Compounds derived from menthol and use as refreshing agent

Preparation of (1R,2S,5R)-3-methyl methoxyacetate

A solution of (−)-menthol (50 g, 320 mmol), methoxyacetic acid (29 g, 320 mmol) and monohydrated p-toluenesulphonic acid (5 g, 26 mmol) is brought to reflux for 3 h in 500 ml of toluene. The water released during the reaction is separated by azeotropic distillation. The mixture is washed 3 times with 100 ml of a 5% NaOH solution, then twice with 100 ml of brine, the organic solvent is dried on Na 2 SO 4 and the solvent evaporated under vacuum. Distillation is then performed under vacuum to recover 51 g (81%) of a colourless liquid (boiling point 75° C./3 Pa) with a purity≧99%.

MS(EI): 83(100), 45(52), 55(48), 69(36), 139(28), 41(26), 97(19), 95(18),29(14), 123(6), 155(1), 185(1), 213(1)

1 H-NMR (400 MHz, CDCl 3 ): 4.81(dt, J=11.0, 4.4 Hz, 1H)); 4.04, 3.98 (AB, 2H); 3.45 (s, 3H); 2.02, 1.99 (2m, 1H); 1.82 (m, 1H); 1.71, 1.68 (2m, 2H); 1.50 (m, 1H); 1.40 (m, 1H); 1.14-0.82 (series of multiplets, 3H); 0.91 (d, J=5.6 Hz, 3H); 0.89 (d, J=6.8 Hz, 3H); 0.77 (d, J=6.8 Hz, 3H) δ ppm

13 C-NMR(90 MHz, CDCl 3 ): 169.8 (s); 74.8 (d), 70.0 (t), 59.3 (q), 47.0 (d); 40.9 (t); 34.2 (t); 31.4(d); 26.3 (d): 23.4 (t); 22.0(q); 20.7 (q); 16.3 (q) δ ppm

Preparation of (1R,2S,5R)-3-menthyl 3,6-dioxaheptanoate

A solution of (−)-menthol (5 g, 32 mmol), (2-methoxyethoxy)acetic acid (4.3 g, 32 mmol) and monohydrated p-toluenesulphonic acid (0.5 g, 2.63 mmol) is brought to reflux for 3 h in 50 ml toluene. The water generated during the reaction is separated by azeotropic distillation. 150 ml toluene is added and the mixture is washed 3 times with 50 ml of a 5% NaOH solution, then twice with 50 ml of brine, the organic solvent is dried on Na 2 SO 4 and the solvent evaporated under vacuum. Distillation under vacuum is then performed to recover 6.47 g (74%) of a colourless liquid (boiling point 110° C./3 Pa) with a purity of 98%.

MS(EI): 83(100), 55(45), 59(38), 69(36), 138(28), 45(23), 97(19), 29(16), 123(6), 109(3), 192(2), 155(1)

1 H-NMR (400 MHz, CDCl 3 ): 4.78 (dt, J=10.4, 4.4 Hz, 1H); 4.16, 4.08 (AB, 2H); 3.72 3.50 (2m, 4H); 3.40 (s, 3H); 2.02, 1.99 (2m, 1H); 1.82 (m, 1H); 1.71, 1.68 (2m, 2H); 1.50 (m, 1H); 1.39 (m, 1H); 1.14-0.82 (series of multiplets, 3H); 0.92 (d, J=6.3 Hz, 3H); 0.89 (d, J=6.8 Hz, 3H); 0.77 (d, J=6.8 Hz, 3H) δ ppm

13 C-NMR(90 MHz, CDCl 3 ): 170.0 (s); 74.8 (d), 71.9 (t), 70.7 (t), 68.8 (t); 59.0 (q); 47.0 (d); 40.9 (t); 34.2(t): 31.4 (d); 26.3 (d); 23.4(t); 22.0 (q); 20.7 (q); 16.3 (q) δ ppm

Preparation of (1R,2S,5R)-3-menthyl 3,6,9-trioxadecanoate

A solution of (−)-menthol (5 g, 32 mmol), [2-(2-methoxyethoxy)ethoxy]acetic acid (5.7 g, 32 mmol) and monohydrated p-toluenesulphonic acid (0.6 g, 3.2 mmol) is brought to reflux for 3 h in 20 ml toluene. The water given off during the reaction is separated by azeotropic distillation. 150 ml toluene is added, the mixture is washed 3 times with 50 ml of a 5% NaOH solution, then twice with 50 ml of brine, the organic solvent is dried on Na 2 SO 4 and the solvent evaporated under vacuum. Distillation is then performed under vacuum to recover 8.61 g (80%) of a colourless liquid (boiling point 160° C./1 Pa) with a purity of 96%.

