METHODS FOR PREPARING O-DESMETHYLVENLAFAXINE
This invention relates to methods for preparing O-desmethylvenlafaxine.
BACKGROUND OF THE INVENTION
O-desmethylvenlafaxine is a major metabolite of venlafaxine. Methods to
make O-desmethylvenlafaxine are described in U.S. Patent No. 4,535,186. This
method uses benzyl blocking groups leading to relatively low throughput.
A process of making O-desmethylvenlafaxine is also described in WO
00/59851 in which venlafaxine is allowed to react with diphenyl phosphide in THF
(generated by adding n-butyl thium in THF to diphenylphosphine in THF below 0°C)
at reflux for an overnight period. The yield was reported to be 73.8%. Furthermore,
the method involved extraction steps involving large volumes of solvent.
The present invention provides a process of making O-desmethylvenlafaxine
which is both time and material efficient.
DESCRIPTION OF THE INVENTION
In accordance with the present invention is provided a method of making O-
desmethylvenlafaxine comprising the steps of demethylating a compound of Formula I
to provide a compound of Formula II as described in Scheme I.


As described in Scheme I the starting material, venlafaxine (Formula I), is
demethylated. Venlafaxine may be prepared in accordance with procedures known in
the art such as described in U.S. Patent No. 4.535.186.
In accordance with the present invention, demethylation is performed using a
high molecular weight alkane, arene, or arylalkyl thiolate anion, such as straight or
branched chain alkane thiolate unions having 8 to 20 carbon atoms, mono or bicyclic
arene thiolate anions having 6 to 10 carbon atoms, or mono or bicyclic arylalkyl
thiolate anions having 7 to 12 carbon atoms in the presence of a protic or aprotic
solvent. Optionally, a base such as an alkoxide comprised of a straight or branched
chain alkyl group of from 1 to 6 carbon atoms may be present to generate the thiolate
anion.
Preferably the aliphatic thiol has from 10 to 20 carbon atoms and most
preferably the aliphatic thiol is dodecanethiol. The aromatic thiol is preferably
benzenethiol. The arylalkyl thiolate anion is preferably ∞-toluenethiol or
naphthylmethanethiol.
When present, the alkoxide is preferably a lower alkoxide, e.g., of 1 to 6 carbon
atoms (e.g., methoxide, ethoxide and the like) such as sodium methoxide (sodium
methylate, sodium methanolate).
The solvent is preferably a hydroxylic or ethereal solvent or mixtures thereof,
and more preferably an alcohol ethylene glycol or ether of ethylene glycol. Ethers of
ethylene glycol include, but Ere not limited to, ethylene glycol monoethyl ether,
triethylene glycol dimethyl ether and polyethylene glycol. Preferably, the solvent is an
inert, polar, high boiling point ether of ethylene glycol such as polyethylene glycol and
most preferably PEG 400 (polyethylene glycol having a molecular weight range of from
about 380-420).
The reaction is performed at a temperature of from about 150°C to about
220°C, more preferably from about 170°C to about 220°C, and most preferably from
about 180°C to about 200°C. The reaction is generally allowed to progress until,
ideally, not more than 1% venlafaxine remains. In some aspects of the invention the

reaction is complete in from about 2 hours to about 5 hours and more preferably in
from about 2 to about 3.5 hours.
The thiolate anion can be prepared separately or in situ. In some preferred
embodiments of the present invention, venafaxine base is dissolved in polyethylene
glycol 400 containing dodecanethiol and sodium methylate as a solution in methanol
as the temperature is increased to from about 180°C to about 200°C, with stirring for
about 2 to about 3.5 hours. In other preferred embodiments of the present invention,
venlafaxine base is dissolved in polyethylene glycol containing dodecanethiolate and
stirred for about 2 to about 3.5 hours at from about 180°C to about 200°C with stirring.
Conveniently the process may be carried out in a molar excess of thiolate,
preferably the molar ratio of thiclate to verlafaxine is up to about 3.0:1, e.g., in the
range from about 1.05:1 to about 2.8:1, preferably about 1.15:1 to about 2.5:1.
Thereafter the reaction mixture may be cooled to between about 65°C and
about 75°C and an alcohol may be added as a diluent before neutralization to the
isoelectric point (about pH9.5 to about pH10.0) with an appropriate neutralization
agent such as hydrochloric acid. The alcoholic medium may also aid in the
crystallization of the product as neutralization is initiated.
Preferably the alcohol comprises a straight or branched chain alkyl group of 1
to 6 carbon atoms, such as methanol, ethanol, isopropanol, butanol, and the like, and
mixtures thereof. In some preferred embodiments of the invention, the alcohol is
isopropanol.
Yields of the present invention are greater than about 75% and generally from
about 85% to greater than 90%.
The following Examples a e illustrative but are not meant to be limiting of the
present invention.

