1,2-Dichloroethane → Tert-butyl 3-{[4-((2rs)-2-{[5-chloro-1-(3,5-dichlorophenyl)-1h-indol-2-yl]carbonyl}pentyl)benzoyl]amino}propanoate

Temperature

110 °C

To a vial containing the title compound of Example 3 Step D (100 mg, 0.26 mmol), were added 3,5-dichloro iodobenzene (0.045 mL, 0.31 mmol), copper iodide (2.5 mg, 0.012 mmol), potassium phosphate (116 mg, 0.55 mmol), and 1,2-trans-N,N-dimethylcyclohexane diamine (0.0082 mL, 0.05 mmol). The reaction mixture was placed under a nitrogen atmosphere, and anhydrous toluene (0.300 mL, deoxygenated via nitrogen sparge), was added. The vial was then capped and placed in a pre-heated oil bath (110° C.) and stirred rapidly for 20 h. The mixture was allowed to cool to room temperature, then was filtered through a silica gel plug, eluting with EtOAc. The filtrate was concentrated in vacuo: LCMS B, tr=3.10 min, m/z 528.1 [M+H]+. The crude adduct was dissolved in 1,4-dioxane (1.5 mL). 2 N aq. LiOH (1.3 mL, 2.6 mmol) was added, and the resultant mixture was stirred at 50° C. for 1 h. The mixture was allowed to cool to room temperature whereupon it was quenched by the addition of 2 N aq. HCl. The aqueous phase was extracted with EtOAc, and the organic phase was dried over Na2SO4 and concentrated in vacuo. To the crude carboxylic acid obtained above were added EDC (150 mg, 0.78 mmol), HOBt (105 mg, 0.78 mmol), and beta-alanine tert-butyl ester hydrochloride (141 mg, 0.78 mmol). The resultant mixture was dissolved in DMF (2 mL), DIEA (0.275 mL, 1.56 mmol) was added, and the reaction mixture was stirred at 50° C. for 18 h. The reaction mixture was quenched by addition of sat. aq. NH4Cl, and the aqueous phase was extracted with EtOAc. The organic phase was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 70%, then 70 to 100% EtOAc in hexanes) provided the title compound: LCMS B, tr=3.01 min, m/z 663.1 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J=2.0 Hz, 1H), 7.66 (s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.46 (t, J=7.0 Hz, 1H), 7.27-7.21 (m, 4H), 6.96 (d, J=8.0 Hz, 2H), 8.87 (t, J=5.5 Hz, 1H), 3.65 (q, J=6.0 Hz, 2H), 3.64-3.59 (m, 1 H), 3.04 (dd, J=14.0, 9.0 Hz, 1H), 2.83 (dd, J=14.0, 5.5 Hz, 1H), 2.52 (t, J=6.0 Hz, 1H), 1.80-1.73 (m, 1H), 1.59-1.52 (m, 1H), 1.44 (s, 9H), 1.41-1.33 (m, 2H), 0.92 (t, J=7.0 Hz, 3H).

1. customThe vial was then capped
2. customplaced in a pre-heated oil bath
3. temperatureto cool to room temperature
4. filtrationwas filtered through a silica gel plug
5. washeluting with EtOAc
6. concentrationThe filtrate was concentrated in vacuo
7. customLCMS B, tr=3.10 min, m/z 528.1 [M+H]+
8. dissolutionThe crude adduct was dissolved in 1,4-dioxane (1.5 mL)
9. temperatureto cool to room temperature whereupon it
10. customwas quenched by the addition of 2 N aq. HCl
11. extractionThe aqueous phase was extracted with EtOAc
12. dry with materialthe organic phase was dried over Na2SO4
13. concentrationconcentrated in vacuo
14. customTo the crude carboxylic acid obtained
15. stirringthe reaction mixture was stirred at 50° C. for 18 h
16. customThe reaction mixture was quenched by addition of sat. aq. NH4Cl
17. extractionthe aqueous phase was extracted with EtOAc
18. concentrationThe organic phase was concentrated in vacuo
19. customPurification by flash chromatography on silica gel (0 to 70%

ORD record

ord-7ebe4ee8eacc4243b2574a6c57948306

Source dataset

uspto-grants-2009_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07598398B2