Title of Invention

A PROCESS FOR THE PREPARATION OF PHENETHYLAMINE DERIVATIVE, AN INTERMEDIATE OF VENLAFAXINE HYDROCHLORIDE

Abstract

A process for the preparation of compound of formula (3) (R=OMe, OH) said process comprising the steps of: dissolving the substituted phenylacetonitrile (2) (R=OMe, OH) in an alcohol and ammonium salt to obtain a reaction mixture, and treating the reaction mixture with hydrazine hydrate in the presence of a noble metal catalyst to obtain l-[2-amino-l-(4-substituted phenyl)ethyl]cyclohexanol (3), an important intermediate for the synthesis Venlafaxine (R=OMe, R1=Me) and its acid addition salts.

Full Text

A PROCESS FOR THE PREPARATION OF PHENETHYLAMINE DERIVATIVE, AN INTERMEDIATE OF VENLAFAXINE HYDROCHLORIDE Field of Invention The present invention relates to an improved process for the preparation of phenethylamine derivatives by reduction of substituted phenylacetonitrile compounds. The present invention particularly relates to a process for the preparation of pure l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe), an important intermediate for the synthesis Venlafaxine (4) (R=OMe, R1=Me) and its acid addition salts. 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 (+)-l-[2-(dimethylamino)-l-(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 Wherein R is methoxy or hydroxy, R1 is methyl and the reaction conditions are; a. LDA in cyclohexanone at -78°C b. RI1/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 cyclohexanone at -78°C under the influence of n-butyl lithium following the methods 2 known in the literature (Sauvette et al., Tetrahedron, 34, 2135, 1978) to form l-[cyano-(4-methoxyphenyl)methyl]cyclohexanol (2) (R=OMe), as represented in Scheme-1, followed by reduction under high pressure to an amine (3) (R=OMe), 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) viz. 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 carbonyl 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 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), with cyclohexanone to generate compound of formula (2) (R=OMe), Scheme-1, using a base selected from NaOH, KOH or 10% aqueous NaOH or 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 l-[2-amino-l-(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=OMe), 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 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 in an 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. Objects of the present invention The primary object of the present invention is to provide a process for the preparation of substantially pure l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (3) (R=OMe), an important intermediate for the synthesis of Venlafaxine (4) (R=OMe, R1=Me) and its acid addition salts. 5 An object of the present invention is to provide a simple and commercially viable process for the preparation of a pure l-[2-amino-l-(4-substituted phenyl)ethyl]cyclohexanol (3) intermediate of formula (3) (R=OMe, OH) from a substituted phenylacetonitrile (2) (R= OMe, OH). Another object of the present invention is to provide a process for the preparation of pure l-[2-amino-l-(4-substitutedphenyl)ethyl]cyclohexanol (3) (R=OMe, OH) intermediate from substituted phenylacetonitrile compounds of formula (2) (R=OMe, OH) without using highly inflammable hydrogen gas for reduction. Yet another object of the present invention is to provide a simple process for the preparation of a pure l-[2-amino-l-(4-substituted phenyl)ethyl]cyclohexanol intermediate of formula (3) (R=OMe, OH) by avoiding toxic and corrosive chemicals such as formic acid, acetic acid, in the reduction step of cyano to amino compound. It is also an object of the present invention to provide a process for the preparation of a pure l-[2-amino-l-(4»substituted phenyl)ethyl]cyclohexanol intermediate of formula (3) (R=OMe, OH) by avoiding the use of halogenated hydrocarbon solvents for extraction. It is a further object of the present invention to provide a process for the preparation of 1- [2-amino-l-(4-substituted phenyl)ethyl]cyclohexanol intermediate of formula (3) (R=OMe, OH) that does not require an elaborate work up or purification processes like chromatography for the isolation of end products. Summary of the Invention The present invention provides a process for the preparation of compound of formula (3) (R=OMe, OH) said process comprising the steps of: dissolving the substituted phenylacetonitrile (2) (R=OMe, OH) in an alcohol and ammonium salt to obtain a reaction mixture, and treating the reaction mixture with hydrazine hydrate in the presence of a noble metal catalyst to obtain l-[2-amino-l-(4-substituted phenyl)ethyl]cyclohexanol (3), an important intermediate for the synthesis Venlafaxine (R=OMe, R1=Me) and its acid addition salts. Detailed Description of the Invention Accordingly, the present invention provides an improved process for the preparation of 1- [2-amino-l-(4-substituted phenyl)ethyl]cyclohexanol of compound of general formula (3) (R=OMe, OH), more particularly l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol 6 (3) (R-OMe) which is an important intermediate in the synthesis of the antidepressant