Title of Invention

"A PROCESS FOR PREPARING 1-METHYL-3-PHENYLPIPERAZINE"

Abstract The present invention describes an industrially advantageous process to prepare highly pure l-methyl-3-phenylpiperazine of Formula I, 1 that makes use of a novel piperazine derivative, 4-benzyl-1 -methyl-2-oxo-3-1 phenylpiperazine, represented by Formula II. The process to prepare compound of Formula 11 is also disclosed. l-MethyI-3-phenylpiperazine is a useful intermediate in the preparation of antidepressant Mirtazapine.
Full Text

FIELD OF THE INVENTION
The present invention relates to the process for preparing l-methyl-3-phenylpiperazine of Formula I from 4-benzyl-l-methyl-2-oxo-3-phenylpiperazine,

BACKGROUND OF THE INVENTION
Mirtazapine, also known as 2-methyl-1,2,3,4,10,14b-hexahydrobenzo[c]pyrazinO" (1,2-a) pyrido[3,2-f]azepine, is an antidepressant drug suitable for oral administration. Mirtazapine belongs to piperazinoazepine group of compounds and has the following chemical structure,

l-Methyl-3-phenylpiperazine is the key intermediate in the preparation of Mirtazapine. US Patent 4,062,848 has described the synthesis of Mirtazapine using l-methyl-3-phenylpiperazine as starting material. It is believed that the earliest synthesis of this key intermediate is that of Roderick et. al., J, Med. Chem. 19o6, 181-185. This publication has reported the preparation of l-methyl-3-phenylpiperazine starting from a-bromophenylacetic acid ester and ethyienediamine resulting in the formation of 2-oxo-3-phenylpiperazine which is then subjected to

lithium aluminium hydride reduction and subsequently methylated with methyl iodide and triethylamine in acetone.

The drawback of this method is the non-selective methylation at 1-position. /. mixture of products like unreacted 2-phenylpiperazine, l-methyl-2-phenylpiperazine and 1,4-dimethyl-2-phenylpiperazine along with the desired 1 -methyl-3-phenylpiperazine is obtained. Therefore, extensive purification is required to obtain pure l-methyl-3-phenylpiperazine.


us Patent 6,495,685 has described the preparation of l-methyl-3-phenylpiperazine by reacting A^-(2-chloroethyl)-A^-methyI-p-chloro-p-phenylethylamine (the dichloride) of Formula III with ammonia.

This dichloride of Formula III has been prepared by chlorination of the corresponding diol, N-(2-hydroxyethyl)-A^-methyl-p-hydroxy*p-phenylethyiamine of Formula IV.

In US Patent 6,495,685, this diol has been obtained by reacting styrene oxide with A'-methyIethanolamine. However, the described preparation of diol results in the formation of substantial amount of isomeric compound of Formula V due to non-selectivity in this reaction.

The presence of isomeric diol of Formula V results in the formation of corresponding l-methyl-2-phenylpiperazine isomer, which contaminates the product and results ir lower productivity.
Next, the same dichloride of Formula III has been treated with/7-toluenesulfonamide in the US Patent 6,339,156 to obtain tosyl piperazine, which is hydrolyzed to produce

l-methyl-3-phenyIpiperazine. However, preparation of dichloride and its isomeric purity has not been discussed in this US Patent.
In view of the prior art described above, the present invention provides a new process for preparing highly pure l-methyl-3-phenylpiperazine where the formation of 2-phenylpiperazine, l-methyl-2-phenylpiperazine isomer and I,4-dimethyl-2-phenylpiperazine has been avoided.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing l-methyI-3-phenylpiperazine represented by Formula I,

which comprises the steps of, debenzylation of the compound of Formula II

by hydrogenation in acetic acid in the presence of palladium-carbon catalyst to prepare a compound of Formula VII


and reduction of compound of Formula VII with lithium aluminium hydride.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a new process for preparing highly pure l-methyl-3-phenylpiperazine suitable for use in the synthesis of Mirtazapine and other tetracyclic compounds. The present invention also relates to a novel intermediate used to carryout this process.
According to the present invention, there is provided a process for preparing a nove' compound, 4-benzyl-l-methyl-2-oxo-3-phenylpiperazine, of Formula II

