Dimethylamine → 1-{5-tert-Butyl-2-[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((R)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

HRID 630921ノート

反応式

HRID 630921 の反応式
[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18]O)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:52][N:53](C(C)C)[CH:54](C)C.CS(Cl)(=O)=O.C([O-])(O)=O.[Na+].CNC>C(Cl)Cl.C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][N:53]([CH3:54])[CH3:52])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]

参加物

9

反応物 5

HCID 674DimethylamineHCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 866872051-{5-tert-Butyl-2-[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((R)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

生成物 1

HCID 866872071-{5-tert-Butyl-2-[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((R)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea収率 87.3%

試薬・触媒・溶媒 3

HCID 962Water溶媒HCID 6344Dichloromethane溶媒HCID 8028Tetrahydrofuran溶媒

実験手順

To a solution of Intermediate 123a (108 mg, 0.159 mmol) and DIPEA (0.083 mL, 0.48 mmol) in DCM (4 mL) was added methanesulfonyl chloride (36.5 mg, 0.318 mmol) and the resulting yellow solution stirred at RT for 20 min. Water (2 mL) and sat. aq. NaHCO3 solution (2 mL) were added, then the aqueous extracted with DCM (4 mL). The combined organics were passed through a hydrophobic fit and concentrated in vacuo to leave a yellow solid. The solid was dissolved in THF (2 mL), then dimethylamine (2 M in THF, 1.6 mL, 3.2 mmol) added, and the mixture stirred at 60° C. in a sealed vial for 18 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (1 mL), applied to an SCX-2 cartridge (5 g), washed with MeOH (20 mL) and eluted with 2 M NH3 in MeOH (20 mL); concentration in vacuo gave a glassy yellow solid (98 mg). MDAP (Method 7) gave a pale yellow solid (63 mg). Additional purification by HPLC (Gemini C18, 15-65% MeCN in water, 0.1% HCO2H, 20 min, ×2) gave the title compound as a white solid (18.6 mg, 17%). LCMS (Method 5): Rt 3.62 min, m/z 706.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.88 (3H, d, J=6.3 Hz), 1.28 (9H, s), 1.48-1.56 (2H, m), 1.65-1.71 (2H, m), 1.76-1.96 (4H, m), 2.00-2.14 (2H, m), 2.17 (6H, s), 2.59 (2H, t, J=5.8 Hz), 2.95 (1H, ddd, J=12.2, 8.1, 4.8 Hz), 3.18 (1H, dt, J=12.1, 4.3 Hz), 3.26-3.29 (1H, m), 4.07 (2H, t, J=5.8 Hz), 4.81 (1H, td, J=8.6, 5.6 Hz), 5.53 (1H, t, J=4.3 Hz), 6.31 (1H, s), 6.95 (1H, dd, J=8.4, 2.2 Hz), 7.09 (2H, m), 7.18 (1H, dd, J=9.8, 2.2 Hz), 7.25-7.41 (6H, m), 7.64 (1H, d, J=9.9 Hz), 7.70 (1H, d, J=2.1 Hz), 8.34 (1H, s), 8.50 (0.3H, s).

後処理

  1. extractionthe aqueous extracted with DCM (4 mL)
  2. concentrationconcentrated in vacuo
  3. customto leave a yellow solid
  4. stirringthe mixture stirred at 60° C. in a sealed vial for 18 h
  5. concentrationThe cooled solution was concentrated in vacuo
  6. dissolutionredissolved in MeOH (1 mL)
  7. washwashed with MeOH (20 mL)
  8. washeluted with 2 M NH3 in MeOH (20 mL)
  9. concentrationconcentration in vacuo

出典と根拠

ORDレコード
ord-b1f302be3f2e4d148b0ae112fa406c3a
出典データセット
uspto-grants-2016_04
特許番号
US09315503B2

反応ノート

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