MS(EI): 83(100), 59(74), 55(45), 103(44), 69(36), 138(34), 45(34), 95(22), 29(22), 133(16), 147(10), 178(8), 284(1)

1 H-NMR (400 MHz, CDCl 3 ): 4.78(dt, J=10.4, 4.4 Hz, 1H)); 4.15, 4.09 (AB, 2H); 3.75 3.71, 3.66, 3.55 (4m, 4H); 3.38 (s, 3H); 2.02, 1.99 (2m, 1H); 1.82 (m, 1H); 1.71, 1.68 (2m, 2H); 1.50 (m, 1H); 1.39 (m, 1H); 1.13-0.82 (series of multiplets, 3H); 0.92 (d, J=6.3 Hz, 3H); 0.89 (d, J=6.8 Hz, 3H); 0.76 (d, J=6.8 Hz, 3H) δ ppm

13 C-NMR(90 MHz, CDCl 3 ): 170.1 (s); 74.8 (d); 72.0, 70.9, 70.64, 70.58, 68.8 (5t); 59.1 (q); 47.0 (d); 40.9 (t); 34.2 (t); 31.4 (d); 26.3 (d); 23.5 (t); 22.0(q); 20.7 (q); 16.3 (q) δ ppm

Preparation of (1R,2S,5R)-3-menthyl 3.6,9-trioxadecanoate

This substance was synthesised in two stages:

a) For the first stage, a solution of (−)-menthol (1.56 g, 10 mmol), 2-bromoacetic acid (1.39 g, 10 mmol) and monohydrated p-toluenesulphonic acid (0.5 g, 2.6 mmol) was brought to reflux for 3 h in 100 ml toluene. The water given off during the reaction is separated by azeotropic distillation. 100 ml toluene is added, and the mixture is washed 3 times with 10 ml of a 5% NaOH solution, then twice with 100 ml of brine, the organic solvent is dried on Na 2 SO 4 and the solvent evaporated under vacuum. The menthyl 2-bromoacetate obtained (2.45 g, 89%) is used in the next step without purification.

b) The second stage consists in what is known as a “Williamson” reaction.

The tetraethylene glycol monomethyl ether alcoholate (1.87 g, 9 mmol) is produced by heating the said alcohol with sodium (0.23 g, 10 mmol) in dimethyl formamide (20 ml) for 4 h at 60° C. The menthyl bromoacetate obtained earlier (2.45 g, 9 mmol) is then added and the mixture stirred for 3 h at 60-80° C. and then 16 h at ambient temperature. 200 ml ethyl acetate is added and the mixture is washed 3 times with 20 ml of a 5% KHSO 4 solution, then 3 times with a 5% NaOH solution, and then twice with 20 ml of brine. The organic solvent is dried on Na 2 SO 4 and the solvent evaporated under vacuum. The product is purified by flash chromatography on silica gel eluted with a mixture of cyclohexane/ethyl acetate (60/40). 0.5 g of a slightly yellow oil (14%) is obtained. The reaction has not been optimised.

MS(CI, NH 3 ): 422(100, M + NH 4 + ), other fragments minimal

1 H-NMR (400 MHz, CDCl 3 ): 4.78(dt, J=10.4, 4.4 Hz, 1H)); 4.15, 4.08 (AB, 2H); 3.72-3.50 (m series, 24H); 3.38 (s, 3H); 2.02, 1.99 (2m, 1H); 1.82 (m, 1H); 1.71, 1.68 (2m, 2H); 1.50 (m, 1H); 1.39 (m, 1H); 1.14-0.82 (series of multiplets, 3H); 0.92 (d, J=6.3 Hz, 3H); 0.89 (d, J=6.8 Hz, 3H); 0.77 (d, J=6.8 Hz, 3H) δ ppm

13 C-NMR(90 MHz, CDCl 3 ): 170.1 (s); 74.8 (d); 72.0(t); series of triplets at 72.0 (t); 70.9(t), 70.6(t), 70.5(t) and 68.8 (t); 59.0 (q); 47.0 (d); 40.9 (t); 34.2 (t); 31.4 (d); 26.3 (d); 23.4 (t); 22.0 (q); 20.7 (q); 16.3 (q) δ ppm

Preparation of (1R,2S,5R)-3-menthyl (2-hydroxyethoxy)acetate

This substance was synthesised in three stages:

a) For the first step, NaH (60% in mineral oil, 1.97 g, 1.5 eq) is added in portions to a solution of 2-benzyloxyethanol (5 g, 32.85 mmol; source: Aldrich Chemicals) in 25 ml THF under argon. The resulting solution is brought to reflux for 1 h, then cooled to 25°.

