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CAS No. : | 80745-61-5 | MDL No. : | |
Formula : | C9H13IO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AEMUWTWTDIUOLJ-UHFFFAOYSA-N |
M.W : | 280.10 | Pubchem ID : | 53248317 |
Synonyms : |
|
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
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* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sulfuric acid In dichloromethane for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With hydrogen iodide; acetic anhydride for 120h; Heating; | |
Multi-step reaction with 2 steps 1: 58 percent / t-butyl hypoiodite / 1,1,2-trichloro-1,2,2-trifluoro-ethane / Irradiation 2: 55 percent / 55percent aq. HI / 48 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With hydrogen iodide for 48h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride at 80℃; | ||
With Dichloromethyl methyl ether In chloroform-d1 at 50℃; for 72h; Inert atmosphere; | ||
With thionyl chloride at 50℃; for 2h; | 4 Example 4. Preparation of A44-iodobicyclo[2.2.2]octyl-1-carboxylic acid chloride: 100g(357.1mmol) 4-iodobicyclo[2.2.2]octyl-1-carboxylic acid was added with 63.7g (535.7mmol) thionyl chloride, stirred at 50 for 2h, the reaction solution was directly concentrated under reduced pressure and used 3*5mL The toluene washing reaction solution was continuously concentrated for use. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With dimethylsulfide borane complex In tetrahydrofuran; diethyl ether at 0℃; for 0.333333h; | |
With dimethylsulfide borane complex In tetrahydrofuran | ||
With methanol; dimethylsulfide borane complex; sodium methylate 1.) THF, overnight, 2.) MeOH, reflux, 1 h, 3.) reflux; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1.) borane-methyl sulfide, 3.) MeONa, MeOH / 1.) THF, overnight, 2.) MeOH, reflux, 1 h, 3.) reflux 2: 97 percent / pyridine / 1 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 92 percent / H2SO4 / CH2Cl2 / 24 h / Heating 2: iodine monochloride / CCl4 / 48 h / Ambient temperature 3: 91 percent / aq. KOH / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 92 percent / H2SO4 / CH2Cl2 / 24 h / Heating 2: iodine monochloride / CCl4 / 48 h / Ambient temperature 3: 91 percent / aq. KOH / ethanol 4: BH3*(CH3)2S / tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 92 percent / H2SO4 / CH2Cl2 / 24 h / Heating 2: iodine monochloride / CCl4 / 48 h / Ambient temperature 3: 91 percent / aq. KOH / ethanol 4: 44 percent Turnov. / sulfur tetrafluoride / 48 h / 150 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 92 percent / H2SO4 / CH2Cl2 / 24 h / Heating 2: iodine monochloride / CCl4 / 48 h / Ambient temperature 3: 91 percent / aq. KOH / ethanol 4: BH3*(CH3)2S / tetrahydrofuran 5: pyridinium chlorochromate / CH2Cl2 / 15 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: BH3*(CH3)2S / tetrahydrofuran 2: pyridinium chlorochromate / CH2Cl2 / 15 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: BH3*(CH3)2S / tetrahydrofuran 2: pyridinium chlorochromate / CH2Cl2 / 15 h / Ambient temperature 3: 88 percent / tetrahydrofuran / -100 °C 4: 1.) n-BuLi / 1.) ether, THF, hexane, -100 deg C, 2.) ether, THF, hexane, reflux, 2 h 5: 1.) t-BuLi / 1.) ether, pentane, from -100 deg C to -80 deg C, 15 min, 2.) from -100 deg C to RT 6: tetrahydrofuran / 1.) from -100 deg C to RT, 2.) reflux, 24 h 7: KF*2H2O / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 92 percent / H2SO4 / CH2Cl2 / 24 h / Heating 2: iodine monochloride / CCl4 / 48 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 92 percent / H2SO4 / CH2Cl2 / 24 h / Heating 2: iodine monochloride / CCl4 / 48 h / Ambient temperature 3: 91 percent / aq. KOH / ethanol 4: BH3*(CH3)2S / tetrahydrofuran 5: pyridinium chlorochromate / CH2Cl2 / 15 h / Ambient temperature 6: tetrahydrofuran / 1.) from -100 deg C to RT, 2.) reflux, 24 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: BH3*(CH3)2S / tetrahydrofuran 2: pyridinium chlorochromate / CH2Cl2 / 15 h / Ambient temperature 3: 88 percent / tetrahydrofuran / -100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 92 percent / H2SO4 / CH2Cl2 / 24 h / Heating 2: iodine monochloride / CCl4 / 48 h / Ambient temperature 3: 91 percent / aq. KOH / ethanol 4: 45 percent Spectr. / sulfur tetrafluoride / 48 h / 150 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: BH3*(CH3)2S / tetrahydrofuran 2: pyridinium chlorochromate / CH2Cl2 / 15 h / Ambient temperature 3: 88 percent / tetrahydrofuran / -100 °C 4: 1.) n-BuLi / 1.) ether, THF, hexane, -100 deg C, 2.) ether, THF, hexane, reflux, 2 h 5: 1.) t-BuLi / 1.) ether, pentane, from -100 deg C to -80 deg C, 15 min, 2.) from -100 deg C to RT |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: BH3*(CH3)2S / tetrahydrofuran 2: pyridinium chlorochromate / CH2Cl2 / 15 h / Ambient temperature 3: 88 percent / tetrahydrofuran / -100 °C 4: 1.) n-BuLi / 1.) ether, THF, hexane, -100 deg C, 2.) ether, THF, hexane, reflux, 2 h 5: 1.) t-BuLi / 1.) ether, pentane, from -100 deg C to -80 deg C, 15 min, 2.) from -100 deg C to RT 6: tetrahydrofuran / 1.) from -100 deg C to RT, 2.) reflux, 24 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: BH3*(CH3)2S / tetrahydrofuran 2: pyridinium chlorochromate / CH2Cl2 / 15 h / Ambient temperature 3: 88 percent / tetrahydrofuran / -100 °C 4: 1.) n-BuLi / 1.) ether, THF, hexane, -100 deg C, 2.) ether, THF, hexane, reflux, 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: SOCl2 / 80 °C 2: NaN3 / acetone / 1 h / 0 - 5 °C 3: 2.) conc. HCl / 1.) C6H6, reflux, 2.) reflux, 3 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: 4-iodobicyclo<2.2.2>octane-1-carboxylic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -30℃; for 1h; Stage #2: With ammonia In tetrahydrofuran at -20℃; for 0.833333h; Stage #3: With pyridine In tetrahydrofuran at 0℃; for 2h; | 20.A.1; 20.A.2; 20.A.3 Step A. Intermediate 20A. Preparation of 4-iodobicyclo[2.2.2]octane-1-carbonitrile To a 250 mL round bottomed flask were added Intermediate 4B (0.56 g, 2.0 mmol), THF (20 mL) and TEA (0.42 mL, 3.0 mmol). The mixture was cooled to -30° C., then ethyl chloroformate (0.23 mL, 2.4 mmol) was added dropwise. The mixture was stirred for 1 h at -30° C. The reaction was filtered, both flask and filter cake were washed with an additional amount of ice cold THF (15 mL), and the reaction was cooled to -20° C. The mixture generated above was cooled to -20° C. and ammonia gas was dispersed through the mixture for 10 min. After stirring at this temperature for 40 min, the solvent was concentrated and the residue was taken onto the next step without purification or characterization. The residue from above was dissolved in THF (12 mL), pyridine (0.53 mL, 6.6 mmol) was added and the mixture was cooled to 0° C. To this mixture was added trifluoroacetic anhydride (0.57 mL, 4.0 mmol) and the reaction was stirred at this temperature for 2 h. To this mixture was added MeOH (5 mL) and 1 M K2HPO4 (aq.) (5 mL) and stirred for 30 min. The mixture was diluted with water (100 mL) and extracted with EtOAc (2×50 mL). The organic phase was combined, washed with 1 M HCl (aq.), brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (40 g silica gel cartridge; A=Hex, B=EtOAc; 20 min grad.; 0% B to 50% B; flow rate=40 mL/min). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (0.37 g, 1.4 mmol, 71% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 2.56-2.46 (m, 6H), 2.14-2.04 (m, 6H). |
Multi-step reaction with 3 steps 1: SOCl2 / 80 °C 2: 88 percent / NH3 / diethyl ether / -5 °C 3: 80 percent / (CF3CO)2O, pyridine / dioxane / 3 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: SOCl2 / 80 °C 2: 88 percent / NH3 / diethyl ether / -5 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: SOCl2 / 80 °C 2: NaN3 / acetone / 1 h / 0 - 5 °C 3: 2.) conc. HCl / 1.) C6H6, reflux, 2.) reflux, 3 h 4: 74 percent / benzene / 2 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: SOCl2 / 80 °C 2: NaN3 / acetone / 1 h / 0 - 5 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: sodium hydride / 1,2-dimethoxyethane; mineral oil / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: Inert atmosphere; Heating 2.1: hydrogenchloride / chloroform / 7 h / 0 °C / Inert atmosphere 3.1: Raney nickel (Ra-Ni) / ethanol / 4 h / Inert atmosphere; Reflux 4.1: potassium hydroxide / ethanol / Reflux 5.1: iodine; mercury(II) oxide / dichloromethane / 1 h / 80 - 90 °C / Inert atmosphere 6.1: potassium hydroxide / ethanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium hydroxide In ethanol at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: Raney nickel (Ra-Ni) / ethanol / 4 h / Inert atmosphere; Reflux 2: potassium hydroxide / ethanol / Reflux 3: iodine; mercury(II) oxide / dichloromethane / 1 h / 80 - 90 °C / Inert atmosphere 4: potassium hydroxide / ethanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: iodine; mercury(II) oxide / dichloromethane / 1 h / 80 - 90 °C / Inert atmosphere 2: potassium hydroxide / ethanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium hydroxide / ethanol / Reflux 2: iodine; mercury(II) oxide / dichloromethane / 1 h / 80 - 90 °C / Inert atmosphere 3: potassium hydroxide / ethanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: Dichloromethyl methyl ether / chloroform-d1 / 72 h / 50 °C / Inert atmosphere 2: triethylamine / chloroform-d1 / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: Dichloromethyl methyl ether / chloroform-d1 / 72 h / 50 °C / Inert atmosphere 2.1: triethylamine / chloroform-d1 / 0.17 h / Inert atmosphere 2.2: 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate; 1,2-dichloro-ethane at 80℃; for 5h; Inert atmosphere; | 15.F Step F. Intermediate 15F. Preparation of tert-butyl 4-fluoro-2-(4-iodobicyclo[2.2.2]octan-1-yl)benzo[d]thiazole-6-carboxylate To a 100 mL pear shaped flask were added Intermediate 15E (0.35 g, 1.3 mmol), Intermediate 4B (0.46 g, 1.5 mmol), pyridine (0.30 mL, 3.8 mmol) and DCE (8 mL). To this mixture was added T3P (1.9 mL, 3.1 mmol) (50% w/v solution in EtOAc) and the reaction was stirred at 80° C. under N2 for 5 h. The solvent was concentrated and the crude product was purified by flash column chromatography (40 g silica gel cartridge; A=Hex, B=EtOAc; 20 min grad.; 0% B to 100% B; flow rate=40 mL/min). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (0.17 g, 0.35 mmol, 28% yield) as a pale yellow solid. 1H NMR (500 MHz, DICHLOROMETHANE-d2) δ 8.35 (d, J=1.4 Hz, 1H), 7.84-7.72 (m, 1H), 2.70-2.62 (m, 6H), 2.30-2.21 (m, 6H), 1.64 (s, 9H). MS (ESI) 488 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 18h; | To a 20 mL scintillation vial were added Intermediate 4B (0.30 g, 1.1 mmol), <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> (0.29 g, 1.6 mmol), DMAP (0.26 g, 2.1 mmol) followed by DMF (5 mL). To this mixture was added EDC (0.41 g, 2.1 mmol) and the vial was capped and stirred for 18 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (2*25 mL). The organic phase was combined, washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (40 g silica gel cartridge; A=Hex, B=EtOAc; 15 min grad.; 0% B to 100% B; flow rate=40 mL/min). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (0.17 g, 0.38 mmol, 36% yield) as a pale yellow oil. 1H NMR (500 MHz, METHANOL-d4) delta 7.73-7.68 (m, 1H), 7.68-7.63 (m, 1H), 6.87-6.77 (m, 1H), 4.37-4.25 (m, 2H), 2.60-2.51 (m, 6H), 2.13-2.05 (m, 6H), 1.42-1.32 (m, 3H). MS (ESI) 443 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | Stage #1: methyl 3-(hydrazinecarbonyl)benzoate; 4-iodobicyclo<2.2.2>octane-1-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide for 2h; Stage #2: With diphosphorus pentasulfide In tetrahydrofuran at 50℃; for 18h; | 19.A.1; 19.A.2 Step A. Intermediate 19A. Preparation of methyl 3-(5-(4-iodobicyclo[2.2.2]octan-1-yl)-1,3,4-thiadiazol-2-yl)benzoate To a mixture of Intermediate 4B (0.24 g, 0.84 mmol), methyl 3-(hydrazinecarbonyl)benzoate (0.16 g, 0.84 mmol) (Bradner, J. E. et al. WO 2014/071247), TEA (0.18 mL, 1.3 mmol) and HOBT (0.039 g, 0.25 mmol) in DMF (6 mL) was added EDC (0.24 g, 1.3 mmol) and the resulting mixture was stirred. After 2 h, the reaction was diluted with water (50 mL) and extracted with EtOAc (2×25 mL). The organic phase was combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dried in vacuo and taken onto the next step without characterization. Step 2: The product of Step 1 was dissolved in THF (5 mL), phosphorus pentasulfide (0.48 g, 2.2 mmol) was added and the reaction was stirred at 50° C. After 18 h, the reaction was cooled, filtered and the filtrate was concentrated. The crude product was purified by flash column chromatography (40 g silica gel cartridge; A=Hex, B=EtOAc; 20 min grad.; 0% B to 60% B; flow rate=40 mL/min). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (60 mg, 0.13 mmol, 16% yield) as a white solid. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ 8.41 (t, J=1.5 Hz, 1H), 8.05 (td, J=7.9, 1.4 Hz, 2H), 7.48 (t, J=7.8 Hz, 1H), 3.85 (s, 3H), 2.58-2.50 (m, 6H), 2.17-2.05 (m, 6H). MS (ESI) 455 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | Stage #1: methyl 3-(hydrazinecarbonyl)benzoate; 4-iodobicyclo<2.2.2>octane-1-carboxylic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In acetonitrile for 2h; Stage #2: With N-ethyl-N,N-diisopropylamine; p-toluenesulfonyl chloride In acetonitrile for 18h; Inert atmosphere; | 18.A Step A. Intermediate 18A. Preparation of methyl 3-(5-(4-iodobicyclo[2.2.2]octan-1-yl)-1,3,4-oxadiazol-2-yl)benzoate To a mixture of Intermediate 4B (0.24 g, 0.84 mmol), methyl 