FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for Preparation of 2-cyclohexylcarbonyl-4-oxo-l,2,3,6,7,llb-hexahydro-4H-pyrazino[2,l-a]isoquinoIine
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at
116 Vardhman Industrial Complex, L.B.S Marg,
Thane (W), Mumbai - 400 601, India
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention relates to a novel, cost-effective process for preparation of a 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino-[2,l-a]isoquinoline derivative. Specifically, it relates to a process for the preparation of pure praziquantel free of US pharmacopeia specified impurities and oxidative impurities.
BACKGROUND OF THE INVENTION
Praziquantel having chemical name 2-cyclohexylcarbonyl-4-oxo-1,2,3,6,7,1 lb-hexahydro-4H-pyrazino[2,l-a]isoquinoline of formula I, is a member of the 2-Acyl-4-oxopyrazinoisoquinoline compounds, which are used as a drug indicated for the treatment of a variety of worm infections. Praziquantel is primarily used against parasites known as "cestodes" and it is also effective against flukes.

There are number of literatures available which describe the process for preparation of praziquantel. US patent 4001411 describes a process for preparation of praziquantel by acylating 4-0X0-1,2,3,6,7,1 lb-hexahydro-4H-pyrazino[2,l-a]isoquinoline with cyclohexanoylchloride in chloroform and triethylamine.
KR2002076486 describes a process for preparation of praziquantel by reacting phenylethylamine with chloroacetyl chloride to obtain 2-chIoro-N-

phenethylacetamide. Treating 2-chloro-N-phenethylacetamide with pthalimide to give 2-pthalimido-N-phenethylacetamide and treating further 2-pthalimido-N-phenethylacetamide with hydrazine monohydrate to give 2-amino-N-phenylethylacetamide, which on further treatment with bromoacetal gives 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenyIethyl)acetamide. This compound on further cyclization and acylation using cyclohexanoylchloride forms praziquantel.
WO2009115333 describes many processes in one of which 3-phenylpropanenitrile is reacted with aminoacetal in presence of formaldehyde to obtain 2-[(2,2-diaIkoxyethyl)amino]-N-(2-phenyIethyl)acetamide, which is further cyclised and acylated using cyclohexanoylchloride to form praziquantel.
Eur. J. Org. Chem. 2008, 895-913 describes a process comprising: a) reacting phenylethylamine with chloroacetyl chloride in presence of sodium bicarbonate to obtain 2-chloro-N-phenethylacetamide, b) treating 2-chloro-N-phenethylacetamide with aminoacetaldehyde dimethylacetal to give 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, c) making hydrochloride salt of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, and d) cyclising using sulphuric acid to form praziquanamine (i.e.4-oxo-l,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1 -a]isoquinoline).
Most of the reported prior art process for the preparation of praziquantel involves formation of oxidative impurities such as 2-(cyclohexylcarbonyl)-11b-hydroperoxy-1,2,3,6,7,1 lb-hexahydro-4H-pyrazino[2, l-a]isoquinolin-4-one, which is very difficult to remove from the final compound. Also, the presence of cyclohexylcarboxylic acid as an impurity in the final API gives a characteristic odour which is not suitable for formulation. Thus there is a need to develop a process for the preparation of praziquantel, which avoids the formation of oxidative impurities as well as to remove the cyclohexycarboxylic acid to less than 10ppm to make suitable for formulation.
The present inventors have developed a cost effective process for preparing praziquantel which avoids the formation of above stated oxidative impurities

which leads to preparation of highly pure praziquantel in good yield. Thus the present invention provides a cost effective process for preparing Praziquantel in good yield and good purity on a commercial scale.
SUMMARY OF THE INVENTION
The principal aspect of the present invention is to provide a process for the preparation of 2-cyclohexylcarbonyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,l-a]isoquinoline of formula I, which comprises:
a) acylation of 4-oxo-l,2,3,6,7,11b-hexahydro-4H-pyrazino[2,l-a]isoquinoline of formula II with cyclohexanoylchloride of formula III in presence of a base and solvent;
b) separating the product layer;
c) distilling the solvent to obtain a thick slurry;
d) dissolving in an alcoholic solvent;
e) stirring the reaction mass after adding an antioxidant; and
f) filtering, distilling the solvent and optional seeding to obtain Praziquantel
of formula I.
The process of the present invention may be illustrated as in the scheme below:


