Triethylamine → (2R)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide

HRID 896864Notes

Reaction equation

HRID 896864 reaction equation
Cl.Cl.[NH2:3][CH2:4][C@@H:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:6].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[I:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[O:37][C@@H:36]([C:41](O)=[O:42])[CH2:35][CH2:34]2>ClCCl>[OH:6][C@H:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][NH:3][C:41]([C@H:36]1[CH2:35][CH2:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([I:30])[CH:32]=2)[O:37]1)=[O:42]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 9966213(2R)-6-Iodochromane-2-carboxylic acidHCID 69103521(1R)-2-amino-1-(3-pyridyl)ethanol dihydrochloride

Product 1

HCID 59118145(2R)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-6-iodo-3,4-dihydro-2H-chromene-2-carboxamideYield 74%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

(1R)-2-Amino-1-(3-pyridinyl)ethanol dihydrochloride (U.S. Pat. No. 6,051,586) (5.73 g, 27.1 mmol), 1-hydroxybenzotriazole (6.67 g, 49.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcabodiimide hydrochloride (9.46 g, 49.3 mmol), and triethylamine (13.8 mL, 9.98 g, 98.7 mmol) were added successively to a stirred solution of (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, Method A, 7.50 g, 24.7 mmol) in dichloromethane (100 mL). The reaction was stirred for 18 hours and then diluted with dichloromethane (300 mL). The solution was washed with saturated aqueous sodium bicarbonate (300 mL) and then the aqueous layer was back-extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 5-10% methanol/ethyl acetate gave the product (7.80 g, 74%) as a white solid: 1H NMR (acetone-d6, δ): 8.55 (d, J=1.6 Hz, 1 H), 8.44 (dd, J=4.7, 1.6 Hz, 1 H), 7.71 (ddd, J=7.9, 1.8, 1.8 Hz, 1 H), 7.59 (s, 1 H), 7.35-7.42 (m, 2 H), 7.27 (dd, J=7.9, 4.7 Hz, 1 H), 6.63 (d, 9.6 Hz, 1 H), 4.98 (d, J=4.2 Hz, 1 H), 4.85-4.93 (m, 1 H), 4.53 (dd, J=8.8, 3.4 Hz, 1 H), 3.38-3.70 (m, 2 H), 2.61-2.91 (m, 4 H), 2.16-2.28 (m, 2 H), 1.85-1.99 (m, 1 H); mass spectroscopy gave m/z=425.1 [M+H]+.

Workup

  1. washThe solution was washed with saturated aqueous sodium bicarbonate (300 mL)
  2. extractionthe aqueous layer was back-extracted with dichloromethane (2×100 mL)
  3. washThe combined organic extracts were washed with brine
  4. dry with materialdried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-2aca2dedbcee4bcf966a5280dca8b0ed
Source dataset
uspto-grants-2005_07
Patent number
US06919371B2

Reaction notes

Loading…