Preparation method for praziquantel and intermediate compounds thereof

Abstract

Disclosed is a preparation method for praziquantel and intermediates thereof. The method includes: obtaining a target product praziquantel by using ?-phenethylamine as an initial raw material through a condensation reaction with chloroacetyl chloride, a substitution reaction with ethanolamine, and an acylation reaction with cyclohexanecarbonyl chloride, followed by an oxidation reaction and cyclization reaction. Also disclosed are two key intermediates, namely, a compound of formula IV and a compound of formula V for preparing praziquantel. The preparation method is reasonable and simple in its technological design, uses moderate reaction conditions, and is economical and environmentally friendly. Additionally, the raw materials are inexpensive and easy to obtain, the key intermediates are easy to prepare, and the total reaction yield and purity of the obtained target compound praziquantel is high, so that industrialized mass production is easy to achieve.

Claims

1. A process for preparing Praziquantel, comprising the steps of: 1) subjecting ?-phenethylamine and chloroacetyl chloride to condensation reaction in the presence of alkaline substance to give the compound of formula II; ##STR00011## 2) subjecting the compound of formula II and ethanolamine to substitution reaction to give the compound of formula III; ##STR00012## 3) subjecting the compound of formula III and cyclohexanecarbonyl chloride to acylation reaction in the presence of alkaline substance to give the compound of formula IV; ##STR00013## 4) subjecting the compound of formula IV to oxidation reaction in the presence of oxidizing agent to give the compound of formula V; and ##STR00014## 5) subjecting the compound of formula V to cyclization reaction in the presence of cyclizing agent to give Praziquantel as the compound of formula I ##STR00015##

2. The process according to claim 1, wherein, step 1), step 2), step 3), step 4) or step 5) is performed without solvent or performed with at least one aprotic organic solvent as solvent.

3. The process according to claim 1, wherein, step 2) is performed without solvent and step 1), step 3), step 4) or step 5) is performed with at least one aprotic organic solvent as solvent.

4. The process according to claim 2, wherein, the aprotic organic solvent is at least one selected from the group consisting of ethers solvent, aromatic hydrocarbons solvent, hydrocarbons or halogenated hydrocarbons solvent and esters solvent.

5. The process according to claim 4, wherein, the ethers solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, 1,2-dimethoxylethane, methyl tert-butyl ether and 2-methyltetrahydrofuran; the aromatic hydrocarbons solvent is selected from the group consisting of benzene, toluene, ethylbenzene and xylene; the hydrocarbons or halogenated hydrocarbons solvent is selected from the group consisting of n-hexane, cyclohexane, n-heptane, dichloromethane, trichloromethane and dichloroethane; the esters solvent is selected from the group consisting of methyl formate, ethyl formate, methyl acetate, ethyl acetate and isopropyl acetate.

6. The process according to claim 1, wherein, the reaction temperature of step 1), step 2), step 3), step 4) or step 5) is ?10? C. to 100? C.

7. The process according to claim 1, wherein, step 1), step 2), step 3), step 4) or step 5) is performed under ice water bath, room temperature or 0? C. to 40? C.

8. The process according to claim 1, wherein, step 1), step 3) or step 5) is performed under ice water bath, step 2) is performed at room temperature, and step 4) is performed at 0? C. to 40? C.

9. The process according to claim 1, wherein, the alkaline substance in step 1) and step 3) is one or more each independently selected from the group consisting of triethylamine, imidazole, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, diisopropylamine, dimethylisopropylamine, diisopropylethylamine, NaOH, Na.sub.2CO.sub.3, NaHCO.sub.3, KOH and K.sub.2CO.sub.3.

10. The process according to claim 1, wherein, the molar ratio of the compound of formula II to ethanolamine in step 2) is 1:2-1:15.

11. The process according to claim 1, wherein, the oxidizing agent in step 4) is at least one group selected from the group consisting of: NaClO/TEMPO/NaBr, Ca(ClO).sub.2/TEMPO/NaBr, TCCA/TEMPO, DMSO/SO.sub.3-Py/Et.sub.3N, NaNO.sub.2/FeCl.sub.3/TEMPO/air, and NaNO.sub.2/FeCl.sub.3/TEMPO/O.sub.2.

