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-hydroxyphenyl)ethyl] cyclohexanol, also known as O-desmethylvenlafaxine (ODMV), by demethylating Venlafaxine 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] ODMV, chemically “1-[2-(Dimethylamino)-1-(4-hydroxyphenyl) ethyl]cyclohexanol” is used as Antidepressant and marketed under the name Pristiq. ODMV is the major active metabolite of the antidepressant Venlafaxine, a medication used to treat major depressive, generalized anxiety, social anxiety and panic disorders.
[0004] There are various routes to synthesize O-desmethylvenlafaxine by demethylation of Venlafaxine with different demethylating agents in a number of suitable solvents.
[0005] US Patent US6,689,912 B2 discloses preparation of O-desmethylvenlafaxine by demethylating Venlafaxine by using C8-C20 alkanethiol, sodium or potassium alkoxide in hydroxylic/ethereal solvent e.g. ethylene glycol, polyethylene glycol or ether of ethylene glycol etc.
[0006] US Patent US7,674,935 B2 discloses C1-C8 alkylthiol, alkali metal carbonate in N-methyl-2-pyrrolidone (NMP), N,N-dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methyl-2-pyridone solvent for demethylating reaction.
[0007] US Patent application US20100210719 discloses Dodecanethiol, alkali metal hydroxide/carbonate/bicarbonate in N,N-dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethyl phospharamide, cellosolve solvent for demethylating reaction.
[0008] US Patent application US20100016638 discloses alkyl or aryl polythiolate having 2-6 thiol group, alkali metal hydroxide/alkoxide or hydride in di or triethylene glycol, polyethylene glycol, N,N-dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methyl-2-pyrrolidone solvent for demethylating reaction.
[0009] US Patent application US20110118357 discloses straight or branched chain alkyl thiol having 1-20 carbon atom or inorganic thiol, alkali metal alkoxide in alcohol, ethylene glycol, ether of ethylene glycol, polyethylene glycol, cellosolve or 1-butanol as solvent for demethylating reaction.
[0010] Indian patent application IN1630/MUM/2009 discloses dodecanethiol, alkoxide in nonhydroxyl solvent or azeotrope mixture e.g. N,N-dimethylformamide, dimethylsulfoxide, glycerol, heavy paraffin as solvent for demethylating reaction.
[0011] Indian patent application IN1900/MUM/2008 discloses sodium Dodecanethiolate/arenethiolate or metal sulfide and hydroxide/carbonate or bicarbonate as base in Toluene, N,N-dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, N-methyl-2-pyridone, dimethylacetamide, polyethylene glycol, N,N'-dimethylpropyleneurea, dimethylolethyleneurea, hexamethyl phospharamide, diethylforamamide, diethylenediamine, morpholine or sulfolane as solvent for demethylating reaction.
[0012] In the prior art references, various thiol derivatives are reported for demethylating Venlafaxine but none of the reference discloses sulphur as demethylating agent.
[0013] Although in the prior art references, various thiol derivatives, various bases and different types of solvents are reported for demethylating Venlafaxine but none of the reference discloses combination of sodium thiol with specific solvent(s) as disclosed here in this invention.
[0014] 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 O-desmethylvenlafaxine 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.
[0015] 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
[0016] It is an object of the present disclosure to provide a simple and efficient process for preparing O-desmethylvenlafaxine by demethylating Venlafaxine or its pharmaceutically acceptable salts.
[0017] It is a further object of the present disclosure to provide a process for preparing O-desmethylvenlafaxine by demethylating Venlafaxine or its pharmaceutically acceptable salts using sulphur as demethylating agent in a suitable solvent.
[0018] It is another object of the present disclosure to demethylate Venlafaxine using sodium thiol (NaSH) in presence of a solvent.
[0019] It is another object of the present disclosure to provide a process for preparing O-desmethylvenlafaxine 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 O-desmethylvenlafaxine which involves effective degree of required demethylation resulting in competitive high yield of the O-desmethylvenlafaxine with optimum purity at commercial scale.
[0021] It is another object of the present disclosure to provide a process for preparing O-desmethylvenlafaxine in mild reaction condition without any adverse effect on yield, purity & stability of final compound.
[0022] It is another object of the present disclosure to provide a process for preparing O-desmethylvenlafaxine which does not corrode the equipments used.

