062] In certain embodiments, the aromatic cyclized compound is hydrogenated to form musk indenofuran. In certain embodiments, the method includes hydrogenating the aromatic cyclized compound in the presence of a hydrogenation catalyst, a solvent and hydrogen (H2) in a reaction zone to produce a product mixture comprising musk indenofuran. In certain embodiments, the hydrogenation catalyst is a heterogeneous catalyst comprising rhodium metal supported on a carrier. In certain embodiments, the carrier is carbon, such as activated carbon. In certain embodiments, the content of the rhodium element is 1wt% to 20wt% or 1wt% to 15wt% or 2wt% to 10wt% based on the gross weight of the catalyst. Examples of solvents include alcohols, ethers, and combinations thereof. Examples of alcohols include methanol, ethanol, 1-propanol, isopropanol, butanol and isomers thereof, amyl alcohol and isomers thereof, and combinations thereof. Examples of ethers include THF, dioxane, and combinations thereof. In certain embodiments, the solvent is ethanol and / or THF. In certain embodiments, the solvent is ethanol. The hydrogenation reaction temperature can be in the range of about 25°C to about 160°C, or about 100°C to about 160°C, or about 130°C to about 160°C, or about 130°C to about 150°C. In some embodiments, the hydrogenation process can be carried out under 10-100 bar of H2, or 20-60 bar of H2. The reaction time can be in the range of about 1 hr to about 48 hr, or about 6 hr to about 36 hr, or about 10 hr to about 24 hr. In some embodiments, the yield of musk indenofuran is at least 50%, or at least 60%, or at least 70%, or at least 80%.

[0063] In certain embodiments, cyclization process and hydrogenation process can be carried out in the same reaction zone.For example, cyclization process can be carried out in the presence of oxygen, zeolite catalyst and solvent in reaction zone to produce the product mixture comprising aromatic cyclization compound, and the solvent is selected from the group consisting of: alcohol (for example, ethanol), ether (for example, THF) and mixture thereof.After cyclization process, hydrogenation catalyst can be fed into reaction zone, and hydrogenation process can be carried out in situ without separating or purifying aromatic cyclization compound from product mixture and without removing zeolite catalyst and solvent from reaction zone.In certain embodiments, after cyclization process and before hydrogenation catalyst is added in reaction zone, zeolite catalyst is removed from reaction zone.

[0064] The present disclosure also provides a method for preparing musk indenofuran. The method comprises: (a) alkylating indoles musk ketone with methallyl chloride under conditions that effectively produce methallyl indoles musk ketone, (b) cyclizing methallyl indoles musk ketone under conditions that effectively produce aromatic cyclized compounds, and (c) hydrogenating aromatic cyclized compounds under conditions that effectively produce musk indenofuran. In some embodiments, the corresponding conditions for effectively producing methallyl indoles musk ketone, aromatic cyclized compounds or musk indenofuran have been described in the present disclosure.

[0065] The present disclosure also provides a method for preparing musk indenofuran. The method comprises: (a) alkylating indoles musk ketone with isobutylene oxide under conditions effective to produce hydroxyisobutyl indoles musk ketone, (b) cyclizing hydroxyisobutyl indoles musk ketone under conditions effective to produce aromatic cyclized compounds, and (c) hydrogenating aromatic cyclized compounds under conditions effective to produce musk indenofuran. In some embodiments, the corresponding conditions effective to produce hydroxyisobutyl indoles musk ketone, aromatic cyclized compounds or musk indenofuran have been described in the present disclosure.

[0066] The present disclosure also provides a one-pot method for preparing musk indenofuran by using hydroxyisobutylindole musk ketone as a starting material. The method includes contacting hydroxyisobutylindole musk ketone with a hydrogenation catalyst in a reaction zone in the presence of a solvent and hydrogen (H2) to produce a product mixture comprising musk indenofuran. In this embodiment, hydroxyisobutylindole musk ketone is cyclized and hydrogenated in the presence of a hydrogenation catalyst to form musk indenofuran. The method can be carried out in a single reaction zone without separating or purifying the intermediate compounds produced during the method.

