Potassium Sodium Tartrate → (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-N-(5-fluoropyridin-2-yl)-2-hydroxypropanamide

HRID 1098255Notes

Reaction equation

HRID 1098255 reaction equation
C[Al](C)C.[F: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].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[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]([F:5])=[CH:11][N:10]=2)=[O:28])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]

Participants

7

Reactant 4

HCID 9357Potassium Sodium TartrateHCID 27377012-Amino-5-fluoropyridineHCID 16682925TrimethylaluminumHCID 57504648(S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate

Product 1

HCID 57504700(S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-N-(5-fluoropyridin-2-yl)-2-hydroxypropanamideYield 51.7%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (2M solution in toluene) (15.89 mL, 31.79 mmol) was added to 5-fluoropyridin-2-amine (3.10 g, 27.64 mmol) in toluene (80 mL) cooled to 0° C. under nitrogen over a period of 10 minutes. The resulting solution was stirred at 0° C. for 10 minutes. (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (8 g, 27.64 mmol) in toluene (20 mL) was added over 10 minutes and the reaction was allowed to warm to room temperature and then heated at 90° C. for 2 hours. The reaction mixture was cooled and poured into a 20% solution of Rochelle's salt (50 mL), diluted with ethyl acetate (200 mL) and stirred for 2 hours. The organic phase was separated, washed with water and brine, dried (MgSO4) filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 80 to 100% EtOAc in isohexane to afford the product (5.28 g, 51.7%). 1H NMR (400 MHz, CDCl3) δ 0.028 (3H, s), 0.033 (3H, s), 0.87 (9H, s), 2.90 (2H, d), 3.02-3.08 (2H, m), 3.68-3.74 (2H, m), 4.00 (1H, t), 4.41-4.48 (1H, m), 7.41-7.45 (1H, m), 8.15 (1H, d), 8.21-8.24 (1H, m), 9.85 (1H, s); m/z (ES+) (M+H)+=370; HPLC tR=1.97 min.

Workup

  1. temperatureto warm to room temperature
  2. temperatureheated at 90° C. for 2 hours
  3. temperatureThe reaction mixture was cooled
  4. stirringstirred for 2 hours
  5. customThe organic phase was separated
  6. washwashed with water and brine
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. customevaporated
  10. customThe crude product was purified by flash silica chromatography, elution gradient 80 to 100% EtOAc in isohexane

Sources & evidence

ORD record
ord-e52f56d2c5c7458db7eaf4813e9f3194
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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