CN115572218B - 一种2-溴-3-羟基苯甲醛及其相关化学发光底物中间体的制备方法 - Google Patents
一种2-溴-3-羟基苯甲醛及其相关化学发光底物中间体的制备方法 Download PDFInfo
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- OHXPHMPERMIICA-UHFFFAOYSA-N 2-bromo-3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1Br OHXPHMPERMIICA-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000000758 substrate Substances 0.000 title abstract description 13
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 13
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims abstract description 10
- URAZVWXGWMBUGJ-UHFFFAOYSA-N di(propan-2-yl)azanium;chloride Chemical compound [Cl-].CC(C)[NH2+]C(C)C URAZVWXGWMBUGJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 48
- 239000007787 solid Substances 0.000 claims description 15
- 230000035484 reaction time Effects 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- 238000005286 illumination Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 14
- 239000000543 intermediate Substances 0.000 abstract description 11
- 230000029918 bioluminescence Effects 0.000 abstract description 3
- 238000005415 bioluminescence Methods 0.000 abstract description 3
- 239000003999 initiator Substances 0.000 abstract description 3
- 238000003541 multi-stage reaction Methods 0.000 abstract description 3
- 238000003745 diagnosis Methods 0.000 abstract description 2
- 238000002059 diagnostic imaging Methods 0.000 abstract description 2
- 238000000338 in vitro Methods 0.000 abstract description 2
- 239000000523 sample Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000003760 magnetic stirring Methods 0.000 description 6
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- XYIPYISRNJUPBA-UHFFFAOYSA-N [3-(3'-methoxyspiro[adamantane-2,4'-dioxetane]-3'-yl)phenyl] dihydrogen phosphate Chemical compound O1OC2(C3CC4CC(C3)CC2C4)C1(OC)C1=CC=CC(OP(O)(O)=O)=C1 XYIPYISRNJUPBA-UHFFFAOYSA-N 0.000 description 3
- 239000012445 acidic reagent Substances 0.000 description 3
