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Preparative Example 4 Weighed out 4.15 g of indazole and azeoptroped water with 2 toluene (100 ML) washings, pulling off toluene azeotrope by rotovap. Dried thoroughly under high vaccuum and performed argon purges. Dissolved in 40 ml dry THF and 92 ml dry ether under argon. Cooled to 5C in ice water bath. Charged 3 eq of isopropylmagnesium chloride ( (6 ML of a 2M solution in THF) and stired for 0.5 hr at room temp. Carefully charged 1N HC1 (240 ml) and stired for 1 H. Monitored reaction by TLC. Extracted with EtOAc, rotovaped and produced desired product. LCMS [M+H] = 219
With hydrogenchloride; In tetrahydrofuran; diethyl ether; at 5 - 20℃; for 0.5h;
Weighed out 4.15 g of indazole and azeoptroped water with 2 toluene (100 ml) washings, pulling off toluene azeotrope by rotovap. Dried thoroughly under high vaccuum and performed argon purges. Dissolved in 40 ml dry THF and 92 ml dry ether under argon. Cooled to 5C in ice water bath. Charged 3 eq of isopropylmagnesium chloride (6 ml of a 2M solution in THF) and stirred for 0.5 hr at room temp. Carefully charged IN HCl (240 ml) and stired for 1 h. Monitored reaction by TLC. Extracted with EtOAc, rotovaped and produced desired product. LCMS [M+H] = 219
Weighed out 4.15 g of indazole and azeoptroped water with 2 toluene (100 ml) washings, pulling off toluene azeotrope by rotovap. Dried thoroughly under high vaccuum and performed argon purges. Dissolved in 40 ml dry THF and 92 ml dry ether under argon. Cooled to 50C in ice water bath. Charged 3 eq of isopropylmagnesium chloride (6 ml of a 2M solution) in THF and- 16 - <n="18"/>stired for 0.5 hr at room temp. Carefully charged IN HCl (240 ml) and stired for 1 h. Monitored reaction by TLC. Extracted with EtOAc, rotovaped and produced desired product.LCMS [M+H] = 219
Weighed out 4.15 g of indazole and azeoptroped water with 2 toluene (100 ml) washings, pulling off toluene azeotrope by rotovap. Dried thoroughly under high vaccuum and performed argon purges. Dissolved in 40 ml dry THF and 92 ml dry ether under argon. Cooled to 50C in ice water bath. Charged 3 eq of isopropylmagnesium chloride (6 ml of a 2M solution) in THF and- 16 - <n="18"/>stired for 0.5 hr at room temp. Carefully charged IN HCl (240 ml) and stired for 1 h. Monitored reaction by TLC. Extracted with EtOAc, rotovaped and produced desired product.LCMS [M+H] = 219
In tetrahydrofuran; diethyl ether; at 5 - 20℃; for 0.5h;Cooling with ice;
[0108] Weighed out 4.15 g of indazole and azeoptroped water with 2 toluene (100 ml) washings, pulling off toluene azeotrope by rotovap. Dried thoroughly under high vaccuum and performed argon purges. Dissolved in 40 ml dry THF and 92 ml dry ether under argon. Cooled to 5 C. in ice water bath. Charged 3 eq of isopropylmagnesium chloride ((6 ml of a 2M solution in THF) and stired for 0.5 hr at room temp. Carefully charged 1N HCl (240 ml) and stired for 1 h. Monitored reaction by TLC. Extracted with EtOAc, rotovaped and produced desired product. LCMS [M+H]=219
[0106] Nitrile (1.5 g) obtained from Preparative Example 2 was dissolved in 20 mL of dry THF and under argon 3 equiv. of PhMgBr (1M in THF) was added at 5 C. The reaction mixture was stirred at room temperature for 1 h. The reaction was carefully quenched by addition of water and 1N HCl (15 mL). The quenched reaction mixture was stirred at room temperature for 1 hour then extracted with ethyl acetate (20 mL×3); combined organic phases were dried over sodium sulfate and concentrated to a solid residue which was azeotroped with toluene three times. LCMS [M+H]=253
[0126] To a solution of intermediate from preparative Example 2 (1.00 g, 5.75 mmol) dissolved in THF (15 mL) was added cyclopentyl magnesium bromide (6.32 mL, 12.65 mmol) at 0 C. The reaction was allowed to warm to ambient temperature and was quenched with saturated NH4Cl upon completion. The resulting reaction mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The product was purified via SiO2 gel chromatography to yield 580 mg of the desired product. 1H NMR (CDCl3) delta: 1.702 (2 H, m), 1.803 (2 H, m), 2.005 (4 H, m), 3.904 (3 H, s), 4.070 (1 H, m), 6.915 (1 H, s), 7.010 (1 H, d), 8.272 (1 H, d).
With tert.-butylnitrite; acetic acid; at 90℃; for 1.5h;
To a solution of scheme 10-2 compound S4 (1.6 g, 9.9 mmol) in AcOH (10 mL) was added tert-butyl nitrite (1.5 g, 14.8 mmol). The reaction was stirred at 90 C for 1.5 h. The mixture was concentrated to dryness and diluted with EtOAc, washed with saturated aq.NaHCO3 solution and brine successively. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluted with EtOAc/ petroleum ether =1/ 3) to give scheme 10-2 compound S5 (1.5 g, 86.9% yield) as a yellow solid.
With hydrogenchloride; sodium nitrite; In water; at 5 - 20℃; for 1h;
lOg of benzylnitrile derivative was dissolved in THF 20 mL followed by dilution with 50 mL of methanol. The reaction mixture was taken in a pressure tube, Pd-C (10% wt/10 mole %) was added and the reaction mixture was hydrogenated at 40 psi. After the requisite amount of hydrogen for the reduction of the NO2 group was consumed the reaction was stopped. TLC analysis indicated a spot to spot conversion. The reaction mixture was filtered over a pad of celite and the filtrate was concentrated to a solid and used in the next step directly. Crude aniline derivative (52 mmoles was dissloved/suspended in 2N HC1 (150 ML), cooled to 5 OC followed by the addition of 5.4g of sodium nitrite in 10 mL of water. The reaction mixture was allowed to stir for lh with gradual warming to room temperature. TLC analysis indicated complete consumption of SM and the formation of a new spot. The reaction mixture was extratced with ethyl acetate (100 mL X 4); organic phase was collected, dried and concentrated. The residue was purified by SGC to give desired product. LCMS [M+H]. = 174
With hydrogenchloride; sodium nitrite; In water; at 5 - 20℃; for 1h;
10 g of the benzylnitrile derivative was dissolved in 20 mL THF followed by dilution with 50 mL of methanol. The reaction mixture was taken in a pressure tube, Pd-C (10% wt/ 10 mole %) was added and the reaction mixture was hydrogenated at 40 psi. After the requisite amount of hydrogen for the reduction of the NO2 group was consumed the reaction was stopped. TLC analysis indicated a spot to spot conversion. The reaction mixture was filtered over a pad of Celite and the filtrate was concentrated to a solid and used in the next step directly. Crude aniline derivative (52 mmoles was dissloved/suspended in 2N HCl (150 mL), cooled to 5 0C followed by the addition of 5.4 g of sodium nitrite in 10 mL of water. The reaction mixture was allowed to stir for Ih with gradual warming to room temperature. TLC analysis indicated complete consumption of SM and the formation of a new spot. The reaction mixture was extracted with ethyl acetate (100 mL x 4); organic phase was collected, dried and concentrated. The residue was purified by SGC to give desired product. LCMS [M+H] = 174
With hydrogenchloride; sodium nitrite; In water; at 5 - 20℃; under 2068.65 Torr; for 1h;
[0104] 10 g of benzylnitrile derivative was dissolved in THF 20 mL followed by dilution with 50 mL of methanol. The reaction mixture was taken in a pressure tube, Pd-C (10% wt/10 mole %) was added and the reaction mixture was hydrogenated at 40 psi. After the requisite amount of hydrogen for the reduction of the NO2 group was consumed the reaction was stopped. TLC analysis indicated a spot to spot conversion. The reaction mixture was filtered over a pad of celite and the filtrate was concentrated to a solid and used in the next step directly. Crude aniline derivative (52 mmoles was dissloved/suspended in 2N HCl (150 mL), cooled to 5 C. followed by the addition of 5.4 g of sodium nitrite in 10 mL of water. The reaction mixture was allowed to stir for 1 h with gradual warming to room temperature. TLC analysis indicated complete consumption of SM and the formation of a new spot. The reaction mixture was extratced with ethyl acetate (100 mL×4); organic phase was collected, dried and concentrated. The residue was purified by SGC to give desired product. LCMS [M+H]=174
