2-Amino-5-methylpyridine → (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide

HRID 1098176Notes

Reaction equation

HRID 1098176 reaction equation
C[Al](C)C.[CH3:5][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]([CH3:5])=[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 153482-Amino-5-methylpyridineHCID 16682925TrimethylaluminumHCID 57504648(S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate

Product 1

HCID 57504650(S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamideYield 76.2%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (2M in toluene) (0.993 mL, 1.99 mmol) was added to 5-methylpyridin-2-amine (205 mg, 1.90 mmol) in toluene (10 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) (500 mg, 1.73 mmol) in toluene (4 mL) was added and the reaction was allowed to warm to room temperature and then heated at 80° C. for 4 hours. The reaction mixture was concentrated in vacuo. 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 to afford the product (482 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 0.05 (6H, s), 0.88 (9H, s), 2.30 (3H, s), 3.15-3.23 (1H, m), 3.37-3.51 (3H, m), 4.15-4.30 (2H, m), 4.32-4.39 (1H, m), 4.58-4.66 (1H, m), 7.48-7.53 (1H, m), 8.04 (1H, d), 8.12-8.15 (1H, m), 9.46 (1H, s); m/z (ES+) (M+H)+=366.53; HPLC tR=1.50 min.

Workup

  1. temperatureto warm to room temperature
  2. temperatureheated at 80° C. for 4 hours
  3. concentrationThe reaction mixture was concentrated in vacuo
  4. additiondiluted with water
  5. extractionextracted with EtOAc
  6. dry with materialThe combined organics were dried (MgSO4)
  7. customevaporated

Sources & evidence

ORD record
ord-1f2f365c6408466993c617b183a619b2
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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