DESC:FIELD OF THE INVENTION
[0001] The present disclosure pertains to synthesis of organic compounds. In particular, the present disclosure pertains to a novel and efficient process for preparing 1-[2-(Dimethylamino)-1-(4-Methoxyphenyl)ethyl]cyclohexanol, also known as Venlafaxine, and its pharmaceutically acceptable salts such as hydrochloride. The process comprising preparation of intermediate (1-hydroxy cyclohexyl) (4-methoxyphenyl) acetonitrile via novel route and converting it into Venlafaxine free base or its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Venlafaxine, chemically “1-[2-(Dimethylamino)-1-(4-methoxyphenyl) ethyl] cyclohexanol” is used as Antidepressant. Venlafaxine selectively inhibits the neuronal uptake of serotonin-norepinephrine and to a lesser extent dopamine. Studies indicate that it has comparable or possibly slightly greater efficacy to other selective serotonin reuptake inhibitors (SSRI's). It appears to be as effective as standard antidepressants such as imipramine. Venlafaxine's unique chemical structure and neuro-pharmacological activity give it a broader spectrum of activity than other antidepressants. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder and social phobia. Venlafaxine marketed under the name Effexor, Effexor XR and Trevilor.
[0004] U.S. Pat. No. 4,535,186 describes a class of hydroxycyclo alkanephenethyl amines as being useful antidepressants and exemplifies the compound now known as Venlafaxine hydrochloride. In this patent, condensation of different arylacetonitriles with cyclohexanone reported using n-butyl lithium as the base at -70° C with <50% yield.
[0005] UK Patent No GB 2 227 743 A (1990) of Peter Gerald Shepherd discloses the condensation of 4-methoxyphenylacetonitrile with cyclohexanone using lithium diisopropylamide in hydrocarbon solvents like hexane, toluene or cyclohexane at ambient temperature thereby improving the yield to 79%.
[0006] U.S. Pat. No. 6,620,960B2 discloses the condensation of 4-methoxyphenylacetonitrile with cyclohexanone in the presence of an aqueous sodium hydroxide or potassium hydroxide and quaternary ammonium salt, a quaternary phosphonium salt or a crown ether as phase transfer catalyst.
[0007] U.S. Pat. No. 6,504,044 B2 discloses the condensation of different 1-[(cyano) aryl methyl] cyclohexanols with cyclohexanone using a base selected from the group consisting of sodium hydroxide and potassium hydroxide in water and in the presence of or absence of a phase transfer catalyst.
[0008] IN Patent IN194085 discloses the condensation of 4-methoxy phenylacetonitrile with cyclohexanone in the presence of alkali metal hydroxide in alcoholic solvent.
[0009] IN Patent IN213511 discloses the condensation of 4-methoxy phenylacetonitrile with cyclohexanone in the presence of alkali metal hydroxide or alkali metal alkoxide in lower aliphatic alcohol or ether solvent.
[0010] IN Patent IN191023 discloses the condensation of 4-methoxy phenylacetonitrile with cyclohexanone in the presence of alkali metal hydroxide or alkali metal carbonate in aqueous medium and in presence of phase transfer catalyst.
[0011] IN Patent IN226298 discloses the condensation of 4-methoxy phenylacetonitrile with cyclohexanone in the presence of alkali metal alkoxide in C1-C4alcoholic solvent.
[0012] The use of butyllithium or lithium diisopropylamide, causes great inconvenience in large-scale preparation since these are very hazardous. The need for setting up plants for operating at very low temperatures combined with the high cost of butyllithium & lithium diisopropylamide make these methods unacceptable for industrial preparations.
[0013] Although in the prior art references, various bases and different types of solvents are reported for condensing 4-methoxy phenylacetonitrile with cyclohexanone, but none of the reference discloses sodium sulfide in aqueous medium and moreover none of the reference discloses recycling of filtrate mother liquor.
[0014] Thus there is a need for an improved process for condensing 4-methoxy phenyl acetonitrile with cyclohexanone to prepare (1-hydroxy cyclohexyl) (4-methoxyphenyl) acetonitrile that avoids any hazardous and toxic chemicals. Also, the reaction should be easy to operate and eco-friendly with higher competitive yield.
[0015] Based on the further scope in the processes known in the prior art, it would be highly desirable to have an new process for the production of venlafaxine which is suitable for industrial use, simple, low-cost, highly efficient and environmentally friendly. The present invention provides a process, which is suitable on the above scales. Furthermore, the present inventors have intensively studied based on above mentioned findings and tried to complete the present invention more closely to green chemistry.
[0016] The present invention satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.

