Dimethylformamide → 4-{6-Bromo-3-[(2,6-dimethylmorpholin-4-yl)carbonyl]indazol-1-yl}pyrimidin-2-amine

HRID 1398581Notes

Reaction equation

HRID 1398581 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]([Br: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.CN(C=O)C.[CH3:30][CH:31]1[O:36][CH:35]([CH3:37])[CH2:34][NH:33][CH2:32]1>C(Cl)Cl>[Br:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18]([N:33]3[CH2:32][CH:31]([CH3:30])[O:36][CH:35]([CH3:37])[CH2:34]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

6

Reactant 4

HCID 6228DimethylformamideHCID 24386Thionyl ChlorideHCID 1108622,6-DimethylmorpholineHCID 681819661-(2-Aminopyrimidin-4-yl)-6-bromoindazole-3-carboxylic acid

Product 1

HCID 681819174-{6-Bromo-3-[(2,6-dimethylmorpholin-4-yl)carbonyl]indazol-1-yl}pyrimidin-2-amine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxylic acid (0.38 g, 1.12 mmol)) in DCM (5 mL), was added thionyl chloride (0.49 ml, 6.74 mmol) followed by a drop of DMF. The mixture was stirred at 40° C. overnight. The reaction mixture was concentrated in vacuo and DCM added and the concentration repeated (×2). The acid chloride intermediate was suspended in DCM (10 ml), 2,6-dimethylmorpholine (0.55 ml, 4.49 mmol) added. The reaction was stirred at RT for 0.5 hr and then concentrated in vacuo. The residue was diluted with more DCM and water and the organics extracted (2×20 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Crude material purified by column chromatography, (9:1 DCM:methanol, Rf=0.6). Elution with DCM:methanol 98:2 to 90:10 gave the mixture of cis and trans 2,6-dimethylmorpholin-4-yl compound (200 mg): 1H NMR (500 MHz, CDCl3) delta 1.21 (3H, d, J=6.2 Hz), 1.30 (3H, d, J=6.1 Hz), 2.64 (1H, dd, J=13.1, 10.8 Hz), 2.99 (1H, dd, J=13.2, 10.6 Hz), 4.84-3.26 (6H, m), 5.23 (2H, s), 7.23-7.19 (1H, m), 7.50 (1H, dd, J=8.6, 1.6 Hz), 7.98 (1H, d, J=8.6 Hz), 8.37 (1H, dd, J=5.6, 2.2 Hz), 9.01 (1H, d, J=1.2 Hz); LC-MS: m/z=+430.95/432.85 (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 for 0.5 hr
  5. concentrationconcentrated in vacuo
  6. additionThe residue was diluted with more DCM and water
  7. extractionthe organics extracted (2×20 ml)
  8. dry with materialThe combined organic layers were dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customCrude material purified by column chromatography, (9:1 DCM:methanol, Rf=0.6)
  12. washElution with DCM:methanol 98:2 to 90:10
  13. customgave

Sources & evidence

ORD record
ord-91b78af40f484c02962ed3f67fd9f497
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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