FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
I. Title of the invention. - A PROCESS FOR THE PREPARATION OF
PYRAZINOISOQUINOLINONE DERIVATIVE

2. Applicant(s)
(a) NAME :
(b) NATIONALITY:
(c) ADDRESS :

ALEMBIC LIMITED
An Indian Company.
Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of the invention
The present invention relates to an improved process for the preparation of Pyrazinoisoquinolinone derivative particularly Praziquantel (I).

Background of the invention
Praziquantel (I) is a pyrazinoisoquinolinone derivative which is chemically known as 2-(Cyclohexylcarbonyl)- 1, 2, 3, 6, 7, 11b- hexahydro- 4H -pyrazino [2,1-a]isoquinolin-4-one, having molecular formula C19H24N2O2 and molecular weight 312.41. The current pharmaceutical product containing this drug is being sold by Bayer Pharms using the tradename Biltricide® in the form of tablets.
2-amino-N-(2-phenylethyl) acetamide (II) is an important intermediate of Praziquantel, having molecular formula C14H14N2O and molecular weight 178.23.

(II)
Praziquantel (I) is useful in the treatment of infections due to the following species of schistosoma: (Schistosoma haematobium, Schistosoma japonicum, Schistosoma


mansoni, and Schistosoma mekongi), and infections due to the liver flukes Clonorchis sinensis / Opisthorchis viverrini. The current pharmaceutical product containing this drug is being sold by Bayer Pharms using the tradename Biltricide ® in the form of tablets.
Praziquantel is first disclosed in US 4001411 which also describe its process for the preparation wherein Praziquantel is prepared by using various types of starting materials particularly N - ( 2- chloroacetyl -1, 2, 3, 4 - tetrahydroisoquinolinyl -1-methyl) - cyclohexylcarboxylic acid amide, 2-cyclohexylcarbonyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino [2,1-a] isoquinoline and 2-(3-cyclohexenyl-1carbonyl)- 2-cyclohexylcarbonyl-4-oxo-1,2,3,6,7-11b hexahydro-4H-pyrazino [2,1-a] isoquinoline. However, these processes do not describe about preparation, purity or yield of starting materials as purity of final product depends upon these parameters.
US 4497952 discloses process for the preparation of praziquantel (I) by cyclizing N-(2-phenyl) ethyl-a-[N-(2, 2-dimethoxy) ethyl-N-cyclohexanecarbonyl] glycine amide or 1-(2-phenyl) ethyl-4-cyclohexanecarbonyl-2-hydroxypiperazine-6-one with acid. However, these processes also silent about preparation of starting materials as purity of final product depends upon this parameter.
US 4523013 disclose a process for the preparation of Praziquantel (I) by using 4-cyclohexylcarbonyl)-2, 6-dioxo-1-phenylethylpiperazine. This process involves hydrogenation reaction and column chromatography technique which is difficult to handle at an industrial scale and also requires specifically designed reactor equipment and extraordinary handling precautions.
CN 1683346 disclose a process for the preparation of Praziquantel (I) comprising steps of i) reacting -phenylethylamine with aminoacetyl chloride hydrochloride followed by the addition of 1,1-dimethoxy-2-chloroethane to give the acetamide intermediate; ii) the acetamide intermediate obtained in step (i) was treated with heteropoly acids in dichloromethane followed by the addition of cyclohexylcarbonyl


chloride to give Praziquantel (57.7%). The major drawback of this process is use of aminoacetyl chloride as its unstable nature due to polymerization and it is not easy to prepare aminoacetyl chloride feasibly. Therefore, this reaction results in low yield of Praziquantel.

KR 2002076486 discloses a process for the preparation of praziquantel (I) which is described schematically as follows,

The major drawback of this process is uncontrolled reaction of compound of the formula (VI) with (A) and reaction of compound of the formula (B) with (C). These reactions involves large amount of formation of by product due to intermolecular reaction of i) compound of the formula (VI) with (B), ii) compound of the formula (A) with (B) and iii) compound of the formula (B) with (D) which results in low yield and purity of desired compound of the formulae (II) and (I).
In summary, prior art suffers with many disadvantages as mentioned hereinabove. Therefore the present inventors have directed their research work towards developing a process which is devoid of drawbacks associated with the prior art processes.