12. The process according to claim 1, wherein, the cyclizing agent in step 5) is one or more selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, perchloric acid and concentrated sulfuric acid.

13. The process according to claim 5, wherein, the ethers solvent is methyl tert-butyl ether; the aromatic hydrocarbons solvent is toluene; the hydrocarbons or halogenated hydrocarbons solvent is dichloromethane; and the esters solvent is ethyl acetate or isopropyl acetate.

14. The process according to claim 6, wherein, the reaction temperature of step 1), step 2), step 3), step 4) or step 5) is 0? C. to 40? C.

15. The process according to claim 6, wherein, the reaction temperature of step 1), step 2), step 3), step 4) or step 5) is 5? C. to 15? C.

16. The process according to claim 8, wherein, step 1), step 3) or step 5) is performed under ice water bath, step 2) is performed at room temperature, and step 4) is performed at 5? C. to 15? C.

17. The process according to claim 8, wherein, step 1), step 3) or step 5) is performed under ice water bath, step 2) is performed at room temperature, and step 4) is performed at 10? C. to 15? C.

18. The process according to claim 9, wherein, the alkaline substance in step 1) and step 3) is one or more each independently selected from the group consisting of triethylamine, NaOH, Na.sub.2CO.sub.3, NaHCO.sub.3, KOH and K.sub.2CO.sub.3.

19. The process according to claim 10, wherein, the molar ratio of the compound of formula II to ethanolamine in step 2) is 1:3-1:8.

20. The process according to claim 12, wherein, the cyclizing agent in step 5) is one or more selected from the group consisting of concentrated sulfuric acid and methanesulfonic acid.

Description

DETAILED DESCRIPTION

(1) The invention will be further illustrated by the following Examples, which however should not be understood as any limitation thereto. A person skilled in the art can make modification or improvement according to the prior art, which are within the scope of the invention. The protection scope and spirit are defined by the claims and the technical solutions equivalent thereto.

(2) .sup.1HNMR is recorded with AM 400 Nuclear Magnetic Resonance Spectrometer with the chemical shift shown as ? (ppm).

(3) Mass spectrum is determined through Shimadzu LCMS-2010 HPLC-MS.

(4) The terms used in the description and claims are provided as follows. Unless stated otherwise, other undefined terms have the general meaning in the art.

(5) TEMPO: 2,2,6,6-tetramethylpiperidine-1-oxyl free radical

(6) TCCA: trichloroisocyanuric acid

(7) SO.sub.3-Py: sulfur trioxide pyridine

(8) The above reagents are purchased from Sinopharm Chemical Reagent Co., Ltd.

Example 1

(9) Step 1): to a 500 ml reaction bottle were successively added ?-phenethylamine (15.36 g, 126.75 mmol), CH.sub.2Cl.sub.2 (150 ml) and NaOH (7.30 g, 182.50 mmol), to which was added dropwise chloroacetyl chloride (15.0 g, 132.80 mmol) under ice water bath. After addition, the reaction was performed for 1 h. Then to the reaction liquid was added 150 ml water and the mixture was stirred and allowed to stand and the organic layer was separated. The organic layer was washed with diluted hydrochloric acid aqueous solution (50 ml) and then with water (100 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give 24.73 g of the compound of formula II as white solid (yield: 98.7%).

(10) .sup.1HNMR (CDCl.sub.3) ?: 2.86 (t, 2H), 3.57 (q, 2H), 4.02 (s, 2H), 6.59 (s, 1H), 7.20-7.35 (m, 5H).

(11) MS (ESI) m/z: 198.07 ([M+1].sup.+), 220.05 ([M+Na].sup.+)

(12) Step 2): To a 250 ml reaction bottle were successively added the compound of formula II prepared above (22.90 g, 115.85 mmol) and ethanolamine (42.60 g, 697.45 mmol) and the mixture was stirred at room temperature for 12 h. The ethanolamine was distilled off under reduced pressure to give 23.67 g of the compound of formula III as yellow oil (yield 91.9%).

(13) .sup.1HNMR(CDCl.sub.3) ?: 2.37 (s, 2H), 2.64 (t, 2H), 2.83 (t, 2H), 3.23 (s, 2H), 3.44 (s, 1H), 3.51-3.58 (m, 4H), 7.20-7.32 (m, 5H).

(14) MS (ESI) m/z: 223.15 ([M+1].sup.+), 245.13 ([M+Na].sup.+)

(15) Step 3): To a 500 ml reaction bottle were successively added the compound of formula III prepared above (18.50 g, 83.23 mmol), CH.sub.2Cl.sub.2 (150 ml) and triethylamine (12.64 g, 124.91 mmol), to which was added dropwise cyclohexanecarbonyl chloride (12.77 g, 87.10 mmol) under ice water bath. After addition, the reaction was performed for 2 h. To the reaction liquid was added diluted hydrochloric acid aqueous solution (150 ml), which was then stirred and allowed to stand. The organic layer was separated, washed with water (100 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting solid was slurried with methyl tert-butyl ether to give 25.62 g of the compound of formula IV as white solid (yield 92.6%).

(16) .sup.1HNMR(CDCl.sub.3) ?: 1.20-1.79 (m, 1014), 2.58 (m, 1H), 2.81 (t, 2H), 3.49-3.58 (m, 4H), 3.70 (t, 2H), 3.83 (s, 2H), 3.98 (s, 1H), 6.48 (s, 1H), 7.18-7.31 (m, 5H).

(17) MS (ESI) m/z: 333.23 ([M+1].sup.+), 355.21 ([M+Na].sup.+)

(18) Step 4): To a 500 ml reaction bottle were successively added the compound of formula IV prepared above (10.20 g, 30.68 mmol), CH.sub.2Cl.sub.2 (150 ml), 15 wt % NaBr aqueous solution (10.53 g, 15.35 mmol) and TEMPO (0.05 g, 0.32 mmol) and the temperature in the bottle was controlled at 5-10? C. and then NaClO aqueous solution (180 g, 32.24 mmol) of which the pH had been adjusted to 8-9 with saturated NaHCO.sub.3 aqueous solution was added dropwise. The reaction was performed for 20 h. The aqueous layer was separated and extracted with 30 ml CH.sub.2Cl.sub.2. The organic layer was combined, washed with sodium thiosulfate aqueous solution (100 ml?2), washed with water (100 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give 8.92 g of the compound of formula V as light yellow solid (yield 88.0%).

(19) .sup.1HNMR(CDCl.sub.3) ?: 1.21-1.76 (m, 10H), 2.43 (m, 1H), 2.88-2.99 (m, 2H), 3.21-3.65 (m, 2H), 3.88-3.99 (m, 2H), 4.32-4.80 (m, 3H), 7.19-7.31 (m, 5H)

(20) MS (ESI) m/z: 331.21 ([M+1].sup.+), 353.19 ([M+Na].sup.+)

(21) Step 5): To a 100 ml reaction bottle was added concentrated sulfuric acid (15 ml), to which was added dropwise the solution of the compound of formula V prepared above (5.60 g, 16.95 mmol) in CH.sub.2Cl.sub.2 (15 ml) under ice water bath. The reaction was performed for 8 h. The reaction liquid was poured into 150 ml of ice water and extracted with CH.sub.2Cl.sub.2 (50 ml?2). The organic layer was combined, washed with saturated Na.sub.2CO.sub.3 aqueous solution (50 ml), washed with water (50 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give light yellow solid, which was recrystallized with ethanol to give 4.45 g of the compound of formula I Praziquantel as white solid (HPLC purity 99.92%, yield 84.0%)

(22) .sup.1HNMR(CDCl.sub.3) ?: 1.46-1.79 (m, 10H), 2.45 (m, 1H), 2.75-3.01 (m, 4H), 4.06 (d, 1H), 4.45 (d, 1H), 4.78-4.80 (m, 2H), 5.15 (dd, 1H), 7.16-7.26 (m, 4H)

(23) MS (ESI) m/z: 313.21 ([M+1].sup.+), 335.19 ([M+Na].sup.+)

Example 2

(24) Except that the compound of formula II in step 1) was prepared according to the following procedures, other steps were the same as those of Example 1.

