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Potassium bis(trimethylsilyl)amide → tert-butyl {3-[(2-chloro-5-cyano-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}carbamate

HRID 577676
Notes
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Reaction equation

HRID 577676 reaction equation
[Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=2[N:7]=1.[OH:22][CH:23]1[CH2:26][CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:24]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:22][CH:23]2[CH2:24][CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:26]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=2[N:7]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 3251421Potassium bis(trimethylsilyl)amideHCID 22594430tert-Butyl (3-hydroxycyclobutyl)carbamateHCID 577494742,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

Product 1

HCID 86679622tert-butyl {3-[(2-chloro-5-cyano-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}carbamateYield 73.4%

Reagents, catalysts & solvents

1
HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (481 mg, 1.4 mmol) in THF (12 mL) was added a 1:1 cis:trans mixture of tert-butyl (3-hydroxycyclobutyl)carbamate (see Radchenko et al., Journal of Organic Chemistry, 75(17):5941-5952 (2010)) (288 mg, 1.54 mmol) and KHMDS (419 mg, 2.1 mmol). The reaction solution was stirred at rt for 1 hr. The reaction was quenched with brine (5 mL), then partitioned between EtOAc (120 mL) and water (30 mL). The organic layer was separated, washed with brine (20 mL), dried over Na2SO4 and evaporated to give a light yellow gum. The gum was purified using flash chromatography eluting with a gradient of 0%-40% EtOAc in heptanes. The product fractions were combined and evaporated to afford the title compound (508 mg, 73 yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (s, 1H) 7.27-7.52 (m, 1H) 5.63 (s, 2H) 5.04-5.60 (m, 1H) 3.73-4.32 (m, 1H) 3.53-3.69 (m, 2H) 2.88 (m, J=9.35, 6.91, 6.91, 3.02 Hz, 1H) 2.50-2.56 (m, 2H) 2.13-2.28 (m, 1H) 1.46 (d, J=4.78 Hz, 9H) 0.92 (t, J=8.06 Hz, 2H) 0.00 (d, J=1.51 Hz, 9H). m/z (APCI+) for C22H32ClN5O4Si 440.0 (M−tBu+H)+.

Workup

  1. customThe reaction was quenched with brine (5 mL)
  2. custompartitioned between EtOAc (120 mL) and water (30 mL)
  3. customThe organic layer was separated
  4. washwashed with brine (20 mL)
  5. dry with materialdried over Na2SO4
  6. customevaporated
  7. customto give a light yellow gum
  8. customThe gum was purified
  9. washeluting with a gradient of 0%-40% EtOAc in heptanes
  10. customevaporated

Sources & evidence

ORD record
ord-d995476ebe9441c78a7b220e5e9a8b51
Source dataset
uspto-grants-2015_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09040547B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes