Field of the invention
The present invention relates to an improved method for the synthesis of O-desmethyl-
venlafaxine (I) by demethylation of venlafaxine (II). This invention also relates to a novel
polymorph of crystalline O-desmethylvenlafaxine.

Background of the invention
O-Desmethylvenlafaxine [l-[2-(dimethylamino)-l-(4-phenol)ethyl]-cyclohexanol, CAS
registration no. 93413-62-8], an invention of American Home Products Corporation, is a
potent 5-HT reuptake inhibitor and useful as an antidepressant. It is an active metabolite
of venlafaxine [l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]-cyclohexanol, CAS
registration no. 93413-69-5], a popular drug of choice in the same therapeutic category.
Both O-Desmethylvenlafaxine and venlafaxine are covered in US 4,535,186. Example 26
of this patent discloses a method for the preparation of O-Desmethylvenlafaxine by
hydrogenolysis of l-[l-(4-benzyloxyphenyl)-2-(dimethylamino)ethyl]cyclohexanol; The
reaction involves catalytic debenzylation in presence of Pd/C. No process for the
preparation of O-Desmethylvenlafaxine from venlafaxine is disclosed herein.
However, there is another route of synthesis for the production of O-Desmethyl-
venlafaxine (I) is reported in the art that involves O-demethylation of venlafaxine (II),
represented herein as Scheme-1.

