MXPA01008341A - Preparation of carvone - Google Patents

Abstract

A process for the preparation of carvone comprises hydrogenating carvoxime in the presence of a selectively poisoned catalyst. Preferred catalysts include noble metals supported on inorganic materials poisoned with a catalyst modifier. In a preferred embodiment of the process defined herein, the crude carvone reaction product produced in accordance with the process of the invention, is purified by treating the crude carvone product with an organometallic compound M(X)n wherein M is a polyvalent metal, n is the valence of M and X denotes an inorganic or organic atom or group.

Description

PREPARATION OF CARVONA FIELD OF THE INVENTION This invention relates to the preparation of carvone (5-isopropenyl-2-methyl-2-cyclohexen-1-one) and in particular the conversion of carvoxime (5-isopropenyl-2-methyl-2-cyclohexen-l-one oxime ) to carvona.

BACKGROUND OF THE INVENTION L-carvone (5 (R) -isopropenyl-2-methyl-2-cyclohexen-1-one) is widely used as a component that provides odor or flavor (odorant or flavoring) for toothpaste or tooth powder, chewing gum, mouth rinses, et cetera. In these dental applications, it is important that carvone has a high purity, and in particular, it is important that hydroxy compounds, such as -terpineol, a common byproduct of carvone synthesis, are present in a low concentration. These materials can often not be separated from the carvone by distillation and a laborious, costly, and expensive effluent-intensive bisulfite extraction process and washing is generally needed to remove contaminants. An alternative method, which is suitable for separating by-products such as a-erpineol is described in U.S. Patent 5 302 759. The process described in this patent utilizes the reaction between an organometallic compound and an alcohol to carry out an separation of an alcohol from a ketone. Unfortunately, this purification process is not economical when the amount of hydroxy compounds present in the carvone is relatively high. In a process for preparing carvone, carvoxy is hydrolysed by transoximation under acidic conditions with sulfuric acid and acetone. Although hydrolysis provides reasonable yields of carvone, substantial amounts of a-terpineol, which is formed from limonene, and hydroxycarvone, are formed. In addition, stoichiometric amounts of acetoxime, a suspected carcinogen, are formed as side products and a large amount of sulphate effluent is produced. Therefore, the process, although practical, involves a significant environmental burden. In addition, the amount of -terpineol and hydroxycarvone generated from the process means that the purification method described in U.S. Patent 5 302 759 can not be economically applied and therefore bisulfite treatment is necessary to purify the carvone. resulting in order to produce a dental quality product. This results in an additional environmental burden. In the search for an environmentally safe carvona production process, one of the important objectives is the elimination of toxic acetoxime formation which occurs in the process mentioned above, as shown in the following scheme: OH One solution is to the reductive deximaximation of carvoxime which is described in Japanese Patent Application JP 50 071 648 in which it is used for the reduction of metallic iron in aqueous carboxylic acid. A side product of this process is the ammonium salt, and therefore the production of acetoxime is eliminated. However, a skethometric amount of iron is used and a skethometric amount of iron / iron oxide salt is formed as a side product. Catalytic hydrogenation is a well known and useful industrial technique that can be applied in large scale manufacturing and which uses a cheap reducing agent, specifically hydrogen. The problem with the use of hydrogenation in the reductive desoximase of carvoxime is that the reagent can not be selective. Therefore, the two olefin functional groups can be easily saturated to produce dihydrocarvones or tetrahydrocarvones, or both. Hydrogenation has been used to synthesize olefins from alkynes, hydrogenation is best known as Lindlar hydrogenation (Lindlar, H, Dubuis, R. Organic Synthesis Coil, Vol. V, 1973, p.880). The hydrogenation of Lindlar usually uses a palladium catalyst on calcium carbonate or palladium on barium sulfate which is selectively poisoned, for example, with a lead salt or quinoline. It is known and that the formation of hydroxy compounds such as -terpineol during the synthesis of carvone can be minimized by using a hydrogenation process to convert carvoxime to carvone. Surprisingly, it has been found that hydrogenation catalysts such as the Lindlar catalyst effectively convert carvoxime to carvone.

BRIEF DESCRIPTION OF THE INVENTION According to the invention, there is provided a process for the preparation of carvone comprising hydrogenating carvoxime in the presence of a selectively poisoned catalyst.

The process is illustrated by the following reaction scheme.

