PROCESS FOR THE PREPARATION OF DELTA-TOCOTRIENOL

Abstract

The present invention relates to a process for the preparation of a Vitamin E derivative, in particular to a process for the synthesis of -tocotrienol of formula (I).

##STR00001##

Claims

1. Process for the preparation of -tocotrienol of formula (I) ##STR00029## comprising the following steps: c) reacting a compound of formula (V) ##STR00030## with a compound of formula (VII) ##STR00031## wherein P represents a protecting group selected from benzoyl, acetyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, p-toluenesulfonate, methansulfonate, benzensulfonate, p-toluenesulfonate ester, benzensulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, 2-tetrahydrofuranyl ether, methoxymethyl ether, X is a halogen atom selected from bromine, iodine, chlorine, Z represents a halogen atom selected from bromine, iodine, chlorine in the presence of magnesium metal, a magnesium-activating agent and an optional additive, to provide the compound of formula (VIII) ##STR00032## and d) deprotecting the obtained compound of formula (VIII) to give the desired -tocotrienol of formula (I).

2. Process according to claim 1, in which magnesium metal is added in an amount comprised between 1.0 and 10.0 molar equivalents, preferably between 5.0 and 7.0 molar equivalents, with respect to the molar amount of the compound of formula (V).

3. Process according to any one of the preceding claims, in which said magnesium activating agent is selected from iodine, dichloroethane, dibromoethane, trimethylsilyl chloride.

4. Process according to claim 3, in which said magnesium activating agent is added to the reaction mixture in an amount comprised between 0.01 and 1.0 molar equivalents, with respect to the molar amount of the compound of formula (V).

5. Process according to any one of the preceding claims, in which said optional additive is a lithium, zinc, cobalt, nickel, copper, palladium, or iron salt selected from lithium chloride, lithium bromide, lithium iodide, zinc chloride, zinc bromide, zinc iodide, cobalt chloride, cobalt dichloride, nickel chloride, copper(I) chloride, copper(II) chloride, copper(I) bromide, copper(II) dibromide, copper iodide, copper triflate, palladium chloride, iron(III) chloride, preferably lithium chloride, and/or an organic chelating compound selected from tetramethylethylenediamine (TMEDA), 1,2-Dimethylethylenediamine (DMEDA), ethanolamine (ETA), triphenylphosphine (PPh.sub.3), 1,3-bis(diphenylphosphino)propane (DPPP), 1,3-butadiene, isoprene.

6. Process according to any one of the preceding claims, in which the temperature of step c) is comprised between 20 C. and 100 C., preferably of about 80 C.

7. Process according to any one of the preceding claims, in which X is iodine and Z is bromine.

8. Process according to any one of the preceding claims, in which the compound of formula (V) is prepared by the following steps: a) selectively protecting the aromatic hydroxyl group of 8-methylcroman-2-methanol of formula (II) in single enantiomer form ##STR00033## in the presence of a protecting agent, to give the intermediate of formula (IV) ##STR00034## wherein P has the above reported meanings, b) converting the compound of formula (IV) into the corresponding halide derivative of formula (V) ##STR00035## wherein X is a halogen atom selected from bromine, iodine, chlorine.

9. Process according to any one of claims 1-7, in which the compound of formula (V) is prepared by the following steps: a) selectively protecting the aromatic hydroxyl group of 8-methylcroman-2-methanol of formula (II) in single enantiomer form ##STR00036## in the presence of a protecting agent, to give the intermediate of formula (IV) ##STR00037## wherein P has the above reported meanings, b1) converting the compound of formula (IV) Into the corresponding compound of formula (VI) ##STR00038## Wherein P has the above-mentioned meanings and LG represents a sulfonate leaving group selected from tosyl, mesyl, nosyl, triflate, nonaflate, preferably tosyl; b2) halogenating the compound of formula (VI) thus obtained to provide the desired compound of formula (V) ##STR00039##

10. Process according to any one of the preceding claims, in which said compound of formula (VII) ##STR00040## wherein Z represents a halogen atom selected from chlorine, bromine, iodine, is obtained by halogenating the compound of formula (IX) ##STR00041## in the presence of a halogenating agent.

