3,5-Bis(trifluoromethyl)benzyl alcohol → 4-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine

HRID 363116

반응식

HRID 363116 반응식
[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+].[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]O.C(=O)(O)[O-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:40][C:39]2[CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[CH:44]=[C:37]([C:36]([F:35])([F:49])[F:50])[CH:38]=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

참가 물질

8

반응물 4

HCID 1229333,5-Bis(trifluoromethyl)benzyl alcoholHCID 516892Sodium BicarbonateHCID 3611392Lithium tri-s-butylborohydrideHCID 15871960(3S)-4-Benzyl-3-phenylmorpholin-2-one

생성물 1

HCID 107438244-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine수율 73%

시약·촉매·용매 3

HCID 1140Toluene용매HCID 8028Tetrahydrofuran용매2회HCID 8857Ethyl Acetate용매

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온도
-75 °C

실험 절차

A solution of 0.500 g (1.87 mmole) of N-benzyl-3-(S)-phenylmorpholin-2-one (from Example 14) in 10 mL of dry THF was cooled to -75° C. under nitrogen and was treated dropwise with 2.06 mL (2.06 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-bis(trifluoromethyl)benzyl alcohol, trifluoromethanesulfonate ester in toluene was added by cannula so that the internal temperature was maintained below -60° C. The resulting solution was stirred at -75° C. for 1 hr and then between -38° C. and 50° C. for 2 hr. The solution was then poured into a mixture of 25 mL of ethyl acetate and 20 mL of saturated aqueous sodium bicarbonate, and the layers were separated. The aqueous phase was extracted with 2×30 mL of ethyl acetate, 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 130 g of silica eluting with 2 L of 100:5 hexanes:ethyl acetate to give 0.68 g (73%) of an oil, which by 1H NMR is a 20:1 mixture of cis:trans morpholines.

후처리

  1. temperaturewas maintained below -60° C
  2. stirringThe resulting solution was stirred at -75° C. for 1 hr
  3. waitbetween -38° C. and 50° C. for 2 hr
  4. customthe layers were separated
  5. extractionThe aqueous phase was extracted with 2×30 mL of ethyl acetate
  6. dry with materialthe combined organic layers were dried over sodium sulfate
  7. filtrationthe mixture was filtered
  8. concentrationthe filtrate concentrated in vacuo
  9. customThe residue was purified by flash chromatography on 130 g of silica eluting with 2 L of 100:5 hexanes

출처 및 근거

ORD 기록
ord-f5d3df63b2be4482b6b19e1df1a0f0d6
출처 데이터셋
uspto-grants-1999_02
특허 번호
US05872116

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