1,2-Dichloroethane → Methyl 2-((s)-1-((s)-2-(benzyloxycarbonylamino)-3-(4-hydroxyphenyl)propanamido)-2-methylpropyl)-5-(7-bromo-1h-indol-3-yl)oxazole-4-carboxylate

HRID 1689736Notes

Reaction equation

HRID 1689736 reaction equation
Br.[NH2:2][C@H:3]([C:7]1[O:8][C:9]([C:16]2[C:24]3[C:19](=[C:20]([Br:25])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:11]=1)[CH:4]([CH3:6])[CH3:5].C1C=CC2N(O)N=NC=2C=1.[NH:36]([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])[C@H:37]([C:46](O)=[O:47])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1.C(N(CC)C(C)C)(C)C.C(Cl)CCl>CCOC(C)=O.CN(C=O)C>[CH2:52]([O:51][C:49]([NH:36][C@@H:37]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[C:46]([NH:2][C@H:3]([C:7]1[O:8][C:9]([C:16]2[C:24]3[C:19](=[C:20]([Br:25])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:11]=1)[CH:4]([CH3:6])[CH3:5])=[O:47])=[O:50])[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 712438N-benzyloxycarbonyl-l-tyrosineHCID 66889567methyl 2-((S)-1-amino-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylate hydrobromide

Product 1

HCID 59595033Methyl 2-((s)-1-((s)-2-(benzyloxycarbonylamino)-3-(4-hydroxyphenyl)propanamido)-2-methylpropyl)-5-(7-bromo-1h-indol-3-yl)oxazole-4-carboxylateYield 87%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

DMF (100 mL) was added to methyl 2-((S)-1-amino-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylate hydrobromide (9.16 g, 19.4 mmol), HOBt (3.17 g, 23.5 mmol), and Cbz-Tyr-OH (6.44 g, 20.4 mmol) in a round-bottom flask. N,N-Diisopropylethylamine (4.22 mL, 3.13 g, 129 mmol) was added, followed by EDC (4.15 g, 21.6 mmol). After stirring for 24 h at 25° C., the solution was diluted with EtOAc (500 mL) and the mixture was washed with 1 N aqueous HCl (250 mL), saturated aqueous NaHCO3 (250 mL), and saturated aqueous NaCl (250 mL). The solution was dried (Na2SO4), decanted, and evaporated to give a tan solid. This material was dissolved in 2-PrOH (180 mL) at 90° C. Hexanes (85 mL) were added and the solution was allowed to cool to RT. After standing overnight, the mixture was cooled to 5° C. for 4 h. The solid was separated by filtration and washed with 1:1 2-PrOH/hexanes (140 mL). This material, which at this point held residual solvent, was dried on a vacuum manifold to give methyl 2-((S)-1-((S)-2-(benzyloxycarbonylamino)-3-(4-hydroxyphenyl)propanamido)-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylate (11.58 g, 87% yield). 1H NMR (300 MHz, DMSO-d6): consistent with proposed structure. MS: m/z=689.0 (M+1).

Workup

  1. washthe mixture was washed with 1 N aqueous HCl (250 mL), saturated aqueous NaHCO3 (250 mL), and saturated aqueous NaCl (250 mL)
  2. dry with materialThe solution was dried (Na2SO4)
  3. customdecanted
  4. customevaporated
  5. customto give a tan solid
  6. temperatureto cool to RT
  7. waitAfter standing overnight
  8. temperaturethe mixture was cooled to 5° C. for 4 h
  9. customThe solid was separated by filtration
  10. washwashed with 1:1 2-PrOH/hexanes (140 mL)
  11. customwas dried on a vacuum manifold

Sources & evidence

ORD record
ord-4733ce0f06304abc95bbb8d42fd2022f
Source dataset
uspto-grants-2012_04
Patent number
US08153619B2

Reaction notes

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