Tetrahydrofuran → 1,4-anhydro-2-O-(2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-deoxy-L-threo-pentitol

HRID 577495Notes

Reaction equation

HRID 577495 reaction equation
CC(C)([O-])C.[K+].O1CCCC1.[Cl:12][C:13]1[CH:22]=[C:21]([O:23][C@H:24]2[CH2:41][O:40][C@@H:26]([CH2:27][O:28]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:25]2)[C:20]([Cl:42])=[C:19]2[C:14]=1[CH2:15][CH2:16][NH:17][C:18]2=[O:43].[CH2:44]([O:51][C:52]1[C:57]([CH2:58]Cl)=[C:56]([CH3:60])[CH:55]=[C:54]([CH3:61])[N:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:44]([O:51][C:52]1[C:57]([CH2:58][N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[C:20]([Cl:42])[C:21]([O:23][C@@H:24]4[CH2:25][C@H:26]([CH2:27][OH:28])[O:40][CH2:41]4)=[CH:22][C:13]=3[Cl:12])[C:18]2=[O:43])=[C:56]([CH3:60])[CH:55]=[C:54]([CH3:61])[N:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 23665647Potassium tert-butoxideHCID 612578682-(Benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine2×HCID 867237192,5-anhydro-3-deoxy-4-O-(5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-O-(4-nitrobenzoyl)-L-threo-pentitol

Product 1

HCID 867237211,4-anhydro-2-O-(2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-deoxy-L-threo-pentitolYield 26%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

Potassium tert-butoxide solution in tetrahydrofuran (1.0 M, 645 μL, 0.645 mmol) was added dropwise to a cooled (0° C.) solution of 2,5-anhydro-3-deoxy-4-O-(5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-O-(4-nitrobenzoyl)-L-threo-pentitol (296n, 120 mg, 0.249 mmol) in anhydrous N,N-dimethylformamide (4 mL). After stirring for 30 minutes, a solution of 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (compound Z, 71 mg, 0.273 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added and stirring continued at 0° C. for 30 more minutes. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane), affording 1,4-anhydro-2-O-(2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-deoxy-L-threo-pentitol (296o, 36 mg, 26% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=7.21 Hz, 2H), 7.29-7.40 (m, 3H), 6.94 (s, 1H), 6.62 (s, 1H), 5.43 (s, 2H), 4.92 (br. s., 1H), 4.87 (s, 2H), 4.15-4.26 (m, 2H), 3.91 (dd, J=10.39, 3.91 Hz, 1H), 3.75-3.84 (m, 1H), 3.66-3.75 (m, 1H), 3.25 (t, J=6.05 Hz, 2H), 2.69 (t, J=6.05 Hz, 2H), 2.42 (s, 3H), 2.34-2.40 (m, 1H), 2.32 (s, 3H), 2.03-2.16 (m, 2H). MS: 557 [M+1].

Workup

  1. stirringstirring
  2. customcontinued at 0° C. for 30 more minutes
  3. washwashed with water (2×50 mL) and brine (50 mL)
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated to dryness
  6. custompurified by silica gel chromatography (
  7. washeluting with a gradient of 0-100% ethyl acetate in heptane),

Sources & evidence

ORD record
ord-6e889eb358834770931746c0d061fb2e
Source dataset
uspto-grants-2015_05
Patent number
US09040515B2

Reaction notes

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