FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. -"Novel Intermediates, Process For Their Preparation And Process For Preparation Of O-Desmethyl Venlafaxine By Using The Said Novel Intermediates"
2. Applicant(s)
(a) NAME: CALYX CHEMICALS AND PHARMACEUTICALS LTD.
(b) NATIONALITY: An Indian Company
(c) ADDRESS: A-37/38, MIDC Phase-I, Golavli, Kalyan-Shil Road, Dombivli (East)
Dist-Thane 421 203.
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

FIELD OF INVENTION
The present invention relates to a novel process for the preparation of 4-(2-(dimethylamino)-l-(l-hydroxycyclohexyl) ethyl) phenol, commonly known as O-desmethylvenlafaxine of formula I and pharmaceutically acceptable salts thereof.

formula I
The present invention also relates to the novel intermediates of formula VIA and formula VIIA and process for their preparation.
CH3
I


formula VIA

formula VIIA

The present invention particularly relates to a novel process for the preparation of O-desmethyl venlafaxine of formula I by employing the novel intermediates of formula VIA and formula VIIA.
BACKGROUND OF THE INVENTION
O-Desmethyl venlafaxine is a major metabolite of well known antidepressant drug venlafaxine. O-Desmethyl venlafaxine was first disclosed in EP112669. Succinate salt of O-desmethyl venlafaxine has been found to be a serotonin-norepinephrine


reuptake inhibitor (SNRI) and is pre-registered as a treatment for adult patients with major depressive disorder (MDD) in men and women and as a treatment for moderate to severe vasomotor symptoms (VMS) associated with menopause. It is also in phase II/III and phase III clinical trials to evaluate its potential use in fibromyalgia and neuropathic pain respectively.
Various methods are known for making O-desmethyl venlafaxine. Many of these processes start from venlafaxine in which O-desmethyl venlafaxine is obtained by demethylation of venalafaxine as shown in the scheme below.


MeO

The patent US6342533 describes demethylation of venlafaxine by reacting with lithium diphenylphosphide (prepared in situ from diphenyl methane and butyl lithium) in tetrahydrofuran to get O-desmethyl venlafaxine. The disadvantage of this process is very low concentration of the material in the solvent.
The patent US6689912 discloses the preparation of O-desmethyl venlafaxine by reacting venlafaxine with a high molecular weight alkane or arenethiolate anion in an alcohol such as ethylene glycol, polyethylene glycol, or their mixtures at 150-200 °C. The drawback of this process is the use of thiol derivatives which are not environment friendly and are hazardous.
The publication WO2007071404 describes a process for preparing O-desmethyl venlafaxine by demethylation of venlafaxine by using metal sulfide and optionally using selenium as a demethylating agent.


The above mentioned processes suffer from many drawbacks. Most of the prior art processes for the preparation of O-desmethyl venlafaxine start from venlafaxine.
The present inventors have surprisingly found out the new intermediates which can be easily and conveniently converted into O-desmethyl venalafaxine. The present inventors have also invented a novel process for preparing O-desmethyl venlafaxine using the aforesaid intermediates.
OBJECT OF THE INVENTION
It is an object of the present invention to provide a novel process for the preparation of O-desmethyl venlafaxine of formula I from 2-(4-methoxyphenyl)acetonitrile.
It is another object of the present invention to provide a novel intermediate of formula VIA.
It is yet another object of the present invention to provide a process for the preparation of the novel intermediate of formula VIA
It is yet another object of the present invention to provide a novel intermediate of formula VILA.
It is yet another object of the present invention to provide a process for the preparation of the novel intermediate of formula VILA.
It is yet another object of the present invention to provide a novel process for the preparation of O-desmethyl venlafaxine of formula I using the novel intermediates of formula VIA and formula VILA.


