CN115960051B - 一种稳定同位素标记嘧霉胺内标试剂的制备方法 - Google Patents
一种稳定同位素标记嘧霉胺内标试剂的制备方法 Download PDFInfo
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- CN115960051B CN115960051B CN202210378712.1A CN202210378712A CN115960051B CN 115960051 B CN115960051 B CN 115960051B CN 202210378712 A CN202210378712 A CN 202210378712A CN 115960051 B CN115960051 B CN 115960051B
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- pyrimethanil
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- ZLIBICFPKPWGIZ-UHFFFAOYSA-N pyrimethanil Chemical compound CC1=CC(C)=NC(NC=2C=CC=CC=2)=N1 ZLIBICFPKPWGIZ-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 239000005828 Pyrimethanil Substances 0.000 title claims abstract description 50
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 239000000126 substance Substances 0.000 claims abstract description 10
- 150000001555 benzenes Chemical class 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- IDQNBVFPZMCDDN-UHFFFAOYSA-N 2-Amino-4,6-dimethylpyrimidine Chemical compound CC1=CC(C)=NC(N)=N1 IDQNBVFPZMCDDN-UHFFFAOYSA-N 0.000 claims description 8
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- 239000002274 desiccant Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- -1 di-tert-butylphosphino Chemical group 0.000 claims description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 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 4
- NFHFRUOZVGFOOS-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.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 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 4
- 235000011009 potassium phosphates Nutrition 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 4
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 claims description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052805 deuterium Inorganic materials 0.000 claims 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 claims description 2
- JBGICSFDKZAWFJ-UHFFFAOYSA-N ditert-butyl(2,2-dimethylpropyl)phosphane Chemical compound CC(C)(C)CP(C(C)(C)C)C(C)(C)C JBGICSFDKZAWFJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- JGBZTJWQMWZVNX-UHFFFAOYSA-N palladium;tricyclohexylphosphane Chemical compound [Pd].C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 JGBZTJWQMWZVNX-UHFFFAOYSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- IGNTWNVBGLNYDV-UHFFFAOYSA-N triisopropylphosphine Chemical compound CC(C)P(C(C)C)C(C)C IGNTWNVBGLNYDV-UHFFFAOYSA-N 0.000 claims description 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 2
- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims 1
- TVJJMJNPQDVCRT-UHFFFAOYSA-N CC1=C(C=CC=C1)C1=CC=CC=C1.[P] Chemical group CC1=C(C=CC=C1)C1=CC=CC=C1.[P] TVJJMJNPQDVCRT-UHFFFAOYSA-N 0.000 claims 1
- SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 claims 1
- 235000013305 food Nutrition 0.000 abstract description 19
- 238000001514 detection method Methods 0.000 abstract description 17
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
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- 231100000331 toxic Toxicity 0.000 abstract description 5
- 230000002588 toxic effect Effects 0.000 abstract description 5
- 239000002085 irritant Substances 0.000 abstract description 4
- 231100000021 irritant Toxicity 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 4
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 abstract description 2
- 238000012827 research and development Methods 0.000 abstract description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract 2
- 229910021529 ammonia Inorganic materials 0.000 abstract 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 244000269722 Thea sinensis Species 0.000 description 3
- 150000004768 bromobenzenes Chemical class 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- RZVPFDOTMFYQHR-UHFFFAOYSA-N 2-chloro-4,6-dimethylpyrimidine Chemical compound CC1=CC(C)=NC(Cl)=N1 RZVPFDOTMFYQHR-UHFFFAOYSA-N 0.000 description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
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- 244000052769 pathogen Species 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- WTAPZWXVSZMMDG-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 WTAPZWXVSZMMDG-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- 244000291564 Allium cepa Species 0.000 description 1
- 235000002732 Allium cepa var. cepa Nutrition 0.000 description 1
- 240000008067 Cucumis sativus Species 0.000 description 1
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 1
- XZRUNZCMOCXTDJ-UHFFFAOYSA-N P.CC1(C)c2ccccc2Oc2ccccc12 Chemical compound P.CC1(C)c2ccccc2Oc2ccccc12 XZRUNZCMOCXTDJ-UHFFFAOYSA-N 0.000 description 1
- 240000003768 Solanum lycopersicum Species 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000008059 anilinopyrimidines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- XDSYAIICRRZSJX-UHFFFAOYSA-N carbamimidoyl(phenyl)azanium;hydrogen carbonate Chemical compound OC(O)=O.NC(N)=NC1=CC=CC=C1 XDSYAIICRRZSJX-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
