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 630951Notes

Reaction equation

HRID 630951 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 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).

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 C, 18 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-0381288709a14b9fa808f4d986a0beb8
Source dataset
uspto-grants-2016_04
Patent number
US09315503B2

Reaction notes

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