FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"IMPROVED PROCESS FOR PREPARATION OF ANTHELMINTIC AGENT"
2. APPLICANT:
(a) NAME: CIPLA LIMITED
(b)NATIONALITY.' Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3.PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to an improved process for preparation of an anthelmintic agent.
BACKGROUND OF THE INVENTION:
Praziquantel is an old anthelmintic drug used to treat infestations of schistosoma (a type of worm that lives in the bloodstream), liver fluke (a type of worm that lives in or near the liver) and tapeworm. It works by killing these worms.
Praziquantel is also known as 2-cyclohexy1carbonyl-4-oxo-l,2,3,6,7,llb-hexahydro-4H-pyrazino[2,l-a]isoquinoline and has following structural formula (1).

Though praziquantel is an old drug, even today it is of great importance as it is the sole existing drug in the treatment & control of infection of schistosoma.
Praziquantel has one chiral centre and exists as 2 optical isomers. Currently praziquantel is synthesized and administered as a racemate.
However, R-(-)-praziquantel has been identified as an active component against schistosoma. Further, it has also been observed that the R-(-)-enantiomer of praziquantel is significantly less bitter than racemic praziquantel.
The first patent of praziquantel, US4001411 describes praziquantel & its preparation. It also describes that optically active praziquantel can be prepared from optically active

starting material ie. optically active Praziquanamine (HPI). Racemic praziquantel can be treated with optically active auxiliary agent such as optically active bases or optically active acids. Optically active acids include (+) & (-) forms of tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, camphoric acid, P-camphorsulfonic acid, mandelic acid, malic acid, 2-phenylbutyric acid, dinitrodiphenic acid, lactic acid or quinic acid. However, the patent does not explicitly describe any process for preparation of (-)-praziquantel from (-)-praziquanamine or resolution of racemic praziquantel to yield (-)-praziquantel.
Michael Wolfle on Synaptic Leap on 11th May 2010 (link http://www.thesynapticleap.org/node/313), describes that the process disclosed in US3993760 which uses D-quinic acid for the resolution of racemic praziquanamine. However, the procedure provides less information about the yield obtained. Further, by repeating such process, the enantiomeric excess of (-)-praziquanamine obtained also less.
Further, attempts have been made to resolve the racemic praziquantel as well as its racemic intermediate, praziquanamine (HPI) using optically active auxiliary agent but the yield obtained by such processes are low.
Roszkowski et al (Tetrahedron Asymmetry, 17, 2006, pages 1415-1419) described enantioselective synthesis of (R)-(-)praziquantel which resulted in 77% of (R)-(-) praziquantel with final purification using column chromatography. This synthesis is multi-step process and requires expensive chiral Ruthenium catalyst.
Laurent et al (Eur. J. Org. Chem., 2008, 895-913) made many attempts to prepare (-) praziquanamine. They tried enantioselective synthesis, diastereomeric resolution, kinetic resolution by enzymes as well as separation by converting covalent diastereomers. The separation by covalent diastereomers was successful.
The covalent diastereomers were prepared using Mosher's acid and a coupling reagent PyBOP which are expensive. These diastereomers were first separated by silica gel columns as a single isomer of Mosher's amide. These isomers of Mosher's amide on

