Toluene → HCID 178501098, compound

HRID 2068517Notes

Reaction equation

HRID 2068517 reaction equation
[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@@H:8]1[C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=2[NH:12][CH2:11][CH2:10][CH2:9]1.[Na].[CH:37]([C@H:39]1[CH2:44][CH2:43][C@H:42]([C:45]([O-:47])=[O:46])[CH2:41][CH2:40]1)=O.[NH4+].[Cl-].[C:50]1(C)C=CC=CC=1>O.C(#N)C>[CH3:50][O:47][C:45]([C@H:42]1[CH2:43][CH2:44][C@H:39]([CH2:37][N:12]2[C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[C@@H:8]([N:7]([CH2:6][C:5]3[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:4]=3)[C:21]3[N:22]=[N:23][N:24]([CH3:26])[N:25]=3)[CH2:9][CH2:10][CH2:11]2)[CH2:40][CH2:41]1)=[O:46]

Participants

8

Reactant 5

HCID 1140TolueneHCID 25517Ammonium ChlorideHCID 5360545SodiumHCID 49847999HCID 49847999, compoundHCID 178520958HCID 178520958, compound

Product 1

HCID 178501098HCID 178501098, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

Cool a suspension of (5S)—N-[3,5-bis(trifluoromethyl)benzyl]-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine (3.40 g, 6.82 mmol), sodium triacetoxyborohydrate (3.01 g, 13.64 mmol), and ACN (28 mL) to −12° C. to −10° C. in an ice/acetone bath and add a solution of (trans)-4-formylcyclohexanecarboxylate (2.03 g, 11.93 mmol) in toluene (18.5 mL) over 30 min via a syringe pump (0.66 mL/min). Continue stirring the reaction in an ice/acetone bath for 2 hours. Add 44 mL of 10% (by weight) NH4Cl in water to the reaction and stir for 30 min at room temperature. Stop stirring and there are two layers. Separate the layers, concentrate the organic layer down to one volume of solvent. Add 24 mL of ethanol and concentrate to a solid (or to one volume). Add 24 mL of ethanol, 2 mL of water and heat to 60° C. (still a suspension). Add 2 mL of water dropwise. Allow the suspension to cool to room temperature and stir overnight at room temperature. After stirring overnight at room temperature, cool the suspension to −10° C. for 0.5 h, then filter. Wash the filter solids with 3 mL of −10° C. EtOH:water (4:1). Dry the solids overnight in a vacuum oven at 50° C. to give 4.24 g of methyl-trans-4-{[(5S)-5-{[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}-7,9-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]methyl}cyclohexanecarboxylate as a colorless solid. HPLC shows 99.75% pure.

Workup

  1. temperatureCool
  2. customthe reaction in an ice/acetone bath for 2 hours
  3. customto the reaction
  4. stirringstir for 30 min at room temperature
  5. stirringStop stirring
  6. customSeparate the layers
  7. concentrationconcentrate the organic layer down to one volume of solvent
  8. additionAdd 24 mL of ethanol
  9. concentrationconcentrate to a solid (or to one volume)
  10. additionAdd 24 mL of ethanol, 2 mL of water
  11. additionAdd 2 mL of water dropwise
  12. temperatureto cool to room temperature
  13. stirringstir overnight at room temperature
  14. stirringAfter stirring overnight at room temperature
  15. temperaturecool the suspension to −10° C. for 0.5 h
  16. filtrationfilter
  17. washWash the filter solids with 3 mL of −10° C
  18. customDry the solids overnight in a vacuum oven at 50° C.

Sources & evidence

ORD record
ord-8beae5a5bf244771bba438665f3fbbc3
Source dataset
uspto-grants-2012_10
Patent number
US08299060B2

Reaction notes

Loading…