OBJECTS OF THE INVENTION
[0017] It is an object of the present disclosure to provide a novel and efficient process for preparing 1-[2-(Dimethylamino)-1-(4-Methoxyphenyl) ethyl] cyclohexanol, also known as Venlafaxine, and its pharmaceutically acceptable salts.
[0018] It is a further object of the present disclosure to provide a process for preparing intermediate (1-hydroxycyclohexyl)(4-methoxyphenyl)acetonitrile of formula-III via novel route using sodium sulfide (Na2S) as condensing agent in a suitable solvent without any adverse effect on yield, purity & stability of final compound.
[0019] It is another object of the present disclosure to provide a process for preparing Venlafaxine intermediate of formula-I, which is simple, safe, time saving, having convenient operational steps at commercial scale and environment friendly.
[0020] It is another object of the present disclosure to provide a process for preparing Venlafaxine intermediate of formula-I, which involves effective degree of required reaction completion resulting in competitive high yield of the intermediate of formula I with optimum purity at commercial scale.
[0021] It is another object of the present disclosure to provide a process for preparing Venlafaxine intermediate of formula-I which does not corrode the equipments used.

SUMMARY OF THE INVENTION
[0022] Aspects of the present disclosure relate to process for preparation of intermediate (1-hydroxycyclohexyl)(4-methoxyphenyl)acetonitrile of formula-I,

Formula I
wherein the process can include the step of: reacting a compound of formula (II)

Formula II
with a compound of formula (III)

Formula III
in presence of sodium sulfide.
[0023] In an embodiment, the compound of formula I can be prepared by reacting compound of formula II and compound of formula III in presence of sodium sulfide in an amount that can range from 0.15 mole to 0.5 mole, preferably 0.2 mole.
[0024] In an alternative embodiment, the compound of formula I can be prepared by reacting compound of formula II and compound of formula III in presence of sodium sulfide and a phase transfer catalyst.
[0025] In an embodiment, the phase transfer catalyst that can be used in the reaction can be selected from the group consisting of tetrabutylammonium hydrogensulphate, tetrabutylammonium bromide, tetrabutylammonium chloride, and tetrabutylammonium iodide and benzyltriethyl ammonium chloride.
[0026] According to embodiments of the present disclosure, the process for preparation of compound of formula I can include the steps of: combining in a solvent the compound of formula (II), the compound of formula (III); the sodium sulfide, and optionally a phase transfer catalyst to provide a reaction mixture, maintaining the reaction mixture under stirring for a time and at a temperature effective to form compound of formula (I); isolating the compound of formula (I); and purifying the isolated compound of formula I.
[0027] In an embodiment, the filtrate mother liquor of the condensation reaction can be recycled multiple times as such in same reaction repeatedly. The reuse of filtrate mother liquor can be valuable to reduce the effluent load on industrial scale and to make the process environment friendly.
[0028] In another embodiment, filtrate mother liquor of purification step can be recycled multiple times as such in same reaction repeatedly. The reuse of filtrate mother liquor can be valuable to reduce the effluent load on industrial scale and to make the process environment friendly.
[0029] In still another embodiment, the compound of formula-I can be converted into Venlafaxine free base or its pharmaceutically acceptable salts.
[0030] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION
[0031] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0032] Each of the appended claims defines a separate invention, which for infringement purposes is recognized as including equivalents to the various elements or limitations specified in the claims. Depending on the context, all references below to the "invention" may in some cases refer to certain specific embodiments only. In other cases it will be recognized that references to the "invention" will refer to subject matter recited in one or more, but not necessarily all, of the claims.
[0033] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0034] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0035] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
[0036] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0037] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0038] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0039] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0040] The present disclosure relates to a novel and efficient process for preparing an intermediate (1-hydroxycyclohexyl)(4-methoxyphenyl)acetonitrile of formula-I. Further, the present disclosure provides a process for preparing 1-[2-(Dimethylamino)-1-(4-Methoxyphenyl)ethyl]cyclohexanol, also known as Venlafaxine, and its pharmaceutically acceptable salts such as hydrochloride using the intermediate compound of formula I (Scheme 1).

