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With manganese(IV) oxide In dichloromethane at 20℃; for 12 h;
Step 2. 4-Bromo-2-nitrobenzaldehydeManganese (IV) oxide (4eq) was added to a 0.18M solution of (4-bromo-2-nitrophenyl)methanol in dichloromethane. The suspension was stirred at ambient temperature under Argon for 12 h. The reaction mixture was filtered through celite and filter cake was washed with dichloromethane. The combined filtrate was concentrated to give brown color solid in 78percent yield.
Stage #1: With borane-THF In tetrahydrofuran at 20℃; for 72 h; Stage #2: With water; sodium hydrogencarbonate In tetrahydrofuran
Step 1. Borane tetrahydrofuran complex solution (1 M in tetrahydrofuran, 13 mL, 13 mmol) was added over 5 min to a solution of 4-bromo-2-nitrobenzoic acid (2.00 g, 8.13 mmol) at room temperature, then after 72 h the reaction mixture was carefully poured upon sat. aq. sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated to produce (4-bromo-2-nitro-phenyl)-methanol (1.85 g, 96percent). White solid, 1H-NMR (300 MHz, CDCl3): 8.25 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.67 (d, J=8.1, 1H), 4.96 (d, J=6.3, 2H), 2.37 (t, J=6.3, 1H).
95%
Stage #1: With borane In tetrahydrofuran at 0 - 20℃; for 48 h; Stage #2: With methanol In tetrahydrofuran at 0℃;
Example 25 Synthesis of 4-(7-( 1 -isobutyl- 1 H-pyrazol-4-yl)quinazolin-2-ylamino)-N-(3-(pyrrolidin- 1 - yl)propyl)benzenesulfonamide (Compound 709)Stepl. (4-Bromo-2-nitrophenyl)methanolTo a 0.5M suspension of 4-bromo-2-nitrobenzoic acid in THF in an ice bath was slowly added borane (1.0M /THF, 4eq). The reaction mixture was stirred at ambient temperature for 48 h. LCMS showed the reaction was complete. The mixture was recooled to 00C and quenched with methanol and concentrated to remove solvent. The residue was taken into ethyl acetate and organic phase was washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give yellow solid in 95percent yield.
Reference：
[1] Patent: US2007/191603, 2007, A1, . Location in patent: Page/Page column 40
[2] Patent: WO2007/117607, 2007, A2, . Location in patent: Page/Page column 333
[3] MedChemComm, 2018, vol. 9, # 5, p. 862 - 869
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8402 - 8416
3
[ 5551-12-2 ]
[ 22996-19-6 ]
Yield
Reaction Conditions
Operation in experiment
97%
With sodium tetrahydroborate In ethanol; water at 0℃; for 17.5 h;
Preparation of Compound 217, (4-bromo-2-nitrophenyl)methanol [00300] To a stirring suspension of 4-bromo-2-nitrobenzaldehyde (550 mg, 2.391 mmol) in ethanol (14 mL) and water (7 mL) at 0 °C was added sodium borohydride (452 mg, 1 1 .96 mmol) and the reaction left to stir at 0 °C for 17.5 h. The reaction was diluted with water (30 ml), and extracted with EtOAc (2 x 30 ml) - brine was added to clear. The combined organic layer was washed with brine (30 ml), dried (MgS04) and concentrated in vacuo to afford the title compound as a yellow solid (536 mg, 97percent).1H NMR (500 MHz, Chloroform-d) δ 8.27 (d, J = 2.0 Hz, 1 H), 7.82 (dd, J = 8.3, 2.0 Hz, 1 H), 7.69 (d, J = 8.3 Hz, 1 H), 4.98 (s, 2H).
Reference：
[1] Patent: WO2015/49535, 2015, A1, . Location in patent: Paragraph 00300
[2] Chemical Communications, 2011, vol. 47, # 26, p. 7428 - 7430
With N-Bromosuccinimide; triphenylphosphine In N,N-dimethyl-formamide for 0.0333333 h;
Example 5; Synthesis of (3R)-3-amino-7-bromo-1-hydroxy-3,4-dihydroquinolin-2(1H)-one (29); 4-Bromo-1-(bromomethyl)-2-nitrobenzene (23); To a stirred solution of (4-bromo-2-nitrophenyl)methanol (22) (1.00 g, 4.31 mmol) in DMF (40 mL) was added NBS (1.6 g, 9.0 mmol) and triphenylphosphine (2.4 g, 9.2 mmol). After two minutes, the reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM, and the aqueous layer was extracted with additional DCM. The combined organic layers were concentrated and the residue was purified by silica gel chromatography (Gradient: 0percent to 20percent EtOAc in heptane) to provide the product (880 mg, 69percent). 1H NMR (400 MHz, CDCl3) δ 4.78 (s, 2H), 7.47 (d, J=8.2 Hz, 1H), 7.75 (dd, J=8.2, 2.1 Hz, 1H), 8.20 (d, J=2.1 Hz, 1H).
With iron; ammonium chloride In ethanol; water at 75℃; for 1 h;
Step 2. A mixture of (4-bromo-2-nitro-phenyl)-methanol (1.85 g, 7.97 mmol), iron powder (2.23 g, 39.9 mmol), ammonium chloride (213 mg, 3.99 mmol), ethanol (20 mL), and water (10 mL) was heated at 75° C. for 1 h, then after cooling filtered through a pad of diatomaceous earth. The filtrate was evaporated and the residue partitioned between ethyl acetate and water, the organic layer was washed with brine, dried (MgSO4), and evaporated to produce (2-amino-4-bromo-phenyl)-methanol (1.53 g, 90percent). Off-white solid, MS (EI)=201.0 (M+).
With manganese(IV) oxide; In dichloromethane; at 20℃; for 12h;
Step 2. 4-Bromo-2-nitrobenzaldehydeManganese (IV) oxide (4eq) was added to a 0.18M solution of <strong>[22996-19-6](4-bromo-2-nitrophenyl)methanol</strong> in dichloromethane. The suspension was stirred at ambient temperature under Argon for 12 h. The reaction mixture was filtered through celite and filter cake was washed with dichloromethane. The combined filtrate was concentrated to give brown color solid in 78% yield.
Step 1. Borane tetrahydrofuran complex solution (1 M in tetrahydrofuran, 13 mL, 13 mmol) was added over 5 min to a solution of 4-bromo-2-nitrobenzoic acid (2.00 g, 8.13 mmol) at room temperature, then after 72 h the reaction mixture was carefully poured upon sat. aq. sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated to produce (4-bromo-2-nitro-phenyl)-methanol (1.85 g, 96%). White solid, 1H-NMR (300 MHz, CDCl3): 8.25 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.67 (d, J=8.1, 1H), 4.96 (d, J=6.3, 2H), 2.37 (t, J=6.3, 1H).
95%
Example 25 Synthesis of 4-(7-( 1 -isobutyl- 1 H-pyrazol-4-yl)quinazolin-2-ylamino)-N-(3-(pyrrolidin- 1 - yl)propyl)benzenesulfonamide (Compound 709)Stepl. (4-Bromo-2-nitrophenyl)methanolTo a 0.5M suspension of 4-bromo-2-nitrobenzoic acid in THF in an ice bath was slowly added borane (1.0M /THF, 4eq). The reaction mixture was stirred at ambient temperature for 48 h. LCMS showed the reaction was complete. The mixture was recooled to 00C and quenched with methanol and concentrated to remove solvent. The residue was taken into ethyl acetate and organic phase was washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give yellow solid in 95% yield.
With iron; ammonium chloride; In ethanol; water; at 75℃; for 1.0h;
Step 2. A mixture of <strong>[22996-19-6](4-bromo-2-nitro-phenyl)-methanol</strong> (1.85 g, 7.97 mmol), iron powder (2.23 g, 39.9 mmol), ammonium chloride (213 mg, 3.99 mmol), ethanol (20 mL), and water (10 mL) was heated at 75° C. for 1 h, then after cooling filtered through a pad of diatomaceous earth. The filtrate was evaporated and the residue partitioned between ethyl acetate and water, the organic layer was washed with brine, dried (MgSO4), and evaporated to produce (2-amino-4-bromo-phenyl)-methanol (1.53 g, 90percent). Off-white solid, MS (EI)=201.0 (M+).
With N-Bromosuccinimide; triphenylphosphine; In N,N-dimethyl-formamide; for 0.0333333h;
Example 5; Synthesis of (3R)-3-amino-7-bromo-1-hydroxy-3,4-dihydroquinolin-2(1H)-one (29); 4-Bromo-1-(bromomethyl)-2-nitrobenzene (23); To a stirred solution of <strong>[22996-19-6](4-bromo-2-nitrophenyl)methanol</strong> (22) (1.00 g, 4.31 mmol) in DMF (40 mL) was added NBS (1.6 g, 9.0 mmol) and triphenylphosphine (2.4 g, 9.2 mmol). After two minutes, the reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM, and the aqueous layer was extracted with additional DCM. The combined organic layers were concentrated and the residue was purified by silica gel chromatography (Gradient: 0% to 20% EtOAc in heptane) to provide the product (880 mg, 69%). 1H NMR (400 MHz, CDCl3) delta 4.78 (s, 2H), 7.47 (d, J=8.2 Hz, 1H), 7.75 (dd, J=8.2, 2.1 Hz, 1H), 8.20 (d, J=2.1 Hz, 1H).
