Formaldehyde → (3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester

HRID 391846Notes

Reaction equation

HRID 391846 reaction equation
[CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:32][C@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C=O.F[C:46](F)(F)C(O)=O>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:46][N:32]1[C@H:33]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:34][CH3:35])=[O:42]

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 6422Trifluoroacetic acidHCID 58327352(S)-3-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester

Product 1

HCID 58327464(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent2×

Procedure

(S)-3-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (1.0 g) was dissolved in 37 mL dry dioxane and 149 mg paraformaldehyde added. 30 mL dry dioxane and 17 mL trifluoroacetic acid were mixed, cooled on ice and added to the reaction mixture. The reaction was stirred for 20 hours at room temperature and diluted with EtOAc. The organic layer was washed with 10% sodium, dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (DCM+0.2% TEA) to give 934 mg of product after drying. 1H NMR (400 MHz, acetone-d6): 7.71 (d, 1H), 7.61 (d, 1H), 7.50-7.41 (m, 3H), 7.38-7.26 (m, 5H), 7.09 (m, 2H), 6.67 (s, 1H), 6.60 (s, 1H), 5.19 (s, 2H), 5.10 (m, 1H), 4.32 (m, 1H), 4.12 (m, 2H), 4.01 (m, 1H), 3.92 (m, 1H), 3.59 (m, 1H), 3.51 (s, 3H), 2.97-2.78 (m, 2H), 2.16 (m, 1H), 1.68 (m, 1H), 0.66 (t, 3H).

Workup

  1. temperaturecooled on ice
  2. additionadded to the reaction mixture
  3. washThe organic layer was washed with 10% sodium
  4. dry with materialdried over Na2SO4
  5. customevaporated
  6. customThe residue was purified by silica gel flash chromatography (DCM+0.2% TEA)

Sources & evidence

ORD record
ord-783f910cd52e4badb51da7b4563fea0f
Source dataset
uspto-grants-2013_02
Patent number
US08383644B2

Reaction notes

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