[0067] In some embodiments, the hydrogenation catalyst is a heterogeneous catalyst. In some embodiments, the heterogeneous catalyst is selected from the group consisting of: ruthenium (Ru) catalyst, rhodium (Rh) catalyst, palladium (Pd) catalyst, platinum (Pt) catalyst, and mixtures thereof. Ruthenium catalyst is a ruthenium-containing catalyst, wherein ruthenium can exist as a mixture of ruthenium in metallic form and one or more ruthenium compounds, i.e., ruthenium can be in an oxidation state of 0, I, II or III. The typical form of ruthenium is as metal nanoparticles or as an oxide. Rhodium catalyst is a rhodium-containing catalyst, wherein rhodium can exist as a mixture of rhodium in metallic form and one or more rhodium compounds, i.e., rhodium can be in an oxidation state of 0 or I. The typical form of rhodium is as metal nanoparticles or as an oxide. Palladium catalyst is a palladium-containing catalyst, wherein palladium can exist as a mixture of palladium in metallic form and one or more palladium compounds, i.e., palladium can be in an oxidation state of 0 or II. The typical form of palladium is as metal nanoparticles or as an oxide. Platinum catalysts are platinum-containing catalysts in which the platinum is present as a mixture of platinum in metallic form and one or more platinum compounds, ie the platinum can be in oxidation state 0 or II. Typical forms of platinum here are as metal nanoparticles or as oxides.

[0068] In some embodiments, the heterogeneous hydrogenation catalyst is supported on a catalyst carrier. In some embodiments, the carrier is carbon, such as activated carbon. Other suitable carriers include aluminum oxide, silicon dioxide, and mixtures thereof. In some embodiments, the content of ruthenium element is 1wt% to 20wt% or 1wt% to 15wt% or 2wt% to 10wt% based on the total weight of the ruthenium catalyst and the carrier. In some embodiments, the content of ruthenium element, palladium element or platinum element is 1wt% to 20wt% or 1wt% to 15wt% or 2wt% to 10wt% based on the total weight of the corresponding catalyst and the carrier.

[0069] In some embodiments, the amount of the ruthenium catalyst is such that the total amount of ruthenium contained in the catalyst is at least 0.05 mol%, or at least 0.1 mol%, or at least 0.2 mol%, or at least 0.3 mol%, or at least 0.4 mol% based on the total molar amount of the hydroxyisobutylindole musk ketone starting material. In some embodiments, the amount of the ruthenium catalyst is such that the total amount of ruthenium contained in the catalyst is no more than 5 mol%, or no more than 4 mol%, or no more than 3 mol%, or no more than 2 mol%, or no more than 1 mol%, or no more than 0.8 mol%, or no more than 0.6 mol% based on the total molar amount of the hydroxyisobutylindole musk ketone starting material.

[0070] In some embodiments, the amount of the rhodium catalyst, palladium catalyst or platinum catalyst is such that the total amount of the rhodium element, palladium element or platinum element contained in the corresponding catalyst is at least 0.05 mol%, or at least 0.1 mol%, or at least 0.2 mol%, or at least 0.3 mol%, or at least 0.4 mol% based on the total molar amount of the hydroxyisobutylindole musk ketone starting material. In some embodiments, the amount of the rhodium catalyst, palladium catalyst or platinum catalyst is such that the total amount of the rhodium element, palladium element or platinum element contained in the corresponding catalyst is no more than 5 mol%, or no more than 4 mol%, or no more than 3 mol%, or no more than 2 mol%, or no more than 1 mol%, or no more than 0.8 mol%, or no more than 0.6 mol% based on the total molar amount of the hydroxyisobutylindole musk ketone starting material.

[0071] Examples of solvents include alcohols, ethers, and combinations thereof. Examples of alcohols include methanol, ethanol, 1-propanol, isopropanol, butanol and isomers thereof, amyl alcohol and isomers thereof, and combinations thereof. Examples of ethers include THF, dioxane, and combinations thereof. In some embodiments, the solvent is ethanol and / or THF. In some embodiments, the solvent is ethanol.

[0072] The reaction temperature of the one-pot process for preparing musk indenofuran can be in the range of about 70°C to about 250°C, or 80°C to about 220°C, or about 90°C to about 200°C, or about 100°C to about 180°C, or about 120°C to about 160°C. In some embodiments, the one-pot process can be carried out under 10-100 bar of H2, or 20-60 bar of H2. The reaction time can be in the range of about 1 hr to about 48 hr, or about 6 hr to about 36 hr, or about 10 hr to about 24 hr. In some embodiments, the yield of musk indenofuran is at least 55%, or at least 60%, or at least 65%.

