Title of Invention	AN IMPROVED PROCESS FOR THE PRODUCTION OF 3,4,5,6,7,8-HEXAHYDRO-1-(ARYL METHYL) ISOQUINOLINES
Abstract	An improved process for the production of 3,4,5,6,7,8-hexahydro-l-(arylmethyl) isoquinolines of formula (2) wherein R is H or methoxy, which comprises stirring N-2-[l'- cyclohexenyl] ethyl-aryl autamide of formula (1) wherein R is H or methoxy group in an organic solvent with a Lewis acid and metal halide such as herein described at a temperature in the range of 0 to 80 °C, for a period in the range of 4-12 hours, removing the solvent by distillation under reduced pressure ,treating the above said reaction mixture with ammonia solution, extracting the product using a water immiscible organic solvent, washing the organic layer with sodium thiosulphate solution ,and removing the solvent under reduced pressure to get compound of formula (2).

Title of Invention

AN IMPROVED PROCESS FOR THE PRODUCTION OF 3,4,5,6,7,8-HEXAHYDRO-1-(ARYL METHYL) ISOQUINOLINES

Abstract

An improved process for the production of 3,4,5,6,7,8-hexahydro-l-(arylmethyl) isoquinolines of formula (2) wherein R is H or methoxy, which comprises stirring N-2-[l'- cyclohexenyl] ethyl-aryl autamide of formula (1) wherein R is H or methoxy group in an organic solvent with a Lewis acid and metal halide such as herein described at a temperature in the range of 0 to 80 °C, for a period in the range of 4-12 hours, removing the solvent by distillation under reduced pressure ,treating the above said reaction mixture with ammonia solution, extracting the product using a water immiscible organic solvent, washing the organic layer with sodium thiosulphate solution ,and removing the solvent under reduced pressure to get compound of formula (2).

