Dimethylamine → 1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-(4-dimethylaminomethyl-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 2200041Notes

Reaction equation

HRID 2200041 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:46])[NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH:37]([CH2:40]OS(C)(=O)=O)[CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][CH3:49].C1C[O:53]CC1>>[CH:12]([OH:46])=[O:53].[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH:37]([CH2:40][N:48]([CH3:49])[CH3:47])[CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:46])[N:8]([CH3:10])[N:9]=1)([CH3:3])([CH3:4])[CH3:2]

Participants

4

Reactant 3

HCID 674Dimethylamine2×HCID 8028TetrahydrofuranHCID 117728708Methanesulfonic acid 1-(6-{(1R,4S)-4-[3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-1,2,3,4-tetrahydro-naphthalen-1-yloxy}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-piperidin-4-ylmethyl ester

Product 1

HCID 906465281-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-(4-dimethylaminomethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate saltYield 35%

Conditions

Temperature
65 °C

Procedure

A solution of Intermediate 14h (57 mg, 0.08 mmol) and dimethylamine (2M in THF, 0.873 mL, 1.75 mmol) in THF (4 mL) was heated at 60° C. for 18 h. A further 1.4 mL of dimethylamine (2M in THF) was added and the reaction mixture was heated at 65° C. for 48 h. The reaction mixture was cooled to RT and the solvent was removed by air, to leave a residue which was purified by MDAP (Method 7), to afford the title compound (18 mg, 35%). LCMS (Method 5): Rt: 3.00 min, m/z 600.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.20 (9H, s), 1.32-1.47 (2H, m), 1.64-1.76 (1H, m), 1.76-1.86 (211, m), 1.87-2.12 (4H, m), 2.13-2.21 (9H, m), 2.86-2.99 (2H, m, obscured by water), 3.35-3.48 (2H, m, obscured by water), 3.57 (2H, s, obscured by water), 4.82-4.91 (1H, m), 5.57 (1H, t, J=4.5 Hz), 6.02 (1H, s), 6.91 (1H, d, J=8.8 Hz), 7.18 (1H, dd, J=9.8, 1.9 Hz), 7.26-7.33 (1H, m), 7.34-7.43 (3H, m), 7.62 (1H, d, J=10.0 Hz), 7.65 (1H, d, J=1.8 Hz), 8.19 (1H, s), 8.27 (1H, s).

Workup

  1. temperatureThe reaction mixture was cooled to RT
  2. customthe solvent was removed by air
  3. customto leave a residue which
  4. customwas purified by MDAP (Method 7)

Sources & evidence

ORD record
ord-8af3cd29d2ae45488b570bf7e4017304
Source dataset
uspto-grants-2016_06
Patent number
US09359354B2

Reaction notes

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