CN115141146A - Synthesis method of hypoglycemic active compound 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt - Google Patents
Synthesis method of hypoglycemic active compound 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt Download PDFInfo
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- CN115141146A CN115141146A CN202110369575.0A CN202110369575A CN115141146A CN 115141146 A CN115141146 A CN 115141146A CN 202110369575 A CN202110369575 A CN 202110369575A CN 115141146 A CN115141146 A CN 115141146A
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- chlorophenyl
- acid
- trimethyl
- pyrazolium
- ketone
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- -1 compound 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt Chemical class 0.000 title claims abstract description 38
- 230000002218 hypoglycaemic effect Effects 0.000 title abstract description 7
- 238000001308 synthesis method Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 20
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 claims abstract description 17
- PUOANGABHCKUFR-UHFFFAOYSA-N 4-(4-chlorophenyl)-1,2,3-trimethylpyrazol-1-ium Chemical class CC(N(C)[N+](C)=C1)=C1C(C=C1)=CC=C1Cl PUOANGABHCKUFR-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 claims abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- WEJRYKSUUFKMBC-UHFFFAOYSA-N 1-(4-chlorophenyl)propan-2-one Chemical compound CC(=O)CC1=CC=C(Cl)C=C1 WEJRYKSUUFKMBC-UHFFFAOYSA-N 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 claims description 6
- 239000012535 impurity Substances 0.000 claims description 6
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 claims description 6
- YFKBXYGUSOXJGS-UHFFFAOYSA-N 1,3-Diphenyl-2-propanone Chemical compound C=1C=CC=CC=1CC(=O)CC1=CC=CC=C1 YFKBXYGUSOXJGS-UHFFFAOYSA-N 0.000 claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 238000006683 Mannich reaction Methods 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 230000003078 antioxidant effect Effects 0.000 claims description 4
- 235000006708 antioxidants Nutrition 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 3
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 claims description 3
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 claims description 3
- 229930003268 Vitamin C Natural products 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000000543 intermediate Substances 0.000 claims description 3
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 claims description 3
- QCCDLTOVEPVEJK-UHFFFAOYSA-N phenylacetone Chemical compound CC(=O)CC1=CC=CC=C1 QCCDLTOVEPVEJK-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 229960001285 quercetin Drugs 0.000 claims description 3
- 235000005875 quercetin Nutrition 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 235000019154 vitamin C Nutrition 0.000 claims description 3
- 239000011718 vitamin C Substances 0.000 claims description 3
- FGYOIRTXWYVZHP-UHFFFAOYSA-N 1,3-bis(4-chlorophenyl)propan-2-one Chemical compound C1=CC(Cl)=CC=C1CC(=O)CC1=CC=C(Cl)C=C1 FGYOIRTXWYVZHP-UHFFFAOYSA-N 0.000 claims description 2
- GJYCVCVHRSWLNY-UHFFFAOYSA-N 2-butylphenol Chemical compound CCCCC1=CC=CC=C1O GJYCVCVHRSWLNY-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 2
- 229940073608 benzyl chloride Drugs 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 231100000053 low toxicity Toxicity 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 235000010288 sodium nitrite Nutrition 0.000 claims description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 2
- PLWSZOQYWKLNIL-UHFFFAOYSA-N 1-butyl-2-chloro-3-methyl-2h-imidazole Chemical compound CCCCN1C=CN(C)C1Cl PLWSZOQYWKLNIL-UHFFFAOYSA-N 0.000 claims 1
- 150000008065 acid anhydrides Chemical class 0.000 claims 1
- 150000001299 aldehydes Chemical class 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims 1
- 239000002440 industrial waste Substances 0.000 abstract description 8
- 239000002699 waste material Substances 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000002244 precipitate Substances 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 9
- RREANTFLPGEWEN-MBLPBCRHSA-N 7-[4-[[(3z)-3-[4-amino-5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidin-2-yl]imino-5-fluoro-2-oxoindol-1-yl]methyl]piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(\N=C/3C4=CC(F)=CC=C4N(CN4CCN(CC4)C=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C4CC4)F)C\3=O)=NC=2)N)=C1 RREANTFLPGEWEN-MBLPBCRHSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000009835 boiling Methods 0.000 description 6
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 6
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical class CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000003219 pyrazolines Chemical class 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- AKGGYBADQZYZPD-UHFFFAOYSA-N benzylacetone Chemical compound CC(=O)CCC1=CC=CC=C1 AKGGYBADQZYZPD-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- VDFKKLMKUNQLDX-UHFFFAOYSA-N 1,1-dimethylhydrazine;1,2-dimethylhydrazine Chemical class CNNC.CN(C)N VDFKKLMKUNQLDX-UHFFFAOYSA-N 0.000 description 1
