FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of O-desmethyl-venlafaxine a vcnlafaxine metabolite, and its pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
O-Desmethyl-venlafaxine of formula I, is a major metabolite of venlafaxine and has been shown to inhibit norepinephrine and serotonin uptake and is chemically named as 1 -[2-(dimethylamino)-1 -(4-phenol)ethyl]-cyclohexanol.

(Formula Removed) Formula I
O-Desmethyl-venlafaxine was first disclosed in U.S. Patent No. 4,535.186 wherein it is exemplified as a tumarate salt. The process for the preparation of O-desmethyl-venlafaxine includes the reaction of p-benzyloxyphenylacetic acid with dimethyl amine in the presence of oxalyl chloride to obtain 4-benzyloxy-N,N-dimethy]benzenc acetamide which is further reacted with cyclohexanone in the presence of butyl lithium at a temperature of-70°C to yield l-[(4-benzyloxyphenyl)[(dimethyamino) carbonyl]methyl]cyclohexanol which is then hydrogenated using lithium aluminium hydride to 1 -[1 -(4-benzyloxyphenyl)-2-(dimethylamino)ethyl]cyclohexanol. The resulting benzyl analogue is debenzylated using palladium on carbon as disclosed in the following scheme:


(Formula Removed) Formula-l
The above process involves the use of n-butyl lithium and lithium aluminium hydride for the preparation of 0-desmethyl-venlafaxinc, which are not advisable for use on commercial scale and are very expensive.
U.S. patent no. 6,673,838 claims a process of preparing O-desmethyl-venlafaxine by demethylating venlafaxine with high molecular weight alkane, arene or arylalkyl thiolate anion such as straight or branched chain thiolate anions having 8-20 carbon atoms, mono or bicyclic arene thiolate anions having 6 to 1 0 carbon atoms, or mono or bicyclic arylalkyl thiolate anions having 7 to 12 carbon atom, which are very expensive and are not commercially available, hence unviable for industrial use. This patent also discloses demethylation of venlafaxine with an alkali metal salt of a trialkylborohydrides such as selectride (tri-sec-butylborohydride) or triethylborohydride. These reagents are also very costly and are difficult to use on industrial scale. Further the use of trialkylborohydrides are not advisable as these hydrides produce hazardous boron containing byproducts such as tris (I-
methylpropyl)borane and tris(l-methylpropyl)boroxin which have to be oxidized using oxidizing agents viz. alkaline perborate solution, thereby increasing the cost and time cycle of the manufacturing process.
U.S. patent application no. 2002/0086904 discloses a process of preparing O-desmethyl-venlafaxine by demethylating venlafaxine with diphenylphosphide in tetrahydrofuran (generated by adding n-butyl lithium to diphenylphosphine in tetrahydrofuran below 0°C) at reflux for an overnight period. Diphenylphosphine and n-butyl lithium are moisture sensitive, difficult to handle and are not industrially friendly. Furthermore, the method involves extraction steps using large volumes of solvent.
It is well known that dcmethylation of 0-methyl derivatives having tert-alcohol under acidic reaction conditions like using hydrobromic acid, aluminium triiodide. trimethylsilyliodide etc. may lead to formation of side product such as dehydrated analogues. Therefore it is not advisable to use acidic reaction conditions to accomplish demethylation of venlafaxine. In our hands also we have observed formation of lot of impurities when demethylation of venlafaxine was attempted using trimethylsilyliodide. The purity of resulting product does not meet the strict requirements imposed either by the pharmacopia or health authorities and quality directives. Thus the preferred reaction conditions to conduct demethylation of venlafaxine can be under basic reaction medium.
It is, therefore, desirable to solve the problems associated with the prior art and to provide an efficient process for the preparation of O-desmethyl-venlafaxine which improves the economics by employing easily available, less expensive and less hazardous raw materials and avoid using corrosive and harmful acidic reagents as well as stringent reaction conditions.
The present invention provides an industrially advantageous process of making O-desmethyl-venlafaxine in high yield and purity by demethylation of venlafaxine using mild reaction conditions, cheap and less hazardous reagents. The process of present invention is convenient to operate on a commercial scale and gives the desired product in good yield and quality.
SUMMARY OF THE TNVENTTQN
The present invention provides a method of making O-desmethyl-venlafaxine of Formula T. or its pharmaceutically acceptable salts.

(Formula Removed) Formula I
comprising demethylating venlafaxine of Formula II. or its pharmaceutically acceptable salts.
