CN114805164A - Recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole - Google Patents
Recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole Download PDFInfo
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- CN114805164A CN114805164A CN202210325785.4A CN202210325785A CN114805164A CN 114805164 A CN114805164 A CN 114805164A CN 202210325785 A CN202210325785 A CN 202210325785A CN 114805164 A CN114805164 A CN 114805164A
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- Prior art keywords
- methyl
- thiadiazole
- compound
- formula
- hydroxy
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 35
- FGLWYEULLSTVMA-UHFFFAOYSA-N 5-methyl-3h-1,3,4-thiadiazol-2-one Chemical compound CC1=NN=C(O)S1 FGLWYEULLSTVMA-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000004064 recycling Methods 0.000 title claims abstract description 24
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 claims abstract description 22
- 229960004796 rosuvastatin calcium Drugs 0.000 claims abstract description 22
- 239000006227 byproduct Substances 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- NSMKWTGDPQHTDH-UHFFFAOYSA-N 2-bromo-5-methyl-1,3,4-thiadiazole Chemical compound CC1=NN=C(Br)S1 NSMKWTGDPQHTDH-UHFFFAOYSA-N 0.000 claims description 13
- IPLGMBJDQYRJLJ-UHFFFAOYSA-N 2-chloro-5-methyl-1,3,4-thiadiazole Chemical compound CC1=NN=C(Cl)S1 IPLGMBJDQYRJLJ-UHFFFAOYSA-N 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 12
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000012535 impurity Substances 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- -1 (acetonide) hexanoate Chemical compound 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 3
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical group S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims description 3
- 239000012265 solid product Substances 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 2
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 2
- 229950009390 symclosene Drugs 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- TUFCAMATOSLRHA-UHFFFAOYSA-N trichloro(methylidene)-lambda5-phosphane Chemical compound ClP(Cl)(Cl)=C TUFCAMATOSLRHA-UHFFFAOYSA-N 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 230000031709 bromination Effects 0.000 claims 1
- 238000005893 bromination reaction Methods 0.000 claims 1
- 239000012320 chlorinating reagent Substances 0.000 claims 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims 1
- 229960000672 rosuvastatin Drugs 0.000 claims 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims 1
- RBBWNXJFTBCLKT-UHFFFAOYSA-M sodium;ethanethioate Chemical compound [Na+].CC([S-])=O RBBWNXJFTBCLKT-UHFFFAOYSA-M 0.000 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- FPVUWZFFEGYCGB-UHFFFAOYSA-N 5-methyl-3h-1,3,4-thiadiazole-2-thione Chemical compound CC1=NN=C(S)S1 FPVUWZFFEGYCGB-UHFFFAOYSA-N 0.000 abstract description 12
- 239000002699 waste material Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000007787 solid Substances 0.000 description 26
- 238000003756 stirring Methods 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 235000019441 ethanol Nutrition 0.000 description 11
- 238000010992 reflux Methods 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- MMTXSCWTVRMIIY-PHDIDXHHSA-N (3r,5s)-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)C=C MMTXSCWTVRMIIY-PHDIDXHHSA-N 0.000 description 1
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- QGAVSDVURUSLQK-UHFFFAOYSA-N ammonium heptamolybdate Chemical compound N.N.N.N.N.N.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.[Mo].[Mo].[Mo].[Mo].[Mo].[Mo].[Mo] QGAVSDVURUSLQK-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
The invention discloses a recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole, and belongs to the technical field of pharmaceutical chemistry. The method converts the byproduct 5-methyl-2-hydroxy-1, 3, 4-thiadiazole generated in the preparation process of the rosuvastatin calcium intermediate into 5-methyl-2-mercapto-1, 3, 4-thiadiazole; meanwhile, the recovered 5-methyl-2-mercapto-1, 3, 4-thiadiazole is further used for preparing a rosuvastatin calcium intermediate or rosuvastatin calcium. The invention realizes the reasonable recycling of the byproduct 5-methyl-2-hydroxy-1, 3, 4-thiadiazole, fully utilizes the raw materials, reduces the production cost of the rosuvastatin calcium and the intermediate thereof, and reduces the discharge of three wastes.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and relates to a method for recycling a byproduct in a rosuvastatin calcium intermediate preparation process, in particular to a method for recycling 5-methyl-2-hydroxy-1, 3, 4-thiadiazole.