Full Text	This invention relates to an improved process for the preparation of 3,4,5,6,7,8-hexahydro-l-(aryl methyl) isoquinolines. This invention particularly relates to an improved process for the production of 3, 4, 5, 6, 7, 8- hexahydro-l-(4-methoxy phenyl/phenyl methyl) isoquino lines of formula (2) wherein R is H or methoxy group. Dextromethorphan is an important and efficient anti-tussive drug of the present time.lt is prepared from an intermediate N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl methyl acetamide (la) wherein R is methoxy group. .The present invention relates to an improved process for the preparation of 3, 4, 5, 6, 7, 8- hexahydro-l-(4-methoxyphenyl/phenyl methyl) isoquinolines (2) from N-2-(l'-cyclohexenyl)ethyl-4-methoxy- phenyl/phenyl acetamides (1) particularly using Lewis acids like AlCls and ZnCl2, more particularly using anhydrous aluminium chloride and potassium iodide in a solvent .The compound (2) is one of the important intermediates for the production of dextromethorphan (3-methoxy,17- methyl (9α,13α, 14α ,morphinan) and its analogues. (Formula Removed) The literature on the cyclization of N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) to 3,4,5,6,7,8-hexahydro-l-(4-methoxy phenyl methyl) isoquinoline (2a) is scanty .The following are the references so far available in the literature . Hitherto 3,4,5,6,7,8- hexahydro-l-(4-methoxyphenylmethyl)- isoquinoline ( 2a) has been prepared by the methods described below : By cyclodehydration of amide (1) with phosphorous oxychloride (Tet. Lett,28,(41),pp- 4829 -32,1987). According to the method disclosed in this paper, the amide(l) is allowed to react with phosphorous oxycholoride in benzene in its reflux temperature .The drawback of the method is that heating is essential and benzene, a health hazard is used as solvent along with phosphorous oxychloride .The yield of (2) is also not mentioned in the reference. By cyclodehyd rat ion of amide (l)with phosphorous pentoxide( Helv .Chim. Acta. 33, pp 1437-1448 ,1950 ;ibid, 34,2211,1951) In this reported cyclization process the amide (1) is treated with phosphorous pentoxide in warm benzene .After completion of the reaction ,the reaction mixture is treated with ice and made strongly alkaline and extracted with ether and worked-up. The drawback of the method is that phosphorous pentoxide being very much hygroscopic and corrosive chemical has to be handled with outmost caution and also the solvent benzene is a health hazard . The yield of the process is 78% only . In this process several side products are also formed which are difficult to account for. By cycloaddition of amide (1) with phosphorous oxychloride ( US Patent,4270000, May 16, 1981 and U S Patent, 5892,044, April 6,1994 ). US database patent search revealed that according to the methods described in the above two patents the amide (1) is allowed to react with phosphorous oxychloride in a solvent and the mixture is heated at the reflux temperature of the solvent (toluene). The drawbacks of the process are same with those described in methods 1 and 2 above. The main objective of the present invention is to provide an improved process for the preparation of 3,4,5,6,7,8-hexahydro-l-(aryl methyl) isoquinolines. Another objective of the present invention is to provide a method for cyclization of N-2-(l'-cyclohexenyl )ethyl-4-methoxyphenyl acetamide (la) to 3,4,5,6,7,8-hexahydro-l-(4-methoxyphenylmethyl) isoquinoline (2a). Yet another objective of the present invention is to provide cyclization of N-2-(l'-cyclohexen-yl )ethyl-4-methoxy phenyl acetamide (la) to3,4,5,6,7,8-hexahydro-l-(4-methoxyphenylmethyl) isoquinoline (2a) by elimiminating the use of benzene as solvent. Accordingly, the present invention provides an improved process for the production of 3,4,5,6,7,8-hexahydro-l-(arylmethyl) isoquinolines of formula (2) wherein R is H or methoxy, shown in the drawing accompanying this specification which comprises stirring N-2-[l'- cyclohexenyl] ethyl-aryl autamide of formula (1) wherein R is H or methoxy group in an organic solvent with a Lewis acid and potassium halide at a temperature in the range of 0 to 80 °C, for a period in the range of 4-12 hours, removing the solvent by distillation under reduced pressure ,treating the above said reaction mixture with ammonia solution, extracting the product using a water immiscible organic solvent, washing the organic layer with sodium thiosulphate solution ,and removing the solvent under reduced pressure to get compound of formula (2). (Formula Removed) In an embodiment of the present invention the Lewis acid used may be halides of metal such as AlCl3, and ZnCl2 In another embodiment of the invention the ratio of metal