- IYKFYARMMIESOX-UHFFFAOYSA-N adamantanone Chemical compound C1C(C2)CC3CC1C(=O)C2C3 IYKFYARMMIESOX-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000006418 Brown reaction Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- JDIIGWSSTNUWGK-UHFFFAOYSA-N 1h-imidazol-3-ium;chloride Chemical compound [Cl-].[NH2+]1C=CN=C1 JDIIGWSSTNUWGK-UHFFFAOYSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000005081 chemiluminescent agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- -1 with bubbles Chemical compound 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4075—Esters with hydroxyalkyl compounds
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- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Abstract
本发明公开了一种2‑溴‑3‑羟基苯甲醛及其相关化学发光底物中间体的制备方法,将3‑羟基苯甲醛与二溴海因在二异丙胺盐酸盐及溶剂存在下,反应得到所述2‑溴‑3‑羟基苯甲醛,该方法操作简单且反应物二溴海因价廉易得,适于批量制备2‑溴‑3‑羟基苯甲醛。此外,本发明以上述2‑溴‑3‑羟基苯甲醛为起始物,通过多步反应得到系列化合物,这类化合物可作为中间体用于制备化学发光底物,在体外诊断、医学成像和生物发光探针等方面具有良好的应用前景。
Description
技术领域
本发明涉及有机化学合成技术领域,具体涉及一种2-溴-3-羟基苯甲醛及其相关化学发光底物中间体的制备方法。
背景技术
化学发光是在各种化学和生物应用中实现高信噪比的最灵敏方法之一,在化学发光反应中参与能量转移并最终以发射光子的形式释放能量的化合物称为化学发光剂或发光底物。例如目前已被广泛用作化学发光免疫分析仪器上的化学发光底物4-甲氧基-4-(3-磷酸酰苯基)螺[1,2-二氧环乙烷-3-2’-金刚烷],二钠盐(简称AMPPD),该化合物能发出高强度光信号,用于化学发光免疫分析方面具有检测灵敏度高的优点。
但AMPPD的发光速度与碱性磷酸酶的浓度相关,而酶易受环境的影响,所以AMPPD试剂在实际使用中存在激发时间长,测试速度慢以及不稳定性等缺点。本发明通过设计和合成的关键中间体在苯环上引入卤素溴以有效的改善激发时间长、测试速度慢等方面性能,使分子本身在应用环境下更加稳定,大大改善发光性能的同时使其适合在不同生物发光领域应用。
发明内容
本发明要解决的技术问题是提供一种2-溴-3-羟基苯甲醛及其相关化学发光底物中间体的制备方法,本发明以3-羟基苯甲醛与二溴海因为反应物制备2-溴-3-羟基苯甲醛,该制备方法操作简单且反应物二溴海因价廉易得,适于批量生产。此外,本发明以上述反应制备得到的2-溴-3-羟基苯甲醛为起始物,通过多步反应得到系列化学发光底物的中间体。
为解决上述技术问题,本发明提供以下技术方案:
本发明第一方面提供了一种2-溴-3-羟基苯甲醛的制备方法,光照条件下,将3-羟基苯甲醛与二溴海因在催化剂及溶剂的存在下反应,反应完全后,将反应液加至饱和亚硫酸钠溶液中搅拌,析出固体,得到所述2-溴-3-羟基苯甲醛。
进一步地,所述3-羟基苯甲醛与二溴海因的投料摩尔比为1:1~1.5。
进一步地,所述催化剂为二异丙胺盐酸盐。
进一步地,所述二异丙胺盐酸盐由二异丙胺与氯化氢气体在溶剂存在下反应得到。
进一步地,所述反应的温度为-10~5℃,反应的时间为3~6h;反应的温度优选0℃。
进一步地,先将3-羟基苯甲醛、催化剂与溶剂混合均匀,置于-10~5℃冷却并分批加入二溴海因反应,反应完全后将反应液倒入预冷的饱和亚硫酸钠水溶液中,淬灭反应,析出白色固体,经重结晶得到所述2-溴-3-羟基苯甲醛。
本发明第二方面提供了一种化学发光底物中间体的制备方法,包括以下步骤:
(1)将2-溴-3-羟基苯甲醛与叔丁基二甲基氯硅烷在咪唑及溶剂的存在下反应,反应完全后将反应液经浓缩、纯化得到化合物1;
(2)将步骤(1)制备得到的化合物1与原甲酸三甲酯在酸试剂及溶剂的存在下反应,反应完全后将反应液经浓缩、纯化得到化合物2;
(3)将步骤(2)制备得到的化合物2与亚磷酸三甲酯在路易斯酸及溶剂的存在下反应,反应完全后将反应液加至饱和亚硫酸钠溶液中淬灭,然后经萃取、洗涤、干燥及纯化后得到化合物3;