Background
Rosuvastatin calcium, chemical name: bis- [ E-7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -pyrimidin-5-yl ] (3R,5S) -3, 5-dihydroxyhept-6-enoic acid ] calcium salt (2: 1). It is a selective HMG-CoA reductase inhibitor developed and developed by Aslicon, and is marketed in several countries and regions of the United states, Japan, Europe, China, etc. The structural formula is as follows:
a compound I: [ E-7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -pyrimidin-5-yl ] (3R,5S) -3, 5-dioxo (acetonide) ylhept-6-enoic acid tert-butyl ester is an important intermediate for the preparation of rosuvastatin calcium drugs. The main synthetic route is as follows:
in the preparation of the intermediate compound I of the rosuvastatin calcium medicament, a byproduct compound II is generated: 5-methyl-2-hydroxy-1, 3, 4-thiadiazole:
if the byproduct compound II is not recycled, the raw material waste is caused, the three-waste discharge is increased, and the production cost of the product is increased.
Meanwhile, the intermediate compound I of the rosuvastatin calcium medicament has high production cost and relatively high market price; if the byproduct compound II can be converted into the compound I and the final product rosuvastatin calcium, waste can be changed into valuable, and the reasonable recycling of the byproduct 5-methyl-2-hydroxy-1, 3, 4-thiadiazole can be realized.
Therefore, the research on the recycling method of the byproduct 5-methyl-2-hydroxy-1, 3, 4-thiadiazole has great economic and environmental protection values. However, so far, there are few reports on the recycling method of this by-product.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a method for recycling 5-methyl-2-hydroxy-1, 3, 4-thiadiazole aiming at the defects of the prior art. The method realizes reasonable recycling of the byproduct 5-methyl-2-hydroxy-1, 3, 4-thiadiazole, reduces the production cost of rosuvastatin calcium and an intermediate thereof, and reduces the discharge of three wastes.
Compound II: the 5-methyl-2-hydroxy-1, 3, 4-thiadiazole is mainly present in crystallization mother liquor (including dichloromethane for leaching) of compound I after synthesis treatment, and the content of a water phase is low. Before use, methanol is removed by drying under reduced pressure or the like.
The technical scheme is as follows: the purpose of the invention is realized by the following technical scheme:
the invention provides a recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole, which comprises the following steps:
(1) converting the compound of formula II to a compound of formula iii;
(2) the compound shown in the formula III is further synthesized into an intermediate compound shown in the formula I of rosuvastatin calcium and/or rosuvastatin calcium, so that the compound shown in the formula II is recycled.
In the step (1), firstly, converting the compound shown in the formula II into 5-methyl-2-chloro-1, 3, 4-thiadiazole or 5-methyl-2-bromo-1, 3, 4-thiadiazole; and then the 5-methyl-2-chloro-1, 3, 4-thiadiazole or the 5-methyl-2-bromo-1, 3, 4-thiadiazole is further converted into a compound shown in the formula III.
The method for converting the compound of formula II into 5-methyl-2-chloro-1, 3, 4-thiadiazole is as follows: the mol ratio of the 5-methyl-2-hydroxy-1, 3, 4-thiadiazole to the chlorine-containing reaction reagent is 1: 0.45-3, reacting in a solvent at 20-115 ℃ for 9-12 hours; after the reaction is finished, carrying out post-treatment, concentrating the system under reduced pressure until the system is dry, and then recrystallizing with methanol or ethanol; the chlorination reaction reagent is one or a mixture of more of thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, triphosgene, methylene phosphorus trichloride, chlorine, cyano trichloromethane, NCS and trichloroisocyanuric acid. The solvent is toluene, 1, 2-dichloroethane or thionyl chloride.