halide & potassium halide used may be in the range of 1:4 to 1:6. In yet another embodiment of the invention the organic solvent may be such as acetonitrile, chloroform and dichloromethane. Water immicible solvent used may be such as diethyl ether, ethyl acetate and dichloromethane. Ammonia solution used may be in the range of 15% to30% The process of production of 3,4,5,6,7,8-hexahydro-l-(4-methoxy phenyl/phenylmethyl) isoquinoline ( 2) by cyclization of N-2-(l'-cyclohexenyl )ethyl -4-methoxy phenyl/phenyl acetamide of the formula (1) shown in the drawing (Scheme l) accompanying this specification which comprises stirring of (1) in an organic solvent like dichloromethane, chloroform, acetonotrile with anhydrous aluminium chloride-halides of potassium Like potassium iodide or potassium bromide in a ratio in the range of 1:4 to 1:6 at room temperature ,removing the solvent by distillation under reduced pressure ,treating with ammonia solution, extracting the product using a water immisscible organic solvent like diethyl ether, ethyl acetate, dichloromethane, washing the organic layer with 10 % sodium thiosulphate ,drying over anhydrous sodium sulphate and removing the solvent under reduced pressure . The details of the method disclosed in this invention have been described in the following specific examples which are provided to illustrate the invention only and therefore, these should not be construed to limit the scope of the present invention EXAMPLE 1: To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry acetonitrile (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(l'-cyclohexenyl)ethyl-4- methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 8 hr at room temperature . The solvent is removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the reaction mixture ( 00C) and then the reaction mixture is treated with 30% ammonia solution.This is then extracted with ethyl acetate (50x2 ml ) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure to get the desired product (2a), yield 2.41 gm, 95 %. Example 2 : To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry acetonitrile (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(1-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 4 hr at room temperature .The solvent is removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the o reaction mixture ( 0 C) and then the reaction mixture is treated with 30% ammonia solution.This is then extracted with ethyl acetate (50x2 ml) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure to get the desired product (2a). TLC has shown the presence of starting material and product. The product was separated by column chromatography over SiO2, yield 1.21 gm, 48 %. Example 3 : To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry acetonitrile (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 12 hr at room temperature. The solvent is removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the reaction mixture ( 00C) and then the reaction mixture is treated with 30% ammonia solution.This is then extracted with ethyl acetate (50x2 ml ) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure to get the desired product (2a). yield 2.35 gm, 94 %. Example 4 : To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry acetonitrile (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 12 hr at 0°C . The solvent is removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the reaction mixture ( o 0 C) and then the reaction mixture is treated with 30% ammonia solution.This is then extracted with ethyl acetate (50x2 ml) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure and chromatographed over silica gel using 9:1 petroleum -ether and ethyl acetate and after distillation of the solvent gave the desired product (2a). yield 2 gm, 80 %. Example 5 : To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry acetonitrile (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and refluxed for 12 hr at 80°C .The solvent is removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the reaction mixture ( 00C) and then the reaction mixture is treated with 30% ammonia solution.This is then extracted with ethyl acetate (50x2 ml) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure and chromatographed over silica gel using 9:1 petroleum -ether and ethyl acetate and after distillation of the solvent gave the desired product (2a). yield 1.01 gm, 40 %. Example 6 : To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry chloroform (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 12 hr at 25°C . The solvent is removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the reaction mixture ( 00C) and then the reaction mixture is treated with 30% ammonia