Diisopropylethylamine → (S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one

HRID 270509Notes

Reaction equation

HRID 270509 reaction equation
[Si:1]([O:18][C@@H:19]([CH3:23])[C:20]([OH:22])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.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:57]([CH2:60][CH2:61][CH2:62][C:63]1([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[NH:67][N:66]=[C:65]([C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=2[F:75])[S:64]1)=[N+:58]=[N-:59]>C(#N)C>[N:57]([CH2:60][CH2:61][CH2:62][C@:63]1([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[N:67]([C:20](=[O:22])[C@@H:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:23])[N:66]=[C:65]([C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=2[F:75])[S:64]1)=[N+:58]=[N-:59]

Participants

6

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 11232725Propanoic acid, 2-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-, (2S)-HCID 866048312-(3-Azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole

Product 1

HCID 86604833(S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-oneYield 25.1%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

To a solution of (S)-2-(t-butyldiphenylsilyloxy)propanoic acid (339 mg, 1.09 mmol) in acetonitrile (6 mL) was added HATU (550 mg, 1.45 mmol) followed by DIEA (0.378 mL, 2.17 mmol). After stirring at room temperature for 15 minutes, a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (260 mg, 0.72 mmol) in acetonitrile (4 mL) was added. After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO3 (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The brown oil was chromatographed (9:1 hexanes/ethyl acetate) to provide the less polar diastereomer, (S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (121 mg) and the more polar diastereomer, (S)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (175 mg) as pale yellow oils. Absolute stereochemistry was assigned by examination of a protein:inhibitor co-crystal structure of Eg5 and (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Workup

  1. stirringAfter stirring at room temperature for 16 hours
  2. concentrationthe mixture was concentrated under reduced pressure
  3. custompartitioned between saturated NaHCO3 (50 mL) and ethyl acetate (50 mL)
  4. extractionThe aqueous layer was extracted with ethyl acetate (2×30 mL)
  5. washthe combined organic phases were washed with brine (20 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe brown oil was chromatographed (9:1 hexanes/ethyl acetate)

Sources & evidence

ORD record
ord-f8cca52a4c7643b8b7dac896b5b5d9c8
Source dataset
uspto-grants-2008_11
Patent number
US07449486B2

Reaction notes

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