2-Amino-5-chloropyridine → (2S)-3-[3-(tert-butyl-dimethylsilyl)oxyazetidin-1-yl]-N-(5-chloropyridin-2-yl)-2-hydroxypropanamide

HRID 1098172Notes

Reaction equation

HRID 1098172 reaction equation
C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH:21]1[CH2:24][N:23]([CH2:25][C@H:26]([OH:31])[C:27](OC)=[O:28])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[Si:13]([O:20][CH:21]1[CH2:24][N:23]([CH2:25][C@H:26]([OH:31])[C:27]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=2)=[O:28])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]

Participants

5

Reactant 3

HCID 661742-Amino-5-chloropyridineHCID 16682925TrimethylaluminumHCID 57504648(S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate

Product 1

HCID 57504646(2S)-3-[3-(tert-butyl-dimethylsilyl)oxyazetidin-1-yl]-N-(5-chloropyridin-2-yl)-2-hydroxypropanamideYield 65%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (5.75 mL, 11.50 mmol) was added to 5-chloropyridin-2-amine (1.285 g, 10.00 mmol) in toluene (50 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes, (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (2.894 g, 10.00 mmol) in toluene (20 mL) was added, the reaction allowed to warm to room temperature and then heated at 80° C. for 4 hours. The reaction mixture was cooled, concentrated in vacuo and the residue neutralised with 1M citric acid (30 mL), diluted with water (25 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried (MgSO4) and evaporated to afford crude product which was purified by flash silica chromatography with EtOAc as eluent to afford the product (2.5 g, 65%). 1H NMR (400 MHz, DMSO) δ 0.01 (6H, s), 0.84 (9H, m), 2.65-2.70 (2H, m), 2.76-2.83 (2H, m), 3.56-3.59 (2H, m), 4.07-4.10 (1, m), 4.28-4.34 (1H, m), 5.78 (1H, s), 7.92 (1H, dd), 8.12 (1H, dd), 8.36-8.37 (1H, m), 9.87 (1H, s); m/z (ESI+) (M+H)+=386; HPLC tR=1.64 min.

Workup

  1. temperatureto warm to room temperature
  2. temperatureheated at 80° C. for 4 hours
  3. temperatureThe reaction mixture was cooled
  4. concentrationconcentrated in vacuo
  5. additiondiluted with water (25 mL)
  6. extractionextracted with EtOAc (2×30 mL)
  7. dry with materialThe combined organic extracts were dried (MgSO4)
  8. customevaporated
  9. customto afford crude product which
  10. customwas purified by flash silica chromatography with EtOAc as eluent

Sources & evidence

ORD record
ord-65062b00fc5348ad852d759bed4d85dc
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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