CN115806556B - Preparation method of ametoctradin metabolite - Google Patents
Preparation method of ametoctradin metabolite Download PDFInfo
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- CN115806556B CN115806556B CN202211586263.6A CN202211586263A CN115806556B CN 115806556 B CN115806556 B CN 115806556B CN 202211586263 A CN202211586263 A CN 202211586263A CN 115806556 B CN115806556 B CN 115806556B
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- ametoctradin
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- GGKQIOFASHYUJZ-UHFFFAOYSA-N ametoctradin Chemical class NC1=C(CCCCCCCC)C(CC)=NC2=NC=NN21 GGKQIOFASHYUJZ-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 18
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims abstract description 16
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000001590 oxidative effect Effects 0.000 claims abstract description 15
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims abstract description 12
- RXCPQSJAVKGONC-UHFFFAOYSA-N Flumetsulam Chemical compound N1=C2N=C(C)C=CN2N=C1S(=O)(=O)NC1=C(F)C=CC=C1F RXCPQSJAVKGONC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000007800 oxidant agent Substances 0.000 claims abstract description 10
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 9
- 229940126062 Compound A Drugs 0.000 claims abstract description 7
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- SEFDFCVDRHHCFS-UHFFFAOYSA-N 5-ethyl-6-iodo-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine Chemical compound NC1=C(I)C(CC)=NC2=NC=NN21 SEFDFCVDRHHCFS-UHFFFAOYSA-N 0.000 claims abstract description 6
- UCZLBERYFYDXOM-UHFFFAOYSA-N ethenyltin Chemical compound [Sn]C=C UCZLBERYFYDXOM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 125000003172 aldehyde group Chemical group 0.000 claims abstract description 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 5
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical group [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 5
- 229960002218 sodium chlorite Drugs 0.000 claims description 5
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 claims description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- -1 vinyltin compound Chemical class 0.000 claims description 4
- 239000002207 metabolite Substances 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000012285 osmium tetroxide Substances 0.000 claims description 2
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- QJPQVXSHYBGQGM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 239000004317 sodium nitrate Substances 0.000 claims description 2
- 235000010344 sodium nitrate Nutrition 0.000 claims description 2
- 235000010288 sodium nitrite Nutrition 0.000 claims description 2
- MZIYQMVHASXABC-UHFFFAOYSA-N tetrakis(ethenyl)stannane Chemical compound C=C[Sn](C=C)(C=C)C=C MZIYQMVHASXABC-UHFFFAOYSA-N 0.000 claims description 2
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical group C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 claims description 2
- 230000002503 metabolic effect Effects 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 238000004809 thin layer chromatography Methods 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 9
- 238000000746 purification Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 238000003809 water extraction Methods 0.000 description 5
- 239000005726 Ametoctradin Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 241000233866 Fungi Species 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 239000005869 Pyraclostrobin Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical group CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- HZRSNVGNWUDEFX-UHFFFAOYSA-N pyraclostrobin Chemical compound COC(=O)N(OC)C1=CC=CC=C1COC1=NN(C=2C=CC(Cl)=CC=2)C=C1 HZRSNVGNWUDEFX-UHFFFAOYSA-N 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 108010078777 Colistin Proteins 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- SYJGKVOENHZYMQ-UHFFFAOYSA-N Penoxsulam Chemical class N1=C2C(OC)=CN=C(OC)N2N=C1NS(=O)(=O)C1=C(OCC(F)F)C=CC=C1C(F)(F)F SYJGKVOENHZYMQ-UHFFFAOYSA-N 0.000 description 1
- 241000233679 Peronosporaceae Species 0.000 description 1
- 241000233614 Phytophthora Species 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960003346 colistin Drugs 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000021393 food security Nutrition 0.000 description 1
- 235000012055 fruits and vegetables Nutrition 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000003673 groundwater Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000006540 mitochondrial respiration Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 description 1
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 description 1
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical group [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a preparation method of an ametoctradin metabolite, which comprises the following steps: (1) Taking a compound A, namely 5-ethyl-6-iodo- [1,2,4] triazolo [1,5-a ] pyrimidine-7-amine as a raw material, adding BOC anhydride and alkali, and reacting to obtain a compound B; (2) Reacting the compound B with vinyl tin under the catalysis of a palladium catalyst at 50-100 ℃ to obtain a compound C; (3) Oxidizing the terminal carbon-carbon double bond into aldehyde under the oxidation action of an oxidant to obtain a compound D; (4) Continuing to oxidize the compound D, and oxidizing the terminal aldehyde group into acid to obtain a compound E; (5) Removing the protection of BOC on amino under the action of acid to obtain a compound F, namely an ametoctradin metabolite; the purity of the product can reach more than 99.0%, and the product can be used for pharmacokinetic research, provides a test sample for metabolic mechanism research of the flumetsulam, and has important application value.
