CN100503582C - Praziquantel synthetic process - Google Patents
Praziquantel synthetic process Download PDFInfo
- Publication number
- CN100503582C CN100503582C CNB2005100379112A CN200510037911A CN100503582C CN 100503582 C CN100503582 C CN 100503582C CN B2005100379112 A CNB2005100379112 A CN B2005100379112A CN 200510037911 A CN200510037911 A CN 200510037911A CN 100503582 C CN100503582 C CN 100503582C
- Authority
- CN
- China
- Prior art keywords
- praziquantel
- reaction
- synthetic process
- synthetic
- condensation reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The improved praziquantel synthesizing process has beta-phenylethylamine, aminoacetyl halide hydrochloride, halogeno acetal and cyclohexyl formyl chloride as material and includes condensation, cyclization and acylation. The improved praziquantel synthesizing process has the features of low cost, easy-to-obtain material, low toxicity, high production safety, simple technological process, etc.
Description
Technical field
The invention relates to the improvement to Praziquantel synthetic process, specifically a kind of technology is succinct, raw material is easy to get, and toxicity is low, operational safety, pollution is little, yield is high Praziquantel synthetic process.
Background technology
Praziquantel (praziquantel) is a kind of universality medicine for parasitic disease, it all has killing action to Schistosoma japonicum, Schistosoma haematobium, Schistosoma mansoni, paragonimus (lung fluke), clonorchis sinensis, Echinococcus hydatid cyst, cysticercus, Meng Shi pleroceroid, fasciloopsis, tapeworm etc., has become the choice drug of the multiple parasitosis of treatment now.
The disclosed preparation Praziquantel synthetic process of German patent DE 2504250 and DE2508947; be to be main raw material with isoquinoline 99.9, potassium cyanide, Benzoyl chloride, chloroacetyl chloride and cyclohexanecarbonyl chloride etc.; by reaction shown in Figure 1, make praziquantel through steps such as acidylate, nitrogenize, shortening, basic hydrolysis, acidylate, cyclization, alkaline hydrolysis, acidylates.This technology exists yield on the low side, only is about 15%, and because of adopting the prussiate raw material, production process toxicity is big, and produces to the high-pressure hydrogenation operation, and is greatly dangerous, the process complexity, and three wastes discharge amount is big, the cost height.
U.S. Pat 4523013 disclosed preparation Praziquantel synthetic process; with diacetonitrile amine, cyclohexanecarbonyl chloride, Sodium Nitrite, sodium borohydride, Beta-bromo ethylbenzene, oxammonium hydrochloride is main raw material; by reaction shown in Figure 2, make praziquantel through reactions such as acidylate, hydroxylamination, diazotization, hydrocarbylation and chemical reduction, cyclisation.The raw materials used toxicity of this technology descends to some extent, and operational condition relaxes, and total recovery can be increased to 35%.Yet sodium borohydride is inflammable and explosive, it is relatively more dangerous to use, and diacetonitrile amine raw material is rare, and because of diacetonitrile amine and sodium borohydride large usage quantity, causes cost higher, thereby has seriously limited the industrial applications of this technology.
It is the synthetic praziquantel technology of raw material that Korean Patent KR2002076486 proposes with β-phenylethylamine, chloroacetyl chloride, aminoacetaldehyde dimethyl acetal and cyclohexanecarbonyl chloride.Yet also exist chloroacetyl chloride extremely unstable, and toxicity is big, operation with use relative dangerously, and it is lower because of the too big selectivity of activity during with β-phenylethylamine condensation, causes yield control difficult.The aminoacetaldehyde dimethyl acetal price is higher, and reactive behavior is low, needs to react under comparatively high temps, and can cause more side reaction.These all are unfavorable for suitability for industrialized production.
Summary of the invention
The objective of the invention is to overcome the deficiency of above-mentioned prior art, provide that a kind of technology is succinct, raw material is easy to get toxicity is low, operational safety, pollution is little, yield is high Praziquantel synthetic process.
The object of the invention realizes that main the improvement is that employing is a raw material with β-phenylethylamine, glycyl halogen hydrochlorate, halo acetaldehyde acetal and cyclohexanecarbonyl chloride, through condensation, cyclisation, the synthetic praziquantel of acidylate, synthetic route such as Fig. 3.Specifically, Praziquantel synthetic process of the present invention is characterized in that:
The first step is carried out condensation reaction by β-phenylethylamine and glycyl halogen hydrochlorate, and generate intermediate A: N-β-styroyl amino acetamide, setting-up point are-20 ℃~80 ℃;
Second step under alkaline condition, was carried out condensation reaction generation intermediate B: N-(2-phenyl) ethyl-2-[(acetaldehyde acetal with gained intermediate A and halo acetaldehyde acetal) amino] ethanamide, setting-up point is 0~150 ℃;
The 3rd step generated intermediate C:4-carbonyl-1,2,3,6,7 with the cyclisation under an acidic catalyst catalysis of gained intermediate B, 11b-six hydrogen-4H-pyrazinyl [2,1-a] isoquinoline 99.9, and the cyclisation temperature is-10 ℃~100 ℃;
The 4th step is with intermediate C and encircle formyl chloride, generates the target product praziquantel-10 ℃~60 ℃ reactions.
