Title of Invention	"AN IMPROVED PROCESS FOR THE PREPARATION OF 1-(4-ARLYPIPERAZIN)-W-(SUBSTITUTED AMINO)ALKANE"
Abstract	The present invention provides an improved large scale high yielding simple and economically viable process for the preparation of 1-(4-arylpiperazin1-yl)-ω-(N-substituted amino) alkane which would be useful for the treatment of hypertension and other related CVS and CNS disorders. The process steps involves condensing an arylpiperazin with a substituted amino alkyl chloride (R1-CI) , in the presence of an organic base selected from triethyl amine, tripropylamine, diethylaniline, dimethyl benzyl amine and N-methylmorpholine , in an organic solvent , at a temperature ranging from 50°-110°C for a period ranging between 4 to 16 hrs to obtain the desired 1[4-arylpiperazin-1-yl]-ω -(N-substituted amino) alkane.

Title of Invention

"AN IMPROVED PROCESS FOR THE PREPARATION OF 1-(4-ARLYPIPERAZIN)-W-(SUBSTITUTED AMINO)ALKANE"

Abstract

The present invention provides an improved large scale high yielding simple and economically viable process for the preparation of 1-(4-arylpiperazin1-yl)-ω-(N-substituted amino) alkane which would be useful for the treatment of hypertension and other related CVS and CNS disorders. The process steps involves condensing an arylpiperazin with a substituted amino alkyl chloride (R1-CI) , in the presence of an organic base selected from triethyl amine, tripropylamine, diethylaniline, dimethyl benzyl amine and N-methylmorpholine , in an organic solvent , at a temperature ranging from 50°-110°C for a period ranging between 4 to 16 hrs to obtain the desired 1[4-arylpiperazin-1-yl]-ω -(N-substituted amino) alkane.