It is yet another object of the present invention to provide a novel process for the preparation of pharmaceutical salts containing O-desmethyl venlafaxine.
It is further object of the invention is to provide a cost effective process for the preparation of O-desmethyl venlafaxine.
SUMMARY OF THE INVENTION
The present invention provides a novel process for the preparation of O-desmethyl venlafaxine of formula I from 2-(4-methoxyphenyl)acetonitrile.

formula I
The present invention also provides a novel intermediate of formula VIA and a process for preparing the same.

formula VIA
wherein, R is methoxyethoxymethyl (MEM), methoxymethyl (MOM), aryloyl, arylsulfonyl, tetrahydropyranyl or substituted silyl.
The present invention also provides a novel intermediate of formula VIIA and a process for preparing the same.



formula VIIA
wherein, R is methoxyethoxymethyl (MEM), methoxymethyl (MOM), aryloyl, arylsulfonyl, tetrahydropyranyl or trimethylsilyl.
The present inventors have surprisingly found a novel process for the preparation of O-desmethyl venlafaxine by using novel intermediates of formula VIA and formula VIIA.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to a novel process for the preparation of O-desmethyl venlafaxine of formula I. The present invention further relates to the novel intermediates of formula VIA and formula VIIA and processes for their preparation.
The present invention particularly relates to a novel process for the preparation of O-desmethyl venlafaxine by using novel intermediates of formula VIA and formula VIIA.


The process of preparation of O-desmethyl venlafaxine is as depicted in Scheme-1:


formula II

Demethylation
HO

formula III

/>'

Base, THF,
Protecting reagent

RO

formula IV

S

Base, PTC


HN(Me)2.HCl, MeOH Pd catalyst, H2
formula VII
Deprotection

formula V
formula VI

HX

HO'

O-Desmethyl venlafaxine formula I

O-Desmethyl venlafaxine salt

wherein, R is a phenol protecting group, alkyl, aryl, aralkyl.
Scheme-1


According to an aspect of the present invention there is provided a novel process for the preparation of O-desmethyl venlafaxine of formula I

formula I
The preferred embodiment of the present invention comprises the following steps as stated herein:
i) converting 2-(4-methoxyphenyl)acetonitrile of formula II to 2-(4-
hydroxyphenyl)acetonitrile of formula III;
ii) reacting compound of formula III with protecting reagents to obtain
compound of formula IV;
iii) reacting compound of formula IV with cyclohexanone of formula V in
the presence of an organic or inorganic base and phase transfer catalyst
to obtain compound of formula VI;
iv) reacting compound of formula VI with dialkylamine and/or it's salt in
the presence of transition metal catalyst, in the presence of tertiary
amine or without adding tertiary amine, under hydrogen pressure at
room temperature or at an elevated temperature to obtain compound of
formula VII;
v) reacting compound of formula VII with a deprotecting reagent to
obtain O-desmethyl venlafaxine of formula I.
According to another aspect of the present invention is to provide a novel intermediate of formula VIA

formula VIA
wherein, R is methoxyethoxymethyl (MEM), methoxymethyl (MOM), aryloyl, arylsulfonyl, tetrahydropyranyl or substituted silyl.
According to yet another aspect of the present invention is to provide a process for the preparation of novel intermediate of formula VIA which comprises the following steps:
i) converting 2-(4-methoxyphenyl)acetonitrile of formula II to 2-(4-
hydroxyphenyl)acetonitrile of formula III;
ii) reacting compound of formula III with protecting reagents to obtain
compound of formula IV;
iii) reacting compound of formula IV with cyclohexanone of formula V in the presence of an organic or inorganic base and phase transfer catalyst to obtain novel intermediate of formula VIA.
According to yet another aspect of the present invention is to provide a novel intermediate of formula VIIA.

RO'
formula VIIA


wherein, R is methoxyethoxymethyl (MEM), methoxymethyl (MOM), aryloyl, arylsulfonyl, tetrahydropyranyl or trimethylsilyl.
According to the further aspect of the present invention is to provide a process for the preparation of novel intermediate of formula VIIA which comprises the following steps:
i) converting 2-(4-methoxyphenyl)acetonitrile of formula II to 2-(4-
hydroxyphenyl)acetonitrile of formula III;
ii) reacting compound of formula III with protecting reagents to obtain compound of formula IV;
iii) reacting compound of formula IV with cyclohexanone of formula V in the presence of an organic or inorganic base and phase transfer catalyst to obtain novel intermediate of formula VIA;
iv) reacting compound of formula VIA with dialkylamine and/ or its salt in the presence of transition metal catalyst, in the presence of tertiary amine or without adding tertiary amine, under hydrogen pressure at room temperature or at an elevated temperature to obtain compound of formula VIIA.
In the preferred embodiment of the present invention, 2-(4-methoxyphenyl)acetonitrile of formula II is converted to 2-(4-hydroxyphenyl)acetonitrile of formula III by using Aluminium chloride (A1C13) in hot toluene.
In another embodiment of the process, compound of formula III is protected by reacting with protecting reagents in the presence of base in presence of solvent such as THF.
The protecting reagent is selected from a group of well-known phenol protecting reagents comprising methoxyethoxymehylhalide, methoxymethylhalide, aryloylhalide, arylsulfonylhalide, dihydropyrane or trimethylsilylhalide,