Object of the invention
It is therefore an object of the present invention is to provide an improved process for the preparation of Praziquantel (I).
Another object of the present invention is to provide an improved process for the preparation of Praziquantel (I) which is operationally simple, easy to handle and applicable at an industrial scale.
Another object of the present invention is to provide an improved process for the preparation of Praziquantel (I) with greater yield and purity.
Another object of the present invention is to provide an improved process for the preparation of Praziquantel (I) comprising a step of treating compound of the formula (III) or its salt with compound of the formula (VI) in the presence of base and suitable solvent to obtain compound of the formula (II),

Wherein, R1 represents substituted or unsubstituted alkyl, aryl

Another object of the present invention is to provide an improved process for the preparation of Praziquantel (I) comprising steps of:
(i) treating compound of the formula (III) or its salt with compound of the formula (VI) in the presence of base or its salt and suitable solvent to obtain compound of the formula (II),

(ii) treating compound of the formula (II) obtained in step (i) with compound of the formula (VII) to obtain compound of the formula (VIII),

(iii) cyclizing compound of the formula (VIII) obtained in step (ii) to obtain compound of the formula (IX),

(iv) treating compound of the formula (IX) obtained in step (iii) with compound of the formula (X) to obtain crude Praziquantel

(v) purifying crude Praziquantel obtained in step (iv) wherein, R1 represents as defined above
R2 represents halogen
Detailed description of the invention
In an embodiment, the present invention provides an improved process for the preparation of compound of the formula (II) comprising a step of treating compound of the formula (III) or its salt with compound of the formula (VI) in the presence of base or its salt and suitable solvent to obtain compound of the formula (II),

wherein, R1 represents as defined above
In another embodiment, the present invention provides provide an improved process for the preparation of Praziquantel (I) comprising steps of:
(i) treating compound of the formula (III) or its salt with compound of the formula (VI) in the presence of base or its salt and suitable solvent to obtain compound of the formula (II),

(ii) treating compound of the formula (II) obtained in step (i) with compound of the formula (VII) to obtain compound of the formula (VIII),

(iii) cyclizing compound of the formula (VIII) obtained in step (ii) to obtain compound of the formula (IX),

(iv) treating compound of the formula (IX) obtained in step (iii) with compound of the formula (X) to obtain crude Praziquantel

(v) purifying crude Praziquantel obtained in step (iv) wherein, R1 and R2 represents as defined above
For the purpose of this specification, the meaning of the term "treating" as used hereinabove includes suspending, combining, dissolving, washing, mixing or adding in any of the suitable solvent.

The term "purifying" as used hereinabove includes any method known to a person skilled in the art such as purification from single suitable solvent or combination of suitable solvents by dissolving the compound optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as solvent/antisolvent or precipitation.
The term "salt" as used hereinabove includes but not limited to organic or inorganic acid addition salts such as formic acid, oxalic acid, mandelic acid, adipic acid, succinic acid, p-toluene sulfonic acid, methane sulfonic acid, tartaric acid, citric acid, hydrochloric acid, hydrobromic acid, hydroiodoic acid, hydrofluoric acid, nitric acid, sulphuric acid, phosphous acid, polyphosphoric acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid, acetic acid, benzoic acid, butyric acid, lactic acid, malic acid, methanethiol oxalic acid, propionic acid, pyruvic acid, valeric acid and the like.
The term "cyclizing" as used hereinabove includes cyclization of compound of formula (VIII) in suitable solvent.
The term "suitable solvent" as used hereinabove includes but not limited to substituted or unsubstituted; i) alcoholic solvent, ii) halogenated hydrocarbon solvent, iii) aliphatic or aromatic hydrocarbon solvent, iv) ester solvent, v) ether solvent, vi) cyclic ether solvent, vii) nitrile solvent, viii) aqueous solvent, ix) ketonic solvent x) polar or nonpolar protic solvent, xi) polar or nonpolar aprotic solvent and the like or mixture thereof. The preferred suitable solvents for step (i) are toluene, methanol and dimethyl sulfoxide. The preferred suitable solvent for step (ii) is dimethylformamide. The preferred suitable solvent for step (iii) and (iv) is dichloromethane. The preferred suitable solvent for step (v) is mixture of ether and hexane.


