Process of making 2-(octahydro-1h-4,7-methanoinden-5-yl)acetaldehyde and its intermediate compounds

Abstract

The application relates to a process involving: contacting 5- ethynyloctahydro-lH-4,7-methanoinden-5-ol (Compound III) with an acid in a reaction zone in the presence of a catalyst and a solvent to form a product mixture comprising 2-(octahydro-5H-4,7- methanoinden-5-ylidene)acetaldehyde (Compound II). The application also relates to a process involving: contacting Compound II with hydrogen in a reaction zone in the presence of a hydrogenation catalyst to form a product mixture comprising 2-(octahydro-lH-4,7- methanoinden-5-yl)acetaldehyde (Compound I). The application also relates to a process involving: (i) converting octahydro-5H-4,7- methanoinden-5-one (Compound IV) to Compound III; (ii) contacting Compound III with an acid in the presence of a catalyst to produce Compound II; and (iii) hydrogenating Compound II in the presence of a hydrogenation catalyst to form a product mixture comprising Compound I. The application also relates to a compound of structural formula (III) and a compound of structural formula (II) respectively in the form of any one of its stereoisomers or a mixture thereof.

Description

[0001] TITLE

[0002] Process of Making 2-(Octahydro-1 H-4,7-methanoinden-5-yl)acetaldehyde and Its Intermediate

[0003] Compounds

[0004] BACKGROUND

[0005] Field of the Disclosure

[0006] The present disclosure relates to a process of making 2-(octahydro-1 H-4,7- methanoinden-5-yl)acetaldehyde (Compound I, Aquaflora™ fragrance). The present disclosure also relates to a process of making 2-(octahydro-5H-4,7-methanoinden-5-ylidene)acetaldehyde (Compound II) which can be used as an intermediate to make Compound I. The present disclosure also relates to new compounds 5-ethynyloctahydro-1 H-4,7-methanoinden-5-ol (Compound III) and 2-(octahydro-5H-4,7-methanoinden-5-ylidene)acetaldehyde (Compound II), and the processes of making them respectively.

[0007] Description of Related Art

[0008] IFF Aquaflora™ fragrance is a powerful watery, clean floralizer, even at low dosages. It offers violet undertones and can modernize orris notes. With outstanding bloom performance on skin and cloth, Aquaflora™ fragrance boosts naturalcy and freshness.

[0009] US8,633,144 disclosed the synthesis of the Aquaflora™ fragrance via a three-steps process shown below:

[0010] The process involves a methyl Grignard addition, an acid catalyzed dehydration and a hydroformylation reaction. The Aquaflora™ fragrance product is obtained as a mixture of isomers.

[0011] However, the hydroformylation reaction typically employs Rh catalysts which are expensive. Therefore, there is an ongoing need to develop new processes to make the Aquaflora™ fragrance.

[0012] BRIEF SUMMARY OF THE DISCLOSURE The present disclosure provides a process for making 2-(octahydro-5H-4,7- methanoinden-5-ylidene)acetaldehyde (Compound II). The process comprises: contacting 5- ethynyloctahydro-1 H-4,7-methanoinden-5-ol (Compound III) with an acid in a reaction zone in the presence of a catalyst and a solvent to form a product mixture comprising Compound II.

[0013] The present disclosure also provides a process for making 2-(octahydro-1 H-4,7- methanoinden-5-yl)acetaldehyde (Compound I). The process comprises: contacting 2-(octahydro- 5H-4,7-methanoinden-5-ylidene)acetaldehyde (Compound II) with hydrogen in a reaction zone in the presence of a hydrogenation catalyst to form a product mixture comprising Compound I.

[0014] The present disclosure also provides a process for making 2-(octahydro-1 H-4,7- methanoinden-5-yl)acetaldehyde (Compound I). The process comprises: (i) converting octahydro- 5H-4,7-methanoinden-5-one (Compound IV) to 5-ethynyloctahydro-1 H-4,7-methanoinden-5-ol (Compound III); (ii) contacting Compound III with an acid in the presence of a catalyst to produce 2-(octahydro-5H-4,7-methanoinden-5-ylidene)acetaldehyde (Compound II); and (iii) hydrogenating Compound II in the presence of a hydrogenation catalyst to form a product mixture comprising Compound I.

[0015] The present disclosure also provides a compound of structural formula (III) in the form of any one of its stereoisomers or a mixture thereof.

[0016] The present disclosure also provides a compound of structural formula (II) in the form of any one of its stereoisomers or a mixture thereof.

[0017] DETAILED DESCRIPTION

[0018] The foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as defined in the appended claims. Other features and benefits of any one or more of the embodiments will be apparent from the following detailed description, and from the claims. 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).