Description

EXAMPLES

Example 1. Synthesis of (S)-(6-(benzyloxy)-2,8-dimethylchroman-2-yl)methanol

[0089] In a reaction flask 20.0 g of 8-methylcroman-2-methanol (MCM, 1 eq), 100 mL of dimethylformamide (5 vol), 19.9 g of potassium carbonate (1.5 eq) and 18.1 g of benzyl bromide (1.1 eq) are charged.

[0090] The reaction mixture is left under stirring at room temperature overnight.

[0091] At the end of the reaction, 150 mL of water and 150 mL of ethyl acetate are added and the organic phase is washed with water (3100 mL) and brine (lx 50 mL). The collected organic phase is filtered on celite and charcoal and then dried with magnesium sulphate. After evaporation of the solvent, 28.42 g of (S)-(6-(benzyloxy)-2,8-dimethylchroman-2-yl)methanol is obtained (99.3%).

[0092] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.46-7.34 (m, 5H), 6.70-6.69 (d, 1H), 6.58-6.57 (d, 1H), 5.00 (s, 2H), 3.69-3.59 (m, 2H) 2.89-2.71 (m, 2H), 2.18 (s, 3H), 2.07-1.96 (m, 2H), 1.74-1.65 (m, 1H), 1.27 (s, 1H).

[0093] .sup.13C-NMR (CDCl.sub.3, 400 MHz): 151.87, 145.73, 137.59, 128.54, 127.82, 127.49, 127.19, 121.11, 115.97, 112.32, 70.58, 69.41, 27.81, 22.29, 20.84, 16.28.

Example 2. Synthesis of (S)-(6-(benzyloxy)-2,8-dimethylchroman-2-yl)methyl 4-methylbenzenesulfonate

[0094] In a reaction flask 25.0 g of (S)-(6-(benzyloxy)-2,8-dimethylchroman-2-yl)methanol (1 eq), 250 mL of dichloromethane (10 vol), 18.8 g of 4-dimethylaminopyridine (DMAP, 2 eq) are charged.

[0095] The reaction mixture is cooled to 10 C. and 19.1 g of tosyl chloride (1.2 eq) are added. The reaction is left under stirring at room temperature overnight.

[0096] At the end of the reaction, 50 mL of water are added. The organic phase is washed with a 6 N solution of hydrochloric acid (120 mL) and water (250 mL) to reach a pH value of 6. The collected organic phase is dried with magnesium sulphate. After evaporation of the solvent, 37.63 g of (S)-(6-(benzyloxy)-2,8-dimethylchroman-2-yl)methyl 4-methylbenzenesulfonate is obtained (99.2%).

[0097] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.84-7.82 (d, 2H), 7.45-7.35 (m, 7H), 6.69-6.68 (d, 1H), 6.54-6.53 (d, 1H), 5.00 (s, 2H), 4.07-3.95 (dd, 2H), 2.72-2.69 (m, 2H), 2.48 (s, 3H), 2.11 (s, 3H), 1.95-1.93 (m, 1H), 1.80-1.76 (m, 1H), 1.34 (s, 3H). .sup.13C-NMR (CDCl.sub.3, 400 MHz): 152.00, 145.25, 144.95, 137.53, 132.75, 129.94, 128.56, 127.95, 127.85, 127.48, 127.31, 120.55, 116.10, 112.13, 73.97, 73.51, 70.52, 28.16, 22.38, 21.93, 21.68, 16.14.