[0222] To a solution of 2-chloro-5-iodopyridine in THF was added isopropyl magnesium chloride (0.5 ml, 2N in diethyl ether) at -78 C. The mixture was warmed up to RT for a couple hours to complete iodide-magnesium exchange and re-cooled to -78 C. when Intermediate from Preparative Example 2 was added to the reaction mixture. The resulting solution was stirred at RT for 16 h and quenched with 1N NaOH, exacted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under vacuum.
Preparative Example 3 Nitrile (1.5 g) obtained from Preparative Example 2 was dissolved in 20 mL of dry THF and under argon 3 equiv. of PhMgBr (1M in THF) was added at 5C. The reaction mixture was stirred at room temperature for lh. The reaction was carefully quenched by addition of water and 1N HC1 (15 ML). The quenched reaction mixture was stirred at room temperature for LHOUR then extracted with ethyl acetate (20 nE X3); combined organic phases were dried over sodium sulfate and concentrated to a solid residue which was azeotroped with toluene three times. LCMS [M+H] = 253
Nitrile (1.5 g) obtained from Preparative Example 2 was dissolved in 20 mL of dry THF and under argon and 3 equiv. of PhMgBr (IM in THF) was added at 5C. The reaction mixture was stirred at room temperature for Ih. The reaction was carefully quenched by addition of water and IN HCl (15 mL). The quenched reaction mixture was stirred at room temperature for 1 hour then extracted with ethyl acetate (20 mL x 3); combined organic phases were dried over sodium sulfate and concentrated to a solid residue which was azeotroped with toluene three times. LCMS [M+H] = 253
To a solution of intermediate from preparative Example 2 (1.00 g, 5.75 mmol) dissolved in THF (15 mL) was added cyclopentyl magnesium bromide (6.32 mL, 12.65 mmol) at 0 0C. The reaction was allowed to warm to ambient temperature and was quenched with saturated NH4Cl upon completion. The resulting reaction mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The product was purified via SiO2 gel chromatography to yield 580 mg of the desired product. 1H NMR (CDCl3) delta : 1.702 (2 H, m), 1.803 (2 H, m), 2.005 (4 H, m), 3.904 (3 H, s), 4.070 (1 H, m), 6.915 (1 H, s), 7.010 (1 H, d), 8.272 (1 H, d).
In tetrahydrofuran; at -70 - 20℃;Inert atmosphere;
To a solution of scheme 10-2 compound S5 (1.5 g, 8.6 mmol) in THF (5 mL) was added methylmagnesium bromide (12.5 mL, 25 mmol, 2mol/L in THF) drop-wise at -70 C under N2 atmosphere. The mixture was stirred at 0C for 1 h and at room temperature overnight. The reaction was quenched with aq. NH4C1 solution and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluted with EtOAc/ petroleum ether =1/ 3) to give scheme 10-2 compound S5 (1.4 g, 86.0% yield) as a white solid.
(2S,4R)-1-(2-(3-acetyl-6-(undec-10-en-1-yloxy)-1H-indazol-1-yl)acetyl)-N-(3-chloro-2-fluoro-5-((E)-prop-1-en-1-yl)benzyl)-4-fluoropyrrolidine-2-carboxamide[ No CAS ]
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