1,2-Dichloroethane → (R)-N-(2,3-Dihydroxypropoxy)-6-fluoro-7-(2-fluoro-4-iodophenylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxamide

HRID 910148Notes

Reaction equation

HRID 910148 reaction equation
[F:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([C:20](O)=[O:21])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])[CH2:7][CH2:6][CH2:5]2.CC1(C)[O:29][C@@H:28]([CH2:30][O:31][NH2:32])[CH2:27][O:26]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C(N(CC)CC)C.O.CN(C=O)C>[OH:29][C@H:28]([CH2:27][OH:26])[CH2:30][O:31][NH:32][C:20]([C:9]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:2]([F:1])[C:3](=[O:23])[N:4]2[C:8]=1[CH2:7][CH2:6][CH2:5]2)=[O:21]

Participants

10

Reactant 5

HCID 111,2-DichloroethaneHCID 6101p-Toluenesulfonic acidHCID 757711-HydroxybenzotriazoleHCID 11298047(R)-O-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamineHCID 252657696-Fluoro-7-(2-fluoro-4-iodophenylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid

Product 1

HCID 42606202(R)-N-(2,3-Dihydroxypropoxy)-6-fluoro-7-(2-fluoro-4-iodophenylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxamideYield 48.5%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8471TriethylamineSolvent2×

Procedure

Example 1 (82 mg, 0.19 mmol), (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxyamine (see Bailey et al., J. Med. Chem., 34, 1991, 51-65; 56 mg, 0.38 mmol), and HOBt (28 mg, 0.21 mmol) were stirred in CH2Cl2 (4 mL) with DMF (0.5 mL) at r.t. EDC (47 mg, 0.25 mmol) and then triethylamine (40 μL, 0.29 mmol) were added, and the reaction stirred for 16 h. The solution was washed with 0.1N HCl and brine, dried (MgSO4), and concentrated in vacuo. The residue was stirred in MeOH (2.0 mL) and water (200 μL) with p-toluensulfonic acid (16 mg, 0.08 mmol) for 4 h. Triethylamine (50 μL) was added, and the solution was concentrated in vacuo. Purification by prep-HPLC gave 48 mg (48%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.50 (s, 1H), 8.04 (s, 1H), 7.57 (d, 1H, J=8.8 Hz), 7.40 (d, 1H, J=8.8 Hz), 6.79 (t, 1H, J=8.8 Hz), 4.00 (t, 2H, J=7.6 Hz), 3.77-3.84 (m, 1H), 3.63-3.68 (m, 2H), 3.28-3.36 (m, 2H), 3.17 (t, 2H, J=7.6 Hz), 2.01-2.09 (m, 2H). MS (ES) [m+H] calc'd for C18H18F2IN3O5, 522. found 522.

Workup

  1. washThe solution was washed with 0.1N HCl and brine
  2. dry with materialdried (MgSO4)
  3. concentrationconcentrated in vacuo
  4. stirringThe residue was stirred in MeOH (2.0 mL)
  5. concentrationthe solution was concentrated in vacuo
  6. customPurification

Sources & evidence

ORD record
ord-43e8ce61e0674440b491378c0caed473
Source dataset
uspto-grants-2011_09
Patent number
US08022057B2

Reaction notes

Loading…