WO2000/076955 discloses the O-demethylation of separated R(-) and S(+) enantiomers
of venlafaxine using ethanethiol anion in presence of sodium hydride as base. The
process utilizes a mole ratio as high as 2.6 times of ethanethiol with respect to the pure
enantiomer of venlafaxine. Moreover ethanethiol being a low-boiling liquid (boiling
point 35°C) is presumably volatile at the specified reaction temperature of 150°C,
causing health hazards. This document, however, does not disclose a demethylation
process suitable for the production of (+) racemic O-Desmethylvenlafaxine.
US 6,348,494 mentions the O-demethylation of separated enantiomers of venlafaxine
using ethanethiol anion. This document, however, lacks enabling disclosure and thus the
methodology is not practically feasible.
US 6,673,838 and US 6,689,912 disclose and enable a process for O-demethylation of
venlafaxine for the preparation of O-desmethylvenlafaxine in presence of higher
molecular weight alkyl-, arene-, arylalkyl- thiolate anions, preferably alkane thiolate
anions having 10-20 carbon atoms. The most preferable such thiolate anion is disclosed
as dodecanethiolate. These patents further exemplified the process where such O-
demethylation is carried out with dodecanethiolate in presence of sodium methanolate or
sodium ethanolate as base.
The present inventors have carefully reproduced the teachings of the prior art processes
mentioned hereinbefore in the applicant's laboratory for the preparation of O-
desmethylvenlafaxine from venlafaxine. The results are summarized in the Table-1,
entries 1-3. It is noticed that all such demethylation processes mentioned hereinbefore
suffer from one or more of the following shortcomings:
(i) Use of highly moisture sensitive reagents like sodium hydride, methoxide or
ethoxide requires further precautionary measures like moisture proof
environment,
(ii) The process involves preparation of the thiolate anion in a separate reaction
vessel and hence is more complex during scale up.
(iii) The process involves use of reagents in high molar ratio with respect to the
substrate venlafaxine, thus increases cost,
(iv) The process involves use of pyrophoric and user-unfriendly reagents like
sodium hydride, which are expensive as well.
Despite the use of expensive chemicals in higher quantity, the prior art processes for
demethylation, when reproduced in the applicant's laboratory for the preparation of O-
desmethyl venlafaxine from venlafaxine, could merely provide reactant-to-product
conversion upto 84% with molar yield maximum upto 73%. The corresponding purity of
the isolated products for such processes is obtained not more than 98.2%. In some cases
the product also contains unreacted venlafaxine as the major impurity, which is present
upto 11.2%.
Hence there exists a need for providing an improved, industrially viable process for
producing O-Desmethylvenlafaxine by O-demethylation of venlafaxine.
Furthermore, none of the above mentioned prior arts disclose any polymorphic form of
O-desmethylvenlafaxine base.
The present inventors have surprisingly found a novel polymorph of O-
desmethylvenlafaxine when venlafaxine is subjected to the novel process of O-
demethylation of the present invention.
Objects of the Invention
Accordingly an object of the present invention is to provide an improved process for the
preparation of O-desmethyl venlafaxine from venlafaxine and a novel polymorph of O-
desmethylvenlafaxine by O-demethylation of venlaflaxine, using novel reagents.
Summary of the invention
Accordingly, in a major aspect the present invention provides an improved process for
the preparation of O-desmethylvenlafaxine from venlafaxine by O-demethylation of
venlafaxine, which comprises reaction of venlafaxine with a novel reagent selected from
dithiols, disulfides and amino thiol.
Another object of the present invention is to provide a process for the preparation of O-
desmethylvenlafaxine from venlafaxine by O-demethylation of venlafaxine with dithiols
like 1.2-ethanedithiol, such that the major impurity level comprising venlaflaxine is low.
Another object is to provide a process for the preparation of O-desmethylvenlafaxine
comprising the reaction of venlafaxine or an acid addition salt of venlafaxine with 2-
(diethylamino)ethanethiol in the presence of a base in a one-pot reaction.
Another object of the present invention is to provide a one-step process for the
preparation of O-desmethylvenlafaxine from venlafaxine.
In another major embodiment the present invention provides a novel polymorph of O-
desmethylvenlafaxine.
Brief description of the accompanying figures
Fig. 1: Powder X-ray diffraction pattern of the polymorphic Form A of O-
desmethylvenlafaxine of the present invention
Fig. 2: DSC thermogram of the polymorphic Form A of O-desmethylvenlafaxine of the
present invention
Fig. 3: IR spectrum of the polymorphic Form A of O-desmethylvenlafaxine of the
present invention
Detailed Description of the invention
The present inventors have developed an improved process for O-desmethyl venlaflaxine
from venlafaxine by O-demethylation of the former, employing a novel reagent. The O-
demethylation process of the present invention involves the use of commercially less
expensive, readily affordable as well as chemically safe reagents and chemicals, in lower
quantities, thus renders the process more cost effective, easily scalable and relatively
hazard-free.
According to the said process, both venlafaxine as well as an acid addition salt of
venlafaxine like venlafaxine hydrochloride are used as the starting material for the O-
desmethylation reaction. Thus the word "venlafaxine", as used herein, encompasses
venlafaxine free base as well as the acid addition salts of venlafaxine.
The preparation of O-desmethyl venlafaxine from venlafaxine by O-demethylation of
venlafaxine, is carried out by the reaction of venlafaxine with an O-demethylating agent
selected from dithiols disulfides and diamino thiol. The said O-demethylating agent is
used in the said reaction at an equimolar quantity to the substrate venlafaxine, or even
less, wherein the O-demethylating agent is a dithiol, especially 1,2-ethanedithiol.
However, the O-demethylating agent can be used in a molar ratio as high as five times
with respect to the said starting material, without affecting yield and purity of the
product.
In a preferred aspect, when the said O-demethylating agent is a dithiol, it is selected from
1,2-ethanedithiol and 1,3-propane dithiol.
In another preferred aspect, when the said O-demethylating agent is a disulfide, it is an
amino acid like L-cystein.
In a further preferred aspect the O-demethylating agent is a diamino thiol like 2-
(diethylamino) ethanethiol
In another preferred aspect of the present invention, the said O-demethylation reaction is
carried out using dithiols like 1,2-ethanedithiol as the O-demethylating agent at a molar
ratio between 0.5 and 1.2 with respect to the said starting material. Most preferably 1,2-
ethanedithiol and the starting material is used at an equimolar ratio to achieve the most
optimum yield and purity.
Preferably, the said method for O-demethylation of venlafaxine, comprises the reaction
of venlafaxine or an acid addition salt thereof with the said demethylating agent in the
presence of a base selected from alkali metal hydrides, hydroxides or carbonates such as
sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium
hydroxide, sodium carbonate, potassium carbonate, potassium tertiarybutoxide, sodium
tertiary butoxide and the like.
Preferably, the said O-demethylation reaction of the present invention is accomplished in
a high boiling liquid employed as medium, such as PEG 400.
The preferred temperature condition for the said O-demethylation reaction is at a higher
temperature, for example, 125°C to 185°C.
The O-demethylation process of the present invention is equally useful in obtaining any
of the pure enantiomers of O-Desmethylvenlafaxine from the corresponding enantiomer
of venlafaxine.
Yet in another aspect, the present invention provides an improved method for the
preparation of O-desmethylvenlafaxine from venlafaxine by O-demethylation,
comprising of the reaction of venlafaxine with the dithiolate anion wherein the said
dithiolate anion is generated in situ during the course of reaction, from the dithiol and the
base. Thus avoids the use of multiple reaction vessels as described in the prior art cited
hereinbefore.
For example, in one reaction vessel, Venlafaxine or any of its acid addition salts is taken
in PEG 400 and to the same vessel the dithiol and the base are added. The reaction mass
was then gradually heated to I00-200°C, preferably to 140-I90°C, and maintained at this
high temperature for about 12-36hrs. Thus, unlike the prior art described methods, when
the starting material is an acid addition salt of venlafaxine, the neutralization of the said
salt as well as in situ generation of the dithiolate anion take place in a single vessel.
Therefore, in a preferred embodiment, the process of the present invention provides a
one-pot reaction.
According to another preferred embodiment there is provided a process for the
preparation of O-desmethylvenlafaxine of formula I comprising the reaction of
venlafaxine of formula II or an acid addition salt of venlafaxine with 2-
(diethylamino)ethanethiol in the presence of a base in a one-pot reaction.
0-desmethylvenlafaxine so obtained by the process described hereinbefore may
optionally be purified further. In a preferred embodiment such a purification is carried out
by making an acid addition salt of the product O-desmethylvenlafaxine and subsequently
neutralizing the said salt. In a preferred embodiment such an acid addition salt of O-
desmethylvenlafaxine is a hydrochloride salt.
For example, O-desmethylvenlafaxine is taken in water and the pH of the mass is
adjusted to 1 - 5, preferably to 1.5 - 4, with an acid like cone. HCI. The undissolved
mass is removed; the residue is washed with dil. HC1, all fractions of the filtrate aqueous
layers are then combined and extracted with dichloromethane. The organic layer is
discarded as it contains impurities and the pH of the aqueous layer is adjusted to 11-14
using a base solution like aq. KOH solution. A clear solution results, which is then
extracted repeatedly with toluene. The organic layer contains the impurities and hence is
discarded. Finally, the pH of the aqueous layer is adjusted to 7 - 10, preferably at 9 - 9.5,
with cone. HC1 to precipitate the purified product.
It is surprisingly found that the crystalline O-desmethylvenlafaxine obtained in the
process of the present invention exists in the polymorphic form, "Form A". The said
Form A is characterized by powder X-ray diffraction (PXRD) pattern, differential
scanning calorimetry (DSC) and thermogravimetric analysis (TGA) data.
Thus the said crystalline Form A O-desmethylvenlafaxine is also characterized by the
PXRD pattern as in the Fig. 1. The characteristic peaks of the diffraction pattern is
observed at 2 theta values as follows:

