1,2-Dichloroethane → N-(6-Bromo-5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl)-L-alanine 1,1-dimethylethyl Ester

HRID 843711Notes

Reaction equation

HRID 843711 reaction equation
[CH:1]1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.Cl.[C:14]([O:18][C:19](=[O:23])[C@H](C)N)([CH3:17])([CH3:16])[CH3:15].NC1C=[CH:32][C:31]([Br:34])=[C:30]([CH3:35])[C:26]=1[C:27](O)=[O:28].C(N(CC)CC)C.C(Cl)CCl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:17][C:14]([O:18][C:19](=[O:23])[C@H:2]([CH3:1])[NH:3][C:6]1[O:7][C:27](=[O:28])[C:26]2[C:30]([CH3:35])=[C:31]([Br:34])[CH:32]=[CH:10][C:9]=2[N:8]=1)([CH3:15])[CH3:16]

Participants

9

Reactant 5

HCID 111,2-DichloroethaneHCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 11275390tert-Butyl alaninate hydrochlorideHCID 158858096-Amino-3-bromo-2-methylbenzoic acid

Product 1

HCID 15885810N-(6-Bromo-5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl)-L-alanine 1,1-dimethylethyl EsterYield 8%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 1049PyridineSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To an ice cooled suspension of CDI (0.309 g, 1.91 mol) in 2 mL of pyridine was added L-alanine tert-butyl ester hydrochloride (0.317 g, 1.74 mmol). After stirring at 0° C. for 30 minutes, 2-amino-5-bromo-6-methylbenzoic acid (0.494 g, 1.60 mmol) and 25 mg of DMAP was added. The ice bath was removed and the reaction was stirred at 65° C. for 2.5 hours. The reaction mixture was cooled to room temperature and diluted with 2 mL of DMF and 2 mL of CH2Cl2. Triethylamine (0.257 g, 2.54 mmol) and EDC (0.457 g, 2.38 mmol) were added sequentially. After stirring at room temperature for 2 hours, the reaction mixture was diluted with EtOAc and washed with 1N HCl, dried (MgSO4), filtered and evaporated under reduced pressure. Silica gel chromatography of the residue (1:1 EtOAc/hexane) afforded 49 mg of product: 1H-NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.50 (d, J=7 Hz, 3H), 2.83 (s, 3H), 4.47 (q, J=7 Hz, 1H), 5.60 (br. s, 1H, exchangeable), 6.97 (d, J=9 Hz, 1H), 7.73 (d, J=9 Hz, 1H).

Workup

  1. customThe ice bath was removed
  2. stirringthe reaction was stirred at 65° C. for 2.5 hours
  3. temperatureThe reaction mixture was cooled to room temperature
  4. additiondiluted with 2 mL of DMF and 2 mL of CH2Cl2
  5. stirringAfter stirring at room temperature for 2 hours
  6. washwashed with 1N HCl
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-f532eda4125849489021c84bd84cd011
Source dataset
uspto-grants-2002_04
Patent number
US06380189B1

Reaction notes

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