1-Hydroxybenzotriazole → 6-[(S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoylamino]-nicotinic acid methyl ester

HRID 1925889Notes

Reaction equation

HRID 1925889 reaction equation
[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH2:14][N:15](C)[C@@H:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[C:6]([CH:12]=[O:13])[O:7]2.[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30][CH:29]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:17](=[O:19])[C@@H:16]([N:15]2[CH2:14][C:5]3[CH2:4][C:3]4[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:8]=4[O:7][C:6]=3[C:12]2=[O:13])[CH2:20][CH:21]([CH3:22])[CH3:23])=[N:30][CH:29]=1

Participants

6

Reactant 3

HCID 757711-HydroxybenzotriazoleHCID 737487Methyl 6-aminonicotinateHCID 86660536(S)-2-[(5-chloro-2-formyl-4H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid

Product 1

HCID 547676366-[(S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoylamino]-nicotinic acid methyl esterYield 28.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of (S)-2-[(5-chloro-2-formyl-4H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid (300 mg, 2.1 mmol) (Example 3, Step 1), commercially available 6-amino-nicotinic acid methyl ester (163 mg, 1.07 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (190 mg, 0.98 mmol), and N-hydroxybenzotriazole (HOBt) (132 mg, 0.982 mmol) in methylene chloride (15 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)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoylamino]-nicotinic acid methyl ester (143 mg, 3%), as a white solid. 1H NMR (DMSO-d6) δ: 11.36 (s, 1H), 8.87 (s, 1H), 8.29 (dd, J=8.8, 2.0 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.18-7.39 (m, 2H), 7.09 (dd, J=6.8, 2.0 Hz, 1H), 5.09 (dd, J=10.8, 4.4 Hz, 1H), 4.43 (d, J=19.1 Hz, 1H), 4.08 (d, J=19.1 Hz, 1H), 3.86 (s, 3H), 3.75 (s, 2H), 1.78-1.92 (m, 1H), 1.63-1.76 (m, 1H), 1.47 (br. s., 1H), 0.93 (t, J=5.9 Hz, 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-1e58778716bb45a68593280208976aee
Source dataset
uspto-grants-2012_05
Patent number
US08178689B2

Reaction notes

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