Ethylenediamine → 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide

HRID 246170ノート

反応式

HRID 246170 の反応式
[F:1][CH:2]1[CH2:5][N:4]([C:6](=[O:42])[C@H:7]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH2:8][O:9][CH3:10])[CH2:3]1.C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[F:1][CH:2]1[CH2:3][N:4]([C:6](=[O:42])[C@H:7]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH2:8][O:9][CH3:10])[CH2:5]1

参加物

5

反応物 3

HCID 3301EthylenediamineHCID 6422Trifluoroacetic acidHCID 712884162-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide

生成物 1

HCID 712884212-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide収率 65%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

実験手順

In a 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide (47 mg, 0.076 mmol) and TFA (1.2 ml, 15.6 mmol) were combined with dichloromethane (4 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (4 mL) and ethylenediamine (0.36 ml, 5.3 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (dichloromethane/heptane) to afford 24 mg (64%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide as an off-white solid. MS: [M+H]+=486; 1H NMR (300 MHz, DMSO-d6) δ: 12.85 (br. s., 1H), 9.16 (s, 1H), 8.76 (dd, J=8.7, 5.3 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.49 (s, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.24 (d, J=9.1 Hz, 1H), 5.23-5.58 (m, 1H), 4.97 (dt, J=8.1, 5.8 Hz, 1H), 4.56-4.82 (m, 1H), 4.21-4.56 (m, 2H), 4.18 (s, 3H), 3.87-4.10 (m, 1H), 3.68 (qd, J=9.8, 5.7 Hz, 2H), 3.28 (app. d, J=3.4 Hz, 3H).

後処理

  1. customto give an orange solution
  2. concentrationthen concentrated under reduced pressure
  3. dissolutionThe resultant crude solid was dissolved in dichloromethane (4 mL)
  4. stirringThe reaction mixture was stirred at room temperature for 18 h
  5. concentrationthen concentrated
  6. customthe residue was precipitated with water
  7. stirringThe suspension was stirred for 1 h
  8. filtrationthe crude solid collected by filtration
  9. customThe crude solid was purified by trituration (dichloromethane/heptane)

出典と根拠

ORDレコード
ord-542bd42ec0c74c738335abc4dc1ca2c7
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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