A method of synthesizing praziquantel
By using glycine and cyclohexyl chloride as starting materials and combining them with the photocatalytic free radical deacidification Minisci reaction, praziquantel was synthesized, solving the problems of low yield and high cost in the existing praziquantel synthesis technology, and realizing efficient and safe industrial production of praziquantel.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- WUHAN CHANGHE PHARMACEUTICAL TECHNOLOGY CO LTD
- Filing Date
- 2026-01-29
- Publication Date
- 2026-05-29
Smart Images
Figure CN122103135A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of drug synthesis technology, and specifically to a method for synthesizing praziquantel. Background Technology
[0002] Praziquantel is a broad-spectrum antiparasitic drug primarily used for the treatment and prevention of schistosomiasis, cysticercosis, paragonimiasis, echinococcosis, fascioliasis, echinococcosis, and helminth infections. It works by disrupting the parasite's surface structure and inducing muscle spasms, prompting the expulsion of the parasite. Its chemical structure is as follows:
[0003]
[0004] Currently, the main methods for synthesizing praziquantel reported in the literature are as follows:
[0005] (1) The process route developed by Bayer AG in Germany is lengthy, with an overall yield of only about 15%. Furthermore, the production process involves the use of highly toxic cyanide, posing significant safety risks. Additionally, it generates large amounts of waste gas, wastewater, and solid waste, resulting in high environmental treatment costs. The route is as follows:
[0006]
[0007] (2) The synthetic routes disclosed in patents CN10373960, CN111072656, and WO2021135891 require the use of relatively expensive aminoacetaldehyde dimethyl acetal as a raw material, and the amount used is large (more than 2 equivalents), which is not conducive to cost control in large-scale production of praziquantel. The routes are as follows:
[0008]
[0009] (3) Patent CN115466261 discloses a synthetic route, which is relatively long and uses a large number of raw materials. In particular, it involves the selective reduction of amides using expensive and dangerous stoichiometric sodium borohydride (NaBH4) reducing agent, which is not conducive to large-scale production and cost control of praziquantel. The route is as follows:
[0010] Summary of the Invention
[0011] To address the shortcomings of the existing technology, this invention provides a method for synthesizing praziquantel. This invention uses readily available and inexpensive glycine and cyclohexyl chloride as starting materials to synthesize cyclohexylglycine. Then, through a photocatalytic free radical deacidification Minisci reaction strategy, cyclohexylglycine is reacted with isoquinoline to efficiently prepare the key intermediate N-(1-isoquinoline-1-ylmethyl)-cyclohexylcarboxamide, finally synthesizing praziquantel.
[0012] To achieve the above objectives, the specific technical solution of the present invention is as follows:
[0013] A method for synthesizing praziquantel includes the following steps:
[0014] (1) Glycine is reacted with cyclohexyl chloride to obtain cyclohexylglycine, and the reaction formula is as follows:
[0015] ;
[0016] (2) Cyclohexanoylglycine and isoquinoline were reacted under light irradiation in the presence of a photocatalyst and ammonium persulfate to obtain N-(1-isoquinoline-1-ylmethyl)-cyclohexanoamide, as shown in the following reaction formula:
[0017] ;
[0018] (3) N-(1-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide was hydrogenated to obtain N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexanecarboxamide, as shown in the following reaction formula:
[0019] ;
[0020] (4) N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexaneamide was reacted with chloroacetyl chloride to form cyclohexane to obtain praziquantel, as shown in the following reaction formula:
[0021] .
[0022] Preferably, in step (1), the glycine reacts with cyclohexyl chloride in the presence of a base to obtain cyclohexylglycine, wherein the base includes potassium phosphate.
[0023] Preferably, the molar ratio of glycine, cyclohexyl chloride, and base is 1:(1.05-1.2):(1.5-3).
[0024] Preferably, step (1) is performed as follows: cyclohexyl chloride and base are mixed in tetrahydrofuran, and glycine is added and reacted at room temperature; after the reaction is completed, water is added to quench the reaction, and the mixture is extracted, washed with water, dried and concentrated to obtain cyclohexylglycine.
[0025] Preferably, in step (2), the molar ratio of isoquinoline, cyclohexylglycine, photocatalyst, and ammonium persulfate is 1:(1.5-3):(0.0001-0.0005):(2-3).
[0026] Preferably, in step (2), the photocatalyst comprises [Ir(dF(CF3)ppy)2(dtbbpy)]PF6.
[0027] Preferably, in step (2), the light is blue light.
[0028] Preferably, step (2) is performed as follows: cyclohexylglycine, isoquinoline, photocatalyst, and ammonium persulfate are mixed in dimethyl sulfoxide under an inert gas atmosphere and reacted under blue light irradiation at room temperature; after the reaction is completed, dichloromethane is added for dilution, followed by washing with saturated sodium bicarbonate aqueous solution, washing with saturated brine, drying, concentration, and purification to obtain N-(1-isoquinoline-1-ylmethyl)-cyclohexylcarboxamide.
