A process for preparation of praziquantel and intermediates therefor

Abstract

The present invention pertains to novel, cost-effective process for preparation of praziquantel and intermediates therefor. More specifically, the invention provides a process of obtaining a high purity praziquantel having the structure of Formula-I having purity not less than 99.90%, using an intermediate compound of Formula-II.

Description

[0001]TITLE OF THE INVENTION: A PROCESS FOR PREPARATION OF PRAZIQUANTEL AND INTERMEDIATES THEREFOR FIELD OF THE INVENTION The present invention relates to an improved process for synthesis and purification of praziquantel having the structure of Formula-I. More specifically, the invention provides a process of obtaining a high purity praziquantel having the structure of Formula-I, with purity not less than 99.90%. The present invention also provides a process for preparing praziquantel of high purity using an intermediate compound of Formula-II. BACKGROUND OF INVENTION Praziquantel of Formula-I, having the chemical name 2-(cyclohexylcarbonyl)-4-oxo- 1,2,3,6,7,11b-hexahydro-4H pyrazino [2,1-a] isoquinolin, is a member of the 2-acyl-4- oxopyrazinoisoquinolin compounds and is represented by structural Formula as shown in below. Praziquantel, sold under the brand name Biltricide, among others, is a medication used to treat a number of types of parasitic worm infections in mammals, birds, amphibians, reptiles, and fish. In humans specifically, it is sued to treat schistosomiasis, clonorchiasis, opisthorchiasis, tapeworm infections, cysticercosis, echinococcosis, paragonimiasis, faciolopsiasis, and fasciolosis. It is usually administered orally. There are number of literature references which describe the process for preparation of praziquantel. IN303319 outlines a process for synthesizing praziquantel. It involves several steps: a) converting ß-phenylethylamine with chloroacetylchloride to obtain 2-chloro-N- phenethylacetamide; b) converting benzylamine with chloroacetaldehyde dimethylacetal to obtain N-benzyl-2,2-dimethoxyethanamine; c) condensing the products from steps a) and b) to obtain 2- [(2,2-dimethoxyethyl)benzylamino]-N-phenethylacetamide ; d) reducing the compound obtained in step c) to obtain 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide. Additionally, the IN’319 patent also includes another process for praziquantel preparation, involving: a) cyclizing 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide to obtain 4-oxo-1,2,3,6,7,11b- hexahydro-4H-pyrazino [2,1-a] isoquinolin using an acid; b) acylating the product from step a) with cyclohexanoyl chloride to obtain praziquantel. The disclosed process involves multiple steps and complexity which increase the risk of errors, lower yields, and elevate production costs. Also, the process disclosed uses hazardous reagents. Due to the multistep nature of the process, the overall yield of praziquantel is relatively low. Low yields can increase production costs and limit the scalability of the synthesis for commercial purposes. This process can be time-consuming and resource-intensive. The intermediate obtained, 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino [2, 1- a]isoquinolin is less stable. The main drawback of the process disclosed in IN303319 is the low purity of the intermediates, which results in impurities being carried forward to subsequent steps. Consequently, these impurities affect the final product, making it extremely difficult to achieve high purity praziquantel through a single purification step, consequently leading to increased cost of production. US patent application US20130029997 describes Deuterated Pyrazinoisoquinolin Compounds. Deuterated compounds prepared by the process disclosed therein requires complex synthesis routes and purification techniques, which is costly and time-consuming. The major drawback of the process disclosed in US20130029997 is the use of aminoacetaldehyde dimethyl acetal, a very expensive raw material. Additionally, in step II, dimer formation occurs with 2,2- dimethoxyethanamine, and the dimer is eliminated by forming a salt with HCl. This leads to a low yield of the HCl salt, making the process commercially non-viable. PCT application WO2009115333A1 discloses novel synthesis of praziquantel. Synthesis routes disclosed in this application involve multiple steps, each requiring precise conditions and reagents. The complexity of the synthesis can increase the risk of impurities, side reactions, and low yields, making scale-up, high cost and commercialization challenging. The compound of Formula IX prepared in the disclosed process is less stable. Indian patent application IN201721018493 relates to novel intermediate useful in the process for the preparation of praziquantel. A process for preparation of praziquantel comprising: a) N- alkylation of the intermediate of Formula (III) prepared with chloroacetaldehyde dimethylacetal in the presence of a solvent and a base to obtain 2-[(2,2-dimethoxyethyl)amino]-N-(2- phenylethyl)acetamide of Formula (V); b) cyclization of 2-[(2,2-dimethoxyethyl)amino]-N-(2- phenylethyl)acetamide of Formula V prepared in step a), using an acid in the presence of solvent to obtain 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin of Formula (VI); and c) acylation of 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin of Formula (VI) with cyclohexanoyl chloride in presence of a base and a solvent to obtain