Inhibitors of nedd8-activating enzyme
A technology of compounds, chemical entities, applied in the field of cell proliferation disorders, active compounds
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[0142] abbreviation
[0143]
[0144]
[0145] one method
[0146] X-ray powder diffraction. XRPD was performed using a Bruker AXS D8 advanced X-ray diffractometer. Approximately 100 mg of sample was gently flattened onto a 50 mm diameter quartz sample disk for powder measurements. Samples were scanned continuously from 2.9 to 29.6° 2Θ using 2Θ / Θ locked coupling angles. Each angular interval is 0.05° 2Θ and data is collected for 2 seconds. Sample runs were performed under ambient conditions and all data were analyzed using EVA version 9.0 software.
[0147] thermal analysis. Thermal events were analyzed using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). A TA Instruments DSC Q200 and TGA Q500 were used for all sample runs. Thermograms were analyzed using Thermal Advantage for Q-Series software.
[0148] Differential Scanning Calorimetry. Samples (1-2 mg) were sealed in aluminum pans with lids. The sample was heated from 25 °C t...
example 1
[0150] Example 1. Synthesis of (1R,2S)-5-chloro-2-methoxyindan-1-amine (8)
[0151] Step 1: rel-(1aR,6aS)-4-Chloro-6,6a-dihydro-1aH-indeno[1,2-b]oxirane (2).
[0152] To a stirred solution of 4-phenylpropylpyridine-N-oxide (278 mg, 1.31 mmol) in dichloromethane (20 mL) at 0°C was added (R,R)-Jacobson's catalyst (237.0 mg, 0.3732mmol) and sodium hypochlorite solution (2.0M aqueous solution; 16mL, 32mmol). The resulting brown suspension was stirred at 0 °C for 15 minutes, then a solution of 6-chloro-1H-indene (1) (2.81 g, 18.6 mmol) in dichloromethane (20 mL) was added via syringe along with additional sodium hypochlorite (2.0 M in water; 16 mL, 32 mmol). The reaction was stirred at 0 °C for 1 hour, then the ice bath was removed and the reaction was stirred at room temperature for 1 hour. An aliquot was taken and TLC on silica gel (hexanes) showed that all starting material was consumed. The reaction was poured into brine and extracted with dichloromethane. The combined ext...
example 2
[0164] Example 2. Sulfamic acid {(1S, 2S, 4R)-4-[(6-{[(1R, 2S)-5-chloro-2-methoxy-2,3-dihydro-1H-indene- Synthesis of 1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl ester (I-216)
[0165] Step 1: rel-(1R,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopent-2-en-1-ol (10).
[0166] To rel-(1R,5R)-5-(hydroxymethyl)cyclopent-2-en-1-ol (47.20g, 0.4135mol), N,N-dimethylamino To a solution of pyridine (2.52 g, 0.0207 mol) and 1H-imidazole (30.97 g, 0.4549 mol) in dichloromethane (800 mL, 10 mol) was added tert-butyldimethylsilyl chloride (28.0 g, 0.186 mol). The reaction was stirred at 0 °C for 2.5 h at which time tert-butyldimethylsilyl chloride (28.0 g, 0.186 mol) was added. The reaction was stirred for another 2 hours. The reaction was quenched by adding saturated aqueous NaCl (200 mL) and water (200 mL). The layers were separated and the organic layer was washed with water (3×200 mL) and brine (1×200 mL), washed with Na 2 SO 4 Dry, filter and concentrate in ...
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