Title of Invention

PROCESS FOR THE PREPARATION OF 2-{ (DIMETHYLAMINO) METHYL]-1-(3- METHOXY-PHENYL) CYCLOHEXANOL.

Abstract The invention relates to a method for the production of 2-|(dimethyIamino(methyl)- l-(3-methoxyphenyI)cyclohex-anol with high stereoselectivity and in high yield.
Full Text Process for the preparation of 2- [ (dimethylamino)methyl] -1-(3-methoxyphenyl)cyclohexanol
The invention provides a process for the preparation of 2-[ {dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol with a high stereoselectivity of the trans form from the enantiomers (1R,2R)- and (IS,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol.
Tramadol, which is called "trans isomer" for historical reasons and comprises the trans form from the enantiomers (1R,2R)- and (1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, has an analgesic action and is therefore employed as an analgesic.
As is known, 2- [(dimethylamino)methyl] -1- (3-methoxyphenyl)cyclohexanol can be prepared by a Grignard reaction of 2-[(dimethylamino)methyl]cyclohexanone and the Grignard compound of 3-bromoanisole. Both the cis and the trans form are formed in this reaction.

The trans form, called trans isomer in the following, comprises the R,R and S,S enantiomers with the following
two formulae:

2

The cis form, called cis isomer in the following, comprises the S,R and R,S isomers with the following two formulae:

In the preparation of tramadol with the aid of a Grignard reaction, a highest possible yield of the trans isomer, the tramadol Grignard base, is aimed for. The influence of solvents and salt additives on the diastereoselectivity in the Grignard reaction is already known in this context.
According to the doctrine of WO99/61405, a shift in the trans : cis isomer ratio from approx. 80:20 to 90:10 in the preparation of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol by the use of amine or ethers is described. However, the yield achieved is in some cases only comparable to a reaction without additions, and in some cases even significantly poorer.

3
Savelyev et al. (International Conference on Natural Products and Physiologically Active Substances, Novosibirsk, 30.11.-6.12.1998, poster) also describe an increase in the diastereoselectivity in the preparation of 2-[(dimethylamino)methyl] -1-(3-methoxyphenyl)cyclohexanol by addition of dioxanes, but the yield of cis and trans isomer of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol in total is impaired.
There was therefore the object of providing a process for the preparation of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol with a high stereoselectivity for the trans isomer and in high yields.
This object is achieved according to the invention by an
improved process for the preparation of 2-
[(dimethylamino)methyl] -1-(3-methoxyphenyl)cyclohexanol.
The invention therefore provides a process for the preparation of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol by a Grignard reaction of 2-
[(dimethylamino)methyl]cyclohexanone with the Grignard compound of 3-bromoanisole, working up of the reaction mixture and optionally purification of the corresponding cyclohexanol, characterized in that 2-
[(dimethylamino)methyl]cyclohexanone and the Grignard compound of 3-bromoanisole are reacted in a suitable solvent in the presence of an inorganic lithium salt and an -di- (C1-3) -alkoxy- (C1-C3) alkane.
Preferably, the Grignard compound of 3-bromoanisole is initially introduced into the reaction vessel in a suitable

4
solvent, an inorganic lithium salt and a corresponding dialkoxy compound are added to the solution, and the mixture is optionally subsequently stirred and then reacted with 2-[(dimethylamino)methyl]cyclohexanone.
The solution of the Grignard compound of 3-bromoanisole is preferably prepared by reaction of 3-bromoanisole with magnesium in a suitable solvent, particularly preferably directly before the reaction with the Mannich base.
The inorganic lithium salt is preferably employed in amounts of 0.5-1 equivalent, based on the 3-bromoanisole. Preferably, a lithium halide, particularly preferably lithium chloride, is used as the inorganic lithium salt.
The dialkoxyalkane is preferably added in amounts of 20-120 vol.%, based on the abovementioned solvent. 1,2-Dimethoxyethane is preferably used as the dialkoxyalkane.
The reaction of magnesium and 3-bromoanisole to give the Grignard compound is preferably carried out at a temperature of 50-100 °C.
An organic solvent is preferably used as the solvent for the Grignard compound, particularly preferably tetrahydrofuran.
The addition of the inorganic lithium salt, the dialkoxyalkane and 2-[{dimethylamino)methyl]cyclohexanone to the solution of the Grignard compound of 3-bromoanisole and the reaction are preferably carried out at a

5
temperature of 0-60 °C, particularly preferably at a temperature of 15-35 °C.
For working up of the reaction mixture, the reaction mixture is preferably introduced into cooled aqueous ammonium chloride solution and, after separation of the phases, the organic phase is freed from the solvent.
Surprisingly, by the procedure according to the invention it is possible to improve both the yield of the Grignard base and the stereoselectivity in favour of the desired trans isomer, i.e. to increase the trans : cis isomer ratio significantly with a high yield of the Grignard base.
The mixture of the diastereomeric Grignard bases obtained with the process according to the invention can be converted in a known manner, for purification and, in particular, separation of the trans isomer from the cis isomer, into the hydrochloride by reaction with hydrochloric acid and the tramadol hydrochloride can preferably be recrystallized from dioxane/water.
The desired trans isomer can of course be isolated by any conventional separation method from the Grignard base of the trans and cis isomer obtained according to the
invention.
The tramadol HCl obtained according to the invention can be employed as an analgesic active compound.

