HK1136295B - Production of dihydronepetalactone by hydrogenation of nepetalactone - Google Patents

Description

Production of dihydronepetalactones by hydrogenation of nepetalactones

This patent application claims priority to U.S. provisional application 60/876,568 filed on 21/12/2006, which is incorporated in its entirety as part of this document for various purposes.

Technical Field

The present invention relates to a process for the preparation of dihydronepetalactones.

Background

Dihydronepetalactones are useful compounds that have been shown to have insect repellent properties [ see, e.g., Jefson et al, "j.chemical Ecology" (1983) 9: 159-180; and WO03/79786 ]. Methods for preparing dihydronepetalactones are known from sources such as Regnier et al [ Phytochemistry (1967) 6: 1281-1289 ]; waller and Johnson [ proc.oklahoma acad.sci. (1984) 64: 49-56 ]; and US 7,067,677 (Manzer). Generally, those methods have described methods for producing mixtures comprising dihydronepetalactone isomers by contacting purified nepetalactones with hydrogen in the presence of a catalyst.

However, there remains a need for a process that can convert a mixture comprising trans-cis nepetalactone and cis-trans nepetalactone to dihydronepetalactone while limiting the production of the undesirable by-product 1-methyl-3-isopropylcyclopentanecarboxylic acid.

Summary of The Invention

In one embodiment, the invention relates to a process for preparing dihydronepetalactone by (a) reacting, in a reaction mixture, at one or more first temperatures, an initial amount of trans-cis nepetalactone (described by the structure of formula I) and an initial amount of cis-trans nepetalactone (described by the structure of formula II)

Contacting hydrogen and a first solid hydrogenation catalyst until the amount of trans-cis nepetalactone in the reaction mixture is no more than about 50% by weight of its starting amount to form a first product mixture; and (b) contacting the first product mixture with hydrogen and a second solid hydrogenation catalyst at one or more second temperatures to form dihydronepetalactone; wherein the one or more second temperatures are higher than the one or more first temperatures.

In another embodiment, the invention is directed to a process for preparing dihydronepetalactone by (a) subjecting a starting mixture comprising trans-cis nepetalactone (described by the structure of formula I) and cis-trans nepetalactone (described by the structure of formula II)

Contacting hydrogen and a first solid hydrogenation catalyst to form a first product mixture; and (b) contacting the first product mixture with hydrogen and a second solid hydrogenation catalyst to form dihydronepetalactone; wherein the first and second catalysts are different.

In another embodiment, the invention is directed to a method of making dihydronepetalactone by subjecting a starting mixture comprising trans-cis nepetalactone (described by the structure of formula I) and cis-trans nepetalactone (described by the structure of formula II)

Contacting hydrogen and a solid hydrogenation catalyst; wherein the ratio of the content by weight of cis-trans nepetalactone to the content by weight of trans-cis nepetalactone in the starting mixture is at least about 2/1.

Detailed Description

Definition of：

In describing the methods herein, for certain terms employed in various portions of the specification, the following defined structures are provided:

the term "nepetalactone" refers to a compound having the general structure of formula II:

a preferred source of nepetalactone is catmint oil from plants of the genus Nepeta. Different types of plants of the genus nepeta have been reported to have different nepetalactone stereoisomer ratios [ Regnier et al, "Phytochemistry", 6: 1281-1289 (1967); DePooter et al, "Flavourand Fragrance Journal", 3: 155-; handjieva and Popov, "j.essential Oil res", 8: 639-643(1996) ], two of the stereoisomers thereof are shown below:

dihydronepetalactones are defined by formula VII:

formula II

The term "dihydronepetalactone" refers to any mixture of dihydronepetalactone isomers, unless otherwise specified. Each of these isomers can vary in molar or mass composition relative to the entire dihydronepetalactone composition.

The term "1-methyl-3-isopropylcyclopentanecarboxylic acid" refers to a compound having the general structure of formula III:

formula III

The term "catalyst" refers to a substance that can affect the rate of reaction rather than the equilibrium of the reaction and is present in the process chemically unchanged.

