Hydrochloric Acid → HCID 19919631, compound

HRID 1648356Notes

Reaction equation

HRID 1648356 reaction equation
C[Al](C)C.[Cl-:5].[NH4+:6].C(O[C:10]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([N:21]3[CH2:26][CH2:25][N:24](CC4C=CC=CC=4)[CH2:23][CH2:22]3)[C:14]=2[CH:13]=1)=O)C.Cl.[C:35]1([CH3:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl.C(O)C.O>[ClH:5].[C:35]1([CH2:41][N:24]2[CH2:25][CH2:26][N:21]([C:20]3[C:14]4[CH:13]=[C:12]([C:10]#[N:6])[S:16][C:15]=4[CH:17]=[CH:18][CH:19]=3)[CH2:22][CH2:23]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 1140TolueneHCID 25517Ammonium ChlorideHCID 15289950HCID 15289950, compoundHCID 16682925Trimethylaluminum

Product 1

HCID 19919631HCID 19919631, compound

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
150 °C

Procedure

Add trimethyl aluminum (11.8 mL of a 2M solution in toluene, 23.7 mmol) to dry ammonium chloride (1.27 g, 23.7 mmol) in anhydrous dichloromethane (155 mL) at room temperature. After 33 minutes, add ethyl-4-[4-(phenylmethyl)-1-piperazinyl]-benzo[b]thiophene-2-carboxylate (3.00 g in 27 mL of dichloromethane, 7.89 mmol, prepared in example 1) and heat at reflux under nitrogen for 21 hours. Cool the reaction, cautiously pour into water (250 mL) and extract with dichloromethane (3×100 mL). Combine the organic extracts and wash with brine (100 mL), dry over anhydrous magnesium sulfate/sodium sulfate, filter and concentrate under vacuum. Separate the free base from the resulting mixture by flash chromatography (ethyl acetate:hexane, 40:60, TLC Rf =0.4, then 100:0) to yield 0.62 g. Dissolve the free base in ethanol (25 mL), treat with 1M hydrochloric acid (2 mL) and concentrate under vacuum. Triturate the solid with ether (20 mL) and heat at 150° C. for 3 days under vacuum to provide the title compound (0.68 g) as a tan solid, mp 256°-259° C. dec.; 1H NMR (DMSO-d6) δ 11.56 (1H, bs), 8.49 (1H, s), 7.80 (1H, d, J=8.1 Hz), 7.71 (2H, bs), 7.57-7.49 (4H, m), 7.06 (1H, d, J=7.6 Hz), 4.43 (2H, bs), 3.57 (2H, bm), 3.37 (6H, bm); 13C NMR (DMSO-d6) δ 148.05, 142.50, 134.81, 131.60, 131.43, 131.33, 129.51, 129.26, 128.73, 117.49, 114.74, 113.85, 107.07, 58.51, 50.74, 48.27; IR (KBr) 1564, 1456, 953, 699 cm-1; EI/MS (70 eV) 333(54%), 91(100%). IC50 =180 nM (5HT1ABinding Affinity) IC50 =>1000 nM (5HT1DBinding Affinity)

Workup

  1. temperatureheat
  2. temperatureat reflux under nitrogen for 21 hours
  3. temperatureCool
  4. customthe reaction
  5. extractionextract with dichloromethane (3×100 mL)
  6. washCombine the organic extracts and wash with brine (100 mL)
  7. dry with materialdry over anhydrous magnesium sulfate/sodium sulfate
  8. filtrationfilter
  9. concentrationconcentrate under vacuum
  10. customSeparate the free base from the resulting mixture by flash chromatography (ethyl acetate
  11. customhexane, 40:60, TLC Rf =0.4, then 100:0) to yield 0.62 g
  12. concentrationconcentrate under vacuum
  13. customTriturate the solid with ether (20 mL)

Sources & evidence

ORD record
ord-4e6117aa8dff4ba7ad938241822b097d
Source dataset
uspto-grants-1995_07
Patent number
US05436246

Reaction notes

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