Title of Invention	A PROCESS FOR THE PREPARATION OF 1-[2- (DIMETHYLAMINO)-1-(4-METHOXYPHENYL) ETHYL] CYCLOHEXANOL HYDROCHLORIDE.
Abstract	A process for the preparation of 1 -[2-(dimethylamino)-1 -(4-methoxyphenyl)ethyl]cyclohexanol (venlafaxin) of formula (4) (R=OMe, R]=Me), said process comprising the steps of; dissolving compound (3) (R=OMe) or its acid addition salt in an alcohol, to form an alcoholic solution of compound (3), adding formaldehyde to the alcoholic solution, in the presence of a noble metal catalyst, passing hydrogen gas into said solution, under reduced pressure and at ambient temperature, till the completion of the reaction and to obtain reaction mass, neutralizing the reaction mass with a weak alkali till the desired pH is achieved, extracting l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol of formula (4) (R=OMe, R1=Me) with an organic solvent and treating it with an alcohol saturated with dry hydrogen chloride gas, refluxing the reaction mixture, and cooling the same to obtain hydrochloride salt of l-[2-(dimethylamino)-1 -(4-methoxyphenyl)ethyl]cyclohexanol of formula (4) (R=OMe, R1=Me).

Title of Invention

A PROCESS FOR THE PREPARATION OF 1-[2- (DIMETHYLAMINO)-1-(4-METHOXYPHENYL) ETHYL] CYCLOHEXANOL HYDROCHLORIDE.

Abstract

A process for the preparation of 1 -[2-(dimethylamino)-1 -(4-methoxyphenyl)ethyl]cyclohexanol (venlafaxin) of formula (4) (R=OMe, R]=Me), said process comprising the steps of; dissolving compound (3) (R=OMe) or its acid addition salt in an alcohol, to form an alcoholic solution of compound (3), adding formaldehyde to the alcoholic solution, in the presence of a noble metal catalyst, passing hydrogen gas into said solution, under reduced pressure and at ambient temperature, till the completion of the reaction and to obtain reaction mass, neutralizing the reaction mass with a weak alkali till the desired pH is achieved, extracting l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol of formula (4) (R=OMe, R1=Me) with an organic solvent and treating it with an alcohol saturated with dry hydrogen chloride gas, refluxing the reaction mixture, and cooling the same to obtain hydrochloride salt of l-[2-(dimethylamino)-1 -(4-methoxyphenyl)ethyl]cyclohexanol of formula (4) (R=OMe, R1=Me).

