Process for preparing indene acryladehyde derivatives

Abstract

The present invention relates to the field of perfumery. More particularly, it concerns valuable new chemical intermediates for producing perfuming ingredients. Moreover, the present invention also comprises a process for producing compound of formula (I). ##STR00001##

Claims

1. A process for the preparation of a compound of formula ##STR00019## in the form of any one of their stereoisomers or a mixture thereof, and wherein R.sup.1 and R.sup.2, independently from each other, represent a hydrogen atom or a C.sub.1-2 alkyl group; R.sup.9 represents a hydrogen atom or a methyl group; R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8, independently from each other, represent a hydrogen atom or a C.sub.1-4 alkyl group; or two groups among R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are taken together and form a C.sub.3-8 cycloalkyl or C.sub.5-8 cycloalkenyl group and the other groups have the same meaning as defined above; comprising the steps of a) converting a compound of formula ##STR00020## in the form of any one of their stereoisomers or a mixture thereof, and wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 have the same meaning as defined above; into an acetal of formula ##STR00021## in the form of any one of their stereoisomers or a mixture thereof, and wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 have the same meaning as defined above; R.sup.a and R.sup.b, independently from each other, represent a C.sub.1-4 alkyl group or R.sup.a and R.sup.b, when taken together, represent a C.sub.2-5 alkanediyl group; b) treating the acetal obtained in step a) with an acid and a compound of formula CHR.sup.1CHOR.sup.c; wherein R.sup.c represents a C.sub.1-4 alkyl group and R.sup.1 has the same meaning as defined above; to obtain a compound of formula ##STR00022## in the form of any one of their stereoisomers or a mixture thereof, and wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.a, R.sup.b and R.sup.c have the same meaning as defined above; and c) treating the compound of formula (IV) with an acid to obtain a compound of formula (I).

2. The process according to claim 1, wherein R.sup.a and R.sup.b, independently from each other, represent a C.sub.1-3 alkyl group.

3. The process according to claim 1, wherein R.sup.a and R.sup.b, independently from each other, represent a methyl group.

4. The process according to claim 1, wherein Reis a methyl or ethyl group.

5. The process according to claim 1, wherein R.sup.c is an ethyl group.

6. The process according to claim 1, wherein R.sup.1 and R.sup.2, independently from each other, represent a hydrogen atom or a methyl group.

7. The process according to claim 1, wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8, independently from each other, represent a hydrogen atom or a C.sub.1-3 alkyl group.

8. The process according to claim 1, wherein one or two groups among R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 represent a C.sub.1-3 alkyl group and the others represent a hydrogen atom.

9. The process according to claim 1, wherein step a) is carried out in the presence of an acid and a reagent selected from the group consisting of C.sub.1-4 trialkyl orthoformate, C.sub.1-4 alcohol and C.sub.2-5 diol.

10. The process according to claim 1, wherein the acid used in step b) is selected from the group consisting of boron trifluoride complexes, anhydrous zinc chloride, and para toluene sulfonic acid.

11. The process according to claim 1, wherein the acid used in step c) is selected from the group consisting of acetic acid, aqueous acetic acid, propionic acid, aqueous sulfuric acid, sulfuric acid and aqueous hydrochloric acid.

12. The process according to claim 6, wherein R.sup.1 and R.sup.2, independently from each other, represent a hydrogen atom.

13. The process according to claim 1, wherein R.sup.a and R.sup.b, independently from each other, represent a methyl group, R.sup.c is an ethyl group, R.sup.1 and R.sup.2, independently from each other, represent a hydrogen atom; and R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8, independently from each other, represent a hydrogen atom or a C.sub.1-3 alkyl group.

14. The process according to claim 13, wherein one or two groups among R.sup.3, R.sup.4, R.sup.5, R, R.sup.7 and R.sup.8 represent a C.sub.1-3 alkyl group and the others represent a hydrogen atom.

15. The process according to claim 1, wherein: step a) is carried out in the presence of an acid and a reagent selected from the group consisting of C.sub.1-4 trialkyl orthoformate, C.sub.1-4 alcohol and C.sub.2-5 diol; the acid used in step b) is selected from the group consisting of boron trifluoride complexes, anhydrous zinc chloride, and para toluene sulfonic acid; and the acid used in step c) is selected from the group consisting of acetic acid, aqueous acetic acid, propionic acid, aqueous sulfuric acid, sulfuric acid and aqueous hydrochloric acid.

16. A process for the preparation of a compound of formula V, comprising: preparing a compound of formula (I) according to the process of claim 1; and hydrogenating the compound of formula (I) into a compound of formula ##STR00023## in the form of any one of their stereoisomers or a mixture thereof, and wherein R.sup.1 and R.sup.2, independently from each other, represent a hydrogen atom or a C.sub.1-2 alkyl group; R.sup.9 represents a hydrogen atom or a methyl group; R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8, independently from each other, represent a hydrogen atom or a C.sub.1-4 alkyl group; or two groups among R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are taken together and form a C.sub.3-8 cycloalkyl or C.sub.5-8 cycloalkenyl group and the other groups have the same meaning as defined above.