Description
Technical Field
The invention relates to a preparation method of a compound, in particular to a preparation method of an ametoctradin metabolite.
Background
Azoxamide (Ametoctradin), chemical name: 5-methyl-6-octyl- [1,2,3] triazolo [1,5-a ] pyrimidin-7-amine is a triazole pyrimidine bactericide, is a high-selectivity bactericide, belongs to mitochondrial respiration inhibitors, has a control effect on downy mildew and phytophthora oomycetes fungi, and has extremely strong residual activity and rain resistance. The study confirms that the flumetsulam has a unique action mode, and the flumetsulam can be combined with the colistin subsite in the fungus respiratory complex, so that the fungus activity is inhibited. This makes flumetsulam the only fungicide in this class, with no cross-resistance to other commercial fungicides, an ideal tool for fungal resistance. Therefore Ametoctradin is approved by many countries for controlling fungal diseases of fruits and vegetables.
European Food Security Agency (EFSA) in EFSA Journal 2012;10 (11) up to 10.3. Mu.g/L Ametoctradin metabolite M650F04 (i.e., the inventive method of producing the metabolite of flumetsulam) was reported in 2921 in plants and groundwater. However, no method for synthesizing the metabolite is found in the literature, so that the preparation method of the metabolite of the pyraclostrobin plays a very important role in researching the metabolic mechanism of the pyraclostrobin.
Disclosure of Invention
The invention aims to: the invention aims to provide a preparation method of a high-purity ametoctradin metabolite for researching the metabolism mechanism of ametoctradin.
The technical scheme is as follows: the preparation method of the penoxsulam metabolite disclosed by the invention comprises the following steps of:
(1) The method comprises the steps of taking a compound A, namely 5-ethyl-6-iodo- [1,2,4] triazolo [1,5-a ] pyrimidine-7-amine as a raw material, dissolving the raw material in an organic solvent, adding BOC anhydride and alkali, and reacting the mixture to obtain a compound B;
(2) Adding the compound B into an organic solvent, adding a vinyl tin compound and a palladium catalyst, and reacting at 50-100 ℃ to obtain a compound C;
(3) Adding the compound C into an organic solvent, adding an oxidant, and oxidizing a terminal carbon-carbon double bond into aldehyde by reaction to obtain a compound D;
(4) Adding the compound D into an organic solvent, adding an oxidant and inorganic base, and oxidizing terminal aldehyde groups into acid through reaction to obtain a compound E;
(5) Adding the compound E into an organic solvent, adding acid, and removing the protection of BOC on amino groups by reaction to obtain a compound F, namely an ametoctradin metabolite;
the synthetic route is as follows:
In the step (1), BOC anhydride is adopted to protect the amino group of the compound A. Preferably, the organic solvent is tetrahydrofuran, methanol, DMF or dioxane. Preferably, the base is triethylamine, N-diisopropylethylamine, sodium carbonate, potassium carbonate or sodium hydroxide. Preferably, the molar ratio of the compound A to the BOC anhydride is 1:1-1:4, and the molar ratio of the compound A to the base is 1:1-1:5. Preferably, the reaction temperature is 20-60 ℃, and the reaction time is 10-20 hours; the reaction progress was monitored by thin layer chromatography with normal hexane/ethyl acetate as mobile phase.
