PROCESS FOR PREPARING CYCLIC ALPHA-KETO ALCOHOLS FROM CYCLIC ALPHA-KETO ENOLS

Abstract

The invention relates to a method for preparing a cyclic α-ketoalcohol, particularly a 6-hydroxycyclohexenone from a cyclic α-ketoenol, particularly a 6-hydroxycyclohexadienone, using a reducing agent. This reducing agent is selected from hydrogen gas; a secondary alcohol, formic acid and the salts of formic acid or a mixture of at least two representatives of these compound classes. The invention further comprises the use of an α-ketoenol, in particular a 6-hydroxycyclohexadienone, as intermediate for preparing astaxanthin.

Claims

1.-15. (canceled)

16. A method for preparing a 6-hydroxycyclohexenone selected from the group consisting of 6-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one of the formula (1a) and 6-hydroxy-3-[(1E/Z,3E/Z)-5-hydroxy-3-methylpenta-1,3-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one of the formula (1b) ##STR00024## in which the asymmetric center in position 6 is racemic or has (S) or (R) configuration, wherein a 6-hydroxycyclohexadienone selected from the group consisting of 6-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohexa-2,5-dien-1-one of the formula (2a) and 6-hydroxy-3-[(1E/Z,3E/Z)-5-hydroxy-3-methylpenta-1,3-dienyl]-2,4,4-trimethylcyclohexa-2,5-dien-1-one of the formula (2b) ##STR00025## is reacted non-stereoselectively or stereoselectively with a reducing agent.

17. The method according to claim 16, wherein the reducing agent is at least one compound selected from the group consisting of hydrogen gas; a secondary alcohol; formic acid and the salts of formic acid.

18. The method according to claim 16, wherein the reducing agent is at least one compound selected from the group consisting of hydrogen gas; isopropanol or butan-2-ol; formic acid, an alkali metal, alkaline earth metal or ammonium formate or a mono-, di-, tri- or tetra(C1-C4)-alkylammonium formate.

19. The method according to claim 16, wherein the 6-hydroxycyclohexadienone is reacted non-stereoselectively or stereoselectively with the reducing agent in the presence of a transition metal catalyst.

20. The method according to claim 16, wherein the 6-hydroxycyclohexadienone is reacted non-stereoselectively or stereoselectively with the reducing agent in the presence of an achiral or optically active transition metal catalyst.

21. The method according to claim 18, wherein the transition metal catalyst comprises a transition metal selected from the group consisting of Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn, Re, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag and Au.

22. The method according to claim 18, wherein the transition metal catalyst comprises a transition metal selected from the group consisting of Ru, Ir, Ni and Pd.

23. The method according to claim 18, wherein the transition metal catalyst comprises at least one ligand selected from amines and/or phosphanes.

24. The method according to claim 20, wherein the ligand is a phosphane of the general formula (3), ##STR00026## where R, R′ and R″ are each independently selected from the group consisting of at least one of the residues C1-C4-alkyl, phenyl, mono- up to tri-C1-C4-alkyl-substituted aryl and a triarylphosphane.

25. The method according to claim 20, wherein the ligand is a phosphane of the general formula (3), ##STR00027## where R, R′ and R″ are each independently selected from the group consisting of a triphenylphosphane.

26. The method according to claim 18, wherein the transition metal catalyst comprises at least one ligand selected from the group consisting of H.sub.2N—CH.sub.2—CH.sub.2—OH, MeHN—CH.sub.2—CH.sub.2—OH, H.sub.2N—CH.sub.2—CH.sub.2—NH.sub.2, TsNH—CH.sub.2—CH.sub.2—NH.sub.2, TsNH—CH.sub.2—CH.sub.2—NH—(CH.sub.2).sub.n—O.sub.m—(CH.sub.2).sub.o-aryl where n=1-4, m=0 or 1 and o=1-4 and aryl=phenyl or mono-, di-, tri-C1-C4-alkylphenyl, optically active compound.

27. The method according to claim 18, wherein the transition metal catalyst comprises at least one ligand selected from the group consisting of an optically active amine.

28. The method according to claim 18, wherein the transition metal catalyst comprises at least one ligand selected from the group consisting of H.sub.2N—CHPh-CHPh-OH, H.sub.2N—CHMe-CHPh-OH, MeHN—CHMe-CHPh-OH, TsNH—CHPh-CHPh-NH.sub.2, (1S,2S)—N-p-toluenesulfonyl-1,2-diphenylethylenediamine, (1R,2R)—N-p-toluenesulfonyl-1,2-diphenylethylenediamine, N-[(1S,2S)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzene sulfonamide, N-[(1R,2R)-1,2-diphenyl.