hydrolysis followed by column purification resulted in corresponding R & S isomers of praziquanamine.
The enantiomeric excess (ee) obtained by this process was more than 95%. However, the yield of the reaction was less. This resolution process is not industrially feasible as it requires several column separation steps which required highly inflammable solvent like diethyl ether. Further, the reaction is carried out at higher temperature and for prolonged time.
Further, Laurent et al (Eur. J. Org. Chem., 2008, 895-913) tried to resolve racemic intermediate, praziqaunamine, through crystallization of diastereomeric chiral ammonium salts prepared from chiral acids such as tartaric acid, camphor sulphonic acid, mandelic acid & Mosher's acid in various solvent mixtures. But it resulted in co-precipitation of both the diastereomers.
They further tried separation of diastereomeric salts by HPLC & also tried direct resolution of praziqaunamine by chiral HPLC. But both the attempts of separation by HPLC failed.
Michael Wolfle on ourexperiment.org describes use of various resolving agents such as (+)-di-p-anisoyl-D-tartaric acid, (-)-di-benzoyl-L-tartajic acid, to resolve racemic praziquanamine to get R-(-) praziquanamine.
Boajn Milic on ourexperiment.org discusses the use of tartaric acid derivatives of L-series such as Di-pivaloyl-L-tartaric acid and Di-p-toluoyl-L-tartaric acid. It concludes that Di-p-toluoyl-L-tartaric acid was successful in the resolution of praziquanamine to yield R-(-)-praziquanamine with yield of 44% and 79% ee and successful enantioselective synthesis of R-(-)-praziquantel with yield of 83% and 90% ee while Di-pivaloyl-L-tartaric acid could not be used as a resolving agent in the resolution of praziquanamine.
This discussion further describes the use of di-4-chlorobenzoyl-L-tartaric acid, di-4-bromobenzoyl-L-tartaric acid to get (+)-praziquanamine.

Many attempts have also been made to resolve racemic praziquantel using various column chromatography techniques. However, these chromatographic techniques require complex set up & also are not suitable for large scale industrial synthesis.
The prior art describes use of Di-p-toluoyl-L-tartaric acid to get R-(-)-praziquanamine and while use of Di-pivaloyl-L-tartaric acid was unsuccessful. Under the same set of reaction conditions, use of Dextro rotatory isomers did not give good yield and enantiomeric excess..
However, it is now surprisingly found that optically active antipodes of these tartaric acid derivatives provide improved yield as well as enantiomeric excess compared to prior art. Further, this resolution process is industrially feasible, economical and provides higher enantiomeric purity & improved yield.
SUMMARY OF THE INVENTION:
According to the first aspect of the present invention, there is provided a process for the preparation of R-(-)-praziquanamine by the resolution of racemic praziquanamine using optically active antipodes of tartaric acid derivatives as resolving agent.
In another aspect of the present invention, there is provided process for preparation of racemic or enantiomer of praziquantel from racemic or enantiomer of praziquanamine in water.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 1 depicts an X-ray diffraction pattern of crystalline R-(-)-praziquantel obtained by following the example 3.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first aspect of the present invention, there is provided a process for the preparation of R-(-)-praziquanamine by the resolution of racemic praziquanamine.

The process comprises contacting racemic praziqaunamine with dextro rotatory isomers of tartaric acid derivatives as resolving agent in a suitable organic solvent to form corresponding diastereomeric salt of praziqaunamine.
The suitable resolving agent used is selected from Di-p-toluoyl-D-tartaric acid (DPTTA), Di-pivaloyl-D-tartaric acid.
Suitable organic solvent for preparation of diastereomeric salt may be selected from water, alcohols such as ethanol, methanol, butanol, isopropanol; esters such as ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; ethers such as tert. butyl methyl ether, diisopropyl ether, dioxane, tetrahydrofuran; optionally substituted hydrocarbons such as toluene, xylene, n-hexane, n-heptane, methylene dichloride (MDC); nitrites such as acetonitrile, propionitrile or mixtures thereof. The preferred solvent is isopropanol.
The addition of resolving agent to racemic praziqaunamine is carried out at 20-30cC & then the temperature is raised to 40-5 5°C.
Further, the molar ratio of racemic praziquanamine to resolving agent is 1:0.8 to 1:0.25, preferably 1:0.5.
In the prior art, the reaction time is quite lengthy where levo rotatory isomers of tartaric acid derivatives are used as resolving agent. The reaction time varies from 10 hours to 40 hours wherein the reaction mixture kept standing. Some processes also require keeping in fridge at 5°C over 4 days. All these processes are industrially less feasible & suitable. In the process of the present invention, the reaction time is very less and requires simple stirring for 10 to 30 minutes to get the desired product.
The crude diastereomeric salt of praziquanamine is, if required, further purified using a solvent may be selected from water & water miscible organic solvent such as alcohols selected from ethanol, methanol, butanol, isopropanol; ketones selected from acetone,

