METHOD OF PRODUCING FARNESYL ACETONE

Abstract

The present invention relates to a process for preparing farnesyl acetone.

Claims

1.-9. (canceled)

10. A process for preparing keto compounds of the general formula (I) ##STR00014## where R.sup.1 is hydrogen or a C(O)OR.sup.3 radical, where R.sup.3 is C.sub.1-C.sub.4-alkyl; R.sup.2 is C.sub.1-C.sub.4-alkyl; X.sup.1 and X.sup.2 are both hydrogen or together are the second bond of a double bond between the carbon atoms to which they are bound; X.sup.3 and X.sup.4 are both hydrogen or together are the second bond of a double bond between the carbon atoms to which they are bound; X.sup.5, X.sup.6, X.sup.7 and X.sup.8 are each hydrogen; where one of the combinations of the radicals X.sup.5 and X.sup.7, X.sup.6 and X.sup.7 or X.sup.7 and X.sup.8 can also be the second bond of a double bond between the carbon atoms to which they are bound, and isomers and mixtures thereof, where a) at least one farnesene compound of the general formula (II) ##STR00015## where X.sup.1 and X.sup.2 together are the second bond of a double bond between the carbon atoms to which they are bound; X.sup.3 and X.sup.4 together are the second bond of a double bond between the carbon atoms to which they are bound; X.sup.5 and X.sup.7 together are the second bond of a double bond between the carbon atoms to which they are bound, with the proviso that X.sup.6 is hydrogen; or X.sup.6 and X.sup.7 together are the second bond of a double bond between the carbon atoms to which they are bound, with the proviso that X.sup.5 is hydrogen, and X.sup.8 is hydrogen; is subjected to a reaction with a -keto ester of the general formula (III)
R.sup.2COCH.sub.2R.sup.1(III) where R.sup.1 is a C(O)OR.sup.3 radical, where R.sup.3 is C.sub.1-C.sub.4-alkyl R.sup.2 is C.sub.1-C.sub.4-alkyl; in the presence of a catalyst and a solvent/water mixture, where the reaction mixture is subjected to dispersing using at least one mixer at a Reynolds number of greater than 10.sup.4, to give a compound of the formula (I-a), ##STR00016## where R.sup.1 is a C(O)OR.sup.3 radical, where R.sup.3 is C.sub.1-C.sub.4-alkyl; R.sup.2 is C.sub.1-C.sub.4-alkyl; X.sup.1 and X.sup.2 together are the second bond of a double bond between the carbon atoms to which they are bound; X.sup.3 and X.sup.4 together are the second bond of a double bond between the carbon atoms to which they are bound; one of the combinations of the radicals X.sup.5 and X.sup.7, X.sup.6 and X.sup.7 or X.sup.7 and X.sup.8 together is the second bond of a double bond between the carbon atoms to which they are bound and the remaining radicals X.sup.5, X.sup.6, X.sup.7 and X.sup.8 are each hydrogen; and isomers and mixtures thereof; b) the reaction mixture obtained in step a) is optionally subjected to a decarboxylation to give a compound of the formula (I-b), ##STR00017## where R.sup.2 is C.sub.1-C.sub.4-alkyl; one of the combinations of the radicals X.sup.5 and X.sup.7, X.sup.6 and X.sup.7 or X.sup.7 and X.sup.8 together is the second bond of a double bond between the carbon atoms to which they are bound and the remaining radicals X.sup.5, X.sup.6, X.sup.7 and X.sup.8 are each hydrogen; and isomers and mixtures thereof; c) the reaction mixture obtained in step b) is optionally subjected to a hydrogenation to give a compound of the formula (I-c) ##STR00018## where R.sup.2 is C.sub.1-C.sub.4-alkyl.

11. The process according to claim 10 for preparing farnesyl acetone of the formula (I-aA), ##STR00019## where one of the combinations of the radicals X.sup.5 and X.sup.7, X.sup.6 and X.sup.7 or X.sup.7 and X.sup.8 together is the second bond of a double bond between the carbon atoms to which they are bound and the remaining radicals X.sup.5, X.sup.6, X.sup.7 and X.sup.8 are each hydrogen, and isomers and mixtures thereof, wherein the process comprises the steps a) and b).

