HCID 90311407、化合物 → HCID 131734131、化合物

HRID 716200ノート

反応式

HRID 716200 の反応式
FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]2[N:26]3[N:27]=[C:28]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=4[F:38])[CH:29]=[CH:30][C:25]3=[N:24][N:23]=2)[CH2:10]1.FC(F)(F)C(O)=O.N[C@H]1CCCN(C2C=CN=CC=2NC2N3C=CC=CC3=NN=2)C1.ClC1C=CC2N(C(NC3C=NC=CC=3N3CCC[C@H](N[C:93](=[O:99])[O:94][C:95]([CH3:98])([CH3:97])[CH3:96])C3)=NN=2)N=1.[Br-].FC1C=CC=C(F)C=1[Zn+]>>[F:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([F:38])[C:31]=1[C:28]1[CH:29]=[CH:30][C:25]2[N:26]([C:22]([NH:21][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:15]=3[N:11]3[CH2:12][CH2:13][CH2:14][C@H:9]([NH:8][C:93](=[O:99])[O:94][C:95]([CH3:98])([CH3:97])[CH3:96])[CH2:10]3)=[N:23][N:24]=2)[N:27]=1

参加物

5

反応物 4

HCID 90311407HCID 90311407、化合物HCID 90311664HCID 90311664、化合物HCID 131734132HCID 131734132、化合物HCID 178505730HCID 178505730、化合物

生成物 1

HCID 131734131HCID 131734131、化合物

反応条件

温度
90 °C

実験手順

(S)-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine 2,2,2-trifluoroacetate (Example 67) and (S)-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine 2,2,2-trifluoroacetate (Example 68). A glass microwave reaction vessel was charged with (S)-tert-butyl (1-(3-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)pyridin-4-yl)piperidin-3-yl)carbamate (175 mg, 0.39 mmol) and 2,6-difluorophenylzinc bromide (0.5 M in THF, 2.36 mL, 1.18 mmol, Rieke Metals, Inc.) followed by A-Phos (14 mg, 0.020 mmol, Sigma-Aldrich). The reaction mixture was stirred and heated at 90° C. for 2 h. The mixture was cooled to RT and quenched with EDTA solution (pH 7.4) and extracted with CHCl3/i-PrOH (4/1). The combined organic layers were dried over MgSO4, filtered and concentrated to give (S)-tert-butyl (1-(3-((6-(2,6-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)pyridin-4-yl)piperidin-3-yl)carbamate (206 mg), which was used in the next reaction without further purification. A mixture of (S)-tert-butyl (1-(3-((6-(2,6-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)pyridin-4-yl)piperidin-3-yl)carbamate (206 mg, 0.39 mmol) and TFA (0.2 mL, 2.69 mmol) in DCM (1 mL) was stirred for 15 min at RT. The mixture was concentrated and the residue was purified with prep HPLC (5-30% MeCN in water with 0.1% TFA for 30 min) using Phenomenex Gemini C18 column (100×50 mm, 10 μm) at 90 mL/min. with UV detection at 254 nm to give (S)-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine 2,2,2-trifluoroacetate (70 mg, 0.13 mmol, 33% yield, Example 67) as a yellow solid. MS (ESI, pos. ion) m/z: 422.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (1 H, br. s.), 8.84 (1 H, s), 8.45 (1 H, d, J=9.6 Hz), 8.39 (1 H, d, J=6.5 Hz), 8.02 (3 H, br. s.), 7.67-7.77 (1 H, m), 7.53 (1 H, d, J=9.8 Hz), 7.33-7.44 (3 H, m), 3.82 (1 H, d, J=12.5 Hz), 3.30-3.38 (3 H, m), 3.21 (1 H, dd, J=11.8, 6.9 Hz), 1.93 (1 H, dd, J=8.2, 4.1 Hz), 1.73-1.85 (1 H, m), 1.61-1.71 (1 H, m), 1.41-1.53 (1 H, m). 19F NMR (376 MHz, DMSO-d6) δ ppm −74.04, −113.49; and (S)-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine 2,2,2-trifluoroacetate (27 mg, 0.09 mmol, Example 68) as a light yellow solid. MS (ESI, pos. ion) m/z: 311.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (1 H, s), 8.36 (1 H, d, J=6.5 Hz), 8.09 (3 H, br. s.), 7.43 (1 H, d, J=6.5 Hz), 7.24 (1 H, d, J=11.7 Hz), 5.92-6.13 (1 H, m), 3.76 (1 H, d, J=12.5 Hz), 3.43-3.59 (1 H, m), 2.99-3.30 (3 H, m), 1.88-2.04 (2 H, m), 1.54-1.78 (2 H, m).

後処理

  1. customA glass microwave reaction vessel
  2. temperatureThe mixture was cooled to RT
  3. customquenched with EDTA solution (pH 7.4)
  4. extractionextracted with CHCl3/i-PrOH (4/1)
  5. dry with materialThe combined organic layers were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated

出典と根拠

ORDレコード
ord-1a8027423ebc4dceb10d8bc7c74ead40
出典データセット
uspto-grants-2015_11
特許番号
US09187486B2

反応ノート

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