Acetic Anhydride → 5-(3-(Cyclopropanecarboxamido)isoquinolin-7-yl)-6-methylpyridin-3-yl acetate

HRID 468785ノート

反応式

HRID 468785 の反応式
B(F)(F)F.CCOCC.N[C:11]1[CH:12]=[C:13]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[C:23]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[N:24]=[CH:25]3)=[CH:20][CH:19]=2)[C:14]([CH3:17])=[N:15][CH:16]=1.COCCOC.N(OC(C)(C)C)=O.[C:47]([O:50]C(=O)C)(=[O:49])[CH3:48]>CCCCC>[C:47]([O:50][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[C:13]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[C:23]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[N:24]=[CH:25]3)=[CH:20][CH:19]=2)[CH:12]=1)(=[O:49])[CH3:48]

参加物

7

反応物 5

HCID 7918Acetic AnhydrideHCID 8000Boron trifluoride etherateHCID 80711,2-DimethoxyethaneHCID 10906Tert-Butyl nitriteHCID 57411326N-(7-(5-amino-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

生成物 1

HCID 679748595-(3-(Cyclopropanecarboxamido)isoquinolin-7-yl)-6-methylpyridin-3-yl acetate

試薬・触媒・溶媒 1

HCID 8003Pentane溶媒

反応条件

温度
-15 °C

実験手順

To a flask containing boron trifluoride etherate (0.100 mL, 0.789 mmol) at −15° C. (brine/ice bath) was added a solution of N-(7-(5-amino-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (119.1 mg, 0.3741 mmol) in 1,2-dimethoxyethane (1.0 mL, 9.6 mmol). tert-Butyl nitrite (67.0 uL, 0.563 mmol) was then added dropwise and the reaction mixture was stirred at −15° C. for one hour. 3 mL pentane was added and the mixture stirred for 5 minutes. The pentane layer was decanted, and the remaining oil was then dissolved in acetic anhydride (0.60 mL, 6.4 mmol) and stirred at 100° C. for 1.5 hours. The solvent was evaporated in vacuo, and the residue was suspended in 2M aqueous Na2CO3 and extracted twice with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to yield 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-6-methylpyridin-3-yl acetate. This material was dissolved in tetrahydrofuran (3 mL, 40 mmol) and 1.0 M of lithium hydroxide in Water (1.0 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then neutralized with 10% aqueous citric acid and extracted 3× with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 30-100% ethyl acetate in dichloromethane) followed by reverse phase HPLC to yield 3.3 mg (3%) of N-(7-(5-hydroxy-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=3.237, M+H=320.1, method=E; 1H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 9.17 (s, 1H), 8.49 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.6 Hz, 1H), 7.69 (d, J=9.7 Hz, 1H), 7.04 (s, 1H), 2.33 (s, 3H), 2.14-2.03 (m, 1H), 0.91-0.78 (m, 4H).

後処理

  1. stirringthe mixture stirred for 5 minutes
  2. customThe pentane layer was decanted
  3. stirringstirred at 100° C. for 1.5 hours
  4. customThe solvent was evaporated in vacuo
  5. extractionextracted twice with dichloromethane
  6. dry with materialThe combined organic extracts were dried over MgSO4
  7. filtrationfiltered
  8. customevaporated in vacuo
  9. customThe crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane)

出典と根拠

ORDレコード
ord-fe6b806fd5c44b82addb85875518e29e
出典データセット
uspto-grants-2014_01
特許番号
US08623889B2

反応ノート

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