Diisopropylethylamine → N1-(3-Fluoro-4-(5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl)-N3-(4-fluoro-phenyl)malonamide

HRID 2117091

반응식

HRID 2117091 반응식
FC1C=C(NC(=O)[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:22])C=CC=1OC1C2SC=CC=2N=CN=1.[F:32][C:33]1[CH:34]=[C:35]([NH:52][C:53](NC(=O)CC2C=CC(F)=CC=2)=S)[CH:36]=[CH:37][C:38]=1[O:39][C:40]1[C:45]2=[C:46]([CH3:51])[C:47](OC)=[CH:48][N:44]2[N:43]=[CH:42][N:41]=1.C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C([O:87]N1N=NC2C1=CC=CC=2)=[N+](C)C)C>CN(C=O)C>[F:32][C:33]1[CH:34]=[C:35]([NH:52][C:53](=[O:87])[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:22])[CH:36]=[CH:37][C:38]=1[O:39][C:40]1[C:45]2=[C:46]([CH3:51])[CH:47]=[CH:48][N:44]2[N:43]=[CH:42][N:41]=1

참가 물질

6

반응물 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 116271861-(3-Fluoro-4-(6-methoxy-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea2회HCID 58798989N-(3-Fluoro-4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl)-N3-(4-fluorophenyl)malonamide2회

생성물 1

HCID 11546617N1-(3-Fluoro-4-(5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl)-N3-(4-fluoro-phenyl)malonamide수율 75.4%

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

실험 절차

To a homogeneous solution of 3-fluoro-4-(5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (52 mg, 0.20 mmol, Compound B of Example 28) and 3-(4-fluorophenylamino)-3-oxopropanoic acid (39 mg, 0.20 mmol, Compound A of Example 25) in anhydrous DMF (2 mL), at room temperature under nitrogen atmosphere, was added diisopropylethylamine (52 μL, 0.30 mmol). The mixture was stirred for 5 minutes before o-benzotriazol-l-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (96 mg, 0.30 mmol) was added in one portion. The mixture was stirred for 17.5 h before the reaction was concentrated in vacuo to remove volatiles. The resultant residue was diluted with ethyl acetate and washed twice with 10% aqueous lithium chloride before being concentrated in vacuo. Purification by silica gel (Merck KGaA, 230-400 mesh particle size) flash chromatography, eluting with 1% methanol in chloroform, afforded an off-white solid that was triturated and sonicated in the presence of anhydrous ethyl ether (3 mL). The title compound (66 mg, 75%) was isolated by filtration as a white solid. 1H NMR (CDCl3) δ 9.28 (s, 1H), 8.67 (s, 1H), 7.83 (s, 1H), 7.80-7.73 (m, 1H), 7.67 (d, 1H, J=2.5 Hz), 7.54-7.49 (m, 2H), 7.28-7.26 (m, 2H), 7.10-7.02 (m, 2H), 6.64 (d, 1H, J=2.3 Hz), 3.56 (s, 2H), 2.60 (s, 3H); HRMS(ESI), 436.1221 (M+H)+ calc, 436.1230 (M+H)+ found.

후처리

  1. additionwas added in one portion
  2. concentrationwas concentrated in vacuo
  3. customto remove volatiles
  4. additionThe resultant residue was diluted with ethyl acetate
  5. washwashed twice with 10% aqueous lithium chloride
  6. concentrationbefore being concentrated in vacuo
  7. customPurification by silica gel (Merck KGaA, 230-400 mesh particle size) flash chromatography
  8. washeluting with 1% methanol in chloroform
  9. customafforded an off-white solid
  10. customthat was triturated
  11. customsonicated in the presence of anhydrous ethyl ether (3 mL)

출처 및 근거

ORD 기록
ord-db9bc08d80ad43bcb0ecd4911d5d5b2f
출처 데이터셋
uspto-grants-2008_10
특허 번호
US07439246B2

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