Optically pure dipeptide derivative, preparation method and medical application thereof
A pharmaceutical and compound technology, applied in the field of dipeptidyl peptidase inhibitors and treatment of diabetes, can solve problems such as poor chemical stability
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Embodiment 1
[0114] (R)-N-(1,1-Dimethylethoxycarbonyl)-2-(3-hydroxyadamantyl-1-yl)glycine
[0115] (1) (R)-2-adamantyl-2-((S)-1-phenyl-2-hydroxyethylamino)acetonitrile
[0116] Suspend 50g of adamantane formaldehyde in 500mL of water and cool to 0°C. 31.7g of sodium bisulfite and 14.9g of sodium cyanide were added to the suspension in turn. Finally, 41.7g of S-phenylglycinol was dissolved in 180mL of methanol, and slowly dropped into the reaction system. After stirring at room temperature for 2 hours, it was heated to reflux for 16 hours, and then cooled to room temperature. Dilute with 350mL ethyl acetate, separate layers, and extract the aqueous phase with ethyl acetate again. The organic phases were combined, washed twice with saturated brine, and dried over anhydrous sodium sulfate to obtain a brown oil. The crude product could be recrystallized from methanol and water to obtain 51 g (61%) of white crystals. 1 H-NMR (300MHz, CDCl 3 )1.56-1.78(m, 13H), 2.03(m, 3H), 2.87(s, 1H), 3.5...
Embodiment 2
[0126] (R)-2-adamantyl-2-((R)-1-phenyl-2-hydroxyethylamino)acetonitrile
[0127] Since the d.e. value of the stereoselective strecker reaction is about 90%, the generated product mainly contains the target product (S)-2-adamantyl-2-((R)-1-phenyl-2-hydroxyethylamino) Acetonitrile and (R)-2-adamantyl-2-((R)-1-phenyl-2-hydroxyethylamino)acetonitrile, it is necessary to separate the optical isomer (R)-2-adamantyl -2-((R)-1-phenyl-2-hydroxyethylamino)acetonitrile, as a reference substance, so as to establish a method for monitoring the d.e. value of the reaction. The separation method adopts column chromatography, and the eluent ratio is petroleum ether / ethyl acetate 20 / 1, which is too pure. 1 H-NMR (300MHz, CDCl 3 )1.66-1.78(m, 13H), 2.06(m, 3H), 3.20(s, 1H), 3.70(m, 1H), 3.77(m, 1H), 3.93(m, 1H), 7.35-7.38(m ,5H); 13 C-NMR (300MHz, CDCl 3 )28.2, 29.8, 36.7, 38.8, 60.1, 63.6, 65.6, 119.2, 127.4, 128.3, 128.9, 140.1; ESI-MSm / z: 311.1 [M+H] + .
Embodiment 3
[0129] (R)-2-((2S)-2-Amino-2-(3-hydroxyadamantyl-1-yl)acetamido)phenylpropanoic acid
[0130] (1) (R)-2-((2S)-2-(1,1-dimethylethoxycarbonylamino)-2-(3-hydroxyadamantyl-1-yl)acetamido)phenylpropanoid methyl ester
[0131] 1g (S)-N-(1,1-dimethylethoxycarbonyl)-2-(3-hydroxyadamantyl-1-yl)glycine and 1.24g N-hydroxybenzotriazole (HOBt ) was dissolved in 35 mL of dichloromethane, cooled to 0°C, 948 mg of 1,3-dicyclohexylcarbodiimide (DCC) was dissolved in 35 mL of dichloromethane, and slowly dropped into the reaction flask. After the dropwise addition, 729 mg of D-phenylalanine methyl ester hydrochloride was added in batches, and then 1.27 mL of triethylamine was added, and the reaction was carried out at room temperature for 24 hours. The solvent was evaporated, and 200 mL of ether was added to the reaction flask to dissolve the product, and the insoluble solid was removed by filtration. The filtrate was collected, washed twice with 1 mol / L sodium hydroxide, 1 mol / L hydrochlori...
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