2-(alkoxy or aryloxy carbonyl)-4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-2-enoic acid compounds, its preparation and use

Abstract

Compounds of the formula 1 ##STR00001##
wherein, R is hydrogen, alkyl or substituted alkyl, aryl or substituted aryl, are useful intermediates in the synthesis of fragrance ingredients such as Ambrox 2 ##STR00002##

Claims

1. A compound of formula 1 ##STR00024## wherein R is aryl or substituted aryl.

2. A compound of formula 1 ##STR00025## wherein R is hydrogen.

Description

EXAMPLE 1

Dimethyl 2-(2-methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butylidene)malonate 3a

(1) ##STR00016##

(2) Under water-free conditions titanium(IV) chloride (91 g, 0.5 mol) in tetrachloromethane (120 ml) are added dropwise within 45 min to tetrahydrofuran at 0 C. The mixture is stirred for another 30 min at this temperature, then 2-Methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butanal 5 (50 g, 0.24 mol) (M. Matsui et al., Agric. Biol. Chem. 50, 1475-1480, 1986) and dimethyl malonate (31.7 g, 0.24 mol) in tetrahydrofuran (50 ml) are added within 15 min at 0 C. followed by dropwise addition of pyridine (76 g) in tetrahydrofuran (240 ml) over 90 min at 0 C. The orange-brown suspension is stirred for 18 h at 25 C., then poured upon ice/water and extracted with tert-butyl methyl ether. The combined organic layers are washed with water and conc. NaCl and dried over MgSO.sub.4. After filtration and evaporation of the solvents the crude product (75 g) is short-path-distilled giving 62.5 g 3a at 170 C./0.07 mbar (81% yield, purity>98%). Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): 0.95 (s, 6 H), 1.1 (d, 3 H), 1.4-1.5 (4H), 1.5-1.6 (2 H), 1.58 (s, 3 H), 1.8-2.0 (2 H), 2.5 (m, 1 H), 3.8 (s, 3 H), 3.85 (s, 3 H), 6.85 (d, 1 H) ppm. .sup.13C-NMR (400 MHz, CDCl.sub.3): 19.45 (t), 19.55 (q), 19.75 (q), 26.4 (t), 28.5 (q), 32.7 (t), 34.8 (s), 35.7 (d), 36.8 (t), 39.7 (t), 52.1 (q), 52.2 (q), 126.7 (s), 127.1 (s), 136.8 (s), 154.9 (d), 164.4 (s), 166.0 (s). MS (EI): m/z (%) 322 (M.sup.+, 10), 307 ([M-15].sup.+, 2), 275 (6), 259 (7), 243 (16), 215 (11), 200 (18), 187 (19), 175 (20), 173 (16), 172 (100), 153 (22), 145 (28), 140 (70), 137 (27), 135 (34), 123 (60), 122 (28), 121 (42), 109 (35), 108 (34), 95 (62), 93 (36), 81 (44), 79 (33), 55 (36), 41 (35). IR (film): 2950 (m), 2926 (m), 2865 (m), 1725 (s), 1642 (w), 1454 (w), 1433 (m), 1363 (w), 1327 (w), 1246 (s), 1221 (s), 1204 (s), 1168 (w), 1104 (w), 1054 (m), 991 (w), 945 (w), 925 (w), 833 (w), 762 (w).

EXAMPLE 2

2,2-Dimethyl-5-(2-methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butylidene)-1,3-dioxane-4,6-dione 3b

