1,1'-Carbonyldiimidazole → 4-Amino-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide hydrate

HRID 617196Notes

Reaction equation

HRID 617196 reaction equation
[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([OH:13])=O)=[CH:4][C:3]=1[Cl:14].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:27][O:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>O1CCCC1.C(N1C=CN=C1)(N1C=CN=C1)=O.COCCCN1CCC(N)CC1>[OH2:10].[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([NH:38][CH:35]2[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][CH2:29][O:28][CH3:27])[CH2:33][CH2:34]2)=[O:13])=[CH:4][C:3]=1[Cl:14]

Participants

7

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 106324014-Amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acidHCID 120880931-(3-Methoxypropyl)-4-piperidinamine

Product 1

HCID 183607994-Amino-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide hydrateYield 181.1%

Reagents, catalysts & solvents 3

HCID 682631,1'-CarbonyldiimidazoleCatalystHCID 120880931-(3-Methoxypropyl)-4-piperidinamineCatalystHCID 8028TetrahydrofuranSolvent3×

Procedure

Reaction under N2 flow. 4-Amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.18 mol) was dissolved in tetrahydrofuran (360 ml) and this solution was stirred and cooled to ±3° C. 1,1'-Carbonylbis-1H-imidazole (0.18 mol) was added in one portion and cooling was stopped. The mixture was stirred for 75 minutes (became homogeneous after 30 minutes). A solution of 1-(3-methoxypropyl)-4-piperidinamine (0.18 mol) in tetrahydrofuran (90 ml) was added dropwise (exothermic temperature rise from 23° C. to 27° C.). The reaction mixture was stirred for 24 hours. More 1,1'-Carbonylbis-1H-imidazole (0.0125 mol) was added and the reaction mixture was stirred for 75 minutes. More 1-(3-methoxypropyl)-4-piperidinamine (0.0125 mol) was added (in 10 ml THF). The resulting reaction mixture was stirred for 3 hours at room temperature, then for 2.5 hours at reflux temperature. Then, the mixture was stirred for 13 hours, allowing it to cool to room temperature. The solvent was evaporated. The residue was stirred for 8 hours in water (360 ml) and the precipitate was filtered off, washed with water, then dried (vacuum; 30° C.), yielding 62.9 g (95%) 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide monohydrate; mp. 90.7° C. (comp. 2).

Workup

  1. customReaction under N2 flow
  2. temperaturecooled
  3. customto ±3° C
  4. temperaturecooling
  5. stirringThe mixture was stirred for 75 minutes (became homogeneous after 30 minutes)
  6. stirringThe reaction mixture was stirred for 24 hours
  7. stirringthe reaction mixture was stirred for 75 minutes
  8. customThe resulting reaction mixture
  9. stirringwas stirred for 3 hours at room temperature
  10. temperaturefor 2.5 hours at reflux temperature
  11. stirringThen, the mixture was stirred for 13 hours
  12. customThe solvent was evaporated
  13. stirringThe residue was stirred for 8 hours in water (360 ml)
  14. filtrationthe precipitate was filtered off
  15. washwashed with water
  16. customdried (vacuum; 30° C.)

Sources & evidence

ORD record
ord-bfde49916e4641ea97b84616c378338a
Source dataset
uspto-grants-1999_09
Patent number
US05948794

Reaction notes

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