The characteristic DSC thermogram of the crystalline Form A O-desmethylvenlafaxine of
the invention is shown in the Fig. 2. The characteristic DSC (25 °C to300 °C @ 10 °C/
min) peak is obtained in the range of 226-228°C with the onset at 223-224°C.
The said crystalline Form A O-desmethylvenlafaxine is also characterized by the IR
(KBr) absorption bands shown in the Fig. 3. The identifying peaks/bands are located at
cm"1 3114.5,2937.66, 1877, 1618, 1595, 1517, 1447, 1384, 1273, 1100, 569, 554.
The product O-Desmethylvenlafaxine obtained by the said process can be converted to its
pharmaceutically accepted salts by any method available in the literature. Preferable salts
for the intended purpose are fumarate and succinate. O-desmethylvenlafaxine obtained by
the process of the present invention and its pharmaceutically acceptable salts are suitable
for intended therapeutic use.
The invention is described below by the following non-limiting illustrative examples.
Example-1 : Preparation of O-desmethylvenlafaxine from venlafaxine
In a round bottom flask lOg Venlafaxine (0.036 mole) was taken in 100ml of PEG 400 at
25-30°C. To the same 3g (0.32 mole) of 1,2-ethanedithiol and 4g (0.07 mole) of
potassium hydroxide were added and the mixture was stirred for about 30mins. The
reaction mass was then gradually heated to 140-190°C and maintained at this temperature
under stirring for about 24hrs. The progress of the reaction was monitored by HPLC
whereupon the substrate-to-product conversion was obtained as 92%. After the
completion of the reaction, the reaction mass was cooled to 25-30°C and 100ml water
was added to the same. The reaction mass was extracted with toluene and the
corresponding organic layer was discarded. The aqueous part was then acidified by dilute
hydrochloric acid, further extracted with 50ml of dichloromethane and the corresponding
organic layer was discarded.
Finally, the pH of the residual aqueous layer was adjusted to 9-9.5 with dilute ammonia.
The precipitated mass was stirred at 25-30°C for about lhr and then filtered, washed with
50ml of water and finally dried.
Yield: 8.8g
Molar yield: 88%
Purity: 99.8%
Unreacted venlafaxine: not detectable
Example 2 : Preparation of O-desmethylvenlafaxine from venlafaxine
The process of preparation of O-desmethylvenlafaxine from venlafaxine with said O-
demethylation step is summarized in the Table-1
The entries 1,2,3 are prior art methods. The entries 4 and 5 are prepared according to the
process of present invention. The entry 5 being prepared as in example 1 while entry 4 is
prepared in same manner except using NaOH in place of K.OH.
It has been observed that the process of the present invention provides substrate-to-
product conversion ratio as high as 91% by in-process high performance liquid
chromatography. The said process also provides a high molar yield, for example, more
than 85%. The purity of the resultant O-desmethylvenlafaxine is found always more than
99% which is very high when compared to the prior art processes. It has also been
noticed that the resulting O-desmethylvenlafaxine contains even less than 0.1% of the
major impurity, which is none other than the starting material venlafaxine and present in
high amount when the said O-demethylation is carried out following prior art processes
Example 3 : Preparation of O-desmethylvenlafaxine from venlafaxine
In a round bottom flask, 25g (0.0797 mole) venlafaxine.HC1 was added to 175ml of PEG-
400, under N2-atmosphere, at 25-30 °C and stirred for l0min. To the same, 31.35gm
(0.559 mole) potassium hydroxide and 29.0 gm (0.0239 mole) L-cystine were added and
the mixture was stirred for about 30 min. The reaction mass was then gradually heated to
100-110°C and maintained at this temperature for 60-90 min. The temperature of the
reaction mass was further raised to 150-155°C and maintained for 45-50hr under constant
stirring. The progress of the reaction was monitored by HPLC whereupon the substrate-
to-product conversion was obtained as 60-65 %. After 45-50hrs, the reaction mass was
cooled to 55-65°C and 600 ml water was added slowly to the same. The reaction mass
was then cooled to 25-30°C under stirring and 125ml toluene was added to the same,
whereupon solid started precipitating out. The pH of the reaction mass was then adjusted
at 9-9.5 by dropwise addition of cone. HC1 at 25-30°C. The reaction mass was further
cooled to 0-5 °C and stir for lHr at this temperature to complete the precipitation. The
solid precipitate was filtered and washed with water (3x 50ml). The solid product, O-
desmethyl venlafaxine, was then dried under vacuum at 40-45 °C for about 12hr.
Net weight of the product = 18 gm.
HPLC purity = 86 %.