Full Text	A PROCESS FOR THE PREPARATION OF l-[2-(DIMETHYLAMINO)-l-(4-METHOXYPHENYL) ETHYL] CYCLOHEXANOL HYDRO CHLORIDE, VENLAFAXINE HYDROCHLORIDE Field of Invention The present invention relates to an improved process for the preparation of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol (4) (R=OMe, R0=Me) and its acid addition salts by the reductive methylation of 1 -[2-amino-1 -(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe). Background of the Invention Tricyclic antidepressants that show potential, as cardiovascular and anticholinergic agents have been developed recently. Most of these compounds have shown promise in the treatment of cerebral function disorders such as Parkinson’s disease and senile dementia Appropriate references are cited in patents viz. WO 94/000047 and WO 94/000114. Venlafaxine referred to in this invention is a non-tricyclic compound, chemically named as (±)-1 -[2-(dimethylamino)-1 -(4-methoxyphenyl)ethyl]-cyclohexanol, an antidepressant studied extensively and described in U.S. Pat. No. 4,761,501 and by Pento, J.T. in Drugs of Future, 13(9): 839-840(1988). Its hydrochloride salt is commercially available in the United States under the name EffexorR which is a racemate of (+) and (-) enantiomers of venlafaxine and is indicated for the treatment of depression. The synthesis of venlafaxine and its derivatives has been described in J. Med.Chem. 33, 2899-2905 (1990) and U.S. Patent No.5043466 by Yardley, J. P., et al., the disclosure of which is incorporated by reference. The referred method, which was adopted, for the synthesis of the compounds of invention is shown in Scheme-1. 1 Scheme-1 Wherein R is methoxy and R1 is methyl and the reaction conditions are; a. LDA in cyclohexanone at -78°C b. Rh/AI2O3 and hydrogen c. HCHO/HCOOH, H2O and reflux. The final product by step ‘c’ is isolated by methods known to those skilled in the art, including preparative high performance liquid chromatography (HPLC). The term “isolate” used herein encompasses the isolation of a compound from the reaction mixture and purification. This method suffers from the following drawbacks, which are not economical. The reaction requires very low temperature, - 78°C, which is practically unattainable in tropical conditions or attained with great difficulty and excess of cyclohexanone is used as a solvent. The use of highly toxic and pyrophoric reagents like LDA (Lithiumdiisopropylamide) and highly expensive reduction catalyst Rhodium / Alumina makes the process economically unviable. Hubbards et al. in U.S. Patent No. 4535186 (1985) and EP 0112669B describe a method for the synthesis of venlafaxine. Venlafaxine is prepared by the reaction of 4-methoxyphenyl acetonitrile (1), (R=OMe) (herein after referred to as PMPA) with 2 cyclohexanone at -78°C under the influence of n-butyl lithium following the methods known in the literature (Sauvette et al., Tetrahedron, 34, 2135, 1978) to form l-[cyano-(4-methoxyphenyl)methylDcyclohexanol (2) (R=OMe), as represented in Scheme-1, followed by reduction under high pressure to an amine (3), using Rhodium catalyst. Symmetrical N,N-dimethylation following the modified Eschweiler-Clarke procedure, employing formic acid, formaldehyde and large excess of water as illustrated by Tillord et al., and Jerussy Thomas in J. Am. Chem. Soc, 76, 2431, 1954 and WO 00159851 respectively, affords venlafaxine (4) (R=OMe, R1=Me). The process suffers from the following major drawbacks; use of very low temperatures, pyrophoric lithium components and large volumes of water for isolating free amine. Moreover the amine (3) (R=OMe), i.e., l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol, obtained from the above procedure has been found to be highly unstable and needs to be processed immediately to venlafaxine. All these factors make this process unattractive for industry. As a modification to the prior art described in J. Med. Chem. 33, 2899-2905 (1990), Robin Gerald Shepherd et al. [U.K. Patent No.GB 2 227 743A (1990)] have condensed the PMPA with cyclohexanone in presence of LDA in hydrocarbon solvents such as hexane, toluene, cyclohexane and like at ambient temperature thereby improving the yield of alpha-4-anisyl-alpha-(l-hydroxycyclohexyl)acetonitrile (2) (R=OMe) to 71%. Further processing involved reduction of the above nitrile to the amine followed by dimethylation to produce venlafaxine. The disadvantages associated with this process are use of highly dangerous LDA, use of expensive reduction catalysts for reducing cyano compound, isolation of unstable l-[2-amino-l- (4-methoxyphenyl) ethyl] cyclohexanol (3) (R=OMe) and tedious work up procedures in the isolation and purification of venlafaxine. Chinese researchers Zhou Jimpei et al. [J. China Pharm. Univ., 30(4), 249-50, 1999] have acylated anisole to the chloroacetyl derivative, which was then aminated using N,N-dimethylamine to obtain alpha-dimethylamino-4-methoxyacetophenone. The carboxyl group was reduced to alcohol and converted to the bromo compound using methods known to those skilled in the art. The bromo compound was converted to the Grignard reagent and reacted with cyclohexanone to obtain venlafaxine. This method is 3 unattractive because it involves the use of obnoxious reagents and furthermore the product yields are poor. Spanish workers, Nalot, I. A. et al., describe a process to obtain venlafaxine from 4-methoxyphenyl acetic acid in their patent (WO 01/07397). The method which can be adopted for the synthesis of venlafaxine is shown in Scheme-2. This process involves Grignard reaction, which is cumbersome and hazardous and moreover yields are unattractive. The use of reagents like Grignard reagent, LDA, n-butyl lithium, anhydrous A1C13, PBra, etc. pose several problems in the preparation of venlafaxine. Indian chemists Chavan et al. (U.S. Patent No. 6,504,044 B2) came up with yet another modification for the synthesis of said compound under invention. The authors reacted PMPA (1) (R=OMe), with cyclohexanone to generate compound of formula (2) (R=OMe), Scheme-1, using a base selected from NaOH, KOH or 10% aqueous NaOH or 4 50% NaOH. The process uses a phase transfer catalyst and gives a solid, which needs to be crushed and purified further. On a large scale this type of operation leads to difficulties. Furthermore, in the subsequent step the nitrile (2) (R=OMe) is reduced to the amino compound 1 -[2-amino-1 -(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) using Raney Ni in yields as low as 15% and the maximum yield achieved was 30%. The process further involves the separation of the amine (3) (R=0Me), an air and light sensitive amine, and recycling the unreacted nitrile to optimize the yield. This type of operation is not only expensive but also cumbersome on an industrial scale and highly unattractive for large-scale preparation of compounds like venlafaxine. A similar process for the manufacture of venlafaxine hydrochloride has been described in the U.S. Patent No. 6,620,960 B2. Reddy et al. in their patent application US 2005/0033088A1 describe a process by which the nitrile (2) (R=OMe) is reduced in acetic acid medium with palladium on carbon catalyst. In this process, acetic acid is evaporated and the resulting compound is neutralized and extracted with an organic solvent to obtain the free base. The free base is then converted to the acetate salt by the addition of acetic acid. When this process was repeated at our end to obtain the acetate salt, it resulted with impure product in poor yield. As the amine acetate is heated to higher temperature to remove traces of acetic acid, the salt tends to decompose rapidly forming impurities, which affect the final conversion to venlafaxine hydrochloride. Removal of traces of acetic acid is very difficult and requires high vacuum and the conversion of acetate salt to pure amine by neutralization and isolation of the amine in the pure form is cumbersome and time consuming. In one of our earlier patents we have provided a simple, convenient and economically viable method for the large scale preparation of compounds (2) and (3) and also described a method for preparing the acid addition salts of compound (3) (R=OMe). 5 (A) NaOMe and cyclohexanone in methanol (B) Hydrazine hydrate and a noble metal catalyst (C) HCHO/HCOOH, H2O and reflux The process (Scheme 3) involves the condensation of cyclohexanone with 4-methoxyphenyl acetonitrile (1) (R=OMe) in presence of sodium methoxide and reduction of the nitrile to amine acetate under controlled conditions. The amine acetate is in turn used in Eschweiler-Clarke reaction to obtain venlafaxine base, which is converted to hydrochloride by conventional methods. Objects of the present invention The primary object of the present invention is to provide an improved process for the preparation of a pure l-[2-(dimethylamino)-l-(4-methoxylphenyl) ethyl] cyclohexanol of formula (4) (R=OMe, Ri=Me) and its salts thereof from l-[2-amino-l-(4-methoxylphenyl)ethyl]cyclohexanol of formula (3) (R=OMe) without using corrosive reagents such as formic acid. 6 An object of the present invention is to provide an improved process for the preparation of a pure l-[2-(dimethylamino)-l-(4-methoxylphenyl) ethyl] cyclohexanol of formula (4) (R-OMe, R1=Me) and its salts thereof without cumbersome extraction procedures. Another object of the present invention is to provide an improved process for the preparation of a pure l-[2-(dimethylamino)-l-(4-methoxylphenyl) ethyl] cyclohexanol of formula (4) (R=OMe, R1=Me) wherein reductive methylation is adopted at lower pressure and temperature levels. Yet another object of the present invention is to provide an improved process for the preparation of a pure l-[2-(dimethylamino)-l-(4-methoxylphenyl) ethyl] cyclohexanol of formula (4) (R-OMe, R1=Me) in the presence of commercially available and less expensive Raney nickel and palladium on charcoal catalysts. It is a further object of the present invention to provide an improved process for the preparation of a pure l-[2-(dimethylamino)-l-(4-methoxylphenyl) ethyl] cyclohexanol of formula (4) (R=OMe, R1=Me) that does not require an elaborate work up or purification processes like chromatography for the isolation of end product. Summary of the Invention Accordingly, the present invention provides a process for the preparation of l-[2-(dimethylamino)-1 -(4-methoxyphenyl)ethyl]cyclohexanol (venlafaxin) of formula (4) (R=OMe, Ri=Me), said process comprising the steps of; dissolving compound (3) (R=OMe) or its acid addition salt in an alcohol, to form an alcoholic solution of compound (3), adding formaldehyde to the alcoholic solution, in the presence of a noble metal catalyst, passing hydrogen gas into said solution, under reduced pressure and at ambient temperature, till the completion of the reaction and to obtain reaction mass, neutralizing the reaction mass with a weak alkali till the desired pH is achieved, extracting l”[2”(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol of formula (4) (R=OMe, Rj=Me) with an organic solvent and treating it with an alcohol saturated with dry hydrogen chloride gas, refluxing the reaction mixture, and cooling the same to obtain hydrochloride salt of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol of formula (4) (R=OMe, R,=Me). 