Halogen element in the glycyl halogen hydrochlorate of the present invention, a kind of Cl, Br, I that adopts in the halogen element that be preferably, raw material is easy to get, and reaction is carried out easily.Halogen element in the said halo acetaldehyde acetal is preferably Cl, the Br, the I that adopt in the halogen element equally.Its acetal can be common alcohols, wherein is preferably to adopt C1-C8 alcohol, especially C1-C4 alcohol, and it is refining to adopt low-carbon alcohol more to help subsequent product.
For making condensation reaction that higher yield be arranged, reaction is thorough, and the first step condensation reaction and the 4th step building-up reactions better are to carry out under alkaline condition.The 4th step is synthetic better to be to carry out in polar aprotic solvent, as carrying out in halohydrocarbon, low-carbon (LC) ethers, methyl-sulphoxide, the dimethyl formamide etc., is good with halohydrocarbon again wherein, and favourable reaction is easy to recovery of applied.
Alkaline condition of the present invention is the employed basic cpd of reaction down, can be organic basic compound, for example as triethylamine, pyridine, β-phenylethylamine, nitrogenous organic base etc., also can be inorganic alkaline compound, for example as CaO, MgO, Na
2CO
3, NaHCO
3, KOH, NaOH, K
2CO
3, KHCO
3, Na
2O etc.Wherein in the first step condensation to adopt the moderate NaHCO of base strength
3For good, to adopt higher NaOH or the Na2CO3 of base strength, be better to adopt Na2CO3, K2CO3 in the 4th step acidylate is synthetic in the second step condensation, the synthetic Semi-polarity aprotic solvent of the 4th step acidylate is a halon.
Condensation reaction of the present invention, cyclization better are to carry out in polar solvent (for example halohydrocarbon, aromatic hydrocarbons, alcohols, ethers, methyl-sulphoxide, tetrahydrofuran (THF) etc.), so more help the carrying out that react, wherein the first step condensation employing aromatic hydrocarbons preferably and halohydrocarbon, second step condensation employing alcohols preferably and the aromatic hydrocarbons.
Said an acidic catalyst of the 3rd step can be the strongly-acid organic acid, as formic acid, acetate etc.Also can be the strongly-acid inorganics, as sulfuric acid, hydrochloric acid, phosphoric acid, heteropolyacid, load-type solid acid and strong-acid ion exchange resin etc.The present invention better adopts the vitriol oil, heteropolyacid and strong-acid ion exchange resin, especially liquid acid.
For reaction is had than highly selective and yield, reaction mass is fully used, the first step condensation reaction β-phenylethylamine, glycyl halogen hydrochlorate, basic cpd equivalence ratio are preferably 1:1:1.2~1:1.6:5, more preferably 1:1.2:1.8~1:1.4:3.0.Suitable temperature of reaction is-5 ℃~15 ℃.Reaction times 0.5h~5h.The second step condensation reaction intermediate A, halo acetaldehyde acetal, basic cpd equivalence ratio are preferably 1:1:1.3~1:1.5:4.5, more preferably 1:1.1:1.5~1:1.4:3.0.Suitable temperature of reaction is 20~100 ℃.Reaction times 0.5~4h.The mass ratio of the 3rd step cyclization intermediate B and an acidic catalyst is preferably 1:0.1~1:3, wherein is more preferably 1:0.5~1:2.Suitable temperature of reaction is 10~40 ℃.Reaction times 2~6h.The 4th step building-up reactions intermediate C, cyclohexanecarbonyl chloride, basic cpd equivalence ratio are preferably 1:1:1.3~1:1.5:5, more preferably 1:1.1:1.5~1:1.4:3.0.Suitable temperature of reaction is 5~30 ℃.Reaction times 0.5~5h.
The more above-mentioned prior art preparation technology of the present invention makes raw material because of adopting β-phenylethylamine, glycyl halogen hydrochlorate, halo acetaldehyde acetal, cyclohexanecarbonyl chloride, have raw material inexpensive, be easy to get, low toxicity, production safety, technology are simple; Glycyl halogen hydrochlorate and β-phenylethylamine condensation, activity is moderate and yield is higher; The reaction of halo acetaldehyde acetal and intermediate A, because of halogen wherein is easy to remove, reaction is easy to carry out, and also is favourable to improving yield; Secondly, synthetic reaction condition of the present invention relaxes, atmospheric operation, and operational safety, synthesis step is succinct, and total recovery can surpass 50%; And the building-up process effluent discharge is few, pollutes for a short time, is a kind of clean and effective synthesis technique, and production cost can reduce about 30%.