(3) ##STR00017##

(4) Under stirring and nitrogen first L-prolin (0.26 g, 2.2 mmol), then 2-Methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butanal 5 (10 g, 45 mmol) (M. Matsui et al., Agric. Biol. Chem. 50, 1475-1480, 1986) are added to 2,2-dimethyl-1,3-dioxane-4,6-dione (6.65 g, 45 mmol) in acetonitrile (100 ml) at 25 C. After 90 h at this temperature the solvent is stripped off under reduced pressure. Tert-butyl methyl ether and 2 M HCl are added to the residue. Phase separation, extraction of the aqueous phase with tert-butyl methyl ether, washing of the combined organic phase with water, conc. NaHCO.sub.3 and water, drying over MgSO.sub.4, filtration and evaporation under reduced pressure gives 16 g of an oily residue. Flash chromatography over Silicagel (hexane/tert-butyl methyl ether 9:1) and evaporation of the solvents gives 0.8 g (8%) of aldehyde 5 and 12.8 g (87%) of 3b as colorless oils. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): 0.95 (s, 6 H), 1.15 (d, 3 H), 1.4 (3H), 1.5-1.6 (3 H), 1.55 (s, 3 H), 1.75 (s, 6 H), 1.85-1.9 (3 H), 2.05 (m, 1 H), 3.7 (m, 1 H), 3.85 (s, 3 H), 7.7 (d, 1 H) ppm. .sup.13C-NMR (400 MHz, CDCl.sub.3): 19.0 (q), 19.4 (t), 19.8 (q), 26.6 (t), 27.6 (2 q), 28.5 (q), 28.6 (q), 32.7 (t), 34.8 (s), 35.7 (d), 36.9 (t), 39.7 (t), 104.7 (s), 117.1 (s), 127.6 (s), 136.5 (s), 159.8 (s), 162.0 (s), 172.9 (d). MS (DIP, EI): m/z (%) 334 (M.sup.+, 4), 227 (26), 276 (79), 261 (12), 259 (47), 258 (100), 248 (72), 243 (81), 233 (28), 230 (21), 220 (26), 215 (34), 202 (41), 189 (31), 187 (24), 175 (28), 150 (55), 137 (19), 135 (71), 123 (31), 122 (33), 121 (26), 107 (17), 95 (16). IR (film): 2930 (m), 2866 (m), 1736 (s), 1624 (m), 1455 (w), 1367 (m), 1276 (s), 1201 (s), 1014 (m), 924 (m), 800 (m).

EXAMPLE 3

(E)-2-(Methoxycarbonyl)-4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-3-enoic acid 1a

(5) ##STR00018##

(6) Conjugated malonate 3a (0.5 g, 1.5 mmol, from a 5% stock solution in methanol) was incubated with 375 Units Pig Liver Esterase (Sigma-Aldrich) in 100 mM potassium phosphate buffer pH 7.5, at 25 C. and with constant stirring. After 20 h of incubation the pH of the reaction mixture was set to 9 with 30% NaOH followed by incubation at room temperature for 30 min with constant stirring. The reaction mixture was then extracted 3 times with 250 ml tert-butyl methyl ether. The organic phase was washed twice with 125 ml deionized water and once with saturated NaCl solution, dried over Na.sub.2SO.sub.4 and finally evaporated under reduced pressure at 45 C. 0.4 g of conjugated malonate 3a were recovered. The pH of the aqueous phase left from the basic (pH 9) extraction was set to 3 with conc. HCl. Extraction with tert-butyl methyl ether, washing with water and saturated NaCl, drying over Na.sub.2SO.sub.4, filtration and evaporation under reduced pressure at 45 C. gave 62 mg (13%) of deconjugated half malonate 1a as colorless oil and E/Z 72:28 according to NMR. The suppression of byproduct 1b depends on the quality of the PLE employed, with aged PLE (>1 year) giving exclusively isomer 1a. Analytical data of the E-isomer: .sup.1H-NMR (400 MHz, CDCl.sub.3): 0.96 (s, 6 H), 1.56 (3 H), 1.67 (s, 3 H), 1.4 (2 H), 1.5 (2 H), 1.9 (2 H), 2.0 (4 H), 3.6 (s, 3 H, OMe), 4.2 (d, 1 H), 5.4 (d, 1 H) ppm. .sup.13C-NMR (400 MHz, CDCl.sub.3): 16.4 (q), 19.1 (t), 19.6 (q), 27.2 (t), 28.4 (2q), 32.3 (t), 34.6 (s), 39.3 (t), 39.7 (t), 50.9 (d), 52.2 (q), 116.3 (d), 126.8 (s), 136.3 (s), 141.0 (s), 169.1 (s), 169.6 (s). Configuration of the E/Z isomers determined by NMR-analysis on a freshly prepared solution of 1a in DMSO-D.sub.6: COSY, HSQC, HMBC and NOESY.