[0019] Furthermore, "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0020] Also, use of "a" or "an" are employed 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.

[0021] The term "approximately" or "about" is used herein to mean approximately, roughly, around, or in the regions of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" may modify a numerical value above and below the stated value by a variance of, e.g., 10 percent, up or down (higher or lower). In some embodiments, the term indicates deviation from the indicated numerical value by ± 10%, ±5%, ±4%, ±3%, ±2%, ± 1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, or ±0.01%. In some embodiments, "about" indicates deviation from the indicated numerical value by ± 10%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±5%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±4%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±3%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±2%. In some embodiments, "about" indicates deviation from the indicated numerical value by ± 1%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.9%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.8%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.7%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.6%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.5%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.4%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.3%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.1%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.05%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.01%..

[0022] 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 embodiments 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.

[0023] 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.

[0024] 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.

[0025] Within the disclosure, the expressions "comprising substantially", "consisting substantially", "comprising essentially" and "consisting essentially" are used interchangeably and intend to mean, when used with regard to a composition, method, or apparatus, that the composition, method, or apparatus includes the then specified elements or steps to a significant extent, but not necessarily exclusively, and therefore allows for the presence of other unlisted components or steps to the extent that does not change materially affect the overall nature function or purpose of the composition, method, or apparatus (minor additional components or steps).

[0026] Some of the compounds of the present disclosure have stereoisomers. Unless explicitly indicated, a compound of the present disclosure includes its stereoisomers and any combinations or mixtures of the stereoisomers.

[0027] Before addressing details of embodiments described below, some terms are defined or clarified.

[0028] The term "Compound I", as used herein, is the chemical compound named 2-(octahydro- 1 H-4,7-methanoinden-5-yl)acetaldehyde and represented by the following structural formula (I):

[0029] The term "Compound II", as used herein, is the chemical compound named 2-(octahydro- 5H-4,7-methanoinden-5-ylidene)acetaldehyde and represented by the following structural formula (II):

[0030] The wavy line in the structural formula (II) indicates E or Z configuration, that is, Compound II is Compound Ila and / or Compound lib. In some embodiments, Compound II is a mixture of Compound Ila and Compound lib.

[0031] The term "Compound Ila", as used herein, is the chemical compound named (E)-2- (octahydro-5H-4,7-methanoinden-5-ylidene)acetaldehyde and represented by the following structural formula (Ila): The term "Compound lib", as used herein, is the chemical compound named (Z)-2- (octahydro-5H-4,7-methanoinden-5-ylidene)acetaldehyde and represented by the following structural formula (lib):

[0032] The term "Compound III", as used herein, is the chemical compound named 5- ethynyloctahydro-1 H-4,7-methanoinden-5-ol and represented by the following structural formula (III):

[0033] The term "Compound IV", as used herein, is the chemical compound named octahydro- 5H-4,7-methanoinden-5-one and represented by the following structural formula (IV):

[0034] The term "Compound V", as used herein, is the chemical compound named 6- methyloctahydro-1 H-4,7-methanoindene-5-carbaldehyde and represented by the following structural formula (V):

[0035] The term "under an anhydrous condition", as used herein with respect to a reaction, means the reaction is conducted in the substantial absence of water. In some embodiments, it means the water content in the reaction zone is no more than 5%, 2%, 1%, 0.5%, 0.2%, 0.1%, 0.05%, 0.02%, or 0.01%, based on the total weight of the reaction mixture (including reactants, products, solvents, catalysts, etc., if present) present in the reaction zone. Typically, "anhydrous conditions", may be obtained by using solvents, reagents and other materials of "anhydrous quality" as commercially provided by suppliers, for which the water content is indicated as 0.1% or below. Alternatively, the solvents or reagents may be dried before use by subjecting them to appropriate procedure which may consist in one or more techniques such as distillation, distillation over drying agents, azeotropic distillation, vacuum drying, thermal drying, dessication and use substances that chemically bind, absorb or react with water. Further, the reactions may be carried out under inert atmosphere, such as nitrogen or argon, to prevent exposure to atmospheric moisture.

[0036] The term "mol%", as used herein, means percentage by mole. The term "wt%", as used herein, means percentage by weight. As used herein, the terms "kg", "g", and "mg" refer to "kilogram", "gram", and "milligram" respectively. The terms "L" and "mL" refer to "liter" and "milliliter" respectively. The terms "mM" and "M" refer to molar concentration units "millimolar" (mmol / L) and "molar" (mol / L) respectively.