A preferred technical scheme of the invention is as follows: taking thionyl chloride as a solvent and a reaction reagent, adding N, N-dimethylformamide which is 1 wt% of the thionyl chloride to improve the activity of the thionyl chloride, and heating the mixture to reflux for reaction.
The method for converting the compound of formula II into 5-methyl-2-bromo-1, 3, 4-thiadiazole is as follows: the mol ratio of the 5-methyl-2-hydroxy-1, 3, 4-thiadiazole to the bromine-containing reaction reagent is 1: 0.5 to 1.5, and reacting in toluene or carbon tetrachloride at the temperature of 20 to 115 ℃ for 8 to 12 hours; after the reaction is finished, carrying out post-treatment, concentrating the system under reduced pressure until the system is dry, and then recrystallizing with methanol or ethanol; the brominating reagent is one or a mixture of more of phosphorus tribromide, NBS, phosphorus pentabromide, phosphorus oxybromide and phosphorus oxychloride plus bromine.
A preferred technical scheme of the invention is as follows: carbon tetrachloride is used as a solvent, phosphorus pentabromide is used as a reaction reagent, and the reaction is carried out under reflux.
Preferably, in the method for converting the compound of the formula II into 5-methyl-2-chloro-1, 3, 4-thiadiazole or 5-methyl-2-bromo-1, 3, 4-thiadiazole, the reaction temperature is 60-115 ℃.
The synthesis method of the compound shown in the formula III comprises the following steps: adding 5-methyl-2-chloro/bromo-1, 3, 4-thiadiazole and thiourea into ethanol or ether solvent in a molar ratio of 1: 1.2-2.0, heating to 50-60 ℃, and reacting for 9-12 hours; cooling to below 30 ℃, adding inorganic base, heating to 40-50 ℃, and reacting for 3-4 hours; after the reaction is finished, cooling to room temperature, adding water, concentrating to remove the solvent, extracting with ethyl acetate or dichloromethane to remove impurities, adjusting the pH value to acidity with hydrochloric acid, and precipitating a solid product.
Ethanol is preferred as a solvent in the present invention. If ethers such as isopropyl ether are used as the solvent, the conversion of the product is relatively slow.
If sodium hydrosulfide is used instead of thiourea, no target product is found in the reaction, even if the reaction temperature is increased to 80 ℃.
Preferably, the inorganic base is one or a mixture of sodium hydroxide, potassium hydroxide and cesium carbonate.
Preferably, the molar ratio of the inorganic base to the 5-methyl-2-chloro/bromo-1, 3, 4-thiadiazole is 0.5-4.0: 1.
in step (1), the compound of formula II may also be converted to the compound of formula III in one step.
Preferably, the molar ratio of the compound of formula II to the sulfurizing agent is 1: 0.2 to 1.2, preferably 1: 0.6.
preferably, the reaction is carried out in a solvent at the temperature of 20-30 ℃ for 1-3 hours; the solvent is tetrahydrofuran, dioxane or anhydrous ethylene glycol dimethyl ether, and is preferably tetrahydrofuran.
Preferably, the sulfurizing agent is phosphorus pentasulfide;
in the step (2), the method for further synthesizing the rosuvastatin calcium intermediate compound shown as the formula I by the compound shown as the formula III comprises the following steps: the compound of formula III reacts with tert-butyl (3R,5S) -6-chloro-3, 5-dioxo (acetonide) hexanoate, and then is oxidized and reacts with 2- (N-methyl-N-methylsulfonyl) amino-4- (4-fluorobenzene) group-6-isopropylpyrimidine-5-formaldehyde to obtain the compound of formula I. The reaction route is as follows:
the recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole is also applicable to the compound shown in the formula II-b:
the 5-methyl-2-hydroxy-1, 3, 4-thiadiazole actually belongs to the same substance due to tautomerism and the two different structures.
The invention further researches a post-treatment method of the reaction:
(1) after the synthesis reaction of 5-methyl-2-chloro-1, 3, 4-thiadiazole is completed, post-treatment is carried out:
the first scheme is as follows: concentrating the system under reduced pressure to dryness, and recrystallizing with methanol or ethanol;
scheme II: concentrating the system under reduced pressure until the system is dry, adding a small amount of ethanol, reducing the pressure until the system is dry, and performing recrystallization (directly adding a solvent to the next reaction).