The term "promoter" refers to an element of the periodic table of elements, or an alloy or compound thereof, that is added to enhance the physical or chemical effectiveness of the catalyst. The promoter may be any element of the periodic table of elements added to the catalyst to enhance its activity or selectivity. Promoters may also be added to retard undesirable side reactions and/or affect the rate of reaction. Catalysts, promoters and their use are also described in sources such as "The Handbook of heterogenous catalysis for Organic Synthesis" by Shigeo Nishimuru (John Wiley (2001), ISBN: 0-471-. A "metal promoter" is a promoter that is a metal compound.

The present invention relates to a process for preparing dihydronepetalactone from a mixture comprising trans-cis nepetalactone and cis-trans nepetalactone. A reaction mixture comprising trans-cis nepetalactone and cis-trans nepetalactone is first contacted with hydrogen in the presence of at least one hydrogenation catalyst under conditions optimal for the preferential conversion of trans-cis nepetalactone to dihydronepetalactone. In the second step of the process, the hydrogenation of cis-trans nepetalactone to dihydronepetalactone is optimized.

It has been found that under less severe hydrogenation conditions, including lower temperatures, trans-cis nepetalactone can be reduced to the desired end product dihydronepetalactone, whereas under more severe hydrogenation conditions, including higher temperatures, trans-cis nepetalactone can be converted to 1-methyl-3-isopropylcyclopentanecarboxylic acid. Under less severe hydrogenation conditions, including lower temperatures, cis-trans nepetalactone is not significantly converted to dihydronepetalactone, whereas under more severe conditions, including higher temperatures, cis-trans nepetalactone is converted to dihydronepetalactone without significant production of 1-methyl-3-isopropylcyclopentanecarboxylic acid.

Thus, the process herein provides a first hydrogenation reaction and a second hydrogenation reaction to produce dihydronepetalactone from a mixture comprising trans-cis and cis-trans nepetalactones.

A first hydrogenation reaction:

in a first hydrogenation reaction, a reaction mixture comprising a starting amount of trans-cis nepetalactone (described by the structure of formula IV) and a starting amount of cis-trans nepetalactone (described by the structure of formula V) is reacted at one or more first temperatures, optionally in the presence of a solvent

Formula IV formula V

Contacting hydrogen in the presence of at least one solid hydrogenation catalyst until the amount of trans-cis nepetalactone in the reaction mixture is no more than about 50% by weight of its starting amount to form a first product mixture. In other embodiments of the invention, the amount of trans-cis nepetalactone in the reaction mixture is no more than about 40%, or about 30%, or about 20%, or about 10%, or about 5%, or about 1%, by weight of its starting amount.

Accordingly, as a result of the first hydrogenation reaction, the amount of cis-trans nepetalactone in the reaction mixture is at least about 50% by weight of its initial amount, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 99% of its initial amount.

The amount of time it takes until the starting amount of trans-cis nepetalactone is reduced to a selected degree (as described above) will vary depending on the choice of reaction temperature, catalyst/promoter, and hydrogen feed rate. As a result of the first hydrogenation reaction, the reaction mixture can comprise, for example, at least one dihydronepetalactone isomer.

The first hydrogenation reaction may be carried out at one or several temperatures, including a range of temperatures. In one embodiment, the first hydrogenation reaction is carried out at one or more temperatures in the range of from about 0 ℃ to about 100 ℃. In another embodiment, the temperature may range from about 0 ℃ to about 60 ℃, or from about 0 ℃ to about 50 ℃, or from about 10 ℃ to about 50 ℃. Preferably, the first hydrogenation reaction is carried out at a temperature at which trans-cis nepetalactone, but not cis-trans nepetalactone, is preferentially converted to dihydronepetalactone.

The solid hydrogenation catalyst useful in the first hydrogenation reaction may comprise a catalytic metal selected from the group consisting of the following elements: iron, ruthenium, rhenium, copper, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, alloys or compounds thereof; and combinations thereof. In one embodiment, the catalytic metal is selected from palladium, platinum, nickel; alloys or compounds thereof; and combinations thereof.

If used, the metal promoter may be selected from group 3 to group 8, group 11 and group 12 metals of the periodic table of elements including, but not limited to, tin, zinc, copper, gold, silver, iron, molybdenum, alloys or compounds thereof, and combinations thereof. Metal promoters may be used to influence the reaction, for example by increasing activity and catalyst life. The metal promoters are generally used in amounts up to about 2 wt.%, based on the total weight of the metals used in the reaction.