[0037] The present disclosure provides a process for making 2-(octahydro-1 H-4,7- methanoinden-5-yl)acetaldehyde (Compound I). The process comprises: (i) converting octahydro- 5H-4,7-methanoinden-5-one (Compound IV) to 5-ethynyloctahydro-1 H-4,7-methanoinden-5-ol (Compound III); (ii) contacting Compound III with an acid in the presence of a catalyst to produce 2-(octahydro-5H-4,7-methanoinden-5-ylidene)acetaldehyde (Compound II); and (iii) hydrogenating Compound II in the presence of a hydrogenation catalyst to form a product mixture comprising Compound I.

[0038] In step (i), Compound IV can be converted, under conditions effective, to Compound III. In some embodiments, Compound IV can be converted to Compound III through Grignard addition. In some embodiments, Compound IV is contacted with ethynyl magnesium halide (HC CMgX) in a reaction zone in the presence of a solvent to generate a product mixture comprising Compound III, wherein X is Cl, Br or I, preferably Br. In some embodiments, the reaction is conducted under an anhydrous condition. In some embodiments, the mole ratio of Compound IV to ethynyl magnesium halide fed into the reaction zone is from about 1 :0.8 to about 1 :2, or from about 1 :0.9 to about 1 :2, or from about 1 :0.9 to about 1 :1.5, or from about 1 :1 to about 1 :1.5, or from about 1 :1 to about 1 :1.2. The reaction temperature can be in a range of from about -20 °C to about 60 °C, or from about -10 °C to about 40 °C, or from about 0 °C to about 20 °C. The reaction time can be in a range of from about 1 hr (hour) to about 24 hrs (hours), or from about 4 hrs to about 12 hrs. In some embodiments, the solvent is selected from the group of diethyl ether, THF (tetra hydrofuran), ethylbenzene, toluene, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 2- methyltetrahydropyran, dioxane, and combinations thereof. In some embodiments, the reaction is conducted under an inert gas such as nitrogen. In some embodiments, the process further comprises recovering Compound III from the product mixture at the end of the reaction. Compound III can be separated and recovered by methods known in the art such as crystallization, distillation and chromatography. In some embodiments, the yield of Compound III is at least 50%, 60%, 65%, 70%, 75%, or 80%.

[0039] In some embodiments, Compound IV can be converted to Compound III through ethyne (HC CH) addition. In some embodiments, Compound IV is contacted with ethyne in a reaction zone in the presence of a base and a solvent to generate a product mixture comprising Compound III. In some embodiments, the mole ratio of Compound IV to ethyne fed into the reaction zone is from about 1 :0.8 to about 1 :10, or from about 1 :0.9 to about 1:10, or from about 1 :1 to about 1 :10, or from about 1:1 to about 1 :5, or from about 1 :1 to about 1:3, or from about 1 :1 to about 1 :2. The reaction temperature can be in a range of from about -20 °C to about 80 °C, or from about 0 °C to about 40 °C, or from about 10 °C to about 30 °C. The reaction time can be in a range of from about 4 hrs to about 24 hrs, or from about 6 hrs to about 12 hrs. In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is selected from the group of DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), NMP (N-methyl-2-pyrrolidone), DMAc (dimethylacetamide), toluene, ethylbenzene, and combinations thereof. In some embodiments, the base is a metal alkoxide. In some embodiments, the base is an alkali metal alkoxide such as sodium alkoxide and / or potassium alkoxide. In some embodiments, the alkali metal alkoxide is selected from the group of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium butoxide, sodium sec-butoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium butoxide, potassium sec- butoxide, potassium tert-butoxide, potassium tert-pentoxide, and combinations thereof. In some embodiments, the mole ratio of Compound IV to the base fed into the reaction zone is from about 20:1 to about 1 :5, or from about 10:1 to about 1 :4, or from about 5:1 to about 1:3, or from about 2:1 to about 1 :2. In some embodiments, the process further comprises recovering Compound III from the product mixture at the end of the reaction. Compound III can be separated and recovered by methods known in the art such as crystallization, distillation and chromatography. In some embodiments, the yield of Compound III is at least 60%, 65%, 70%, or 75%.

