Pyridine → HCID 117872741, compound

HRID 1477157Notes

Reaction equation

HRID 1477157 reaction equation
N1C(F)=NC(F)=NC=1F.[C:10]([O:14][C:15]([N:17]([CH3:30])[C@@H:18]([CH3:29])[C:19]([NH:21][C@@H:22]([CH:26]([CH3:28])[CH3:27])[C:23]([OH:25])=O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][C@H:38]1[C:46]([O:48][CH2:49][CH3:50])=[O:47].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl>[CH2:49]([O:48][C:46]([C@@H:38]1[CH2:39][C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:37]1[C:23](=[O:25])[C@@H:22]([NH:21][C:19](=[O:20])[C@@H:18]([N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[CH3:30])[CH3:29])[CH:26]([CH3:28])[CH3:27])=[O:47])[CH3:50]

Participants

7

Reactant 5

HCID 1049PyridineHCID 12664Cyanuric fluorideHCID 685102,6-Di-tert-butylpyridineHCID 11030625(S)-Indoline-2-carboxylic acid ethyl esterHCID 86702355HCID 86702355, compound

Product 1

HCID 117872741HCID 117872741, compoundYield 51.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
23 °C

Procedure

Cyanuric fluoride (3.25 g, 2.08 mL, 24.1 mmol) was added to a solution of (S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyric acid (5.4 g, 17.9 mmol) and pyridine (1.95 mL, 24.1 mmol) in CH2Cl2 (100 mL). The reaction mixture was stirred at 23° C. for 2.5 h. The resulting precipitate was filtered off and the mother liquor was concentrated. The residue was dissolved in EtOAc (250 mL), and the solution was washed with saturated NaHCO3, 0.5 M citric acid and brine. The organic layer was dried over Na2SO4, filtered, concentrated and dried under vacuum. The resulting yellow oil was taken up in CH2Cl2 (35 mL) and cooled in a dry ice-MeOH bath. To this solution was added a solution of (S)-ethyl indoline-2-carboxylate (2.3 g, 12.0 mmol) and 2,6-di-tert-butylpyridine (4.6 g, 5.31 mL, 24.1 mmol) in 25 mL of CH2Cl2. The resulting mixture was stirred at rt overnight. The crude material was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexanes) to give (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (2.93 g), m/z=476 (M+H).

Workup

  1. filtrationThe resulting precipitate was filtered off
  2. concentrationthe mother liquor was concentrated
  3. dissolutionThe residue was dissolved in EtOAc (250 mL)
  4. washthe solution was washed with saturated NaHCO3, 0.5 M citric acid and brine
  5. dry with materialThe organic layer was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customdried under vacuum
  9. temperaturecooled in a dry ice-MeOH bath
  10. stirringThe resulting mixture was stirred at rt overnight
  11. customThe crude material was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexanes)

Sources & evidence

ORD record
ord-7fef70c8536f443b91a5a30b048d060b
Source dataset
uspto-grants-2016_08
Patent number
US09403768B2

Reaction notes

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