Ammonia → 2-{(3R)-7-Chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetamide

HRID 1054187Notes

Reaction equation

HRID 1054187 reaction equation
[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@H:7]([CH2:10][C:11]([O:13]CC)=O)[CH2:8][O:9][C:4]=2[CH:3]=1.[NH3:31]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@H:7]([CH2:10][C:11]([NH2:31])=[O:13])[CH2:8][O:9][C:4]=2[CH:3]=1

Participants

3

Reactant 2

HCID 222AmmoniaHCID 131736336Ethyl {(3R)-7-chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate2×

Product 1

HCID 1185996332-{(3R)-7-Chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetamideYield 27.4%

Procedure

Ethyl {(3R)-7-chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 21b, 2.00 g, 4.64 mmol) dissolved in ammonia (7 M in MeOH) (49.7 mL, 348.2 mmol) sealed and stirred at rt for 45 h. The solvent was evaporated and the residue (616 mg crude brown oil) was dissolved in DMSO and MeOH. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-50% ACN in H2O/ACN/FA 95/5/0.2 buffer over 20 min with a flow of 100 mL/min. The compounds were detected by UV at 253/280 nm. Pure fractions were pooled and the most of the ACN was evaporated. The residue was partitioned between EtOAc and water. The combined organic phases were concentrated in vacuo. Addition of DMSO/ACN and water a precipitate was observed. The solvents were removed in vacuo and water was added to the residue and stirred at rt over night and filtered off to give pure title compound according to LCMS. 511 mg of off white solids were isolated, yield 27.4%.

Workup

  1. customsealed
  2. customThe solvent was evaporated
  3. dissolutionthe residue (616 mg crude brown oil) was dissolved in DMSO
  4. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm)
  5. custombuffer over 20 min
  6. customthe most of the ACN was evaporated
  7. customThe residue was partitioned between EtOAc and water
  8. concentrationThe combined organic phases were concentrated in vacuo
  9. additionAddition of DMSO/ACN and water a precipitate
  10. customThe solvents were removed in vacuo and water
  11. additionwas added to the residue
  12. stirringstirred at rt over night
  13. filtrationfiltered off

Sources & evidence

ORD record
ord-07baa38c66994e4184abdb2b4a73c697
Source dataset
uspto-grants-2016_07
Patent number
US09394291B2

Reaction notes

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