The catalyst used in the hydrogenation may be supported or unsupported. Supported catalysts are those in which the catalytic metal is deposited on a support by any of a number of methods, such as spraying, soaking or physical mixing, followed by drying, calcination, and, if desired, activation by methods such as reduction or oxidation/reduction. Supported catalysts may also be prepared by co-precipitation or blending of the active component and support material, followed by drying, calcination, and, if desired, activation by methods such as reduction or oxidation/reduction. Materials commonly used as catalyst supports are porous solids having a high total surface area (external and internal) which can provide a high concentration of active sites per unit weight of catalyst. The catalyst support may enhance the efficacy of the catalyst.

The catalyst support useful herein can be any solid material including, but not limited to, oxides such as silica, alumina, titania, and combinations thereof; barium sulfate; calcium carbonate; carbon; and combinations thereof. The catalyst support may be in the form of a powder, granules, pellets, extrudates, and the like.

In one embodiment, the supported catalyst (comprising the catalytic metal and the catalyst support) used in the hydrogenation reaction may be selected from the group consisting of palladium on carbon, palladium on calcium carbonate, palladium on barium sulfate, palladium on alumina, palladium on titania, platinum on carbon, platinum on alumina, platinum on silica, iridium on carbon, iridium on alumina, rhodium on carbon, rhodium on silica, rhodium on alumina, nickel on carbon, nickel on alumina, nickel on silica alumina, rhenium on carbon, rhenium on silica, rhenium on alumina, ruthenium on carbon, ruthenium on alumina, ruthenium on silica, and combinations thereof; wherein the catalytic metal is present in an amount of about 0.1 wt% to about 70 wt% based on the weight of the catalytic metal plus support.

In a preferred embodiment, the combination of catalytic metal and catalyst support useful in the present invention is selected from the group consisting of palladium on carbon, platinum on carbon, iridium on carbon, rhodium on carbon, ruthenium on carbon, iridium on silica, and combinations thereof.

The preferred amount of catalytic metal in the supported catalyst for the process of the present invention will depend on the choice of catalyst and support. In one embodiment, the catalytic metal is present in the supported catalyst in an amount from about 0.1% to about 70% by weight of the supported catalyst based on the sum of the weight of the catalytic metal and the weight of the support.

The catalyst not supported on the catalyst support material is a non-supported catalyst. The unsupported catalyst may be of any porous structure, powder such as platinum black or Raney catalyst(s) ((R))Catalytic product from W.R.Grace&Co., Columbia, MD), or a combination thereof. The active metals in the Raney catalyst include nickel, copper, cobalt, iron, rhodium, rutheniumRhenium, osmium, iridium, platinum, palladium; a compound thereof; and combinations thereof. At least one metal promoter may be added to the base raney metal to affect the selectivity and/or activity of the raney catalyst. The metal promoter of the raney catalyst may be selected from the group consisting of transition metals of groups 3 to 8, 11 and 12 of the periodic table of the elements, alloys or compounds thereof, and combinations thereof. Examples of suitable metal promoters include chromium, molybdenum, platinum, rhodium, ruthenium, osmium, palladium, alloys or compounds thereof, and combinations thereof, typically used in amounts up to 2 weight percent of the total metal.

The catalysts and promoters (if used) selected for use in the first hydrogenation reaction are preferably those which can preferentially convert trans-cis nepetalactone to dihydronepetalactone instead of 1-methyl-3-isopropylcyclopentanoic acid, and/or which can preferentially convert trans-cis nepetalactone to dihydronepetalactone instead of cis-trans nepetalactone.

Contacting the reaction mixture of trans-cis nepetalactone and cis-trans nepetalactone with hydrogen in the presence of a solid hydrogenation catalyst in the presence of a solvent. Solvents useful in the process of the present invention include, but are not limited to, alcohols such as ethanol or isopropanol, alkanes such as hexane or cyclohexane; esters such as ethyl acetate; and ethers such as dioxane, tetrahydrofuran or diethyl ether.

The first product mixture may optionally be separated from the solid hydrogenation catalyst prior to the second hydrogenation step. For this purpose, known separation methods can be used, including distillation, decantation and filtration.