7 Detailed Description of the Invention The instant invention relates to an improved process for the preparation, of venlafaxine having formula (4) and pharmaceutically acceptable salts thereof, which are important antidepressants of the central nervous system, developed by Wyeth Ayerst and Company. As mentioned earlier, this is achieved by N,N-dimethylation of amine (3) as the free base or preferably its acetate or oxalate salt in solution in a small to medium chain alcohol ranging from C1-C8 alcohols, preferably methanol containing formalin, paraformaldehyde or any of its derivatives. Process for l-[cyano-(4-methoxyphenyl)methyI]cyclohexanol (2) (R=OMe) 4-Methoxyphenyl acetonitrile (1) (R=OMe) is mixed with cyclohexanone at room temperature and cooled to 0°C. This is added to the chilled sodium methoxide solution and stirred at -2°C for 4-5 hours to obtain l-[cyano-(4-methoxyphenyl)methyl]cyclohexanol (2) (R=OMe). The reaction mixture is centrifuged at -5°C to 0°C and the product (2) (R=OMe) is separated. Process for l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) For this purpose, alpha”4-anisyl-alpha-(l-hydroxycyclohexyl)acetonitrile (2) (R=OMe) is converted to 1 -[2-amino-1 -(4-methoxyphenyl)ethyl]cyclohexanol of formula (3) (R=OMe) by the method reported by us in a separate patent application. The said process comprises of reacting nitrile (2) (R=OMe) with hydrazine hydrate and Raney nickel in presence of an alcohol viz. methyl, ethyl or isopropyl, and the like for the efficient conversion to 1 -[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) without using hydrogen gas. The process is industrially viable where facility for catalytic hydrogenation is not available. This also avoids the constraints associated with the capacity of hydrogenator and the risks associated with handling hydrogen gas. The reaction can be performed in a stainless steel reactor. The process can be performed without the expensive noble metal catalysts, thereby avoiding recurring cost of regeneration and recycling of the catalyst. Simple and easily available Raney nickel can be used as the preferred catalyst for this process. The compound thus obtained is isolated from the reaction mixture by means of procedures known to people skilled in the art. The usual method followed is filtration of the catalyst, removal of alcohol by distillation and isolation of the product and conversion 8 to other acid addition salts viz. HC1, lactate, tartarate, maleate, sulfate and the like, in particular, the acetate and the oxalate following the methods known to those skilled in the art. Process for l-[2-(dimethylamino)-l-(4-methoxyphenyI)ethyl]cycIohexanol (4) (R=OMe, R,=Me) For this purpose which is the embodiment of the present invention, the l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) or its acid addition salt is converted to venlafaxine (4) (R=OMe, Ri=Me) and its acid addition salt in particular the hydrochloride salt viz. venlafaxine hydrochloride with out using large volumes of water, formic acid and formaldehyde mixture. This not only avoids the cumbersome work up but also prevents the use of corrosive formic acid and avoids the neutralization step in the Eschweiler-Clarke reaction. The amine is generally taken in an alcoholic solvent viz. methanol, ethanol, isopropanol and the like, preferably methanol and treated with formaldehyde (37-40%) and a catalyst like Raney nickel or palladium on charcoal. The mixture is hydrogenated to obtain the venlafaxine base, which can be distilled and purified by normal procedures known to those skilled in the art or converted to its acid addition salt such as hydrochloride. For the reductive dimethylation, the amino alcohol (3) (R=OMe) can also be advantageously used as its salts with mineral or organic acids. The latter can be any common organic carboxylic or sulphonic acid, Carboxylic acids may be monobasic with carbon atoms from 2 onwards, e.g., acetic acid or dibasic acids like oxalic, malonic, succinic acid, tartaric acid, and the like. The reductive methylation is carried out with hydrogen gas (3-10 Kg/cm ) and is catalyzed by noble metal catalysts like palladium on charcoal (5-50% w/w with respect to the starting material) or Raney nickel (10-100% w/w with respect to the starting material). This process not only avoids the use of corrosive and dangerous formic acid, which needs to be used in higher strength for efficient reaction in the Eschweiler-Clarke method but also avoids the extensive work up mentioned in the literature. In this method, the solvent is evaporated under reduced pressure after filtering off the catalyst from the reaction mixture and the base is converted to its hydrochloride salt by methods known to those skilled in the art. Furthermore, the catalyst for this reductive methylation can be chosen 9 from the available noble metal catalysts in particular platinum, palladium, or rhodium doped with alumina or activated carbon or a homogeneous catalyst which is generally sold as halide or any acid addition salt thereof. The reaction can be carried out in the absence of water thereby avoiding distillation at higher temperature to obtain the product. This makes the conversion to the final product much easier and venlafaxine hydrochloride is obtained in better purity. Venlafaxine has been known to exhibit polymorphism based on the solvent used and also based on the residual HC1 gas entrapped in crystal lattice. To achieve the correct polymorph, which is clinically most active, the hydrogen chloride salt made in ethyl acetate is refluxed with a solvent such as isopropanol for several hours ranging from 1-5 hours and preferably between 1-2 hours to get the desired polymorph. The reaction scheme of the process steps of the present invention is as follows: An embodiment of the present invention is to provide a process for the preparation of 1-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol (venlafaxin) of formula (4) (R=OMe, R1=Me), said process comprising the steps of: dissolving compound (3) (R=OMe) or its acid addition salt in an alcohol, to form an alcoholic solution of compound (3), adding formaldehyde to the alcoholic solution, in the presence of a noble metal catalyst, passing hydrogen gas into said solution, under reduced pressure and at ambient temperature, till the completion of the reaction and to obtain reaction mass, neutralizing the reaction mass with a weak alkali till the desired pH is achieved, extracting l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol of formula (4) (R=OMe, R1=Me) with an organic solvent and treating it with an alcohol saturated with dry hydrogen chloride gas, refluxing the reaction mixture, and cooling the same to obtain 10 hydrochloride salt of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol of formula (4) (R=OMe, R,=Me). It is an embodiment of the present invention wherein the salt of the compound (3) is derived from acetic acid or oxalic acid or sulfonic acid, preferably acetic acid or oxalic acid. It is also an embodiment of the present invention wherein the alcohol is selected from the group consisting of C1-C8 alcohols, preferably methanol. Yet another embodiment of the present invention wherein the noble metal catalyst is palladium on carbon or cobalt or Raney nickel. Further embodiment of the present invention wherein Raney nickel is in the range of 10- 100%w/w. It is an embodiment of the present invention wherein the palladium on carbon in the range of 5-50% w/w, preferably 10%. It is also an embodiment of the present invention wherein the hydrogen gas pressure is in the range of 3-10 Kg/cm2 , preferably 4 Kg/cm2 . It is an embodiment of the present invention wherein the hydrogenation reaction time is about 3-12 hours, preferably 4 hours. Yet another embodiment of the present invention wherein the weak alkali is potassium carbonate or sodium carbonate or potassium bicarbonate or sodium bicarbonate, preferably potassium carbonate. Still another embodiment of the present invention wherein the pH is in the range of 10- 12, preferably 11. It is an embodiment of the present invention wherein the organic solvent is ethyl acetate or benzene or toluene, preferably ethyl acetate. It is also an embodiment of the present invention wherein the alcohol used for dissolving hydrogen chloride gas is selected from methanol or ethanol or isopropyl alcohol, preferably isopropyl alcohol. The invention is further defined by reference to the following examples describing in detail the preparation and composition of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practised without departing from the purpose and interest of the invention. The process 11 of the present invention is described by the following examples, which are illustrative only and should not be construed as limit to the scope of the reaction in any manner. Example 1 Preparation of alpha-4-anisyl-alpha-(l-hydroxycyclohexyl)acetonitrile (2) (R=OMe) 4-Methoxyphenyl acetonitrile (1) (R=OMe) (100 Kg, 679.44 mol) is mixed with cyclohexanone (153.2 Kg, 1042 mol) in a clean stainless steel reactor. The mixture is stirred at room temperature for 15-20 min. and then cooled to 0°C by applying brine in the reactor. In another stainless steel reactor, sodium methoxide solution (25%, commercial, 400 L) is charged and cooled to 20°C. To this solution is added anhydrous methanol (400 L). The mixture is stirred and mixed thoroughly and cooled to -5°C. To the chilled sodium methoxide solution is added the mixture of PMPA and cyclohexanone at such a rate that the temperature of the reaction mixture does not go above -2°C. After the addition is complete the reaction mixture is stirred for 4-5 hours or until there is no more of starting material as indicated by TLC. Once the reaction is complete, the reaction mass is centrifuged at - 5°C to 0°C and the wet product is slurried in 600 L of water containing 15 L of acetic acid at 25-30°C and centrifuged, the wet product is washed with 200 L of water. The material is unloaded and dried at room temperature to obtain a free flowing white crystalline solid (145 Kg, 589.4 mol, 86.75%) of 99.8% purity, m.p. 112-118°C. 1HNMR. (CDC13): 7.30, 6.90 (q, 4H), 3.80 (s, 3H), 3.75 (s, 1H), 1.55 (m, 10H); I3C NMR (CDCI3): 159.8, 130.8, 123.8, 120.00, 114.1, 72.9, 55.55, 