An improved process for production of intermediate of antidepressant agent
Technical field:
The present invention relates to an improved process for the synthesis of an intermediate of venlafaxine, an aryl alkylamine compound, more particularly to substituted phenyl ethylamine derivative. The present invention particularly relates to an improved process for preparation of l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol by reducing 1- [cyano(4-methoxyphenyl)methyl]cyclohexanol with Raney nickel by using advantageously selected solvent like C1 or homolpgous branched or unbranched alcohols which permits lower catalyst loading, and substantially increases the use of substrate concentration thereby enhancing the throughput per reactor volume. This intermediate is converted into further intermediates using improved processes leading to better cost benefits, yields and purity.
Background and prior art:
Venlafaxine is a phenethylamine bicyclic derivative, chemically not related to tricyclic, tetracyclic or other available antidepressant agents. Studies indicate that it has comparable or possibly slightly greater efficacy and also lesser side effects compared to other selective serotonin reuptake inhibitors. Venlafaxine' s unique chemical structure and neuro-pharmacological activity gives it a broad spectrum of activity over other antidepressants. Venlafaxine is chemically known as (±)-l-[2-dimethylamino-l- (4-methoxy- phenyl)ethyl]-cyclohexanol. There are many prior art documents available for preparation of venlafaxine and its intermediates.
US4535186 discloses the preparation of l-[2-amino-l- (4-methoxyphenyl)ethyl] cyclohexanol by dissolving l-fcyanotø-methoxypheny^methyljcyclohexanol in a mixture of ammonia and ethanol and hydrogenating over 5% Rh/ Alumina.
WO0059851 describes the reduction of l-[cyano(p-methoxyphenyl)methyl] cyclohexanol carried out with cobalt chloride and sodium borohydride in methanol to yield l-[2-amino- l-(4-methoxyphenyl)ethyl]cyclohexanol.
Preparation of l-[2-amino-l- (4-methoxyphenyl)ethyl]cyclohexanol was reported in US6756502 wherein 2-(4-methoxy-phenyl)-l-oxa-spiro[2.5]octane-2-carbonitrile was reduced with Raney nickel catalyst in ammoniacal ethanol at room temperature under a pressure of 500IcPa for 7 hrs.
EPOl 12669 reports a group of substituted phenyl ethylamine derivatives prepared by reducing the nitrile group to primary amine group by using various reducing agents such as Pd/C(10%) and hydrogen in ethanol media, lithium aluminium hydride in acid media and Rh/ Alumina in ammoniacal ethanol.
US2004106818 describes the reduction of * l-[cyano (p-methoxyphenyl)methyl] cyclohexanol with Raney nickel approximately 50%w/w with reference to starting compound in presence of ammoniacal methanol.
Such conventional processes tend to suffer from one or more of the following disadvantages: they use expensive and/or hazardous reagents such as Rh/ Alumina and costly reducing agents like sodium borohydride and BF3 etherate; they use expensive organic catalysts; they have proved difficult to commercialize and/or scale up in practice; they generate low product yields and/or low product purity.
WO03080560 describes the synthesis of phenyl ethylamine compounds wherein l-[cyano (p-methoxyphenyl)methyl] cyclohexanol was reduced with Raney nickel in a concentration of 20-75%w/w with reference to the compound l-[cyano(p- methoxyphenyl)methyl]cyclohexanol in presence of ammoniacal methanol. This patent application states that the lower catalyst amounts leads to reduced retrogression product of the starting material.
The draw back of the above prior art is the use of catalyst concentration which is very high with reference to the stalling compound. This ultimately leads to high cost at the industrial scale. The low concentration of the starting material with reference to catalyst
(adverse ratio) leads to increased cost of manufacturing of the phenyl ethylamines. Also the problem with prior art reaction is carrying out the reduction reaction at steady temperature/ pressure, which gives inconsistent results and poor yields. Hence, the present inventors have made extensive investigations and developed the reaction conditions which ensure the consistency in yield and quality of the final product. So, this leaves ample scope for further investigation to carry out the reduction in industrially viable manner at economic costs.
The present invention overcomes this problem by advantageously selecting a solvent like C1 and other homologous branched and unbranched alcohols which permits the lower catalyst loading of Raney nickel and also allows a substantial increase in the use of substrate concentration thereby enhancing the throughput per reactor volume. The lower catalyst loading was also achieved, at least partly, by carrying out the reaction with a ramped temperature / pressure profile rather than a steady profile discussed in prior art.