Full Text	The invention relates to an improved process for the preparation of 1-(4-arylpiperzin-1-yl)-ω- (N-substituted amino) alkane. The invention relates to an industrial process for the synthesis of 1-(4-arlypiperazin-1-yl)-ω- (N-substituted amino) alkane and related compounds known to be useful as antihypertensive and other related CVS and CMS disorders. The 1-(4-arlypiperazin-1-yl)- ω-(N-substituted amino) alkane prepared by the process of the present invention having the formula III as shown in the drawing accompanying this specification, where R is H, a lower alkyl group having a straight or branched chain alkyl radial such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert butyl, n-aryl, n-hexyl, 2-ethyl butyl or an alkyl halide such as methyl trifluoride or halide radicals such as F, Cl, Br, or I, a hydroxy or a lower alkoxy group such as methoxy, ethoxy etc. where R1 is a substituted amino alkyl group having a straight or branched chain containing 1 to 6 carbon atoms such as defined above in R or constituted a cyclic polymethylene system containing the nitrogen atom, in N(CH2)n where in n=2-6 or it's derivative 3 to 6 membered lactones such as 2-pyrrolidinone etc. Similar compounds in formula III are hitherto known to be synthesized by two different methods covered under Indian patent application, No.496/Del/95 and No.501/Del/95 where in the first method 1-arylpiperazins of the formula I where R has meaning given above is condensed with R1-CI such as 1-chloro-3 (2-oxopyrrolidin-1-yl) propane in presence of essentially inorganic base Na2CO3 or K2CO3 and catalyst like Nal or Kl in an organic solvent DMF or acetone at temperature 70-150°C for a varying period between 8hrs to 14 hrs. On strictly following these conditions it was observed that 1. The reaction does not complete even if carried out for 48hrs and the yield is very low. 2. The costly solvent DMF has been used which is difficult to remove completely without losing it in substantial amount. Other solvent also did not give better result under these conditions 3. Use of DMF also produces an unwanted compound i.e. 1-formyl-4- (4- fluorophenyl)piperazine which adds to its impurities. 4. Purification by chromatography requires lot of solvent as eluent and time which is not acceptable to large-scale preparation (in the industry). 5. All the above conditions make the process uneconomical. In the second hitherto known process 1-(4-arylpiperazin-1-yl) alkyl halide is condensed with substituted amine such as 2-pyrrolidone in an organic solvent where in some times use of sodium metal or even sodium hydride is very essential for the reaction to take place. Use of Na or NaH needs extra precautions in their handling for being very hygroscopic and pyrophoric in nature. In this process the yields of the final compound of formula III is even much less than the 1st hitherto known process. The main objective of the present invention is to provide an improved large scale high yielding simple and economically viable process for the preparation of 1-(4-arylpiperazin1-yl)-ω-(N-substituted amino) alkane having formula III as defined above which would be useful for the treatment of hypertension and other related CVS and CNS disorders. Accordingly, the present invention provides an improved process for the preparation of 1[4-arylpiperazin-1-yl]-ω-(N-substituted amino) alkane of the formula III shown in the drawing accompanying this specification where R is selected from the group consists of H, a lower alkyl group having a straight or branched chain alkyl radial selected from the group consisting of such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert butyl, n-aryl, n-hexyl, 2-ethyl butyl and trifluoromethyl, halide radical selected from F, Cl, Br and I, a hydroxyl and a lower alkoxy group selected from methoxy and ethoxy, where R1 is a substituted amino alkyl group having a straight or branched chain containing 1 to 6 carbn atoms such as defined above in R or constituted a cyclic polymethylene system containing the nitrogen atom, in N(CH2)n wherein n=2-6 or it's derivative, 3-6 membered lactones such as a 2-pyrrolidinone , said process comprises condensing an arylpiperazin of formula I with a substituted amino alkyl chloride (R1-CI) of formula II having meaning as above , in the presence of an organic base selected from triethyl