49.5, 34.9, 25.3, 21.6; IR (KBr): 3491, 3410cm~1(-OH), 2251cm-1 (-CN). Example - 2 Preparation of l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) A round-bottomed flask of 2000 ml capacity equipped with stirrer and nitrogen inlet is charged with cyanoalcohol (2) (R=OMe) (50 g, 0.204 mol) dissolved in isopropyl alcohol (400 ml) and ammonium carbonate (9.7 g). Commercially available Raney nickel (60 g, wet) is washed with demineralised water until it is free of alkali or until the water washings are neutral to litmus. The Raney nickel is further washed with isopropyl alcohol to remove any residual water in the catalyst. The freshly washed Raney nickel is charged into the reaction vessel and the reaction mass is 12 stirred vigorously and treated under reflux at 70-76°C with 99% hydrazine hydrate (100 ml). The mixture is maintained at this temperature for 4-6 hours or until the TLC of the reaction mixture indicates completion of the reaction. The reaction mass is cooled to room temperature and the catalyst is filtered off. The solvent used in the reaction is distilled off under vacuum to obtain a clear, colorless liquid. Ethyl acetate (320 ml) is added to the mixture followed by acetic acid (11 ml). The mixture is stirred under reflux for 1-2 hours. The ethyl acetate solution is cooled to 25-30°C to obtain a white solid, which has been characterized as the acetate salt. The acetate salt thus obtained is further crystallized from ethyl acetate to obtain the pure salt (42 g, 67%, purity by HPLC 98.8%),m.p.l63-165°C. Example- 2 A Reduction of cyanoalcohol (2) (R=OMe) and preparation of (3) (R=OMe) oxalate Alpha-4-anisyl-alpha-(l-hydroxycyclohexyl)acetonitrile (2) (R=OMe) (100 g), oxalic acid (100 g), methanol (1 L) and 10% palladium on charcoal (20 g, 50% wet) are charged into an autoclave and purged with nitrogen. Nitrogen and air are vented out. The operation is repeated twice with nitrogen and then thrice with hydrogen. The autoclave is now pressurized with hydrogen to 8-10 Kg/cm2 . The contents are stirred at this pressure and at about 35°C for 12 hours. The completion of reduction is ascertained by TLC or HPLC. The contents are cooled to 20-25°C and filtered. The clear filtrate is concentrated under vacuum at less than 60°C. Toluene (200 ml) is added to the residue. The mixture is cooled to 25-30°C and the oxalate salt is filtered off and air-dried for 8-12 hours. Yield 147 g (> 99%), purity about 95% (HPLC), m.p.l84°C. The acetate salt of (3) can be prepared likewise by carrying out the reduction of (2) in acetic acid using 10% palladium on charcoal catalyst. Example - 3 Preparation of l-[2-Dimethylamino-l-(4-methoxyphenyl)ethyl]cyclohexanol (4) (R=OMe, R1=Me) hydrochloride (Venlafaxine hydrochloride) from the acetate salt of(3)(R=OMe) A glass lined reactor is charged with 1 -[2-Amino-1 -(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) as its acetate salt (10 g, 0.0326 mol) dissolved in methyl alcohol (70 ml). To this solution is added formaldehyde solution 13 (37-40%) (8 ml) and Raney nickel (4 g). The reaction vessel is pressurized with nitrogen and nitrogen is vented out. The reaction vessel is again pressurized with hydrogen up to 4 Kg/cm2 . The mixture is stirred at room temperature, preferably at 20-25°C for a period of 8 hours or until TLC of the reaction mixture shows the absence of the starting material. Once the reaction is complete the catalyst is filtered off carefully through a hyflo bed. The filtrate is concentrated under vacuum. The product thus obtained is taken in water and neutralized with an inorganic base such as sodium or potassium carbonate or sodium or potassium bicarbonate, preferably potassium carbonate until the pH of the solution is 11. The neutralized solution is extracted with ethyl acetate (50×3 ml). The combined ethyl acetate layer is washed with water and dried over anhydrous sodium sulfate. The sodium sulfate is filtered off and ethyl acetate is concentrated under vacuum. The material thus obtained is the venlafaxine base, which is dissolved in ethyl acetate (100ml) and taken in a round-bottomed flask equipped with a stirrer and an addition funnel. Isopropyl alcohol saturated with dry hydrogen chloride gas is now added to the ethyl acetate mixture over a period of 2-3 hours at 20-25°C till a pH of 2 is reached. The exothermicity of this reaction is controlled by the rate of addition. Finally once the addition is complete, the mixture is refluxed for 1-2 hours and cooled to room temperature and finally to 0°C. The product is kept stirring at this temperature for another 1-2 hours and the precipitated solid is filtered off to obtain a white solid. The solid has been identified as venlafaxine hydrochloride (8 g, 80%, purity 98.5%). Example - 3 A Preparation of l-[2-Dimethylamino-l-(4-methoxyphenyl)ethyl]cyclohexanol] (4) (R=OMe, R]-Me) hydrochloride the acetate salt of (3) (R=OMe) A glass lined reactor is charged with 1 -[2-Amino-l -(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) as its acetate salt (10 g, 0.0326 mol) dissolved in methyl alcohol (70 ml). To this solution is added formaldehyde solution (37-40%) (8 ml) and palladium on carbon (2 g). The reaction vessel is pressurized with nitrogen and nitrogen is vented out. The reaction vessel is again pressurized with hydrogen up to 4 Kg/cm2 of hydrogen pressure. The mixture is stirred at room temperature, preferably at 20-25°C for a period of 8 hours or until TLC of the reaction mixture shows the absence of the starting material. 14 Once the reaction is complete the catalyst is filtered off carefully through a hyflo bed. The filtrate is concentrated under vacuum. The product thus obtained is taken in water and neutralized with potassium carbonate until the pH of the solution is 11. The neutralized solution is extracted with ethyl acetate (50x3 ml). The combined ethyl acetate layer is washed with water and dried over anhydrous sodium sulfate. The sodium sulfate is filtered off and ethyl acetate is concentrated under vacuum. The material thus obtained is venlafaxine base, which is dissolved in ethyl acetate (100ml) taken in a round-bottomed flask equipped with a stirrer and an addition funnel. Isopropyl alcohol saturated with dry hydrogen chloride gas is now added to the ethyl acetate mixture over a period of 2-3 hours at 20-25°C till a pH of 2 is reached. The exothermicity of this reaction is controlled by the rate of addition. Finally, once the addition is complete, the mixture is refluxed for 1-2 hours and cooled to room temperature and finally to 0°C. The product is kept stirring at this temperature for another 1-2 hours and the precipitated solid is filtered off to obtain a white solid. The solid has been identified as venlafaxine hydrochloride (7.5 g, 75%, purity 98.9%) Example - 3B Preparation of l-[-2-Dimethylamino-l-(4-methoxyphenyl)ethyl]cyclohexanol (4) (R=OMe, R1=Me) hydrochloride from (3) (R=OMe) A glass lined reactor is charged with 1 -[2-Amino-l -(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) (free base) (10 g, 0.0326 mol) dissolved in methyl alcohol (70 ml). To this solution is added formaldehyde solution (37-40%) (8 ml) and Raney nickel (4 g). The reaction vessel is pressurized with nitrogen and nitrogen is vented out. The reaction vessel is again pressurized with hydrogen up to 4 Kg/cm2 of hydrogen pressure. The mixture is stirred at room temperature, preferably at 20-25°C for a period of 8 hours or until TLC of the reaction mixture shows the absence of the starting material. Once the reaction is complete the catalyst is filtered off carefully through a hyflo bed and the filtrate is concentrated under vacuum. The product thus obtained is taken in water and treated with potassium carbonate to make the mixture strongly alkaline (pH 11). The mixture is extracted with ethyl acetate (50x3 ml). The combined ethyl acetate layer is washed with water and dried over anhydrous sodium sulfate. The sodium sulfate is 15 filtered off and ethyl acetate is concentrated under vacuum. The material thus obtained is venlafaxine base, which is dissolved in ethyl acetate (100 ml) and taken in a round-bottomed flask equipped with a stirrer and an addition funnel. Isopropyl alcohol saturated with dry hydrogen chloride gas is now added to the ethyl acetate mixture at 20-25 °C over a period of 2-3 hours till a pH of 2 is reached. The exothermicity of this reaction is controlled by the rate of addition. Finally once the addition is complete, the mixture is refluxed for 1-2 hours and cooled to room temperature and then to 0°C. The product is kept stirring at this temperature for another 1-2 hours and the precipitated solid filtered off to obtain a white solid. The solid has been identified as venlafaxine hydrochloride (6 g, 60%, purity 99.2%). Example 3C Preparation of l-[-2-Dimethylamino-l-(4-methoxyphenyl)ethyl]cyclohexanol (4) (R=OMe, R1=Me) hydrochloride from the oxalate salt of (3) (R=OMe) The oxalate salt of the aminoalcohol (3) (R=OMe) (80 g), methanol (1 L), 10% palladium on charcoal (20 g, 50% wet) and aqueous formaldehyde (about 37%, 80 ml) are charged into an autoclave. Nitrogen gas is purged in and vented out to replace air. The operation is repeated twice and then with nitrogen gas thrice. The autoclave is pressurized with hydrogen gas to 8-10 Kg/cm2 and maintained with stirring at this pressure and about 30°C for 12 hours. After the completion of reaction, as ascertained by HPLC, the contents are cooled to 20-25°C and filtered. The bed is washed with methanol (80 ml). The combined filtrates are concentrated to 80 ml. Toluene (200 ml) and solid sodium carbonate (30 g) are added and the mixture is stirred for 1 hr and filtered. The clear filtrate is washed with water (3x40 ml) and then with distilled under vacuum below 70°C to remove the solvents. Isopropyl alcohol (80 ml) is added to the residue and distilled off under vacuum. The residual mass is cooled, dissolved in isopropanol (120 ml) and treated with isopropanolic hydrogen chloride to pH 1. The mixture is stirred at 25-30°C for 30 min. and then at 0-5°C and filtered. The precipitate is dried on the filter for 30 min. to get venlafaxine hydrochloride (28.5 g) of purity 98% (HPLC). We have described above the invention with respect to particular embodiments; it will be apparent to those skilled in the art that various changes and modifications may be made 16 without departing from the spirit and scope of the invention as defined in the claims. Such conditions are also intended to fall with in the scope of the appended claims. Advantages of the present invention 1. The process steps of the present invention can be carried out at lower pressure and temperature levels. 2. The process of the present invention avoids the use of corrosive reagents such as formic acid.

