Diisopropylethylamine → HCID 178490952、化合物

HRID 1943408ノート

反応式

HRID 1943408 の反応式
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

参加物

8

反応物 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、化合物

生成物 1

HCID 178490952HCID 178490952、化合物収率 63%

試薬・触媒・溶媒 2

HCID 962Water溶媒2 回HCID 6228Dimethylformamide溶媒

反応条件

温度
80 °C

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-5497f8fb0d424a7b8ed3db2648ee52e8
出典データセット
uspto-grants-2013_03
特許番号
US08389527B2

反応ノート

読み込み中…