amine, tripropylamine, diethylaniline, dimethyl benzyl amine and N-methylmorpholine , wherein ratio of arylpiperin : substituted amino alkyl chloride : base ranges from 1:1:1 to 0.1:1:1 , in an organic solvent as herein described , at a temperature ranging from 50°-110°C for a period ranging between 4 to 16 hrs to obtain the desired 1[4-arylpiperazin-1-yl]-ω -(N-substituted amino) alkane. In an embodiment of the present invention the organic base used is selected from the group consisting of triethyl amine, tripropylamine, diethylaniline, dimethyl benzyl amine and N-methylmorpholine. In an another embodiment of the present invention the base used is recovered as hydrochloride and is recycled after converting into freebase. In an another embodiment of the present invention the organic solvent used is selected from the group consisting of benzene, xylene, toluene, dioxane and THF. In yet another embodiment of the present invention the compound of the formula III is obtained in 78-90% yield. In still anther embodiment of the present invention the compound 1-(4-arlypiperazin)-ω-(N-substituted amino)alkane obtained is selected from 1-(4-arlypiperazin)-ω-(N-substituted amino)ethane and 1-(4-arlypiperazin)-ω-(N-substituted amino)propane. The following examples are given to illustrate the details of the invention and should not be constrained to limit the scope of the present invention. Preparations Example 1 1-(4-(4-fluorophenyl) piperazin-1-yl)-3-(2-oxopvrrolidin-1-yl) propane. A mixture of 1-chloro-3- [2-oxopyrrolidine-1-yl] propane (100gm, 0.62mol), 1-(4- fluorophenyl)piperazin (111.6gm, 0.62 mol) & triethylamine (69gm/103 ml, 0.63mol) in dry toluene(1 lit) was stirred under reflux conditions at 110°C for 14hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2S04 and concentrated under reduced pressure to give 1-[4-(4- fluorophenyl) piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl] propane as an oil. Yield 170gm (90%). Example 2 1-(4-(4-fluorophenyl) piperazin-1-yl)-3-(2-oxopvrrolidin-1-yl) propane. A mixture of 1-chloro-3- [2-oxopyrrolidine-1-yl] propane (16gm, 0.1 mol), 1-(4-fluorophenyl) piperazin (18gm, 0.1 mol) & triethylamine (11gm, 16 ml, 0.1 mol) in dry Benzene(200 ml) was stirred under reflux conditions for 14hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(4-fluorophenyl) piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl] propane as an oil. Yield 244gm (80%). Example 3 1-\|4-(4-fluorophenyl) piperazin-1-yl)-3-(2-oxopvrrolidin-1-vl) propane. A mixture of 1-chloro-3- [2-oxopyrrolidine-1-yl] propane (1.61gm, 0.01 mol), 1-(4-fluorophenyl) piperazin (1.80gm, 0.01 mol) & triethylamine (1.11gm/1.66 ml, 0.011 mol) in dry dioxane(20 ml) was stirred under reflux conditions at 101°C for 14hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(4-fluorophenyl) piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl] propane as an oil. Yield 2.60gm (85%). Example 4 1-(4-(3-trifluoromethvlphenvn piperazin-1-vn-3-r2-oxopvrrolidin-1- vll propane. A mixture of 1-chloro-3- [2-oxopyrrolidine-1-yl] propane (1.5gm, 0.0065mol), 1-(3-trifluoromethylphenyl)piperazin (1.1 gm, 0.065 mol) & triethylamine (0.707gm/1 ml, 0.065mol) in dry toluene (20ml) was stirred under reflux conditions at 110°C for 14hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(3-trifluoromethylphenyl) piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl] propane as an oil. Yield 1.8gm(78%). Example 5 1-(4-(4-fluorophenyl) piperazin-1-yl)-2-(N. N-dimethylamino)ethane. A mixture of 2-chloro-N,N-dimethylethylamino hydrochloride(0.745gm, 0.0051mol), 1-(4-fluorophenyl) piperazin (0.93gm, 0.0051 mol) & triethylamine (1.05gm, 0.012 mol) in dry benzene(15 ml) was stirred under reflux conditions at 80°C for 6hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2S04 and concentrated under reduced pressure to give 1-[4-(4-fluorophenyl) piperazin-1-yl]-2-(N, N-dimethyl amino) ethane as an oil. Yield 0.65gm(84%). Example 6 1-(4-(4-fluorophenvl)piperazin-1-yl)-2-(N. N-diethvlamino)ethane. A mixture of 2-chloro-N, N-diethylethylamino hydrochloride (1.21gm, 0.007mol), 1-(4-fluorophenyl)piperazin (1.275gm, 0.007 mol) & triethylamine (1.4gm, 0.014 mol) in dry toluene(15 ml) was stirred under reflux conditions at 80°C for 5hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(4-fluorophenyl) piperazin-1-yl]-2-(N, N-dimethyl amino) ethane as an oil. Yield 