[0041] For the purpose to implement an industrial process efficient, cost effective and with good yield and purity of the final product for the synthesis of venlafaxine, particular attention has to be given to the starting materials, solvents and reagents as well as to the reaction conditions of the all steps of synthesis.
[0042] At this purpose the applicant has developed novel process for the synthesis of Venlafaxine starting from the condensation of 4-methoxy phenylacetonitrile with cyclohexanone and further converting the resulting intermediate into Venlafaxine free base or its pharmaceutically acceptable salts by conventional methods. Condensation reaction as reported in this invention is environment friendly and economical. Reaction conditions are in consideration of the industrial need to operate in mild conditions and with easy available and easy to handle reagents. Therefore, it is an embodiment of the present invention to develop a process for the synthesis of (1-hydroxycyclohexyl) (4-methoxyphenyl)acetonitrile of formula I.
[0043] In an aspect, the present disclosure provides a process for preparation of intermediate (1-hydroxycyclohexyl)(4-methoxyphenyl)acetonitrile of formula-I,

Formula I
wherein the process can include the step of: reacting a compound of formula (II)

Formula II
with a compound of formula (III)

Formula III
in presence of sodium sulfide.
[0044] In an embodiment, the compound of formula I can be prepared by reacting compound of formula II and compound of formula III in presence of sodium sulfide in an amount that can range from 0.15 mole to 0.5 mole, preferably 0.2 mole.
[0045] In an alternative embodiment, the compound of formula I can be prepared by reacting compound of formula II and compound of formula III in presence of sodium sulfide and a phase transfer catalyst.
[0046] In an embodiment, the phase transfer catalyst that can be used in the reaction can be selected from the group consisting of tetrabutylammonium hydrogensulphate, tetrabutylammonium bromide, tetrabutylammonium chloride, and tetrabutylammonium iodide and benzyltriethyl ammonium chloride.
[0047] According to embodiments of the present disclosure, the intermediate compound of formula I can be prepared by following the steps of: combining in a solvent the compound of formula (II), the compound of formula (III), the sodium sulfide, and optionally a phase transfer catalyst to provide a reaction mixture; maintaining the reaction mixture under stirring for a time and at a temperature effective to form compound of formula (I); isolating the compound of formula (I); and purifying the isolated compound of formula I.
[0048] In an embodiment, the reaction mixture can be maintained under stirring at a temperature preferably ranging from -10°C to 25°C for a time period of 2 to 10 hours.
[0049] In an embodiment, the reaction between compound of formula III and compound of formula II can be effected at a temperature ranging from 0°C to 15°C. After the completion of reaction, the remaining reaction mixture can be filtered off to provide a wet cake and a filtrate. The wet can be dispersed in water and the resulting water dispersion can be acidified to a pH ranging from 6.5 to 7 to precipitate the compound formula I. An acid, preferably acetic acid, hydrochloric acid or sulphuric acid can be used for the acidification. The precipitated compound of formula I can be separated from the remaining reaction mixture in a solid state by filtration.
[0050] In an embodiment, the filtrate (i.e. mother liquor) left after separation of the precipitated compound of formula (I) can be recycled 4-5 times as such in same reaction repeatedly.
[0051] In an embodiment, the isolated compound of formula (I) can be subjected to a step of purification. The purification step can include combining the isolated compound of formula (I) and a solvent to provide a mass; heating the mass for a time and at a temperature sufficient to form a clear solution; cooling the solution to form a pure compound of formula (I); and separating the pure compound of formula (I).
[0052] In an embodiment, the filtrate mother liquor of purification step can be recycled multiple times (e.g. 4-5 times) as such in same reaction repeatedly.
[0053] In a preferred embodiment, compound of formula I can be prepared by following the steps of (i) combining in water the compound of formula II and compound of formula III at 25-30°C, (ii) adding a phase transfer catalyst and sodium sulfide to the combination to obtain a reaction mixture, (iii) maintaining the reaction mixture under stirring for a time and at a temperature effective to form compound of formula (I), and monitoring the reaction for completion by HPLC; (iv) filtering off the remaining reaction mixture to obtain a wet cake; (v) adding water to the wet cake and adjusting pH of the resulting aqueous dispersion in a range from 6.5 to 7 using an acid; (vi) filtering to provide a wet cake comprising a crude compound of formula I; (vii) adding toluene to the wet cake and raising the temperature to get a clear solution; (viii) separating the layers and cooling the organic layer to 0 to -5°C to precipitate pure compound of formula I; and (ix) separating the precipitated solid and drying to obtain pure compound of formula I.
[0054] According to embodiments of the present disclosure, the sequence of adding the compound of formula (II), formula (III), phase transfer catalyst, base and solvent as mentioned in above steps can be interchanged according to the suitability of the reaction conditions.
[0055] In accordance with embodiments of the present disclosure, intermediate (1-hydroxy cyclohexyl)(4-methoxyphenyl)acetonitrile of formula I can be obtained in a yield of over 95%, more preferably over 97%, with respect to the starting amount of the compound.
[0056] Intermediate (1-hydroxycyclohexyl)(4-methoxyphenyl)acetonitrile produced in accordance with the processes disclosed herein can have an assay of greater than about 99%, more preferably assay of greater than about 99.5%. Assay can be determined by HPLC, for example, or other methods known in the art.
[0057] In another aspect, the present disclosure provides a process for preparing venlafaxine or its pharmaceutically acceptable salts, wherein the process can include the steps of: (a) reacting a compound of formula (II)

