4-Methylmorpholine → N-({4-[(2R,3R)-1-(4-Fluorophenyl)-3-({2-hydroxy-2-[4-(methylthio)phenyl]ethyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-D-valine

HRID 254057ノート

反応式

HRID 254057 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]([OH:24])[C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([OH:33])=O)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.Cl.[NH2:37][CH2:38][C:39]([NH:41][C@@H:42]([C:46]([O:48]C(C)(C)C)=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[BH4-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[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]([OH:24])[C:16]3[CH:17]=[CH:18][C:19]([S:22][CH3:23])=[CH:20][CH:21]=3)[C@H:9]2[C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:37][CH2:38][C:39]([NH:41][C@@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])=[O:33])=[CH:34][CH:35]=2)=[CH:6][CH:7]=1

参加物

8

反応物 5

HCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 4311764Sodium borohydrideHCID 66842720{4-[(2R,3R)-1-(4-fluorophenyl)-3-({2-hydroxy-2-[4-(methylthio)phenyl]ethyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetic acidHCID 86613090tert-butyl glycyl-D-valinate hydrochloride

生成物 1

HCID 66843291N-({4-[(2R,3R)-1-(4-Fluorophenyl)-3-({2-hydroxy-2-[4-(methylthio)phenyl]ethyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-D-valine収率 72.1%

試薬・触媒・溶媒 2

HCID 6344Dichloromethane溶媒HCID 6422Trifluoroacetic acid溶媒

実験手順

A solution of {4-[(2R,3R)-1-(4-fluorophenyl)-3-({2-hydroxy-2-[4-(methylthio)phenyl]ethyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetic acid (0.015 g, 0.029 mmol), tert-butyl glycyl-D-valinate hydrochloride (0.009 g, 0.034 mmol) and N-Methylmorpholine (0.013 ml, 0.118 mmol) in DCM (3 ml) was stirred at RT for 10 min, after which TBTU (0.014 g, 0.044 mmol) was added. After 17 h the conversion to the intermediate (m/z: 724.7, M+1) was completed. The solution was diluted with TFA (2 ml) and the mixture was allowed to stir for 2 h. The resulting acid (m/z: 668.6, M+1) was concentrated and the residue was dissolved in MeOH (3 ml). To this solution was added NaBH4 (80 mg, 2.11 mmol) in portions until the reduction of the ketone was completed (LC/MS). The reaction was quenched by the addition of a 0.1M ammonium acetate buffer (3 ml) before most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC, using a gradient of 20-50% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product (0.014 g, 70%) as a white solid.

後処理

  1. concentrationThe resulting acid (m/z: 668.6, M+1) was concentrated
  2. dissolutionthe residue was dissolved in MeOH (3 ml)
  3. customThe reaction was quenched by the addition of a 0.1M ammonium acetate buffer (3 ml) before most of the methanol
  4. customwas removed under reduced pressure
  5. customThe remaining solution was purified by preparative HPLC
  6. customFreeze-drying of the pure fractions

出典と根拠

ORDレコード
ord-d1b005e96a64497eb19333d39be058aa
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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