Oxalyl chloride → (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (5-chloro-pyridin-2-yl)-amide

HRID 1925887Notes

Reaction equation

HRID 1925887 reaction equation
[Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]4[CH2:20]CCC[CH2:16]4)[C:11](O)=[O:12])[C:7](=[O:21])[C:6]=3[O:22][C:23]=2[CH:24]=[CH:25][CH:26]=1.C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1>C(Cl)Cl.O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:11](=[O:12])[C@@H:10]([N:8]2[CH2:9][C:5]3[CH2:4][C:3]4[C:2]([Cl:1])=[CH:26][CH:25]=[CH:24][C:23]=4[O:22][C:6]=3[C:7]2=[O:21])[CH2:14][CH:15]([CH3:16])[CH3:20])=[N:38][CH:39]=1

Participants

6

Reactant 3

HCID 65578Oxalyl chlorideHCID 661742-Amino-5-chloropyridineHCID 67520747(S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid

Product 1

HCID 54767634(S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (5-chloro-pyridin-2-yl)-amideYield 36.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 2.1 mmol) (from Example 3, Step 1c), in methylene chloride (10 mL) was treated with oxalyl chloride (0.12 mL, 1.07 mmol) at 0° C. The mixture was warmed to 25° C. and stirred for additional 2 hours. Then, the reaction mixture was cooled to 0° C., and N,N′-diisopropylethyl amine (0.61 mL, 3.57 mmol) and commercially available 5-chloro-pyridin-2-ylamine (137 mg, 1.07 mmol), were added. The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (5-chloro-pyridin-2-yl)-amide (145 mg, 36.3%), as a white solid. 1H NMR (DMSO-d6) δ: 11.11 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.90 (dd, J=8.8, 2.4 Hz, 1H), 7.21-7.38 (m, 2H), 7.09 (dd, J=7.1, 2.2 Hz, 1H), 5.06 (dd, J=10.5, 4.6 Hz, 1H), 4.42 (d, J=18.6 Hz, 1H), 4.07 (d, J=19.1 Hz, 1H), 3.75 (s, 2H), 1.77-1.89 (m, 1H), 1.61-1.73 (m, 1H), 1.46 (br. s., 1H), 0.93 (t, J=6.4 Hz, 6H).

Workup

  1. temperatureThen, the reaction mixture was cooled to 0° C.
  2. stirringThe reaction mixture was stirred for 16 hours at 25° C
  3. extractionextracted with ethyl acetate (2×)
  4. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  5. concentrationconcentrated in vacuo
  6. washhexane-ethyl acetate gradiant elution

Sources & evidence

ORD record
ord-1ba970221d144540aa577086bb990d4e
Source dataset
uspto-grants-2012_05
Patent number
US08178689B2

Reaction notes

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