Bicyclol amino-acid ester as well as preparation method and application for same
A technology of amino acid esters and bicyclols, applied in pharmaceutical formulations, active ingredients of heterocyclic compounds, medical preparations containing active ingredients, etc., can solve the problems of low oral bioavailability and poor solubility of bicyclols, and achieve low cost, Easy operation and high yield
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Embodiment 1
[0057] The preparation of embodiment 1 bicyclic alcohol-selenomethioninate
[0058] (1) Esterification reaction
[0059]
[0060] Weigh 503mg of N-fluorenylmethoxycarbonyl-selenomethionine (1.2mmol) and dissolve it in 15mL of anhydrous dichloromethane (DCM), cool in an ice bath, add 13mg of 4-dimethylaminopyridine (DMAP) (0.1mmol) and 230mg1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) (1.2mmol), stirred for 10min, added 390mg of bicyclic alcohol (1mmol), reacted for 3h. The reaction solution was washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried to obtain a solid.
[0061] (2) Deprotection group reaction
[0062]
[0063] The solid obtained in step (1) was dissolved in 10 mL of 20% piperidine / DCM mixed system, reacted at room temperature for 30 min, and TLC detected that the reaction was complete. The reaction solution was washed successively with dilute acetic acid solution and sat...
Embodiment 2
[0066] The preparation method of this example is basically the same as that of Example 1, except that the selected protected amino acids are N-fluorenylmethoxycarbonyl-methionine, N-fluorenylmethoxycarbonyl-leucine, N-fluorene methoxycarbonyl-tryptophan, N-fluorenylmethoxycarbonyl-isoleucine, N-fluorenylmethoxycarbonyl-phenylalanine, N-fluorenylmethoxycarbonyl-glycine, N-fluorenylmethoxycarbonyl-proline Acid, N-fluorenylmethoxycarbonyl-alanine, side chain amino group is N-fluorenylmethoxycarbonyl-lysine protected by fluorenylmethoxycarbonyl group, side chain amino group is N-fluorenylmethoxycarbonyl protected by fluorenylmethoxycarbonyl group Ornithine, bicyclyl alcohol-methionine ester, bicyclyl alcohol-leucine ester, bicyclyl alcohol-tryptophan ester, bicyclyl alcohol-isoleucine ester, bicyclyl alcohol-phenylalanine ester, bicyclyl alcohol -Glycine ester, Bicyclol-proline ester, Bicyclol-alanine ester, Bicyclol-lysine ester, Bicyclol-ornithine ester.
Embodiment 3
[0067] The preparation of embodiment 3 bicyclol-serine ester
[0068] (1) Esterification reaction
[0069] Weigh 1.25g of N-fluorenylmethoxycarbonyl-serine (2.2mmol) whose hydroxyl group is trityl-protected, dissolve it in 30mL of anhydrous dichloromethane (DCM), cool in an ice bath, add 24mg of 4-dimethylaminopyridine (DMAP ) (0.2mmol) and 460mg1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) (2.4mmol), stirred for 10min, added 780mg bicyclic alcohol (2mmol) , Reaction 2h. The reaction solution was washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried, and spin-dried to obtain 1.79 g of white foamy solid.
[0070]
[0071] (2) Deprotection group reaction
[0072] (2.1) Dehydroxyl protecting group
[0073]
[0074] Dissolve the white foamy solid obtained in step (1) in 50mL (volume ratio: methylene chloride / triisopropylsilane / trifluoroacetic acid=94 / 1 / 5) solution, react for 1.5h, TLC detects ...
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