Below in conjunction with several embodiments, further specify the present invention
Description of drawings
Fig. 1: German patent DE 2504250 and DE2508947 praziquantel synthetic route sketch plan.
Fig. 2: U.S. Pat 4523013 praziquantel synthetic route sketch plans.
Fig. 3: praziquantel synthetic route sketch plan of the present invention.
Embodiment
Embodiment 1:
The preparation of intermediate A: in reaction flask, add 61.0g β-phenylethylamine (0.5mol) and 138gNaHCO
3(1.3mol) and the 300ml methylene dichloride, ice bath to 0 ℃, under well-beaten situation to wherein slowly adding 77.5g glycyl villaumite hydrochlorate (0.6mol), in the reinforced process, controlled temperature is about 5 ℃, and feeding in raw material finishes, continuation is stirred 1h at 15 ℃, react and finish the back adds 0~5 ℃ in reaction water 200ml, fully stirring, layering, the anhydrous MgSO of oil reservoir
4After the drying, suction filtration, boil off solvent, obtain light brown solid 79.6g, high pressure liquid chromatographic analysis (HPLC) purity 97.6%, the intermediate A yield is 87.3%, MS:m/z:178,164,122,107,71.
The preparation of intermediate B: in reaction flask, add 54.7g (97.6%, 0.3mol) intermediate A, 64g Na
2CO
3With 200ml ethanol, fully be stirred under the room temperature and drip 41g monochloroacetaldehyde dimethyl acetal in half an hour, (78~80 ℃) reaction 1.5h then refluxes, reaction is cooled to 10 ℃ with reactant, in reaction mixture impouring 500ml frozen water after finishing, obtain light brown oily thing, MgSO
4Dry, suction filtration gets product 69g, and the HPLC purity assay is 94.8%, and yield is 82%, MS:m/z:234 (M
+-CH
3OH), 191,134,118,105,86,75.
The preparation of intermediate C: in reaction flask, add 56.2g (94.8%, 0.2mol) intermediate B, 200ml methylene dichloride, below the ice-water bath to 5 ℃, add heteropolyacid (H3PW12040) 20g under the violent stirring, continue then at stirring at room reaction 4h, after reaction finishes, in reactant impouring mixture of ice and water, it is 11~12 that the NaOH solution with 20% is regulated PH, tells organic layer, water layer is used MgSO with 2 * 100ml dichloromethane extraction
4Dry, steam solvent, the solids recrystallizing methanol that obtains obtains white crystal 38.3g, M.P.117~119 ℃, the HPLC purity assay is 99.6%, intermediate C yield is 94.4%.MS:m/z:202,173,145,131,117,103,77。
Purpose product praziquantel preparation: in reaction flask, add 21g K
2CO
3(0.15mol), 21g intermediate C (0.1mol) and 60ml methylene dichloride, ice bath drips 16g cyclohexanecarbonyl chloride (0.11mol) down, after dropwising, at stirring at room reaction 2.5h, adds 50mlH then in reaction flask
2O tells organic layer, uses anhydrous MgSO
4Dry, steam solvent, the solid recrystallization in ether and hexane (1:1) with obtaining obtains light yellow solid 26.8g, the HPLC purity assay is 99.5%, the praziquantel yield is 85.5%.MS:m/z:312,201,185,173,145,132,113,83,55。
From β-phenylethylamine be: 57.7% to the praziquantel total recovery.
Embodiment 2:
The preparation of intermediate A: in reaction flask, add 61.0g β-phenylethylamine (0.5mol) and 138g NaHCO
3(1.3mol) and the 300ml orthodichlorobenzene, ice bath to 0 ℃, under well-beaten situation to wherein slowly adding 65g glycyl villaumite hydrochlorate (0.5mol), in the reinforced process, controlled temperature is about 5 ℃, and feeding in raw material finishes, continuation is stirred 1h at 15 ℃, react and finish the back adds 0~5 ℃ in reaction water 200ml, fully stirring, layering, the anhydrous MgSO of oil reservoir
4After the drying, suction filtration, boil off solvent, obtain light brown solid 72.3g, high pressure liquid chromatographic analysis (HPLC) purity 96.2%, the intermediate A yield is 78.1%, MS:m/z:178,164,122,107,71.