(7) ##STR00019##

EXAMPLE 4

2-(Methoxycarbonyl)-4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-2-enoic acid 1b

(8) ##STR00020##

(9) Conjugated malonate 3a (10 g, 29.5 mmol) in THF (130 ml) is vigorously stirred with NaOH (4.8 g, 118 mmol) in water (120 ml) at 25 C. for 5 h. After addition of conc. NaHCO.sub.3 the mixture is extracted with tert-butyl methyl ether. The organic phase, which contains aldehyde 5, is discarded. The water phase is acidified with conc. HCl to pH 2 and extracted with tert-butyl methyl ether. The organic phase is dried over MgSO.sub.4, filtered and evaporated under reduced pressure giving 7.5 g (82%) of crude 1b with Z-configuration, which isomerizes upon standing slowly to an E/Z 1:1 mixture. Analytical data of the Z-isomer: .sup.1H-NMR (400 MHz, CDCl.sub.3): 0.96 (s, 6 H), 1.1 (d, 3 H), 1.4-1.6 (6 H), 1.56 (s, 3 H), 1.85-2.0 (4 H), 3.8 (m, 1 H), 3.9 (s, 3 H), 7.2 (d, 1 H) ppm. .sup.13C-NMR (400 MHz, CDCl.sub.3): 19.41 (t), 19.42 (q), 19.8 (q), 26.4 (t), 28.56 (q), 28.57 (q), 32.7 (t), 34.8 (s), 36.0 (d), 36.8 (t), 39.7 (t), 52.6 (t), 124.0 (s), 127.3 (s), 136.7 (s), 161.0 (d), 166.6 (s), 167.3 (s). Z-Configuration determined on freshly prepared 1b by non-decoupled .sup.13C-NMR-(method described in J. Med. Chem. 50, 1322-1334, 2007), HSQC- and HMBC-analysis in DMSO-D.sub.6. MS (DIP, EI): m/z (%) 308 (M.sup.+, 65), 290 (10), 275 (20), 259 (24), 243 (76), 215 (29), 190 (27), 175 (32), 158 (100), 140 (43), 123 (29), 121 (22).

EXAMPLE 5

(10) Alternative preparation of conjugated half-malonate 1b: Conjugated malonate 3a (10 g, 29 mmol) and KOH (1.9 g, 29 mmol) in dry methanol (60 ml) are stirred at 25 C. for 70 h. The mixture is diluted with water and extracted with tert-butyl methyl ether. The organic phase, which contains aldehyde 5, E-ester 4a and substrate 3a (4 g after evaporation of the solvents) is discarded. The aqueous phase is acidified to pH 2 and extracted with tert-butyl methyl ether, dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 6.7 g (76%) of crude 1b with an E/Z ratio of 1:1 and analytical data identical to the ones obtained for the E/Z mixture in example 4.

EXAMPLE 6

(11) Alternative preparation of conjugated half-malonate 1b from Meldrum's acid derivative 3b: Compound 3b (10 g, 28.5 mmol) in dry methanol (60 ml) containing KOH (1.9 g, 28.5 mmol) is stirred at 65 C. for 4 h. After cooling to 25 C. the mixture is diluted with water and extracted with tert-butyl methyl ether. The organic phase (1.5 g after evaporation of the solvents) is discarded. The aqueous phase is acidified to pH 2 and extracted with tert-butyl methyl ether, dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 7.6 g (86%) of crude 1b as E/Z 1:1 mixture. The analytical data are identical to the ones obtained for the E/Z mixture in example 4.

