Reacción #2039739

Ecuación de reacción

HBTU

HOBt

2-thiophenecarboxylic acid

triethylamine

(S)-3-tert-Butoxycarbonylamino-2-[(4-methyl-2-{2-[1-(tetrahydro-pyran-2-yl)-1H-indazol-4-yl]-acetylamino}-thiazole-5-carbonyl)-amino]-propionic acid methyl ester

dioxane

→

(S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester

Rendimiento 42.9%

Disolventes

Methanol

HCl

Condiciones de reacción

Tratamiento posterior

1. 1
   ConcentraciónThe reaction solution was concentrated under reduced pressure
2. 2
   workup.ADDITIONadded ether (2×)
3. 3
   Concentraciónwith concentrating under reduced pressure
4. 4
   workup.DISSOLUTIONTo the resulting white solid dissolved in anhydrous DMF (3 mL)
5. 5
   workup.STIRRINGto stir at 25° C. for 1 h
6. 6
   Concentraciónconcentrated under reduced pressure
7. 7
   Otroto remove most of the DMF
8. 8
   workup.ADDITIONEthyl acetate (80 mL) was added
9. 9
   Lavadowashed with 3/1 water/brine (20 mL), aqueous 1N HCl (20 mL), brine (20 mL)
10. 10
    Secadodried over MgSO4
11. 11
    Filtraciónfiltered
12. 12
    Concentraciónconcentrated under reduced pressure
13. 13
    OtroThe resulting crude compound was purified by flash chromatography (50% to 100% EtOAc in hexanes)

Procedimiento

A solution of (S)-3-tert-Butoxycarbonylamino-2-[(4-methyl-2-{2-[1-(tetrahydro-pyran-2-yl)-1H-indazol-4-yl]-acetylamino}-thiazole-5-carbonyl)-amino]-propionic acid methyl ester (96.1 mg, 0.160 mmol) in 4M HCl in dioxane (4 mL, 16 mmol) was stirred at room temp for 40 min. Methanol (0.5 mL) was added to the gummy precipitate and the resulting solution was stirred at room temp for 5½ h. The reaction solution was concentrated under reduced pressure, added ether (2×) with concentrating under reduced pressure. To the resulting white solid dissolved in anhydrous DMF (3 mL) was added HBTU (91 mg, 0.240 mmol), HOBt (32 mg, 0.237 mmol), 2-thiophenecarboxylic acid (26 mg, 0.203 mmol) and triethylamine (0.12 mL, 0.861 mmol). The solution was allowed to stir at 25° C. for 1 h and concentrated under reduced pressure to remove most of the DMF. Ethyl acetate (80 mL) was added, washed with 3/1 water/brine (20 mL), aqueous 1N HCl (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (50% to 100% EtOAc in hexanes) to give (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (36.1 mg, 42.9%) as a white solid. MS m/e 527.6 (M+H+).

Fuente