CN115806556A - Preparation method of ametoctradin metabolite - Google Patents
Preparation method of ametoctradin metabolite Download PDFInfo
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- CN115806556A CN115806556A CN202211586263.6A CN202211586263A CN115806556A CN 115806556 A CN115806556 A CN 115806556A CN 202211586263 A CN202211586263 A CN 202211586263A CN 115806556 A CN115806556 A CN 115806556A
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- ametoctradin
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- acid
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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 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 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 17
- 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
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 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 13
- 230000001590 oxidative effect Effects 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000007800 oxidant agent Substances 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- UCZLBERYFYDXOM-UHFFFAOYSA-N ethenyltin Chemical compound [Sn]C=C UCZLBERYFYDXOM-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 7
- 239000011203 carbon fibre reinforced carbon 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
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 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
- 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
- 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
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [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.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 NFHFRUOZVGFOOS-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
- 239000005726 Ametoctradin Substances 0.000 abstract description 9
- 238000011160 research Methods 0.000 abstract description 6
- 230000002503 metabolic effect Effects 0.000 abstract description 3
- 125000003277 amino group Chemical group 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
- QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 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
- 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
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- 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
- 238000000746 purification Methods 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 241000233866 Fungi Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 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 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- 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 description 2
- 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
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003899 bactericide agent Substances 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
- 239000011541 reaction mixture Substances 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- DARPYRSDRJYGIF-PTNGSMBKSA-N (Z)-3-ethoxy-2-naphthalen-2-ylsulfonylprop-2-enenitrile Chemical compound C1=CC=CC2=CC(S(=O)(=O)C(\C#N)=C/OCC)=CC=C21 DARPYRSDRJYGIF-PTNGSMBKSA-N 0.000 description 1
- 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
- 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
- 241000233679 Peronosporaceae Species 0.000 description 1
- 241000233614 Phytophthora Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- -1 ametoctradin metabolite compound Chemical class 0.000 description 1
- 239000002585 base Substances 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
- 235000013305 food 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
- 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
- 125000002924 primary amino group Chemical group [H]N([H])* 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
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical compound BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Images
Classifications
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- 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 ametoctradin metabolite, which comprises the following steps: (1) Taking a compound A5-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 at 50-100 ℃ under the catalysis of a palladium catalyst to obtain a compound C; (3) Oxidizing the terminal carbon-carbon double bond of the compound C into aldehyde under the oxidation action of an oxidant to obtain a compound D; (4) Continuously oxidizing the compound D to oxidize the terminal aldehyde group into acid to obtain a compound E; (5) Removing the protection of the BOC on the amino group of the compound E under the action of acid to obtain a compound F, namely the ametoctradin metabolite; the purity of the product can reach more than 99.0 percent, and the method is used for pharmacokinetic research, provides a test sample for the metabolic mechanism research of ametoctradin, and has important application value.
Description
Technical Field
The invention relates to a preparation method of a compound, and particularly relates to a preparation method of an ametoctradin metabolite.
Background
Ametoctradin (Ametoctradin) with the chemical name: 5-ethyl-6-octyl- [1,2,3] triazoyl [1,5-a ] pyrimidin-7-amine is a triazolopyrimidine bactericide, is a high-selectivity bactericide, belongs to a mitochondrial respiration inhibitor, has a control effect on downy mildew and phytophthora oomycetes fungi, and has extremely strong residual activity and rain resistance. The researches confirm that the ametoctradin has a unique action mode, and the ametoctradin can be combined with a mepiquat chloride subsite in a fungus respiratory complex, so that the activity of fungi is inhibited. This makes ametoctradin the only fungicide in this category, which is not cross-resistant to other commercial fungicides, an ideal tool for fungal resistance. Accordingly, aminovitradin is approved by many countries for the control of fungal diseases in fruits and vegetables.