Full Text

A PROCESS FOR THE PREPARATION OF l-[2-(DIMETHYLAMINO)-l-(4-METHOXYPHENYL) ETHYL] CYCLOHEXANOL HYDRO CHLORIDE, VENLAFAXINE HYDROCHLORIDE
Field of Invention
The present invention relates to an improved process for the preparation of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol (4) (R=OMe, R0=Me) and its acid addition salts by the reductive methylation of 1 -[2-amino-1 -(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe).
Background of the Invention
Tricyclic antidepressants that show potential, as cardiovascular and anticholinergic agents have been developed recently. Most of these compounds have shown promise in the treatment of cerebral function disorders such as Parkinson’s disease and senile dementia Appropriate references are cited in patents viz. WO 94/000047 and WO 94/000114. Venlafaxine referred to in this invention is a non-tricyclic compound, chemically named as (±)-1 -[2-(dimethylamino)-1 -(4-methoxyphenyl)ethyl]-cyclohexanol, an antidepressant studied extensively and described in U.S. Pat. No. 4,761,501 and by Pento, J.T. in Drugs of Future, 13(9): 839-840(1988). Its hydrochloride salt is commercially available in the United States under the name EffexorR which is a racemate of (+) and (-) enantiomers of venlafaxine and is indicated for the treatment of depression. The synthesis of venlafaxine and its derivatives has been described in J. Med.Chem. 33, 2899-2905 (1990) and U.S. Patent No.5043466 by Yardley, J. P., et al., the disclosure of which is incorporated by reference. The referred method, which was adopted, for the synthesis of the compounds of invention is shown in Scheme-1.
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Scheme-1
Wherein R is methoxy and R1 is methyl and the reaction conditions are;
a. LDA in cyclohexanone at -78°C
b. Rh/AI2O3 and hydrogen
c. HCHO/HCOOH, H2O and reflux.
The final product by step ‘c’ is isolated by methods known to those skilled in the art, including preparative high performance liquid chromatography (HPLC). The term “isolate” used herein encompasses the isolation of a compound from the reaction mixture and purification. This method suffers from the following drawbacks, which are not economical. The reaction requires very low temperature, - 78°C, which is practically unattainable in tropical conditions or attained with great difficulty and excess of cyclohexanone is used as a solvent. The use of highly toxic and pyrophoric reagents like LDA (Lithiumdiisopropylamide) and highly expensive reduction catalyst Rhodium / Alumina makes the process economically unviable.
Hubbards et al. in U.S. Patent No. 4535186 (1985) and EP 0112669B describe a method for the synthesis of venlafaxine. Venlafaxine is prepared by the reaction of 4-methoxyphenyl acetonitrile (1), (R=OMe) (herein after referred to as PMPA) with
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cyclohexanone at -78°C under the influence of n-butyl lithium following the methods known in the literature (Sauvette et al., Tetrahedron, 34, 2135, 1978) to form l-[cyano-(4-methoxyphenyl)methylDcyclohexanol (2) (R=OMe), as represented in Scheme-1, followed by reduction under high pressure to an amine (3), using Rhodium catalyst. Symmetrical N,N-dimethylation following the modified Eschweiler-Clarke procedure, employing formic acid, formaldehyde and large excess of water as illustrated by Tillord et al., and Jerussy Thomas in J. Am. Chem. Soc, 76, 2431, 1954 and WO 00159851 respectively, affords venlafaxine (4) (R=OMe, R1=Me). The process suffers from the following major drawbacks; use of very low temperatures, pyrophoric lithium components and large volumes of water for isolating free amine. Moreover the amine (3) (R=OMe), i.e., l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol, obtained from the above procedure has been found to be highly unstable and needs to be processed immediately to venlafaxine. All these factors make this process unattractive for industry. As a modification to the prior art described in J. Med. Chem. 33, 2899-2905 (1990), Robin Gerald Shepherd et al. [U.K. Patent No.GB 2 227 743A (1990)] have condensed the PMPA with cyclohexanone in presence of LDA in hydrocarbon solvents such as hexane, toluene, cyclohexane and like at ambient temperature thereby improving the yield of alpha-4-anisyl-alpha-(l-hydroxycyclohexyl)acetonitrile (2) (R=OMe) to 71%. Further processing involved reduction of the above nitrile to the amine followed by dimethylation to produce venlafaxine. The disadvantages associated with this process are use of highly dangerous LDA, use of expensive reduction catalysts for reducing cyano compound, isolation of unstable l-[2-amino-l- (4-methoxyphenyl) ethyl] cyclohexanol (3) (R=OMe) and tedious work up procedures in the isolation and purification of venlafaxine.
Chinese researchers Zhou Jimpei et al. [J. China Pharm. Univ., 30(4), 249-50, 1999] have acylated anisole to the chloroacetyl derivative, which was then aminated using N,N-dimethylamine to obtain alpha-dimethylamino-4-methoxyacetophenone. The carboxyl group was reduced to alcohol and converted to the bromo compound using methods known to those skilled in the art. The bromo compound was converted to the Grignard reagent and reacted with cyclohexanone to obtain venlafaxine. This method is
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unattractive because it involves the use of obnoxious reagents and furthermore the product yields are poor.
Spanish workers, Nalot, I. A. et al., describe a process to obtain venlafaxine from 4-methoxyphenyl acetic acid in their patent (WO 01/07397). The method which can be adopted for the synthesis of venlafaxine is shown in Scheme-2.
This process involves Grignard reaction, which is cumbersome and hazardous and moreover yields are unattractive.
The use of reagents like Grignard reagent, LDA, n-butyl lithium, anhydrous A1C13, PBra,
etc. pose several problems in the preparation of venlafaxine.
Indian chemists Chavan et al. (U.S. Patent No. 6,504,044 B2) came up with yet another
modification for the synthesis of said compound under invention. The authors reacted
PMPA (1) (R=OMe), with cyclohexanone to generate compound of formula (2)
(R=OMe), Scheme-1, using a base selected from NaOH, KOH or 10% aqueous NaOH or
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50% NaOH. The process uses a phase transfer catalyst and gives a solid, which needs to be crushed and purified further. On a large scale this type of operation leads to difficulties. Furthermore, in the subsequent step the nitrile (2) (R=OMe) is reduced to the amino compound 1 -[2-amino-1 -(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) using Raney Ni in yields as low as 15% and the maximum yield achieved was 30%. The process further involves the separation of the amine (3) (R=0Me), an air and light sensitive amine, and recycling the unreacted nitrile to optimize the yield. This type of operation is not only expensive but also cumbersome on an industrial scale and highly unattractive for large-scale preparation of compounds like venlafaxine. A similar process for the manufacture of venlafaxine hydrochloride has been described in the U.S. Patent No. 6,620,960 B2. Reddy et al. in their patent application US 2005/0033088A1 describe a process by which the nitrile (2) (R=OMe) is reduced in acetic acid medium with palladium on carbon catalyst. In this process, acetic acid is evaporated and the resulting compound is neutralized and extracted with an organic solvent to obtain the free base. The free base is then converted to the acetate salt by the addition of acetic acid. When this process was repeated at our end to obtain the acetate salt, it resulted with impure product in poor yield. As the amine acetate is heated to higher temperature to remove traces of acetic acid, the salt tends to decompose rapidly forming impurities, which affect the final conversion to venlafaxine hydrochloride. Removal of traces of acetic acid is very difficult and requires high vacuum and the conversion of acetate salt to pure amine by neutralization and isolation of the amine in the pure form is cumbersome and time consuming.
In one of our earlier patents we have provided a simple, convenient and economically viable method for the large scale preparation of compounds (2) and (3) and also described a method for preparing the acid addition salts of compound (3) (R=OMe).
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(A) NaOMe and cyclohexanone in methanol
(B) Hydrazine hydrate and a noble metal catalyst
(C) HCHO/HCOOH, H2O and reflux
The process (Scheme 3) involves the condensation of cyclohexanone with 4-methoxyphenyl acetonitrile (1) (R=OMe) in presence of sodium methoxide and reduction of the nitrile to amine acetate under controlled conditions. The amine acetate is in turn used in Eschweiler-Clarke reaction to obtain venlafaxine base, which is converted to hydrochloride by conventional methods.
Objects of the present invention
The primary object of the present invention is to provide an improved process for the preparation of a pure l-[2-(dimethylamino)-l-(4-methoxylphenyl) ethyl] cyclohexanol of formula (4) (R=OMe, Ri=Me) and its salts thereof from l-[2-amino-l-(4-methoxylphenyl)ethyl]cyclohexanol of formula (3) (R=OMe) without using corrosive reagents such as formic acid.
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An object of the present invention is to provide an improved process for the preparation of a pure l-[2-(dimethylamino)-l-(4-methoxylphenyl) ethyl] cyclohexanol of formula (4) (R-OMe, R1=Me) and its salts thereof without cumbersome extraction procedures. Another object of the present invention is to provide an improved process for the preparation of a pure l-[2-(dimethylamino)-l-(4-methoxylphenyl) ethyl] cyclohexanol of formula (4) (R=OMe, R1=Me) wherein reductive methylation is adopted at lower pressure and temperature levels.
Yet another object of the present invention is to provide an improved process for the preparation of a pure l-[2-(dimethylamino)-l-(4-methoxylphenyl) ethyl] cyclohexanol of formula (4) (R-OMe, R1=Me) in the presence of commercially available and less expensive Raney nickel and palladium on charcoal catalysts.
It is a further object of the present invention to provide an improved process for the preparation of a pure l-[2-(dimethylamino)-l-(4-methoxylphenyl) ethyl] cyclohexanol of formula (4) (R=OMe, R1=Me) that does not require an elaborate work up or purification processes like chromatography for the isolation of end product.
Summary of the Invention
Accordingly, the present invention provides a process for the preparation of l-[2-(dimethylamino)-1 -(4-methoxyphenyl)ethyl]cyclohexanol (venlafaxin) of formula (4) (R=OMe, Ri=Me), said process comprising the steps of; dissolving compound (3) (R=OMe) or its acid addition salt in an alcohol, to form an alcoholic solution of compound (3), adding formaldehyde to the alcoholic solution, in the presence of a noble metal catalyst, passing hydrogen gas into said solution, under reduced pressure and at ambient temperature, till the completion of the reaction and to obtain reaction mass, neutralizing the reaction mass with a weak alkali till the desired pH is achieved, extracting l”[2”(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol of formula (4) (R=OMe, Rj=Me) with an organic solvent and treating it with an alcohol saturated with dry hydrogen chloride gas, refluxing the reaction mixture, and cooling the same to obtain hydrochloride salt of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol of formula (4) (R=OMe, R,=Me).
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Detailed Description of the Invention
The instant invention relates to an improved process for the preparation, of venlafaxine having formula (4) and pharmaceutically acceptable salts thereof, which are important antidepressants of the central nervous system, developed by Wyeth Ayerst and Company. As mentioned earlier, this is achieved by N,N-dimethylation of amine (3) as the free base or preferably its acetate or oxalate salt in solution in a small to medium chain alcohol ranging from C1-C8 alcohols, preferably methanol containing formalin, paraformaldehyde or any of its derivatives.
Process for l-[cyano-(4-methoxyphenyl)methyI]cyclohexanol (2) (R=OMe)
4-Methoxyphenyl acetonitrile (1) (R=OMe) is mixed with cyclohexanone at room temperature and cooled to 0°C. This is added to the chilled sodium methoxide solution and stirred at -2°C for 4-5 hours to obtain l-[cyano-(4-methoxyphenyl)methyl]cyclohexanol (2) (R=OMe). The reaction mixture is centrifuged at -5°C to 0°C and the product (2) (R=OMe) is separated.
Process for l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe)
For this purpose, alpha”4-anisyl-alpha-(l-hydroxycyclohexyl)acetonitrile (2) (R=OMe) is converted to 1 -[2-amino-1 -(4-methoxyphenyl)ethyl]cyclohexanol of formula (3) (R=OMe) by the method reported by us in a separate patent application. The said process comprises of reacting nitrile (2) (R=OMe) with hydrazine hydrate and Raney nickel in presence of an alcohol viz. methyl, ethyl or isopropyl, and the like for the efficient conversion to 1 -[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) without using hydrogen gas. The process is industrially viable where facility for catalytic hydrogenation is not available. This also avoids the constraints associated with the capacity of hydrogenator and the risks associated with handling hydrogen gas. The reaction can be performed in a stainless steel reactor. The process can be performed without the expensive noble metal catalysts, thereby avoiding recurring cost of regeneration and recycling of the catalyst. Simple and easily available Raney nickel can be used as the preferred catalyst for this process.
The compound thus obtained is isolated from the reaction mixture by means of procedures known to people skilled in the art. The usual method followed is filtration of the catalyst, removal of alcohol by distillation and isolation of the product and conversion
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to other acid addition salts viz. HC1, lactate, tartarate, maleate, sulfate and the like, in particular, the acetate and the oxalate following the methods known to those skilled in the art.
Process for l-[2-(dimethylamino)-l-(4-methoxyphenyI)ethyl]cycIohexanol (4) (R=OMe, R,=Me)
For this purpose which is the embodiment of the present invention, the l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) or its acid addition salt is converted to venlafaxine (4) (R=OMe, Ri=Me) and its acid addition salt in particular the hydrochloride salt viz. venlafaxine hydrochloride with out using large volumes of water, formic acid and formaldehyde mixture. This not only avoids the cumbersome work up but also prevents the use of corrosive formic acid and avoids the neutralization step in the Eschweiler-Clarke reaction. The amine is generally taken in an alcoholic solvent viz. methanol, ethanol, isopropanol and the like, preferably methanol and treated with formaldehyde (37-40%) and a catalyst like Raney nickel or palladium on charcoal. The mixture is hydrogenated to obtain the venlafaxine base, which can be distilled and purified by normal procedures known to those skilled in the art or converted to its acid addition salt such as hydrochloride. For the reductive dimethylation, the amino alcohol (3) (R=OMe) can also be advantageously used as its salts with mineral or organic acids. The latter can be any common organic carboxylic or sulphonic acid, Carboxylic acids may be monobasic with carbon atoms from 2 onwards, e.g., acetic acid or dibasic acids like oxalic, malonic, succinic acid, tartaric acid, and the like.
The reductive methylation is carried out with hydrogen gas (3-10 Kg/cm ) and is catalyzed by noble metal catalysts like palladium on charcoal (5-50% w/w with respect to the starting material) or Raney nickel (10-100% w/w with respect to the starting material).
This process not only avoids the use of corrosive and dangerous formic acid, which needs to be used in higher strength for efficient reaction in the Eschweiler-Clarke method but also avoids the extensive work up mentioned in the literature. In this method, the solvent is evaporated under reduced pressure after filtering off the catalyst from the reaction mixture and the base is converted to its hydrochloride salt by methods known to those skilled in the art. Furthermore, the catalyst for this reductive methylation can be chosen
9

