CN101845057A - Substituted phenol for methylal phosphate anesthetic and sedative drugs and preparation method thereof - Google Patents
Substituted phenol for methylal phosphate anesthetic and sedative drugs and preparation method thereof Download PDFInfo
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- CN101845057A CN101845057A CN200910058726A CN200910058726A CN101845057A CN 101845057 A CN101845057 A CN 101845057A CN 200910058726 A CN200910058726 A CN 200910058726A CN 200910058726 A CN200910058726 A CN 200910058726A CN 101845057 A CN101845057 A CN 101845057A
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Abstract
The invention discloses a substituted phenol for methylal phosphate anesthetic and sedative drugs and a preparation method thereof. The medicinal compound is a 2,6-diisopropyl phenol methylal phosphate disodium salt hydrate the molecular structure of which comprises 1-10 crystal water. The preparation method comprises the following steps: completely dissolving the 2,6-diisopropyl phenol methylal phosphate disodium salt hydrate in water, adding water-soluble organic solvent, and separating the hydrate by crystallization to obtain the medical compound. The medical compound in the form of a hydrate is not easy to absorb moisture, has good stability and easily controlled quality, and satisfactorily solves the urgent problems that the moisture content in the existing phosphate disodium salt compound is difficult to be controlled and the quality standard of existing phosphate disodium salt compound is difficult to be established due to strong moisture absorption of the existing phosphate disodium salt compound.
Description
Technical field
What the present invention relates to is that a kind of methylal phosphate anesthetic and sedative drugs of fortified phenol is with compound and preparation method.
Background technology
Shown in the formula (II) 2 of structure, 6-diisopropyl phenol (Disoprofol) is a kind of medicinal compound with effects such as calmness, hypnosis, anesthesia commonly used, is widely used at clinical anesthesia and ICU calmness etc.This compound is the derivative of alkylphenol, has fat-solubility, is oily under the room temperature, and is water insoluble.
Kay in 1977 and Rolly reported first the Disoprofol of formula (II) structure be used for the clinical trial of anesthesia induction.Its early stage clinical preparation for 16% polyoxy ethyl Viscotrol C solution (cremophor EL) be solubilizing agent make 1% 2, the 6-diisopropyl phenol aqueous solution.Said preparation is eliminated because of there are some problems in clinical application.Nineteen eighty-three changed into now clinically still use contain 1% 2,2 of 6-diisopropyl phenol (w/v), 10% soybean oil (w/v), 2.25% glycerine (w/v), 1.2% purifying Yelkin TTS (w/v), the emulsion of 6-diisopropyl phenol, in fact this is a kind of high-fat emulsion of pastille, in many countries clinical application is widely arranged all at present.Yet still there are many problems in said preparation in clinical application.Except producing pharmacological untoward reactions such as the blood pressure drops relevant with drug dose, decreased heart rate, breathlessness, other untoward reaction is main to be that the preparation of carrier is relevant with the lipomul with said preparation.-as the breaking and obstruction, anaphylaxis and propofol infusion syndrome (propofol infusion syndrome) or the like of transfer line when causing injection site pain, thrombophlebitis, hyperlipidaemia, potential mortality infectation of bacteria, long-term infusion.
Therefore, the Disoprofol to formula (II) structure is still continuing in the research aspect the preparation.Wherein, the prodrug (Prodrug) of seeking water miscible formula (II) analogue (analogues) and/or water-soluble formula (II) compound is one of main research direction, and with the prodrug of water-soluble formula (II) compound prospect is arranged most.
The propofol organic phosphate disodium salt of formula (III) structure is the water-soluble prodrug of Disoprofol, can enter human body by injection system etc. discharges Disoprofol very soon and produces tranquilizing soporific or anesthetic action, at U.S. Pat 6204257B1, US6451776B2, US6872838B2, WO03059255 and publication number are all existing report in the documents such as Chinese patent of CN1357000A.But, caused being difficult to control the content of its moisture and formulated difficulty on its quality standard because the water absorbability of propofol organic phosphate disodium salt in preparation of this formula (III) is stronger.
