Lithium Hexamethyldisilazide → HCID 86687729, compound

HRID 1473656Notes

Reaction equation

HRID 1473656 reaction equation
[F:1][C:2]1[S:6][C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:50][CH3:51])=[C:22]([C:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[C:27](=[O:49])[NH:26][N:25]=2)[CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:50][CH3:51])=[C:22]([C:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34]([N:7]([C:5]4[S:6][C:2]([F:1])=[CH:3][N:4]=4)[CH2:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[C:27](=[O:49])[NH:26][N:25]=2)[CH:23]=1

Participants

5

Reactant 3

HCID 2733832Lithium Hexamethyldisilazide2×HCID 86687419HCID 86687419, compoundHCID 86687720HCID 86687720, compound

Product 1

HCID 86687729HCID 86687729, compoundYield 59%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A vial was charged with 5-fluoro-N-(4-methoxybenzyl)thiazol-2-amine (67.1 mg, 0.282 mmol), perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (100 mg, 0.188 mmol), and THF (938 μl). The resulting solution was cooled to 0° C. for 10 min. Then lithium bis(trimethylsilyl)amide (1M in THF) (413 μl, 0.413 mmol) was added drop wise. LCMS after 15 min showed incomplete conversion of SM. Additional LHMDS (400 μL, 1M in THF) was added. After 15 min, TLC showed complete conversion of PFP-sulfonate to a lower spot. 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-(5-fluorothiazol-2-yl)-N-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (65 mg, 59.0% yield) as a brown solid. m/z (ESI) 587.0 (M+H)+, 609.0 (M+Na)+. 1-(5-Chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(5-fluorothiazol-2-yl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (65 mg, 0.105 mmol) was dissolved in DCM (1053 μl, 0.105 mmol) and then TFA (40.6 μl, 0.527 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 impure product. The product was purified further by RPLC on the acidic Gilson. Fractions containing the product were combined and washed with sat. NaHCO3. The product was extracted with DCM. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated to afford 1-(5-chloro-2-methoxyphenyl)-N-(5-fluorothiazol-2-yl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (1.3 mg, 2.64% yield) as off-white solid. m/z (ESI) 467.0 (M+H)+.

Workup

  1. waitAfter 15 min
  2. customThe crude material was absorbed onto a plug of silica gel
  3. custompurified by chromatography through a Redi-Sep pre-packed silica gel column (12 g)
  4. washeluting with a gradient of 0% to 70% EtOAc in heptane

Sources & evidence

ORD record
ord-7143e25990e144c08f6a496b807d25c1
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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