European Food Safety Agency (EFSA) in EFSA Journal 2012;10 (11) Ametoctradin metabolite M650F04 (i.e.the Ametoctradin metabolite produced according to the invention) was reported to be found in plants and ground water at up to 10.3. Mu.g/L in 2921. However, no literature report on a method for synthesizing the metabolism is found, so that the preparation method of the ametoctradin metabolite disclosed by the invention has a very important effect on the research on the metabolic mechanism of ametoctradin.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a preparation method of a high-purity ametoctradin metabolite for researching the metabolic mechanism of ametoctradin.
The technical scheme is as follows: the preparation method of the ametoctradin metabolite comprises the following steps:
(1) Dissolving a compound A5-ethyl-6-iodo- [1,2,4] triazolo [1,5-a ] pyrimidine-7-amine serving as a raw material in an organic solvent, and adding BOC anhydride and alkali to react 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 reacting to oxidize terminal carbon-carbon double bonds into aldehyde to obtain a compound D;
(4) Adding the compound D into an organic solvent, adding an oxidant and an inorganic base, and reacting to oxidize a terminal aldehyde group into an acid to obtain a compound E;
(5) Adding the compound E into an organic solvent, adding acid, reacting to remove the protection of BOC on amino, and obtaining a compound F, namely the 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 compound a to BOC anhydride is 1 to 1. Preferably, the reaction temperature is 20-60 ℃, and 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 (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 tetravinyl tin, and the molar ratio of the compound B to the vinyl tin compound is 1; preferably, the palladium catalyst is tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium dichloride, palladium acetate or bis (triphenylphosphine) palladium acetate, and the molar ratio of the compound B to the palladium catalyst is 1. 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 in the reaction process, 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 into 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 to 10 hours, the reaction process is monitored by adopting thin-layer chromatography, and the mobile phase is dichloromethane/methanol.
In the step (4), the aldehyde group of the 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. Preferably, the oxidant is sodium chlorite, sodium nitrite, sodium chlorate or sodium nitrate, the molar ratio of the compound D to the oxidant is 1.
In the step (5), BOC protection is removed from the amino protected by BOC in the compound E. 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, the reaction temperature is 20-60 ℃, the reaction time is 0.5-10 hours, the reaction process is monitored by thin-layer chromatography, and the mobile phase is dichloromethane/methanol.
Has the advantages that: compared with the prior art, the invention has the following remarkable advantages: the ametoctradin metabolite compound F is prepared through five-step reaction, the purity can reach more than 99.0%, the method can be used for pharmacokinetic research, a test sample is provided for the metabolism mechanism research of the ametoctradin, and the method has important application value.
Drawings
FIG. 1 is a synthetic route of a method for preparing an ametoctradin metabolite of the present invention;
FIG. 2 is a mass spectrum of the product of step (1) in example 1;
FIG. 3 is a mass spectrum of the product of step (2) in example 1;
FIG. 4 is a mass spectrum of the product of step (5) in example 1;
FIG. 5 is a hydrogen spectrum of the product of step (5) in example 1;
FIG. 6 is a HPLC chromatogram of the product of step (5) in example 1.
Detailed Description
The technical solution of the present invention is further illustrated by the following 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 were taken in tetrahydrofuran, 95.62g of sodium carbonate was added, the mixture was reacted at 30 ℃ for 15 hours, thin layer chromatography showed completion of the reaction, the reaction mixture was concentrated to remove tetrahydrofuran, and silica gel column purification was carried out to obtain 61.00g of compound B in a yield of 72.08%.
As shown in FIG. 2, MS:490.3[ M ] +H] + ； 1 H NMR(400MHz,DMSO)δ18.67(s,1H),3.16(q,2H),1.31(m,21H)。
(2) 60.0g of the compound B was dissolved in chloroform, 38.88g of tributylvinyltin and 1.72g of palladium acetate were added, the reaction was carried out at 70 ℃ for 15 hours, thin-layer chromatography showed that the reaction was complete, water was added for extraction, and silica gel column purification was carried out to obtain 39.20g of the compound C with a yield of 82.08%.
