تفاعل #47462

معادلة التفاعل

1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol

(S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide hydrochloride

(S)-2-[4-(2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid

(S)-2-[4-(2-Fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

1-hydroxybenzotriazole

→

(S)-2-[4-(2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide

المردود 74.0%

المذيبات

dichloromethane

dichloromethane

ظروف التفاعل

المعالجة

1. 1
   workup.STIRRINGThe reaction mixture was stirred for 18 h at 25° C., under nitrogen
2. 2
   غسيلwashed with 2N hydrochloric acid, saturated sodium bicarbonate solution
3. 3
   تجفيفa saturated sodium chloride solution and dried over magnesium sulfate
4. 4
   أخرىThe crude product obtained
5. 5
   تركيزafter concentration
6. 6
   أخرىwas purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 10% methanol/dichloromethane)

الإجراء التجريبي

A solution of (S)-2-[4-(2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 166, 200 mg, 0.65 mmol) in dichloromethane (20 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (110 mg, 0.72 mmol) and 1-hydroxybenzotriazole (93 mg, 0.68 mmol). The reaction mixture was stirred at 25° C. for 1 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 121 mg, 0.78 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after concentration, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 10% methanol/dichloromethane) to afford (S)-2-[4-(2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (177 mg, 74%) as a light yellow powder: LR-ES-MS m/z calculated for C23H29FN4O4 [M+H]+ 444, observed 445; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.05 (br. s., 3H), 1.06 (br. s., 3H), 1.37-1.65 (m, 2H), 1.69-1.84 (m, 1H), 3.89 (s, 2H), 4.22 (d, J=18.4 Hz, 1H), 4.61 (d, J=18.4 Hz, 1H), 4.68 (s, 1H), 4.86 (s, 1H), 4.87-4.93 (m, 1H), 6.44 (d, J=1.8 Hz, 1H), 7.25-7.52 (m, 4H), 7.53 (d, J=1.8 Hz, 1H), 10.80 (s, 1H).

المصدر