Objectives of the invention:
It is an object of the present invention to ameliorate at least one of the disadvantages of the prior art and/or to provide as useful alternative a process for the preparation of substituted aryl alkylamine compounds.
Another objective of the present invention is to provide simple and cost effective process for preparation of substituted phenyl ethylamine compounds.
Another objective of the invention is to reduce the catalyst loading by advantageously changing the solvent thereby providing cost effective method.
Further objective of the present invention is to make use of the substrate in higher concentration thereby increasing the throughput per reactor volume.
Yet another objective of the present invention is to provide the isolation of the amine in very high purity in the form of suitable salts.
Summary of the invention:
The present invention discloses an improved process for the synthesis of an intermediate of venlafaxine an aryl alkylamine compound, '.more particularly, substituted phenyl ethylamine derivative. The preferred embodiment of the present invention discloses an improved process for preparation of l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol by reducing l-[cyano( 4-methoxyphenyl)methyl] cyclohexanol with Raney nickel by using an advantageously selected solvent such as C1 and homologous branched/unbranched alcohols which permits lower catalyst loading and substantially increases the use of substrate concentration thereby enhancing the throughput per reactor volume. This intermediate is converted into further intermediates using improved processes leading to better-cost benefits, yields and purity.
Detailed description:
According to the present invention there is provided a process for preparation of substituted aryl alkylamine compounds comprising the steps for providing a correspondingly substituted aryl acetonitrile substrate and contacting the substrate under conditions effective for the reduction of the substrate with a suitable reducing agent in the presence of an alcoholic solvent selected from Cl to C4 alcohol and using a catalyst,
Raney nickel, wherein the reduction is carried out during an initial period using a first reaction conditions and, during a subsequent period, in a second reaction conditions different from the first.
The first reaction condition may comprise a first temperature condition, in which case the second reaction condition comprises a second temperature condition different from the first.
Preferably the second temperature condition is higher than the first temperature condition.
The first temperature condition is preferably at least 100C. The first temperature condition may be in the range of from about 10° C to about 15°C.
The second temperature condition is preferably at least about 5° C, more preferably at least about 1O0C3 still more preferably at least about 15°C, most preferably at least about 20°C or 25°C higher than the first temperature condition.
The first reaction condition may comprise a first pressure condition, in which case the second reaction condition comprises a second pressure condition different from the first. Preferably the second pressure condition is higher than the first pressure condition.
The first pressure condition is preferably at least about 1.5 kg/cm2 of hydrogen, more preferably at least about 2.0 kg/cm2' of hydrogen. The second pressure condition is preferably at least about 3.5 kg/cm2 of hydrogen, most preferably at least about 4. kg/cm2 of hydrogen, or 5.0 kg/cm2 of hydrogen higher than the first pressure condition.
The second pressure condition is preferably at least about 5 kg/cm2 of hydrogen, more preferably at least about 6.0 kg/cm2 of hydrogen , most preferably at least about 7.0 kg/cm2 of hydrogen.
The reduction may be carried out at 10-15°C at a pressure of 1.5-2 kg/cm2 of hydrogen for one hour. After one hour the temperature may be raised to 350C and the pressure of the reaction may be raised to 5- 7 kg/cm2, most preferably 7kg/cm2. The reaction may be carried out for about 6 to 8 hrs under the specified conditions to allow the complete transformation to the desired product.
Suitable reducing agents for use in this ramped temperature and/or pressure profile process of the invention include hydrogen. Suitable catalysts include Raney nickel. Suitable solvents include C1 to C4 alcoholic solvents selected from methanol, ethanol, isopropanol, and tertiary butanol.
Isopropanol is one preferred solvent for use in the process of the invention. The substituted aryl acetonitrile substrate is preferably a substituted phenyl acetonitrile substrate and/or a substituted alkoxy aryl acetonitrile substrate, more preferably a substituted alkoxy phenyl acetonitrile, most preferably a substituted 4-methoxy-phenyl
acetonitrile. One particularly preferred substrate is l-[cyano( 4- methoxyphenyl)methyl]cyclohexanol.
One preferred process according to the invention is for the production of l-[2-amino-l-
(4-methoxyphenyl)ethyl] cy clohexanol .