SUMMARY OF THE INVENTION
[0023] Aspects of the present disclosure relate to process for preparation of 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol, also known as O-desmethylvenlafaxine (ODMV), represented by formula (I)

I
wherein, the process can include the step of:
O-demethylating a compound of formula (II) or a salt thereof

II
in a medium comprising at least one demethylating agent, at least one solvent, and optionally a base.
[0024] In an embodiment, the demethylating agent that can O-demethylate the compound of formula II can be selected from sulphur or sodium thiol. Further, the demethylating agent can be used in the form of powder, solid, flake or an aqueous solution thereof.
[0025] In an embodiment, the molar ratio of the demethylating agent to the compound of formula (II) can range from 0.1: 10 to 10: 0.1.
[0026] In an embodiment, the at least one solvent that can be used in the step of O-demethylation of Venlafaxine can be selected from the group comprising of toluene, N,N-dimethylformamide, dimethylsulfoxide, l-methyl-2-pyrolidinone, N-methyl-2-pyridone, dimethylacetamide, N,N'-dimethylpropyleneurea, dimethylolethyleneurea, hexamethylphospharamide, diethylformamide, diethylenediamine, morpholine and sulfolane.
[0027] 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
[0028] 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.
[0029] 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.
[0030] 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.”
[0031] 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.
[0032] 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.
[0033] 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.
[0034] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0035] 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.
[0036] 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.
[0037] The present disclosure relates to a process for preparation of 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol, also known as O-desmethylvenlafaxine (ODMV), represented by Formula (I), comprising demethylation of 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol, also known as Venlafaxine, represented by Formula (II) or a salt thereof, in a medium comprising at least one demethylating agent, at least one solvent and optionally a base.

