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 246091노트

반응식

HRID 246091 반응식
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

참가 물질

8

반응물 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

생성물 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]-amide수율 70%

시약·촉매·용매 3

HCID 962Water용매HCID 6342Acetonitrile용매HCID 8857Ethyl Acetate용매

실험 절차

(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).

후처리

  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)

출처 및 근거

ORD 기록
ord-c1b0567da66d4951a5a84377be22e976
출처 데이터셋
uspto-grants-2014_02
특허 번호
US08658646B2

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