solution.This is then extracted with ethyl acetate (50x2 ml) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure and chromatographed over silica gel using 9:1 petroleum -ether and ethyl acetate and after distillation of the solvent gave the desired product (2a). yield 1.75 gm, 70 %. Example 7 : To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry dichloromethane (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 12 hr at 25°C . The solvent is removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the reaction mixture ( 00C) and then the reaction mixture is treated with 30% ammonia solution.This is then extracted with ethyl acetate (50x2 ml ) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure and chromatographed over silica gel using 9:1 petroleum -ether and ethyl acetate and after distillation of the solvent gave the desired product (2a). yield 1.6 gm, 65 %. EXAMPLE 8: To a mixture of anhydrous aluminium chloride ( 1.33 gm , 0.01 mole ) in dry acetonitrile (50 ml) was added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N -2- (l'-cyclohexenyl)ethyl phenyl acetamide (Ib) 2.42 gm ,0.01 mole ) and stirred for 9 hr at room temperature . The solvent is removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the reaction mixture ( 50C) and then the reaction mixture is treated with 30% ammonia solution.This is then extracted with ethyl acetate (50x2 ml ) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure to get the desired product (2b) 3,4,5,6,7,8-hexahydro-l -(phenyl methyl) isoquinoline, yield 2.14 gm, 96 %. EXAMPLE 9: To a mixture of anhydrous Zinc chloride (1.35 gm,0.01mole ) in dry acetonitrile (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(r-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 8 hr at room temperature . The solvent is removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the reaction mixture ( 00C) and then the reaction mixture is treated with 30% ammonia solution. This is then extracted with ethyl acetate (50x2 ml ) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure to get the desired product (2a), yield 0.63 gm, 25 %. The main advantages of the present invention are : 1 The method is very simple and can be carried out at one- pot at room temperature 2 The work-up procedure is very simple 3 The product obtained from the reaction mixture is highly pure and the yield is 95 % 4 In this process the toxic solvent benzene is replaced with acetonitrile. We claim : 1. An improve process for the production of 3,4,5,6,7,8-hexahydro-l-(arylmethyl) isoquinolines of formula (2) wherein R is H or methoxy, shown in the drawing accompanying this specification which comprises stirring N-2-[l'- cyclohexenyl] ethyl-aryl autamide of formula (1) wherein R is H or methoxy group in an organic solvent with a Lewis acid and potassium halide at a temperature in the range of 0 to 80 °C, for a period in the range of 4-12 hours, removing the solvent by distillation under reduced pressure .treating the above said reaction mixture with ammonia solution, extracting the product using a water immiscible organic solvent, washing the organic layer with sodium thiosulphate solution ,and removing the solvent under reduced pressure to get compound of formula (2). (Formula Removed) 2. An improved process as claimed in claim 1 wherein the Lewis acid used is metal halide such as alumonium chloride, zinc chloride. 3. An improved process as claimed in claims 1 - 2 wherein the Lewis acid used in combination with alkali metal halide such as KI, KBr in the ratio of 1:4 tol :6 preferably in the ratio 1:4. 4. An improved preocess as claimed in claims 1 & 3 , wherein the organic solvent used are such as chloroform, dilchloromethane, acetonitrile, more particulary acetonitrile. 5. An improved process as claimed in claims 1 to 4 , wherein the reaction mixture is stirred at a temperature at a range of 0-80 °C, particularly in the range of 15 -30 °C for a period in range of 8-12 hr 6. An improved process as claimed in claims 1 to 5 , wherein the water immiscible solvent used for the extration of the product is selected from ethyl acetate ,chloroform,dichloroform, petroleum-ether particularly ethyl acetate. 7. An improved process as claimed in claims 1 to 6, wherein the drying step is effected by using a drying agent selected from sodium ,magnesium ,and potassium sulphate ..particularly anhydrous sodium sulphate. 8. 8. An improved process as claimed in claims 1 to 7, wherein the distillation of organic solvent is effected a temperature of 20-40 "C under reduced pressure. 9. An improved process for the preparation of 3,4,5,6,7,8-hexahydro-l-(aryl methyl) isoquinolines substantially as herein described with reference to the examples.