In one process according to the invention the product is itself an intermediate in the manufacture of Venlafaxine. This intermediate may be converted into further intermediates, and ultimately into Venlafaxine, using conventional, suitable or improved processes.
The selection of the solvent in the process of the invention and/or the selection of the reduction catalyst, and/or the selection of the rammed temperature and/or pressure profile provides an advantage in that higher substrate to catalyst ratios and also higher substrate concentration can be achieved than has hitherto been possible, thereby providing a cost effective method for manufacturing Venlafaxine intermediates. As a result, cost savings may be realized both by using less catalyst and by increasing the throughput of the substrate through the reaction vessel.
The substrate to catalyst (s/c) ratio in the process of the invention is preferably at least about 20:1, more preferably at least about 10:1, most preferably at least about 6:1. i.e. the catalyst loading with reference to the substrate is at least 5%, more preferably about 10%, most preferably about 17%. The catalyst . concentration used in the reaction is generally 5-17% in relation to that of substrate.
One advantage of the invention is that the substrate concentration is preferably in the range of 10-25% w/v, more preferably in the range of 15-22% w/v.
Another advantage of the invention is that the product amine may be isolated in very high purity in the form of suitable salts.
The process of the invention preferably comprises, after the reduction, recovering the catalyst from the reaction mixture (by filtration for example) and then removing the solvent by, for example, vacuum distillation, and isolating the product in the form of a suitable salt, such as hydrochloride, formate, acetate, tartrate or maleate.
The yield of the desired amine product is preferably at least about 75%, more preferably at least about 80%, most preferably at least about 85%.
The purity of the desired amine product is preferably at least about 90%, more preferably at least about 95%, still more preferably at least about 97% and most preferably at least about 98%.
Therefore one preferred process according to the invention comprises producing l-[2- amino-l-(4-methoxyphenyl)ethyl]cyclohexanol by reducing l-[cyano(4- methoxyphenyl)methyl]cyclohexanol with a suitable reducing agent and a Raney nickel catalyst in the presence of a homologous branched or straight chain alcoholic solvent, using a substrate to catalyst ratio effective to permit lower catalyst loading and also substantial increase in the use of substrate poncentration thereby enhancing the throughput per reactor volume. The present invention advantageously selected isopropanol as a solvent and a ramped temperature / pressure profile rather than a steady profile to reduce the catalyst loading. Thus, the use of lower catalyst loading ultimately brings down the cost of catalyst and increases the yield of the final product. The lower catalyst ratio may be achieved, at least partly, by carrying out the reaction with a ramped temperature / pressure profile rather than a steady profile discussed in prior ait. The synthetic route is shown in scheme 1 below.
Scheme 1
l-[2-amino-l-(p-methoxyphenyl)ethyl]cyclohexanol l-[cyano(p-methoxyphenyl)methyl]cyclohexanol
An autoclave was charged with a mixture of isopropanol, water and aq. ammonia, and the reaction mass cooled to 100C, l-[cyano (p-methoxyphenyl)methyl] cyclohexanol added.
The reduction was carried out with Raney nickel catalyst at a temperature range of 10- 350C at a pressure of 1.5-7kg/cm2 as described above.
The reaction was monitored by TLC and HPLC. After the completion of the reaction the catalyst was filtered and isopropanol was distilled off to obtain the l-[2-amino-l-(4- methoxyphenyl)ethyi]cyclohexanol. The product was extracted with suitable solvent and treated with suitable acids selected from hydrochloric acid, formic acid, acetic acid, tartaric acid, or with maleic acid and isolated the product in the form of salt of the acid used. The free base is then generated by common methods known to an expert in the field. This results in isolation of the desired product with high purity.
The invention will now be more particularly described with reference to the following Examples.
Example 1
450ml isopropanol , 100ml aq. ammonia (22%) and 50 ml water was charged in an autoclave and the mass cooled to 10°C. 100 gms of l-[cyano( 4-methoxyphenyl)methyl] cyclohexanol was added to it. To this reaction mixture 17 gms of Raney nickel was added. The reduction was carried out at 10-15°C at a pressure of 2 kg/cm of hydrogen. After one hour the temperature was raised to 350C and the pressure of the reaction was also raised to 7 kg/cm2' The reduction was carried out at these conditions until the conversion is complete as monitored by TLC / HPLC. The reaction takes 6-8hrs to complete. After the completion of the reaction, the catalyst was filtered and isopropyl alcohol distilled off under vacuum. The product was extracted with ethyl acetate (600ml), followed by addition of. glacial acetic acid (20gms) leading to the isolation of l-[2- amino-l-(4-methoxyphenyl)ethyl] cyclohexanol aqetate. Typically, the yield of the final purified product is 80-85% with the purity >99%.