alkylhalide, aralkyl. In the preferred embodiment, halide is selected from either chloride or bromide.
In the preferred embodiment of the present invention, the novel intermediate of formula VIA is obtained by the condensation reaction of compound of formula IV with cyclohexanone of formula V. The condensation reaction is carried out using organic or inorganic base and phase transfer catalyst in the presence of an inert solvent or without addition of solvent.
The organic or inorganic base is selected from a group comprising alkali metal hydroxide, alkaline earth metal hydroxide. In the preferred embodiment of the process, the base is alkali hydroxide, more preferably sodium hydroxide.
The phase transfer catalyst is selected from a group comprising quaternary ammonium salts, polyethylene glycols. In the preferred embodiment of the process, the phase transfer catalyst is quaternary ammonium salts, more preferably Tetrabutyl ammonium bromide (TBAB).
Futher, the novel intermediate of formula VIIA, is prepared from novel intermediate of formula VIA.
The reaction is carried out as the process disclosed in our pending application 1610/MUM/2006 which is incorporated herein by reference.
In the preferred embodiment of the present invention, the novel intermediate of formula VIA is reacted with a dialkylamine and/or its salt in the presence of transition metal catalyst, in presence of a tertiary amine or without adding tertiary amine, at room temperature or at an elevated temperature under hydrogen pressure to obtain novel intermediate of formula VIIA.


In the preferred embodiment of the process, dialkylamine is dimethylamine, more preferably dimethylamine hydrochloride.
The transition metal catalyst is selected from a group comprising palladium, platinum, rhodium, nickel. The catalyst is supported or unsupported. In the preferred embodiment of the process, the catalyst is selected from palladium oxide, palladium hydroxide or 5-20% palladium supported on carbon, alumina, calcium carbonate or barium sulphate,
Tertiary amine is selected from a group comprising trialkylamine, alkylarylamine, triarylamine. In the preferred embodiment of the process, the tertiary amine is trialkyl amine.
The reaction temperature is in the range of 25°-150° C.
Hydrogen pressure is from 1-20 Kg/cm2.
Intermediate of formula VII is then deprotected by using a deprotecting reagent and by adjusting pH to obtain O-desmethyl venlafaxine.
According to the present invention O-desmethyl venlafaxine is converted to its salt by well known prior art procedures.
Alternatively, O-desmethyl venlafaxine is also prepared by the process as shown in Scheme-2:


o


N
formula III

#

formula V
Base, PTC

HO'

formula VIII

HN(Me)2 HC1, MeOH, Pd catalyst, H2



HX

O-Desmethyl venlafaxine salt

formula I

Scheme-2
The invention is now demonstrated by the following non limiting illustrative example.
EXAMPLES
Example 1
Preparation of O-desmethyl venlafaxine from 2-(4-
methoxyphenyI)acetonitrile:
i) 2-(4-Hydroxyphenyl)acetonitriIe (formula III)
Anhydrous aluminium chloride (824g, 6.1796 moles) was added lot wise to the stirred solution of 2-(4-methoxyphenyl)acetonitrile (300g, 2.038 moles) in toluene