Formula (I) Formula (II)
O-Desmethylvenlafaxine (ODMV) Venlafaxine
[0038] 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 O-Desmethylvenlafaxine, particular attention has to be given to the starting materials, solvents and reagents as well as to the reaction conditions of all steps of synthesis.
[0039] At this purpose the Applicant has developed new process for the synthesis of O-Desmethylvenlafaxine by demethylating Venlafaxine using environment friendly and economic reaction conditions but taking in consideration the industrial need to operate in mild conditions and with easy available and easy to handle reagents. These synthesis processes has been surprisingly found more favorable either for purity and yield of the final product, while costing advantageous and easily available starting products and reagents are used. Therefore, it is an embodiment of the present invention to develop a process for the synthesis of O-desmethylvenlafaxine by following process.
[0040] In an embodiment, the demethylating agent that can O-demethylate the compound of formula II can be selected from sulphur or sodium thiol. The demethylating agent can be used in the form of powder, solid, flake or an aqueous solution thereof.
[0041] In an embodiment, the molar ratio of the demethylating agent to the compound of formula (II) can range from 0.1: 10 to 10: 0.1.
[0042] In an embodiment, the at least one solvent that can be employed in the step of O-demethylation of Venlafaxine can be selected from the group comprising of toluene, N,N-dimethylformamide, dimethylsulfoxide, l-methyl-2-pyrolidinone, N-methyl-2-pyridone, dimethylacetamide, N,N'-dimethylpropyleneurea, dimethylolethyleneurea, hexamethylphospharamide, diethylformamide, diethylenediamine, morpholine and sulfolane.
[0043] In an embodiment, the step of O-demethylation of Venlafaxine can optionally be carried out in presence of a base which can preferably be selected from the group consisting of alkali and alkaline earth metal alkoxides, hydroxides, hydrides, amides, carbonates, bicarbonates, oxides and combination thereof.
[0044] According to embodiments, the step of O-demethylation of compound of formula (II) or a salt thereof can include the steps of (i) combining the compound of formula (II), the at least one demethylating agent and the optional base in at least one solvent to provide a reaction mixture; and (ii) heating the reaction mixture for a time and at a temperature sufficient to form compound of formula (I). Thus formed compound of formula (I) can be isolated in a solid state from the reaction mixture.
[0045] In an embodiment, the reaction mixture can heated at a temperature ranging from 100°C to 165°C, preferably 160° to 165°C, to effect formation of compound of formula (I).
[0046] In an embodiment, the step of isolation of compound of formula (I) can include (i) concentrating the reaction mixture containing compound of formula (I) by distillation to provide a residue; (ii) adding water to the residue to provide an aqueous dispersion; (iii) precipitating the compound of formula (I) by adjusting pH of the aqueous dispersion to about 9.0 using an acid; (iv) and optionally subjecting the isolated compound of formula (I) to a step of purification.
[0047] In an embodiment, hydrochloric acid or sulphuric acid can be used to acidify the aqueous dispersion to precipitate the compound of formula (I). The precipitated compound can be filtered off and dried to yield a crude wet cake of compound of formula (I). The wet cake can be dissolved in a solvent and refluxed for sufficient time, preferably from 30 mins to 2 hrs, and the resulting mass can be cooled to room temperature to obtain pure compound of formula (I).
[0048] In an embodiment, crude compound of formula (I) can be recrystallized in C1-C4 alcohol, preferably methanol, isopropanol or a mixture thereof.
[0049] In a preferred embodiment, compound of formula (I) can be prepared by following the steps of (i) combining sulphur or sodium thiol and a solvent at 25-30°C, (ii) adding a compound of formula (II) to the combination to obtain a reaction mixture, (iii) optionally adding a base, (iv) heating the reaction mixture at 160° to 165°C, (v) optionally distilling out water simultaneously (if used in prior steps), (vi) maintaining the reaction mixture at elevated temperature and monitoring the reaction for completion, (vii) distilling out the solvent under vacuum completely to leave a residue upon completion of the reaction, (viii) adding a quantity of water to the residue at 25-30°C and adjust pH to ~9.0 using an acid, (ix) filter off the precipitated solid to obtain compound of formula (I) as a crude wet cake, and (x) adding isopropanol to the wet cake and refluxing for sufficient time, and cooling to 20-25°C to obtain pure compound of formula (I).
[0050] According to embodiments, sequence of adding the compound of formula (II), solvent, base and demethylating agent as mentioned in above steps can be interchanged according to the suitability of the reaction conditions.
[0051] According to embodiments of the present disclosure, O-desmethylvenlafaxine can be obtained in a yield of over 90%, more preferably over 95%, with respect to the starting amount of compound of formula (II). Further, O-desmethylvenlafaxine produced in accordance with the processes disclosed herein can have a purity of greater than about 95%, more preferably a purity of greater than about 99%. Purity can be determined by HPLC, for example, or other methods known in the art.