by methylation of 4-benzyl-2-oxo-3-phenylpiperazine of Formula VI


with methyl iodide in A^.A^-dimethyiformamide in presence of sodium hydride. Typically, the methylation is carried out with 1.1 to 1.2 moles of methyl iodide and sodium hydride each per one mole of compound of Formula VI. It is preferred to carryout the methylation by adding compound of Formula VI to the sodium hydride slurry in A^,A^-dimethylformamide followed by methyl iodide addition. The temperature during methylation is maintained at 10°C to 25'C and usually it takes 1 hour to complete the reaction.
The debenzylation of the above mentioned novel piperazine compound of Formula II is carried out by catalytic hydrogenation. The removal of benzyl group is performed by dissolving the compound of Formula II in acetic acid and subjecting it to hydrogenation at 20°C to 30°C in the presence of 5% palladium-carbon catalyst, at a hydrogen pressure of 80 psi to 100 psi. End point of the reaction is readily confirmed by high performance liquid chromatography and thereafter acetic acid is removed by distillation. An aqueous alkali such as sodium hydroxide is added to the reaction mass containing l-methyl-2-oxo-3-phenylpiperazine of Formula VII to make the solution alkaline, for instance, to pH 11.0 to 12.0. l-Methyl-2-oxo-3-phenylpiperazine can be isolated by extracting with toluene, methylene chloride, ethyl acetate, cyclohexane or the like, preferably methylene chloride is used.
Finally l-methyl-3-phenylpiperazine of Formula I is obtained by the reduction of the compound of Formula VII. The reduction can be carried out with lithium aluminirm hydride in tetrahydrofuran. This reduction is accomplished at a temperature 40°C to 70°C and preferably at the reflux temperature. l-Methyl-3-phenylpiperazine of Formula I is isolated in high purity (>99.5% by HPLC) using conventional work-up procedures.

The major advantage of the present invention is that l-methyl-3-phenylpiperazine thus obtained contains none of the impurities like 2-phenylpiperazine, l-methyl-2-phenylpiperazine isomer and l,4-dimethyl-2-phenylpiperazine.
l-Methyl-3-phenylpiperazine as obtained by the method described in this invention can be used in the preparation of Mirtazapine.
The invention is further illustrated by the following examples.
Example 1
PREPARATION OF 4-BENZYL-1-METHYL-2-OXO-3-PHENYLPIPERAZINE
15.3 g of sodium hydride (65% dispersion in mineral oil, 0.414 moles) was suspendea in 250 ml of MA^-dimethylformamide at 10°C. To this suspension, 100 g of 4-benzyl-2-0X0-3-phenylpiperazine (0.376 moles) was added portion-wise over a period of 30 min and stirred for 15 min. A solution of 64 g of methyl iodide (0.45 moles) in 50 ml of A/;A^-dimethylformamide was added slowly in 45 min maintaining the temperature below 25°C and maintained for 1 hour. After completion of the reaction, mass was poured slowly in 1000 ml of cold water (15°C). The product was extracted with toluene (1x500 ml, 1x300 ml) from aqueous phase. Toluene layer was washed with water (2x200 ml) and concentrated. To the residue, 250 ml of cyclohexane was added and cooled to 10°C with stirring. Filtered the product and washed with pre-cooled cyclohexane to obtain 98.5 g of 4-benzyl-l-methyl-2-oxo-3-phenylpiperazine product (yield: 93.8%, purity: 99.15 by HPLC).
MASS : m/z; 281.0 [(MH)*]

'H NMR (300 MHz) in CDCh : S(ppm); 2.49-2.57 (m, 1H), 2.97 {s, 3H),
2.99-3.03 (w, IH), 3.14-3.18 (m, 2H), 3.54-3.77 (m,2H), 4.06(5, IH), 7.21-7.53 (m, lOH).
Example 2
PREPARATION OF 1.METHYL-2-OXO-3-PHENYLPIPERAZINE
4-Benzyl-l-methyl-2-oxo-3-phenylpipera2ine (15 g, 0.535 moles) was dissolved in acetic acid (120 ml) and added 5% palladium-carbon (50% wet, 1.5 g). Reaction ftiass was hydrogenated at 100 psi. After completion of the reaction, reaction mixture was filtered and acetic acid was distilled under reduced pressure. Residue was dissolved in DM water (75 ml). pH was adjusted to 11.0-12.0 with 50% aqueous sodium hydroxide solution. The product was extracted with methylene chloride (2x75 ml) and washed with DM water (75 ml). The methylene chloride layer was concentrated under reduced pressure to obtain 10.1 g of 1 -methyl-2-oxo-3-phenylpiperazine.
'H NMR (300 MHz) in CDCl,: S(ppmy, 1.99 {bs, IH), 3.04 (5, 3H), 3.05-3.19 (m, 2H),
3.31-3,56 (m,2H), 4.58 (5, IH), 7.27-7.43 (m, 5H).
PREPARATION OF l-METHYL-3-PHENYLPIPERAZINE
Lithium aluminium hydride (3.04 g, 0.8 moles) was suspended in tetrahydroftiran (60 ml) under nitrogen atmosphere, A solution of l-methyl-2-oxo-3-phenylpiperazine (10 g in 10 ml of tetrahydrofuran) was added at 10-15X. Slowly raised the temperature of reaction mass and refluxed for 2 hours. Cooled the reaction

mass to 5^C and quenched successively with 3 ml of water, 3 ml of 15% aqueous sodium hydroxide solution and 9 ml of water. Reaction mass was stirred for 1 hour at 25-30*^C. Filtered the reaction mass and the filtrate was concentrated under reduced pressure. Dissolved the residue in DM water (25 ml) and concentrated hydrochloric acid (8 ml) and the solution was washed v^th cyclohexane (20 ml). pH was adjusted to 11.0-12.0 with 50% w/w aqueous sodium hydroxide solution and extracted the product with methylene chloride (2x50 ml). Methylene chloride layer was concentrated under reduced pressure and 7.54 g of pure l-methyl-3-phenylpiperaziae was isolated in cyclohexane having HPLC purity 99.7%.
*H NMR (300 MHz) in Ci)C/,: 5(ppmy, 1.80 (fo, IH), 1.95-2.18 (w, 2H), 2.31 (5, 3H),
2.79-3.12 (m, 4H), 3.85-3.89 (w, IH), 7.23-7.40 (m, 5H).




FIELD OF THE INVENTION
The present invention relates to the process for preparing l-methyl-3-phenylpiperazine of Formula I from 4-benzyl-l-methyl-2-oxo-3-phenylpiperazine,

BACKGROUND OF THE INVENTION
Mirtazapine, also known as 2-methyl-1,2,3,4,10,14b-hexahydrobenzo[c]pyrazinO" (1,2-a) pyrido[3,2-f]azepine, is an antidepressant drug suitable for oral administration. Mirtazapine belongs to piperazinoazepine group of compounds and has the following chemical structure,

l-Methyl-3-phenylpiperazine is the key intermediate in the preparation of Mirtazapine. US Patent 4,062,848 has described the synthesis of Mirtazapine using l-methyl-3-phenylpiperazine as starting material. It is believed that the earliest synthesis of this key intermediate is that of Roderick et. al., J, Med. Chem. 19o6, 181-185. This publication has reported the preparation of l-methyl-3-phenylpiperazine starting from a-bromophenylacetic acid ester and ethyienediamine resulting in the formation of 2-oxo-3-phenylpiperazine which is then subjected to

lithium aluminium hydride reduction and subsequently methylated with methyl iodide and triethylamine in acetone.

The drawback of this method is the non-selective methylation at 1-position. /. mixture of products like unreacted 2-phenylpiperazine, l-methyl-2-phenylpiperazine and 1,4-dimethyl-2-phenylpiperazine along with the desired 1 -methyl-3-phenylpiperazine is obtained. Therefore, extensive purification is required to obtain pure l-methyl-3-phenylpiperazine.


us Patent 6,495,685 has described the preparation of l-methyl-3-phenylpiperazine by reacting A^-(2-chloroethyl)-A^-methyI-p-chloro-p-phenylethylamine (the dichloride) of Formula III with ammonia.

This dichloride of Formula III has been prepared by chlorination of the corresponding diol, N-(2-hydroxyethyl)-A^-methyl-p-hydroxy*p-phenylethyiamine of Formula IV.

In US Patent 6,495,685, this diol has been obtained by reacting styrene oxide with A'-methyIethanolamine. However, the described preparation of diol results in the formation of substantial amount of isomeric compound of Formula V due to non-selectivity in this reaction.

The presence of isomeric diol of Formula V results in the formation of corresponding l-methyl-2-phenylpiperazine isomer, which contaminates the product and results ir lower productivity.
Next, the same dichloride of Formula III has been treated with/7-toluenesulfonamide in the US Patent 6,339,156 to obtain tosyl piperazine, which is hydrolyzed to produce

l-methyl-3-phenyIpiperazine. However, preparation of dichloride and its isomeric purity has not been discussed in this US Patent.
In view of the prior art described above, the present invention provides a new process for preparing highly pure l-methyl-3-phenylpiperazine where the formation of 2-phenylpiperazine, l-methyl-2-phenylpiperazine isomer and I,4-dimethyl-2-phenylpiperazine has been avoided.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing l-methyI-3-phenylpiperazine represented by Formula I,

which comprises the steps of, debenzylation of the compound of Formula II

by hydrogenation in acetic acid in the presence of palladium-carbon catalyst to prepare a compound of Formula VII


and reduction of compound of Formula VII with lithium aluminium hydride.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a new process for preparing highly pure l-methyl-3-phenylpiperazine suitable for use in the synthesis of Mirtazapine and other tetracyclic compounds. The present invention also relates to a novel intermediate used to carryout this process.
According to the present invention, there is provided a process for preparing a nove' compound, 4-benzyl-l-methyl-2-oxo-3-phenylpiperazine, of Formula II

by methylation of 4-benzyl-2-oxo-3-phenylpiperazine of Formula VI


with methyl iodide in A^.A^-dimethyiformamide in presence of sodium hydride. Typically, the methylation is carried out with 1.1 to 1.2 moles of methyl iodide and sodium hydride each per one mole of compound of Formula VI. It is preferred to carryout the methylation by adding compound of Formula VI to the sodium hydride slurry in A^,A^-dimethylformamide followed by methyl iodide addition. The temperature during methylation is maintained at 10°C to 25'C and usually it takes 1 hour to complete the reaction.
The debenzylation of the above mentioned novel piperazine compound of Formula II is carried out by catalytic hydrogenation. The removal of benzyl group is performed by dissolving the compound of Formula II in acetic acid and subjecting it to hydrogenation at 20°C to 30°C in the presence of 5% palladium-carbon catalyst, at a hydrogen pressure of 80 psi to 100 psi. End point of the reaction is readily confirmed by high performance liquid chromatography and thereafter acetic acid is removed by distillation. An aqueous alkali such as sodium hydroxide is added to the reaction mass containing l-methyl-2-oxo-3-phenylpiperazine of Formula VII to make the solution alkaline, for instance, to pH 11.0 to 12.0. l-Methyl-2-oxo-3-phenylpiperazine can be isolated by extracting with toluene, methylene chloride, ethyl acetate, cyclohexane or the like, preferably methylene chloride is used.
Finally l-methyl-3-phenylpiperazine of Formula I is obtained by the reduction of the compound of Formula VII. The reduction can be carried out with lithium aluminirm hydride in tetrahydrofuran. This reduction is accomplished at a temperature 40°C to 70°C and preferably at the reflux temperature. l-Methyl-3-phenylpiperazine of Formula I is isolated in high purity (>99.5% by HPLC) using conventional work-up procedures.

The major advantage of the present invention is that l-methyl-3-phenylpiperazine thus obtained contains none of the impurities like 2-phenylpiperazine, l-methyl-2-phenylpiperazine isomer and l,4-dimethyl-2-phenylpiperazine.
l-Methyl-3-phenylpiperazine as obtained by the method described in this invention can be used in the preparation of Mirtazapine.
The invention is further illustrated by the following examples.
Example 1
PREPARATION OF 4-BENZYL-1-METHYL-2-OXO-3-PHENYLPIPERAZINE
15.3 g of sodium hydride (65% dispersion in mineral oil, 0.414 moles) was suspendea in 250 ml of MA^-dimethylformamide at 10°C. To this suspension, 100 g of 4-benzyl-2-0X0-3-phenylpiperazine (0.376 moles) was added portion-wise over a period of 30 min and stirred for 15 min. A solution of 64 g of methyl iodide (0.45 moles) in 50 ml of A/;A^-dimethylformamide was added slowly in 45 min maintaining the temperature below 25°C and maintained for 1 hour. After completion of the reaction, mass was poured slowly in 1000 ml of cold water (15°C). The product was extracted with toluene (1x500 ml, 1x300 ml) from aqueous phase. Toluene layer was washed with water (2x200 ml) and concentrated. To the residue, 250 ml of cyclohexane was added and cooled to 10°C with stirring. Filtered the product and washed with pre-cooled cyclohexane to obtain 98.5 g of 4-benzyl-l-methyl-2-oxo-3-phenylpiperazine product (yield: 93.8%, purity: 99.15 by HPLC).
MASS : m/z; 281.0 [(MH)*]