(Formula Removed) Formula II
using alkali metal sulphide under mild reaction conditions.
BRIEF DESCRIPTION OF THE DRAWINGS
FTG. 1 shows a powdered X-ray diffraction pattern (PXRD) of O-desmethyl-venlafaxine.
FIG.2 shows the differential scanning calorimetric thermogram (DSC) of O-desmethyl-venlafaxine.
FIG.3 shows an Infra-red spectrum (IR) of O-desmethyl-venlafaxine. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of O-desmethyl-venlafaxine of Formula I, or its pharmaceutically acceptable salts.
(Formula Removed) Formula I
by demethylation of venlafaxine of Formula II.
(Formula Removed) Formula II
or its pharmaceutically acceptable salt thereof using mild demethylating agents like alkali metal sulphide under mild reaction conditions.
The starting material, vcnlafaxinc or pharmaceutical ly acceptable salts thereof may be procured from the market or may be prepared in accordance with procedures known in the art such as there described in U.S. Pat, Nos. 4. 535. 186. and 5,043.466 and PCT application WO 2007/049302.
The pharmaceutically acceptable acid addition salts of the starting material, venlafaxine are formed conventionally by reaction of the tree base with an equivalent amount of corresponding acid. The acids are either inorganic or organic, including hydrochloric, hydrobromic, fumaric, maleic, succinic, sulfuric, phosphoric, tartaric. acetic, citric, oxalic and similar acids.
In accordance with the present invention, demethylation of venlafaxine or pharmaceutically acceptable acid addition salt thereof is performed using alkali metal sulphide. Alkali metal sulphides are readily available, less expensive and industrially viable. The formation of side products is minimized by using alkali metal sulphide and hence the final product is obtained in good yield and purity. The appropriate alkali metal sulphide can be selected from sodium sulphide, potassium sulphide, lithium sulphide and the like or mixture thereof. Preferably sodium sulphide is used. In the preferred embodiment of the present invention, alkali metal sulphide is taken as 2-12 mole equivalents, preferably 2.5- 4.0 mole equivalents.
In the preferred embodiment of the present invention, venlafaxine base or pharmaceutically acceptable acid addition salt thereof is dissolved in a suitable solvent and stirred at ambient temperature. The solvent employed is preferably high boiling solvent selected from, but not limited to N-methyl-2-pyrrolidone, N', N'-dimethylacctamidc, N,N-dimethylformamidc. the like and mixtures thereof Preferably the solvent employed is N-methyl-2- pyrrolidone.
During demethylation of venlafaxine base or its pharmaceutically acceptable salt viz. hydrochloride salt using sodium sulphide in solvents like N-methyl-2-pyrrolidone, it is observed that the by-products like venlafaxine-N-oxide or O-desmethyl-venlafaxine-N-oxide so formed are found to be nearly absent after workup. In the final product, these impurities are formed in amount less than 1%. preferably less than 0.5%, most preferably less than 0.1%.
The reaction can be performed in the presence or absence of catalyst. The catalyst employed can be selected from amongst, but not limited to telrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulphate. crown ethers like 15-crown-5. 18-crown-6. and the like. Preferably the catalyst employed is tetrabutylammonium bromide. The reaction is performed at a temperature of from about 110°C to about 180°C, more preferably from about 130°C to about 170°C, and most preferably from about 150°C to about 160°C.
The reaction mass is stirred for few minutes to few hours, preferably the reaction mass is stirred for a period of about 10-80 hours at 130-170 °C. Most preferably the reaction mass is stirred for a period of about 30-55 hours at 150-16()°C. The reaction completion can be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) for the presence or absence of starting material. The reaction is generally conducted until, ideally, not more than 1 % of the starting material remains. In some aspects of the invention the reaction is completed over a period of about 10 hours to 100 hours and more preferably about 20 to 60 hours and most preferably from 30-55 hours. After completion of the reaction, the solvent is recovered under vacuum.
Tn another embodiment of the present reaction, the isolation of O-desmethyl-venlafaxine from reaction mass can further be performed in two ways. According to one aspect of the present invention, the pH of the reaction mass, after solvent
recovery, is adjusted to 8.5-10 with mineral acid. The pH is preferably adjusted to 8.7-9.3 with concentrated hydrochloric acid. The precipitated solid is further stirred for few minutes to few hours, preferably 1 hour at a temperature of below 20oC and isolated.