[0040] In step (ii), Compound III can be contacted with an acid in the presence of a catalyst, under conditions effective, to produce Compound II. In some embodiments, Compound III can be converted to Compound II through Meyer-Schuster rearrangement. In some embodiments, the present disclosure also provides a process for making Compound II. The process comprises: contacting Compound III with an acid in a reaction zone in the presence of a catalyst and a solvent to form a product mixture comprising Compound II. In some embodiments, the reaction is conducted under substantial absence of oxygen (O2). By "substantial absence of oxygen" means the amount of oxygen present or fed in the reaction zone is no more than 10 mol%, 5 mol%, 2 mol%, 1 mol%, 0.5 mol%, 0.2 mol%, 0.1 mol%, or 0.05 mol%, based on the amount of the starting material (i.e., Compound III in this reaction) fed into the reaction zone. A reaction carried out in "absence of oxygen" intends to refer to a reaction carried out under "inert atmosphere". In some embodiments, the reaction is conducted under an inert gas such as nitrogen. In some embodiments, the acid is an organic acid. In some embodiments, the acid is selected from the group of toluic acid, acetic acid, formic acid, benzoic acid, anisic acid, and combinations thereof. In some embodiments, the toluic acid comprises or is o-toluic acid. In some embodiments, the acid (e.g., organic acid) has pKa in a range of from about 2 to about 5, or from about 3 to about 5, or from about 3.5 to about 5, or from about 3.5 to about 4.5. In some embodiments, the acid (e.g., organic acid) has pKa of at least 1.5, 2, 2.5, 3, 3.5, 4, or 4.5. In some embodiments, the acid (e.g., organic acid) has pKa of no more than 6, 5.5, 5, or 4.5. In some embodiments, the mole ratio of Compound III to acid (e.g., organic acid) fed into the reaction zone is from about 50:1 to about 2:1, or from about 30:1 to about 3:1, or from about 20:1 to about 4:1. In some embodiments, the mole ratio of Compound III to acid (e.g., organic acid) fed into the reaction zone is at least 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1. In some embodiments, the mole ratio of Compound III to acid (e.g., organic acid) fed into the reaction zone is no more than 100:1, 80:1, 60:1, 50:1, 40:1, 30:1, 20:1, or 15:1.

[0041] In some embodiments, the catalyst is selected from the group of molybdenum trioxide (MoOs), mixtures of a titanium alkoxide and a cuprous halide, and combinations thereof. In some embodiments, the catalyst comprises or is a mixture of a titanium alkoxide and a cuprous halide. In some embodiments, the titanium alkoxide is selected from the group of tetraisopropyl titanate (Ti(OCH(C Fh also known as titanium tetraisopropoxide or TTIP), titanium butoxide, titanium propoxide, titanium ethoxide, tetraisobutyl orthotitanate, and combinations thereof. In some embodiments, the titanium alkoxide comprises or is tetraisopropyl titanate. In some embodiments, the cuprous halide is selected from the group of cuprous chloride (CuCI), cuprous bromide (CuBr), cuprous iodide (Cui), and combinations thereof. In some embodiments, the cuprous halide comprises or is cuprous chloride (CuCI). In some embodiments, the catalyst comprises or is a mixture of tetraisopropyl titanate and cuprous chloride. In some embodiments, the mole ratio of titanium alkoxide to cuprous halide fed into the reaction zone is from about 10:1 to about 1 :2, or from about 5:1 to about 1 :1, or from about 3:1 to about 2:1. In some embodiments, the mole ratio of titanium alkoxide to cuprous halide fed into the reaction zone is at least 1 :3, 1 :2, 1 :1, 1.5:1, 2:1, 2.5:1, 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1. In some embodiments, the mole ratio of titanium alkoxide to cuprous halide fed into the reaction zone is no more than 15:1, 12:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, or 3:1. In some embodiments, the amount of titanium alkoxide fed into the reaction zone is from about 0.1 mol% to about 50 mol%, or from about 1 mol% to about 10 mol%, or from about 1.7 mol% to about 5 mol%, based on the amount of Compound III fed into the reaction zone. In some embodiments, the amount of titanium alkoxide fed into the reaction zone is at least 0.1 mol%, 0.2 mol%, 0.5 mol%, 1 mol%, 1.5 mol%, 1.7 mol%, or 2 mol%, based on the amount of Compound III fed into the reaction zone. In some embodiments, the amount of titanium alkoxide fed into the reaction zone is no more than 80 mol%, 50 mol%, 30 mol%, 20 mol%, 10 mol%, 7 mol%, 5 mol%, 4 mol%, or 3 mol%, based on the amount of Compound III fed into the reaction zone. In some embodiments, the amount of cuprous halide fed into the reaction zone is from about 0.1 mol% to about 10 mol%, or from about 0.5 mol% to about 5 mol%, or from about 0.9 mol% to about 2.5 mol%, based on the amount of Compound III fed into the reaction zone. In some embodiments, the amount of cuprous halide fed into the reaction zone is at least 0.05 mol%, 0.1 mol%, 0.2 mol%, 0.5 mol%, 0.6 mol%, 0.7 mol%, 0.8 mol%, 0.9 mol%, or 1 mol%, based on the amount of Compound III fed into the reaction zone. In some embodiments, the amount of cuprous halide fed into the reaction zone is no more than 20 mol%, 15 mol%, 10 mol%, 7 mol%, 5 mol%, 4 mol%, 3 mol%, 2.5 mol%, or 2 mol%, based on the amount of Compound III fed into the reaction zone.

