Citric Acid → Methyl 4-[5-(2-carboxy-1-hydroxy-2-methylpropyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate

HRID 330200Notes

Reaction equation

HRID 330200 reaction equation
[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH:27]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][CH2:39][CH3:40])[CH:33]=[C:32]2[CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][C:43]=1[O:52][CH3:53])=[O:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.O1CCCC1>[C:1]([C:2]([CH3:4])([CH3:3])[CH:27]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][CH2:39][CH3:40])[CH:33]=[C:32]2[CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][C:43]=1[O:52][CH3:53])[OH:28])([OH:6])=[O:5]

Participants

9

Reactant 6

HCID 311Citric AcidHCID 6590Isobutyric AcidHCID 7912DiisopropylamineHCID 2724682Lithium diisopropylamideHCID 14882683Methyl 4-(5-formyl-1-propylindol-3-ylmethyl)-3-methoxybenzoateHCID 178418339Butyllithium

Product 1

HCID 19870544Methyl 4-[5-(2-carboxy-1-hydroxy-2-methylpropyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoateYield 40%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8058HexaneSolvent

Procedure

Isobutyric acid (1.2 g, redistilled) was slowly added dropwise to a stirred solution of lithium di-isopropylamide [prepared from di-isopropylamine (2.74 g) and n-butyl lithium (13.6 ml of a 2M solution in hexane)] in dry tetrahydrofuran (50 ml) at 0° under an atmosphere of nitrogen. The mixture was stirred at 0° for 40 min, heated to 45° for 2 hr, and allowed to cool to room temperature. This solution was then added dropwise to a stirred solution of methyl 4-(5-formyl-1-propylindol-3-ylmethyl)-3-methoxybenzoate (3.0 g, prepared as described in Example 61, part a) in dry retrahydrofuran (25 ml) under an atmosphere of nitrogen. After 1 hr, the mixture was poured into 20% (w/v) aqueous citric acid solution (150 ml) and extracted with ethyl acetate. The combined extracts were washed (water (twice), brine), dried (MgSO4), and evaporated to give a dark oil. The product was purified by flash chromatography, eluting with 80:20:2 toluene ethyl acetate:acetic acid, to give methyl 4-[5-(2-carboxy-1-hydroxy-2-methylpropyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (1.47 g, 40%) as a yellow foam: partial NMR (250 MHz, DMSO-d6): 0.81(m, 6H, CH2CH3, C(CH3)), 0.97(s, 3H, C(CH3)), 1.71(m, 2H, CH2CH3), 3.82(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.05(m, 4H, NCH2, ArCH2Ar'), 4.85(m, 1H, CH(OH), 5.29(d, 1H, CH(OH), 12.02(br s, 1H, COOH).

Workup

  1. temperatureheated to 45° for 2 hr
  2. customprepared
  3. waitAfter 1 hr
  4. extractionextracted with ethyl acetate
  5. washThe combined extracts were washed (water (twice), brine),
  6. dry with materialdried (MgSO4)
  7. customevaporated
  8. customto give a dark oil
  9. customThe product was purified by flash chromatography
  10. washeluting with 80:20:2 toluene ethyl acetate

Sources & evidence

ORD record
ord-be9d6f277cdc4a28ac163fdae24287c5
Source dataset
uspto-grants-1990_01
Patent number
US04894386

Reaction notes

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