praziquantel. The compound (4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin of Formula (VI) obtained in this process is less stable. The major drawback of the process disclosed in IN20171018493 is the conversion of chloro to amine, which involves a pressurized reaction with ammonia. This step has the potential to produce deschloro impurities. Additionally, during the N-alkylation reaction, there is a possibility of forming N,N-dialkyl impurities. These impurities result in low yields in subsequent steps, making the process commercially non-viable. CN103739601A describes a one-pot synthesis of praziquantel involving the steps where β-phenylethylamine is condensed with chloroacetyl chloride in a chloroalkane-based alkaline medium to form intermediate 1, followed by reaction of the intermediate 1 with aminoacetaldehyde dimethyl acetal, to yield intermediate 2, which is subsequently cyclized in the presence of an acidic catalyst to generate intermediate 3. The final step involves acylation of intermediate 3 with cyclohexylcarbonyl chloride in an organic solvent, followed by solvent-based crystallization to obtain praziquantel. The process achieves a reported yield of 65.6%, with a HPLC purity of 99.2%. While this one-pot synthesis may be possible at a smaller scale, large scale industrial production in one-pot is not easy, and leads to significant losses, and is usually not commercially viable. CN103059018A discloses an alternative process for praziquantel synthesis wherein 1,2,3,6,7,11β-hexahydro-4-hydro-pyrazino[2,1-α]isoquinolin-4-one phosphate is prepared by hydrolyzing 2-benzoyl-1,2,3,6,7,11β-hexahydro-4-hydro-pyrazino[2,1-α]isoquinolin-4-one with phosphoric acid. The phosphate intermediate is then reacted with cyclohexanecarbonyl chloride in an organic solvent to yield crude praziquantel, which is subsequently purified using activated carbon. This process requires the use of advanced intermediates that are not easily available, and also lead to increased cost of production. Accordingly, there is a need to develop a novel, cost-effective process for preparation of praziquantel at large industrial scale. Especially, there is a need to develop a novel, cost-effective process for preparation of praziquantel which will result in highly pure praziquantel. The present invention offers a cost-efficient method that utilizes affordable solvents and process conditions. These adjustments make it suitable for large-scale commercial production. SUMMARY OF THE INVENTION In an aspect of the present invention, there is provided a process for preparation of an intermediate for praziquantel, 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4 (11bH)-one phosphate of Formula-II, comprising the steps of: (a) cyclization of 2-(2,2-dimethoxyethylamino)-N-(2-phenylethyl) acetamide hydrochloride of Formula-III, using an acid in the presence of a solvent, to obtain a compound of Formula-II A: (b) reacting the compound of Formula-II A in the presence of a solvent and salt forming agent to form 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4(11bH)-one phosphate of Formula-II. In the above method, the acid used in step (a) is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p- toluenesulfonic acid, benzenesulfonic acid, perchloric acid and sulfuric acid and combinations thereof. The solvent used in step (a) and step (b) is a halogenated solvent selected from the group consisting of dichloromethane, ethylene dichloride, trichloromethane, trichloroethylene, tetrachloroethylene, 1,1,1-trichloroethane, 1,1-dichloroethane, 1,2-dichloroethane (ethylene dichloride), carbon tetrachloride, chlorobenzene, vinyl chloride and methylene chloride, and combinations thereof. The salt forming agent used in step (b) is selected from the group consisting of orthophosphoric acid, pyrophosphoric acid, polyphosphoric, hypophosphorous acid, trimetaphosphoric acid, tetrametaphosphoric acid, metaphosphoric acid and diphosphoric acid and combinations thereof. Step (a) and step (b) are carried out at a temperature from about 25°C to about 35°C. The step (a) of the method further comprises addition of base selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and combinations thereof. In another aspect of the present invention, there is provided an intermediate compound, 2,3,6,7- tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4 (11bH)-one phosphate of Formula-II, wherein the said compound has a purity of not less than 99.80% as measured by HPLC. In yet another aspect of the present invention, there is provided a process for preparation of praziquantel having a structure of Formula-I comprising the steps of: (i) reacting 2-(2,2-dimethoxyethylamino)-N-(2-phenylethyl) acetamide of Formula-IV in the presence of a solvent and an acid to form 2-(2,2-dimethoxyethyl amino)-N-(2-phenylethyl) acetamide hydrochloride of Formula-III: (ii) cyclization of 2-(2,2-dimethoxyethylamino)-N-(2-phenylethyl) acetamide hydrochloride of Formula-III obtained in step (i), using an acid in the presence of a solvent, to obtain a compound of Formula-II A: (iii) reacting the compound of Formula-II A in the presence of a solvent and salt forming agent to form 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4(11bH)-one phosphate of Formula-II: (iv) subjecting 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one phosphate of Formula-II obtained in step (iii) and cyclohexanecarbonyl chloride to acylation reaction in the presence