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

HRID 1098244Notes

Reaction equation

HRID 1098244 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 58.5%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (2M in toluene) (6.21 mL, 12.42 mmol) was added to 6-aminonicotinonitrile (1.480 g, 12.42 mmol) in toluene (80 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes. (S)-Methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (2.5 g, 6.21 mmol) in toluene (20 mL) was added. The reaction was heated to 110° C. for 2 hours and cooled to RT. The reaction mixture was concentrated. The residue was neutralised with citric acid (1M, aq) and then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (1.780 g, 58.5%). 1H NMR (400 MHz, CDCl3) δ 1.04 (9H, s), 3.65-3.69 (3H, m), 3.81-3.91 (4H, m), 4.35 (1H, q), 7.35-7.45 (6H, m), 7.65-7.67 (4H, m), 7.92-7.95 (1H, m), 8.36-8.38 (1H, m), 8.55-8.56 (1H, m), 9.40 (1H, s); m/z (ES+) (M+H)+=490; HPLC tR=3.07 min.

Workup

  1. temperatureThe reaction was heated to 110° C. for 2 hours
  2. temperaturecooled to RT
  3. concentrationThe reaction mixture was concentrated
  4. additiondiluted with water
  5. extractionextracted with EtOAc
  6. dry with materialThe combined organics were dried (MgSO4)
  7. customevaporated
  8. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane

Sources & evidence

ORD record
ord-9729c56890b94594a9b4163ca032bc38
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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