Methyl iodide → 6-(Methoxymethyl)-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-3-carbonitrile

HRID 2183477Notes

Reaction equation

HRID 2183477 reaction equation
[OH:1][CH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[CH3:29]C([O-])(C)C.[K+].CI>CN(C=O)C.C1COCC1>[CH3:29][O:1][CH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1

Participants

5

Reactant 3

HCID 6328Methyl iodide2×HCID 221795096-(Hydroxymethyl)-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-3-carbonitrileHCID 23665647Potassium tert-butoxide2×

Product 1

HCID 221795656-(Methoxymethyl)-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-3-carbonitrile

Reagents, catalysts & solvents 1

HCID 21974620tetrahydrofuran N,N-dimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of compound 3B (9.0 mg, 0.025 mmol) in DMF:THF (1:1, 1 mL) at 0° C. was added KOtBu (1.5 M in THF, 0.025 mL, 0.038 mmol). After stirring for 45 min at 0° C., methyl iodide (2 μL, 0.025 mmol) was added and the reaction mixture was stirred for an additional 1 h, warmed to 25° C., and stirred for 3 h. No reaction was observed during this time. The reaction mixture was cooled once more to 0° C., additional KOtBu (1.5 M in THF, 0.25 mL, 0.38 mmol) was added and the reaction mixture was stirred for 30 min, after which time additional methyl iodide (20 μL, 0.25 mmol) was added. After stirring for an additional 2 h at 0° C., the reaction was quenched by the addition of saturated aqueous NH4Cl (10 mL) and dichloromethane (10 mL). The layers were separated, the aqueous phase was extracted with dichloromethane (2×10 mL) and the combined organic extracts were dried over MgSO4, filtered, concentrated, and purified by preparative HPLC (YMC S5 ODS 20×100 mm, eluting with 30-100% aqueous methanol over 15 min containing 0.1% TFA, 20 mL/min) to afford the desired product as a yellow semi-solid. HPLC: 100% at 4.27 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 385.21 [M+H]+.

Workup

  1. stirringthe reaction mixture was stirred for an additional 1 h
  2. temperaturewarmed to 25° C.
  3. stirringstirred for 3 h
  4. temperatureThe reaction mixture was cooled once more to 0° C.
  5. stirringthe reaction mixture was stirred for 30 min
  6. stirringAfter stirring for an additional 2 h at 0° C.
  7. customthe reaction was quenched by the addition of saturated aqueous NH4Cl (10 mL) and dichloromethane (10 mL)
  8. customThe layers were separated
  9. extractionthe aqueous phase was extracted with dichloromethane (2×10 mL)
  10. dry with materialthe combined organic extracts were dried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. custompurified by preparative HPLC (YMC S5 ODS 20×100 mm, eluting with 30-100% aqueous methanol over 15 min containing 0.1% TFA, 20 mL/min)

Sources & evidence

ORD record
ord-511b8cf8b7264cfb979bfe197ca96740
Source dataset
uspto-grants-2005_05
Patent number
US06900208B2

Reaction notes

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