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-(4-hydroxyphenyl)butanoic acid

HRID 254041Notes

Reaction equation

HRID 254041 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(O)=O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CC[O:43][CH2:42]C1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Br.[NH2:69][C@H:70]([CH2:74][CH2:75][C:76]1[CH:81]=[CH:80][C:79]([OH:82])=[CH:78][CH:77]=1)[C:71]([OH:73])=[O:72].[BH4-].[Na+].C([O-])(=O)C.[NH4+]>CN(C=O)C.CO>[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][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:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:42]([NH:69][C@H:70]([CH2:74][CH2:75][C:76]3[CH:77]=[CH:78][C:79]([OH:82])=[CH:80][CH:81]=3)[C:71]([OH:73])=[O:72])=[O:43])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1

Participants

9

Reactant 6

HCID 79724-MethylmorpholineHCID 517165Ammonium AcetateHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 4311764Sodium borohydrideHCID 56777052(R)-2-Amino-4-(4-hydroxyphenyl)butanoic acid hydrobromideHCID 66842760N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio)-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine

Product 1

HCID 66842852(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-(4-hydroxyphenyl)butanoic acid

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (15.2 mg, 0.028 mmol) and N-methylmorpholine (15 μl, 0.14 mmol) were dissolved in DMF (2 ml). TBTU (10.5 mg, 0.033 mmol) was added and after 20 minutes (2R)-2-amino-4-(4-hydroxyphenyl)butanoic acid hydrobromide (9.2 mg, 0.033 mmol) was added. The reaction mixture was stirred for 1.5 h. The formation of the intermediate acid was confirmed. M/z: 718.3. MeOH (2 ml) and sodium borohydride (10.7 mg, 0.28 mmol) were added and the mixture was stirred for 20 minutes. Ammonium acetate (34 mg) was added and the methanol was removed under reduced pressure. The residue was 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 (9.6 mg, 47%). H-NMR (400 MHz, DMSO-d6): 1.75-1.86 (m, 1H), 1.89-1.98 (m, 1H), 2.41 (t, 2H), 2.81-2.98 (m, 2H), 3.78 (d, 2H), 3.97-4.05 (m, 1H), 4.27 (d, 0.5M), 4.31 (d, 0.5H), 4.53 (s, 2H), 4.67-4.76 (m, 1H), 5.02 (d, 0.5H), 5.05 (d, 0.5H), 6.62 (d, 2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.05-7.16 (m, 4H), 7.20-7.25 (m, 2H), 7.30-7.39 (m, 4H), 7.87-7.97 (m, 1H), 8.30 (t, 1H), 8.91-9.30 (br, 1H). M/z: 718.0 (M−H).

Workup

  1. additionwas added
  2. stirringthe mixture was stirred for 20 minutes
  3. customthe methanol was removed under reduced pressure
  4. customThe residue was purified with preparative HPLC on a C8 column

Sources & evidence

ORD record
ord-1b500299aca0451f9a104391c076706e
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

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