Diisopropylethylamine → HCID 178490952, Verbindung

HRID 1943408Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1943408
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.BrC1C2N(C(C(NC3C=CN=CC=3F)=O)=CN=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(CC)C(C)C)(C)C.[NH2:65][C@H:66]1[CH2:71][CH2:70][C@H:69]([NH2:72])[CH2:68][CH2:67]1>CN(C=O)C.O>[NH2:65][C@H:66]1[CH2:71][CH2:70][C@H:69]([NH:72][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)[CH2:68][CH2:67]1

Komponenten

8

Edukt 5

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-carboxamideHCID 178511674HCID 178511674, Verbindung

Produkt 1

HCID 178490952HCID 178490952, VerbindungAusbeute 63 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterLösungsmittel2×HCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

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 8A (3 g, 8.6 mmol), N-(4-methoxybenzyl)cyclopropanamine (1.79 g, 10.12 mmol) and N,N-diisopropylethylamine (2.41 mL, 13.80 mmol) were suspended in DMF (30 mL) and heated at 80° C. for 1 hr. The reaction mixture was concentrated, dried under reduced pressure for 16 hrs, suspended in methanol (20 mL) and an off-white solid collected via Buchner filtration (2×10 mL methanol rinse) and taken to the next step without further purification. The reaction mixture was combined with trans-1,4-diaminocyclohexane (16.28 g, 143 mmol) and heated at 160° C. for 2.5 hours. The reaction was cooled to room temperature, and water (40 mL) was added, and the solid collected via Buchner filtration. The crude product was purified with silica gel chromatography using a stepwise gradient of 10% methanol/chloroform to 25% methanol/chloroform/1% triethylamine to isolated a foamy solid. The solid was suspended in water (50 mL) and collected with Buchner filtration (2×25 mL water wash) and dried for 16 hrs under reduced pressure to isolate 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (3.2 g, 5.58 mmol, 63% yield) as a 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=1.68 (M+H=545.22).

Aufarbeitung

  1. concentrationThe reaction mixture was concentrated
  2. customdried under reduced pressure for 16 hrs
  3. filtrationan off-white solid collected via Buchner filtration (2×10 mL methanol rinse)
  4. customtaken to the next step without further purification
  5. temperatureheated at 160° C. for 2.5 hours
  6. temperatureThe reaction was cooled to room temperature
  7. filtrationthe solid collected via Buchner filtration
  8. customThe crude product was purified with silica gel chromatography
  9. customto isolated a foamy solid
  10. filtrationcollected with Buchner filtration (2×25 mL water wash)
  11. customdried for 16 hrs under reduced pressure

Quellen und Nachweise

ORD-Eintrag
ord-5497f8fb0d424a7b8ed3db2648ee52e8
Quelldatensatz
uspto-grants-2013_03
Patentnummer
US08389527B2

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