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With phosphorus(V) oxybromide; In N,N-dimethyl-formamide; at 130℃; for 1.0h;
Example 6(b) 2-Bromo-5-chloro-3-fluoropyridine. To solid <strong>[514797-96-7]5-chloro-3-fluoro-2-hydroxypyridine</strong> (75 g, 0.51 mmol) was added melted POBr3 (150 g, 0.52 mmol). DMF (2 mL) was then added by pipet, and the mixture was heated at 130 C. for 1 h. The excess POBr3 was quenched by the careful addition of water to the reaction mixture at 0 C., and the resulting mixture was dissolved in a 2:1 mixture of EtOAc:water. The organic layer was washed three times with water and once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting yellow oil was passed through a plug of silica gel (10% Et2O:90% hexanes) to provide the title compound as a white solid (79.4 g, 74%). The product was characterized by 1H NMR.
Second step Phosphorus oxybromide (100 g) was dissolved in toluene (100 mL), and the mixture was heated and dissolved at 60C. The crude product (129) (25.7 g) was slowly added at the same temperature, and the mixture was stirred at the 110C for 4 hours. After cooled to room temperature, ice water was added at 0C, 10 mol/L sodium hydroxide (174 mL) was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate and a sodium chloride aqueous solution, and dried over sodium sulfate to afford the crude product (130) (40.3 g).
Example 6(a) 5-Chloro-3-fluoro-2-hydroxypyridine. To a solution of NaOH (101 g, 2.5 mol) in water (500 mL) was added 5-chloro-2,3-difluoropyridine (101 g, 0.68 mol) as a liquid, and the resulting mixture was heated to reflux overnight. After cooling to room temperature, the mixture was filtered through a pad of celite and the pH was adjusted to 1 by the addition of concentrated HCl. The resulting solid was removed by filtration and dissolved in ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The title compound was obtained as a white solid (78 g, 78%) and was used without additional purification. The product was characterized by 1H NMR.
First step A starting material (128) (35 g) and sodium hydroxide (20.6 g) were dissolved in water (300 mL), and the mixture was heated at reflux for 2.5 hours. After cooled to 0 C, concentrated hydrochloride acid (44.7 mL) was added, water (120 mL) was added, and the precipitated solid was collected by filtration to afford the crude product (129) (25.9 g). To the filtrate was added a 4 mol/L sodium hydroxide aqueous solution to make the solution neutral, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate to afford the crude product (2) (5.29 g).
tert-butyl (3-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-1-((1r,4r)-4-hydroxycyclohexyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)(ethyl)carbamate[ No CAS ]
tert-butyl (1-((1s,4S)-4-((5-chloro-3-fluoropyridin-2-yl)oxy)cyclohexyl)-3-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)(ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54 mg
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran;
[00611] Step B: A solution of triphenylphosphine (37 mg, 0.14 mmol) in THF (1 mL) was treated with DIAD (28 muL, 0.14 mmol). After stirring for 15 min, tert-butyl (3-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-1-((1r,4r)-4-hydroxycyclohexyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)(ethyl)carbamate (50 mg, 0.09 mmol) was added as a solid, followed by <strong>[514797-96-7]5-chloro-3-fluoropyridin-2-ol</strong> (41 mg, 0.28 mmol) and stirred overnight. The reaction mixture was partitioned between water (10 mL) and EtOAc (10 mL) and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (30-80% EtOAc in hexanes) to afford tert-butyl (1-((1s,4S)-4-((5-chloro-3-fluoropyridin-2-yl)oxy)cyclohexyl)-3-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)(ethyl)carbamate (54 mg, 87.1% yield).
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