Acetic Acid Mixture with Hydrobromic Acid → (S)-3-Amino-5-phenyl-1-(pyridin-2-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one

HRID 593479Notes

Reaction equation

HRID 593479 reaction equation
[O:1]=[C:2]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][CH:3]1[NH:25]C(=O)OCC1C=CC=CC=1.Br.CC(O)=O>CCOCC>[NH2:25][C@@H:3]1[C:2](=[O:1])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4]1

Participants

4

Reactant 2

HCID 21893785Acetic Acid Mixture with Hydrobromic AcidHCID 90082795benzyl 2-oxo-5-phenyl-1-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate

Product 1

HCID 90082697(S)-3-Amino-5-phenyl-1-(pyridin-2-yl)-1H-benzo[e][1,4]diazepin-2(3H)-oneYield 42.4%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Procedure

Intermediate 1A (5.24 g, 11.33 mmol) and 33% HBr/HOAc (50 mL, 11.33 mmol) were combined and stirred at room temperature for 2 h. The reaction mixture was diluted with 300 mL of ether. The resulting precipitate was collected by filtration, rinsed with ether (2×50 mL), then dried under vacuum. The solid was dissolved in 100 mL of water and made basic by the addition of solid NaHCO3. The mixture was extracted with EtOAc (2×200 mL), and the combined organic extracts were washed with water (1×40 mL) and brine (1×50 mL), then dried (MgSO4), filtered and concentrated in vacuo to give the crude racemic amine. This solid was purified by preparative SFC chromatography (Berger SFC MGII, AD-H 250×30 mm ID, 5 μm, 78/22 CO2/MeOH with 0.1% DEA, 85 mL/min). After the fractions containing product were concentrated and dried overnight under vacuum, Intermediate 1B (1.576 g, 42.4%) was obtained as a colorless solid: 1H NMR (400 MHz, DMSO-d6) δ 8.47 (1 H, dd, J=4.73, 1.65 Hz), 7.98 (1 H, td, J=7.70, 1.98 Hz), 7.62 (3 H, dd, J=14.75, 7.48 Hz), 7.45-7.57 (5 H, m), 7.26-7.43 (3 H, m), 6.92 (1 H, d, J=8.14 Hz), 4.57 (1 H, br. s.), 2.67 (1 H, br. s.); Chiral HPLC: RT=5.160 min (Berger SFC, AD-H 250×4.6 mm ID, 5 μm, 75/25 CO2/MeOH with 0.1% DEA, 2.0 mL/min); HPLC: RT=1.290 min (CHROMOLITH® ODS 4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 minutes containing 0.% TFA, 4 mL/min, monitoring at 220 nm); MS(ES): m/z=329.0 [M+H]+.

Workup

  1. filtrationThe resulting precipitate was collected by filtration
  2. washrinsed with ether (2×50 mL)
  3. customdried under vacuum
  4. dissolutionThe solid was dissolved in 100 mL of water
  5. additionmade basic by the addition of solid NaHCO3
  6. extractionThe mixture was extracted with EtOAc (2×200 mL)
  7. washthe combined organic extracts were washed with water (1×40 mL) and brine (1×50 mL)
  8. dry with materialdried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customto give the crude racemic amine
  12. customThis solid was purified by preparative SFC chromatography (Berger SFC MGII, AD-H 250×30 mm ID, 5 μm, 78/22 CO2/MeOH with 0.1% DEA, 85 mL/min)
  13. additionAfter the fractions containing product
  14. concentrationwere concentrated
  15. customdried overnight under vacuum

Sources & evidence

ORD record
ord-5504d876235d492a9f94c59cd5ea9d46
Source dataset
uspto-grants-2016_01
Patent number
US09242940B2

Reaction notes

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