The reaction product, carvone, can exist as optical isomers. The most useful and preferred isomer, L-carvone, although the process is equally suitable for producing D-carvone. The carvone that is produced using this process contains a relatively small amount of hydroxy compounds, particularly α-terpineol, and therefore the process of U.S. Patent 5 302 759 can be used economically to purify the product. Therefore, in a preferred embodiment, the process of the invention further comprises a purification of the carvone reaction product by treating the crude carvone product with an organometallic compound M (X) n wherein M is a polyvalent metal, n is the valence of an M and X indicates an inorganic or organic atom or group.

The initial material, carvoxime, in the process of the invention, can be prepared by any suitable method. Typically, lignin (d-) is reacted with nitrosyl chloride to provide a chloronitrosylated product which, upon dehydrochlorination and tauturization, provides the carvoxime. This crude carvoxima product is then converted to carvone using the process of the invention. Alternatively, crude carvoxime can be purified before use. Carvoxime is hydrogenated by heating carvoxime in the presence of a hydrogen source and a selectively poisoned catalyst. The preferred reaction temperature is in the range of 80 ° C to 180 ° C and, more preferably, in the range of 120 ° C to 155 ° C. A suitable and preferred source of hydrogen for use herein is hydrogen gas. In this case, the reaction is preferably carried out at a pressure above atmospheric pressure, typically at a pressure in the range of 1.0 to 10.0 MPa, and more preferably in the range of 4.0 to 6.0 MPa. Alternatively, the source of hydrogen can be any compound which is a hydrogen donor. Suitable examples include formic acid; formate salts such as sodium formate, secondary alcohols such as isopropanol; cyclohexene; cyclohexadienes; tetralin; terpinolens; limonene or other saturated cycloalkanes. Preferably, the hydrogen donor is formic acid which is buffered by a salt. Salts suitable for use herein include, but are not limited to, sodium acetate, bicarbonates, carboxylates, acid phosphate, diacid phosphate or ammonium salts. Preferably, the salt is sodium acetate. When the hydrogen source is a hydrogen donor, the reaction can be carried out at atmospheric pressure and thus can be carried out using a conventional apparatus. According to the invention, the reaction is carried out in the presence of a poisoned catalyst. By "poisoned catalyst" is meant a catalyst which is active in promoting the conversion of the oxime group to a ketone group but which does not hydrogenate the carbon-carbon double bonds significantly in the carvoxime molecule. Typically, the catalyst is a supported metal catalyst, especially a noble metal catalyst and the affective catalyst includes, but is not limited to, metals such as palladium, supported on a material such as barium sulfate or alumina, which has been poisoned at mix it with a catalyst modifier such as a lead or quinoline compound. A particularly preferred catalyst is palladium on barium sulfate poisoned by red lead oxide (Pb304). Generally, the catalyst is present in an amount in the range of 0.1% to 10.0% by weight of carvoxime, and preferably in an amount in the range of 3.0% to 6.0% by weight of the carvoxime. The hydrogenation of carvoxime produces ammonia as a by-product and preferably an acid is added to the reaction mixture to neutralize the ammonia that is produced. Many acids can be used, which include organic and inorganic acids, but preferred acids include carboxylic acids such as acetic acid or formic acid. The hydrogenation of carvoxime using the process according to the invention has been found to introduce very few hydroxy compounds, if any, into the carvone, although certain hydroxy compounds are produced in the initial stages of the usual synthesis from limonene. In a preferred embodiment of the process defined herein, the carvone, prepared according to the process of the present invention, is purified according to the process described in U.S. Patent 5 302 759, the teachings of which are incorporated herein by reference. present as a reference, wherein the crude carvone is treated with an organometallic compound of the formula M (X) n, as defined above.

M is a polyvalent metal atom, which is preferably selected from titanium, aluminum or boron. n is the valence of a metal, ie n is equal to 4 for titanium and 3 for aluminum or boron. X is an alkoxy group, typically having 1 to 10 carbon atoms and preferably having 1 to 4 carbon atoms. Particularly preferred alkoxy groups for use herein are methoxy, ethoxy, protoxy or butoxy. Preferably, when the added organometallic compound is an alkoxide, there will be a by-product of alcohol (e.g. isopropanol from tetraisopropoxytitanium) which is volatile enough to be removed from the carvone before the carvone is dlled. The amount of organometallic compound used will depend mainly on the amount of hydroxy compound present in the crude carvone product. Usually, the amount of M (X) n added to the crude carvone is sufficient to produce a molar ratio of M (X) n to the hydroxy compound in the range of 0.5: 1 to 1.5: 1, and preferably in the range from 0.75: 1 to 1: 1. The carvone produced according to the preferred process of the invention is particularly useful for dental flavorings and generally contains low concentrations of undesirable impurities.