(4)在惰性气氛下,将步骤(3)制备得到的化合物3与2-金刚烷酮在二异丙基氨基锂及溶剂存在下反应,反应完全后将反应液加至预冷的水中淬灭,然后经萃取、洗涤、干燥及纯化后得到化合物4;
(5)将步骤(4)制备得到的化合物4与四丁基氟化铵在溶剂存在下反应,反应完全后将反应液加至饱和的碳酸氢钠溶液中,然后经萃取、洗涤、干燥及纯化后得到化合物5;
所述化合物发光底物中间体为化合物1~化合物5中任意一种;
所述化合物1~5的结构式如下所示:
进一步地,步骤(1)中,所述2-溴-3-羟基苯甲醛为权利要求1~3任一所述制备方法制备得到。
进一步地,步骤(1)中,所述2-溴-3-羟基苯甲醛与叔丁基二甲基氯硅烷的投料摩尔比为1:1~2。
进一步地,步骤(1)中,所述反应的温度为-10~35℃,反应的时间为8~24h;反应的温度优选25℃,反应的时间优选16h。
进一步地,步骤(1)中,先将2-溴-3-羟基苯甲醛、咪唑与溶剂混合均匀得到均一溶液,置于-10~0℃冷却并加入叔丁基二甲基氯硅烷反应。
进一步地,步骤(2)中,所述化合物1、原甲酸三甲酯与酸试剂的投料摩尔比为1:4~5:05~1。
进一步地,步骤(2)中,所述酸试剂为乙酸、盐酸、对甲苯磺酸、苯磺酸或四丁基溴化铵。
进一步地,步骤(2)中,所述反应的温度为65~85℃,反应的时间为16h~24h。
进一步地,步骤(3)中,所述化合物2、亚磷酸三甲酯与路易斯酸的投料摩尔比为1:1~2:1~2。
进一步地,步骤(3)中,所述路易斯酸为四氯化钛、三氟化硼、三氯化钛或三氟甲磺酸。
进一步地,步骤(3)中,所述反应的温度为-5~5℃,反应的时间为30min~2h。
进一步地,步骤(3)中,先将化合物2、亚磷酸三甲酯与溶剂混合,置于-5~5℃冷却并滴加四氯化钛反应;所述四氯化钛在1~3h内滴加完,例如2h。
进一步地,步骤(4)中,所述化合物3、2-金刚烷酮与二异丙基氨基锂的投料摩尔比为1:1~1.5:1~1.5。
进一步地,步骤(4)中,所述反应的温度为-80~25℃,反应的时间为16h~24h。
进一步地,步骤(5)中,所述化合物4与四丁基氟化铵的投料摩尔比为1:1~1.5。
进一步地,步骤(5)中,所述反应的温度为10~25℃,反应的时间为20min~60min。
进一步地,步骤(1)~步骤(5)中,所述纯化包括过硅胶洗脱的过程,洗脱液为正己烷与乙酸乙酯的混合溶剂。
与现有技术相比,本发明的有益效果在于:
本发明以3-羟基苯甲醛与二溴海因为反应物制备2-溴-3-羟基苯甲醛,相较于传统以溴素为溴化试剂制备2-溴-3-羟基苯甲醛的方法,本发明所述制备方法操作简单,反应产物无需过硅胶柱纯化处理,且反应物二溴海因价廉易得,适于大规模生产。另外,本发明以上述2-溴-3-羟基苯甲醛为起始物,通过多步反应得到系列溴取代化合物,可作为中间体用于制备化学发光底物,在体外诊断、医学成像和生物发光探针等方面具有良好的应用前景。
具体实施方式
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“及/或”包括一个或多个相关的所列项目的任意的和所有的组合。
下面结合具体实施例对本发明作进一步说明,以使本领域的技术人员可以更好地理解本发明并能予以实施,但所举实施例不作为对本发明的限定。
实施例1
本实施例涉及一种2-溴-3-羟基苯甲醛的制备,具体过程如下:
(1)二异丙胺盐酸盐的制备:二异丙胺溶于二氯甲烷(DCM)/甲醇(MeOH)混合溶剂,室温通HCl气体,浓缩干,用DCM打浆,收集固体,作为催化剂备用。
(2)2-溴-3-羟基苯甲醛的制备:在磁力搅拌和烤灯(提供光源)条件下,于1L三口圆底烧瓶中加入3-羟基苯甲醛(50g,409.7mmol,1eq.)、自制催化剂二异丙胺盐酸盐(1.2g,8.72mmol,0.02eq.)和甲苯(500mL),搅匀,置于冰盐浴中冷却内温至0℃以下,光照条件下,分批加二溴海因(128.5g,452.75mmol,1.1eq.),约5min加完。加完后,体系保持0℃及光照条件,继续反应约4h,得淡黄色浑浊液。取反应液加饱和亚硫酸钠水溶液淬灭,EA萃取点板,原料反应完全,反应液倒入搅拌的冷的饱和亚硫酸钠水溶液(500mL)中充分搅拌,有大量类白色固体析出,抽滤收集固体,滤饼用H2O充分洗涤,抽干,刮出,烤灯烘干,得类白色固体约39g。粗品加乙腈(330mL),于50℃水浴中,搅拌溶清,然后倒入搅拌的水(约500mL)中,然后于冷肼中冷却一会儿,抽滤收集固体,滤饼水洗2次,刮出、烤灯烘干,得类白色固体94g,产率:47%,纯度:98.89%,1H NMR(400MHz,DMSO)δ10.30(s,1H),7.54-7.51(m,1H),7.39-7.35(m,1H),7.31-7.27(m,1H),5.90(s,1H)。
