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 2285248Notes

Reaction equation

HRID 2285248 reaction equation
[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]

Participants

4

Reactant 3

HCID 8028TetrahydrofuranHCID 12219N-Methylethylamine2×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

Product 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 saltYield 11%

Conditions

Temperature
60 °C

Procedure

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 C18 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).

Workup

  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 C18 column, 10-98% MeCN in H2O, 0.1% formic acid)
  6. customfollowed by evaporation of the fractions and trituration with Et2O

Sources & evidence

ORD record
ord-039f2dc0eeff4b0bb03bb31de16b7f34
Source dataset
uspto-grants-2015_09
Patent number
US09145413B2

Reaction notes

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