Bis(2-bromoethyl) ether → Methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-7-(morpholinomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate

HRID 572507ノート

反応式

HRID 572507 の反応式
[NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Br[CH2:43][CH2:44][O:45][CH2:46][CH2:47]Br>C1(C)C=CC=CC=1.CCOC(C)=O>[C:21]([O:20][CH:15]([C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]2[C:6]([C:7]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[CH:5][CH:4]=[C:3]([CH2:2][N:1]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])([CH3:22])([CH3:23])[CH3:24]

参加物

6

反応物 3

HCID 21521Bis(2-bromoethyl) ether2 回HCID 81531Diisopropylethylamine2 回HCID 68295579Methyl [7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate

生成物 1

HCID 68295788Methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-7-(morpholinomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate収率 79.5%

試薬・触媒・溶媒 2

HCID 1140Toluene溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
90 °C

実験手順

A solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (17 mg, 0.039 mmol) in toluene (750 μl) was treated with DIEA (13.60 μl, 0.078 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (5.87 μl, 0.047 mmol). The mixture was stirred at 90° C. for 6 hours. Additional DIEA (13.60 μl, 0.078 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (5.87 μl, 0.047 mmol) were added, the reaction was stirred at 90° C. overnight. The reaction was cooled to rt, diluted with EtOAc, washed with water, brine, dried with Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-10% MeOH/DCM) to afford methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-7-(morpholinomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (15.6 mg, 0.031 mmol, 79% yield). The methyl ester was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(4-(3,4-dimethyl phenyl)-2-methyl-7-(methylsulfonamidomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid (14 mg, 0.027 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.42 (s, 1 H), 7.71-7.61 (m, 1 H), 7.24-7.33 (m, 1 H), 7.26-7.17 (m, 2 H), 7.07-6.96 (m, 1 H), 5.35 (s, 1 H), 4.40-4.22 (m, 2 H), 4.03-3.81 (m, 4 H), 3.71 (s, 3 H), 3.59-3.37 (m, 2 H), 2.92 (br. s., 2 H), 2.37 (s, 3 H), 2.32 (s, 1.5 H), 2.29 (s, 1.5 H). 1.06 (s, 4.5 H), 1.05 (s, 4.5 H); LCMS (m/z) ES+=493 (M+1).

後処理

  1. stirringthe reaction was stirred at 90° C. overnight
  2. temperatureThe reaction was cooled to rt
  3. washwashed with water, brine
  4. dry with materialdried with Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by column chromatography (0-10% MeOH/DCM)

出典と根拠

ORDレコード
ord-7e11b9a5c0604882927bb66050fb5941
出典データセット
uspto-grants-2015_05
特許番号
US09029391B2

反応ノート

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