[0042] In some embodiments, the catalyst comprises or is molybdenum trioxide. In some embodiments, the amount of molybdenum trioxide fed into the reaction zone is from about 0.1 mol% to about 10 mol%, or from about 0.5 mol% to about 5 mol%, or from about 0.6 mol% to about 2 mol%, based on the amount of Compound III fed into the reaction zone. In some embodiments, the amount of molybdenum trioxide fed into the reaction zone is at least 0.05 mol%, 0.1 mol%, 0.2 mol%, 0.3 mol%, 0.4 mol%, 0.5 mol%, 0.6 mol%, 0.7 mol%, or 0.8 mol%, based on the amount of Compound III fed into the reaction zone. In some embodiments, the amount of molybdenum trioxide fed into the reaction zone is no more than 15 mol%, 10 mol%, 7 mol%, 5 mol%, 4 mol%, 3 mol%, 2 mol%, or 1 mol%, based on the amount of Compound III fed into the reaction zone.

[0043] In some embodiments, the solvent is selected from the group of ethylbenzene, toluene, DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), NMP (N-methyl-2-pyrrolidone), DMAc (dimethylacetamide), and combinations thereof. In some embodiments, the reaction temperature is in a range of from about 80 °C to about 160 °C, or from about 100 °C to about 150 °C, or from about 120 °C to about 130 °C. In some embodiments, the reaction temperature is at least 60 °C, 70 °C, 80 °C, 90 °C, 100 °C, 110 °C, or 120 °C. In some embodiments, the reaction temperature is no more than 240 °C, 200 °C, 180 °C, 160 °C, 150 °C, 140 °C, or 130 °C. In some embodiments, the reaction time is in a range of from about 1 hr to about 24 hrs, or from about 3 hrs to about 20 hrs. In some embodiments, the reaction time is at least 0.5 hr, 1 hr, 2 hrs, 3 hrs, 4 hrs, or 5 hrs. In some embodiments, the reaction time is no more than 72 hrs, 48 hrs, 24 hrs, 20 hrs, 16 hrs, or 12 hrs. In some embodiments, the process further comprises recovering Compound II from the product mixture at the end of the reaction. Compound II can be separated and recovered by methods known in the art such as crystallization, distillation and chromatography. In some embodiments, the yield of Compound II is at least 70%, 75%, 80%, or 85%.

[0044] In step (iii), Compound II is hydrogenated in the presence of hydrogen (H2) and a hydrogenation catalyst under conditions effective to produce Compound I. In some embodiments, the present disclosure also provides a process for making Compound I. The process comprises: contacting Compound II with hydrogen (H2) in a reaction zone in the presence of a hydrogenation catalyst to form a product mixture comprising Compound I. In some embodiments, the hydrogenation catalyst is a heterogeneous catalyst. In some embodiments, the heterogeneous hydrogenation catalyst is a noble metal catalyst selected from the group of ruthenium (Ru) catalyst, rhodium (Rh) catalyst, palladium (Pd) catalyst, platinum (Pt) catalyst, and combinations thereof. The ruthenium catalyst is a ruthenium-containing catalyst wherein ruthenium can be present as a mixture of ruthenium in metal form and ruthenium compound(s), that is, ruthenium can be in an oxidation state of 0, I, II or III. A typical form of ruthenium here is as a metal nanoparticle or as an oxide. The rhodium catalyst is a rhodium-containing catalyst wherein rhodium can be present as a mixture of rhodium in metal form and rhodium compound(s), that is, rhodium can be in an oxidation state of 0 or I. A typical form of rhodium here is as a metal nanoparticle or as an oxide. The palladium catalyst is a palladium-containing catalyst wherein palladium can be present as a mixture of palladium in metal form and palladium compound(s), that is, palladium can be in an oxidation state of 0 or II. A typical form of palladium here is as a metal nanoparticle or as an oxide. The platinum catalyst is a platinum-containing catalyst wherein platinum can be present as a mixture of platinum in metal form and platinum compound(s), that is, platinum can be in an oxidation state of 0 or II. A typical form of platinum here is as a metal nanoparticle or as an oxide.

