Hydrochloric Acid → HCID 86644325, compound

HRID 1518365Notes

Reaction equation

HRID 1518365 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:15][CH2:14][C@@H:13]3[C@H:16]([NH:17]C(=O)OC(C)(C)C)[C@H:9]2[CH2:10][CH2:11][CH2:12]3)=[CH:4][CH:3]=1.[H-].[Na+].[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37]([C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:48]=1[CH2:47][N:46]([C:49]1[S:50][C:51]([CH2:59][CH2:60][CH2:61]I)=[C:52]([C:54]([O:56]CC)=[O:55])[N:53]=1)[CH2:45][CH2:44]2)=[O:38].Cl.[OH-].[Na+]>CN(C=O)C>[NH2:17][C@H:16]1[C@@H:13]2[CH2:12][CH2:11][CH2:10][C@H:9]1[C@@H:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:61][CH2:60][CH2:59][C:51]3[S:50][C:49]([N:46]4[CH2:45][CH2:44][C:43]5[C:48](=[C:39]([C:37](=[O:38])[NH:36][C:28]6[S:27][C:31]7[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=7[N:29]=6)[CH:40]=[CH:41][CH:42]=5)[CH2:47]4)=[N:53][C:52]=3[C:54]([OH:56])=[O:55])=[CH:7][CH:6]=1)[CH2:15][CH2:14]2

Participants

7

Reactant 5

HCID 313Hydrochloric Acid2×HCID 14798Sodium HydroxideHCID 24758Sodium hydrideHCID 59447467ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-iodopropyl)thiazole-4-carboxylateHCID 86644326HCID 86644326, compound

Product 1

HCID 86644325HCID 86644325, compoundYield 7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Tert-butyl (1S,2S,5R,9S)-2-(4-hydroxyphenyl)bicyclo[3.3.1]nonan-9-ylcarbamate 80A (40.5 mg, 0.11 mmol) in DMF (1 ml) was treated with NaH (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 1.5 hours. HCl (4N HCl in dioxane) (2.5 ml, 10 mmol) was added and the mixture was stirred overnight at room temperature and then at 60° C. for 6 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was slurried with 1N HCl, filtered, rinsed with water, slurried in Et2O, filtered and rinsed with additional Et2O. The solid was purified by column chromatography on silica gel using a gradient of 0 to 5% MeOH in CH2Cl2. The solid was dissolved in dioxane (2 ml), treated with NaOH (4N aqueous) (0.25 mL, 1 mmol) and stirred overnight at rt. The reaction mixture was acidified with 1N HCl to induce precipitation of the product. The solid was filtered, rinsed with water, slurried in Et2O, filtered and rinsed with additional Et2O. The solid was purified by HPLC (Preparative reverse phase HPLC was performed on an automated Gilson HPLC system, using a SymmetryPrep Shield RP18 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 80 in 7% yield as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.85 (1H, s), 12.50 (1H, s), 8.03 (1H, d), 7.97 (2H, d), 7.97 (1H, d), 7.47 (2H, m), 7.37 (2H, m), 7.13 (2H, d), 6.88 (2H, m), 4.83 (2H, s), 3.95 (2H, t), 3.72 (2H, t), 3.17 (2H, m), 3.02 (2H, m), 2.19 (2H, m), 1.98 (5H, m), 1.80 (5H, m), 1.59 (2H, m), 1.40 (3H, m). MS (ESI(+)) m/e 708 (M+H).

Workup

  1. stirringstirring
  2. waitwas continued for 1.5 hours
  3. stirringthe mixture was stirred overnight at room temperature
  4. waitat 60° C. for 6 hours
  5. temperatureThe reaction mixture was cooled to room temperature
  6. concentrationconcentrated
  7. filtrationfiltered
  8. washrinsed with water
  9. filtrationfiltered
  10. washrinsed with additional Et2O
  11. customThe solid was purified by column chromatography on silica gel using a gradient of 0 to 5% MeOH in CH2Cl2
  12. dissolutionThe solid was dissolved in dioxane (2 ml)
  13. stirringstirred overnight at rt
  14. customprecipitation of the product
  15. filtrationThe solid was filtered
  16. washrinsed with water
  17. filtrationfiltered
  18. washrinsed with additional Et2O
  19. customThe solid was purified by HPLC (Preparative reverse phase HPLC

Sources & evidence

ORD record
ord-4e5ed98b84d247fcba9c52db000ea3ab
Source dataset
uspto-grants-2012_07
Patent number
US08232273B2

Reaction notes

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