(25) To a 500 ml reaction bottle were successively added ?-phenethylamine (15.36 g, 126.75 mmol), CH.sub.2Cl.sub.2 (150 ml) and NaHCO.sub.3 (21.30 g, 253.54 mmol), to which was added dropwise chloroacetyl chloride (15.0 g, 132.80 mmol) under ice water bath. After addition, the reaction was performed for 1 h. To the reaction liquid was added 150 ml of water, which was stirred and allowed to stand. The organic layer was separated and the organic phase was washed with diluted hydrochloric acid aqueous solution (50 ml), washed with water (100 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give 24.85 g of the compound of formula II as white solid (yield 99.2%).

Example 3

(26) Except that the compound of formula II in step 1) was prepared according to the following procedures, other steps were the same as those of Example 1.

(27) To a 500 ml reaction bottle were successively added ?-phenethylamine (15.36 g, 126.75 mmol), CH.sub.2Cl.sub.2 (150 ml) and Na.sub.2CO.sub.3 (20.15 g, 190.11 mmol), to which was added dropwise chloroacetyl chloride (15.0 g, 132.80 mmol) under ice water bath. After addition, the reaction was performed for 1 h. Then to the reaction liquid was added 150 ml of water, which was stirred and allowed to stand. The organic layer was separated and the organic phase was washed with diluted hydrochloric acid aqueous solution (50 ml), washed with water (100 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give 24.38 g of the compound of formula II as white solid (yield 97.3%).

Example 4

(28) Except that the compound of formula II in step 1) was prepared according to the following procedures, other steps were the same as those of Example 1.

(29) To a 500 ml reaction bottle were successively added ?-phenethylamine (15.36 g, 126.75 mmol), CH.sub.2Cl.sub.2 (150 ml) and K.sub.2CO.sub.3 (26.27 g, 190.07 mmol), to which was added dropwise chloroacetyl chloride (15.0 g, 132.80 mmol) under ice water bath. After addition, the reaction was performed for 1 h. Then to the reaction liquid was added 150 ml of water, which was stirred and allowed to stand.

(30) The organic layer was separated and the organic phase was washed with diluted hydrochloric acid aqueous solution (50 ml), washed with water (100 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give 24.45 g of the compound of formula II as white solid (yield 97.6%).

Example 5

(31) Except that the compound of formula II in step 1) was prepared according to the following procedures, other steps were the same as those of Example 1.

(32) To a 500 ml reaction bottle were successively added ?-phenethylamine (15.36 g, 126.75 mmol), toluene (150 ml) and NaOH (7.30 g, 182.50 mmol), to which was added dropwise chloroacetyl chloride (15.0 g, 132.80 mmol) under ice water bath. After addition, the reaction was performed for 1 h. Then to the reaction liquid was added 150 ml of water, which was stirred and allowed to stand. The organic layer was separated and the organic phase was washed with diluted hydrochloric acid aqueous solution (50 ml), washed with water (100 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give 24.43 g of the compound of formula II as white solid (yield 97.5%).

Example 6

(33) Except that the compound of formula II in step 1) was prepared according to the following procedures, other steps were the same as those of Example 1.

(34) To a 500 ml reaction bottle were successively added ?-phenethylamine (15.36 g, 126.75 mmol), methyl tert-butyl ether (150 ml) and NaOH (7.30 g, 182.50 mmol), to which was added dropwise chloroacetyl chloride (15.0 g, 132.80 mmol) under ice water bath. After addition, the reaction was performed for 1 h. Then to the reaction liquid was added 150 ml of water, which was stirred and allowed to stand. The organic layer was separated and the organic phase was washed with diluted hydrochloric acid aqueous solution (50 ml), washed with water (100 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give 24.25 g of the compound of formula II as white solid (yield 96.8%).