'H NMR (300 MHz) in CDCh : S(ppm); 2.49-2.57 (m, 1H), 2.97 {s, 3H),
2.99-3.03 (w, IH), 3.14-3.18 (m, 2H), 3.54-3.77 (m,2H), 4.06(5, IH), 7.21-7.53 (m, lOH).
Example 2
PREPARATION OF 1.METHYL-2-OXO-3-PHENYLPIPERAZINE
4-Benzyl-l-methyl-2-oxo-3-phenylpipera2ine (15 g, 0.535 moles) was dissolved in acetic acid (120 ml) and added 5% palladium-carbon (50% wet, 1.5 g). Reaction ftiass was hydrogenated at 100 psi. After completion of the reaction, reaction mixture was filtered and acetic acid was distilled under reduced pressure. Residue was dissolved in DM water (75 ml). pH was adjusted to 11.0-12.0 with 50% aqueous sodium hydroxide solution. The product was extracted with methylene chloride (2x75 ml) and washed with DM water (75 ml). The methylene chloride layer was concentrated under reduced pressure to obtain 10.1 g of 1 -methyl-2-oxo-3-phenylpiperazine.
'H NMR (300 MHz) in CDCl,: S(ppmy, 1.99 {bs, IH), 3.04 (5, 3H), 3.05-3.19 (m, 2H),
3.31-3,56 (m,2H), 4.58 (5, IH), 7.27-7.43 (m, 5H).
PREPARATION OF l-METHYL-3-PHENYLPIPERAZINE
Lithium aluminium hydride (3.04 g, 0.8 moles) was suspended in tetrahydroftiran (60 ml) under nitrogen atmosphere, A solution of l-methyl-2-oxo-3-phenylpiperazine (10 g in 10 ml of tetrahydrofuran) was added at 10-15X. Slowly raised the temperature of reaction mass and refluxed for 2 hours. Cooled the reaction

mass to 5^C and quenched successively with 3 ml of water, 3 ml of 15% aqueous sodium hydroxide solution and 9 ml of water. Reaction mass was stirred for 1 hour at 25-30*^C. Filtered the reaction mass and the filtrate was concentrated under reduced pressure. Dissolved the residue in DM water (25 ml) and concentrated hydrochloric acid (8 ml) and the solution was washed v^th cyclohexane (20 ml). pH was adjusted to 11.0-12.0 with 50% w/w aqueous sodium hydroxide solution and extracted the product with methylene chloride (2x50 ml). Methylene chloride layer was concentrated under reduced pressure and 7.54 g of pure l-methyl-3-phenylpiperaziae was isolated in cyclohexane having HPLC purity 99.7%.
*H NMR (300 MHz) in Ci)C/,: 5(ppmy, 1.80 (fo, IH), 1.95-2.18 (w, 2H), 2.31 (5, 3H),
2.79-3.12 (m, 4H), 3.85-3.89 (w, IH), 7.23-7.40 (m, 5H).



Documents:

328-che-2004 abstract original.pdf

328-che-2004 claims granted.pdf

328-che-2004 form 3.pdf

328-che-2004-abstract.pdf

328-che-2004-claims.pdf

328-che-2004-correspondnece-others.pdf

328-che-2004-correspondnece-po.pdf

328-che-2004-description(complete).pdf

328-che-2004-form 1.pdf

328-che-2004-form 19.pdf

328-che-2004-form 3.pdf


Patent Number 236545
Indian Patent Application Number 328/CHE/2004
PG Journal Number 47/2009
Publication Date 20-Nov-2009
Grant Date 09-Nov-2009
Date of Filing 02-Jun-2003
Name of Patentee AUROBINDO PHARMA LIMITED
Applicant Address PLOT NO.2, MAITRIVIHAR COMPLEX (REGD OFFICE), AMEERPET, ADHRA PRADESH, HYDERABAD-500 038, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 VIJAY KUMAR HANDA AUTOBINDO PHARMA LIMITED, PLOT NO.2, MAITRIVIHAR COMPLEX (REGD OFFICE), AMEERPET, ADHRA PRADESH, HYDERABAD-500 038, INDIA.
2 DIVVELA VENKATA NAGA SRINIVASA RAO AUTOBINDO PHARMA LIMITED, PLOT NO.2, MAITRIVIHAR COMPLEX (REGD OFFICE), AMEERPET, ADHRA PRADESH, HYDERABAD-500 038, INDIA.
3 MEENAKSHISUNDERAM SIVAKUMARAN AUTOBINDO PHARMA LIMITED, PLOT NO.2, MAITRIVIHAR COMPLEX (REGD OFFICE), AMEERPET, ADHRA PRADESH, HYDERABAD-500 038, INDIA.
PCT International Classification Number A61K 31/495
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA