Formaldehyde → 6-Benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid isopropyl ester

HRID 36329Notes

Reaction equation

HRID 36329 reaction equation
[CH2:1]=O.[CH:3]([O:6][C:7](=[O:31])[CH:8]([NH2:30])[CH:9]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[NH:15][CH:14]=1)[CH2:10][O:11][CH3:12])([CH3:5])[CH3:4]>O.Cl>[CH:3]([O:6][C:7]([CH:8]1[CH:9]([CH2:10][O:11][CH3:12])[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[NH:15][C:14]=2[CH2:1][NH:30]1)=[O:31])([CH3:5])[CH3:4]

Participants

5

Reactant 2

HCID 712Formaldehyde2×HCID 140762742-Amino-3-(5-benzyloxyindol-3-yl)-4-methoxybutyric acid isopropyl ester

Product 1

HCID 110800626-Benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid isopropyl esterYield 85%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolvent2×HCID 962WaterSolvent2×

Conditions

Temperature
80 °C

Procedure

A solution is prepared from 3.8 g of 2-amino-3-(5-benzyloxyindol-3-yl)-4-methoxybutyric acid isopropyl ester (10 mmol) in 80 ml of xylene and added dropwise to a suspension of 360 mg of paraformaldehyde in 60 ml of xylene heated for 45 minutes to 100° C. The mixture is then refluxed for 2 hours on a water trap. After concentration, the residue is chromatographed over silica gel with methylene chloride:acetone=1:1 as the eluent, yielding 2.5 g of 6-benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester (65% yield as an oil); or a suspension of 2.56 g of paraformaldehyde in 8 ml of water and 0.8 ml of concentrated hydrochloric acid is refluxed at 80° C. for 1 hour. One-tenth of the thus-obtained clear solution is added dropwise, after cooling to room temperature, to a solution of 3.8 g (10 mmol) of 2-amino-3-(5-benzyloxyindol-3 -yl)-4-methoxybutyric acid isopropyl ester in 500 ml of water and 10 ml of concentrated hydrochloric acid (pH=3). After 1/2 hour of agitation, an estimate of the amount of amino compound still remaining is made by thin-layer chromatography, and a corresponding quantity of formaldehyde solution is added. Thereupon, the mixture is stirred for another hour and then extracted twice by shaking with 50 ml of toluene, respectively. The organic phase is discarded. The aqueous phase is adjusted, after adding 100 ml of toluene, to a pH of 5.3 with 27% strength sodium hydroxide solution. After extraction by shaking, the mixture is additionally extracted by shaking twice with 50 ml of toluene; these 3 organic phases are combined, dried over sodium sulfate, filtered, and concentrated, thus obtaining 3.3 g (85%) of 6-benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester as an oil.

Workup

  1. additionOne-tenth of the thus-obtained clear solution is added dropwise
  2. extractionextracted twice
  3. stirringby shaking with 50 ml of toluene
  4. additionafter adding 100 ml of toluene
  5. extractionAfter extraction
  6. stirringby shaking
  7. extractionthe mixture is additionally extracted
  8. stirringby shaking twice with 50 ml of toluene
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-1df44383f9f64ae9b72874a994139ae6
Source dataset
uspto-grants-1995_05
Patent number
US05414002

Reaction notes

Loading…