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Alexan 5'-O-amino acid ester hydrochloride and preparation method thereof

A technology of valyl cytarabine hydrochloride and phenylalanyl cytarabine hydrochloride, applied in the field of medicine, can solve the problem of poor permeability of small intestine membrane, poor permeability of cytarabine membrane, poor permeability of cytarabine Cytarabine oral bioavailability and other issues to achieve the effect of improving membrane permeability

Active Publication Date: 2008-08-27
KUNMING JIDA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the polarity of the cytarabine molecule is very large, resulting in poor membrane permeability of the small intestine, so the poor membrane permeability makes the oral bioavailability of cytarabine very low (about 20%)
Therefore, it is necessary to find a way to improve the poor membrane permeability of cytarabine, and then improve its oral bioavailability

Method used

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  • Alexan 5'-O-amino acid ester hydrochloride and preparation method thereof
  • Alexan 5'-O-amino acid ester hydrochloride and preparation method thereof
  • Alexan 5'-O-amino acid ester hydrochloride and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0030] N-tert-butoxyformyl-L-valine reacts with carbonyldiimidazole, the reaction solvent is anhydrous tetrahydrofuran, dichloromethane or cyclohexane, the reaction temperature is from 0°C to the boiling point of the solvent, preferably 20-60°C, the reaction The time is 110 minutes; the reaction solution is slowly added dropwise to the mixed solution of compound VIII, 4-dimethylaminopyridine, triethylamine and N,N-dimethylformamide. After the addition is complete, the reaction is continued for 1-2 hours at a temperature of 50-100°C, preferably 60-90°C. The low boiling point solvent was evaporated under reduced pressure, the remaining N,N-dimethylformamide solution was adjusted to pH 7.69 with glacial acetic acid, N,N-dimethylformamide was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate Dilute and wash with distilled water and saturated brine successively. The organic layer was concentrated to a certain extent, palladium carbon was added and c...

Embodiment 2

[0032] N-tert-butoxyformyl-D-valine reacts with carbonyldiimidazole, the reaction solvent is anhydrous tetrahydrofuran, dichloromethane or cyclohexane, the reaction temperature is from 0°C to the boiling point of the solvent, preferably 20-60°C, the reaction The time is 110 minutes; the reaction solution is slowly added dropwise to the mixed solution of compound VIII, 4-dimethylaminopyridine, triethylamine and N,N-dimethylformamide. After the addition is complete, the reaction is continued for 1-2 hours at a temperature of 50-100°C, preferably 60-90°C. The low boiling point solvent was evaporated under reduced pressure, the remaining N,N-dimethylformamide solution was adjusted to pH 7.69 with glacial acetic acid, N,N-dimethylformamide was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate Dilute and wash with distilled water and saturated brine successively. The organic layer was concentrated to a certain extent, palladium carbon was added and c...

Embodiment 3

[0034] N-tert-butoxyformyl-L-isoleucine reacts with carbonyldiimidazole, the reaction solvent is anhydrous tetrahydrofuran, dichloromethane or cyclohexane, and the reaction temperature is from 0°C to the boiling point of the solvent, preferably 20-60°C, The reaction time was 110 minutes; the reaction solution was slowly added dropwise to the mixed solution of compound VIII, 4-dimethylaminopyridine, triethylamine and N,N-dimethylformamide. After the addition is complete, the reaction is continued for 1-2 hours at a temperature of 50-100°C, preferably 60-90°C. The low boiling point solvent was evaporated under reduced pressure, the remaining N,N-dimethylformamide solution was adjusted to pH 7.69 with glacial acetic acid, N,N-dimethylformamide was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate Dilute and wash with distilled water and saturated brine successively. The organic layer was concentrated to a certain extent, palladium carbon was added...

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Abstract

The invention discloses a 5'-O-amino acid ester hydrochloride, relating to the drug 1-beta-D-arabinofuranose-4-amino-2(1H)-cytosine ketone with interference on DNA synthesis, belonging to medical technique, in particular to a 5'-O-amino acid ester hydrochloride and a preparation method. The 5'-O-amino acid ester hydrochloride comprises 5'-O-L-valyl cytarabine hydrochloride, 5'-O-D-valyl cytarabine hydrochloride, 5'-O-L-isoleucyl cytarabine hydrochloride and 5'-O-L-tryptophanyl cytarabine hydrochloride. The preparation method is simple and suitable for industrial production, while the prepared product can effectively improve the membrane permeability of cytarabine, and the absolute biological utilization of mouse after oral taking can be improved from 21.6% to 60%.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and relates to the 5'-O-amino acid ester hydrochloride of 1-β-D-arabinofuranosyl-4-amino-2(1H)-cytosine, which interferes with DNA synthesis, namely 5'-O-amino acid ester hydrochloride of cytarabine and its preparation method. Background technique: [0002] The chemical name of the compound commonly known as cytarabine is 1-β-D-arabinofuranosyl-4-amino-2(1H)-cytosine. Cytarabine is converted into active cytarabine triphosphate in the body. Cytarabine triphosphate inhibits DNA polymerase and penetrates into DNA in a small amount, prevents DNA synthesis and inhibits cell growth. Clinically, cytarabine mainly For the treatment of acute myeloid leukemia. However, the molecular polarity of cytarabine is very large, which leads to poor membrane permeability of the small intestine, so the poor membrane permeability makes the oral bioavailability of cytarabine very low (about 20%). Therefore, it is ...

Claims

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Application Information

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IPC IPC(8): C07H19/09
Inventor 何仲贵孙勇兵孙进施世良许佑君张天虹
Owner KUNMING JIDA PHARMA
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