Oxalyl chloride → (S)-N-(5-chloro-pyridin-2-yl)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamide

HRID 1925895Notes

Reaction equation

HRID 1925895 reaction equation
[CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12](O)=[O:13])[C:8](=[O:22])[C:7]=3[O:23][C:24]=2[CH:25]=[CH:26][CH:27]=1.C(Cl)(=O)C(Cl)=O.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=1>C(Cl)Cl.O>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:12](=[O:13])[C@@H:11]([N:9]2[CH2:10][C:6]3[CH2:5][C:4]4[C:3]([O:2][CH3:1])=[CH:27][CH:26]=[CH:25][C:24]=4[O:23][C:7]=3[C:8]2=[O:22])[CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:39][CH:40]=1

Participants

6

Reactant 3

HCID 65578Oxalyl chlorideHCID 661742-Amino-5-chloropyridineHCID 67521459(S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid

Product 1

HCID 54767805(S)-N-(5-chloro-pyridin-2-yl)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamideYield 26.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 0.64 mmol) (from Example 7, Step 2c), in methylene chloride (10 mL) was treated with oxalyl chloride (0.07 mL, 0.64 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 (0.34 mL, 1.92 mmol) and commercially available 5-chloro-pyridin-2-ylamine (83 mg, 0.64 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)—N-(5-chloro-pyridin-2-yl)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamide (68 mg, 26.3%), as a white solid. 1H NMR (DMSO-d6) δ: 11.07 (s, 1H), 8.39 (s, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.22 (t, J=8.3 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.07 (d, J=5.9 Hz, 1H), 4.37 (d, J=18.6 Hz, 1H), 4.03 (d, J=19.1 Hz, 1H), 3.82 (s, 3H), 3.55 (s, 2H), 1.48-2.00 (m, 7H), 0.85-1.32 (m, 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-a1c837e97a044d83b72f675462c94a04
Source dataset
uspto-grants-2012_05
Patent number
US08178689B2

Reaction notes

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