[0029] Preferably, step (3) is performed as follows: N-(1-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide is dissolved in methanol and glacial acetic acid, Pt / C is added, and the reaction is carried out under a hydrogen pressure of 5-8 bar at 60-80 °C; after the reaction is completed, the reaction solution is filtered, alkalized, extracted, dried and concentrated to obtain N-(1,2,3,4-tetrahydro-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide.
[0030] Preferably, the mass ratio of N-(1-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide to Pt / C is 1:(0.02-0.05); and the volume ratio of methanol to glacial acetic acid is 10:(0.1-0.5).
[0031] Preferably, in step (4), N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexaneamide is reacted with chloroacetyl chloride in the presence of a base to obtain praziquantel, wherein the base includes sodium bicarbonate.
[0032] Preferably, the molar ratio of N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexanecarboxamide, chloroacetyl chloride, and base is 1:(1.05-1.3):(2-3).
[0033] Preferably, step (4) is performed as follows: N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexanecarboxamide and base are mixed in ethyl acetate, and then chloroacetyl chloride is added dropwise to the system. After the addition is complete, the reaction is carried out at room temperature first, and then heated to reflux conditions for further reaction. After the reaction is completed, the mixture is cooled, filtered to remove insoluble matter, washed with water, dried, and concentrated to obtain praziquantel.
[0034] Compared with the prior art, the advantages of the present invention are:
[0035] This invention utilizes a photocatalytic free radical deacidification Minisci reaction as a key step to synthesize praziquantel, providing an important basis and method for reducing the cost of large-scale industrial production of praziquantel. Compared with existing technologies, the synthesis method of this invention has advantages such as inexpensive and readily available raw materials, simple and safe reaction operation, mild reaction conditions, low photocatalyst dosage (as low as 0.01 mol%), simple post-reaction processing, and high yield, providing a novel and possible solution for the industrial-scale preparation of praziquantel. Attached Figure Description
[0036] Figure 1 The 1H NMR spectrum of cyclohexylglycine;
[0037] Figure 2 The image shows the carbon NMR spectrum of cyclohexanoylglycine.
[0038] Figure 3 The 1H NMR spectrum of N-(1-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide;
[0039] Figure 4 The carbon NMR spectrum of N-(1-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide;
[0040] Figure 5 The image shows the 1H NMR spectrum of praziquantel.
[0041] Figure 6 This is the carbon NMR spectrum of praziquantel. Detailed Implementation
[0042] To enable those skilled in the art to clearly and completely understand the technical solution of the present invention, the present invention will be further described in detail below with reference to embodiments. Obviously, the embodiments described herein are only for explaining the present invention and are not intended to limit the scope of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.
[0043] Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art. Unless otherwise specified, the reagents, methods and equipment used in this invention are conventional reagents, methods and equipment in the art.
[0044] This invention provides a method for synthesizing praziquantel, comprising the following steps:
[0045] (1) Glycine is reacted with cyclohexyl chloride to obtain cyclohexylglycine, and the reaction formula is as follows:
[0046] ;
[0047] In some examples, the glycine reacts with cyclohexyl chloride in the presence of a base to yield cyclohexylglycine, wherein the base includes potassium phosphate; the molar ratio of glycine, cyclohexyl chloride, and base is 1:(1.05-1.2):(1.5-3).
[0048] (2) Cyclohexanoylglycine and isoquinoline were reacted under blue light in the presence of a photocatalyst and ammonium persulfate to obtain N-(1-isoquinoline-1-ylmethyl)-cyclohexanoamide, as shown in the following reaction formula:
[0049] ;
[0050] In some examples, the molar ratio of isoquinoline, cyclohexylglycine, photocatalyst, and ammonium persulfate is 1:(1.5-3):(0.0001-0.0005):(2-3); the photocatalyst comprises [Ir(dF(CF3)ppy)2(dtbbpy)]PF6.
[0051] (3) N-(1-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide was hydrogenated under Pt / C catalysis to obtain N-(1,2,3,4-tetrahydro-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide, and the reaction formula is as follows:
[0052] ;
[0053] In some examples, the mass ratio of N-(1-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide to Pt / C is 1:(0.02-0.05).
[0054] (4) N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexaneamide was reacted with chloroacetyl chloride to form cyclohexane to obtain praziquantel, as shown in the following reaction formula:
[0055] .
[0056] In some examples, N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexaneformamide is subjected to a cyclization reaction with chloroacetyl chloride in the presence of a base to obtain praziquantel, wherein the base includes sodium bicarbonate; the molar ratio of N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexaneformamide, chloroacetyl chloride, and the base is 1:(1.05-1.3):(2-3).
