2,6-Diaminopyridine → 6-(6-Aminopyridin-2-ylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrile

HRID 889452노트

반응식

HRID 889452 반응식
Cl[C:2]1[CH:3]=[C:4]([N:13]([CH:23]2[CH2:25][CH2:24]2)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[N:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:33].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[NH2:33][C:27]1[N:26]=[C:31]([NH:32][C:2]2[CH:3]=[C:4]([N:13]([CH:23]3[CH2:25][CH2:24]3)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH:30]=[CH:29][CH:28]=1

참가 물질

8

반응물 4

HCID 88612,6-DiaminopyridineHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 593137576-Chloro-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrile

생성물 1

HCID 593138346-(6-Aminopyridin-2-ylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrile수율 23.4%

시약·촉매·용매 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)촉매HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 80711,2-Dimethoxyethane용매

반응 조건

온도
125 °C

실험 절차

A sealed tube was charged with DME (1.5 mL) and purged with argon. The vessel was then charged with 1G (0.050 g, 0.14 mmol), pyridine-2,6-diamine (0.039 g, 0.35 mmol), cesium carbonate (0.184 g, 0.57 mmol), copper(I) iodide (0.013 g, 0.071 mmol), Xantphos (0.016 g, 0.028 mmol), and Pd2(dba)3 (0.013 g, 0.014 mmol), in one portion. The resulting suspension was pump/purged with argon three times. The cap was placed on the vessel, and the suspension heated to 125° C. overnight. The solids were filtered off, and the filtrate was concentrated in vacuo. The crude product was dissolved in a small amount of DCM and charged to a 24 g silica gel cartridge which was eluted at 30 mL/min with a 20 min gradient from 100% DCM to 60% EtOAc/DCM, monitoring at 254 nm, affording 2A (0.014 g, 23% yield) as a tan solid. HPLC: Rt=3.62 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=427.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.19-8.28 (1 H, m), 7.41 (1H, s), 7.03-7.12 (3H, m), 6.96-7.03 (1H, m), 6.79-6.86 (2H, m), 6.13 (1H, s), 5.49 (2H, s), 3.68 (3H, s), 3.49-3.65 (3H, m), 2.45 (1H, d, J=3.78 Hz), 0.91-0.98 (2H, m), 0.74 (2H, m).

후처리

  1. custompurged with argon
  2. customThe resulting suspension was pump/purged with argon three times
  3. filtrationThe solids were filtered off
  4. concentrationthe filtrate was concentrated in vacuo
  5. dissolutionThe crude product was dissolved in a small amount of DCM
  6. additioncharged to a 24 g silica gel cartridge which
  7. washwas eluted at 30 mL/min with a 20 min gradient from 100% DCM to 60% EtOAc/DCM

출처 및 근거

ORD 기록
ord-db7ee7376dd24e708a15ba16c005d841
출처 데이터셋
uspto-grants-2012_08
특허 번호
US08252795B2

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