6
Examples Example 1
A) Grignard reaction
The reaction was carried out in a 90 1 tank. 1.46 kg (60 mol) magnesium filings were initially introduced into the reaction vessel and were heated thoroughly at 120 °C. After addition of 18 1 tetrahydrofuran, the mixture was heated up to an internal temperature of 55 °C and 0.5 kg 3-bromoanisole was added dropwise to start the reaction. After the Grignard reaction had started up, a further 10.73 kg (in total: 11.23 kg; 60 mol) 3-bromoanisole were added dropwise and the mixture was subsequently stirred.
The reaction product was then cooled to 25 °C, 1.91 kg (45 mol; 0.75 eq, based on the 3-bromoanisole) lithium chloride and 18 1 dimethoxyethane were added and the mixture was subsequently stirred for 30 min. 10.25 kg (66 mol) 2-[(dimethylamino)methyl]cyclohexanone were then added dropwise over the course of 2 h, the internal temperature being kept below 3 0 °C. After the addition, the mixture was subsequently stirred. The reaction mixture was introduced slowly into a cooled" ammonium chloride solution of 7.80 kg ammonium chloride in 28.5 1 water and the mixture was subsequently stirred for 0.5 h. After separation of the phases, the aqueous phase was extracted several times with tetrahydrofuran. The organic phases were combined and filtered over magnesium sulfate.
The solvent was then removed in vacuo, a red-brown coloured crude product of the cis and trans isomer of 2-

7
[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol being obtained.
Yield: 10.8 kg {68 % of theory, HPLC) trans/cis isomer ratio: 92 %:8 %
B) Hydrochloride precipitation
1 kg of the crude product of the cis and trans isomer obtained according to A) was dissolved in ether, and dry hydrogen chloride was added. The trans isomer of the hydrochloride of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol formed was separated practically completely from the cis isomer by recrystallization from dioxane/water.
Yield: 76 % of theory Comparison example 1
A) Grignard reaction
The reaction was carried out in a 90 1 tank. 1.46 kg (60 mol) magnesium filings were initially introduced into the reaction vessel and were heated thoroughly at 120 °C. After addition of 18 1 tetrahydrofuran, the mixture was heated up to an internal temperature of 55 °C and 0.5 kg 3-bromoanisole was added dropwise to start the reaction. After the Grignard reaction had started up, a further 10.73 kg (in total: 11.23 kg; 60 mol) 3-bromoanisole were added dropwise and the mixture was subsequently stirred.
The reaction product was then cooled to 25 °C, 1.91 kg (45 mol; 0.75 eq, based on the 3-bromoanisole) lithium

8
chloride and 14.7 1 tetrahydrofuran were added and the mixture was subsequently stirred for 30 min. 10.25 kg (66 mol) 2-[(dimethylamino)methyl]cyclohexanone were then added dropwise over the course of 2 h, the
internal temperature being kept below 3 0 °C. When the addition was complete, the mixture was subsequently stirred.
The reaction mixture was introduced slowly into a cooled ammonium chloride solution of 7.80 kg ammonium chloride in
28.5 1 water and the mixture was subsequently stirred for 0.5 h. After separation of the phases, the aqueous phase was extracted several times with tetrahydrofuran. The organic phases were combined and filtered over magnesium sulfate.
The solvent was then removed in vacuo, a red-brown coloured crude product of the cis and trans isomer of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol being obtained.
Yield: 10.8 kg (68 % of theory, HPLC) trans/cis isomer ratio: 83 %:17 %
B) Hydrochloride precipitation
1 kg of the crude product of the cis and trans isomer obtained according to A) was dissolved in ether, and dry hydrogen chloride was added. The trans isomer of the hydrochloride of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol formed was separated from the cis isomer by recrystallization from dioxane/water.
Yield: 60 % of theory

9
Example 2 and comparison examples 2 and 3
Further experiments were carried out in accordance with example 1 and comparison example 1 with and without lithium chloride or dimethoxyethane, the amounts of the reaction components and additives being shown in Table 1 together with an overview for example 1 and comparison example 1.