Summary of the invention
At above-mentioned situation, the present invention will provide a kind of methylal phosphate anesthetic and sedative drugs compound of fortified phenol, a kind of water-soluble precursor medicinal compound of propofol organic phosphate disodium salt of new form particularly, and the preparation method of this compound, to reach the problem that satisfied solution formula (III) compound was controlled the content of its moisture and formulated the difficulty on its quality standard because of being difficult to of causing more by force of water absorbability.
The methylal phosphate anesthetic and sedative drugs compound of said this fortified phenol of the present invention, for in the molecular structure shown in the formula (I), containing 2 of 1-10 crystal water, 6-diisopropyl phenol methylal disodium phosphate salt hydrate, i.e. propofol organic phosphate disodium salt hydrate:
X in the formula is 1～10 integer, more usually X=1～4.
The preparation of the above-mentioned propofol organic phosphate disodium salt hydrate of the present invention, can with derive from present existing bibliographical information and/or using method formula (III) structure 2, after 6-diisopropyl phenol methylal organic phosphate disodium salt is soluble in water fully, add water-miscible organic solvent, making crystallization fully separate out precipitation and separate obtains, can cooperate the operation that cools by common mode in case of necessity, complete in order to crystallization.Said water-miscible organic solvent can comprise as C commonly used such as methyl alcohol, ethanol, Virahol
1-3Ketone compounds, N that alcoholic solvent, acetone etc. are commonly used, dinethylformamide, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) etc., but be not limited only to this, serve as preferred wherein with Virahol or acetone.2 of the formula that obtains (I) structure, 6-diisopropyl phenol methylal disodium phosphate salt hydrate can be directly used in the follow-up pharmaceutical preparation.
Test-results shows, in the above-mentioned preparation process, the first step is during to the dissolving of (III) structure propofol organic phosphate disodium salt, and not remarkable from room temperature to influence of temperature variation between boiling point, the service temperature during therefore to dissolving there is no too much requirement.The aqueous solution is mixed with said water-miscible organic solvent, promptly have crystallization and separate out.Be to adopt the aqueous solution is added said organic solvent during crystallization operation, or said organic solvent is added in the aqueous solution, all allow.Kind by changing said water-miscible organic solvent and/or the hybrid mode when crystallization is separated out etc. can change and adjust the crystal water content in the said hydrate of the present invention.
Further test shows, when carrying out said dissolving and crystallization, the propofol organic phosphate disodium salt hydrate that makes formula (I) crystallization is more satisfactorily separated out, 2, the mole dosage ratio of 6-diisopropyl phenol methylal organic phosphate disodium salt, water and water-miscible organic solvent is 1: (2～5): result preferably can be arranged in (10～50) scope, when wherein using Virahol or acetone, 2, the preferred molar ratio of 6-diisopropyl phenol methylal organic phosphate disodium salt, water and water-miscible organic solvent can be 1: 2: 15.
As batch preparations, the water content that the above-mentioned propofol organic phosphate disodium salt hydrate of the present invention is every mole is 5%～35%, and water content ranges commonly used generally can be 5%～15%.
The propofol organic phosphate disodium salt hydrate that the present invention is above-mentioned, can be by present usual manner and one or more other compositions such as acceptable carrier, vehicle pharmaceutically, be prepared into corresponding operational pharmaceutical preparation, supply clinical application with corresponding route of administration.For example, can be intravenous formulations as preferred preparation, wherein the content of this prodrug can be in big as 0.5～30% (w/v) scope, and more commonly used can change in the scope of 2～10% (w/v), and dosage, mode etc. then there is no particular restriction.
Test-results shows, the medicinal compound of the above-mentioned propofol organic phosphate disodium salt hydrate forms of the present invention, have the moisture absorption of being difficult for, good stability and remarkable advantage such as easy to control the quality, thereby solved the pressing issues that at present corresponding Di-Sodium Phosphate salt compound was controlled its moisture content and formulated quality standard because of being difficult to of causing by force of water absorbability satisfactorily.
Below in conjunction with the embodiment of accompanying drawing illustrated embodiment, foregoing of the present invention is described in further detail again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Description of drawings
Fig. 1 is the crystalline structure figure of propofol organic phosphate disodium salt hydrate X-ray single crystal diffraction of the present invention.