Second hydrogenation reaction：

Contacting the first product mixture with hydrogen in the presence of at least one solid hydrogenation catalyst in a second hydrogenation reaction at one or more second temperatures to form a second product mixture comprising at least one dihydronepetalactone isomer. The one or more second temperatures are higher than the one or more first temperatures. Preferably, the second hydrogenation reaction is carried out at a temperature at which cis-trans nepetalactone, but not trans-cis nepetalactone, is preferentially converted to dihydronepetalactone. In one embodiment, the second hydrogenation reaction is carried out at a temperature in the range of from about 50 ℃ to about 150 ℃, or in the range of from greater than 60 ℃ to about 150 ℃.

The hydrogenation catalyst and promoter (if used) used in the second hydrogenation reaction may be any of those described above for the first hydrogenation reaction; and may be used in the same or similar amounts. The hydrogenation catalyst/promoter used in the second hydrogenation reaction may be the same or different from the hydrogenation catalyst/promoter used in the first hydrogenation reaction. The hydrogenation catalyst/promoter used in the second hydrogenation reaction is preferably different from the hydrogenation catalyst/promoter used in the first hydrogenation reaction and is a catalyst/promoter that can preferentially convert cis-trans nepetalactone, but not trans-cis nepetalactone, to dihydronepetalactone.

The hydrogen pressure useful in the first or second hydrogenation reaction is from about 0.1MPa to about 20.7 MPa. In one embodiment, the hydrogen is maintained at a pressure such that the hydrogen reaches a saturation level in the mixture at the reaction temperature.

The second product mixture obtained after the second hydrogenation reaction is separated from the hydrogenation catalyst. Separation methods are well known to those skilled in the art and include distillation, decantation and filtration.

The process of the present invention may be carried out in a batch mode in a single reactor, in a sequential batch mode in a series of reactors, in the reaction zone of one or more reactors, or in a continuous mode in any apparatus commonly used for continuous processing. For example, different temperatures and/or different catalysts may be used in any two or more successive zones or reactors, provided that trans-cis nepetalactone is converted primarily to dihydronepetalactone and not 1-methyl-3-isopropylcyclopentanoate, and/or that a substantial amount of trans-cis nepetalactone is preferentially converted to dihydronepetalactone before cis-trans nepetalactone is converted.

In an alternative embodiment of the process herein, dihydronepetalactone can be produced in a one-step process in which the starting material is predominantly cis-trans nepetalactone, rather than trans-cis nepetalactone. In this reaction, the ratio of the content by weight of cis-trans nepetalactone to the content by weight of trans-cis nepetalactone in the starting reaction mixture may be, for example, at least about 1/1. In alternative embodiments, the ratio of the content by weight of cis-trans nepetalactone to the content by weight of trans-cis nepetalactone may be at least about 2/1, or at least about 3/1, or at least about 5/1, or at least about 10/1. In this alternative process, the same catalyst/promoter, temperature and hydrogen feed rate as described above for the second hydrogenation reaction may be used.

In another embodiment herein, the level by weight of cis-trans nepetalactone in the reaction mixture is reduced to less than about 20% of its initial amount. In alternative embodiments, the level of cis-trans nepetalactone by weight in the reaction mixture is reduced to less than about 10%, or less than about 5%, of its initial amount.

In another embodiment of the process herein, the concentration of 1-methyl-3-isopropylcyclopentanecarboxylic acid produced in the reaction is less than about 10 weight percent, based on the total weight of the reaction product. In another embodiment, the amount of 1-methyl-3-isopropylcyclopentanecarboxylic acid produced in the reaction is less than about 5% by weight, based on the total weight of the reaction product. In another embodiment of the methods herein, the amount of 1-methyl-3-isopropylcyclopentanoic acid produced by the method in its product is less than about 10 weight percent, or less than about 5 weight percent, based on the total weight of the starting amount of trans-cis nepetalactone and the starting amount of the cis-trans nepetalactone component.