The experimental result shows that the reaction of the step (2) is respectively carried out by the two schemes, and the yield of the product after the post-treatment is reduced by about 10% in the first scheme under the same reaction condition, but the purity of the product is not obviously different.
(2) Post-treatment of the compound 5-methyl-2-mercapto-1, 3, 4-thiadiazole synthesis reaction of formula iii:
reacting 5-methyl-2-chloro-1, 3, 4-thiadiazole or 5-methyl-2-bromo-1, 3, 4-thiadiazole with thiourea, adding water after the reaction is finished, concentrating to remove the solvent, extracting with ethyl acetate or dichloromethane to remove a small amount of organic impurities, and adjusting the pH value to acidity with hydrochloric acid to precipitate a solid; the yield of pH 2-3 can be the highest by adjusting pH to 1, 2-3, and 4-5 respectively.
Experiments prove that the 5-methyl-2-mercapto-1, 3, 4-thiadiazole obtained by the method can be used for preparing rosuvastatin calcium intermediate and/or rosuvastatin calcium.
Has the advantages that:
the invention converts the byproduct compound shown in formula II into the compound shown in formula III, and then further synthesizes the intermediate compound shown in formula I of rosuvastatin calcium and/or rosuvastatin calcium. The method realizes reasonable recycling of the byproduct compound shown as the formula II, reduces the production cost of the rosuvastatin calcium and the intermediate thereof, and reduces the discharge of three wastes. Experiments prove that the recovery amount of the byproduct II is about 0.2 kg (the recovery rate reaches 90%) when 1 kg of the rosuvastatin calcium intermediate I is produced, the byproduct II is converted into the compound I according to the method, the yield of the compound I is increased within the range of 0.19-0.25 kg without calculating secondary recovery, the cost is saved by more than 10% when the same amount of I is produced, and the three wastes are reduced.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of compound I synthesized by the present invention.
Detailed Description
The technical solution of the present invention is described in detail by the following specific examples, but the scope of the present invention is not limited to the examples.
Extracting 5-methyl-2-hydroxy-1, 3, 4-thiadiazole from a post-synthesis treatment mother liquor of a compound of formula I:
and combining the post-treatment crystallization mother liquor of the compound shown in the formula I, concentrating, and carrying water with toluene until the toluene is dry for later use.
Example 1
5-methyl-2-chloro-1, 3, 4-thiadiazole synthesis:
20 g (0.172mol) of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole is placed in a reaction bottle, 100 ml of toluene is added, 11.6 g of phosphorus pentachloride (0.078mol) is added, the mixture is heated to reflux for reaction, and the reaction is finished after 10 hours. After removal of excess solvent under reduced pressure, the crude product was recrystallized once from ethanol to give 16.2 g of product in 70% yield.
5-methyl-2-mercapto-1, 3, 4-thiadiazole synthesis:
15 g (0.111mol) of 5-methyl-2-chloro-1, 3, 4-thiadiazole is added, 60 ml of absolute ethyl alcohol is added, 16.3 g (0.214mol) of thiourea is added, and the mixture is heated to 60 ℃ under full stirring and reacted for 10 hours. Cooled to 30 ℃, added with 8.4 g of sodium hydroxide solid, slowly heated to 50 ℃ and reacted for 3 hours.
Cooling to room temperature, adding 30 ml of water into a reaction system, removing a solvent under reduced pressure, adding 50ml of dichloromethane for extraction, stirring, separating liquid, removing an organic layer, slowly adding 3mol/L hydrochloric acid into a water phase under stirring to adjust the pH value to be 2-3, separating out a solid, performing suction filtration, and performing vacuum drying to obtain 11.3 g of the solid, wherein the yield is 77%, the HPLC purity is 98.3%, and the melting point is 182-189 ℃.
If further purification is needed, the product is dissolved in alkali solution and slowly acidified to separate out solid.
