Naphthyridines as integrin antagonists
A compound, naphthyridine technology, applied in the field of pyrrolidine compounds, can solve problems such as reducing theoretical possibilities
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[0340] Preparation of intermediates
[0341] Intermediate 1: (1S,2R,5S)-2-oxopyrrolidine-3-carboxylic acid 2-isopropyl-5-methylcyclohexyl ester (compound XIX)
[0342]
[0343] (+)-menthol (5.12g, 32.8mmol) (purchased from Alfa Aesar), ethyl 2-oxopyrrolidine-3-carboxylate (5g, 31.8mmol) (purchased from Aldrich) and DMAP (1.943g, 15.91 mmol) in toluene (40 mL) was heated at reflux in a Dean-Stark apparatus for 72 hours, periodically removing the concentrated toluene / ethanol mixture and replacing it with an equivalent amount of toluene. The solution was cooled and treated with 2M aqueous hydrochloric acid (100 mL) and ethyl acetate (100 mL). The layers were separated and the organic layer was concentrated in vacuo to give a yellow oil. The crude oil was purified by column chromatography (silica 330 g, 0 to 100% TBME in cyclohexane over 10 CV, visual at 220 nm). Relevant fractions were combined and concentrated in vacuo to afford the title compound (8.494 g, 100%) as a ...
Embodiment 1
[0497] Example 1: (S)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl) pyrrolidine- 1-yl)-3-(3-(((R)-tetrahydrofuran-2-yl)methoxy)phenyl)butanoic acid.
[0498]
[0499] To (S)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidine- 1-yl)-3-(3-(((R)-tetrahydrofuran-2-yl)methoxy)phenyl)butanoic acid methyl ester (Intermediate 13) (190 mg, 0.361 mmol) in THF (7.5 mL) A solution of LiOH (87 mg, 3.61 mmol) in water (4.8 mL) was added to the solution in , and the reaction mixture was stirred for 12 hours. The reaction mixture was concentrated in vacuo, and the residue (200 mg) was purified by HPLC on an Xbridge C18 column (150 mm x 30 mm) using a gradient elution of MeCN-0.1% TFA in water at a flow rate of 28 mL / min to give 150 mg, which was then Diastereomers were passed through a (R,R)Whelk-01 column (250mm x 30mm) (with 50% CO 2 and preparative chiral SFC purification on 50% MeOH (containing 0.5% diethylamine), total flow ...
Embodiment 2
[0500] Example 2: (S)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl) pyrrolidine- 1-yl)-3-(3-(((S)-tetrahydrofuran-2-yl)methoxy)phenyl)butanoic acid.
[0501]
[0502] To (S)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidine- 1-yl)-3-(3-(((S)-tetrahydrofuran-2-yl)methoxy)phenyl)butanoic acid methyl ester (Intermediate 16) (300 mg, 0.571 mmol) in THF (7.5 mL) A solution of LiOH (137 mg, 5.71 mmol) in water (4.8 mL) was added to the solution in , and the reaction mixture was stirred for 12 hours. The reaction mixture was concentrated in vacuo, co-distilled with MeOH to give an off-white solid, and processed on a (R,R)Whelk-01 column (250mm x 30mm) with 50% CO 2 and 50% MeOH (containing 0.5% diethylamine)), total flow = 100 g / min, back pressure = 100 bar, detection at 323 nm, afforded the title compound (33 mg, 11%) as Oil: LCMS (system C) RT=0.88min, ES+ve m / z 512(M+H) + ; 1 H NMR (DMSO-d 6 ,600MHz)7.18(t,J=8.1Hz...
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