Claims:We Claim:
1. An intermediate for the synthesis of praziquantel, said intermediate of formula (III),

(III)

2. A process for preparation of an intermediate of formula (III),

(III)

wherein said process comprises:

a) condensation of 2-phenylethylamine with 2-chloroacetyl chloride in the presence of a solvent and a base to obtain 2-chloro-N-phenethylacetamide;
b) treatment of 2-chloro-N-phenethylacetamide prepared in step a) with aqueous ammonia in the presence of an inorganic base to prepare the said intermediate of formula (III). The aqueous ammonia after product extraction can be used several times, preferably 4-5 times for the production of intermediate of formula (III).

3. The process according to claim 2, wherein the solvent in step a) is toluene or water and the base in step a) is alkali metal carbonate.

4. The process according to claim 2, wherein the base in step b) is alkali metal carbonate.

5. The process according to claim 2, wherein the base in step a) and step b) is selected from the group comprising of sodium carbonate, potassium carbonate and calcium carbonate.

6. A process for preparation of praziquantel comprising:

a) N-alkylation of the intermediate of Formula (III) prepared according to claim 2 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);

(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]isoquinoline of formula (VI); and

(VI)
c) acylation of 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline of Formula (VI) with cyclohexanoyl chloride in presence of a base and a solvent to obtain praziquantel which is reported in US8754215.

7. The process according to claim 6, wherein the solvent in step a) is selected from the group comprising of toluene, cyclohexane and xylene and the base in step a) is alkali metal carbonates.

8. The process according to claim 6, wherein cyclization in step b) is carried out in the presence of sulphuric acid or Methane sulphonic acid (MSA)

9. The process according to claim 6, wherein the cyclized product, 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline of formula (VI) obtained from step b), is extracted in solvent dichloromethane from an aqueous quench.

10. The process according to claim 6 wherein, acylation in step c) is carried out in presence of sodium carbonate as the base and dichloromethane as the solvent and this compound is purified by crystallization from acetone.

Deshmukh Sharayu
(On Behalf of Delta Finochem Pvt Ltd)
, Description:NOVEL INTERMEDIATE IN THE PROCESS FOR THE PREPARATION OF PRAZIQUANTEL
FIELD OF THE INVENTION
[0001] The present disclosure relates to a novel intermediate of Formula (III). Specifically, it relates to an economical process for the preparation of praziquantel involving the novel intermediate of Formula (III).
BACKGROUND OF THE INVENTION
[0002] Research on praziquantel is rapidly increasing worldwide as the drug of choice for the treatment of worm disease schistosomiasis, caused by trematodes of genus Schistosoma. The pathogens of schistosomiasis known as blood fluke cause life-threatening symptoms such as fever, chills, cough, headache and enlargement of the liver, lymph nodes and spleen.
[0003] Schistosomiasis accounts for an extraordinarily high level of suffering around the world, however, it is termed a "neglected" tropical disease owing to low level of investment in treatments, prevention and research. Praziquantel is providing treatment to these infected people in a single dose. Further, it is effective and safe for pregnant women and children infected by worm. It saves immense economic damage, caused by worm infestation of pets and livestock.
[0004] Praziquantel is also used to treat diseases caused by infection with other types of internal/gastrointestinal, and external parasites, including: Hydatid disease caused by infection of various organs with larval stages of tapeworms of the genus Echinococcus; and Cysticercosis caused by infection of the brain and/or muscles with the eggs and larvae of the pork tapeworm Taenia solium.
[0005] Praziquantel is also used in cats and dogs whose gastrointestinal tract is infected with the tapeworms, Dipylidium caninum or Taenia taeniaeformis, respectively. It is also often used in a fixed combination with pyrantel embonate against the roundworms (ascarids), Toxocara cati and Toxascaris leonina. Praziquantel is also effective against Echinococcus multilocularis.
[0006] There are number of processes described in the prior art for the preparation of praziquantel.
[0007] US4001411A discloses a process which involves a reaction between 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline and a carboxylic acid compound to form an acylated intermediate. This intermediate upon cyclisation and reaction with a reducing agent results in the formation of praziquantel.
[0008] US8754215B2 discloses a process for the preparation of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide as an intermediate involved in the formation of praziquantel. This process involves a total of six steps for the preparation of praziquantel.
[0009] WO2009/115333A1 discloses several processes for the preparation of praziquantel. One of such process involves the reaction between phenylethyl isocyanide and aminoacetal in the presence of formaldehyde to yield 2-[(2,2-dialkoxyethyl)amino]-N-(2-phenylethyl)acetamide, which after cyclisation and acylation forms praziquantel. This method utilizes aminoacetaldehyde dimethyl acetal, which is a very expensive raw material. Another drawback in this process is that two moles of the expensive aminoacetaldehyde dimethyl acetal is required, wherein one mole is consumed in the reaction and the other mole is lost and cannot be recovered.
[0010] Therefore, there is a need to develop an efficient process for the preparation of praziquantel, which is economical and avoids the use of costly aminoacetaldehyde dimethylacetal to reduce the overall cost of production.
[0011] Thus, the present disclosure provides an economical and green process, requiring five synthetic steps and a novel intermediate, for preparing praziquantel on a commercial scale.
[0012] Further limitations and disadvantages of conventional and traditional approaches will become apparent to those skilled in the art, through the comparison of described process with some aspects of the present disclosure, as set forth in the remainder of the present application.

