CN106749057A - A kind of synthetic method of midbody compound and prothioconazoles - Google Patents
A kind of synthetic method of midbody compound and prothioconazoles Download PDFInfo
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- CN106749057A CN106749057A CN201611264830.0A CN201611264830A CN106749057A CN 106749057 A CN106749057 A CN 106749057A CN 201611264830 A CN201611264830 A CN 201611264830A CN 106749057 A CN106749057 A CN 106749057A
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- CN
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- Prior art keywords
- prothioconazoles
- reaction
- synthetic method
- compound
- triazoles
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 91
- 238000010189 synthetic method Methods 0.000 title claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 33
- 239000000460 chlorine Substances 0.000 claims abstract description 10
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 150000000178 1,2,4-triazoles Chemical class 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 7
- -1 (2 chlorphenyl) 2 propyl Chemical group 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 21
- 239000012074 organic phase Substances 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 17
- 239000000047 product Substances 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 16
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 239000005864 Sulphur Substances 0.000 claims description 11
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 239000013078 crystal Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical group [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- 239000011505 plaster Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000012265 solid product Substances 0.000 claims description 5
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- MOFINMJRLYEONQ-UHFFFAOYSA-N [N].C=1C=CNC=1 Chemical class [N].C=1C=CNC=1 MOFINMJRLYEONQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims 2
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 239000004411 aluminium Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 32
- 238000000034 method Methods 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 abstract description 3
- 230000002860 competitive effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000012805 post-processing Methods 0.000 abstract description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 201000010099 disease Diseases 0.000 description 6
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 150000003852 triazoles Chemical class 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 4
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 4
- BASMANVIUSSIIM-UHFFFAOYSA-N 1-chloro-2-(chloromethyl)benzene Chemical class ClCC1=CC=CC=C1Cl BASMANVIUSSIIM-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241000209140 Triticum Species 0.000 description 3
- 235000021307 Triticum Nutrition 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 2
- 240000005979 Hordeum vulgare Species 0.000 description 2
- 235000007340 Hordeum vulgare Nutrition 0.000 description 2
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- BQPPJGMMIYJVBR-UHFFFAOYSA-N (10S)-3c-Acetoxy-4.4.10r.13c.14t-pentamethyl-17c-((R)-1.5-dimethyl-hexen-(4)-yl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C BQPPJGMMIYJVBR-UHFFFAOYSA-N 0.000 description 1
- CHGIKSSZNBCNDW-UHFFFAOYSA-N (3beta,5alpha)-4,4-Dimethylcholesta-8,24-dien-3-ol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21 CHGIKSSZNBCNDW-UHFFFAOYSA-N 0.000 description 1
- QEASJVYPHMYPJM-UHFFFAOYSA-N 1,2-dihydrotriazol-5-one Chemical class OC1=CNN=N1 QEASJVYPHMYPJM-UHFFFAOYSA-N 0.000 description 1
- XYTLYKGXLMKYMV-UHFFFAOYSA-N 14alpha-methylzymosterol Natural products CC12CCC(O)CC1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C XYTLYKGXLMKYMV-UHFFFAOYSA-N 0.000 description 1
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- FPTJELQXIUUCEY-UHFFFAOYSA-N 3beta-Hydroxy-lanostan Natural products C1CC2C(C)(C)C(O)CCC2(C)C2C1C1(C)CCC(C(C)CCCC(C)C)C1(C)CC2 FPTJELQXIUUCEY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 241001530056 Athelia rolfsii Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- BKLIAINBCQPSOV-UHFFFAOYSA-N Gluanol Natural products CC(C)CC=CC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(O)C(C)(C)C4CC3 BKLIAINBCQPSOV-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- LOPKHWOTGJIQLC-UHFFFAOYSA-N Lanosterol Natural products CC(CCC=C(C)C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 LOPKHWOTGJIQLC-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010027146 Melanoderma Diseases 0.000 description 1
- 206010068052 Mosaicism Diseases 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-methyl-pyrrolidinone Natural products CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CAHGCLMLTWQZNJ-UHFFFAOYSA-N Nerifoliol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C CAHGCLMLTWQZNJ-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- VEZNCHDBSQWUHQ-UHFFFAOYSA-N chlorocyclopropane Chemical class ClC1CC1 VEZNCHDBSQWUHQ-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- QBSJHOGDIUQWTH-UHFFFAOYSA-N dihydrolanosterol Natural products CC(C)CCCC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 QBSJHOGDIUQWTH-UHFFFAOYSA-N 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 229940058690 lanosterol Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000030208 low-grade fever Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000003765 sex chromosome Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/12—Oxygen or sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of midbody compound and the synthetic method of prothioconazoles, wherein method includes, by 5,5 ' dithiobises (1,2,4 triazoles) obtain key intermediate compound with the generation substitution reaction of 2 (1 chlorine cyclopropyl) 3 chlorine 1 (2 chlorphenyl) 2 propyl alcohol；Then target product prothioconazoles are obtained through reduction.Synthesis technique conversion ratio of the present invention and selectivity are high, and synthesis material is cheap and easily-available, reduces production cost.Also, the technological reaction mild condition that the present invention is used is easily-controllable, easy to operate, product purification is easy, can directly be recrystallized to give product.Wherein, body controlling means are simple, accurate in the middle of each step, and product yield is higher, and Atom economy is preferable, it is to avoid cumbersome post processing, with very big competitive advantage and industrial production value.Simultaneously, it is to avoid using raw materials such as highly basic, the three wastes are extremely low, meet the theory of Green Chemistry.
Description
Technical field
The invention belongs to organic synthesis field, and in particular to the synthesis side of a kind of midbody compound and prothioconazoles
Method.
Background technology
Prothioconazoles are a kind of demethylation inhibitors (DMIs), its mechanism of action be suppress the precursor of sterol in fungi-
Lanosterol l4- demethylation reaction.Prothioconazoles not only have a good systemic activity, excellent protection, treatment and shovel
Except activity, and lasting period are long.Substantial amounts of field control effectiveness test result shows that prothioconazoles not only have good safety to crop
Property, preventing disease theraping effect is good, and volume increase is obvious, and compared with triazole bactericidal agent, prothioconazoles have broader spectrum of sterilized living
Property.
Prothioconazoles are currently used primarily in preventing and treating cereal crop such as wheat, barley, rape, peanut, paddy rice and beans and make
Numerous diseases such as thing.Prothioconazoles almost have good prevention effect, such as white powder of wheat and barley to all wheat class diseases
Disease, banded sclerotial blight, droop, leaf spot, rust, sclerotiniose, net blotch, moire disease etc..Prothioconazoles can also prevent and treat rape and flower
Raw soil-borne disease, such as sclerotiniose, and main foliage disease, such as gray mold, black spot, brown spot, balck shank and rust.
Source according to sulphur atom is different, and the preparation strategy of prothioconazoles can be divided into two major classes.The first kind prepares rosickyite bacterium
The strategy of azoles is, with hydroxyl triazole compounds as key intermediate, prothioconazoles (US4913727) to be obtained with sulfur reaction.Sulphur exists
As the source of prothioconazoles compound sulphur atom in this kind of reaction.The key intermediate of the method can be with chloride
Or epoxide (US5146001) is that initiation material and triazole are substituted reaction and are obtained (US4913727).This substitution reaction
Considerable amount of region isomer can simultaneously be produced, it is necessary to pass through refined removal, cause yield not good enough (51~53%).In the middle of crucial
Body can also chloro ketone be that raw material and triazole react, then be obtained with RMgBr reaction, the method equally exists regional choice
Sex chromosome mosaicism.
United States Patent (USP) US5789430 discloses the method for preparing prothioconazoles with compound and sulphur direct reaction.This is anti-
Prothioconazoles should be reacted 44 hours to obtain at 200 DEG C with N- N-methyl 2-pyrrolidone Ns as solvent, yield is 20%.US5789430 is simultaneously
Also disclose that the improved method that prothioconazoles are prepared with compound and sulfur reaction.The improved method is that compound is molten in THF
First pull out hydrogen with n-BuLi in agent, then and sulfur reaction, the yield of gained prothioconazoles is greatly improved (93%), but the technical scheme
Anhydrous and oxygen-free and ultralow temperature consersion unit and condition are needed, while need to use being tried more than the n-BuLi of the high risk of two equivalents
Agent, makes the technical scheme high cost, and operation is dangerous, is unfavorable for industrialized production.
In addition, the technical scheme is also perplexed by itself chemical regions selectivity simultaneously, for example：(1) in key intermediate
If being pulled out during hydrogen with n-BuLi, control is improper will to cause the generation of regional isomerism impurity 11；(2) when key intermediate is prepared
If it is clean that region isomer is not completely segregated purification, the generation of regional isomerism impurity will be caused.The separation of these high requests
Purification not only produces a large amount of three wastes, while greatly increasing cost.
US2013005985 is disclosed one kind and compound is pulled out instead of n-BuLi using RMgBr such as i-PrMgCl
Vulcanize the method for preparing prothioconazoles after hydrogen again.This method solve using n-BuLi reagent dangerous problems, but the technical side
Case needs for anhydrous and oxygen-free and ultralow temperature consersion unit and condition, while the RMgBr more than two equivalents is needed to use, and
And yield declines to a great extent (drop to 68% from the 93% of n-BuLi).
The content of the invention
The purpose of this part is to summarize some aspects of embodiments of the invention and briefly introduce some preferable implementations
Example.May be done in this part and the description of the present application summary and denomination of invention a little simplified or omitted to avoid making our department
Point, the purpose of specification digest and denomination of invention obscure, and this simplification or omission cannot be used for limiting the scope of the present invention.
In view of the technological gap of above-mentioned and/or existing synthesis prothioconazoles, it is proposed that the present invention.
Therefore, one of purpose of the invention is to provide a kind of midbody compound, and the midbody compound can be used
In the synthesis of prothioconazoles.
In order to solve the above technical problems, the invention provides following technical scheme：A kind of midbody compound, its chemistry knot
Structure formula is：
The present invention another purpose therein is the deficiency for solving prothioconazoles synthetic method in the prior art, is improved each
The conversion ratio of step, reduces accessory substance, simplifies reaction condition, and reducing energy consumption shortens the reaction time, improves atom utilization, reduces
The three wastes.
