Sodium Bicarbonate → (+/-)-3-(5-Cyanobenzo[d]oxazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)-2,2-dimethylpropanoic acid

HRID 2174141Notes

Reaction equation

HRID 2174141 reaction equation
[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11](O)[C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4C(OC(C)(C)C)=O)=[N:8][C:7]=2[CH:32]=1)#[N:2].C[O:34][C:35]([O:39][Si](C)(C)C)=[C:36]([CH3:38])[CH3:37].C([O-])(O)=O.[Na+]>C(Cl)Cl.O.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][NH:16]4)[C:36]([CH3:38])([CH3:37])[C:35]([OH:39])=[O:34])=[N:8][C:7]=2[CH:32]=1)#[N:2]

Participants

7

Reactant 3

HCID 516892Sodium BicarbonateHCID 552336Silane, ((1-methoxy-2-methyl-1-propenyl)oxy)trimethyl-HCID 86701709tert-Butyl-4-((5-cyanobenzo[d]oxazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

Product 1

HCID 86701793(+/-)-3-(5-Cyanobenzo[d]oxazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)-2,2-dimethylpropanoic acid

Reagents, catalysts & solvents 3

HCID 24193Titanium TetrachlorideCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of (±)-tert-butyl 4-((5-cyanobenzo[d]oxazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 125-A) (133 mg, 0.31 mmol) in DCM (10 mL) was treated with TiCl4 (1M in DCM, 1 mL, 1 mmol) at 0° C. The reaction mixture was stirred for 15 min, followed by the addition of ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (0.36 g, 2 mmol). The mixture was allowed to reach room temperature over 1 h. The reaction mixture was then poured into aqueous NaHCO3. The organic layer was extracted with ethyl acetate (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated to provide a residue. The resulting residue was suspended in water (5 mL) and was treated wtih Dowex ion exchange resin (200% w/w) (washed with water twice). The reaction was stirred at 120° C. overnight in a sealed tube. Reaction was cooled, filtered and directly subjected to purification by FCC1-5% (MeOH:DCM) to obtain the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.05 (br. s., 1H) 7.46-7.61 (m, 1H) 7.23 (t, J=2.78 Hz, 1H) 7.10 (d, J=8.34 Hz, 2H) 6.69 (s, 1H) 6.31-6.51 (m, 1H) 4.19 (s, 1H) 3.72 (s, 3H) 2.45 (s, 3H) 1.60 (s, 3H) 0.93 (s, 3H). HMRS calcd. for C23H21N3O4 (M+H)+ 404.1602. found 404.1595.

Workup

  1. waitto reach room temperature over 1 h
  2. extractionThe organic layer was extracted with ethyl acetate (2×50 mL)
  3. dry with materialthe combined organic layers were dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto provide a residue
  7. additionwas treated wtih Dowex ion exchange resin (200% w/w) (
  8. washwashed with water twice)
  9. stirringThe reaction was stirred at 120° C. overnight in a sealed tube
  10. customReaction
  11. temperaturewas cooled
  12. filtrationfiltered
  13. customdirectly subjected to purification by FCC1-5% (MeOH:DCM)

Sources & evidence

ORD record
ord-7aadc31ca7ba450994807d19283f2845
Source dataset
uspto-grants-2015_06
Patent number
US09056874B2

Reaction notes

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