تفاعل #47581

معادلة التفاعل

oxalyl chloride

2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(trans-3-methyl-cyclobutyl)-propionic acid

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

2,6-lutidine

→

2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(trans-3-methyl-cyclobutyl)-propionamide

المردود 36.0%

المذيبات

dichloromethane

dichloromethane

dichloromethane

ظروف التفاعل

المعالجة

1. 1
   أخرىIn a round bottom flask under argon was placed
2. 2
   أخرىat 25° C
3. 3
   أخرىwhich resulted in gas evolution
4. 4
   تركيزconcentrated in vacuo
5. 5
   workup.ADDITIONadded dropwise into another flask
6. 6
   workup.STIRRINGstirred for 1.5 h at 25° C.
7. 7
   أخرىquenched with methanol
8. 8
   workup.ADDITIONThe mixture was diluted with dichloromethane
9. 9
   غسيلwashed with a 1N aqueous hydrochloric acid solution
10. 10
    أخرىThe organic layer was separated
11. 11
    تجفيفdried over sodium sulfate
12. 12
    تركيزconcentrated in vacuo with silica gel (2 g)
13. 13
    أخرىPurification by Biotage flash chromatography (40S column, 25% ethyl acetate/hexanes)

الإجراء التجريبي

In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(trans-3-methyl-cyclobutyl)-propionic acid (100 mg, 0.29 mmol), dichloromethane (5 mL) and N,N-dimethylformamide (3 drops) at 25° C. To this mixture was added a 2.0M solution of oxalyl chloride in dichloromethane (180 μL, 0.36 mmol) dropwise, which resulted in gas evolution. The mixture was stirred for 15 min at 25° C. and then concentrated in vacuo. This residue was taken up in dichloromethane (5 mL) and added dropwise into another flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in US20080021032, Example 80, 55 mg, 0.35 mmol), dichloromethane (5 mL) and 2,6-lutidine (180 μL, 0.58 mmol) at 25° C. and stirred for 1.5 h at 25° C. and then quenched with methanol. The mixture was diluted with dichloromethane and washed with a 1N aqueous hydrochloric acid solution. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 25% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(trans-3-methyl-cyclobutyl)-propionamide (51 mg, 36%) as a light amber foam: HR-ES-MS m/z calculated for C25H31N4O4Cl [M+H]+ 487.2107, observed 487.2107; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06 (d, J=6.8 Hz, 9H), 1.48-1.57 (m, 1H), 1.65-1.73 (m, 1H), 1.75-1.83 (m, 1H), 1.88-2.01 (m, 3H), 2.14-2.26 (m, 1H), 2.28-2.37 (m, 1H), 3.90 (s, 2H), 4.20 (d, J=18.6 Hz, 1H), 4.58 (d, J=18.6 Hz, 1H), 4.66 (s, 1H), 4.73 (dd, J=9.3, 6.3 Hz, 1H), 4.78 (s, 1H), 6.44 (d, J=2.4 Hz, 1H), 7.37 (td, J=7.8, 1.5 Hz, 1H), 7.47 (td, J=7.8, 1.5 Hz, 1H), 7.51 (dd, J=7.8, 1.5 Hz, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.65 (dd, J=7.8, 1.5 Hz, 1H), 10.75 (s, 1H).

المصدر