[0045] In some embodiments, the noble metal (i.e., Ru, Rh, Pd, or Pt) is loaded on a catalyst support. In some embodiments, the catalyst support is selected from the group of carbon (e.g., activated carbon), alumina, silica, and mixtures thereof. In some embodiments, the noble metal catalyst is a palladium catalyst comprising palladium loaded on an activated carbon. In some embodiments, the noble metal content is from 0.5 wt% to 20 wt%, or from 0.5 wt% to 15 wt%, or from 1 wt% to 10 wt%, or from 1 wt% to 5 wt%, based on the total weight of the noble metal catalyst. In some embodiments, the amount of the noble metal catalyst is such that the total amount of the noble metal (in metal form or in a form of a compound) contained in the noble metal catalyst is at least 0.001 mol%, 0.005 mol%, 0.01 mol%, or 0.02 mol%, based on the total molar amount of the starting material Compound II. In some embodiments, the amount of the noble metal catalyst is such that the total amount of the noble metal (in metal form or in a form of a compound) contained in the noble metal catalyst is no more than 0.5 mol%, 0.3 mol%, 0.2 mol%, 0.1 mol%, 0.08 mol%, or 0.05 mol%, based on the total molar amount of the starting material Compound II.

[0046] In some embodiments, a basic salt is fed into the reaction zone to adjust the catalytic activity of the noble metal catalyst in the hydrogenation reaction. In such embodiments, Compound II is contacted with hydrogen (H2) in a reaction zone in the presence of a noble metal catalyst and a basic salt to form a product mixture comprising Compound I. In some embodiments, the basic salt is selected from the group of sodium acetate, potassium acetate, zinc acetate, calcium acetate, magnesium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and combinations thereof. In some embodiments, the noble metal catalyst comprises or is a palladium catalyst and the basic salt comprises or is potassium acetate. In some embodiments, the weight ratio of the basic salt to the total amount of the noble metal (in metal form or in a form of a compound) contained in the noble metal catalyst is at least 0.2:1, 0.5:1, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 8:1, or 10:1. In some embodiments, the weight ratio of the basic salt to the total amount of the noble metal (in metal form or in a form of a compound) contained in the noble metal catalyst is no more than 200:1, 150:1, 100:1, 50:1, 40:1, 30:1, 20:1, or 15:1.

[0047] In some embodiments, the hydrogenation reaction is carried out in the presence of a solvent. In some embodiments, the solvent is selected from the group of alcohols, ethers, and combinations thereof. Examples of alcohol include methanol, ethanol, 1 -propanol, isopropanol, butanol and its isomers, pentanol and its isomers, and their combinations. Examples of ether include THF, dioxane, and their combinations. In some embodiments, the solvent comprises or is ethanol and / or THF. In some embodiments, the solvent comprises or is ethanol. In some embodiments, the amount of the solvent present in the reaction zone is at least 40 wt%, 50 wt%, 60 wt%, 70 wt%, or 80 wt%, based on the total weight of the reaction mixture. In some embodiments, the amount of the solvent present in the reaction zone is no more than 99 wt%, 98 wt%, 97 wt%, 96 wt%, 95 wt%, 92 wt%, or 90 wt%, based on the total weight of the reaction mixture.

[0048] In some embodiments, the hydrogenation reaction is carried out in substantial absence of a solvent. In some embodiments, the amount of the solvent present in the reaction zone is no more than 10 wt%, 5 wt%, 2 wt%, 1 wt%, 0.5 wt%, 0.2 wt%, or 0.1 wt%, based on the total weight of the reaction mixture.

[0049] The hydrogenation reaction temperature can be in a range of from about 25 °C to about 160 °C, or from about 50 °C to about 130 °C, or from about 60 °C to about 120 °C, or from about 70 °C to about 110 °C. In some embodiments, the hydrogenation reaction can be carried out under 100-1000 psig (pounds per square inch gauge) of H2, or 200-800 psig of H2, or 300-600 psig of H2. The reaction time can be in a range of from about 1 hr to about 24 hrs, or from about 2 hrs to about 18 hrs, or from about 4 hrs to about 12 hrs. In some embodiments, the process further comprises recovering Compound I from the product mixture at the end of the reaction. Compound I can be separated and recovered by methods known in the art such as crystallization, distillation and chromatography. In some embodiments, the yield of Compound I is at least 75%, 80%, or 85%.

[0050] In some embodiments, essentially no Compound V is generated in step (iii) or the hydrogenation process. In some embodiments, the yield of Compound V in step (iii) or the hydrogenation process is less than 5%, 2%, 1%, 0.5%, 0.2%, 0.1%, 0.05%, 0.02%, or 0.01%.

[0051] The present disclosure also provides a compound of structural formula (III) (i.e., Compound III, 5-ethynyloctahydro-1 H-4,7-methanoinden-5-ol) in the form of any one of its stereoisomers or a mixture thereof. Compound III can be used as an intermediate to make Compound I which is a popular IFF (International Flavors & Fragrances, Inc.) Aquaflora™ fragrance ingredient. The present disclosure also provides a compound of structural formula (II) (i.e., Compound II, 2-(octahydro-5H-4,7-methanoinden-5-ylidene)acetaldehyde) in the form of any one of its stereoisomers or a mixture thereof. Compound II can also be used as an intermediate to make Compound I which is a popular IFF Aquaflora™ fragrance ingredient.