DETAIL DESCRIPTION OF THE INVENTION
Accordingly in an embodiment of the invention, the acylation of 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,l-a]isoquinoIine of formula II with cyclohexanoylchloride is carried out in presence of a base selected from an alkali metal carbonates and bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate etc. preferably sodium carbonate and an organic solvent, preferably a chlorinated solvent selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride etc. most preferably dichloromethane. The reaction is carried out preferably in the temperature range 25 to 30°C.
In another embodiment of the invention, the product formed is separated using water and the solvent is distilled under vacuum at 40 to 50°C to obtain thick slurry. The obtained slurry is dissolved in an alcoholic solvent preferably methanol and an antioxidant selected from ascorbic acid, ascorbyl palmitate, butylatedhydroxylanisole (BHA), butylated hydroxyl toluene (BHT), citrate acid, ethoxyquin, methylparaben, propul gallate, sodium bisulphite, sodium metabisulphite, sorbic acid, trihydroxy-butyrophenone (THBP), tertiary-butylhydroquinone (TBHQ), and toluehydroquinone, preferably butylated hydroxyl toluene (BHT) is added. Activated charcoal is also added to the above reaction mass and stirred at temperature 35 to 50°C preferably at 40 to 45°C.
In still another embodiment of the invention, the product after charcolisation is filtered washed with an alcoholic solvent preferably methanol and the solvent is distilled under vacuum. The product is optionally seeded with pure praziquantel to obtain highly pure praziquantel having purity more than 99.8%.
The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
Example 1: Preparation of 2-cyclohexylcarbonyl-4-oxo-l,2,3,6,7,11b-hexahydro-4H-pyrazino[2, l-a]isoquinoline

4-0x0-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,l-a]isoquinoline (0.83kg), dichloromethane (4.15 L) and sodium carbonate (0.4 kg) were stirred at 25-30°C for 15min, cooled to 0-5°C. Cyclohexanoyl chloride (0.63 kg) was added slowly, and the reaction mass was allowed to attain 25-30°C and stirred for 2 hrs. After completion of reaction, DM water was added, stirred and the layers were separated. A combined organic layer was distilled under vacuum. Methanol was added to the above reaction mass and heated to 40-45°C. Butylated hydroxyl toluene (0.0042 kg) and activated charcoal (0.071 kg) were added, stirred and filtered over Hyflo super cell bed. Hyflo super cell bed was washed with methanol and the filtrate was distilled to remove methanol, cooled to 20-30°C. The above reaction mass was further seeded with pure praziquantel (0.1 g), stirred for 4 hrs and cooled to 0-5°C. The reaction mass was further stirred for 2 hrs, filtered, washed with methanol and suck dried to obtain pure praziquantel having total impurity less than 0.15% and cyclohexylcarboxylic acid less than 10ppm.

We claim:
1. A process for preparation of 2-cyclohexylcarbonyl-4-oxo-l,2,3,6,7,11b-
hexahydro-4H-pyrazino[2,1-a]isoquinoline comprising:
a) acylation of . 4-oxo-1,2,3,6,7,11b-hexahydro-4H-oyrazinor[2,1-
a]isoquinoline of formula II with cyclohexanoylchloride of formula III in presence of a base and solvent;

b) separating the product layer;
c) distilling the solvent to obtain a thick slurry;
d) dissolving in an alcoholic solvent;
e) stirring the reaction mass after adding an antioxidant; and
f) filtering, distilling the solvent and optional seeding to obtain Praziquantel of formula I.

2. A process according to claim 1, wherein the solvent is an organic solvent selected from chlorinated solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride etc. preferably dichloromethane.
3. A process according to claim 1, wherein the base is selected from an alkali metal carbonates and bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate etc. preferably sodium carbonate.
4. A process according to claim 1, wherein the thick slurry obtained in step (c) is dissolved in methanol.
5. A process according to claim 1, wherein the antioxidant is selected from ascorbic acid, ascorbyl palmitate, BHA, butylated hydroxyl toluene, citrate

acid, ethoxyquin, methylparaben, propul gallate, sodium bisulphite, sodium metabisulphite, sorbic acid, trihydroxy-butyrophenone, tertiary-butylhydroquinone, and toluehydroquinone.
6. A process according to claim 5, wherein the antioxidant is butylated hydroxyl toluene.
7. A process according to claim 1, wherein the antioxidant is dissolved in methanol before adding to the thick slurry in step (d).
8. A process according to claim 1, wherein acylation is carried out at 25 to 30°C.