Piperonal → Methyl (1S,3S)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate

HRID 1986890Notes

Reaction equation

HRID 1986890 reaction equation
Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH:18]1[C:23]([CH:24]=O)=[CH:22][C:21]2[O:26][CH2:27][O:28][C:20]=2[CH:19]=1>C(O)(C)C>[CH3:2][O:3][C:4]([C@H:5]1[NH:6][C@@H:24]([C:23]2[CH:18]=[CH:19][C:20]3[O:28][CH2:27][O:26][C:21]=3[CH:22]=2)[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:17]

Participants

4

Reactant 2

HCID 8438PiperonalHCID 11448200methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate hydrochloride

Product 1

HCID 10861060Methyl (1S,3S)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateYield 101.6%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
70 °C

Procedure

D-Tryptophan methyl ester hydrochloride (50.0 kg, 196 mol) was suspended in isopropyl alcohol (500 L) and treated with piperonal (32.4 kg, 216 mol) at ambient temperature under an N2 atmosphere. The mixture was stirred between 70° C. and reflux (82° C.) for 16 to 18 hours. At this time, the reaction mixture contained less than 3% Compound IIa. The reaction mixture then was cooled to 0° C., filtered, and washed with cold isopropyl alcohol (150 L). The product was dried under vacuum at less than 60° C. to yield 69.8 kg (92%) of cis-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (Compound II)). 1H NMR (400 MHz DMSO) δ: 10.81 (1H, s), 10.67 (1H, exch.), 10.21 (1H, exch.), 7.52 (1H, d, J=8.0 Hz), 7.27 (1H, d, J=8.0 Hz), 7.11 (1H, m), 7.05-6.95 (4H, m), 6.08 (2H, s); 5.85 (1H, m), 4.71 (1H, m), 3.82 (3H, s), 3.39-3.23 (2H, m). HPLC Details: Column: SB-Phenyl 4.6×250 mm; ACN/(H2O+0.1% TFA) gradient; Temperature: 40° C.; Flow Rate=1 mL/min; UV Det.=285 μm; Injection Volume=20 μL; Diluent=1:1 ACN/H2O; Sample concentration: about 0.1 mg/mL; and Retention time=6.0 min.

Workup

  1. temperaturereflux (82° C.) for 16 to 18 hours
  2. temperatureThe reaction mixture then was cooled to 0° C.
  3. filtrationfiltered
  4. washwashed with cold isopropyl alcohol (150 L)
  5. customThe product was dried under vacuum at less than 60° C.

Sources & evidence

ORD record
ord-542c2d930df5493cb2fdb919d8599819
Source dataset
uspto-grants-2009_06
Patent number
US07550479B2

Reaction notes

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