As shown in FIG. 3, MS:390.3[ M ] +H] + 。
(3) 39.00g of the compound C is dissolved in dichloromethane, ozone is introduced at-60 ℃ for reaction for 4 hours, thin layer chromatography shows that the reaction is complete, dimethyl sulfide is quenched, concentration is carried out until the reaction is dry, and silica gel column purification is carried out to obtain 30.00g of the compound D, wherein the yield is 71.53%.
(4) 30.00g of the compound D is dissolved in n-butanol, 13.86g of sodium chlorite and 45.98g of sodium dihydrogen phosphate are added under ice bath, the mixture reacts for 8 hours at the temperature of 20 ℃, thin layer chromatography shows complete reaction, concentration and water extraction are carried out, and a crude product is purified by a silica gel column to obtain 20.00g of the compound E, and the yield is 64.12%.
(5) 20.00g of compound E is dissolved in dichloromethane, 84.04g of trifluoroacetic acid is added under ice bath, the reaction is carried out for 1 hour at 50 ℃, thin layer chromatography shows that the reaction is complete, concentration is carried out till dryness, and a crude product C18 column is purified to obtain 7.50g of compound E, and the yield is 73.74%.
As shown in FIG. 4, MS:208.1[ 2 ], [ M + H ]] + (ii) a As shown in figure 5 of the drawings, 1 HNMR (400MHz, DMSO). Delta.13.60 (br, 1H), 8.69 (br, 2H), 8.50 (S, 1H), 3.10 (q, 2H), 1.22 (t, 3H); as shown in fig. 6, the product purity was 99.59%.
Example 2
The preparation method of the ametoctradin metabolite comprises the following steps:
(1) 40.00g of 5-ethyl-6-iodo- [1,2,4] was taken]Triazolo [1,5-a ]]Adding 11.07g of sodium hydroxide into 90.60g of BOC anhydride and pyrimidine-7-amine in tetrahydrofuran, reacting the mixed solution at 20 ℃ for 12 hours, completely reacting by thin layer chromatography, concentrating the reaction solution to remove tetrahydrofuran, and purifying by a silica gel column to obtain 45.10g of compound B with the yield of 66.61%; MS 490.3[ deg. ] M +H] + 。
(2) Dissolving 45.00g of the compound B in chloroform, adding 58.32g of tributylvinyltin and 2.58g of bis-triphenylphosphine palladium dichloride, reacting at 50 ℃ for 16 hours, indicating that the reaction is complete by thin layer chromatography, adding water for extraction, and purifying by a silica gel column to obtain 20.50g of a compound C with the yield of 57.23%; MS:390.3[ deg. ] M +H] + 。
(3) 28.00g of the compound C is dissolved in dichloromethane, ozone is introduced at-80 ℃ for reaction for 8 hours, thin layer chromatography shows that the reaction is complete, dimethyl sulfide is quenched, concentration is carried out until the reaction is dry, silica gel column purification is carried out to obtain 21.30g of the compound D, and the yield is 75.69%.
(4) 20.00g of the compound D is dissolved in tert-butyl alcohol, 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 complete reaction, concentration and water addition extraction are carried out, and a crude product is purified by a silica gel column to obtain 14.20g of the compound E, and the yield is 68.27%.
(5) 16.00g of the compound E is dissolved in dichloromethane, 59.72g of concentrated hydrochloric acid is added under ice bath to react for 4 hours at 60 ℃, thin layer chromatography shows complete reaction, concentration is carried out until the reaction is dry, and a crude product C18 column is purified to obtain 5.00g of the compound E, the yield is 61.42 percent, MS is 208.1, M + H] + ， 1 H-NMR was the same 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 were added to tetrahydrofuran, 21.93g of sodium carbonate was added, the mixture was reacted at 60 ℃ for 8 hours, thin layer chromatography showed completion of the reaction, the reaction mixture was concentrated to remove tetrahydrofuran, and silica gel column purification was carried out to obtain 22.10g of compound B in a yield of 73.67%.
