Methanol → HCID 86727499, compound

HRID 519115Notes

Reaction equation

HRID 519115 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:30])([C@@H:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:31]Br.CO.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C@H:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[Br:31])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH3:13])([CH3:30])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 4

HCID 887MethanolHCID 24408BromineHCID 90495Di-tert-butyl dicarbonateHCID 90220660HCID 90220660, compound

Product 1

HCID 86727499HCID 86727499, compoundYield 38%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent2×

Procedure

To a solution of 3-methyl-3-[(R)-1-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester (diastereomer 1, 0.283 g, 0.683 mmol) in AcOH (1 mL) was added a solution of bromine (0.070 mL, 1.366 mmol) in AcOH (1 mL) drop-wise and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was quenched by the addition of saturated aqueous NaS2O3 solution and aqueous NaHCO3 solution to pH 7-8. MeOH (5 mL), TEA (0.146 g, 1.439 mmol) and di-tert-butyl dicarbonate (0.188 g, 0.864 mmol) were added in sequence to the above mixture and the reaction mixture was stirred at ambient temperature for 1.5 h. The aqueous solution was extracted with EtOAc (3×10 mL) and the combined organic phase was washed with saturated brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by prep-TLC (eluting with 50% EtOAc in petroleum ether) to give 3-[(R)-1-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.128 g, 36%) as a solid. LC/MS (Table 1, Method 25) Rt=0.913 min.; MS m/z: 437 [M+H−56]+ and 439 [M+H−56]+. 1H NMR (CDCl3, 400 MHz): δ 8.26 (brs, 1H), 7.25 (s, 1H), 6.70 (s, 1H), 4.75-4.70 (m, 1H), 4.60 (d, J=12.8 Hz, 2H), 3.98-3.91 (m, 2H), 3.55 (m, 2H), 3.44 (d, J=8.4 Hz, 1H), 1.52 (d, J=6.8 Hz, 3H), 1.46 (s, 9H), 1.32-1.27 (m, 6H).

Workup

  1. customThe reaction mixture was quenched by the addition of saturated aqueous NaS2O3 solution and aqueous NaHCO3 solution to pH 7-8
  2. stirringthe reaction mixture was stirred at ambient temperature for 1.5 h
  3. extractionThe aqueous solution was extracted with EtOAc (3×10 mL)
  4. washthe combined organic phase was washed with saturated brine (10 mL)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. customThe filtrate was evaporated to dryness
  8. customthe residue was purified by prep-TLC (eluting with 50% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-ba2110bac2f54602bbf2abeb2891d7fb
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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