Diisopropylethylamine → HCID 178490952, compound

HRID 1943492Notes

Reaction equation

HRID 1943492 reaction equation
Cl[C:2]1[CH:3]=[C:4](Cl)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.BrC1C2[N:25]([C:30]([C:33](NC3C=CN=CC=3F)=O)=[CH:31]N=2)N=C(Cl)C=1.[CH3:43][O:44][C:45]1[CH:55]=[CH:54][C:48]([CH2:49][NH:50][CH:51]2[CH2:53][CH2:52]2)=[CH:47][CH:46]=1.C([N:59](CC)[CH:60]([CH3:62])[CH3:61])(C)C>CN(C=O)C.O>[NH2:25][C@H:30]1[CH2:33][CH2:61][C@H:60]([NH:59][C:2]2[CH:3]=[C:4]([N:50]([CH:51]3[CH2:53][CH2:52]3)[CH2:49][C:48]3[CH:54]=[CH:55][C:45]([O:44][CH3:43])=[CH:46][CH:47]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:62][CH2:31]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 4721289N-((4-methoxyphenyl)methyl)cyclopropanamineHCID 596244958-Bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamideHCID 596245496,8-Dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Product 1

HCID 178490952HCID 178490952, compoundYield 58.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
160 °C

Procedure

A ˜1:1 mixture of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide) and 8-bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (850 mg, 2.61 mmol, 5A), N-(4-methoxybenzyl)cyclopropanamine (508 mg, 2.87 mmol) and N,N-diisopropylethylamine (0.683 mL, 3.91 mmol) were heated in DMF (10 mL) at 80° C. After 1 hr, the reaction mixture was concentrated to dryness under reduced pressure, suspended in methanol (20 mL), and the solid was isolated via Buchner filtration. The solid was combined with 4.8 g of trans-cyclohexane)-1,4-diamine and heated at 160° C. After 2.5 hrs, the reaction was cooled to room temperature, suspended in water (20 mL), and the isolated solid was purified with silica gel chromatography (10% methanol to 20% methanol/chloroform). The desired fractions were concentrated, and the solid suspended in water (25 mL), and filtered to isolate 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (834 mg, 1.531 mmol, 58.8% yield) as an off-white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.69 minutes. [M+H]=545.35.

Workup

  1. concentrationthe reaction mixture was concentrated to dryness under reduced pressure
  2. customthe solid was isolated via Buchner filtration
  3. waitAfter 2.5 hrs
  4. temperaturethe reaction was cooled to room temperature
  5. customthe isolated solid was purified with silica gel chromatography (10% methanol to 20% methanol/chloroform)
  6. concentrationThe desired fractions were concentrated
  7. filtrationfiltered

Sources & evidence

ORD record
ord-59d9c53b4f364ab9b8562ba8102119ad
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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