Glycine → 1H-1,4-Benzodiazepine-2,5-dione, 7-chloro-3,4-dihydro-1-methyl-

HRID 1930229Notes

Reaction equation

HRID 1930229 reaction equation
N#N.[NH2:3][CH2:4][C:5]([OH:7])=O.[Cl:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13](C)[C:14](=O)[O:15][C:16](=O)[C:11]=2[CH:10]=1.C([O-])(O)=O.[Na+].[OH-].[Na+]>CCOC(C)=O.CC(O)=O>[Cl:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13]([CH3:14])[C:5](=[O:7])[CH2:4][NH:3][C:16](=[O:15])[C:11]=2[CH:10]=1

Participants

8

Reactant 5

HCID 750GlycineHCID 947NitrogenHCID 14798Sodium HydroxideHCID 267242H-3,1-Benzoxazine-2,4(1H)-dione, 6-chloro-1-methyl-HCID 516892Sodium Bicarbonate

Product 1

HCID 6142081H-1,4-Benzodiazepine-2,5-dione, 7-chloro-3,4-dihydro-1-methyl-Yield 44%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
130 °C

Procedure

In a 2 L RBF equipped with mechanical stir, condenser and N2 inlet, glycine (38 g, 0.506 mol) was added to crude B1 (107 g, 0.506 mol) followed by the addition of AcOH (500 mL). Reaction flask was heated in a 130° C. oil bath for 7 h. Solvent was evaportated under suction with heating (50-60° C.). To the thick syrupy crude product was added 1 L of EtOAc followed by the slow addition of aqueous NaHCO3 (saturated) to adjust the pH to ˜7. Then 10 mL of 2 M NaOH was added to adjust the pH to ˜9-10. The mixture gave a solid along with organic and aqueous layers. The solid was filtered to give product containing some impurity. The solid was partitioned between 400 mL dichloromethane (DCM) and 200 mL NaHCO3, and the resultant slurry was stirred for 20 min, then filtered to remove an insoluble impurity. The DCM layer was separated and washed with 3% NaHCO3 and then brine (200 mL). The DCM layer was dried (MgSO4), filtered and concentrated to give 50 g of pure product. EtOAc layer was concentrated to give 67 g of solid product with some impurity. The aqueous layer was extracted with EtOAc (2×400 mL). Combined organics were dried over Na2SO4, filtered and concentrated to give an additional 6.7 g of crude product. Total of 123.4 g of product was obtained, 50 g of which was very clean (yield quantitative). 1H NMR (300 MHz, CDCl3) δ 3.2 (s, 3H), 3.5 (m, 1H), 3.8 (m, 1H), 7.35 (d, 1H), 7.6 (m, 2H), 8.8 (t, 1H).

Workup

  1. customReaction flask
  2. temperaturewith heating (50-60° C.)
  3. customThe mixture gave a solid along with organic and aqueous layers
  4. filtrationThe solid was filtered
  5. customto give product
  6. additioncontaining some impurity
  7. customThe solid was partitioned between 400 mL dichloromethane (DCM) and 200 mL NaHCO3
  8. filtrationfiltered
  9. customto remove an insoluble impurity
  10. customThe DCM layer was separated
  11. washwashed with 3% NaHCO3
  12. dry with materialThe DCM layer was dried (MgSO4)
  13. filtrationfiltered
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-82cc1e87849d48d8a08154adb3f57c22
Source dataset
uspto-grants-2012_05
Patent number
US08188072B2

Reaction notes

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