Reacción #44205

Ecuación de reacción

Thiosemicarbazide

Et3N

4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

EDCI

HOBt

PPh3

Et3N

CCl4

→

desired product

Rendimiento 33.0%

5-(5-Amino-[1,3,4]thiadiazol-2-yl)-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-one

Rendimiento 33.0%

Disolventes

NH4Cl

DMF

ethyl acetate

methylene chloride

MeCN

Condiciones de reacción

Tratamiento posterior

1. 1
   Extracciónextracted with ethyl acetate
2. 2
   SecadoThe combined organic extracts were dried (MgSO4)
3. 3
   Concentraciónconcentrated under reduced pressure
4. 4
   OtroPurification by flash column chromatography (5% to 10% MeOH in methylene chloride)
5. 5
   Otrogave 70 mg partially pure intermediate adduct
6. 6
   TemperaturaAfter cooling to room temperature
7. 7
   Lavadowashed with water
8. 8
   Secadodried (MgSO4)
9. 9
   Concentraciónconcentrated under reduced pressure
10. 10
    OtroPurification by flash column chromatography (twice) (4% MeOH in methylene chloride)

Procedimiento

A mixture of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (200 mg, 0.557 mmol), EDCI (214 mg, 1.11 mmol) and HOBt (151 mg, 1.11 mol) were stirred in DMF (10 mL) for 30 minutes. Thiosemicarbazide (51 mg, 0.562 mmol) and Et3N (0.116 mL, 1.5 mmol) were added. After 1 hour, the reaction mixture was diluted with saturated aqueous NH4Cl, and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (5% to 10% MeOH in methylene chloride) gave 70 mg partially pure intermediate adduct. PPh3 (78 mg, 0.30 mmol), Et3N (0.10 mL, 0.74 mmol), and CCl4 (0.029 mL, 0.30 mmol) were added to a stirred suspension of intermediate adduct (40 mg, 0.093 mmol) in 1:1 methylene chloride:MeCN (4 mL). The reaction mixture was heated to 50° C. for 5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (twice) (4% MeOH in methylene chloride) gave clean desired product (10 mg, 33%); MS APCI (+) m/z 414, 416 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 7.80 (s, 1H), 7.31 (dd, 1H), 7.25 (d, 1H), 7.02 (td, 1H), 3.64 (s, 3H).

Fuente