12. The process according to claim 10 for preparing hexahydrofarnesyl acetone (6,10,14-trimethyl-2-pentadecanone) of the formula (I-bB), ##STR00020## wherein the process comprises the steps a), b), and c).

13. The process according to claim 10, wherein the solvent of the solvent/water mixture in step a) is selected from among C.sub.1-C.sub.5-alkanols, C.sub.2-C.sub.6-dialkanols, saturated cyclic ethers, saturated acyclic ethers, nitriles, saturated ketones, lactams, esters of saturated C.sub.1-C.sub.6-monocarboxylic acids with C.sub.1-C.sub.6-alkanols, C.sub.1-C.sub.6-alkylamides and di-C.sub.1-C.sub.6-alkylamides of saturated C.sub.1-C.sub.6-monocarboxylic acids and mixtures thereof.

14. The process according to claim 10, wherein the solvent/water mixture in step a) is present in a volume ratio of from 1:5 to 5:1 calculated as pure material.

15. The process according to claim 10, wherein the solvent/water mixture in step a) is present in a volume ratio of from 2:1 to 1:2 calculated as pure material.

16. The process according to claim 10, wherein the solvent/water mixture in step a) is present in a volume ratio of 1:1 calculated as pure material.

17. The process according to claim 10, wherein dispersing in step a) is carried out at a power input in the range from 0.1 to 5000 W/l.

18. The process according to claim 10, wherein dispersing in step a) is carried out at a power input in the range from 10 to 600 W/l.

19. The process according to claim 10, wherein dispersing in step a) is carried out at a power input in the range from 20 to 100 W/l.

20. The process according to claim 10, wherein dispersing in step a) is carried out using a stirrer at a circumferential velocity in the range from 1 to 80 m/s.

21. The process according to claim 10, wherein dispersing in step a) is carried out using a stirrer at a circumferential velocity in the range from 1.8 to 30 m/s.

22. The process according to claim 10, wherein dispersing in step a) is carried out at a temperature in the range from 50 to 200 C.

23. The process according to claim 10, wherein dispersing in step a) is carried out at a temperature in the range from 60 to 150 C.

24. The process according to claim 10, wherein dispersing in step a) is carried out at a temperature in the range from 70 to 120 C.

25. A process for preparing vitamin E, isophytol, dehydroisophylol, hexahydrofarnesyl acetone or tetrahydrofamesyl acetone which comprises utilizing the farnesyl acetone obtainable by the process as defined in claim 10.

Description

DESCRIPTION OF FIGURES AND EXAMPLES

[0125] The invention is illustrated below by FIGS. A1 to C1 and the associated examples A1 to E1.

[0126] FIG. A1 shows the course of reaction of a process according to the prior art using a solvent mixture of methanol and water in a volume ratio of 3:1, in each case calculated as pure material, with mixing at a stirrer speed of 500 rpm and a power input of 11 W/l,

[0127] FIG. A2 shows the course of reaction of a process according to the prior art using a solvent mixture of methanol and water in a volume ratio of 1:3, in each case calculated as pure material, with mixing at a stirrer speed of 500 rpm and a power input of 11 W/l,

[0128] FIG. A3 shows the course of reaction of a process according to the prior art using a solvent mixture of methanol and water in a volume ratio of 1:3, in each case calculated as pure material, with mixing at a stirrer speed of 20 000 rpm and a power input of 662 W/l,

[0129] FIG. A4 shows the course of reaction of a process according to the prior art using a solvent mixture of methanol and water in a volume ratio of 1:1, in each case calculated as pure material, with mixing at a stirrer speed of 20 000 rpm and a power input of 662 W/l,

[0130] FIG. B1 shows the course of reaction of the process of the invention using a solvent mixture of ethanol and water in a volume ratio of 1:1 with mixing at a stirrer speed of 500 rpm and a power input of 11 W/l,

[0131] FIG. B2 shows the course of reaction of the process of the invention using a solvent mixture of ethanol and water in a volume ratio of 1:1, in each case calculated as pure material, with mixing at a stirrer speed of 20 000 rpm and a power input of 662 W/l,

