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 603904노트

반응식

HRID 603904 반응식
[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

참가 물질

6

반응물 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

생성물 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

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

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온도
30 °C

실험 절차

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).

후처리

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

출처 및 근거

ORD 기록
ord-4eb6969eb6a049489124e4575f7b5a2c
출처 데이터셋
uspto-grants-2011_03
특허 번호
US07906502B2

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