In order to solve the above technical problems, the invention provides following technical scheme：A kind of synthetic method of prothioconazoles, bag
Include, with 1,2,4- triazoles are that raw material obtains sulfydryl -1,2,4- triazoles through sulphur oxidation；Sulfydryl -1,2,4- triazoles are oxidized
Form 5,5 '-disulfide group-bis- (1,2,4- triazole)；Sent out with 2- (1- chlorine cyclopropyl) the chloro- 1- of -3- (2- chlorphenyls) -2- propyl alcohol
Raw substitution reaction obtains midbody compound as claimed in claim 1；Target product prothioconazoles are obtained through reduction.
As a kind of preferred scheme of the synthetic method of prothioconazoles of the present invention, wherein：It is described with 1,2,4- tri- nitrogen
Azoles obtains sulfydryl -1 for raw material is aoxidized through sulphur, 2,4- triazoles, including, by 1,2,4- triazoles are dissolved in organic solvent, are added
It is 1 with 1,2,4- triazole mol ratios：3~1：6 sulphur, is heated to 100~180 DEG C, reacts 2~8h, it is cooled to room temperature, mistake
Filter, filtrate is washed with saturated sodium-chloride, is extracted through ethyl acetate, separates organic phase, is dried, and ethyl acetate is evaporated off and obtains sulfydryl -1,
2,4- triazoles；Wherein, organic solvent is one or more in DMF or toluene or DMSO；Wherein, drying uses solid drier
It is one or more in anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, dead plaster or activated alumina.
As a kind of preferred scheme of the synthetic method of prothioconazoles of the present invention, wherein：It is described be heated to 100~
180 DEG C, its temperature is preferably 110~160 DEG C.
As a kind of preferred scheme of the synthetic method of prothioconazoles of the present invention, wherein：2~8h of the reaction, its
Reaction time is preferably 3~6h.
As a kind of preferred scheme of the synthetic method of prothioconazoles of the present invention, wherein：Sulfydryl -1,2,4- tri-
The oxidized formation 5 of nitrogen azoles, 5 '-disulfide group-bis- (1,2,4- triazole), including, by sulfydryl -1,2,4- triazoles are dissolved in DCM,
Pyridine is added, temperature is controlled for -2 DEG C~6 DEG C, stirring adds benzene sulfonyl chloride, DCM is removed after reaction, residue adds water and second
Acetoacetic ester, is filtered after reaction, and is washed with water and ethyl acetate, and the solid product that will be filtrated to get is dried, and obtains solid chemical combination
Thing (V) is 5,5 '-disulfide group-bis- (1,2,4- triazole)；Wherein, drying uses solid drier for anhydrous magnesium sulfate, anhydrous
One or more in calcium chloride, anhydrous sodium sulfate, dead plaster or activated alumina.
As a kind of preferred scheme of the synthetic method of prothioconazoles of the present invention, wherein：The reaction temperature is preferred
It is 0 DEG C~4 DEG C.
As a kind of preferred scheme of the synthetic method of prothioconazoles of the present invention, wherein：Described and 2- (1- chlorine rings third
Base) there is substitution reaction in the chloro- 1- of -3- (2- chlorphenyls) -2- propyl alcohol, including, by the solid chemical compound (V) and organic solvent,
Potassium carbonate stirring mixing, is heated to 20 DEG C~100 DEG C, adds 2- (1- chlorine cyclopropyl) the chloro- 1- of -3- (2- chlorphenyls) -2- propyl alcohol
Midbody compound, is cooled to room temperature, suction filtration after reaction, filtrate uses saturated common salt water washing, ethyl acetate extraction, organic phase to use
Saturated common salt water washing, separates organic phase, dries, and revolving obtains compound (VI)；Wherein, organic solvent is methyl alcohol, ethanol, different
One or more in propyl alcohol, acetonitrile, acetone or DMF；Wherein, solid chemical compound (V) is 1 with potassium carbonate mol ratio：2~1：4；
Wherein, solid chemical compound (V) same to 2- (1- chlorine cyclopropyl) the chloro- 1- of -3- (2- chlorphenyls) -2- propanol compounds (II) mol ratio is
1：2~1：5；Wherein, it is anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, dead plaster that drying uses solid drier
Or one or more in activated alumina.
As a kind of preferred scheme of the synthetic method of prothioconazoles of the present invention, wherein：The solid drier, it is excellent
Elect anhydrous sodium sulfate as.
As a kind of preferred scheme of the synthetic method of prothioconazoles of the present invention, wherein：It is described be heated to 20 DEG C~
100 DEG C, preferably 40 DEG C~80 DEG C.
As a kind of preferred scheme of the synthetic method of prothioconazoles of the present invention, wherein：The organic solvent is, excellent
Elect DMF as.
As a kind of preferred scheme of the synthetic method of prothioconazoles of the present invention, wherein：It is described to obtain mesh through reduction
Mark product prothioconazoles, including, compound (VI) is dissolved in organic solvent, add reducing agent, 20 DEG C of -60 DEG C of bars of reaction temperature
Under part after stirring reaction, recrystallization separates out crystal and filters to obtain target compound prothioconazoles.Wherein, organic solvent is methyl alcohol, second
One or more in alcohol, isopropanol, acetonitrile, acetone；Wherein, reducing agent is in TCEP, DTT, Zn, sodium borohydride, lithium aluminium hydride reduction
One or more.
As a kind of preferred scheme of the synthetic method of prothioconazoles of the present invention, wherein：The organic solvent, preferably
It is methyl alcohol.
As a kind of preferred scheme of the synthetic method of prothioconazoles of the present invention, wherein：The reaction temperature, preferably
It is 30 DEG C~50 DEG C.
As a kind of preferred scheme of the synthetic method of prothioconazoles of the present invention, wherein：The reducing agent, preferably
Metal Zn.
Beneficial effects of the present invention：
(1) synthesis technique conversion ratio of the present invention and selectivity are high, and synthesis material is cheap and easily-available, reduces production cost.
(2) reaction condition is gently easily-controllable, easy to operate, and product purification is easy, can directly be recrystallized to give product.
(3) body controlling means are simple, accurate in the middle of each step, and product yield is higher, and Atom economy is preferable, it is to avoid cumbersome
Post processing, with very big competitive advantage and industrial production value.
(4) avoid using raw materials such as highly basic, the three wastes are extremely low, meet the theory of Green Chemistry.
Brief description of the drawings
Technical scheme in order to illustrate more clearly the embodiments of the present invention, below will be to that will use needed for embodiment description
Accompanying drawing be briefly described, it should be apparent that, drawings in the following description are only some embodiments of the present invention, for this
For the those of ordinary skill of field, without having to pay creative labor, other can also be obtained according to these accompanying drawings
Accompanying drawing.Wherein：
Fig. 1 is the MS collection of illustrative plates of compounds Ⅳ；
Fig. 2 is the MS collection of illustrative plates of compound V；
Fig. 3 is the MS collection of illustrative plates of compound VI；
Fig. 4 is the MS collection of illustrative plates of compound VII；
Fig. 5 is compound VII1H-NMR collection of illustrative plates, wherein,1H NMR (400MHz, Chloroform-d) δ 11.92 (s,
1H), 7.85 (s, 1H), 7.59-7.50 (m, 1H), 7.40-7.33 (m, 1H), 7.21 (tt, J=7.3,5.3Hz, 2H), 4.79
(d, J=14.6Hz, 1H), 4.50 (d, J=14.6Hz, 1H), 4.27 (s, 1H), 3.62 (d, J=14.0Hz, 1H), 3.17 (d,
J=14.0Hz, 1H), 1.02-0.85 (m, 2H), 0.85-0.73 (m, 2H).
Specific embodiment
To enable the above objects, features and advantages of the present invention more obvious understandable, with reference to specific embodiment pair
Specific embodiment of the invention is described in detail.
Many details are elaborated in the following description in order to fully understand the present invention, but the present invention can be with
Other manner described here is different from using other to implement, those skilled in the art can be without prejudice to intension of the present invention
In the case of do similar popularization, therefore the present invention is not limited by following public specific embodiment.
Secondly, " one embodiment " or " embodiment " referred to herein refers to that may be included at least one realization side of the invention
Special characteristic, structure or characteristic in formula." in one embodiment " that different places occur in this manual not refers both to
Same embodiment, nor the single or selective embodiment mutually exclusive with other embodiment.
In order to describe convenience of the invention, routine and unconventional abbreviation using various reagents.These abbreviations are this areas
Familiar to technical staff, but in order to clearly be listed below：
THF：Tetrahydrofuran
DMF：DMF
DMSO：Dimethyl sulfoxide (DMSO)
DCM：Dichloromethane
TCEP：Three (2- carboxyethyls) phosphines
DTT：Dithiothreitol (DTT)
Embodiment 1：
The synthesis of 2- (1- chlorine cyclopropyl) the chloro- 1- of -3- (2- chlorphenyls) -2- propyl alcohol
Under the 250mL flask with three necks,round bottom devices of persevering pressure titration funnel and condenser pipe, anhydrous and oxygen-free operation nitrogen is carried out
Under the conditions of gas shielded, 10g (0.062mol) 2- chlorobenzyl chlorides are mixed with 50mLTHF solution and is placed in constant pressure funnel, three
The THF solution and a small amount of iodine of 1.8g (0.074mol) magnesium chips and 10ml are added in mouth flask, the THF of 2ml 2- chlorobenzyl chlorides is instilled
Solution, low-grade fever triggers, and places a device into and be slowly added dropwise in ice bath (drop/3s) until dripping off, and 1h is reacted after dripping off again, by above-mentioned lattice
THF (30mL) solution that family name's reactant slowly instills the chloro- 1- chloracetyls cyclopropane of 9.0g (0.058mol) 1- is slowly added dropwise
(drop/3s) drips off continuation and reacts 1h up to dripping off, and device is consistently placed in ice bath.Finally slowly reaction solution is slowly added into
Reaction is quenched in the NH4Cl ice water solutions of saturation, 1h is stirred, organic phase is separated with separatory funnel, add anhydrous sodium sulfate drying
Afterwards, THF is evaporated off to obtain, obtains 14.45g compounds (II) pale yellowish oil liquid, yield is 89%.
Embodiment 2：
The synthesis of prothioconazoles
The synthesis of compound (IV)
The triazoles of 5g (0.072mol) 1,2,4- are dissolved in the DMF of 15ml, 6.9g (0.216mol) sublimed sulfur is added, plus
Heat after reaction 3.5h, is cooled to room temperature to 140 DEG C, filters, and filtrate is washed with saturated sodium-chloride, and ethyl acetate extraction has been separated
Machine phase, with anhydrous sodium sulfate drying, is evaporated off ethyl acetate and obtains solid chemical compound (IV) 6.95g, and yield is 95%.
