2-Amino-5-chloropyridine → HCID 57504701, compound

HRID 1098257Notes

Reaction equation

HRID 1098257 reaction equation
C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[OH:13][C@@H:14]([CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C:15](OC)=[O:16]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:15](=[O:16])[C@@H:14]([OH:13])[CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:26])[CH3:27])[CH:31]([CH3:32])[CH3:33])=[N:10][CH:11]=1

Participants

5

Reactant 3

HCID 661742-Amino-5-chloropyridineHCID 16682925TrimethylaluminumHCID 59279456HCID 59279456, compound

Product 1

HCID 57504701HCID 57504701, compoundYield 72.6%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (2M solution in toluene) (2.99 mL, 5.98 mmol) was added to a solution of 5-chloropyridin-2-amine (0.769 g, 5.98 mmol) in toluene (20 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 20 mins and then (S)-methyl 2-hydroxy-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (Intermediate AU5) (1 g, 2.99 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 (0.935 g, 72.6%). 1H NMR (400 MHz, CDCl3) δ 1.05-1.13 (24H, m), 3.62-3.67 (3H, m), 3.81-3.84 (1H, m), 4.02-4.06 (1H, m), 4.20 (1H, d), 4.31 (1H, q), 7.65-7.67 (1H, m), 8.22-8.25 (2H, m), 9.23 (1H, s); m/z (ES−) (M−H)−=429; HPLC tR=3.81 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-bb7943e0345f4067833b0e9b9b97f88b
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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