1,4-Dioxane → HCID 178502295, compound

HRID 535121Notes

Reaction equation

HRID 535121 reaction equation
[CH3:1][O:2][C:3](=[O:60])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33](=O)[CH2:34][NH:35][C:36]([CH:38]4[CH2:42][C:41]5(CCOCC5)[CH2:40][N:39]4[C:48](=[O:58])[C@@H:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])=O)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:65].[O:66]1[CH2:71][CH2:70]O[CH2:68][CH2:67]1>C(OCC)(=O)C>[CH3:52][CH:50]([CH3:51])[C@H:49]([NH:53][C:54](=[O:55])[O:56][CH3:57])[C:48]([N:39]1[CH2:40][CH2:41][CH2:42][C@H:38]1[C:36]1[NH:35][CH:34]=[C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:19]4[N:20]=[C:16]([CH:12]5[CH2:13][C:14]6([CH2:70][CH2:71][O:66][CH2:67][CH2:68]6)[CH2:15][N:11]5[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:60])[CH:6]([CH3:7])[CH3:8])[NH:17][CH:18]=4)=[CH:26][CH:25]=3)=[CH:28][CH:29]=2)[N:65]=1)=[O:58]

Participants

5

Reactant 3

HCID 312751,4-DioxaneHCID 517165Ammonium AcetateHCID 178502296HCID 178502296, compound2×

Product 1

HCID 178502295HCID 178502295, compoundYield 34%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

A solution of methyl((1S)-2-methyl-1-{[(2S)-2-(4-{4′-[({[2-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-8-oxa-2-azaspiro[4.5]dec-3-yl]carbonyl}amino)acetyl]-4-biphenylyl}-1H-imidazol-2-yl)-1-pyrrolidinyl]carbonyl}propyl)carbamate (Intermediate 104) (131 mg, 0.16 mmol) and ammonium acetate (122 mg, 1.6 mmol) in dioxane (2 mL) was degassed and heated to 110° C. in a sealed tube for 18 h. The reaction was cooled to room temperature and diluted with ethyl acetate and filtered and concentrated in vacuo. The residue was purified by C18 RP chromatography eluting with 10-90% water/acetonitrile/0.2% NH4OH, to afford an off-white solid (44 mg, 34% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.55-7.87 (m, 8H) 7.32 (br. s., 4H) 5.02-5.23 (m, 3H) 4.13-4.34 (m, 4H) 3.93-4.04 (m, 1H) 3.88 (br. s., 2H) 3.49-3.84 (m, 8H) 1.86-2.54 (m, 10H) 1.45-1.84 (m, 4H) 0.69-1.12 (m, 12H). HRMS for C44H57N8O7 (M+H)+ calc: 809.4350. found: 809.4346. Purity (LC-MS): 96%.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. filtrationfiltered
  3. concentrationconcentrated in vacuo
  4. customThe residue was purified by C18 RP chromatography
  5. washeluting with 10-90% water/acetonitrile/0.2% NH4OH

Sources & evidence

ORD record
ord-735bd067546549ce8b3ede18dab51b82
Source dataset
uspto-grants-2014_10
Patent number
US08853416B2

Reaction notes

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