Fig. 2 is corresponding crystalline structure cell part-structure figure with Fig. 1.
Embodiment
Embodiment 1
In 50ml single port bottle, add propofol organic phosphate disodium salt (commercial or prepare by present document mode) 13.0g, add water 40ml in 50 ℃ of stirring and dissolving, add an amount of decolouring of gac 15 minutes after molten entirely, filter, 400ml acetone is added in the filtrate under stirring, be stirred to after the room temperature refrigeration and place, treat that crystallization fully after.Filter, the small amount of acetone washing, drying, propofol organic phosphate disodium salt hydrate white crystals 16.1g, dry that to record water content to the constant weight be 35% for 105 ℃, yield 80.5%.(instrument: America NI COLET MX-1 type FT-IR infrared spectrometer), the result is as shown in table 1 for the IR analyzing and testing to measure infrared absorption spectrum with pellet technique.
Table 1IR determination data and analysis result
This water and the thing monocrystalline cultivated are with this understanding carried out X-ray diffraction with CAD4 type monocrystalline determinator, and crystalline structure that it is actual and cell configuration are respectively as depicted in figs. 1 and 2.As can be seen from the figure, be combined with 8 water moleculess around two sodium ions, wherein two water moleculess are that two sodium ions are shared, also contain two dissociating water molecules in the structure cell.From the monocrystalline structure cell, can see in its each molecule and can contain 10 water moleculess.
Embodiment 2
The propofol organic phosphate disodium salt 13.0g of adding formula (III) in 50ml single port bottle, add water 26ml in 50 ℃ of stirring and dissolving, add an amount of decolouring of gac 15 minutes after molten entirely, filter, filtrate adds in the 300ml Virahol under stirring, reflux is placed refrigerator for cold after being stirred to room temperature, treats that crystallization is complete.Filter, washing, drying, propofol organic phosphate disodium salt hydrate white crystals 13.2g, dry to constant weight in 105 ℃, recording water content is 21%, yield 80.2%.The result is as shown in table 2 for the IR analyzing and testing.
Table 2IR determination data and analysis result
Embodiment 3
The propofol organic phosphate disodium salt of adding formula (III) in 50ml single port bottle (commercial or prepare by present document mode) 13.0g, add water 30ml in 50 ℃ of stirring and dissolving, add an amount of decolouring of gac 15 minutes after molten entirely, filter, filtrate is added to 400ml N under stirring, in the dinethylformamide, reflux, place refrigerator for cold after being stirred to room temperature, treat that crystallization is complete.Filter, washing, drying, propofol organic phosphate disodium salt hydrate white crystals 12.3g, dry to constant weight in 105 ℃, recording water content is 10%, yield 85.2%.
Embodiment 4
The propofol organic phosphate disodium salt of adding formula (III) in 50ml single port bottle (commercial or prepare by present document mode) 13.0g, add water 35ml in 50 ℃ of stirring and dissolving, add an amount of decolouring of gac 15 minutes after molten entirely, filter, the 350ml tetrahydrofuran (THF) is added in the filtrate under stirring, reflux is placed refrigerator for cold after being stirred to room temperature, treats that crystallization is complete.Filter, washing, drying, propofol organic phosphate disodium salt hydrate white crystals 12.8g, dry to constant weight in 105 ℃, recording water content is 15%, yield 83.7%.
Embodiment 5
The propofol organic phosphate disodium salt of adding formula (III) in 50ml single port bottle (commercial or prepare by present document mode) 13.0g, add water 30ml in 50 ℃ of stirring and dissolving, add an amount of decolouring of gac 15 minutes after molten entirely, filter, filtrate is added in the 400ml dimethyl sulfoxide (DMSO) under stirring, reflux is placed refrigerator for cold after being stirred to room temperature, treats that crystallization is complete.Filter, washing, drying, propofol organic phosphate disodium salt hydrate white crystals 12.8g, dry to constant weight in 105 ℃, recording water content is 6%, yield 92.6%.