The preparation of intermediate B: in reaction flask, add 55.5g (96.2%, 0.3mol) intermediate A, 64g Na
2CO
3With 200ml ethanol, fully be stirred in Dropwise 5 6g bromoacetaldehyde dimethyl acetal in half an hour under the room temperature, continue at room temperature to react 3.0h, reaction is cooled to 10 ℃ with reactant after finishing, and in reaction mixture impouring 500ml frozen water, obtains light brown oily thing, MgSO
4Dry, decompression desolventizing gets product 71.3g, and the HPLC purity assay is 96.3%, and yield is 86.0%, MS:m/z:234 (M+-CH3OH), 191,134,118,105,86,75.
The preparation of intermediate C: in reaction flask, add 55.9g (95.2%, 0.2mol) intermediate B, 250ml ethylene dichloride, below the ice-water bath to 5 ℃, drip vitriol oil 70ml under the violent stirring, drip off the back and continue at stirring at room reaction 4h, after reaction finishes, in reactant impouring mixture of ice and water, it is 11~12 that the NaOH solution with 20% is regulated PH, tells organic layer, water layer is used MgSO with the extraction of 2 * 100ml ethylene dichloride
4Dry, steam solvent, the solids recrystallizing methanol that obtains obtains white crystal 37.6g, M.P.117~119 ℃, the HPLC purity assay is 99.5%, intermediate C yield is 92.6%.MS:m/z:202,173,145,131,117,103,77。
Purpose product praziquantel preparation: in reaction flask, add 21g K
2CO
3(0.15mol), 21g intermediate C (0.1mol) and 60ml chloroform, ice bath drips 17.6g cyclohexanecarbonyl chloride (0.12mol) down, after dropwising, at stirring at room reaction 2.0h, adds 60mlH then in reaction flask
2O tells organic layer, uses anhydrous MgSO
4Dry, steam solvent, the solid recrystallization in ether and hexane (1:1) with obtaining obtains light yellow solid 25.6g, the HPLC purity assay is 99.6%, the praziquantel yield is 81.7%.MS:m/z:312,201,185,173,145,132,113,83,55。
From β-phenylethylamine be: 50.8% to the praziquantel total recovery.
Embodiment 3:
The preparation of intermediate A: in reaction flask, add 61.0g β-phenylethylamine (0.5mol) and 138g NaHCO
3(1.3mol) and the 300ml orthodichlorobenzene, ice bath to 0 ℃, under well-beaten situation to wherein slowly adding 65g glycyl villaumite hydrochlorate (0.5mol), in the reinforced process, controlled temperature is about 5 ℃, and feeding in raw material finishes, continuation is stirred 1h at 15 ℃, react and finish the back adds 0~5 ℃ in reaction water 200ml, fully stirring, layering, the anhydrous MgSO of oil reservoir
4After the drying, suction filtration, boil off solvent, obtain light brown solid 72.3g, high pressure liquid chromatographic analysis (HPLC) purity 96.2%, the intermediate A yield is 78.1%, MS:m/z:178,164,122,107,71.
The preparation of intermediate B: in reaction flask, add 55.5g (96.2%, 0.3mol) intermediate A, 64g Na
2CO
3With 200ml toluene, fully be stirred under the room temperature and drip 40g monochloroacetaldehyde dimethyl acetal in half an hour, (110~112 ℃) reaction 1.0h then refluxes, reaction is cooled to 10 ℃ with reactant, in reaction mixture impouring 500ml frozen water after finishing, obtain light brown oily thing, MgSO
4Dry, decompression desolventizing gets product 67.5g, and the HPLC purity assay is 95.2%, and yield is 80.5%, MS:m/z:234 (M
+-CH
3OH), 191,134,118,105,86,75.
The preparation of intermediate C: in reaction flask, add 55.9g (95.2%, 0.2mol) intermediate B, 250ml ether, below the ice-water bath to 5 ℃, drip vitriol oil 70ml under the violent stirring, drip off the back and continue at stirring reaction 4h below 5 ℃, after reaction finishes, in reactant impouring mixture of ice and water, it is 11~12 that the NaOH solution with 20% is regulated PH, tells organic layer, water layer is used MgSO with 2 * 100ml extracted with diethyl ether
4Dry, steam solvent, the solids recrystallizing methanol that obtains obtains white crystal 31.3g, M.P.117~119 ℃, the HPLC purity assay is 99.4%, intermediate C yield is 77.0%.MS:m/z:202,173,145,131,117,103,77。
Purpose product praziquantel preparation: in reaction flask, add 27.6g K
2CO
3(0.0.2mol), 21g intermediate C (0.1mol) and 60ml chloroform, ice bath drips 17.6g cyclohexanecarbonyl chloride (0.12mol) down, after dropwising, at stirring at room reaction 2.0h, adds 60mlH then in reaction flask
2O tells organic layer, uses anhydrous MgSO
4Dry, steam solvent, the solid recrystallization in ether and hexane (1:1) with obtaining obtains light yellow solid 26.1g, the HPLC purity assay is 99.5%, the praziquantel yield is 83.2%.MS:m/z:312,201,185,173,145,132,113,83,55。
From β-phenylethylamine be: 40.3% to the praziquantel total recovery.
