Process for the preparation of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol

Patent metadata

Field	Value
Publication number	US-11739049-B2
Application number	US-202117142325-A
Country	US
Kind code	B2
Filing date	Jan 6, 2021
Priority date	Jul 24, 2006
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

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

First claim

What is claimed is:

1. A process for preparing (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof, comprising the steps of:
(a) reacting a compound of general formula (I),

wherein R represents —C 1-6 -alkyl, —C 3-8 -cycloalkyl, —C 1-3 -alkylene-phenyl, —C 1-3 -alkylene -naphthyl, tetrahydropyranyl or —C(═O)—C 1-6 -alkyl,
with ethyl magnesium halide in an inert reaction medium under Grignard conditions,
(b) converting the thus obtained compound of general formula (II),

wherein R has the above defined meaning,
to a compound of general formula (III),

wherein R has the above defined meaning,
optionally in the 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 the formula (IV),

and
(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 , wherein 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 3 , —C(═O)—C 2 H 5 , —C(═O)—CH(CH 3 ) 2 or —C(═O)—C(CH 3 ) 3 .

3. A process according to claim 1 , wherein the ethyl magnesium halide used in step (a) is the chloride or bromide.

4. A process according to claim 1 , wherein the inert reaction medium is selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl-methylether, diisopropylether or any mixture thereof.

5. A process according to claim 1 , wherein a compound of general formula (I) was obtained by (a′) reacting a compound of general formula (V),

wherein R represents —C 1-6 -alkyl, —C 3-8 -cycloalkyl, —C 1-3 -alkylene-phenyl, —C 1-3 -alkylene -naphthyl, tetrahydropyranyl or —C(═O)—C 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),

wherein R has the above defined meaning,
with D-(-)-tartaric acid, subsequent separation of the thus obtained salt and liberation of the corresponding compound of general formula (I) in the form of the free base.

6. A process according to claim 1 , wherein the converting 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),

wherein R represents —C 1-6 -alkyl, —C 3-8 -cycloalkyl, —C 1-3 -alkylene-phenyl, —C 1-3 -alkylene -naphthyl, tetrahydropyranyl or —C(═O)—C 1-6 -alkyl,
using a suitable catalyst in an inert reaction medium in the presence of hydrogen.

7. A process according to 127, wherein step b) is a direct replacement reaction of the OH group by H.

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

9. A process according to claim 8 , wherein R represents methyl, benzyl or tetrahydropyranyl.

10. A process according to claim 5 , wherein 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 3 , —C(═O)—C 2 H 5 , —C(═O)—CH(CH 3 ) 2 or —C(═O)—C(CH 3 ) 3 .

11. A process according to claim 10 , wherein R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or —C(═O)—CH 3 .

12. A process according to claim 11 , wherein R represents methyl, benzyl or tetrahydropyranyl.

13. A process according to claim 5 , wherein 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.

14. A process according to claim 6 , wherein 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 3 , —C(═O)—C 2 H 5 , —C(═O)—CH(CH 3 ) 2 or —C(═O)—C(CH 3 ) 3 .

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

16. A process according to claim 15 , wherein R represents methyl, benzyl or tetrahydropyranyl.

17. A process according to claim 6 , wherein after the dehydration step (b′) the hydrogenation in step (b″) is effected via homogeneous catalysis.

18. A process according to claim 6 , wherein the dehydration step (b′) is acid-catalysed.

19. A process according to claim 18 , wherein 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 claim 6 , wherein the hydrogenation of step (b″) is effected via heterogeneous catalysis.

21. A process according to claim 20 , wherein 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 claim 6 , wherein 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 claim 7 , wherein said direct replacement reaction is a one-pot reaction.

Assignees

• Gruenenthal Gmbh

Inventors

• Hell Wolfgang
• Zimmer Oswald
• Buschmann Helmut Heinrich
• Holenz Joerg
• Gladow Stefan

Classifications

• C07C213/00 Primary

  Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton · CPC title

• C07B57/00

  Separation of optically-active compounds · CPC title

• C07C213/08 Primary

  by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups · CPC title

• C07C221/00

  Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton · CPC title

• C07C215/54

  linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring · CPC title