A solution of sodium bromoacetate is prepared by adding NaH in portions (1.3 g, 1 eq) to a solution of bromoacetic acid (4.56 g, 32.85 mmol) in 25 ml THF.

This solution of bromoacetate is added dropwise to the prepared solution of benzyloxyethanolate anion, and the mixture is heated at reflux for 19 h. The reaction is stopped with 5% KHSO 4 . 250 ml ethyl acetate is added and the organic phase is extracted three times with the aid of 5% NaOH. The pH of the alkaline phase is reduced to 1 with 10% HCl and extraction is performed twice with EtOAc. The organic phase is washed three times with sodium chloride solution, dried on Na 2 SO 4 , and evaporated to obtain 6.4 g (93%) 7-phenyl-3,6-dioxaheptanoic acid in the form of a colourless liquid.

b) A mixture of 7-phenyl-3,6-dioxaheptanoic acid (6.36 g, 30.3 mmol), (−)menthol (4.73 g, 1 eq) and p-toluenesulphonic acid (0.63 g, 0.11 eq.) is heated azeotropically at reflux for 3 h in 40 ml toluene. Ethyl acetate is added, and the organic phase is washed three times with the aid of 5% NaHCO 3 , three times with brine, then dried on NaSO 4 and evaporated to obtain 10.9 g of a pale yellow oil which is distilled under vacuum to obtain 8.96 g (85%, b.p. 145-147°/10-2 mmHg) of a colourless oil corresponding to (1R,2S,5R)-menthyl 7-phenyl-3,6-dioxaheptanoate.

c) The (1R,2S,5R)-menthyl 7-phenyl-3,6-dioxaheptanoate (8.9 g, 25.5 mmol) is hydrolysed for 16 h in 50 ml THF with the aid of Pd on 10% wood charcoal (0.89 g) as the catalyst. Ethyl acetate is added, then the reaction mixture is filtered on a Celite® bed, washed three times with brine, dried on Na 2 SO 4 and evaporated. Flash chromatography is performed on silica gel (cyclohexane/EtOAc; 80/20) to obtain (1R,3R,4S)-menthyl (2-hydroxyethoxy)acetate in the form of a pale yellow liquid (5.37 g; 89.8%). Purity: 99.2% by gas-phase chromatography (DBI column, 15 m, 70° for 0.5 min then 70-220° at 10°/min, RT=11.76 min).

MS(EI): 83(100), 81(86), 95(85), 71(64),138(51), 123(50), 55(43), 41(24), 102(19), 109(16), 29(12), 155(2)

1 H-NMR (CDCl 3 ): 4.81 (dt, J=10.7, 4.4 Hz, 1H); 4.16-4.09 (AB, J=16.7 Hz, 2H); 3.76 (m, 2H); 3.69 (m, 2H); 3.06 (s broad, 1H, OH exchangeable); 2.03-2.00 (2m, 1H); 1.83 (m, 1H); 1.72-1.68 (2m, 2H); 1.52 (m, 1H); 1.44-1.37 (m, 1H); 1.09-0.83 (m,3H); 0.93; 0.91 (2d, J=6.8 Hz, 6H); 0.78 (d, J=7.1 Hz, 3H) δ ppm

13 C-NMR(CDCl 3 ): 170.8 (s); 75.4 (d); 73.6 (t); 68.5 (t); 61.5 (t); 47.0 (d); 40.9 (t); 34.1 (t); 31.4 (d); 26.4 (d); 23.5 (t); 22.0 (q); 20.7 (q); 16.3 (q) δ ppm

Taste: (1R,2S,5R)-menthyl (2-hydroxyethoxy)acetate is immediately and intensely cooling when tasted.