The preparation of intermediate A: in reaction flask, add 61.0g β-phenylethylamine (0.5mol) and 150ml orthodichlorobenzene, ice bath to 0 ℃, to wherein slowly adding 77.5g glycyl villaumite hydrochlorate (0.6mol), in the reinforced process, controlled temperature is about 10 ℃ under well-beaten situation, reinforced finishing, continuation is stirred 4h at 55 ℃, and reaction finishes the back adds 0~5 ℃ in reaction water 200ml, regulates pH8~9 with NaOH, fully stirring, layering, the anhydrous MgSO of oil reservoir
4After the drying, suction filtration, boil off solvent, obtain light brown solid 68.5g, high pressure liquid chromatographic analysis (HPLC) purity 95.8%, the intermediate A yield is 73.7%, MS:m/z:178,164,122,107,71.
The preparation of intermediate B: in reaction flask, add 55.7g (95.8%, 0.3mol) intermediate A, 64g Na
2CO
3With 200ml ethanol, fully be stirred under the room temperature and drip 70g monochloroacetaldehyde two butanols that contract in half an hour, then back flow reaction 2.0h, reaction is cooled to 10 ℃ with reactant after finishing, and in reaction mixture impouring 500ml frozen water, obtains light brown oily thing, MgSO
4Dry, suction filtration gets product 71.6g, and the HPLC purity assay is 93.6%, and yield is 84.0%, MS:m/z:234 (M
+-CH
3OH), 191,134,118,105,86,75.
The preparation of intermediate C: in reaction flask, add 56.8g (93.6%, 0.2mol) intermediate B, below the ice-water bath to 5 ℃, slowly splash into vitriol oil 40g under the violent stirring, continue then at 40 ℃ of stirring reaction 4h, after reaction finishes, in reactant impouring mixture of ice and water, it is 11~12 that the NaOH solution with 20% is regulated PH, tells organic layer, water layer is used MgSO with 2 * 100ml dichloromethane extraction
4Dry, steam solvent, the solids recrystallizing methanol that obtains obtains white crystal 32.7g, M.P.117~119 ℃, the HPLC purity assay is 99.5%, intermediate C yield is 80.5%.MS:m/z:202,173,145,131,117,103,77。
Purpose product praziquantel preparation: in reaction flask, add 27g K
2CO
3(0.2mol), 20.3g intermediate C (0.1mol) and 100ml methylene dichloride, ice bath drips 16g cyclohexanecarbonyl chloride (0.14mol) down, after dropwising, at 5 ℃ of stirring reaction 5h, adds 100mlH then in reaction flask
2O tells organic layer, uses anhydrous MgSO
4Dry, steam solvent, the solid recrystallization in ether and hexane (1:1) with obtaining obtains light yellow solid 29.2g, the HPLC purity assay is 99.6%, the praziquantel yield is 93.2%.MS:m/z:312,201,185,173,145,132,113,83,55。
From β-phenylethylamine be: 46.4% to the praziquantel total recovery.
The preparation of intermediate A: in reaction flask, add 61.0g β-phenylethylamine (0.5mol) and 150ml orthodichlorobenzene, ice bath to 0 ℃, under well-beaten situation to wherein slowly adding 104g glycyl bromine hydrochloride (0.6mol), in the reinforced process, controlled temperature is about 5 ℃, and reinforced finishing continues to stir 4h at 30 ℃, reaction finishes the back adds 0~5 ℃ in reaction water 250ml, uses Na
2CO
3Regulate pH8~9, fully stirring, layering, the anhydrous MgSO of oil reservoir
4After the drying, suction filtration, boil off solvent, obtain light brown solid 81.4g, high pressure liquid chromatographic analysis (HPLC) purity 96.1%, the intermediate A yield is 87.9%, MS:m/z:178,164,122,107,71.
All the other are with embodiment 1.
From β-phenylethylamine be: 58.1% to the praziquantel total recovery.
