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[ CAS No. 1214336-88-5 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 1214336-88-5
Chemical Structure| 1214336-88-5
Chemical Structure| 1214336-88-5
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Product Details of [ 1214336-88-5 ]

CAS No. :1214336-88-5 MDL No. :MFCD14698110
Formula : C7H5BrFNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :PXHKAVXJQLVUBI-UHFFFAOYSA-N
M.W :234.02 Pubchem ID :46311203
Synonyms :

Safety of [ 1214336-88-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1214336-88-5 ]

* 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.

  • Downstream synthetic route of [ 1214336-88-5 ]

[ 1214336-88-5 ] Synthesis Path-Downstream   1~37

  • 1
  • [ 1214336-88-5 ]
  • [ 2165357-45-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2: Dess-Martin periodane / dichloromethane / 20 °C
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2: Dess-Martin periodane / dichloromethane / 20 °C
  • 2
  • [ 1214336-88-5 ]
  • [ 2165357-46-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: isopropylmagnesium chloride; lithium chloride / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: TurboGrignard / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C
  • 3
  • [ 1214336-88-5 ]
  • [ 18621-18-6 ]
  • [ 2165357-44-6 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 19h; 8.1 Step 1: methyl 5-fluoro-6-(3-hydroxyazetidin-1-yl)nicotinate Step 1: methyl 5-fluoro-6-(3-hydroxyazetidin-1-yl)nicotinate (0261) A mixture of 102 azetidin-3-ol hydrochloride (2.8 g, 26 mmol), 103 methyl 6-bromo-5-fluoronicotinate (5.0 g, 21 mmol), and 23 potassium carbonate (7.4 g, 53 mmol) up in 8 DMF (100 mL) was heated at 65° C. for 19 hours. The mixture was purified by flash chromatography (silica gel) to provide the desired 104 product. LCMS-ESI+(m/z): [M+H]+ calcd for C10H12FN2O3: 227.1; found: 227.0.
With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 19h; 3.1 Step 1: methyl 5-fluoro-6-(3-hydroxyazetidin-1-yl)nicotinate (3a) Step 1: methyl 5-fluoro-6-(3-hydroxyazetidin-1-yl)nicotinate (3a) A mixture of azetidin-3-ol hydrochloride (2.8 g, 26 mmol), methyl 6-bromo-5-fluoronicotinate (5.0 g, 21 mmol), and potassium carbonate (7.4 g, 53 mmol) in DMF (100 mL) was heated at 65 °C for 19 hours. The mixture was purified by flash chromatography (silica gel) to provide the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C10H12FN2O3: 227.1; found: 227.0.
  • 4
  • [ 1214336-88-5 ]
  • [ 2165357-47-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: isopropylmagnesium chloride; lithium chloride / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: TurboGrignard / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C
  • 5
  • [ 1214336-88-5 ]
  • [ 2166106-19-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: isopropylmagnesium chloride; lithium chloride / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C 5.1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 18 h / 60 °C
  • 6
  • [ 1214336-88-5 ]
  • [ 2166106-00-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: isopropylmagnesium chloride; lithium chloride / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C 5.1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 18 h / 60 °C 6.1: lithium hydroxide monohydrate / tetrahydrofuran; water / 18 h / 20 °C
  • 7
  • [ 1214336-88-5 ]