Preparation of (1R,2S,5R)-menthyl 11-hydroxy-3,6,9-trioxaundecanoate

This substance was synthesised in two stages:

a) For the first stage, (−)-menthol (20 g; 127 mmol) and 3,6,9-trioxaundecandioic acid (56.9 g; 2 eq; source: Fluka) is heated without solvent for 16 h at 120°, while drawing off the water continuously by distillation at 10 mmHg. The reaction mixture is diluted in ethyl acetate, washed 8 times with deionised water, dried on Na 2 SO 4 , and evaporated. Chromatography of the crude product is performed on silica gel (65/35 cyclohexane/ EtOAc with 1% acetic acid, then 40/60 with 1% ethanol) to obtain 25 g (1R,2S,5R)-menthyl hydrogeno-3,6,9-trioxaundecanedioate (54%) in the form of a colourless viscous liquid.

b) A borane tetrahydrofuran complex (1M, 20 ml) is added dropwise to a solution of (1R,2S,5R)-menthyl hydrogeno-3,6,9- trioxaundecanedioate (7.21 g; 20 mmol) in 72 ml THF at ambient temperature. The reaction is maintained with stirring for 4.5 h, then cooled to 0°. 5 ml NaOH is then added dropwise. The mixture is maintained with stirring for a further 10 min. Ethyl acetate is added, and the organic phase is washed 3 times with the aid of 5% NaHCO 3 , three times with 5% KHSO 4 , three times with brine, then dried on Na 2 SO 4 and evaporated. Flash chromatography is performed on silica gel (cyclohexane/EtOAc; 40/60) to obtain (1R,2S,5R)-menthyl 11-hydroxy-3,6,9-trioxaundecanoate in the form of a pale yellow liquid (2.22 g, 32%). Purity: 99.9% by gas-phase chromatography (DBI column, 15 m, 150° for 15 min, then 150-240° at 10°/min, RT=9.17 min).

MS(EI): 83(100), 45(52), 89(46), 138(45), 103(39), 69(31), 55(30) 147(15), 121 (15), 208(7), 163(6), 190(6), 177(5)

1 H-NMR (CDCl 3 ): 4.78 (dt, J=10.7, 4.4 Hz, 1H); 4.16; 4.09 (AB, J=16.7 Hz, 2H); 3.76-3.61 (m, 12H); 2.78 (s broad, 1H, OH exchangeable); 2.02; 1.98 (2m, 1H);

1.83 (m, 1H); 1.70; 1.66 (2m, 2H); 1.49 (m, 1H); 1.42-1.34 (m, 1H); 1.01-0.80 (m, 3H); 0.93; 0.91 (2d, J=5.9 Hz, 6H); 0.78 (d, J=6.7 Hz, 3H) δ ppm

13 C-NMR(CDCl 3 ): 170.1 (s); 75.0 (d); 72.7 (t); 70.7; 70.6; 70.5; 70.2 (4t); 68.7 (t); 61.6 (t); 47.0 (d); 40.9 (t); 34.2 (t); 31.4 (d); 26.3 (d); 23.4 (t); 22.0 (q); 20.7 (q); 16.3 (q) δ ppm

Taste: (1R,2S,5R)-menthyl 11-hydroxy-3,6,9-trioxaundecanoate has a slightly bitter, mentholated taste. Its cooling effect develops more particularly on the tongue and in the throat.

Preparation of a dentifrice gel and a dentifrice paste

(1R,2S,5R)-3-menthyl methoxyacetate and (1R,2S,5R)-3-menthyl 3,6-dioxaheptanoate were each added in a dosage of 0.4% to a dentifrice gel and a dentifrice paste of the conventional type, which had been prepared, for example, from the following ingredients:

Dentifrice gel

Dentifrice paste:

1) A silica-based thickening agent; source: Crosfield Chemicals Ltd, Great Britain

The products were then tested and evaluated by expert tasters under blind conditions. After use and rinsing of the mouth it was found that, in the case of both the products, a freshness which developed after rinsing lasted for 15 to 20 min. In a comparison with menthol, the substances of the invention cited above were judged to yield a freshness with a slow-release effect by comparison with that of menthol and, in addition, the typical taste of menthol was not perceived.

By introducing a mixture of the two previously mentioned compounds to the finished product in a dosage of 0.25% of each, a highly advantageous effect was obtained in this type of application by reducing both the fruitiness of (1R,3R,4S)-3-menthyl methoxyacetate and the bitterness of (1R,3R,4S)-3-menthyl-3,6-dioxaheptanoate by comparison with the products described above, which contained only one or the other of these compounds.

Preparation of Sweets

Grapefruit-flavoured sweets were prepared from boiled sugar, 1% citric acid, and 0.05% of a grapefruit flavouring of the following formula:

Under blind conditions, expert flavourists then compared these sweets, without any additives, with sweets of the same composition to which certain compounds according to the invention had been added.