[0132] FIG. B3 shows the course of reaction of the process of the invention using a solvent mixture of ethanol and water in a volume ratio of 1:1 with mixing at a stirrer speed of 500 rpm and a power input of 11 W/l and using a farnesene isomer mixture as starting material,

[0133] FIG. B4 shows the course of reaction of the process of the invention using a solvent mixture of ethanol and water in a volume ratio of 1:1, in each case calculated as pure material, with mixing at a stirrer speed of 20 000 rpm and a power input of 662 W/l and using a farnesene isomer mixture as starting material,

[0134] FIG. C1 shows the course of reaction of a process using water as solvent with mixing at a stirrer speed of 500 rpm and a power input of 11 W/l.

[0135] FIG. A1 shows the course of reaction of a process according to the prior art using a solvent mixture of methanol and water in a volume ratio of 3:1, calculated as volume ratio of the pure materials, with mixing at a stirrer speed of 500 rpm and a power input of 11 W/l. The reaction time in minutes is shown on the x axis. The respective composition of the reaction mixture, expressed as % by area of a gas-chromatographic analysis, with certain individual measurements over the course of the reaction is shown on the y axis. Farnesene is represented by a triangle symbol, the target product methyl (4E,8E)-2-acetyl-5,9,13-trimethyltetradeca-4,8,12-trienoate (and isomers thereof), also referred to as X, by a square symbol, farnesyl acetone Y (and isomers thereof) by a circle symbol and the product total by a star symbol.

[0136] FIG. A2 shows the course of reaction of a process according to the prior art using a solvent mixture of methanol and water in a volume ratio of 1:3, calculated as volume ratio of the pure materials, with mixing at a stirrer speed of 500 rpm and a power input of 11 W/l. The reaction time in minutes is shown on the x axis. The respective composition of the reaction mixture, expressed as % by area of a gas-chromatographic analysis, with certain individual measurements over the course of the reaction is shown on the y axis.

[0137] Farnesene is represented by a triangle symbol, the target product methyl (4E,8E)-2-acetyl-5,9,13-trimethyltetradeca-4,8,12-trienoate (and isomers thereof), also referred to as X, by a square symbol, farnesyl acetone Y (and isomers thereof) by a circle symbol and the product total by a star symbol.

[0138] FIG. A3 shows the course of reaction of a process according to the prior art using a solvent mixture of methanol and water in a volume ratio of 1:3, calculated as volume ratio of the pure materials, with mixing at a stirrer speed of 20 000 rpm and a power input of 662 W/l,

[0139] FIG. A4 shows the course of reaction of a process according to the prior art using a solvent mixture of methanol and water in a volume ratio of 1:1, calculated as volume ratio of the pure materials, with mixing at a stirrer speed of 20 000 rpm and a power input of 662 W/l. The reaction time in minutes is shown on the x axis. The respective composition of the reaction mixture, expressed as % by area of a gas-chromatographic analysis, with certain individual measurements over the course of the reaction is shown on the y axis.

[0140] Farnesene is represented by a triangle symbol, the target product methyl (4E,8E)-2-acetyl-5,9,13-trimethyltetradeca-4,8,12-trienoate (and isomers thereof), also referred to as X, by a square symbol, farnesyl acetone Y (and isomers thereof) by a circle symbol and the product total by a star symbol.

[0141] FIGS. A1 and A2 show time/conversion curves according to the prior art. The reaction rate is not significantly increased in the case of faster mixing (high power input), as comparison of Examples A2 and A3 shows. The conversion to the target product is less than 40% after 6 hours reaction time, even at a high power input.

[0142] It has surprisingly been found that the reaction rate increases significantly (Example B2) in comparison with the prior art (Example A4) when a specific solvent/water ratio (here ethanol:water=1:1) is set and mixing is then carried out at a high power input.

[0143] FIG. B1 shows the course of reaction of the process of the invention using a solvent mixture of ethanol and water in a volume ratio of 1:1 with mixing at a stirrer speed of 500 rpm and a power input of 11 W/l. The reaction time in minutes is shown on the x axis. The respective composition of the reaction mixture, expressed as % by area of a gas-chromatographic analysis, with certain individual measurements over the course of the reaction is shown on the y axis.

[0144] Farnesene is represented by a triangle symbol, the target product methyl (4E,8E)-2-acetyl-5,9,13-trimethyltetradeca-4,8,12-trienoate (and isomers thereof), also referred to as X, by a square symbol, farnesyl acetone Y (and isomers thereof) by a circle symbol and the product total by a star symbol.

[0145] FIG. B2 shows the course of reaction of the process of the invention using a solvent mixture of ethanol and water in a volume ratio of 1:1 with mixing at a stirrer speed of 20 000 rpm and a power input of 662 W/l. The reaction time in minutes is shown on the x axis. The respective composition of the reaction mixture, expressed as % by area of a gas-chromatographic analysis, with certain individual measurements over the course of the reaction is shown on the y axis.

[0146] Farnesene is represented by a triangle symbol, the target product methyl (4E,8E)-2-acetyl-5,9,13-trimethyltetradeca-4,8,12-trienoate (and isomers thereof), also referred to as X, by a square symbol, farnesyl acetone Y (and isomers thereof) by a circle symbol and the product total by a star symbol.

[0147] FIG. B3 shows the course of reaction of the process of the invention under the same conditions as in FIG. B1, except that a farnesene isomer mixture was used as starting material. The values, which relate to the conversion and thus to the y axis located at right, are the target product methyl (4E,8E)-2-acetyl-5,9,13-trimethyltetradeca-4,8,12-trienoate (and isomers thereof, square symbol), also referred to as X, farnesyl acetone Y (and isomers thereof, circle symbol), and the product total (star symbol) comprising farnesyl acetone Y (and isomers thereof) and X (and isomers thereof). The farnesene represented by a triangle symbol, on the other hand, is shown on the y axis located at left.

[0148] FIG. B4 shows the course of reaction of the process of the invention under the same conditions as in FIG. B2, except that a farnesene isomer mixture was used as starting material. The values, which relate to the conversion and thus to the y axis located at right, are the target product methyl (4E,8E)-2-acetyl-5,9,13-trimethyltetradeca-4,8,12-trienoate (and isomers thereof, square symbol), also referred to as X, farnesyl acetone Y (and isomers thereof, circle symbol), and the product total (star symbol) comprising farnesyl acetone Y (and isomers thereof) and X (and isomers thereof). The farnesene represented by a triangle symbol, on the other hand, is shown on the y axis located at left.

[0149] FIG. C1 shows the course of reaction of the process of the invention using water as solvent in a volume ratio of 1:1 with mixing at a stirrer speed of 500 rpm and a power input of 11 W/l. The reaction time in minutes is shown on the x axis. The respective composition of the reaction mixture, expressed as % by area of a gas-chromatographic analysis, with certain individual measurements over the course of the reaction is shown on the y axis.

[0150] Farnesene is represented by a triangle symbol, the target product methyl (4E,8E)-2-acetyl-5,9,13-trimethyltetradeca-4,8,12-trienoate (and isomers thereof), also referred to as X, by a square symbol, farnesyl acetone Y (and isomers thereof) by a circle symbol and the product total by a star symbol.

[0151] FIG. C1 shows time/conversion curves according to the prior art using pure water as solvent. The reaction rate here is, at the same power input, comparable to the experiments in which ethanol or methanol are added (compare C1 with A2 and B1).

[0152] Surprisingly, a specific solvent combination together with at the same time greatly increased power inputs (B 2) thus leads to significantly increased reaction rates, which are necessary for an economical process.

[0153] The following examples relate in terms of their designations to the associated figures. The catalytic reaction according to the invention of -E-farnesene (Bedoukian Res., 90% of -E-farnesene, >98% total of all farnesene isomers) with methyl acetoacetate as in all examples is shown in scheme 1 below. The product mixture formed in the reaction comprises farnesyl acetone (and isomers thereof), designated by Y (and isomers thereof) and methyl (4E,8E)-2-acetyl-5,9,13-trimethyltetradeca-4,8,12-trienoate (and isomers thereof), designated by X (and isomers thereof). The sum of X and Y is referred to as sum of the products in all figures and examples.

