Hydrochloric Acid → HCID 46836649, compound

HRID 1518361Notes

Reaction equation

HRID 1518361 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:17]C(=O)C)=[CH:4][CH:3]=1.[H-].[Na+].[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[NH:32][C:33]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:44]=1[CH2:43][N:42]([C:45]1[S:46][C:47]([CH2:55][CH2:56][CH2:57]I)=[C:48]([C:50]([O:52]CC)=[O:51])[N:49]=1)[CH2:41][CH2:40]2)=[O:34].[OH-].[Na+].Cl>CN(C=O)C>[NH2:17][C:9]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:57][CH2:56][CH2:55][C:47]3[S:46][C:45]([N:42]4[CH2:41][CH2:40][C:39]5[C:44](=[C:35]([C:33](=[O:34])[NH:32][C:24]6[S:23][C:27]7[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=7[N:25]=6)[CH:36]=[CH:37][CH:38]=5)[CH2:43]4)=[N:49][C:48]=3[C:50]([OH:52])=[O:51])=[CH:7][CH:6]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 24758Sodium hydride2×HCID 59447467ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-iodopropyl)thiazole-4-carboxylateHCID 59447644HCID 59447644, compound

Product 1

HCID 46836649HCID 46836649, compoundYield 31%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Compound 77B (32 mg, 0.12 mmol) in DMF (1 ml) was treated with NaH (60% oil dispersion) (12 mg, 0.3 mmol). After stirring at ambient temperature for 5 minutes, compound 2C (63 mg, 0.1 mmol) was added and stirring was continued for 1 hour. Additional NaH (60% oil dispersion) (12 mg, 0.3 mmol) was added and the mixture was stirred at ambient temperature overnight. NaOH (4 N aq.) (0.25 ml, 1 mmol) was added and the mixture was stirred at ambient temperature for 4 hours. HCl (4N in dioxane) (2.5 ml, 10 mmol) was added and the mixture was heated at 70° C. for several hours. When the reaction was shown to be complete by LCMS, the reaction mixture was concentrated, 1N HCl was added to induce any further precipitation of the product. The solid was filtered and rinsed with water. The solid was slurried in Et2O, filtered and rinsed with additional Et2O. The solid was dissolved in 1:1 DMSO/MeOH, filtered via syringe filter to remove undissolved salts and impurities and purified by HPLC (Preparative reverse phase HPLC was performed on an automated Gilson HPLC system, using a SymmetryPrep Shield RP 18 prep cartridge, 250 mm×21.20 mm i.d., 10 um, and a flow rate of 25 mL/min; λ=214, 245 nm; mobile phase A, 0.1% TFA in H2O; mobile phase B, CH3CN; linear gradient 20-90% of B in 40 min) to provide the title compound 77 in 31% yield as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 12.90 (1H, s), 12.83 (1H, s), 8.44 (2H, s), 8.02 (1H, d), 7.79 (1H, d), 7.68 (1H, d), 7.41 (8H, m), 7.17 (3H, m), 6.93 (1H, d), 4.84 (2H, s), 4.10 (2H, t), 3.74 (2H, t), 3.23 (2H, m), 3.04 (2H, t), 2.07 (2H, m). MS (ESI(+)) m/e 702 (M+H).

Workup

  1. stirringstirring
  2. waitwas continued for 1 hour
  3. stirringthe mixture was stirred at ambient temperature overnight
  4. stirringthe mixture was stirred at ambient temperature for 4 hours
  5. temperaturethe mixture was heated at 70° C. for several hours
  6. concentrationthe reaction mixture was concentrated
  7. addition1N HCl was added
  8. customany further precipitation of the product
  9. filtrationThe solid was filtered
  10. washrinsed with water
  11. filtrationfiltered
  12. washrinsed with additional Et2O
  13. dissolutionThe solid was dissolved in 1:1 DMSO/MeOH
  14. filtrationfiltered via syringe
  15. filtrationfilter
  16. customto remove undissolved salts and impurities
  17. custompurified by HPLC (Preparative reverse phase HPLC

Sources & evidence

ORD record
ord-b2a67d9807f2488ab912b5261f57ae36
Source dataset
uspto-grants-2012_07
Patent number
US08232273B2

Reaction notes

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