Imidazole → [1-[3-(3-chloro-6-oxo-1(6H)-pyridazinyl)propyl]-4-piperidinyl]methyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate

HRID 392076Notes

Reaction equation

HRID 392076 reaction equation
N1C=CN=C1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10](=[O:24])[N:11]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]2)[N:12]=1.[H-].[Na+].[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][O:36][C:32]=2[C:31]([C:37](N2C=CN=C2)=[O:38])=[CH:30][C:29]=1[Cl:44]>C1COCC1>[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][O:36][C:32]=2[C:31]([C:37]([O:23][CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][N:11]3[C:10](=[O:24])[CH:9]=[CH:8][C:7]([Cl:6])=[N:12]3)[CH2:17][CH2:18]2)=[O:38])=[CH:30][C:29]=1[Cl:44]

Participants

6

Reactant 4

HCID 795ImidazoleHCID 24758Sodium hydrideHCID 22662740(4-Amino-5-chloro-2,3-dihydrobenzofuran-7-yl)(1H-imidazol-1-yl)methanoneHCID 226627606-chloro-2-[3-[4-(hydroxymethyl)-1-piperidinyl]propyl]-3(2H)-pyridazinone

Product 1

HCID 22662763[1-[3-(3-chloro-6-oxo-1(6H)-pyridazinyl)propyl]-4-piperidinyl]methyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylateYield 42.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

1H-imidazole (2.72 g) was added to a solution of 6-chloro-2-[3-[4-(hydroxymethyl)-1-piperidinyl]propyl]-3(2H)-pyridazinone (2.62 g) in THF (100 ml). NaH (60%, 0.4 g) was added, under nitrogen atmosphere. The mixture was stirred for 10 minutes. 1-[(4-Amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]-1H-imidazole (2.64 g) was added and the resulting reaction mixture was stirred for 15 minutes at room temperature. The solvent was evaporated. The residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane/(CH3OH/NH3) 50/45/5). The desired fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE with a drop of ACN. The precipitate was filtered off, washed and dried, yielding 1.88 g (39%) of [1-[3-(3-chloro-6-oxo-1(6H)-pyridazinyl)propyl]-4-piperidinyl]methyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate (compound 21, mp: 137° C.) In a similar way, [1-[3-(3-methyl-6-oxo-1(6H)-pyridazinyl)propyl]-4-piperidinyl]-methyl 7-amino-6-chloro-1,3-benzodioxole-4-carboxylate (compound 22) was also prepared.

Workup

  1. customthe resulting reaction mixture
  2. stirringwas stirred for 15 minutes at room temperature
  3. customThe solvent was evaporated
  4. customThe residue was partitioned between water and DCM
  5. customThe organic layer was separated
  6. customdried
  7. filtrationfiltered
  8. customthe solvent was evaporated
  9. customThe residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane/(CH3OH/NH3) 50/45/5)
  10. customThe desired fractions were collected
  11. customthe solvent was evaporated
  12. customThe residue was crystallized from DIPE with a drop of ACN
  13. filtrationThe precipitate was filtered off
  14. washwashed
  15. customdried

Sources & evidence

ORD record
ord-884a3c5d8d1e4eb396da9d8119bc3033
Source dataset
uspto-grants-2004_10
Patent number
US06800628B2

Reaction notes

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