Description

EXAMPLES

(1) The invention will now be described in further detail by way of the following examples, wherein the abbreviations have the usual meaning in the art, the temperatures are indicated in degrees centigrade ( C.). NMR spectra were acquired using either a Bruker Avance II Ultrashield 400 plus operating at 400 MHz, (.sup.1H) and 100 MHz (.sup.13C) or a Bruker Avance III 500 operating at 500 MHz (.sup.1H) and 125 MHz (.sup.13C) or a Bruker Avance III 600 cryoprobe operating at 600 MHz (.sup.1H) and 150 MHz (.sup.13C). Spectra were internally referenced relative to tetramethyl silane 0.0 ppm. .sup.1H NMR signal shifts are expressed in ppm, coupling constants (J) are expressed in Hz with the following multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad (indicating unresolved couplings) and were interpreted using Bruker Topspin software. .sup.13C NMR data are expressed in chemical shift ppm and hybridization from DEPT 90 and DEPT 135 experiments, C, quaternary; CH, methine; CH.sub.2, methylene; CH.sub.3, methyl.

Example 1

Preparation of a mixture comprising 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde following the invention's process

a) Step a): preparation of a mixture comprising 6-(diethoxymethyl)-1,1-dimethyl-2,3-dihydro-1H-indene and 6-(diethoxymethyl)-3,3-dimethyl-2,3-dihydro-1H-indene

(2) In a three-neck flask, a mixture of 3,3-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde and 1,1-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde (15 g, 1 eq), ethanol (15 mL) and triethyl orthoformate (19.1 g, 1.5 eq) were added at rt. p-TSA (0.13 g, 0.008 eq) was dissolved into 5 mL ethanol and was added slowly. The reaction mixture was heated to 50-55 C. and the progress of the reaction was monitored by GC. After completion of the reaction, sodium ethoxide (21%) (0.141 g, 0.02 eq) was added and it was cooled to rt. The solvents were removed at reduced pressure to give crude mixture of 6-(diethoxymethyl)-1,1-dimethyl-2,3-dihydro-1H-indene and 6-(diethoxymethyl)-3,3-dimethyl-2,3-dihydro-1H-indene. The purification of crude products by flash distillation gave (20 g, 92%) pure diethylacetals mixture comprising 6-(diethoxymethyl)-1,1-dimethyl-2,3-dihydro-1H-indene and 6-(diethoxymethyl)-3,3-dimethyl-2,3-dihydro-1H-indene in the same ratio than the starting material.

(3) .sup.1H (CDCl.sub.3, 500 MHz): 7.37-7.06 (m, 3H), 5.46, 5.44 (each s, 1H), 3.69-3.48 (m, 4H), 2.91-2.83 (m, 2H), 1.92, 1.91 (each t, J 7.3, 2H), 1.26-1.21 (m, 15H) ppm.

(4) .sup.13C (CDCl.sub.3, 125 MHz) 152.7, 152.6, 142.9, 142.8, 137.4, 137.2, 124.9, 127.8, 122.6, 121.6, 120.2, 102.1 (d), 61.3, 61.2, 43.9, 43.7, 41.6, 41.5, 30.0, 29.8, 28.6, 15.2 ppm.

b) Step b): preparation of a mixture comprising 1,1-dimethyl-6-(1,3,3-triethoxypropyl)-2,3-dihydro-1H-indene and 3,3-dimethyl-6-(1,3,3-triethoxypropyl)-2,3-dihydro-1H-indene

(5) Under an atmosphere of nitrogen anhydrous zinc chloride (0.03 eq, 172 mg) was added to a stirred solution of diethylacetals obtained in step a) (9.3 g, 42.3 mmol) in dichloromethane (50 mL) at 20 C. (water bath). Ethyl vinyl ether (3.2 g, 44 mmol) was then added slowly dropwise over 20 minutes using the water bath to maintain the reaction temperature between 15-20 C. The reaction mixture was stirred for a further 90 minutes at ambient temperature then tripotassium citrate solution (1.0 M) was added and the mixture stirred for a further 60 minutes at ambient temperature. The organic phase was re extracted with dichloromethane, then the combined organic phase was washed with water, sodium bicarbonate solution, brine then dried over MgSO.sub.4 and filtered. The solvents were removed in vacuo and then the residue further purified by Kgelrohr distillation (110-115 C., 0.1 mbar) to give 9.8 g, of a mixture comprising 1,1-dimethyl-6-(1,3,3-triethoxypropyl)-2,3-dihydro-1H-indene and 3,3-dimethyl-6-(1,3,3-triethoxypropyl)-2,3-dihydro-1H-indene which was used without further purification in the next step.

