CN103044422B - A kind of preparation method of praziquantel - Google Patents
A kind of preparation method of praziquantel Download PDFInfo
- Publication number
- CN103044422B CN103044422B CN201210595943.4A CN201210595943A CN103044422B CN 103044422 B CN103044422 B CN 103044422B CN 201210595943 A CN201210595943 A CN 201210595943A CN 103044422 B CN103044422 B CN 103044422B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- preparation
- praziquantel
- dichloromethane
- 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.)
- Active
Links
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 229960002957 praziquantel Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims abstract description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229940125758 compound 15 Drugs 0.000 claims abstract description 11
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000004471 Glycine Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 9
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 229940126543 compound 14 Drugs 0.000 claims description 9
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 229940125797 compound 12 Drugs 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 229940126142 compound 16 Drugs 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 239000000376 reactant Substances 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- -1 compound 8 Chemical compound 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- 229960003280 cupric chloride Drugs 0.000 claims description 3
- 229940117803 phenethylamine Drugs 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 3
- 238000000034 method Methods 0.000 abstract description 15
- 239000003814 drug Substances 0.000 abstract description 4
- 238000011084 recovery Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000013461 design Methods 0.000 abstract description 2
- 239000000273 veterinary drug Substances 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000010410 layer Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 8
- 238000010792 warming Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- LAOOXBLMIJHMFO-UHFFFAOYSA-N 1-[2-(diethylamino)ethylamino]-4-methylthioxanthen-9-one;hydron;chloride Chemical compound Cl.S1C2=CC=CC=C2C(=O)C2=C1C(C)=CC=C2NCCN(CC)CC LAOOXBLMIJHMFO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 230000001843 schistosomicidal effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 241001327965 Clonorchis sinensis Species 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 201000000077 Cysticercosis Diseases 0.000 description 1
- 206010014096 Echinococciasis Diseases 0.000 description 1
- 208000009366 Echinococcosis Diseases 0.000 description 1
- 241000244160 Echinococcus Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001480233 Paragonimus Species 0.000 description 1
- 241000935974 Paralichthys dentatus Species 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 241000242683 Schistosoma haematobium Species 0.000 description 1
- 241000242677 Schistosoma japonicum Species 0.000 description 1
- 241000242680 Schistosoma mansoni Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- MPTQRFCYZCXJFQ-UHFFFAOYSA-L copper(II) chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Cu+2] MPTQRFCYZCXJFQ-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000590 parasiticidal effect Effects 0.000 description 1
- 239000002297 parasiticide Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 208000004441 taeniasis Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
The preparation method that the present invention relates to a kind of veterinary drug praziquantel, belongs to field of medicaments. The invention provides a kind of method preparing praziquantel of novelty. The method raw materials used such as chloracetyl chloride, glycine, cheap and easy to get; Reaction routine, simple to operate, equipment is not had particular/special requirement; In reaction scheme, we devise key intermediate 14 and carry out intramolecular cyclization generation compound 15 1 step, and this is a brand-new design, has no bibliographical information; Whole piece route reaction yield is higher, and total recovery is up to 50%, and the solvent major part used in course of reaction can reclaim, and has both saved cost, has alleviated again ambient pressure, greatly reduce cost, has been a route having very much prospects for commercial application.
Description
Technical field:
The preparation method that the present invention relates to a kind of veterinary drug praziquantel (Praziquantcl), belongs to field of medicaments.
Background of invention:
Praziquantel have another name called praziquantel, 8440, for broad-spectrum anti-parasite disease medication, Schistosoma japonicum, Schistosoma haematobium, Schistosoma mansoni etc. are all had killing action. Additionally, paragonimus (lung fluke), clonorchis sinensis, Echinococcus hydatid cyst, cysticercosis, Meng Shi pleroceroid, fasciloopsis, cestode etc. are also had killing action by it. Except for human body, praziquantel is also widely used as the parasiticide treatment of animal, poultry etc.
First praziquantel is synthesized in 1975 by Seubere et al., and pharmaceutical preparation is successfully developed in Merck KGaA and Bayer two pharmaceutical factory. Merck KGaA company in 1980 takes the lead in listing with trade name " Cesol ", and its action character is that curative effect is high, dosage is little, short treating period, metabolism is fast, toxicity is little and convenient oral, thus is deeply welcome by patient. Praziquantel is after listing, and sales volume is continuously increased, and market share expands rapidly, is quickly become the choice drug for the treatment of schistosomicide and multiple parasitic disease in the world.
In recent years, the Schistosomiasis Epidemic of some countries expands to some extent in the world, and China's some areas schistosomicide also has new line phenomenon. Therefore, strengthen the research of praziquantel new synthesis route is had important practical significance and practical value.