Full Text

This invention relates to an improved process for the preparation of 3,4,5,6,7,8-hexahydro-l-(aryl methyl) isoquinolines. This invention particularly relates to an improved process for the production of 3, 4, 5, 6, 7, 8- hexahydro-l-(4-methoxy phenyl/phenyl methyl) isoquino lines of formula (2) wherein R is H or methoxy group. Dextromethorphan is an important and efficient anti-tussive drug of the present time.lt is prepared from an intermediate N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl methyl acetamide (la) wherein R is methoxy group. .The present invention relates to an improved process for the preparation of 3, 4, 5, 6, 7, 8- hexahydro-l-(4-methoxyphenyl/phenyl methyl) isoquinolines (2) from N-2-(l'-cyclohexenyl)ethyl-4-methoxy- phenyl/phenyl acetamides (1) particularly using Lewis acids like AlCls and ZnCl2, more particularly using anhydrous aluminium chloride and potassium iodide in a solvent .The compound (2) is one of the important intermediates for the production of dextromethorphan (3-methoxy,17- methyl (9α,13α, 14α ,morphinan) and its analogues.
(Formula Removed)
The literature on the cyclization of N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) to 3,4,5,6,7,8-hexahydro-l-(4-methoxy phenyl methyl) isoquinoline (2a) is scanty .The following are the references so far available in the literature .
Hitherto 3,4,5,6,7,8- hexahydro-l-(4-methoxyphenylmethyl)- isoquinoline ( 2a) has been prepared by the methods described below :
By cyclodehydration of amide (1) with phosphorous oxychloride (Tet. Lett,28,(41),pp- 4829 -32,1987).
According to the method disclosed in this paper, the amide(l) is allowed to react with phosphorous oxycholoride in benzene in its reflux temperature .The drawback of the method is that heating is essential and benzene, a health hazard is used as solvent along with phosphorous oxychloride .The yield of (2) is also not mentioned in the reference.
By cyclodehyd rat ion of amide (l)with phosphorous pentoxide( Helv .Chim. Acta. 33, pp 1437-1448 ,1950 ;ibid, 34,2211,1951)
In this reported cyclization process the amide (1) is treated with phosphorous pentoxide in warm benzene .After completion of the reaction ,the reaction mixture is treated with ice and made strongly alkaline and extracted with ether and worked-up. The drawback of the method is that phosphorous pentoxide being very much hygroscopic and corrosive chemical has to be handled with outmost caution and also the solvent benzene is a health hazard . The yield of the process is 78% only . In this process several side products are also formed which are difficult to account for.
By cycloaddition of amide (1) with phosphorous oxychloride ( US Patent,4270000, May 16, 1981 and U S Patent, 5892,044, April 6,1994 ).
US database patent search revealed that according to the methods described in the above two patents the amide (1) is allowed to react with phosphorous oxychloride in a solvent and the mixture is heated at the reflux temperature of the solvent (toluene). The drawbacks of the process are same with those described in methods 1 and 2 above.
The main objective of the present invention is to provide an improved process for the preparation of 3,4,5,6,7,8-hexahydro-l-(aryl methyl) isoquinolines.
Another objective of the present invention is to provide a method for cyclization of N-2-(l'-cyclohexenyl )ethyl-4-methoxyphenyl acetamide (la) to 3,4,5,6,7,8-hexahydro-l-(4-methoxyphenylmethyl)
isoquinoline (2a).
Yet another objective of the present invention is to provide cyclization of N-2-(l'-cyclohexen-yl )ethyl-4-methoxy phenyl acetamide (la) to3,4,5,6,7,8-hexahydro-l-(4-methoxyphenylmethyl) isoquinoline (2a) by elimiminating the use of benzene as solvent.
Accordingly, the present invention provides an improved process for the production of 3,4,5,6,7,8-hexahydro-l-(arylmethyl) isoquinolines of formula (2) wherein R is H or methoxy, shown in the drawing accompanying this specification which comprises stirring N-2-[l'- cyclohexenyl] ethyl-aryl autamide of formula (1) wherein R is H or methoxy group in an organic solvent with a Lewis acid and potassium halide at a temperature in the range of 0 to 80 °C, for a period in the range of 4-12 hours, removing the solvent by distillation under reduced pressure ,treating the above said reaction mixture with ammonia solution, extracting the product using a water immiscible organic solvent, washing the organic layer with sodium thiosulphate solution ,and removing the solvent under reduced pressure to get compound of formula (2).
(Formula Removed)
In an embodiment of the present invention the Lewis acid used may be halides of metal such as AlCl3, and ZnCl2
In another embodiment of the invention the ratio of metal halide & potassium halide used may be in the range of 1:4 to 1:6.
In yet another embodiment of the invention the organic solvent may be such as acetonitrile, chloroform and dichloromethane.
Water immicible solvent used may be such as diethyl ether, ethyl acetate and dichloromethane.
Ammonia solution used may be in the range of 15% to30%
The process of production of 3,4,5,6,7,8-hexahydro-l-(4-methoxy phenyl/phenylmethyl) isoquinoline ( 2) by cyclization of N-2-(l'-cyclohexenyl )ethyl -4-methoxy phenyl/phenyl acetamide of the formula (1) shown in the drawing (Scheme l) accompanying this specification which comprises stirring of (1) in an organic solvent like dichloromethane, chloroform, acetonotrile with anhydrous aluminium chloride-halides of potassium Like potassium iodide or potassium bromide in a ratio in the range of 1:4 to 1:6 at room temperature ,removing the solvent by distillation under reduced pressure ,treating with ammonia solution, extracting the product using a water immisscible organic solvent like diethyl ether, ethyl acetate, dichloromethane, washing the organic layer with 10 % sodium thiosulphate ,drying over anhydrous sodium sulphate and removing the solvent under reduced pressure .
The details of the method disclosed in this invention have been described in the following specific examples which are provided to illustrate the invention only and therefore, these should not be construed to limit the scope of the present invention EXAMPLE 1:
To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry acetonitrile (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(l'-cyclohexenyl)ethyl-4-
methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 8 hr at room temperature . The solvent is removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling
the reaction mixture ( 00C) and then the reaction mixture is treated with 30% ammonia solution.This is then extracted with ethyl acetate (50x2 ml ) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure to get the desired product (2a), yield 2.41 gm, 95 %. Example 2 :
To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry acetonitrile (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(1-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 4 hr at room temperature .The solvent is
removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the
o reaction mixture ( 0 C) and then the reaction mixture is treated with 30% ammonia solution.This is then
extracted with ethyl acetate (50x2 ml) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure to get the desired product (2a). TLC has shown the presence of starting material and product. The product was separated by column chromatography over SiO2, yield 1.21 gm, 48 %. Example 3 :
To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry acetonitrile (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 12 hr at room temperature. The solvent is
removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the