ethyl methyl ketone, methyl isobutyl ketone; ethers selected from dioxane, tetrahydrofuran; nitriles such as acetonitrile, propionitrile or mixtures thereof.
The ratio of water to water miscible organic solvent is 1:9 to 9:1, preferably 1.5:1 to 1:1.5,more preferably 1:1.
R-(-)-praziqaunamine is then released from the diastereomeric salt. The process of breaking of the diastereomeric salt is carried out using suitable organic or inorganic base in suitable solvent. Inorganic base may be selected from alkali & alkaline earth metal hydroxides, carbonates & bicarbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide; sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate.
Organic base may be selected from ammonia or amine such as trimethyl amine, triethyl amine, diisopropylethyl amine, pyridine.
The solvent used for preparation of R-(-)-praziqaunamine base is selected from water and water immiscible solvents such as esters selected from ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate; hydrocarbons selected from toluene, xylene, n-hexane, n-heptane; halogenated hydrocarbon solvents selected from dichloromethane, 1,2-dichloroethane; ethers selected from diethyl ether, diisopropyl ether; or mixture thereof.
In another aspect of the present invention, there is provided process for preparation of racemic or enantiomer of praziquantel from racemic or enantiomer of praziquanamine which process comprises acylating racemic or enantiomer of praziqaunamine with cyclohexane carbonyl chloride in water to obtain racemic or enantiomer of praziquantel. In an embodiment, there is provided process for preparation of R-(-)-praziquantel from R-(-)-praziquanamine which process comprises acylating R-(-)-praziqaunamine with cyclohexane carbonyl chloride in water to obtain R-(-)-praziquantel in crystalline form.
The acylation is carried out in presence of a base.
Base used is selected from inorganic base or organic base.

The inorganic base used is same as that described for the preparation of R-(-)-praziquanamine.
Organic base is selected from trimethyl amine, triethyl amine, diisopropyl amine or pyridine.
The XRPD of the crystalline R-(-)-praziquantel obtained by the above process is measured on a Rigaku X-ray powder diffractometer using a Cu Ka radiation source and is characterized by its XRPD pattern as shown in Figure 1.
The XRD of the crystalline R-(-)-praziquantel obtained by the process of the present invention is characterized by having an X-Tay powder diffraction (XRPD) pattern comprising peaks at the ° 2θ position (± 0.2 °θ) as shown in table below :

°2θ(±0.2°2θ) 1/1°
7.04 14
8.40 44
13.42 10
14.12 8
15.08 97
15.60 18
16.62 19
17.44 91
17.94 46
18.22 18
19.04 17
19.68 54
21.64 38
21.90 100
23.08 7
23.66 15
23.96 7

24.34 72
27.44 39
27.84 8
29.04 12
30.86 8
33.62 6
39.46 9
In an alternate embodiment, diastereomeric salt of R-(-)-praziqaunamine can be used directly for preparation of R-(-)-praziquantel in crystalline form wherein R-(-)-praziqaunamine diastereomeric salt is converted to R-(-)-praziquantel without isolating R-(-)-praziqaunamine.
The process involves following steps:
1) dissolving diastereomeric salt of R-(-)-praziqaunamine in a suitable solvent,
2) adding base to the solution in step 1) to liberate R-(-)-praziqaunamine and stirring the reaction mass,
3) extracting R-(-)-praziqaunamine with the same solvent and separating the layers,
4) adding base to the organic layer containing R-(-)-praziqaunamine and
5) adding cyclohexyl carbonyl chloride to the reaction mass at 10-20°C under stirring.
The suitable solvent used may be selected from water, mixture of water & organic solvent.
The organic solvent may be selected from acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethyl formamide (DMF), dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 1,4-dioxane, diglyme, toluene, xylene, methylene dichloride (MDC), ethylene dichloride (EDC), hexane, heptane, cyclohexane, diisopropyl ether, diethyl ether, methyl tert-butyl ether, ethyl acetate, methyl acetate, isopropyl acetate.

The base used in step 2) is same as that described for preparation of R-(-)-
praziquanamine.
The base used in.step 4) is same as that described for preparation of racemic or
enantiomer of praziquantel.
The process of the present invention can be summarized in a scheme below.

