Diisopropylethylamine → Methyl 2-((s)-2-(benzyloxycarbonylamino)-3-methylbutanamido)-3-(7-bromo-1h-indol-3-yl)propanoate

HRID 494375Notes

Reaction equation

HRID 494375 reaction equation
Cl.[NH2:2][CH:3]([CH2:8][C:9]1[C:17]2[C:12](=[C:13]([Br:18])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:41]([NH:51][C@H:52]([C:56](O)=[O:57])[CH:53]([CH3:55])[CH3:54])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH2:44]([O:43][C:41]([NH:51][C@@H:52]([CH:53]([CH3:55])[CH3:54])[C:56]([NH:2][CH:3]([CH2:8][C:9]1[C:17]2[C:12](=[C:13]([Br:18])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5])=[O:57])=[O:42])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 726987N-Carbobenzoxy-L-valineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 688713437-Bromo-L-tryptophan Methyl Ester Hydrochloride

Product 1

HCID 59595036Methyl 2-((s)-2-(benzyloxycarbonylamino)-3-methylbutanamido)-3-(7-bromo-1h-indol-3-yl)propanoateYield 93.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

The title compound of Example 3 (256.6 g, 770 mmol), TBTU (296.4 g, 1.2 eq) and Cbz-L-valine (212.7 g, 1.1 eq) were dissolved in dimethylformamide (DMF, anhydrous, 2,700 mL) and cooled to 0° C. for 30 min. Diisopropylethylamine (DIEA, 268 mL) was added slowly and the solution was allowed to warm to room temperature. Stirring was continued for 4 hours at which time HPLC indicated completion of reaction. The reaction was diluted with ethyl acetate (11 L) and water (7.5 L). The mixture was stirred for 1 hour and allowed to separate. The organic layer was washed once with water (7.5 L), twice with brine (7.5 L) and twice with saturated NaHCO3 (7.5 L). The material was dried with sodium sulfate and concentrated to brown black solid. The material was taken up in methylene chloride (7.5 L) and combined with 22.2 g of another lot of similar quality material and silica gel (400 g). The solvent was removed to support the crude compound on silica. This material was divided in half and each half was chromatographed on a 6 in×4 ft silica gravity column. Each was eluted with methylene chloride (20 L) followed by 5% acetone in methylene chloride (20 L) followed by 8% acetone in methylene chloride (30 L) to give the title compound (383 g, 89% yield). 1H NMR (CDCl3): consistent with proposed structure.

Workup

  1. temperatureto warm to room temperature
  2. customcompletion of reaction
  3. stirringThe mixture was stirred for 1 hour
  4. customto separate
  5. washThe organic layer was washed once with water (7.5 L), twice with brine (7.5 L) and twice with saturated NaHCO3 (7.5 L)
  6. dry with materialThe material was dried with sodium sulfate
  7. concentrationconcentrated to brown black solid
  8. customThe solvent was removed
  9. customeach half was chromatographed on a 6 in×4 ft silica gravity column
  10. washEach was eluted with methylene chloride (20 L)

Sources & evidence

ORD record
ord-5545ebd323974020bb9f6e883b98b9e6
Source dataset
uspto-grants-2009_05
Patent number
US07538129B2

Reaction notes

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