4-Methylmorpholine → (2R)-2-[(N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl)amino]-4-phenylbutanoic acid

HRID 254040Notes

Reaction equation

HRID 254040 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(NCC(O)=O)=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[CH3:39][N:40]1CC[O:43][CH2:42][CH2:41]1.CN(C([O:53]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:68][C@H:69]([CH2:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:70]([OH:72])=[O:71].[BH4-].[Na+].C([O-])(=O)C.[NH4+]>CN(C=O)C.CO>[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:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:39]([NH:40][CH2:41][C:42]([NH:68][C@H:69]([CH2:73][CH2:74][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)[C:70]([OH:72])=[O:71])=[O:43])=[O:53])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1

Participants

9

Reactant 6

HCID 79724-MethylmorpholineHCID 517165Ammonium AcetateHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 4311764Sodium borohydrideHCID 6950302D-HomophenylalanineHCID 66842760N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio)-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine

Product 1

HCID 66842968(2R)-2-[(N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl)amino]-4-phenylbutanoic acid

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
30 °C

Procedure

N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (14.4 mg, 0.027 mmol) and N-methylmorpholine (15 μl, 0.14 mmol) were dissolved in DMF (3 ml). After 5 minutes, TBTU (10.3 mg, 0.032 mmol) was added and the mixture was stirred at 30° C. for 20 minutes. (2R)-2-Amino-4-phenylbutanoic acid (5.7 mg, 0.032 mmol) was added and the mixture was stirred at ambient temperature for 1.5 hors. The formation of the intermediate acid was confirmed. M/z: 702.0. MeOH (2.5 ml) and sodium borohydride were added and the mixture was stirred for 20 minutes. Ammonium acetate (31 mg) was added. The mixture was concentrated and purified with preparative HPLC on a C8 column. A gradient from 20% to 45% MeCN in 0.1M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid (9.4 mg, 50%). H-NMR (400 MHz, DMSO-d6): 1.74-1.87 (m, 1H), 1.89-1.99 (m, 1H), 2.49-2.53 (m, 2H), 2.82-2.98 (m, 2H), 3.77 (d, 2H), 3.94-4.01 (m, 1H), 4.27 (d, 0.5H), 4.31 (d, 0.5M), 4.53 (s, 2H), 4.68-4.77 (m, 1H), 5.02 (d, 0.5H), 5.05 (d, 0.5H), 6.99 (d, 2H), 7.05-7.16 (m, 7H), 7.19-7.26 (m, 4H), 7.30-7.38 (m, 4H), 7.78-7.88 (dd, 1H), 8.35 (t, 1H). M/z: 702.0 (M−H).

Workup

  1. stirringthe mixture was stirred at ambient temperature for 1.5 hors
  2. stirringthe mixture was stirred for 20 minutes
  3. concentrationThe mixture was concentrated
  4. custompurified with preparative HPLC on a C8 column

Sources & evidence

ORD record
ord-6975b9d4d35643c9b7b0f1741a24520c
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

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