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

HRID 254030

Reaction equation

HRID 254030 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](NCC(O)=O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.C[N:40]1CC[O:43][CH2:42][CH2:41]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:68][C:69]1([C:74]([OH:76])=[O:75])[CH2:73][CH2:72][CH2:71][CH2:70]1.[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:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:40][CH2:41][C:42]([NH:68][C:69]3([C:74]([OH:76])=[O:75])[CH2:73][CH2:72][CH2:71][CH2:70]3)=[O:43])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1

Participants

9

Reactant 6

HCID 2901CycloleucineHCID 79724-MethylmorpholineHCID 517165Ammonium AcetateHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 4311764Sodium borohydrideHCID 66842760N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio)-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine

Product 1

HCID 668429941-[(N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl)amino]cyclopentanecarboxylic acidYield 49.2%

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 (0.015 g, 0.028 mmol), NMM (0.012 ml, 0.109 mmol) and TBTU (0.011 g, 0.034 mmol) were dissolved in DMF (2 ml) at 30° C. After 30 min 1-amino-1-cyclopentanecarboxylic acid (0.004 g, 0.030 mmol, 97%) was added and the mixture was stirred at 30° C. for 1 h. The reaction was quenched with water (0.2 ml) and the mixture was diluted with MeOH (2 ml). NaBH4 (0.015 g, 0.397 mmol) was added and the mixture was stirred for 10 min. Ammonium acetate buffer (0.1M, 3 ml) was added and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC, using a gradient of 20-50% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, the title compound (0.009 g, 49% yield) was obtained as a white solid. M/z: 654.0. 1H NR (DMSO, 400 M/z): δ 1.56-1.66 (m, 4H), 1.78-1.87 (m, 2H), 1.97-2.07 (m, 2H), 2.84-2.94 (m, 2H), 3.74 (d, 2H), 4.24-4.29 (m, 1H), 4.51 (s, 2H), 4.68-4.76 (m, 1H), 5.02-5.07 (m, 1H), 6.92-7.00 (m, 2H), 7.05-7.26 (m, 6H), 7.29-7.39 (m, 4H), 8.09-8.15 (m, 2H).

Workup

  1. customThe reaction was quenched with water (0.2 ml)
  2. additionthe mixture was diluted with MeOH (2 ml)
  3. stirringthe mixture was stirred for 10 min
  4. customwas removed under reduced pressure
  5. customThe remaining solution was purified by preparative HPLC
  6. customAfter freeze-drying

Sources & evidence

ORD record
ord-55860c20686641c6bb0cbe16ddd4c970
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Linked notes

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