With sodium tetrahydroborate; In ethanol; water; at 0℃; for 17.5h;
Preparation of Compound 217, (4-bromo-2-nitrophenyl)methanol[00300] To a stirring suspension of 4-bromo-2-nitrobenzaldehyde (550 mg, 2.391 mmol) in ethanol (14 mL) and water (7 mL) at 0 C was added sodium borohydride (452 mg, 1 1 .96 mmol) and the reaction left to stir at 0 C for 17.5 h. The reaction was diluted with water (30 ml), and extracted with EtOAc (2 x 30 ml) - brine was added to clear. The combined organic layer was washed with brine (30 ml), dried (MgS04) and concentrated in vacuo to afford the title compound as a yellow solid (536 mg, 97%).1H NMR (500 MHz, Chloroform-d) delta 8.27 (d, J = 2.0 Hz, 1 H), 7.82 (dd, J = 8.3, 2.0 Hz, 1 H), 7.69 (d, J = 8.3 Hz, 1 H), 4.98 (s, 2H).
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In dichloromethane; water; at 20℃; for 20h;
Preparation of Compound 218, 4-bromo-1-(methoxymethyi)-2-nitrobenzene[00301] To a stirring solution of Compound 217 (313 mg, 1 .349 mmol) in DCM (4.0 mL) was added a solution of sodium hydroxide (405 mg, 10.12 mmol) in water (4.0 ml_). The reaction was allowed to stir for 10 min before tetrabutylammonium hydrogen sulfate (458 mg, 1 .349 mmol) was added, followed by dimethyl sulfate (0.256 ml_, 2.70 mmol). The reaction was left to stir at room temperature for 20 h, then diluted with DCM (20 ml) and washed with water (20 ml), brine (20 ml), dried (Na2S04) and concentrated in vacuo to give the crude product as a yellow/brown oil. Purification by columnchromatography using a gradient of 5 to 40% EtOAc/cyclohexane gave the title compound as a pale yellow solid (289 mg, 87%).1H NMR (500 MHz, Chloroform-d) delta 8.24 (d, J = 2.0 Hz, 1 H), 7.79 (dd, J = 8.4, 2.0 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 1 H), 4.80 (s, 2H), 3.51 (s, 3H).
To a solution of <strong>[22996-19-6](4-bromo-2-nitrophenyl)methanol</strong> (24.0 g, 103 mmol) and water (300 ml) in dichloromethane (300 ml) was added sodium hydroxide (29.0 g, 724 mmol) in portions, the mixture was stirred at room temperature for 15 minutes, tetra-n-butylammonium sulfate (60.1 g, 103 mmol, 50% purity in water) was added in one portion at room temperature, then dimethyl sulfate (26.1 g, 207 mmol) was added dropwise at room temperature. After stirring at room temperature for 16 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (1000 mesh, petroleum ether: ethyl acetate = 1 : 0 to 100: 1) to give the title compound (22.0 g, 90% purity, 78%> yield) as a yellow oil.'H NMR (400MHZ, CDCI3) delta [ppm] = 8.23 (d, 1H), 7.77 (d, 1H), 7.69 (d, 1H), 4.79 (s, 2H), 3.50 (s, 3H)
To a solution of <strong>[22996-19-6](4-bromo-2-nitrophenyl)methanol</strong> (24.0 g, 103 mmol) and water (300 ml) indichloromethane (300 ml) was added sodium hydroxide (29.0 g, 724 mmol) in portions, the mixture wasstirred at room temperature for 15 minutes, tetra-n-butylammonium sulfate (60.1 g, 103 mmol, 50% purity in water) was added in one portion at room temperature, then dimethyl sulfate (26.1 g, 207 mmol) was added dropwise at room temperature. After stirring at room temperature for 16 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, driedover sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (1000 mesh, petroleum ether: ethyl acetate = 1: 0 to 100: 1) to give the title compound (22.0 g, 90% purity, 78% yield) as a yellow oil.?H NMR (400MHz, CDC13) [ppm] = 8.23 (d, 1H), 7.77 (d, 1H), 7.69 (d, 1H), 4.79 (s, 2H), 3.50 (s, 3H)
With caesium carbonate; at 100℃; for 16h;Schlenk technique; Inert atmosphere;
0.5 mmol of <strong>[22996-19-6]4-bromo-2-nitrobenzyl alcohol</strong> was added to the schlenk tube,0.25 mmol of cesium carbonate and 1 ml of 1-phenylethanol were charged, protected with N2,After the reaction was stirred at 100 C for 16 hours, the heating and stirring were stopped,After cooling to room temperature, the reaction mixture was diluted with 5 mL of ethyl acetate, filtered under atmospheric pressure,The resulting filtrate was dried under reduced pressure,The crude product was obtained and purified by column chromatography (silica gel) to give the title product,The column eluate used was a petroleum ether with a volume ratio of 30: 1:Ethyl acetate mixed solvent, yield 82%.
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