(1500 ml) over a period of 10 minutes. Reaction mixture was then gradually heated to 70°-75° C and was maintained for 3-4 hours. Reaction progress was monitored by TLC. After completion of reaction; it was quenched into ice cold water (3000 ml) and concentrated hydrochloric acid (400 ml). Toluene layer was extracted with ethyl acetate (2 x 1000 ml). Combined organic layer was washed with water (2 x 1500 ml).
The organic layer was dried over anhydrous sodium sulphate (50g). Organic layer
was distilled off under reduced pressure to obtain crude residue (235.Og). Above
crude residue was stirred with hexane (200 ml) for 30-45 minutes and brown
colored solid thus obtained was filtered out and washed with hexane (100 ml).
Finally pure compound was dried under high vacuum at room temperature for 3
hrs.
Yield: 215.0g (79.2%), HPLC Purity: 98.75 %.
ii) 2-(4-((2-Methoxyethoxy) methoxy) phenyl) acetonitirle (formula IV)
Sodium hydride (NaH) (25.2g; 65% dipersion in oil = actual 15.12g, 0.6302 moles) was washed with hexane (2 x 100 ml) under nitrogen atmosphere. Dry tetrahydrofuran (300 ml) was added to NaH and the suspension was cooled with stirring to 0°-5° C. A solution of 2-(4-hydroxyphenyl)acetonitirle (50g, 0.3755 moles) in dry tetrahydrofuran (150 ml) was added drop wise over a period of 1 hr at 0°-5° C. Reaction mixture was stirred for 25-30 minutes. Methoxyethoxymethyl chloride (MEM-C1) (59.2g, 0.4752 moles) in dry tetrahydrofuran (50 ml) was added drop wise at 0°-5° C over a period of 30 minutes and was stirred for further 15 minutes at the same temperature. Reaction mixture was then gradually warmed to 25°-30° C and stirred for another 24 hrs at room temperature. Reaction progress was monitored by TLC. After completion of reaction, it was quenched by drop wise addition of methanol (100 ml) at 0°-5° C. Reaction solvent was removed completely under reduced pressure and the residue was poured into ice-water (400 ml). Aqueous portion was extracted with ethyl acetate (3 x 200 ml). Combined organic layer was washed with water (200 ml) followed by brine (200 ml).


Organic layer was dried over sodium sulphate (50g). Solvent was distilled off under vacuum to obtain crude product (90g, HPLC purity: 95%). Crude product was then purified by flash column chromatography using ethyl acetate/hexane as a gradient eluent. Evaporation of the column fractions gave pure liquid compound. Yield: 72.25g (87%); HPLC purity: 97.18%
*H NMR in CDC13: 5 7.24 (dd, 2H, Ar-H), 7.06 (dd, 2H, Ar-H), 5.27 (s, 2H, -OCH20.), 3.82 (t, 2H,-OCH2), 3.69 (s, 2H,-CH2CN), 3.55 (t, 2H, -OCH2), 3.38 (s, 3H, -OCH3),
IR (KBr): 2926.01, 2893.22, 2249.0, 1612.49, 1512.19, 1454.33, 1367.53, 1309.67, 1282.66, 1228.66, 1103.28,999.13, 846.75, 813.96 cm"1.
GC-MS: 221 (M+), 89, 59 (100%).
iii) (l-Hydroxycyclohexyl)-(4-(2-methoxyethoxy)methoxy)phenyl acetonitrile (formula VI)
To the stirred solution of sodium hydroxide (10.4g, 0.26 moles) in water (300 ml) was added TBAB (3g, 0.0093 moles) and allowed to stir for 10 minutes at room temperature. A clear solution thus obtained was then cooled to 0°-5° C and mixture of cyclohexanone (30g, 0.1356 moles) was added dropwise over a period of 1 hr at 0°-5° C. Reaction mixture was then stirred for 10 hrs at 0°-5° C. Reaction progress was monitored by TLC as well as by HPLC. After completion of reaction, aqueous portion was extracted with ethyl acetate 3 x 200 ml). Combined organic layer was washed with water (200 ml) ollowed by brine (200 ml) and dried over anhydrous sodium sulphate (50g). Solvent was distilled off under vacuum to obtain crude oily product (46g, HPLC purity: 71%). Small amount of crude product was purified by flash chromatography using ethyl acetate/hexane as a gradient elent to prepare anlytical sample. Evaporation of the column fractions gave pure liquid compound.


