Hydrochloric Acid → HCID 19919632, compound

HRID 1648360Notes

Reaction equation

HRID 1648360 reaction equation
[Cl-:1].[NH4+:2].C[Al](C)C.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]([CH2:27][CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:23][CH2:22]3)[C:14]=2[CH:13]=1)=O)C.Cl>C1(C)C=CC=CC=1.ClCCl.C(O)C.O>[ClH:1].[C:30]1([CH2:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][N:21]([C:20]3[C:14]4[CH:13]=[C:12]([C:10]#[N:2])[S:16][C:15]=4[CH:17]=[CH:18][CH:19]=3)[CH2:22][CH2:23]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 25517Ammonium ChlorideHCID 15289962HCID 15289962, compoundHCID 16682925Trimethylaluminum

Product 1

HCID 19919632HCID 19919632, compoundYield 35.8%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 962WaterSolventHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent2×

Procedure

Add dry dichloromethane (100 mL) to dry ammonium chloride (0.820 g, 15.3 mmol) and treat with trimethyl aluminum (7.8 mL of a 2M solution in toluene, 15.3 mmol). After 30 minutes, add a solution of ethyl-4-[4-(3-phenylpropyl)-1-piperazinyl]-benzo[b]thiophene-2-carboxylate (2.09 g, 5.12 mmol, prepared in example 14) in dry dichloromethane (19 mL) to the reaction and heat at reflux for 19 hours. After cooling, cautiously pour the reaction into water (200 mL) and extract with dichloromethane (4×100 mL). Combine the organic extracts and wash with brine (100 mL), dry over anhydrous magnesium sulfate/sodium sulfate, filter and concentrate under vacuum. The free base is separated from the resulting mixture by flash chromatography (ethyl acetate:hexane, 40:60, TLC Rf =0.4) to yield 0.69 g. Dissolve the free base in ethanol (25 mL) and treat with 1M hydrochloric acid (2 mL) and concentrate under vacuum. Triturate the solid with ether (30 mL) and collect by suction filtration to provide the title compound (0.73 g) as an off white solid, 241°-245° C. dec; 1H NMR (DMSO-d6) δ 11.19 (1H, bs), 8.48 (1H, s), 7.81 (1H, d, J=8.2 Hz), 7.55 (1H, t, J=7.9 Hz) 7.28 (5H, m), 7.08 (1H, d, J=7.6 Hz), 3.55 (4H, m), 3.21 (6H, m), 2.69 (2H, t, J=7.8 Hz), 2.10 (2H, m); 13C NMR (DMSO-d6) δ 6 148.07, 142.47, 140.53, 134.77, 131.46, 129.22, 128.40, 128.22, 126.09, 117.50, 114.73, 113.95, 107.08, 55.19, 51.06, 48.52, 32.06, 24.72; IR (KBr) 2969, 2231, 2220, 1461, 1455 cm-1 ; CI/MS (CH4) 362(100%). IC50 =21 nM (5HT1ABinding Affinity) IC50 =173 nM (5HT1DBinding Affinity)

Workup

  1. customto the reaction
  2. temperatureheat
  3. temperatureat reflux for 19 hours
  4. temperatureAfter cooling
  5. additioncautiously pour
  6. extractionextract with dichloromethane (4×100 mL)
  7. washCombine the organic extracts and wash with brine (100 mL)
  8. dry with materialdry over anhydrous magnesium sulfate/sodium sulfate
  9. filtrationfilter
  10. concentrationconcentrate under vacuum
  11. customThe free base is separated from the resulting mixture by flash chromatography (ethyl acetate:hexane, 40:60, TLC Rf =0.4)
  12. customto yield 0.69 g
  13. concentrationconcentrate under vacuum
  14. customTriturate the solid with ether (30 mL)
  15. filtrationcollect by suction filtration

Sources & evidence

ORD record
ord-946f83799c95457aaf9576ee4f79d402
Source dataset
uspto-grants-1995_07
Patent number
US05436246

Reaction notes

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