Ammonium Chloride → (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid

HRID 625895Notes

Reaction equation

HRID 625895 reaction equation
[NH2:1][C@@H:2]([C@H:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].O=C1CCC(=O)N1[C:36]([O:38][CH2:39][CH:40]1[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37].[Cl-].[NH4+]>O.C1COCC1>[CH:51]1[C:52]2[CH:40]([CH2:39][O:38][C:36]([NH:1][C@@H:2]([C@H:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH:9]=3)[CH3:7])[C:3]([OH:5])=[O:4])=[O:37])[C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:47]=2[CH:48]=[CH:49][CH:50]=1

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 516892Sodium BicarbonateHCID 108817731-Pyrrolidinecarboxylic acid, 2,5-dioxo-, 9H-fluoren-9-ylmethyl esterHCID 15547324(2S,3S)-2-amino-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid

Product 1

HCID 11307239(2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

(2S,3S)-2-amino-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid (2197 mg, 6.9 mmol) was dissolved in a mixture of Water (35 mL) and THF (100 mL). Sodium bicarbonate (2174 mg, 25.9 mmol) and (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidine-1-carboxylate (4434 mg, 13.80 mmol) were added to the solution and the reaction was stirred for 16 h. Saturated ammonium chloride solution (200 mL) was added to the reaction and the solvent was then removed under vacuum. The remaining aqueous layer was extracted with EtOAc. The organic layer was then collected, dried over sodium sulfate, and concentrated under vacuum. The crude material was purified by rev. phase BIOTAGE® C-18 column using a gradient of 20-80% ACN/water with 0.1% TFA modifier over 20 min. The product fractions were collected, diluted with water and extracted with EtOAc. The organic layer washed with water, then brine, dried over sodium sulfate, and concentrated under vacuum to give (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid, 500 mg (13%). ESI-MS(+) m/z 541.5 (M+H). 1H NMR (500 MHz, DMSO-d6) δ 12.79 (br. s., 1H), 8.03 (d, J=8.2 Hz, 1H), 7.90-7.85 (m, 2H), 7.73 (dd, J=8.1, 4.7 Hz, 2H), 7.62 (d, J=7.4 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.53 (s, 1H), 7.39 (td, J=7.4, 4.0 Hz, 2H), 7.35-7.30 (m, 1H), 7.28-7.18 (m, 3H), 4.45 (t, J=8.2 Hz, 1H), 4.30-4.25 (m, 1H), 4.21-4.15 (m, 1H), 4.15-4.09 (m, 1H), 3.48 (quin, J=7.2 Hz, 1H), 1.57 (s, 9H), 1.34 (d, J=7.3 Hz, 3H).

Workup

  1. customthe solvent was then removed under vacuum
  2. extractionThe remaining aqueous layer was extracted with EtOAc
  3. customThe organic layer was then collected
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated under vacuum
  6. customThe crude material was purified by rev
  7. customover 20 min
  8. customThe product fractions were collected
  9. additiondiluted with water
  10. extractionextracted with EtOAc
  11. washThe organic layer washed with water
  12. dry with materialbrine, dried over sodium sulfate
  13. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-19cbe932aada4005a0c35db64487a8f2
Source dataset
uspto-grants-2016_04
Patent number
US09308236B2

Reaction notes

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