Example 7

(35) Except that the compound of formula III in step 2) was prepared according to the following procedures, other steps were the same as those of Example 1.

(36) To a 250 ml reaction bottle were successively added the compound of formula II prepared above (24.50 g, 123.95 mmol) and ethanolamine (30.28 g, 495.74 mmol), which was stirred at room temperature for 12 h. Ethanolamine was distilled off under reduced pressure to give 24.66 g of the compound of formula III as yellow oil (yield 89.5%).

Example 8

(37) Except that the compound of formula III in step 2) was prepared according to the following procedures, other steps were the same as those of Example 1.

(38) To a 250 ml reaction bottle were successively added the compound of formula II prepared above (12.70 g, 64.25 mmol) and ethanolamine (31.40 g, 514.08 mmol), which was stirred at room temperature for 12 h. Ethanolamine was distilled off under reduced pressure to give 13.25 g of the compound of formula III as yellow oil (yield 92.8%).

Example 9

(39) Except that the compound of formula IV in step 3) was prepared according to the following procedures, other steps were the same as those of Example 1.

(40) To a 500 ml reaction bottle were successively added the compound of formula III prepared above (28.60 g, 128.67 mmol), CH.sub.2Cl.sub.2 (300 ml) and NaOH (7.72 g, 193.0 mmol), to which was added dropwise cyclohexanecarbonyl chloride (19.81 g, 135.12 mmol) under ice water bath. After addition, the reaction was performed for 2 h. To the reaction liquid was added 150 ml of diluted hydrochloric acid aqueous solution, which was stirred and allowed to stand. The organic layer was separated, washed with water (100 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting solid was slurried with methyl tert-butyl ether to give 40.42 g of the compound of formula IV as white solid (yield 94.5%).

Example 10

(41) Except that the compound of formula IV in step 3) was prepared according to the following procedures, other steps were the same as those of Example 1.

(42) To a 250 ml reaction bottle were successively added the compound of formula III prepared above (7.50 g, 33.74 mmol), CH.sub.2Cl.sub.2 (100 ml) and NaHCO.sub.3 (5.67 g, 67.49 mmol), to which was added dropwise cyclohexanecarbonyl chloride (5.20 g, 35.47 mmol) under ice water bath. After addition, the reaction was performed for 2 h. To the reaction liquid was added 50 ml of diluted hydrochloric acid aqueous solution, which was stirred and allowed to stand. The organic layer was separated, washed with water (50 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting solid was slurried with methyl tert-butyl ether to give 10.04 g of the compound of formula IV as white solid (yield 89.5%).

Example 11

(43) Except that the compound of formula IV in step 3) was prepared according to the following procedures, other steps were the same as those of Example 1.

(44) To a 250 ml reaction bottle were successively added the compound of formula III prepared above. (7.50 g, 33.74 mmol), toluene (250 ml) and NaOH (2.70 g, 67.49 mmol), to which was added dropwise cyclohexanecarbonyl chloride (5.20 g, 35.47 mmol) under ice water bath. After addition, the reaction was performed for 2 h. To the reaction liquid was added 50 ml of diluted hydrochloric acid aqueous solution, which was stirred and allowed to stand. The organic layer was separated, washed with water (50 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting solid was slurried with methyl tert-butyl ether to give 9.60 g of the compound of formula IV as white solid (yield 85.6%).

Example 12

(45) Except that the compound of formula IV in step 3) was prepared according to the following procedures, other steps were the same as those of Example 1.