Example 2
5-methyl-2-chloro-1, 3, 4-thiadiazole synthesis:
20 g (0.172mol) of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole is placed in a reaction bottle, 61.4 g (0.516mol) of thionyl chloride is added, 0.5 ml of DMF and 70 ml of toluene are added, then the mixture is heated to reflux, and the reaction is finished after 9 hours. After removal of excess thionyl chloride under reduced pressure, 23 g of crude product were obtained. 10 ml of absolute ethanol are added and the mixture is dried under reduced pressure and then is not purified.
5-methyl-2-mercapto-1, 3, 4-thiadiazole synthesis:
the solid is directly added into 80 ml of absolute ethyl alcohol, then 21 g (0.275mol) of thiourea is added, and the mixture is heated to 60 ℃ under full stirring and reacts for 9 h. Cooled to 25 ℃, added with 12.6 g of sodium hydroxide solid, slowly heated to 50 ℃ and reacted for 3 hours.
Cooling to room temperature, adding 50ml of water into the reaction system, removing the solvent under reduced pressure, adding 100 ml of dichloromethane for extraction to remove organic impurities, slowly adding 3mol/L hydrochloric acid into the water phase under stirring to adjust the pH value to be 2-3, separating out a solid, performing suction filtration, and performing vacuum drying to obtain 14.3 g of the solid, wherein the product purity is 98.0%, and the total yield in two steps is 62.8%.
Example 3
Synthesis of 5-methyl-2-bromo-1, 3, 4-thiadiazole:
15 g (0.129mol) of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole is added, 100 ml of carbon tetrachloride and 29.9 g (0.07mol) of phosphorus pentabromide are added, and the mixture is heated to reflux and reacted for 8 hours. After completion of the reaction, the reaction system was poured into 200 g of ice water. After stirring and separation, the aqueous phase was extracted twice with 100 ml of dichloromethane, the organic phases were combined, washed once with 50ml of sodium bicarbonate solution and once with 50ml of water, dried and concentrated to dryness under reduced pressure to give 17.9 g of a solid with a yield of 77.7%. The crude product is recrystallized once by ethanol for later use.
5-methyl-2-mercapto-1, 3, 4-thiadiazole synthesis:
adding 15.8 g of 5-methyl-2-bromo-1, 3, 4-thiadiazole (0.09mol) into 80 ml of absolute ethyl alcohol, adding 10.6 g (0.139mol) of thiourea, heating to 60 ℃, reacting for 9 hours, cooling to 25 ℃, adding 6.4 g of sodium hydroxide solid, slowly heating to 50 ℃, and reacting for 3 hours.
Cooling to room temperature, adding 50ml of water into the reaction system, removing the solvent under reduced pressure, adding 80 ml of dichloromethane for extraction to remove organic impurities, slowly adding 3mol/L hydrochloric acid into the water phase under stirring to adjust the pH value to be 2-3, separating out a solid, performing suction filtration, and performing vacuum drying to obtain 11.6 g of the solid, wherein the purity is 97.3%, and the total yield of the two steps is 67.8%.
Example 4
The reaction was performed as in example 1, except that 5-methyl-2-chloro-1, 3, 4-thiadiazole was not crystallized from alcohol, giving an overall yield of two steps of 59%.
Example 5
Synthesis of 5-methyl-2-bromo-1, 3, 4-thiadiazole:
20 g (0.172mol) of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole is placed in a reaction bottle, 100 ml of toluene is added, 68.1 g of phosphorus tribromide solid (0.252mol) is added, the mixture is heated to reflux for reaction, and the reaction is finished after 9 hours. After the temperature is reduced to room temperature, the reaction mixture is carefully poured into ice water (150 g of ice and 100 g of water), 100 ml of dichloromethane is added, liquid separation is carried out (after the ice is completely melted), the water phase is extracted once with 100 ml of dichloromethane, the combined organic phase is dried by anhydrous sodium sulfate, reduced pressure distillation is carried out until no liquid flows down, ethanol is added for recrystallization once, and 20.6 g of a product is obtained, wherein the yield is 66.9%.
