Hemiasterlin derivatives and antibody-drug conjugates including same
A compound and bonding technology that can be used in drug combinations, antibodies, anti-tumor drugs, etc., to solve problems such as toxicity, side effects, and cytotoxicity
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reference example 1
[1282] N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophan methyl ester
[1283]
[1284] a) Production of methyl 2-(1-methyl-1H-indol-3-yl)propionate (compound Q1)
[1285] After adding hexamethyldisilazane potassium salt (1 mol / L tetrahydrofuran solution, 65.5 mL) dropwise to a solution of methyl indole-3-acetate (3.8 g) in tetrahydrofuran (87 mL) at -78°C under a nitrogen atmosphere , stirred at 0 °C for 2 hours. After cooling the reaction solution to -78°C, iodomethane (23 g) was added dropwise, followed by stirring at 0°C for 3 hours. After the reaction, water was added and extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate), whereby Compound Q1 (3.95 g) was obtained.
[1286] 1 H-NMR (400MHz, CDCl 3 ):1.60(3H,d,J=7.1Hz),3.67(3H,s),3.76(3H,s)...
reference example 2
[1322] N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophanyl-N-{(3S,4E)-6-[(2,5-dioxopyrrolidine -1-yl)oxy]-2,5-dimethyl-6-oxohex-4-en-3-yl}-N,3-dimethyl-L-valinamide
[1323]
[1324] a) Production of N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophan (compound A11)
[1325] To a water (11 mL)-methanol (44 mL) solution of Reference Example 1 (639 mg) was added 1 mol / L lithium hydroxide (13.5 mL), and stirred at 60° C. for 24 hours. After completion of the reaction, a 1 mol / L oxalic acid aqueous solution was added to bring the reaction solution to pH 4, water was added, and extraction was performed with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; chloroform:methanol) to obtain compound A11 (610 mg).
[1326] 1 H-NMR (400MHz, CDCl 3 ): 1.43(9H,s), 1.53(3H,s), 1.63(3H,s)...
reference example 3
[1339] (6S,9S,12S,13E,17R)-9-tert-butyl-17-(ethoxycarbonyl)-2,2,5,11,14-pentamethyl-6-[2-(1-methyl Base-1H-indol-3-yl)propan-2-yl]-4,7,10,15-tetraoxo-12-(propan-2-yl)-3-oxa-5,8,11 ,16-Tetraazaeicos-13-ene-20-carboxylic acid
[1340]
[1341] Reference example 2 (160mg), D-glutamic acid α-ethyl ester trifluoroacetate (122mg), N,N-diisopropylethylamine (100mg) and N,N-dimethylformamide ( 2.2 mL) was stirred at 25°C for 6 hours. After the reaction, adjust the pH to 4 with 1mol / L oxalic acid aqueous solution, and extract with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; chloroform:methanol), whereby Reference Example 3 (155 mg) was obtained.
[1342] 1 H-NMR (400MHz, CDCl 3 ):8.26 and 7.97 (1H, 2d, J = 7.9Hz), 7.32-7.05 (4H, m), 6.71 (1H, t, J = 6.7Hz), 6.45 (1H, d, J = 8.6...
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