Preparation method of bcl-2 selective inhibitor
A selected, basic technology, applied in the field of compound preparation, can solve the problems of unsuitable for industrialization, complicated operation, low yield, etc.
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Embodiment 1
[0136] Example 1: 2-((1H-pyrro[2,3-b]pyridin-5-yl)oxy)-4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine Synthesis of -4-yl)benzoic acid (compound 2)
[0137]
[0138] Compound 1 (710 g), methanol (4.2 L) and tetrahydrofuran (4.2 L) were added to a 20 L four-neck flask, and the mixture was stirred to dissolve. A solution of lithium hydroxide (199 g) and water (2 L) was added dropwise, the temperature was controlled below 25°C, and the dropwise addition was completed in 1 hour. Controlled at this temperature, the reaction was continued for 3 hours. After the reaction was completed, the temperature was controlled below 10°C, 1N aqueous hydrochloric acid was used to adjust pH=6, the solvent was evaporated to dryness, the residue was slurried with water (2L) and methanol (3L), respectively, and the compound 2 was obtained by suction filtration, which was an off-white solid 636g, The yield was 92.4%, and the purity was 98.6%.
[0139] 1 H NMR (400MHz, CDCl 3 )δ: 9.48 (1...
Embodiment 2
[0140] Example 2: Synthesis of 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide (compound 5)
[0141]
[0142] Compounds 3 (100 g), 4 (92.4 g), and acetonitrile (2 L) were added to a 3-L three-necked flask, stirred to dissolve, heated to 50° C. and stirred for 3 hours. Spin to remove the solvent, add acetonitrile (1L), beating for 2 hours, and suction filtration to obtain compound 5 as a bright yellow solid 107.5g, the yield is 71.0%, and the purity is 99.4%.
[0143] 1 H NMR (400MHz, DMSO-d6) δ: 8.58 (1H, t, J=6.0Hz), 8.45 (1H, d, J=2.0Hz), 7.81 (1H, dd, J=9.2Hz, 2.0Hz), 7.40 (1H, d, J=9.2 Hz), 7.33 (2H, s), 3.74-3.71 (4H, m), 3.54-3.47 (2H, m), 1.88-1.67 (4H, m).
Embodiment 3
[0144] Example 3: 6-(Bromomethyl)-4'-chloro-2'-fluoro-3,3-dimethyl-2,3,4,5-tetrahydro-1,1'-biphenyl (compound 7) Synthesis
[0145]
[0146] A mixture of compound 6 (100 g), carbon tetrabromide (185 g) and dichloromethane (600 mL) was stirred and dissolved, and the temperature was lowered to -10°C. The temperature was controlled below 10°C, triphenylphosphine (146 g) was added in 5 batches, and the reaction was carried out for 1 hour. Silica gel (200 g) was added, the solvent was spun off, and the solution was passed through a flash chromatography column using petroleum ether as the eluent. The solvent was removed by swirl, acetonitrile (250 mL) was added to make slurry for 2 hours, suction filtration, and the obtained solid was vacuum-dried at 30-35° C. to constant weight to obtain compound 7 as a yellow solid 112 g with a yield of 90.78% and a purity of 99.95%.
[0147] 1 H-NMR (400MHz, CDCl 3 )δ: 7.19-7.13 (2H, m), 7.10 (1H, dd, J=9.6Hz, 2.0 Hz), 3.78 (2H, s), 2.58-1...
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