- SRVMEDXBUHMMCI-UHFFFAOYSA-N 1,2-dimethyl-3h-pyrazole Chemical class CN1CC=CN1C SRVMEDXBUHMMCI-UHFFFAOYSA-N 0.000 description 1
- KEQXNNJHMWSZHK-UHFFFAOYSA-L 1,3,2,4$l^{2}-dioxathiaplumbetane 2,2-dioxide Chemical compound [Pb+2].[O-]S([O-])(=O)=O KEQXNNJHMWSZHK-UHFFFAOYSA-L 0.000 description 1
- IAZSXUOKBPGUMV-UHFFFAOYSA-N 1-butyl-3-methyl-1,2-dihydroimidazol-1-ium;chloride Chemical compound [Cl-].CCCC[NH+]1CN(C)C=C1 IAZSXUOKBPGUMV-UHFFFAOYSA-N 0.000 description 1
- YHTXYPYMMZBOQY-UHFFFAOYSA-N CC(=O)CC1=CC=CC=C1.CC(=O)CC1=CC=CC=C1 Chemical compound CC(=O)CC1=CC=CC=C1.CC(=O)CC1=CC=CC=C1 YHTXYPYMMZBOQY-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- GIKDYMRZQQJQFB-UHFFFAOYSA-N Methylhydrazine hydrochloride Chemical compound Cl.CNN GIKDYMRZQQJQFB-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001339 alkali metal compounds Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A method for synthesizing 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt as hypoglycemic active compound. The invention overcomes the defects in the prior art, solves the industrial large-scale production process technology of the hypoglycemic active five-membered ring compound 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt, simultaneously solves the problem that the 1, 2-dimethylhydrazine industrial waste is fully utilized, avoids the environmental pollution and the resource waste caused by the dangerous compound, and provides a reliable method which directly uses the 1, 2-dimethylhydrazine industrial waste to develop the synthesis process of the 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt, is safe, reliable, high in purity, low in cost and high in yield and is suitable for industrial production in order to better realize the waste recycle of industrial waste liquid.
Description
Technical Field
The invention relates to the field of medical intermediates, in particular to a synthesis method of 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt.
Background
Pyrazoline is an important five-membered heterocyclic compound containing nitrogen as a heteroatom. Nowadays, pyrazoles have attracted much attention as biomolecules having special pharmacological properties, and pyrazoline derivatives are now widely used in the fields of medicines, pesticides, dyes, and the like.
The pyrazoline derivatives have wide application prospects as molecular units of medicaments, and researches show that the pyrazoline derivatives have important biological activities in the aspects of antibiosis, antidiabetic, anticonvulsant, anti-inflammatory, antidepressant, antitumor, antiepileptic, antivirus, pain-relieving and inflammation-diminishing and the like. In recent years, there have been many reports on the research on 1, 3-substituted pyrazoline derivatives, and the references for preparing such compounds are generally aryl-substituted hydrazines, monomethylhydrazines (MMH) and Unsymmetrical Dimethylhydrazines (UDMH) as starting materials to obtain the target products by Mannich reaction, and further purification of the obtained target products is described in the literature of Indian Journal of Heterocyclic Chemistry 2001, 10 (3): 197-200 and Molicules 2018, 23, 134, and the like, which are described in the literature, use solvent extraction techniques such as cyclohexane, diethyl ether, ethyl acetate, acetone, and the like which are extremely dangerous, or some alkali metal compounds with severe reaction sensitivity, and the method is only limited to laboratory research significance and is not suitable for industrial production. Chinese patent application publication No. CN109970649A also discloses that a large amount of byproduct 1, 2-dimethylhydrazine generated in the industrial production of monomethylhydrazine (MMH) is taken as a waste liquid treatment problem. The literature on 1, 2-substituted pyrazoline derivatives obtained from 1, 2-dimethylhydrazine (SDMH) as a starting material is very few, and no commercial use thereof has been found. The U.S. literature now reports that novel compositions of 1, 2-di-lower alkyl aryl pyrazolium salts possess unique pharmacological and biological activities, and are attracting much attention due to their interesting hypoglycemic pharmacological properties. Wherein the 1, 2-dimethyl-3-substituted pyrazoline composition has more prominent hypoglycemic pharmacological activity. Preparation of 1, 2-dimethylpyrazoline derivatives Mannich bases of 1-lower alkylpyrazolines "(Mannich bases) are also commonly obtained by cyclization of monomethylhydrazine (MMH) or monomethylhydrazine hydrochloride thereof as a starting material with a carbonyl compound containing an active hydrogen and paraformaldehyde by a Mannich reaction. The lower alkyl Mannich alkali is further alkylated by alkyl halide or dimethyl sulfate to obtain the corresponding 1, 2-di-lower alkyl pyrazolium salt, but a large amount of waste water and waste gas containing toxic halide or dimethyl sulfate residue can be generated in the production process, so that the environmental pollution is large, the production process is long, the yield is low, and the industrial production is not facilitated.