EXAMPLE 7

2-(2-Methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butylidene)malonic acid 1c

(12) ##STR00021##

(13) Dimethyl malonate 3a (10 g, 28 mmol), TEBAC (0.33 g, 1.4 mmol) (or 18-Crown 6) and 1N NaOH (120 ml) are stirred at 100 C. for 3 days. Cooled to 25 C. the mixture is extracted with tert-butyl methyl ether and the organic phase, which contains aldehyde 5, is discarded. 100 ml 2 N HCl are added to the aqueous phase, which is extracted with tert-butyl methyl ether. The organic phase is washed with water, dried over MgSO.sub.4, filtered and evaporated to give 7.15 g of crude bis-acid 1e (87%). Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): 0.96 (s, 6 H), 1.13 (d, 3 H), 1.35-1.6 (6 H), 1.56 (s, 3 H), 1.85-2.1 (4 H), 3.5 (m, 1 H), 7.6 (d, 1 H) ppm. .sup.13C-NMR (400 MHz, CDCl.sub.3): 19.1 (q), 19.4 (t), 19.8 (q), 26.5 (t), 28.5 (2q), 32.7 (t), 34.8 (s), 35.6 (d), 36.9 (t), 39.7 (t), 120.0 (s), 127.3 (s), 136.8 (s), 168.3 (s), 169.2 (d), 1669.7 (s). MS (DIP, EI): m/z (%) 294 (M.sup.+, 67), 279 (8), 276 (14), 261 (18), 258 (17), 243 (100), 233 (12), 215 (22), 190 (16), 187 (15), 175 (32), 151 (14), 144 (44), 135 (32), 126 (14), 123 (31), 121 (16), 107 (9), 95 (9). IR (film): 2969 (m), 2929 (m), 2867 (m), 1701 (s), 1367 (m), 1262 (m), 1237 (m), 1199 (s), 1172 (m), 1067 (m), 842 (m), 761 (m).

EXAMPLE 8

(14) Alternative preparation of 1c from aldehyde 5 by condensation with malonic acid: Aldehyde 5 (50 g, 0.24 mol), malonic acid (31 g, 0.3 mol), and piperidine (1 g, 12 mmol) in 100 ml iso-propanol are heated to 95 C. The iso-propanol/water azeotrope is continuously distilled off at 80 C. and replaced with dry iso-propanol. After 7 h the solvent is stripped off under reduced pressure. The residue is dissolved in cyclohexane and washed with 2 M aqueous HCl. The organic phase is concentrated under reduced pressure to give 75 of a viscous residue, which is dissolved in hexane (400 ml), heated to reflux and slowly cooled to 25 C. The precipitate is filtered, washed with cold hexane and dried to give 31.5 g (45%) of 1c in form of white crystals. Mp 110 C. The analytical data are identical to the ones obtained for this compound in example 7.

EXAMPLE 9

(E)-Methyl4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-3-enoate 4a

(15) ##STR00022##

(16) Conjugated malonate 3a (0.5 g, 1.5 mmol), anhydrous lithium chloride (93 mg, 2.2 mmol) and water (53 mg, 3 mmol) in N-methyl-pyrrolidone (2.9 g, 29 mmol) are heated under stirring to 130 C. After 4 h at this temperature the mixture is poured upon 2 M HCl and extracted with tert-butyl methyl ether. The combined organic layers are washed with conc. NaHCO.sub.3, conc. NaCl and dried over MgSO.sub.4. After filtration and evaporation of the solvent the crude product (0.64 g) is bulb-to-bulb-distilled to give 0.4 g of 4a at 120 C./0.1 mbar. E/Z ratio 82:18. Analytical data of the E-isomer: .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.0 (s, 6 H), 1.4 (m, 2 H), 1.55 (m, 2 H), 1.6 (s, 3 H), 1.7 (s, 3 H), 1.9 (m, 2 H), 2.1 (4 H), 3.05 (d, 2 H), 3.7 (s, 3 H), 5.35 (t, 1 H) ppm. .sup.13C-NMR (400 MHz, CDCl.sub.3): 16.35 (t), 19.5 (t), 19.8 (q), 27.5 (t), 28.6 (q, 2C), 32.8 (t), 33.5 (t), 34.95 (s), 39.8 (t), 40.0 (t), 51.6 (q), 115.0 (d), 127.1 (s), 136.9 (s), 139.9 (s), 172.9 (s). MS (EI): m/z (%) 264 (M.sup.+, 4), 249 ([M-15].sup.+, 1), 190 (3), 175 (3), 138 (10), 137 (100), 136 (21), 121 (12), 106 (11), 95 (73), 81 (45), 55 (19), 41 (21). Retention times (GC): 9.47 (Z), 9.56 (,), 9.62 (E) min. The mass spectra of the E- and Z-isomers are identical. IR (film): 2972 (m), 2865 (m), 1738 (s), 1434 (m), 1258 (m), 1199 (m), 1148 (m).

EXAMPLE 10

(17) Alternative preparation of E-Cyclohomofarnesyl ester 4a by decarboxylation of 1b in the GC column: Half-malonate 1b is dissolved at 0.1% in tert-butyl methyl ether and is injected. Temperature program: 50 C./2 min, 20 C./min.fwdarw.200 C., 35 C./min.fwdarw.270 C. GC/MS: Agilent 5973 MSD with HP 6890 Series GC system. Non-polar column: BPX5 from SGE, 5% phenyl 95% dimethylpolysiloxan 0.2 mm0.25 m12 m. Carrier Gas: Helium. Injector temperature: 230 C. Split 1:50. Flow: 1.0 ml/min. Transfer line: 250 C. MS-Quadrupol: 106 C. MS-Source: 230 C. Retention times: 9.48 (15%, Z-4a), 9.63 (57%, E-4a), 9.87 (12%, ,-isomer). The mass-spectra of Z-4a and E-4a are identical. The analytical data are identical to the ones obtained for the EIZ mixture in example 9.

EXAMPLE 11

(18) Alternative preparation of E-Cyclohomofarnesyl ester 4a by decarboxylation of 1a in DMSO: The NMR-tube containing the solution of 1a in DMSO-D.sub.6, as prepared in Example 3 for NMR-analysis, is left at 25 C. as such. Repeated NMR-analysis after 3 days shows complete decarboxylation to 4a (E/Z ratio 78:22). The other analytical data are identical with the ones obtained for the E/Z mixture from example 9.

EXAMPLE 12

(19) (E)-4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-3-enoic acid 6: decarboxylation of 1c in the presence of LiCl.

(20) ##STR00023##

(21) Conjugated malonic acid 1c (2 g, 6.7 mmol) and anhydrous lithium chloride (0.3 g, 6.7 mmol) in N-methyl-pyrrolidone (4.5 g, 45 mmol) are heated under stirring to 100 C. After 2 h at this temperature the mixture is poured at 25 C. upon 2 M HCl and extracted with tert-butyl methyl ether. The combined organic layers are washed with water, conc. NaHCO.sub.3 and conc. NaCl and dried over MgSO.sub.4. Filtration and evaporation of the solvent under vacuum gives 1.9 g of crude 6 (quant). E/Z ratio 86:14 (.sup.13C-NMR). The analytical data of 6 are identical to the ones described for this compound in EP 550889 (Kuraray, 1991).

EXAMPLE 13

(22) Conjugated malonic acid 1c (3 g, 10 mmol) and 1-ethyl-3-methylimidazolium chloride (EMIMCl) (1.5 g, 10 mmol) in N-methyl-pyrrolidone (6.6 g, 66 mmol) are heated under stirring and nitrogen to 100 C. After 5 h at this temperature the mixture is poured at 25 C. upon 2 M HCl and extracted with tert-butyl methyl ether. The combined organic layers are washed with 2 M HCl, water and conc. NaHCO.sub.3 and are dried over MgSO.sub.4. Filtration and evaporation of the solvent under vacuum gives 2.6 g of crude 6 (quant). E/Z ratio 83:17 (.sup.13C-NMR). The analytical data of 6 are identical to the ones described for this compound in EP 550889 (Kuraray, 1991).