(Note: Crude product with 71% purity was used as such for the next step.)
*H NMR in CDC13: 57.26 (d, 2H, Ar-H), 7.06 (d, 2H, Ar-H), 5.27 (s , 2H, -OCH20-), 3.82 (t, 2H,-OCH2), 3.74 (s, 1H, -CHCN), 3.56 (t, 2H, -OCH2), 3.37 (s, 3H,-OCH3), 1.83-1.50 (3 xm, 10H, 5 x-CH2).
13C NMR in CDC13: 5 157.42, 130.69, 125.01, 119.84, 116.38, 93.46, 72.74, 71.64, 67.79, 59.04, 49.42, 35.01, 34.87, 25.21, 21.58, 21.51.
IR (KBr): 3469.94, 3458.37, 3444.87, 2933.73, 2860.43, 2239.36, 1737.86, 1610.56, 1512.19, 1450.47, 1228.66, 1001.06, 989.48, 840.96,786.96, 540.07 cm"1
GC-MS: 221 (M+- cyclohexanone), 89, 59 (100%).
HPLC Purity: 99.27 %
iv) l-(2-(Dimethylamino)-l-(4-((2-methoxyethoxy) methoxy) phenyl) ethyl) cyclohexanol (formula VII):
To the stirred solution of (l-hydroxycyclohexyl)(4-(2-methoxyethoxy)methoxy) phenyl acetonitrile (6g, 0.01878 moles) in methanol (60.0 ml) was added dimethylamine hydrochloride (6.1g, 0.0748 moles) and stirred for 10 minutes at room temperature to form clear solution. Reaction mixture was purged with nitrogen and 10% palladium on carbon (1.2g, 50% wet) was added under nitrogen atmosphere. Reaction mixture was then purged with nitrogen (2 times) followed by hydrogen (2 times) and then allowed to stir under hydrogen balloon pressure for 12 hrs. Reaction progress was monitored by TLC as well as by HPLC. After 12 hrs reaction mixture showed 60% conversion to required product. Catalyst from the reaction mixture was filtered out through celite and washed with methanol. Combined filtrate was evaporated to dryness under reduced pressure to obtain thick residue. Above residue was poured into water (50 ml) and basified


with dilute sodium hydroxide to pH 8-10. Aqueous portion was then extracted with ethyl acetate (3 x 75 ml). Combined organic layer was washed with water (50 ml) followed by brine (50 ml). Organic layer was dried over anhydrous sodium sulphate (lOg). Solvent was distilled out completely under vacuum to obtain an oily residue (4.6g, HPLC purity: 62%). Crude product was then purified by flash column chromatography using methanol/ dichloromethane as a gradient eluent. Evaporation of the column fractions gave pure liquid compound.
Yield: 2.7g (43%), HPLC purity = >98%
*H NMR in CDC13: 5 7.05 (d, 2H, Ar-H), 6.96 (d, 2H, Ar-H), 5.26 (s, 2H, -OCH20-), 3.85-3.82 (m, 2H, -OCH2), 3.59-3.55 (m, 2H, -OCH2), 3.38 (s, 3H, -OCH3), 3.29 (t, 1H, -CHPh), 2.95 (dd, 1H, -CHN(Me)2), 2.33 (s, 6H, 2 x -NCH3), 2.28 (dd, 1H, -CHN(Me)2), 1.76-0.85 (3 x m, 10H, 5 x -CH2).
IR (KBr): 2935.66, 2858.51, 2825.72, 1610.56, 1510.26, 1465.9, 1224.80, 1103.28, 1008.77, 842.89 cm-'
v) 4-(2-(DimethyIamino)-l-(l-hydroxycyclohexyl)ethyl)phenol (O-desmethyl venlafaxine, formula I)
To the stirred solution of l-(2-(dimethylamino)-l-(4-((2-methoxyethoxy) methoxy)phenyl)ethyl) cyclohexanol (0.6g, 0.00170 moles), in dichloromethane (50 ml) was added trifluoroacetic acid (3 ml) in dichloromethane (3 ml) at 0°-5° C over a period of 5 minutes. Reaction mixture was continued to stir at the same temperature for 4-5 hrs. Reaction progress was monitored by TLC. After completion of reaction, pH was adjusted to 10-12 with dilute sodium hydroxide solution and stirred for 5 minutes. Dichloromethane layer was separated out to recover starting material. The pH of the aqueous layer was adjusted to 4-5 using dilute hydrochloric acid and again basified to pH 8-9 using aqueous sodium bicarbonate. This basic aqueous layer was extracted with dichloromethane (3x50


