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

HRID 1502303노트

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HRID 1502303 반응식
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]

참가 물질

7

반응물 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

생성물 1

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

시약·촉매·용매 1

HCID 8003Pentane용매

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온도
-15 °C

실험 절차

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).

후처리

  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)

출처 및 근거

ORD 기록
ord-7a8f5e713d054cfaa2479bd66af4202c
출처 데이터셋
uspto-grants-2015_12
특허 번호
US09206175B2

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