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- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- NDEMNVPZDAFUKN-UHFFFAOYSA-N guanidine;nitric acid Chemical compound NC(N)=N.O[N+]([O-])=O.O[N+]([O-])=O NDEMNVPZDAFUKN-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
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- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004750 isotope dilution mass spectroscopy Methods 0.000 description 1
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- 239000000447 pesticide residue Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
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- 238000011002 quantification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种食品安全检测用稳定同位素标记嘧霉胺内标试剂的制备方法,属于食品安全检测用标准物质研发领域。本发明的稳定同位素标记嘧霉胺内标试剂的制备方法,采用市售可得的中间体及稳定同位素标记卤代苯为原料,经一步Buchwald‑Hartwig交叉偶联反应直接得到稳定同位素标记嘧霉胺。本发明方法所使用的原料简单易得且价格低廉、避免使用有毒刺激性原料、合成步骤短、反应条件温和、反应收率高;最终产品副产物少、易于分离提纯、化学纯度高、同位素丰度不稀释。最终产物稳定同位素标记嘧霉胺化学纯度大于98%,同位素丰度大于98%。本制备方法制得的稳定同位素标记嘧霉胺内标试剂能满足食品安全检测用液相色谱串联质谱法所需稳定同位素标记内标试剂的技术要求。
Description
技术领域
本发明涉及一种食品安全检测用稳定同位素标记嘧霉胺内标试剂的制备方法,属于食品安全检测用标准物质研发领域。
背景技术
嘧霉胺(Pyrimethanil,Cas No.:53112-28-0)是由法国安万特公司研发,20世纪末投入使用的一种苯氨基嘧啶类新型内吸性杀菌剂,其作用机理独特,能通过抑制病菌浸染酶的产生从而阻止病菌的侵染并杀死病菌,具有叶片穿透、根部内吸活性,对葡萄、草莓、番茄、黄瓜、洋葱、茄子及观赏植物等的灰霉病具有优异防治效果。近年来,嘧霉胺在蔬菜、茶叶等植物源性食品生产中使用量不断增加,由于其直接喷洒在农作物上,通过食用进入人体,其残留量过大不可避免的对人体健康造成危害。美国、日本和欧盟等已相继对蔬菜中嘧霉胺的最高残留量做了限量规定,欧盟也于2014年起对进口茶叶正式实施新农残限量标准,其中把嘧霉胺的残留限量规定为0.05ppm。我国也在《GB 2763-2021食品安全国家标准食品中农药最大残留限量》中规定了嘧霉胺在各类食品中最高残留限量。同时,我国检测该物质的相关标准有《GB 23200.121-2021食品安全国家标准植物源性食品中331种农药及其代谢物残留量的测定液相色谱-质谱联用法》、《GB 23200.13-2016食品安全国家标准茶叶中448种农药及相关化学品残留量的测定液相色谱-质谱法》等。
因国内无相对应的稳定同位素标记内标化合物供应,而国外产品进口价格昂贵、供货周期长且供应不稳定,目前上述检测标准都采用外标法来进行定量检测。稳定同位素稀释质谱法是国际上公认的痕量检测的“金标准”,能够显著的降低基质效应,提高检测结果的精确度,使用该化合物对应的稳定同位素标记的化合物作为内标使用内标法来进行检测定量会显著提高检测结果的准确性,降低该化合物的检出限。因此,研制稳定同位素标记嘧霉胺内标试剂对于我国食品安全监督检测工作相关领域具有重要意义。
目前,现有技术中该天然丰度的化合物合成文献有很多,例如路线一:授权中国发明专利“一种嘧霉胺的制备方法”(CN 102816122 B)、“一种高纯度嘧霉胺的制备方法及用于制备高纯度嘧霉胺的设备”(CN 10461016 B)、国际专利“METHOD FOR PRODUCING(4,6-DIMETHYLPYRIMIDINE-2-YL)-PHENYLAMINE(PYRIMETHANIL)”(WO2011067362(A1))中均是以苯胺、盐酸、单氰胺、碳酸钠为原料进行加成成盐反应,合成苯基胍碳酸盐,最后与乙酰丙酮进行环合反应制得嘧霉胺。
路线二:周艳丽,薛超.杀菌剂嘧霉胺的合成研究[J].农药科学与管理,2005,26(9):24-25.中报道的嘧霉胺的合成方法是以硝酸胍、乙酰丙酮、碳酸钾为原料先合成2-氨基-4,6-二甲基嘧啶,然后再与亚硝酸钠和稀盐酸进行重氮化反应得到2-氯-4,6-二甲基嘧啶,最后与苯胺加成得到嘧霉胺。
上述路线一中采用的原料单氰胺有毒,极刺激腐蚀皮肤、呼吸道、粘膜;路线二中苯胺的化学当量接近2当量,此两条路线均不适合用来合成稳定同位素标记嘧霉胺内标试剂。