The invention is illustrated by the following non-limiting examples.

Example 1 To a mixture of 10.07 g of pure L-carvoxime, 0.5672 g of Pd catalyst 5% in BaSC4 and 0.1325 g of Pb304 in a Parr microautoclave are added 15 ml of acetic acid and 10 ml of water. The mixture is washed with nitrogen and then with hydrogen and heated to 100 ° C under a hydrogen pressure of 4.5 MPa and maintained at that temperature and pressure for 23 hours. The progress of the reaction is followed by taking samples of the reaction mixture and analyzing the samples taken by gas chromatography. It is found that the reaction mixture has the following composition after 23 hours: Compound% relative peak area Dihydrocarvonas 2.72 L-carvone 95.37 5-isopropenyl-2-methylphenol 0.54 Hydroxycarvone 0.57 The chromatography conditions are as follows: Hewlett Packard HP 6890.

Column: Model HP 19091J-412; HP-5 5% capillary phenylmethylsiloxane: 30 m x 320 μm x 0.25 μm nominal. Carrier gas: nitrogen, pressure of 0.11 MP, flow, 0.8 ml / min, average speed, 29 cm / sec. Program: 50 ° C, hold for 5 minutes, ramp 10 ° C / min up to 280 ° C, hold 15 minutes.

EXAMPLE 2 The output of a CLAR pump is connected to a Parr microreactor by stainless steel pipe (1.6 mm internal diameter). A solution of 22.23% by weight of pure L-carvoxime in acetic acid is prepared (by dissolving 35 g of pure L-carvoxime in 122.4 g of acetic acid). The vial of the solution is placed on a scale and the inlet tube of the CLAR pump, equipped with a filter, is held in place by a clamp, which is immersed in the solution. To a Parr reactor of 100 ml, add 20 ml of acetic acid, 1 ml of water, 0.0507 g of catalyst (Pd 5% in BaS04) and 0.0109 g of red lead oxide. The reactor is then purged with hydrogen, pressurized (with hydrogen) to 4.59 MPa and heated to 127 ° C. The pump, which is adjusted to a flow rate of 0.03 ml / min, is then ignited and the addition of the solution comprising L-carvoxime in acetic acid is initiated. During the reaction, the temperature, pressure and weight of the L-carvoxime solution are monitored. The addition is finished after 5.5 h, during which time 16.70 g of feed solution is added to the Parr reactor. It is found that the reaction is incomplete. The reaction mixture is then stirred for an additional 8.5 h under the same conditions, after which time the reaction is considered complete. The reaction mixture is cooled to room temperature (room temperature as used herein is 23 ° C) and then filtered to obtain 35 754 g of filtrate. This is then analyzed by GC (gas chromatography) with internal standard to determine the content of L-carvone, which is found to be 7.1% by weight. It is found that the internal standard GC feed solution contains 19.1% by weight of L-carvoxime. The yield of the reaction is 87.54%. The chromatography conditions were as follows. System: Hewlett Packard HP 5890sII. Column: Model HP 19091Z102; capillary: -25 mx 0.2 mm nominal Carrier gas: nitrogen, column flow 0.42 ml / min, average speed 22.3 cm / sec, divided flow 77.0 ml / min, division ratio 183: 1. Program: 100 ° C up to 280 ° C, at 6 ° C per minute.

The internal standard GC procedure is as follows: An internal standard solution is first prepared by weighing 1.00 g of tridecane in a 100 ml volumetric flask and bringing it to the mark with toluene (CLAR grade, from Fisher Scientific). The standard solution is mixed carefully before use.

Calibration procedure To calibrate the GC, nine standard solutions of each of carvone / carvoxime are prepared at varying concentrations by adding 0.0100, 0.0200, 0.0500, 0.1000, 0.1500, 0.2000, 0.2500, 0.30000, 0.5000 g of each to 10 ml volumetric flasks. To each volumetric flask is added 1 ml of the internal standard (IS) by means of a syringe (part #: 5182-9604 of HP) and diluted to the 10 ml mark with toluene. The solutions are mixed carefully and each solution that is prepared is run under GC conditions described above. The peak area data obtained from each carvone / carvoxime and the IS standard that is run are used to make a graph of the peak area ratio (either carvone or carvoxime / IS) against the corresponding concentration of carvone / carvoxime ( g / 10 ml of toluene). Using a linear regression analysis, the gradient and the y-axis intersection for the carvoxime / carvone graph are determined.

