Plk1 inhibitor and its preparation method and application
A R16, R12 technology, applied in the field of medicinal chemistry, can solve the problems of oligonucleotide small molecule RNA difficult to penetrate cell membrane, small molecule kinase inhibitor drug resistance, decreased binding force, etc., to overcome the problem of drug resistance. Effect
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Embodiment 1
[0094] The preparation of embodiment 1 compound 1
[0095] (a) Resin swelling: Add 400mg Fmoc-protected phenylhydrazine resin (0.66mmol / g, 0.264mmol) and 3mL CH to a 10mL solid phase reactor 2 Cl 2 , the resin was swollen for 30min, and the CH 2 Cl 2 ,spare;
[0096] (b) Remove the Fmoc protecting group: add 3mL of 20% piperidine / DMF solution to the resin after step (a) swelling, N 2 Bubble and mix well, after 10min, remove the solvent, then add 3mL 20% piperidine / DMF solution, N 2 Bubble and mix well, after 10min, wash the resin with DMF (4×3mL), then wash the resin with 3mL anhydrous DMF, set aside;
[0097] (c) Amino acid condensation: 4-tert-butoxycarbonylamino-1-methyl-1H-pyrrole-2-carboxylic acid (254 mg, 1.056 mmol) and triphosgene (BTC, 128 mg, 0.433 mmol) were dissolved in 2 mL of anhydrous THF, slowly add collidine (collidine, 488μL, 3.696mmol) dropwise to the solution, the reaction immediately produces a large amount of white precipitate, after adding the reac...
Embodiment 2
[0113] The preparation of embodiment 2 compound 2
[0114] The peptide loaded on the phenylhydrazine resin shown in formula (5) is prepared by the same steps as in Example 1, and step (b) in Example 1 is used to remove the peptide loaded on the phenylhydrazine resin shown in formula (5). The Fmoc protecting group in the peptide above;
[0115] The Hurst acid derivative Ht-1 (539mg, 1.056mmol) and PyBOP (550mg, 1.056mmol) were dissolved in 3mL of anhydrous DMF, DIEA (350μL, 2.112mmol) was added, reacted for 5min, and the reaction solution was transferred to the Among the peptides loaded on the phenylhydrazine resin except Fmoc represented by the formula (5), N 2 Bubble and mix, condense for 1 hour, remove the reaction solution, wash the resin with DMF (4×3mL); take out the resin, add 1mL DMF, 200μL dimethylaminopropylamine and 10mg Cu(OAc) 2 , shake at room temperature for 12h, filter off the resin, and wash with 20mL CH 2 Cl 2 The resin was washed; the organic phase was co...
Embodiment 3
[0119] The preparation of embodiment 3 compound 3
[0120] The peptide loaded on the phenylhydrazine resin shown in formula (5) is prepared by the same steps as in Example 1, and step (b) in Example 1 is used to remove the peptide loaded on the phenylhydrazine resin shown in formula (5). The Fmoc protecting group in the peptide above;
[0121] Will Boc 2 O (243 μL, 1.056 mmol) was dissolved in 3 mL of anhydrous DMF, DIEA (350 μL, 2.112 mmol) was added, and the reaction solution was transferred to the peptide loaded on the phenylhydrazine resin represented by the formula (5) to remove Fmoc, N 2 Mix well by bubbling, and condense for 20 minutes. The reaction solution was extracted, and the resin was washed with DMF (4×3mL) to obtain the peptide loaded on the phenylhydrazine resin represented by Boc-protected formula (6);
[0122]
[0123] Take out the resin obtained above, add 1mL DMF, 200μL N,N-bis(3-aminopropyl)methylamine, shake at 90°C for 1h, cool to room temperature, ...
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