Acetonitrile → Cis-4-amino-2-(2-amino-2-oxoethoxy)-5-chloro-N-{1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl}benzamide sesquihydrate

HRID 620282Notes

Reaction equation

HRID 620282 reaction equation
[NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:11][C@H:10]2[O:26][CH3:27])=[O:7])=[C:4]([OH:31])[CH:3]=1.[H-].[Na+].Br[CH2:35][C:36]([O:38]C)=[O:37].[C:40](#[N:42])[CH3:41]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH2:7].[NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:11][C@H:10]2[O:26][CH3:27])=[O:7])=[C:4]([O:31][CH2:35][C:36]([NH2:42])=[O:38])[CH:3]=1.[OH2:37].[OH2:7].[NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:11][C@H:10]2[O:26][CH3:27])=[O:7])=[C:4]([O:31][CH2:41][C:40](=[O:37])[NH2:42])[CH:3]=1

Participants

6

Reactant 4

HCID 6342AcetonitrileHCID 24758Sodium hydrideHCID 60984Methyl bromoacetateHCID 14372589Cis-4-amino-5-chloro-N-{1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-hydroxybenzamide

Product 1

HCID 131715866Cis-4-amino-2-(2-amino-2-oxoethoxy)-5-chloro-N-{1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl}benzamide sesquihydrate

Reagents, catalysts & solvents 1

HCID 74236Tetrabutylammonium BromideCatalyst

Conditions

Temperature
40 °C

Procedure

Cis-4-amino-5-chloro-N-{1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl}-2-hydroxybenzamide (1.35 g, 3 mmoles) (prepared in Example 61, Step A) was added to a stirred suspension of sodium hydride (0.12 g, 3 mmoles of 60% emulsion, washed with petroleum ether) in acetonitrile (20 ml) followed by tetrabutylammonium bromide (0.96 g, 3 mmoles). The reaction mixture was heated to 40° C. for 15 minutes and then treated with methyl bromoacetate (0.92 g, 6 mmoles). After stirring for 2 days the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried, concentrated in vacuo and the residue was chromatographed over deactivated silica using a methylene chloride (100), methanol (2), ammonia (0.5) solvent system. The appropriate fractions were combined and the solvent evaporated. The residue was dissolved in methylene chloride by adding methanol and the solution was saturated with gaseous ammonia in the cold. After 30 minutes the solvent was evaporated and the residue crystallized from ethanol-water to yield 0.3 g of the title compound as a sesquihydrate (19%), mp. 173°-175° C.

Workup

  1. customwas partitioned between water and ethyl acetate
  2. customThe organic phase was dried
  3. concentrationconcentrated in vacuo
  4. customthe residue was chromatographed over deactivated silica using a methylene chloride (100), methanol (2), ammonia (0.5) solvent system
  5. customthe solvent evaporated
  6. dissolutionThe residue was dissolved in methylene chloride
  7. additionby adding methanol
  8. customAfter 30 minutes the solvent was evaporated
  9. customthe residue crystallized from ethanol-water

Sources & evidence

ORD record
ord-7c3aca40282e43b4814bd0c229a1002c
Source dataset
uspto-grants-1989_04
Patent number
US04820715

Reaction notes

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