[0073] During the one-pot process, intermediate compounds such as endocyclic diene I and / or endocyclic diene II may be formed. The method is carried out by using hydroxyisobutylindole musk ketone as a starting material to prepare musk indenofuran without isolating or purifying any intermediate compounds. At the end of the reaction, the desired product musk indenofuran may be separated and recovered by methods known in the art such as distillation and chromatography.

[0074] The present disclosure also provides a phosphine derivative compound having a structural formula (X):

[0075]

[0076] Wherein R is selected from the group consisting of: alkyl, cycloalkyl, phenyl, substituted phenyl, and perfluoroalkyl. In some embodiments, R is phenyl (Ph). In some embodiments, R is a cycloalkyl selected from the group consisting of: cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. In some embodiments, R is cyclohexyl. In some embodiments, R is cyclopentyl. In some embodiments, R is a straight chain alkyl. In some embodiments, R is selected from the group consisting of: methyl, ethyl, isopropyl, and tert-butyl ( t In some embodiments, R is isopropyl. In some embodiments, R is tert-butyl.

[0077] The phosphine derivative compound having structural formula (X) ("phosphine derivative compound") can be used as a ligand to form a metal-phosphine complex, which can be used as a catalyst for, for example, carbon-carbon, carbon-amine or carbon-oxygen cross-coupling reactions.

[0078] The phosphine derivative compound having the structural formula (X) can be synthesized using an aromatic cyclized compound as a starting material, as shown in Scheme 1.

[0079]

[0080] Scheme 1. Synthesis of phosphine derivative compounds

[0081] The present disclosure also provides a method for preparing a phosphine derivative compound having a structural formula (X). The method comprises: (a) brominating an aromatic cyclized compound in the presence of a brominating agent and a solvent to form 5-bromo-2,2,6,6,7,8,8-heptamethyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan (aromatic bromide compound), (b) contacting the aromatic bromide compound with a lithiating agent in the presence of a solvent in a reaction zone to form a reaction mixture, and (c) adding a chlorinated phosphine compound having a formula R2PCl to the reaction mixture to form a phosphine derivative compound having a structural formula (X) (phosphine derivative compound).

[0082] The method includes a bromination reaction (step (a)) and a phosphorylation reaction (steps (b) and (c)). In the bromination reaction, in some embodiments, the brominating agent is selected from the group consisting of bromine (Br2), N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), N-bromobenzamide, pyridinium hydrobromide perbromide (PyHBr3), and mixtures thereof. In some embodiments, the brominating agent is selected from the group consisting of bromine (Br2), N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), and mixtures thereof. In some embodiments, the amount of the brominating agent used in the reaction is about 5 to about 1 stoichiometric equivalents, or about 2 to about 1 stoichiometric equivalents, or about 1.5 to about 1 stoichiometric equivalents, or about 1.2 to about 1 stoichiometric equivalents, or about 1.1 to about 1 stoichiometric equivalents. Examples of solvents for bromination reactions include dichloromethane, hexane, acetonitrile, ethers such as diethyl ether, tert-butyl methyl ether and 1,4-dioxane, n-pentane, cyclohexane, and combinations thereof. The bromination reaction temperature may be in the range of about 0°C to about 50°C. In some embodiments, the bromination reaction is carried out at room temperature. The bromination reaction time may be 1 to 120 min (minutes), or 5 to 60 min, or 10 to 30 min. In some embodiments, the yield of the aromatic bromide compound is at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%.

