Water → (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-3-hydroxy-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester

HRID 391762Notes

Reaction equation

HRID 391762 reaction equation
[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:16])=[C:11]([OH:15])[CH:12]=2)[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].[Cl:24][C:25]1[CH:26]=[C:27]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:37][C@@:36]([C:33]4[CH:34]=[CH:35][C:30]([O:29][CH2:28][C:27]5[CH:39]=[CH:40][C:41]([Cl:42])=[C:25]([Cl:24])[CH:26]=5)=[CH:31][CH:32]=4)([OH:38])[O:16][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4]

Participants

6

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 27750311-(4-((3,4-Dichlorobenzyl)oxy)phenyl)ethanoneHCID 667196016,7-Dihydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester

Product 1

HCID 66719236(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-3-hydroxy-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl esterYield 63.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

6,7-Dihydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (0.76 g) was dissolved in anhydrous DMF (20 mL). To this solution 1-[4-(3,4-dichloro-benzyloxy)-phenyl]-ethanone (0.93 g) and potassium carbonate (0.7 g) were added and heated to 100° C. The reaction mixture was stirred at this temperature for 12 hours. After the reaction was complete, the reaction mixture was poured into water and extracted with ethyl acetate (50 mL) and washed with brine (2×50 mL), dried over (sodium sulfate) and concentrated in vacuo to give the crude product. The residue was then purified by flash column chromatography (hexanes:ethyl acetate 90:10 to 60:40) to give the desired product, (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-3-hydroxy-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (0.92 g). 1H NMR (400 MHz, CDCl3): 7.91 (d, 2H), 7.82 (d, 1H), 7.58 (d, 1H), 7.54 (d, 1H), 7.47 (m, 1H), 7.00 (m, 2H), 6.78 (m, 1H), 5.32 (s, 1H), 5.09 (s, 2H), 4.70 (m, 1H), 4.40 (m, 1H), 3.62 (s, 3H), 3.06 (m, 1H), 1.51 (s, 9H), 1.26 (m, 2H), and 0.88 (t, 2H).

Workup

  1. extractionextracted with ethyl acetate (50 mL)
  2. washwashed with brine (2×50 mL)
  3. dry with materialdried over (sodium sulfate)
  4. concentrationconcentrated in vacuo
  5. customto give the crude product
  6. customThe residue was then purified by flash column chromatography (hexanes:ethyl acetate 90:10 to 60:40)

Sources & evidence

ORD record
ord-6314167919674194a6aabf978ff17f39
Source dataset
uspto-grants-2013_02
Patent number
US08383644B2

Reaction notes

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