Formula II
with a compound of formula (III)

Formula III
in presence of sodium sulfide to provide a compound of formula (I)

Formula I
(b) converting the compound of formula I into venlafaxine or its pharmaceutically acceptable salts by conventional methods.

EXAMPLES
[0058] The present disclosure is further explained in the form of following examples. However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.
EXAMPLE 1
Preparation of (1-hydroxycyclohexyl)(4-methoxyphenyl)acetonitrile
[0059] In a 1L RBF, charged 4-methoxyphenyl acetonitrile (100g; 0.680mol), cyclohexanone (75g; 0.765mol), tetrabutyl ammonium bromide (TBAB) (2.0g; 0.0062mol) and water (300ml). Stir the reaction mass for 10 min and cool to 5-10°C. Slowly added sodium sulfide (49g; 0.204mol) in lots in 0.5-1 h, maintaining 5-10 °C. After addition of sodium sulfide, maintained the reaction mass at 5-10 °C for 8-10 h. Added water (200ml) to reaction mass to get free flowing slurry. Monitor the reaction on HPLC till 4-methoxyphenyl acetonitrile content below 0.50%. Filter the reaction mass and washed with 50ml water to get wet cake (175-190g) (Keep the Filtrate mother liquor for further use.). Charged the wet-cake in another RBF and add water (500 ml). Stir at 23-25°C for 10 min and adjusted pH to 6.5-7.0 by acetic acid (0.4-0.6 ml). Again stir for 1h. Filter the reaction mass and washed with 50ml water to get crude titled compound as wet cake (180-190g).
EXAMPLE 2
Purification of (1-hydroxycyclohexyl)(4-methoxyphenyl)acetonitrile
[0060] Charged wet-cake (180-190 g) from Example-1 and toluene (300ml) in a 1L RBF attached with condenser. Heat the reaction mass to 70-75oC to get clear solution and allowed the layers to separate. Aqueous layer was removed and organic layer was allowed to naturally cool to room temperature. It was further cooled to -5 to 0°C, and maintained there for 2-3 h. Filtered the solid, and washed with toluene (2x30ml). (Filtrate mother liquor was stored and used as such at the same step of next batch.) Suck-dried well, unloaded the wet-cake and dried under vacuum for 8-10h at 40-45°C to get pure titled compound (154–159g).

EXAMPLE 3-6
Preparation of (1-hydroxycyclohexyl)(4-methoxyphenyl)acetonitrile by recycling of filtrate mother liquor of Example 1
[0061] Filtrate mother liquor of Example-1 was used as such in the same reaction and again repeated the same filtrate mother liquor in further reactions. The repetition of Filtrate mother liquor is valuable in reducing the effluent load on industrial scale and to make the process environment friendly. The results are summarized in the following table-1.
Table-1:
Example No. Remarks Out-put
(Wet)
Example 3 Same process followed as of Example-1 with same inputs of RMs except addition of sodium sulfide and TBAB. Filtrate mother liquor of Example 1 was used as such as aq. reaction medium. 178g
Example 4 Same process followed as of Example-1 with same inputs of RMs except addition of sodium sulfide and TBAB. Filtrate mother liquor of Example 3 was used as such as aq. reaction medium. 175g
Example 5 Same process followed as of Example-1 with same inputs of RMs except addition of sodium sulfide and TBAB. Filtrate mother liquor of Example 4 was used as such as aq. reaction medium. 188g
Example 6 Same process followed as of Example-1 with same inputs of RMs except addition of sodium sulfide and TBAB. Filtrate mother liquor of Example 5 was used as such as aq. reaction medium. 185g
(RMs=Raw materials)