EXAMPLE 14

One-Pot-Preparation of Acid 6 from Aldehyde 5 Catalyzed by Ammonium Acetate

(23) Under stirring and nitrogen aldehyde 5 (104 g, 0.5 mol), ammonium acetate (3.85 g, 50 mmol) and malonic acid (62.4 g, 0.6 mol) are heated in cyclohexane (250 ml) and tert-butanol (25 ml) to reflux (78 C.). After 2 h 5.5 ml water are collected in the Dean-Stark trap and after 4 h complete conversion is checked by TLC (system as above). 210 ml cyclohexane are distilled under reduced pressure (350 mbar). Magnesium chloride (24 g) in N-methyl-pyrrolidine (100 ml) are added within 5 min. After 5 h at 75 C. complete conversion of intermediate 1c to monoacid 6 is detected by TLC (system as above). The reaction mixture is cooled to 25 C. and poured upon water (400 ml). Extraction with hexane, washing of the combined organic layers with water, drying over MgSO4, filtration and evaportion of the combined organic phases under reduced pressure gives 123 g of an oily residue residue, which slowly solidifies upon standing. Purity=61% (E), according to .sup.1H-NMR with internal standard dioxane. Yield: 56% based on aldehyde 5 and corrected by purity. Ratio E/Z/conj=85:8:7 (.sup.13 C-NMR in CDCl.sub.3). The other analytical data of acid 6 obtained by this method are identical with the ones obtained for this compound (examples 12, 15, 16 and literature).

EXAMPLE 15

One-Pot-Preparation of Acid 6 from Aldehyde 5 Catalyzed by Proline

(24) Under stirring and nitrogen aldehyde 5 (50 g, 0.24 mol), L-proline (2.8 g, 24 mmol) and malonic acid (31 g, 0.3 mol) are heated in cyclohexane (60 ml) and tert-butanol (40 ml) to reflux (80-85 C.). The cyclohexane/tert-butanol/water azeotropes are continuously distilled off and replaced with dry cyclohexane/tert-butanol. After 3 h complete conversion to bisacid 1c is detected by TLC. 60 ml of cyclohexane/tert-butanol/water azeotrope are distilled off at 80-85 C. Water-free Magnesium chloride (11.5 g, 0.12 mol) in dry N-methyl-pyrrolidinone (157 g, 1.55 mol) is added and the mixture heated for another 3 hours at 80-85 C. The solution is cooled to 25 C. and poured upon 2N aqueous HCl. Extraction with cyclohexane, washing of the organic phase with aqueous 2N HCl, extraction of the combined aqueous layers with cyclohexane and evaportion of the combined organic phases under reduced pressure gives a residue, which is further dried with cyclohexane under reduced pressure giving 63 g of a yellow oil with a purity of 79.5% (E+Z, determined by .sup.1H-NMR with internal standard dioxane). E/Z ratio: 90:10 (according to .sup.13C-NMR). The crude product is dissolved in hexane and slowly cooled to 20 C. The precipitate is filtered, washed with cold hexane to give 39.5 g of pure E-acid 6 (66% from aldehyde 5). Purity=96%, according to .sup.1H-NMR with internal standard dioxane. Mp=49 C. The other analytical data of acid 6 obtained by this method are identical with the ones obtained for this compound (examples 12, 14, 16 and literature).

EXAMPLE 16

One-Pot-Preparation of Acid 6 from Aldehyde 5 Catalyzed by Glycinyl Glycine

(25) Prepared as described in example 14 from aldehyde 5 (50 g, 0.24 mol), H-Gly-Gly-OH (3.2 g, 24 mmol), malonic acid (31 g, 0.3 mol), magnesium chloride (11.5 g, 0.12 mol) in dry N-methyl-pyrrolidinone (71 g, 0.71 mol) using the same amount of solvents cyclohexane and t-Butanol within 3 h (for condensation) and 4 h (for decarboxylation). Work-up gave 70 g of crude 6 with a purity of 70% (E+Z, determined by .sup.1H-NMR with internal standard dioxane). EIZ ratio: 90:10 (according to .sup.13C-NMR). Yield: 74% (corrected and based on the E-isomer). The other analytical data of acid 6 obtained by this method are identical with the ones obtained for this compound (examples 12, 14, 15 and literature).