(2) 20.0g of the compound B was dissolved in chloroform, and 14.60g of tributylvinyltin and 0.63g of bis-triphenylphosphine palladium dichloride were added to the solution to react at 100 ℃ for 12 hours, and thin layer chromatography showed that the reaction was completed, and water was added to extract the solution, and the product was purified by silica gel column to obtain 14.20g of the compound C with a yield of 81.09%.
(3) 14.00g of the compound C is dissolved in dichloromethane, ozone is introduced at-40 ℃ for reaction for 4 hours, thin layer chromatography shows that the reaction is complete, dimethyl sulfide is quenched, concentration is carried out until the reaction is dry, and silica gel column purification is carried out to obtain 10.50g of the compound D, wherein the yield is 74.63%.
(4) 30.00g of the compound D is dissolved in n-butanol, 2.31g of sodium chlorite and 9.2g of sodium dihydrogen phosphate are added under ice bath, the mixture reacts for 8 hours at the temperature of 60 ℃, thin layer chromatography shows complete reaction, concentration and water addition extraction are carried out, and a crude product is purified by a silica gel column to obtain 6.30g of the compound E, and the yield is 60.52%.
(5) 6.00g of the compound E is dissolved in dichloromethane, 25.21g of trifluoroacetic acid is added under ice bath, the reaction is carried out for 1 hour at 20 ℃, thin layer chromatography shows complete reaction, concentration is carried out till dryness, and a crude product C18 column is purified to obtain 7.50g of the compound E, and the yield is 73.74%.
Claims (10)
1. The preparation method of the ametoctradin metabolite is characterized by comprising the following steps of:
(1) Dissolving a compound A5-ethyl-6-iodine- [1,2,4] triazolo [1,5-a ] pyrimidine-7-amine serving as a raw material in an organic solvent, adding BOC anhydride and alkali, and reacting 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 reacting to oxidize terminal carbon-carbon double bonds into aldehyde to obtain a compound D;
(4) Adding the compound D into an organic solvent, adding an oxidant and an inorganic base, and reacting to oxidize a terminal aldehyde group into an acid to obtain a compound E;
(5) Adding the compound E into an organic solvent, adding acid, reacting to remove the protection of BOC on amino, and obtaining a compound F, namely the ametoctradin metabolite;
the synthetic route is as follows:
2. the method for preparing ametoctradin metabolite according to claim 1, characterized in that, in the step (2), the vinyl tin compound is tributyl vinyl tin or tetravinyl tin.
3. The method for preparing an ametoctradin metabolite according to claim 1, characterized in that in the step (2), the palladium catalyst is tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium dichloride, palladium acetate or bis (triphenylphosphine) palladium acetate.
4. The method for preparing the ametoctradin metabolite according to claim 1, characterized in that in the step (2), the molar ratio of the compound B to the vinyl tin compound is 1-1.
5. The method for preparing ametoctradin metabolite according to claim 1, characterized in that, in the step (2), the molar ratio of the compound B to the palladium catalyst is 1.
6. The method for preparing an ametoctradin metabolite according to claim 1, characterized in that, in the step (2), the organic solvent is dichloromethane, 1, 2-dichloroethane, chloroform or carbon tetrachloride.
7. The method for preparing ametoctradin metabolite 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 ℃.
8. The method for preparing ametoctradin metabolite according to claim 1, characterized in that in the step (4), the oxidant is sodium chlorite, sodium nitrite, sodium chlorate or sodium nitrate, and the reaction temperature is 20-60 ℃.
9. The method for preparing ametoctradin metabolite according to claim 1, characterized in that in the step (5), the acid is hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid or formic acid, and the reaction temperature is 20-60 ℃.
10. The method for preparing ametoctradin metabolite according to claim 1, characterized in that, in the step (1), the reaction temperature is 20-60 ℃.
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Non-Patent Citations (1)
| Title |
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| EUROPEAN FOOD SAFETY AUTHORITY: "Conclusion on the peer review of the pesticide risk assessment of the active substance ametoctradin (BAS 650 F)", 《EFSA JOURNAL》, vol. 10, no. 11, pages 2921 * |
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