  • [ 2165357-64-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: TurboGrignard / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C 5.1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 65 °C
  • 8
  • [ 1214336-88-5 ]
  • [ 2165357-33-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: TurboGrignard / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C 5.1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 65 °C 6.1: lithium hydroxide monohydrate / tetrahydrofuran; water / 20 °C
  • 9
  • [ 823-96-1 ]
  • [ 1214336-88-5 ]
  • [ 1253383-91-3 ]
YieldReaction ConditionsOperation in experiment
76% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane at 110℃; for 18h; Inert atmosphere; Sealed tube; 3.1 Step 1: Methyl 5-fluoro-6-methylnicotinate The commercially available methyl 6-bromo 5-fluoronicotinate (360 mg, 1.54 mmol) was mixed with trimethyl-1,3,5,2,4,6-trioxatriborinane (966 mg, 7.69 mmol), K2CO3 (319 mg, 2.31 mmol), and Pd(Ph3P)4 (196 mg, 0.169 mmol) in 1,4-dioxane (5 mL). The mixture was sparged with N2 and stirred at 110 o C in a sealed tube under N2 atmosphere for 18 h. After cooled, the reaction was added ethyl acetate and washed with water. The organic layer was dried (Na2SO4) and filtered through Celite. Solvent was evaporated and the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 1:1) to afford the title compound, 198 mg (76%). LC-MS: m/z [M+H]+ 170.1
  • 10
  • [ 1214336-88-5 ]
  • [ 73930-39-9 ]
  • [ 2637453-28-0 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In 1-Methylnaphthalene at 120℃; for 18h; Inert atmosphere; 8.1 Step 1: Methyl 6-((2.3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate General procedure: To a solution of methyl 5-fluoro-6-bromonicotinate (100 mg, 0.47 mmol) in NMP (2 mL) was added 2,3-dihydro-1H-inden-2-amine (62.6 mg, 0.47 mmol) and K2CO3 (195 mg, 1.41 mmol) in a vial. The reaction mixture was stirred and heated at 120 o C under N2 for 18 h. After cooled and diluted with ethyl acetate, the organic layer was washed with water. Dried (Na2SO4), filtered and concentrated, the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as a brown oil, 38 mg (31%). LC- MS: m/z [M+H]+ 287.3
  • 11
  • [ 1214336-88-5 ]
  • [ 2637453-23-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 1,4-dioxane / 18 h / 110 °C / Inert atmosphere; Sealed tube 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 48 h / 75 °C
  • 12
  • [ 1214336-88-5 ]
  • [ 2637453-84-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 4.08 h / 110 °C / Inert atmosphere 2: hydroxylamine; potassium hydroxide / methanol; tetrahydrofuran; water / 0.17 h / 0 - 20 °C
  • 13
  • [ 1214336-88-5 ]
  • [ 2637453-24-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 1,4-dioxane / 18 h / 110 °C / Inert atmosphere; Sealed tube 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 48 h / 75 °C 3: potassium carbonate / acetonitrile / 18 h / 77 °C / Inert atmosphere
  • 14
  • [ 1214336-88-5 ]
  • [ 2637453-52-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 1,4-dioxane / 18 h / 110 °C / Inert atmosphere; Sealed tube 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 48 h / 75 °C 3: potassium carbonate / acetonitrile / 18 h / 77 °C / Inert atmosphere 4: sodium cyanoborohydride; acetic acid / water; acetonitrile / 0.25 h / 20 °C
  • 15
  • [ 2975-41-9 ]
  • [ 1214336-88-5 ]
  • [ 2637453-26-8 ]
YieldReaction ConditionsOperation in experiment