Example 2
450 ml t-butanol, 100ml aq. ammonia (22%) and 50 ml water was charged in an autoclave and cooled the mass to 10°C. 100 gms of l-[cyano( 4-methoxyphenyl)methyl] cyclohexanol was added to it. To this reaction mixture 17 gms of Raney nickel was added. The reduction was carried out at 10-15°C at a pressure of 2 kg/cm2 of hydrogen. After one hour the temperature was raised to 350C and the pressure of the reaction was also raised to 7 kg/cm2' The reduction was carried out at these conditions until the conversion is complete as monitored by TLC / HPLC. The reaction takes 6-8hrs to complete. After the completion of. the reaction, the catalyst was filtered and t-butanol distilled off under vacuum. The resultant product l-[2-amino-l- (4- methoxyphenyl)ethyl]cyclohexanol was then isolated in the form of a suitable salt. The yield of the isolated purified product ranges from 80-85%. The purity of the final product > 99 %
Example 3
900 ml isopropanol , 100ml aq. ammonia (22%) and 50 ml water was charged in an autoclave and cooled the mass to 100C. 100 gms of l-[cyano( 4-methoxyphenyl)methyl] cyclohexanol was added to it. To this reaction mixture 17 gms of Raney nickel was added. The reduction was carried out at 10-15°C at a pressure of 2 kg/cm2 of hydrogen. After one hour the temperature was raised to 350C and the pressure of the reaction was also raised to 7 kg/cm2' The reduction was carried out at these conditions until the conversion is complete as monitored by TLC / HPLC. The reaction takes 6-8hrs to complete. After the completion of the reaction, the catalyst was filtered and isopropyl alcohol distilled off under vacuum. The resultant product l-[2-amino-l- (4- methoxyphenyl)ethyl] cyclohexanol was then isolated in the form of a suitable salt. The yield of the isolated purified product ranges from 80-85%. The purity of the final product: >99 %.
Example 4
450 ml isopropanol , 100ml aq. ammonia and 50 ml water was charged in an autoclave and the mass cooled to 100C. 100 gms of l-[cyano( 4-methoxyρhenyl)methyl]
cyclohexanol was added to it. To this reaction mixture 5 gms of Raney nickel was added. The reduction was carried out at 10-150C at a pressure of 2 kg/cm2 of hydrogen. After one hour the temperature was raised to 350C and the pressure of the reaction was also raised to 7 kg/cm2' The reduction was carried out at these conditions until the conversion is complete as monitored by TLC / HPLC. The reaction takes 6-8hrs to complete. After the completion of the reaction, the catalyst was filtered and isopropyl alcohol distilled off under vacuum. The resultant product l-[2-amino-l-(4- methoxyphenyl)ethyl] cyclohexanol was then isolated in the form of a suitable salt like hydrochloride, formate, acetate, tartarate and maleate. Typically, the yield of the final product is 80-85% with the purity >99%.
Example 5
1200 ml methanol , 100ml aq. ammonia and 50 ml water was charged in an autoclave and the mass cooled to 10°C. 100 gms of l-[cyano( 4-methoxyphenyl)methyl] cyclohexanol was added to it. To this reaction mixture 17 gms of Raney nickel was added. The reduction was carried out at 10-15°C at a pressure of 2 kg/cm2 of hydrogen. After one hour the temperature was raised to 350C and the pressure of the reaction was also raised to 7 kg/cm ' The reduction was carried out at these conditions until the conversion is complete as monitored by TLC / HPLC. The reaction takes 6-8hrs to complete. After the completion of the reaction, the catalyst was filtered and methanol distilled off under vacuum. The resultant product l-[2-amino-l-(4- methoxyphenyl) ethyl] cyclohexanol was then isolated in the form of a suitable salt like hydrochloride, formate, acetate, tartarate and maleate. Typically, the yield of the final purified product is 80-85% with the purity >99%.