Potassium Phosphate, Tribasic → 5-[(1S,4R,5S,15R)-5-(3,5-difluoro-benzyl)-4-hydroxy-7-oxo-14-oxa-2,6-diaza-tricyclo[13.6.1.016,21]docosa-11,16(21),17,19-tetraen-19-yl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester

HRID 501766

반응식

HRID 501766 반응식
C(O[C@H]1C2C(=CC(Br)=CC=2)[C@@H](NC[C@@H](O)[C@@H](N)CC2C=C(F)C=C(F)C=2)C1)C=C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH2:46]1[CH:50]2[CH2:51][NH:52][CH2:53][CH:49]2[CH2:48][N:47]1[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55].Br[C:62]1[CH:63]=[CH:64][C:65]2[C@H:66]3[CH2:83][C@@H:80]([C:81]=2[CH:82]=1)[NH:79][CH2:78][C@@H:77]([OH:84])[C@H:76]([CH2:85][C:86]1[CH:91]=[C:90]([F:92])[CH:89]=[C:88]([F:93])[CH:87]=1)[NH:75][C:74](=[O:94])[CH2:73][CH2:72][CH2:71][CH:70]=[CH:69][CH2:68][O:67]3>O.CCOC(C)=O.[Cu]I.CS(C)=O>[C:57]([O:56][C:54]([N:47]1[CH2:48][CH:49]2[CH:50]([CH2:51][N:52]([C:62]3[CH:63]=[CH:64][C:65]4[C@H:66]5[CH2:83][C@@H:80]([C:81]=4[CH:82]=3)[NH:79][CH2:78][C@@H:77]([OH:84])[C@H:76]([CH2:85][C:86]3[CH:87]=[C:88]([F:93])[CH:89]=[C:90]([F:92])[CH:91]=3)[NH:75][C:74](=[O:94])[CH2:73][CH2:72][CH2:71][CH:70]=[CH:69][CH2:68][O:67]5)[CH2:53]2)[CH2:46]1)=[O:55])([CH3:60])([CH3:59])[CH3:58]

참가 물질

10

반응물 5

HCID 62657Potassium Phosphate, TribasicHCID 145742L-ProlineHCID 4142526Tert-butyl octahydropyrrolo(3,4-c)pyrrole-2-carboxylateHCID 68464298(1S,4R,5S,15R)-19-bromo-5-(3,5-difluoro-benzyl)-4-hydroxy-14-oxa-2,6-diaza-tricyclo[13.6.1.016,21]docosa-11,16(21),17,19-tetraen-7-oneHCID 68465135(2R,3S)-1-((1S,3R)-3-(Allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-difluorophenyl)butan-2-ol

생성물 1

HCID 675743285-[(1S,4R,5S,15R)-5-(3,5-difluoro-benzyl)-4-hydroxy-7-oxo-14-oxa-2,6-diaza-tricyclo[13.6.1.016,21]docosa-11,16(21),17,19-tetraen-19-yl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester수율 61.6%

시약·촉매·용매 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)촉매HCID 679Dimethyl Sulfoxide용매HCID 962Water용매HCID 8857Ethyl Acetate용매

실험 절차

Step FF (1): Copper(I) iodide (20 mg, 0.104 mmol), K3PO4 (67 mg, 0.316 mmol), L-proline (9.2 mg, 0.080 mmol), and DMSO (1 mL) were combined in a 1 dram vial. tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (40.7 mg, 0.192 mmol) and (1S,4R,5S,15R)-19-bromo-5-(3,5-difluoro-benzyl)-4-hydroxy-14-oxa-2,6-diaza-tricyclo[13.6.1.016,21]docosa-11,16(21),17,19-tetraen-7-one (39 mg, 0.073 mmol, TFA salt of Example 68) were added to the mixture. The vial was capped, shaken, and placed into a heating block preheated to 90° C. The reaction was allowed to stir magnetically for 16 h at 90° C. The reaction was cooled to rt, and diluted with water and EtOAc. The mixture was extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuo. The crude residue was purified by flash column chromatography on a small pre-packed silica gel column, eluted with 30% EtOAc/hexane, then 5-10% methanol/DCM. The pure fractions were pooled (Rf=0.54 in 5% methanol/DCM) and concentrated in vacuo to afford 30 mg (55% yield) of the title compound as a brown solid/residue. This material was determined to be a mixture of cis and trans isomers by proton NMR. Analytical HPLC conditions (methanol/0.1% TFA water, 4.6×50 mm, 5 micron, Waters X-Bridge C18 column, 5 mL/min, 254 nm wavelength) showed a purity of 90% and a Rt of 4.79 min.

후처리

  1. customThe vial was capped
  2. custompreheated to 90° C
  3. stirringto stir magnetically for 16 h at 90° C
  4. extractionThe mixture was extracted with EtOAc
  5. dry with materialThe combined organic layers were dried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under vacuo
  8. customThe crude residue was purified by flash column chromatography on a small pre-packed silica gel column
  9. washeluted with 30% EtOAc/hexane
  10. concentrationconcentrated in vacuo

출처 및 근거

ORD 기록
ord-72877d749c97424b957fea02ef012516
출처 데이터셋
uspto-grants-2010_08
특허 번호
US07772221B2

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