According to yet another aspect of the present invention, the pH of the reaction mass is adjusted to 1-2 with mineral acid. The pH is preferably adjusted to 1.2-1.4 with aqueous 5N-hydrochloric acid. The aqueous layer is washed with dichloromethane and treated with adsorbent to assist in impurity removal; it is effective to treat the substrate with active charcoal. After charcoalization, the pH of the aqueous layer is adjusted to 8.7 with suitable base selected from salts of alkali metal such as bicarbonatcs or carbonates or hydroxides at a temperature of below 20 C. preferably 10-15 C. Preferably saturated aqueous potassium carbonate solution is used. The precipitated solid is further stirred for a period of 1 hour at a temperature of below 20oC, preferably 10-15°C and then isolated. Product can be isolated by the methods known in prior art preferably by filtration. However, other equivalent separation or isolation procedures could, also be used. The wet solid is then washed with demineralized water to give pure O-desmethyl-venlafaxine.
(Formula Removed) Formula III
It is generally observed that under acidic conditions, O-desmethyl-venlafaxinc is dehydrated to give 4-(l-cyclohex-l-enyl-2-dimethylamino-ethyl)-phenol of formula III,
as an impurity. But in our hands, following the procedure reported in the present invention, the product is found to be free from the above impurity up to an amount less than 1%. preferably less than 0.5%, most preferably less than 0.1%.
According to yet another aspect of the present invention, the O-desmethyl-venlafaxine so formed can optionally be purified with a suitable solvent to give O-desmethyl-venlafaxine in purity above 99% by HPLC. The solvent employed can be selected from, but is not limited to alcohol, esters, halogenated solvents, nitriles. ketones, aromatic hydrocarbon or mixtures thereof; preferably the solvent employed is selected from isopropyl alcohol, ethyl acetate or mixtures thereof.
The O-desmethyl-venlafaxine, so formed by the process of the present invention, is characterized by at least one of Karl Fisher or TGA, powdered X-Ray diffraction (PXRD), Infra-red spectroscopy (IR) or differential scanning calorimetry (DSC).
O-desmethyl-venlafaxine as prepared by the process of present invention is having about less than 0.7% moisture by weight as measured by Karl Fisher or Thermogravimetric analysis (TGA). Preferably, the moisture content is less than 0.5% by weight, most preferably less than 0.1% by weight. O-Desmethyl-venlafaxine so synthesi/ed displays X-ray powder diffraction pattern as shown in Fig.l. It further displays differential scanning calorimetric thermogram (DSC) as shown in Fig.2 with the onset temperature at 228°C. O-Desmethyl-venlafaxine is further characterized by an infra-red analysis and peaks are same as shown in Fig.3.
X-ray diffraction of O-desmethyl-venlafaxine is measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities. One ordinarily skilled in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation or other factors.
All infrared measurements are made on Perkin Elmer Spectrum 100 spectrometer using KBr pellets having the characteristic absorption bands expressed in reciprocal centimeter. DSC was conducted using a Metier Toledo DSC 823e a sample weight of about 4-5 mg.
O-Desmethyl-venlafaxine so formed can be converted to its pharmaceutically acceptable acid addition salt by suspending the free base of O-desmethyl-venlafaxine along with the corresponding acid in a suitable solvent for a time sufficient to convert to its pharmaceutically acceptable acid addition salt. Pharmaceutically acceptable acid addition salt includes inorganic or organic salt, selected from, but are not limited to, hydrochloric, hydrobromic, fumaric, maleic. succinic. tartarate. sulfuric. phosphoric, tartaric, acetic, and citric acid. Preferably O- dcsmcthyl-venlafaxinc is isolated as corresponding succinate salt.
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples. It is intended that the specification, including the examples, is considered exemplary only, with the scope and spirit of the invention being indicated by the claims which follow.
EXAMPLES:
EXAMPLE -1
Venlafaxine (25 g, 0.09 mol) and sodium sulphide (21.12 g, 0.27 mol) were suspended in N-methyl-2-pyrrolidone (250ml) at 25-30°C, heated to 150-155oC and the progress of the reaction was monitored by TLC. After completion of reaction, the solvent was recovered under vacuum to give a residue which was diluted with dcmincralized water (375 ml), and pH of the reaction mass was adjusted to 9.0 with
concentrated hydrochloric acid. The precipitated solid was stirred for 1 hour at 10-15°C and filtered. The wet solid was washed with demineralized water (3 x 375 ml) and recrystallized from a mixture of isopropyl alcohol (75 ml) and ethyl acetate (25ml) to give 16 g (yield 67.3%) of 0-desmethyl-venlafaxine as a white solid.