3-(hydrazinecarbonyl) benzoate (0.16 g, 0.84 mmol) (Bradner, J. E. et al. WO 2014/071247) and DIEA (0.44 mL, 2.5 mmol) in MeCN (10 mL) was added TBTU (0.30 g, 0.92 mmol). After stirring 2 h, DIEA (0.29 mL, 1.7 mmol), followed by p-toluenesulfonyl chloride (0.48 g, 2.5 mmol) were successively added and the resulting reaction mixture was stirred under N2. After 18 h, the mixture was diluted with 1 M K2HPO4 (aq.) (50 mL) and extracted with EtOAc (2*25 mL). The organic phase was combined, washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (40 g silica gel cartridge; A=Hex, B=EtOAc; 15 min grad.; 0% B to 100% B; flow rate=40 mL/min). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (0.063 g, 0.14 mmol, 17% yield) as a white solid. 1H NMR (500 MHz, DICHLOROMETHANE-d2) δ 8.69-8.60 (m, 1H), 8.31-8.19 (m, 2H), 7.69-7.60 (m, 1H), 3.99 (s, 3H), 2.70-2.61 (m, 6H), 2.24 (br d, J=8.3 Hz, 6H). MS (ESI) 439 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 4-iodobicyclo<2.2.2>octane-1-carboxylic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In acetonitrile for 0.5h; Stage #2: 4-amino-3-(aminomethyl)benzoic acid methyl ester hydrochloride With N-ethyl-N,N-diisopropylamine In acetonitrile for 2h; Inert atmosphere; | 24.A Step A. Intermediate 24A. Preparation of methyl 4-amino-3-((4-iodobicyclo[2.2.2]octane-1-carboxamido)methyl)benzoate To a 50 mL round bottomed flask were added Intermediate 4B (0.19 g, 0.69 mmol), MeCN (7 mL) and HBTU (0.31 g, 0.83 mmol). After stirring for 30 min, a solution of methyl 4-amino-3-(aminomethyl)benzoate dihydrochloride (0.26 g, 0.69 mmol) (Pascal, R. et al. Eur. J. Org. Chem. 2000, 22, 3755-3761) and DIEA (0.48 mL, 2.8 mmol) dissolved in MeCN (3 mL) was added and the reaction was stirred under N2. After 2 h, the solvent was concentrated and the crude product was purified by flash column chromatography (40 g silica gel cartridge; A=Hex, B=EtOAc; 20 min grad.; 0% B to 100% B; flow rate=40 mL/min). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (0.29 g, 0.66 mmol, 95% yield) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.81-7.77 (m, 1H), 7.76-7.73 (m, 1H), 6.63-6.56 (m, 1H), 5.85-5.73 (m, 1H), 4.94-4.84 (m, 2H), 3.87 (s, 3H), 2.53-2.45 (m, 6H), 1.95-1.86 (m, 6H). MS (ESI) 443 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: lead(IV) tetraacetate; iodine / chlorobenzene / 2.5 h / 80 °C / Inert atmosphere; Irradiation 2: sodium hydroxide; water / tetrahydrofuran / 18 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With water; sodium hydroxide In tetrahydrofuran for 18h; | 4.B Step B. Intermediate 4B. Preparation of 4-iodobicyclo[2.2.2]octane-1-carboxylic acid To a 100 mL pear shaped flask were added Intermediate 4A (1.3 g, 4.4 mmol), 1 M NaOH (aq.) (31 mL, 31 mmol), and THF (30 mL). After stirring 18 h, the reaction was diluted with 5% citric acid (aq.) (150 mL) and extracted with EtOAc (2*75 mL). The organic phase was combined, washed with brine, dried over Na2SO4, filtered and concentrated. The product was dried in vacuo to afford the title compound (1.2 g, 4.28 mmol, 98% yield) as a white solid. 