The preparation of intermediate A: in reaction flask, add 61.0g β-phenylethylamine (0.5mol), cryostat is to-18 ℃, under well-beaten situation to wherein slowly adding 77.5g glycyl villaumite hydrochlorate (0.6mol), in the reinforced process, controlled temperature is about-10 ℃, and feeding in raw material finishes, continuation is stirred 1h at-10 ℃, reaction finishes the back and add frozen water 200ml in reaction, fully stirs, it is 10~11 that NaOH solution with 20% is regulated PH, suction filtration, obtain light brown solid 70.2g, high pressure liquid chromatographic analysis (HPLC) purity 78.5%, the intermediate A yield is 55.1%, MS:m/z:178,164,122,107,71.
The preparation of intermediate B: in reaction flask, add 55.5g (96.2%, 0.3mol) intermediate A, 64g Na
2CO
3With the 200ml chlorobenzene, fully be stirred in Dropwise 5 6g bromoacetaldehyde dimethyl acetal in half an hour under 60 ℃, then 140 ℃ of reaction 0.5h, reaction is cooled to 10 ℃ with reactant after finishing, and in reaction mixture impouring 500ml frozen water, obtains light brown oily thing, MgSO
4Dry, decompression desolventizing gets product 67.1g, and the HPLC purity assay is 95.2%, and yield is 80.0%, MS:m/z:234 (M+-CH3OH), 191,134,118,105,86,75.
The preparation of intermediate C: in reaction flask, add 56.2g (94.8%, 0.2mol) intermediate B, 200ml chlorobenzene, 15 ℃, add heteropolyacid (H3PW12O40) 30g under the violent stirring, continue then at 95 ℃ of stirring reaction 2h, after reaction finishes, in reactant impouring mixture of ice and water, it is 11~12 that the NaOH solution with 20% is regulated PH, tells organic layer, water layer is used MgSO with the extraction of 2 * 100ml chlorobenzene
4Dry, steam solvent, the solids recrystallizing methanol that obtains obtains white crystal 30.1g, M.P.115~118 ℃, the HPLC purity assay is 98.6%, intermediate C yield is 73.4%.MS:m/z:202,173,145,131,117,103,77。
The preparation of purpose product praziquantel: add 21g intermediate C (0.1mol) and 60ml trichloromethane in reaction flask, ice bath drips 16g cyclohexanecarbonyl chloride (0.11mol) down, after dropwising, at 50 ℃ of stirring reaction 2.0h, adds 50mlH then in reaction flask
2O tells organic layer, uses anhydrous MgSO
4Dry, steam solvent, the solid recrystallization in ether and hexane (1:1) with obtaining obtains light yellow solid 21.5g, the HPLC purity assay is 99.5%, the praziquantel yield is 68.6%.MS:m/z:312,201,185,173,145,132,113,83,55。
From β-phenylethylamine be: 22.2% to the praziquantel total recovery.
Claims (15)
1, a kind of Praziquantel synthetic process is characterized in that:
The first step is carried out condensation reaction by β-phenylethylamine and glycyl halogen hydrochlorate, and generate intermediate A: N-β-styroyl amino acetamide, setting-up point are-20 ℃~80 ℃;
Second step under alkaline condition, was carried out condensation reaction generation intermediate B with gained intermediate A and halo acetaldehyde acetal; N-(2-phenyl) ethyl-2-[(acetaldehyde acetal) amino] ethanamide, setting-up point is 0~150 ℃;
The 3rd step generated intermediate C:4-carbonyl-1,2,3,6,7 with the cyclisation under an acidic catalyst catalysis of gained intermediate B, 11b-six hydrogen-4H-pyrazinyl [2,1-a] isoquinoline 99.9, and the cyclisation temperature is-10 ℃~100 ℃;
The 4th step generated the target product praziquantel with intermediate C and cyclohexanecarbonyl chloride-10 ℃~60 ℃ reactions.
2, according to the described Praziquantel synthetic process of claim 1, it is characterized in that halogen element is C1, Br, I in described glycyl halogen hydrochlorate and the halo acetaldehyde acetal, the acetal in the said halo acetaldehyde acetal is C1~C8 alcohol.
3, according to claim 1 or 2 described Praziquantel synthetic process, it is characterized in that the first step condensation reaction and the 4th step building-up reactions carry out under basic cpd promotes, the 4th step synthesized in polar aprotic solvent and carries out.
4,, it is characterized in that described basic cpd is NaHCO in the first step condensation according to the described Praziquantel synthetic process of claim 3
3, in the 4th step acidylate is synthetic, be Na
2CO
3, K
2CO
3, the synthetic Semi-polarity aprotic solvent of the 4th step acidylate is a halon.
5,, it is characterized in that described condensation reaction carries out in polar solvent according to the described Praziquantel synthetic process of claim 3.
6, according to the described Praziquantel synthetic process of claim 5, it is characterized in that the first step condensation reaction carries out in aromatic hydrocarbons and halohydrocarbon, the second step condensation reaction is carried out in alcohols and aromatic hydrocarbons, and the 3rd step cyclization carries out in halohydrocarbon.