of an alkaline substance and an organic solvent, to obtain crude 2-(cyclohexanecarbonyl)- 2,3,6,7-tetrahydro-1H-pyrazino[2,2-a]isoquinolin-4(11bH)-one of Formula-I A: (v) purifying crude 2-(cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino [2,2-a] isoquinolin- 4(11bH)-one of Formula-IA obtained in step (iv), in the presence of a protic solvent and an antioxidant, to obtain praziquantel having the structure of Formula-I: The solvent used in step (i) of the aforementioned method is isopropyl alcohol and the acid used in step (i) is hydrochloric acid. The acid used in step (ii), is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, perchloric acid, sulfuric acid and combinations thereof. Further, the solvent used in step (ii) and step (iii) is a halogenated solvent selected from the group consisting of dichloromethane, ethylene dichloride, trichloromethane, trichloroethylene, tetrachloroethylene, 1,1,1-trichloroethane, 1,1-dichloroethane, 1,2-dichloroethane (ethylene dichloride), carbon tetrachloride, chlorobenzene, vinyl chloride, methylene chloride and combinations thereof. The salt forming agent used in step (iii) is selected from the group consisting of orthophosphoric acid, pyrophosphoric acid, polyphosphoric, hypophosphorous acid, trimetaphosphoric acid, tetrametaphosphoric acid, metaphosphoric acid, diphosphoric acid and combinations thereof. Step (ii) of the method further comprises addition of base selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and combinations thereof. Steps (ii) and (iii) of the method are carried out at a temperature of about 25°C to about 35°C. The alkaline substance in step (iv) is triethylamine (TEA). The organic solvent in step (iv) is acetone. Step (iv) of the method is carried out at a temperature of about 15°C to about 25°C. The solvent used in step (v) is methanol. The antioxidant used in step (v) is butyrated hydroxytoluene. Step (v) of the method is carried out at a temperature ranging from about 40°C to about 45°C. In an aspect of the present invention, the purity of praziquantel of Formula-I is not less than 99.90%, as measured by HPLC. In another aspect of the present invention, the yield of praziquantel of Formula-I, is not less than 80%w / w. BRIEF DESCRIPTION OF DRAWINGS FIG.1: shows proton nuclear magnetic resonance (¹H NMR) results of 2,3,6,7-tetrahydro-1H- pyrazino[2,1-a] isoquinolin-4 (11bH)-one phosphate (Formula-II); FIG.2: shows carbon-13 nuclear magnetic resonance (¹³C NMR) results of 2,3,6,7-tetrahydro-1H- pyrazino[2,1-a] isoquinolin-4 (11bH)-one phosphate (Formula-II); FIG. 3: shows X-ray diffraction (XRD) results of 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4 (11bH)-one phosphate (Formula-II). DETAILED DESCRIPTION OF THE INVENTION Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference herein in their entirety for all purposes. As used herein, “a,” “an,” or “the” can mean one or more than one. The term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ±10% of the specified amount. Unless stated to the contrary, any of the words “contains”, “containing”, "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention. The present invention provides a novel and efficient route of synthesis for praziquantel having the structure of Formula-I, bearing the chemical name 2-(cyclohexylcarbonyl)-4-oxo-1,2,3,6,7,11b- hexahydro-4H pyrazino [2,1-a] isoquinolin. This novel process involves conversion of a key intermediate (Formula-IIA) into its phosphate salt (Formula-II); further subjecting the phosphate salt to acylation reaction to obtain crude praziquantel and thereafter purifying the crude praziquantel to obtain praziquantel with high purity. Accordingly, in one aspect of the present invention, there is provided an intermediate compound, 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4 (11bH)-one phosphate, having a structure of Formula-II. In another aspect of the present invention, a process is provided for the preparation of the intermediate compound, 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4 (11bH)-one phosphate, having a structure of Formula-II. The process is completed in two steps: Step 1: Cyclization Cyclization is a chemical reaction that forms a fused ring system through intramolecular bond formation. Cyclization occurs via nucleophilic attack by the amide nitrogen on an electrophilic carbon, resulting in the formation of a new C-N bond. Acids act as cyclizing agents by protonating the methoxy group of the acetal to form the electrophile. A compound, 2-(2,2-dimethoxyethylamino)-N-(2-phenylethyl) acetamide, having the structure of Formula-IIIA, undergoes cyclization in the presence of an acid and solvent to yield a highly unstable intermediate, Formula-IIA. This step 1 is illustrated below: Step 2: Salt formation In the second step, the compound having the structure of Formula-II A is reacted in the presence of a solvent and salt forming agent to form 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin- 4(11bH)-one phosphate having the structure of Formula-II. This step 2 is depicted below: In another aspect of the present invention, another process is provided for the preparation of the intermediate compound, 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4 (11bH)-one phosphate, having a structure of Formula-II. The process is completed in two steps: Step 1: Cyclization A compound, 2-(2,2-dimethoxyethylamino)-N-(2-phenylethyl) acetamide hydrochloride, having the