PROCESS FOR THE PREPARATION OF (1R,2R)-3-(3-DIMETHYLAMINO-1-ETHYL-2-METHYL-PROPYL)-PHENOL

Abstract

The present invention relates to a process for the preparation of (1R,2R)-3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol.

Claims

1. A process for preparing (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof, comprising the step of (a) reacting a compound of general formula (I), ##STR00011## wherein R represents —C.sub.1-6-alkyl, —C.sub.3-8-cycloalkyl, —C.sub.1-3-alkylene-phenyl, —C.sub.1-3-alkylene-naphthyl, tetrahydropyranyl or —C(═O)—C.sub.1-6-alkyl, with ethyl magnesium halide in an inert reaction medium under Grignard conditions, (b) transferring the thus obtained compound of general formula (II), ##STR00012## wherein R has the above defined meaning, to a compound of general formula (III), ##STR00013## wherein R has the above defined meaning, optionally in form of an acid addition salt, (c) deprotecting the thus obtained compound of general formula (III) to obtain (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (IV), ##STR00014## (d) optionally converting the thus obtained (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol into an acid addition salt.

2. A process according to claim 1, characterized in that R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, —C(═O)—CH.sub.3, —C(═O)—C.sub.2H.sub.5, —C(═O)—CH(CH.sub.3).sub.2 or —C(═O)—C(CH.sub.3).sub.3.

3. A process according to claim 1 or 2, characterized in that R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or —C(═O)—CH.sub.3.

4. A process according to any of claims 1 to 3, characterized in that R represents methyl, benzyl or tetrahydropyranyl.

5. A process according to any of claims 1 to 4, characterized in that the ethyl magnesium halide used in step (a) is the chloride or bromide.

6. A process according to any one of claims 1 to 5, characterized in that the inert reaction medium is selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl-methylether, diisopropylether or any mixture thereof.

7. A process according to any one of claims 1 to 6, characterized in that a compound of general formula (I) was obtained by (a′) reacting a compound of general formula (V), ##STR00015## wherein R represents —C.sub.1-6-alkyl, —C.sub.3-8-cycloalkyl, —C.sub.1-3-alkylene-phenyl, —C.sub.1-3-alkylene-naphthyl, tetrahydropyranyl or —C(═O)—C.sub.1-6-alkyl, with dimethylamine hydrochloride and paraformaldehyde in an inert reaction medium under Mannich conditions and (a″) subsequent resolution of the thus obtained compound of general formula (VI), ##STR00016## wherein R has the above defined meaning.

8. A process according to claim 7, characterized in that R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, —C(═O)—CH.sub.3, —C(═O)—C.sub.2H.sub.5, —C(═O)—CH(CH.sub.3).sub.2 or —C(═O)—C(CH.sub.3).sub.3.

9. A process according to claim 7 or 8, characterized in that R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or —C(═O)—CH.sub.3.

10. A process according to any of claims 7 to 9, characterized in that R represents methyl, benzyl or tetrahydropyranyl.

11. A process according to any of claims 7 to 10, characterized in that the resolution in step (a″) is performed by reacting a compound of general formula (VI) with a chiral acid selected from the group consisting of L-(−)-dibenzoyl tartaric acid, L-(−)-dibenzoyl tartaric acid.H.sub.2O and D-(−)-tartaric acid, subsequent separation of the thus obtained salt and liberation of the corresponding compound of general formula (I) in form of the free base.

12. A process according to claim 11, characterized in that the resolution is performed in an alcoholic reaction medium selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol and any mixture thereof.

13. A process according to any of claims 1 to 12, characterized in that the transfer according to step (b) is performed by (b′) subjecting the compound of general formula (II) to dehydration and (b″) hydrogenation of the thus obtained compound of general formula (VII), ##STR00017## wherein R represents —C.sub.1-6-alkyl, —C.sub.3-8-cycloalkyl, —C.sub.1-3-alkylene-phenyl, —C.sub.1-3-alkylene-naphthyl, tetrahydropyranyl or —C(═O)—C.sub.1-6-alkyl, using a suitable catalyst in an inert reaction medium in the presence of hydrogen.

14. A process according to claim 13, characterized in that R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, —C(═O)—CH.sub.3, —C(═O)—C.sub.2H.sub.5, —C(═O)—CH(CH.sub.3).sub.2 or —C(═O)—C(CH.sub.3).sub.3.