Table 1

THF = tetrahydrofuran DME = 1,2-dimethoxyethane

11
We Claim:
1. Process for the preparation of 2-[(dimethylamino)methyl]-l-(3-
methoxyphenyl) cyclohexanol by a Grignard reaction of 2-
[(dimethylamino) methyl] cyclohexanone with the Grignard
compound of 3-bromoanisole, working up of the reaction mixture
and optionally purification of the reaction mixture, characterized in
that 2-[(dimethylamino) methyl] cyclohexanone and the Grignard
compound of 3-bromoanisole are reacted in a suitable solvent in
the presence of an inorganic lithium salt and an -di (C1-3)-
alkoxy - (C1-C3)-alkane.
2. Process as claimed in claim 1, wherein the Grignard compound of
3-bromoanisole is initially introduced into the reaction vessel in a
suitable solvent, an inorganic lithium salt and an a, co-di (C1-3)-
alkoxy - (C1-C3)-alkane is added to the solution, and 2-
[(dimethylamino)methyl] cyclohexanone is added to the mixture
and reacted with the Grignard compound.
3. Process as claimed in claim 1 or 2, wherein the solution of the
Grignard compound of 3-bromoanisole has been prepared directly
before the Grignard reaction by reaction of 3-bromoanisole and
magnesium in a suitable solvent.

12
4. Process as claimed in one of claims 1-3, wherein the lithium salt is
employed in amounts of 0.5-1 equivalent, based on the 3-
bromoanisole.
5. Process as claimed in one of claims 1-4, wherein lithium chloride
is used as the lithium salt.
6. Process as claimed in one of claims 1-5, wherein the dialkoxy- a,
- alkane is added in amounts of 20-120 vol.%, based on the
solvent.
7. Process as claimed in one of claims 1-6, wherein 1,2-
dimethoxyethane is used as the dialkoxyalkane.
8. Process as claimed in one of claims 1 -7, wherein tetrahydrofuran is
used as the solvent.
9. Process as claimed in one of claims 1-8, wherein the Grignard
reaction is carried out at a temperature of 0-60°C.
10. Process as claimed in claim 8, wherein the Grignard reaction is
carried out at a temperature of 15-35°C.

13
11. Process as claimed in one of claims 1-8, wherein the preparation of
the Grignard compound is carried out at a temperature of 50-
100°C.
12. Process as claimed in one of claims 1-11, wherein for working up,
the reaction mixture is introduced into cooled ammonium chloride
solution and, after separation of the phases, the organic phase is
freed from the solvent.
13. Process for the preparation of tramadol HC1 as claimed in one of
claims 1-12, wherein, to separate off the trans isomer (tramadol),
the worked-up reaction mixture is treated with hydrochloric acid
and the hydrochloride is recrystallized from dioxane/water.
The invention relates to a method for the production of 2-|(dimethyIamino(methyl)- l-(3-methoxyphenyI)cyclohex-anol with high stereoselectivity and in high yield.

Documents:

00363-kolnp-2005-abstract.pdf

00363-kolnp-2005-claims.pdf

00363-kolnp-2005-correspondence.pdf

00363-kolnp-2005-description(complete).pdf

00363-kolnp-2005-form-1.pdf

00363-kolnp-2005-form-18.pdf

00363-kolnp-2005-form-2.pdf

00363-kolnp-2005-form-3.pdf

00363-kolnp-2005-form-5.pdf

00363-kolnp-2005-letters patent.pdf

00363-kolnp-2005-others.pdf

00363-kolnp-2005-priority document.pdf

363-KOLNP-2005-FORM-27.pdf

363-kolnp-2005-granted-abstract.pdf

363-kolnp-2005-granted-claims.pdf

363-kolnp-2005-granted-correspondence.pdf

363-kolnp-2005-granted-description (complete).pdf

363-kolnp-2005-granted-form 1.pdf

363-kolnp-2005-granted-form 18.pdf

363-kolnp-2005-granted-form 2.pdf

363-kolnp-2005-granted-form 26.pdf

363-kolnp-2005-granted-form 3.pdf

363-kolnp-2005-granted-form 5.pdf

363-kolnp-2005-granted-letter patent.pdf

363-kolnp-2005-granted-reply to examination report.pdf

363-kolnp-2005-granted-specification.pdf

363-kolnp-2005-granted-translated copy of priority document.pdf


Patent Number 213652
Indian Patent Application Number 363/KOLNP/2005
PG Journal Number 02/2008
Publication Date 11-Jan-2008
Grant Date 09-Jan-2008
Date of Filing 08-Mar-2005
Name of Patentee GRUNENTHAL GMBH.
Applicant Address ZIELLERSTRASSE 6, 52078 ASCHEN
Inventors:
# Inventor's Name Inventor's Address
1 FINKAM, MICHAEL SALIERLLE 18, 52066 AACHEN,
2 AKTERIES FRANZ WALLRAFF STRASSE 169, 52078 GERMANY
PCT International Classification Number CO7B 49/00
PCT International Application Number PCT/EP03/008746
PCT International Filing date 2003-08-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 102 36510.5 2002-08-09 Germany