structure of Formula-III, undergoes cyclization in the presence of an acidic agent and solvent to yield a highly unstable intermediate, Formula-IIA. This step 1 is illustrated below: Step 2: Salt formation In the second step, the compound having the structure of Formula-II A is reacted in the presence of a solvent and salt forming agent to form 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4 (11bH)-one phosphate having the structure of Formula-II. This step 2 is depicted below: In an embodiment of the present invention, the acid used in the step 1 may be selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, perchloric acid and sulfuric acid and combinations thereof. In a preferred embodiment, the acid used in the cyclization step is concentrated sulfuric acid. In an embodiment of the present invention, the solvent used in the step 1 may be a halogenated solvent. In an embodiment, the halogenated solvent used in step 1 may be selected from the group consisting of dichloromethane, ethylene dichloride, trichloromethane, trichloroethylene, tetrachloroethylene, 1,1,1-trichloroethane, 1,1-dichloroethane, 1,2-dichloroethane (ethylene dichloride), carbon tetrachloride, chlorobenzene, vinyl chloride and methylene chloride, and combinations thereof. In a preferred embodiment, the solvent is dichloromethane. In an embodiment of the present invention, the solvent used in the step 2 may be a halogenated solvent. In an embodiment, the halogenated solvent may be selected from the group consisting of dichloromethane, ethylene dichloride, trichloromethane, trichloroethylene, tetrachloroethylene, 1,1,1-trichloroethane, 1,1-dichloroethane, 1,2-dichloroethane (ethylene dichloride), carbon tetrachloride, chlorobenzene, vinyl chloride and methylene chloride, and combinations thereof. In a preferred embodiment, the solvent is dichloromethane. In an embodiment of the present invention, the salt forming agent used in step 2 may be selected from the group consisting of orthophosphoric acid, pyrophosphoric acid, polyphosphoric, hypophosphorous acid, trimetaphosphoric acid, tetrametaphosphoric acid, metaphosphoric acid and diphosphoric acid and combinations thereof. In a preferred embodiment of the present disclosure, the salt forming agent is orthophosphoric acid. In an embodiment of the present invention, the cyclization is carried out in the presence of a base to adjust the pH of the reaction. The base may be selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide and potassium carbonate and combinations thereof. In a preferred embodiment, the base is sodium hydroxide. In an embodiment of the present invention, the process for preparation of compound having the structure represented by Formula-II is carried out at 25°C to about 35°C. In a preferred embodiment of the present invention, the cyclization step is carried out using the compound represented by Formula-IIIA or a pharmaceutically acceptable salt thereof. In a preferred embodiment of the present invention, the salt is hydrochloride salt of Formula-IIIA. The present invention also relates to a process for preparation of praziquantel comprising the steps of: Step I: Formation of Hydrochloride Salt Reacting a 2-(2,2-dimethoxyethylamino)-N-(2-phenethyl) acetamide of Formula-IV in the presence of a solvent and a salt forming agent to form 2-(2,2-dimethoxyethylamino)-N-(2 phenethyl) acetamide hydrochloride salt of Formula-III: Step II: Cyclization Cyclization of 2-(2,2-dimethoxyethylamino)-N-(2-phenylethyl) acetamide hydrochloride of Formula III prepared in step I), using an acid in the presence of a salt-forming agent and solvent, to obtain 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4(11bH)-one phosphate of Formula- II: Step III: Acylation Subjecting 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4(11bH)-one phosphate of Formula-II obtained in step-II, and cyclohexanecarbonyl chloride, to acylation reaction in the presence of an alkaline substance, to give crude 2-(cyclohexanecarbonyl)-2,3,6,7-tetrhydro-1H- pyrazino 2,2-a]isoquinolin-4(11bH)-one of Formula-IA: Step IV: Purification Purifying crude 2-(cyclohexanecarbonyl)-2,3,6,7-tetrhydro-1H-pyrazino 2,2-a] isoquinolin- 4(11bH)-one of Formula (I-A) obtained in step-III in the presence of a protic solvent and a suitable antioxidant to obtain high-purity praziquantel of Formula-I. In one aspect, the solvent used in Step I is isopropyl alcohol (IPA), and the salt-forming agent is hydrochloric acid (HCl). The salt formation is conducted at a temperature ranging from about 0°C to about 30°C, preferably about 0°C to about 10°C. In another aspect, cyclization is carried out at room temperature in the presence of an acid such as sulfuric acid, a salt-forming agent such as orthophosphoric acid, and a solvent such as methylene chloride (MDC), along with sodium hydroxide, to obtain 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4(11bH)-one phosphate (Formula-II). In yet another aspect, the acylation of 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4(11bH)- one phosphate having the structure of Formula-II, is carried out with cyclohexanecarbonyl chloride in the presence of an alkaline substance, preferably triethylamine (TEA), and in the presence of an organic solvent, preferably acetone, at a temperature range from about 15°C to about 25°C, to obtain 2-(cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,2-a] isoquinolin-4(11bH)-one having the structure of Formula-IA. In