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Entecavir salt, and preparation

A technology of entecavir and cavir base salt, which is applied in the field of pharmaceutical preparations and anti-hepatitis B virus, and can solve the problems that the entecavir base salt is not stable enough and does not teach the preparation method of entecavir acid addition salt

Inactive Publication Date: 2007-07-25
MAI DE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Therefore, in order to increase the water solubility of Entecavir, thereby improving the bioavailability of Entecavir, while overcoming the insufficient stable defect of Entecavir base salt, it is necessary to find and prepare a new, more stable or more suitable Entecavir salt for the preparation of pharmaceutical preparations, Acid addition salts of entecavir
Acid addition salts of entecavir and processes for their preparation are not taught in the documents cited above and in other existing documents

Method used

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  • Entecavir salt, and preparation
  • Entecavir salt, and preparation
  • Entecavir salt, and preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: the preparation of entecavir hydrochloride salt

[0047] 3g entecavir (prepared by the method of document US5,206244 example K) is dissolved in 20 milliliters of dimethylacetamide (DMA), slowly add 10 milliliters of 2N hydrochloric acid ethanol solution, constantly stir the reaction solution, react at room temperature for 1 After 1 hour, the reaction product was filtered, and the solid product was washed with a little anhydrous ether. The product was vacuum-dried (40° C., 30 mmHg) and recrystallized from anhydrous ethanol solvent to obtain 2.4 g (yield 80%) of entecavir hydrochloride salt white crystals (melting point greater than 250° C.). Elemental analysis result C 12 h 16 N 5 o 3 Cl, calcd: C, 45.94; H, 5.14; Cl, ​​11.30; N, 22.32; O, 15.30. Experimental values: C, 45.90, H5.11, Cl, 11.35, N, 22.30.

[0048] The NMR spectrum data are as follows: 1 H NMR (DMSO-d 6 , 300MHz, ppm), 11.89(brs, 1H), 7.46(s, 2H), 8.86(s, 1H), 5.22(t, J=12Hz, 2H), 5.1...

Embodiment 2

[0050] Embodiment 2: the preparation of entecavir bromate salt

[0051] 2.0g entecavir (prepared according to the method of file US5,206244 example K) was dissolved in 20 milliliters of dimethylacetamide (DMA), slowly added 10 milliliters of 2N hydrobromic acid ethanol solution, constantly stirring the reaction solution, at room temperature After reacting for 1 hour, the reaction product was filtered, and the solid product was washed with a little anhydrous ether. The product was vacuum-dried (40° C., 30 mmHg) and recrystallized from anhydrous ethanol solvent to obtain 1.7 g (yield 85%) of entecavir bromate salt as white crystals (melting point greater than 260° C.). Elemental analysis result C 12 h 16 N 5 o 3 Br, calcd: C, 40.24; H, 4.50; Br, 22.31; N, 19.55; O, 13.40. Found: C, 40.30, H, 4.52, Br, 22.35, N, 19.50. The nuclear magnetic resonance spectrum data is identical with embodiment 1.

Embodiment 3

[0052] Embodiment 3: the preparation of entecavir sulfate salt

[0053] 2.0g entecavir (prepared according to the method of document US5,206244 example K) was dissolved in 20 ml of dimethylacetamide (DMA), slowly added 10 ml of 1N ethanol sulfuric acid solution, the reaction solution was constantly stirred, and reacted at room temperature After 1 hour, the reaction product was filtered, and the solid product was washed with a little anhydrous ether. The product was vacuum-dried (40° C., 30 mmHg) and recrystallized from absolute ethanol to obtain 1.5 g (yield 75%) of entecavir sulfate white crystals (melting point greater than 280° C.). Elemental analysis results [C 12 h 16 N 5 o 3 ] 2 SO 4 , calcd: C, 44.17, H, 4.94; N, 21.46; O, 24.52; S, 4.91. Experimental values: C, 44.13; H, 4.91; N, 21.41; S, 4.87. The nuclear magnetic resonance spectrum data is identical with embodiment 1.

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Abstract

This invention discloses a method for preparing entecavir acid-addition salts, entecavir magnesium salt and entecavir barium salt. The entecavir acid-addition salts are prepared from entecavir and inorganic or organic acids, and are preferential entecavir hydrochloride, entecavir bromate, entecavir sulfate, entecavir phosphate, entecavir sulfonate, and entecavir benzenesulfonate. The entecavir slats are stable, and have higher water solubility than entecavir itself, thus are more suitable to manufacture anti-HBV drugs.

Description

technical field [0001] The present invention relates to entecavir acid addition salt and entecavir base salt. The present invention also relates to a preparation method of the entecavir salt, a pharmaceutical preparation and an anti-hepatitis B virus application thereof. Background technique [0002] Entecavir (entecavir or BMS-200475), chemical name: [1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-hydroxymethyl]- 2-Methylenecyclopentyl]-6H-purin-6-one, the molecular structure is as follows: [0003] [0004] Entecavir is a 2'-pentanecyclodeoxyguanosine analogue that can effectively inhibit the replication of hepatitis B virus (HBV), and is used for the treatment of hepatitis B (B). Entecavir was well tolerated, and adverse reactions were mild and reversible. The drug is 100 to 1,000 times more effective than lamivudine in reducing the HBV viral load in patients and inhibiting viral replication. [0005] US patent (US5,206,244) discloses entecavir and its preparati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18A61K31/522A61K9/14A61K9/20A61K9/02A61K9/48A61K9/08A61P31/20
Inventor 黄才古何慧敏
Owner MAI DE
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