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With hydrazine hydrate In ethanol at 100℃; for 1 h; Microwave irradiation
Part B: A solution of compound 301 B (1.02 g, 4.2 mmol) in 8 ml_ EtOH was treated with hydrazine monohydrate (4.0 mL, 80 mmol) and the reaction mixture stirred at 100 °C for 30 minutes in a Biotage microwave. Conversion was incomplete as determined by LCMS; therefore, the mixture was concentrated, and fresh EtOH (6 mL) and hydrazine monohydrate (6 mL) were added. The reaction mixture was again stirred at 100 0C for 30 minutes in a microwave apparatus, then concentrated to dryness to provide desired product 301 C (801 mg, 89percent). HPLC-MS tR = 1.21 min (UV 254 nm); mass calculated for formula C7H5BrN2O 212.0/214.0, observed LCMS m/z 213.1/215.1 (M+H).
43%
With hydrazine hydrate In ethanol at 100℃; for 2 h; Microwave irradiation
CAP-004-20-1 (500 mg, 2.15 mmol) and hydrazine hydrate (2 ml) were added to ethanol (3ml). This reaction mixture was stirred for 2 h at 100 oc under microwave. The mixture was purified by preparative TLC (petroleum ether/ethyl acetate = 1 /2) to afford CAP-004-20-2(200 mg, 43 percent) as a white solid.
With hydrazine hydrate; In ethanol; at 100.0℃; for 1.0h;Microwave irradiation;
Part B: A solution of compound 301 B (1.02 g, 4.2 mmol) in 8 ml_ EtOH was treated with hydrazine monohydrate (4.0 mL, 80 mmol) and the reaction mixture stirred at 100 C for 30 minutes in a Biotage microwave. Conversion was incomplete as determined by LCMS; therefore, the mixture was concentrated, and fresh EtOH (6 mL) and hydrazine monohydrate (6 mL) were added. The reaction mixture was again stirred at 100 0C for 30 minutes in a microwave apparatus, then concentrated to dryness to provide desired product 301 C (801 mg, 89%). HPLC-MS tR = 1.21 min (UV 254 nm); mass calculated for formula C7H5BrN2O 212.0/214.0, observed LCMS m/z 213.1/215.1 (M+H).
43%
With hydrazine hydrate; In ethanol; at 100.0℃; for 2.0h;Microwave irradiation;
CAP-004-20-1 (500 mg, 2.15 mmol) and hydrazine hydrate (2 ml) were added to ethanol (3ml). This reaction mixture was stirred for 2 h at 100 oc under microwave. The mixture was purified by preparative TLC (petroleum ether/ethyl acetate = 1 /2) to afford CAP-004-20-2(200 mg, 43 %) as a white solid.
With hydrazine hydrate; In ethanol; at 110.0℃; for 0.75h;Microwave irradiation;
A mixture of methyl 5-bromo-2-fluorobenzoate (2.0 g), hydrazine monohydrate (4.25mL) and ethanol (10 mL) was heated to 110C by microwave irradiation for 45 minutes. After cooling to RT, the mixture was evaporated and the residue purified by preparative HPLC to provide the title compound. MS ESI: mlz = 213 [M+H].
Stage #1: 5-Bromo-2-aminobenzoic acid With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5h;
Stage #2: With sodium sulfite In water at 0 - 20℃; for 2h;
2.a
To a solution of 2-amino-5-bromobenzoic acid (50 g) in water (200 mL) was added HCl (46 mL). To the mixture was added aqueous NaNO2 solution (17.7 g/37 mL) at 0° C., and [0229] the mixture was stirred at 0° C. for 30 minutes. To the reaction solution was added dropwise aqueous Na2SO3 solution (79.3 g/200 mL) at 0° C., and the mixture was stirred at room temperature for 2 hours. To the mixture was added HCl (70 mL), and the mixture was stirred at room temperature for 18 hours and then at 80° C. for 4 hours. The precipitated solid was dissolved by basifying the reaction solution, and then the solution was acidified to precipitate a solid. The solid was collected by filtration and dried under reduced pressure to give Compound Q2 (36 g). [0230] 1H-NMR (400 MHz, d-DMSO): 7.28 (1H, d, J=8.0 Hz), 7.39 (1H, d, J=8.0 Hz), 7.82 (1H, s), 10.67 (1H, s), 11.75 (1H, s)
36 g
Stage #1: 5-Bromo-2-aminobenzoic acid With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5h;
Stage #2: With sodium sulfite In water at 0 - 20℃; for 2h;
2.a preparation of 5- Bromo -1H- indazol-3-ol (Compound Q2)
a hydrochloric acid aqueous solution (200 mL) of 2-amino-5-bromobenzoicacid (50 g) (46 mL) was added a solution of sodium nitrite at 0 the aqueous solution (17.7g / 37mL) was added,and the mixture was stirred for 30 minutes at 0 .Thereafter, sodium sulfite aqueous solution(79.3g / 200mL) was added dropwise at 0 to the reaction solution and stirred for 2hours at room temperature. After the addition of hydrochloric acid (70mL),the mixture was stirred for 18 hours at room temperature, and the mixture wasstirred for 4 hours at 80 . By the reaction solution basic, afterdissolving the precipitated solid by again acidified to precipitate asolid. The solid was collected by filtration, by drying under reducedpressure, to give compound Q2 (36g).
Stage #1: 5-Bromo-2-aminobenzoic acid With hydrogenchloride; sodium nitrite In water at 5℃;
Stage #2: With sodium sulfite In water at 5℃; for 2h;
4.4 General procedure for synthesis of 1H-indazol-3-ols
General procedure: The solution of sodium nitrite was added dropwise to a continuously stirred and ice cooled suspension of anthranilic acid in water and conc. hydrochloric acid, at such a rate that the temperature remains below 5°C. After the sodium nitrite was all been added, stirring was continued for 30min more and a solution of sodium sulfite in water was added all at once. After 2h conc. hydrochloric acid was added and the mixture was stirred overnight. Then it was slowly heated to 80°C and kept at this temperature for 2h. After cooling to room temperature, the pH was adjusted to 5.5 with 1M sodium hydroxide. The precipitate was filtered and triturated with small amount of ethanol.
With toluene-4-sulfonic acid; In tetrahydrofuran; at 20.0℃; for 16.0h;Inert atmosphere;
General procedure: 3,4-Dihydro-2H-pyran (7.48 mL; 82.0 mmol; 1.10 eq.) was added dropwise to a solution of 1,2-dihydro-3H-indazol-3-one (10.0 g; 74.6 mmol; 1.00 eq.), tetrahydrofuran (50.0 mL) andp-toluenesulfonic acid monohydrate (2.84 g; 14.9 mmol; 0.20 eq.) in a round bottom flask. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted in ethyl acetate (100 mL). The organic layer was washed with a saturated solution of NH4Cl (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using heptane/ethyl acetate (1/1) as eluent.1-(Tetrahydro-2H-pyran-2-yl)-1,2-dihydro-3H-indazol-3-one was isolated as a white solid (7.80 g; 47.9 %).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 145.0℃; for 1.5h;Microwave irradiation;
CAP-004-20-2 (11 0 mg, 0.52 mmol), phenylboronic acid (94 mg, 0.78 mmol), Pd(1, 1'bis(diphenylphosphanyl)ferrocene)CI2 (8 mg) and K2C03 (142 mg, 1.03 mmol) were addedto 1 ,4-dioxane (2 ml). This reaction mixture was stirred for 1.5 h at 145 oc under microwave. The mixture was filtered and purified by preparative HPLC to afford CAP-004-20 (12 mg, 11 %) as a white solid.
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