from the available noble metal catalysts in particular platinum, palladium, or rhodium doped with alumina or activated carbon or a homogeneous catalyst which is generally sold as halide or any acid addition salt thereof. The reaction can be carried out in the absence of water thereby avoiding distillation at higher temperature to obtain the product. This makes the conversion to the final product much easier and venlafaxine hydrochloride is obtained in better purity.
Venlafaxine has been known to exhibit polymorphism based on the solvent used and also based on the residual HC1 gas entrapped in crystal lattice. To achieve the correct polymorph, which is clinically most active, the hydrogen chloride salt made in ethyl acetate is refluxed with a solvent such as isopropanol for several hours ranging from 1-5 hours and preferably between 1-2 hours to get the desired polymorph. The reaction scheme of the process steps of the present invention is as follows:
An embodiment of the present invention is to provide a process for the preparation of 1-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol (venlafaxin) of formula (4) (R=OMe, R1=Me), said process comprising the steps of: dissolving compound (3) (R=OMe) or its acid addition salt in an alcohol, to form an alcoholic solution of compound (3), adding formaldehyde to the alcoholic solution, in the presence of a noble metal catalyst, passing hydrogen gas into said solution, under reduced pressure and at ambient temperature, till the completion of the reaction and to obtain reaction mass, neutralizing the reaction mass with a weak alkali till the desired pH is achieved, extracting l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol of formula (4) (R=OMe, R1=Me) with an organic solvent and treating it with an alcohol saturated with dry hydrogen chloride gas, refluxing the reaction mixture, and cooling the same to obtain
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hydrochloride salt of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol of
formula (4) (R=OMe, R,=Me).
It is an embodiment of the present invention wherein the salt of the compound (3) is
derived from acetic acid or oxalic acid or sulfonic acid, preferably acetic acid or oxalic
acid.
It is also an embodiment of the present invention wherein the alcohol is selected from the
group consisting of C1-C8 alcohols, preferably methanol.
Yet another embodiment of the present invention wherein the noble metal catalyst is
palladium on carbon or cobalt or Raney nickel.
Further embodiment of the present invention wherein Raney nickel is in the range of 10-
100%w/w.
It is an embodiment of the present invention wherein the palladium on carbon in the
range of 5-50% w/w, preferably 10%.
It is also an embodiment of the present invention wherein the hydrogen gas pressure is in
the range of 3-10 Kg/cm2 , preferably 4 Kg/cm2 .
It is an embodiment of the present invention wherein the hydrogenation reaction time is
about 3-12 hours, preferably 4 hours.
Yet another embodiment of the present invention wherein the weak alkali is potassium
carbonate or sodium carbonate or potassium bicarbonate or sodium bicarbonate,
preferably potassium carbonate.
Still another embodiment of the present invention wherein the pH is in the range of 10-
12, preferably 11.
It is an embodiment of the present invention wherein the organic solvent is ethyl acetate
or benzene or toluene, preferably ethyl acetate.
It is also an embodiment of the present invention wherein the alcohol used for dissolving
hydrogen chloride gas is selected from methanol or ethanol or isopropyl alcohol,
preferably isopropyl alcohol.
The invention is further defined by reference to the following examples describing in
detail the preparation and composition of the invention. It will be apparent to those
skilled in the art that many modifications, both to materials and methods, may be
practised without departing from the purpose and interest of the invention. The process
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of the present invention is described by the following examples, which are illustrative only and should not be construed as limit to the scope of the reaction in any manner.
Example 1
Preparation of alpha-4-anisyl-alpha-(l-hydroxycyclohexyl)acetonitrile (2) (R=OMe)
4-Methoxyphenyl acetonitrile (1) (R=OMe) (100 Kg, 679.44 mol) is mixed with cyclohexanone (153.2 Kg, 1042 mol) in a clean stainless steel reactor. The mixture is stirred at room temperature for 15-20 min. and then cooled to 0°C by applying brine in the reactor.
In another stainless steel reactor, sodium methoxide solution (25%, commercial, 400 L) is charged and cooled to 20°C. To this solution is added anhydrous methanol (400 L). The mixture is stirred and mixed thoroughly and cooled to -5°C. To the chilled sodium methoxide solution is added the mixture of PMPA and cyclohexanone at such a rate that the temperature of the reaction mixture does not go above -2°C. After the addition is complete the reaction mixture is stirred for 4-5 hours or until there is no more of starting material as indicated by TLC. Once the reaction is complete, the reaction mass is centrifuged at - 5°C to 0°C and the wet product is slurried in 600 L of water containing 15 L of acetic acid at 25-30°C and centrifuged, the wet product is washed with 200 L of water. The material is unloaded and dried at room temperature to obtain a free flowing white crystalline solid (145 Kg, 589.4 mol, 86.75%) of 99.8% purity, m.p. 112-118°C. 1HNMR. (CDC13): 7.30, 6.90 (q, 4H), 3.80 (s, 3H), 3.75 (s, 1H), 1.55 (m, 10H); I3C NMR (CDCI3): 159.8, 130.8, 123.8, 120.00, 114.1, 72.9, 55.55, 49.5, 34.9, 25.3, 21.6; IR (KBr): 3491, 3410cm~1(-OH), 2251cm-1 (-CN).
Example - 2
Preparation of l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe)
A round-bottomed flask of 2000 ml capacity equipped with stirrer and nitrogen inlet is charged with cyanoalcohol (2) (R=OMe) (50 g, 0.204 mol) dissolved in isopropyl alcohol (400 ml) and ammonium carbonate (9.7 g).
Commercially available Raney nickel (60 g, wet) is washed with demineralised water until it is free of alkali or until the water washings are neutral to litmus. The Raney nickel is further washed with isopropyl alcohol to remove any residual water in the catalyst. The freshly washed Raney nickel is charged into the reaction vessel and the reaction mass is
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stirred vigorously and treated under reflux at 70-76°C with 99% hydrazine hydrate (100 ml). The mixture is maintained at this temperature for 4-6 hours or until the TLC of the reaction mixture indicates completion of the reaction. The reaction mass is cooled to room temperature and the catalyst is filtered off. The solvent used in the reaction is distilled off under vacuum to obtain a clear, colorless liquid. Ethyl acetate (320 ml) is added to the mixture followed by acetic acid (11 ml). The mixture is stirred under reflux for 1-2 hours. The ethyl acetate solution is cooled to 25-30°C to obtain a white solid, which has been characterized as the acetate salt. The acetate salt thus obtained is further crystallized from ethyl acetate to obtain the pure salt (42 g, 67%, purity by HPLC 98.8%),m.p.l63-165°C.
Example- 2 A
Reduction of cyanoalcohol (2) (R=OMe) and preparation of (3) (R=OMe) oxalate Alpha-4-anisyl-alpha-(l-hydroxycyclohexyl)acetonitrile (2) (R=OMe) (100 g), oxalic acid (100 g), methanol (1 L) and 10% palladium on charcoal (20 g, 50% wet) are charged into an autoclave and purged with nitrogen. Nitrogen and air are vented out. The operation is repeated twice with nitrogen and then thrice with hydrogen. The autoclave is now pressurized with hydrogen to 8-10 Kg/cm2 . The contents are stirred at this pressure and at about 35°C for 12 hours. The completion of reduction is ascertained by TLC or HPLC. The contents are cooled to 20-25°C and filtered. The clear filtrate is concentrated under vacuum at less than 60°C. Toluene (200 ml) is added to the residue. The mixture is cooled to 25-30°C and the oxalate salt is filtered off and air-dried for 8-12 hours. Yield 147 g (> 99%), purity about 95% (HPLC), m.p.l84°C.
The acetate salt of (3) can be prepared likewise by carrying out the reduction of (2) in acetic acid using 10% palladium on charcoal catalyst.
Example - 3
Preparation of l-[2-Dimethylamino-l-(4-methoxyphenyl)ethyl]cyclohexanol (4) (R=OMe, R1=Me) hydrochloride (Venlafaxine hydrochloride) from the acetate salt of(3)(R=OMe)
A glass lined reactor is charged with 1 -[2-Amino-1 -(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) as its acetate salt (10 g, 0.0326 mol) dissolved in methyl alcohol (70 ml). To this solution is added formaldehyde solution
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(37-40%) (8 ml) and Raney nickel (4 g). The reaction vessel is pressurized with nitrogen and nitrogen is vented out. The reaction vessel is again pressurized with hydrogen up to 4 Kg/cm2 . The mixture is stirred at room temperature, preferably at 20-25°C for a period of 8 hours or until TLC of the reaction mixture shows the absence of the starting material. Once the reaction is complete the catalyst is filtered off carefully through a hyflo bed. The filtrate is concentrated under vacuum. The product thus obtained is taken in water and neutralized with an inorganic base such as sodium or potassium carbonate or sodium or potassium bicarbonate, preferably potassium carbonate until the pH of the solution is 11. The neutralized solution is extracted with ethyl acetate (50×3 ml). The combined ethyl acetate layer is washed with water and dried over anhydrous sodium sulfate. The sodium sulfate is filtered off and ethyl acetate is concentrated under vacuum. The material thus obtained is the venlafaxine base, which is dissolved in ethyl acetate (100ml) and taken in a round-bottomed flask equipped with a stirrer and an addition funnel. Isopropyl alcohol saturated with dry hydrogen chloride gas is now added to the ethyl acetate mixture over a period of 2-3 hours at 20-25°C till a pH of 2 is reached. The exothermicity of this reaction is controlled by the rate of addition. Finally once the addition is complete, the mixture is refluxed for 1-2 hours and cooled to room temperature and finally to 0°C. The product is kept stirring at this temperature for another 1-2 hours and the precipitated solid is filtered off to obtain a white solid. The solid has been identified as venlafaxine hydrochloride (8 g, 80%, purity 98.5%).
Example - 3 A
Preparation of l-[2-Dimethylamino-l-(4-methoxyphenyl)ethyl]cyclohexanol] (4) (R=OMe, R]-Me) hydrochloride the acetate salt of (3) (R=OMe)
A glass lined reactor is charged with 1 -[2-Amino-l -(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) as its acetate salt (10 g, 0.0326 mol) dissolved in methyl alcohol (70 ml). To this solution is added formaldehyde solution (37-40%) (8 ml) and palladium on carbon (2 g). The reaction vessel is pressurized with nitrogen and nitrogen is vented out. The reaction vessel is again pressurized with hydrogen up to 4 Kg/cm2 of hydrogen pressure. The mixture is stirred at room temperature, preferably at 20-25°C for a period of 8 hours or until TLC of the reaction mixture shows the absence of the starting material.
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Once the reaction is complete the catalyst is filtered off carefully through a hyflo bed. The filtrate is concentrated under vacuum. The product thus obtained is taken in water and neutralized with potassium carbonate until the pH of the solution is 11. The neutralized solution is extracted with ethyl acetate (50x3 ml). The combined ethyl acetate layer is washed with water and dried over anhydrous sodium sulfate. The sodium sulfate is filtered off and ethyl acetate is concentrated under vacuum. The material thus obtained is venlafaxine base, which is dissolved in ethyl acetate (100ml) taken in a round-bottomed flask equipped with a stirrer and an addition funnel. Isopropyl alcohol saturated with dry hydrogen chloride gas is now added to the ethyl acetate mixture over a period of 2-3 hours at 20-25°C till a pH of 2 is reached. The exothermicity of this reaction is controlled by the rate of addition. Finally, once the addition is complete, the mixture is refluxed for 1-2 hours and cooled to room temperature and finally to 0°C. The product is kept stirring at this temperature for another 1-2 hours and the precipitated solid is filtered off to obtain a white solid. The solid has been identified as venlafaxine hydrochloride (7.5 g, 75%, purity 98.9%)
Example - 3B
Preparation of l-[-2-Dimethylamino-l-(4-methoxyphenyl)ethyl]cyclohexanol (4) (R=OMe, R1=Me) hydrochloride from (3) (R=OMe)
A glass lined reactor is charged with 1 -[2-Amino-l -(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe) (free base) (10 g, 0.0326 mol) dissolved in methyl alcohol (70 ml). To this solution is added formaldehyde solution (37-40%) (8 ml) and Raney nickel (4 g). The reaction vessel is pressurized with nitrogen and nitrogen is vented out. The reaction vessel is again pressurized with hydrogen up to 4 Kg/cm2 of hydrogen pressure. The mixture is stirred at room temperature, preferably at 20-25°C for a period of 8 hours or until TLC of the reaction mixture shows the absence of the starting material.
Once the reaction is complete the catalyst is filtered off carefully through a hyflo bed and the filtrate is concentrated under vacuum. The product thus obtained is taken in water and treated with potassium carbonate to make the mixture strongly alkaline (pH 11). The mixture is extracted with ethyl acetate (50x3 ml). The combined ethyl acetate layer is washed with water and dried over anhydrous sodium sulfate. The sodium sulfate is
15