Disclosure of Invention
The invention overcomes the defects in the prior art, solves the industrial large-scale production process technology of the hypoglycemic active five-membered ring compound 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt, simultaneously solves the problem that the 1, 2-dimethylhydrazine industrial waste is fully utilized, avoids the environmental pollution and the resource waste caused by the dangerous compounds, and provides a reliable method which directly uses the 1, 2-dimethylhydrazine industrial waste to develop the synthesis process of the 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt, is safe, reliable, high in purity, low in cost and high in yield, and is suitable for industrial production in order to better realize the waste recycle of industrial waste liquid.
The invention aims to solve the technical problems, the technical scheme is that a related impurity eliminating agent which can react with key impurities and does not influence a target product is added into an industrial raw material 1, 2-dimethylhydrazine before a reactant in a first working section is mixed for treatment, a benzyl compound, formaldehyde and a proper amount of antioxidant are selected to carry out a conventional mannich reaction in a reactant in a second working section, a solvent used in the whole set of reaction and crude product purification steps is selected from a low-toxicity, safe and environment-friendly common solvent which is industrially required, and the obtained intermediate is acidified by an acid to form a corresponding pyrazolium salt, and a method for obtaining the high-purity bulk drug 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt by the conventional methods of cooling crystallization, centrifugal separation, drying and the like comprises the following steps: the molecular formula of the component 1, 2-dimethylhydrazine is CH 3 NHNHCH 3 (ii) a The molecular formula of paraformaldehyde is (CH) 2 O) n; the benzyl compound is one of benzyl chloride, benzyl ketone, dibenzyl ketone, benzyl acetone, p-chlorobenzyl ketone and p-chlorophenyl acetone; the molecular formula of the target product 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt is C 12 N 2 H 18 X; the related impurity eliminating agent is acylAmine, acetic acid and relative salts thereof, formic acid and relative salts thereof, sodium nitrite, anhydride, methyl formate or aldehyde ketone or a mixture of two of them; the antioxidant is at least one of resorcinol, phosphite, vitamin C, 1-butyl-1-methylpyrrolidine chloride, quercetin, 6-butyl phenol, chloride (1-butyl-3-methylimidazole), tert-butyl-p-diphenol and citric acid; the common solvent is at least one of absolute ethyl alcohol, isopropanol, dimethylformamide, dimethyl sulfoxide, methanol and glycol solvent; the X onium anion is formed from one of fumaric acid, acetic acid, oxalic acid, hydrochloric acid, sulfuric acid, perchloric acid, boric acid, or trityl chloride.
Compared with the prior art for preparing the 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt, the method has the advantages that the industrial waste 1, 2-dimethylhydrazine really realizes commercial application, changes waste into valuable, reduces cost, realizes commercial large-scale production, has simple equipment and easy operation and the like.
Specific details of the process of the present invention are set forth in the following examples, which are provided as examples and should not be construed as limiting the scope of the invention.
Detailed Description
Example 1
According to known methods, mannich bases of benzyl methyl ketone (phenyl acetone) are prepared by reacting formaldehyde with dimethylamine hydrochloride in ethanol. Adding a solution of 0.1 mole of Mannich base of methylbenzyl ketone and 0.1 mole of 1, 2-dimethylhydrazine to 100ml of absolute ethanol, heating the solution at reflux temperature for 12 hours, then concentrating in vacuum, adding a ferric chloride catalyst to perform chlorination reaction to obtain a residue containing 1,2, 3-dimethyl-4- (p-chlorophenyl) -pyrazoline, distilling and purifying the residue to collect distillate with the boiling point of 155-160 ℃/8.0mmHg, adding toluene, distilling and dehydrating to obtain a waxy solid, and keeping the Mp ℃ at: 48-50 ℃. 0.01mol of 1,2, 3-trimethyl-4-p-chlorophenyl-3-pyrazoline is dissolved in 35ml of ethanol, 0.01mol of perchloric acid is added thereto with stirring, the solution is diluted to about 2-fold volume with a less polar solvent and left to stand at about 5 ℃ for 24 hours. Filtering and drying the obtained precipitate, wherein the precipitate contains 1,2, 3-trimethyl-4 (p-chlorophenyl) -perchlorate pyrazole salt, and the crude product is recrystallized by ethanol, filtered and vacuum-dried at 60 ℃ to obtain light yellow powder, the yield is 76.1 percent, and the purity is 93.4 percent.
