Ammonia → 4-benzyl-2-(S)-(3,5-dichlorobenzyloxy)-3-(S)-phenylmorpholine

HRID 989141Notes

Reaction equation

HRID 989141 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([Cl:44])[CH:43]=1)[CH2:39]O.N>C1COCC1.C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:39][C:38]2[CH:37]=[C:36]([Cl:35])[CH:43]=[C:42]([Cl:44])[CH:41]=2)[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

9

Reactant 4

HCID 222AmmoniaHCID 432363,5-Dichlorobenzylic alcoholHCID 3611392Lithium tri-s-butylborohydrideHCID 15871960(3S)-4-Benzyl-3-phenylmorpholin-2-one

Product 1

HCID 228607764-benzyl-2-(S)-(3,5-dichlorobenzyloxy)-3-(S)-phenylmorpholineYield 54%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-75 °C

Procedure

A solution of 5.11 g (19.1 mmole) of N-benzyl-3-(S)-phenylmorpholin-2-one (from Example 14) in 100 mL of dry THF was cooled to −75° C. under nitrogen and was treated dropwise with 20.5 mL (20.5 mmole) of a 1M solution of lithium tri(sec-butyl)borohydride (L-Selectride®) in THF. After stirring the solution at −75° C. for 30 min, a solution of 3,5-dichlorobenzyl alcohol, trifluoromethanesulfonate ester in toluene (from Example 44, Step A) was added by cannula so that the internal temperature was maintained below −60° C. The resulting solution was stirred between −38° C. and −50° C. for 9 hr, and was then treated with 14 mL of aqueous ammonia and stored at −20° C. for 12 hours. The solution was then poured into a mixture of 50 mL of ethyl acetate and 100 mL of water, and the layers were separated. The aqueous phase was extracted with 2×100 mL of ethyl acetate, each extract was washed with brine, the combined organic layers were dried over sodium sulfate, the mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on 235 g of silica eluting with 1.5 L of 100:2 hexanes:ethyl acetate, then 1.5 L of 100:3 hexanes:ethyl acetate and then 1.9 L of 100:5 hexanes:ethyl acetate to give 4.4 g (54%) of an oil, which by 1H NMR is a 8:1 mixture of cis:trans morpholines.

Workup

  1. temperaturewas maintained below −60° C
  2. stirringThe resulting solution was stirred between −38° C. and −50° C. for 9 hr
  3. waitstored at −20° C. for 12 hours
  4. customthe layers were separated
  5. extractionThe aqueous phase was extracted with 2×100 mL of ethyl acetate
  6. washeach extract was washed with brine
  7. dry with materialthe combined organic layers were dried over sodium sulfate
  8. filtrationthe mixture was filtered
  9. concentrationthe filtrate concentrated in vacuo
  10. customThe residue was purified by flash chromatography on 235 g of silica eluting with 1.5 L of 100:2 hexanes

Sources & evidence

ORD record
ord-f15e199648924daa8f34bc0da6733e1e
Source dataset
uspto-grants-2003_10
Patent number
US06638930B2

Reaction notes

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