The meaning of the term "base" as used herein above includes organic bases such as substituted or unsubstituted aliphatic amines, aromatic amines, primary, secondary and tertiary amines and the like or mixture thereof. It includes triethyl amine, diethyl amine, methylamine, ethylene diamine, propylene diamine, butylene diamine, hexamethylene diamine t-butylamine, pyrrolidine, di-N-propylamine, morpholine, n-butylamine, isopropylamine, piperidine, pyridine, picolines, luridines, collidines, NMM, NMP, 1,8 diazabicyclo [5,4,0] undec 7-ene (DBU), tetramethyl guanidine (TMG), 1,4 diazabicyclo [2,2,2] octane (DABCO), 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), dicyclohexyl amine (DCHA) and the like or mixture thereof. The most preferred bases are ethylene diamine and trietyl amine or mixture thereof.
The step (i) as described hereinabove may also involve use of phase transfer catalyst if inorganic base has been used instead of organic base. The inorganic base may includes ammonia, magnesium hydroxide, calcium carbonate, magnesium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide and the like and mixture thereof. The phase transfer catalyst may includes tetra butyl ammonium bromide, tetra propyl ammonium bromide, tri butyl benzyl ammonium chloride, tetra ethyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium hydrogen sulphate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, tetrahexyl ammonium chloride, tetra-n-butylammonium fluoride, phenyltrimethyl ammonium chloride, ethyl triphenyl phosphonium bromide, ethyl triphenyl phosphonium iodide, ethyl triphenyl phosphonium chloride, butyl triphenyl phosphonium bromide, methyl triphenyl phosphonium bromide, methyl triphenyl phosphonium iodide, methyl triphenyl phosphonium chloride, tetra phenyl phosphonium bromide, benzyl triphenyl phosphonium chloride, 18-crown-6, dibenzo-18-crown-6, 15-crown-5 and the like and mixture thereof.


The compound obtained in step (i), (ii), (iii) and (iv) as mentioned herein above may be isolated or not isolated.
All compounds are isolated from reaction mass by conventional isolation procedure such as filtration, centrifugation, washing the wet cake, crystallization and drying or by evaporation of solvent.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Example-1a
Glycine ethyl ester hydrochloride (5gm), ethylene diamine dihydrochloride (5gm) and triethyl amine (15gm) was reacted with p-phenylethylamine (5g) in Toluene (25 ml) at temperature between 100°C 115°C for 35-55 hours. After completion of reaction, the reaction mass was dumped in water. The layers was separated and extracted, the organic extracts were dried and distilled to give the oily product N-(2-phenylethyl)--amino acetamide (-3-6 gm).
HPLC purity ~ 70 to 90 %
% Yield -60 to 80 %
Example-1b
Glycine ethyl ester hydrochloride (5 gm), ethylene diamine (2.5 gm) and triethyl amine (4 gm) was reacted with p-phenylethylamine (5 gm) in toluene (25 ml) at 100°C 115°C for 35-55 hours. The layers was separated and extracted, the organic extracts were dried and distilled to give the oily product N-(2-phenylethyl)--
amino acetamide (-3-6 gm).
HPLC purity - 70 to 90 %
% Yield -60 to 80 %
Example-1c
Glycine ethyl ester hydrochloride (5gm), ethylene diamine dihydrochloride (5gm) and triethyl amine (15gm) was reacted with p-phenylethylamine (5gm) in Methanol (25