c) Step c): preparation of a mixture comprising 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde

(6) A solution of the triethylacetals obtained in step b) (9.8 g, 33.5 mmol) and 1,4 dioxane (18 g) and 10% H.sub.2SO.sub.4 (2.0 g) was heated at 100 C. for 12 hours then cooled and the mixture was partitioned between diethyl ether and water. The aqueous phase was re extracted with diethyl ether, then the combined organic phase was washed with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and the solvents removed in vacuo to yield the mixture comprising 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde, 6.6 g. Further purification by Kgelrohr distillation (110-115 C., 0.5 mbar) gave a mixture comprising 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde in the same ratio than the starting material, 5.8 g.

(7) .sup.1H (CDCl.sub.3, 500 MHz): 9.68 (d, J 3.2, 1H), 9.66 (d, J 3.2, 1H), 9.49 (d, 7.1, 1H), 7.44 (d, J 7.1, 1H), 7.41-7.21 (m, 3H), 7.18 (d, J 7.9, 1H), 6.74-6.64 (m, 2H), 2.92 (t, J 7.3, 2H), 1.95 (t, J 7.3, 2H), 1.28 (s, 3H), 1.27 (s, 3H) ppm.

(8) .sup.13C (CDCl.sub.3, 125 MHz) 193.8 (d), 156.8, 153.7, 153.6, 153.5, 147.2, 143.9, 132.6, 132.2, 127.6, 127.5, 127.5, 127.3, 125.2, 124.4, 122.6, 121.9, 44.1, 43.8, 41.3, 41.2, 30.2, 29.7, 28.5, 28.3 ppm.

Example 2

Preparation of a mixture comprising 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde following the one pot invention's process

(9) pTSA (0.8 g, 1 mol %) was added in one portion to a solution of 3,3-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde and 1,1-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde (82.1 g, 462 mmol) and triethyl orthoformate (96.2 g, 650 mmol) and the mixture heated at 90 C. for 60 minutes then cooled to 60 C. and zinc chloride (1.9 g, 0.03 eq) was added and then butyl vinyl ether (55.0 g, 550 mmol) slowly dropwise over 60 minutes. The mixture was stirred at 60 C. for 5 hours then at 20 C. overnight. Hydroquinone (2.0 g) was added followed by isopropanol (160 g) and 10% sulfuric acid (80 g over 15 minutes) and the reaction mixture heated at 90 C. for 6 hours and the volatiles collected. The solution was cooled, diluted with toluene (200 g) and washed with water (2100 g), then saturated sodium bicarbonate solution (120 g) dried over MgSO.sub.4, filtered and the solvents removed in vacuo to give the crude mixture comprising 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde, 113.7 g. Further distillation, 100-120 C. at 0.5 mbar gave the pure mixture comprising 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde in the same ratio than the starting material, 65.5 g, (71% overall yield).

Example 3

Hydrogenation of a mixture comprising 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde

(10) A suspension of palladized charcoal (5% Pd/C, 0.2 g), the mixture obtained in example 1 (5.8 g, 29 mmol), potassium acetate (60 mg) in ethyl acetate (20 mL) was evacuated in vacuo and then purged with hydrogen gas (3) then stirred under an atmosphere of hydrogen for 12 hours then filtered. The solvent was removed in vacuo and the residue (6.2 g) was purified by flash chromatography (220 g cartridge, heptane:MTBE 99:1-3:97 as eluant) to separate the small amount of alcohol formed (ca. 20%) and gave the desired aldehyde as a mixture of regioisomers (same ratio than the starting material), 4.0 g which was further purified by Kgelrohr distillation (105-110 C., 1.0 mbar) to give the pure aldehyde 3.2 g, 54% as a mixture of regioisomers (same ratio than the starting material).

(11) .sup.1H (CDCl.sub.3, 500 MHz): 9.82-9.80 (m, 1H), 7.12-6.94 (m, 3H), 2.93 (q, J 7.8, 2H), 2.87-2.82 (m, 2H9, 2.78-2.73 (m, 2H), 1.91 (t, J 7.2, 2H), 1.24 (s, 3H), 1.23 (s, 3H) ppm.

(12) .sup.13C (CDCl.sub.3, 125 MHz) 201.9, 201.9 (d), 153.1, 150.7 (s), 143.3, 140.9 (s), 138.4, 138.2 (s), 126.4, 126.2 (d), 124.5, 124.4 (d), 122.0, 121.9 (d), 45.7, 45.5 (t), 43.9, 43.6 (s), 41.6, 41.5 (t), 29.9, 29.6 (t), 28.6, 28.5 (q), 28.6 (q), 28.2, 28.0 (t) ppm.