HCID 58266674, compound → HCID 44546492, compound

HRID 1888610Notes

Reaction equation

HRID 1888610 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]2[N:29]=[CH:28][C:27]3[N:26](COCC[Si](C)(C)C)[C:25]4[N:38]=[CH:39][C:40]([C:42]5[CH:43]=[N:44][N:45]([CH3:47])[CH:46]=5)=[CH:41][C:24]=4[C:23]=3[CH:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH3:47][N:45]1[CH:46]=[C:42]([C:40]2[CH:39]=[N:38][C:25]3[NH:26][C:27]4[CH:28]=[N:29][C:21]([C:16]5[CH:17]=[N:18][CH:19]=[CH:20][C:15]=5[O:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:22][C:23]=4[C:24]=3[CH:41]=2)[CH:43]=[N:44]1

Participants

3

Reactant 1

HCID 58266674HCID 58266674, compound

Product 1

HCID 44546492HCID 44546492, compoundYield 39.2%

Reagents, catalysts & solvents 1

HCID 2724141Tetrabutylammonium FluorideSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 4-{3-[3(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanylethoxy methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl]-pyridin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.15 mmol) in TBAF (1N in THF, 10 mL) was heated at 50° C. for 19 h. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo, to afford a residue which was purified by flash chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM). This resultant residue was dissolved in DCM (5 mL) and TFA (1 mL) and left to stir for 30 minutes. The mixture was diluted with DCM and water. The aqueous layer was separated, evaporated and the resultant residue was loaded onto an SCX-2 cartridge and washed with methanol and 2M ammonia in methanol. The combined basic fraction was purified by HPLC (C18 column, eluting with 5-60% MeCN in water (with 20 mM triethylamine) over 20 minutes) to afford the title compound as a white solid (25 mg, 39%). 1H NMR (MeOD, 400 MHz): 8.97 (s, 1H), 8.83-8.78 (m, 2H), 8.72 (s, 1H), 8.58 (s, 1H), 8.43 (d, J=5.9 Hz, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.28 (d, J=6.0 Hz, 1H), 4.91-4.80 (m, 1H), 3.98 (s, 3H), 3.01-2.91 (m, 2H), 2.80-2.70 (m, 2H), 2.11-2.00 (m, 2H), 1.83-1.73 (m, 2H) plus 2 exchangeables not observed. LCMS (Method A): RT=4.0 min, M+H+=426.

Workup

  1. customThe cooled reaction mixture
  2. customwas partitioned between water and ethyl acetate
  3. customThe organic layer was separated
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto afford a residue which
  8. customwas purified by flash chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM)
  9. dissolutionThis resultant residue was dissolved in DCM (5 mL)
  10. waitTFA (1 mL) and left
  11. additionThe mixture was diluted with DCM and water
  12. customThe aqueous layer was separated
  13. customevaporated
  14. washwashed with methanol and 2M ammonia in methanol
  15. customThe combined basic fraction was purified by HPLC (C18 column, eluting with 5-60% MeCN in water (with 20 mM triethylamine) over 20 minutes)

Sources & evidence

ORD record
ord-e40479f5ac924a448f86a695d2548dac
Source dataset
uspto-grants-2013_08
Patent number
US08501765B2

Reaction notes

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