The starting mixture comprising trans-cis nepetalactone and cis-trans nepetalactone may be obtained from plants of the genus nepeta, such as nepeta cataria. Oils containing nepetalactone isomers, such as the trans-cis and cis-trans isomers, can be obtained from plants of the genus nepeta by a variety of separation methods including, but not limited to, steam distillation, organic solvent extraction, microwave-assisted organic solvent extraction, supercritical fluid extraction, mechanical extraction, and cold absorption (enfleurage) (first cold extraction into fat, then organic solvent extraction). The oil may be used in its natural form or nepetalactone may be further purified from the oil, for example by distillation. In addition to trans-cis nepetalactone and cis-trans nepetalactone, the mixture contains additional components, including unsaturated compounds such as carvone, limonene, and other monoterpenes, as well as caryophyllene and other sesquiterpenes, which can be reduced by the methods of the invention.

Examples

The advantageous features and effects of the method of the invention can be appreciated from a series of examples as described below. The method embodiments on which these examples are based are representative only, and the selection of those embodiments to illustrate the invention does not indicate that materials, conditions, arrangements, components, reactants, techniques or configurations not described in these examples are not suitable for practicing these methods, or that subject matter not described in these examples is excluded from the scope of the appended claims and equivalents thereof.

In the examples, the following abbreviations are used: GC is gas chromatography; GC-MS is gas chromatography/mass spectrometry; FID is flame ion detector; NMR is nuclear magnetic resonance; c is centigrade, MPa is megapascal; rpm is revolutions per minute; mL is milliliter; CMO is catmint oil; the weight percent is weight percent; TOS is the reaction running time; NPL is nepetalactone; c, t-NPL is cis-trans nepetalactone; t, c-nepetalactone is trans-cis nepetalactone, and DHN is dihydronepetalactone; h is hour; conc is concentration; conv. is conversion; temperature is used as temperature; press, pressure, deg.C, degree Celsius.

Determination of catmint oil components and hydrogenated Compounds thereof：

Samples were diluted with internal standard solution and injected onto a DB FFAP column using HP5890(Agilent Technologies, Palo Alto, CA) GC equipped with FID detector. The injection temperature and the detector temperature were 250 ℃. The column temperature was ramped linearly from 50 ℃ to 250 ℃ over 20min and was maintained at 250 ℃ during the continuous run. Split-flow mode injection ports were used. The identification of the major component peaks and relative response factors were determined using calibration standards for nepetalactone, dihydronepetalactone, and 1-methyl-3-isopropylcyclopentanoic acid.

Examples 1 to 14

Commercially available catnip oil samples were obtained from George Thacker Sons (Alberta, Canada) and were extracted by steam distillation of herbal material from Nepeta cataria. Ethanol, hexane and 2-propanol were obtained from Aldrich.

Catalysts are commercially available from the following manufacturers: ESCAT 142 and ESCAT 268: EngelhardCorp. (Iselin, NJ); Rh/C: acros (Hampton, NH); Ru/C: strem Chemicals, Inc. (Newburyport, MA)

The example reaction was carried out in a 50mL stirred batch autoclave reactor to which catmint oil solution and powdered catalyst were added. The reactor was sealed and then purged and evacuated several times with nitrogen to remove oxygen. After these purges, two rapid purges with hydrogen were performed to minimize residual nitrogen in the reactor. The reactor was equipped with a magnetically coupled gas-entrained stirrer that rotated at a speed of about 1000rpm during the reaction. The reactor temperature was controlled by either a propylene glycol/water mixture flowing from the recirculating bath through an external coil, or by using an external electric coil. Since hydrogen is consumed by the reaction, hydrogen is continuously supplied into the reactor during the reaction to maintain a specified pressure. After the reaction, the reactor was cooled via external cooling coils and vented. Product analysis was performed by Gas Chromatography (GC) as described above, using 1, 2-dibromobenzene as the internal standard added after the reaction. For separate examples, additional reaction conditions and corresponding reaction summaries are provided below to show the conversion of nepetalactone to dihydronepetalactone, along with the major by-products.

Example 1 (comparative example)

Hydrogenation of catmint oil at 100 ℃

At 100 ℃, the yield loss of both cis-nepetalactone and trans-nepetalactone converted to dihydronepetalactone, and simultaneously to 1-methyl-3-isopropylcyclopentanoic acid, was high.

CMOConc. (wt%)	Solvent(s)	Catalyst and process for preparing same	Catalyst feed (% by weight of CMO)	H2Pressure (MPa)	TOS(h)	Temp.(℃)	NPLConv.(％)	c，t-NPLConv.(％)	t，c-NPLConv.(％)	DHN yield (%)	Yield (%) -of 1-methyl-3-isopropylcyclopentanecarboxylic acid
												50	Ethanol	ESCAT1425％Pd/C	10	8.46	0.17	102	20.8	13.6	22.8	85.9	6.8
					0.50	97	91.7	64.4	99.3	82.7	18.3
																	1.00	98	97.3	88.8	100.0	81.1	18.6
					1.78	100	99.4	98.2	100.0	78.1	20.6
																	2.75	100	99.7	99.3	100.0	72.7	25.4
					4.00	100	99.8	99.4	100.0	67.3	29.6
																	5.18	101	99.8	99.4	100.0	62.7	33.3

Example 2

Two-step process

This example shows that the reaction is first carried out at 15 ℃ for 4 hours and then at 100 ℃ for a further 2 hours. The DHN yield was higher and the 1-methyl-3-isopropylcyclopentanecarboxylic acid yield was lower by carrying out the reaction in two steps, relative to the yield obtained at a single temperature of 100 ℃ as shown in comparative example 1.

CMOconc. (wt%)	Solvent(s)	Catalyst and process for preparing same	Catalyst feed (% by weight of CMO)	H2Press.(MPa)	TOS(h)	Temp.(℃)	NPLConv.(％)	c，t-NPLConv.(％)	t，c-NPLConv.(％)	DHN yield (%)	Yield (%) -of 1-methyl-3-isopropylcyclopentanecarboxylic acid
												50	Ethanol	ESCAT1425％Pd/C	10	8.36	0.17	15	8.6	2.7	10.8	94.4	1.1
					0.50	15	15.0	3.3	19.4	-	1.4
																	1.00	15	36.4	8.3	47.1	99.5	1.7
					1.88	15	64.2	19.2	81.4	97.6	2.5
																	2.75	15	76.1	27.5	94.7	99.5	2.9
					4.00	15	82.7	40.2	99.3	98.7	3.2
																	5.00	100	97.7	92.5	99.9	96.7	3.6
					5.17	101	99.3	98.0	100.0	96.8	3.7
																	7.00	99	99.6	98.7	100.0	97.9	3.6

Examples 3 to 14

Two-step process

These examples show reactions carried out under different CMO concentrations, pressures, catalyst feeds and catalyst conditions in a two-step process.

Examples	CMOconc. (wt%)	Solvent(s)	Catalyst and process for preparing same	Catalyst feed (% by weight of CMO)	H2Press.(MPa)	TOS(h)	Temp.(℃)	NPLConv.(％)	c，t-NPLConv.(％)	t，c-NPLConv.(％)	DHN yield (%)	Yield (%) -of 1-methyl-3-isopropylcyclopentanecarboxylic acid
													3	30	Hexane (C)	ESCAT1425％Pd/C	10	3.58	0.17	25	81.3	-	89.5	93.5	9.8
						0.50	25	93.1	-	99.6	93.1	9.6
																			1.00	25	95.2	21.4	99.9	93.7	9.3
						4.00	25	96.7	42.1	99.9	92.2	9.0

4	10	2-propanol	ESCAT1425％Pd/C	10	3.47	0.17	25	9.3	5.7	11.0	44.8	4.9
																			0.50	25	12.2	1.8	16.7	95.2	7.5
						1.00	25	24.3	5.0	32.7	92.2	5.3
																			2.00	25	41.7	8.5	56.2	94.6	3.4
						3.00	25	55.1	13.8	73.2	92.0	2.7
																			6.00	25	72.2	22.9	93.8	87.8	8.4
													5	20	Ethanol	ESCAT1425％Pd/C	10	3.50	0.17	25	9.5	4.3	11.5	63.8	4.5
						1.00	25	37.4	9.5	47.8	86.7	2.8
																			2.00	25	55.8	14.3	71.4	83.2	7.6
						3.00	25	63.0	17.8	80.0	82.8	7.6
																			6.00	25	79.9	26.7	100.0	81.6	6.8
													6	20	Ethanol	ESCAT1425％Pd/C	10	3.51	0.17	50	27.7	9.0	34.7	78.1	3.9
						1.00	50	79.2	24.0	100.0	79.1	7.4
																			2.00	50	82.6	37.1	100.0	85.0	7.4
						6.00	50	90.2	66.5	100.0	87.8	7.3
													7	20	Ethanol	ESCAT1425％Pd/C	10	3.51	0.17	48	53.1	17.5	66.5	77.1	11.6
						0.50	50	76.1	29.2	93.8	77.6	11.9
																			1.00	50	82.7	38.6	99.6	83.4	12.9
						2.00	90	91.8	72.0	100.0	84.1	12.1
																			6.00	101	99.8	99.8	100.0	82.5	11.2
													8	20	Ethanol	ESCAT1425％Pd/C	10	3.49	0.17	26	28.3	8.1	35.8	80.1	4.2
						1.03	25	75.7	24.4	94.8	82.2	8.0
																			2.00	25	81.1	33.2	99.3	84.2	8.2
						4.05	99	99.6	98.7	100.0	86.9	7.7
																			6.00	100	99.9	99.7	100.0	87.3	7.8
													9	20	Ethanol	ESCAT1425％Pd/C	10	8.04	0.17	25	42.7	11.1	54.3	85.7	3.2
						1.00	25	79.4	29.3	98.1	89.5	2.8
																			1.50	25	81.9	35.5	99.4	89.6	2.8
						3.00	98	98.0	93.5	100.0	89.8	3.3
																			6.00	99	99.9	99.7	100.0	91.6	3.2

