Reaction #1531818

Reaction equation

LiOH

HCl

methyl 2-bromo-1-{2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl}-3-cyclohexyl1H-indole-6-carboxylate

2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

K3PO4

dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine

→

3-[2-(2-aminophenyl)-3-cyclohexyl-6-(methoxycarbonyl)-1H-indol-1-yl]-N-(tert-butoxycarbonyl)alanine

Solvents

nBuOH H2O

Conditions

Workup

1. 1
   TemperatureAfter cooling to RT
2. 2
   Extractionextracted (twice) with EtOAc
3. 3
   WashThe combined organics were washed with brine
4. 4
   Dryingdried over Na2SO4
5. 5
   Filtrationbefore being filtered
6. 6
   Concentrationconcentrated in vacuo
7. 7
   workup.DISSOLUTIONThe crude product mixture was redissolved in THF:H2O (1:1, 0.08 M)
8. 8
   OtherThe volatiles were removed in vacuo
9. 9
   Otherthe residue partitioned between EtOAc and H2O
10. 10
    WashThe organics were washed with brine
11. 11
    Dryingdried over Na2SO4
12. 12
    Filtrationbefore being filtered
13. 13
    Concentrationconcentrated in vacuo

Procedure

To a solution of methyl 2-bromo-1-{2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl}-3-cyclohexyl1H-indole-6-carboxylate in nBuOH:H2O (9:1, 0.08 M) were added 1.5 eq of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, 6 eq of K3PO4, 5 mol % of dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine and 2.5 mol % of palladium acetate. The mixture was heated at 90° C. for 4 h. After cooling to RT, the mixture was acidified with HCl (IN) and extracted (twice) with EtOAc. The combined organics were washed with brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude product mixture was redissolved in THF:H2O (1:1, 0.08 M) and 2 eq LiOH added. After stirring for 1 h, ester deprotection was complete as evidenced by RP-HPLC analysis. The volatiles were removed in vacuo and the residue partitioned between EtOAc and H2O. The organics were washed with brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude residue was used directly in the next step; MS (ES+) m/z 536 (M+H)+, 558 (M+Na)+.

Source