Example 1
Dodecanethiol (122 g), venlafaxine (111 g), and a methanolic solution of
sodium methanolate (30%, 90 g) and PEG 400 are heated to 190°C. The methanol is
distilled off and the solution is stirred 2 h at 190°C. Then the temperature is lowered, 2-
propanol (450 g) is added end the pH is adjusted to 9.5 with aqueous HCI. The
precipitate is collected by suction filtration, and the cake is washed with 2-propanol,
toluene, 2-propanol and water. The wet O-desmethylvenlafaxine is dried in vacuo.
Yield: 87g.
1H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ = 9.11 (s, br, 1H; OH), 6.98 (d,
br, J = 8.4, 2H; arom.), 6.65 (d, br, J = 8.4, 2H; arom.), 5.32 (s, br, 1H; OH), 3.00 (dd,
J = 12.3 and 8.5, 1H), 2.73 (dd, J = 8.5 and 6.3, 1H), 2.36 (dd, J = 12.3 and 6.3, 1H),
2.15 (s, 6H, 2 x Me), 1.7-0.8 (m, 10H, c-hex).
Example 2
Venlafaxine (5.6 g) and benzenethiol sodium salt(6.9 g) are charged to PEG
400 (25 g). The reaction mixture is heated to 160°C for 5 h. Then the temperature is
lowered and water is added (60 g). The pH is adjusted to 3.5 with H3PO4. The organic
by-products are removed by extraction with heptanes (25 g). The pH of the aqueous
layer is then adjusted to 9.5 with aqueous ammonia. The precipitate is collected by
suction filtration, re-slurried in water (100 g), isolated by suction filtration and dried in
vacuo.
Yield 1 g.
1H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ = 9.11 (s, br, 1H; OH), 6.98 (d,
br, J = 8.4, 2H; arom.), 6.65 (d, br, J = 8.4, 2H; arom.), 6.32 (s, br, 1H; OH), 3.00 (dd,
J = 12.3 and 8.5, 1H), 2.73 (dd, J = 8.5 and 6.3, 1H), 2.36 (dd, J = 12.3 and 6.3, 1H),
2.15 (s, 6H, 2 x Me), 1.7-0.8 (m, 10H, c-hex).
Example 3
Dodecanethiol (69 g) venlafaxine (55 g) and an ethanolic solution of sodium
ethanolate (21%, 82 g) are charged to a pressure vessel. The temperature is raised to
150°C and the reaction mixture is stirred for 2 days. Then the temperature is lowered
and the solution is filtered. The pH of the filtrate is adjusted to 9.5 with aqueous

