对硝基苯甲酸 → (S)-1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethanol

HRID 16373

反应方程式

HRID 16373 反应方程式
[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C@H:16]([OH:18])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[O-].[Na+]>O.C(OCC)(=O)C.CO.O1CCCC1>[F:9][C:6]1[CH:5]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C@@H:16]([OH:18])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:3]=[C:2]([F:1])[C:7]=1[F:8]

参与物

10

反应物 5

HCID 6108对硝基苯甲酸HCID 11776三苯基膦HCID 75555偶氮二甲酸二异丙酯HCID 10942334甲醇钠HCID 67374002(R)-1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]ethanol

产物 1

HCID 68716490(S)-1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethanol收率 52.9%

试剂、催化剂与溶剂 4

HCID 887(5BETA,17BETA)-17-羟基-17-(甲基-D3)-2'H-雄甾-2-烯并[3,2-C]吡唑-5'(1'H)-酮溶剂HCID 962聚[6-[4-(4-氰基苯基)苯氧基]己基甲基丙烯酸酯]溶剂HCID 8028四氢呋喃溶剂HCID 8857乙酸乙酯溶剂

实验过程

Under a nitrogen atmosphere, to a tetrahydrofuran (50 mL) solution containing (R)-1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethanol (2.25 g), triphenylphosphine (4.51 g) and 4-nitrobenzoic acid (2.88 g) was dropwise added diisopropyl azodicarboxylate (3.39 mL) while cooling with ice. The resultant solution was stirred at the same temperature for 30 minutes, and then at room temperature for 2 hours. The reaction solution was diluted with water and ethyl acetate, and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was crudely purified by silica gel column chromatography (heptane/ethyl acetate 8/2→1/1), to thereby obtain a crude product (3.6 g) of 4-nitrobenzoic acid (S)-1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethyl ester. A solution of the obtained crude product (3.53 g) in methanol (300 mL) was added sodium methoxide (4.39 mL, 28% methanol solution), and the resultant solution was stirred at room temperature for 1 hour. Solvent was removed by distillation under reduced pressure, and the resultant product was diluted with ethyl acetate and water. The organic layer was partitioned, washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate 9/1→1/1), to thereby obtain the titled compound (1.19 g). The physical properties of the compound were as follows.

后处理

  1. temperaturewhile cooling with ice
  2. customthe organic layer was partitioned
  3. washThe organic layer was washed with brine
  4. dry with materialdried over anhydrous magnesium sulfate
  5. customSolvent was removed by distillation under reduced pressure
  6. customthe resulting residue was crudely purified by silica gel column chromatography (heptane/ethyl acetate 8/2→1/1)
  7. customto thereby obtain a crude product (3.6 g) of 4-nitrobenzoic acid (S)-1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethyl ester
  8. customSolvent was removed by distillation under reduced pressure
  9. additionthe resultant product was diluted with ethyl acetate and water
  10. customThe organic layer was partitioned
  11. washwashed with brine
  12. dry with materialdried over anhydrous magnesium sulfate
  13. customSolvent was removed by distillation under reduced pressure
  14. customthe resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate 9/1→1/1)

来源与证据

ORD记录
ord-2c3fd82969b3442389151fd8092ec402
来源数据集
uspto-grants-2010_06
专利号
US07737141B2

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