Drug conjugates with self-stabilizing linkers having improved physiochemical properties
A technology of conjugates and compounds, applied in the field of ligand-drug conjugates, can solve problems such as loss of heterogeneity in stereochemical control
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[1237] General information. All commercial anhydrous solvents were used without further purification. Analytical thin layer chromatography was performed on silica gel 60F254 aluminum plates (EMD Chemicals, Gibbstown, NJ). Radial chromatography was performed on a Chromatotron apparatus (Harris Research, Palo Alto, CA). In Biotage Isolera One TM Column chromatography was performed on a flash purification system (Charlotte, NC). On a VarianProStar equipped with a Varian ProStar 330PDA detector TM Analytical HPLC was performed on a 210 solvent delivery system. Samples with C12Phenomenex Synergi TM 2.0×150mm, 4μm, Reverse phase column elution. The acidic mobile phase consisted of acetonitrile and water, both containing 0.05% trifluoroacetic acid or 0.1% formic acid (as indicated for each compound). Compounds were eluted using a linear gradient of acidic acetonitrile from 5% at 1 min to 95% at 11 min after injection, followed by isocratic 95% acetonitrile up to 15 min (...
example 1
[1238] Example 1: (Z)-1-(tert-butoxycarbonyl)-3-(3-carboxyacrylamido)-azetidine-3-carboxylic acid
[1239]
[1240] Into a 20 mL vial equipped with a stir bar was charged azetidine amino acid (0.89 g, 4.1 mmol), maleic anhydride (0.40 g, 4.1 mmol) and AcOH (8 mL). The mixture was stirred at 40°C for 10 minutes, then at room temperature for 3 hours. The solvent was removed in vacuo and the residue was dissolved in DMSO / 0.1% TFA in HO 2 O solution (1:1, 2.0 mL). The reaction was purified by preparative HPLC and the product fractions were lyophilized to afford 0.84 g (65% yield) of the title compound.
[1241] Analytical UPLC-MS: t R = 0.84 minutes, calculated for m / z (ES+) 315.11 (M+H) + , the experimental value is 315.13. 1 HNMR (400MHZ, DMF-d 7 ): δ10.2(s,1H),6.78(d,J=12.4Hz,1H),6.54(d,J=12.4Hz,1H),4.94(br m,2H),4.29(br m,2H) ,1.59(s,9H). 13 C NMR (100MHz, DMF-d 7 ): δ171.7, 166.3, 165.7, 133.3, 131.5, 79.5, 53.7, 27.8
example 2
[1242] Example 2: 1-(tert-butoxycarbonyl)-3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)azetidine-3-carboxylic acid (Boc- mAze)
[1243]
[1244] Azetidine diacid (460 mg, 1.46 mmol), DMA (20 mL) and Molecular sieves (1.4 g). The reaction was stirred at 95°C for 16 hours. The reaction was cooled to room temperature and filtered through celite. Solvent was removed in vacuo. The residue was dissolved in DMSO (4 mL) and water (1 mL), and purified by preparative HPLC. The product fractions were collected and lyophilized to afford 120 mg (28% yield) of the title compound.
[1245] Analytical UPLC-MS: t R = 1.04 minutes, calculated for m / z (ES+) 319.09 (M+Na) + , the experimental value is 319.10. 1 HNMR (400MHZ, DMF-d 7 ): δ7.14 (s, 2H), 4.57 (br m, 2H), 4.39 (br m, 2H), 1.44 (s, 9H). 13 C NMR (100MHz, DMF-d7 ): δ172.6, 172.0, 156.8, 136.4, 80.4, 54.3, 28.7
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