[0083] In the phosphorylation reaction, in some embodiments, the lithiating agent is selected from the group consisting of: n-butyl lithium (n-BuLi), phenyl lithium (PhLi), tert-butyl lithium (tert-BuLi), sec-butyl lithium (sec-BuLi), a 1:1 mixture of n-BuLi and tert-BuONa (sodium tert-butoxide), metallic lithium, and mixtures thereof. In some embodiments, the lithiating agent is n-BuLi. In some embodiments, the molar ratio of the lithiating agent to the aromatic bromide compound is from about 2:1 to about 1:1, or from about 1.5:1 to about 1:1, or about 1.25:1. Examples of solvents for the phosphorylation reaction include THF, hexane, diethyl ether, tert-butyl methyl ether, 1,4-dioxane, n-pentane, cyclohexane, and combinations thereof. In some embodiments, the temperature of contacting step (b) is about -90°C to about 25°C, or about -90°C to about 0°C, or about -85°C to about -10°C, or about -80°C to about -20°C, or about 0°C to about 25°C, or about -78°C. In some embodiments, the contact time (of contacting step (b)) is about 5 to 60 min, or about 5 to 40 min, or about 10 to 30 min. In some embodiments, the reaction temperature of step (c) is about 10°C to about 100°C, or about 15°C to about 80°C, or about 20°C to about 60°C, or about 20°C to about 40°C, or about room temperature. In some embodiments, the molar ratio of the chlorophosphine compound fed to the reaction zone to the aromatic bromide compound fed to the reaction zone is about 2:1 to about 1:1, or about 1.5:1 to about 1:1, or about 1.2:1 to about 1:1, or about 1.1:1 to about 1:1. In some embodiments, the reaction time of step (c) is about 30 to 240 min, or about 60 to 180 min, or about 60 to 120 min. In some embodiments, the yield of the phosphine derivative compound is at least about 20%, or at least about 25%, or at least about 30%.

[0084] Many aspects and embodiments have been described above and are exemplary rather than limiting. After reading this specification, a skilled person will appreciate that other aspects and embodiments are possible without departing from the scope of the present invention.

[0085] Examples

[0086] The concepts described herein will be further described in the following examples, which do not limit the scope of the invention described in the claims.

[0087] Overview

[0088] Glassware was dried in an oven at 175°C before use. Cyclization reactions were performed in vials or round-bottom flasks equipped with a magnetic stirrer and open to air. Unless otherwise indicated, reagents and solvents were obtained from commercial sources and used without further purification. 1 H- and 13 The products were characterized by C-NMR, and DEPT (distortionless polarization transfer enhancement). Gas chromatography was performed on an instrument equipped with a 25 m capillary column with 5% benzyl silicone. n-Dodecane was used as an external standard. GC / MS analysis was performed on a spectrometer equipped with the same column as the GC and operated under the same conditions. The wavelengths were recorded on a 300 MHz instrument using CDCl3 as solvent and TMS as an internal standard. 1 H. 13 C and DEPT measurements.

[0089] Example 1: Cyclization of methyl allyl indole musk ketone to aromatic cyclized compounds using various acid catalysts

[0090]

[0091] Scheme 2. Cyclization of methyl allyl indole musk ketone to aromatic cyclized compounds

[0092] Cyclization of Methallyl Indole Musk Ketone Using Homogeneous Acid Catalyst

[0093] In a 50ml (milliliter) round-bottom flask equipped with a magnetic stirring bar, an acid catalyst MSA (65 μl) is added to a solution of methyl allyl indole musk ketone (1.3g, 5mmol) in toluene (25ml). The reaction mixture is open to air and magnetically stirred for 18 hours at room temperature, and then concentrated under vacuum. Flash chromatography (100% hexane) produces 320mg (25% yield) of aromatic cyclized compounds in the form of yellow oil. The results are shown in Table 1.

[0094] The same procedure as above was followed except that pTsOH (172 mg) was used as the acid catalyst. Flash chromatography (100% hexanes) yielded 256 mg (20% yield) of the aromatic cyclized compound as a yellow oil. The results are shown in Table 1.

[0095] Cyclization of Methallyl Indole Musk Ketone Using Zeolite

[0096] In a 25 ml round bottom flask equipped with a magnetic stirring bar and the corresponding zeolite (H-Beta CP-811 or H-USY CBV-720, 260 mg, calcined under vacuum at 300 ° C in advance), a solution of methyl allyl indole musk ketone (260 mg, 1 mmol) in toluene (5 ml) was added. The reaction mixture was opened to air and stirred under reflux at 110 ° C. After 12 hours, an aliquot of the reaction mixture was dissolved in AcOEt (1 ml) and filtered through a 20 μm nylon filter, and the resulting filtrate was analyzed by GC and GC-MS. The results are shown in Table 1.

[0097] Table 1

[0098]

[0099] Note: In the table, T means reaction temperature; t means reaction time; Conv means conversion.

