Réaction #44205

Équation de réaction

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

Rendement 33.0%

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

Rendement 33.0%

Solvants

NH4Cl

DMF

ethyl acetate

methylene chloride

MeCN

Conditions de réaction

Traitement

1. 1
   Extractionextracted with ethyl acetate
2. 2
   SéchageThe combined organic extracts were dried (MgSO4)
3. 3
   Concentrationconcentrated under reduced pressure
4. 4
   AutrePurification by flash column chromatography (5% to 10% MeOH in methylene chloride)
5. 5
   Autregave 70 mg partially pure intermediate adduct
6. 6
   TempératureAfter cooling to room temperature
7. 7
   Lavagewashed with water
8. 8
   Séchagedried (MgSO4)
9. 9
   Concentrationconcentrated under reduced pressure
10. 10
    AutrePurification by flash column chromatography (twice) (4% MeOH in methylene chloride)

Mode opératoire

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).

Source