Sodium hydride → Methyl N-((6-chloro-4-hydroxy-2-oxo-1'-(tert-butoxycarbonyl)-spiro[naphthalene-1,4'-piperidin]-3-yl)carbonyl)glycinate

HRID 2078276Notes

Reaction equation

HRID 2078276 reaction equation
[H-].[Na+].C(=N/[OH:11])\C1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:32](OCC)=[O:33])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[C:15]([C:37]#[C:38][C:39](OCC)=[O:40])[CH:14]=1.Cl.[CH3:45][O:46][C:47](=[O:50])[CH2:48][NH2:49].CCN(C(C)C)C(C)C>O1CCOCC1.CN(C=O)C.CCOC(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[C:19]1([CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1)[C:32](=[O:33])[C:38]([C:39]([NH:49][CH2:48][C:47]([O:46][CH3:45])=[O:50])=[O:40])=[C:37]2[OH:11]

Participants

9

Reactant 5

HCID 24758Sodium hydrideHCID 81531DiisopropylethylamineHCID 122755Glycine methyl ester hydrochlorideHCID 5324611Benzaldehyde OximeHCID 67099573HCID 67099573, compound

Product 1

HCID 67099715Methyl N-((6-chloro-4-hydroxy-2-oxo-1'-(tert-butoxycarbonyl)-spiro[naphthalene-1,4'-piperidin]-3-yl)carbonyl)glycinate

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent2×HCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
23 °C

Procedure

A suspension of NaH (60% dispersion in mineral oil (17 mg, 423 μmol)) in dioxane (2.5 mL) was treated with a solution of (E)-benzaldehyde oxime (51 mg, 423 μmol) in DMF (1.5 mL). The reaction was stirred at 23° C. under nitrogen. After 30 minutes, the reaction was cooled to 0° C. and then a solution of 1-tert-butyl ethyl 4-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)piperidine-1,4-dicarboxylate (157 mg, 338 μmol) in DMF (3.5 mL) was added in a dropwise fashion over 10 minutes. After 1 hour, the reaction mixture was diluted with EtOAc (100 mL) and washed with saturated NaHCO3 solution (75 mL), water (75 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 1-8% MeOH/DCM), affording the cyclized product. The cyclized product was mixed with glycine methyl ester hydrochloride (28 mg, 220 μmol) and DIPEA (48 μL, 275 μmol) in 1,4-dioxane (4 mL) and heated to 95° C. in a sealed vessel. After 18 hours, the reaction was cooled to 23° C., diluted with EtOAc (75 mL) and washed with saturated NaHCO3 solution (50 mL) and brine (50 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 28-100% EtOAc/hexane) affording the title compound in 40 mg. MS m/e=501.2 (M+Na)+.

Workup

  1. temperaturethe reaction was cooled to 0° C.
  2. waitAfter 1 hour
  3. washwashed with saturated NaHCO3 solution (75 mL), water (75 mL) and brine (75 mL)
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated in vacuo
  6. custompurified by silica gel chromatography (eluant: 1-8% MeOH/DCM)
  7. customaffording the cyclized product
  8. temperatureheated to 95° C. in a sealed vessel
  9. waitAfter 18 hours
  10. temperaturethe reaction was cooled to 23° C.
  11. washwashed with saturated NaHCO3 solution (50 mL) and brine (50 mL)
  12. dry with materialdried over MgSO4
  13. concentrationconcentrated in vacuo
  14. custompurified by silica gel chromatography (eluant: 28-100% EtOAc/hexane)

Sources & evidence

ORD record
ord-e0d666aa455a44fe9f225ca3957bdfb9
Source dataset
uspto-grants-2011_04
Patent number
US07928139B2

Reaction notes

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