Diisopropylethylamine → 2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-amide

HRID 246091ノート

反応式

HRID 246091 の反応式
FC(F)(F)C(O)=O.[NH2:8][C@H:9]([CH3:18])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11].[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([C:30]3[N:31]=[C:32]4[C:38]([C:39](O)=[O:40])=[CH:37][N:36]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:33]4=[N:34][CH:35]=3)=[N:25][N:26]2[CH3:29])=[CH:22][CH:21]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(#N)C.C(OCC)(=O)C.O>[F:17][C@H:14]1[CH2:15][CH2:16][N:12]([C:10](=[O:11])[C@H:9]([NH:8][C:39]([C:38]2[C:32]3[C:33](=[N:34][CH:35]=[C:30]([C:24]4[C:23]5[C:27](=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=5)[N:26]([CH3:29])[N:25]=4)[N:31]=3)[N:36]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:37]=2)=[O:40])[CH3:18])[CH2:13]1

参加物

8

反応物 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 712796712-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acidHCID 71280348(R)-2-amino-1-((S)-3-fluoro-pyrrolidin-1-yl)-propan-1-one trifluoroacetate

生成物 1

HCID 712861822-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-amide収率 70%

試薬・触媒・溶媒 3

HCID 962Water溶媒HCID 6342Acetonitrile溶媒HCID 8857Ethyl Acetate溶媒

実験手順

(R)-2-Amino-1-((S)-3-fluoro-pyrrolidin-1-yl)-propan-1-one trifluoroacetate (crude from Step 2) was dissolved in acetonitrile (4 ml) to which was then added 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (60 mg, 0.13 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (63 mg, 0.197 mmol) and N,N-diisopropylethylamine (0.092 ml, 0.52 mmol). The reaction was stirred at room temperature for 18 h and then water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford 55 mg (70%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-amide. 1H NMR (300 MHz, CDCl3) δ: 9.29 (s, 1H), 8.88-8.93 (m, 1H), 8.85 (d, J=8.1 Hz, 1H), 8.32 (s, 1H), 7.43-7.46 (m, 1H), 7.35-7.39 (m, 1H), 5.70-5.74 (m, 2H), 5.21-5.26 (m, 1H), 4.15 (s, 3H), 3.61-4.00 (m, 5H), 3.54-3.61 (m, 2H), 2.06-2.46 (m, 2H), 1.59 (d, J=6.6 Hz, 3H), 0.90-0.97 (m, 2H), −0.05 (s, 9H).

後処理

  1. customThe layers were separated
  2. extractionthe aqueous layer was extracted once more with ethyl acetate
  3. washThe combined organic layers were washed with sodium chloride solution
  4. dry with materialdried over sodium sulfate
  5. customAfter evaporation
  6. customthe residue was purified by silica gel chromatography (ethyl acetate/hexanes)

出典と根拠

ORDレコード
ord-c1b0567da66d4951a5a84377be22e976
出典データセット
uspto-grants-2014_02
特許番号
US08658646B2

反応ノート

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