Water → tert-Butyl 6-bromo-4-oxo-3,4-dihydro-1'H-spiro[1,3-benzoxazine-2,4'-piperidine]-1'-carboxylate

HRID 518184Notes

Reaction equation

HRID 518184 reaction equation
[Br:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1CCCC1.O>C1(C)C=CC=CC=1>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22]2([NH:9][C:7](=[O:8])[C:6]3[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[O:11]2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]

Participants

6

Reactant 4

HCID 962WaterHCID 31268PyrrolidineHCID 728765-BromosalicylamideHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylate

Product 1

HCID 2794762tert-Butyl 6-bromo-4-oxo-3,4-dihydro-1'H-spiro[1,3-benzoxazine-2,4'-piperidine]-1'-carboxylateYield 40%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A mixture of 5-bromo salicylamide (2.5 g, 11.6 mmol), N—BOC-4-piperidone (2.30 g, 11.6 mmol) and pyrrolidine (0.96 ml, 11.6 mmol) in toluene (40 ml) was heated to reflux under N2 atmosphere. After 3 h, the mixture was cooled down to RT, poured into water and extracted with AcOEt. The organic phase was washed with a 2 M solution of NaOH (150 ml) and then with 2 M HCl (150 ml), dried over Na2SO4, filtered and the solvent was evaporated under vacuum. The crude mixture was purified by column chromatography using DCM/MeOH 90/10 as eluent, to give 1.82 g of 6-bromo-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-1′-carboxylic acid tert-butyl ester as a white solid (40%). Reaction with methyl acrylate according to the procedure for preparation of Intermediate 1, Step B, gave (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (1.3 g, 71%) as a yellow solid.

Workup

  1. temperaturewas heated
  2. temperatureto reflux under N2 atmosphere
  3. extractionextracted with AcOEt
  4. washThe organic phase was washed with a 2 M solution of NaOH (150 ml)
  5. dry with materialwith 2 M HCl (150 ml), dried over Na2SO4
  6. filtrationfiltered
  7. customthe solvent was evaporated under vacuum
  8. customThe crude mixture was purified by column chromatography

Sources & evidence

ORD record
ord-74cecb64d4b54f2bae8b25dae759d710
Source dataset
uspto-grants-2015_08
Patent number
US09115148B2

Reaction notes

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