SUMMARY OF THE INVENTION

[0013] Various embodiments disclosed herein provide a process for the preparation of a novel intermediate of formula III, a useful precursor for praziquantel I, presented in Figure 3. An exemplary process of making the compound of formula III and praziquantel is illustrated in Figure 3.
[0014] In accordance with an embodiment of the present disclosure, an intermediate for the synthesis of praziquantel, the said intermediate of formula III as claimed in claim 1.
[0015] In accordance with an embodiment, a process for the preparation of an intermediate of formula III (2-amino-N-(2-phenylethylamino) acetamide), wherein the process comprises:
a) Condensation of 2-phenylethylamine with 2-chloroacetyl chloride in the presence of a solvent and a base to obtain 2-chloro-N-phenethylacetamide; and
b) Treatment of 2-chloro-N-phenethylacetamide prepared in step a) with aqueous ammonia in the presence of an inorganic base to prepare the said intermediate of Formula III.
[0016] In accordance with an embodiment, the process for the preparation of an intermediate of formula III, wherein the solvent in step a) is toluene or water and the base in step a) is alkali metal carbonate.
[0017] In accordance with an embodiment, the process for the preparation of an intermediate of formula III, wherein the base in step b) is alkali metal hydroxides.
[0018] In accordance with an embodiment, the process for the preparation of an intermediate of formula III, wherein the base in step a) and step b) is selected from the group comprising of sodium bicarbonate, potassium bicarbonate and calcium bicarbonate.
[0019] In accordance with an embodiment, a process for the preparation of praziquantel, which comprises:
a) N-alkylation of the intermediate of Formula (III) prepared according to claim 2 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]isoquinoline of formula (VI); and
c) acylation of 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline of Formula (VI) with cyclohexane carbonylchloride in presence of a base and a solvent to obtain praziquantel of Formula (I).
[0020] In accordance with an embodiment, the process for the preparation of praziquantel, wherein the solvent in step a) is selected from the group comprising of toluene, cyclohexane and xylene and the base in step a) is alkali metal carbonate.
[0021] In accordance with an embodiment, the process for the preparation of praziquantel, wherein cyclization in step b) is carried out in the presence of sulphuric acid or MSA.
[0022] In accordance with an embodiment, the process for the preparation of praziquantel, wherein the cyclized product, 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline of formula (VI) obtained from step b), is extracted in solvent form from an aqueous quench.
[0023] In accordance with an embodiment, the process for the preparation of praziquantel, wherein acylation in step c) is carried out in presence of sodium carbonate as the base and dichloromethane as the solvent.
[0024] In accordance with an embodiment, the process for the preparation of praziquantel, wherein the praziquantel obtained in step c) is purified by crystallization from methanol.
[0025] These and other features and advantages of the present disclosure may be appreciated from a review of the following detailed description of the present disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS
[0026] The accompanying drawings, which are included to provide a further understanding of the disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure and together with the description serve to explain the principles of the disclosure. In the drawings:
[0027] FIG. 1 shows the chemical structure of praziquantel represented by Formula (I), in accordance with an embodiment of the present disclosure;
[0028] FIG. 2 shows the chemical structure of a novel intermediate of Formula (III), in accordance with an embodiment of the present disclosure;
[0029] FIG. 3 shows a process for the preparation of praziquantel represented by Formula (I), in accordance with an embodiment of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION
[0030] Accordingly, in various embodiments disclosed herein, the condensation of 2-phenylethylamine with 2-chloroacetyl chloride is carried out in the presence of a solvent preferably an aromatic solvent such as toluene and a base selected from an alkali metal hydrogen carbonate, preferably selected from sodium bicarbonate, potassium bicarbonate and calcium bicarbonate, in the temperature range -5 to 15° C., preferably in the range 0 to 5°C, to obtain 2-chloro-N-phenethylacetamide.
[0031] In certain embodiments disclosed herein, the condensation in step a) is carried out in an aqueous solvent, preferably water and a base selected from sodium bicarbonate, potassium bicarbonate and calcium bicarbonate, in the temperature range -10 to 20°C , preferably at 0-5 °C., to obtain 2-chloro-N-phenethylacetamide.
[0032] In certain embodiments disclosed herein, the displacement reaction in step b) is carried out in aqueous ammonia in the presence of an inorganic base selected from alkali metal hydroxides, preferably selected from sodium hydroxide, potassium hydroxide and calcium hydroxide, to obtain the intermediate of Formula (III).
[0033] In certain embodiments disclosed herein, the N-alkylation of the intermediate of Formula (III) is carried out with chloroacetaldehyde dimethylacetal in the presence of a solvent selected from the group comprising of toluene, cyclohexane and xylene and a base selected from an alkali metal carbonate, to obtain 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide of Formula (V).
[0034] In certain embodiments disclosed herein, the cyclization of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide is carried out in presence of an acid, selected from sulphuric acid or MSA and in presence of an organic solvent selected from dichloromethane or dichloroethane or chloroform or carbon tetrachloride preferably dichloromethane. This reaction is conducted preferably in the temperature range 25 to 30° C to obtain 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline of Formula (VI).
[0035] In certain embodiments disclosed herein, the acylation of 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline of Formula (VI) is carried out with cyclohexanoylchloride, in presence of a base, preferably sodium carbonate and in presence of an organic solvent, preferably dichloromethane, in the temperature range 25 to 30°C to obtain praziquantel.
[0036] In further embodiments disclosed herein, praziquantel is purified by crystallization from polar solvents such as methanol, ethanol, acetone preferably acetone.
[0037] The process of making praziquantel disclosed herein avoids the use of an expensive raw material aminoacetaldehyde dimethylacetal. Instead, the process of making praziquantel disclosed herein involves a novel intermediate of Formula III. The production of this intermediate is economical and green, as lesser chemical waste is produced. The process involving the use of this novel intermediate for the preparation of praziquantel is ecofriendly, economical and involves fewer synthetic steps.
[0038] The process of making praziquantel disclosed herein can be illustrated by the following examples, which are not intended to limit the scope of invention.
[0039] Example 1 Preparation of Intermediate of Formula (III)
(a) Preparation of 2-chloro-N-phenethylacetamide
(b) Preparation of Intermediate of Formula (III)
(c) Preparation of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide
(d) Preparation of 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline
(e) Preparation of Praziquantel of Formula (I)

