Trifluoroacetic acid → 6-cyano-N-[4-cyclopentyl-5-hydroxy-2-(piperazin-1-ylmethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide

HRID 383433Notes

Reaction equation

HRID 383433 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([O:26]C(OC)=O)=[CH:17][C:16]=2[NH:31][C:32]([CH:34]2[O:39][C:38]3[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:37]=3[N:36](C(OCC)=O)[CH2:35]2)=[O:33])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:44]([C:42]1[CH:41]=[CH:40][C:38]2[O:39][CH:34]([C:32]([NH:31][C:16]3[CH:17]=[C:18]([OH:26])[C:19]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)=[CH:20][C:15]=3[CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:33])[CH2:35][NH:36][C:37]=2[CH:43]=1)#[N:45]

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 59394951ethyl 2-(2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-4-cyclopentyl-5-(methoxycarbonyloxy)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate

Product 1

HCID 593949666-cyano-N-[4-cyclopentyl-5-hydroxy-2-(piperazin-1-ylmethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamideYield 29.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of ethyl 2-(2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-4-cyclopentyl-5-(methoxycarbonyloxy)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (15 mg, 0.022 mmol) in dichloromethane (500 μL) was added TFA (3 μL, 0.04 mmol) and the reaction was stirred overnight at room temperature. The reaction was quenched with aqueous NaHCO3 and the layers separated. The aqueous layer was extracted with dichloromethane, dried over MgSO4, filtered and concentrated. The crude product was dissolved in methanol and 1M NaOH and the reaction was heated at reflux for 5 min. The reaction was quenched with 1M HCl and the aqueous layer was extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated. Purification by HPLC (10-99% CH3CN/0.05% TFA) provided 6-cyano-N-[4-cyclopentyl-5-hydroxy-2-(piperazin-1-ylmethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (3 mg, 24% yield). LC/MS m/z 462.5 [M+H]+.

Workup

  1. customThe reaction was quenched with aqueous NaHCO3
  2. customthe layers separated
  3. extractionThe aqueous layer was extracted with dichloromethane
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. dissolutionThe crude product was dissolved in methanol
  8. temperature1M NaOH and the reaction was heated
  9. temperatureat reflux for 5 min
  10. customThe reaction was quenched with 1M HCl
  11. extractionthe aqueous layer was extracted with dichloromethane
  12. dry with materialThe organic layer was dried over MgSO4
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customPurification by HPLC (10-99% CH3CN/0.05% TFA)

Sources & evidence

ORD record
ord-3085af576ae44f9fa98d8d52e34aa0ab
Source dataset
uspto-grants-2013_02
Patent number
US08367660B2

Reaction notes

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