4-Methylmorpholine → N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-seryl-D-serine

HRID 254028ノート

反応式

HRID 254028 の反応式
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:40]=[CH:39][C:27]([O:28][CH2:29][C:30](N[C@@H](C(O)=O)CO)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.C([O:46][C:47](=[O:56])[C@@H:48]([CH2:50][O:51]C(C)(C)C)[NH2:49])(C)(C)C.C[N:58]1[CH2:63][CH2:62][O:61]CC1.CN([C:67]([O:71]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:40]=[CH:39][C:27]([O:28][CH2:29][C:30]([NH:58][C@@H:63]([C:67]([NH:49][C@@H:48]([C:47]([OH:46])=[O:56])[CH2:50][OH:51])=[O:71])[CH2:62][OH:61])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1

参加物

6

反応物 4

HCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 56777372H-D-Ser(tBu)-OtBu.HClHCID 66842695N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-([2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-serine

生成物 1

HCID 66842863N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-seryl-D-serine収率 54.1%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

実験手順

A solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-serine (0.008 g, 0.014 mmol), O-tert-butyl-D-serine tert-butyl ester hydrochloride (0.005 g, 0.019 mmol) and N-Methylmorpholine (0.006 ml, 0.055 mmol) in DCM (3 ml) was stirred for 5 min. TBTU (0.008 g, 0.025 mmol) was added. After 3 days the conversion to the ester (M/z: 772.5) was complete and the mixture was concentrated under reduced pressure. The residue was dissolved in formic acid (3 ml) and the solution was stirred at RT for 26 h. The mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (4 ml) and TEA (1 ml). The solution was stirred at 40° C. for 6 h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20-50% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.005 g (52% yield) of the title compound was obtained as a white solid. M/z: 660.1. 1H NMR (DMSO, 400 MHz): δ 2.83-0.95 (m, 2H), 3.42-3.66 (m, 4), 3.91-4.01 (m, 1H), 4.25-4.31 (m, 1H), 4.32-4.39 (m, 1H), 4.54 (ABq, 2H), 4.68-4.76 (m, 1H), 5.02-5.06 (m, 1H), 5.68 (bs, 1H), 6.94-7.00 (m, 2H), 7.05-7.18 (m, 4H), 7.19-7.26 (m, 2H), 7.29-7.39 (m, 4H), 7.74-7.81 (m, 1H), 7.99 (d, 1H).

後処理

  1. concentrationthe mixture was concentrated under reduced pressure
  2. dissolutionThe residue was dissolved in formic acid (3 ml)
  3. concentrationThe mixture was concentrated under reduced pressure
  4. dissolutionthe residue was dissolved in MeOH (4 ml)
  5. stirringThe solution was stirred at 40° C. for 6 h
  6. customThe solvent was removed under reduced pressure
  7. customThe residue was purified by preparative HPLC
  8. customAfter freeze-drying

出典と根拠

ORDレコード
ord-b3fc3f3f1fff441e9222367bd6a203ee
出典データセット
uspto-grants-2011_01
特許番号
US07871998B2

反応ノート

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