one aspect of the present invention, the purification of crude 2-(cyclohexanecarbonyl)-2,3,6,7- tetrahydro-1H-pyrazino [2,2-a] isoquinolin-4(11bH)-one having the structure of Formula-IA, is carried out by crystallisation in the presence of a protic solvent, preferably an alcohol, and most preferably methanol, and an antioxidant, preferably butylate hydroxytoluene, at a temperature ranging from about 40°C to about 45°C. In a further aspect, the compound of Formula-IIA, which is unstable, attains improved stability and purity when isolated as its phosphate salt (Formula-II). This isolation is easy as the removal of phosphoric acid is facilitated due to its high solubility in water. The purified compound of Formula-II can then be converted into high-purity praziquantel (Formula-I) via a reaction with cyclohexane carbonyl chloride. In an embodiment, the present invention provides a praziquantel intermediate compound of Formula-II, characterized by its XRD, with observed d-spacing values at 6.70, 8.47, 11.00, 12.82, 15.19, 15.36, 16.71, 17.00, 18.33, 18.80, 20.18, 21.55, 22.12, 23.43, 24.05, 25.05, 25.81, 26.22, 27.47, 29.14, 29.29, 29.78,31.46, 32.87, 33.16, 33.42, 33.78, 37.55,39.42. The present invention also provides a process for the preparation of praziquantel involving a novel praziquantel intermediate compound of Formula-II, wherein the obtained praziquantel of Formula- I is characterized by its XRD, with observed d-spacing values at 3.96, 6.28, 6.63, 7.94, 8.16, 12.18, 12.27, 13.30, 14.51,14.72, 15.31, 16.38, 16.96, 17.59,17.86, 18.44, 18.87, 19.27, 20.04, 20.65, 21.12, 21.92, 22.24, 22.55, 23.00, 24.30, 25.54, 26.49, 26.83. In yet another embodiment, the present invention provides a novel intermediate compound of Formula-II with a purity of not less than 99.80%, as measured by HPLC. In another embodiment, the present invention provides praziquantel of Formula-I, prepared using a process involving the novel intermediate compound of Formula-II, wherein praziquantel has a purity of not less than 99.95%, not less than 99.90%, not less than 99.00% as measured by HPLC. In still another embodiment, the present disclosure provides a process for preparation of praziquantel involving a novel praziquantel intermediate compound of Formula-II, wherein the yield of praziquantel is not less than 80% w / w. The following examples are provided to illustrate the invention and are not to be construed as limiting the invention in any manner. Examples: Example 1: Preparation of 2-(2,2-dimethoxyethylamino)-N-(2-phenethyl) acetamide hydrochloride (Formula-III) To a stirred and pre-cooled (0-10 °C) solution of compound of Formula-IV (500g, 1.877 moles) in isopropyl alcohol (1500 mL), about 390mL of isopropyl alcohol hydrochloride was added at the same temperature. The resulting off-white slurry mass was stirred for 1-2 hours at 0-10 °C. The precipitated solid was filtered and the wet cake was washed with about 500mL of chilled isopropyl alcohol. The obtained wet cake was further slurried in 300mL of isopropyl alcohol at 0-10 °C. After filtration, the wet cake was dried at a temperature of about 50°C to about 55°C to afford 450 g (79.16%) of the compound of Formula-III as an off-white solid. The obtained compound exhibited a purity of 99.60%, as determined by HPLC. Example 2: Preparation of 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4 (11bH)-one phosphate (Formula-II) A solution of compound of Formula-III, obtained in example 1, was prepared by dissolving 100 grams of the compound in about 250mL of dichloromethane under stirring. The solution was pre- cooled to 0-5 °C, and sulfuric acid (162g, 1.65 moles) was added to this solution. Upon addition, the solution turned brown and was stirred continuously for 5 to 6 hours at room temperature. The progress of the reaction was monitored by thin layer chromatography (TLC). Once, the initial material was fully consumed, the reaction mass was quenched with about 400mL of Ice-water, maintaining the temperature below 30 °C. The biphasic reaction mass was continuously stirred for 15 to 20 minutes at room temperature to allow separation of the organic and aqueous layers. The aqueous layer was extracted with 250 mL of dichloromethane, and its pH was adjusted to 7– 8 using an aqueous sodium hydroxide solution. The organic layer was treated with activated carbon and filtered to obtain a clear filtrate. To this filtrate, orthophosphoric acid (44.1 g, 0.396 moles) was added at room temperature. The resulting slurry was stirred for 2–3 hours at room temperature and then filtered. The obtained wet cake was washed with 50 mL of dichloromethane and further converted into a slurry using 300 mL of dichloromethane. After vacuum drying at about 50°C to 55°C, 99.0 g (99.14%) of Formula II was obtained as a cream-colored solid with a purity of 99.80% (measured by HPLC). High-Performance Liquid Chromatography (HPLC) analysis and characterization Chromatographic conditions: Gradient time program: Buffer Preparation: A buffer solution was prepared by accurately weighing 8.71 g of dipotassium hydrogen phosphate (K₂HPO₄) and transferring it into a 1000 mL beaker. The compound was dissolved in 1000 mL of purified water with continuous stirring. The pH of the solution was adjusted to 8.0 using ortho-phosphoric acid. The solution was mixed thoroughly to ensure homogeneity. Mobile Phase Preparation: Mobile Phase A: A mixture of buffer and acetonitrile was prepared in a 75:25 (v / v) ratio and mixed thoroughly to ensure homogeneity. Mobile Phase B: A mixture of buffer and acetonitrile was prepared in a 40:60 (v / v) ratio and mixed thoroughly to ensure homogeneity. Thermal stability analysis of 2,3,6,7-Tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one Phosphate (Formula II): The thermal stability of 2,3,6,7-tetrahydro-1H-pyrazino[2,1- a]isoquinolin-4(11bH)-one phosphate (Formula II) was evaluated by subjecting it to a temperature of 50°C for a duration of 50 hours. The results of the stability study are summarized in Table 1 below. Table 1: Thermal Stability of 2,3,6,7-Tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)- one Phosphate (Formula II) RRT: Relative Retention Time ND: Not determined Additional parameters measured are described a follows:1H NMR (400 MHz, DMSO-d6) δ 9.061 (s, 6H), 7.177-7.318 (m, J = 56.0 Hz, 4H), 5.068-5.105 (dd, J = 12.0 Hz, 1H) 4.530-4.589 (m, J = 23.6 Hz, 1H) 4.002-4.041(dd, J = 15.6 Hz, 1H) 3.606-3.700 (q, J = 37.6 Hz, 2H) 2.906-2.966 (t, J = 24.0 Hz, 1H) 2.704-2.865 (m, J = 64.4 Hz, 3H) ppm.13C NMR (400 MHz, DMSO-d6): δ 162.758 (C), 134.789 (C), 133.061 (C), 129.187(CH), 127.216 (CH),126.785 (CH), 125.414(CH), 52.813 (CH), 45.839(CH2), 45.421 (CH2), 38.140 (CH2), 28.153 (CH2) ppm. Mass m / z: 203.1 (M+H)+MS: Calc. [C12H14N2O+H]+: 203.25, found 203.1. Example 3: Preparation of 2-(cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino [2,1-a] isoquinolin- 4(11bH)-one (Formula-IA). A solution of compound of Formula-II, obtained in example 2, was prepared by dissolving 100 gm (0.333 moles) of the compound in 500 mL of acetone and 200 mL of water under stirring. To this solution, 85 g (0.840 moles) of triethylamine was added, and the resulting mixture was stirred until a clear solution was formed. The clear solution was cooled to 15–25°C, and 49 g (0.334 moles) of cyclohexanecarbonyl chloride was slowly added while maintaining the temperature at 25°C. After the addition, the reaction temperature was gradually raised to 25–35°C. The resulting brown- colored clear solution was stirred for 2–3 hours at 25–35°C, with the reaction progress monitored by thin-layer chromatography (TLC). Upon complete consumption of the starting material, a biphasic mixture was formed, to which 1000 mL of water was added. The resulting off-white slurry was stirred for 1–2 hours at 25–35°C, then filtered. The wet cake obtained was washed with 200 mL of water, followed by reslurrying in 500 mL of water. After drying, 90.0 g (86.53%) of Formula- IA was obtained as an off-white solid with a purity of 99.85% (measured by HPLC). Example 4: Preparation of 2-(cyclohexylcarbonyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4Hpyrazino [2,1- a]isoquinolin (Formula-I) About 100 grams of compound of Formula-IA, obtained in example 3, was mixed with about 300mL of methanol to form a solution. To this, about 0.25 grams of butylate hydroxytoluene (BHT) was added, and the resulting mixture was stirred continuously. The slurry mass was heated to a temperature of about 40-55oC, forming a clear solution. The resulting clear solution was treated with activated carbon, and the filtrate obtained was cooled to 0-5oC with continuous stirring for 2-3 hours. The resulting precipitate was filtered through a buckner funnel, and the wet cake obtained was washed with 100 mL of chilled methanol. The wet cake was vacuum dried at a temperature of about 50°C to about 55°C and about 80.0g of compound of Formula-I was obtained as a white solid, with a purity of 99.95%, measured by HPLC. High-Performance Liquid Chromatography (HPLC) analysis and Characterization HPLC parameters: The validation data for Praziquantel of Formula-I is presented in Table 2 below: Table 2: HPLC analysis of Praziquantel of Formula-I validation experiments RRT: Relative Retention Time ND: Not determined IMP A: unknown impurity A IMP B: unknown impurity B Additional Characterization Parameters: 1H NMR (400 MHz, CDCl₃): δ 7.225-7.296 (m, J = 28.40 Hz, 1H), 7.172-7.189 (d, J = 6.80 Hz, 3H), 5.135-5.175 (dd, J = 16.0 Hz, 1H), 4.791-4.868 (m, J = 30.8 Hz, 3H), 4.448-4.491 (d, J = 17.2 Hz, 1H), 4.057-4.100 (d, J = 17.2 Hz, 1H), 2.765-3.018 (m, J = 101.2 Hz, 5H), 2.442-2.500 (t, J = 23.3 Hz, 1H), 1.727-1.811 (m, J = 33.6 Hz, 6H), 1.508-1.650 (m, J = 56.8 Hz, 2H) ppm. 13C NMR (400 MHz, CDCl₃): δ 174.723 (C), 164.379 (C), 134.733 (C), 132.789 (C), 129.279 (CH), 127.427 (CH), 126.958 (CH), 125.453 (CH), 55.78 (CH), 54.931 (CH₂), 49.015 (CH), 45.141 (CH₂), 40.763 (CH₂), 29.228 (CH₂), 28.998 (CH₂), 28.714 (CH₂), 25.712 (CH₂) ppm. Mass Spectrometry (MS): m / z: 313.1 (M+H)⁺ Calculated: [C₁₉H₂₄N₂O₂+H]⁺: 313.41, found 313.10 Calculated: [C₁₉H₂₄N₂O₂+Na]⁺: 335.41, found 334.9 Powder X-Ray Diffraction (P-XRD): d-spacing values observed at 3.96, 6.28, 7.94, 8.16, 12.18, 15.31, 16.38, 18.87, 19.27, 20.04 Differential Scanning Calorimetry (DSC): Peak observed at 142.03°C Thermogravimetric Analysis (TGA): Weight loss from 30-145°C: 1.023% w / w Weight loss from 145-244°C: 2.653% w / w Weight loss from 244-352°C: 95.256% w / w Weight loss from 352-497°C: 4.767% w / w Weight loss from 497-649°C: 5.496% w / w Yield: 80% w / w EXAMPLE 5: Scale-up Batch Preparation 5.1 Scale-up Batch preparation of 2-(2,2-dimethoxyethylamino)-N-(2-phenethyl) acetamide hydrochloride (Formula-III) To a stirred and pre-cooled solution of the compound of Formula-IV (500 kg, 1877.3 mol) in isopropyl alcohol (1500 L), maintained at 