2-Amino-5-cyanopyridine → (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-cyanopyridin-2-yl)-2-hydroxypropanamide

HRID 1098206Notes

Reaction equation

HRID 1098206 reaction equation
C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([OH:41])[C:37](OC)=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([OH:41])[C:37]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)=[O:38])([C:27]([CH3:30])([CH3:28])[CH3:29])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1

Participants

5

Reactant 3

HCID 8182602-Amino-5-cyanopyridineHCID 16682925TrimethylaluminumHCID 59279512(S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate

Product 1

HCID 57504676(S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-cyanopyridin-2-yl)-2-hydroxypropanamideYield 66.5%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (2M in toluene) (0.621 mL, 1.24 mmol) was added to a solution of 6-aminonicotinonitrile (148 mg, 1.24 mmol) in toluene (10 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 20 mins and then (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (250 mg, 0.62 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 4 hours. The reaction mixture was allowed to cool to room temperature and the concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water and DCM (50 mL). The organic layer was separated and the aqueous layer re-extracted with DCM (30 mL). The combined organics were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (202 mg, 66.4%). 1H NMR (400 MHz, CDCl3) 1.04 (9H, s), 3.65-3.67 (2H, m), 3.81-3.91 (4H, m), 4.36 (1H, t), 7.35-7.45 (6H, m), 7.65-7.67 (4H, m), 7.92-7.95 (1H, m), 8.36-8.39 (1H, m), 8.54-8.56 (1H m), 9.43 (1H, s); m/z (ES+) (M+H)+=490; HPLC tR=3.08 min.

Workup

  1. temperatureto warm to room temperature
  2. temperatureheated
  3. temperatureat reflux under nitrogen for 4 hours
  4. temperatureto cool to room temperature
  5. concentrationthe concentrated in vacuo
  6. additiondiluted with water and DCM (50 mL)
  7. customThe organic layer was separated
  8. extractionthe aqueous layer re-extracted with DCM (30 mL)
  9. dry with materialThe combined organics were dried (MgSO4)
  10. filtrationfiltered
  11. customevaporated in vacuo
  12. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane

Sources & evidence

ORD record
ord-17df19ad2bdf4b04b4add0e63f3add45
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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