Embodiment 6
Above-mentioned propofol organic phosphate disodium salt hydrate is prepared into the lyophilized injectable powder of required propofol organic phosphate disodium salt content according to the ordinary method of present preparation lyophilized injectable powder, and through packing, analyzing can be for trying out after qualified.
Embodiment 7
With 40 of the kunming mices of male and female half and half, the test group (n=20) and positive control medicine Diprivan (DiprivanTM) control group (n=20) that are divided into injection propofol organic phosphate disodium salt hydrate of the present invention at random adopt sequential method to measure the median effective dose ED of the anesthesia of propofol phosphate for injection disodium salt hydrate and Diprivan (DiprivanTM)
50Through the mouse tail vein injection administration, (Forepaw Righting Reflex FRR) disappears as the terminal point index of judging anesthesia with the righting reflex of mouse fore paw in the test; The righting reflex of mouse fore paw reverts to the anesthesia recovery index.The result shows: propofol organic phosphate disodium salt hydrate ED of the present invention
50Be 60mg/kg, 95% credibility interval is 56～73mg/kg, the ED of Diprivan (DiprivanTM) control group
50Be 7mg/kg, 95% credibility interval is 6～8mg/kg.At ED
50In the mensuration process, the righting reflex loss time of observing propofol organic phosphate disodium salt hydrate group of the present invention is 141.3 ± 38.9 seconds, be 500.6 ± 186.2 seconds time of recovery, its onset time obviously is longer than 17 ± 3 seconds of Diprivan (DiprivanTM) control group, does not see notable difference time of recovery.
Claims (8)
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011160268A1 (en) * | 2010-06-23 | 2011-12-29 | 四川大学华西医院 | Phosphoric acid ester compound of hydroxy acid substituted phenyl ester, synthesis method and medical use thereof |
| CN102558224A (en) * | 2012-01-11 | 2012-07-11 | 陕西合成药业有限公司 | Phosphorus propofol sodium hydrate and preparation method and purpose thereof |
| CN102633831A (en) * | 2011-08-08 | 2012-08-15 | 陕西合成药业有限公司 | Methyl phosphorus propofol disodium dihydrate and preparation method and application thereof |
| CN103172658A (en) * | 2011-12-26 | 2013-06-26 | 宜昌人福药业有限责任公司 | Prodrug crystal form suitable for medicine, preparation method and pharmaceutical composition |
| WO2025026231A1 (en) * | 2023-07-28 | 2025-02-06 | 成都麻沸散医药科技有限公司 | Substituted phenol derivative and use thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6204257B1 (en) * | 1998-08-07 | 2001-03-20 | Universtiy Of Kansas | Water soluble prodrugs of hindered alcohols |
| CN100413508C (en) * | 2001-12-21 | 2008-08-27 | Mgigp公司 | Process for the preparation of water-soluble phosphonooxymethyl derivatives of alcohols and phenols |
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2009
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011160268A1 (en) * | 2010-06-23 | 2011-12-29 | 四川大学华西医院 | Phosphoric acid ester compound of hydroxy acid substituted phenyl ester, synthesis method and medical use thereof |
| US9243009B2 (en) | 2010-06-23 | 2016-01-26 | West China Hospital, Sichuan University | Phosphate ester compound of hydroxy acid substituted phenol ester, preparation method and medical use thereof |
| CN102633831A (en) * | 2011-08-08 | 2012-08-15 | 陕西合成药业有限公司 | Methyl phosphorus propofol disodium dihydrate and preparation method and application thereof |
| CN103172658A (en) * | 2011-12-26 | 2013-06-26 | 宜昌人福药业有限责任公司 | Prodrug crystal form suitable for medicine, preparation method and pharmaceutical composition |
| CN103172658B (en) * | 2011-12-26 | 2016-01-20 | 宜昌人福药业有限责任公司 | A kind of applicable medicinal prodrug crystal formation, preparation method and medicinal compositions |
| CN102558224A (en) * | 2012-01-11 | 2012-07-11 | 陕西合成药业有限公司 | Phosphorus propofol sodium hydrate and preparation method and purpose thereof |
| WO2025026231A1 (en) * | 2023-07-28 | 2025-02-06 | 成都麻沸散医药科技有限公司 | Substituted phenol derivative and use thereof |
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