0–10^°C, isopropyl alcohol hydrochloride (390 L) was added while maintaining the same temperature. The resulting off-white slurry was stirred for 1–2 hours at 0–10^°C. Upon completion, the reaction mixture was filtered, and the solid was washed with chilled isopropyl alcohol (500 L). The obtained wet cake was further slurred in isopropyl alcohol (1500 L) at 0–10^°C, followed by filtration and drying to yield 445.4 kg (78.35% yield) of the compound of Formula-III as an off-white solid. The results are provided in Table 3 below: Table 3: Results for Scale-up Batch preparation of compound of Formula-III NMT: Not more than, NLT: Not less than, BDL: Below detection limit, Prazole I: [2-Chloro-N-(2- phenylethyl)acetamide] Prazole II: [N-benzyl-2,2-dimethylethanamine], Prazole III: [2-[(2,2-Dimethoxyethyl)benzylamino]-N-(2-phenylethyl)acetamide], Dimer Impurity: [N-benzyl-N-(2,2- dimethyoxyethyl)-2,2- dimethoxyethanamine] 5.2 Scale-up Batch preparation of 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4 (11bH)-one phosphate (Formula-II) To a stirred and pre-cooled (0–5^°C) solution of the compound of Formula-III (435^kg, 1436.6^mol) in dichloromethane (1088^L), sulfuric acid (705^kg, 7193.9^mol) was added while maintaining the temperature at 0–5^°C. The resulting brown solution was stirred at room temperature for 5–6 hours, and the progress of the reaction was monitored by thin-layer chromatography (TLC). Upon complete consumption of the starting material (as confirmed by TLC), the reaction mixture was quenched with ice-water (1740^L), maintaining the temperature below 30^°C. The resulting biphasic mixture was stirred at room temperature for 15–20 minutes, after which the organic and aqueous layers were separated. Dichloromethane (1088^L) was added to the aqueous layer, and the pH was adjusted to 7–8 using an aqueous sodium hydroxide solution. After stirring for an additional 15–20 minutes at room temperature, the layers were separated again. The aqueous phase was further extracted with dichloromethane (435^L).The combined organic extracts were treated with activated carbon, filtered, and the filtrate was subsequently treated with ortho-phosphoric acid (192^kg, 1959.2^mol) at room temperature. The resulting slurry was stirred for 2–3 hours, then filtered, and the wet cake was washed with dichloromethane (218^L). The wet material was further slurried in dichloromethane (870^L), and after drying, yielded 409.37^kg (94.9% yield) of the compound of Formula-II as a cream-colored solid. The results are provided in table 4 below: Table 4: Results for Scale-up Batch preparation of compound of Formula-II NMT: Not more than, NLT: Not less than, Prazole I: [2-Chloro-N-(2- phenylethyl)acetamide], Prazole II: [N-benzyl-2,2-dimethylethanamine], Prazole III: [2-[(2,2-Dimethoxyethyl)benzylamino]-N-(2-phenylethyl)acetamide] Dimer Impurity: [N-benzyl-N-(2,2- dimethyoxyethyl)-2,2- dimethoxyethanamine] 5.3 Scale-up Batch preparation of 2-(cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino [2,1-a] isoquinolin-4(11bH)-one (Formula-IA) To a stirred solution of the compound of Formula-II (360^kg, 1199^mol) in acetone (1800^L) and process water (720^L), triethylamine (306^kg, 3024^mol) was added. The resulting clear solution was cooled to 15–25^°C, and cyclohexane carbonyl chloride (176.4^kg, 1203^mol) was added slowly while maintaining the temperature below 25^°C. Upon completion of the addition, the reaction mixture was gradually heated to 25–35^°C. The resulting brown-colored clear solution was stirred at 25–35^°C for 2–3 hours, and the progress of the reaction was monitored by thin-layer chromatography (TLC). Upon complete consumption of the starting material (as confirmed by TLC), process water (3600^L) was added to the biphasic mixture. The resulting off-white slurry was stirred for 1–2 hours at 25–35^°C. The solid product was then filtered, and the wet cake was washed with process water (720^L). The wet material was further slurried in process water (1800^L), followed by filtration and drying to afford 281.16^kg (75.1% yield) of the compound of Formula-IA as an off-white solid. The results are provided in table 5 below: Table 5: Results for Scale-up Batch preparation of compound of Formula-IA NMT: Not more than IMP A: (2-benzoyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1- a] isoquinolin-4-one) IMP B: (2-(cyclohexylcarbonyl)-2,3,6,7-tetrahydro-4H-pyrazino [2,1-a]isoquinolin-4-one) 5.4 Scale-up Batch preparation of 2-(cyclohexylcarbonyl)-4-oxo-1,2,3,6,7,11b-hexahydro- 4Hpyrazino [2,1-a]isoquinolin (Formula-I) To a stirred solution of the compound of Formula-IA (160^kg) in methanol (480^L), butylated hydroxytoluene (0.4^kg) was added. The resulting slurry was heated to 40–45^°C until a clear solution was obtained. This solution was treated with activated carbon, and after adequate contact, the mixture was filtered. The filtrate was then cooled to 0–5^°C and stirred at this temperature for 2–3 hours. The precipitated product was filtered, and the wet cake was washed with chilled methanol (160^L). The obtained material was dried to afford 128^kg of the compound of Formula-I as a white solid, corresponding to a yield of 96.43%. The product complies with the specifications of the European Pharmacopoeia (Ph. Eur.). Process conditions The results are provided in table 6 below: Table 6: Results for Scale-up Batch preparation of compound of Formula-I NMT: Not more than BDL: Below detection limit