In the step (2), the terminal I of the compound A is substituted by a carbon-carbon double bond. Preferably, the vinyl tin compound is tributyl vinyl tin or tetra vinyl tin, and the molar ratio of the compound B to the vinyl tin compound is 1:1-1:5; preferably, the palladium catalyst is tetraphenylphosphine palladium, ditolylphosphine palladium dichloride, palladium acetate or bis (triphenylphosphine) palladium acetate, and the molar ratio of the compound B to the palladium catalyst is 1:0.1-1:0.5. Preferably, the organic solvent is dichloromethane, 1, 2-dichloroethane, chloroform or carbon tetrachloride. Preferably, the reaction temperature is 50-100 ℃, the reaction time is 10-20 hours, the reaction process is monitored by adopting thin layer chromatography, and the mobile phase is n-hexane/ethyl acetate.
In the step (3), the terminal carbon-carbon double bond of the compound C is oxidized to aldehyde. Preferably, the oxidant is potassium permanganate, osmium tetroxide, potassium dichromate, oxygen or ozone, the reaction temperature is-80 to-40 ℃, the reaction time is 2-10 hours, the reaction process is monitored by adopting thin layer chromatography, and the mobile phase is methylene dichloride/methanol.
In said step (4), the aldehyde group of compound D is further oxidized to an acid. Preferably, the solvent is n-propanol, isopropanol, n-butanol or tert-butanol. Preferably, the inorganic base is potassium bicarbonate, disodium hydrogen phosphate, sodium carbonate or sodium bicarbonate, and the molar ratio of the compound D to the inorganic base is 1:1-1:5. Preferably, the oxidant is sodium chlorite, sodium nitrite, sodium chlorate or sodium nitrate, the mol ratio of the compound D to the oxidant is 1:2-1:10, the reaction temperature is 20-60 ℃, the reaction time is 1-10 hours, the reaction process is monitored by adopting thin layer chromatography, and the mobile phase is methylene dichloride/methanol.
In the step (5), the BOC-protected amino group in the compound E is deprotected. Preferably, the acid is hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid or formic acid, the molar ratio of the compound E to the acid is 1:5-1:50, the reaction temperature is 20-60 ℃, the reaction is carried out for 0.5-10 hours, the reaction process is monitored by adopting thin layer chromatography, and the mobile phase is methylene dichloride/methanol.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages: the method prepares the ametoctradin metabolite compound F through five steps of reactions, has the purity of more than 99.0 percent, can be used for pharmacokinetics research, provides a test sample for the metabolism mechanism research of the ametoctradin, and has important application value.
Drawings
FIG. 1 is a synthetic route for the preparation of the inventive ametoctradin metabolite;
FIG. 2 is a mass spectrum of the product of step (1) of example 1;
FIG. 3 is a mass spectrum of the product of step (2) of example 1;
FIG. 4 is a mass spectrum of the product of step (5) of example 1;
FIG. 5 is a hydrogen spectrum of the product of step (5) of example 1;
FIG. 6 is a HPLC profile of the product of step (5) of example 1.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Example 1
The preparation method of the ametoctradin metabolite comprises the following steps:
(1) 50.00g of 5-ethyl-6-iodo- [1,2,4] triazolo [1,5-a ] pyrimidin-7-amine and 113.25g of BOC anhydride in tetrahydrofuran were taken, 95.62g of sodium carbonate was added, the mixture was reacted at 30℃for 15 hours, the reaction was completed by thin layer chromatography, the reaction solution was concentrated to remove tetrahydrofuran, and purification by silica gel column gave 61.00g of compound B in a yield of 72.08%.
As shown in FIG. 2, MS:490.3[ M+H ] +;1 H NMR (400 MHz, DMSO) delta 18.67 (s, 1H), 3.16 (q, 2H), 1.31 (m, 21H).
(2) 60.0G of compound B was dissolved in chloroform, 38.88g of tributylvinyltin and 1.72g of palladium acetate were added and reacted at 70℃for 15 hours, the reaction was completed by thin layer chromatography, water extraction was carried out, and purification by silica gel column was carried out to obtain 39.20g of compound C, yield 82.08%.
As shown in FIG. 3, MS is 390.3[ M+H ] +.