1.68gm(85%). Example 7 1-(4-(4-fluorophenyl) piperazin-1-yl)-2-(pyrrolidin-1- yl) ethane A mixture of 2-chloroethylpyrrolidinehydrochloride (1.70gm, 0.01mol), 1-(4- fluorophenyl)piperazin (1.8m, 0.01 mol) & triethylamine (1.18gm, 0.02mol) in dry toluene(20 ml) was stirred under reflux conditions at 110°C for 6hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(4-trifluorophenyl) piperazin-1-yl]-2-(pyrrolidin-1- yl) ethane as an oil. Yield 2.25gm(81%). Example 8 1-r4-(3-chlorophenyl) piperazin-1-yl1-3-(2-oxopvrrolidin-1- yl) propane A mixture of 1-chloro-3-[2-oxopyrrolidine-1-yl]propane ( 0.4gm, 0.0025mol ), 1-(3-chlorophenyl) piperazin ( 0.491 gm, 0.00025 mol) & triethylamine (0.6gm, 0.0025 mol) in dry toluene(15 ml) was stirred under reflux conditions at 110°C for 12hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(4-trifluorophenyl) piperazin-1-yl]-2-(pyrrolidin-1- yl) ethane as an oil. Yield 0.65gm(82.5%). The novelty of the present invention lies in the process for the preparation of 1-(-4-arylpiperazin-1-yl)-ω-(N-substituted amino) alkane which does not require any additional catalyst like Nal or Kl and the reaction carried out in a cheap solvent avoiding formation of unwanted compounds and the use of organic amine base facilitate the reaction to go smoothly and give much better yield, 78-90% as compared to the hitherto known processes. The amine hydrochloride formed in the reaction can be filtered easily and made use of repeatedly in the reaction there by improving the economics of the process. Purification of the compound is done by simple filtering through a small bed of silica gel, thus avoiding the use of column chromatography where in lot of solvent and time was consumed which effects the cost of production. The present process avoids the use of Na of NaH which are hazardous to handle in large scale preparation. Reaction can be carried out at low temperature between 50-110°C thus saving energy. The time period required for various reactions is between 6 hrs to 16 hrs only. The process is technically and economically feasible for the large-scale preparation in the industry. We Claim: 1. An improved process for the preparation of 1[4-arylpiperazin-1-yl]-ω -(N- substituted amino) alkane of the formula III shown in the drawing accompanying this specification where R is selected from the group consists of H, a lower alkyl group having a straight or branched chain alkyl radial selected from the group consisting of such as methyl, ethyl, n- propyl, isopropyl, n-butyl, tert butyl, n-aryl, n-hexyl, 2-ethyl butyl and trifluoromethyl, halide radical selected from F, Cl, Br and I, a hydroxyl and a lower alkoxy group selected from methoxy and ethoxy, where R1 is a substituted amino alkyl group having a straight or branched chain containing 1 to 6 carbn atoms such as defined above in R or constituted a cyclic polymethylene system containing the nitrogen atom, in N(CH2)n wherein n=2-6 or it's derivative, 3-6 membered lactones such as a 2- pyrrolidinone said process comprises condensing an arylpiperazin of formula I with a substituted amino alkyl chloride (R1-CI) of formula II having meaning as above , in the presence of an organic base selected from triethyl amine, tripropylamine, diethylaniline, dimethyl benzyl amine and N-methylmorpholine , wherein ratio of arylpiperin : substituted amino alkyl chloride : base ranges from 1:1:1 to 0.1:1:1 , in an organic solvent as herein described , at a temperature ranging from 50°-110°C for a period ranging between 4 to 16 hrs to obtain the desired 1[4-arylpiperazin- 1-yl]-ω -(N-substituted amino) alkane. 2. An improved process as claimed in claims 1 wherein, the base used is recovered as hydrochloride and is recycled after converting into freebase. 3. An improved process as claimed in claims 1 - 2 wherein, the organic solvent used is selected from the group consisting of benzene, xylene, toluene, dioxane and THF. 4. An improved process as claimed in claims 1 -3, wherein the compound 1-(4-arylpiperazin)-ω-(N-substituted amino) alkane obtained is selected from 1-(4-arylpiperazin)-ω-(N-substituted amino) ethane and 1-(4-arylpiperazin)-ω-(N-substituted amino)propane. 5. An improved process for the preparation of 1[4-arylpiperazin-1-yl]-ω-(N-substituted amino) alkane substantially as herein described with reference to the examples and drawings accompanying this specification.

