Isobutyl chloroformate → 5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

HRID 988611Notes

Reaction equation

HRID 988611 reaction equation
[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[NH2:21][C:22]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:23]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)=[O:25]>CN(C=O)C.C1COCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:22]([NH:21][C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]2)=[O:12])=[C:23]([CH:34]=1)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)=[O:25]

Participants

5

Reactant 3

HCID 62365Isobutyl chloroformateHCID 64841871-Isopropylpiperidine-4-Carboxylic AcidHCID 219064182-Amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide

Product 1

HCID 99126505-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideYield 83%

Reagents, catalysts & solvents 1

HCID 21974620tetrahydrofuran N,N-dimethylformamideSolvent2×

Procedure

A slurry of 1-isopropylpiperidine-4-carboxylic acid (501.0 mg, 2.92 mmol) and 50% DMF/THF (6.3 mL) was cooled in an ice bath, and a solution of iso-butyl chloroformate (0.34 mL, 2.63 mmol) and 50% DMF/THF (0.7 mL) was added over 10 min via syringe. The ice bath was removed at addition's end, and the mixture was allowed to warm to ambient temperature. After 1 h, 2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide (414.8 mg, 1.47 mmol) was added in one portion, and the slurry was heated to 70° C. in an oil bath. Analysis by HPLC after 17 h showed only 2.5% of unacylated amine remained, so the volatiles were removed under reduced pressure, and EtOAc (25 mL) and water (20 mL) were added. The organic layer was extracted with saturated NaHCO3 (2×20 mL), and the combined aqueous layers were back-extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to 0.97 g of yellow solid which was found to be contaminated with 45 wt % DMF. Corrected yield was 0.53 g (83% yield), and no further purification was performed:

Workup

  1. customThe ice bath was removed at addition's end
  2. temperaturethe slurry was heated to 70° C. in an oil bath
  3. waitAnalysis by HPLC after 17 h showed only
  4. customwere removed under reduced pressure, and EtOAc (25 mL) and water (20 mL)
  5. additionwere added
  6. extractionThe organic layer was extracted with saturated NaHCO3 (2×20 mL)
  7. extractionthe combined aqueous layers were back-extracted with CH2Cl2 (2×20 mL)
  8. dry with materialThe combined organic layers were dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated to 0.97 g of yellow solid which
  11. customCorrected yield was 0.53 g (83% yield), and no further purification

Sources & evidence

ORD record
ord-0b14c85a52cd432b825d4586784cdc42
Source dataset
uspto-grants-2003_10
Patent number
US06635657B1

Reaction notes

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