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

HRID 1695914Notes

Reaction equation

HRID 1695914 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)-oneYield 66.7%

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) 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-H2O 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 3.071 g spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one free base as a white crystalline solid. An additional 800 mg 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-H2O 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-df6438575e864116bd0b2c334e42d86a
Source dataset
uspto-grants-2012_04
Patent number
US08163737B2

Reaction notes

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