Example 3. Synthesis of (S)-6-(benzyloxy)-2-(iodomethyl)-2,8-dimethylchromane

[0098] In a reaction flask 2.9 g of (S)-(6-(benzyloxy)-2,8-dimethylchroman-2-yl)methyl 4-methylbenzenesulfonate (1 eq), 29 mL of dimethylformamide (10 vol) and 5.3 g of potassium iodide (5 eq) are charged. The temperature is brought at 150 C. and the reaction mixture is left under stirring in these conditions for about 10 hours.

[0099] At the end of the reaction, 30 mL of water and 30 mL of ethyl acetate are added, the phases are separated and the aqueous phase is extracted with 20 mL of ethyl acetate. Then, the organic phases are combined and washed with water (350 mL) and brine (120 mL).

[0100] The collected organic phase is filtered on celite and charcoal and then dried with magnesium sulphate. After evaporation of the solvent, 2.34 g of (S)-6-(benzyloxy)-2-(iodomethyl)-2,8-dimethylchromane is obtained (89.6%).

[0101] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.46-7.34 (m, 5H), 6.71-6.70 (d, 1H), 6.58-6.57 (d, 1H), 5.01 (s, 2H), 3.36 (m, 2H), 2.76-2.73 (m, 2H), 2.19 (s, 3H), 2.13-2.08 (m, 1H), 1.96-1.91 (m, 1H), 1.49 (s, 3H).

[0102] .sup.13C-NMR (CDCl.sub.3, 400 MHz): 152.08, 145.62, 137.63, 128.59, 127.87, 127.63, 127.53, 120.61, 116.16, 112.20, 73.71, 70.58, 30.28, 25.60, 22.61, 16.39, 15.24.

Example 4. Synthesis of (S)-6-(benzyloxy)-2-(bromomethyl)-2,8-dimethylchromane

[0103] In a reaction flask 4.2 g of (S)-(6-(benzyloxy)-2,8-dimethylchroman-2-yl)methyl 4-methylbenzenesulfonate (1 eq), 40 mL of dimethylformamide (10 vol) and 12.0 g of sodium bromide (15 eq) are charged. The temperature is brought at 150 C. and the reaction mixture is left under stirring in these conditions for about 10 hours.

[0104] At the end of the reaction, 50 mL of water and 50 mL of ethyl acetate are added, the phases are separated and the aqueous phase is extracted with 20 mL of ethyl acetate. Then, the organic phases are combined and washed with water (350 mL) and brine (120 mL).

[0105] The collected organic phase is filtered on celite and charcoal and then dried with magnesium sulphate. After evaporation of the solvent, 3.40 g of (S)-6-(benzyloxy)-2-(bromomethyl)-2,8-dimethylchromane is obtained (98.0%).

Example 5 Synthesis of (S)-2,8-dimethyl-2-((tosyloxy)methyl)chroman-6-yl 4-methylbenzenesulfonate

[0106] In a reaction flask 0.5 g of 8-methylcroman-2-methanol (MCM, 1 eq), 5.0 mL of dichloromethane (10 vol), 0.73 g of triethylamine (3 eq) and 0.05 4-dimethylaminopyridine (DMAP, 0.2 eq) are charged. 1.09 g of tosyl chloride (2.4 eq) is added and the reaction mixture is left under stirring at room temperature overnight.

[0107] At the end of the reaction, 5 mL of dichloromethane and 10 mL of 1 N solution of hydrochloric acid are added. The phases are separated and the organic phase is washed with water (210 mL) to reach a pH value of 6. The collected organic phase is dried with magnesium sulphate. After evaporation of the solvent, 1.20 g of (S)-2,8-dimethyl-2-((tosyloxy)methyl)chroman-6-yl 4-methylbenzenesulfonate is obtained (97%).

[0108] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.78-7.76 (d, 2H), 7.73-7.70 (d, 2H), 7.35-7.31 (m, 4H), 6.55-6.52 (d, 2H), 4.00-3.90 (dd, 2H), 2.63-2.59 (m, 2H), 2.45 (s, 6H), 1.98 (s, 3H), 1.89-1.87 (m, 1H), 1.73-1.70 (m, 1H), 1.27 (s, 3H).