Claims

Claims:

1. A process for preparation of an intermediate for praziquantel, 2,3,6,7-tetrahydro-1H- pyrazino[2,1-a] isoquinolin-4 (11bH)-one phosphate of Formula-II, comprising the steps of: (a) cyclization of 2-(2,2-dimethoxyethylamino)-N-(2-phenylethyl) acetamide hydrochloride of Formula-III, using an acid in the presence of a solvent, to obtain a compound of Formula-II A:(b) reacting the compound of Formula-II A in the presence of a solvent and salt forming agent to form 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4(11bH)-one phosphate of Formula-II.

2. The process as claimed in claim 1, wherein the acid used in step (a) is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, perchloric acid and sulfuric acid and combinations thereof.

3. The process as claimed in claim 1, wherein the solvent used in step (a) and step (b) is a halogenated solvent selected from the group consisting of dichloromethane, ethylene dichloride, trichloromethane, trichloroethylene, tetrachloroethylene, 1,1,1-trichloroethane, 1,1-dichloroethane, 1,2-dichloroethane (ethylene dichloride), carbon tetrachloride, chlorobenzene, vinyl chloride and methylene chloride, and combinations thereof.

4. The process as claimed in claim 1, wherein the salt forming agent used in step (b) is selected from the group consisting of orthophosphoric acid, pyrophosphoric acid, polyphosphoric, hypophosphorous acid, trimetaphosphoric acid, tetrametaphosphoric acid, metaphosphoric acid and diphosphoric acid and combinations thereof.

5. The process as claimed in claim 1, wherein step (a) and step (b) are carried out at a temperature from about 25°C to about 35°C.

6. The process as claimed in claim 1, wherein step (a) further comprises addition of base selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and combinations thereof.

7. An intermediate compound, 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4 (11bH)- one phosphate of Formula-II, wherein the said compound has a purity of not less than 99.80% as measured by HPLC.

8. A process for preparation of praziquantel having a structure of Formula-I comprising the steps of: (i) reacting 2-(2,2-dimethoxyethylamino)-N-(2-phenylethyl) acetamide of Formula-IV in the presence of a solvent and an acid to form 2-(2,2-dimethoxyethyl amino)-N-(2-phenylethyl) acetamide hydrochloride of Formula-III:(ii) cyclization of 2-(2,2-dimethoxyethylamino)-N-(2-phenylethyl) acetamide hydrochloride of Formula-III obtained in step (i), using an acid in the presence of a solvent, to obtain a compound of Formula-II A:(iii) reacting the compound of Formula-II A in the presence of a solvent and salt forming agent to form 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a] isoquinolin-4(11bH)-one phosphate of Formula-II:(iv) subjecting 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one phosphate of Formula-II obtained in step (iii) and cyclohexanecarbonyl chloride to acylation reaction in the presence of an alkaline substance and an organic solvent, to obtain crude 2- (cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,2-a]isoquinolin-4(11bH)-one of Formula-I A:(v) purifying crude 2-(cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino [2,2-a] isoquinolin-4(11bH)-one of Formula-IA obtained in step (iv), in the presence of a protic solvent and an antioxidant, to obtain praziquantel having the structure of Formula-I:

9. The process as claimed in claim 8, wherein the solvent used in step (i) is isopropyl alcohol and the acid used in step (i) is hydrochloric acid.

10. The process as claimed in claim 8, wherein the acid used in step (ii), is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, perchloric acid, sulfuric acid and combinations thereof.

11. The process as claimed in claim 8, wherein the solvent used in step (ii) and step (iii) is a halogenated solvent selected from the group consisting of dichloromethane, ethylene dichloride, trichloromethane, trichloroethylene, tetrachloroethylene, 1,1,1-trichloroethane, 1,1-dichloroethane, 1,2-dichloroethane (ethylene dichloride), carbon tetrachloride, chlorobenzene, vinyl chloride, methylene chloride and combinations thereof.

12. The process as claimed in claim 8, wherein the salt forming agent used in step (iii) is selected from the group consisting of orthophosphoric acid, pyrophosphoric acid, polyphosphoric, hypophosphorous acid, trimetaphosphoric acid, tetrametaphosphoric acid, metaphosphoric acid, diphosphoric acid and combinations thereof.

13. The process as claimed in claim 8, wherein step (ii) further comprises addition of base selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and combinations thereof.

14. The process as claimed in claim 8, wherein steps (ii) and (iii) are carried out at a temperature of about 25°C to about 35°C.

15. The process as claimed in claim 8, wherein the alkaline substance in step (iv) is triethylamine (TEA).

16. The process as claimed in claim 8, wherein the organic solvent in step (iv) is acetone.

17. The process as claimed in claim 8, wherein step (iv) is carried out at a temperature of about 15°C to about 25°C.

18. The process as claimed in claim 8, wherein the solvent used in step (v) is methanol.

19. The process as claimed in claim 8, wherein the antioxidant used in step (v) is butyrated hydroxytoluene.

20. The process as claimed in claim 8, wherein step (v) is carried out at a temperature ranging from about 40°C to about 45°C.

21. The process as claimed in claim 8, wherein the purity of praziquantel of Formula-I is not less than 99.90%, as measured by HPLC.

22. The process as claimed in claim 8, wherein the yield of praziquantel of Formula-I, is not less than 80%w / w.

Images