Reaction #47230

Reaction equation

(S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid

oxalyl chloride

5-amino-3-methyl-1,2,4-thiadiazole

2,6-lutidine

→

(S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-N-(3-methyl-[1,2,4]thiadiazol-5-yl)-propionamide

Solvents

dichloromethane

methylene chloride

Conditions

Workup

1. 1
   ConcentrationThe reaction mixture was concentrated
2. 2
   workup.DISSOLUTIONdissolved in N,N-dimethylformamide (2 mL)
3. 3
   workup.STIRRINGThe reaction mixture was stirred at 25° C., under nitrogen for 18 h
4. 4
   Washwashed with 2N aqueous hydrochloric acid, saturated sodium chloride solution
5. 5
   Otherdried
6. 6
   ConcentrationThe organic layer was concentrated
7. 7
   Otherthe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 4 g; 0% to 35% methanol/dichloromethane)

Procedure

A solution of (S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (prepared as in Example 1, 102 mg, 0.40 mmol) in dichloromethane (2 mL) was treated with oxalyl chloride (218 μL of 2M solution in dichloromethane), and N,N-dimethylformamide (1 drop). Effervescence was observed. The reaction mixture was stirred for 0.5 h at 25° C., under nitrogen. The reaction mixture was concentrated, and dissolved in N,N-dimethylformamide (2 mL) and treated with 5-amino-3-methyl-1,2,4-thiadiazole (48 mg, 0.41 mmol), and 2,6-lutidine (64 mg, 0.60 mmol). The reaction mixture was stirred at 25° C., under nitrogen for 18 h. The reaction mixture was diluted with methylene chloride, washed with 2N aqueous hydrochloric acid, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 4 g; 0% to 35% methanol/dichloromethane) to afford ((S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-N-(3-methyl-[1,2,4]thiadiazol-5-yl)-propionamide (30 mg, 22% as a white powder: LR-ES-MS m/z calculated for C16H22N4O3S [M]+ 350, observed [M+H]+ 351; 1H NMR (300 MHz, CDCl3) δ ppm 0.74-0.96 (m, 1H) 1.03-1.42 (m, 3H) 1.38-2.15 (m, 7H) 2.53 (s, 3H) 3.83 (s, 3H) 3.98 (d, J=17.8 Hz, 1H) 4.13 (d, J=17.8 Hz, 1H) 5.24 (t, J=7.7 Hz, 1H) 5.38 (s, 1H).

Source