ml) at 65°C for 16-22 hours. After completion of reaction methanol was distilled out and the oily product extracted by dichloromethane. The organic extracts were dried and distilled to give the oily product N-(2-phenylethyl)--
amino acetamide (-3-7 gm).
HPLC purity - 70 to 90 %
% Yield -60 to 80 %
Example-Id
Glycine ethyl ester hydrochloride (5gm), ethylene diamine dihydrochloride (5gm) and triethyl amine (15gm) was reacted with p-phenylethylamine (5gm) in dimethyl sulfoxide (25 ml) at 75-85 °C for 38-42 hours. After completion of reaction, the reaction mixture was poured into water and extracted with dichloromethane. The organic extracts were dried and distilled to give the oily product N-(2-phenylethyl)--amino acetamide (-3-6 gm).
HPLC purity - 70 to 90 %
% Yield -60 to 80 %
Example-2
N-(2-phenylethyl)-a-amino acetamide (10 gm) and chloroacetaldehyde dimethyl acetal (5 gm) was added to a solution of sodium hydroxide (2 gm) in dimethyl formamide (40 ml) and the solution was heated at reflux for 3 to 5 hours. After completion of reaction, the mixture was poured into 10% aqueous sodium chloride and extracted with dichloromethane. The combined organic layer was washed with brine, dried and concentrated to give oily product (~ 8 to 13 gm).
HPLC purity - 80 to 90 %
% Yield - 75 to 90 %
Example-3
Methanesulphonic acid (45gm) was added to a solution of oily product obtained in example 2 (10gm) in dichloromethane (120ml). The reaction mixture was heated at refluxing temperature for 2 days. After completion of reaction, the reaction mixture was neutralized by 10% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The


combined organic layer was washed with brine, dried and concentrated to give off-white solid (~ 10 to 15 gm).
HPLC purity ~ 90 to 95 %
% Yield ~ 75 to 85 %
Example-4
Cyclohexane carboxylic chloride (15gm) was added to a mixture of potassium carbonate (20 gm), off-white solid obtained in example 3 (20gm) in dichloromethane (60ml) under cooling. This reaction mixture was stirred for 3 to 5 hours. After completion of reaction, water was added in the reaction mixture. The organic layer was separated and dried. The solvent was distilled and the solid was recrystallised in ether-hexane to give white solid of praziquantel (~15 to 20 gm).
HPLC purity ~ 99 % '
% Yield ~ 65 to 85 %


We claim:
1. A process for the preparation of Praziquantel (I) comprising a step of treating compound of the formula (III) or its salt with compound of the formula (VI) in the presence of base and suitable solvent to obtain compound of the formula (II),

Wherein, R1 represents substituted or unsubstituted alkyl, aryl
2. A process for the preparation of Praziquantel (I) comprising steps of:
(i) treating compound of the formula (III) or its salt with compound of the formula (VI) in the presence of base or its salt and suitable solvent to obtain compound of the formula (II),

(ii) treating compound of the formula (II) obtained in step (i) with compound of the formula (VII) to obtain compound of the formula (VIII),

(iii) cyclizing compound of the formula (VIII) obtained in step (ii) to obtain compound of the formula (IX),

(iv) treating compound of the formula (IX) obtained in step (iii) with compound of the formula (X) to obtain crude Praziquantel

(v) purifying crude Praziquantel obtained in step (iv) wherein, R1 represents substituted or unsubstituted alkyl, aryl R2 represents halogen
3. The process according to claim 1 and 2, wherein the base used is selected from the group consisting of triethyl amine, diethyl amine, methylamine,

ethylene diamine, propylene diamine, butylene diamine, hexamethylene diamine, t-butylamine, pyrrolidine, di-N-propylamine, morpholine, n-butylamine, isopropylamine, piperidine, pyridine, picolines, luridines, collidines, NMM, NMP, 1,8 diazabicyclo [5,4,0] undec 7-ene (DBU), tetramethyl guanidine (TMG), 1,4 diazabicyclo [2,2,2] octane (DABCO), 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), dicyclohexyl amine (DCHA) or mixture thereof.
4. The process according to claim 3, wherein the base used is triethyl amine, ethylene diamine or mixture thereof.
5. The process according to claim 1 and 2, wherein the suitable solvent used is selected from the group consisting of substituted or unsubstituted alcoholic solvent, halogenated hydrocarbon solvent, aliphatic or aromatic hydrocarbon solvent, ester solvent, ether solvent, cyclic ether solvent, nitrile solvent, aqueous solvent, ketonic solvent, polar or nonpolar protic solvent, polar or nonpolar aprotic solvent or mixture thereof.
6. The process according to claim 5, wherein the suitable solvent used is toluene, methanol, dimethyl sulfoxide, dimethyl formamide, dichloromethane, water or mixture thereof.

Title : A PROCESS FOR THE PREPARATION OF PYRAZINOISOQUINOLINONE DERIVATIVE
ABSTRACT
Present invention relates to an improved process for the preparation of Praziquantel of formula (I).