ml). Combined organic layer was washed with water (50 ml) followed by brine (50 ml).). Dichloromethane layer was dried over anhydrous sodium sulphate (5g). Solvent was distilled out completely under vacuum to obtain a product (0.41g, 91%). Crude product was then purified by flash column chromatography using methanol/ dichloromethane as a gradient eluent. Evaporation of the column fractions gave pure white solid.
Yield: 0.3 lg (70%); HPLC Purity: >98.0%
'H NMR in CDC13: 5 7.0 (d, 2H, Ar-H), 6.77 (d, 2H, Ar-H), 3.36 (t, 1H, -CHPh), 2.98 (dd, 1H, -CHN(Me)2), 2.50 (dd, 1H, -CHN(Me)2), 2.39 (s, 6H, 2 x -NCH3), 1.71-0.87 (4 xm, 10H, 5x-CH2).
13C NMR in CDCb: 5 155.0, 131.76, 130.27, 115.15,74.37,60.95,51.8-1,45.21, 37.54, 31.45, 29.70, 25.80, 21.50, 21.40.
IR (KBr): 2937.59, 1678.07, 1618.28, 1516.05, 1446.61, 1384.89, 1273.02, 1240.23, 1147.65, 962.48, 840.96, 732.95, 555.50 cm"1.
ESI-MS: 264.1 (M+l)+, 246.3.
vi) 4-(2-(Dimethylamino)-l-(l-hydroxycyclohexyl)ethyl)phenol succinate
(O-Desmethyl venlafaxine succinate salt)
To the sitrred solution of O-desmethyl venlafaxine (0.3g, 0.0011 moles) in methanol (7 ml) was added succinic acid (0.1345g, 0.0011 moles) and stirred at room temperature for 2-3 hrs. White solid which precipitaed out was filtered out and washed with methanol. Finally white solid was dried at 60° C under high vacuum. Yield: 0.4g (90%); HPLC purity: 98%.


!H NMR in DMSO-d6: 8 6.8 (d, 2H, Ar-H), 6.64 (d, 2H, Ar-H), 3.11 (dd, 1H, -CHPh), 2.74 (t, 1H, -CHN(Me)2), 2.59 (dd, 1H, -CHN(Me)2), 2.33 (s, 6H, 2 x -NCH3), 2.24 (s, 4H, 2 x COCH2-), 1.5-0.87 (2 x m, 10H, 5 x -CH2).
13C NMR in DMSO-d6: 5 174.67, 156.06, 131.16, 130.45, 114.83, 72.69, 60.14, 51.55, 45.07, 37.19, 32.86, 30.75, 25.88, 21.47.
IR (KBr): 3450.65, 2941.44, 2709.99, 2627.05, 1604.77, 1271.09, 952.84, 803.17,769.60,572.86 cm"1.
Example 2;
Preparation of O-desmethyl venlafaxine from 2-(4-
hydroxyphenyl)acetonitrile:
i)_2-(l-hydroxycyclohexyl)-2-(4-hydroxyphenyi)acetonitrile (formula VIII)
To the stirred solution of cyclohexanone (440.0g, 4.48 moles) and 2-(4-hydroxyphenyl)acetonitrile (200.0g, 1.498 moles) was added potassium tert-butoxide (156.0g, 1.39 moles) in lots at room temperature and reaction mixture was allowed to stir at room temperature for 4-6 hrs. Water (1000 ml) and ethyl acetate (1000 ml) were added to above reaction mixture and acidified with dilute HCl to pH 3-4. Organic layer was separated out and aqueous portion was extracted with ethyl acetate (500 ml). Combined ethyl acetate layer was washed with brine (500 ml) and dried over sodium sulphate. Solvent was evaporated under reduced pressure to obtain thick residue. Heptane (500 ml) was added to the residue and solvent was partially evaporated to obtain off-white solid. The crude off-white solid was purified using ethyl acetate (250 ml) at 50°-60° C. Solid was filtered out, washed with ethyl acetate and dried under vacuum at 50°-60° C for 2 hrs to obtain pure off-white solid. Yield: 197g(74%).
XH NMR in DMSO-d6: 5 9.49 (s, 1H, Ar-OH), 7.1 (d, 2H, Ar-H), 6.72 (d, 2H, Ar-H), 4.80 (s, 1H, -OH), 3.92 (s, 1H, -CHCN), 1.62-1.0 (m, 10H, 5 x -CH2).


