Isopropyl iodide → ethyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoate

HRID 511575

반응식

HRID 511575 반응식
[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]2)[O:12]1.C(=O)([O-])[O-].[K+].[K+].[CH:40](I)([CH3:42])[CH3:41]>C(#N)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH:40]([CH3:42])[CH3:41])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]2)[O:12]1

참가 물질

5

반응물 3

HCID 6362Isopropyl iodide2회HCID 11430Potassium CarbonateHCID 67774002ethyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate

생성물 1

HCID 67775331ethyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoate수율 15%

시약·촉매·용매 1

HCID 6342Acetonitrile용매

반응 조건

온도
90 °C

실험 절차

A solution of the above crude ethyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate in acetonitrile (30 mL) was treated with potassium carbonate (6.3 g, 46 mmol) and isopropyl iodide (3.9 mL, 39 mmol). The reaction mixture in a sealed tube was heated at 90° C. for 6.5 h; HPLC indicated a 4:1 mixture of product to starting material. The reaction mixture was stirred overnight (17.5 h) at rt, treated with additional isopropyl iodide (2.0 mL, 20 mmol), and heated at 90° C. for 3 h; HPLC/LC MS indicated nearly complete conversion. The reaction mixture was cooled to rt and the solids were removed by vacuum filtration, rinsing with CH3CN, and the filtrate was concentrated in vacuo to afford a dull orange oil with precipitate. Purification by column chromatography (5×14.5 cm silica; 0-10% 7 N methanolic NH3/CH2Cl2) afforded the title compound (0.49 g, 15%) as a white foam/colorless oil. The mixed fractions containing product were repurified by column chromatography (4×10.5 cm silica; 0-5% 7 N methanolic NH3/CH2Cl2) to afford the title compound (1.66 g, 40%) as a white foam/colorless oil contaminated with the bisreductive amination byproduct from Step 1: MS (ESI+) for C25H38N6O5 m/z 503.2 (M+H)+.

후처리

  1. additiona 4:1 mixture of product
  2. temperatureheated at 90° C. for 3 h
  3. temperatureThe reaction mixture was cooled to rt
  4. customthe solids were removed by vacuum filtration
  5. washrinsing with CH3CN
  6. concentrationthe filtrate was concentrated in vacuo
  7. customto afford a dull orange oil with precipitate
  8. customPurification by column chromatography (5×14.5 cm silica; 0-10% 7 N methanolic NH3/CH2Cl2)

출처 및 근거

ORD 기록
ord-f48243289ecd48afa4548e92d254a4db
출처 데이터셋
uspto-grants-2015_08
특허 번호
US09096634B2

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