Praziquantel has following formula chemical constitution:
German patent DE 2504250 and DE2508947 disclose the synthetic route of praziquantel early stage:
This processing step is longer, has 8 step reactions; Total recovery is only about 15%. Production to be used severe poisonous chemicals cyanide toxicity bigger. Meanwhile, the high-pressure hydrogenation operating process in production, dangerous big, easily have an accident. And, three wastes discharge amount is big, and environment protection treating is costly.
For many years, people are studying praziquantel new technique for synthesizing always, in recent years achieved with many achievements.Especially 2005, the improvement that Praziquantel synthetic process is carried out by Jiangsu Polytechnic University of China Dan Yuhua et al., apply for Chinese invention patent 200510037911.2, and obtain mandate:
This technique, with ��-phenethylamine, glycyl halogen hydrochlorate for raw material, obtains compound 9 through condensation; Compound 9 and Haloacetaldehydes acetal and compound 10, be substituted and be obtained by reacting compound 11; Compound 11 cyclisation under strongly acidic conditions obtains compound 7; Compound 7 synthesizes praziquantel through acidylate.
This synthetic reaction condition relaxes, atmospheric operation, operates safety, and synthesis step is succinct, and total recovery can more than 50%; And building-up process discharge waste is few, pollute little, be a kind of clean and effective synthesis technique. But some reagent used in process, for instance glycyl halogen hydrochlorate, Haloacetaldehydes acetal are not extremely easy to get, and price is higher, still has room for improvement.
Summary of the invention:
The main purpose of the present invention is to provide a kind of with low cost, simple to operation method preparing praziquantel.
The technical scheme is that
A kind of preparation method of praziquantel, it is characterised in that
Compound 12 is prepared in first step ��-phenethylamine and chloracetyl chloride reaction,
Second step compound 12 and glycine reactant prepare compound 13,
3rd step compound 13 prepares compound 14 with cyclohexanecarbonyl chloride reaction,
4th step compound 14 carries out intramolecular cyclization and obtains compound 15,
5th step compound 15 obtains compound 16 through reduction,
6th step compound 16 carries out intramolecular cyclization under strongly acidic conditions, obtains praziquantel, i.e. compound 8,
First step reaction is under sodium bicarbonate exists, the mixed solution of chloracetyl chloride and this chloralkane it is slowly added dropwise in the chloralkane agent system containing ��-phenethylamine, the wherein preferred dichloromethane of chloralkane, controls temperature in reaction system and, less than 10 DEG C, prepares compound 12 in dropping process;
Second step reacts in the presence of an organic base, and compound 12 and glycine are at C1-C3Alcohol apoplexy due to endogenous wind, prepares compound 13 under counterflow condition, wherein the preferred triethylamine of organic base, C1-C3The preferred methanol of alcohol;
In the presence of a base, compound 13 and cyclohexanecarbonyl chloride are in chloralkane, and compound 14 is prepared in reaction for three-step reaction, process control in system warm less than 10 DEG C, the wherein preferred dichloromethane of chloralkane, alkali is selected in sodium hydroxide, sodium carbonate, potassium carbonate, it is preferable that potassium carbonate;
Four-step reaction be compound 14 under the effect of cyclization reagent, occur intramolecular cyclization, obtain compound 15, wherein cyclization reagent be selected from acetic anhydride, thionyl chloride, it is preferable that thionyl chloride; When cyclization reagent is acetic anhydride, acetic anhydride had both done reaction dissolvent, did again the cyclization reagent reacted; When cyclization reagent is thionyl chloride, reaction dissolvent is selected from chloralkane, it is preferable that dichloromethane;
5th step reaction is the reduction of compound 15, goes back original reagent selected from potassium borohydride, potassium borohydride/Copper dichloride dihydrate, it is preferable that potassium borohydride/Copper dichloride dihydrate; Being dividedly in some parts in reducing agent process, in controlling, temperature is less than 10 DEG C, and reaction dissolvent is selected from methanol, ethanol, Isosorbide-5-Nitrae-dioxane;
Six-step process is that compound 16 carries out cyclisation under concentrated hydrochloric acid effect, obtains praziquantel.
The invention has the beneficial effects as follows a kind of method preparing praziquantel providing novelty. The method is raw materials used cheap and easy to get, for instance chloracetyl chloride, glycine; Reaction routine, simple to operate, equipment is not had particular/special requirement;In reaction scheme we devise key intermediate 14 carry out intramolecular cyclization generate compound 15 1 step, this is a brand-new design, has no bibliographical information; Whole piece route reaction yield is higher, and total recovery is up to 50%, and the solvent major part used in course of reaction can reclaim, and has both saved cost, has alleviated again ambient pressure, greatly reduce cost, has been a route having very much prospects for commercial application.