reaction mixture ( 00C) and then the reaction mixture is treated with 30% ammonia solution.This is then
extracted with ethyl acetate (50x2 ml ) and the organic layer is washed with 10 % sodium thiosulphate
solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure to get the desired product (2a). yield 2.35 gm, 94 %. Example 4 :
To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry acetonitrile (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 12 hr at 0°C . The solvent is removed under
reduced pressure and water (100 ml) is added to the reaction mixture by cooling the reaction mixture (
o 0 C) and then the reaction mixture is treated with 30% ammonia solution.This is then extracted with
ethyl acetate (50x2 ml) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure and chromatographed over silica gel using 9:1 petroleum -ether and ethyl acetate and after distillation of the solvent gave the desired product (2a). yield 2 gm, 80 %. Example 5 :
To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry acetonitrile (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and refluxed for 12 hr at 80°C .The solvent is removed
under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the reaction
mixture ( 00C) and then the reaction mixture is treated with 30% ammonia solution.This is then
extracted with ethyl acetate (50x2 ml) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure and chromatographed over silica gel using 9:1 petroleum -ether and ethyl acetate and after distillation of the solvent gave the desired product (2a). yield 1.01 gm, 40 %.
Example 6 :
To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry chloroform (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 12 hr at 25°C . The solvent is removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the reaction
mixture ( 00C) and then the reaction mixture is treated with 30% ammonia solution.This is then extracted with ethyl acetate (50x2 ml) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure and chromatographed over silica gel using 9:1 petroleum -ether and ethyl acetate and after distillation of the solvent gave the desired product (2a). yield 1.75 gm, 70 %. Example 7 :
To a mixture of anhydrous aluminium chloride (1.33 gm,0.01mole ) in dry dichloromethane (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(l'-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 12 hr at 25°C . The solvent is removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the
reaction mixture ( 00C) and then the reaction mixture is treated with 30% ammonia solution.This is then extracted with ethyl acetate (50x2 ml ) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure and chromatographed over silica gel using 9:1 petroleum -ether and ethyl acetate and after distillation of the solvent gave the desired product (2a). yield 1.6 gm, 65 %. EXAMPLE 8:
To a mixture of anhydrous aluminium chloride ( 1.33 gm , 0.01 mole ) in dry acetonitrile (50 ml) was added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under
nitrogen atmosphere for 1 hour. To this reaction mixture is then added N -2- (l'-cyclohexenyl)ethyl phenyl acetamide (Ib) 2.42 gm ,0.01 mole ) and stirred for 9 hr at room temperature . The solvent is
removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the
reaction mixture ( 50C) and then the reaction mixture is treated with 30% ammonia solution.This is then
extracted with ethyl acetate (50x2 ml ) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure to get the desired product (2b) 3,4,5,6,7,8-hexahydro-l -(phenyl methyl) isoquinoline, yield 2.14 gm, 96 %. EXAMPLE 9:
To a mixture of anhydrous Zinc chloride (1.35 gm,0.01mole ) in dry acetonitrile (50 ml) is added potassium iodide ( 6.64 gm, 0.04 mole) and the mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. To this reaction mixture is then added N-2-(r-cyclohexenyl)ethyl-4-methoxy phenyl acetamide (la) (2.72 gm, 0.01 mole ) and stirred for 8 hr at room temperature . The solvent is
removed under reduced pressure and water (100 ml) is added to the reaction mixture by cooling the
reaction mixture ( 00C) and then the reaction mixture is treated with 30% ammonia solution. This is then
extracted with ethyl acetate (50x2 ml ) and the organic layer is washed with 10 % sodium thiosulphate solution, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure to get the desired product (2a), yield 0.63 gm, 25 %. The main advantages of the present invention are :
1 The method is very simple and can be carried out at one- pot at room temperature
2 The work-up procedure is very simple
3 The product obtained from the reaction mixture is highly pure and the yield is 95 %
4 In this process the toxic solvent benzene is replaced with acetonitrile.