7,, it is characterized in that described the 3rd step an acidic catalyst is the vitriol oil, heteropolyacid and strong-acid ion exchange resin according to claim 1,2 or 5 described Praziquantel synthetic process.
8,, it is characterized in that described the first step condensation reaction β-phenylethylamine, glycyl halogen hydrochlorate, basic cpd equivalence ratio are 1:1:1.2~1:1.6:5 according to the described Praziquantel synthetic process of claim 3.
9,, it is characterized in that described the first step temperature of reaction is-5 ℃~15 ℃, reaction times 0.5h~5h according to claim 1 or 5 described Praziquantel synthetic process.
10,, it is characterized in that the described second step condensation reaction intermediate A, halo acetaldehyde acetal, basic cpd equivalence ratio are 1:1:1.3~1:1.5:4.5 according to claim 1 or 5 described Praziquantel synthetic process.
11,, it is characterized in that the described second step temperature of reaction is 20~100 ℃, reaction times 0.5~4h according to claim 1 or 5 described Praziquantel synthetic process.
12,, it is characterized in that the mass ratio of described the 3rd step cyclization intermediate B and an acidic catalyst is 1:0.1~1:3 according to claim 1 or 5 described Praziquantel synthetic process.
13,, it is characterized in that described three-step reaction temperature is 10~40 ℃, reaction times 2~6h according to the described Praziquantel synthetic process of claim 9.
14,, it is characterized in that described the 4th step building-up reactions intermediate C, cyclohexanecarbonyl chloride, basic cpd equivalence ratio are 1:1:1.3~1:1.5:5 according to the described Praziquantel synthetic process of claim 3.
15,, it is characterized in that described the 4th step synthesis reaction temperature is 5~30 ℃, reaction times 0.5~5h according to claim 1 or 5 described Praziquantel synthetic process.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB2005100379112A CN100503582C (en) | 2005-03-01 | 2005-03-01 | Praziquantel synthetic process |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB2005100379112A CN100503582C (en) | 2005-03-01 | 2005-03-01 | Praziquantel synthetic process |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1683346A CN1683346A (en) | 2005-10-19 |
CN100503582C true CN100503582C (en) | 2009-06-24 |
Family
ID=35262870
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2005100379112A Expired - Fee Related CN100503582C (en) | 2005-03-01 | 2005-03-01 | Praziquantel synthetic process |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN100503582C (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010107791A2 (en) | 2009-03-17 | 2010-09-23 | Concert Pharmaceuticals, Inc. | Pyrazinoisoquinoline compounds |
CN105622606A (en) * | 2016-04-06 | 2016-06-01 | 宜兴市新宇化工有限公司 | Preparation method of praziquantel |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101538223B (en) * | 2008-03-18 | 2013-02-06 | 上海医药工业研究院 | Preparation method for N-(2-phenyl)ethyl-2-[(2,2-dimethoxyethyl)amino]acetamide halate |
CN101538222B (en) * | 2008-03-18 | 2012-12-26 | 上海医药工业研究院 | Preparation method for N-(2-phenyl)ethyl-2-[(2,2-dimethoxyethyl)amino]acetamide halate |
CN102786520A (en) * | 2011-05-17 | 2012-11-21 | 中国医学科学院药物研究所 | Praziquantel crystal A substance, its preparation method and its applications in medicines and healthcare products |
CN102786519B (en) * | 2011-05-17 | 2017-04-19 | 中国医学科学院药物研究所 | Praziquantel crystal B substance, its preparation method and its applications in medicines and healthcare products |
CN102285985B (en) * | 2011-05-30 | 2012-08-08 | 苏州大学 | Preparation method of 10-hydroxyl praziquantel and application thereof as anti-schistosomiasis medicine |
CN104844606B (en) * | 2011-05-31 | 2017-03-01 | 山东大学(威海) | Parasiticide pyrazine isoquinoline derivative |
CN102925528B (en) * | 2011-10-26 | 2014-07-02 | 苏州同力生物医药有限公司 | Method for producing intermediate of levo-praziquantel and levo-praziquantel |
CN103044422B (en) * | 2012-12-27 | 2016-06-08 | 迪沙药业集团有限公司 | A kind of preparation method of praziquantel |
CN103739601A (en) * | 2013-12-12 | 2014-04-23 | 江苏诚信制药有限公司 | Method for preparing praziquantel |
EP3257852B1 (en) * | 2015-02-12 | 2020-01-01 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Preparation method for praziquantel and intermediate compounds thereof |