10	50	Ethanol	ESCAT1425％Pd/C	1	8.65	0.47	15	0	0	0	0	0
																			2.75	15	0	0	0	0	0
						4.03	100	9.4	6.4	2.0	90.3	2.4
																			5.80	99	24.8	15.2	21.8	86.7	3.9
						6.90	100	41.6	26.3	42.7	89.7	4.3
11	50	Ethanol	ESCAT1425％Pd/C	3.5	8.44	0.50	15	6.5	1.4	0.5	105.6	1.1
																			1.00	15	13.8	3.3	10.7	103.1	1.7
						1.75	15	21.1	5.1	20.9	106.0	2.1
																			2.83	15	28.4	6.3	31.3	107.4	2.1
						4.00	15	35.7	8.7	41.3	100.4	1.9
12	50	Ethanol	ESCAT2685％Pt/C	10	8.36	0.50	27	43.8	12.0	53.7	82.1	17.0
																			1.00	25	65.4	19.6	81.1	91.4	11.5
						2.00	24	81.9	31.0	97.7	90.0	8.9
																			3.00	24	83.3	36.9	97.8	93.7	9.4
						3.32	96	93.3	76.1	98.7	95.2	9.4
																			3.82	100	99.5	98.6	99.8	100.6	11.1
													13	50	Ethanol	Acros5％Rh/C	10	8.51	0.17	25	5.3	13.7	-	3.2	7.0
						0.50	25	3.8	7.3	-	2.5	9.7
																			1.00	28	78.6	44.8	89.0	52.1	43.1
						2.00	25	99.5	98.3	99.9	56.0	40.7
																			5.50	100	99.9	99.7	100.0	39.9	51.8
14	50	Ethanol	StremChem.5％Ru/C	10	8.48	0.17	26	8.3	10.6	-	43.3	35.6
																			0.50	25	30.8	22.3	18.8	27.0	64.7
						1.00	25	49.5	29.1	47.2	35.8	65.7
																			2.00	25	85.8	46.8	97.7	35.2	59.2
						3.00	25	93.4	76.0	98.6	39.6	60.5
																			3.40	95	100.0	100.0	100.0	39.6	56.5
						3.90	101	99.9	99.8	100.0	28.8	63.1
																			5.40	99	99.9	99.9	100.0	30.5	65.3

Where a range of numerical values is described herein, the range includes the endpoints thereof, and all the individual integers and fractions within the range, and also includes each of the narrower ranges therein formed by all the various possible combinations of those endpoints and internal integers and fractions to form subgroups of the larger group of values within the stated range to the same extent as if each of those narrower ranges were explicitly described. Where a range of numerical values is described herein as being greater than a stated value, the range is nevertheless limited and its upper limit is defined by values operable in the context of the invention as described herein. When a range of values is described herein as being less than a stated value, the range is still bounded on its lower limit by non-zero values.

