4-Methylmorpholine → HCID 67995196, compound

HRID 2361390Notes

Reaction equation

HRID 2361390 reaction equation
[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[C:18]([CH3:36])=[C:19]([NH:23][CH2:24][C:25]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=5[C:27](O)=[O:28])[CH:20]=[CH:21][CH:22]=4)=[N:15][N:14]=[C:13]([C:37](=[O:39])[NH2:38])[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[CH2:24][C:25]6[C:26](=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=6)[C:27]5=[O:28])[C:18]=4[CH3:36])=[N:15][N:14]=[C:13]([C:37]([NH2:38])=[O:39])[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2]

Participants

6

Reactant 3

HCID 79724-MethylmorpholineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 67994931HCID 67994931, compound

Product 1

HCID 67995196HCID 67995196, compoundYield 11%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 2-((3-(7-acetyl-4-carbamoyl-5H-pyridazino[4,5-b]indol-1-yl)-2-methylphenylamino)methyl)-5-methoxybenzoic acid (0.336 g, the crude product from previous step), BOP (0.852 g, 1.925 mmol), and N-methylmorpholine (0.635 mL, 5.78 mmol) in DMF (4 mL) was stirred at 45° C. for 1 hr. The mixture was diluted with ethyl acetate (100 mL), washed with water (2×25 mL) and brine (25 mL), and dried over anhydrous MgSO4. After solvent was removed under vacuum, the residue were divided into 4 portions and purified by reverse phase HPLC. The correct fractions were combined and concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (40 mg, 0.077 mmol, 11% yield over 3 steps) as a yellow solid. LCMS (M+H)+=506.29. 1H NMR (500 MHz, DMSO-d6) δ: 12.67 (s, 1H), 8.83 (s, 1H), 8.52 (s, 1H), 8.09 (s, 1H), 7.83 (dd, J1=8.5 Hz, J2=1.5 Hz, 1H), 7.77 (dd, J1=7.8 Hz, J2=1.1 Hz, 1H), 7.63-7.60 (m, 2H), 7.55 (d, J=6.4 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 7.27 (dd, J1=8.3 Hz, J2=2.5 Hz, 1H), 5.02 (d, J=17.2 Hz, 1H), 4.91 (d, J=17.2 Hz, 1H), 3.86 (s, 3H), 2.68 (s, 3H), 1.89 (s, 3H).

Workup

  1. washwashed with water (2×25 mL) and brine (25 mL)
  2. dry with materialdried over anhydrous MgSO4
  3. customAfter solvent was removed under vacuum
  4. custompurified by reverse phase HPLC
  5. concentrationconcentrated under vacuum
  6. extractionextracted with ethyl acetate (3×35 mL)
  7. extractionThe combined extract
  8. washwas washed with brine (30 mL)
  9. dry with materialdried over anhydrous MgSO4
  10. customRemoval of solvent under vacuum

Sources & evidence

ORD record
ord-3e7cd0c90fda4e09b5e4974617aa6cb0
Source dataset
uspto-grants-2014_04
Patent number
US08685969B2

Reaction notes

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