1,4-Dioxane hydrochloride → HCID 86723187, compound

HRID 1050306Notes

Reaction equation

HRID 1050306 reaction equation
[CH2:1]([N:8]([CH2:16][C@H:17]1[CH2:21][C@@H:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][N:18]1[C:30](OC(C)(C)C)=[O:31])[CH2:9][CH2:10]C(OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C[C@@H]1C[C@@H](OCC2C=CC=CC=2)CN1C(OC(C)(C)C)=O)CCC(OCC)=O)C1C=CC=CC=1.Cl.O1CCOCC1>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][C:30](=[O:31])[N:18]2[CH2:19][C@H:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:21][C@@H:17]2[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 204431481,4-Dioxane hydrochlorideHCID 86723188HCID 86723188, compoundHCID 86723189HCID 86723189, compound

Product 1

HCID 86723187HCID 86723187, compoundYield 35%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
22.5 °C

Procedure

To a 2:3 mixture of tert-butyl (2R,4R)-2-{[benzyl(3-ethoxy-3-oxopropyl)amino]methyl}-4-(benzyloxy)pyrrolidine-1-carboxylate and tert-butyl (2S,4R)-2-{[benzyl(3-ethoxy-3-oxopropyl)amino]methyl}-4-(benzyloxy)pyrrolidine-1-carboxylate (25 g, 0.050 mol, Part B) in methanol (125 mL) was added a solution of 4.0 M HCl/dioxane (125 mL) while maintaining the internal temperature below 5° C. The reaction mixture was allowed to stir at 20-25° C. for 22 hours and was then concentrated. The residue was stirred with toluene (250 mL) and 1 M sodium carbonate solution (250 mL). The organic layer was separated, washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and filtered. The toluene filtrate was heated to reflux at 115° C. for four hours and was then concentrated. The isomers were separated by silica gel column chromatography eluted with ethyl acetate/hexane (60:40) to give (8R,9aR)-2-benzyl-8-(benzyloxy)octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one (6.2 g, 35%) as dark brown oil. HPLC (column: Agilent ZORBAX® RX-C8, 150 mm×4.6 mm, 5 μm; gradient: 10-80% acetonitrile in 0.1% phosphoric acid/water over 13 minutes with a hold at 80% for an additional five minutes; flow rate: 1.0 mL/minute; temperature: 30° C.). Retention time for the titled isomer was 7.147 minutes and for the (8R,9aS) isomer, 6.704 minutes. 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.23 (m, 10 H), 4.62-4.47 (m, 2 H), 4.11-3.96 (m, 2 H), 3.83-3.75 (m, 1 H), 3.64-3.56 (m, 3 H), 3.02-2.74 (m, 3 H), 2.61-2.53 (m, 1 H), 2.47-2.36 (m, 3 H), 1.88-1.79 (m, 1 H).

Workup

  1. temperaturewhile maintaining the internal temperature below 5° C
  2. concentrationwas then concentrated
  3. stirringThe residue was stirred with toluene (250 mL) and 1 M sodium carbonate solution (250 mL)
  4. customThe organic layer was separated
  5. washwashed with water (100 mL) and brine (100 mL)
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. temperatureThe toluene filtrate was heated
  9. temperatureto reflux at 115° C. for four hours
  10. concentrationwas then concentrated
  11. customThe isomers were separated by silica gel column chromatography
  12. washeluted with ethyl acetate/hexane (60:40)

Sources & evidence

ORD record
ord-532e6009bad544069d0219dfd6fcde9e
Source dataset
uspto-grants-2016_07
Patent number
US09382258B2

Reaction notes

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