5-methyl-2-mercapto-1, 3, 4-thiadiazole synthesis:
20 g (0.112mol) of the product was added with 60 ml of absolute ethanol, and then 7.6 g (0.14mol) of thiourea was added, and the mixture was heated to 60 ℃ with sufficient stirring to react for 10 hours. Cooled to 30 ℃, added with 18.3 g of cesium carbonate solid, and slowly warmed to 50 ℃ for reaction for 3 hours.
Cooling to room temperature, adding 30 ml of water into the reaction system, removing the solvent under reduced pressure, adding 50ml of dichloromethane for extraction, stirring, separating liquid, removing an organic layer, slowly adding 3mol/L hydrochloric acid into a water phase under stirring to adjust the pH value to be 2-3, separating out a solid, performing suction filtration, and performing vacuum drying to obtain 11.1 g of the solid with the yield of 75%.
Example 6
Synthesis of 5-methyl-2-bromo-1, 3, 4-thiadiazole:
10.5 g (0.09mol) of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole is added, 95 ml of carbon tetrachloride and 38.7 g (0.09mol) of phosphorus pentabromide are added, the mixture is heated to reflux, and the reaction is carried out for 8 hours. After completion of the reaction, the reaction system was poured into 250 g of ice water. After stirring and separation, the aqueous phase was extracted twice with 100 ml of dichloromethane, the organic phases were combined, washed once with 50ml of sodium bicarbonate solution and once with 50ml of water, dried and concentrated to dryness under reduced pressure to give 12 g of a solid with a yield of 74.7%. The crude product is recrystallized once by ethanol for standby.
5-methyl-2-mercapto-1, 3, 4-thiadiazole synthesis:
adding 12 g of 5-methyl-2-bromo-1, 3, 4-thiadiazole (0.067mol) into 80 ml of absolute ethyl alcohol, adding 6.1 g (0.08mol) of thiourea, heating to 60 ℃, reacting for 10 hours, cooling to 25 ℃, adding 13 g of sodium hydroxide solid, slowly heating to 50 ℃, and reacting for 3 hours.
Cooling to room temperature, adding 40 ml of water into the reaction system, removing the solvent under reduced pressure, adding 75 ml of dichloromethane for extraction to remove organic impurities, slowly adding 3mol/L hydrochloric acid into the water phase under stirring to adjust the pH value to be 2-3, separating out a solid, performing suction filtration, and performing vacuum drying to obtain 7.7 g of the solid, wherein the purity is 97.6%, and the yield is 86.4%.
The melting point of the 5-methyl-2-mercapto-1, 3, 4-thiadiazole obtained in the above example is 182-189 ℃, which is close to the value of relevant literature.
Example 7
5-methyl-2-mercapto-1, 3, 4-thiadiazole synthesis:
11.7 g (0.1mol) of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole is dissolved in 14.3mL tetrahydrofuran, 1.33 g of phosphorus pentasulfide (0.06mol) is added in batches under the ice bath condition, stirring is continued under the ice bath condition for 10min after the addition is completed, and the reaction is carried out for 2h at the temperature of 25 ℃. Suction filtration and vacuum drying to obtain solid 8.6 g, yield 65% and purity 97.8%.
Example 8
Preparation of compound I from compound IV prepared by recovering byproduct II:
30.6 g (0.11mol) of tert-butyl (3R,5S) -6-chloro-3, 5-dioxa (acetonide) hexanoate was dissolved in 150ml of DMF, 13.2g of 5-methyl-2-mercapto-1, 3, 4-thiadiazole (0.10mol) was added, 15.2 g of anhydrous potassium carbonate (0.11mol) was added, the mixture was stirred at 90 ℃ for 20 hours, and the plaque was charged with no starting material (EA: PE: 1, 1ml +1 drop of triethylamine, Rf: 0.3, leading edge). The reaction mixture was cooled to room temperature, 600ml of isopropyl ether and 600ml of water were added, liquid separation was performed with stirring, the aqueous layer was extracted with 300ml of isopropyl ether, the organic layers were combined, washed with 600ml of water, 600ml of 10% sodium bicarbonate solution and 600ml of saturated sodium chloride, and dried to obtain 35.1g of an oil (yield 94%).