[0100] Example 2: Cyclization of methyl allyl indole musk ketone to aromatic cyclized compounds using pTsOH at different temperatures

[0101] In a 250ml round-bottom flask equipped with a magnetic stirring bar, an acid catalyst pTsOH (7g) was added to a solution of methyl allyl indole musk ketone (52g, 0.2mol) in toluene (100ml). The reaction mixture was open to air and magnetically stirred for a certain reaction time at a certain temperature (25°C, 50°C or 70°C). After cooling, the mixture was neutralized with a 10% aqueous sodium bicarbonate solution. The aqueous phase was extracted with hexane and washed with brine. The combined organic phases were dried over MgSO4, filtered and concentrated under vacuum. The product aromatic cyclization compound was purified and recovered using flash chromatography (100% hexane). Reaction conditions and results are shown in Table 2.

[0102] Table 2

[0103]

[0104] Example 3: Cyclization of methyl allyl indole musk ketone to aromatic cyclized compounds using pTsOH in various solvents

[0105] In the 8ml vial equipped with a magnetic stirring bar and containing an acid catalyst pTsOH (140mg), a solution of methyl allyl indole musk ketone (1.04g, 4mmol) in a solvent (2ml) was added. The reaction mixture was opened to air and stirred at a certain temperature for 24 hours. After this, the mixture was cooled and neutralized with a 10% sodium bicarbonate aqueous solution. The aqueous phase was extracted with hexane and washed with brine. The organic phase merged was dried over MgSO4, filtered and concentrated under vacuum. The aliquot was dissolved in AcOEt (1ml) and filtered through a 20μm nylon filter, and the resulting filtrate was analyzed by GC and GC-MS. Reaction conditions and results are shown in Table 3.

[0106] Table 3

[0107]

[0108] Example 4: Cyclization of methyl allyl indole musk ketone to aromatic cyclized compounds using various heterogeneous acid catalysts

[0109] In the 8ml vial equipped with a magnetic stirring bar and containing a heterogeneous acid catalyst (1.04g), a solution of methyl allyl indole musk ketone (1.04g, 4mmol) in toluene (2ml) was added. The reaction mixture was opened to air and stirred at 70°C for 24hr. After this, an aliquot was dissolved in AcOEt (1ml) and filtered through a 20 μm nylon filter, and the resulting filtrate was analyzed by GC and GC-MS. Reaction conditions and results are shown in Table 4.

[0110] Table 4

[0111]

[0112]

[0113] Sodium zeolites NaX and NaY are neutral (have no Bronsted acid sites) and do not produce aromatic cyclized compounds.

[0114] Example 5: Cyclization of methyl allyl indole musk ketone to aromatic cyclized compounds using pTsOH at 70 °C for different reaction times

[0115] In an 8ml vial equipped with a magnetic stirring bar and containing an acid catalyst pTsOH (140mg), a solution of methyl allyl indole musk ketone (1.04g, 4mmol) in toluene (2ml) was added. The reaction mixture was opened to air and stirred at 70°C for a certain reaction time. Thereafter, the mixture was cooled and neutralized with a 10% aqueous sodium bicarbonate solution. The aqueous phase was extracted with hexane and washed with brine. The combined organic phase was dried over MgSO4, filtered and concentrated under vacuum. An aliquot was dissolved in AcOEt (1ml) and filtered through a 20μm nylon filter, and the resulting filtrate was analyzed by GC and GC-MS. Reaction conditions and results are shown in Table 5.

[0116] Table 5

[0117]

[0118]

[0119] Example 6: Alkylation of indole musk ketone with methyl allyl chloride to prepare methyl allyl indole musk ketone

[0120]

[0121] Scheme 3. Alkylation of indolemusk ketone with methylallyl chloride

[0122] In the 50ml round-bottom flask equipped with a magnetic stirring bar, at room temperature under continuous stirring, during 5-10min (minute), a suspension of sodium amide (242mg, 5.6mmol) in toluene (1.8ml) is slowly added to the 3M toluene solution of musk indole (1ml, 5.6mmol). After 20min, the 3M toluene solution of methyl allyl chloride (550 μl, 5.6mmol) is added to the flask, and stirring is continued for 12hr, while the reaction mixture is refluxed. After cooling, the mixture is neutralized with the HCl aqueous solution, extracted with ether and washed with salt water. The organic phase merged is dried through MgSO4, filtered and concentrated under vacuum. Flash column chromatography (2% AcOEt in hexane) provides 946mg (65% yield) of methyl allyl musk indole in yellow oil.

