Citric Acid → (S)-2-(tert-butyldimethylsilyloxy)-3-isopropoxy-N-(5-(methylthio)pyridin-2-yl)propanamide

HRID 1098197Notes

Reaction equation

HRID 1098197 reaction equation
C[Al](C)C.[CH3:5][S:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.[Si:14]([O:21][C@@H:22]([CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:23](OC)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.CCOC(C)=O>[Si:14]([O:21][C@@H:22]([CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([S:6][CH3:5])=[CH:12][N:11]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]

Participants

8

Reactant 4

HCID 311Citric AcidHCID 151797975-(Methylsulfanyl)pyridin-2-amineHCID 16682925TrimethylaluminumHCID 59279534(S)-methyl 2-(tert-butyldimethylsilyloxy)-3-isopropoxypropanoate

Product 1

HCID 57504670(S)-2-(tert-butyldimethylsilyloxy)-3-isopropoxy-N-(5-(methylthio)pyridin-2-yl)propanamideYield 56.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (2M in toluene) (10.40 mL, 20.80 mmol) was added to 5-(methylthio)pyridin-2-amine (CAS no. 77618-99-6) (2.54 g, 18.09 mmol) in toluene (100 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-methyl 2-(tert-butyldimethylsilyloxy)-3-isopropoxypropanoate (Intermediate C7b) (5 g, 18.09 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was allowed to stir at room temperature for 1 hour. The temperature was increased to 60° C. and stirred for a further 24 hours. The reaction mixture was neutralised with citric acid (1M, aq) and then diluted with water and EtOAc (200 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (100 mL). The combined organics were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% Et2O in isohexane to afford the product (3.95 g, 56.8%). 1H NMR (400 MHz, DMSO) δ 0.10-0.13 (6H, d), 0.90-0.92 (9H, m), 1.04-1.07 (6H, m), 2.40 (3H +DMSO, s), 3.54-3.63 (3H, m), 4.42-4.44 (1H, m), 7.77-7.80 (1H, dd), 8.03-8.06 (1H, d), 8.26 (1H, d), 9.49 (1H, s); m/z (ES+) (M+H)+=385; HPLC tR=3.66 min.

Workup

  1. temperatureto warm to room temperature
  2. stirringto stir at room temperature for 1 hour
  3. temperatureThe temperature was increased to 60° C.
  4. stirringstirred for a further 24 hours
  5. customThe organic layer was separated
  6. extractionthe aqueous layer re-extracted with EtOAc (100 mL)
  7. dry with materialThe combined organics were dried (MgSO4)
  8. filtrationfiltered
  9. customevaporated in vacuo
  10. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 50% Et2O in isohexane

Sources & evidence

ORD record
ord-95c246d54882428d9c1789548abb1259
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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