EXAMPLE 7-10
Purification of (1-hydroxycyclohexyl)(4-methoxyphenyl)acetonitrile by recycling of filtrate mother liquor of Example 2
[0062] Filtrate mother liquor of Example-2 was used as such in the same reaction and again repeated the same filtrate mother liquor in further reactions. The repetition of Filtrate mother liquor is valuable in reducing the effluent load on industrial scale and to make the process environment friendly. The results are summarized in the following table-2.
Table-2:
Example
No. Remarks Out-put
(Dried) Assay by HPLC
Example 7 Same process followed as of Example-2 using out-put (wet) of Example-3. Filtrate mother liquor of Example 2 was used as such in place of toluene. 160.2g 99.53%
Example 8 Same process followed as of Example-2 using out-put (wet) of Example-3. Filtrate mother liquor of Example 7 was used as such in place of toluene. 162.0g 99.84%
Example 9 Same process followed as of Example-2 using out-put (wet) of Example-3. Filtrate mother liquor of Example 8 was used as such in place of toluene. 162.5g 99.88%
Example 10 Same process followed as of Example-2 using out-put (wet) of Example-3. Filtrate mother liquor of Example 9 was used as such in place of toluene. 162.8g 99.74%

[0063] Intermediate (1-hydroxycyclohexyl)(4-methoxyphenyl)acetonitrile as prepared in the above examples was further converted into Venlafaxine free base or its pharmaceutically acceptable salts by conventional methods.
,CLAIMS:1. A process for preparing a compound of formula (I),

Formula I
comprising the step of: reacting a compound of formula (II)

Formula II
with a compound of formula (III)

Formula III
in presence of sodium sulfide.

2. The process as claimed in claim 1, wherein said sodium sulfide is used in an amount of from 0.15 mole to 0.5 mole.

3. The process as claimed in claim 1, wherein said sodium sulfide is used in an amount of 0.2 mole.

4. The process as claimed in claim 1, wherein said reaction comprising, combining in a solvent said compound of formula (II), said compound of formula (III), said sodium sulfide, and optionally a phase transfer catalyst to provide a reaction mixture; maintaining said reaction mixture under stirring for a time and at a temperature effective to form compound of formula (I); and isolating said compound of formula (I).

5. The process as claimed in claim 4, wherein said reaction mixture is maintained at a temperature ranging from 0°C to 15°C.

6. The process as claimed in claim 4, wherein said phase transfer catalyst is selected from the group consisting of tetrabutyl ammonium hydrogen sulphate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide and benzyltriethyl ammonium chloride.

7. The process as claimed in claim 4, wherein said isolation comprising, filtering off said reaction mixture to provide a wet cake and a filtrate; adding water to said wet cake to provide an aqueous dispersion; adjusting pH of said aqueous dispersion in a range from 6.5 to 7 using an acid to provide a crude compound of formula (I); and optionally subjecting said crude compound of formula (I) to a step of purification.

8. The process as claimed in claim 7, further comprising recycling all or a portion of said filtrate.

9. The process as claimed in claim 7, wherein said acid is selected from the group consisting of acetic acid, hydrochloric acid and sulphuric acid.

10. The process as claimed in claim 7, wherein said step of purification comprising, combining said crude compound of formula (I) and a solvent to provide a mass; heating said mass for a time and at a temperature sufficient to form a solution; cooling said solution to form a pure compound of formula (I); and separating said pure compound of formula (I) from said solution.

11. The process as claimed in claim 10, further comprising recycling all or portion of a filtrate left after separation of said pure compound of formula (I) from said solution.

12. The process as claimed in claim 10, wherein said pure compound of formula I has a purity of greater than 96% as measured by HPLC.

13. A process for preparing venlafaxine or its pharmaceutically acceptable salts, comprising the steps of: (a) reacting a compound of formula (II)

Formula II
with a compound of formula (III)

Formula III
in presence of sodium sulfide to provide a compound of formula (I)

Formula I
(b) converting said compound of formula I into venlafaxine or its pharmaceutically acceptable salts.