4-Methylmorpholine → (R)-3-Cyclohexyl-2-[2-(2-{4-[(2R,3R)-3-[2-(2,3-dihydro-benzofuran-6-yl)-2-hydroxy-ethylsulfanyl]-1-(4-fluoro-phenyl)-4-oxo-azetidin-2-yl]-phenoxy}-acetylamino)-acetylamino]-propionic acid

HRID 1366311Notes

Reaction equation

HRID 1366311 reaction equation
[O:1]1[C:5]2[CH:6]=[C:7]([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:8]=[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]([CH2:75][CH:76]1[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]1)[C:72]([OH:74])=[O:73])=[O:69].[BH4-].[Na+]>CN(C=O)C>[CH:76]1([CH2:75][C@@H:71]([NH:70][C:68](=[O:69])[CH2:67][NH:66][C:31](=[O:32])[CH2:30][O:29][C:28]2[CH:27]=[CH:26][C:25]([C@@H:14]3[C@@H:13]([S:12][CH2:11][CH:10]([C:7]4[CH:8]=[CH:9][C:4]5[CH2:3][CH2:2][O:1][C:5]=5[CH:6]=4)[OH:36])[C:16](=[O:17])[N:15]3[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:35][CH:34]=2)[C:72]([OH:74])=[O:73])[CH2:77][CH2:78][CH2:79][CH2:80][CH2:81]1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 4311764Sodium borohydrideHCID 66842930Glycyl-3-cyclohexyl-D-alanineHCID 66934526HCID 66934526, compound

Product 1

HCID 66934591(R)-3-Cyclohexyl-2-[2-(2-{4-[(2R,3R)-3-[2-(2,3-dihydro-benzofuran-6-yl)-2-hydroxy-ethylsulfanyl]-1-(4-fluoro-phenyl)-4-oxo-azetidin-2-yl]-phenoxy}-acetylamino)-acetylamino]-propionic acid

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of {4-[(2R,3R)-3-[2-(2,3-dihydro-benzofuran-6-yl)-2-oxo-ethylsulfanyl]-1-(4-fluoro-phenyl)-4-oxo-azetidin-2-yl]-phenoxy}-acetic acid (33 mg, 0.065 mmol) in DMF (3 mL) at RT was added N-methylmorpholine (22 μl, 0.198 mmol) and TBTU (22 mg, 0.069 mmol). The mixture was stirred for 30 min before (R)-2-(2-amino-acetylamino)-3-cyclohexyl-propionic acid (15 mg, 0.066 mmol) was added. After 2 h 30 min, the reaction was quenched by the addition of water (1 mL) The mixture was diluted with MeOH (1 mL) and then added NaBH4 (35 mg, 0.925 mmol). After 15 min, the reaction was quenched by the addition of 1M HCl (3 mL) and the resulting solution was purified by preparative HPLC using a gradient of 0-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product.

Workup

  1. additionwas added
  2. customthe reaction was quenched by the addition of water (1 mL) The mixture
  3. additionwas diluted with MeOH (1 mL)
  4. waitAfter 15 min
  5. customthe reaction was quenched by the addition of 1M HCl (3 mL)
  6. customthe resulting solution was purified by preparative HPLC
  7. customFreeze-drying of the pure fractions

Sources & evidence

ORD record
ord-8b10b9af192945b6bb82de9085646b90
Source dataset
uspto-grants-2011_02
Patent number
US07893048B2

Reaction notes

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