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

HRID 630951ノート

反応式

HRID 630951 の反応式
[CH2:1]([NH:3][CH3:4])[CH3:2].[C:5]([C:9]1[CH:13]=[C:12]([NH:14][C:15]([NH:17][C@@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:21]([O:28][C:29]3[CH:30]=[CH:31][C:32]4[N:33]([C:35]([N:38]5[C@H:43]([CH3:44])[CH2:42][CH2:41][CH2:40][C@@H:39]5[CH3:45])=[N:36][N:37]=4)[CH:34]=3)[CH2:20][CH2:19]2)=[O:16])[N:11]([C:46]2[CH:47]=[C:48]([CH:57]=[CH:58][CH:59]=2)[O:49][CH2:50][CH2:51][O:52]S(C)(=O)=O)[N:10]=1)([CH3:8])([CH3:7])[CH3:6].C1C[O:63]CC1>>[CH:51]([OH:52])=[O:63].[C:5]([C:9]1[CH:13]=[C:12]([NH:14][C:15]([NH:17][C@@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:21]([O:28][C:29]3[CH:30]=[CH:31][C:32]4[N:33]([C:35]([N:38]5[C@H:39]([CH3:45])[CH2:40][CH2:41][CH2:42][C@@H:43]5[CH3:44])=[N:36][N:37]=4)[CH:34]=3)[CH2:20][CH2:19]2)=[O:16])[N:11]([C:46]2[CH:59]=[CH:58][CH:57]=[C:48]([O:49][CH2:50][CH2:51][N:3]([CH2:1][CH3:2])[CH3:4])[CH:47]=2)[N:10]=1)([CH3:6])([CH3:8])[CH3:7]

参加物

4

反応物 3

HCID 8028TetrahydrofuranHCID 12219N-Methylethylamine2 回HCID 86687259Methanesulfonic acid 2-{3-[3-tert-butyl-5-(3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-pyrazol-1-yl]-phenoxy}-ethyl ester

生成物 1

HCID 866872611-(5-tert-Butyl-2-{3-[2-(ethyl-methyl-amino)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt収率 11%

反応条件

温度
60 °C

実験手順

N-Ethylmethylamine (37 μL, 0.43 mmol) was added to a solution of Intermediate 96f (111 mg, 0.14 mmol) in THF (2 mL). The reaction was heated to 60° C. in a sealed vial overnight. N-Ethylmethylamine (37 μL, 0.43 mmol) was added and the reaction continued for a further 24 h. The mixture was cooled, evaporated in vacuo and the residue was purified by FCC, using 0-15% MeOH in DCM, then triturated with Et2O. Further purification by HPLC (Gemini C, 18 column, 10-98% MeCN in H2O, 0.1% formic acid) followed by evaporation of the fractions and trituration with Et2O gave the title compound (12 mg, 11%) as an off-white solid. LCMS (Method 5): Rt 3.85 min, m/z 734.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.55 (3H, d, J=6 Hz), 0.58 (3H, d, J=6 Hz), 0.89 (3H, t, J=7.0 Hz), 1.23 (9H, m), 1.33-1.57 (3H, m), 1.62-1.70 (2H, m), 1.71-1.95 (3H, m), 1.96-2.09 (2H, m), 2.13 (3H, s), 2.35 (2H, q, J=7.2 Hz), 2.63 (2H, t, J=5.7 Hz), 3.06-3.20 (3H, m), 3.21-3.36 (2H, m, obscured by solvent), 4.03 (2H, t, J=5.7 Hz), 4.74-4.83 (1H, m), 5.48 (1H, t, J=5.5 Hz), 6.28 (1H, s), 6.88-6.94 (1H, m), 7.00-7.10 (3H, m), 7.16 (1H, dd, J=9.8, 2.0 Hz), 7.18-7.26 (2H, m), 7.26-7.32 (2H, m), 7.35 (1H, t, J=8.0 Hz), 7.62 (1H, d, J=9.8 Hz), 7.81-7.86 (1H, m), 8.09 (1H, s), 8.37 (0.2H, s).

後処理

  1. temperatureThe mixture was cooled
  2. customevaporated in vacuo
  3. customthe residue was purified by FCC
  4. customtriturated with Et2O
  5. customFurther purification by HPLC (Gemini C, 18 column, 10-98% MeCN in H2O, 0.1% formic acid)
  6. customfollowed by evaporation of the fractions and trituration with Et2O

出典と根拠

ORDレコード
ord-0381288709a14b9fa808f4d986a0beb8
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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