40ml of dimethylformamide (40ml) was taken in a reaction flask under nitrogen
atmosphere, 5.4g of Diethylaminoethanethiol.HCl at 25-30°C and stirred for 5 mins. The
reaction mass was cooled to 0-5°C and 8.1g of potassium ter-butoxide was added to the
same in one lot under stirring. The reaction mass was gradually warmed to room
temperature (25-30°C) and stirred for 15mins. To this 5.0g of venlafaxine base was added
in one lot followed by 10ml of dimethylformamide. The reaction mass to was heated
gradually to 140-145°C and stirred for 4-10 hrs. at 140-145°C. The progress of the
reaction was monitored by HPLC. The reaction was found to be completed within 4-
1 Ohrs at the specified temperature.
After completion of reaction the reaction mass was cooled to 25-30°C, diluted with
150ml of DM Water and the pH of resulted slurry was adjusted to 13-14 by adding
potassium hydroxide solid at 25-30°C to obtain a clear solution. Toluene was added
(50ml x 3times) to the mass and the impurities were extracted out maintaining the pH at
13-14 by additional usage of potassium hydroxide, as and when required.
The aqueous layer was retained and its pH was adjusted to 1.5-2.0 with cone. HC1
(~25ml) at 25-30°C. Dichloromethane was added to the mass and the impurities were
extracted (50ml x 3times) out maintaining the pH at 1.5-2.0 strictly.
The final aqueous layer was collected and its pH was adjusted to 9-9.5 with aq. ammonia
(~25ml) at 25-30°C whereupon the product O-desmethylvenlafaxine is found to be
precipitated.
The reaction mass was cooled to 0-5°C and stir for one hr. at 0-5°C. The product was
then filtered and washed with water (50 ml x 2times). The product was oven dried under
vacuum at 45-50°C to afford approx. 4g of O-desmethylvenlafaxine having moisture
content <1.0% w/w.
Example 5: Purification of O-desmethyivenlafaxine
In a round bottom flask, 18gm O-desmethyl venlafaxine obtained in the above Example 3
was taken in 250ml water and stirred for 10-15min at 25-30°C. The pH of the reaction
mass was adjusted to 2 - 3.5 by dropwise addition of cone HC1 at 25-30°C and then
stirred for 60 min. The undissolved mass was filtered out and the residue was washed
with 40 ml dil. HC1 (6N). All fractions of the filtrate aqueous layers were pooled and
repeatedly extracted with dichloromethane at 25-30°C. The organic layer was discarded.
The aqueous layer was then transferred to a round bottom flask and the pH was adjusted
to 13-14 using 20% aq. KOH solution. Stirred for 30-45 min at 25-30°C to obtain a clear
solution, which was then extracted repeatedly with toluene. The organic layej; was
discarded and the aqueous layer was then transferred to a round bottom flask. The pH of
the aqueous layer was adjusted to 9-9.5 with dropwise addition of cone. HC1 at 25-30°C .
Cooled the reaction mass to 0-5°C and maintained for 1 hr at this temperature under
stirring. Filtered the purified solid, repeatedly washed the cake on the filtration bed.
Finally, the product was dried under vacuum at 40-45°C till Moisture content< 1.0% w/w.
Wt of solid=13.5gm.
HPLC purity = >99 %.
We claim
1. A process for the preparation of O-desmethylvenlafaxine of formula I