##STR00012##

[0154] In Examples A1 to C1, chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.07 mmol; 35 mg), trisodium tri(3-sulfonatophenyl)phosphine hydrate (1.1 mmol; 622 mg) and sodium carbonate (0.25 mmol; 26.8 mg) were placed under a protective gas atmosphere in a 250 ml glass flask. Farnesene (trans--farnesene or a farnesene isomer mixture corresponding to Table 2, 68.9 mmol; 14.1 g), methyl acetoacetate (170 mmol; 19.7 g) were admixed with water (HPLC grade) and ethanol or methanol in the ratios indicated in Table 2. The substances used are specified further in Table 1. The two-phase mixture was heated while stirring (500 rpm, precision glass stirrer, Teflon stirrer blade having a half-moon shape and a diameter of 7 cm, or an Ultra-Turrax at 20 000 rpm; model IKA T-25 Digital) for 24 hours at an internal temperature of 85 C. The respective reaction conversion was determined by gas-chromatographic analysis at various points in time (sample taken from the dispersed mixture and conversion determined from the organic phase). The gas-chromatographic parameters were: separation column: 60 m*0.25 mm HP5, 1.0 m film thickness, detector: FID, carrier gas:hydrogen, temp. program; 80 C., 10 min, 20 C./min, 250 C., 30 min; comment: integration is stopped from 0.0 to 9.0 minutes. t.sub.R (farnesenes)=18.5-20 min, t.sub.R (AME)=10.5-12.2 min, t.sub.R (X+isomers)=29.0-32.5 min, t.sub.R (farnesyl acetone Y+isomers)=23.2-25.2 min.

TABLE-US-00001 TABLE 1 Overview of the substances used in Examples A1 to D1 and manufacturer's data. no d. means no data. Man- CAS No. Substance Molar mass Purity ufacturer number 1 trans--Farnesene 204.35 g/mol no d. Bedoukian 18794-84-8 2 Farnesene isomer 204.35 g/mol no d. Sigma- 502-61-4 mixture Aldrich 3 Methyl 116.12 g/mol 99.0% Sigma- 105-45-3 acetoacetate Aldrich (AME) 4 Water 18.01 g/mol 99.0% J. T. Baker 7732-18-5 (HPLC grade) 5 Ethanol 46.07 g/mol 94.0% Alfa Aesar 64-17-5 6 Chloro(1,5-cyclo- 493.08 g/mol no d. no d. 12092-47-6 octadiene) rhodium(I) dimer 7 Tri(3- 568.40 g/mol 85.0% Alfa Aesar 63995-70-0 sulfonatophenyl)- phosphine hydrate, sodium salt 8 Sodium carbonate 105.99 g/mol 99.8% Riedel-de 497-19-8 Han

TABLE-US-00002 TABLE 2 Overview of the ratios of amounts, rotational speeds of the stirrer and power inputs used in Examples A1 to C1 Internal Power temp. input Solvent, Example [ C.] rpm [W/l] Farnesene volumes A1 85 500 11 trans-- methanol:water = farnesene 7.5 ml:2.5 ml A2 85 500 11 trans-- methanol:water = farnesene 2.5 ml:7.5 ml A3* 85 20 000 662 trans-- methanol:water = farnesene 3.8 ml:11.2 ml A4* 85 20 000 662 trans-- methanol:water = farnesene 7.5 ml:7.5 ml B1 85 500 11 trans-- ethanol:water = farnesene 5 ml:5 ml B2* 85 20 000 662 trans-- ethanol:water = farnesene 7.5 ml:7.5 ml B3 85 500 11 farnesene ethanol:water = isomer 5 ml:5 ml mixture B4* 85 20 000 662 farnesene ethanol:water = isomer 7.5 ml:7.5 ml mixture C1 85 500 11 trans-- Water (10 ml) farnesene *Batch size of all solvents, volumes and reagents were increased by a factor of 1.5.