截至目前,稳定同位素标记的嘧霉胺内标试剂的合成路线及工艺均无文献报道。
因此,亟需开发一种原料易得、操作简单、避免使用有毒刺激性原料、反应条件温和、反应路线短、最终产品总收率高且易分离提纯、同位素丰度不稀释的稳定同位素标记嘧霉胺内标试剂的制备方法,以满足该化合物在国内食品安全监督监管方面日益增长的应用需求。
发明内容
本发明的目的是提供一种适用于食品安全检测用稳定同位素标记嘧霉胺内标试剂的制备路线方法。该制备路线方法原料易得、操作简单、避免使用有毒刺激性原料、反应条件温和、反应路线短、最终产品总收率高且易分离提纯、同位素丰度不稀释。
本发明的目的可以通过以下技术方案来实现:1.一种稳定同位素标记嘧霉胺内标试剂的制备方法,该稳定同位素标记嘧霉胺内标试剂的化学结构如式(稳定同位素标记嘧霉胺)所示:
其中*为12C或13C,X为H或D,其特征在于,其制备路线为:
其中*为12C或13C,X为H或D,Y为Cl、Br或I,制备步骤如下:
(1)在氮气保护、加入稳定同位素标记卤代苯(I),然后加入2-氨基-4,6-二甲基嘧啶、催化剂、配体、有机溶剂、碱存在条件下,在30℃~150℃条件下,反应6~48小时;TLC跟踪反应原料反应完全后,反应混合溶液用水淬灭,过滤,滤液用有机溶剂萃取,合并有机相,依次用水洗涤、饱和碳酸氢钠溶液洗涤,饱和氯化钠溶液洗涤,加入干燥剂干燥,减压蒸馏除去溶剂,残留物经柱层析得到稳定同位素标记嘧霉胺。
所述步骤(1)中,催化剂为三(二亚苄基丙酮)二钯、双二亚苄基丙酮钯、醋酸钯、氯化钯、四(三苯基膦)钯、双(二苯基膦二茂铁)二氯化钯、双(三环己基膦)二氯化钯、双(三苯基膦)二氯化钯中的任意一种或几种;配体为三(邻甲基苯基)磷、三(环己基)磷、三(2-呋喃基)膦、三(异丙基)磷、三(叔丁基)磷、二叔丁基新戊基膦、2-二环己基磷-2’-甲基联苯、2-二环己基磷-2’,6’-二甲基联苯、2-二环己基膦-2’,4’,6’-三异丙基联苯、2-二环己基膦-2’,6’-二甲氧基-联苯、2-二-叔丁膦基-2’,4’,6’-三异丙基联苯、正丁基二(1-金刚烷基)膦、1,1’-联萘-2,2’-双二苯膦、4,5-双二苯基膦-9,9-二甲基氧杂蒽、双(2-二苯基磷苯基)醚、2-二环己膦基-2’-(N,N-二甲胺)-联苯、1,2-双(二苯基膦)乙烷、1,3-双(二苯基膦)丙烷、1,2,3,4,5-戊苯基-1’-(二叔丁基磷基)二茂铁、1,1’-双(二苯基膦)二茂铁、1,1’-双(二叔丁基膦)二茂铁、N,N-二甲基-1-(2-联苯膦基)二茂铁乙胺中的任意一种或几种;溶剂为四氢呋喃、二氧六环、甲苯、二甲苯、2-甲基四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜中的任意一种或几种;碱为碳酸锂、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、叔丁醇钠、叔丁醇钾、氢氧化钠、氢氧化钾、磷酸钾中的任意一种或几种;稳定同位素标记的卤代苯为氘标记、13C标记的氯苯、溴苯、碘苯中的任意一种;反应温度为30℃~150℃;反应时间为12~48小时。
优选地,所述步骤(1)中的催化剂为三(二亚苄基丙酮)二钯、双二亚苄基丙酮钯、醋酸钯中;所述化合物(I)与催化剂的摩尔比为(1:0.001)~(1:0.05);
优选的,所述步骤(1)中配体为三(叔丁基)磷、1,1’-联萘-2,2’-双二苯膦、4,5-双二苯基膦-9,9-二甲基氧杂蒽、2-二环己基膦-2’-(N,N-二甲胺)-联苯、2-二环己基膦-2’,4’,6’-三异丙基联苯、1,3-双(二苯基膦)丙烷;所述化合物(I)与配体的摩尔比为(1:0.005)~(1:0.1);
优选地,所述步骤(1)中的有机溶剂为N,N-二甲基甲酰胺、二氧六环、甲苯中的任意一种;
优选地,所述步骤(1)中的碱为碳酸钾、碳酸铯、磷酸钾、叔丁醇钠、叔丁醇钾中的一种;所述化合物(I)与碱的摩尔比为(1:1)~(1:3);
优选地,所述化合物(I)与2-氨基-4,6-二甲基嘧啶的摩尔比为(1:1~1:1.5)。
优选地,所述步骤(1)中的反应温度为80℃~120℃。
优选地,所述步骤(1)中的反应时间为12~24小时。
与现有技术相比,本发明的有益效果在于:本发明的食品安全检测用稳定同位素标记嘧霉胺内标试剂的制备方法,采用市售可得的中间体及稳定同位素标记卤代苯为原料,经一步Buchwald-Hartwig交叉偶联反应直接得到稳定同位素标记嘧霉胺。本发明方法所使用的原料简单易得且价格低廉、避免使用有毒刺激性原料、合成步骤仅需一步、反应条件温和、反应收率高;同时具有最终产品副产物少、易于分离提纯、化学纯度高、同位素丰度不稀释等优点。该稳定同位素标记嘧霉胺内标试剂的制备路线及方法未有文献报道,该方法制备所得的稳定同位素标记嘧霉胺化学纯度大于98%,同位素丰度大于98%。本制备方法所制得的食品安全检测用稳定同位素标记嘧霉胺内标试剂对我国相关的食品安全监督检测领域的发展具有重要意义。
附图说明:
图1:嘧霉胺(苯基-D5)的1HNMR图
图2:嘧霉胺(苯基-D5)的HRMS图
图3:嘧霉胺(苯基-D5)的HPLC图
具体实施方式
下面结合实施例及其附图进一步叙述本发明,但它并不是对本发明的范围的任何限制。
实施例1:
在25mL三口瓶中,在氮气保护下,加入氘代溴苯(810mg,5mmol)、醋酸钯(16.8mg,0.075mmol)、三(叔丁基)磷(60.7mg,0.3mmol)、磷酸钾(1.59g,7.5mmol)、2-氨基-4,6-二甲基嘧啶(647mg,5.25mmol)、甲苯(10mL);在100℃下反应24小时,TLC跟踪反应原料反应完全后,反应液冷却至室温,加入20mL水,用乙酸乙酯(3×20mL)萃取,合并有机相,依次用饱和碳酸氢钠溶液洗涤,饱和氯化钠溶液洗涤,加入无水硫酸钠干燥,抽滤除去干燥剂,减压蒸馏除去溶剂,残留物经柱层析得到稳定同位素标记嘧霉胺(苯基-D5)(847mg,收率83%)。
