A non-peptide inhibitor of apoptosis protein antagonist and its synthesis method and application
An apoptosis inhibitory protein and antagonist technology, applied in the field of novel small molecule anticancer non-peptide drugs and non-peptide apoptosis inhibitory protein antagonists, can solve the problems of low bioavailability, poor in vivo stability, etc. The effect of obvious peptide characteristics, strong binding affinity and good application prospects
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Embodiment 1
[0047] The synthetic method of intermediate A is as follows:
[0048]
[0049] (S)-1-Benzyl-5-oxopyrrolidine-2-carboxylic acid (2)
[0050]
[0051] Triethylamine (38 mL, 0.273 mol) was added to a methanol solution (200 mL) of L-glutamic acid (20.0 g, 0.140 mol) and benzaldehyde (17.4 g, 0.160 mol). After the mixture was stirred at room temperature for 1 hour, the temperature of the solution was lowered to 0 °C, and then NaBH 4 (5.67g, 0.150mol) was slowly added to the reaction solution. After stirring for 2 hours, the reaction solution was poured into iced 4M HCl solution (50 mL). The resulting suspension was concentrated under reduced pressure and heated until the solids were all dissolved. After cooling for a period of time, the solid obtained by filtration is compound 1. The next reaction can be carried out directly without purification. A solution of 1 in water (300 mL) was heated to reflux and stirred overnight. The reaction solution was cooled to room temper...
Embodiment 2
[0073] Example 2 (non-peptide inhibitor of apoptosis protein antagonist L1)
[0074] (R)-3-(2-((2R,5S)-1-benzyl-5-tert-butyl carboxyl)pyrrolidine)ethylthio)-2-(tert-butoxycarboxamido)propionic acid ( Intermediate C)
[0075]
[0076] At -10°C, methanesulfonyl chloride (174 μL, 2.25 mmol), DMAP (15 mg, 0.125 mmol), triethylamine (1 mL) were added to a solution of Intermediate A (765 mg, 2.5 mmol) in dichloromethane (10 mL) , stirred for 60 minutes, the reaction solution was diluted with dichloromethane, washed with dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated brine, dried over magnesium sulfate, and concentrated to obtain intermediate B. The next reaction was carried out directly without purification.
[0077] At -10°C, NaH (96 mg, 4 mmol) was added to a DMF solution (10 mL) of Boc-Cys-OH (443 mg, 2 mmol), and the suspension was stirred for 60 min. Then the DMF solution of B (10 mL) was added to the reaction solution, the mixture was...
Embodiment 3
[0097] Embodiment 3 (compound K2)
[0098] (R)-3-(2-((2R,5S)-1-benzyl-5-tert-butyl carboxyl)pyrrolidine)ethylthio)-2-(tert-butoxycarboxamido)propionic acid ( Intermediate C)
[0099]
[0100] At 0°C, methanesulfonyl chloride (580 μL, 7.5 mmol), DMAP (458 mg, 3.75 mmol), and DIEA (1 mL) were added to intermediate A (765 mg, 2.5 mmol) in chloroform (10 mL), and stirred for 30 minutes. The reaction solution was diluted with chloroform, washed successively with saturated ammonium chloride solution, saturated sodium carbonate solution, and saturated brine, dried over sodium sulfate, and concentrated to obtain intermediate B. The next reaction was carried out directly without purification.
[0101] At 0°C, NaH (240 mg, 10 mmol) was added to a DMF solution (10 mL) of Boc-Cys-OH (1660 mg, 7.5 mmol), and the suspension was stirred for 30 min. Then the DMF solution of B (10 mL) was added to the reaction solution, the mixture was stirred at room temperature for 5 hours, concentrate...
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