filtered off and ethyl acetate is concentrated under vacuum. The material thus obtained is venlafaxine base, which is dissolved in ethyl acetate (100 ml) and taken in a round-bottomed flask equipped with a stirrer and an addition funnel. Isopropyl alcohol saturated with dry hydrogen chloride gas is now added to the ethyl acetate mixture at 20-25 °C over a period of 2-3 hours till a pH of 2 is reached. The exothermicity of this reaction is controlled by the rate of addition. Finally once the addition is complete, the mixture is refluxed for 1-2 hours and cooled to room temperature and then to 0°C. The product is kept stirring at this temperature for another 1-2 hours and the precipitated solid filtered off to obtain a white solid. The solid has been identified as venlafaxine hydrochloride (6 g, 60%, purity 99.2%).
Example 3C
Preparation of l-[-2-Dimethylamino-l-(4-methoxyphenyl)ethyl]cyclohexanol (4) (R=OMe, R1=Me) hydrochloride from the oxalate salt of (3) (R=OMe) The oxalate salt of the aminoalcohol (3) (R=OMe) (80 g), methanol (1 L), 10% palladium on charcoal (20 g, 50% wet) and aqueous formaldehyde (about 37%, 80 ml) are charged into an autoclave. Nitrogen gas is purged in and vented out to replace air. The operation is repeated twice and then with nitrogen gas thrice. The autoclave is pressurized with hydrogen gas to 8-10 Kg/cm2 and maintained with stirring at this pressure and about 30°C for 12 hours.
After the completion of reaction, as ascertained by HPLC, the contents are cooled to 20-25°C and filtered. The bed is washed with methanol (80 ml). The combined filtrates are concentrated to 80 ml. Toluene (200 ml) and solid sodium carbonate (30 g) are added and the mixture is stirred for 1 hr and filtered.
The clear filtrate is washed with water (3x40 ml) and then with distilled under vacuum below 70°C to remove the solvents. Isopropyl alcohol (80 ml) is added to the residue and distilled off under vacuum. The residual mass is cooled, dissolved in isopropanol (120 ml) and treated with isopropanolic hydrogen chloride to pH 1. The mixture is stirred at 25-30°C for 30 min. and then at 0-5°C and filtered. The precipitate is dried on the filter for 30 min. to get venlafaxine hydrochloride (28.5 g) of purity 98% (HPLC). We have described above the invention with respect to particular embodiments; it will be apparent to those skilled in the art that various changes and modifications may be made
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without departing from the spirit and scope of the invention as defined in the claims. Such conditions are also intended to fall with in the scope of the appended claims.
Advantages of the present invention
1. The process steps of the present invention can be carried out at lower pressure and temperature levels.
2. The process of the present invention avoids the use of corrosive reagents such as formic acid.

