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(S)-3-cyclohexyl-2-[2-oxo-4-(2-propyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

1-hydroxybenzotriazole

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

N,N-diisopropylethyl amine

→

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

수율 29.2%

용매

dichloromethane

ethyl acetate

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후처리

1. 1
   기타at room temperature
2. 2
   세척washed with a saturated aqueous ammonium chloride solution
3. 3
   세척The organic layer was then washed with a saturated aqueous sodium chloride solution
4. 4
   기타separated
5. 5
   건조dried over sodium sulfate
6. 6
   농축concentrated in vacuo
7. 7
   기타to afford the crude product, which
8. 8
   기타was purified by flash column chromatography (silica gel (100-200 mesh)) which

실험 절차

To a stirred solution of (S)-3-cyclohexyl-2-[2-oxo-4-(2-propyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (160 mg, 0.43 mmol) in dichloromethane (12 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) and N,N-diisopropylethyl amine (260 mg, 2.0 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (184 mg, 1.2 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 63 mg, 0.39 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[2-oxo-4-(2-propyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide (58 mg, 26%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.90 (t, J=7.3 Hz, 3H), 0.94-1.08 (m, 2H), 1.14 (br. s., 3H), 1.15 (br. s., 3H), 1.17-1.33 (m, 4H), 1.51-1.58 (m, 2H), 1.61-1.79 (m, 5H), 1.83 (d, J=12.7 Hz, 1H), 1.87-1.97 (m, 1H), 2.39-2.63 (m, 2H), 3.61 (br. s., 1H), 3.93 (s, 2H), 4.07 (d, J=17.9 Hz, 1H), 4.26 (d, J=17.9 Hz, 1H), 4.85 (s, 1H), 4.85-4.90 (m, 1H), 6.68 (d, J=2.0 Hz, 1H), 7.09 (d, J=7.8 Hz, 1 H), 7.15-7.23 (m, 3H), 7.29 (d, J=2.0 Hz, 1H), 8.57 (br. s., 1H).

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