Analysis of the crude product To a 10 ml volumetric flask is added a sample of dry crude reaction product (0.10-1.00 g) and 1 ml of an internal standard solution. The contents of the flask are then diluted to the 10 ml mark with toluene and carefully mixed, 1 ml of this solution is then injected into the GC. The amount of carvone / carvoxime in the crude reaction product / feed solution is calculated as follows: 1. The peak area ratio for each graph is calculated, in which: Peak area ratio = carvone / carvoxime peak area peak IS 2. Using this relationship and the intersection point on the y-axis and a gradient from the calibration graph, calculate the carvone / carvoxime content (%) in the product / solution as follows: Calculated mass of carvone / carvoxime (g) = [ratio of peak area + intercept to y axis] / gradient and then,% of carvone / carvoxime calculated from carvone / carvoxime (a) 1 x 100 [weight of sample taken] EXAMPLE 3 To a reflux suspension of 20 g of anhydrous zodium acetate dissolved in 40 ml of water, 250 ml of acetic acid, 20.1 g of 5% Pd catalyst in BaSO4 and 1.94 g of red lead oxide is added dropwise, for 6 hours at 112-117 ° C, a solution of L-carvoxime in formic acid (534.27 g containing 36% carvoxime, prepared from d-limonene, as described above). The reaction is further refluxed for another 8 hours. Then, from GC analysis, when the reaction is complete, it is cooled to room temperature. Then 400 ml of deionized water is added, with stirring to the reaction mixture. The organic phase and the aqueous phase are separated and the solvent of the organic layer is removed in vacuo to provide 434.44 g of the crude product. The crude product is found to contain 39.1% carvone per GC of internal standard (the method and chromatography conditions are indicated above in Example 2), and therefore the yield of the reaction is 81.35%.

Claims (24)

1. A process for the preparation of carvone, comprising hydrogenating carvoxime in the presence of a selectively poisoned catalyst.

2. A process as described in claim 1, wherein the carvone product is L-carvone.

3. A process, as described in claims 1 to 2, wherein the carvoxime is hydrogenated by heating the carvoxime in the presence of a hydrogen source and a selectively poisoned catalyst.

4. A process, as described in any of the preceding claims, wherein the source of hydrogen is hydrogen gas.

5. A process, as described in claim 4, wherein the reaction is carried out at a pressure in the range of 1.0 MPa to 10.0 MPa.

6. A process, as described in any of claims 1 to 3, wherein the source of hydrogen is any compound which is a hydrogen donor.

7. A process, as described in the claim 6, wherein the hydrogen donor is formic acid buffered by a salt.

8. A process, as described in the claim 7, in which the salt is sodium acetate.

9. A process, as described in any of claims 6 to 8, wherein the reaction is carried out at atmospheric pressure.

10. A process, as described in any of the preceding claims, wherein the carvoxime is hydrogenated at a temperature in the range of 80 ° C to 180 ° C.

11. A process, as described in any of the preceding claims, wherein the catalyst is a noble metal catalyst supported on a material which is poisoned upon mixing with a catalyst modifier.

12. A process, as described in claim 11, wherein the catalyst modifier is a lead compound.

13. A process, as described in any of claims 11 or 12, wherein the lead compound is red lead oxide.

14. A process, as described in any of claims 11 or 13, wherein the palladium catalyst supported on barium sulfate poisoned with red lead oxide (Pb304).

15. A process, as described in any of the preceding claims, wherein the catalyst is present in an amount in the range of 0.1% to 10.0% by weight of carvoxime.

16. A process, as described in any of the preceding claims, wherein the reaction mixture additionally comprises an acid which neutralizes the by-product of ammonia that is formed.

17. A process, as described in the claim 16, wherein the acid is a carboxylic acid.

. 18. A process, as described in claim 16 or 17, wherein the carboxylic acid is acetic acid or formic acid.

19. A process, as described in any of the preceding claims, wherein additionally, the carvone reaction product is purified by treating the crude carvone product with an organometallic compound M (X) n wherein M is a polyvalent metal, n is a valence of M and X indicates an inorganic or organic atom or group.

20. A process, as described in claim 19, wherein M is selected from titanium, aluminum or boron.

21. A process, as described in any of claims 19 or 20, wherein X is an alkoxy group.

22. A process, as described in any of claims 19 to 21, wherein the amount of M (X) n adds to the crude carvone is sufficient to produce a molar ratio of M (X) n to hydroxy compounds in the range from 0. 5: 1 to 1.5: 1.

23. The carvone, prepared by the method of any of claims 1 to 22.

24. L-carvone, prepared by the method of any of claims 1 to 22.