The present invention will now be further illustrated by the following examples, which do not limit the scope of the invention in any way.
Examples Example 1
Resolution of racemic praziquanamine to diastereomeric salt of praziquanamine 100.0 g (0.495 mol) of racemic praziquanamine was charged with 1500 ml of isopropyl alcohol (IPA) to reaction flask at 25°C and stirred for 15 minutes. 95.54 g (0.247 mol) of (+)-Di-p-toluoyl-D-tartaric acid was added to this reaction mixture in one lot and again stirred for 15 minutes. The reaction mass was heated to 45 to 50°C and maintained for half an hour at 45°C followed by cooling gradually to room temperature at 25°C-30°C.

The solid obtained was filtered and washed with isopropyl alcohol and dried at 45-50°C to yield 135.0 g of diastereomeric salt of praziquanamine.
The crude solid material along with 3375 ml of isopropyl alcohol & water 1:1 ratio was taken in the reaction flask. The reaction mixture was heated to 65 to 70°C and maintained for 1 hour at 65°C. The reaction mass was cooled gradually at room temperature at 25°C-30°C and stirred for 10-12 hours. The solid obtained was filtered and washed with mixture of isopropyl alcohol-water and dried under vacuum at 50- 55°C. Weight - 72.0 g. Chiral Purity - >99.0%
Example 2
Preparati on of R-(-)-praziquanamine
50.0 g of (0.085 mol) R-(-)-Praziquanamine (+)-Di-p-toluoyl-D-tartaric acid salt was
charged with 250ml water to a reaction flask at 25°C and cooled to 10-15°C & followed
by dropwise addition of aqueous ammonia, 350.0 ml dichloromethane was added to the
reaction mass and stirred for 1 hour at 10-15°C. The layers were separated and aqueous
layer was extracted with 2x100m] dichloromethane solvent. All dichloromethane layers
were combined and washed with water. Dichloromethane layer was dried over Na2SO4,
distilled under vacuum at 40°C.
Weight- 14.0 g.
Example 3
Preparation of R-M-Praziquantel
14.0 g (0.69 mo!) R-(-)-Praziquanamine was charged along with 98.0 ml water to 250 ml
reaction flask followed by addition of 11.5 ml (0.082 mol) of triethylamine in one lot at
25-30°C. The reaction mass was stirred at room temperature for 10 minutes and cooled to
10-15°C. 10.0 ml (0.076 mol) Cyclohexyl carbonyl chloride was added dropwise. The
temperature was raised to 20-25°C & stirred for 2.5 hours. The solid obtained was filtered
& washed with water. 100.0 ml water was added to this solid to make a slurry & stirred
for 2 hours. The solid was filtered & washed with heptane solvent and dried at 50-55°C to
obtain R-(-)- Praziquantel in crystalline form. .
Chiral Purity of R isomer - >99%

Chromatographic Purity - >99% Weight-13.0g
Example 4
Preparation of R-(-)-Praziquantel
305 g (0.519 mol) of R-(-)-Praziquanamine (+)-Di-p-toluoyl-D-tartaric acid salt was charged with 1500 ml of water to reaction flask at room temperature and cooled to 15-20°C. Aqueous ammonia was added dropwise within 30 minutes and stirred for 1 hour at 10-15°C followed by addition of 900 ml of dichloromethane. Organic and aqueous layers were separated and aqueous layer was extracted with 3 X 200 ml of dichloromethane. The combined dichloromethane layers were collected, washed with water, dried over sodium sulphate and charged alongwith 70 ml (0.505 mol) of triethylamine in reaction flask and stirred for 10 minutes. The reaction mass was cooled to 10-15°C and 62 ml (0.452 mol) of eyelohexyl carbonyl chloride was added dropwise within 30 minutes. The reaction mass was warmed to 25-30°C & stirred for 2 hours.
The reaction mass was washed with water. Dichloromethane layer was treated with 8.5 g of activated charcoal and stirred for 1 hour at 25-30°C followed by filtering through celite and washing with 150 ml of dichloromethane. The filtrate was distilled under vacuum at 40°C to get a residue which was dissolved in 150 ml acetone , concentrated and then 500 ml of n-heptane was added to it, stirred for 1 hour at 25-30°C, filtered, washed with n-heptane and dried under vacuum at 45-50°C to obtain R-(-)- Praziquantel in crystalline form,
Chiral Purity ->99.0% Chromatographic Purity - >99.0% Weight- 16.0 g

