Triethylamine → N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-[3-(2-methyl-2-aminopropyl)phenoxy]propylamine, dihydrochloride

HRID 902715Notes

Reaction equation

HRID 902715 reaction equation
Cl.[C:2]1([CH:8]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:9][N:10]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:30]=2[Cl:39])[CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16](C)([CH3:26])C(C(C)C(O)=O)[CH:18]=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:48](CC)CC.[CH2:53](OC([Cl:60])=O)[CH:54]([CH3:56])[CH3:55].[N-]=[N+]=[N-].[Na+]>O>[ClH:39].[ClH:60].[C:2]1([CH:8]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:9][N:10]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:26]([CH2:53][C:54]([CH3:56])([NH2:48])[CH3:55])[CH:16]=2)[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[C:30]=2[Cl:39])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 33557Sodium AzideHCID 62365Isobutyl chloroformateHCID 131726845HCID 131726845, compound

Product 1

HCID 131726844N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-[3-(2-methyl-2-aminopropyl)phenoxy]propylamine, dihydrochlorideYield 55%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Procedure

A solution of N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-2,2-dimethyl-3-(3-aminopropoxy)phenylpropionic acid, hydrochloride (158 mg, 0.24 mmole) in 10 mL of Me2CO was treated with Et3N (56 mg, 0.55 mmole) and cooled in an ice bath. A solution of isobutylchloroformate (37 mg, 0.27 mmole) in 2 ml of Me2CO was added dropwise to the cold solution, and the reaction was stirred at 0° for 30 minutes. A solution of NaN3 (40 mg, 0.6 mmole) in 2 mL of H2O was added to the cold solution, and stirring was continued for 30 minutes. The reaction was diluted with H2O, and extracted with Et2O. The extracts were washed with H2O, and dried. The ethereal solution of the acyl azide was slowly added with stirring to 50 mL of refluxing toluene. After the addition, the toluene solution is stirred at 105° for 30 minutes, and all the solvents are removed. The residue is dissolved in 5 mL of dioxane, treated with 5 mL of 6N HCl and heated at 100° for 30 minutes. The reaction was cooled, diluted with H2O, made basic with aqueous NaOH and extracted with Et2O. The extracts were washed with H2O, dried, and the solvents removed. The residue was chromatographed on a silica gel column and the product was eluted with 10% MeOH in EtOAc. The chromatographed product was converted to the dihydrochloride salt in Et2O and isopropanol with 4N HCl in dioxane, and gave the titled product, 78 mg (55% yield). MS (ESI) 596 (MH+).

Workup

  1. temperaturecooled in an ice bath
  2. stirringstirring
  3. waitwas continued for 30 minutes
  4. extractionextracted with Et2O
  5. washThe extracts were washed with H2O
  6. customdried
  7. additionThe ethereal solution of the acyl azide was slowly added
  8. stirringwith stirring to 50 mL of refluxing toluene
  9. additionAfter the addition
  10. stirringthe toluene solution is stirred at 105° for 30 minutes
  11. customall the solvents are removed
  12. dissolutionThe residue is dissolved in 5 mL of dioxane
  13. additiontreated with 5 mL of 6N HCl
  14. temperatureheated at 100° for 30 minutes
  15. temperatureThe reaction was cooled
  16. additiondiluted with H2O
  17. extractionextracted with Et2O
  18. washThe extracts were washed with H2O
  19. customdried
  20. customthe solvents removed
  21. customThe residue was chromatographed on a silica gel column
  22. washthe product was eluted with 10% MeOH in EtOAc

Sources & evidence

ORD record
ord-30702b0b34db4e23afe378d25ae74670
Source dataset
uspto-grants-2008_04
Patent number
US07365085B2

Reaction notes

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