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Hydrochloric Acid → {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile

HRID 1617376
Notes
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Reaction equation

HRID 1617376 reaction equation
[F:1][C:2]1[C:3]([C:19]2[CH:20]=[N:21][N:22]([C:24]3([CH2:28][C:29]#[N:30])[CH2:27][NH:26][CH2:25]3)[CH:23]=2)=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.O=[C:32]1[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.O1CCOCC1>C1COCC1>[F:1][C:2]1[C:3]([C:19]2[CH:20]=[N:21][N:22]([C:24]3([CH2:28][C:29]#[N:30])[CH2:27][N:26]([CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[CH2:25]3)[CH:23]=2)=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[C:5]2=[N:6][CH:7]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 5049666Sodium triacetoxyborohydrideHCID 86657619{3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile

Product 1

HCID 67421534{3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a mixture of {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile.2[HCl] (3.10 g, 5.78 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (1.152 g, 5.784 mmol) and N,N-diisopropylethylamine (3.022 mL, 17.35 mmol) in THF (100.0 mL) was added sodium triacetoxyborohydride (2.452 g, 11.57 mmol). The mixture was stirred at room temperature for 2 hours and quenched with brine. The resulting solution was extracted with EtOAc (2 times). The combined extracts were washed with water, brine and dried over Na2SO4. After filtration and evaporation, the residue was purified by flash chromatography on silica gel eluting with 50-100% EtOAc/hexanes. The purified intermediate ([M+H]+=610.3) was dissolved in THF (50 mL). To the solution at 10° C. was added a 4.0 M solution of hydrogen chloride in 1,4-dioxane (50.0 mL, 200 mmol). The mixture was stirred at room temperature for 2 hours and concentrated to give 3.57 g of {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile.3[HCl] as an off-white solid. LC/MS found: 510.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6), δ 9.41 (s, 1H), 8.81 (s, 1H), 8.72 (s, 1H), 8.35 (d, 1H), 8.32 (s, 1H), 7.85 (d, 1H), 7.00 (d, 1H), 5.63 (s, 2H), 4.93 (d, 2H), 4.55 (d, 2H), 3.78-3.60 (m, 1H), 3.55 (s, 2H), 3.51 (t, 2H), 3.47-3.37 (m, 2H), 2.79 (m, 2H), 2.11 (m, 2H), 1.80 (m, 2H), 0.81 (t, 2H), −0.12 (s, 9H).

Workup

  1. customquenched with brine
  2. extractionThe resulting solution was extracted with EtOAc (2 times)
  3. washThe combined extracts were washed with water, brine
  4. dry with materialdried over Na2SO4
  5. filtrationAfter filtration and evaporation
  6. customthe residue was purified by flash chromatography on silica gel eluting with 50-100% EtOAc/hexanes
  7. dissolutionThe purified intermediate ([M+H]+=610.3) was dissolved in THF (50 mL)
  8. stirringThe mixture was stirred at room temperature for 2 hours
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-1cb6076d79e44a5ca817e8fdeba59985
Source dataset
uspto-grants-2014_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08765734B2

Reaction notes

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