Potassium Sodium Tartrate → (S)-3-(3-(tert-butyldimethylsilyl-oxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide

HRID 655116Notes

Reaction equation

HRID 655116 reaction equation
C[Al](C)C.[CH3:5][C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[C:13]([Si:17]([CH3:31])([CH3:30])[O:18][CH:19]1[CH2:22][N:21]([CH2:23][C@H:24]([OH:29])[C:25](OC)=[O:26])[CH2:20]1)([CH3:16])([CH3:15])[CH3:14].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Si:17]([O:18][CH:19]1[CH2:22][N:21]([CH2:23][C@H:24]([OH:29])[C:25]([NH:12][C:9]2[CH:8]=[N:7][C:6]([CH3:5])=[CH:11][N:10]=2)=[O:26])[CH2:20]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:31])[CH3:30]

Participants

8

Reactant 4

HCID 9357Potassium Sodium TartrateHCID 3132155-Methylpyrazin-2-amineHCID 16682925TrimethylaluminumHCID 57504648(S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate

Product 1

HCID 57504705(S)-3-(3-(tert-butyldimethylsilyl-oxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamideYield 59.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (6.22 mL, 12.44 mmol) was added to 5-methylpyrazin-2-amine (1.357 g, 12.44 mmol) in anhydrous toluene (20 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. (S)-methyl 3-(3-(tert-butyldimethyl-silyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (2 g, 6.91 mmol) in anhydrous toluene (10 mL) was added and the resulting solution was allowed to warm to room temperature and then heated at 80° C. overnight. The reaction was allowed to cool to room temperature and a solution of Rochelle salt in water (20%, 75 ml) was added. The mixture diluted with water (25 mL) and ethyl acetate (75 mL) and allowed to stir for 2 hours. The organic layer was separated and the aqueous was extracted with ethyl acetate (75 mL). The combined organics were washed with brine (75 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 20 to 50% ethyl acetate in isohexane. This was further purified by flash silica chromatography, eluting with 0 to 10% methanol in dichloromethane, to afford the product (1.50 g, 59.2%). 1H NMR (400 MHz, CDCl3) δ 0.03 (3H, d), 0.04 (3H, s), 0.87 (9H, q), 2.54 (3H, s), 2.93 (2H, d), 3.09 (2H, q), 3.71-3.77 (2H, m), 4.04 (1H, t), 4.46 (1H, t), 8.13 (1H, d), 9.39 (1H, d), 9.81 (1H, s); m/z (ES+) (M+H)+=367.34; HPLC tR=1.76 min.

Workup

  1. temperatureto warm to room temperature
  2. temperatureheated at 80° C. overnight
  3. temperatureto cool to room temperature
  4. stirringto stir for 2 hours
  5. customThe organic layer was separated
  6. extractionthe aqueous was extracted with ethyl acetate (75 mL)
  7. washThe combined organics were washed with brine (75 mL)
  8. dry with materialdried (MgSO4)
  9. filtrationfiltered
  10. customevaporated
  11. customThe crude product was purified by flash silica chromatography
  12. washeluting with 20 to 50% ethyl acetate in isohexane
  13. customThis was further purified by flash silica chromatography
  14. washeluting with 0 to 10% methanol in dichloromethane

Sources & evidence

ORD record
ord-2a961c3ea08944c1b8444fde543c17cf
Source dataset
uspto-grants-2011_12
Patent number
US08071585B2

Reaction notes

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