CN109336885B (en) * | 2018-11-16 | 2021-04-13 | 周口师范学院 | Preparation method of praziquantel |
CN111072656B (en) * | 2019-12-31 | 2022-11-25 | 江苏诚信药业有限公司 | Praziquantel synthesis method |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2504250A1 (en) * | 1975-02-01 | 1976-08-05 | Merck Patent Gmbh | TETRAHYDROISOCHINOLINE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION |
DE2508947A1 (en) * | 1975-03-01 | 1976-09-09 | Merck Patent Gmbh | PROCESS FOR THE PREPARATION OF 4-OXO-HEXAHYDRO-PYRAZINOISOCHINOLINE DERIVATIVES |
US4523013A (en) * | 1982-01-29 | 1985-06-11 | Sanofi, S.A. | 4-Acyl-2,6-dioxo-1-phenethyl piperozines |
-
2005
- 2005-03-01 CN CNB2005100379112A patent/CN100503582C/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2504250A1 (en) * | 1975-02-01 | 1976-08-05 | Merck Patent Gmbh | TETRAHYDROISOCHINOLINE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION |
DE2508947A1 (en) * | 1975-03-01 | 1976-09-09 | Merck Patent Gmbh | PROCESS FOR THE PREPARATION OF 4-OXO-HEXAHYDRO-PYRAZINOISOCHINOLINE DERIVATIVES |
US4523013A (en) * | 1982-01-29 | 1985-06-11 | Sanofi, S.A. | 4-Acyl-2,6-dioxo-1-phenethyl piperozines |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010107791A2 (en) | 2009-03-17 | 2010-09-23 | Concert Pharmaceuticals, Inc. | Pyrazinoisoquinoline compounds |
CN105622606A (en) * | 2016-04-06 | 2016-06-01 | 宜兴市新宇化工有限公司 | Preparation method of praziquantel |
Also Published As
Publication number | Publication date |
---|---|
CN1683346A (en) | 2005-10-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100503582C (en) | Praziquantel synthetic process | |
EA003245B1 (en) | Benzamidine derivatives and the pharmaceutical composition based thereof | |
WO2012100399A1 (en) | Novel process for synthesizing fingolimod hydrochloride | |
CN101348471B (en) | Process for the preparation of 4- (3'chloro-4'-fluoroanilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline | |
CA1315287C (en) | Substituted bis-(4-aminophenyl)-sulfones, their preparation and their use as pharmaceutical compositions | |
CN101456788B (en) | Method and equipment for preparing difluoromonochloroethane by photochemical catalyst | |
EP1870403A1 (en) | Optically active quaternary ammonium salt having axial asymmetry and process for producing -amino acid and derivative thereof with the same | |
CN101323575A (en) | Synthetic method of nitrobenzene methyl aldehyde | |
CN103044422B (en) | A kind of preparation method of praziquantel | |
CN108129513A (en) | A kind of method for synthesizing Bouguer and replacing Buddhist nun's intermediate | |
FI57259B (en) | FOERFARANDE FOER FRAMSTAELLNING AV BRONKOLYTISKA OCH SECRETOLYTISKA 6,11-DIHYDRO-6-METHYL-5H-PYRIDO / 2,3-B // 1,5 / BENZODIAZEPIN-5-ONER OCH 5,11-DIHYDRO-5-METHYL-6H- pyrido / 2,3-b // 1,4 / benzodiazepine-6-oner | |
Song et al. | PEG 400-enhanced synthesis of gem-dichloroaziridines and gem-dichlorocyclopropanes via in situ generated dichlorocarbene | |
CN110183357A (en) | It is a kind of to be used to prepare preparation method of the Sha Ku than bent intermediate | |
PT85689B (en) | Process for the preparation of novel naphthalene and indanodecylated compounds and pharmaceutical compositions containing them | |
CN105037212B (en) | By ammonia and the method for carbon dioxide production urea | |
CN102295552B (en) | Method for increasing yield of 3,6-dichloro-2-hydroxybenzoic acid | |
CN102731328B (en) | Preparation method of bupropion hydrochloride | |
CN111454164A (en) | Preparation method of terbutaline sulfate | |
CN109574935A (en) | Process for preparing 3, 4-dimethylpyrazole and its phosphate | |
CN105601537B (en) | A kind of preparation method of 2- (7- methoxy-1-naphthyls) acetonitrile | |
CN102432558B (en) | Method for synthesizing irbesartan and intermediate thereof | |
CN107473294A (en) | A kind of handling process and processing system of acrylonitrile recovery tower tower bottoms | |
CN111763149A (en) | Preparation method of phenylenediamine and phenylenediamine inorganic salt | |
CN101151235B (en) | Process for producing glyceryl ether | |
CN106279114B (en) | A kind of synthetic method of Taladegib |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090624 Termination date: 20150301 |
|
EXPY | Termination of patent right or utility model |