Example 2
According to the known method, mannich bases of methyl p-chlorobenzyl ketone (p-chloropropiophenone) are prepared by reacting formaldehyde with dimethylamine hydrochloride in ethanol. Adding a solution of 0.1 mol of mannich base of methyl-p-chlorobenzyl ketone and 0.1 mol of 1, 2-dimethylhydrazine to 100ml of absolute ethanol, heating the solution at reflux temperature for 12 hours, then evaporating the solvent in vacuum to obtain a residue containing 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazoline, distilling and purifying the residue to collect distillate with the boiling point of 155-160 ℃/8.0mmHg, adding toluene, distilling and dehydrating to obtain waxy solid, and the Mp ℃ is: 48-50 ℃. 0.01mol of 1,2, 3-trimethyl-4-p-chlorophenyl-3-pyrazoline is dissolved in 35ml of methanol, 0.01mol of perchloric acid is then added and stirred, and the solution is left for 24 hours at approximately below 5 ℃. Filtering and drying the obtained precipitate, wherein the precipitate contains 1,2, 3-trimethyl-4 (p-chlorophenyl) -perchlorate pyrazolate, and the crude product is recrystallized by ethanol, filtered and vacuum-dried at 60 ℃ to obtain light yellow powder, the yield is 83.8 percent, and the purity is 96.5 percent.
Example 3
According to the known method, mannich bases of methyl p-chlorobenzyl ketone (p-chloropropiophenone) are prepared by reacting formaldehyde with dimethylamine hydrochloride in ethanol. Adding 0.1 mol of Mannich base of methyl-p-chlorobenzyl ketone and 0.1 mol of solution of 1, 2-dimethylhydrazine and a small amount of quercetin and citric acid into 100ml of absolute ethanol, heating the solution at reflux temperature for 12 hours, then evaporating the solvent in vacuum to obtain a residue containing 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazoline, distilling and purifying the residue to collect distillate with the boiling point of 155-160 ℃/8.0mmHg, adding toluene, distilling and dehydrating to obtain waxy solid, and keeping the Mp ℃ at: 48-50 ℃. 0.01mol of 1,2, 3-trimethyl-4-p-chlorophenyl-3-pyrazoline is dissolved in 35ml of isopropanol, 0.01mol of perchloric acid is then added with stirring, the solution is diluted to about 5-fold volume with a less polar solvent and left for 24 hours at about 5 ℃ or below. Filtering and drying the obtained precipitate, wherein the precipitate contains 1,2, 3-trimethyl-4 (p-chlorophenyl) -perchlorate pyrazole salt, and the crude product is recrystallized by dimethyl sulfoxide, filtered and dried in vacuum at 60 ℃ to obtain light yellow powder, the yield is 86.2 percent, and the purity is 98.6 percent.
Example 4
According to the known method, mannich bases of methyl p-chlorobenzyl ketone (p-chloropropiophenone) are prepared by reacting formaldehyde with dimethylamine hydrochloride in ethanol. Adding 0.1 mole of Mannich base of methyl-p-chlorobenzyl ketone and 0.1 mole of 1, 2-dimethylhydrazine solution and a small amount of resorcinol and acetic anhydride into 100ml of absolute ethanol, heating the solution at reflux temperature for 12 hours, evaporating the solvent in vacuum to obtain a residue containing 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazoline, distilling and purifying the residue to collect distillate with boiling point of 155-160 ℃/8.0mmHg, adding toluene, distilling and dehydrating to obtain waxy solid, mp ℃:48-50 ℃. 0.01mol of 1,2, 3-trimethyl-4-p-chlorophenyl-3-pyrazoline is dissolved in 35ml of isopropanol, then 0.01mol of fumaric acid is added and stirred, the solution is diluted to about 4-fold volume with a solvent of low polarity and left to stand below about 5 ℃ for 24 hours. Filtering and drying the obtained precipitate, wherein the precipitate contains 1,2, 3-trimethyl-4 (p-chlorophenyl) -fumarate pyrazole salt, and the crude product is recrystallized by ethanol, filtered, and dried in vacuum at 60 ℃ to obtain milk white powder with the yield of 86.2% and the purity of 98.7%.