The synthesis of compound (V)
3.03g (30mmol) compound (IV) is dissolved in 30mLDCM, adds 2.37g (30mmol) to steam pyridine again.Ice bath
Under stirring condition, 2.64g (15mmol) benzene sulfonyl chloride, 1h or so completion of dropping is added dropwise.Ice-water bath is removed, 5h is stirred at room temperature.
DCM is boiled off, residue adds 15mL water and 10mL ethyl acetate, react 1h, filtering, and washed with appropriate water and ethyl acetate
Wash.The solid product that will be filtrated to get is drained in vacuum drying chamber, obtains solid chemical compound (V) 2.88g, and yield is 96%.
The synthesis of compound (VI)
By 4g (20mmol) compound (V) and the stirring mixing of 20ml DMF, 5.52g (40mmol) potassium carbonate, 50 are heated to
℃.Compound (II) 11.74g (42mmol) is added dropwise, 2h completion of dropping continues to react h, stops reaction, is cooled to room temperature.Take out
Filter, filtrate uses saturated common salt water washing, ethyl acetate extraction, organic phase saturated common salt water washing three times, separates organic phase, nothing
Aqueous sodium persulfate is dried, the product of revolving.Compound (VI) 11.4g is obtained, yield is 83%.
The synthesis of target compound (VII) prothioconazoles
Take 5g (0.0072mol) compound (VI) to be dissolved in the methyl alcohol of 30ml, add 0.97g (0.015mol) metal Zn,
30 DEG C of stirring reaction 3h, stop reaction, directly recrystallize, and separate out crystal and filter to obtain target compound (VII) prothioconazoles 4.3g,
Yield is 86%.
The present invention redesigns synthetic route to reduce production cost in above-described embodiment mode, improves each step
Conversion ratio,, with 1,2,4- triazoles are that raw material obtains sulfydryl -1,2,4- triazoles through sulphur oxidation, then form two sulphur through peroxidating for it
Key, then with as the chloro- 1- chloracetyls cyclopropane of 1- with 2- chlorobenzyl chlorides through grignard reaction obtained in 2- (1- chlorcyclopropanes) -3- it is chloro-
There is substitution reaction in 1- (2- chlorphenyls) -2- propyl alcohol, then just obtain target product prothioconazoles through reduction.Its principle is by chemistry
Formula is expressed as：
Comparative example 1：
The synthesis of prothioconazoles
The synthesis of compound (IV)
The triazoles of 5g (0.072mol) 1,2,4- are dissolved in the DMSO of 15ml, 11.52g (0.36mol) sublimed sulfur is added,
180 DEG C are heated to, after reaction 5h, room temperature is cooled to, filtered, filtrate is washed with saturated sodium-chloride, ethyl acetate extraction has been separated
Machine phase, with anhydrous sodium sulfate drying, is evaporated off ethyl acetate and obtains solid chemical compound (IV) 5.89g, and yield is 81%.
The synthesis of compound (V)
3.03g (30mmol) compound (IV) is dissolved in 30mLDCM, adds 3.16g (40mmol) to steam pyridine again.6℃
Under stirring condition, 3.53g (20mmol) benzene sulfonyl chloride, 1h or so completion of dropping is added dropwise.4h is stirred at room temperature.DCM is boiled off, it is remaining
Thing adds 20mL water and 20mL ethyl acetate, reacts 1h, filtering, and washed with appropriate water and ethyl acetate.To be filtrated to get
Solid product drained in vacuum drying chamber, obtain solid chemical compound (V) 2.49g, yield is 83%.
The synthesis of compound (VI)
By 4g (20mmol) compound (V) and 40ml acetonitriles, 8., the stirring mixing of 28g (60mmol) potassium carbonate is heated to
80℃.Compound (II) 21.24g (80mmol) is added dropwise, 2h completion of dropping continues to react 4h, stops reaction, is cooled to room temperature.
Suction filtration, filtrate uses saturated common salt water washing, ethyl acetate extraction, organic phase saturated common salt water washing three times, separates organic phase,
Anhydrous sodium sulfate drying, the product of revolving.Compound (VI) 10.7g is obtained, yield is 78%.
The synthesis of target compound (VII) prothioconazoles
Take 5g (0.0072mol) compound (VI) to be dissolved in the ethanol of 30ml, add 1.98g (0.0079mol) TCEP, 50
DEG C stirring reaction 3h, stops reaction, directly recrystallizes, and separates out crystal and filters to obtain target compound (VII) prothioconazoles 4.1g, receipts
Rate is 82%.
Comparative example 2：
The synthesis of prothioconazoles
The synthesis of compound (IV)
The triazoles of 5g (0.072mol) 1,2,4- are dissolved in the toluene of 20ml, 9.22g (0.288mol) sublimed sulfur is added,
100 DEG C are heated to, after reaction 10h, room temperature is cooled to, filtered, filtrate is washed with saturated sodium-chloride, ethyl acetate extraction is separated
Organic phase, with anhydrous sodium sulfate drying, is evaporated off ethyl acetate and obtains solid chemical compound (IV) 4.07g, and yield is 56%.
