Dichloromethane → HCID 86687730, compound

HRID 1473657Notes

Reaction equation

HRID 1473657 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:40][CH3:41])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4OC)[C:22]4[S:23][C:24]([F:27])=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:39])[NH:10][N:9]=2)[CH:7]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:40][CH3:41])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:23][C:24]([F:27])=[CH:25][N:26]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[C:11](=[O:39])[NH:10][N:9]=2)[CH:7]=1

Participants

4

Reactant 3

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 86687731HCID 86687731, compound

Product 1

HCID 86687730HCID 86687730, compoundYield 2.7%

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. customPurification
  2. customto afford impure product
  3. customThe product was purified further by RPLC on the acidic Gilson
  4. additionFractions containing the product
  5. washwashed with sat. NaHCO3
  6. extractionThe product was extracted with DCM
  7. washThe organic phase was washed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-8d73db52a1a54eb58176326d711c0672
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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