Adding 250 ml of the oily substance and isopropyl ether into a reaction bottle, stirring at 25 ℃, adding 12.2g of ammonium heptamolybdate, and dropwise adding 30% H by mass concentration 2 O 2 26.7 g (0.235mol), the product is generated after 3h of reaction, the reaction is continued for 20h, and the raw materials are completely reacted to obtain the product with approximate single point. Adding 300ml EA, 120ml water, stirring thoroughly, adding 300ml 10% Na 2 S 2 O 3 Washing the solution with 300ml of water and 300ml of saturated sodium chloride, drying and spin-drying to obtain 42.8g of oily matter, adding 3 times of isopropyl ether, heating to reflux (not completely dissolved), stirring, naturally cooling, standing in a refrigerator at the temperature of 24 ℃ below zero for 0.5h when the temperature is reduced to room temperature, carrying out suction filtration and drying to obtain 20.5g of white solid. Mother liquor spin-drying, using EA: PE ═ 1: 5g of the product is obtained by column chromatography, 25.5g of solid is obtained in total, and the yield is 62.7%.
23.2 g (0.057mol) of the product obtained by the synthesis and 20 g (0.057mol) of 2- (N-methyl-N-methylsulfonyl) amino-4- (4-fluoro) phenyl-6-isopropylpyrimidine-5-formaldehyde are added into a reaction bottle, 400 ml of dried tetrahydrofuran is added, the temperature is reduced to below minus 70 ℃ after nitrogen replacement, and 43 ml (1.6mol/L, 0.069mol) of LiHMDS is slowly dropped. Keeping the temperature between 70 ℃ below zero and 78 ℃ below zero for reaction for about 8 hours, slowly adding ammonium chloride solid to quench the reaction. Adding a small amount of sodium chloride saturated solution, separating liquid, drying an organic phase, and concentrating under reduced pressure to dryness. Adding proper methanol to dissolve at 55 ℃, slowly cooling to 0 ℃, preserving heat and stirring for 1 hour. The mixture is filtered when the mixture is cold, and the solid is dried after being leached once by ice-cold methanol to obtain 22.4 g of a white solid product, namely the compound I with the purity of 98.6 percent and the yield of 68 percent. 1 H-NMR(400MHz，CDCl 3 )：δ1.20-1.22(m，6H)，1.33-1.39((m，15H)，1.41-1.50(dd，2H)，2.19-2.41(2H)，3.27-3.33(q，1H)，3.44-3.51(s+s，6H)，4.17-4.38(m，2H)，5.36-5.43(m，1H)，6.42-6.47(dd，1H)，6.98-7.04(t，2H)，7.56-7.60(m，2H)。 1 The H-NMR chart corresponds to the actual structure of the compound I.
As noted above, while the present invention has been shown and described with reference to certain preferred embodiments, it is not to be construed as limited thereto. Various changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention.
Claims (11)
1. A recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole is characterized by comprising the following steps: converting a compound shown in a formula II into a compound shown in a formula III;
and (2) further synthesizing the compound shown in the formula III into an intermediate compound shown in the formula I of rosuvastatin calcium and/or rosuvastatin calcium, and recycling the by-product.
2. The method for recycling 5-methyl-2-hydroxy-1, 3, 4-thiadiazole according to claim 1, wherein in the step (1), the compound of formula II is converted into 5-methyl-2-chloro-1, 3, 4-thiadiazole or 5-methyl-2-bromo-1, 3, 4-thiadiazole; and further converting the 5-methyl-2-chloro-1, 3, 4-thiadiazole or the 5-methyl-2-bromo-1, 3, 4-thiadiazole into the compound shown in the formula III.
