Pyridine → HCID 117873136, compound

HRID 1477160Notes

Reaction equation

HRID 1477160 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1F.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@H:35]1[C:43]([O:45][CH2:46][CH3:47])=[O:44].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl>[CH2:46]([O:45][C:43]([C@@H:35]1[CH2:36][C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:34]1[C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:44])[CH3:47]

Participants

7

Reactant 5

HCID 1049PyridineHCID 12664Cyanuric fluorideHCID 685102,6-Di-tert-butylpyridineHCID 11010409(2S)-2-(((tert-butoxy)carbonyl)amino)-2-phenylacetic acidHCID 11030625(S)-Indoline-2-carboxylic acid ethyl ester

Product 1

HCID 117873136HCID 117873136, compoundYield 62.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
23 °C

Procedure

To a solution of (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (5.26 g, 20.9 mmol, Eq: 2) and pyridine (2.8 mL, 34.5 mmol, Eq: 3.3) in DCM (60 mL), cyanuric fluoride (4.66 g, 2.99 mL, 34.5 mmol, Eq: 3.3) was added. The reaction mixture was stirred at 23° C. for 2 h. The resulting precipitate was filtered off and the mother liquor was concentrated in vacuo. The residue was taken up in EtOAc, and washed with saturated aqueous NaHCO3, 0.5 M aqueous citric acid and brine, and concentrated in vacuo. The light brown oil was taken up in DCM (20 mL) and cooled in an ice bath. To this acid fluoride solution was added a solution of (S)-ethyl indoline-2-carboxylate (2 g, 10.5 mmol, Eq: 1) and 2,6-di-tert-butylpyridine (4.00 g, 4.62 mL, 20.9 mmol, Eq: 2) in DCM (20 mL). The resulting mixture was stirred at rt overnight. The reaction was concentrated in vacuo and the crude material was purified by flash chromatography (silica gel, 5% to 20% EtOAc in hexanes) to give (S)-1-((S)-2-tert-butoxycarbonylamino-2-phenyl-acetyl)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (2.78 g) as a light yellow foam, m/z=425 (M+H).

Workup

  1. filtrationThe resulting precipitate was filtered off
  2. concentrationthe mother liquor was concentrated in vacuo
  3. washwashed with saturated aqueous NaHCO3, 0.5 M aqueous citric acid and brine
  4. concentrationconcentrated in vacuo
  5. temperaturecooled in an ice bath
  6. stirringThe resulting mixture was stirred at rt overnight
  7. concentrationThe reaction was concentrated in vacuo
  8. customthe crude material was purified by flash chromatography (silica gel, 5% to 20% EtOAc in hexanes)

Sources & evidence

ORD record
ord-acc07c843ec541e581383cd10c03ee13
Source dataset
uspto-grants-2016_08
Patent number
US09403768B2

Reaction notes

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