1,1'-Carbonyldiimidazole → (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4 dihydro-2H-1-benzopyran-3-yl)-4-(morpholinocarbonyl)benzamide

HRID 131144Notes

Reaction equation

HRID 131144 reaction equation
[O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[O:8])[CH2:3][CH2:2]1.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.N[C@H]1C[C:35]([N:37]2[CH2:42][CH2:41][N:40](C)[CH2:39][CH2:38]2)=COC1.[O:44]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[CH:47]=[CH:46][CH2:45]1>CN(C)C=O>[CH3:35][N:37]1[CH2:42][CH2:41][N:40]([C:53]2[C:48]3[CH2:47][C@H:46]([NH:20][C:13](=[O:15])[C:12]4[CH:11]=[CH:10][C:9]([C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[O:8])=[CH:17][CH:16]=4)[CH2:45][O:44][C:49]=3[CH:50]=[CH:51][CH:52]=2)[CH2:39][CH2:38]1

Participants

5

Reactant 3

HCID 682631,1'-Carbonyldiimidazole2×HCID 47142364-(Morpholine-4-carbonyl)benzoic acidHCID 69212987(S)-3-Amino-5-(4-methylpiperazin-1-yl)-3,4 dihydropyran 2H-1-benzopyran

Product 1

HCID 69211129(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4 dihydro-2H-1-benzopyran-3-yl)-4-(morpholinocarbonyl)benzamideYield 53%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
75 °C

Procedure

4-(Morpholinocarbonyl)benzoic acid (100 mg, 0.43 mmol; described in: J. Med. Chem. 1994, 37(26), 4538-4554) and 1,1′-carbonyldiimidazole (76 mg, 0.47 mmol) were dissolved in N,N-dimethylformamide (3 mL) and heated to 75° C. for 3.5 h. Additional 1,1′-carbonyldiimidazole (36 mg, 0.22 mol) was added and the solution was stirred for 30 min. (S)-3-Amino-5-(4-methylpiperazin-1-yl)-3,4 dihydropyran-2H-1-benzopyran (100 mg, 0.40 mmol), dissolved in N,N-dimethylformamide (2 mL), was added and the reaction mixture was stirred for 18 h at 50° C. The solvent was evaporated and the residue was partitioned between ethyl acetate (30 mL) and water (5 mL). The organic layer was washed with water (5 mL) and brine (5 mL) and dried (MgSO4). The solvent was evaporated in vacuo giving 180 mg of a crude product. Purification by preparative TLC twice using chloroform/methanol/concentrated ammonia 95:5:0.5 and chloroform/ethanol (saturated with NH3) 12:1 as the eluents afforded 98 mg (53% yield) of the title compound as a white solid: mp 222° C. (decomposes); EIMS (70 eV) m/z (relative intensity) 464 (68, M+); [α]22D −12° (c 0.44, chloroform).

Workup

  1. additionwas added
  2. customThe solvent was evaporated
  3. customthe residue was partitioned between ethyl acetate (30 mL) and water (5 mL)
  4. washThe organic layer was washed with water (5 mL) and brine (5 mL)
  5. dry with materialdried (MgSO4)
  6. customThe solvent was evaporated in vacuo
  7. customgiving 180 mg of a crude product
  8. customPurification by preparative TLC twice using chloroform/methanol/concentrated ammonia 95:5:0.5 and chloroform/ethanol (saturated with NH3) 12:1 as the eluents

Sources & evidence

ORD record
ord-da5f786b71f445b3a6a92a02f519241c
Source dataset
uspto-grants-2008_06
Patent number
US07384943B2

Reaction notes

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