实施例2:
在25mL三口瓶中,在氮气保护下,加入氘代溴苯(810mg,5mmol)、双二亚苄基丙酮钯(86mg,0.15mmol)、1,1’-联萘-2,2’-双二苯膦(187mg,0.3mmol)、叔丁醇钠(671mg,7mmol)、2-氨基-4,6-二甲基嘧啶(677mg,5.5mmol)、甲苯(10mL);在110℃下反应16小时;TLC跟踪反应原料反应完全后,反应液冷却至室温,加入20mL水,用乙醚(3×20mL)萃取,合并有机相,依次用饱和碳酸氢钠溶液洗涤,饱和氯化钠溶液洗涤,加入无水硫酸钠干燥,抽滤除去干燥剂,减压蒸馏除去溶剂,残留物经柱层析得到稳定同位素标记嘧霉胺(苯基-D5)(950mg,收率93%)。
实施例3:
在25mL三口瓶中,在氮气保护下,加入氘代溴苯(810mg,5mmol)、三(二亚苄基丙酮)二钯(92mg,0.1mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(87mg,0.15mmol)、碳酸铯(2.6g,8mmol)、2-氨基-4,6-二甲基嘧啶(739mg,6mmol)、二氧六环(10mL);在80℃下反应20小时,TLC跟踪反应原料反应完全后,反应液冷却至室温,加入20mL水,用乙酸乙酯(3×20mL)萃取,合并有机相,依次用饱和碳酸氢钠溶液洗涤,饱和氯化钠溶液洗涤,加入无水硫酸钠干燥,抽滤除去干燥剂,减压蒸馏除去溶剂,残留物经柱层析得到稳定同位素标记嘧霉胺(苯基-D5)(990mg,收率97%)。1H NMR(CDCl3,300MHz):δ7.29(brs,1H),6.50(s,1H),2.39(s,6H),参见附图1;HRMS(ESI+)205.14879[M+H]+,参见附图2;HPLC测得化学纯度=99.55%,参见附图3;同位素丰度=98.76%,参见表1。
表1嘧霉胺(苯基-D5)的同位素丰度
质量标准满足食品安全检测用液相色谱串联质谱法所需稳定同位素标记内标试剂质量要求。
13C标记的稳定同位素标记嘧霉胺合成路线工艺同上述实施例中稳定同位素标记嘧霉胺的合成路线工艺。
以上所述为本发明的较佳实施例而已,但本发明不应该局限于该实施例所公开的内容。所以凡是不脱离本发明所公开的精神下完成的等效或修改,都落入本发明保护的范围。
Claims (3)
1.一种稳定同位素标记嘧霉胺内标试剂的制备方法,该稳定同位素标记嘧霉胺内标试剂的化学结构如式(稳定同位素标记嘧霉胺)所示:
(稳定同位素标记嘧霉胺)
其中*为12C或13C,X为H或D,其特征在于,其制备路线为:
其中*为12C或13C,X为H或D,Y为Cl、Br或I,制备步骤如下:
在氮气保护、加入稳定同位素标记卤代苯(I),然后加入2-氨基-4,6-二甲基嘧啶、催化剂、配体、有机溶剂、碱存在条件下,在30℃~150℃条件下,反应6~48小时;TLC跟踪反应原料反应完全后,反应混合溶液用水淬灭,过滤,滤液用有机溶剂萃取,合并有机相,依次用水洗涤、饱和碳酸氢钠溶液洗涤,饱和氯化钠溶液洗涤,加入干燥剂干燥,减压蒸馏除去溶剂,残留物经柱层析得到稳定同位素标记嘧霉胺。
2.根据权利要求1所述的一种稳定同位素标记嘧霉胺内标试剂的制备方法,其特征在于:所述步骤(1)中,催化剂为三(二亚苄基丙酮)二钯、双二亚苄基丙酮钯、醋酸钯、氯化钯、四(三苯基膦)钯、双(二苯基膦二茂铁)二氯化钯、双(三环己基膦)二氯化钯、双(三苯基膦)二氯化钯中的任意一种或几种;配体为三(邻甲基苯基)磷、三(环己基)磷、三(2-呋喃基)膦、三(异丙基)磷、三(叔丁基)磷、二叔丁基新戊基膦、2-二环己基磷-2’-甲基联苯、2-二环己基磷-2’,6’-二甲基联苯、2-二环己基膦-2’,4’,6’-三异丙基联苯、2-二环己基膦-2’,6’-二甲氧基-联苯、2-二-叔丁膦基-2’,4’,6’-三异丙基联苯、正丁基二(1-金刚烷基)膦、1,1’-联萘-2,2’-双二苯膦、4,5-双二苯基膦-9,9-二甲基氧杂蒽、双(2-二苯基磷苯基)醚、2-二环己膦基-2’-(N,N-二甲胺)-联苯、1,2-双(二苯基膦)乙烷、1,3-双(二苯基膦)丙烷、1,2,3,4,5-戊苯基-1’-(二叔丁基磷基)二茂铁、1,1’-双(二苯基膦)二茂铁、1,1’-双(二叔丁基膦)二茂铁、N,N-二甲基-1-(2-联苯膦基)二茂铁乙胺中的任意一种或几种;溶剂为四氢呋喃、二氧六环、甲苯、二甲苯、2-甲基四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜中的任意一种或几种;碱为碳酸锂、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、叔丁醇钠、叔丁醇钾、氢氧化钠、氢氧化钾、磷酸钾中的任意一种或几种;稳定同位素标记的卤代苯为氘标记、13C标记的氯苯、溴苯、碘苯中的任意一种;反应温度为30℃~150℃;反应时间为12~48小时。
3.根据权利要求1或2任意一项所述的一种稳定同位素标记嘧霉胺内标试剂的制备方法,其特征在于:所述化合物(I)与催化剂的摩尔比为(1:0.001)~(1:0.05);所述化合物(I)与配体的摩尔比为(1:0.005)~(1:0.1);所述化合物(I)与碱的摩尔比为(1:1)~(1:3);所述化合物(I)与2-氨基-4,6-二甲基嘧啶的摩尔比为(1:1~1:1.5);反应温度为80℃~120℃;反应时间为12~24小时。
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