1-Hydroxybenzotriazole → 6-[(S)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionylamino]-nicotinic acid methyl ester

HRID 1925897Notes

Reaction equation

HRID 1925897 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.[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33][CH:32]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([NH:37][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:33][CH:32]=1

Participants

6

Reactant 3

HCID 757711-HydroxybenzotriazoleHCID 737487Methyl 6-aminonicotinateHCID 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 547678076-[(S)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionylamino]-nicotinic acid methyl esterYield 18.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

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, 0.54 mmol) (Example 7, Step 2c), commercially available 6-amino-nicotinic acid methyl ester (98 mg, 0.64 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (113 mg, 0.59 mmol), and N-hydroxybenzotriazole (HOBt) (80 mg, 0.59 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). 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 gradient elution, afforded 6-[(S)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionylamino]-nicotinic acid methyl ester (50 mg, 18.4%), as a white solid. 1H NMR (DMSO-d6) δ: 11.32 (br. s., 1H), 8.87 (br. s., 1H), 8.28 (d, J=8.8 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.10 (br. s., 1H), 4.38 (d, J=18.6 Hz, 1H), 4.04 (d, J=19.1 Hz, 1H), 3.84 (d, J=15.7 Hz, 6H), 3.55 (br. s., 2H), 1.48-1.89 (m, 7H), 0.85-1.29 (m, 6H).

Workup

  1. extractionextracted with ethyl acetate (3×)
  2. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  3. concentrationconcentrated in vacuo
  4. washhexane-ethyl acetate gradient elution

Sources & evidence

ORD record
ord-58c75d57c16d4702b5cf13a1fa3b0bb7
Source dataset
uspto-grants-2012_05
Patent number
US08178689B2

Reaction notes

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