4-Methylmorpholine → N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-S-(4-methoxybenzyl)-D-cystein

HRID 254061Notes

Reaction equation

[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][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:68][O:69][C:70]1[CH:83]=[CH:82][C:73]([CH2:74][S:75][CH2:76][C@H:77]([C:79]([OH:81])=[O:80])[NH2:78])=[CH:72][CH:71]=1>CN(C=O)C>[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:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:78][C@@H:77]([C:79]([OH:81])=[O:80])[CH2:76][S:75][CH2:74][C:73]3[CH:72]=[CH:71][C:70]([O:69][CH3:68])=[CH:83][CH:82]=3)=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1

Participants

Conditions

Temperature: 30 °C

Procedure

To a stirred solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine, (21.3 mg, 0.039 mmol) in DMF (3 ml) was added N-methylmorpholine (20μl, 0.18 mmol). TBTU (15.1 mg, 0.047 mmol) was added and the mixture was stirred at 30° C. for 35 minutes. S-(4-methoxybenzyl)-D-cysteine (12.8 mg, 0.053 mmol) was added and the mixture was stirred 1 hour at 30° C. and 1.5 hours at ambient temperature. The formation of the ketone of the title compound was confirmed. M/z: 764.11 (M+1) and 762.06 (M−1). Methanol (3 ml) and sodium borohydride (15 mg, 0.40 mmol) were added and the mixture was stirred for 20 minutes. Ammonium acetate (25 mg) was added and the methanol was removed under reduced pressure. The remaining DMF-solution was purified with preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 47% MeCN in 0.1M NH4OAc was used as eluent. The MeCN was removed from the collected fractions under reduced pressure. The remaining water solution was acidified to pH 1 with KHSO4 (2M) and extracted with DCM. The organic phase was concentrated under reduced pressure and the residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained as a white solid (10.7 mg, 36%). H-NMR (400 MHz, DMSO-d6): 2-60-2.80 (m, 2H), 2.83-2.97 (m, 2H), 3.63-3.66 (bd, 2H), 3.69 (s, 3H), 3.77-3.81 (bd, 2H), 4.24-4.33 (m, 2H), 4.52 (s, 2H), 4.67-4.76 (m, 1H), 5.03 (d, 0.5H), 5.06 (d, 0.5H), 5.60-5.90 (b, 1H), 6.82 (d, 2H), 6.98 (d, 2H), 7.05-7.25 (m, 8H), 7.30-7.38 (m, 4H), 8.00-8.10 (b, 1H), 8.30 (t, 1H). M/z: 764.07 (M−1).

Workup

stirringthe mixture was stirred 1 hour at 30° C. and 1.5 hours at ambient temperature

Sources & evidence

ORD record: ord-362eefb3f47e43cc970924016db17ad2
Source dataset: uspto-grants-2011_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07871998B2

Reaction notes

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