The synthesis of compound (V)
3.03g (30mmol) compound (IV) is dissolved in 30mLDCM, adds 3.16g (40mmol) to steam pyridine again.-2℃
Under stirring condition, 3.53g (20mmol) benzene sulfonyl chloride, 1h or so completion of dropping is added dropwise.5h is stirred at room temperature.DCM is boiled off, it is remaining
Thing adds 20mL water and 20mL ethyl acetate, reacts 1h, filtering, and washed with appropriate water and ethyl acetate.To be filtrated to get
Solid product drained in vacuum drying chamber, obtain solid chemical compound (V) 2.1g, yield is 70%.
The synthesis of compound (VI)
4g (20mmol) compound (V) and 40ml acetone, the stirring mixing of 11.04g (80mmol) potassium carbonate are heated to
30℃.Compound (II) 21.24g (60mmol) is added dropwise, 2h completion of dropping continues to react 4h, stops reaction, is cooled to room temperature.
Suction filtration, filtrate uses saturated common salt water washing, ethyl acetate extraction, organic phase saturated common salt water washing three times, separates organic phase,
Anhydrous sodium sulfate drying, the product of revolving.Compound (VI) 7.0g is obtained, yield is 51%.
The synthesis of target compound (VII) prothioconazoles
Take 5g (0.0072mol) compound (VI) to be dissolved in the acetone of 30ml, add 0.55g (0.0144mol) hydroboration
Sodium, 20 DEG C of stirring reaction 5h stop reaction, directly recrystallize, and separate out crystal and filter to obtain target compound (VII) prothioconazoles
2.72g, yield is 55%.
Embodiment 3
The synthesis of compound (VI)
By 6g (30mmol) compound (V) and the stirring mixing of 30ml DMF, 12.42g (90mmol) potassium carbonate, it is heated to
60℃.Compound (II) 17.61g (63mmol) is added dropwise, 2h completion of dropping continues to react, and stops reaction, is cooled to room temperature.Take out
Filter, filtrate uses saturated common salt water washing, ethyl acetate extraction, organic phase saturated common salt water washing three times, separates organic phase, nothing
Aqueous sodium persulfate is dried, the product of revolving.Compound (VI) 17.31g is obtained, yield is 84%.
The synthesis of target compound (VII) prothioconazoles
Take 6.25g (0.009mol) compound (VI) to be dissolved in the methyl alcohol of 30ml, add 1.21g (0.019mol) metal
Zn, 40 DEG C of stirring reaction 3h, stop reaction, directly recrystallize, and separate out crystal and filter to obtain target compound (VII) prothioconazoles
5.5g, yield is 88%.
Embodiment 4
The synthesis of compound (VI)
By 6g (30mmol) compound (V) and the stirring mixing of 30ml DMF, 12.42g (90mmol) potassium carbonate, it is heated to
80℃.Compound (II) 17.61g (63mmol) is added dropwise, 2h completion of dropping continues to react, and stops reaction, is cooled to room temperature.Take out
Filter, filtrate uses saturated common salt water washing, ethyl acetate extraction, organic phase saturated common salt water washing three times, separates organic phase, nothing
Aqueous sodium persulfate is dried, the product of revolving.Compound (VI) 16.49g is obtained, yield is 80%.
The synthesis of target compound (VII) prothioconazoles
Take 6.25g (0.009mol) compound (VI) to be dissolved in the methyl alcohol of 30ml, add 0.97g (0.015mol) metal boron
Sodium hydride, 50 DEG C of stirring reaction 3h stop reaction, directly recrystallize, and separate out crystal and filter to obtain target compound (VII) rosickyite bacterium
Azoles 5.06g, yield is 81%.
Embodiment 5
The synthesis of compound (VI)
By 6g (30mmol) compound (V) and the stirring mixing of 30ml DMF, 12.42g (90mmol) potassium carbonate, it is heated to
100℃.Compound (II) 17.61g (63mmol) is added dropwise, 2h completion of dropping continues to react, and stops reaction, is cooled to room temperature.Take out
Filter, filtrate uses saturated common salt water washing, ethyl acetate extraction, organic phase saturated common salt water washing three times, separates organic phase, nothing
Aqueous sodium persulfate is dried, the product of revolving.Compound (VI) 11.54g is obtained, yield is 56%.
The synthesis of target compound (VII) prothioconazoles
Take 6.25g (0.009mol) compound (VI) to be dissolved in the methyl alcohol of 30ml, add 0.97g (0.015mol) metal
TECP, 20 DEG C of stirring reaction 3h, stop reaction, directly recrystallize, and separate out crystal and filter to obtain target compound (VII) prothioconazoles
3.44g, yield is 55%.
The reaction principle of embodiment 3~5 is：
In above-described embodiment 1~5, the key intermediate compound of synthesising target compound is generated, its chemical constitution
Formula is：
Based on the data that above-described embodiment is provided, it is known that the synthetic method of the prothioconazoles that the present invention is provided, can obtain
To more excellent yield.
In the particular embodiment, embodiment 1 and 2, using present invention offer on organic solvent selection, temperature control
Scope processed and the preferred scheme of reducing agent selection, so the yield in each phase targets compound is more excellent.Compared to it
Under, comparative example 1, and preferred scheme is followed substantially, and in synthetic route, this is provided without in the synthesis of individual target compound
The preferred scheme of the temperature or reducing agent for providing is invented, corresponding yield is undesirable.In comparative example 2, each step targeted
With the synthesis of thing, preferred model of the present invention on the selection of reaction time, reaction temperature, organic solvent and reducing agent is provided without
Enclose.