[0109] .sup.13C-NMR (CDCl.sub.3, 400 MHz): 149.63, 145.19, 145.10, 141.98, 132.66, 132.58, 129.69, 129.68, 128.47, 127.87, 127.63, 122.27, 120.71, 120.11, 74.60, 73.35, 27.59, 22.21, 21.70, 21.65, 21.55, 15.91.

Example 6. Synthesis of (S)-2-(iodomethyl)-2,8-dimethylchroman-6-yl 4-methylbenzenesulfonate

[0110] In a reaction flask 24.8 g of (S)-2,8-dimethyl-2-((tosyloxy)methyl)chroman-6-yl 4-methylbenzenesulfonate (1 eq), 250 mL of dimethylformamide (10 vol), 39.8 g of potassium iodide (5 eq) are charged. The temperature is brought at 150 C. and the reaction mixture is left under stirring in these conditions for about 10 hours.

[0111] At the end of the reaction, 250 mL of water and 250 mL of ethyl acetate are added, the phases are separated and the aqueous phase is extracted with 200 mL of ethyl acetate. Then, the organic phases are combined and washed with water (3250 mL) and brine.

[0112] The collected organic phase is filtered on celite and charcoal and then dried with magnesium sulphate. After evaporation of the solvent, 20.9 g of (S)-2-(iodomethyl)-2,8-dimethylchroman-6-yl 4-methylbenzenesulfonate is obtained (92%).

[0113] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.74-7.72 (d, 2H), 7.34-7.32 (d, 2H), 6.59-6.56 (d, 2H), 3.32 (m, 2H), 2.66 (m, 2H), 2.46 (s, 3H), 2.10 (s, 3H), 2.06 (m, 1H), 1.89 (m, 1H), 61.45 (s, 3H).

[0114] .sup.13C-NMR (CDCl.sub.3, 400 MHz): 149.94, 145.11, 141.98, 132.77, 129.65, 128.50, 127.85, 122.24, 6120.76, 120.16, 75.22, 29.79, 25.32, 21.92, 21.72, 16.09, 14.76 Example 7. Synthesis of (2E,6E)-1-bromo-3,7,11-trimethyldodeca-2,6,10-triene.

[0115] In a reaction flask 5.0 g of trans,trans-farnesol (1 eq), 25 mL of tetrahydrofuran (5 vol) are charged. The reaction mixture is cooled to 0 C. and 2.8 g of phosphorus tribromide (0.46 eq) are added dropwise for about 40 minutes. The reaction mixture is left under stirring in these conditions for about 3 hours.

[0116] Once the reaction is over, 12.5 mL of water are added dropwise, maintaining the temperature at 0 C. After bringing the reaction to room temperature, 12.5 mL of methyl-tetrahydrofuran are added and the phases are separated. The aqueous phase is extracted with 10 mL of methyl-tetrahydrofuran and the combined organic phases are washed with a saturated solution of sodium bicarbonate (3250 mL) and brine (15 mL).

[0117] The collected organic phase is dried with magnesium sulphate and the solvent is evaporated giving 6.4 g of (2E,6E)-1-bromo-3,7,11-trimethyldodeca-2,6,10-triene (99.8%).

[0118] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.55 (t, 1H), 5.12-5.09 (m, 2H), 4.05-4.03 (d, 2H), 2.13-1.99 (m, 8H), 1.75 (s, 3H), 1.70 (s, 3H), 1.62 (s, 6H).

[0119] .sup.13C-NMR (CDCl.sub.3, 400 MHz): 143.55, 135.59, 131.28, 124.34, 123.40, 120.61, 39.69, 39.53, 29.60, 26.71, 26.11, 25.71, 17.71, 16.05, 15.97

Example 8. Synthesis of (R)-2,8-dimethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-6-yl 4-methylbenzenesulfonate

[0120] In a reaction flask 32.0 g of magnesium turnings (6 eq), 200 mL of methyl-tetrahydrofuran (2 vol) are charged under nitrogen atmosphere. The reaction mixture is slowly warmed up to 70 C. and a solution of 105.0 g of (S)-6-(benzyloxy)-2-(iodomethyl)-2,8-dimethylchromane (1 eq) and (2E,6E)-1-bromo-3,7,11-trimethyldodeca-2,6,10-triene (76.0 g 1.2 eq) in 300 ml of methyl-tetrahydrofuran (3 vol) are added dropwise for about 1.30 hours. The reaction mixture is left under stirring at reflux in these conditions for about 1 hour.

[0121] Once the reaction is over, the reaction is brought to room temperature and the solid magnesium turnings is removed. The solvent is evaporated and the crude (R)-2,8-dimethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-6-yl 4-methylbenzenesulfonate is extracted with exhane (2250 mL). The organic phases are combined and after the evaporation of the solvent the crude product obtained is taken as such for the next step.

[0122] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.75-7.73 (d, 2H), 7.33-7.31 (d, 2H), 6.56 (s, 2H), 5.13 (m, 3H), 2.67 (m, 2H), 2.46 (s, 3H), 2.09 (m, 9H), 2.01 (m, 4H), 61.76 (m, 2H) 1.70 (m, 3H), 1.62 (m, 9H), 1.28 (m, 5H).

[0123] .sup.13C-NMR (CDCl.sub.3, 400 MHz): 150.67, 144.96, 141.43, 135.30, 134.97, 132.89, 131.20, 129.57, 128.53, 127.43, 124.37, 124.16, 124.06, 121.89, 121.09, 120.18, 76.07, 39.81, 39.73, 39.69, 30.88, 26.77, 26.58, 25.71, 23.99, 22.31, 22.12, 21.67, 17.69, 16.04, 16.02, 15.88.

Example 9. Coupling reaction for the (R)-2,8-dimethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-6-yl 4-methylbenzenesulfonate (Comparative)

[0124] The coupling reaction is carried out following the experimental conditions disclosed in the prior art WO 2005/035490 (Example 1step 2). There is no evidence about the formation of the desired product.

Example 10. Synthesis of -tocotrienol

[0125] In a reaction flask 15.5 g of crude (R)-2,8-dimethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-6-yl 4-methylbenzenesulfonate (1 eq), 140 mL of tetrahydrofuran (9 vol), 15 mL of water (1 vol), 19.5 g of potassium carbonate (5 eq) are charged under nitrogen atmosphere. The reaction mixture is left under stirring at reflux in these conditions overnight

[0126] Once the reaction is over, the reaction is brought to room temperature and the solvent is removed by evaporation. The crude product is dissolved in methyl-tetrahydrofuran (10 vol) and water (10 vol), the phases are separated and the organic one is washed with brine and dried with magnesium sulfate. The solvent is evaporated and 10.8 g of -tocotrienol are obtained (97%)

[0127] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 6.52-6.51 (d, 1H), 6.43-6.42 (d, 1H), 5.19-5.15 (m, 3H), 5.05 (s, 1H), 2.74-2.71 (t, 2H), 2.17-2.10 (m, 9H), 2.02 (m, 4H), 1.85-1.82 (m, 2H), 1.80 (m, 4H) 1.78-1.73 (m, 10H), 1.31 (m, 3H).

[0128] .sup.13C-NMR (CDCl.sub.3, 400 MHz): 148.17, 147.75, 145.97, 135.15, 134.99, 131.28, 127.35, 124.46, 124.34, 124.24, 121.28, 115.78, 6112.73, 75.37, 39.75, 39.73, 31.42, 26.79, 26.63, 25.73, 24.04, 22.51, 22.21, 17.72, 16.09, 16.04, 15.91.