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Bicyclol phosphate ester compound and preparing method, preparation and application thereof

A technology for bicyclic alcohol phosphate esters and compounds, which is applied in the directions of phosphorus organic compounds, chemical instruments and methods, compounds of elements of Group 5/15 of the periodic table, etc. It can improve the route of administration, prolong the retention time, and improve the water solubility.

Inactive Publication Date: 2016-06-29
BEIJING UNION PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] 5) Prodrug modification: The above strategies directly modify the structure of the compound, but inappropriate chemical modification may affect the activity or safety of the compound
[0010] At present, there are many research reports on the structural modification of bicycloalcohol, Chinese patent "bicycloalcohol-leucinamide and its preparation method and application" (application number 201210535804, open date March 27, 2013), Chinese patent "bicycloalcohol - Tiopronin Ester and Its Preparation Method and Application” (Application No. 201210535803, Publication Date December 13, 2012), Chinese Patent “Bicyclool Glycoside Compounds and Its Preparation Method and Application” (Application No. 200510077441, Publication Date 2013 March 27, 2010), the Chinese patent "Bicyclyl valine ester and its preparation method and its pharmaceutical composition and use" (application number 201010184424, published on May 27, 2010) and the Chinese patent "Adenine bicycloalcohol Esters and their preparation method" (Application No. 200410024276, published on June 16, 2004) discloses various bicyclic alcohol derivatives obtained by structural modification respectively, but does not provide for whether the water solubility of bicyclic alcohol has been improved in the above-mentioned patent Clear experimental data, it is difficult to explain the effect of improving water solubility

Method used

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  • Bicyclol phosphate ester compound and preparing method, preparation and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0085] The preparation of embodiment 1 bicyclic alcohol phosphate

[0086] Dissolve phosphoric acid (56ml, 0.96mol) in acetonitrile (800ml), slowly add pyridine (320ml), triethylamine (224ml), acetic anhydride (152ml), bicyclic alcohol (80g, 0.205mol) under stirring in a water bath at room temperature, and reflux Under the conditions, react until the raw materials disappear (about 20 hours), let stand at room temperature for 6-8 hours, add water (100ml) to the reaction solution, and continue to reflux for 2h, then concentrate under reduced pressure to remove the solvent, add water and ethyl acetate to the concentrate for extraction, water Layer through LSA-21 macroporous resin (1kg) column, gradient elution with water and ethanol, the product eluate was concentrated and dried to give bicyclyl phosphate (44g, 45.6%).

Embodiment 2

[0087] The preparation of embodiment 2 bicyclol calcium phosphate

[0088] Dissolve bicyclyl phosphate (16g, 0.034mol) in 500ml of methanol, slowly add calcium acetate (8g, 0.051mol) water (32ml) solution dropwise, stir at room temperature for 30min, filter to obtain a white solid, add this solid to 10% In methanol aqueous solution (2000ml), reflux and stir for 4h, hot filter, the filtrate is extracted three times with ethyl acetate, the water layer is concentrated under reduced pressure to 200ml, stand for crystallization for 2h, filter and dry to get bicycloalcohol calcium phosphate (10g, 57.6% ).

[0089] ESI-MS: m / z[M-H]=509.0

[0090] HNMR (D 2 O, 500MH Z )δ3.708(s, 3H); 3.984, 3.990(d, 6H); 5.921, 5.946, 6.060, 6.125(s, 4H); 4.534-4.653(q, 3H); s, 1H).

Embodiment 3

[0091] The preparation of embodiment 3 bicyclyl sodium phosphate

[0092]Take bicyclyl calcium phosphate (3g, 0.006mol), sodium carbonate (0.6g, 0.006mol), water (50ml), stir at room temperature for 2h, filter, and extract the filtrate three times with ethyl acetate, concentrate the water layer to dryness under reduced pressure, add Anhydrous methanol (80ml), stirred in a water bath at 50°C for 30min, filtered out insoluble matter, the filtrate was concentrated to dryness under reduced pressure, added absolute ethanol (50ml)), stirred and dissolved in a water bath at 80°C, frozen and crystallized, filtered and dried to obtain bicyclic alcohol phosphoric acid Sodium (2.0 g, 64.5%).

[0093] ESI-MS: m / z[M-H]=515.1

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Abstract

The invention relates to bicyclol phosphate ester (salt), a preparing method and preparation thereof, and application of the bicyclol phosphate ester (salt) to the preparing of anti-inflammation drugs. The formula (I) of the bicyclol phosphate ester (salt) is as shown in the description, wherein M1 and M2 respectively independently represent H, metal ions, ammonium ion (NH4+) or amino. Bicyclol phosphate ester is prepared by the phosphorylation reaction of bicyclol and phosphorylation reagent in the presence of catalyst and acid-binding agent, and the bicyclol phosphate ester salt is prepared by allowing the bicyclol phosphate ester to react with alkali or salt. The bicyclol phosphate ester (salt) and the preparing method thereof have the advantages that phosphate groups are introduced into the molecule structure of the bicyclol, the lipo-hydro partition coefficient of the drugs is improved by the high electronegativity, namely high hydrophilicity of the phosphate groups, and drug water solubility is increased under the premise that the activity and safety of the bicyclol are unaffected; the prepared bicyclol phosphate ester (salt) can increase the targeting effect of the bicyclol on the liver, improve the administration route, and prolong the in-vivo retention time of the drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a bicyclyl alcohol phosphate compound, a preparation method, a preparation thereof and the use of the bicyclyl alcohol phosphate compound in preparing anti-inflammatory drugs. Background technique [0002] Bicyclol, the chemical name is 4,4'-dimethoxy-5,6,5',6'-bis(methylenedioxy)-2-hydroxymethyl-2'-methoxycarbonyl biphenyl. It is an innovative anti-hepatitis drug with independent intellectual property rights developed by the Institute of Materia Medica, Chinese Academy of Medical Sciences. It has obtained patent protection in 16 countries and regions, and is currently on the market in the form of oral tablets. The raw material of bicyclol and its tablets obtained the new drug certificate and production approval in 2001, and are exclusively produced by Beijing Union Medical College Pharmaceutical Factory. Bicyclol can reduce the increase of aminotransfe...

Claims

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Application Information

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IPC IPC(8): C07F9/09A61K31/661A61P29/00
CPCC07F9/091A61K9/0019A61K9/08A61K9/2059A61K47/12C07F9/097
Inventor 李传波王迷娟张猛李强
Owner BEIJING UNION PHARMA FACTORY
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