[0052] Many aspects and embodiments have been described above and are merely exemplary and not limiting. After reading this specification, skilled artisans appreciate that other aspects and embodiments are possible without departing from the scope of the invention.

[0053] EXAMPLES

[0054] 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.

[0055] Example 1: Preparation of Compound III by Grignard Addition

[0056] A flame-dried, 3 L 3-necked jacketed reactor equipped with a mechanical stirrer and a thermocouple was charged with ethynyl magnesium bromide in THF (0.5 M, 2.0 L) under nitrogen. The reactor was cooled to and maintained at a temperature of 0-5 °C using a circuit cooling pump. Compound IV (135 g, 0.9 mol) was fed into the reactor for 3 hours. The reaction temperature was allowed to rise to 10 °C and maintained at 10 °C for one hour. Then THF was recovered using rotary evaporator and ethylbenzene (150 g) was added into the reactor. The reaction mixture was subsequently quenched with 20 wt% acetic acid solution (720 g, 2.4 mol) at 20 °C. Then the organic layer was separated and washed with 5 wt% sodium carbonate solution (212 g, 0.1 mol) to provide the crude product. The crude product was purified through crystallization at 0-5 °C to generate the product Compound III (130 g, 82% yield) as a pale yellow solid.

[0057] Example 2: Preparation of Compound III by Ethyne Addition

[0058] A flame-dried, 1 L 3-necked jacketed reactor equipped with a mechanical stirrer and a thermocouple was charged with DMF (127 g) and sodium methoxide (59.4 g, 1.1 mol) under nitrogen. The reactor was cooled to and maintained at a temperature of 10 °C using a circuit colling pump. Ethyne gas was purged into the reactor at 10 °C for 1 hour, and the ethyne pressure in the reactor was 0.1 MPa (megapascal). Then Compound IV (150 g, 1.0 mol) was fed into the reactor for 2 hours along with the purging of ethyne gas. The reaction temperature was maintained at 10 °C for 7 hours. Then the reaction mixture was quenched with water (200 g) at 10-20 °C. The product Compound III was precipitated from the liquid. After being filtered and washed with water, the product Compound III (145 g, 82% yield) was obtained as a pale yellow solid.1H-NMR analysis of Compound III is shown below:

[0059] 1H-NMR (CDCb, 400 MHz): 2.56 ppm (dd, 1 H, J=8 Hz), 2.48 ppm (s, 1 H), 2.18 ppm (s, 1 H), 2.19 ppm (dd, 1 H, J = 6 Hz), 1.98 ppm (d, 1 H, J=4.6 Hz), 1.85-1.94 ppm (m, 3H), 1.78 ppm (s, 1 H), 1.66 ppm (dt, 1 H, J=6 Hz), 1.46-1.54 ppm (m, 2H), 1.28 ppm (dd, 1 H, J = 3.12 Hz), 1.15-1.29 ppm (m, 1 H), 0.90-1.02 ppm (m, 2H).

[0060] Example 3: Preparation of Compound II by Meyer-Schuster Rearrangement

[0061] A flame-dried, 1 L 3-necked flask equipped with a mechanical stirrer, a condenser and a thermocouple was charged with Compound III (352 g, 2 mol) and ethylbenzene (340 g) under nitrogen. The flask was heated to and maintained at a temperature of 120 °C. Tetraisopropyl titanate (Ti(O / Pr)4, 28.4 g, 0.1 mol), cuprous chloride (CuCI, 4.95 g, 0.05 mol) and o-toluic acid. (68 g, 0.5 mol) were added to the flask. The reaction temperature was maintained at 120 °C for six hours. Then the product mixture was cooled to 40 °C and distilled to generate the product Compound II (235.8 g, 67% yield) as a pale yellow oil.1H-NMR analysis of Compound II is shown below:

[0062] 1H-NMR (CDCb, 400 MHz): 9.86 ppm (d, 0.4H, J = 8.3 Hz), 9.71 ppm (d, 0.6H, J=8 Hz), 5.92 ppm (d, 0.6H, J = 8 Hz), 5.77 ppm (d, 0.4H, J = 12 Hz), 3.40 ppm (s, 0.4H), 2.64 ppm (s, 0.6H), 2.55-2.49 ppm (m, 0.6H), 2.40-2.30 ppm (m, 1.4H), 2.26-1.82 ppm (m, 5H), 1.70-1.53 ppm (m, 2H), 1.24-0.97 ppm (m, 4H).