In the opinion of the tasters, addition of 0.05% (1R,2S,5R)-3-menthyl methoxyacetate yielded a freshness which does not modify the organoleptic profile of the base composition, that is, the sweets described above.

Addition of the same quantity of (1H,2S,5R)-3-menthyl-3,6-dioxaheptanoate yielded a similar freshness and, in addition, a bitterness which reinforced the natural bitterness of the grapefruit essence.

Preparation of Gelatin-based Confectioneries

By a method which is known per se, grapefruit-flavoured confectioneries were prepared from 30 g gelatin, 175 g water, 150 g sugar and 200 g glucose. We then added 0.8% citric acid and 0.08% of a grapefruit flavouring of the formula given in Example 6.

Under blind conditions, expert flavourists then compared this base preserve, without any additives, with preserve of the same composition to which certain compounds according to the invention had been added.

In the opinion of the tasters, addition of 0.05% of (1R,2S,5R)-3-menthyl methoxyacetate by weight to the base preserve leaves a freshness in the mouth. Addition of 0.05% (1R,2S,5R)-3-menthyl 3,6-dioxaheptanoate has the same freshness effect, while also reinforcing the bitterness of the grapefruit flavouring.

Preparation of Lemon Sorbets

Lemon sorbets were prepared from the following ingredients using conventional techniques:

1) A mixture of carob gum E410, guar gum E412, carrageenan E407, gelatin, emulsifier E471; source: Meyhall Chemical AG, Kreuzlingen, Switzerland

0.5% citric acid and 0.01% of lemon flavouring of the following formula were then added:

Under blind conditions, expert flavourists then compared this lemon sorbet, without any additives, with sorbets of the same composition to which certain compounds according to the invention had been added.

In the opinion of the tasters, addition of 0.05% by weight of (1R,2S,5R)-3-menthyl methoxyacetate to the above prepared base sorbet gave it a pleasant freshness in the mouth.

Addition of 0.003% (1H,2S,5R)-3-menthyl 3,6-dioxaheptanoate has a similar effect, but this compound also confers a bitterness which reinforces the “zesty” note of the lemon flavouring.

Preparation of Chewing Gum

Chewing gum was prepared from a Cafosa Navada Plus T 413-01chewing-gum base (18 parts by weight) (source: Cafosa Gum Products Technology, Barcelona, Spain), sugar (60 parts by weight, glucose (20 parts by weight) and glycerol (0.5 parts by weight). 0.8 parts by weight of citric acid and 1 part by weight of lemon flavouring according to the formula given in Example 8 were then added to this mixture. Under blind conditions, expert tasters then compared this chewing-gum base, without any additives, with chewing gums of the same composition to which certain compounds according to the invention had been added.

Thus the addition of 0.4 parts by weight respectively of (1R,3R,4S)-3-menthyl methoxyacetate or (1R,3R,4S)-3-menthyl 3,6-dioxaheptanoate to the chewing gum gives it a prolonged freshness, the fresh sensation occurring in the mouth after chewing.

Preparation of an Orange Drink

An orange-flavoured drink was prepared from a 65° Brix syrup which had been diluted to 10%, acidified with 1.5% citric acid and then flavoured with 0.01% of an orange flavouring of the following formula:

Under blind conditions, expert tasters then compared this base drink, without any additives, with drinks of the same composition to which certain compounds according to the invention had been added.

In the opinion of the tasters, addition of 0.003% (1R,2S,5R)-3-menthyl methoxyacetate give a sensation of freshness which develops as an after-taste.

Addition of 0.003% (1R,2S,5R)-3-menthyl 3,6-dioxaheptanoate has a similar effect, but this compound also confers a bitterness which reinforces the “zesty” note of the flavouring.

Comparative Example 1

Preparation of After-shave Lotions

Two after-shave lotions were prepared by a method which is known per se, starting with the following ingredients:

1) Hydrogenated and ethoxylated ricin oil; source: BASF AG, Ludwigshafen, Germany

2) (1R,2S,5R)-3-menthyl lactate; source: Haarmann & Reimer GmbH, Holzminden, Germany

1) See lotion A

The two lotions thus obtained were poured into an aerosol-type bottle. They were then applied in a quantity of 300 mg to the forearm and cheek of each of the two people constituting the panel, and compared under blind conditions.

In the opinion of the panel, the lotion containing the compound according to the invention exhibited a cooling effect superior to that of the lotion containing the cooling agent of the prior art in 3 out of 4 tests conducted.