(3) 39.00G of compound C is dissolved in dichloromethane, ozone is introduced at the temperature of minus 60 ℃ for reaction for 4 hours, the reaction is complete by thin layer chromatography, dimethyl sulfide is quenched, concentrated to dryness, and 30.00g of compound D is obtained by silica gel column purification, and the yield is 71.53%.
(4) 30.00G of compound D is dissolved in n-butanol, 13.86g of sodium chlorite and 45.98g of sodium dihydrogen phosphate are added under ice bath to react for 8 hours at 20 ℃, thin layer chromatography shows that the reaction is complete, concentration and water extraction are carried out, and the crude product is purified by a silica gel column to obtain 20.00g of compound E, and the yield is 64.12%.
(5) 20.00G of Compound E was dissolved in methylene chloride, 84.04g of trifluoroacetic acid was added under ice bath and reacted at 50℃for 1 hour, the reaction was completed by thin layer chromatography, and the crude product was concentrated to dryness, and purified by a C18 column to obtain 7.50g of Compound E in 73.74% yield.
As shown in FIG. 4, MS is 208.1[ M+H ] +; as shown in FIG. 5, 1 HNMR (400 MHz, DMSO) δ13.60 (br, 1H), 8.69 (br, 2H), 8.50 (S, 1H), 3.10 (q, 2H), 1.22 (t, 3H); as shown in FIG. 6, the purity of the product was 99.59%.
Example 2
The preparation method of the ametoctradin metabolite comprises the following steps:
(1) Taking 40.00g of 5-ethyl-6-iodo- [1,2,4] triazolo [1,5-a ] pyrimidine-7-amine and 90.60g of BOC anhydride in tetrahydrofuran, adding 11.07g of sodium hydroxide, reacting the mixed solution at 20 ℃ for 12 hours, concentrating the reaction solution to remove tetrahydrofuran, purifying by a silica gel column to obtain 45.10g of compound B, wherein the yield is 66.61%; MS, 490.3[ M+H ] +.
(2) Dissolving 45.00g of compound B in chloroform, adding 58.32g of tributylvinyltin and 2.58g of bis (triphenylphosphine) palladium dichloride, reacting at 50 ℃ for 16 hours, performing thin-layer chromatography to show that the reaction is complete, adding water for extraction, and purifying by a silica gel column to obtain 20.50g of compound C with the yield of 57.23%; MS 390.3[ M+H ] +.
(3) 28.00G of compound C is dissolved in dichloromethane, ozone is introduced at the temperature of minus 80 ℃ for reaction for 8 hours, the reaction is complete by thin layer chromatography, dimethyl sulfide is quenched, concentrated to dryness, and a silica gel column is used for purification to obtain 21.30g of compound D, and the yield is 75.69%.
(4) 20.00G of compound D is dissolved in tertiary butanol, 4.62g of sodium chlorite and 16.25g of sodium carbonate are added under ice bath to react for 10 hours at 40 ℃, thin layer chromatography shows that the reaction is complete, concentration and water extraction are carried out, and the crude product is purified by a silica gel column to obtain 14.20g of compound E, and the yield is 68.27%.
(5) 16.00G of Compound E was dissolved in methylene chloride, 59.72g of concentrated hydrochloric acid was added under ice bath and reacted at 60℃for 4 hours, the reaction was completed by thin layer chromatography, concentration to dryness and purification of the crude product by C18 column gave 5.00g of Compound E in a yield of 61.42% and MS:208.1[ M+H ] +,1 H-NMR as in example 1.
Example 3
The preparation method of the ametoctradin metabolite comprises the following steps:
(1) 30.00g of 5-ethyl-6-iodo- [1,2,4] triazolo [1,5-a ] pyrimidin-7-amine and 67.95g of BOC anhydride in tetrahydrofuran were taken, 21.93g of sodium carbonate was added, the mixture was reacted at 60℃for 8 hours, the reaction was completed by thin layer chromatography, the reaction solution was concentrated to remove tetrahydrofuran, and the silica gel column was purified to obtain 22.10g of compound B, the yield was 73.67%.
