Hydrochloric Acid → HCID 178442046, compound

HRID 2252962Notes

Reaction equation

HRID 2252962 reaction equation
Cl[CH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:16]1[C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([OH:39])[CH:35]=2)[CH:30]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[OH-].[Na+]>CC(C)=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1.CO>[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:16]1[C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:39][CH2:2][C:3]3[NH:7][N:6]=[N:5][N:4]=3)[CH:35]=2)[CH:30]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1

Participants

10

Reactant 5

HCID 313Hydrochloric Acid2×HCID 10796Cesium carbonateHCID 14798Sodium HydroxideHCID 223273436-(1-Benzyl-3-pentyl-1H-indol-2-yl)-2-naphtholHCID 178478452HCID 178478452, compound

Product 1

HCID 178442046HCID 178442046, compoundYield 76.4%

Reagents, catalysts & solvents 4

HCID 466102Benzenesulfonic acid, 4-methyl-, compd. with pyridine (1:1)CatalystHCID 180AcetoneSolventHCID 887MethanolSolventHCID 1140TolueneSolvent2×

Conditions

Temperature
17 °C

Procedure

Pyridinium p-toluenesulfonate (0.16 kg, 0.64 mol) was added to a solution of 5-chloromethyl-1H-tetrazole (2.37 kg, 20.0 mol) and 3,4-dihydro-3H-pyran (2.83 kg, 33.6 mol) in acetone (20 L) and the resultant solution was heated at 45° C. for 3 hours. Additional 3,4-dihydro-3H-pyran (1.46 kg, 17.4 mol) was added and heating was continued for 2 hours. 1-benzyl-2-(6-hydroxynaphthalen-2-yl)-3-pentyl-1H-indole (7.0 kg, 16.7 mol) was added and the solution was stirred at 17° C. Cesium carbonate (6.77 kg, 20.8 mol) was then added. The temperature of the suspension was adjusted to 60° C. and heating was continued for 3 hours, at which time HPLC analysis showed 100% conversion. Toluene (55 L) was added and acetone was removed by atmospheric distillation. The mixture was heated to 100° C. to provide 35 L of residual volume. After cooling the residue to 20° C., a solution of 1 N hydrochloric acid (28.6 L) was added, the mixture was stirred for 30 minutes, and the layers were separated. The upper organic layer was treated with a mixture of concentrated hydrochloric acid (8.3 kg, 84.2 mol) and methanol (28 L) at 20° C. for 30 minutes, the time necessary to complete hydrolysis, followed by dilution with toluene (58 L). A 1 N sodium hydroxide solution (35 L) was added, which changed the pH to 4. The layers were separated and the upper organic layer was washed with a 17% sodium chloride solution (35 L) at 40° C. The toluene layer was slowly cooled to −3° C. (crystallization begins at 21° C.) while being stirred for 1 hour. The suspension was then filtered, and the cake was washed with cold toluene (−3° C., 40 L) to yield, after drying, 6.4 kg (76.4% yield) of the title compound as an off-white solid with 99.26% ar. HPLC purity.

Workup

  1. temperatureheating
  2. customwas adjusted to 60° C.
  3. temperatureheating
  4. waitwas continued for 3 hours, at which time HPLC analysis
  5. customacetone was removed by atmospheric distillation
  6. temperatureThe mixture was heated to 100° C.
  7. customto provide 35 L of residual volume
  8. temperatureAfter cooling the residue to 20° C.
  9. stirringthe mixture was stirred for 30 minutes
  10. customthe layers were separated
  11. customhydrolysis
  12. customThe layers were separated
  13. washthe upper organic layer was washed with a 17% sodium chloride solution (35 L) at 40° C
  14. temperatureThe toluene layer was slowly cooled to −3° C.
  15. custom(crystallization begins at 21° C.)
  16. stirringwhile being stirred for 1 hour
  17. filtrationThe suspension was then filtered
  18. washthe cake was washed with cold toluene (−3° C., 40 L)
  19. customto yield
  20. customafter drying

Sources & evidence

ORD record
ord-61168ae943654359839acfd1121118d5
Source dataset
uspto-grants-2008_01
Patent number
US07323483B2

Reaction notes

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