1H NMR (500 MHz, METHANOL-d4) δ 2.57-2.34 (m, 6H), 2.10-1.86 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.25 h 1.2: 18 h / Inert atmosphere 1.3: 5 h / Reflux 2.1: silver trifluoromethanesulfonate; 2,6-di-tert-butyl-pyridine / 18 h / 80 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1,2-dichloro-ethane; ethyl acetate / 5 h / 80 °C / Inert atmosphere 2: silver trifluoromethanesulfonate; 2,6-di-tert-butyl-pyridine / 18 h / 80 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: triethylamine; chloroformic acid ethyl ester / tetrahydrofuran / 1 h / -30 °C 1.2: 0.83 h / -20 °C 1.3: 2 h / 0 °C 2.1: hydroxylamine hydrochloride; triethylamine / methanol / 18 h / Reflux 3.1: 1,1'-carbonyldiimidazole / dichloromethane / 30 h 3.2: Inert atmosphere 3.3: 2 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / 1,2-dichloro-ethane; ethyl acetate / 5 h / 80 °C / Inert atmosphere 2: silver trifluoromethanesulfonate; 2,6-di-tert-butyl-pyridine / 18 h / 80 °C / Inert atmosphere 3: methanol; potassium hydroxide / tetrahydrofuran / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 18 h 2: acetic acid / 18 h / 115 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: triethylamine; chloroformic acid ethyl ester / tetrahydrofuran / 1 h / -30 °C 1.2: 0.83 h / -20 °C 1.3: 2 h / 0 °C 2.1: hydroxylamine hydrochloride; triethylamine / methanol / 18 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / acetonitrile / 0.5 h 1.2: 2 h / Inert atmosphere 2.1: acetic acid / 18 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / acetonitrile / 0.5 h 1.2: 2 h / Inert atmosphere 2.1: acetic acid / 18 h / Reflux 3.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / tetrahydrofuran / 0.42 h / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: 1,1'-carbonyldiimidazole / dichloromethane / 0.25 h 1.2: 18 h / Inert atmosphere 1.3: 5 h / Reflux 2.1: silver trifluoromethanesulfonate; 2,6-di-tert-butyl-pyridine / 18 h / 80 °C / Inert atmosphere 3.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 45 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 4-iodobicyclo<2.2.2>octane-1-carboxylic acid With 1,1'-carbonyldiimidazole In dichloromethane for 0.25h; Stage #2: methyl (Z)-5-(N'-hydroxycarbamimidoyl)-2-methoxybenzoate In dichloromethane for 18h; Inert atmosphere; Stage #3: In toluene for 5h; Reflux; | 4.D.1; 4.D.2 Step D. Intermediate 4D. Preparation of methyl 5-(5-(4-iodobicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl)-2-methoxybenzoate Step 1: To a 100 mL pear shaped flask were added Intermediate 4B (0.21 g, 0.75 mmol) and DCM (3 mL). To this mixture was added CDI (0.18 g, 1.1 mmol) in one portion, upon which gas evolution was observed. After stirring 15 min, Intermediate 4C (0.25 g, 1.1 mmol) was added and the reaction was stirred under N2 for 18 h. Step 2: The solvent was concentrated and the residue was dissolved in toluene (5 mL) and stirred at reflux. After 5 h, the reaction was cooled and the solvent was concentrated. The residue was dissolved in EtOAc (50 mL), washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (24 g silica gel cartridge; A=Hex, B=EtOAc; 15 min grad.; 0% B to 20% B; flow rate=24 mL/min). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (0.30 g, 0.64 mmol, 85% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.64-8.47 (m, 1H), 8.35-8.14 (m, 1H), 7.44-7.23 (m, 1H), 7.21-7.01 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 2.79-2.57 (m, 6H), 2.36-2.16 (m, 6H). MS (ESI) 469 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
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Multi-step reaction with 2 steps 1: thionyl chloride / 2 h / 50 °C 2: sodium carbonate / acetone / 5 h / 20 °C |