(46) To a 250 ml reaction bottle were successively added the compound of formula III prepared above (7.50 g, 33.74 mmol), isopropyl acetate (150 ml) and NaOH (2.70 g, 67.49 mmol), to which was added dropwise cyclohexanecarbonyl chloride (5.20 g, 35.47 mmol) under ice water bath. After addition, the reaction was performed for 2 h. To the reaction liquid was added 50 ml of diluted hydrochloric acid aqueous solution, which was stirred and allowed to stand. The organic layer was separated, washed with water (50 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting solid was slurried with methyl tert-butyl ether to give 9.28 g of the compound of formula IV as white solid (yield 82.7%).

Example 13

(47) Except that the compound of formula V in step 4) was prepared according to the following procedures, other steps were the same as those of Example 1.

(48) To a 250 ml reaction bottle were successively added the compound of formula IV prepared above (6.10 g, 18.35 mmol), CH.sub.2Cl.sub.2 (100 ml) and TEMPO (0.03 g, 0.19 mmol) with the temperature in the bottle controlled as 5-10? C., to which was then added TCCA (4.30 g, 18.50 mmol). The temperature was raised to room temperature and the reaction was performed for 24 h with stirring. The reaction mixture was filtered and the filter cake was washed with 30 ml of CH.sub.2Cl.sub.2. The filtrate was washed with 200 ml of saturated Na.sub.2CO.sub.3 aqueous solution, washed with water (100 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give 5.16 g of the compound of formula V as light yellow solid (yield 85.1%).

Example 14

(49) Except that the compound of formula V in step 4) was prepared according to the following procedures, other steps were the same as those of Example 1.

(50) To a 1 L reaction bottle were successively added the compound of formula IV prepared above (10.50 g, 31.58 mmol), DMSO (60 ml) and Et.sub.3N (31.96 g, 315.84 mmol) with the temperature in the bottle controlled as 10-15? C., to which was then added dropwise the solution of SO.sub.3Py (30.16 g, 189.50 mmol) in DMSO (110 ml) and the reaction was performed for 10 h. To the reaction liquid was added 300 ml of water, which was extracted with CH.sub.2Cl.sub.2 (100 ml?2). The organic phase was combined, washed with water (50 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give 10.0 g of the compound of formula V as yellow solid (yield 95.8%).

Example 15

(51) Except that the compound of formula V in step 4) was prepared according to the following procedures, other steps were the same as those of Example 1.

(52) To a 500 ml reaction bottle were successively added the compound of formula IV prepared above (10.20 g, 30.68 mmol), CH.sub.2Cl.sub.2 (150 ml), 15 wt % NaBr aqueous solution (10.53 g, 15.35 mmol) and TEMPO (0.05 g, 0.32 mmol), with the temperature in the bottle controlled as 5-10? C., to which was then added dropwise the aqueous solution of Ca(ClO).sub.2 (4.61 g, 32.24 mmol) and the reaction was performed for 20 h. The aqueous layer was separated and extracted with 30 ml of CH.sub.2Cl.sub.2. The organic layer was combined, washed with sodium thiosulfate aqueous solution (100 ml?2), washed with water (100 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give 7.91 g of the compound of formula V as light yellow solid (yield 78.0%).

Example 16

(53) Except that the compound of formula V in step 4) was prepared according to the following procedures, other steps were the same as those of Example 1.

(54) To a 500 ml reaction bottle were successively added the compound of formula IV prepared above (10.20 g, 30.68 mmol), isopropyl acetate (250 ml), 15 wt % NaBr aqueous solution (10.53 g, 15.35 mmol) and TEMPO (0.05 g, 0.32 mmol), with the temperature in the bottle controlled as 5-10? C., to which was added dropwise NaClO aqueous solution (180 g, 32.24 mmol) of which the pH has been adjusted to 8-9 with saturated NaHCO.sub.3 aqueous solution and the reaction was performed for 20 h. The aqueous layer was separated and extracted with 50 ml of isopropyl acetate. The organic layer was combined, washed with sodium thiosulfate aqueous solution (100 ml?2), washed with water (100 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give 7.65 g of the compound of formula V as light yellow solid (yield 75.5%).

Example 17

(55) Except that the compound of formula V in step 4) was prepared according to the following procedures, other steps were the same as those of Example 1.

