Morpholine → HCID 68349364, compound

HRID 1507931Notes

Reaction equation

HRID 1507931 reaction equation
[NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]1([C@H:10]([NH:12][C:13]2[C:14]3[N:15]([CH:22]=[C:23]([C:25]4[O:26][C:27](SC)=[N:28][N:29]=4)[CH:24]=3)[N:16]=[CH:17][C:18]=2[C:19]([NH2:21])=[O:20])[CH3:11])[CH2:9][CH2:8]1>CN1C(=O)CCC1>[CH:7]1([C@H:10]([NH:12][C:13]2[C:14]3[N:15]([CH:22]=[C:23]([C:25]4[O:26][C:27]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[N:28][N:29]=4)[CH:24]=3)[N:16]=[CH:17][C:18]=2[C:19]([NH2:21])=[O:20])[CH3:11])[CH2:9][CH2:8]1

Participants

4

Reactant 2

HCID 8083MorpholineHCID 68291095HCID 68291095, compound

Product 1

HCID 68349364HCID 68349364, compoundYield 45%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
200 °C

Procedure

Morpholine (13 mg, 0.14 mmol) was added in one portion to a solution of (R)-4-(1-cyclopropylethylamino)-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 127, 10 mg, 0.028 mmol) in NMP (0.1 mL). The resulting mixture was heated in the CEM microwave at 200° C. for 1 hour before purifying by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to remove the MeOH and the aqueous slurry of the product was neutralized by addition of ˜1 mL of saturated aqueous sodium bicarbonate. Sonication of the slurry followed by vacuum filtration and air drying in the funnel afforded the title compound (5 mg, 45% yield). HPLC (condition B): retention time=0.73 min. LCMS (condition B): MH+ m/z 398.3. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.84 (1 H, br. s.), 8.28 (1 H, s), 8.15 (1 H, d, J=1.39 Hz), 7.22 (1 H, d, J=1.39 Hz), 3.99 (1 H, d, J=1.39 Hz), 3.68-3.82 (4 H, m), 3.44-3.53 (4 H, m), 1.34 (3 H, d, J=6.38 Hz), 1.11 (1 H, d, J=6.94 Hz), 0.44-0.56 (1H, m), 0.39 (1 H, br. s.), 0.31 (2 H, br. s.).

Workup

  1. custombefore purifying by reverse-phase Prep HPLC (condition A)
  2. additionThe fraction containing the major product
  3. concentrationwas concentrated on the rotovap
  4. customto remove the MeOH
  5. additionthe aqueous slurry of the product was neutralized by addition of ˜1 mL of saturated aqueous sodium bicarbonate
  6. customSonication of the slurry
  7. filtrationfollowed by vacuum filtration and air
  8. customdrying in the funnel

Sources & evidence

ORD record
ord-d4c9a4dac96f424a95b476443b612f6a
Source dataset
uspto-grants-2015_12
Patent number
US09221826B2

Reaction notes

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