HCID 11402477, compound → HCID 67451763, compound

HRID 869159Notes

Reaction equation

HRID 869159 reaction equation
[Li]C(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:19])=[CH:9][N:8]=1.Cl[C:21]1[N:26]=[N:25][C:24]([N:27]([CH2:35][C:36]2([C:40]3[C:45]([F:46])=[CH:44][CH:43]=[CH:42][N:41]=3)[CH2:39][CH2:38][CH2:37]2)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][CH:22]=1>[Cl-].[Zn+2].[Cl-].C1COCC1>[CH3:19][C:14]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([C:21]3[N:26]=[N:25][C:24]([N:27]([CH2:35][C:36]4([C:40]5[C:45]([F:46])=[CH:44][CH:43]=[CH:42][N:41]=5)[CH2:39][CH2:38][CH2:37]4)[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:23][CH:22]=3)=[N:8][CH:9]=2)[C:17]([CH3:18])=[CH:16][CH:15]=1

Participants

6

Reactant 3

HCID 11402477HCID 11402477, compoundHCID 86686131HCID 86686131, compoundHCID 178418306HCID 178418306, compound

Product 1

HCID 67451763HCID 67451763, compoundYield 463.5%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

THF (8.5 mL) was cooled to −78° C. under a nitrogen atmosphere. tBuLi (1.7 mL, 2.9 mmol, 2.0 equiv) was added, followed by the addition of 2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (370 mg, 1.47 mmol, 1.0 equiv dissolved in 2 mL THF) over 2 min. The reaction as stirred for 45 min at −78° C. Zinc chloride (510 mg, 3.75 mmol, 2.5 equiv dissolved in 5 mL of THF) was added and the reaction was allowed to warm to rt and stirred for 3 h. (t-Bu3P)2Pd (41 mg, 0.015 mmol, 0.10 equiv dissolved in 5 mL of THF) and t-butyl 6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (393 mg, 0.1 mmol, 0.07 equiv dissolved in 5 mL of THF) were added and the reaction was refluxed for 4 h followed by dilution with sodium bicarbonate (20 mL), and extraction with ethyl acetate (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (35% EtOAc/hexanes) to give 245 mg (46%) of tert-butyl 6-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.

Workup

  1. customThe reaction
  2. temperatureto warm to rt
  3. additionwere added
  4. temperaturethe reaction was refluxed for 4 h
  5. extractionfollowed by dilution with sodium bicarbonate (20 mL), and extraction with ethyl acetate (40 mL)
  6. dry with materialThe organic layer was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give a crude solid that
  10. customwas purified by silica gel column chromatography (35% EtOAc/hexanes)

Sources & evidence

ORD record
ord-9f11abf9965b432fbc3aabe15cebc3fe
Source dataset
uspto-grants-2015_03
Patent number
US08969346B2

Reaction notes

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