Morpholine → HCID 59006996, compound

HRID 644618Notes

Reaction equation

HRID 644618 reaction equation
CO[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])[CH2:8]2)=[O:4].O.[OH-].[Li+].[Li+].COC1C=C(OC)C=CC=1CN1CC2C(=CC=C(C([O-])=O)C=2)C1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C1COCC1.CO.O>[CH3:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[CH2:14][N:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[O:4])[CH:6]=2)[CH2:10]1

Participants

9

Reactant 6

HCID 8083MorpholineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 168937Lithium hydroxide, monohydrateHCID 59007009HCID 59007009, compoundHCID 666727252-(2,4-Dimethoxy-benzyl)-2,3-dihydro-1h-isoindole-5-carboxylic acid lithium salt

Product 1

HCID 59006996HCID 59006996, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 21892291Methanol tetrahydrofuran waterSolvent

Procedure

A mixture of 2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (4.65 g; 14.2 mmol) and lithium hydroxide monohydrate (660 mg; 1.1 equiv.) in 4:1:1 THF-MeOH-H2O (60 ml) was stirred at room temperature overnight. A further 170 mg of base were added and stirring continued for 7 hours. The reaction was evaporated then re-evaporated with MeOH/toluene (×2). A mixture of the crude 2-(2,4-dimethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid lithium salt (1.5 g; 4.7 mmol), morpholine (820 μl; 2 equiv.), EDAC (1.1 g; 1.2 equiv.) and HOBt (760 mg; 1.2 equiv.) in DMF (25 ml) was stirred at room temperature overnight then evaporated in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3, the EtOAc layer was separated, washed with brine, dried (MgSO4) and evaporated. Purification by flash column chromatography (2% then 5% MeOH/DCM as eluant) gave 1.1 g of [2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindol-5-yl]-morpholin-4-yl-methanone as a red/brown gum. 1H NMR (DMSO-d6) 7.30-7.18 (4H, m), 6.56 (1H, d), 6.52 (1H, dd), 3.85 (4H, s), 3.78 (5H, m), 3.73 (3H, s).

Workup

  1. stirringstirring
  2. waitcontinued for 7 hours
  3. customThe reaction was evaporated
  4. customthen re-evaporated with MeOH/toluene (×2)
  5. stirringwas stirred at room temperature overnight
  6. customthen evaporated in vacuo
  7. customThe residue was partitioned between EtOAc and saturated NaHCO3
  8. customthe EtOAc layer was separated
  9. washwashed with brine
  10. dry with materialdried (MgSO4)
  11. customevaporated
  12. customPurification by flash column chromatography (2%

Sources & evidence

ORD record
ord-78d2c3cdb0c54a80930a26ece66046e3
Source dataset
uspto-grants-2010_04
Patent number
US07700625B2

Reaction notes

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