comprising the reaction of venlafaxine of formula II or an acid addition salt of
venlafaxine with an O-demethylating reagent selected from a dithiol, a disulfide
and amino thiol.
2. The process as claimed in Claim 1, wherein the O-demethylating reagent is a
dithiol selected from 1,2-ethanedithiol and 1,3-propane dithiol.
3. The process as claimed in claim 1, wherein the disulfide is L-cystein.
4. The process as claimed in claim 1 wherein amino thiol is 2-
(diethylamino)ethanethiol
5. A process as claimed in claim 1, wherein the acid addition salt of venlafaxine is
venlafaxine hydrochloride.
6. A process as claimed in claim 1, wherein the reaction is effected in presence of a
base selected from alkali metal hydrides, hydroxides or carbonates.
7. A process as claimed in claim 6, wherein the reaction is effected in presence of a
base selected from lithium hydride, sodium hydride, potassium hydride, lithium
8. A process as claimed in claim 1, wherein the mole ratio of the O-demethylating
reagent is 0.5 to 5.0 with respect to O-desmethylvenlafaxine.
9. A process as claimed in claim 2, wherein the mole ratio of the O-demethylating
reagent is 0.5 to 1. 8 with respect to O-desmethylvenlafaxine.
10. A process as claimed in claim 1, wherein the temperature of the reaction is in the
rangeof l25-185°C.
11. A process for the preparation of O-desmethylvenlafaxine of formula I

comprising the reaction of venlafaxine of formula II or an acid addition salt of
venlafaxine with 1,2-ethanedithiolate anion in the presence of a base in a one-pot
reaction.
12. A process for the preparation of O-desmethylvenlafaxine of formula I

comprising the reaction of venlafaxine of formula II or an acid addition salt of
venlafaxine with 2-(diethylamino)ethanethiol in the presence of a base in a one-
pot reaction.
13. Polymorphic Form A of O-desmethylvenlafaxine.
14. Polymorphic Form A of O-desmethylvenlafaxine characterized by the following
powder X-ray diffraction pattern

15. Polymorphic Form A of O-desmethylvenlafaxine as claimed in Claim 14, further
characterized by DSC peak in the range between 226°C and 228°C.
16. Polymorphic Form A of O-desmethylvenlafaxine as claimed in Claim 15, further
characterized by the DSC onset temperature ranging between 223°C and 224°C.
17. Polymorphic Form A of O-desmethylvenlafaxine as claimed in Claim 1, further
characterized by IR peaks at about cm"1 3114, 2937, 1877, 1618, 1595, 1517,
1447, 1384, 1273, 1100, 569, 554.

A process for the preparation of O-desmethylvenlafaxine of formula I

comprising the reaction of venlafaxine of formula II or an acid addition salt of
venlafaxine with an O-demethylating reagent selected from a dithiol and a disulfide,
amino thiol. A process for the preparation of O-desmethylvenlafaxine of formula I
comprising the reaction of venlafaxine of formula II or an acid addition salt of
venlafaxine with 1.2-ethanedithiolate anion in the presence of a base in a one-pot
reaction. A process for the preparation of O-desmethylvenlafaxine of formula I
comprising the reaction of venlafaxine of formula II or an acid addition salt of
venlafaxine with 2-(diethylamino)ethanethiol in the presence of a base in a one-pot
reaction. Polymorphic Form A of O-desmethylvenlafaxine