Sodium hydride → (+/-)-[3-((4-Methylbenzoyl)-{1-[3-(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl]propyl}-amino)-propyl]-carbamic acid tert-butyl ester

HRID 1795940Notes

Reaction equation

HRID 1795940 reaction equation
C[O:2][C:3](=O)[CH2:4][N:5]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][N:8]2[N:7]=[C:6]1[CH:15]([N:18]([CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH2:16][CH3:17].O[NH:41][C:42](=[NH:44])[CH3:43].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:35]([O:34][C:32](=[O:33])[NH:31][CH2:30][CH2:29][CH2:28][N:18]([C:19](=[O:27])[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[CH:15]([C:6]1[N:5]([CH2:4][C:3]2[O:2][N:44]=[C:42]([CH3:43])[N:41]=2)[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][N:8]2[N:7]=1)[CH2:16][CH3:17])([CH3:37])([CH3:38])[CH3:36]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 69591790(+/-)-(2-{1-[(3-tert-Butoxycarbonylaminopropyl)-(4-methylbenzoyl)-amino]-propyl}-4-oxo-4H-pyrrolo[2,1-f][1,2,4]triazin-3-yl)-acetic acid methyl esterHCID 178465666HCID 178465666, compound

Product 1

HCID 69591854(+/-)-[3-((4-Methylbenzoyl)-{1-[3-(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl]propyl}-amino)-propyl]-carbamic acid tert-butyl esterYield 18%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a mixture of (±)-(2-{1-[(3-tert-butoxycarbonylaminopropyl)-(4-methylbenzoyl) amino]propyl}-4-oxo-4H-pyrrolo[2,1-f][1,2,4]triazin-3-yl)acetic acid methyl ester (Example 7 A, 26 mg, 0.05 mmol) and N-hydroxyacetamidine (Tyger Scientific, 6 mg, 0.08 mmol) in DMF (1 mL), under Ar, was treated with sodium hydride (6.5 mg as 60% dispersion in mineral oil, 0.15 mmol) and stirred at ambient temperature overnight before being diluted with ethyl acetate. The organic layer was washed twice with water and once with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude product was purified by preparative HPLC (YMC S5 ODS, 20×250 mm, 30 minute gradient from 66–90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined, neutralized with saturated aqueous sodium bicarbonate, and then concentrated in vacuo to remove methanol. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed once each with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield the title compound (5 mg, 18%): 1H NMR (CDCl3) δ 7.45 (m, 1H), 7.21–7.08 (m, 4H), 7.07 (m, 1H), 6.59 (m, 1H), 5.97 (m, 1H), 5.83 (m, 1H), 5.47 (m, 1H), 3.92 (m, 1H), 3.36 (m, 2H), 2.74 (m, 2H), 2.38 (s, 3H), 2.34 (s, 3H), 2.30–1.98 (m, 2H), 1.74–0.80 (m, 14H); MS (ESI+) 564.20 (M++H).

Workup

  1. washThe organic layer was washed twice with water and once with brine
  2. dry with materialdried over anhydrous magnesium sulfate
  3. concentrationconcentrated in vacuo
  4. customThe crude product was purified by preparative HPLC (YMC S5 ODS, 20×250 mm, 30 minute gradient from 66–90% aqueous methanol with 0.1% TFA)
  5. concentrationconcentrated in vacuo
  6. customto remove methanol
  7. extractionThe mixture was extracted with ethyl acetate (3×10 mL)
  8. washThe combined organic layers were washed once each with water and brine
  9. dry with materialdried over anhydrous magnesium sulfate
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-a281f885bcbd40a482b75bc7b92b1b55
Source dataset
uspto-grants-2006_04
Patent number
US07030118B2

Reaction notes

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