29. The method according to claim 20, wherein the ligand is deprotonated.

30. The method according to claim 19, wherein the transition metal is applied to a solid support comprising at least one substance selected from the group consisting of carbon, aluminum oxide and silicon dioxide.

31. The method according to claim 16, wherein the 6-hydroxycyclohexadienone is reacted non-stereoselectively or stereoselectively with a reducing agent under basic conditions.

32. The method according to claim 16, wherein the 6-hydroxycyclohexadienone is reacted non-stereoselectively or stereoselectively with a reducing agent in a liquid medium.

33. The method according to claim 32, wherein said liquid medium comprising more than 50% by volume of at least one organic solvent and said organic solvent comprises at least one compound selected from the group consisting of dichloromethane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, ethylene carbonate, propylene carbonate, dimethylformamide, dimethyl sulfoxide, ethyl acetate, n-propyl acetate, toluene, xylene, heptane, hexane, pentane, N-methyl-2-pyrrolidone, dioxane, 2-methyltetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether, di-n-butyl ether, acetonitrile and preferably from the group consisting of dichloromethane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, acetonitrile, ethylene carbonate and propylene carbonate.

34. The method according to claim 16, wherein the 6-hydroxycyclohexadienone is reacted non-stereoselectively or stereoselectively with a reducing agent at a temperature of 10° C. to 85° C.

35. An intermediate for preparing (3R/S, 3′R/S))-astaxanthin (4a), ##STR00028## which comprises utilizing 6-hydroxycyclohexadienone selected from the group consisting of the compound 6-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohexa-2,5-dien-1-one of the formula (2a) and 6-hydroxy-3-[(1E/Z,3E/Z)-5-hydroxy-3-methylpenta-1,3-dienyl]-2,4,4-trimethylcyclohexa-2,5-dien-1-one of the formula (2b) ##STR00029## and/or (3S, 3′S)-astaxanthin (4b), ##STR00030## and/or (3R, 3′R)-astaxanthin (4c). ##STR00031##

Description

EXAMPLES

Example 1: Synthesis of (6R/S)-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one (rac-1a)

[0099] 2.5 g (9.77 mmol) of 6-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohexa-2,5-dien-1-one 2a are charged in 13.36 g of degassed dichloromethane at 20° C. and 7.42 g (73.3 mmol) of triethylamine are added. 47.41 mg (0.1 mmol) of the catalyst chloro{[2-aminoethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II) are dissolved in 1 ml of dichloromethane and are added to the reaction mixture at 22° C. 2.25 g (48.87 mmol) of formic acid are then added dropwise at 20-27° C. over 12 min. The mixture is stirred overnight at 20° C. After addition of 10 ml of water, the phases are separated. The organic phase is washed twice with 10 ml of water and concentrated on a rotary evaporator. 2.45 g (84.87% strength, yield: 85%) of racemic 6-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one (rac-1a) are obtained.

Example 2: Synthesis of (6S)-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one (6S-1a) with DIGLYME and potassium formate

[0100] 7.97 g of a 10% aqueous sodium hydroxide solution and 10 ml of water, and 8.38 g (99.57 mmol) of potassium formate are charged in a 100 ml 3-necked flask under argon and 30.5 g of saturated sodium hydrogen carbonate solution are added. To this solution are added 2.5 g (9.96 mmmol) of 6-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohexa-2,5-dien-1-one 2a and 5 ml of diethylene glycol dimethyl ether (DIGLYME) and the mixture is heated to 40° C. To this are added 2.88 g of catalyst solution consisting of 36.49 mg (0.1 mmol) of (1S,2S)-(+)-N-p-tosyl-1,2-diphenylethylenediamine and 30.49 mg (0.05 mmol) of dichloro(p-cymene)ruthenium(II) dimer in diethylene glycol dimethyl ether (DIGLYME) and the mixture is stirred at 40° C. for 135 min. After cooling to 20° C., 20 ml of dichloromethane are added and the phases are separated. The aqueous phase is extracted twice with 10 ml of dichloromethane each time and the combined organic phases are then washed with 20 ml of water. The product is obtained by evaporation of the solvent. 8.6 g (yield 76.9%) of (6S)-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one (6S-1a) are obtained. The enantiomeric excess is determined by chiral HPLC. The excess is 95% in favor of the (S) enantiomer.