venlafaxine hydrochloride (4) (R=OMe, R1=Me) used for the treatment of diseases of the central nervous system. The invention also describes the isolation of (3) (R=OMe) as its addition salt, particularly acetate and oxalate. Process for the preparation of l-[cyano-(4-methoxyphenyl)methyl]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 the preparation of l-[2-amino-l- (4-methoxyphenyl) ethyl] cyclohexanol (3) (R=OMe) The reaction mixture thus obtained is dissolved in an alcoholic solvent selected from the group consisting of C1-C8 alcohols, preferably isopropyl alcohol and subjected to reduction in presence of a source of ammonia as an ammonium salt such as ammonium acetate or carbonate, in particular ammonium carbonate or an aliphatic tertiary amine like triethyl amine and a source of hydrogen in the presence of a metal catalyst such as Raney nickel or palladium on charcoal. The reaction is carried out in presence of hydrazine hydrate (80-99%) as the preferred source of hydrogen. The temperature of the reaction is kept below 80°C and most preferably below 70°C or between 65-75°C. The reaction is worked up generally by distillation of alcohol and hydrazine hydrate mixture under vacuum to obtain crude amine as a brown liquid. Refluxing with an organic solvent such as low boiling esters or hydrocarbons like benzene or toluene can purify this and the preferred solvent is ethyl acetate. The purification step results in amine of very high purity, which can be directly used for the synthesis of venlafaxine. The amine thus obtained above can be converted to the corresponding acid addition salts viz., hydrochloride or sulfate, acetate, oxalate and like by methods known to those skilled in the art. It is generally known in the literature that hydrazine is used in catalytic amounts as a stabilizer for prolonged storage of any organic amine. In this process the use of hydrazine hydrate as a source of hydrogen for reduction of nitrile to amine yields good quality 7 amine, which can be stored for prolonged periods without decomposition. Furthermore, the presence of traces of hydrazine hydrate by virtue of its reducing properties (antioxidant) enhances stability of the amine. The reaction scheme of the process steps of the present invention is as follows: Accordingly, the present invention provides a process for the preparation of compound of formula (3) said process comprising the steps of: dissolving the substituted phenylacetonitrile (2)(R=OMe, OH) in an alcohol and ammonium salt to obtain a reaction mixture, and treating the reaction mixture with hydrazine hydrate in the presence of a noble metal catalyst to obtain l-[2-amino-l-(4-substitutedphenyl)ethyl]cyclohexanol (3). It is also an embodiment of the present invention wherein substituted phenylacetonitrile (2) is l-[cyano-(4-methoxyphenyl)methyl]cyclohexanol. Another embodiment of the present invention wherein the alcohol is selected from the group consisting of C1-C8 alcohols, preferably isopropanol. 8 It is also an embodiment of the present invention wherein the ammonium salt is ammonium carbonate or ammonium acetate, preferably ammonium carbonate. It is an embodiment of the present invention wherein the concentration of hydrazine hydrate is in the range of about 80-99%, preferably 99%. It is another embodiment of the present invention wherein the noble metal catalyst is palladium on carbon or Raney nickel, preferably Raney nickel. The invention is further defined by reference to the following examples, which are illustrative only and should not be construed as limiting the scope of the present invention. Example 1 Preparation of alpha-4-anisyl-alpha-(l-hydroxycyclohexyl)acetonitrile (2) (R=OMe) 4-Methoxyphenylacetonitrile (1) (R=OMe) (100 Kg, 679.44 mol) is mixed with cyclohexanone (153.2 Kg, 1563 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. Once the addition is complete the reaction mixture is stirred for 4-5hours 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 centrifuged, and washed with 200 L of water. The material is unloaded and dried at room temperature to obtain a free flowing white crystalline solid 9 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 nitrile (2) (R=OMe) (50 g, 0.204 mol) dissolved in isopropyl alcohol (400 ml) and ammonium carbonate (9.7g). Commercially available Raney nickel (60g, 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 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 to colourless liquid. Ethyl acetate (320ml) is added followed by glacial 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 purified in ethyl acetate to obtain the salt (42 g, 67%, purity by HPLC 98.8%), m.p. 163-165°C. The oxalate salt is prepared likewise, > 99% yield, purity about 95% (HPLC), m.p. 184°C. 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 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. By using the process steps of the present invention, especially by adopting the use of hydrazine hydrate, the degradation of the amine (3) (R=OMe) as a result of oxidation from air and light is avoided. 2. The process of the present invention avoids the use of hydrogen gas. 10

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