4-Methylmorpholine → N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-chlorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-cyclohexyl-D-alanine

HRID 603904ノート

反応式

HRID 603904 の反応式
[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)=[O:69]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([NH:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]4[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]4)=[O:69])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1

参加物

6

反応物 4

HCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 66842930Glycyl-3-cyclohexyl-D-alanineHCID 67270870{4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-oxoethyl]thio}-1-(4-chlorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid

生成物 1

HCID 67271797N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-chlorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-cyclohexyl-D-alanine

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

反応条件

温度
30 °C

実験手順

To a stirred solution of {4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-oxoethyl]thio}-1-(4-chlorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (35.4 mg, 0.067 mmol)) in DMF (3 ml) was added N-methylmorpholine (35 μl, 0.23 mmol). TBTU (29.3 mg, 0.091 mmol) was added and the reaction mixture was stirred at 30° C. for 1 hour. Glycyl-3-cyclohexyl-D-alanine (18.4 mg, 0.081 mmol) was added and the mixture was stirred at ambient temperature for 60 hours. The formation of the ketone of the title compound was confirmed. M/z: 736.67 (M+1) and 734.71 (M−1). Without further purification, methanol (2 ml) and sodium borohydride (28.0 mg, 0.740 mmol) was added and the mixture was stirred for 20 minutes. Ammonium acetate (38.4 mg) was added and the solution was purified with preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 45 MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The organic phase was passed through a phase separator and concentrated under reduced pressure. The residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained 1H-NMR (400 MHz, DMSO-d6): 0.70-1.68 (m, 13H), 2.78-2.88 (m, 2H), 3.75 (d, 2H), 4.13-4.21 (m, 1H), 4.23-4.28 (m, 1H), 4.49 (s, 2H), 4.56-4.64 (m, 1H), 5.02 (d, 0.5H), 5.04 (d, 0.5H), 5.56 (b, 1H), 6.70-6.79 (m, 2H), 6.82 (s, 1H), 6.96 (d, 2H), 7.18 (d, 2H), 7.30-7.37 (m, 4H), 8.04 (b, 1H), 8.20 (t, 1H). M/z: 736.69 (M−1).

後処理

  1. stirringthe mixture was stirred at ambient temperature for 60 hours

出典と根拠

ORDレコード
ord-4eb6969eb6a049489124e4575f7b5a2c
出典データセット
uspto-grants-2011_03
特許番号
US07906502B2

反応ノート

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