Example 3: Synthesis of (6S)-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one (6S-1a) with dichloromethane and triethylammonium formate

[0101] 126.06 g (1.25 mol) of triethylamine and 100 ml of water are charged in a 250 ml 3-necked flask under argon and 45.87 g (1 mol) of formic acid are then added dropwise at 20-40° C. over 20 min. After the addition of 25 g (99.66 mmol) of 6-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohexa-2,5-dien-1-one 2a and 50 ml of dichloromethane, the mixture is heated to 30° C. and 634.05 mg (1 mmol) of chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II) dissolved in 10 ml of dichloromethane are added dropwise. The mixture is stirred at 30° C. for 195 min and is then cooled to 20° C. The phases are separated and the aqueous phase is extracted with 50 ml of dichloromethane. The combined organic phases are then washed with 100 ml of water. The organic phase is treated with 100 ml of water and is adjusted with 10.3 g of formic acid to a pH of 6.6. After phase separation, the organic phase is concentrated by rotary evaporation. 24.4 g (83.6% strength, yield: 81.8%) of (6S)-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one (6S-1a) with an enantiomeric excess of 96.7% are obtained.

Example 4: Synthesis of (6S)-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one (6S-1a) with dichloromethane and triethylammonium formate and a quarter of the amount of catalyst

[0102] 2.5 g (9.77 mmol) of 6-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohexa-2,5-dien-1-one 2a are dissolved in 13.36 g of dichloromethane, admixed with 7.42 g (73.3 mmol) of triethylamine and 15.55 mg (0.02 mmol) of chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II) dissolved in 0.5 ml of dichloromethane are added dropwise. After heating the mixture to 40° C., 2.25 g (48.87 mmol) of formic acid are added dropwise over a period of 8 min. The mixture is stirred at 40° C. for 27 h. The mixture is then cooled to 20° C., 10 ml of water are added, the phases are separated and the organic phase is washed twice with 10 ml of water. The organic phase is concentrated. 2.7 g (73.7% strength, yield: 81.3%) of (6S)-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one (6S-1a) with an enantiomeric excess of 93.9% are obtained.

Example 5: Synthesis of (6S)-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one (6S-1a) with N-[(1S,2S)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzene sulfonamide(chloro)ruthenium(II) as catalyst

[0103] 2.5 g (9.96 mmol) of 6-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohexa-2,5-dien-1-one 2a are dissolved in 13.36 g of dichloromethane, admixed with 7.56 g (74.7 mmol) of triethylamine and 2.29 g (49.8 mmol) of formic acid are added dropwise. 64.74 mg (0.1 mmol) of N-[(1S,2S)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)ethyl]-4-methylbenzene sulfonamide(chloro)ruthenium(II) of the formula 5 dissolved in 1 ml of dichloromethane are then added and the mixture is stirred at 25° C. for 17 h. 20 ml of water are then added, the phases are separated and the organic phase is washed twice with 10 ml of water each time and concentrated. 2.44 g (80.55% strength, yield: 78.9%) of (6S)-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one (6S-1a) with an enantiomeric excess of 98.9% are obtained.

Example 6: Synthesis of (6R)-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one (6R-1a) with dichloromethane and triethylammonium formate

[0104] 24.29 g (0.24 mol) of triethylamine are emulsified with 20 ml of water and 8.92 g (0.19 mol) of formic acid are then added dropwise. Following the addition of 10 ml of dichloromethane and 5 g (19.37 mmol) of 6-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohexa-2,5-dien-1l-one 2a, 123.26 mg (0.19 mmol) of chloro{[(1R,2R)-(+)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II) dissolved in 1 ml of dichloromethane are added dropwise at 30° C. and the mixture is stirred for 205 min. The catalyst is deactivated by the addition of 60.13 mg of 2-mercaptonicotinic acid, and the phases are separated at 20° C. The aqueous phase is extracted twice with 30 ml of dichloromethane each time and the combined organic phases are washed with 50 ml of a 10% strength acetic acid solution and then with 50 ml of a saturated sodium hydrogen carbonate solution. The organic phase is concentrated by rotary evaporation at 40° C. 5.1 g (85.2% strength, yield: 89.6%) of (6R)-hydroxy-3-[(1E/Z)-3-hydroxy-3-methylpenta-1,4-dienyl]-2,4,4-trimethylcyclohex-2-en-1-one (6R-1a) with an enantiomeric excess of 96.5% are obtained.

[0105] It can be seen that the invention relates to a method for preparing a cyclic α-ketoalcohol, particularly a 6-hydroxycyclohexenone from a cyclic α-ketoenol, particularly a 6-hydroxycyclohexadienone, using a reducing agent. This reducing agent is selected from hydrogen gas; a secondary alcohol, formic acid and the salts of formic acid or a mixture of at least two representatives of these compound classes. The invention further comprises the use of an α-ketoenol, in particular a 6-hydroxycyclohexadienone, as intermediate for preparing astaxanthin.