2-Aminopyridine → (S)-2-hydroxy-N-(pyridin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide

HRID 1098231Notes

Reaction equation

HRID 1098231 reaction equation
C[Al](C)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[OH:12][C@@H:13]([CH2:18][O:19][C@H:20]([CH3:33])[CH2:21][O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[C:14](OC)=[O:15]>C1(C)C=CC=CC=1>[OH:12][C@@H:13]([CH2:18][O:19][C@H:20]([CH3:33])[CH2:21][O:22][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:25])[CH3:26])[C:14]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1)=[O:15]

Participants

5

Reactant 3

HCID 104392-AminopyridineHCID 16682925TrimethylaluminumHCID 59279456HCID 59279456, compound

Product 1

HCID 57504690(S)-2-hydroxy-N-(pyridin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamideYield 55.4%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (2M in toluene) (2.99 ml, 5.98 mmol) was added to pyridin-2-amine (0.563 g, 5.98 mmol) in toluene (20.18 ml) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-methyl 2-hydroxy-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (1 g, 2.99 mmol) (Intermediate AN1) in toluene (6.73 mL) was added and the reaction was allowed to warm to room temperature and then heated at reflux for 5 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organics were washed with brine (20 ml), then dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (0.657 g, 55.4%). 1H NMR (400 MHz, CDCl3) δ 1.03-1.17 (24H, m), 3.61-3.69 (3H, m), 3.82-3.86 (1H, m), 4.00-4.04 (1H, m), 4.13 (1H, d), 4.32 (1H, q), 7.02-7.06 (1H, m), 7.67-7.72 (1H, m), 8.23 (1H, d), 8.29-8.31 (1H, m), 9.20 (1H, s); m/z (ES+) (M+H)+=397.44; HPLC tR=3.36 min.

Workup

  1. temperatureto warm to room temperature
  2. temperatureheated
  3. temperatureat reflux for 5 hours
  4. temperatureto cool
  5. concentrationconcentrated in vacuo
  6. additiondiluted with water (25 mL)
  7. extractionextracted with EtOAc (2×50 mL)
  8. washThe combined organics were washed with brine (20 ml)
  9. dry with materialdried (MgSO4)
  10. customevaporated
  11. customThe crude product was purified by flash silica chromatography
  12. washeluting with 30 to 50% EtOAc in isohexane

Sources & evidence

ORD record
ord-f0dd1af98b034a8ba6bcdbc5607cb0e7
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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