15. A process according to claim 13 or 14, characterized in that R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or —C(═O)—CH.sub.3.

16. A process according to any of claims 13 to 15, characterized in that R represents methyl, benzyl or tetrahydropyranyl.

17. A process according to any of claims 13 to 16, characterized in that after the dehydration step (b′) the hydrogenation in step (b″) is effected via homogeneous catalysis.

18. A process according to any of claims 13 to 17, characterized in that the dehydration step (b′) is acid-catalysed.

19. A process according to claim 18, characterized in that the acid is selected from the group consisting of formic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, hydrobromic acid or any mixture thereof.

20. A process according to any of claims 13 to 16, characterized in that the hydrogenation of step (b″) is effected via heterogeneous catalysis.

21. A process according to claim 20, characterized in that the catalyst used for hydrogenation is selected from the group consisting of Raney nickel, palladium, palladium on carbon, platinum, platinum on carbon, ruthenium on carbon or rhodium on carbon.

22. A process according to any of claims 13 to 21, characterized in that the reaction medium is selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl-methylether, diisopropylether or any mixtures thereof.

23. A process according to any of claims 1 to 12 characterized in that step b) is a direct replacement reaction of the OH group by H, preferably carried out in a one-pot reaction.

Description

EXAMPLE

Preparation of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol Hydrochloride

[0082] ##STR00010##

Step (a′): Preparation of 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methyl propan-1-one (VIa)

[0083] 1-(3-Methoxyphenyl)propan-1-one (16.42 kg, 100 mol), dimethylamine hydrochloride (8.97 kg, 110 mol), paraformaldehyde (3.30 kg, 110 mol) and aqueous hydrochloric acid (32% by weight, 1.14 kg) were dissolved in ethanol under a nitrogen atmosphere in a 100 L (L=liter) double jacket vessel equipped with an electrical impeller stirrer, a gas transition line, Pt100 temperature measuring equipment and an oil based cooling/heating system. The reaction mixture was refluxed for 16 hours, cooled to 25° C. within 3.5 hours and stirred for 1 hour at that temperature. The suspension was separated via a centrifuge and washed three times with 7 L acetone each. 3-(Dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one hydrochloride was dissolved in water (12.5 L) and tert-butyl-methyl-ether (8.5 L) and stirred at room temperature.

[0084] Aqueous sodium hydroxide solution (32% by weight) was added until a pH value between 10.0 and 10.5 was reached and the phases were allowed to separate. The organic phase was distilled off under reduced pressure until at a temperature of 40° C. a pressure of 5 mbar was reached. 3-(Dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one was obtained as a pale yellow oil (20.75 kg, 94%) that was used in the next step without further purification.

Step (a″): Preparation of (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (Ia)

1. a. Preparation of (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (2R,3R)—O,O′-dibenzoyltartrate in Acetone

[0085] (2R,3R)—O,O′-Dibenzoyl tartaric acid monohydrate (189.1 g, 0.5 mol) was dissolved in acetone (550 mL) in a 2 L reaction plant equipped with a mechanical stirrer, temperature measuring equipment and an oil bath and 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (110.6 g, 0.5 mol) was added. The reaction mixture was heated to 35° C. to 40° C. for 27 hours and allowed to cool to 25° C. The suspension was siphoned off and (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (2R,3R)—O,O′-dibenzoyltartrate was obtained as a colorless solid (233.2 g, 80.5%, ee 96.9%, ee=enantiomeric excess).

1. b. Preparation of (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (2R,3R)—O,O′-dibenzoyltartrate in Acetone/Methanol

[0086] (2R,3R)—O,O′-Dibenzoyl tartaric acid monohydrate (2.1 kg, 5.5 mol) was dissolved in a mixture of methanol (555 mL) and acetone (3340 mL) in a 10 L double jacket vessel equipped with an electrical impeller stirrer, a gas transition line, Pt100 temperature measuring equipment and an oil based cooling/heating system and 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (1.23 kg, 5.56 mol) was added. The reaction mixture was heated to 35° C. to 40° C. for 24 hours and allowed to cool to 25° C. The suspension was siphoned off and (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (2R,3R)—O,O′-dibenzoyltartrate was obtained as a colorless solid (2.38 kg, 74%, ee 98.4%).

2. Preparation of (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (Ia)

[0087] (S)-3-(Dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (2R,3R)—O,O′-dibenzoyltartrate (968 g, 1.67 mmol, ee 98%) was suspended in tert-butylmethyl ether (6 L) in a 10 L double jacket vessel equipped with an electrical impeller stirrer, a gas transition line, Pt100 temperature measuring equipment and an oil based cooling/heating system and diethylamine (384 g, 5.25 mol) was added. The reaction mixture was stirred at 20° C. to 25° C. for 90 minutes and a solid was siphoned off. The filtrate was concentrated at a temperature of 40° C. in vacuo until a pressure of 4 mbar was reached. (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one was obtained as a colorless oil (356.7 g, 96.5%, ee 98%).

Step (a): Preparation of (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol (IIa)

[0088] 1. Magnesium turnings (93.57 g, 3.85 mol) were suspended in dry ethyl ether (2 L) in a 10 L double jacket vessel equipped with an electrical impeller stirrer, a gas transition line, Pt100 temperature measuring equipment and an oil based cooling/heating system and ethyl bromide (25 g, 0.23 mol) was added. After the reaction has started further ethyl bromide (438.6 g, 4.02 mol) was added within 90 minutes below a temperature of 35° C. and the reaction mixture was stirred for another hour. The reaction mixture was cooled to 10° C. to 15° C., (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (774.6 g, 3.5 mol, ee 98%) dissolved in diethyl ether (0.8 L) was added and the reaction mixture was stirred for another two hours. The reaction mixture was cooled to 5° C. and aqueous ammonium hydrogensulfate solution (10% by weight, 2 L) was added. The phases were separated and the organic phase was concentrated in vacuo at 40° C. until a pressure of 5 mbar was reached. (2S,3R)-1-(Dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol (862.3 g, 98%) was obtained as a colorless oil (ee 98%).

[0089] 2. (S)-3-(Dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (774.6 g, 3.5 mol, ee 95%) was dissolved in dry tetrahydrofuran (800 mL) in a 10 L double jacket vessel equipped with an electrical impeller stirrer, a gas transition line, Pt100 temperature measuring equipment and an oil based cooling/heating system and ethyl magnesium bromide (2 L, 2 M in THF) was added at a temperature of 15° C. within 2 hours. The reaction mixture was stirred for two hours at that temperature, cooled to 5° C. and aqueous ammonium hydrogen sulfate solution (10% by weight, 2 L) was added. The phases were separated and the organic phase was concentrated in vacuo at 40° C. until a pressure of 5 mbar was reached. (2S,3R)-1-(Dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol (871.1 g, 99%) was obtained as a colorless oil (ee 95%).

Step (b′): Preparation of (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine (VIIa)

[0090] 1. (2S,3R)-1-(Dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol (754.1 g, 3 mol, ee 95%) were dissolved in acetone (5 L) in a 10 L double jacket vessel equipped with an electrical impeller stirrer, a gas transition line, Pt100 temperature measuring equipment and an oil based cooling/heating system. Hydrogen chloride (110 g, 3.0 mol) was transferred within 15 minutes at a temperature of 15° C. through the reaction mixture. The reaction mixture was cooled to 0° C. to 5° C. and after 24 hours at that temperature siphoned off. The product was stored at 40° C. and 10 mbar for 14 hours in a drying oven. (2S,3R)-1-(Dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride was obtained as a colorless solid (722.3 g, 83.7%, ee 100%).

[0091] 2. (2S,3R)-1-(Dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride obtained as described above was put into a 250 mL three necked flask equipped with a thermometer, a mechanical compressed air stirrer, reflux condenser and oil bath and aqueous hydrogen chloride solution (150 mL, 36% by weight) was added. The reaction mixture was heated to 55° C. for 5 hours and allowed to cool to 20° C. Aqueous sodium hydroxide solution (33% by weight) was added while cooling until a pH value of 11 was reached. Ethyl acetate (150 mL) was added, the reaction mixture was stirred for 10 minutes, the phases were separated and ethyl acetate was removed in vacuo at 60° C. until a pressure of 10 mbar was reached. (R)-3-(3-Methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine (21 g, 90%) was obtained as an oily residue (Z/E ratio 4.5:1).