(2) 20.0G of compound B is dissolved in chloroform, 14.60g of tributylvinyltin and 0.63g of bis (triphenylphosphine) palladium dichloride are added for reaction at 100 ℃ for 12 hours, thin layer chromatography shows that the reaction is complete, water extraction is carried out, and the compound C with 14.20g is obtained after silica gel column purification, and the yield is 81.09%.
(3) 14.00G of compound C is dissolved in dichloromethane, ozone is introduced at the temperature of minus 40 ℃ for reaction for 4 hours, the reaction is complete by thin layer chromatography, dimethyl sulfide is quenched, concentrated to dryness, and a silica gel column is used for purification to obtain 10.50g of compound D, and the yield is 74.63%.
(4) 30.00G of compound D is dissolved in n-butanol, 2.31g of sodium chlorite and 9.2g of sodium dihydrogen phosphate are added under ice bath to react for 8 hours at 60 ℃, thin layer chromatography shows that the reaction is complete, concentration and water extraction are carried out, and crude product silica gel column purification is carried out to obtain 6.30g of compound E, and the yield is 60.52%.
(5) 6.00G of Compound E was dissolved in methylene chloride, 25.21g of trifluoroacetic acid was added under ice bath and reacted at 20℃for 1 hour, the reaction was completed by thin layer chromatography, and the crude product was concentrated to dryness, and purified by a C18 column to obtain 7.50g of Compound E in 73.74% yield.
Claims (8)
1. A method for preparing an ametoctradin metabolite, comprising the steps of:
(1) The method comprises the steps of taking a compound A, namely 5-ethyl-6-iodo- [1,2,4] triazolo [1,5-a ] pyrimidine-7-amine as a raw material, dissolving the raw material in an organic solvent, adding BOC anhydride and alkali, and reacting the mixture to obtain a compound B;
(2) Adding the compound B into an organic solvent, adding a vinyl tin compound and a palladium catalyst, and reacting at 50-100 ℃ to obtain a compound C;
(3) Adding the compound C into an organic solvent, adding an oxidant, and oxidizing a terminal carbon-carbon double bond into aldehyde by reaction to obtain a compound D;
(4) Adding the compound D into an organic solvent, adding an oxidant and inorganic base, and oxidizing terminal aldehyde groups into acid through reaction to obtain a compound E;
(5) Adding the compound E into an organic solvent, adding acid, and removing the protection of BOC on amino groups by reaction to obtain a compound F, namely an ametoctradin metabolite;
in the step (2), the vinyl tin compound is tributyl vinyl tin or tetra vinyl tin; the palladium catalyst is tetraphenylphosphine palladium, ditolylphosphine palladium dichloride, palladium acetate or bis (triphenylphosphine) palladium acetate;
the synthetic route is as follows:
。
2. the method for preparing an ametoctradin metabolite according to claim 1, wherein in the step (2), the molar ratio of the compound B to the vinyltin compound is 1:1 to 1:5.
3. The method for preparing a metabolite of flumetsulam according to claim 1, characterized in that in step (2), the molar ratio of the compound B to the palladium catalyst is 1:0.1 to 1:0.5.
4. The method for preparing a metabolite of flumetsulam according to claim 1, characterized in that in step (2), the organic solvent is dichloromethane, 1, 2-dichloroethane, chloroform or carbon tetrachloride.
5. The method for preparing the metabolite of the flumetsulam according to claim 1, characterized in that in the step (3), the oxidizing agent is potassium permanganate, osmium tetroxide, potassium dichromate, oxygen or ozone, and the reaction temperature is-80 to-40 ℃.
6. The method for preparing the ametoctradin metabolite according to claim 1, wherein in the step (4), the oxidant is sodium chlorite, sodium nitrite, sodium chlorate or sodium nitrate, and the reaction temperature is 20-60 ℃.
7. The method for preparing a metabolite of flumetsulam according to claim 1, characterized in that in step (5), the acid is hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid or formic acid, and the reaction temperature is 20-60 ℃.
8. The method for preparing a metabolite of flumetsulam according to claim 1, characterized in that in step (1), the reaction temperature is 20-60 ℃.
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