Difluorinated Compounds as Cystatins
A compound, suitable technology, applied in the direction of active ingredients of phosphorus compounds, biocides, anti-inflammatory agents, etc.
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[0122] In a particular aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:
[0123] R 1 is hydrogen or alkyl;
[0124] R 2 is hydrogen, alkyl, haloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, Heterocyclylalkyl, cyano or -alkylene-X-R 9 (Where X is -O-, -NR 10 -, -CONR 11 -, -S(O) n1 -, -NR 12 CO-, -CO- or -C(O)O-, wherein n1 is 0-2, and R 9 , R 10 , R 11 and R 12 independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl), where R 2 The aromatic ring or alicyclic ring in is optionally replaced by one, two or three R a substituted, the R a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxyl, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, nitro, aryloxy, benzyloxy, Acyl or arylsulfonyl, and further wherein R ...
Embodiment 1
[0217] Synthesis Example 1-Scheme 1
[0218]
[0219] Scheme 1, Step 1: Synthesis of 1-aminocyclopropanenitrile hydrochloride (1-aminocyclopropanenitrile hydrochloride is commercially available)
[0220]
[0221] Benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) were dissolved in dichloromethane (1000 mL) in a 2 L Erlenmeyer flask at room temperature under nitrogen. The mixture was stirred for five days. The reaction mixture was filtered to remove precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL), washed with water (200 mL) and brine. After drying over magnesium sulfate, the solution was evaporated to give (benzhydrylamino)-acetonitrile (47.89 g).
[0222] Under nitrogen, an aqueous solution (91 mL) of sodium hydroxide (91 g, 2.275 mol) in a 2 L flask was cooled on ice, then, benzyltriethylammonium chloride (2.0 g, 0.008...
Embodiment 2
[0224] Synthetic Example 2: Scheme 2
[0225]
[0226] Scheme 2, Step 1: Synthesis of (S)-methyl 2-(benzyloxycarbonylamino)-4-chloro-4-oxobutanoate
[0227]
[0228] See Synth. Comm. 1993, 23(18):2511-2526. N-benzyloxycarbonyl-L-aspartic acid 2-methyl ester (5 g, 17.7 mmol) was dissolved in 30 ml of anhydrous THF, and 2 and stir at 0 °C. Thionyl chloride (10.5 g, 88.5 mmol, 5 equiv) was added to the solution by syringe at 0° C., and the solution was refluxed for one hour. The solvent was removed in vacuo and the product was crystallized from dichloromethane / hexanes to give methyl 2(S)-2-benzyloxycarbonylamino-3-chlorocarbonylpropionate.
[0229] 1 HNMR (400MHz, CDCl 3 )δ3.48(dd, 1H, J=18.5Hz, J=3.7Hz), 3.56(dd, 1H, J=18.5Hz, J=3.7Hz), 3.74(s, 3H), 4.58(m, 1H) , 5.10 (s, 2H), 5.72 (d, 1H), 7.30-7.35 (m, 5H) ppm.
[0230] Scheme 2, Step 2: (S)-2-(Benzyloxycarbonylamino)-4-oxo-5-phenylpentanoic acid methyl ester
[0231]
[0232] To a suspension of copper(I) brom...
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