Water → HCID 90037528, compound

HRID 1055390Notes

Reaction equation

HRID 1055390 reaction equation
CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.O.Cl.[NH2:37][CH:38]1[C:44]2([CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[O:43][C:42]2[CH:50]=[CH:51][CH:52]=[CH:53][C:41]=2[NH:40][C:39]1=[O:54].[N:55]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])([CH3:61])[C@H:56]([C:58](O)=[O:59])[CH3:57]>CN(C=O)C.[Cl-].[Na+].O>[CH3:61][N:55]([C@@H:56]([CH3:57])[C:58](=[O:59])[NH:37][C@H:38]1[C:44]2([CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)[O:43][C:42]2[CH:50]=[CH:51][CH:52]=[CH:53][C:41]=2[NH:40][C:39]1=[O:54])[C:62](=[O:63])[O:64][C:65]([CH3:68])([CH3:66])[CH3:67]

Participants

8

Reactant 5

HCID 962WaterHCID 757711-HydroxybenzotriazoleHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 7009590(2S)-2-(((tert-butoxy)carbonyl)(methyl)amino)propanoic acidHCID 90037196HCID 90037196, compound

Product 1

HCID 90037528HCID 90037528, compoundYield 37.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 57417360Sodium chloride; waterSolvent

Procedure

A solution of HBTU (43.2 g, 114 mmol, Eq: 1.2) and HOBT.H2O (17.4 g, 114 mmol, Eq: 1.2) in DMF (300 mL) was added to a mixture of 3-amino-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-4(5H)-one hydrochloride (27 g, 94.8 mmol, Eq: 1.00), BOC-N-Me-Ala-OH (23.1 g, 114 mmol, Eq: 1.2) and TEA (38.4 g, 52.9 mL, 379 mmol, Eq: 4) in DMF (300 mL). After 18 h the mixture was poured into brine (750 mL) and the mixture extracted with EtOAc. The combined extracts were washed with 1:1 sat NaHCO3/brine, brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography to afford a mixture of diastereomers (36.2 g) as a light yellow solid. The diastereomers were separated by supercritical fluid chromatography (SFC) using a Daicel AD column (5×25 cm) eluted with 15% MeOH/CO2 at 200 mL/min and 220 nM detection at 100 bar backpressure and 35° C. oven. The first diastereomer eluted from the column afforded the title compound (15.29 g, 37%) as an off-white foam. MS m/z 434.1 (MH+).

Workup

  1. extractionthe mixture extracted with EtOAc
  2. washThe combined extracts were washed with 1:1
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated
  5. customThe residue was purified by flash chromatography
  6. customto afford
  7. additiona mixture of diastereomers (36.2 g) as a light yellow solid
  8. customThe diastereomers were separated by supercritical fluid chromatography (SFC)
  9. washeluted with 15% MeOH/CO2 at 200 mL/min and 220 nM detection at 100 bar backpressure and 35° C. oven
  10. washThe first diastereomer eluted from the column

Sources & evidence

ORD record
ord-2e890cf1a2cf47b09f778ec3621267af
Source dataset
uspto-grants-2016_07
Patent number
US09394263B2

Reaction notes

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