We Claim:
1) A process for the preparation of R-(-)-praziquanamine comprising resolving racemic praziquanamine using dextrorotatory isomers of tartaric acid derivatives as a resolving agent.
2) The process as claimed in claim 1, wherein, the dextrorotatory isomers of tartaric acid derivatives are selected from Di-p-toluoyl-D-tartaric acid (DPTTA) and di-pivaloyl-D-tartaric acid.
3) The process as claimed in claim 1, wherein, the resolution of racemic praziquanamine to obtain diastereomeric salt is conducted in a solvent which is selected from the group consisting of water, alcohols, esters, ketones, ethers, hydrocarbons, nitriles or mixtures thereof.
4) The process as claimed in claim 3, wherein, the solvent is selected from water, ethanol, methanol, butanol, isopropanol, ethyl acetate, methyl acetate, isopropyi acetate, butyl acetate, acetone, ethyl methyl ketone, methyl isobutyl ketone, tert. butyl methyl ether, diisopropyl ether, dioxane, tetrahydrofuran, toluene, xylene, n-hexane, n-heptane, methylene dichloride (MDC), acetonitrile, propionitrile or mixtures thereof.
5) The process as claimed in claim 4, wherein, the solvent is a mixture of water and isopropanol.
6) The process as claimed in claim 1, wherein, the molar ratio of racemic praziquanamine to resolving agent ranges from 1:0.8 to 1:0.25.
7) The process as claimed in claim 6, wherein, the molar ratio of racemic praziquanamine to resolving agent is 1:0.5.
8) The process as claimed in claim 1, wherein, the addition of resolving agent is carried out at a temperature of 20-30°C and then raised to 40-55°C.

9) The process as claimed in claim 3, wherein, the diastereomeric salt of praziquanamine may further be purified using water and water miscible solvent.
10) The process as claimed in claim 9, wherein, the water miscible solvent is selected from the group consisting of ethanol, methanol, butanol, isopropanol, acetone, ethyl methyl ketone, methyl isobutyl ketone, dioxane, tetrahydrofuran, acetonitrile, propionitrile or mixtures thereof.
11) The process as claimed in claim 9, wherein, the ratio of water to water miscible solvent ranges from 1:9 to 9:1.
12) The process as claimed in claim 11, wherein, the ratio of water to water miscible solvent is 1:1.
13) The process as claimed in claim 3, further comprises releasing the R-(-)-praziquanamine from the diastereomeric salt using a suitable inorganic or organic base in a suitable solvent.
14) The process as claimed in claim 13, wherein, suitable inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide; sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate and suitable organic base is selected from ammonia or amine such as trimethyl amine, triethyl amine, diisopropylethyl amine, pyridine.
15) The process as claimed in claim 13, wherein, the solvent is selected from water and water immiscible solvents such as ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, toluene, xylene, n-hexane, n-heptane, dichloromethane, 1,2-dichloroethane, diethyl ether, diisopropyl ether or mixture thereof.
16) A process for preparation of racemic or enantiomer of praziquantel from racemic or enantiomer of praziquanamine which process comprises acylating racemic or

enantiomer of praziqaunamine with cyclohexane carbonyl chloride in water to obtain racemic or enantiomer of praziquantel.
17) The process as claimed in claim 16, wherein, the reaction is carried out in presence of a suitable inorganic or organic base.
18) The process as claimed in claim 17, wherein, the suitable inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide; sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate and organic base is selected from trimethyl amine, triethyl amine, diisopropylethyl amine, pyridine.
19) The process according to 16, wherein, the enantiomer of praziquantel is R-(-)-praziquantel characterized by XRD pattern with peaks at about 8.40, 15.08, 17.44, 17.94, 19.68, 21.90, 24.34 ± 0.2 degrees 2-theta.
20) The process according to 19, wherein, the crystalline form of R-(-)-praziquantel is characterized by XRD pattern illustrated in figure 1.