Hydrochloric Acid → (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

HRID 1529370Notes

Reaction equation

HRID 1529370 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[N:12]=[C:11]3[C:23]2[N:28]=[C:27]([O:29][C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]3)[CH:26]=[N:25][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH:43]1([NH2:46])[CH2:45][CH2:44]1.CCN(C(C)C)C(C)C.Cl>C1COCC1>[CH:43]1([NH:46][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:12]=[C:11]4[C:23]3[N:28]=[C:27]([O:29][C@@H:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:31]4)[CH:26]=[N:25][CH:24]=3)[CH:5]=[CH:4][N:3]=2)[CH2:45][CH2:44]1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 69828CyclopropylamineHCID 81531DiisopropylethylamineHCID 86709777(3R)-tert-butyl 3-(6-(5-(2-chloropyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate

Product 1

HCID 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-carboxylateYield 65.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of (3R)-tert-butyl 3-(6-(5-(2-chloropyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (172 mg, 0.290 mmol), cyclopropylamine (0.12 mL, 1.74 mmol) and DIPEA (0.25 mL, 1.45 mmol) in THF (1.5 mL) was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 30 min and heated at 140° C. for an additional 1 h. 1 M HCl (aq.) was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-50% EtOAc in hexanes, to provide (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, 65% yield) as a clear oil. MS (ESI, pos. ion) m/z: 613.3 (M+1).

Workup

  1. temperatureheated at 140° C. for an additional 1 h
  2. extractionthe mixture was extracted with EtOAc (3×)
  3. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude was purified by silica gel chromatography
  7. washeluting with a gradient of 0-50% EtOAc in hexanes

Sources & evidence

ORD record
ord-32bc3f0269e0487d917bab012af6097d
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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