[0057] Example 1
[0058] A synthetic method for praziquantel, the route is as follows:
[0059]
[0060] Step 1: Synthesis of cyclohexanoylglycine
[0061] Add a magnetic stir bar to a clean 250 mL single-necked round-bottom flask, weigh out cyclohexyl chloride (6.46 g) and potassium phosphate (21.2 g) and add them to the flask, add 100 mL of dry tetrahydrofuran, and then add glycine (3.0 g). Stir at room temperature for 24 hours to allow the reaction to proceed.
[0062] After the reaction was complete, the mixture was quenched with 100 mL of water and 100 mL of ethyl acetate. The mixture was separated, and the ethyl acetate organic phase was extracted three times with water (50 mL × 3). The organic phase was discarded, and the aqueous phases were combined and the pH was adjusted to approximately 2 with concentrated hydrochloric acid. The acidified aqueous phase was extracted three times with ethyl acetate (150 mL × 3). The ethyl acetate organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and the organic phase was concentrated under vacuum to give 7.05 g (95% yield) of a white solid cyclohexylglycine.
[0063] The NMR spectra of praseodymium hydrogen and carbon atoms of cyclohexylglycine are as follows: Figure 1 , Figure 2 As shown, the spectral analysis is as follows: ¹H NMR (500 MHz, DMSO-d⁶) δ 12.46 (br, 1H), 7.99 (t, J = 4.5 Hz, 1H), 3.69 (d, J = 5.0 Hz, 2H), 2.14 (t, J = 11.0 Hz, 1H), 1.69 (d, J = 11.0 Hz, 4H), 1.60 (d, J = 11.0 Hz, 1H), 1.30 (q, J = 11.0 Hz, 2H), 1.24–1.12 (m, 3H). ¹³C NMR (125 MHz, DMSO-d⁶) δ 175.6, 171.6, 43.7, 40.5, 29.2, 25.5, 25.3.
[0064] Step 2: Synthesis of N-(1-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide
[0065] A magnetic stir bar was added to a clean 250 mL Schlenk flask. The photocatalyst [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (3.4 mg), ammonium persulfate (13.69 g), isoquinoline (3.88 g), and cyclohexylglycine (8.34 g) were weighed and added to the reaction flask. The flask was connected to a double-row tube, and three "vacuum-nitrogen purging" cycles were performed to displace the air in the tubes. Under nitrogen protection, 100 mL of dry dimethyl sulfoxide was added to dissolve the flask, which was then sealed and irradiated under a 40 W 456 nm blue LED light source with stirring for 3 hours. After the reaction, the reaction solution was diluted with 150 mL of dichloromethane and washed with excess saturated sodium bicarbonate aqueous solution to remove unreacted cyclohexylglycine. The aqueous phase was extracted three times with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and the organic phase was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting: petroleum ether / ethyl acetate = 6:1 → 2:1 gradient elution), finally yielding 7.41 g (92% yield) of white solid N-(1-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide.
[0066] The NMR spectra of N-(1-isoquinoline-1-yl-methyl)-cyclohexanecarboxamide are as follows: (1H NMR praseodymium and 1C NMR spectra are shown below) Figure 3 and Figure 4 As shown, the spectrum analysis is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 5.6 Hz, 1H), 8.10 (d, J =8.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.65-7.58 (m, 3H), 5.04 (d, J = 3.6 Hz, 2H), 2.35-2.27 (m, 1H), 1.99 (d, J = 13.2 Hz, 2H), 1.84-1.81 (m, 2H), 1.71 (d, J = 9.2 Hz,1H), 1.59-1.50 (m, 2H), 1.38-1.24 (m, 3H). 13 C NMR (100 MHz, CDCl3) δ176.1, 154.7, 140.8, 135.9, 130.4, 127.7, 127.3, 125.8, 123.8, 120.3, 45.5, 41.8, 29.7, 25.8.
[0067] Step 3: Synthesis of N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexanecarboxamide
[0068] In a clean 250 mL single-necked round-bottom flask with a magnetic stir bar, weigh out 7.0 g of N-(1-isoquinoline-1-yl-methyl)-cyclohexanecarboxamide and dissolve it in 70 mL of methanol and 0.7 mL of glacial acetic acid. Then add 0.2 g of wet Pt / C (5 wt%), apply hydrogen pressure at 5 bar, and stir at 60 °C for 10 hours. After the reaction is complete, cool the reaction system to room temperature, vent the gas, filter the reaction solution, and concentrate the filtrate under vacuum. Dissolve the residue in 100 mL of dichloromethane and alkalinize the pH to 12-13 with 5% sodium hydroxide aqueous solution. After phase separation, the aqueous phase was extracted three times with dichloromethane (50 mL × 3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered to remove sodium sulfate, and the organic phase was concentrated under vacuum to give 6.21 g (88% yield) of pale yellow solid N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexaneformamide.