Documents:

257-CHE-2006 AMENDED CLAIMS 22-09-2011.pdf

257-CHE-2006 AMENDED PAGES OF SPECIFICATION 22-09-2011.pdf

257-CHE-2006 CORRESPONDENCE PO.pdf

257-CHE-2006 EXAMINATION REPORT REPLY RECEIVED 22-09-2011.pdf

257-CHE-2006 FORM-18.pdf

257-che-2006-abstract.pdf

257-che-2006-claims.pdf

257-che-2006-correspondence-others.pdf

257-che-2006-description(complete).pdf

257-che-2006-form1.pdf

257-che-2006-form26.pdf

257-che-2006-form3.pdf

257-che-2006-form5.pdf

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Patent Number

250329

Indian Patent Application Number

257/CHE/2006

PG Journal Number

52/2011

Publication Date

30-Dec-2011

Grant Date

26-Dec-2011

Date of Filing

17-Feb-2006

Name of Patentee

HIKAL LIMITED

Applicant Address

32/1, KALENA AGRAHARA, BANNERAGHATTA ROAD, BANGALORE 560 076

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. KUPPUSWAMY NAGARAJAN	32/1, KALENA AGRAHARA, BANNERAGHATTA ROAD, BANGALORE 560 076
2	DR. IYER VENKATACHALAM SANKAR	32/1, KALENA AGRAHARA, BANNERAGHATTA ROAD, BANGALORE 560 076
3	MARIADAS ARUL SELVAN	32/1, KALENA AGRAHARA, BANNERAGHATTA ROAD, BANGALORE 560 076
4	DR, RAJENDRA PERSHAD GUPTA	32/1, KALENA AGRAHARA, BANNERAGHATTA ROAD, BANGALORE 560 076

PCT International Classification Number

C07C87/28

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA