Diisopropylethylamine → tert-Butyl (4-(2-(((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoacetyl)thiazol-2-yl)carbamate

HRID 708317Notes

Reaction equation

HRID 708317 reaction equation
[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:18])[C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:52]1([CH2:57][C@H:58]2[NH:61][C:60](=[O:62])[C@H:59]2[NH2:63])[CH:56]=[N:55][CH:54]=[N:53]1>C(Cl)Cl.CN(C=O)C.CN(C=O)C>[N:52]1([CH2:57][C@@H:58]2[C@H:59]([NH:63][C:15](=[O:17])[C:14]([C:12]3[N:13]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[S:10][CH:11]=3)=[O:18])[C:60](=[O:62])[NH:61]2)[CH:56]=[N:55][CH:54]=[N:53]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 148521192-(2-((Tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acidHCID 118390218(3S,4R)-4-((1H-1,2,4-triazol-1-yl)methyl)-3-aminoazetidin-2-one

Product 1

HCID 118390898tert-Butyl (4-(2-(((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoacetyl)thiazol-2-yl)carbamateYield 68%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 22350042dichloromethane N,N-dimethylformamideSolvent2×

Procedure

To a slurry of 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (2.72 g, 9.99 mmol) and HATU (3.80, 10.0 mmol) in DCM:DMF (3:1, 33.3 mL) at 0° C. was added DIPEA (2.91 mL, 16.7 mmol). A soln of (3S,4R)-4-((1H-1,2,4-triazol-1-yl)methyl)-3-aminoazetidin-2-one (1.39 g, 8.33 mmol) in DCM:DMF (1:1, 32 mL) was added followed by a DMF (3 mL) wash. After stirring for 48 h the dark solution was diluted with EtOAc (150 mL)/brine (140 mL) and the layers were separated. The aqueous was extracted with EtOAc (3×) and the combined organic layers were washed with brine (70 mL). The brine layer wash was re-extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concd in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-10%), affording the title compound (2.38 g, 68%) as a red solid. LCMS: Rt=0.59 min, m/z=422.0 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.70 (d, J=9.3 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 5.28 (ddd, J=9.3, 5.2, 1.5 Hz, 1H), 4.45 (dd, J=14.2, 5.3 Hz, 1H), 4.36 (dd, J=14.1, 7.6 Hz, 1H), 4.18 (dt, J=7.6, 5.3 Hz, 1H), 1.47 (s, 9H).

Workup

  1. washwash
  2. additionwas diluted with EtOAc (150 mL)/brine (140 mL)
  3. customthe layers were separated
  4. extractionThe aqueous was extracted with EtOAc (3×)
  5. washthe combined organic layers were washed with brine (70 mL)
  6. washThe brine layer wash
  7. extractionwas re-extracted with EtOAc
  8. dry with materialThe combined organic layers were dried over Na2SO4 and concd in vacuo
  9. customThe crude residue was purified via silica gel chromatography (MeOH-DCM, 0-10%)

Sources & evidence

ORD record
ord-3a24ef0a72a34b638b84faad7be772ff
Source dataset
uspto-grants-2015_11
Patent number
US09174978B2

Reaction notes

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