13C NMR in CDC13: 8 157.06, 130.72, 123.41, 121.09, 114.94, 71.48, 48.03, 35.31,33.79,25.10,21.20,21.06.
IR (KBr): 3373.50, 3286.70, 2941.44, 2249.0, 1597.06, 1519.91, 1269.16, 966.34,837.11,696.3 cm-1
GC-MS: 231 (M+), 133 (100%), 99, 81, 55.
HPLC Purity: 98.57%
ii)4-(2-(Dimethylamino)-l-(l-hydroxycyclohexyl)ethyl)phenol
(O-desmethyl venlafaxine, formula I)
To the stirred solution of 2-(l-hydroxycyclohexyl)-2-(4-hydroxyphenyl)acetonitrile (20.0g, 0.0865 moles) in methanol (225.0 ml) was added dimethylamine hydrochloride (28.2g, 0.3458 moles) and stirred for 10 minutes at room temperature to form clear solution. Reaction mixture was purged with nitrogen and 10% palladium on carbon (4.0g, 50% wet) was added under nitrogen atmosphere. Reaction mixture was then purged with nitrogen followed by hydrogen and then allowed to stir under hydrogen balloon pressure for 12 hrs. Reaction progress was monitored by TLC as well as by HPLC. After 12 hrs the catalyst from the reaction mixture was filtered out through celite and washed with methanol. Combined filtrate was evaporated to dryness under reduced pressure to obtain crude residue. Above residue was poured into water (200 ml) and basified with sodium bicarbonate to pH ~8. Aqueous portion was then extracted with dichloromethane (3 x 75 ml). Combined organic layer was washed with water (100 ml) followed by brine (50 ml). Organic layer was dried over anhydrous sodium sulphate. Solvent was distilled out completely under vacuum to obtain crude product (17.0g). Crude product was purified by flash column chromatography using dichloromethane/methanol as a gradient eluent. Evaporation of the appropriate column fractions gave pure O-desmethyl venlafaxine. (l0.0g, >90% pure)


Example 3:
Prepration of O-desmethyl venlafaxine from 2-(l-hydroxycyclohexyl)-2-(4-
hydroxyphenyl) acetonitrile:
4-(2-(Dimethylamino)-l-(l-hydroxycyclohexyl)ethyI)phenol
(O-desmethyl venlafaxine, formula I)
To the stirred solution of 2-(l-hydroxycyclohexyl)-2-(4-hydroxyphenyl) acetonitrile (25.0g, 0.1081 moles) in methanol (250.0 ml) was added dimethylamine hydrochloride (35.26g, 0.4324 moles) and triethylamine (1.75 ml) and stirred for 10 minutes at room temperature to form clear solution. Reaction mixture was purged with nitrogen and 10% palladium on carbon (5.0g, 50% wet) was added under nitrogen. The reaction mixture was purged with nitrogen and allowed to stir under hydrogen pressure of 10 kg/cm2 at 80-100° C for 6 hrs. The progress of the reaction was monitored by TLC and HPLC. After 6 hrs, the catalyst from the reaction mixture was filtered out through celite and washed with methanol. Combined filtrate was evaporated to dryness under reduced pressure to obtain crude resdiue. Above residue was poured into water (250 ml) and basified with sodium bicarbonate to pH ~8. Aqueous portion was then extracted with dichloromethane (3 x 100 ml). Combined organic layer was washed with water (100 ml) followed by brine (50 ml). Organic layer was dried over anhydrous sodium sulphate. Solvent was distilled out completely under vacuum to obtain crude product which showed -42% of required product by proton NMR.