Full Text

The invention relates to an improved process for the preparation of 1-(4-arylpiperzin-1-yl)-ω- (N-substituted amino) alkane.
The invention relates to an industrial process for the synthesis of 1-(4-arlypiperazin-1-yl)-ω- (N-substituted amino) alkane and related compounds known to be useful as antihypertensive and other related CVS and CMS disorders.
The 1-(4-arlypiperazin-1-yl)- ω-(N-substituted amino) alkane prepared by the process of the present invention having the formula III as shown in the drawing accompanying this specification, where R is H, a lower alkyl group having a straight or branched chain alkyl radial such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert butyl, n-aryl, n-hexyl, 2-ethyl butyl or an alkyl halide such as methyl trifluoride or halide radicals such as F, Cl, Br, or I, a hydroxy or a lower alkoxy group such as methoxy, ethoxy etc. where R1 is a substituted amino alkyl group having a straight or branched chain containing 1 to 6 carbon atoms such as defined above in R or constituted a cyclic polymethylene system containing the nitrogen atom, in N(CH2)n where in n=2-6 or it's derivative 3 to 6 membered lactones such as 2-pyrrolidinone etc.
Similar compounds in formula III are hitherto known to be synthesized by two different methods covered under Indian patent application, No.496/Del/95 and No.501/Del/95 where in the first method 1-arylpiperazins of the formula I where R has meaning given above is condensed with R1-CI such as 1-chloro-3 (2-oxopyrrolidin-1-yl) propane in
presence of essentially inorganic base Na2CO3 or K2CO3 and catalyst like Nal or Kl in an organic solvent DMF or acetone at temperature 70-150°C for a varying period between 8hrs to 14 hrs.
On strictly following these conditions it was observed that
1. The reaction does not complete even if carried out for 48hrs and the yield is very
low.
2. The costly solvent DMF has been used which is difficult to remove completely
without losing it in substantial amount. Other solvent also did not give better result
under these conditions
3. Use of DMF also produces an unwanted compound i.e. 1-formyl-4- (4-
fluorophenyl)piperazine which adds to its impurities.
4. Purification by chromatography requires lot of solvent as eluent and time which is
not acceptable to large-scale preparation (in the industry).
5. All the above conditions make the process uneconomical.
In the second hitherto known process 1-(4-arylpiperazin-1-yl) alkyl halide is condensed with substituted amine such as 2-pyrrolidone in an organic solvent where in some times use of sodium metal or even sodium hydride is very essential for the reaction to take place. Use of Na or NaH needs extra precautions in their handling for being very hygroscopic and pyrophoric in nature. In this process the yields of the final compound of formula III is even much less than the 1st hitherto known process.
The main objective of the present invention is to provide an improved large scale high yielding simple and economically viable process for the preparation of 1-(4-arylpiperazin1-yl)-ω-(N-substituted amino) alkane having formula III as defined above which would be useful for the treatment of hypertension and other related CVS and CNS disorders.
Accordingly, the present invention provides an improved process for the preparation of 1[4-arylpiperazin-1-yl]-ω-(N-substituted amino) alkane of the formula III shown in the drawing accompanying this specification where R is selected from the group consists of H, a lower alkyl group having a straight or branched chain alkyl radial selected from the group consisting of such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert butyl, n-aryl, n-hexyl, 2-ethyl butyl and trifluoromethyl, halide radical selected from F, Cl, Br and I, a hydroxyl and a lower alkoxy group selected from methoxy and ethoxy, where R1 is a substituted amino alkyl group having a straight or branched chain containing 1 to 6 carbn atoms such as defined above in R or constituted a cyclic polymethylene system containing the nitrogen atom, in N(CH2)n wherein n=2-6 or it's derivative, 3-6 membered lactones such as a 2-pyrrolidinone , said process comprises condensing an arylpiperazin of formula I with a substituted amino alkyl chloride (R1-CI) of formula II having meaning as above , in the presence of an organic base selected from triethyl amine, tripropylamine, diethylaniline, dimethyl benzyl amine and N-methylmorpholine , wherein ratio of arylpiperin : substituted amino alkyl chloride : base ranges from 1:1:1 to 0.1:1:1 , in an organic solvent as herein described , at a temperature ranging from 50°-110°C for a period ranging between 4 to 16 hrs to obtain the desired 1[4-arylpiperazin-1-yl]-ω -(N-substituted amino) alkane.
In an embodiment of the present invention the organic base used is selected from the group consisting of triethyl amine, tripropylamine, diethylaniline, dimethyl benzyl amine and N-methylmorpholine.
In an another embodiment of the present invention the base used is recovered as hydrochloride and is recycled after converting into freebase.
In an another embodiment of the present invention the organic solvent used is selected from the group consisting of benzene, xylene, toluene, dioxane and THF.
In yet another embodiment of the present invention the compound of the formula III is obtained in 78-90% yield.
In still anther embodiment of the present invention the compound 1-(4-arlypiperazin)-ω-(N-substituted amino)alkane obtained is selected from 1-(4-arlypiperazin)-ω-(N-substituted amino)ethane and 1-(4-arlypiperazin)-ω-(N-substituted amino)propane.
The following examples are given to illustrate the details of the invention and should not be constrained to limit the scope of the present invention.
Preparations
Example 1 1-(4-(4-fluorophenyl) piperazin-1-yl)-3-(2-oxopvrrolidin-1-yl) propane.
A mixture of 1-chloro-3- [2-oxopyrrolidine-1-yl] propane (100gm, 0.62mol), 1-(4-
fluorophenyl)piperazin (111.6gm, 0.62 mol) & triethylamine (69gm/103 ml, 0.63mol) in
dry toluene(1 lit) was stirred under reflux conditions at 110°C for 14hrs. The reaction
mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized
out. This was filtered washed with toluene. The organic filtrate was washed with water,
dried over Na2S04 and concentrated under reduced pressure to give 1-[4-(4-
fluorophenyl) piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl] propane as an oil. Yield 170gm
(90%).
Example 2 1-(4-(4-fluorophenyl) piperazin-1-yl)-3-(2-oxopvrrolidin-1-yl) propane. A mixture of 1-chloro-3- [2-oxopyrrolidine-1-yl] propane (16gm, 0.1 mol), 1-(4-fluorophenyl) piperazin (18gm, 0.1 mol) & triethylamine (11gm, 16 ml, 0.1 mol) in dry Benzene(200 ml) was stirred under reflux conditions for 14hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(4-fluorophenyl) piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl] propane as an oil. Yield 244gm (80%).
Example 3 1-|4-(4-fluorophenyl) piperazin-1-yl)-3-(2-oxopvrrolidin-1-vl) propane. A mixture of 1-chloro-3- [2-oxopyrrolidine-1-yl] propane (1.61gm, 0.01 mol), 1-(4-fluorophenyl) piperazin (1.80gm, 0.01 mol) & triethylamine (1.11gm/1.66 ml, 0.011 mol) in dry dioxane(20 ml) was stirred under reflux conditions at 101°C for 14hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(4-fluorophenyl) piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl] propane as an oil. Yield 2.60gm (85%).
Example 4 1-(4-(3-trifluoromethvlphenvn piperazin-1-vn-3-r2-oxopvrrolidin-1- vll
propane.
A mixture of 1-chloro-3- [2-oxopyrrolidine-1-yl] propane (1.5gm, 0.0065mol), 1-(3-trifluoromethylphenyl)piperazin (1.1 gm, 0.065 mol) & triethylamine (0.707gm/1 ml, 0.065mol) in dry toluene (20ml) was stirred under reflux conditions at 110°C for 14hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(3-trifluoromethylphenyl) piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl] propane as an oil. Yield 1.8gm(78%).