(56) To a 500 ml reaction bottle were successively added the compound of formula IV prepared above (10.20 g, 30.68 mmol), methyl tert-butyl ether (300 ml), 15 wt % NaBr aqueous solution (10.53 g, 15.35 mmol) and TEMPO (0.05 g, 0.32 mmol), with the temperature in the bottle controlled as 5-10? C., to which was added dropwise NaClO aqueous solution (180 g, 32.24 mmol) of which the pH has been adjusted to 8-9 with saturated NaHCO.sub.3 aqueous solution and the reaction was performed for 20 h. The aqueous layer was separated and extracted with 50 ml of methyl tert-butyl ether. The organic layer was combined, washed with sodium thiosulfate aqueous solution (100 ml?2), washed with water (100 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give 8.19 g of the compound of formula V as light yellow solid (yield 80.8%).

Example 18

(57) Except that the compound of formula V in step 4) was prepared according to the following procedures, other steps were the same as those of Example 1.

(58) To a 500 ml reactor were successively added the compound of formula IV prepared above (10.20 g, 30.68 mmol), CH.sub.2Cl.sub.2 (100 ml), NaNO.sub.2 (0.21 g, 3.04 mmol), FeCl.sub.3 (0.50 g, 3.08 mmol) and TEMPO (0.10 g, 0.64 mmol), and the reaction was performed for 10 h at room temperature under 0.3 MPa O.sub.2. The reaction liquid was washed with sodium thiosulfate aqueous solution (50 ml?2), washed with water (50 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give 9.94 g of the compound of formula V as light yellow solid (yield 98.0%).

Example 19

(59) Except that the compound of formula I Praziquantel in step 5) was prepared according to the following procedures, other steps were the same as those of Example 1.

(60) To a 100 ml reaction bottle was added methanesulfonic acid (20 ml), to which were added dropwise the solution of the compound of formula V prepared above (5.40 g, 16.34 mmol) in CH.sub.2Cl.sub.2 (10 ml) under ice water bath. After addition, the temperature was raised to room temperature and the reaction was performed for 10 h. The reaction liquid was poured into 100 ml of ice water and extracted with CH.sub.2Cl.sub.2 (50 ml?2). The organic phase was combined, washed with 50 ml of saturated Na.sub.2CO.sub.3 aqueous solution, washed with water (50 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give light yellow solid, which was recrystallized with ethanol to give 4.27 g of the compound of formula I Praziquantel as white solid (HPLC purity 99.83%, yield 83.6%).

Example 20

(61) Except that the compound of formula I Praziquantel in step 5) was prepared according to the following procedures, other steps were the same as those of Example 1.

(62) To a 100 ml reaction bottle was added trifluoroacetic acid (15 ml), to which were added dropwise the solution of the compound of formula V prepared above (5.40 g, 16.34 mmol) in CH.sub.2Cl.sub.2 (10 ml) under ice water bath. After addition, the temperature was raised to room temperature and the reaction was performed for 10 h. The reaction liquid was poured into 100 ml of ice water and extracted with CH.sub.2Cl.sub.2 (50 ml?2). The organic phase was combined, washed with 50 ml of saturated Na.sub.2CO.sub.3 aqueous solution, washed with water (50 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give light yellow solid, which was recrystallized with ethanol to give 3.92 g of the compound of formula I Praziquantel as white solid (HPLC purity 99.93%, yield 76.8%).

Example 21

(63) Except that the compound of formula I Praziquantel in step 5) was prepared according to the following procedures, other steps were the same as those of Example 1.

(64) To a 100 ml reaction bottle was added trifluoromethanesulfonic acid (20 ml), to which were added dropwise the solution of the compound of formula V prepared above (5.40 g, 16.34 mmol) in CH.sub.2Cl.sub.2 (10 ml) under ice water bath. After addition, the temperature was raised to room temperature and the reaction was performed for 10 h. The reaction liquid was poured into 100 ml of ice water and extracted with CH.sub.2Cl.sub.2 (50 ml?2). The organic phase was combined, washed with 50 ml of saturated Na.sub.2CO.sub.3 aqueous solution, washed with water (50 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give light yellow solid, which was recrystallized with ethanol to give 3.60 g of the compound of formula I Praziquantel as white solid (HPLC purity 99.86%, yield 70.5%).

Example 22

(65) Except that the compound of formula I Praziquantel in step 5) was prepared according to the following procedures, other steps were the same as those of Example 1.

(66) To a 100 ml reaction bottle was added benzenesulfonic acid (20 ml), to which were added dropwise the solution of the compound of formula V prepared above (5.40 g, 16.34 mmol) in CH.sub.2O.sub.2 (10 ml) under ice water bath. After addition, the temperature was raised to room temperature and the reaction was performed for 10 h. The reaction liquid was poured into 100 ml of ice water and extracted with CH.sub.2Cl.sub.2 (50 ml?2). The organic phase was combined, washed with 50 ml of saturated Na.sub.2CO.sub.3 aqueous solution, washed with water (50 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give light yellow solid, which was recrystallized with ethanol to give 3.71 g of the compound of formula I Praziquantel as white solid (HPLC purity 99.85%, yield 72.7%).

Example 23

(67) Except that the compound of formula I Praziquantel in step 5) was prepared according to the following procedures, other steps were the same as those of Example 1.

(68) To a 100 ml reaction bottle was added concentrated sulfuric acid (15 ml), to which were added dropwise the solution of the compound of formula V prepared above (5.60 g, 16.95 mmol) in toluene (15 ml) under ice water bath and the reaction was performed for 8 h. The reaction liquid was poured into 150 ml of ice water and extracted with toluene (50 ml?2). The organic phase was combined, washed with 50 ml of saturated Na.sub.2CO.sub.3 aqueous solution, washed with water (50 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give light yellow solid, which was recrystallized with ethanol to give 4.54 g of the compound of formula I Praziquantel as white solid (HPLC purity 99.87%, yield 85.7%).

Example 24

(69) Except that the compound of formula I Praziquantel in step 5) was prepared according to the following procedures, other steps were the same as those of Example 1.

(70) To a 100 ml reaction bottle was added concentrated sulfuric acid (15 ml), to which were added dropwise the solution of the compound of formula V prepared above (5.60 g, 16.95 mmol) in methyl tert-butyl ether (15 ml) under ice water bath and the reaction was performed for 8 h. The reaction liquid was poured into 150 ml of ice water and extracted with methyl tert-butyl ether (50 ml?2). The organic phase was combined, washed with 50 ml of saturated Na.sub.2CO.sub.3 aqueous solution, washed with water (50 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give light yellow solid, which was recrystallized with ethanol to give 4.30 g of the compound of formula I Praziquantel as white solid (HPLC purity 99.85%, yield 81.3%).

Example 25

(71) Except that the compound of formula I Praziquantel in step 5) was prepared according to the following procedures, other steps were the same as those of Example 1.

(72) To a 100 ml reaction bottle was added concentrated sulfuric acid (15 ml), to which were added dropwise the solution of the compound of formula V prepared above (5.60 g, 16.95 mmol) in isopropyl acetate (15 ml) under ice water bath and the reaction was performed for 8 h. The reaction liquid was poured into 150 ml of ice water and extracted with isopropyl acetate (50 ml?2). The organic phase was combined, washed with 50 ml of saturated Na.sub.2CO.sub.3 aqueous solution, washed with water (50 ml?2), dried with anhydrous magnesium sulfate, filtered and concentrated to give light yellow solid, which was recrystallized with ethanol to give 4.27 g of the compound of formula I Praziquantel as white solid (HPLC purity 99.91%, yield 80.6%).

(73) Although typical embodiments have been illustrated herein, the invention should not be limited to the detailed description above. Possible amendments and substitutions can be made to the invention without departing from the spirit thereof. Accordingly, a person skilled in the art can think of modifications and equivalence with conventional experiments and such modifications and equivalence are within the spirit and scope of the invention defined by the appended claims.