Trifluoroacetic acid → 8-(3-aminophenyl)-6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one

HRID 527415ノート

反応式

HRID 527415 の反応式
[CH2:1]([C:3]1[C:28](=[O:29])[N:27]([C:30]2[CH:31]=[C:32]([NH:36]C(=O)OC(C)(C)C)[CH:33]=[CH:34][CH:35]=2)[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:25][CH3:26])[N:9]=[CH:10][C:5]=2[CH:4]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:36][C:32]1[CH:31]=[C:30]([N:27]2[C:6]3[N:7]=[C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)=[CH:14][C:13]=4[O:25][CH3:26])[N:9]=[CH:10][C:5]=3[CH:4]=[C:3]([CH2:1][CH3:2])[C:28]2=[O:29])[CH:35]=[CH:34][CH:33]=1

参加物

4

反応物 2

HCID 6422Trifluoroacetic acidHCID 86732027tert-butyl (3-(6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate

生成物 1

HCID 867320288-(3-aminophenyl)-6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one収率 51%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

実験手順

Steps 3 and 4. tert-Butyl (3-(6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate from above was treated with DCM (10 mL) and TFA (10 mL) and stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure (rotary evaporator) and purified on silica gel on an ISCO Combiflash RF (40 g Redisep column, 5-20% 2M NH3/MeOH in DCM) affording 8-(3-aminophenyl)-6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (392 mg, 0.81 mmol, 51% yield) as a brown/yellow film. m/z (ESI, +ve ion) 486.0 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.67 (1H, s), 7.74 (1H, s), 7.68 (1H, d, J=8.6 Hz), 7.34 (1H, t, J=7.9 Hz), 6.92 (1H, dd, 1=8.1, 1.5 Hz), 6.61-6.67 (2H, m), 6.58 (1H, dd, J=7.6, 1.0 Hz), 6.26 (1H, d, J=7.2 Hz), 5.51 (2H, s), 3.90 (3H, s), 3.30 (4H, br. s), 3.18 (4H, br. s), 2.79 (3H, s), 2.63 (2H, q, J=7.4 Hz), 1.28 (3H, t, J=7.5 Hz). 8-(3-Aminophenyl)-6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (390 mg, 0.80 mmol) in a mixture of DCM (7 mL) and THF (7 mL) at 0° C. was treated with DIEA (0.35 mL, 2.01 mmol) followed by the slow dropwise addition of acryloyl chloride (0.078 mL, 0.964 mmol) over 5 min. The solution was stirred 0° C. for 15 min. LC-MS indicated ca. a 79:11 ratio of desired product m/z (ESI, +ve ion) 539.9 (M+H)+ and starting material m/z (ESI, +ve ion) 486.0 (M+H)+. 2 additional drops of acryloyl chloride were added and the mixture was stirred an additional 2 h at 0° C. The reaction mixture was treated with silica gel and concentrated on the rotovap to dryness. The material was purified on an ISCO Combiflash RF (40 g Redisep column, using a gradient of 0-20% MeOH in DCM) affording enriched product as a yellow powdery solid. It was repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5 u, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water), concentrated on the rotovap to remove the CH3CN and treated with 1N NaOH and extracted with CHCl3 (3×50 mL), dried over Na2SO4, filtered and concentrated affording N-(3-(6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (6) (154 mg, 0.29 mmol, 35% yield) as a bright yellow solid. m/z (ESI, +ve ion) 540.0 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.68 (1H, s), 8.04 (1H, d, J=7.2 Hz), 7.77 (1H, s), 7.58-7.65 (2H, m), 7.49 (1H, d, J=8.4 Hz), 7.08 (1H, d, J=8.0 Hz), 6.58 (1H, d, J=2.5 Hz), 6.34-6.51 (2H, m), 6.14 (1H, d, J=7.0 Hz), 5.80 (1H, dd, J=9.6, 2.2 Hz), 3.88 (3H, s), 3.13 (4H, d, J=3.9 Hz), 2.58-2.69 (6H, m), 2.38 (3H, s), 1.30 (3H, t, J=7.4 Hz).

後処理

  1. concentrationThe reaction mixture was concentrated under reduced pressure (rotary evaporator)
  2. custompurified on silica gel on an ISCO Combiflash RF (40 g Redisep column, 5-20% 2M NH3/MeOH in DCM)

出典と根拠

ORDレコード
ord-b9a961057a6d4fad931a8729545c312d
出典データセット
uspto-grants-2016_05
特許番号
US09346801B2

反応ノート

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