Cesium carbonate → N-Cyclopropyl-3-fluoro-5-(2-{[1-(hydroxymethyl)cyclopropyl]methyl}-4-{[(3S)-3-methylpiperazin-1-yl]methyl}-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide

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Reaktionsgleichung

Br[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[CH2:13][N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[C@@H:16]([CH3:27])[CH2:15]1.CS(O[CH2:33][C:34]1([CH2:37][O:38][Si](C(C)(C)C)(C)C)[CH2:36][CH2:35]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:52]1([NH:55][C:56](=[O:74])[C:57]2[CH:62]=[C:61](B3OC(C)(C)C(C)(C)O3)[C:60]([CH3:72])=[C:59]([F:73])[CH:58]=2)[CH2:54][CH2:53]1>CN(C=O)C.O>[CH:52]1([NH:55][C:56](=[O:74])[C:57]2[CH:62]=[C:61]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:33][C:34]3([CH2:37][OH:38])[CH2:35][CH2:36]3)[CH:6]=[C:5]4[CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:27])[CH2:15]3)[C:60]([CH3:72])=[C:59]([F:73])[CH:58]=2)[CH2:53][CH2:54]1

Komponenten

Reaktionsbedingungen

Temperatur: 75 °C

Versuchsvorschrift

A solution of tert-butyl (2S)-4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl]-2-methylpiperazine-1-carboxylate (Example 34b, 0.26 g) dissolved in DMF (5 mL) was treated with [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl methanesulfonate (example 34d, 0.351 g) and cesium carbonate (0.582 g) under nitrogen. The resulting mixture was stirred at 75° C. for 3 h. The mixture was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.266 g) and Pd-118 (0.019 g) before heating at 80° C. for 1 h. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (250 mL). The organic was dried (MgSO4), filtered and evaporated. The crude product was purified (SiO2 chromatography, elution 100% ethyl acetate). Pure fractions of [tert-butyl (2S)-4-[(6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-2-{[1-(hydroxymethyl)cyclopropyl]methyl}-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl]-2-methylpiperazine-1-carboxylate] were evaporated to dryness. The mixture was treated with trifluoroacetic acid/DCM (1:1, 10 mL) and stirred for 1 h at room temperature. The mixture was evaporated to dryness and the crude material was dissolved in acetonitrile (25 mL) and loaded on to a 10 g SCX cartridge. The impurities were washed through with acetonitrile (50 mL) and discarded. The product was eluted with 1 N methanolic ammonia (100 mL) and evaporated in vacuo. The product was purified by preparative HPLC (XBridge column using a 95-40% gradient of aqueous 0.1% ammonia in acetonitrile as eluent). The fractions were evaporated to afford the title compound (0.050 g).

Aufarbeitung

temperaturebefore heating at 80° C. for 1 h
extractionextracted with ethyl acetate (250 mL)
dry with materialThe organic was dried (MgSO4)
filtrationfiltered
customevaporated
customThe crude product was purified
wash(SiO2 chromatography, elution 100% ethyl acetate)
customPure fractions of [tert-butyl (2S)-4-[(6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-2-{[1-(hydroxymethyl)cyclopropyl]methyl}-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl]-2-methylpiperazine-1-carboxylate] were evaporated to dryness
additionThe mixture was treated with trifluoroacetic acid/DCM (1:1, 10 mL)
stirringstirred for 1 h at room temperature
customThe mixture was evaporated to dryness
dissolutionthe crude material was dissolved in acetonitrile (25 mL)
washThe impurities were washed through with acetonitrile (50 mL)
washThe product was eluted with 1 N methanolic ammonia (100 mL)
customevaporated in vacuo
customThe product was purified by preparative HPLC (XBridge column
customThe fractions were evaporated

Quellen und Nachweise

ORD-Eintrag: ord-a2dc4626653342ad88395e1596d8fe79
Quelldatensatz: uspto-grants-2011_09
DOI: 10.6084/m9.figshare.5104873.v1
Patentnummer: US08012980B2

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