31% With potassium carbonate In 1-Methylnaphthalene at 120℃; for 18h; Inert atmosphere; 7.1 Step 1: Methyl 6-((2.3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate To a solution of methyl 5-fluoro-6-bromonicotinate (100 mg, 0.47 mmol) in NMP (2 mL) was added 2,3-dihydro-1H-inden-2-amine (62.6 mg, 0.47 mmol) and K2CO3 (195 mg, 1.41 mmol) in a vial. The reaction mixture was stirred and heated at 120 o C under N2 for 18 h. After cooled and diluted with ethyl acetate, the organic layer was washed with water. Dried (Na2SO4), filtered and concentrated, the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as a brown oil, 38 mg (31%). LC- MS: m/z [M+H]+ 287.3
  • 16
  • [ 35386-24-4 ]
  • [ 1214336-88-5 ]
  • [ 2637453-30-4 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In 1-Methylnaphthalene at 120℃; for 18h; Inert atmosphere; 9.1 Step 1: Methyl 6-((2.3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate General procedure: To a solution of methyl 5-fluoro-6-bromonicotinate (100 mg, 0.47 mmol) in NMP (2 mL) was added 2,3-dihydro-1H-inden-2-amine (62.6 mg, 0.47 mmol) and K2CO3 (195 mg, 1.41 mmol) in a vial. The reaction mixture was stirred and heated at 120 o C under N2 for 18 h. After cooled and diluted with ethyl acetate, the organic layer was washed with water. Dried (Na2SO4), filtered and concentrated, the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as a brown oil, 38 mg (31%). LC- MS: m/z [M+H]+ 287.3
  • 17
  • [ 98-10-2 ]
  • [ 1214336-88-5 ]
  • [ 2637453-41-7 ]
YieldReaction ConditionsOperation in experiment
34% With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In 1,4-dioxane at 120℃; for 1h; Inert atmosphere; Sealed tube; Microwave irradiation; 15.1 Step 1: Methyl 5-fluoro-6-(phenylsulfonamido)nicotinate The commercially available methyl 6-bromo 5-fluoronicotinate (100 mg, 0.427 mmol) was mixed with benzenesulfonamide (67.2 mg, 0.427 mmol), sodium tert-butoxide (41.1 mg, 0.427 mmol), palladium acetate (2.4 mg, 0.0107 mmol) and Xantphos (12.4 mg, 0.0214 mmol) in 1,4-dioxane under N2 atomasphere in an oven-dried sealed tube, the reaction mixture was stirred and heated at 120 o C for 1 h under microwave. After cooled, the reaction was added saturated NaHCO3, and extracted with ethyl ester (X3). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by chromatography (Silica gel, DCM/15%MeOH in DCM, 1:0 to 0:1) to afford the title compound as a white solid, 45 mg (34%). LC-MS: m/z [M+H]+ 311.3
  • 18
  • [ 91-21-4 ]
  • [ 1214336-88-5 ]
  • [ 2637453-48-4 ]
YieldReaction ConditionsOperation in experiment
87.2% With dmap In N,N-dimethyl-formamide at 80℃; for 3h; Microwave irradiation; 19.1 Step 1: Methyl 6-(3,4-dihydroisoquinolin-2(1H)-yl-5-fluoronicotinate To a solution of methyl 6-bromo-5-fluoropyridine-3-carboxylate (0.15 g, 0.64 mmol) in DMF was added 1,2,3,4-tetrahydroisoquinoline (0.17 g, 1.28 mmol) and DMAP (2.0 mg). The mixture was stirred and heated at 80 o C under microwave for 3 h. After cooled, the reaction was added saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as an oil, 160 mg (87.2%).
  • 19
  • [ 1214336-88-5 ]
  • [ 124-40-3 ]
  • [ 813425-23-9 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In 1-Methylnaphthalene at 120℃; for 18h; Inert atmosphere; 25.1 Step 1: Methyl 6-((2.3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate General procedure: To a solution of methyl 5-fluoro-6-bromonicotinate (100 mg, 0.47 mmol) in NMP (2 mL) was added 2,3-dihydro-1H-inden-2-amine (62.6 mg, 0.47 mmol) and K2CO3 (195 mg, 1.41 mmol) in a vial. The reaction mixture was stirred and heated at 120 o C under N2 for 18 h. After cooled and diluted with ethyl acetate, the organic layer was washed with water. Dried (Na2SO4), filtered and concentrated, the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as a brown oil, 38 mg (31%). LC- MS: m/z [M+H]+ 287.3
  • 20
  • [ 39093-93-1 ]
  • [ 1214336-88-5 ]
  • [ 2637453-57-5 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In 1-Methylnaphthalene at 120℃; for 18h; Inert atmosphere; 26.1 Step 1: Methyl 6-((2.3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate General procedure: To a solution of methyl 5-fluoro-6-bromonicotinate (100 mg, 0.47 mmol) in NMP (2 mL) was added 2,3-dihydro-1H-inden-2-amine (62.6 mg, 0.47 mmol) and K2CO3 (195 mg, 1.41 mmol) in a vial. The reaction mixture was stirred and heated at 120 o C under N2 for 18 h. After cooled and diluted with ethyl acetate, the organic layer was washed with water. Dried (Na2SO4), filtered and concentrated, the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as a brown oil, 38 mg (31%). LC- MS: m/z [M+H]+ 287.3
  • 21
  • [ 109-01-3 ]
  • [ 1214336-88-5 ]
  • [ 2637453-59-7 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In 1-Methylnaphthalene at 120℃; for 18h; Inert atmosphere; 27.1 Step 1: Methyl 6-((2.3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate General procedure: To a solution of methyl 5-fluoro-6-bromonicotinate (100 mg, 0.47 mmol) in NMP (2 mL) was added 2,3-dihydro-1H-inden-2-amine (62.6 mg, 0.47 mmol) and K2CO3 (195 mg, 1.41 mmol) in a vial. The reaction mixture was stirred and heated at 120 o C under N2 for 18 h. After cooled and diluted with ethyl acetate, the organic layer was washed with water. Dried (Na2SO4), filtered and concentrated, the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as a brown oil, 38 mg (31%). LC- MS: m/z [M+H]+ 287.3
  • 22
  • [ 1214336-88-5 ]
  • [ 411235-57-9 ]
  • [ 1354225-34-5 ]
YieldReaction ConditionsOperation in experiment
95% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane at 110℃; for 4.08h; Inert atmosphere; A mixture of methyl 6-bromo-5-fluoropyridine-3-carboxylate (70 mg, 0.3 mmol), cyclopropylboronic acid (128 mg, 1.5 mmol), potassium carbonate (62.0 mg, 0.45 mmol) in 1,4- dioxane (1.5 mL) was flushed with nitrogen for 10 min. [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (43.8 mg, 0.06 mmol) was added and the mixture was flushed with nitrogen again for 5 min and heated in microwave at 110 °C for 4h. LCMS showed complete conversion. The mixture was partitioned in ethyl acetate and water. The layers were separated. The aqueous layer was extracted with ethyl acetate (2x) and the combined organic layers were filtered over a pad of celite. The filtrate was concentrated to half of the volume and washed with water (3x), brine and concentrated to give 169 mg crude volatile oil. This material was purified by column chromatography (4 g SiO2, 0-10% ethyl acetate in hexane). Fractions containing the desired product were combined and collected to 55.3 mg (95%) colorless oil. [00524] Methyl 6-cyclopropyl-5-fluoropyridine-3-carboxylate: [00525] LCMS m/z [M+H]+ C9H9FN2O2 requires: 195.07, found 195.1 [00526] 1H NMR (400 MHz, CDCl3) δ= 8.85 (s, 1 H), 7.85 (dd, J=9.90, 1.59 Hz, 1 H), 3.94 (s, 3 H), 2.35 - 2.45 (m, 1 H), 1.19 - 1.26 (m, 2 H), 1.09 - 1.15 (m, 2 H) ppm.
