Potassium tert-butoxide → 8-Chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one

HRID 2353966Notes

Reaction equation

HRID 2353966 reaction equation
COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=O.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]2[C:15](=[O:17])[CH2:14][CH2:13][CH2:12][NH:11][C:5]=2[CH:6]=1

Participants

4

Reactant 2

HCID 23665647Potassium tert-butoxideHCID 68679427HCID 68679427, compound

Product 1

HCID 104881008-Chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-oneYield 65%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
85 °C

Procedure

Add a mixture of crude 2-[tert-Butoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-4-chloro-benzoic acid methyl ester (141.5 g, ˜0.337 mol) in toluene to potassium t-butoxide (95%, 100 g, 0.847 mol) in anhydrous toluene (4.5 L) at 60° C. over 1 h. After heating of 24 h concentrate the mixture under vacuum. Partition the residue between ethyl acetate (1.5 L) and saturated KH2PO4 (1.5 L). Separate the aqueous layer and extract with ethyl acetate (2×0.5 L). Combine the organics and wash with water (2×0.5 L). Remove solvent under vacuum. Dissolve the residue in acetic acid (250 mL) and dilute with 5N HCl (1 L). After heating at 85° C. for 4 h, cool the mixture to room temperature. Basify (pH=10) with 5N sodium hydroxide (ca. 1.8 L) while cooling in an ice bath. Extract the organics with ethyl acetate (3×0.5 L) and wash with brine (0.75 L). Dry over sodium sulfate, filter and concentrate under vacuum. Pass the beige crude product through a pad of silica (8 cmD×3 cmH), eluting with DCM/hexanes (2/1, ca. 3.5 L). Concentrate the crude product under vacuum to give a yellow solid. Recrystallize from EtOAc/hexanes (1/4) to give the title compound (42.85 g, 65%) as an off white solid: H NMR (CDCl3, 300 MHz) δ 4.20 (m, 2H), 4.85 (t, J=4.2 Hz, 2H), 5.29 (t, J=4.2 Hz, 2H), 6.71 (bs, 1H), 8.79-8.82 (m, 2H), 9.68 (d, J=5.1 Hz, 1H).

Workup

  1. additionAdd
  2. temperatureAfter heating of 24 h
  3. concentrationconcentrate the mixture under vacuum
  4. customPartition the residue between ethyl acetate (1.5 L) and saturated KH2PO4 (1.5 L)
  5. customSeparate the aqueous layer
  6. extractionextract with ethyl acetate (2×0.5 L)
  7. washCombine the organics and wash with water (2×0.5 L)
  8. dissolutionDissolve the residue in acetic acid (250 mL)
  9. additiondilute with 5N HCl (1 L)
  10. temperaturecool the mixture to room temperature
  11. temperatureBasify (pH=10) with 5N sodium hydroxide (ca. 1.8 L) while cooling in an ice bath
  12. extractionExtract the organics with ethyl acetate (3×0.5 L)
  13. washwash with brine (0.75 L)
  14. dry with materialDry over sodium sulfate
  15. filtrationfilter
  16. concentrationconcentrate under vacuum
  17. washPass the beige crude product through a pad of silica (8 cmD×3 cmH), eluting with DCM/hexanes (2/1, ca. 3.5 L)
  18. concentrationConcentrate the crude product under vacuum
  19. customto give a yellow solid
  20. customRecrystallize from EtOAc/hexanes (1/4)

Sources & evidence

ORD record
ord-b97c17da41dc40149faa1352e412b30e
Source dataset
uspto-grants-2010_07
Patent number
US07749992B2

Reaction notes

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