4-Methylmorpholine → (S)-5-bromo-2,3-dihydro-1H-inden-2-amine ((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate

HRID 42986Notes

Reaction equation

HRID 42986 reaction equation
Br.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:12])[CH2:6]2.CN1CCOCC1.[CH3:20][C:21]1([CH3:34])[C@H:25]2[CH2:26][CH2:27][C@:22]1([CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[C:23](=[O:28])[CH2:24]2>CO>[CH3:20][C:21]1([CH3:34])[C@H:25]2[CH2:26][CH2:27][C@:22]1([CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[C:23](=[O:28])[CH2:24]2.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH2:12])[CH2:6]2

Participants

5

Reactant 3

HCID 79724-MethylmorpholineHCID 5771688Camphorsulfonic acid, (-)-HCID 121920575-Bromo-2,3-dihydro-1H-inden-2-amine--hydrogen bromide (1/1)

Product 1

HCID 46899972(S)-5-bromo-2,3-dihydro-1H-inden-2-amine ((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonateYield 37.9%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Conditions

Temperature
60 °C

Procedure

To a suspension of 5-bromo-2,3-dihydro-1H-inden-2-amine hydrobromide (107 mmol, 31.27 g) and N-methylmorpholine (112 mmol, 12.32 mL, 11.33 g) in methanol (66.6 mL) was heated to 58-62° C. and a solution of ((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid (107 mmol, 24.79 g) in methanol (53.4 mL) was added over 3 min maintaining internal temp at 60-65° C. The addition funnel was rinsed with MeOH (13.3 mL) and rinsings added to reaction. The mixture was stirred at 60-65° C. for 10 min until a clear solution was obtained. The reaction was then allowed to cool to room temperature and stirred for a total of 4 h. The solids were collected by filtration and washed with a pre-cooled mixture of isopropyl acetate/methanol 2:1 (2×15 mL) followed by water (2×15 mL). The crude product was dried in a vacuum oven at 50° C. overnight to yield (18.03 g) of a fluffy white solid. This was suspended in methanol (130 mL) and heated to reflux for 4 h then allowed to cool to room temperature with stirring over 2 h and stirring continued at room temperature for a further 1 h. Solids were then isolated by filtration and washed with a pre-cooled solution of isopropylacetate/methanol (2:1, 2×18 mL). The colourless solid (13.82 g) was dried in the vacuum oven for 60 h. Refluxing in methanol followed by washing the solid with isopropyl acetate/methanol was repeated until the desired enantiomeric ratio was obtained. (S)-5-bromo-2,3-dihydro-1H-inden-2-amine((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate was obtained as a colourless solid (12.28 g, e.e. 100:0, 25.9%).

Workup

  1. temperaturemaintaining internal temp at 60-65° C
  2. washThe addition funnel was rinsed with MeOH (13.3 mL) and rinsings
  3. additionadded to reaction
  4. customwas obtained
  5. temperatureto cool to room temperature
  6. stirringstirred for a total of 4 h
  7. filtrationThe solids were collected by filtration
  8. washwashed with a pre-cooled mixture of isopropyl acetate/methanol 2:1 (2×15 mL)
  9. dry with materialThe crude product was dried in a vacuum oven at 50° C. overnight

Sources & evidence

ORD record
ord-99cdb879e88c4a9ea69034f1f905aa87
Source dataset
uspto-grants-2013_09
Patent number
US08536214B2

Reaction notes

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