Example D1

Conversion of -E-Farnesene into Hexahydrofarnesyl Acetone

[0155] ##STR00013##

[0156] A reaction output prepared as described in Example B2 (batch size 16.6 mmol; 3.39 g of -E-farnesene) was allowed to cool to room temperature. The organic phase of the output (yellow, 2-phase) was isolated and the aqueous phase was extracted with toluene (5 ml). The organic phases were combined and the solvent was separated off under reduced pressure at a temperature of 70 C. 4.91 g of a yellow oil were obtained. Water (HPLC grade, 10 ml) was added thereto and the mixture was heated while stirring to a temperature of 180 C. in a 20 ml steel autoclave for 3 hours. A pressure rise to 22 bar absolute occurred. The autoclave was subsequently cooled to room temperature and vented. The output was extracted with toluene (26 ml) and the combined organic phases were dried over magnesium sulfate and the solvent was separated off under reduced pressure. 3.54 g of a yellow oil were obtained. The oil obtained was admixed with THF (water-free, 20 ml) and Pd/C (palladium (10%) on activated carbon, Alfa Aeser, 350 mg). The mixture was transferred to a 60 ml steel autoclave and hydrogen (10 bar) was injected. The mixture was heated while stirring to a temperature of 50 C. for 18 hours. The autoclave was then cooled to room temperature and vented. The reaction output (black suspension) was filtered and the solvent was separated off under reduced pressure. This gave 3.50 g of hexahydrofarnesyl acetone as a colorless oil.

Example E1

[0157] In Tables 3 and 4 below, the parameters for determining the power input as described above in the description are shown for a rotor-stator stirring system.

TABLE-US-00003 TABLE 3 Overview of the parameters for determining the power input of the rotorstator stirring system used (model: IKA T-25 Digital, Ultra-Turrax at 20 000 rpm, carried out using water). Tem- pera- ture Mass Time Temp. cpW.sub.transverse H.sub.transverse Density Vol. rise [kg] [min] [ C.] [kJ/(kg * K)] [kJ/kg] [kg/m.sup.3] [I] [ C.] 0.56 0 22 4.188 2445.8 998.4 0.561 5 26.9 4.9 10 33.8 6.9 15 39.3 5.5 21 46.3 7 25 51.7 5.4 30 57.4 5.7 35 62 4.6 40 67.7 5.7 45 72.7 5 51 79.4 6.7 55 83.2 3.8 60 87.9 4.7 65 92.8 4.9 70 96.5 3.7 0.548 74 98.7 4.218 2267.3 947.9 0.578 2.2

TABLE-US-00004 TABLE 4 Overview of the parameters for determining the power input of a rotor-stator stirring system. Experiment using water Average heat capacity of water cpW.sub.transverse 4.203 kJ/(kg*K) Average enthalpy of H.sub.transverse 2356.6 kJ/kg vaporization of water Average density of water Rho W 973.2 kg/m{circumflex over ()}3 Total quantity of heat q 206863 J Power introduced P 46.6 W Initial volume V.sub.0 0.56 l Power input based on initial P/V.sub.0 83.2 W/l volume Rotational speed of rotor n 20 000 /min Diameter of rotor d.sub.R 0.018 m Power index for rotor Ne 0.68 Circumferential velocity of rotor v.sub.u 18.85 m/s Transmission to reaction mixture Density of reaction mixture 940 kg/m{circumflex over ()}3 Volume of reaction mixture V 0.068 l Transmission of stirring power to P 45 W reaction mixture Power input into reaction P/V 662 W/l mixture

Example E2

[0158] Table 5 below shows the parameters for determining the power input of a stirrer system using a half-moon stirrer.

TABLE-US-00005 TABLE 5 Overview of the parameters for determining the power input of a stirrer system for a half-moon stirrer. Determination of the power input for the half-moon stirrer Diameter of stirrer d.sub.R 0.07 m Volume of reaction mixture V 0.046 l Density of reaction 940 kg/m.sup.3 mixture/system to be stirred Circum- Rotational Stirring Power Power ferential speed Torque power index input velocity n M P Ne P/V v_u [min] [Ncm] [W] [] [W/l] [m/s] 400 0.93 0.39 0.83 8.5 1.47 450 0.95 0.45 0.67 9.7 1.65 500 0.97 0.51 0.56 11 1.83 550 0.99 0.57 0.47 12.4 2.02 600 1.01 0.63 0.4 13.8 2.2