  • 23
  • [ 844470-80-0 ]
  • [ 1214336-88-5 ]
  • [ 2637453-37-1 ]
YieldReaction ConditionsOperation in experiment
15.5% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 1h; Microwave irradiation; 12.4 Step 4: Methyl (S )-6-((cyclopropyl(phenyl)methyl)amino)-5-fluoronicotinate The commercially available methyl 5-bromo-3-fluoronicotinate (50 mg, 0.214 mmol) was mixed with (S)-cyclopropyl(phenyl)methanamine hydrochloride (59 mg, 0.320 mmol) and diisopropylethylamine (166 mg, 1.28 mmol) in DMSO (2 mL). The mixture was stirred and heated under microwave at 100 o C for 1 h. After cooled, the reaction was added water and extracted with ethyl acetate. The organic layers were dried (Na2SO4), filtered and concentrated. The resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 1:1) to afford the title compound, 10 mg (15.5%). LC-MS: m/z [M+H]+ 301.3
  • 24
  • [ 4248-19-5 ]
  • [ 1214336-88-5 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
72.1% With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In 1,4-dioxane at 75℃; for 5h; Sealed tube; Inert atmosphere; 4.1 Step 1: Tert-butyl-(3-fluoro-5-(hydroxycarbamoy)pyridine-2-yl)carbamate Methyl 6-bromo 5-fluoronicotinate (300 mg, 1.28 mmol) was mixed with tert-butyl carbamate (150 mg, 1.28 mmol), sodium tert-butoxide (123 mg, 1.28 mmol), palladium acetate (7.20 mg, 0.032 mmol) and Xantphos (37.1 mg, 0.064 mmol) in 1,4-dioxane in an oven-dried sealed tube. After evacuated and refilled with N2 (X3), the mixture was stirred and heated at 75 o C for 5 h. After cooled, the reaction was added ethyl acetate and washed with water. The organic layer was dried (Na2SO4), concentrated and purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 5:1) to afford a white solid as the title compound, 250 mg (72.1%). LC-MS: m/z [2M+Na]+ 563.5
  • 25
  • [ 1227068-84-9 ]
  • [ 1214336-88-5 ]
  • [ 2758440-93-4 ]
YieldReaction ConditionsOperation in experiment
2.2 g With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; Cs2CO3 In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; 10.1 Step 1: methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (2.0 g, 8.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (2 mL) and water (2 mL), then Cs2CO3 (5.6 g, 17.1 mmol, 2.0 equiv.), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g, 8.5 mmol, 1.0 equiv.) and Pd(dppf)Cl2CH2Cl2 (1.4 g, 1.7 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated overnight at 90 °C, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate (2.2 g) as a yellow solid. LCMS Method A: [M+H]+ = 272.
2.2 g With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; Cs2CO3 In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; 10.1 Step 1: methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (2.0 g, 8.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (2 mL) and water (2 mL), then Cs2CO3 (5.6 g, 17.1 mmol, 2.0 equiv.), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g, 8.5 mmol, 1.0 equiv.) and Pd(dppf)Cl2CH2Cl2 (1.4 g, 1.7 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated overnight at 90 °C, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate (2.2 g) as a yellow solid. LCMS Method A: [M+H]+ = 272.
2.2 g With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; Cs2CO3 In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; 10.1 Step 1: methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (2.0 g, 8.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (2 mL) and water (2 mL), then Cs2CO3 (5.6 g, 17.1 mmol, 2.0 equiv.), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g, 8.5 mmol, 1.0 equiv.) and Pd(dppf)Cl2CH2Cl2 (1.4 g, 1.7 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated overnight at 90 °C, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate (2.2 g) as a yellow solid. LCMS Method A: [M+H]+ = 272.
  • 26
  • [ 1214336-88-5 ]
  • [ 2758440-80-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: Cs2CO3; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / lithium hydroxide monohydrate; 1,4-dioxane / 90 °C 2: hydrogen; Adams’s catalyst / dichloromethane / 20 °C 3: lithium aluminium hydride / tetrahydrofuran / 0.5 h / 0 °C 4: phosphorus tribromide / dichloromethane / 1 h / 0 °C 5: potassium carbonate / acetonitrile / 16 h / 20 °C
  • 27
  • [ 1214336-88-5 ]
  • [ 2758440-81-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: Cs2CO3; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / lithium hydroxide monohydrate; 1,4-dioxane / 90 °C 2: hydrogen; Adams’s catalyst / dichloromethane / 20 °C 3: lithium aluminium hydride / tetrahydrofuran / 0.5 h / 0 °C 4: phosphorus tribromide / dichloromethane / 1 h / 0 °C 5: potassium carbonate / acetonitrile / 16 h / 20 °C 6: sodium hydroxide / methanol; lithium hydroxide monohydrate / 1 h / 80 °C
  • 28
  • [ 1214336-88-5 ]
  • [ 2758440-82-1 ]
  • [ 2758440-83-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: Cs2CO3; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / lithium hydroxide monohydrate; 1,4-dioxane / 90 °C 2: hydrogen; Adams’s catalyst / dichloromethane / 20 °C 3: lithium aluminium hydride / tetrahydrofuran / 0.5 h / 0 °C 4: phosphorus tribromide / dichloromethane / 1 h / 0 °C 5: potassium carbonate / acetonitrile / 2 h / 80 °C
  • 29
  • [ 1214336-88-5 ]
  • [ 2758440-84-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: Cs2CO3; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / lithium hydroxide monohydrate; 1,4-dioxane / 90 °C 2: hydrogen; Adams’s catalyst / dichloromethane / 20 °C 3: lithium aluminium hydride / tetrahydrofuran / 0.5 h / 0 °C 4: phosphorus tribromide / dichloromethane / 1 h / 0 °C 5: potassium carbonate / acetonitrile / 2 h / 80 °C 6: sodium hydroxide / methanol; lithium hydroxide monohydrate / 2 h / 80 °C
  • 30
  • [ 1214336-88-5 ]
  • [ 2758441-80-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: Cs2CO3; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / lithium hydroxide monohydrate; 1,4-dioxane / 90 °C 2: hydrogen; Adams’s catalyst / dichloromethane / 20 °C 3: lithium aluminium hydride / tetrahydrofuran / 0.5 h / 0 °C 4: phosphorus tribromide / dichloromethane / 1 h / 0 °C 5: potassium carbonate / acetonitrile / 2 h / 80 °C 6: sodium hydroxide / methanol; lithium hydroxide monohydrate / 2 h / 80 °C 7: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C
  • 31
  • [ 1214336-88-5 ]
  • [ 2758440-94-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: Cs2CO3; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / lithium hydroxide monohydrate; 1,4-dioxane / 90 °C 2: hydrogen; Adams’s catalyst / dichloromethane / 20 °C
  • 32
  • [ 1214336-88-5 ]
  • [ 2758440-95-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: Cs2CO3; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / lithium hydroxide monohydrate; 1,4-dioxane / 90 °C 2: hydrogen; Adams’s catalyst / dichloromethane / 20 °C 3: lithium aluminium hydride / tetrahydrofuran / 0.5 h / 0 °C
  • 33
  • [ 1214336-88-5 ]
  • [ 2758440-79-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: Cs2CO3; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / lithium hydroxide monohydrate; 1,4-dioxane / 90 °C 2: hydrogen; Adams’s catalyst / dichloromethane / 20 °C 3: lithium aluminium hydride / tetrahydrofuran / 0.5 h / 0 °C 4: phosphorus tribromide / dichloromethane / 1 h / 0 °C
  • 34
  • [ 872-64-0 ]
  • methyl 6-bromo-5-fluoropyridine-3-carboxylate [ No CAS ]
  • methyl 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
5.5 g With potassium carbonate In N,N-dimethyl-formamide at 80℃; 11B.1 Step 1: methyl 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (5.0 g, 21.4 mmol, 1.0 equiv.) was dissolved in DMF (50 mL), then K2CO3 (8.9 g, 64.1 mmol, 3.0 equiv.) and 6-azaspiro[2.5]octane (2.9 g, 25.6 mmol, 1.2 equiv.) were added. The reaction mixture was heated to 80 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na2SO4 and concentrated under vacuum to give methyl 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate (5.5 g) as a light yellow solid. LCMS Method A: [M+H]+ = 265.
5.5 g With potassium carbonate In N,N-dimethyl-formamide at 80℃; 11B.1 Step 1: methyl 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (5.0 g, 21.4 mmol, 1.0 equiv.) was dissolved in DMF (50 mL), then K2CO3 (8.9 g, 64.1 mmol, 3.0 equiv.) and 6-azaspiro[2.5]octane (2.9 g, 25.6 mmol, 1.2 equiv.) were added. The reaction mixture was heated to 80 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na2SO4 and concentrated under vacuum to give methyl 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate (5.5 g) as a light yellow solid. LCMS Method A: [M+H]+ = 265.