3. The method for recycling 5-methyl-2-hydroxy-1, 3, 4-thiadiazole according to claim 2, wherein the method for converting the compound of formula II into 5-methyl-2-chloro-1, 3, 4-thiadiazole is as follows: the molar ratio of the compound of formula II to the chlorinating agent is 1: 0.45-3, reacting in a solvent at 20-115 ℃ for 9-12 hours; after the reaction is finished, carrying out post-treatment, concentrating the system under reduced pressure until the system is dry, and then recrystallizing with methanol or ethanol; the chlorination reagent is one or a mixture of more of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, methylene phosphorus trichloride, chlorine, cyano trichloromethane, NCS and trichloroisocyanuric acid; the preferable reaction temperature is 60-115 ℃; the solvent is toluene, 1, 2-dichloroethane or thionyl chloride.
4. The method for recycling 5-methyl-2-hydroxy-1, 3, 4-thiadiazole according to claim 2, wherein the method for converting the compound of formula II into 5-methyl-2-bromo-1, 3, 4-thiadiazole is as follows: the molar ratio of the compound of formula II to the brominating reagent is 1: 0.5 to 1.5, and reacting in toluene or carbon tetrachloride at the temperature of 20 to 115 ℃ for 8 to 12 hours; after the reaction is finished, carrying out post-treatment, concentrating the system under reduced pressure until the system is dry, and then recrystallizing with methanol or ethanol; the bromination reagent is one or a mixture of more of phosphorus tribromide, NBS, phosphorus pentabromide, phosphorus oxybromide and phosphorus oxychloride and bromine; the preferable reaction temperature is 60-115 ℃.
5. The method for recycling 5-methyl-2-hydroxy-1, 3, 4-thiadiazole according to claim 2, wherein the method for synthesizing the compound of formula iii comprises: adding 5-methyl-2-bromine/chlorine-1, 3, 4-thiadiazole and thiourea into ethanol or ether solvent according to a molar ratio of 1: 1.2-2.0, heating to 50-60 ℃, and reacting for 9-12 hours; cooling to below 30 ℃, adding inorganic base, heating to 40-50 ℃, and reacting for 3-4 hours; after the reaction is finished, cooling to room temperature, adding water, concentrating to remove the solvent, extracting with ethyl acetate or dichloromethane to remove impurities, adjusting the pH value to acidity with hydrochloric acid, and separating out a solid product; the sulfur reagent is preferably, but not limited to, thiourea, potassium thioacetate, sodium thioacetate.
6. The method for recycling 5-methyl-2-hydroxy-1, 3, 4-thiadiazole according to claim 5, wherein the inorganic base is one or a mixture of sodium hydroxide, potassium hydroxide and cesium carbonate.
7. The recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole according to claim 5, wherein the molar ratio of the inorganic base to 5-methyl-2-bromo/chloro-1, 3, 4-thiadiazole is 0.5-4.0: 1.
8. the method for recycling 5-methyl-2-hydroxy-1, 3, 4-thiadiazole according to claim 1, wherein in the step (1), the compound of formula II can be converted into the compound of formula iii in one step.
9. The method of claim 8, wherein the molar ratio of the compound of formula II to the sulfiding agent is 1: 0.2 to 1.2, preferably 1: 0.6; reacting in a solvent at 20-30 ℃ for 1-3 hours; the vulcanizing agent is phosphorus pentasulfide; the solvent is tetrahydrofuran, dioxane or anhydrous glycol dimethyl ether, and is preferably tetrahydrofuran.
10. The method for recycling 5-methyl-2-hydroxy-1, 3, 4-thiadiazole according to claim 1, wherein in the step (2), the method for further synthesizing the intermediate compound of rosuvastatin as shown in formula I by using the compound of formula iii is as follows: after the compound shown in the formula III reacts with tert-butyl (3R,5S) -6-chloro-3, 5-dioxo (acetonide) hexanoate, the compound is oxidized and reacts with 2- (N-methyl-N-methylsulfonyl) amino-4- (4-fluorobenzene) group-6-isopropylpyrimidine-5-formaldehyde to obtain the intermediate compound shown in the formula I;
11. the method of any one of claims 1 to 10, wherein the same applies to the compound of formula II-b:
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