[0123] Example 7a: Alkylation of indole musk ketone with isobutylene oxide to prepare hydroxyisobutyl indole musk ketone

[0124]

[0125] Scheme 4. Alkylation of indolemusk ketone with isobutylene oxide

[0126] In a 100ml round-bottom flask equipped with a magnetic stirring bar, at room temperature under continuous stirring (750rpm) and under N2 atmosphere, indole musk ketone (10ml, 45mmol) is slowly added to a suspension of sodium amide (2.5g, 66mmol) in toluene (45ml) during 15min. Then, the mixture is heated to 45°C. After 30min at 45°C, isobutylene oxide (3.5ml, 66mmol) is slowly added to the flask and continues to stir for 6 hours. After cooling, the reaction mixture is neutralized with NH4Cl. The aqueous phase is extracted with ethyl acetate and washed with brine. The organic phase merged is dried through MgSO4, filtered and concentrated under vacuum. Flash chromatography (1%AcOEt in hexane) gives 8.8g (70% yield) of hydroxyisobutyl indole musk ketone in the form of yellow oil.

[0127] Example 7b: Alkylation of indole musk ketone with isobutylene oxide to prepare hydroxyisobutyl indole musk ketone

[0128] In Example 7b, the same process as in Example 7a was carried out except that the reaction temperature was 60° C. and the reaction time was 12 hours. The yield of hydroxyisobutylindolemusk ketone was 80%.

[0129] Example 8: Hydrogenation of aromatic cyclized compounds to prepare musk indenofurans

[0130]

[0131] Scheme 5. Hydrogenation of aromatic cyclized compounds

[0132] The hydrogenation catalyst used in Example 8 is rhodium (Rh / C) supported on a carbon carrier. The content of rhodium element is 5wt% based on the gross weight of the catalyst. The solvent used in Example 8 is ethanol or THF. Hydrogenation catalyst (Rh / C 5wt%, 145mg), solvent (ethanol or THF, 1ml) and aromatic cyclization compound (50mg, 0.2mmol) are loaded into a 4ml vial containing a magnetic stirring bar. Then, the reaction vial is capped with a diaphragm equipped with a needle and placed in an alloy plate, which is then placed in a 300ml autoclave. Once sealed, the autoclave is purged three times with 20 bar of hydrogen, then pressurized to 40 bar of hydrogen and placed in an aluminum block, which is preheated at 140°C. After 18 hours, the autoclave is cooled in an ice bath, and the remaining hydrogen is carefully released. Finally, the reaction mixture containing musk indenofuran is diluted with ethyl acetate and analyzed by GC and GC-MS. Reaction conditions and results are shown in Table 6.

[0133] Table 6

[0134]

[0135] Example 9: One-pot cyclization / hydrogenation of hydroxyisobutylindole musk ketone to prepare musk indenofuran

[0136]

[0137] Scheme 6. One-pot cyclization / hydrogenation of hydroxyisobutylindole musk ketone

[0138] The hydrogenation catalyst used in Example 9 is ruthenium, rhodium or palladium (Ru / C, Rh / C or Pd / C) supported on a carbon carrier. The content of ruthenium, rhodium or palladium elements is 5wt% based on the gross weight of the corresponding catalyst. The solvent used in Example 9 is ethanol. Hydrogenation catalyst, hydroxyisobutylindole musk ketone (125mg, 0.7mmol) and ethanol are loaded into the 4ml reaction bottle containing a stirring rod. The reaction bottle is then capped with a diaphragm equipped with a needle and placed in an alloy plate, which is then placed in a 300ml autoclave. Once sealed, the autoclave is purged with hydrogen three times, then pressurized to 30 bar or 50 bar and placed in an aluminum block, which is preheated at 130 ℃ or 150 ℃. After 18 hours, the autoclave is cooled in an ice bath, and remaining hydrogen is carefully released. An aliquot of the product mixture containing the musk indenofuran was then dissolved in ethyl acetate (1 ml), the mixture was filtered through a 20 mm nylon filter and the resulting solution was analyzed by GC and GC-MS. The reaction conditions and results are shown in Table 7.

[0139] Table 7

[0140]

[0141]

[0142] Note: "H2P" means hydrogen pressure (bar); "Cat (mol%)" means the amount of catalyst and its Rh, Pd or Ru, in mole percentage based on the mole amount of hydroxyisobutylindolemusk ketone starting material.

[0143] Example 10: Bromination of an aromatic cyclized compound to prepare an aromatic bromide compound

[0144]

[0145] Scheme 7. Bromination of aromatic cyclized compounds

[0146] Aromatic cyclization compound (1.95g, 7.5mmol) is placed in a 250ml round-bottom flask equipped with a magnetic stirrer. Dichloromethane (50ml) is added to the flask. At room temperature under magnetic stirring, the solid is dissolved, and Br2 (390 μl, 7.5mmol) is added dropwise to the flask. After Br2 is added, the resulting reaction mixture is further stirred for 15 minutes, and then treated with Na2S2O3 aqueous solution (aq.), NaHCO3 (aq.) and saline. The organic phase is dried and filtered through Na2SO4. Volatiles are removed from the filtrate under vacuum to give aromatic bromide compounds (2.1g, 87% yield) in the form of yellow oil.

[0147] Example 11: Phosphorylation of aromatic bromide compounds to prepare phosphine derivative compounds

[0148]

[0149] Scheme 8. Phosphorylation of aromatic bromide compounds

[0150] Aromatic bromide compound (340mg, 1mmol) is placed in the 10ml round-bottom flask of drying equipped with magnetic stirring apparatus, is dissolved in anhydrous THF (2ml) under nitrogen atmosphere, and is cooled to-78 ℃.Then, 2.5Mn-BuLi (0.5ml, 1.25mmol) in hexane is added dropwise in flask, and the obtained reaction mixture is changed from yellow to orange.The reaction mixture is stirred for another 15min at-78 ℃ by magnetic force, then chlorodiphenylphosphine (PhPCl, 180 μl, 1.0mmol, 1 equivalent) is added in flask at one time.Then the reaction mixture is warmed to room temperature under agitation for 90min.Then the reaction mixture is quenched with NHCl (aq.) and washed with water and salt water successively.Organic phase is through NaSODry and filter. The desired phosphine derivative compound product ((2,2,6,6,7,8,8-heptamethyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-5-yl)diphenylphosphine) was purified by column chromatography and then by preparative thin layer chromatography [TLC, 3% AcOEt in n-hexane; R f (10% AcOEt in n-hexane) = 0.65] purification gave the desired phosphine derivative compound (colorless solid, 150 mg, 34% yield) after removal of volatiles under vacuum.

[0151] It should be noted that not all of the activities described above in the general description or examples are required, a portion of a specific activity may not be required, and one or more additional activities may be performed in addition to those described. Furthermore, the order in which the activities are listed is not necessarily the order in which they are performed.

[0152] In the foregoing description, concepts have been described with reference to specific embodiments. However, it will be appreciated by those skilled in the art that various modifications and changes may be made without departing from the scope of the invention as set forth in the following claims. Therefore, this description should be considered illustrative rather than restrictive, and all such modifications are intended to be included within the scope of the invention.

[0153] Benefits, other advantages, and solutions to problems have been described above in conjunction with specific embodiments. However, benefits, advantages, solutions to problems, and any one or more features that may cause any benefit, advantage, or solution to appear or make it more obvious should not be construed as key, necessary, or essential features of any or all claims.

[0154] It should be understood that certain features described herein in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features described in the context of a single embodiment for brevity may also be provided separately or in any sub-combination.

Claims

1. A method comprising: The starting material is cyclized in the presence of oxygen, an acid catalyst and a solvent in a reaction zone to form 2,2,6,6,7,8,8-heptamethyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan (aromatic cyclized compound), wherein the acid catalyst is a homogeneous acid catalyst and / or a heterogeneous acid catalyst having a pKa of no more than zero, and the starting material is 1,1,2,3,3-pentamethyl-5-(2-methylallyl)-1,2,3,5,6,7-hexahydro-4H-inden-4-one (methylallylindolemusk ketone) and / or 5-(2-hydroxy-2-methylpropyl)-1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one (hydroxyisobutylindolemusk ketone).

2. The method of claim 1, wherein: The starting material is methyl allyl indole musk ketone.

3. The method according to claim 1 or 2, wherein: The acid catalyst is the homogeneous acid catalyst.

4. The method of claim 3, wherein: The homogeneous acid catalyst is selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, trifluoromethanesulfonic acid, trifluoromethanesulfonimide, trifluoromethanesulfonamide, and mixtures thereof.

5. The method of claim 4, wherein: The homogeneous acid catalyst is selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, and mixtures thereof.

6. The method according to claim 1 or 2, wherein: The acid catalyst is the heterogeneous acid catalyst.

7. The method of claim 6, wherein: The heterogeneous acid catalyst is selected from the group consisting of alumina, silica-alumina, zeolites, silicoaluminophosphates, aluminophosphates, sulfated zirconia, zirconium oxide, sulfonic acid resins, and mixtures thereof.

8. The method of claim 7, wherein: The heterogeneous acid catalyst is selected from the group consisting of zeolites, sulfonic acid resins, and mixtures thereof.

9. The method of claim 8, wherein: The heterogeneous acid catalyst is a zeolite.

10. A method comprising: The starting material is converted into an intermediate compound in the presence of an acid catalyst and a solvent in a reaction zone, wherein the intermediate compound is selected from the group consisting of: 1,1,2,3,3-pentamethyl-5-(2-methylallyl)-2,3-dihydro-1H-inden-4-ol (methylallylphenol compound), 2,2,6,6,7,8,8-heptamethyl-3,4,5,6,7,8-hexahydro-2H-indeno[4,5-b]furan (endocyclic diene I), 2,2,6,6,7,8,8-heptamethyl-3,3a,4,6,7,8-hexahydro-2H-indeno[4,5-b]furan (endocyclic diene II) and mixtures thereof, wherein the conversion process is carried out in the substantial absence of oxygen, the acid catalyst is a homogeneous acid catalyst and / or a heterogeneous acid catalyst having a pKa not exceeding zero, and the starting material is 1,1,2,3,3-pentamethyl-5-(2-methylallyl)-1,2,3,5,6,7-hexahydro-4H-indene-4-one (methylallylindolemusk ketone) and / or 5-(2-hydroxy-2-methylpropyl)-1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-4H-indene-4-one (hydroxyisobutylindolemusk ketone).

11. The method of claim 10, wherein: The starting material is methyl allyl indole musk ketone.

12. The method according to claim 10 or 11, wherein: The acid catalyst is the heterogeneous acid catalyst.

13. The method of any one of claims 10 to 12, further comprising converting the intermediate compound into 2,2,6,6,7,8,8-heptamethyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan (aromatic cyclized compound) in the presence of oxygen.

14. The method according to any one of claims 10 to 12, wherein: The intermediate compound includes an endocyclic diene compound selected from the group consisting of endocyclic diene I, endocyclic diene II, and mixtures thereof, and the endocyclic diene compound is hydrogenated to form 2,2,6,6,7,8,8-heptamethyldecahydro-2H-indeno[4,5-b]furan (musk indenofuran).

15. A method comprising: (a) alkylating indolemusk ketone with methallyl chloride under conditions effective to produce methallyl indolemusk ketone, (b) cyclizing methallylindolemusk ketone under conditions effective to produce an aromatic cyclized compound, and (c) hydrogenating the aromatic cyclized compound under conditions effective to produce the musk indenofuran.

16. A method comprising: Hydroxyisobutylindole musk ketone is contacted with a hydrogenation catalyst in the presence of a solvent and hydrogen (H2) in a reaction zone to produce a product mixture comprising musk indenofuran.

17. The method of claim 16, wherein: The hydrogenation catalyst is a heterogeneous ruthenium catalyst.

18. A phosphine derivative compound having the structural formula (X), wherein R is selected from the group consisting of alkyl, cycloalkyl, phenyl, substituted phenyl, and perfluoroalkyl.

19. The phosphine derivative compound according to claim 18, wherein R is selected from the group consisting of phenyl, cyclohexyl, and tert-butyl.

20. A method for preparing the phosphine derivative compound according to claim 18, comprising: (a) brominating an aromatic cyclized compound in the presence of a brominating agent and a solvent to form 5-bromo-2,2,6,6,7,8,8-heptamethyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan (aromatic bromide compound), (b) contacting an aromatic bromide compound with a lithiating agent in the presence of a solvent in a reaction zone to form a reaction mixture, and (c) adding a chlorophosphine compound having the formula R2PCl to the reaction mixture to form the phosphine derivative compound as claimed in claim 18, wherein R is selected from the group consisting of: alkyl, cycloalkyl, phenyl, substituted phenyl, and perfluoroalkyl.

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