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 572507Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 572507
[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]

Komponenten

6

Edukt 3

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

Produkt 1

HCID 68295788Methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-7-(morpholinomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetateAusbeute 79,5 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 1140TolueneLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

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).

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-7e11b9a5c0604882927bb66050fb5941
Quelldatensatz
uspto-grants-2015_05
Patentnummer
US09029391B2

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