Wherein specific mechanism is as follows：
From in terms of reaction temperature and reaction time angle, too high reaction temperature and long reaction time, it may appear that reaction
When balancing objective product accounts for major portion, reaction is still continuing, and balance is pushed further into so that accessory substance increases；Too low is anti-
Temperature and too short reaction time are answered, can cause that reaction cannot be carried out fully, preferable chemical balance can not be presented, then obtained
Obtain preferably target product and compare yield.The present invention is by the design to synthetic route, and the reaction that each step target product synthesizes
Temperature and the matched design in reaction time, provide preferred control range.
It should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to preferably
Embodiment has been described in detail to the present invention, it will be understood by those within the art that, can be to technology of the invention
Scheme is modified or equivalent, and without deviating from the spirit and scope of technical solution of the present invention, it all should cover in this hair
In the middle of bright right.
Claims (10)
1. a kind of midbody compound, it is characterised in that its chemical structural formula is：
2. a kind of synthetic method of prothioconazoles, it is characterised in that：Including,
5,5 '-disulfide group-bis- (1,2,4- triazole) occurs with 2- (1- chlorine cyclopropyl) the chloro- 1- of -3- (2- chlorphenyls) -2- propyl alcohol
Substitution reaction obtains midbody compound as claimed in claim 1；
Target product prothioconazoles are obtained through reduction.
3. the synthetic method of prothioconazoles according to claim 2, it is characterised in that：In obtaining as claimed in claim 1
Before intermediate compounds therefor, also include,
With 1,2,4- triazoles are that raw material obtains sulfydryl -1,2,4- triazoles through sulphur oxidation；
Sulfydryl -1,2,4- triazoles are oxidized to form 5,5 '-disulfide group-bis- (1,2,4- triazole).
4. the synthetic method of prothioconazoles according to claim 3, it is characterised in that：
It is described that with 1,2,4- triazoles obtain sulfydryl -1 for raw material is aoxidized through sulphur, 2,4- triazoles, including, by 1,2,4- triazoles
It is dissolved in organic solvent, it is 1 to add with 1,2,4- triazole mol ratios：3~1：6 sulphur, is heated to 100~180 DEG C, reaction 2
~8h, room temperature is cooled to, to filter, filtrate is washed with saturated sodium-chloride, is extracted through ethyl acetate, separates organic phase, is dried, and is steamed
Except ethyl acetate obtains sulfydryl -1,2,4- triazoles；Wherein,
The organic solvent is one or more in DMF or toluene or DMSO；
It is anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, dead plaster or activity that the drying uses solid drier
One or more in aluminum oxide.
5. the synthetic method of prothioconazoles according to claim 4, it is characterised in that：It is described to be heated to 100~180 DEG C, its
Temperature is preferably 110~160 DEG C.
6. according to the synthetic method of any prothioconazoles of claim 3~5, it is characterised in that：Sulfydryl -1,2,4- tri-
The oxidized formation 5 of nitrogen azoles, 5 '-disulfide group-bis- (1,2,4- triazole), including,
By sulfydryl -1,2,4- triazoles are dissolved in DCM, add pyridine, control temperature for -2 DEG C~6 DEG C, and stirring adds benzene sulfonyl
Chlorine, removes DCM after reaction, residue adds water and ethyl acetate, is filtered after reaction, and is washed with water and ethyl acetate, incited somebody to action
The solid product that filter is obtained is dried, and obtains 5,5 '-disulfide group-bis- (1,2,4- triazole)；Wherein,
It is anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, dead plaster or active oxidation that drying uses solid drier
One or more in aluminium.
7. the synthetic method of prothioconazoles according to claim 6, it is characterised in that：The reaction temperature is preferably 0 DEG C~4
℃。
8. according to the synthetic method of any prothioconazoles of claim 2~5 or 7, it is characterised in that：Described 5,5 '-two sulphur
There is substitution reaction, bag with 2- (1- chlorine cyclopropyl) the chloro- 1- of -3- (2- chlorphenyls) -2- propyl alcohol in base-bis- (1,2,4- triazole)
Include,
By described 5,5 '-disulfide group-bis- (1,2,4- triazole) and organic solvent, potassium carbonate stirring mixing, be heated to 20 DEG C~
100 DEG C, 2- (1- chlorine cyclopropyl) the chloro- 1- of -3- (2- chlorphenyls) -2- propyl alcohol is added, room temperature, suction filtration, filtrate are cooled to after reaction
Saturated common salt water washing, ethyl acetate extraction, organic phase saturated common salt water washing is used to separate organic phase, dry, revolving is obtained
Midbody compound as claimed in claim 1；Wherein,
The organic solvent is one or more in methyl alcohol, ethanol, isopropanol, acetonitrile, acetone or DMF；
5,5 '-disulfide group-bis- (1,2,4- triazole) is 1 with potassium carbonate mol ratio：2~1：4；
5,5 '-disulfide group-bis- (1,2,4- triazole) same to 2- (1- chlorine cyclopropyl) the chloro- 1- of -3- (2- chlorphenyls) -2- propyl alcohol mole
Than being 1：2~1：5；
It is anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, dead plaster or activity that the drying uses solid drier
One or more in aluminum oxide.
