Reaction #742298

Reaction equation

Trimethylaluminium

5-methylpyrazin-2-amine

Rochelle salt

(S)-methyl 3-(3-(tert-butyldimethyl-silyloxy)azetidin-1-yl)-2-hydroxypropanoate

→

product

Yield 59.2%

(S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide

Yield 59.2%

Solvents

toluene

water

toluene

water

ethyl acetate

Conditions

Workup

1. 1
   Temperatureto warm to room temperature
2. 2
   Temperatureheated at 80° C. overnight
3. 3
   Temperatureto cool to room temperature
4. 4
   workup.STIRRINGto stir for 2 hours
5. 5
   OtherThe organic layer was separated
6. 6
   Extractionthe aqueous was extracted with ethyl acetate (75 mL)
7. 7
   WashThe combined organics were washed with brine (75 mL)
8. 8
   Dryingdried (MgSO4)
9. 9
   Filtrationfiltered
10. 10
    Otherevaporated
11. 11
    OtherThe crude product was purified by flash silica chromatography
12. 12
    Washeluting with 20 to 50% ethyl acetate in isohexane
13. 13
    OtherThis was further purified by flash silica chromatography
14. 14
    Washeluting with 0 to 10% methanol in dichloromethane

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.

Source