hydrogen chloride. The crystals are collected by suction filtration. The cake is washed
with ethanol and dried in vacuo.
Yield: 42g
1H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ = 9.11 (s, br, 1H; OH), 6.98 (d,
br, J = 8.4,2H; arom.), 6.65 (d, br, J = 8.4,2H; arom.), 5.32 (s, br, 1H; OH), 3.00 (dd,
J = 12.3 and 8.5, 1H), 2.73 (dd, J = 8.5 and 6.3, 1H), 2.36 (dd, J = 12.3 and 6.3, 1H),
2.15 (s, 6H, 2 x Me), 1.7-0.8 (m, 10H, c-hex).
Example 4
Step a - Formation of the reagent sodium dodecanethiolate.
Dodecanethiol (246 g) and sodium methylate in methanol 30% (216 g) are charged to
a rotary evaporator. Vacuum is applied and the solvent is abstracted completely using
a bath temperature up to 90°G. The remaining sodium dodecanethiolate (272 g) is
used without further purification in the subsequent step.
Step b - Demethylation
A mixture of sodium dodecane hiolate (272 g) venlafaxine (256 g) and PEG 400 (185
g) is stirred 3 h at 190°C. Then the temperature is lowered and 2-propanol (915 g) is
added and the pH is adjusted to 9.5 with aqueous HCI. The precipitate is collected by
suction filtration, and the cake is washed with 2-propanol and water. The wet O-
desmethylvenlafaxine is dried in vacuo. Yield: 200 g.
1H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ = 9.11 (s, br, 1H; OH), 6.98 (d,
br, J = 8.4, 2H; arom.), 6.65 (d, or, J = 8.4,2H; arom.), 5.32 (s, br, 1H; OH), 3.00 (dd,
J = 12.3 and 8.5, 1H), 2.73 (dd, J = 8.5 and 6.3, 1H), 2.36 (dd, J = 12.3 and 6.3, 1H),
2.15 (s, 6H, 2 x Me), 1.7-0.8 (m 10H, c-hex).

WE CLAIM:
1. A method of preparing O-desmethylvenlafaxine which comprises reacting venlafaxine
with a high molecular weight a kane, arylalkyl or arene thiolate anion in a hydroxylic or
ethereal solvent, or mixture of hydroxylic or ethereal solvents, to provide O-
desmethylvenlafaxine.
2. The method as claimed in claim 1 wherein the solvent is an alcohol, ethylene glycol,
ether of ethylene glycol, or mixture thereof.
3. The method as claimed in claim 1 wherein the solvent is ethylene glycol monoethyl ether,
triethylene glycol, dimethyl ether or polyethylene glycol.
4. The method as claimed in claim 1 wherein the solvent is polyethylene glycol 400.
5. The method as claimed in claim 1 wherein the reaction is performed at about 150°C to
about 220°C.
6. The method as claimed in claim 1 wherein the reaction is performed at from about 170°C
to about 220°C.
7. The method as claimed in claim 1 wherein the reaction is performed at from about 180°C
to about 200°C.
8. The method as claimed in claim 1 wherein the reaction is carried out for about 2 to about
5 hours.
9. The method as claimed in claim 1 wherein the thiolate anion is a straight or branched
chain alkane thiolate anion having 8 to 20 carbon atoms.
10. The method as claimed in claim 1 wherein the alkane thiolate anion is dodecanethiolate.
11. The method as claimed in claim 1 wherein the thiolate anion is an arene thiolate anion
having from 6 to 10 carbon atoms.
12. The method as claimed in c laim 11 wherein the arene thiolate anion is benzenethiolate.
13. The method as claimed in claim 1 wherein the thiolate anion is generated in the presence
of an alkoxide.

14. The method as claimed in claim 13 wherein the alkoxide is methoxide.
15. The method as claimed in claim 1 which is carried out in a stoichiometric excess of
thiolate : venlafaxine up to about 3.0 :1.
16. The method as claimed in claim 15 in which the molar ratio of thiolate : venlafaxine is
from about 1.15 :1 to about 2.5 : 1.
17. The method as claimed in claim 1 further comprising neutralizing the product to the
isoelectric point in the presence of an alcohol comprising a straight or branched chain
alkyl group of from 1 to 6 carton atoms.
18. The method as claimed in claim 17 wherein the alcohol is isopropanol.
19. The method as claimed in claim 17 in which the reaction mixture is cooled to between
about 65°C and about 75°C before the an alcohol is added.
20. The method as claimed in claim 17 wherein the isoelectric point is from about pH 9.5 to
about pH 10.

The present invention provides an efficient method of preparing O-desmethylvenlafaxine.
The method invlolves demthylating venlafaxine
with a high molecular weight alkane, arylalkyl or arene thiolae anion in a
hydroxylic or ethereal solvent or a mixture of hydroxylic and ethereal
solvents. The method is illustrated by Scheme I as follows: