CN115073336A - Preparation method of sulfhydryl alanyl amino acid ester salt of peramivir - Google Patents
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Abstract
The invention belongs to the technical field of medicines, and discloses a preparation method of a sulfhydryl alanyl amino acid ester salt of peramivir, which comprises the following steps: taking (1S,2S3R,4R) -3- ((R) -1-acetamido-2-ethylbutyl) -4- (tert-butyloxycarbonylamino) -2-hydroxycyclopentane carboxylic acid methyl ester as a raw material, and carrying out hydrolysis reaction to obtain the peramivir protected by tert-butyloxycarbonyl; using fluorene methoxycarbonyl-O-benzyl-L-amino acid as raw material, making up protection on carboxyl, removing fluorene methoxycarbonyl to obtain L-amino acid-benzyl ester-tert-butyl ester hydrochloride, using it and alanine protected by tert-butyloxycarbonyl as raw material to make liquid-phase synthesis dipeptide, then making substitution reaction to obtain dipeptide containing mercaptoalanyl; the peramivir protected by the compound A tert-butyloxycarbonyl and the dipeptide containing 2-amino thiopropionic acid are taken as raw materials, a reaction reagent is added for esterification reaction to obtain the ester of the mercapto alanyl amino acid of the peramivir protected by partial groups, and then acid is added to obtain the mercapto alanyl amino acid ester salt of the peramivir.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a sulfhydryl alanyl amino acid ester salt of peramivir.
Background
A compound known colloquially as peramivir, having the chemical name (1S,2S,3S,4R) -3- ((1S) -1-acetylamino-2-ethyl-butyl) -4-guanidino-2-hydroxy-cyclopentane-1-carboxylic acid trihydrate. The groups on the peramivir molecule respectively act on a plurality of active sites of an influenza virus NA molecule, so that the activity of the NA is strongly inhibited, and the replication and release of virus particles of filial generations in host cells are prevented, thereby effectively preventing influenza and relieving influenza symptoms. However, the peramivir molecular structure contains guanidyl, the molecular polarity is very high, so that the permeability of a small intestinal membrane is very low, the oral bioavailability of the peramivir is very low (4.1%), and the peramivir is mainly clinically administered by intravenous injection. Therefore, it is necessary and meaningful to find a way to improve the membrane permeability of peramivir and further improve the oral bioavailability of peramivir. According to a large number of reports in the literature, structural modification of carboxyl groups of cyclopentane drugs may improve membrane permeability and oral bioavailability of the drugs.
Disclosure of Invention
The invention aims to provide a preparation method of a sulfhydryl alanyl amino acid ester salt of peramivir, which can improve the absolute bioavailability of peramivir.
The technical scheme of the invention is as follows:
the structure of the mercaptoalanyl amino acid ester salt of peramivir is as follows:
wherein R is mercaptoalanyl aspartic acid, mercaptoalanyl glutamic acid, mercaptoalanyl serine or mercaptoalanyl tyrosine, and the specific structural formulas of the four compounds are as follows:
the synthesis of the mercaptoalanyl amino acid ester salt of peramivir can be carried out according to the following general route:
the first step is as follows: taking (1S,2S3R,4R) -3- ((R) -1-acetamido-2-ethylbutyl) -4- (tert-butoxycarbonylamino) -2-hydroxy cyclopentane carboxylic acid methyl ester as a raw material, removing tert-butoxycarbonyl and adding a bis-tert-butoxycarbonyl protecting group, and performing hydrolysis reaction to obtain a compound A, namely the peramivir protected by the tert-butoxycarbonyl, and having the following structure:
in the step, the reaction reagent comprises hydrochloric acid-dioxane, N dimethylformamide, 1, 3-di (tert-butyloxycarbonyl) -2-methyl-2-isothiourea, triethylamine, tetrahydrofuran, mercuric chloride, absolute ethyl alcohol and glacial acetic acid.
The second step is that: using fluorene methoxycarbonyl-O-benzyl-L-amino acid as raw material, making up protection on carboxyl, removing fluorene methoxycarbonyl to obtain L-amino acid-benzyl ester-tert-butyl ester hydrochloride, using it and alanine protected by tert-butyloxycarbonyl as raw material to make liquid-phase synthesis of dipeptide, then substituting O-amido bond in the dipeptide with S-amido bond so as to obtain the dipeptide containing mercaptoalanyl.
In the step, the reaction reagent comprises dichloromethane, tert-butyl alcohol, 4-dimethylaminopyridine, dicyclohexylcarbodiimide, piperidine, N-dimethylformamide, O-benzotriazole-tetramethylurea hexafluorophosphate, N-diisopropylethylamine and a Lawson reagent.
The third step: the peramivir protected by the compound A tert-butyloxycarbonyl and the dipeptide containing 2-amino thiopropionic acid are taken as raw materials, a reaction reagent is added for esterification reaction to obtain the ester of the mercapto alanyl amino acid of the peramivir protected by partial groups, and then acid is added to obtain the mercapto alanyl amino acid ester salt of the peramivir.
In the step, the esterification reaction is carried out at room temperature, the esterification reaction reagent comprises dichloromethane, 4-dimethylaminopyridine and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the used acid is trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid, acetic acid or citric acid.
Further, the specific preparation process of the sulfhydryl alanyl amino acid ester salt of peramivir comprises the following steps:
dissolving 0.05-0.2 mol of fluorene methoxycarbonyl-O-benzyl-L-amino acid in 20mL of dry dichloromethane solution, sequentially adding 0.1-0.4 mol of tert-butyl alcohol and 0.05-1 mol of 4-dimethylaminopyridine under the ice bath condition, adding 0.05-0.2 mol of dicyclohexylcarbodiimide within 5 min, continuing to react for 5 min under the ice bath condition, then stirring at room temperature overnight, and monitoring the reaction progress by using a thin layer. After the reaction is finished, filtering to remove white solid dicyclohexylurea, washing the filtrate with 0.5 mol/L hydrochloric acid solution and saturated sodium bicarbonate solution for 2 times respectively, collecting an organic layer, drying the organic layer with anhydrous magnesium sulfate, filtering, concentrating the filtrate, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution with ethyl acetate and petroleum ether to collect column chromatography substances, concentrating, dissolving the residue in 20% piperidine N, N-dimethylformamide solution, stirring at room temperature for 40 min, and removing fluorene methoxycarbonyl groups. The piperidine was removed from the reaction mixture, which was then dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution 2 times to remove N, N-dimethylformamide. Collecting the organic layer and spin-drying to obtain L-amino acid-benzyl ester-tert-butyl ester hydrochloride.
Dissolving 0.05-0.2 mol of alanine protected by tert-butyloxycarbonyl, 0.05-0.2 mol of O-benzotriazole-tetramethylurea hexafluorophosphate and 0.1-0.2 mol of N, N-diisopropylethylamine in 10-15 mL of dry N, N dimethylformamide solution, and activating for 15 min under the condition of argon protection; and dissolving L-amino acid-benzyl ester tert-butyl ester hydrochloride into 3-5 mL of dry N, N dimethylformamide solution, adding into the reaction solution, and stirring at normal temperature for 12 h. After the reaction is finished, the N, N-dimethylformamide solvent is distilled off at 80 ℃, the residue is redissolved by ethyl acetate, and the residue is washed by 10 percent citric acid, saturated sodium bicarbonate and saturated sodium chloride solution in sequence. Collecting the organic layer, drying with anhydrous magnesium sulfate, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution with ethyl acetate and petroleum ether, collecting column chromatography, concentrating, dissolving the residue in 20-25 mL of anhydrous toluene, adding Lawson reagent 0.05-0.2 mol, heating and refluxing at 80 ℃ for 4 h under the protection of argon gas, and finishing the reaction. Filtering to remove precipitated solid, evaporating the filtrate in vacuum to spin-dry the solvent, mixing the residue with silica gel, performing gradient elution by column chromatography ethyl acetate and petroleum ether, collecting column chromatography substance, concentrating, placing the residue in a three-neck flask, pouring liquid ammonia, cooling with dry ice bath, adding metal sodium block under stirring, adding for multiple times, and finishing the adding within 1.5 h. The reaction is monitored by a thin layer until the benzyl group is completely removed, and the dipeptide of mercaptoalanyl is obtained.
Dissolving the dipeptide of mercaptoalanyl in 10-20 mL of dry dichloromethane, adding 0.05-0.2 mol of compound A and 0.01-0.05 mol of 4-dimethylaminopyridine under the protection of argon gas, stirring for 20 min, adding 0.05-0.2 mol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and stirring at normal temperature overnight. After the reaction, the mixture was washed with distilled water and saturated brine in this order, and the organic layer was collected. Drying the organic layer with anhydrous sodium sulfate, vacuum filtering, concentrating the filtrate, dissolving in ethyl acetate, mixing with silica gel, subjecting to column chromatography, gradient eluting with ethyl acetate and petroleum ether, collecting column chromatography, concentrating, and dissolving the residue in 15%Acid(s)Stirring the mixture at room temperature for 5 hours, and monitoring the reaction process by mass spectrum until the tert-butyloxycarbonyl and the tert-butyl are completely removed. Adding toluene with the same volume as dichloromethane into the reaction solution, concentrating under reduced pressure, adding cold diethyl ether, placing in a refrigerator overnight, centrifuging the next day, removing the supernatant, and precipitating to obtain the final product, namely the mercaptoalanyl amino acid ester salt of peramivir.
Wherein, when the end of the dipeptide of the mercaptoalanyl is carboxyl, the method also comprises the steps of dissolving the dipeptide of the mercaptoalanyl in 10-20 mL of dry dichloromethane, adding 0.3-0.8mol of glycol and 0.01-0.02 mol of 4-dimethylamino pyridine under the protection of argon, and stirring for 10 min under the condition of ice water bath; under the condition, 1-ethyl- (3-dimethyl amino propyl) carbonyl diimine hydrochloride of 0.05-0.2 mol is added, and stirring is continued for 10 min and then is carried out for 20 h at normal temperature. After the reaction was completed, the mixture was washed with distilled water and saturated brine in this order, and the dichloromethane layer was collected. Drying the organic layer with anhydrous sodium sulfate, vacuum filtering, concentrating the filtrate, dissolving with ethyl acetate, mixing with silica gel, and separating by column chromatography to obtain ethylene glycol-modified sulfhydryl alanyl dipeptide.
Further, the pharmaceutically acceptable salt formed by the mercaptopropionamino acid ester of peramivir obtained by the esterification reaction in the third step after trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid, acetic acid or citric acid is trifluoroacetate, hydrochloride, sulfate, formate, acetate or citrate.
The application of the sulfhydryl alanyl amino acid ester salt of peramivir in improving oral absorption of peramivir is provided, preferably, the pharmaceutically acceptable salt of the sulfhydryl alanyl amino acid ester of peramivir is trifluoroacetate.
The invention has the advantages that: the invention synthesizes the pharmaceutically acceptable trifluoroacetate of the mercaptoalanyl amino acid ester of the series of peramivir for the first time, and after the mercaptoalanyl amino acid ester salt of the peramivir is orally taken, the absolute bioavailability of the peramivir in a rat body is respectively improved from 3.4 percent to 41.8 percent, 56.7 percent, 20.9 percent and 13.60 percent.
Drawings
Fig. 1 is a blood concentration-time curve (n =5 to 6) of a mercaptoalanyl amino acid ester salt of peramivir and peramivir;
FIG. 2 is an HPLC purity analysis of the mercaptoalanyl aspartate of peramivir;
FIG. 3 is an HPLC purity analysis of the mercaptoalanyl glutamate of peramivir;
FIG. 4 is an HPLC purity analysis of the mercaptoalanyl serine ester of peramivir;
FIG. 5 is a HPLC purity analysis of mercaptoalanyl tyrosine ester of peramivir;
FIG. 6 is a MS analysis of the mercaptoalanyl aspartate of peramivir;
FIG. 7 is MS analysis of the mercaptoalanyl glutamate of peramivir;
FIG. 8 is MS analysis of the mercaptoalanyl serine ester of peramivir;
FIG. 9 is a Mercaptalanyl tyrosine ester MS analysis of peramivir;
FIG. 10 is the mercaptoalanyl aspartate of peramivir 1 H NMR spectrum analysis;
FIG. 11 is the mercaptoalanyl glutamate of peramivir 1 H NMR spectrum analysis;
FIG. 12 is a mercaptoalanylserine ester of peramivir 1 H NMR spectrum analysis;
FIG. 13 is the mercaptoalanyl tyrosine ester of peramivir 1 H NMR spectrum analysis;
FIG. 14 is the mercaptoalanyl aspartate of peramivir 13 C NMR spectrum analysis;
FIG. 15 is the mercaptoalanyl glutamate of peramivir 13 C NMR spectrum analysis;
FIG. 16 is the mercaptoalanyl serine ester of peramivir 13 C NMR spectrum analysis;
FIG. 17 is the mercaptoalanyl tyrosine ester of peramivir 13 C NMR spectrum analysis.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The following compounds were prepared separately according to the general synthetic route.
The specific synthesis process flow of the compound A is as follows:
the reaction parameters of each step are as follows: (i) 4M-dioxane hydrochloride and diethyl ether, and is kept at normal temperature overnight; (ii) triethylamine, BocTU, HgCl2, N-dimethylformamide at room temperature for 2 hours; (iii) 5% NaOH, EtOH, THF, room temperature, 3 hours.
i: 0.1moL of Compound 1, namely methyl (1S,2S3R,4R) -3- ((R) -1-acetylamino-2-ethylbutyl) -4- (tert-butoxycarbonylamino) -2-hydroxycyclopentanecarboxylate, was dissolved in 20mL of diethyl ether, and 10mL of 0.4moL of 4M-dioxane hydrochloride was added under ice-water bath conditions, and further diethyl ether was added to 40 mL of the solution, and stirring was carried out at room temperature until a white solid was formed, and then stirring was carried out at room temperature for 24 hours. Then heating and refluxing for 2 h, cooling to normal temperature, carrying out suction filtration, washing with diethyl ether, and carrying out vacuum drying to obtain a white solid compound 2.
ii: 0.1moL of compound 2 was dissolved in 30 mL of dry N, N-dimethylformamide, and 0.3moL of triethylamine was slowly added under ice-bath conditions, followed by turbidity and exotherm, followed by addition of 0.11 moL of BocTU and 0.011moL of HgCl2 and continued cooling for 20 min. Stirring at normal temperature for 2 h to generate a large amount of white solid compound 3.
iii: under the condition of ice-water bath, 0.1moL of the compound 3 is dissolved in a mixed solution of 30 mL of ethanol and 30 mL of tetrahydrofuran, 0.1moL of 5 percent NaOH solution is added, the mixture is stirred for 3 hours at normal temperature, and the mixture is decompressed and concentrated to obtain white paste. 30 mL of water was added to dissolve the resulting solution, and 0.11 moL of glacial acetic acid was added thereto, followed by stirring to precipitate a white solid. And (4) carrying out suction filtration, washing and drying to obtain a white solid compound A.
Example 1
0.05mol of fluorenyl methoxycarbonyl-O-benzyl-L-aspartic acid is dissolved in 20mL of dry dichloromethane solution, 0.1mol of tert-butyl alcohol and 0.05mol of 4-dimethylaminopyridine are added in turn under ice bath conditions, 0.05mol of dicyclohexylcarbodiimide is added within 5 min, the reaction is continued for 5 min under the ice bath conditions, then the mixture is stirred at room temperature overnight, and the progress of the reaction is monitored by a thin layer. After the reaction is finished, filtering to remove white solid dicyclohexylurea, washing the filtrate with 0.5 mol/L hydrochloric acid solution and saturated sodium bicarbonate solution for 2 times respectively, collecting an organic layer, drying the organic layer with anhydrous magnesium sulfate, filtering, concentrating the filtrate, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution with ethyl acetate and petroleum ether to collect column chromatography substances, concentrating, dissolving the residue in 20% piperidine N, N-dimethylformamide solution, stirring at room temperature for 40 min, and removing fluorene methoxycarbonyl groups. The piperidine was removed from the reaction mixture, which was then dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution 2 times to remove N, N-dimethylformamide. Collecting the organic layer and spin-drying to obtain L-aspartic acid-benzyl ester-tert-butyl ester hydrochloride.
Dissolving 0.05mol of alanine protected by tert-butyloxycarbonyl, 0.05mol of O-benzotriazole-tetramethylurea hexafluorophosphate and 0.1mol of N, N-diisopropylethylamine in 10mL of dry N, N dimethylformamide solution, and activating for 15 min under the condition of argon protection; meanwhile, L-aspartic acid-benzyl ester tert-butyl ester hydrochloride is dissolved in 3 mL of dry N, N dimethylformamide solution and added into the reaction solution, and the mixture is stirred for 12 hours at normal temperature. After the reaction is finished, the N, N-dimethylformamide solvent is distilled off at 80 ℃, the residue is redissolved by ethyl acetate, and the residue is washed by 10 percent citric acid, saturated sodium bicarbonate and saturated sodium chloride solution in sequence. Collecting the organic layer, drying with anhydrous magnesium sulfate, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution with ethyl acetate and petroleum ether, collecting the column chromatography, concentrating, dissolving the residue in 20mL of anhydrous toluene, adding 0.05mol of Lawson reagent, heating and refluxing at 80 ℃ for 4 h under the condition of argon protection, and finishing the reaction. Filtering to remove solid, evaporating the filtrate under vacuum to spin dry the solvent, mixing the residue with silica gel, gradient eluting with column chromatography ethyl acetate and petroleum ether, collecting column chromatography extract, concentrating, placing the residue in a three-neck flask, pouring liquid ammonia, cooling with dry ice bath, adding sodium metal block under stirring, adding in multiple times, and adding for about 1.5 hr. Monitoring the reaction by a thin layer until the benzyl is completely removed to obtain the mercaptoalanyl aspartic acid.
Dissolving mercaptoalanyl aspartic acid in 10mL of dry dichloromethane, adding 0.3mol of ethylene glycol and 0.01mol of 4-dimethylaminopyridine under the protection of argon, and stirring for 10 min under the ice-water bath condition; under these conditions, 0.05mol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and stirring was continued for 10 min and then at room temperature for 20 h. After the reaction was completed, the mixture was washed with distilled water and saturated brine in this order, and the dichloromethane layer was collected. Drying the organic layer with anhydrous sodium sulfate, vacuum filtering, concentrating the filtrate, dissolving with ethyl acetate, mixing with silica gel, and separating by column chromatography to obtain ethylene glycol-modified mercaptoalanyl aspartic acid. This compound was dissolved in 10mL of dry methylene chloride, 0.05mol of Compound A and 0.01mol of 4-dimethylaminopyridine were added under argon protection, and the mixture was stirred for 20 min, 0.05mol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. After the reaction, the mixture was washed with distilled water and saturated brine in this order, and the organic layer was collected. Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate, dissolving with ethyl acetate, mixing the sample with silica gel, performing column chromatography, performing gradient elution with ethyl acetate and petroleum ether, collecting the column chromatography, concentrating, dissolving the residue in 15% trifluoroacetic acid dichloromethane solution, stirring at room temperature for 5 h, and monitoring the reaction process by mass spectrometry until the tert-butyloxycarbonyl group and the tert-butyl group are completely removed. Adding toluene with the same volume as dichloromethane into the reaction solution, concentrating under reduced pressure, adding cold diethyl ether, placing in a refrigerator overnight, centrifuging the next day, removing the supernatant, and precipitating to obtain the final product, namely the mercaptoalanyl aspartate trifluoroacetate of peramivir.
Example 2
Dissolving 0.2mol of fluorenyl methoxycarbonyl-O-benzyl-L glutamic acid in 20mL of dry dichloromethane solution, sequentially adding 0.4mol of tert-butyl alcohol and 1mol of 4-dimethylaminopyridine under ice bath condition, adding 0.2mol of dicyclohexyl carbodiimide within 5 min, continuing to react for 5 min under the ice bath condition, then stirring at room temperature overnight, and monitoring the reaction progress by using a thin layer. After the reaction is finished, filtering to remove white solid dicyclohexylurea, washing the filtrate with 0.5 mol/L hydrochloric acid solution and saturated sodium bicarbonate solution for 2 times respectively, collecting an organic layer, drying the organic layer with anhydrous magnesium sulfate, filtering, concentrating the filtrate, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution with ethyl acetate and petroleum ether to collect column chromatography substances, concentrating, dissolving the residue in 20% piperidine N, N-dimethylformamide solution, stirring at room temperature for 40 min, and removing fluorene methoxycarbonyl groups. The piperidine was removed from the reaction mixture, which was then dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution 2 times to remove N, N-dimethylformamide. Collecting the organic layer, and spin-drying to obtain L-glutamic acid-benzyl ester-tert-butyl ester hydrochloride.
Dissolving 0.2mol of alanine protected by tert-butyloxycarbonyl, 0.2mol of O-benzotriazole-tetramethylurea hexafluorophosphate and 0.2mol of N, N-diisopropylethylamine in 15 mL of dry N, N dimethylformamide solution, and activating for 15 min under the condition of argon protection; meanwhile, L-glutamic acid benzyl ester tert-butyl ester hydrochloride is dissolved in 5mL of dry N, N dimethylformamide solution and added into the reaction solution, and the mixture is stirred for 12 hours at normal temperature. After the reaction is finished, the N, N-dimethylformamide solvent is distilled off at 80 ℃, the residue is redissolved by ethyl acetate, and the residue is washed by 10 percent citric acid, saturated sodium bicarbonate and saturated sodium chloride solution in sequence. Collecting the organic layer, drying with anhydrous magnesium sulfate, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution with ethyl acetate and petroleum ether, collecting the column chromatography, concentrating, dissolving the residue in 25 mL of anhydrous toluene, adding 0.2mol of Lawson reagent, heating and refluxing at 80 ℃ for 4 h under the condition of argon protection, and finishing the reaction. Filtering to remove solid, evaporating the filtrate under vacuum to spin dry the solvent, mixing the residue with silica gel, gradient eluting with column chromatography ethyl acetate and petroleum ether, collecting column chromatography extract, concentrating, placing the residue in a three-neck flask, pouring liquid ammonia, cooling with dry ice bath, adding sodium metal block under stirring, adding in multiple times, and adding for about 1.5 hr. Monitoring the reaction by a thin layer until benzyl is completely removed to obtain the glutamic acid of the mercaptoalanyl.
Dissolving glutamic acid of mercaptoalanyl in 20mL of dry dichloromethane, adding 0.8mol of ethylene glycol and 0.02 mol of 4-dimethylaminopyridine under the protection of argon, and stirring for 10 min under the condition of ice-water bath; under these conditions, 0.2mol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and stirring was continued for 10 min and then at room temperature for 20 h. After the reaction was completed, the mixture was washed with distilled water and saturated brine in this order, and the dichloromethane layer was collected. Drying the organic layer with anhydrous sodium sulfate, vacuum filtering, concentrating the filtrate, dissolving with ethyl acetate, mixing with silica gel, and separating by column chromatography to obtain ethylene glycol-modified mercaptoalanyl glutamic acid. This compound was dissolved in 20mL of dry dichloromethane, 0.2mol of Compound A and 0.05mol of 4-dimethylaminopyridine were added under argon protection, and the mixture was stirred for 20 min, 0.2mol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. After the reaction, the mixture was washed with distilled water and saturated brine in this order, and the organic layer was collected. Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate, dissolving with ethyl acetate, mixing the sample with silica gel, performing column chromatography, performing gradient elution with ethyl acetate and petroleum ether, collecting the column chromatography, concentrating, dissolving the residue in 15% trifluoroacetic acid dichloromethane solution, stirring at room temperature for 5 h, and monitoring the reaction process by mass spectrometry until the tert-butyloxycarbonyl group and the tert-butyl group are completely removed. Adding toluene with the same volume as dichloromethane into the reaction liquid, decompressing and concentrating, adding cold ether, putting the mixture into a refrigerator overnight, centrifuging the next day, removing supernatant fluid, and precipitating to obtain the final product, namely the mercaptoalanyl glutamate trifluoroacetate of peramivir.
Example 3
0.12mol of fluorenyl methoxycarbonyl-O-benzyl-L serine is dissolved in 20mL of dry dichloromethane solution, 0.25mol of tert-butanol and 0.5mol of 4-dimethylaminopyridine are added in turn under ice bath conditions, 0.12mol of dicyclohexylcarbodiimide is added within 5 min, the reaction is continued for 5 min under the conditions, then the mixture is stirred at room temperature overnight, and the progress of the reaction is monitored by a thin layer. After the reaction is finished, filtering to remove white solid dicyclohexylurea, washing the filtrate with 0.5 mol/L hydrochloric acid solution and saturated sodium bicarbonate solution for 2 times respectively, collecting an organic layer, drying the organic layer with anhydrous magnesium sulfate, filtering, concentrating the filtrate, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution with ethyl acetate and petroleum ether to collect column chromatography substances, concentrating, dissolving the residue in 20% piperidine N, N-dimethylformamide solution, stirring at room temperature for 40 min, and removing fluorene methoxycarbonyl groups. The piperidine was removed from the reaction mixture, which was then dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution 2 times to remove N, N-dimethylformamide. Collecting the organic layer, and spin-drying to obtain L-serine-benzyl ester-tert-butyl ester hydrochloride.
Dissolving 0.12mol of tert-butoxycarbonyl protected alanine, 0.12mol of O-benzotriazole-tetramethylurea hexafluorophosphate and 0.15mol of N, N-diisopropylethylamine in 12 mL of dry N, N dimethylformamide solution, and activating for 15 min under the condition of argon protection; meanwhile, L-serine-benzyl ester tert-butyl ester hydrochloride is dissolved in 4mL of dry N, N dimethylformamide solution and added into the reaction solution, and the mixture is stirred at normal temperature for 12 hours. After the reaction is finished, the N, N-dimethylformamide solvent is distilled off at 80 ℃, the residue is redissolved by ethyl acetate, and the residue is washed by 10 percent citric acid, saturated sodium bicarbonate and saturated sodium chloride solution in sequence. Collecting the organic layer, drying with anhydrous magnesium sulfate, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution with ethyl acetate and petroleum ether, collecting the column chromatography, concentrating, dissolving the residue in 22 mL of anhydrous toluene, adding 0.12mol of Lawson reagent, heating and refluxing at 80 ℃ for 4 h under the condition of argon protection, and finishing the reaction. Filtering to remove solid, evaporating the filtrate under vacuum to spin dry the solvent, mixing the residue with silica gel, gradient eluting with column chromatography ethyl acetate and petroleum ether, collecting column chromatography extract, concentrating, placing the residue in a three-neck flask, pouring liquid ammonia, cooling with dry ice bath, adding sodium metal block under stirring, adding in multiple times, and adding for about 1.5 hr. The reaction was monitored by thin layer until the benzyl group was completely removed to give cysteine from mercaptoalanyl.
Mercaptoalanyl serine was dissolved in 15 mL of dry dichloromethane, 0.12mol of Compound A and 0.03mol of 4-dimethylaminopyridine were added under protection of argon, and the mixture was stirred for 20 min, 0.12mol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. After the reaction, the mixture was washed with distilled water and saturated brine in this order, and the organic layer was collected. Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate, dissolving with ethyl acetate, mixing the sample with silica gel, performing column chromatography, performing gradient elution with ethyl acetate and petroleum ether, collecting the column chromatography, concentrating, dissolving the residue in 15% trifluoroacetic acid dichloromethane solution, stirring at room temperature for 5 h, and monitoring the reaction process by mass spectrometry until the tert-butyloxycarbonyl group and the tert-butyl group are completely removed. Adding toluene with the same volume as dichloromethane into the reaction liquid, decompressing and concentrating, adding cold ether, putting the mixture into a refrigerator overnight, centrifuging the next day, removing supernatant fluid, and obtaining the precipitate, namely the final product of the sulfhydryl alanyl serine ester trifluoroacetate of peramivir.
Example 4
Dissolving 0.2mol of fluorenyl methoxycarbonyl-O-benzyl-L tyrosine in 20mL of dry dichloromethane solution, sequentially adding 0.4mol of tert-butyl alcohol and 1mol of 4-dimethylaminopyridine under ice bath conditions, adding 0.2mol of dicyclohexyl carbodiimide within 5 min, continuing to react for 5 min under the ice bath conditions, then stirring at room temperature overnight, and monitoring the reaction progress by using a thin layer. After the reaction is finished, filtering to remove white solid dicyclohexylurea, washing the filtrate with 0.5 mol/L hydrochloric acid solution and saturated sodium bicarbonate solution for 2 times respectively, collecting an organic layer, drying the organic layer with anhydrous magnesium sulfate, filtering, concentrating the filtrate, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution with ethyl acetate and petroleum ether to collect column chromatography substances, concentrating, dissolving the residue in 20% piperidine N, N-dimethylformamide solution, stirring at room temperature for 40 min, and removing fluorene methoxycarbonyl groups. The piperidine was removed from the reaction mixture, which was then dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution 2 times to remove N, N-dimethylformamide. Collecting the organic layer, and spin-drying to obtain L-tyrosine-benzyl ester-tert-butyl ester hydrochloride.
Dissolving 0.2mol of alanine protected by tert-butyloxycarbonyl, 0.2mol of O-benzotriazole-tetramethylurea hexafluorophosphate and 0.2mol of N, N-diisopropylethylamine in 15 mL of dry N, N dimethylformamide solution, and activating for 15 min under the condition of argon protection; meanwhile, L-tyrosine-benzyl ester-tert-butyl ester hydrochloride is dissolved in 5mL of dry N, N dimethylformamide solution and added into the reaction solution, and the reaction solution is stirred at normal temperature for 12 hours. After the reaction is finished, the N, N-dimethylformamide solvent is distilled off at 80 ℃, the residue is redissolved by ethyl acetate, and the residue is washed by 10 percent citric acid, saturated sodium bicarbonate and saturated sodium chloride solution in sequence. Collecting the organic layer, drying with anhydrous magnesium sulfate, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution with ethyl acetate and petroleum ether, collecting the column chromatography, concentrating, dissolving the residue in 25 mL of anhydrous toluene, adding 0.2mol of Lawson reagent, heating and refluxing at 80 ℃ for 4 h under the condition of argon protection, and finishing the reaction. Filtering to remove solid, evaporating the filtrate under vacuum to spin dry the solvent, mixing the residue with silica gel, gradient eluting with column chromatography ethyl acetate and petroleum ether, collecting column chromatography extract, concentrating, placing the residue in a three-neck flask, pouring liquid ammonia, cooling with dry ice bath, adding sodium metal block under stirring, adding in multiple times, and adding for about 1.5 hr. The reaction was monitored by TLC until the benzyl group was completely removed to give the tyrosine as a mercaptoalanyl.
Mercaptoalanyl tyrosine was dissolved in 20mL of dry dichloromethane, 0.2mol of Compound A and 0.05mol of 4-dimethylaminopyridine were added under protection of argon gas, and the mixture was stirred for 20 min, 0.2mol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. After the reaction, the mixture was washed with distilled water and saturated brine in this order, and the organic layer was collected. Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate, dissolving with ethyl acetate, mixing the sample with silica gel, performing column chromatography, performing gradient elution with ethyl acetate and petroleum ether, collecting the column chromatography, concentrating, dissolving the residue in 15% trifluoroacetic acid dichloromethane solution, stirring at room temperature for 5 h, and monitoring the reaction process by mass spectrometry until the tert-butyloxycarbonyl group and the tert-butyl group are completely removed. Adding toluene with the same volume as dichloromethane into the reaction liquid, decompressing and concentrating, adding cold ether, placing in a refrigerator overnight, centrifuging the next day, removing supernatant fluid, and precipitating to obtain the final product of the peramivir, namely the mercaptoalanyl tyrosine ester trifluoroacetate.
First, the basic information of the four compounds synthesized in examples 1 to 4 was analyzed:
1. spectral information
2. HPLC purity analysis
2-1, sulfhydryl alanyl aspartate of peramivir (see figure 2 for specific map information)
TABLE 2
2-2.Mercaptalanyl glutamate of peramivir (see figure 3 for detailed map information)
TABLE 3
2-3. Mercaptalanyl serine ester of peramivir (see figure 4 for detailed map information)
TABLE 4
2-4 mercaptoalanyl tyrosine ester of peramivir (see figure 5 for specific map information)
TABLE 5
3. MS analysis
MS analysis map information of the sulfhydryl alanyl aspartate of the peramivir, the sulfhydryl alanyl glutamate of the peramivir, the sulfhydryl alanyl serine ester of the peramivir and the sulfhydryl alanyl tyrosine ester of the peramivir is shown in the figures 6, 7, 8 and 9.
Second, study of pharmacokinetics in rats
Sprague-Dawely rats of the experimental group and the control group were respectively perfused with aqueous thiogalactosyl aspartate trifluoroacetate solution, aqueous thiogalactosyl glutamate trifluoroacetate solution, aqueous thiogalactosyl serine ester trifluoroacetate solution, aqueous thiogalactosyl tyrosine ester trifluoroacetate solution and aqueous peramivir solution (calculated as peramivir 50 mg/kg), and the concentration of peramivir in plasma was determined. Sprague-Dawely rats were simultaneously injected intravenously with an aqueous solution of peramivir (5 mg/kg).
The plasma concentration-time curves of the mercaptoalanyl amino acid ester salt of peramivir and peramivir are shown in fig. 1.
Table 6 shows the pharmacokinetic parameters of peramivir after oral administration of the mercaptoalanyl amino acid ester salt of peramivir and peramivir.
As can be seen from fig. 1 and table 6, the absorption of peramivir in the experimental group was significantly faster than that in the control group, and the bioavailability of peramivir in the experimental group was 41.8%, 56.7%, 20.9%, and 13.60%, respectively, while that in the control group was only 3.4%. Therefore, the sulfhydryl alanyl amino acid ester salt of the peramivir can obviously improve the oral bioavailability of the peramivir.
Finally, it should be noted that the above-mentioned embodiments are only preferred embodiments of the present invention, and not intended to limit the present invention, and although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications and equivalents can be made in the technical solutions described in the foregoing embodiments, or some technical features thereof can be replaced. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. The sulfhydryl alanyl amino acid ester salt of peramivir is characterized in that: the structure is as follows:
wherein R is mercaptoalanyl aspartic acid, mercaptoalanyl glutamic acid, mercaptoalanyl serine or mercaptoalanyl tyrosine.
2. A process for the preparation of the mercaptoalanyl amino acid ester salt of peramivir according to claim 1, characterized in that: the method comprises the following steps:
(1) removing tert-butyloxycarbonyl group and adding a bis-tert-butyloxycarbonyl protecting group by taking (1S,2S3R,4R) -3- ((R) -1-acetamido-2-ethylbutyl) -4- (tert-butyloxycarbonylamino) -2-hydroxycyclopentanecarboxylic acid methyl ester as a raw material, and performing hydrolysis reaction to obtain a compound A, namely peramivir protected by tert-butyloxycarbonyl;
(2) using fluorene methoxycarbonyl-O-benzyl-L-amino acid as a raw material, carrying out upper protection on carboxyl, removing fluorene methoxycarbonyl to obtain L-amino acid-benzyl ester-tert-butyl ester hydrochloride, carrying out liquid phase synthesis on the L-amino acid-benzyl ester-tert-butyl ester hydrochloride and alanine protected by tert-butyloxycarbonyl as raw materials to obtain dipeptide, and replacing an O-amido bond in the dipeptide with an S-amido bond to obtain dipeptide containing mercaptoalanyl;
(3) taking the compound A and dipeptide containing 2-amino thiopropionic acid as raw materials, adding a reaction reagent to carry out esterification reaction to obtain the valyl alanyl amino acid ester of peramivir with part of groups protected, and then adding acid to obtain the valyl alanyl amino acid ester salt of peramivir.
3. The process for producing a mercaptoalanyl amino acid ester salt of peramivir according to claim 2, characterized in that: the structure of compound a is as follows:
4. the process for producing a mercaptoalanyl amino acid ester salt of peramivir according to claim 2, characterized in that: the reaction reagent in the step (1) comprises hydrochloric acid-dioxane, N dimethylformamide, 1, 3-di (tert-butyloxycarbonyl) -2-methyl-2-isothiourea, triethylamine, tetrahydrofuran, mercuric chloride, absolute ethyl alcohol and glacial acetic acid.
5. The process for producing a mercaptoalanyl amino acid ester salt of peramivir according to claim 2, characterized in that: the reaction reagent for synthesizing the dipeptide in the step (2) comprises dichloromethane, tertiary butanol, 4-dimethylaminopyridine, dicyclohexylcarbodiimide, piperidine, N-dimethylformamide, O-benzotriazole-tetramethylurea hexafluorophosphate, N-diisopropylethylamine and Lawson reagent.
6. The process for producing a mercaptoalanyl amino acid ester salt of peramivir according to claim 2, characterized in that: the esterification reaction in the step (3) is carried out at room temperature, the esterification reaction reagent comprises dichloromethane, 4-dimethylaminopyridine and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the used acid is trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid, acetic acid or citric acid.
7. The process for producing a mercaptoalanyl amino acid ester salt of peramivir according to claim 2, characterized in that: the specific process comprises the following steps:
dissolving 0.05-0.2 mol of fluorenyl methoxycarbonyl-O-benzyl-L-amino acid in 20mL of dry dichloromethane solution, sequentially adding 0.1-0.4 mol of tert-butyl alcohol and 0.05-1 mol of 4-dimethylamino pyridine under ice bath conditions, adding 0.05-0.2 mol of dicyclohexyl carbodiimide within 5 min, continuing to react for 5 min under the conditions, stirring at room temperature overnight, monitoring the reaction process by using a thin layer, filtering to remove white solid dicyclohexyl urea after the reaction is finished, washing the filtrate respectively with 0.5 mol/L hydrochloric acid solution and saturated sodium bicarbonate solution for 2 times, collecting an organic layer, drying by anhydrous magnesium sulfate, filtering, concentrating the filtrate, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution on a collected substance by ethyl acetate and petroleum ether column chromatography, concentrating, dissolving the residue in N of 20% piperidine, stirring at room temperature for 40 min in N-dimethylformamide solution to remove fluorene methoxycarbonyl group, removing piperidine from the reaction solution, dissolving with ethyl acetate, washing with saturated sodium chloride aqueous solution for 2 times to remove N, N-dimethylformamide, collecting the organic layer, and spin-drying to obtain L-amino acid-benzyl ester-tert-butyl ester hydrochloride;
dissolving 0.05-0.2 mol of alanine protected by tert-butyloxycarbonyl, 0.05-0.2 mol of O-benzotriazole-tetramethylurea hexafluorophosphate and 0.1-0.2 mol of N, N-diisopropylethylamine in 10-15 mL of dry N, N dimethylformamide solution, and activating for 15 min under the condition of argon protection; dissolving L-amino acid-benzyl ester tert-butyl ester hydrochloride in 3-5 mL of dry N, N dimethylformamide solution, adding the solution into the reaction solution, stirring at normal temperature for 12 h, evaporating N, N dimethylformamide solvent at 80 ℃ after the reaction is finished, re-dissolving the residue with ethyl acetate, washing with 10% citric acid, saturated sodium bicarbonate and saturated sodium chloride solution in sequence, collecting an organic layer, drying with anhydrous magnesium sulfate, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution with ethyl acetate and petroleum ether, collecting column chromatography, concentrating, dissolving the residue in 20-25 mL of anhydrous toluene, adding Lawson's reagent 0.05-0.2 mol, heating and refluxing at 80 ℃ for 4 h under the protection of argon gas, filtering to remove the precipitated solid, evaporating the filtrate in vacuum to obtain dry solvent, mixing the residue with silica gel, performing gradient elution by column chromatography ethyl acetate and petroleum ether, collecting column chromatography, concentrating, placing the residue in a three-neck flask, pouring liquid ammonia, cooling with dry ice bath, adding metal sodium block under stirring, adding for multiple times, finishing the addition for 1.5 h, and monitoring the reaction by a thin layer until benzyl is completely removed to obtain the dipeptide of mercaptoalanyl;
dissolving the dipeptide of mercaptoalanyl in 10-20 mL of dry dichloromethane, adding 0.05-0.2 mol of compound A and 0.01-0.05 mol of 4-dimethylaminopyridine under the protection of argon, stirring for 20 min, adding 0.05-0.2 mol of 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride, stirring at normal temperature overnight, washing with distilled water and saturated salt water after the reaction is finished, collecting an organic layer, drying the organic layer with anhydrous sodium sulfate, performing suction filtration, concentrating the filtrate, dissolving with ethyl acetate, mixing with silica gel, performing column chromatography, performing gradient elution with ethyl acetate and petroleum ether, collecting column chromatography, concentrating, and dissolving the residue in 15%Acid(s)Stirring the mixture at room temperature for 5 hours, monitoring the reaction process by mass spectrometry until the tert-butyloxycarbonyl group and the tert-butyl group are completely removed, adding toluene which has the same volume with the dichloromethane into the reaction solution, concentrating the reaction solution under reduced pressure, adding cold diethyl ether, putting the mixture into a refrigerator overnight, centrifuging the mixture the next day, removing the supernatant, and precipitating the precipitate to obtain the final product, namely the mercaptoalanyl amino acid ester salt of the peramivir;
wherein, when the end of the dipeptide of the mercaptoalanyl is carboxyl, the method also comprises the steps of dissolving the dipeptide of the mercaptoalanyl in 10-20 mL of dry dichloromethane, adding 0.3-0.8mol of glycol and 0.01-0.02 mol of 4-dimethylamino pyridine under the protection of argon, and stirring for 10 min under the condition of ice water bath; adding 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride of 0.05-0.2 mol under the condition, continuously stirring for 10 min, then stirring for 20 h at normal temperature, after the reaction is finished, sequentially washing with distilled water and saturated salt water, collecting a dichloromethane layer, drying an organic layer with anhydrous sodium sulfate, performing suction filtration, concentrating a filtrate, dissolving with ethyl acetate, mixing with silica gel, and performing column chromatography separation to obtain the ethylene glycol-based dipeptide of mercaptoalanyl.
8. The process for producing a mercaptoalanyl amino acid ester salt of peramivir according to claim 2 or 7, characterized in that: after trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid, acetic acid or citric acid is added into the peramivir mercaptopropylamino-acid ester obtained by the esterification reaction, the pharmaceutically acceptable salt is trifluoroacetate, hydrochloride, sulfate, formate, acetate or citrate.
9. Use of a mercaptoalanyl amino acid ester salt of peramivir according to any of claims 1 to 7 for increasing oral absorption of peramivir, characterized in that: the pharmaceutically acceptable salt of the mercaptoalanyl amino acid ester of peramivir is trifluoroacetate.
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