EXAMPLES
[0052] 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 O-desmethylvenlafaxine
[0053] In a glass reactor, venlafaxine (50gm, 0.18mol), N-methyl-2-pyrrolidone (400gm), sulfur (17gm) and sodium methoxide (33gm) were mixed and reaction mixture was heated slowly up to 150°C. Maintain the reaction for 16hrs and monitored the reaction on HPLC. After the completion of reaction, reaction mass was cooled to 80°C and N-methyl-2-pyrrolidone was distilled out under vacuum. Cool the semisolid residue to 25-30°C and water (500ml) was added. The mass was stirred for 1hr at 20-25°C. pH of the resulting mixture was adjusted to ~9.0 using conc HCl. The slurry was stirred for 1hr at 20-25°C, filtered and washed with water to get the crude product. The crude product obtained above and isopropyl alcohol (400ml) was charged in another glass reactor. Mixture was heated to reflux, maintained for 1hr and cooled to 20-25°C. It is then filtered, washed with isopropyl alcohol and dried to get 35gm of pure product O-desmethylvenlafaxine having a purity of 99.4%.
EXAMPLE 2
Preparation of O-desmethylvenlafaxine
[0054] In a glass reactor, venlafaxine (50gm, 0.18mol), N-methyl-2-pyrrolidone (400gm) and 30% aq. NaSH solution (175gm) were mixed and the reaction mass was slowly heated to 150°C. Water was simultaneously distilled out from the reaction mass while the temperature reached 150°C. Temperature was maintained for 16hrs and monitored the reaction on HPLC. After the completion of reaction, reaction mass was cooled to 80°C and N-methyl-2-pyrrolidone was distilled under vacuum. Cool the semisolid residue to 25-30°C and water (500ml) was added. The mass was stirred for 1hr at 20-25°C. pH of the resulting mixture was adjusted to ~9.0 using conc HCl. The slurry was stirred for 1hr at 20-25°C, filtered and washed with water to get the crude product. The crude product obtained above and isopropyl alcohol (400ml) was charged in another glass reactor. Mixture was heated to reflux, maintained for 1hr and cooled to 20-25°C. It is then filtered, washed with isopropyl alcohol and dried to get 35gm of pure product O-desmethylvenlafaxine having a purity of 99.5%. ,CLAIMS:1. A process for preparing a compound of formula (I),

I
comprising the step of: O-demethylating a compound of formula (II) or a salt thereof

II
in a medium comprising at least one demethylating agent, at least one solvent, and optionally a base.

2. The process as claimed in claim 1, wherein said at least one solvent is selected from the group comprising of toluene, N,N-dimethylformamide, dimethylsulfoxide, l-methyl-2-pyrolidinone, N-methyl-2-pyridone, dimethylacetamide, N,N'-dimethylpropyleneurea, dimethylolethyleneurea, hexamethylphospharamide, diethylformamide, diethylenediamine, morpholine, sulfolane and a mixture thereof.

3. The process as claimed in claim 1, wherein said at least one demethylating agent is selected from sulphur or sodium thiol.

4. The process as claimed in claim 1, wherein said at least one demethylating agent is in the form of powder, solid, flake or an aqueous solution thereof.

5. The process as claimed in claim 1, wherein said base is selected from the group consisting of alkali and alkaline earth metal alkoxides, hydroxides, hydrides, amides, carbonates, bicarbonates, oxides and combination thereof.
6. The process as claimed in claim 1, wherein the molar ratio of said demethylating agent to said compound of formula (II) ranges from 0.1: 10 to 10: 0.1.

7. The process as claimed in claim 1, wherein said step of O-demethylating said compound of formula (II) or a salt thereof comprising, combining said compound of formula (II), said at least one demethylating agent and said optional base in said at least one solvent to provide a reaction mixture; heating said reaction mixture for a time and at a temperature effective to form compound of formula (I); and isolating said compound of formula (I).

8. The process as claimed in claim 7, wherein said reaction mixture is heated at a temperature ranging from 100°C to 165°C.

9. The process as claimed in claim 7, wherein said isolation comprising, concentrating said reaction mixture by distillation to provide a residue; adding water to said residue to provide an aqueous dispersion; adjusting pH of said aqueous dispersion to 9.0 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.

10. The process as claimed in claim 9, wherein said acid is selected from hydrochloric acid or sulphuric acid.

11. The process as claimed in claim 9, 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 cooling said mass to provide a pure compound of formula (I).

12. The process as claimed in claim 11, wherein said solvent is selected from C1-C4 alcohol.

13. The process as claimed in claim 12, wherein said solvent is selected from methanol, isopropanol or a mixture thereof.

14. The process as claimed in claim 11, wherein said pure compound of formula I has a purity of greater than 96% as measured by HPLC.