Entecavir salt compound, preparation method and medicine application thereof

A technology of entecavir and compounds, applied in the field of pharmaceuticals, to achieve good water solubility, good stability, and improve the effect of water solubility

Active Publication Date: 2013-01-30
FUJIAN COSUNTER PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Chinese patent application 200510097848.1 discloses addition salt compounds such as maleate and tartrate of entecavir; Chinese patent application 03135304.5 discloses metal ion salts such as sodium salt and potassium salt of entecavir. Charge transfer occurs, so that the carbonyl group in the entecavir structure becomes a sodium alkoxide or potassium alkoxide group, which changes the original structural form of entecavir, which may bring adverse effects

Method used

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  • Entecavir salt compound, preparation method and medicine application thereof
  • Entecavir salt compound, preparation method and medicine application thereof
  • Entecavir salt compound, preparation method and medicine application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Add 10 ml of methanol, 1.0 g of entecavir and 0.62 g of p-toluenesulfonic acid to a 25 ml eggplant bottle, stir, heat under reflux for 4 h, cool to room temperature, evaporate part of the solvent under reduced pressure, cool the residue to 0 °C, filter with suction, and dry in vacuo , an off-white solid was obtained, which was recrystallized from methanol to obtain 1.2 g of entecavir p-toluenesulfonate as a white crystal, with a yield of 74.1%.

[0056] IR(KBr)cm -1 :

[0057] 3388, 3333, 3191, 3137, 3100~2800, 2925, 1708, 1641, 1603, 1556, 1533, 1474, 1411, 1374, 1169, 1122, 1033, 1009.

[0058] 1 HNMR (DMSO-d 6 )δ:

[0059] 11.48 (brs, 1H, D 2 disappeared after O exchange), 9.04(s, 1H), 7.51(d, 2H), 7.13(d, 2H), 7.00~7.80(brs, 5H, D 2 Disappeared after O exchange), 5.51~5.48(m, 1H), 5.23(m, 1H), 4.85(m, 1H), 4.26(m, 1H), 3.54~3.60(m, 2H), 2.56(m, 1H) ), 2.31~2.35 (m, 1H), 2.29 (s, 3H), 2.15~2.17 (m, 1H).

[0060] 13 CNMR (DMSO-d 6 ):

[0061] 155.43, 153.90...

Embodiment 2

[0065] Add 35 ml of water, 1.0 g of entecavir and 0.62 g of p-toluenesulfonic acid to a 50-ml reaction flask, stir, react at 80°C for 2 h, cool to room temperature, evaporate the solvent under reduced pressure, and recrystallize the residue with methanol to obtain white crystals of p-toluenesulfonic acid Entecavir acid 1.3g, yield 80.2%.

Embodiment 3

[0067] Add 30 ml of ethanol, 2.0 g of entecavir and 1.25 g of p-toluenesulfonic acid to a 50 ml eggplant bottle, stir, heat under reflux for 3 h, cool to room temperature, evaporate part of the solvent under reduced pressure, cool the residue to 0 °C, filter with suction, and dry in vacuo , a white solid was obtained, which was recrystallized with ethanol to obtain 2.0 g of entecavir p-toluenesulfonate as a white crystal with a yield of 61.7%.

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Abstract

The invention provides entecavir acid addition salt compound, in particular relates to addition salt of toluene sulfonic acid (including para-, iso- and o- of methyl in benzene ring) and entecavir, a preparation method and medicine application thereof; the specific preparation method is that: under the condition with the temperature between room temperature and solvent backflow temperature, the entecavir and toluenesulfonic acid are contacted in solvent and are reacted to form salt, and then salt crystallization is carried out under the room temperature condition or at the temperature lower than the room temperature, extraction filtration, water pumping after washing is carried out and drying are carried out to obtain the entecavir toluene sulfonic acid, or the hydrate of the entecavir toluene sulfonic acid; and the invention further relates to the application of the entecavir toluene sulfonic acid to the medicines.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and relates to a derivative salt compound of entecavir, in particular to an addition salt compound of entecavir, a preparation method thereof and their application in medicine. technical background [0002] Entecavir is a guanosine analog with the chemical name 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl ]-1,9-dihydro-6H-purin-6-one, the molecular structure is as follows: [0003] Molecular formula C12H15N5O3, molecular weight 277.3, usually use its monohydrate, molecular formula C12H15N5O3.H2O, molecular weight 295.3. [0004] Entecavir is a highly effective antiviral agent, and clinical studies have shown a good inhibitory effect on hepatitis B virus. Due to the very high activity of entecavir against hepatitis B virus, a very low dose is sufficient to achieve the desired therapeutic effect. Generally, adults take it orally every day. 0.5mg or 1mg entecavir can a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/18C07C309/30A61K31/522A61P1/16A61P31/20
Inventor 康惠燕陈国华
Owner FUJIAN COSUNTER PHARMA CO LTD
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