Detailed description of the invention:
Embodiment 1: the preparation of compound 12
122g phenethylamine (1mol) and 92.4g sodium bicarbonate (1.1mol) are added in 600mL dichloromethane and stir, ice bath is cooled to about 0 DEG C, it is slowly added dropwise the mixed solution of 124.3g chloracetyl chloride (1.1mol) and 120g dichloromethane, after dropwising, it is warming up to 25 DEG C and continues reaction 3h, 0-5 DEG C adds 200mL water in reactant liquor, separate organic layer, by dichloromethane (100mL*2) aqueous layer extracted, after combined dichloromethane layer, dry with anhydrous sodium sulfate, filter, remove dichloromethane under reduced pressure, obtain 189g white solid, yield 96%, fusing point: 120-125 DEG C.
Embodiment 2: the preparation of compound 13
Take 19.7g (0.1mol) compound 12, 12.1g triethylamine (0.12mol) is added in 100mL methanol, stirring 10min, after adding 9g (0.12mol) glycine, temperature rising reflux stirs 8h, decompression steams methanol, 50mL water and the stirring of 100mL dichloromethane is added in residue, stratification, separate dichloromethane layer, water layer is washed with dichloromethane (50mL*2), combined dichloromethane phase, anhydrous sodium sulfate dries, sucking filtration, steam dichloromethane and obtain brown solid, acetone recrystallization, obtain 20.1g off-white color solid, yield 85%, fusing point: 187-189 DEG C.
Embodiment 3: the preparation of compound 14
1. by 23.6g compound 13 (0.1mol), 20.7g potassium carbonate (0.15mol) is added in 100g water and 300mL dichloromethane, 0 DEG C it is cooled under stirring, dropping 17.5g (0.12mol) cyclohexanecarbonyl chloride, it is warming up to after dropwising and 3h is stirred at room temperature, separate dichloromethane layer, water layer dichloromethane (100mL*2) extracts, combined dichloromethane layer, anhydrous sodium sulfate dries, sucking filtration, decompression steams dichloromethane, 100mL petroleum ether is added in residue, 1h is stirred at room temperature, sucking filtration obtains 30.5g off-white color solid, yield 88%, fusing point: 166-168 DEG C.
2. by 23.6g compound 13 (0.1mol), 6g sodium hydroxide (0.15mol) is added in 250mL dichloromethane and 100mL water mixed liquid, 0 DEG C it is cooled under stirring, dropping 17.5g (0.12mol) cyclohexanecarbonyl chloride, backflow it is warming up to after dropwising, stirring 5h, it is cooled to room temperature, 100mL water is added in reactant liquor, separate dichloromethane layer, water layer dichloromethane (50mL*2) extracts, combined dichloromethane layer, anhydrous sodium sulfate dries, sucking filtration, decompression steams dichloromethane, 100mL petroleum ether is added in residue, 1h is stirred at room temperature, sucking filtration, obtain 21.2g off-white color solid, yield 85%, fusing point: 166-168 DEG C.
Embodiment 4: the preparation of compound 15
1. 34.6g (0.1mol) compound 14 is added in 150mL toluene, under stirring, is cooled to about 0 DEG C, dropping 13.1g thionyl chloride (0.11mol), dropwise stirring 1h under rear room temperature, it is warming up to 50 DEG C of stirring 2h, temperature rising reflux stirring 4h, blood pressure lowering solvent evaporated, in residue, 200mL water is added under room temperature, being sufficiently stirred for making beating 2h, sucking filtration, dehydrated alcohol recrystallization obtains 27.9g white solid, yield 85%, fusing point: 91-93 DEG C.
2. being added in 200mL acetic anhydride by 34.6g (0.1mol) compound 14, stirring is warming up to backflow, after insulated and stirred 3h, is cooled to room temperature, after stirring 2h, sucking filtration, 50mL water washing filter cake, dehydrated alcohol recrystallization obtains 24.6g white solid, yield 75%, fusing point: 91-93 DEG C.
