1,2-Dichloroethane → (5-{3-[(5-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester

HRID 221679

Reaction equation

HRID 221679 reaction equation
[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[N+]=[N-])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1COCC(C2C=CC=C(N)C=2)(CF)N=1)(C)(C)C.[Br:49][C:50]1[CH:51]=[CH:52][C:53]([C:56](O)=[O:57])=[N:54][CH:55]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C([O-])(O)=O.[Na+]>CCOC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:56]([C:53]3[CH:52]=[CH:51][C:50]([Br:49])=[CH:55][N:54]=3)=[O:57])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

11

Reactant 6

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 516892Sodium BicarbonateHCID 6085445-Bromopyridine-2-carboxylic acidHCID 66665608[5-(3-amino-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl esterHCID 86650252[5-(3-Azido-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester

Product 1

HCID 66665302(5-{3-[(5-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 4

HCID 131709914Lindlars catalystCatalystHCID 6344DichloromethaneSolvent2×HCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of [5-(3-azido-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (56 mg, 0.161 mmol) in 2 ml of EtOAc was hydrogenated in the presence of Lindlar catalyst (11 mg) for 3 h. The mixture was filtered through Celite, and the filtrate was evaporated. The crude [5-(3-amino-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (50 mg, 0.155 mmol) was taken up in 2 ml of dichloromethane. A mixture of 5-bromo-pyridine-2-carboxylic acid (34.4 mg, 0.170 mmol), HOBT (30.9 mg, 0.17 mmol) and EDC (32.6 mg, 0.17 mmol) in 2 ml of dichloromethane was added, followed by the addition of triethylamine (0.054 ml). The mixture was stirred for 4 h, treated with 5% aqueous NaHCO3 solution and extracted twice with dichloromethane. The organic phase was dried with MgSO4 and evaporated. The residue was chromatographed on silica gel (EtOAc/cyclohexane=1:4) to yield the title compound. TLC (hexane/EtOAc=3:1): Rf=0.16; HPLC: RtH1=2.763 min; 1H-NMR (400 MHz, CDCl3): 9.80 (br, 0.1H), 8.60 (d, 1H), 8.11 (d, 1H), 7.98 (d, 1H), 7.77 (br, 1H), 7.73 (d, 1H), 7.33 (br, 1H), 7.15 (d, 1H), 4.75-3.65 (m, 6H), 1.60 (br; minor rotamer tBu), 1.42 (br; major rotamer tBu); MS: 507, 509 [(M+H)+].

Workup

  1. filtrationThe mixture was filtered through Celite
  2. customthe filtrate was evaporated
  3. additionwas added
  4. extractionextracted twice with dichloromethane
  5. dry with materialThe organic phase was dried with MgSO4
  6. customevaporated
  7. customThe residue was chromatographed on silica gel (EtOAc/cyclohexane=1:4)

Sources & evidence

ORD record
ord-2ff0aee46dfa40f6b739a1ccff80a809
Source dataset
uspto-grants-2012_06
Patent number
US08207164B2

Linked notes

Loading…