EXAMPLES:
Example:1. Preparation of 2- chloro N- (2-phenyl ethyl amino) acetamide-
To a solution of 121 gm (1.0 mole) beta phenyl ethyl amine & 1000 ml dichloromethane added sodium bicarbonate 100 gm (1.2 mole). The reaction mass was further chilled to 0-.5°c. Then 130 gm (1.15 mole) of chloro acetyl chloride was added drop wise, maintained the reaction at ambient temperature and monitored reaction progress on TLC. This is quenched with 2000 ml DM water. On separation of layers & on evaporation of a organic solvent obtained.
2 chloro-N-(2 phenyl ethyl amino) acetamide as white solid.
Yield 177.3 gm 90% yield
Purity by HPLC 99.6% & MR- 55-60°c
1H NMR/CDCl3 d 2.75-2.71 (2H, t), d 3.51-3.46 (2H,m), d 3.93 (2H, s), d 6.56 (1H, br s), d 7.24-7.11 (5H, m), d 8.29 (1H, bs)
13C NMR/DMSO-d6 (d, ppm) 35.39, 40.88, 42.57, 126.63, 128.66, 138.27, 165.74.
Mass (m/z)-198 (M+H)

Example 2. Preparation of 2-amino-N-(2-phenylethylamino) acetamide
To a pressure reactor charged liquid ammonia 1000ml (min 25% assay) 2- chloro-N-(2-Phenylethylamine)acetamide 197.5 gm (1mole), sodium hydroxide 40 gm (1mole) and the reaction pressurized with ammonia gas below 5 kgf/cm², maintained the reaction at ambient temp till complete conversion on TLC. Pressure released. Aqueous layer extracted in dichloromethane. Concentration of organic layer gives 2-amino-N-(2-phenylethylamino) acetamide as thick oil.
Yield -125 gm 70% yield
Purity by HPLC 90.2%
1H NMR/DMSO-d6 d 2.75-2.71 (2H, t), d 3.53-3.30 (q, m), 3.39(2H,m, CH2), d 3.35-3.30 (2H,m), d 3.5 (2H, s), d 7.29-7.17 (5H, m), d 8.31 (3H, br s)
13C NMR/DMSO-d6 (d, ppm) 34.91, 40.02, 40.36, 126.19, 128.37, 128.66, 139.18, 165.73.
Mass (m/z)-179 (M+H)

Example 3. Preparation of 2 [(2,2-dimethoxyethyl) amino] N-(2 phenyl ethyl)acetamide.
To solution of 2-amino-N-(phenyl ethyl amino)acetamide 178 gm (1 mole) in toluene 1000 ml charged potassium carbonate 138 gm (1 mole) & chloro acetaldehyde dimethylacetal 124.5 gm (1 mole). The reaction is maintained at reflux condition till complete conversion. The reaction mass is then cooled to ambient temperature and quenched with de-mineralized (DM) water. Layers separated and aqueous layers again extracted with toluene 200 ml. Combined organic layers on evaporation give 2- [(2,2-dimethylethyl)amino]-N-(2-phenylethyl)acetamide as an oil.
Yield 220 gm 82.7% yield
Purity on HPLC 98.5%
NMR/ CDCl¬3 d 2.87-2.83 (2H, t), d 3.15-3.11 (2H,m), d 3.41 (6H, s), d 3.52-3.11 (2H, m), d 3.99-3.97 (2H, m), d 4.86-4.83 (1H, t), d 7.27-7.15 (5H, m), d 8.56-8.53 (1H, t), d 9.02 (2H, br s).
13C NMR/ CDCl¬3 (d, ppm) 35.31, 41.17, 48.55, 48.73, 54.87, 99.46, 126.40, 128.46, 128.75, 138.54, 164.43.
Mass(m/z)-267 (M+H)

Example 4. Preparation at praziquanamine
Sulphuric acid 479 gm (4.88 mole) is charged into a cleaned reactor and chilled to 5°C. 2-[(2,2-dimehoxyethyl)amino]-N-(2-phenyl ethyl) acetamide 266 gm (1 mole) is added drop wise into chilled sulphuric acid between 7-10°c .The resulting mixture is warmed to ambient temp & maintained till complete conversion on TLC. The reaction mass is quenched on crushed ice and then extracted with dichloromethane which on evaporation gives praziquanamine.
Yield – 170 gm 84 % yield
Purity by HPLC 98.0% & MR 116 -120°C
NMR/ CDCl¬3 d 2.06-2.17 (1H, m), d 2.89-3.01 (2H,d), d 2.76-2.87 (2H, m), d 3.54-3.59 (1H, t), d 3.9-3.76 (2H, t), d 4.84-4.91 (2H, t), d 7.16-7.29 (4H, m), 13C NMR/ CDCl¬3 (d, ppm) 28.69, 38.69, 49.57-49.76, 55.38-56.58, 76.78-77.41, 129.25, 126.92, 126.53, 124.62, 134.78, 134.04, 167.10.
Mass (m/z) - 203(M+H)

Example 5 Preparation of Praziquantel
202 gm (1 mole) of praziquanamine is dissolved in 1000 ml of dichloromethane. 127.2 gm (1.2 mole) of sodium carbonate is then added to above reaction mixture. Then it is chilled to 0°C .161.1 gm (1.1 mole) of cyclohexane carbonyl chloride is added drop wise at 0-5°C. The reaction mixture is then warmed to ambient temperature and maintained for 2 hrs. The reaction progress is monitored on TLC. Then 1500ml DM water is added, separated the layers. Dichloromethane on evaporation gives praziquantel, which on further crystallization in acetone gives purified praziquantel
Yield 235 gm Yield 75.3%
Purity in HPLC 99.7% & MR 136-138 °C
NMR/CDCl¬3 d 1.28-1.33 (2H,m), d1.53-1.56 (2H,m), d1.60-1.62 (2H,m), d1.69-1.72 (2H,m), d1.72-1.75 (2H,m), d1.78-1.84 (2H,t), d2.46-2.58 (1H,m), d2.79-2.86 (2H,t), d2.89-3.04 (2H,d), d4.08-4.84 (2H,s), d5.17-5.20 (1H,t), d7.20-7.30 (4H,m)
13CNMR/CDCl¬3 (d, ppm) 25.60, 28.61, 28.89, 29.12, 38.54-38.98, 38.98-40.67,45.06-46.22,48.92-49.45,54.83-55.68,76.63-77.26,125.05-125.33, 126.84-127.31,127.54,129.15-129.56,132.69, 134.63,164.26,174.62
Mass(m/z)- 313(M+H)