Embodiment 5: the preparation of compound 16
1. 16.4g (0.05mol) compound 15 is added in 50mL methanol, stirring is cooled to 0 DEG C, 8.4g Copper dichloride dihydrate is added in reactant liquor, continue insulated and stirred 0.5h, it is dividedly in some parts 13.5g potassium borohydride, insulated and stirred 1h, blood pressure lowering solvent evaporated, 20mL water is added in residue, 0 DEG C of dropping 1N hydrochloric acid, adjust pH to about 6, ethyl acetate (50mL*2) extracts, 10% sodium bicarbonate aqueous solution washs once, saline solution tries once, anhydrous sodium sulfate dries, decompression steams solvent, gained material diisopropyl ether recrystallization, obtain 14.2g white solid, yield 86%, fusing point: 136.5-138.5 DEG C.
2. being added to by 16.4g (0.05mol) compound 15 in 80mL dioxane and 5mL water, stirring is cooled to 15 DEG C, is dividedly in some parts 15g potassium borohydride in reactant liquor, 1h is stirred at room temperature, it is warming up to 60 DEG C, stirs 2h, be down to room temperature, sucking filtration, filter cake is washed, and gained material diisopropyl ether recrystallization obtains 10.9g white solid, yield 80%, fusing point: 136.5-138.5 DEG C.
Embodiment 6: the preparation of praziquantel
100mL concentrated hydrochloric acid (12N) is added in reaction bulb, it is cooled to 0 DEG C, under stirring, is dividedly in some parts 9.9g compound 16 (0.03mol), 0 DEG C of stirring 1h, it is warming up to and 20h is stirred at room temperature, adding 200mL cold water in reactant liquor, dichloromethane (100mL*3) extracts, and anhydrous sodium sulfate dries, blood pressure lowering is evaporated off solvent, re-crystallizing in ethyl acetate obtains 8.7g white solid praziquantel, yield 93%, fusing point: 133-136 DEG C.
Claims (6)
1. the preparation method of a praziquantel, it is characterised in that
Compound 12 is prepared in first step ��-phenethylamine and chloracetyl chloride reaction,
,
Reaction dissolvent is selected from chloralkane;
Second step compound 12 and glycine reactant prepare compound 13,
,
Reaction dissolvent is selected from C1-C3Alcohols;
3rd step compound 13 prepares compound 14 with cyclohexanecarbonyl chloride reaction,
,
Reaction dissolvent is selected from chloralkane;
4th step compound 14 carries out intramolecular cyclization and obtains compound 15,
,
React solvent-free or that solvent is in toluene, chloralkane one; Cyclization reagent used is selected from acetic anhydride
Or thionyl chloride;
5th step compound 15 obtains compound 16 through reduction,
,
Reaction dissolvent one in methanol, ethanol or 1,4-dioxane;
6th step compound 16 carries out intramolecular cyclization under strongly acidic conditions, obtains praziquantel, i.e. compound 8,
��
2. preparation method according to claim 1, it is characterised in that the one in sodium hydroxide, sodium carbonate or potassium carbonate of the alkali used by three-step reaction.
3. preparation method according to claim 1, it is characterised in that the 5th step reaction reducing agent used is potassium borohydride or potassium borohydride/Copper dichloride dihydrate.
4. preparation method according to claim 1, it is characterised in that first step reaction solvent for use is selected from dichloromethane.
5. preparation method according to claim 1, it is characterised in that second step reaction solvent for use is selected from methanol.
6. preparation method according to claim 1, it is characterised in that three-step reaction solvent for use is selected from dichloromethane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210595943.4A CN103044422B (en) | 2012-12-27 | 2012-12-27 | A kind of preparation method of praziquantel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210595943.4A CN103044422B (en) | 2012-12-27 | 2012-12-27 | A kind of preparation method of praziquantel |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103044422A CN103044422A (en) | 2013-04-17 |
| CN103044422B true CN103044422B (en) | 2016-06-08 |
Family
ID=48057306
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210595943.4A Active CN103044422B (en) | 2012-12-27 | 2012-12-27 | A kind of preparation method of praziquantel |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103044422B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6359208B2 (en) * | 2015-02-12 | 2018-07-18 | 浙江▲海▼正▲薬▼▲業▼股▲フン▼有限公司 | Method for producing praziquantel and its intermediate compound |
| CN105622606A (en) * | 2016-04-06 | 2016-06-01 | 宜兴市新宇化工有限公司 | Preparation method of praziquantel |
| CN108794466A (en) * | 2017-04-26 | 2018-11-13 | 苏州同力生物医药有限公司 | A kind of amorphous levo-praziquantel solid and its preparation method and application |
| CN111995539B (en) * | 2020-09-28 | 2023-08-11 | 郑州原理生物科技有限公司 | Preparation method of lidocaine hydrochloride impurity E |
