3-(Tert-butyldimethylsilyloxy)-2,2-dimethylpropyl methanesulfonate → tert-butyl (2S,4S)-4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfanyl}-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)piperidine-1-carboxylate

HRID 906470Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 906470
[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13][C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:16]([CH2:27][O:28][Si:29]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15]1.CS(O[CH2:51][C:52]([CH3:63])([CH3:62])[CH2:53][O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:51][C:52]([CH3:63])([CH3:62])[CH2:53][O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:56])[CH3:57])[CH:6]=[C:5]2[S:13][C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C@H:16]([CH2:27][O:28][Si:29]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15]1

Komponenten

3

Edukt 2

HCID 574399153-(Tert-butyldimethylsilyloxy)-2,2-dimethylpropyl methanesulfonateHCID 86640978tert-Butyl (2S,4S)-4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfanyl]-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)piperidine-1-carboxylate

Produkt 1

HCID 86640980tert-butyl (2S,4S)-4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfanyl}-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)piperidine-1-carboxylateAusbeute 99,7 %

Versuchsvorschrift

tert-Butyl (2S,4S)-4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfanyl]-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)piperidine-1-carboxylate (Example 67e, 0.68 g) and 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropyl methanesulfonate (0.315 g) were reacted by the method of Example 58c to afford crude tert-butyl (2S,4S)-4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfanyl}-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)piperidine-1-carboxylate (0.87 g) as a colourless oil. This was reacted with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.306 g) by the method of Example 58d to afford tert-butyl (2S,4S)-4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclo-ropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfanyl)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)piperidine-1-carboxylate as a colourless oil. This was diluted in ethanol (3 mL) and treated with 4M HCl in dioxane (1 mL) and stirred at room temperature for 20 h. The volatiles were removed in vacuo. The crude material was dissolved in methanol (2 mL) and loaded on to a 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. The product was eluted with 1N methanolic ammonia (75 mL) and the solvents evaporated in vacuo. Purification by preparative HPLC (Gemini-NX C18 column using a 95-5% gradient of aqueous 0.1% ammonia in methanol as eluent) afforded the title compound (32 mg) as a white solid.

Quellen und Nachweise

ORD-Eintrag
ord-649a89697d294cb697bae5064fde7b82
Quelldatensatz
uspto-grants-2011_09
Patentnummer
US08012980B2

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