9. according to the synthetic method of any prothioconazoles of claim 2~5 or 7, it is characterised in that：It is described to be obtained through reduction
Target product prothioconazoles, including,
Midbody compound as claimed in claim 1 is dissolved in organic solvent, reducing agent, 20 DEG C~60 DEG C of reaction temperature is added
Under the conditions of after stirring reaction, recrystallization separates out crystal and filters to obtain target compound prothioconazoles；Wherein,
Organic solvent is one or more in methyl alcohol, ethanol, isopropanol, acetonitrile, acetone；
Reducing agent is one or more in TCEP, DTT, Zn, sodium borohydride, lithium aluminium hydride reduction.
10. the synthetic method of prothioconazoles according to claim 9, it is characterised in that：The organic solvent, preferably first
Alcohol.
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| CN107628928A (en) * | 2017-09-27 | 2018-01-26 | 长治市晋宁化工有限公司 | The preparation method of 2 (base of 1 chlorcyclopropane 1) 3 chlorine 1 (2 chlorphenyl) 2 propyl alcohol |
| CN108479821A (en) * | 2018-05-10 | 2018-09-04 | 长乐智高生物科技有限公司 | A kind of catalyst and its application for synthesizing prothioconazoles intermediate |
| WO2019171160A1 (en) | 2018-03-06 | 2019-09-12 | Upl Ltd | A process for preparation of fungicidally active triazole compounds |
| WO2019171161A1 (en) * | 2018-03-06 | 2019-09-12 | Upl Ltd | Improved process for preparation of intermediates |
| CN110483243A (en) * | 2019-09-17 | 2019-11-22 | 西安近代化学研究所 | A kind of 1-(2- chlorphenyl) -2-(1- chlorine cyclopropyl) the chloro- 2- propyl alcohol of -3- preparation method |
| CN110981822A (en) * | 2019-11-27 | 2020-04-10 | 海利尔药业集团股份有限公司 | Preparation method of prothioconazole I-type crystal form |
| CN111303059A (en) * | 2020-04-29 | 2020-06-19 | 江苏苏利精细化工股份有限公司 | Synthesis method of prothioconazole |
| CN111689904A (en) * | 2018-06-22 | 2020-09-22 | 华南农业大学 | Preparation method of triazole sulfur (selenium) ketone derivative |
| CN113788797A (en) * | 2021-10-12 | 2021-12-14 | 京博农化科技有限公司 | Desulfurized prothioconazole impurity and synthetic method and application thereof |
| CN114805227A (en) * | 2022-06-02 | 2022-07-29 | 山东海利尔化工有限公司 | Preparation method of dithio-bis-triazole compound |
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| CN107628928A (en) * | 2017-09-27 | 2018-01-26 | 长治市晋宁化工有限公司 | The preparation method of 2 (base of 1 chlorcyclopropane 1) 3 chlorine 1 (2 chlorphenyl) 2 propyl alcohol |
| CN112204016A (en) * | 2018-03-06 | 2021-01-08 | Upl有限公司 | Process for preparing fungicidally active triazole compounds |
| WO2019171160A1 (en) | 2018-03-06 | 2019-09-12 | Upl Ltd | A process for preparation of fungicidally active triazole compounds |
| WO2019171161A1 (en) * | 2018-03-06 | 2019-09-12 | Upl Ltd | Improved process for preparation of intermediates |
| EP3762369A4 (en) * | 2018-03-06 | 2022-06-15 | UPL Ltd | A process for preparation of fungicidally active triazole compounds |
| CN108479821A (en) * | 2018-05-10 | 2018-09-04 | 长乐智高生物科技有限公司 | A kind of catalyst and its application for synthesizing prothioconazoles intermediate |
| CN111689904B (en) * | 2018-06-22 | 2021-06-25 | 华南农业大学 | Preparation method of triazole sulfur (selenium) ketone derivative |
| CN111689904A (en) * | 2018-06-22 | 2020-09-22 | 华南农业大学 | Preparation method of triazole sulfur (selenium) ketone derivative |
| CN110483243A (en) * | 2019-09-17 | 2019-11-22 | 西安近代化学研究所 | A kind of 1-(2- chlorphenyl) -2-(1- chlorine cyclopropyl) the chloro- 2- propyl alcohol of -3- preparation method |
| CN110981822A (en) * | 2019-11-27 | 2020-04-10 | 海利尔药业集团股份有限公司 | Preparation method of prothioconazole I-type crystal form |
| CN111303059A (en) * | 2020-04-29 | 2020-06-19 | 江苏苏利精细化工股份有限公司 | Synthesis method of prothioconazole |
| CN111303059B (en) * | 2020-04-29 | 2022-03-04 | 江苏苏利精细化工股份有限公司 | Synthesis method of prothioconazole |
| CN113788797A (en) * | 2021-10-12 | 2021-12-14 | 京博农化科技有限公司 | Desulfurized prothioconazole impurity and synthetic method and application thereof |
| CN114805227A (en) * | 2022-06-02 | 2022-07-29 | 山东海利尔化工有限公司 | Preparation method of dithio-bis-triazole compound |
| CN114805227B (en) * | 2022-06-02 | 2023-11-21 | 山东海利尔化工有限公司 | Preparation method of dithio-ditriazole compound |
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