EXAMPLE -2
To a stirred suspension of venlafaxine (10 g, 0.036 mol) in 100 ml of N'.N'-dimethylacetamide, sodium sulphide (8.45 g, 0.11 mol) and tetrabutylammonium bromide (0.4 g) were added at 25-30°C. The reaction mixture was stirred at 150-155°C for 14 hours and the progress of the reaction was monitored by TLC. After completion of reaction, the solvent was recovered under vacuum to give a residue which was diluted with demineralized water (150 ml) and pH of the reaction mass was adjusted to 9.1 with cone, hydrochloric acid. The precipitated solid was stirred for 1 hour at 10-15oC, filtered, washed with demineralized water (3x150 ml.) and recrystallized from a mixture of isopropyl alcohol (30 ml) and ethyl acetate (10 ml) to give 4.5 g of O-desmethyl-venlafaxine as a white solid.
EXAMPLE -3
To a stirred suspension of venlafaxine (5 g, 0.018 mol) in 50 ml of N-methyl-2-pyrrolidone, sodium sulphide (4.22 g, 0.054 mol), tetrabutylammonium bromide (0.2 g) were added at 25-30 C. The reaction mixture was stirred at 150-155oC for 14 hrs and the progress of the reaction was monitored by TLC. The solvent was recovered under vacuum to give a residue which was diluted with demineralized water (75 ml) and pH of the reaction mass was adjusted to 9.3 with concentrated hydrochloric acid. The precipitated solid was stirred for 1 hour at 10-15°C and filtered. The wet solid was washed with demineralized water (3x50 ml.) and recrystallized from a mixture of isopropyl alcohol (15 ml) and ethyl acetate (5 ml) to give 2.0g (yield 42.1%) of O-desmethyl-venlafaxine as a white solid.
EXAMPLE -4
To a stirred suspension of venlafaxine hydrochloride (100 g, 0.32 mol) in 1. .0 L of N-methyl-2-pyrrolidone, sodium sulphide (99.6 g, 1.28 mol), was added at 25-30 C. The reaction mixture was stirred at 150-155oC for 14 hrs and the progress of the reaction was monitored by 1 LC. The solvent was recovered under vacuum to give a residue which was diluted with demineralized water (1.5 L) and pH of the reaction mass was adjusted to 9.2 with cone, hydrochloric acid. The precipitated solid was stirred for 1 hour at 10-15°C and filtered. The wet solid was washed with demineralized water (3x1.5 L) and recrystallized with a mixture of isopropyl alcohol (1.0 L) and ethyl acetate (1.0 L) to yield 51.0 g (yield 60.7%) of O-desmethyl-venlafaxine as a white solid.
EXAMPLE -5
To a stirred suspension of venlafaxine hydrochloride (50 g, 0.16 mol) in 500 ml of N-methyl-2-pyrrolidone, sodium sulphide (49.8 g, 0.64 mol) was added at 25-30 C. The reaction mixture was stirred at 150-155°C for 55 hours and the progress of the reaction was monitored by HPLC. The solvent was recovered under vacuum to give a residue which was diluted with demineralized water (750 ml) and pH of the reaction mass was adjusted to 1.3 with aqueous 5N-hydrochloric acid. The aqueous layer was washed with dichloromethane (3x100 ml) and the aqueous layer was treated with activated carbon. After filtration through hyfio the aqueous layer was cooled to 10-15° C was adjusted to 8.7 with saturated aqueous potassium carbonate solution at 10-15oC. The precipitated solid was stirred for 1 hour at 10-15°C and tillered. The wet solid was washed with demineralized water (3x100 ml) and purified from isopropyl alcohol (250 ml) to afford 30 g (yield 71.42%) of O-desmethyl-venlafaxine as a white solid having purity 99.54% by HPLC. EXAMPLE -6
To a stirred suspension of venlafaxine hydrochloride (200 g. 0.64 mol) in 1.6 L of N-methyl-2-pyrrolidone, sodium sulphide (199.14 g, 2.55 mol) and 15-crown-5 (0.05 g)
were added at 25-30°C. The reaction mixture was stirred at 150-155°C for 49 hours and the progress of the reaction was monitored by HPLC. The solvent was recovered under vacuum to give a residue which was diluted with demineralized water (3.0 L) and pH of the reaction mass was adjusted to 1.2 with aqueous 5N-hydrochloric acid. The aqueous layer was washed with dichloromethane (3x400 ml) and the aqueous layer was treated with activated carbon. After charcoalization and the aqueous layer was filtered there is hyflo, the aqueous layer was cooled to 10-15°C. The precipitated solid was stirred for 1 hour at 10-15oC and filtered. The wet solid was washed with demineralized water (3x400 ml) and purified with isopropyl alcohol (800 ml) to afford 135 g (yield 80.9%) of O-desmethyl-venlafaxine as white powder having purity 99.35% by HPLC.