[0063] Example 4: Preparation of Compound I by Hydrogenation

[0064] A 1 L autoclave was charged with Compound II (110 g, 0.625 mol), palladium catalyst comprising palladium loaded on activated carbon (Pd / C with 3 wt% Pd content, 0.66 g) and potassium acetate (0.25 g). The autoclave was flushed and vented three times with nitrogen followed three times with hydrogen. The autoclave was subsequently pressurized to 435 psig with hydrogen and heated to 90 °C. Gas-liquid chromatography (GLC) analysis indicated the completion of the reaction after six hours. The autoclave was then vented and purged three times with nitrogen, and the product mixture was distilled to generate Compound I (93.5 g, 88% yield) as a pale yellow oil.1H-NMR analysis of Compound I is shown below:1H-NMR (CDCh, 400 MHz): 9.73 ppm (t, 0.2H, J = 2 Hz), 9.70 ppm (t, 0.8H, J = 2 Hz), 2.45-2.18 ppm (m, 2.4H), 2.04-1.57 ppm (m, 8.4H), 1.48-0.84 ppm (m, 5.4H), 0.58-0.52 ppm (m, 0.8H).

[0065] Note that not all of the activities described above in the general description or the examples are required, that a portion of a specific activity may not be required, and that one or more further activities may be performed in addition to those described. Still further, the order in which activities are listed are not necessarily the order in which they are performed.

[0066] In the foregoing specification, the concepts have been described with reference to specific embodiments. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth in the claims below. Accordingly, the specification is to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of invention.

[0067] Benefits, other advantages, and solutions to problems have been described above with regard to specific embodiments. However, the benefits, advantages, solutions to problems, and any feature(s) that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as a critical, required, or essential feature of any or all the claims.

[0068] It is to be appreciated that certain features are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

Claims

CLAIMSWhat is claimed is:

1. A process comprising: contacting 5-ethynyloctahydro-1 H-4,7-methanoinden-5-ol (Compound III) with an acid in a reaction zone in the presence of a catalyst and a solvent to form a product mixture comprising 2-(octahydro-5H-4,7-methanoinden-5- ylidene)acetaldehyde (Compound II).

2. The process of claim 1, wherein the acid has pKa of at least 2.

3. The process of claim 1 or 2, wherein the acid is selected from the group of toluic acid, acetic acid, formic acid, benzoic acid, anisic acid, and combinations thereof.

4. The process of any one of the preceding claims, wherein the catalyst is selected from the group of molybdenum trioxide, mixtures of a titanium alkoxide and a cuprous halide, and combinations thereof.

5. The process of claim 4, wherein the catalyst is a mixture of a titanium alkoxide and a cuprous halide.

6. The process of claim 5, wherein the reaction temperature is in a range of from about 80 °C to about 160 °C.

7. The process of claim 5 or 6, wherein the process is conducted under substantial absence of oxygen.

8. A process comprising: contacting 2-(octahydro-5H-4,7-methanoinden-5- ylidene)acetaldehyde (Compound II) with hydrogen in a reaction zone in the presence of a hydrogenation catalyst to form a product mixture comprising 2-(octahydro-1 H-4,7- methanoinden-5-yl)acetaldehyde (Compound I).

9. The process of claim 8, wherein the hydrogenation catalyst is a noble metal catalyst selected from the group of ruthenium catalyst, rhodium catalyst, palladium catalyst, platinum catalyst, and combinations thereof.

10. The process of claim 9, wherein the noble metal is loaded on a catalyst support selected from the group of carbon, alumina, silica, and mixtures thereof.

11. A process comprising:(i) converting octahydro-5H-4,7-methanoinden-5-one (Compound IV) to 5- ethynyloctahydro-1 H-4,7-methanoinden-5-ol (Compound III);(ii) contacting Compound III with an acid in the presence of a catalyst to produce 2- (octahydro-5H-4,7-methanoinden-5-ylidene)acetaldehyde (Compound II); and(iii) hydrogenating Compound II in the presence of a hydrogenation catalyst to form a product mixture comprising 2-(octahydro-1 H-4,7-methanoinden-5-yl)acetaldehyde (Compound I).

12. The process of claim 11, wherein in step (i), Compound IV is contacted with ethynyl magnesium halide (HC CMgX) in a reaction zone in the presence of a solvent to generate a product mixture comprising Compound III.

13. The process of claim 11, wherein in step (i), Compound IV is contacted with ethyne in a reaction zone in the presence of a base and a solvent to generate a product mixture comprising Compound III.

14. A compound of structural formula (III) in the form of any one of its stereoisomers or a mixture thereof.

15. A compound of structural formula (II) in the form of any one of its stereoisomers or a mixture thereof.

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