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

HRID 582092

反応式

HRID 582092 の反応式
[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

参加物

8

反応物 4

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

生成物 1

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

試薬・触媒・溶媒 3

HCID 1140Toluene溶媒HCID 8028Tetrahydrofuran溶媒2 回HCID 8857Ethyl Acetate溶媒

反応条件

温度
-75 °C

実験手順

A solution of 0.500 g (1.87 mmole) of N-benzyl-3-(S)-phenylmorpholine-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.

後処理

  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

出典と根拠

ORDレコード
ord-a5d344eae1664d6cbad12e28e40272b4
出典データセット
uspto-grants-1999_07
特許番号
US05922706

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