Hydrochloric Acid → HCID 178489059, compound

HRID 2174140Notes

Reaction equation

HRID 2174140 reaction equation
[C:1]([C:3]1[CH:39]=[CH:38][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH2:10][C:11]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]4[C:12]=3[CH:13]=[CH:14][N:15]4C(OC(C)(C)C)=O)=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(CC3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)N(COCC[Si](C)(C)C)C=2C=1)#N.[Li+].CC([N-]C(C)C)C.I[CH2:88][CH2:89][CH2:90][C:91]([O:93]C)=[O:92].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO.O>[C:1]([C:3]1[CH:39]=[CH:38][C:6]2[NH:7][C:8]([CH:10]([C:11]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]4[C:12]=3[CH:13]=[CH:14][NH:15]4)[CH2:88][CH2:89][CH2:90][C:91]([OH:93])=[O:92])=[N:9][C:5]=2[CH:4]=1)#[N:2]

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 547991Methyl 4-iodobutanoateHCID 2724682Lithium diisopropylamideHCID 86701791HCID 86701791, compoundHCID 86701792HCID 86701792, compound

Product 1

HCID 178489059HCID 178489059, compound

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
65 °C

Procedure

tert-Butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 145-A) (510 mg, 0.93 mmol) in THF (10 mL) was stirred at −78° C. and then LDA (2.0M in heptane/THF/ethylbenzene, 0.47 mL, 0.93 mmol) was added and the reaction was stirred for 10 minutes. At this point, methyl 4-iodobutanoate (0.5 mL, 3.7 mmol) was added and the dry ice bath was removed and the reaction was stirred for 2.5 hours at rt. The reaction was diluted with ethyl acetate (100 mL) and poured into saturated aq. solution of sodium chloride. The layers were separated and the organic layer was dried over Na2SO4, concentrated and absorbed onto silica to purify via FCC (0-20% EtOAc:hexanes). The resulting residue was deprotected of the SEM and Boc group using the conditions shown in Example 142-C. The resulting residue (170 mg, 0.408 mmol) was dissolved in MeOH (5 mL) and was added potassium carbonate (180 mg, 1.3 mmol), the reaction was heated at 65° C. overnight. The mixture was then poured into water (50 mL) and the pH was adjusted to −1 with 3 M HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate, dried over Na2SO4, and purified by reverse-phase FCC (0-50%) ACN:water to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.04-12.24 (m, 1H) 11.86-12.03 (m, 1H) 10.88 (s, 1H) 7.93-8.22 (m, 1H) 7.63-7.83 (m, 1H) 7.36-7.52 (m, 1H) 7.12 (t, J=2.81 Hz, 1H) 6.79 (s, 1H) 6.05 (br. s., 1H) 4.87 (dd, J=9.41, 5.62 Hz, 1H) 3.76 (s, 3H) 2.52-2.59 (m, 1H) 2.45 (s, 3H) 2.03-2.30 (m, 3H) 1.48-1.64 (m, 1H) 1.30-1.46 (m, 1H). HRMS calcd. for C23H22N4O3 (M+H)+ 403.1770. found 403.1758.

Workup

  1. customthe dry ice bath was removed
  2. stirringthe reaction was stirred for 2.5 hours at rt
  3. additionThe reaction was diluted with ethyl acetate (100 mL)
  4. additionpoured into saturated aq. solution of sodium chloride
  5. customThe layers were separated
  6. dry with materialthe organic layer was dried over Na2SO4
  7. concentrationconcentrated
  8. customabsorbed onto silica
  9. customto purify via FCC (0-20% EtOAc:hexanes)
  10. customThe layers were separated
  11. extractionthe aqueous layer was extracted with ethyl acetate
  12. dry with materialdried over Na2SO4
  13. custompurified by reverse-phase FCC (0-50%) ACN

Sources & evidence

ORD record
ord-0b82513fae6e43ba8a5851b0d62b03ba
Source dataset
uspto-grants-2015_06
Patent number
US09056874B2

Reaction notes

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