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

HRID 1366309Notes

Reaction equation

HRID 1366309 reaction equation
[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]([F: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[CH2:3][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:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=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[CH2:3][CH2:2]1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 66842930Glycyl-3-cyclohexyl-D-alanineHCID 66934449HCID 66934449, compound

Product 1

HCID 66934578N-({4-[(2R,3R)-3-{[2-(2,3-dihydro-1-benzofuran-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-cyclohexyl-D-alanine

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
30 °C

Procedure

To a stirred solution of {4-[(2R,3R)-3-{[2-(2,3-dihydro-1-benzofuran-5-yl)-2-oxoethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 2) (15.7 mg, 0.031 mmol) in DMF (2 ml, dry) was added N-methylmorpholine (10 μl, 0.091 mmol). TBTU (13.1 mg, 0.041 mmol) and additional DMF (2 ml) were added and the reaction mixture was stirred under at 30° C. for 25 minutes. Glycyl-3-cyclohexyl-D-alanine (7.1 mg, 0.031 mmol) (Method 7) was added and the reaction mixture was stirred for 2 hours. The formation of the ketone of the title compound was confirmed. M/z: 716.57 (M−1). Without further purification, methanol (6 ml) and sodium borohydride (16.1 mg, 0.043 mmol) were added and the reaction mixture was stirred for 20 minutes. Ammonium acetate (85.5 mg) was added. The methanol was removed under reduced pressure and the remaining DMF-solution was purified with preparative HPLC on a C8 column. A gradient from 20 to 55% MeCN in 0.1M NH4OAc was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The residue was extracted between EtOAc and water, the water phase was acidified to pH 2 with KHSO4 (2M). The phases were separated and the organic phase was passed through a phase separator. The solvent was removed under reduced pressure. The residue was dissolved in ACN and water. After lyophilisation, the title compound was obtained. H-NMR (400 MHz, DMSO-d6): 0.69-1.67 (m, 13H), 2.76-2.91 (m, 2H), 2.98-311 (m, 2H), 3.75 (d, 2H), 4.15-4.25 (m, 2H), 4.40-4.47 (m, 2H), 4.49 (s, 2H), 4.55-4.64 (m, 1H), 5.00 (b, 1H), 5.54 (b, 1H), 6.61 (dd, 1H), 6.96 (d, 3H), 7.08-7.16 (m, 3H), 7.18-7.24 (m, 2H), 7.34 (d, 2H), 8.07 (d, 1H), 8.19 (t, 1H), 12.51 (b, 1H). M/z: 718.57 (M−1).

Workup

  1. stirringthe reaction mixture was stirred for 2 hours

Sources & evidence

ORD record
ord-df12d21212974a849e19ca0b60c9cdd1
Source dataset
uspto-grants-2011_02
Patent number
US07893048B2

Reaction notes

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