实施例2
本实施例涉及化学发光底物中间体的制备,具体过程如下:
(1)化合物1的制备,其反应方程如下:
在磁力搅拌条件下,于1L单口圆底烧瓶中加入2-溴-3-羟基苯甲醛(54g,270.06mmol,1eq.)、咪唑(47g,690.36mmol,2.5eq.)和无水DCM(500mL),搅匀得棕色透明溶液,置于-5℃乙醇浴中冷却。分批加叔丁基二甲基氯硅烷(TBSCl,62.4g,414.01mmol,1.5eq.),约15min加完,得类白色浑浊液。加完后,体系自然升温至室温,搅拌过夜(约16h),得淡棕色浑浊液反应液。取反应液点板,原料反应完全,反应液直接浓缩,得半固体粗品,用DCM(150mL)溶解分散,抽滤,滤饼用正己烷:乙酸乙酯=25:1(250mL/10mL)和10:1(250mL/25mL)洗涤(滤饼无紫外,认为是咪唑盐酸盐),滤液浓缩得棕色油113g,拌120g硅胶,减压过400g硅胶垫,以正己烷:乙酸乙酯=50:1~10:1洗脱,浓缩洗脱液,得近无色液体约81.6g。产率:96%,纯度:98.63%,1H NMR(500MHz,CDCl3)δ(ppm):10.41(d,J=0.8Hz,1H),7.52(dd,J=7.7,1.6Hz,1H),7.28(td,J=8.0,0.8Hz,1H),7.10(dd,J=8.0,1.6Hz,1H),1.07(s,9H),0.28(s,6H)。
(2)化合物2的制备,其反应方程如下:
在磁力搅拌条件下,于500L单口圆底烧瓶中加入化合物1(81.6g,259.84mmol,1eq.)和无水MeOH(180mL),搅匀得无色透明溶液。室温继续加入原甲酸三甲酯(119.7g,1127.87mmol,4.3eq.)和冰乙酸(8.1g,134.89mmol,0.5eq.),体系无明显变化。装上回流管(上接干燥管),于85℃油浴中回流过夜(约19h)。取反应液点板,原料反应完全,反应液浓缩,用乙酸乙酯(EA,200mL)稀释后,用饱和NaHCO3水溶液洗涤除去乙酸(主要有气泡,保证水相PH值7~8),水相用EA(100mL*1)萃取,合并的有机相用无水硫酸钠(10g)干燥。浓缩得淡黄色油,拌110g硅胶,减压过390g硅胶垫,用上一步回收的正己烷:乙酸乙酯=9:1左右洗脱,浓缩洗脱液并干燥得近无色液体约59.9g。产率:64%,纯度:97.9%,1H NMR(400MHz,CDC13):δ7.32(dd,=7.8,1.5Hz,1H),7.08(t,=7.9Hz,1H),6.83(dd,=8.0,1.5Hz,1H),5.63(s,1H),3.37(s,6H),1.03(s,9H),0.22(s,6H)。
(3)化合物3的制备,其反应方程如下:
在磁力搅拌条件下,于1L三口圆底烧瓶中加入化合物2(59.9g,166.30mmol,1eq.)、亚磷酸三甲酯(30.9g,249.45mmol,1.5eq.)和无水DCM(400mL),搅匀得无色透明溶液。瓶口分别装上低温温度计、恒压滴液漏斗(上接干燥管)和胶塞,置于乙醇浴中冷却内温至0℃。缓慢滴加TiCl4(47.4g,249.45mmol,1.5eq.),约2h后滴加完成,得红褐色反应液;保持0℃继续反应1h。取反应液加入饱和NaHCO3水溶液和少量DCM,有机相点板,原料反应完全,反应液倒入事先于冰柜中冷却1h的饱和NaHCO3水溶液中淬灭,有气泡产生,倒完后搅拌20min左右,保证水相PH为7~8,水相呈白色乳浊状(较难抽滤)用DCM(350mL*4)萃取产品。合并的有机相用卤水(200mL*2)洗涤用、无水硫酸钠(10g)干燥。浓缩得苍白色油约93g,拌100g硅胶,过400g硅胶柱(两根200g),用正己烷:乙酸乙酯=10:1~1:1(大部分为前两步回收溶剂)洗脱,浓缩洗脱液并干燥得浅黄色油约57.6g。产率:79%,纯度:97.77%,1H NMR(400MHz,CDCI3):δ7.34(dt,=7.8,1.9Hz,1H),7.10(t,=7.9Hz,1H),6.88(dt,=7.9,1.6Hz,1H),5.18(d,=15.7Hz,1H),3.76(d,=10.6Hz,3H),3.64(d,=10.5Hz,3H),3.35(s,3H),1.02(s,9H),0.22(s,6H)。
(4)化合物4的制备,其反应方程如下:
在磁力搅拌条件下,于2L三口圆底烧瓶中加入化合物3(57.6g,131.42mmol,1eq.)和干燥四氢呋喃(THF,400mL),搅匀,得近无色透明溶液。瓶口装上低温温度计、恒压滴液漏斗、三通(接N2气球)。N2换气2次后,于乙醇浴中用液氮冷却至内温-78℃左右。滴加2.0M的二异丙基氨基锂(LDA,120mL,240mmol,1.4eq.),约1h加完,得红棕色反应液,保持温度搅拌30min左右。内温-78℃左右,滴加溶于干燥THF(180mL)的2-金刚烷酮(23.7g,204.27mmol,1.2eq.),约45min滴加完成。体系自然升温至室温搅拌过夜(共约18h)。取反应液加水和EA振荡,有机相点板,原料反应完全,将反应液分批倒入搅拌的冰水(1L)中淬灭。分出上层有机相,下层水相用EA(250mL*2)萃取产品;有机相用卤水(200mL*2)洗、无水Na2SO4干燥。浓缩有机相,得黄色半固体约86g。拌90g硅胶,过300g硅胶柱(两根150g),用正己烷:乙酸乙酯=1:0~100:1洗脱,浓缩洗脱液并干燥得白色固体约30.4g。产率:50%,纯度:95%。1H NMR(400MHz,CDC13):δ7.14(t,=8.0Hz,1H),6.87-6.83(m,2H),3.30(s,3H),3.27(s,1H),2.05(s,1H),1.97-1.65(m,12H),1.04(s,9H),0.23(s,6H)。
(5)化合物5的制备,其反应方程如下:
在磁力搅拌条件下,于1L单口圆底烧瓶中加入化合物4(30.4g,65.74mmol,1eq.)和THF(400mL),搅匀,得近无色透明溶液。室温下继续加入1.0M的四丁基氟化铵(TBAF,94.5mL,94.5mmol,1.4eq.),反应液无放热,呈浅黄色透明态。体系室温搅拌40min。取反应液加入饱和氯化铵水溶液中,用EA萃取点板,原料反应结束,将反应液倒入搅拌的饱和NaHCO3(500mL)中。分出上层有机相,下层水相用EA(150mL*2)萃取产品;有机相用卤水(200mL*1)洗、无水Na2SO4干燥。浓缩有机相,得浅黄色粘稠油约47g。拌50g硅胶,过170g硅胶柱,用正己烷:乙酸乙酯=1:0~10:1洗脱,浓缩洗脱液并干燥得无色粘稠油约22.7g(核磁有Si基杂质)。用正己烷打浆,抽滤收集固体,干燥得白色固体12.3g,产率:53.7%,纯度:98.66%(HPLC),1H NMR(400MHz,CDC13):δ7.20(t,=7.8Hz,1H),6.90(dd,=8.2,1.3Hz,1H),6.78(dd,=7.5,1.3Hz,1H),5.58(s,1H),3.32(s,3H),3.27(s,1H),2.10(s,1H),2.00-1.65(m,12H)。
对比例
本对比例涉及一种2-溴-3-羟基苯甲醛的制备,采用溴素为溴化试剂,具体过程如下:
2-溴-3-羟基苯甲醛:在250mL烧瓶中装入3-羟基苯甲醛(16.1g,132mmol,1equiv.)、铁粉(0.56g,10mmol)、无水乙酸钠(21.3g,260mmol,1.97equiv.)和冰醋酸(120mL)。将悬浮液加热直至获得澄清溶液,然后使其缓慢冷却至室温。在15分钟内向混合物中滴加溴(24.0g,150mmol,1.14当量)的冰醋酸(25mL)溶液。不允许反应温度升至室温以上。添加完成1小时后,将反应混合物倒入冰水(800mL)中,用CH2Cl2(3次,200mL)萃取。将合并的有机萃取物干燥(MgSO4)并通过硅胶垫(CH2Cl2)过滤。浓缩并从CH2Cl2(20mL)中结晶得到10.6g(52.8mmol,40%)2-溴-3-羟基苯甲醛。母液的快速柱色谱法(二氧化硅,CH2Cl2;Rf=0.28,石油醚/EtOAc,2:1)得到另外2.7g(13.43mmol,10%)所需产物;熔点145℃(CH2Cl2)。1H NMR(300MHz,CDCl3):δ=5.80(s,1H),7.26(pdd,J=1.7,7.9Hz,1H),7.36(pt,J=7.9Hz,1H),7.45(pdd,J=1.7,7.5Hz,1H),10.03(s,1H)ppm。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例,本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换,均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。
Claims (3)
1.一种2-溴-3-羟基苯甲醛的制备方法,其特征在于,光照条件下,将3-羟基苯甲醛与二溴海因在催化剂及溶剂的存在下反应,反应完全后,将反应液加至饱和亚硫酸钠溶液中搅拌,析出固体,得到所述2-溴-3-羟基苯甲醛;其中,所述催化剂为二异丙胺盐酸盐,所述反应的温度为-10~5℃。
2.根据权利要求1所述的制备方法,其特征在于,所述3-羟基苯甲醛与二溴海因的投料摩尔比为1:1~1.5。
3.根据权利要求1所述的制备方法,其特征在于,反应的时间为3~6h。
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