Example 5 1-(4-(4-fluorophenyl) piperazin-1-yl)-2-(N. N-dimethylamino)ethane. A mixture of 2-chloro-N,N-dimethylethylamino hydrochloride(0.745gm, 0.0051mol), 1-(4-fluorophenyl) piperazin (0.93gm, 0.0051 mol) & triethylamine (1.05gm, 0.012 mol) in dry benzene(15 ml) was stirred under reflux conditions at 80°C for 6hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2S04 and concentrated under reduced pressure to give 1-[4-(4-fluorophenyl) piperazin-1-yl]-2-(N, N-dimethyl amino) ethane as an oil. Yield 0.65gm(84%).
Example 6 1-(4-(4-fluorophenvl)piperazin-1-yl)-2-(N. N-diethvlamino)ethane. A mixture of 2-chloro-N, N-diethylethylamino hydrochloride (1.21gm, 0.007mol), 1-(4-fluorophenyl)piperazin (1.275gm, 0.007 mol) & triethylamine (1.4gm, 0.014 mol) in dry toluene(15 ml) was stirred under reflux conditions at 80°C for 5hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(4-fluorophenyl) piperazin-1-yl]-2-(N, N-dimethyl amino) ethane as an oil. Yield 1.68gm(85%).
Example 7 1-(4-(4-fluorophenyl) piperazin-1-yl)-2-(pyrrolidin-1- yl) ethane
A mixture of 2-chloroethylpyrrolidinehydrochloride (1.70gm, 0.01mol), 1-(4-
fluorophenyl)piperazin (1.8m, 0.01 mol) & triethylamine (1.18gm, 0.02mol) in dry
toluene(20 ml) was stirred under reflux conditions at 110°C for 6hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(4-trifluorophenyl) piperazin-1-yl]-2-(pyrrolidin-1- yl) ethane as an oil. Yield 2.25gm(81%).
Example 8 1-r4-(3-chlorophenyl) piperazin-1-yl1-3-(2-oxopvrrolidin-1- yl) propane A mixture of 1-chloro-3-[2-oxopyrrolidine-1-yl]propane ( 0.4gm, 0.0025mol ), 1-(3-chlorophenyl) piperazin ( 0.491 gm, 0.00025 mol) & triethylamine (0.6gm, 0.0025 mol) in dry toluene(15 ml) was stirred under reflux conditions at 110°C for 12hrs. The reaction mixture was cooled to 20-25°C where by hydrochloride of triethylamine crystallized out. This was filtered washed with toluene. The organic filtrate was washed with water, dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(4-trifluorophenyl) piperazin-1-yl]-2-(pyrrolidin-1- yl) ethane as an oil. Yield 0.65gm(82.5%).
The novelty of the present invention lies in the process for the preparation of 1-(-4-arylpiperazin-1-yl)-ω-(N-substituted amino) alkane which does not require any additional catalyst like Nal or Kl and the reaction carried out in a cheap solvent avoiding formation of unwanted compounds and the use of organic amine base facilitate the reaction to go smoothly and give much better yield, 78-90% as compared to the hitherto known processes.
The amine hydrochloride formed in the reaction can be filtered easily and made use of repeatedly in the reaction there by improving the economics of the process. Purification of the compound is done by simple filtering through a small bed of silica gel, thus avoiding the use of column chromatography where in lot of solvent and time was consumed which effects the cost of production.
The present process avoids the use of Na of NaH which are hazardous to handle in large scale preparation. Reaction can be carried out at low temperature between 50-110°C thus saving energy.
The time period required for various reactions is between 6 hrs to 16 hrs only. The process is technically and economically feasible for the large-scale preparation in the industry.