Step (b″): Preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine Hydrochloride (IIIa)

[0092] 1. (R)-3-(3-Methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine (5 kg, 21.43 mmol) was dissolved in dry ethanol (13 L) at a temperature of 25° C. and rotational stirring frequency of 850±150 per minute in a double jacket hydrogenation apparatus equipped with a stationary mounted lid having a hydrogen and nitrogen supply, electric gassing stirrer, Pt100 temperature measuring equipment, inspecting glass and gas controller “Büchi bpc”. The hydrogenation apparatus was flooded with nitrogen. Palladium on charcoal (375 g, 5% by weight) was suspended in aqueous hydrogen chloride (675 g, 32% by weight) and added to the reaction mixture. The hydrogenation apparatus was flooded again with nitrogen and the reaction was carried out at a primary pressure of hydrogen of 5 bar and an internal hydrogen pressure of 1 bar until the reaction was complete. The hydrogenation apparatus was flooded with nitrogen and the catalyst was filtered off on a one layered filter with filtering earth. The filtrate was concentrated in vacuo. The residue was take up in ethyl acetate and aqueous sodium hydroxide (10% by weight, 3.7 L) was added at 20° C. until a pH value of 10 to 12 was reached. The organic phase was concentrated in vacuo at 45° C. to 50° C. until a pressure of 5 mbar was reached. The oily residue was a mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine (4.5 kg, 95%, ratio 5.5 (R,R):1 (R,S)).

[0093] 2. A mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine (10 kg, 42.56 mol, ratio 5.5:1) was dissolved in acetone (50 L) in a 100 L double jacket vessel equipped with an electrical impeller stirrer, a gas transition line, Pt100 temperature measuring equipment and an oil based cooling/heating system. Hydrogen chloride (1.55 kg, 42.51 mol) was transferred within 15 minutes at a temperature of 5° C. to 25° C. through the reaction mixture. The reaction mixture was cooled to 0° C. to 5° C. and centrifuged after 2 hours of stirring. The humid solid was put into a stirring vessel, acetone (30 L) was added and the reaction mixture was heated to reflux for 15 minutes. After cooling to 15° C. to 20° C. the product was centrifuged and stored at 40° C. to 50° C. and 150 mbar for 14 hours in a drying oven. (2R,3R)-3-(3-Methoxyphenyl)-N,N,2-trimethylpentan-1-amine hydrochloride (7.17 kg, 63%) was obtained as a colorless solid with a diastereomeric excess of 100%).

Step (c): Preparation of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol Hydrochloride (IV)

[0094] 1. (2R,3R)-3-(3-Methoxyphenyl)-N,N,2-trimethylpentan-1-amine hydrochloride (5 kg, 18.4 mol) was dissolved in methane sulfonic acid (19.5 L) in a 100 L double jacket vessel equipped with an electrical impeller stirrer, a gas transition line, Pt100 temperature measuring equipment and an oil based cooling/heating system and methionine (3.35 kg, 22.5 mol) was added. The reaction mixture was stirred at a temperature of 75° C. to 80° C. for 16 hours, cooled to 15° C. to 25° C. and water (12.5 L) was slowly added at that temperature. Aqueous sodium hydroxide solution (ca. 28 L, 32% by weight) was added until a pH value of 10 to 12 was reached while the temperature was kept below 50° C. Ethyl acetate (15 L) was added and the reaction mixture was stirred for 15 minutes at a rotational stirring frequency of 150 per minute. The phases were separated and the organic phase was washed with water (15 L). Activated charcoal (0.05 kg) was added to the organic phase and filtered off after 30 minutes of stirring. The solvent was removed in vacuo at a temperature of 40° C. to 50° C. until a pressure of 50 mbar was reached. The residue was used in the next step without further purification.

[0095] 2. The residue obtained as described above was dissolved in acetone (25 L) while stirring and hydrogen chloride (0.78 kg, 21.4 mol) was transferred through the reaction mixture at a temperature of 20° C. to 25° C. The suspension was stirred for 3 hours at a temperature of 0° C. to 5° C. and centrifuged. Isopropanol (35 L) was added to the humid solid in a reaction vessel and the reaction mixture was heated to reflux for 15 minutes. The reaction mixture was cooled to 0° C. to 5° C. and stirred for 3 hours at that temperature. After centrifugation the product was stored at 30° C. to 40° C. and 150 mbar for 16 hours in a drying oven. (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (4.18 kg, 88%) were obtained as a colorless solid with a purity of 100%.