Reacción #330776

Ecuación de reacción

triethylamine

product

tert-butyl 2-hydroxyethyl[(2-methyl-1,3-thiazol-4-yl)methyl]carbamate

oxalyl chloride

(L)-valine methyl ester

sodium acetate trihydrate

NaCNBH3

DMSO

→

Methyl (2S)-3-methyl-2-[(2-{[(2-methyl-1,3-thiazol-4-yl)methyl]amino}ethyl)amino]butanoate

Disolventes

dichloromethane

methanol water

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.STIRRINGstirred for 15 min
2. 2
   OtroThe mixture was quenched with 20% KH2PO4
3. 3
   Otropartitioned between dichloromethane and water
4. 4
   LavadoThe organic layer was washed with brine
5. 5
   Secadodried over Na2SO4
6. 6
   Filtraciónfiltered
7. 7
   Otrothe solvents were evaporated
8. 8
   workup.ADDITIONwas added portionwise over 30 min
9. 9
   workup.STIRRINGAfter stirring for 1 hour the mixture
10. 10
    Otrowas partitioned between saturated NaHCO3
11. 11
    Extracciónextracted with ethyl acetate (2×)
12. 12
    LavadoThe combined organic layer was washed with brine
13. 13
    Secadodried with Na2SO4
14. 14
    Otroevaporated
15. 15
    workup.ADDITIONThe residue was treated with dichloromethane/trifluoacetic acid (10 mL, 1:1)
16. 16
    workup.STIRRINGstirred at 25° C. for 2 hrs
17. 17
    Concentraciónconcentrated

Procedimiento

A solution of the product of Example 143B (2.26 g) in dichloromethane (20 mL) was treated with oxalyl chloride (5.4 mL, 1.5 equivalents) at −78° C., and stirred for 15 min. DMSO (1.02 mL, 2 equivalents) was added dropwise at −78° C., stirred for 15 min, and quenched with triethylamine (4 mL, 4 equivalents) as the mixture warmed to 0° C. The mixture was quenched with 20% KH2PO4, and partitioned between dichloromethane and water. The organic layer was washed with brine, dried over Na2SO4, filtered, and the solvents were evaporated. To this crude product was added methanol/water (7:2), (L)-valine methyl ester (1.21 g, 1 equivalent), sodium acetate trihydrate (1.96 g, 2 equivalents), and NaCNBH3 (0.95 g, 2 equivalents) was added portionwise over 30 min. After stirring for 1 hour the mixture was partitioned between saturated NaHCO3 and extracted with ethyl acetate (2×). The combined organic layer was washed with brine, dried with Na2SO4, and evaporated. The residue was treated with dichloromethane/trifluoacetic acid (10 mL, 1:1) and stirred at 25° C. for 2 hrs and concentrated.

Fuente