Lithium Hexamethyldisilazide → HCID 86687726, compound

HRID 1473653Notes

Reaction equation

HRID 1473653 reaction equation
[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([O:61][CH3:62])=[C:33]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:47])=[O:46])=[CH:42][CH:43]=3)[C:38](=[O:60])[NH:37][N:36]=2)[CH:34]=1>C1COCC1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([O:61][CH3:62])=[C:33]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([N:6]([CH2:5][C:4]4[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=4[O:2][CH3:1])[C:7]4[S:11][N:10]=[CH:9][N:8]=4)(=[O:47])=[O:46])=[CH:42][CH:43]=3)[C:38](=[O:60])[NH:37][N:36]=2)[CH:34]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 57732216N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amineHCID 86687720HCID 86687720, compound

Product 1

HCID 86687726HCID 86687726, compoundYield 33.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A vial was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (70.7 mg, 0.282 mmol) and THF (938 μl). The resulting solution was cooled to −78° C. for 10 min. Then lithium bis(trimethylsilyl)amide (1M in THF) (413 μl, 0.413 mmol) was added drop wise. The vial was removed from the cold bath temporarily to ensure complete deprotonation of PMB-aminothiadiazole. When the suspension became homogenous, the reaction was cooled back down to −78° C. Then perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (100 mg, 0.188 mmol) in 0.5 mL of THF was added drop wise. LCMS after 15 min showed complete conversion of SM to product. The reaction was warmed to rt, quenched with 1 mL of MeOH and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(5-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (38 mg, 33.7% yield) as white solid. m/z (ESI) 600.0 (M+H)+, 622.0 (M+Na)+. 1-(5-Chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (38 mg, 0.063 mmol) was dissolved in DCM (633 μl, 0.063 mmol) and then TFA (24.4 μl, 0.317 mmol) was added. After 30 min at rt, LCMS showed a complete conversion of SM to product. Purification was done with 0.1% NH4OH in ACN and water as mobile phase to afford 1-(5-chloro-2-methoxyphenyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (17 mg, 59.7% yield) and NH4OH as a triplet at ˜7.07 ppm. To remove NH4OH, the product was dissolved in MeOH (1 mL) and loaded onto a 2 g SCX column. The product was flushed out with MeOH. Concentration afforded 1-(5-chloro-2-methoxyphenyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide as white solid. m/z (ESI) 450.0 (M+H)+.

Workup

  1. customThe vial was removed from the cold bath temporarily
  2. temperaturethe reaction was cooled back down to −78° C
  3. temperatureThe reaction was warmed to rt
  4. customquenched with 1 mL of MeOH
  5. concentrationconcentrated
  6. customThe crude material was absorbed onto a plug of silica gel
  7. custompurified by chromatography through a Redi-Sep pre-packed silica gel column (12 g)
  8. washeluting with a gradient of 0% to 70% EtOAc in heptane

Sources & evidence

ORD record
ord-95a24425bb3d4e048e877b4e73308dcb
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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