5.5 g With potassium carbonate In N,N-dimethyl-formamide at 80℃; 11B.1 Step 1: methyl 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (5.0 g, 21.4 mmol, 1.0 equiv.) was dissolved in DMF (50 mL), then K2CO3 (8.9 g, 64.1 mmol, 3.0 equiv.) and 6-azaspiro[2.5]octane (2.9 g, 25.6 mmol, 1.2 equiv.) were added. The reaction mixture was heated to 80 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na2SO4 and concentrated under vacuum to give methyl 6-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate (5.5 g) as a light yellow solid. LCMS Method A: [M+H]+ = 265.
  • 35
  • [ 144230-47-7 ]
  • [ 1214336-88-5 ]
  • [ 2758668-78-7 ]
YieldReaction ConditionsOperation in experiment
350.0 mg With Cs2CO3 In acetonitrile at 90℃; Step 1: methyl 6-[1,1-difluoro-6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (400.0 mg, 1.7 mmol, 1.0 equiv.) and 1,1-difluoro-6-azaspiro[2.5]octane (251.5 mg, 1.7 mmol, 1.0 equiv.) were dissolved in ACN (40 ml), then Cs2CO3 (1.1 g, 3.4 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 90 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na2SO4 and concentrated under vacuum to give methyl 6-[1,1-difluoro-6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate (350.0 mg) as a pale yellow solid. LCMS Method A-1: [M+H]+ = 301.
350.0 mg With Cs2CO3 In acetonitrile at 90℃; Step 1: methyl 6-[1,1-difluoro-6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (400.0 mg, 1.7 mmol, 1.0 equiv.) and 1,1-difluoro-6-azaspiro[2.5]octane (251.5 mg, 1.7 mmol, 1.0 equiv.) were dissolved in ACN (40 ml), then Cs2CO3 (1.1 g, 3.4 mmol, 2.0 equiv.) was added. The reaction mixture was heated to 90 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na2SO4 and concentrated under vacuum to give methyl 6-[1,1-difluoro-6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-3-carboxylate (350.0 mg) as a pale yellow solid. LCMS Method A-1: [M+H]+ = 301.
  • 36
  • [ 144230-47-7 ]
  • [ 1214336-88-5 ]
  • [ 2758668-77-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: Cs2CO3 / acetonitrile / 90 °C 2: lithium hydroxide monohydrate; water monomer / methanol / 3 h / 20 °C
  • 37
  • [ 1214336-88-5 ]
  • [ 1630907-10-6 ]
  • [ 2758668-90-3 ]
YieldReaction ConditionsOperation in experiment
500.0 mg With potassium carbonate In acetonitrile at 80℃; Step 2: methyl 5-fluoro-6-[6-hydroxy-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (2.1 g, 8.8 mmol, 1.0 equiv.) and 2-azaspiro[3.3]heptan-6-ol hydrochloride (1.0 g, 8.8 mmol, 1.0 equiv.) were dissolved in ACN (20 mL), then K2CO3 (3.7 g, 26.5 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 80 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC using the following conditions: Column, C18 silica gel; mobile phase, H2O/ACN; 10% ACN increasing to 90% within 30 min; Detector, 254 nm. This gave methyl 5-fluoro-6-[6-hydroxy-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate (500.0 mg) as a yellow solid. LCMS Method A-1: [M+H]+ = 267.
500.0 mg With potassium carbonate In acetonitrile at 80℃; Step 2: methyl 5-fluoro-6-[6-hydroxy-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (2.1 g, 8.8 mmol, 1.0 equiv.) and 2-azaspiro[3.3]heptan-6-ol hydrochloride (1.0 g, 8.8 mmol, 1.0 equiv.) were dissolved in ACN (20 mL), then K2CO3 (3.7 g, 26.5 mmol, 3.0 equiv.) was added. The reaction mixture was heated to 80 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC using the following conditions: Column, C18 silica gel; mobile phase, H2O/ACN; 10% ACN increasing to 90% within 30 min; Detector, 254 nm. This gave methyl 5-fluoro-6-[6-hydroxy-2-azaspiro[3.3]heptan-2-yl]pyridine-3-carboxylate (500.0 mg) as a yellow solid. LCMS Method A-1: [M+H]+ = 267.
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