We claim :
1. An improve process for the production of 3,4,5,6,7,8-hexahydro-l-(arylmethyl) isoquinolines of formula (2) wherein R is H or methoxy, shown in the drawing accompanying this specification which comprises stirring N-2-[l'- cyclohexenyl] ethyl-aryl autamide of formula (1) wherein R is H or methoxy group in an organic solvent with a Lewis acid and potassium halide at a temperature in the range of 0 to 80 °C, for a period in the range of 4-12 hours, removing the solvent by distillation under reduced pressure .treating the above said reaction mixture with ammonia solution, extracting the product using a water immiscible organic solvent, washing the organic layer with sodium thiosulphate solution ,and removing the solvent under reduced pressure to get compound of formula (2).

(Formula Removed)
2. An improved process as claimed in claim 1 wherein the Lewis acid used is metal halide such as
alumonium chloride, zinc chloride.
3. An improved process as claimed in claims 1 - 2 wherein the Lewis acid used in combination with
alkali metal halide such as KI, KBr in the ratio of 1:4 tol :6 preferably in the ratio 1:4.
4. An improved preocess as claimed in claims 1 & 3 , wherein the organic solvent used are such as
chloroform, dilchloromethane, acetonitrile, more particulary acetonitrile.
5. An improved process as claimed in claims 1 to 4 , wherein the reaction mixture is stirred at a
temperature at a range of 0-80 °C, particularly in the range of 15 -30 °C for a period in range of 8-12 hr
6. An improved process as claimed in claims 1 to 5 , wherein the water immiscible solvent used for
the extration of the product is selected from ethyl acetate ,chloroform,dichloroform, petroleum-ether
particularly ethyl acetate.
7. An improved process as claimed in claims 1 to 6, wherein the drying step is effected by using a
drying agent selected from sodium ,magnesium ,and potassium sulphate ..particularly anhydrous sodium
sulphate.
8. 8. An improved process as claimed in claims 1 to 7, wherein the distillation of organic solvent is
effected a temperature of 20-40 "C under reduced pressure.
9. An improved process for the preparation of 3,4,5,6,7,8-hexahydro-l-(aryl methyl) isoquinolines
substantially as herein described with reference to the examples.

Documents:

963-del-2000-abstract.pdf

963-del-2000-claims.pdf

963-del-2000-correspondence-others.pdf

963-del-2000-correspondence-po.pdf

963-del-2000-description (complete).pdf

963-del-2000-form-1.pdf

963-del-2000-form-2.pdf

963-del-2000-form-3.pdf

963-del-2000-form-4.pdf

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Patent Number

217733

Indian Patent Application Number

963/DEL/2000

PG Journal Number

17/2008

Publication Date

25-Apr-2008

Grant Date

28-Mar-2008

Date of Filing

01-Nov-2000

Name of Patentee

COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG, NEW DELHI-110001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	DILIP KONWAR	REGIONAL RESEARCH LABORATORY, JORHAT-785006, ASSAM, INDIA.
2	BIRENDRA NATH GOSWAMI	REGIONAL RESEARCH LABORATORY, JORHAT-785006, ASSAM, INDIA.
3	NALEEN BORTHAKUR	REGIONAL RESEARCH LABORATORY, JORHAT-785006, ASSAM, INDIA.

PCT International Classification Number

C07D 217/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA