Potassium Bicarbonate → Hydrochloric Acid

HRID 597870Notes

Reaction equation

HRID 597870 reaction equation
C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:43][C:44]1[CH:48]=[C:47]([NH2:49])[NH:46][N:45]=1.[ClH:50].[Cl:51][C:52]1[CH:53]=[C:54]([CH2:71][N:72]2[CH2:77][CH2:76][O:75][CH2:74][CH2:73]2)[C:55]2[N:56]([C:58]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][C:64]=3[F:70])=[C:59]([CH3:61])[N:60]=2)[N:57]=1.C(=O)(O)[O-].[K+]>CN(C=O)C.[Pd](Cl)Cl>[ClH:51].[ClH:50].[Cl:69][C:66]1[CH:67]=[CH:68][C:63]([CH2:62][C:58]2[N:56]3[N:57]=[C:52]([NH:49][C:47]4[CH:48]=[C:44]([CH3:43])[NH:45][N:46]=4)[CH:53]=[C:54]([CH2:71][N:72]4[CH2:77][CH2:76][O:75][CH2:74][CH2:73]4)[C:55]3=[N:60][C:59]=2[CH3:61])=[C:64]([F:70])[CH:65]=1

Participants

8

Reactant 4

HCID 516893Potassium BicarbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866424894-((6-Chloro-3-(4-chloro-2-fluorobenzyl)-2-methylimidazo[1,2-b]pyridazin-8-yl)methyl)morpholine hydrochlorideHCID 178418690HCID 178418690, compound

Product 2

HCID 313Hydrochloric AcidHCID 468348643-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amine hydrochloride

Reagents, catalysts & solvents 2

HCID 24290Palladium ChlorideCatalystHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
150 °C

Procedure

Prepare active catalyst by combining palladium chloride (160 mg, 0.90 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.10 g, 1.84 mmol) in DMF (25 mL) and warming to form a solution. Add the preformed catalyst to a solution of 3-methyl-1H-pyrazol-5-amine (3.0 g, 29.65 mmol), 4-((6-chloro-3-(4-chloro-2-fluorobenzyl)-2-methylimidazo[1,2-b]pyridazin-8-yl)methyl)morpholine hydrochloride (9.0 g, 20.19 mmol), potassium bicarbonate (6.0 g, 59.93 mmol) in DMF (65 mL) and heat to 150° C. for 1 h. Cool the reaction to 60° C. and add mercaptopropyl functionalized silica (500 mg) and stir for 1 h then filter to remove the silica. Cool to ambient temperature, add 2-methyltetrahydrofuran (125 mL) and extract with water to remove DMF. Add HCl to the organic solution to form the 3-(4-chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amine hydrochloride salt. Add the HCl salt (1.1 g) to sodium hydroxide (10 mL, 1N) in n-butanol (10 mL) and stir. Filter the resulting mixture to obtain 0.22 g of the free base, imidazo[1,2-b]pyridazin-6-amine, 3-[(4-chloro-2-fluorophenyl)methyl]-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(4-morpholinylmethyl), (22% yield, M+1.=470).

Workup

  1. customPrepare active catalyst
  2. temperaturewarming
  3. customto form a solution
  4. temperatureCool
  5. customthe reaction to 60° C.
  6. additionadd mercaptopropyl functionalized silica (500 mg)
  7. filtrationthen filter
  8. customto remove the silica
  9. temperatureCool to ambient temperature
  10. additionadd 2-methyltetrahydrofuran (125 mL)
  11. extractionextract with water
  12. customto remove DMF

Sources & evidence

ORD record
ord-aae758bf35bb400d8b3c44f218d55e75
Source dataset
uspto-grants-2011_03
Patent number
US07897600B2

Reaction notes

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