EXAMPLE -7
To a stirred suspension of venlafaxine hydrochloride (300 g, 0.96 mol) in 2.41, of N-methyl-2-pyrrolidone and sodium sulphide (298.8 g, 3.82 mol) were added at 25-30oC. The reaction mixture was stirred at 160°C for 72 hours and the progress of the reaction was monitored by HPLC. The solvent was recovered under vacuum to give a residue which was diluted with demineralized water (4.5 L). The pH of the reaction mass was adjusted to 1.2 with aqueous 5N-hydrochloric acid. The aqueous layer was washed with dichloromethane (3x900 ml) and treated with activated carbon. After charcoalization and filtration through hyflo, the aqueous layer was cooled to 10-15° C was adjusted to 9.2 with saturated aqueous potassium carbonate solution at 10-15 C. The precipitated solid was stirred for 1 hour at 10-15°C and filtered. The wet solid was washed with demineralized water (3x900 ml) and purified from isopropyl alcohol (1500 ml) to afford 205 g (yield 80.9%) of O-desmethyl-venlafaxine as a white powder having purity 99.52% by HPLC.

WE CLAIM:
1.A process for the preparation of O-desmethyl-venlafaxine. namely 1-[2-(dimethy1amino)-l-(4-hydroxyphenyl)ethyl] cyclohexanol of formula I or pharmaccutically acceptable acid addition salt thereof,
(Formula Removed) Formula I

comprising demethylating venlafaxine of formula II,
(Formula Removed) Formula II
or pharmaccutically acceptable salts thereof using alkali metal sulphide in a suitable solvent at a temperature sufficient to form O-dcsmethyl-venlafaxinc and isolating O-desmethyl-venlafaxine there from and optionally converting the same to pharmaceutically acceptable acid addition salt.
2. A process according to claim 1, wherein alkali metal sulphide is selected from sodium sulphide, potassium sulphide, lithium sulphide, or the mixtures thereof.
3. A process according to claim 1, wherein the suitable solvent is selected from
N-methy1-2-pyrrolidone, N',N-dimethylacetamide. N',N-dimethylformamide.
the like and mixtures thereof.
4. A process according to claim 1, wherein the reaction is performed at a
temperature of from about 110°C to about 170°C, preferably from about
130°C to about 160°C, and most preferably from about 150°C to about 160°C.
5. A process according to claim 1, wherein the reaction can be performed in the
presence or absence of catalyst selected from amongst, tetrabutylammonium
bromide, tetrabutylammonium fluoride, tetrabutylammonium hydrogen
sulphate, crown ethers like 15-crown-5, 18-crown-6 and the like.
6. A process according to claim 1. wherein prior to isolation, the product is
treated with a mineral acid preferably hydrochloric acid to a pH of about 8.7-
9.3.
7. A process according to claim 1, wherein O-desmethyl-venlafaxine is isolated
by treating raw O-desmethyl-venlafaxine. preferably without separating it
from the reaction mixture, with a mineral acid, and then treating the resulting
salt with alkali metal or ammonium hydroxide, bicarbonate or carbonate.
8. A process according to claim 1, wherein the O-desmethyl-venlafaxine is
optionally purified using suitable organic solvent.
9. A process according to claim 1, wherein the O-desmethyl-venlafaxine is
purified using alcohol, esters, halogenated solvents, nitriles, ketones. aromatic
hydrocarbon or mixtures thereof, preferably the solvent employed is isopropyl
alcohol, ethyl acetate or mixtures thereof.
10. A process for the preparation of O-desmethyl-venlafaxine of formula 1 or pharmaceutically acceptable acid addition salt thereof.

(Formula Removed) comprising demethylating venlafaxine of Formula II,

or pharmaceutically acceptable salts thereof using alkali metal sulphide in a suitable solvent at a temperature sufficient to form O-desmethyl-venlafaxine and isolating O-desmethyl-venlafaxine therefrom and converting the same to pharmaceutically acceptable acid addition salt by conventional methods