Trifluoroacetic acid → Spiro[3,1-benzoxazine-4,4'-piperidin]-2(1H)-one

HRID 641181Notes

Reaction equation

HRID 641181 reaction equation
[O:1]=[C:2]1[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[O:3]1.FC(F)(F)C(O)=O>ClCCl>[NH:7]1[CH2:6][CH2:5][C:4]2([O:3][C:2](=[O:1])[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=3)[CH2:9][CH2:8]1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 13050638tert-Butyl 2-oxo-1,2-dihydro-1'H-spiro[3,1-benzoxazine-4,4'-piperidine]-1'-carboxylate

Product 1

HCID 13050639Spiro[3,1-benzoxazine-4,4'-piperidin]-2(1H)-one

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

tert-Butyl 2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate (6.71 g, 21.1 mmol) (A3) was dissolved in dichloromethane (50 mL), treated with trifluoroacetic acid (20 mL) and stirred at room temperature for 45 min. The reaction was concentrated under reduced pressure, re-dissolved in acetonitrile and re-concentrated under reduced pressure. The crude TFA salt was cooled in an ice water bath, dissolved in ice-cold saturated brine (20 mL) and H2O (50 mL) and basified with ice-cold 35% NaOH (aq). A small amount of product (obtained from extraction with 50 mL ethyl acetate) was added to the aqueous layer to initiate crystallization. The suspension obtained was cooled in an ice-H2O bath, filtered, rinsed with ice-cold H2O and dried to afford spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (A4) free base as a white crystalline solid. Additional free base was obtained via extraction of the mother liquor with ethyl acetate (10×50 mL) and subsequent trituration of the crude free base with acetonitrile (overall yield=84%). LC/MS m/z 219.2 [M+H]+, retention time 0.58 min (RP-C18, 10-99% CH3CN/0.05% TFA); 1H-NMR (400 MHz, DMSO-d6) δ 10.17 (br s, 1H), 7.23 (m, 2H), 7.02 (m, 1H), 6.87 (dd, J=8.2, 1.2 Hz, 1H), 2.89 (m, 2H), 2.82 (m, 2H), 1.84 (m, 4H).

Workup

  1. concentrationThe reaction was concentrated under reduced pressure
  2. dissolutionre-dissolved in acetonitrile
  3. concentrationre-concentrated under reduced pressure
  4. temperatureThe crude TFA salt was cooled in an ice water bath
  5. dissolutiondissolved in ice-cold saturated brine (20 mL)
  6. customA small amount of product (obtained from extraction with 50 mL ethyl acetate)
  7. additionwas added to the aqueous layer
  8. customcrystallization
  9. customThe suspension obtained
  10. temperaturewas cooled in an ice-H2O bath
  11. filtrationfiltered
  12. washrinsed with ice-cold H2O
  13. customdried

Sources & evidence

ORD record
ord-48a0457206024b51a2f41e75ea4737ae
Source dataset
uspto-grants-2010_04
Patent number
US07696201B2

Reaction notes

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