We Claim:
1. An improved process for the preparation of 1[4-arylpiperazin-1-yl]-ω -(N-
substituted amino) alkane of the formula III shown in the drawing accompanying this specification where R is selected from the group consists of H, a lower alkyl group having a straight or branched chain alkyl radial selected from the group consisting of such as methyl, ethyl, n- propyl, isopropyl, n-butyl, tert butyl, n-aryl, n-hexyl, 2-ethyl butyl and trifluoromethyl, halide radical selected from F, Cl, Br and I, a hydroxyl and a lower alkoxy group selected from methoxy and ethoxy, where R1 is a substituted amino alkyl group having a straight or branched chain containing 1 to 6 carbn atoms such as defined above in R or constituted a cyclic polymethylene system containing the nitrogen atom, in N(CH2)n wherein n=2-6 or it's derivative, 3-6 membered lactones such as a 2- pyrrolidinone said process comprises condensing an arylpiperazin of formula I with a substituted amino alkyl chloride (R1-CI) of formula II having meaning as above , in the presence of an organic base selected
from triethyl amine, tripropylamine, diethylaniline, dimethyl benzyl amine and N-methylmorpholine , wherein ratio of arylpiperin : substituted amino alkyl chloride : base ranges from 1:1:1 to 0.1:1:1 , in an organic solvent as herein described , at a temperature ranging from 50°-110°C for a period ranging between 4 to 16 hrs to obtain the desired 1[4-arylpiperazin- 1-yl]-ω -(N-substituted amino) alkane.
2. An improved process as claimed in claims 1 wherein, the base used is recovered as hydrochloride and is recycled after converting into freebase.
3. An improved process as claimed in claims 1 - 2 wherein, the organic solvent used is selected from the group consisting of benzene, xylene, toluene, dioxane and THF.
4. An improved process as claimed in claims 1 -3, wherein the compound 1-(4-arylpiperazin)-ω-(N-substituted amino) alkane obtained is selected from 1-(4-arylpiperazin)-ω-(N-substituted amino) ethane and 1-(4-arylpiperazin)-ω-(N-substituted amino)propane.
5. An improved process for the preparation of 1[4-arylpiperazin-1-yl]-ω-(N-substituted amino) alkane substantially as herein described with reference to the examples and drawings accompanying this specification.

Documents:

228-del-2001-abstract.pdf

228-del-2001-claims.pdf

228-del-2001-correspondence-others.pdf

228-del-2001-correspondence-po.pdf

228-del-2001-description (complete).pdf

228-del-2001-drawings.pdf

228-del-2001-form-1.pdf

228-del-2001-form-19.pdf

228-del-2001-form-2.pdf

228-del-2001-form-3.pdf

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Patent Number

218348

Indian Patent Application Number

228/DEL/2001

PG Journal Number

22/2008

Publication Date

30-May-2008

Grant Date

31-Mar-2008

Date of Filing

28-Feb-2001

Name of Patentee

COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH,

Applicant Address

RAFI MARG, NEW DELHI-110 001,INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	VINOD KUMAR SHARMA	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW - 226 001 (U.P.), INDIA.

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA