Water → Acetoacetic Acid

HRID 241216Notes

Reaction equation

HRID 241216 reaction equation
[CH3:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:31]([N:33]=[C:34]=S)[CH3:32].[OH2:36].Cl.CN(C)CCCN=C=NCC.[CH2:49]1[CH2:53][O:52][CH2:51][CH2:50]1>C(#N)C.C(OCC)(=O)C>[CH2:31]([NH:33][C:34]1[NH:30][C:25]2[CH:24]=[C:23]([C:20]3[CH:21]=[CH:22][C:16]4[O:15][CH2:14][CH2:13][N:12]([C:10]5[C:9]6[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=6)[N:3]=[C:2]([CH3:1])[N:11]=5)[CH2:18][C:17]=4[CH:19]=3)[CH:28]=[CH:27][C:26]=2[N:29]=1)[CH3:32].[CH3:53][C:49]([CH2:50][C:51]([OH:15])=[O:52])=[O:36]

Participants

9

Reactant 5

HCID 962Water2×HCID 8028TetrahydrofuranHCID 10966Ethyl isothiocyanateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 668203334-[4-(2-Methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]benzene-1,2-diamine

Product 2

HCID 96Acetoacetic AcidYield 29%HCID 59586149N-ethyl-6-[4-(2-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1H-benzimidazol-2-amine

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 4-[4-(2-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]benzene-1,2-diamine (333 mg, 0.84 mmol) in THF (5 mL) at 0° C. was added ethyl isothiocyanate (74 uL, 0.84 mmol). After stirring for 2 h at 0° C., the reaction mixture was warmed to rt for 1 h and was then heated to 45° C. for 4 h. The mixture was then cooled back to rt and allowed to stir for 3 d. Addition of water was followed by extraction into ethyl acetate. The organic phase was then dried over magnesium sulfate, filtered, and concentrated. The residue obtained was then dissolved in acetonitrile (5 mL) and ethyl acetate (2 mL). To this solution was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (161 mg, 0.84 mmol). The mixture was heated to reflux for 1.5 h and was then cooled to rt. Water and ethyl acetate were then added. The biphasic mixture was filtered to remove solid materials, and the filtrate was then partitioned. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and then concentrated. The residue was purified by reverse-phase preparative HPLC to provide N-ethyl-6-[4-(2-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1H-benzimidazol-2-amine as a diacetate salt (137 mg, 0.24 mmol, 29% yield). 1H NMR (400 MHz, dmso) δ 8.01 (d, 1H), 7.79-7.72 (m, 1H), 7.72-7.67 (m, 1H), 7.60 (d, 1H), 7.47-7.39 (m, 2H), 7.35 (s, 1H), 7.20-7.11 (m, 2H), 6.99 (d, 1H), 6.72 (br s, 1H), 5.02 (s, 2H), 4.47-4.38 (m, 2H), 4.22-4.13 (m, 2H), 3.37-3.27 (m, 2H), 2.48 (s, 3H), 1.89 (s, 7H), 1.18 (t, 3H); MS (EI) for C27H26N6O: 451 (MH+).

Workup

  1. temperaturethe reaction mixture was warmed to rt for 1 h
  2. temperaturewas then heated to 45° C. for 4 h
  3. temperatureThe mixture was then cooled back to rt
  4. stirringto stir for 3 d
  5. extractionwas followed by extraction into ethyl acetate
  6. dry with materialThe organic phase was then dried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue obtained
  10. temperatureThe mixture was heated
  11. temperatureto reflux for 1.5 h
  12. temperaturewas then cooled to rt
  13. filtrationThe biphasic mixture was filtered
  14. customto remove solid materials
  15. customthe filtrate was then partitioned
  16. extractionThe aqueous phase was extracted with ethyl acetate
  17. dry with materialThe combined organic extracts were dried over magnesium sulfate
  18. filtrationfiltered
  19. concentrationconcentrated
  20. customThe residue was purified by reverse-phase preparative HPLC

Sources & evidence

ORD record
ord-0eea6c22188a4d428567a083732a78cf
Source dataset
uspto-grants-2014_02
Patent number
US08648066B2

Reaction notes

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