Hydrochloric Acid → (R)-N-cyclopropyl-4-(3-(6-(piperidin-3-yloxy)pyrazin-2-yl)-1H-indazol-5-yl)pyrimidin-2-amine

HRID 1529371Notes

Reaction equation

HRID 1529371 reaction equation
[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16](C3CCCCO3)[N:15]=[C:14]4[C:26]3[N:31]=[C:30]([O:32][C@@H:33]4[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]4)[CH:29]=[N:28][CH:27]=3)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.Cl>>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][N:15]=[C:14]4[C:26]3[CH:27]=[N:28][CH:29]=[C:30]([O:32][C@@H:33]4[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]4)[N:31]=3)[CH:8]=[CH:7][N:6]=2)[CH2:2][CH2:3]1

Participants

3

Reactant 2

HCID 313Hydrochloric AcidHCID 67959837(3R)-tert-butyl 3-(6-(5-(2-(cyclopropylamino)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate

Product 1

HCID 86709778(R)-N-cyclopropyl-4-(3-(6-(piperidin-3-yloxy)pyrazin-2-yl)-1H-indazol-5-yl)pyrimidin-2-amineYield 94.7%

Procedure

A solution of (3R)-tert-butyl 3-(6-(5-(2-(cyclopropylamino)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (116 mg, 0.19 mmol) and HCl (5-6 M in IPA, 3.8 mL, 18.9 mmol) was heated at 80° C. for 1 h. The reaction was cooled to RT and concentrated to a yellow solid that was slurried with a 1\1 mixture of DCM/MeOH (2 mL) and applied to a pre-washed (5 mL MeOH) of Si-propylsulfonic acid (Silicycle, Cat# R51230B). The column was washed with MeOH (10 mL). The compound was released with 10 mL of 2 M NH3 in MeOH to afford the title compound (75 mg, 0.18 mmol, 92% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 429.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (br. s., 1H), 8.96 (s, 1H), 8.40 (d, J=5.28 Hz, 1H), 8.16-8.26 (m, 2H), 7.74 (d, J=8.80 Hz, 1H), 7.36 (d, J=5.09 Hz, 1H), 5.25-5.35 (m, 1H), 3.36-3.44 (m, 1H), 2.86-2.93 (m, 1H), 2.75-2.82 (m, 1H), 2.67-2.75 (m, 1H), 2.52-2.58 (m, 2H), 2.21-2.32 (m, 1H), 1.55-1.76 (m, 2H), 0.67-0.76 (m, 2H), 0.45-0.59 (m, 2H).

Workup

  1. concentrationconcentrated to a yellow solid
  2. additionthat was slurried with a 1\1 mixture of DCM/MeOH (2 mL)
  3. washa pre-washed (5 mL MeOH) of Si-propylsulfonic acid (Silicycle, Cat# R51230B)
  4. washThe column was washed with MeOH (10 mL)

Sources & evidence

ORD record
ord-232df4f2c62a4f04a606562a3ea9d892
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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