Triphenylphosphine → tert-Butyl 8-((6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

HRID 920245Notes

Reaction equation

HRID 920245 reaction equation
[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:51][CH:52]1[C:61]2[C:56](=[C:57]([CH2:62]O)[CH:58]=[CH:59][CH:60]=2)[CH2:55][N:54]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:53]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[N:14]([CH2:62][C:57]3[CH:58]=[CH:59][CH:60]=[C:61]4[C:56]=3[CH2:55][N:54]([C:64]([O:66][C:67]([CH3:69])([CH3:68])[CH3:70])=[O:65])[CH2:53][CH:52]4[F:51])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:8])=[O:9]

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 97268Di-tert-butyl azodicarboxylateHCID 89525954N-(2,4-dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamideHCID 89526277tert-Butyl 4-fluoro-8-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Product 1

HCID 89526063tert-Butyl 8-((6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a flask containing N-(2,4-dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (11-3) (87 mg, 0.187 mmol), resin bound (PS) TRIPHENYLPHOSPHINE (159 mg, 0.350 mmol), tert-butyl 4-fluoro-8-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-7) (89 mg, 0.316 mmol) & DI-TERT-BUTYL AZODICARBOXYLATE (97 mg, 0.421 mmol) was added THF (2 mL). The reaction mixture was then capped (not under N2) & agitated at room temperature. Followed by LC/MS. After ˜10 min at room temp r×n mixture (clear tan & resin), filtered (to remove resin), then concentrated. Purification by silica gel chromatography (0-50%; EtOAc/Hex; 24 g ISCO); desired fractions concentrated, then the resulting residue was repurified by reverse phase chromatography (10-100% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions free based (suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated) to yield tert-butyl 8-((6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-8).

Workup

  1. customThe reaction mixture was then capped (not under N2) &
  2. filtrationfiltered
  3. custom(to remove resin)
  4. concentrationconcentrated
  5. customPurification by silica gel chromatography (0-50%; EtOAc/Hex; 24 g ISCO)
  6. concentrationdesired fractions concentrated
  7. customthe resulting residue was repurified by reverse phase chromatography (10-100% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column)
  8. washwashed with saturated NaHCO3
  9. dry with materialorganics dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated)

Sources & evidence

ORD record
ord-b9ad9da2357142bb8a4f5184e27da9a2
Source dataset
uspto-grants-2016_03
Patent number
US09273040B2

Reaction notes

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