In this specification, unless explicitly stated otherwise or indicated to the contrary by the context of usage, amounts, sizes, ranges, formulations, parameters and other quantities and characteristics recited herein, particularly when modified by the term "about," may be, but need not be, exact, and may also be close to and/or greater than or less than (as desired) the recited values, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and include within the specified values, those values outside the specified values that have equivalent function and/or operation within the context of the present invention as the specified value.

In this specification, where an embodiment of the inventive subject matter is discussed or described as including, containing, having, encompassing, or containing certain features or elements, one or more features or elements may be present in the embodiment in addition to those explicitly discussed or described, unless explicitly stated otherwise or indicated to the contrary in the context of use. However, an alternative embodiment of the inventive subject matter may be discussed or described as consisting essentially of certain features or elements, in which embodiment features or elements that would materially alter the principle of operation or the distinguishing characteristics of the embodiment are not present therein. Another alternative embodiment of the inventive subject matter may be stated or described as consisting of certain features or elements, in which embodiment, or in insubstantial variations thereof, only the features or elements specifically stated or described are present.

The catalyst suitable for use herein may be selected from any one or more or all of the members of all of the catalyst groups described by name or structure above. However, suitable catalysts may also be selected for use as any one or more or all members of a subgroup of the entire group, where the subgroup may be of any size (e.g., 1, 2, 4, or 6), and where the subgroup is formed by removing any one or more members of the entire group. Thus, in this case, the catalyst may not only be selected for use as one or more or all of any subgroup of any size formed by the entire catalyst population described above, but may also be selected in the absence of members removed from the entire population to form subgroups. For example, in certain embodiments, the catalysts useful herein may be selected as one or more or all members of a subgroup of catalysts that excludes ruthenium on titania from the overall group, and may or may not exclude other catalysts from the overall group.

Claims (9)

1. A process for preparing dihydronepetalactone, the process comprising:

(a) reacting in a reaction mixture, at one or more first temperatures, an initial amount of trans-cis nepetalactone, described by the structure of formula I, and an initial amount of cis-trans nepetalactone, described by the structure of formula I I

Contacting hydrogen and a first solid hydrogenation catalyst until the amount of trans-cis nepetalactone in the reaction mixture is no more than 50% by weight of its starting amount to form a first product mixture; and

(b) contacting the first product mixture with hydrogen and a second solid hydrogenation catalyst at one or more second temperatures to form a dihydronepetalactone reaction product;

wherein step (a) is carried out at one or more temperatures in the range of from 0 ℃ to 50 ℃ and step (b) is carried out at one or more temperatures in the range of from greater than 60 ℃ to 150 ℃;

wherein the temperature or temperatures in step (b) are higher than the temperature or temperatures in step (a); and

wherein the process produces 1-methyl-3-isopropylcyclopentanoic acid in the product thereof in an amount of less than 10 weight percent based on the total weight of the starting amount of trans-cis nepetalactone and the starting amount of the cis-trans nepetalactone component.

2. The process of claim 1, wherein the first catalyst is the same as the second catalyst.

3. The process of claim 1, wherein the first catalyst is different from the second catalyst.

4. The process of claim 1, wherein the first and/or second catalyst comprises a catalytic metal selected from the group consisting of: iron, ruthenium, rhenium, copper, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, alloys or compounds thereof, and combinations thereof.

5. The process of claim 1, wherein the first and/or second catalyst is selected from the group consisting of: platinum black and raney catalysts.

6. The process of claim 1, wherein the first and/or second catalyst is selected from the group consisting of: palladium on carbon, palladium on calcium carbonate, palladium on barium sulfate, palladium on alumina, palladium on titania, platinum on carbon, platinum on alumina, platinum on silica, iridium on carbon, iridium on alumina, rhodium on carbon, rhodium on silica, rhodium on alumina, nickel on carbon, nickel on alumina, nickel on silica, rhenium on carbon, rhenium on silica, rhenium on alumina, ruthenium on carbon, ruthenium on alumina, ruthenium on silica, and combinations thereof.

7. The method of claim 1 wherein the amount of trans-cis nepetalactone in the first product mixture is no more than 10% by weight of its initial amount.

8. The method of claim 1 wherein the amount of cis-trans nepetalactone in the first product mixture is at least 60% of its starting amount by weight.

9. The process of claim 1, wherein the first and/or second catalyst is selected from the group consisting of: palladium on carbon or platinum on carbon.