4-Methylmorpholine → N-({4-[(2R,3R)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-methyl-D-valine

HRID 1176069Notes

Reaction equation

[Si]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36]C(O)=O)=[CH:33][CH:32]=1)(C(C)(C)C)(C)C.CN1CC[O:53][CH2:52]C1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:78][CH2:79][C:80]([NH:82][C@@H:83]([C:88]([OH:90])=[O:89])[C:84]([CH3:87])([CH3:86])[CH3:85])=[O:81].[Si](O[Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>CN(C=O)C>[F:48][C:45]1[CH:46]=[CH:47][C:42]([C@@H:9]([OH:8])[CH2:10][S:11][C@H:12]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:21][CH:22]=3)[C@@H:13]2[C:31]2[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:52]([NH:78][CH2:79][C:80]([NH:82][C@@H:83]([C:88]([OH:90])=[O:89])[C:84]([CH3:85])([CH3:86])[CH3:87])=[O:81])=[O:53])=[CH:33][CH:32]=2)=[CH:43][CH:44]=1

Participants

Conditions

Temperature: 30 °C

Procedure

To a stirred solution of {4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (19.4 mg, 0.027 mmol) and N-methylmorpholine (9 μl, 0.082 mmol) in DMF (1 ml, dry) was added TBTU (13.0 m, 0.040 mmol) and the reaction mixture was stirred at 30° C. for 1 hour. Glycyl-3-methyl-D-valine (7.1 mg, 0.038 mmol) was added and the reaction mixture was stirred for 1 hour. LC-MS showed the formation of the TBDMS-ether of the title compound, M/z: 881.65 (M−1). The reaction mixture was diluted with water and EtOAc. The solution was acidified with KHSO4 (2M) to pH 3. The phases were separated and the organic phase was concentrated. The residue was dissolved in acetic acid (1 ml). Water (100 μl) and LiCl (63 mg, 1.47 mmol) were added and the reaction mixture was stirred over the weekend. The acetic acid was co-evaporated with toluene. The residue was purified with preparative HPLC on a C8 column, UV 235/285 nm. A gradient from 20 to 60% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and most of the MeCN was removed under reduced pressure. The residue was lyophilised to give the title compound. H-NMR (500 MHz, DMSO-d6): 0.89 (s, 9H), 2.92 (d, 2H), 2.97 (s, 8H), 3.82 (d. 2H), 3.98-4.07 (b, 3H), 4.31 (d, 1H), 4.53 (s, 2H), 4.72 (t, 1), 5.09 (d, 1H), 6.99 (d, 2H), 7.07-7.13 (m, 2H), 7.20 (d, 2H), 7.32-7.40 (m, 6H), 7.59 (b, 1H), 7.81 (b, 1H), 8.23 (t, 1H). M/z: 769.39 (M+1) and 767.58 (M−1).

Workup

stirringthe reaction mixture was stirred for 1 hour

Sources & evidence

ORD record: ord-27cfce49595f48558a998f7d5d510766
Source dataset: uspto-grants-2010_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07842684B2

Reaction notes

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