1,1'-Carbonyldiimidazole → 4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-[(3-chlorophenyl)methoxy]benzamide

HRID 2254616Notes

Reaction equation

HRID 2254616 reaction equation
[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH:34]1[CH:39]2[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]2)[CH2:35]1>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:33][CH:34]2[CH:39]3[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]3)[CH2:35]2)=[O:8])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH:3]=1

Participants

5

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 1232383-AminoquinuclidineHCID 197428204-Amino-5-chloro-2-[(3-chlorophenyl)methoxy]benzoic acid

Product 1

HCID 197428264-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-[(3-chlorophenyl)methoxy]benzamideYield 73.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 4-amino-5-chloro-2-[(3-chlorophenyl)methoxy]benzoic acid (3.13 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.87 g, 11.5 mmol), stirred for 45 minutes, and degassed over 15 minutes under a stream of nitrogen. A solution of 3-aminoquinuclidine (1.85 g, 14.7 mmol) in anhydrous tetrahydrofuran (5 mL) was added, and the mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and partitioned between 3N sodium hydroxide (50 mL) and toluene (100 mL) containing some 2-propanol. The organic layer was separated and the aqueous solution was extracted with toluene (50 mL) containing some 2-propanol. The combined organic solution was dried (Na2SO4), concentrated in vacuo, and rinsed with water in order to remove the remaining imidazole by-product. The residue was dried azeotropically with toluene, then taken up in tetrahydrofuran and filtered through a short column of alumina (eluted with 10% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, triturated from cold ether/petroleum ethers (30°-60° C.), and recrystallized from acetonitrile (2 crops) to afford 3.08 g (73%) of pale yellow solid; mp 168°-169° C.

Workup

  1. customdegassed over 15 minutes under a stream of nitrogen
  2. stirringthe mixture was stirred at room temperature for 18 hours
  3. concentrationconcentrated in vacuo
  4. custompartitioned between 3N sodium hydroxide (50 mL) and toluene (100 mL)
  5. additioncontaining some 2-propanol
  6. customThe organic layer was separated
  7. extractionthe aqueous solution was extracted with toluene (50 mL)
  8. additioncontaining some 2-propanol
  9. dry with materialThe combined organic solution was dried (Na2SO4)
  10. concentrationconcentrated in vacuo
  11. washrinsed with water in order
  12. customto remove the remaining imidazole by-product
  13. dry with materialThe residue was dried azeotropically with toluene
  14. filtrationfiltered through a short column of alumina (eluted with 10% methanol/tetrahydrofuran)
  15. concentrationThe filtrate was concentrated in vacuo
  16. customtriturated from cold ether/petroleum ethers (30°-60° C.)
  17. customrecrystallized from acetonitrile (2 crops)

Sources & evidence

ORD record
ord-717c58e9769c4bc2a90513b1db3563c4
Source dataset
uspto-grants-1993_08
Patent number
US05236931

Reaction notes

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