Example 5
According to the known method, mannich bases of methyl p-chlorobenzyl ketone (p-chloropropiophenone) are prepared by reacting formaldehyde with dimethylamine hydrochloride in ethanol. Adding a solution of 0.1 mole of Mannich base of methyl-p-chlorobenzyl ketone and 0.1 mole of 1, 2-dimethylhydrazine and small amounts of vitamin C and acetaldehyde to 100ml of absolute ethanol, heating the solution at reflux temperature for 12 hours, then evaporating the solvent in vacuo to obtain a residue containing 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazoline, purifying by distillation to collect a distillate with a boiling point of 155-160 ℃/8.0mmHg, adding toluene, and distilling off to obtain a waxy solid, mp ℃:48-50 ℃. 0.01mol of 1,2, 3-trimethyl-4-p-chlorophenyl-3-pyrazoline is dissolved in 35ml of isopropanol, and then stirred with the addition of 0.01mol of fumaric acid, the solution is diluted to about 4-fold volume with a less polar solvent and left at about 5 ℃ for 24 hours. The resulting precipitate, which contained 1,2, 3-trimethyl-4 (p-chlorophenyl) -fumarate pyrazolate, was filtered and dried, and the crude product was recrystallized from methanol, filtered, and vacuum dried at 60 ℃ to give a milky white powder with a yield of 82.2% and a purity of 96.8%.
Example 6
Firstly, adding proper benzaldehyde into a crude industrial waste 1, 2-methylhydrazine product, uniformly mixing, and directly feeding for standby, wherein Mannich base of methyl p-chlorobenzyl ketone (p-chloropropiophenone) is prepared by reacting formaldehyde with dimethylamine hydrochloride in isopropanol according to a known method. Adding 0.1 mole of mannich base of methyl p-chlorobenzyl ketone and 0.1 mole of solution of treated 1, 2-dimethyl hydrazine in 100ml of isopropanol, adding a small amount of citric acid, heating the solution at reflux temperature for 12 hours, evaporating the solvent in vacuum to obtain residue containing 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazoline, distilling and purifying the residue to collect distillate with boiling point of 155-160 ℃/8.0mmHg, adding toluene, distilling and dehydrating to obtain waxy solid, mp ℃:48-50 ℃. 0.01mol of 1,2, 3-trimethyl-4-p-chlorophenyl-3-pyrazoline is dissolved in 35ml of isopropanol, 0.01mol of perchloric acid is then added with stirring, the solution is diluted to about 5-fold volume with a less polar solvent and left for 24 hours at about 5 ℃ or below. Filtering and drying the obtained precipitate, wherein the precipitate contains 1,2, 3-trimethyl-4 (p-chlorophenyl) -perchlorate pyrazole salt, and the crude product is recrystallized by dimethyl sulfoxide, filtered and dried in vacuum at 60 ℃ to obtain light yellow powder, the yield is 86.6 percent, and the purity is 98.5 percent.
Claims (2)
1. A technical method for synthesizing 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt is characterized in that: the method is characterized in that a related impurity remover which can react with key impurities and does not influence a target product is added into industrial raw material 1, 2-dimethylhydrazine before mixing of reactants in a first working section, a benzyl compound, formaldehyde and a proper amount of antioxidant are selected as reactants in a second working section to carry out conventional mannich reaction, a solvent used in the whole set of reaction and crude product purification steps is a low-toxicity, safe and environment-friendly common solvent which is industrially required, and the obtained intermediate is acidified by an acid to form corresponding pyrazolium salts, so that high-purity raw material 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salts can be obtained by conventional methods such as cooling crystallization, centrifugal separation, drying and the like.
2. The benzyl compound of claim 1, which is one of benzyl chloride, benzyl ketone, dibenzyl ketone, benzyl ketone, phenyl acetone, p-chlorobenzyl ketone, and p-chlorophenyl acetone; the molecular formula of the target product 1,2, 3-trimethyl-4- (p-chlorophenyl) -pyrazolium salt is C 12 N 2 H 18 X; the related impurity eliminating agent is one or a mixture of two of amides, acetic acid and related salts thereof, formic acid and related salts thereof, sodium nitrite, acid anhydride, methyl formate or aldehydes and ketones; the antioxidant is at least one of resorcinol, phosphorous acid, vitamin C, 1-butyl-1-methylpyrrolidine chloride, quercetin, 6-butylphenol, chloro (1-butyl-3-methylimidazole), tert-butyl-p-diphenol and citric acid; the common solvent is at least one of absolute ethyl alcohol, isopropanol, dimethylformamide, dimethyl sulfoxide, methanol and glycol solvent; the X onium anion is formed from one of fumaric acid, acetic acid, oxalic acid, hydrochloric acid, sulfuric acid, perchloric acid, boric acid, or trityl chloride.
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