[0069] Step 4: Praziquantel Synthesis
[0070] In a 100 mL two-necked round-bottom flask equipped with a reflux condenser and a magnetic stirrer, N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexanecarboxamide (6.21 g), sodium bicarbonate (4.8 g), and 40 mL of ethyl acetate were added. After stirring until homogeneous, chloroacetyl chloride (2.83 g) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 5 hours, and then heated to 80 °C and stirred for another 5 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove insoluble matter, and the ethyl acetate layer was washed successively with water and saturated brine. The layer was dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and concentrated under vacuum to obtain 6.4 g (90% yield) of a white solid praziquantel.
[0071] The NMR spectra of praseodymium hydrogen and carbon atoms of praziquantel are as follows: Figure 5 , Figure 6As shown, the spectral resolution is as follows: ¹H NMR (500MHz, CDCl₃) δ 7.29-7.18 (m, 4H), 5.17-4.80 (m, 3H), 4.49-4.37 (m, 1H), 4.10-3.84 (m, 1H), 3.28-2.77 (m, 4H), 2.58-2.45 (m, 1H), 1.82-1.48 (m, 7H), 1.39-1.24 (m, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 174.6, 174.1, 165.4, 164.2, 135.4, 134.6, 132.6, 132.0, 129.5, 129.1, 127.5, 127.3, 126.8, 125.3, 125.0, 55.6, 54.8, 49.4, 48.8, 46.1, 45.0, 40.6, 38.9, 38.5, 29.4, 29.1, 28.8, 28.7, 28.6, 25.5.
[0072] The above detailed embodiments describe the implementation of the present invention; however, the present invention is not limited to the specific details described in the above embodiments. Within the scope of the claims and technical concept of the present invention, various simple modifications and changes can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.
Claims
1. A method for synthesizing praziquantel, characterized in that, Includes the following steps: (1) Glycine is reacted with cyclohexyl chloride to obtain cyclohexylglycine, and the reaction formula is as follows: ； (2) Cyclohexanoylglycine and isoquinoline were reacted under light irradiation in the presence of a photocatalyst and ammonium persulfate to obtain N-(1-isoquinoline-1-ylmethyl)-cyclohexanoamide, as shown in the following reaction formula: ； (3) N-(1-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide was hydrogenated to obtain N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexanecarboxamide, as shown in the following reaction formula: ； (4) N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexaneamide was reacted with chloroacetyl chloride to form cyclohexane to obtain praziquantel, as shown in the following reaction formula: 。 2. The method for synthesizing praziquantel according to claim 1, characterized in that, In step (1), the glycine reacts with cyclohexyl chloride in the presence of a base to obtain cyclohexylglycine, wherein the base includes potassium phosphate.
3. The method for synthesizing praziquantel according to claim 2, characterized in that, The molar ratio of glycine, cyclohexyl chloride, and base is 1:(1.05-1.2):(1.5-3).
4. The method for synthesizing praziquantel according to claim 1, characterized in that, In step (2), the molar ratio of isoquinoline, cyclohexylglycine, photocatalyst, and ammonium persulfate is 1:(1.5-3):(0.0001-0.0005):(2-3).
5. The method for synthesizing praziquantel according to claim 4, characterized in that, The photocatalyst comprises [Ir(dF(CF3)ppy)2(dtbbpy)]PF6.
6. The method for synthesizing praziquantel according to claim 1, characterized in that, In step (2), the light is blue light.
7. The method for synthesizing praziquantel according to claim 1, characterized in that, Step (3) is performed as follows: N-(1-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide is dissolved in methanol and glacial acetic acid, Pt / C is added, and the reaction is carried out under a hydrogen pressure of 5-8 bar at 60-80 °C. After the reaction is completed, the reaction solution is filtered, alkalized, extracted, dried and concentrated to obtain N-(1,2,3,4-tetrahydro-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide.
8. The method for synthesizing praziquantel according to claim 7, characterized in that, The mass ratio of N-(1-isoquinoline-1-ylmethyl)-cyclohexanecarboxamide to Pt / C is 1:(0.02-0.05), and the volume ratio of methanol to glacial acetic acid is 10:(0.1-0.5).
9. The method for synthesizing praziquantel according to claim 1, characterized in that, In step (4), N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexaneamide is reacted with chloroacetyl chloride in the presence of a base to obtain praziquantel, wherein the base includes sodium bicarbonate.
10. A method for synthesizing praziquantel according to claim 9, characterized in that, The molar ratio of N-(1,2,3,4-tetrahydro-isoquinoline-1-yl-methyl)-cyclohexanecarboxamide, chloroacetyl chloride, and base is 1:(1.05-1.3):(2-3).