Reacción #1755489

Ecuación de reacción

glutaric anhydride

(R)-6-(4-chlorophenyl)-3-(4-(2-cyclopropyl-2-hydroxyethoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one

4-pyrrolidinopyridine

glutaric anhydride

4-pyrrolidinopyridine

→

title compound

Rendimiento 78.0%

(R)-5-(2-(4-(6-(4-Chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-1-cyclopropylethoxy)-5-oxopentanoic acid

Rendimiento 78.0%

Disolventes

CH2Cl2

CH2Cl2

Condiciones de reacción

Tratamiento posterior

1. 1
   TemperaturaThe mixture was cooled to RT
2. 2
   Lavadowashed with 1N HCl, brine-
3. 3
   Filtraciónfiltered
4. 4
   Otroevaporated
5. 5
   Otroto yield a white solid, which
6. 6
   Otrowas purified by Preparative HPLC (PHENOMENEX® Luna Axia 5μ C18 30×100 mm
7. 7
   Otro10 min gradient

Procedimiento

A mixture of glutaric anhydride (73.0 mg, 0.640 mmol), (R)-6-(4-chlorophenyl)-3-(4-(2-cyclopropyl-2-hydroxyethoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (60 mg, 0.128 mmol) prepared in Example 1 and 4-pyrrolidinopyridine (18.96 mg, 0.128 mmol) in CH2Cl2 (4 mL) was stirred at 40° C. for 25 hours. LC-MS indicated about 35% conversion. Additional portions of glutaric anhydride (130 mg) and 4-pyrrolidinopyridine (20 mg) were added. After stirring at 40° C. for another 16h, conversion was complete according to HP LC. The mixture was cooled to RT, diluted with CH2Cl2 (10 mL), washed with 1N HCl, brine-, died (Na2SO4), filtered, and evaporated to yield a white solid, which was purified by Preparative HPLC (PHENOMENEX® Luna Axia 5μ C18 30×100 mm; 10 min gradient from 40% A: 60% B to 0% A:100% B (A=90% H2O/10% MeOH+0.1% TFA); (B=90% MeOH/10% H2O+0.1% TFA); detection at 220 inn) to yield impure title compound (58 mg, 78%) as a white solid. The product was further purified by Preparative HPLC using CH3CN-system (PHENOMENEX® Luna Axia 5® C18 30×100 mm; 10 min gradient from 40% A: 60% B to 0% A: 100% B (A 90% H2O/10% CH3CN+0.1% TFA); (B=90% CH3CN/10% H2O+0.1% TFA); detection at 220 nm) to yield the title compound (40 mg, 0.069 mmol, 53.6% yield) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 0.33-0.43 (m, 1H), 0.45-0.55 (m, 1H), 0.55-0.68 (m, 2H), 1.06-1.18 (m, 1H), 1.85-1.95 (m, 2H), 2.30-2.45 (m, 4H), 3.86 (s, 3H), 4.23-4.35 (m, 2H), 4.64-4.73 (m, 1H), 6.87-6.96 (m, 2H), 7.03 (d, J=7.9 Hz, 2H), 7.44 (d, J=8.35 Hz, 2H), 7.53 (s, 1H), 7.65 (d, J=8.35 Hz, 2H), 8.24 (s, 1H). LC-MS, [M+H]-4=583.5. HPLC Method: Gradient solvent system from 100% A:0% B to 0% A:100% B (A=90% H2O/10% MeOH+0.2% H3PO4; B=90% MeOH/10% H2O+0.2% H3PO4) for 4 min; detection at 220 nm. YMC S3 ODS 4.6×50 mm Ballistic column; Retention time=4.35 min.

Fuente