Morpholine → 4-{6-Iodo-3-[(morpholin-4-yl)carbonyl]indazol-1-yl}pyrimidin-2-amine

HRID 1398582Notes

Reaction equation

HRID 1398582 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18]([OH:20])=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[I:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:20])=[N:9][N:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:12][CH:13]=1

Participants

7

Reactant 3

HCID 8083MorpholineHCID 24386Thionyl ChlorideHCID 681816001-(2-Aminopyrimidin-4-yl)-6-iodoindazole-3-carboxylic acid

Product 1

HCID 681816904-{6-Iodo-3-[(morpholin-4-yl)carbonyl]indazol-1-yl}pyrimidin-2-amineYield 76.8%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×HCID 10340Sodium CarbonateSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carboxylic acid (3 g, 7.87 mmol)) in DCM (40 mL), was added thionyl chloride (6.85 ml, 94.46 mmol) followed by DMF (catalytic, 3 drops). The mixture was stirred at 50° C. for 1 hour. The reaction mixture was concentrated in vacuo and DCM added and the concentration repeated (×2). The crude acid chloride (assumed 7.87 mmol) was suspended in more DCM (30 mL) and morpholine (1.37 ml, 15.74 mmol) was added at 0 dropwise. The reaction was stirred at RT overnight. The reaction mixture was diluted with more DCM (25 ml) and 2M Na2CO3 added (35 ml). A pale brown precipitate was collected by filtration and washed with more DCM. The precipitate was slurried in water:acetonitrile (3:1, 10 ml) and the off-white solid collected by filtration and washed with more water:acetonitrile (3:1, 2×1 ml). The solid was then dried under vacuum to give the title compound (2.72 g, LC-MS purity=86%): 1H NMR (500 MHz, DMSO) delta 3.41-3.76 (6H, m), 3.85-3.97 (2H, m), 7.05 (1H, d, J=5.5 Hz), 7.18 (2H, s), 7.74 (1H, dd, J=8.4, 1.1 Hz), 7.80 (1H, d, J=8.4 Hz), 8.34 (1H, d, J=5.5 Hz), 9.33 (1H, s); LC-MS: m/z=+450.90 (M+H)+.

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo and DCM
  2. additionadded
  3. concentrationthe concentration
  4. stirringThe reaction was stirred at RT overnight
  5. additionadded (35 ml)
  6. filtrationA pale brown precipitate was collected by filtration
  7. washwashed with more DCM
  8. filtrationthe off-white solid collected by filtration
  9. washwashed with more water:acetonitrile (3:1, 2×1 ml)
  10. customThe solid was then dried under vacuum

Sources & evidence

ORD record
ord-956e8ec944a746819d547110704f1fe1
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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