Lithium Hexamethyldisilazide → 3-(2-methoxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine

HRID 588131Notes

Reaction equation

HRID 588131 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.C[Si]([N-:39][Si](C)(C)C)(C)C.[Li+]>CC(OC)(C)C.COC1C=CC=C(OC)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH3:34][O:33][CH2:32][CH2:31][O:30][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH2:39])=[CH:3][C:4]=2[N:10]([C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:9]=1

Participants

4

Reactant 2

HCID 2733832Lithium HexamethyldisilazideHCID 1182724946-chloro-3-(2-methoxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine

Product 1

HCID 1182720223-(2-methoxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amineYield 90.1%

Reagents, catalysts & solvents 1

HCID 71311105SPhos PalladacycleCatalyst

Conditions

Temperature
60 °C

Procedure

6-chloro-3-(2-methoxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (500 mg, 1.064 mmol) and SPHOS Palladacycle (162 mg, 0.213 mmol) were mixed in a pressure release vial, degassed and backfilled with Nitrogen (3×), tetrahydrofuran (8 mL) was added, followed by the addition of lithium bis(trimethylsilyl)amide (1M) (2.128 mL, 2.128 mmol), the resultant mixture was degassed and backfilled with nitrogen (3×), and heated up to 60° C. for overnight. Hydrochloric acid 1M (2 mL) was added, and the mixture was stirred at room temperature for 2 h, the mixture was basified with aqueous sodium hydroxide (1M, ˜4 mL) to pH 9, and the mixture was extracted with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (saturated, lx 10 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc/isohexane=50%-100% to give 3-(2-methoxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (32B, 432 mg, 0.959 mmol, 90% yield) as a brown solid. MS: [M+H]+ m/z 451.

Workup

  1. customdegassed
  2. additionwas added
  3. customthe resultant mixture was degassed
  4. additionHydrochloric acid 1M (2 mL) was added
  5. extractionthe mixture was extracted with ethyl acetate (2×10 mL)
  6. washThe combined organic fractions were washed with brine (saturated, lx 10 mL)
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. customthe solvent was evaporated under reduced pressure
  10. customThe residue was purified by column chromatography on silica gel (40 g)
  11. washeluting with EtOAc/isohexane=50%-100%

Sources & evidence

ORD record
ord-37c1a62f69324536bffec54b403f93c2
Source dataset
uspto-grants-2016_01
Patent number
US09226922B2

Reaction notes

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