| CN115677528A (en) * | 2022-11-03 | 2023-02-03 | 厦门稀土材料研究所 | Method for separating rhenium and technetium |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4497952A (en) * | 1982-07-08 | 1985-02-05 | Korea Advanced Institute Of Science And Technology | Process for the production of (±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives |
| CN1683346A (en) * | 2005-03-01 | 2005-10-19 | 江苏工业学院 | Praziquantel synthetic process |
| WO2009115333A1 (en) * | 2008-03-20 | 2009-09-24 | Doemling Alexander | Novel synthesis of praziquantel |
-
2012
- 2012-12-27 CN CN201210595943.4A patent/CN103044422B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4497952A (en) * | 1982-07-08 | 1985-02-05 | Korea Advanced Institute Of Science And Technology | Process for the production of (±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives |
| CN1683346A (en) * | 2005-03-01 | 2005-10-19 | 江苏工业学院 | Praziquantel synthetic process |
| WO2009115333A1 (en) * | 2008-03-20 | 2009-09-24 | Doemling Alexander | Novel synthesis of praziquantel |
Non-Patent Citations (1)
| Title |
|---|
| "New syntheses of praziquantel:2-(cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one";Daniel Frehel et al.;《Heterocycles》;19831231;第20卷(第9期);第1731-1735页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103044422A (en) | 2013-04-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103044422B (en) | A kind of preparation method of praziquantel | |
| CN112608357B (en) | Preparation method of antiviral drug Molnbupiravir | |
| CN103961340B (en) | A kind of LSD1 inhibitor and its application | |
| CN101798270B (en) | Method for preparing 3-amino-1-adamantane alcohol | |
| CN102351778A (en) | Preparation method of arbidol hydrochloride | |
| CN102503805A (en) | Method for preparing 4-felbinac through rearrangement reaction | |
| CN101417971B (en) | Indolines compounds, preparation method and pharmaceutical application thereof | |
| CN104311518B (en) | A kind of preparation method of 6-methyl scutellarin genin | |
| CN101402573A (en) | Bihydroxyl-2-acyl benzene acetic acid ester, producing method and uses thereof | |
| CN107235853B (en) | A kind of synthetic method being used to prepare Canton love-pea vine A prime and its isomers | |
| CN103508934A (en) | Preparation method of gliclazide | |
| CN103304478B (en) | Alkaloidal intermediate of one class synthesis renieramycins type and preparation method thereof | |
| CN109796461A (en) | A kind of preparation process of Tadalafei impurity I | |
| CN104557902B (en) | A kind of method for preparing thiabendazole | |
| CN103265470A (en) | Synthetic method of silodosin dialkylate | |
| CN104177327B (en) | The preparation method of 6-amino-2-thia spiral shell [3,3] heptane hydrochloride | |
| CN106117212A (en) | A kind of sldenafil synthesis technique of improvement | |
| CN101891689B (en) | Preparation method of hydrochloric acid gamma-hydroxy bendamustine | |
| CN105061430A (en) | Preparation method of anti-tumor compound and application of compound | |
| CN107043385A (en) | A kind of method for preparing DRV intermediate | |
| CN101560178B (en) | Polysubstituted indoline compound, preparation method and medical application thereof | |
| CN106966991A (en) | A kind of new technology for preparing flibanserin | |
| CN112745370B (en) | Preparation method of tulathromycin | |
| CN103755727B (en) | Preparation method of brinzolamide intermediate | |
| CN107759603A (en) | A kind of preparation method of heterocyclic compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: DISHA PHARMACEUTICAL INDUSTRY GROUP CORP., LTD. Free format text: FORMER OWNER: WEIHAI DIZHIYA PHARMACHEM. DEVELOPMENT CO., LTD. Effective date: 20150908 Free format text: FORMER OWNER: DISHA PHARMACEUTICAL INDUSTRY GROUP CORP., LTD. DISHA PHARMACEUTICAL GROUP SHANDONG DISHA PHARMACEUTICAL CO., LTD. Effective date: 20150908 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20150908 Address after: 264205 No. 1 South Qingdao Road, Weihai economic and Technological Development Zone, Shandong, China Applicant after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: 264205 Shandong city of Weihai province by the district Gushan Town No. 18 South Road, No. 19 North Road, No. 3 East Road, the west five Applicant before: WEIHAI DIZHIYA PHARMACHEM DEV Co.,Ltd. Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Applicant before: Shandong Disha Pharmaceutical Co.,Ltd., Disha Phamaceutical Group |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210430 Address after: 264205 Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Patentee before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |
|
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: No. 268, Tianrun Road, Wendeng Economic and Technological Development Zone, Weihai City, Shandong Province, 264200 Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |