CN104513166B - The hydroxybenzoate magnesium Salt And Preparation Method of tool anesthetic action - Google Patents

The hydroxybenzoate magnesium Salt And Preparation Method of tool anesthetic action Download PDF

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CN104513166B
CN104513166B CN201410825302.2A CN201410825302A CN104513166B CN 104513166 B CN104513166 B CN 104513166B CN 201410825302 A CN201410825302 A CN 201410825302A CN 104513166 B CN104513166 B CN 104513166B
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magnesium hydroxide
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hydroxybenzoate
anesthesiophore
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CN104513166A (en
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漆又毛
漆莹贝
顾颖
张冯敏
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Hangzhou Adamerck Pharmlabs Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring

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Abstract

The invention provides the anesthesiophore hydroxybenzoate magnesium salts of a kind of tool, by room temperature compound (II) and distilled water being mixed, add the aqueous solution of magnesium hydroxide under stirring, filter, lyophilize obtains object compound (I).Preparation method's mild condition of the present invention, simple to operate, there is industrial prospect.Compound of the present invention, due to well water-soluble, can not add the auxiliary material that tensio-active agent etc. exists security deficiency when making injection, also can reduce or remove injection pain simultaneously, increases patient compliance; Anesthesia onset is fast, recovery of reviving is fast, and Clinical practice safety, using value is large.The compounds of this invention structural formula is as follows:

Description

The hydroxybenzoate magnesium Salt And Preparation Method of tool anesthetic action
Technical field
The invention belongs to field of medicine and chemical technology, particularly the anesthesiophore hydroxybenzoate magnesium salts of a kind of tool and preparation method and application.
Background technology
Disoprofol is a kind of water-insoluble quick-acting fugitive intravenous anesthetic, has become induction at present, has maintained the drug of first choice of anesthesia, be widely used for Neurological Surgery anesthesia, paediatrics is anaesthetized, the calmness in Monitored anesthesia and ICU ward.But because it is water-soluble bad, be all make fat milk injection by technology of pharmaceutics method, but there is thermodynamics and kinetics unstable as liquid emulsion, be easy to pollute and the shortcoming such as cooperating microorganisms and storage and use inconvenience.Injection pain is Disoprofol modal untoward reaction when anesthesia induction simultaneously, and adult injection pain incidence is 28% to 90%, and children injection pain incidence is 28% to 85%, can only reduce injection pain clinically at present by using lignocaine, ondansetron etc.
In order to improve the water-soluble of Disoprofol, reducing its bad risk, as water-soluble propofol prodrugs---phosphorus propofol sodium is in Nikkei U.S. FDA approval listing December 12 in 2008.The weak point of phosphorus propofol sodium is that its onset is slower than Disoprofol; Revive also slow than Disoprofol; Phosphorus propofol sodium is the prodrug of Disoprofol, while discharging Disoprofol in vivo, also discharges harmful formaldehyde during metabolism.It seems that phosphorus propofol sodium is also difficult to shake and replace the status of Disoprofol at present.Because above-mentioned reason, be also starved of a new safety clinically and can be directly water-soluble intravenous anesthesia preparation to overcome the defect of Disoprofol self.
Summary of the invention
The object of this invention is to provide the anesthesiophore hydroxybenzoate magnesium salts of a kind of tool, have as shown in the formula (I) structure:
Wherein,
R is CH 3, CH 2cH 3, CH 2cH 2cH 3, CH (CH 3) 2, CH 2cH (CH 3) 2, CH 2sCH 3, CH 2oCH 3or CH 2cHF 2in one;
One in n=1 or 2;
As n=1, R 1=H, R 4=H, R 2=R 3=O -; Or
R 1=H、R 2=H，R 3=R 4=O -；
As n=2, R 2=R 4=H, R 1, R 3=O -or in H one; Or
R 1=R 3=H, R 2, R 4=O -or in H one; Or
R 2=R 3=H, R 1, R 4=O -or in H one.
Situation during preferred n=1.
Another object of the present invention is to provide the preparation method of described hydroxybenzoate magnesium salts, is realized by following steps:
Under room temperature, in reaction flask, add compound (II) and distilled water appropriate, adds the aqueous solution of magnesium hydroxide, after adding, continue to stir 2-3 hour, filter under whipped state, filtrate again essence filter once, lyophilize obtains object compound (I).
Described compound (II) with the mol ratio of magnesium hydroxide is: as n=1, compound (II): magnesium hydroxide=1:1; As n=2, compound (II): magnesium hydroxide=2:1.
Reaction formula is:
Wherein R, R 1, R 2, R 3, R 4definition the same.
Another object of the present invention is to provide described hydroxybenzoate magnesium salts and is preparing the application in anaesthetic.
Preparation method's mild condition of the present invention, simple to operate, there is industrial prospect.Compound of the present invention, due to well water-soluble, can not add the auxiliary material that tensio-active agent etc. exists security deficiency when making injection, also can reduce or remove injection pain simultaneously, increases patient compliance; And anesthesia onset is fast, recovery of reviving is fast, Clinical practice safety, using value is large.
Embodiment
The present invention is further elaborated by following examples, but is not limit the invention by any way with it.
embodiment 1
Under room temperature, in reaction flask, add MDB 2.4g (0.0143mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 1, yield 96.4%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 3.88 (CH3, s, 3H), 6.67 (CH, s, H), 7.27 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:191.01(M+1)。
embodiment 2
Under room temperature, in reaction flask, add PCA ethyl ester 2.6g (0.0143mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 2, yield 97%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 1.3 (CH3, s, 3H), 4.29 (CH2, s, 2H), 6.67 (CH, s, H), 7.27 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:205.03(M+1)。
embodiment 3
Under room temperature, in reaction flask, add PCA propyl ester 2.8g (0.0143mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 3, yield 95.3%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 0.96 (CH3, s, 3H), 1.79 (CH2, s, 2H), 4.25 (CH2, s, 2H), 6.67 (CH, s, H), 7.27 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:219.04(M+1)。
embodiment 4
Under room temperature, in reaction flask, add PCA isopropyl ester 2.8g (0.0143mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 4, yield 96.1%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 1.35 (2CH3, s, 6H), 4.31 (CH, s, H), 6.67 (CH, s, H), 7.29 (CH, s, H), 7.38 (CH, s, H) ppm.MS:m/z:219.04(M+1)。
embodiment 5
Under room temperature, in reaction flask, add PCA isobutyl ester 3g (0.0143mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 5, yield 94.7%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 1.01 (2CH3, s, 6H), 2.43 (CH, s, H), 4.21 (CH2, s, 2H), 6.67 (CH, s, H), 7.27 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:233.06(M+1)。
embodiment 6
At 0 DEG C, to PCA (1.12g under anhydrous condition; 0.00724mol) 2; dropwise drip sulfur oxychloride (1.16g, 0.00975mol) in 2-difluoroethanol (15ml) solution, reaction solution is heating reflux reaction under nitrogen protection; TLC tracks to and reacts completely; after reaction terminates, reaction solution concentrating under reduced pressure is except desolventizing, and residue crosses column purification (eluent: ethyl acetate: normal hexane); obtain compound 6, yield 94%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 4.61 (CH2, s, 2H), 5.75 (CH, s, H), 6.67 (CH, s, H), 7.27 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:219.04(M+1)。
embodiment 7
Under room temperature, in reaction flask, add compound 63.12g (0.0143mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 7, yield 96.3%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 4.61 (CH2, s, 2H), 5.75 (CH, s, H), 6.67 (CH, s, H), 7.27 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:241.01(M+1)。
embodiment 8
Under ice bath cooling, PCA 0.39g (2.5mmol) is added, methylene dichloride 40ml and triethylamine 0.3g (3mmol) in reaction flask, add chloromethyl methyl ether 0.24g (3mmol), mixture stirred at ambient temperature, TLC tracks to and reacts completely, and washes with water, anhydrous sodium sulfate drying, filter, concentrate and obtain compound 8, yield 92%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 3.24 (CH3, s, 3H), 6.33 (CH2, s, 2H), 6.67 (CH, s, H), 7.27 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:199.05(M+1)。
embodiment 9
Under room temperature, in reaction flask, add compound 82.83g (0.0143mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 9, yield 95.8%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 3.24 (CH3, s, 3H), 6.33 (CH2, s, 2H), 6.67 (CH, s, H), 7.27 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:221.02(M+1)。
embodiment 10
To PCA (4.62g, 0.03mol) and triethylamine (3.37g, add chloromethyl dimethyl sulfide (3.2g, 0.03mol) in acetonitrile (20ml) solution 0.03mol), stir at 5 DEG C, after adding, mixture rises to room temperature, back flow reaction is to complete, and concentrating under reduced pressure obtains residue, adds benzene (25ml), wash with 10% sodium bicarbonate aqueous solution, decompression removing benzene, distillation obtains compound 10, yield 93.4%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 2.09 (CH3, s, 3H), 5.4 (CH2, s, 2H), 6.67 (CH, s, H), 7.27 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:215.03(M+1)。
embodiment 11
Under room temperature, in reaction flask, add compound 103.1g (0.0143mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 11, yield 96.6%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 2.09 (CH3, s, 3H), 5.4 (CH2, s, 2H), 6.67 (CH, s, H), 7.27 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:237(M+1)。
embodiment 12
Under room temperature, in reaction flask, add 2,3-methyl dihydroxy benzoate 2.4g (0.0143mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 12, yield 97.6%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 3.88 (CH3, s, 3H), 6.67 (CH, s, H), 6.77 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:191.01(M+1)。
embodiment 13
Under room temperature, in reaction flask, add 2,3-dihydric ethyl benzoate 2.6g (0.0143mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 13, yield 96.5%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 1.3 (CH3, s, 3H), 4.29 (CH2, s, 2H), 6.67 (CH, s, H), 6.77 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:205.03(M+1)。
embodiment 14
Under room temperature, in reaction flask, add 2,3-resorcylic acid propyl ester 2.8g (0.0143mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 14, yield 95.5%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 0.96 (CH3, s, 3H), 1.79 (CH2, s, 2H), 4.25 (CH2, s, 2H), 6.67 (CH, s, H), 6.77 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:219.04(M+1)。
embodiment 15
Under room temperature, in reaction flask, add 2,3-resorcylic acid isopropyl ester 2.8g (0.0143mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 15, yield 95.2%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 1.35 (2CH3, s, 6H), 4.31 (CH, s, H), 6.67 (CH, s, H), 6.77 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:219.04(M+1)。
embodiment 16
With reference to the synthetic method of embodiment 6, with 2,3-resorcylic acid for raw material, obtain compound 16, yield 93.9%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 4.61 (CH2, s, 2H), 5.75 (CH, s, H), 6.67 (CH, s, H), 6.77 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:219.04(M+1)。
embodiment 17
Under room temperature, in reaction flask, add compound 163.12g (0.0143mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 17, yield 96.3%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 4.61 (CH2, s, 2H), 5.75 (CH, s, H), 6.67 (CH, s, H), 6.77 (CH, s, H), 7.36 (CH, s, H) ppm.MS:m/z:241.01(M+1)。
embodiment 18
Under room temperature, in reaction flask, add 3,5-methyl dihydroxy benzoate 4.81g (0.0286mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 18, yield 93.7%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 3.88 (2CH3, s, 6H), 6.41 (2CH, s, 2H), 7.00 (4CH, s, 4H) ppm.MS:m/z:359.05(M+1)。
embodiment 19
Under room temperature, in reaction flask, add 3,5-dihydric ethyl benzoate 5.2g (0.0286mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 19, yield 94.6%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 1.30 (2CH3, s, 6H), 4.29 (2CH2, s, 4H), 6.41 (2CH, s, 2H), 7.00 (4CH, s, 4H) ppm.MS:m/z:387.09(M+1)。
embodiment 20
Under room temperature, in reaction flask, add 2,4-dihydric ethyl benzoate 5.2g (0.0286mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 20, yield 93.4%.
These compound H nuclear magnetic resonance spectrum (D2O): δ 1.30 (2CH3, s, 6H), 4.29 (2CH2, s, 4H), 6.31 (2CH, s, 2H), 6.40 (2CH, s, 2H), 7.63 (2CH, s, 2H) ppm.MS:m/z:387.09(M+1)。
embodiment 21
Under room temperature, in reaction flask, add 2,4-resorcylic acid isopropyl ester 5.61g (0.0286mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 21, yield 92.8%.
These compound H nuclear magnetic resonance spectrum (D2O): δ 1.35 (4CH3, s, 12H), 4.31 (2CH, s, 2H), 6.31 (2CH, s, 2H), 6.40 (2CH, s, 2H), 7.65 (2CH, s, 2H) ppm.MS:m/z:415.12(M+1)。
embodiment 22
Under room temperature, in reaction flask, add DHB methyl esters 4.8g (0.0286mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 22, yield 94.7%.
This compound H nuclear magnetic resonance spectrum (D2O): δ 3.88 (2CH3, s, 6H), 6.67 (2CH, s, 2H), 6.77 (2CH, s, 2H), 7.27 (2CH, s, 2H) ppm.MS:m/z:359.06(M+1)。
embodiment 23
Under room temperature, in reaction flask, add DHB propyl ester 5.61g (0.0286mol) and distilled water 50ml.The aqueous solution 10ml of magnesium hydroxide 0.8g (0.0143mol) is added under whipped state.After adding, continue stirring 2 hours, filter, filtrate again essence is filtered once, and lyophilize obtains compound 23, yield 92.4%.
These compound H nuclear magnetic resonance spectrum (D2O): δ 0.96 (2CH3, s, 6H), 1.79 (2CH2, s, 4H), 4.25 (2CH2, s, 4H), 6.67 (2CH, s, 2H), 6.77 (2CH, s, 2H), 7.27 (2CH, s, 2H) ppm.MS:m/z:415.12(M+1)。
embodiment 24solubility test
By Disoprofol, phosphorus propofol sodium and the compounds of this invention some, measure according to the solubility test of Chinese Pharmacopoeia (2010 editions) respectively, result is: Disoprofol solubleness in water is soluble,very slightly, solubleness is for dissolving in water for phosphorus propofol sodium, and the compounds of this invention solubleness in water is also dissolving.The solubleness of the compounds of this invention in water is obviously better than Disoprofol.
embodiment 25effect experiment
Animal: ICR mouse 126, cleaning grade, Quan Xiong, mean body weight 25 ± 3g.
Reagent: the compound that the present invention is representative, Disoprofol (purity 99.46%) (consumption is 20mg/kg), phosphorus propofol sodium, physiological saline, tween 80.
Experimental technique:
(1) mouse weights dividing into groups, often organizes 6, and fasting 12h before test keeps normal water;
(2) respectively organize mouse by setting dosage, tail vein injection is for reagent product, and inject time, unification was be advisable for about 20 seconds;
(3) timing from tail vein injection, record mouse starts to the time (anesthesia onset time) of righting reflex loss with from righting reflex loss to the time (duration of anaesthesia) righting recovery, in table 1 from injection.
The compounds of this invention onset is rapid as shown in Table 1, and after tail intravenously administrable, onset speed is similar to Disoprofol, is better than phosphorus propofol sodium.The compounds of this invention recovers fast, after stopping administration, resume speed obviously faster than Disoprofol, greatly faster than phosphorus propofol sodium.
embodiment 26safety experiment
Get ICR mouse 126, cleaning grade, Quan Xiong, body weight 24 ± 3g, often organize 6.Each group of mouse is by setting dosage, and tail vein injection is for reagent product.Timing from tail vein injection, observes the time of occurrence of the symptom such as mouse anesthesia, death, the effective dose of each trial-product of statistical study and lethal dose.The results are shown in Table 2.
As shown in Table 2, the security of the compounds of this invention is obviously better than Disoprofol and phosphorus propofol sodium.

Claims (5)

1. the anesthesiophore hydroxybenzoate magnesium salts of tool, is characterized in that, has as shown in the formula (I) structure:
Wherein,
R is CH 3, CH 2cH 3, CH 2cH 2cH 3, CH (CH 3) 2, CH 2cH (CH 3) 2, CH 2sCH 3, CH 2oCH 3or CH 2cHF 2in one;
One in n=1 or 2;
As n=1, R 1=H, R 4=H, R 2=R 3=O -; Or
R 1=H、R 2=H，R 3=R 4=O -；
As n=2, R 2=R 4=H, R 1, R 3in one be O -, another is H; Or
R 1=R 3=H, R 2, R 4in one be O -, another is H; Or
R 2=R 3=H, R 1, R 4in one be O -, another is H.
2. the preparation method of the anesthesiophore hydroxybenzoate magnesium salts of a kind of tool according to claim 1, be is characterized in that, realized by following steps:
Under room temperature, in reaction flask, add compound (II) and distilled water appropriate, adds the aqueous solution of magnesium hydroxide, after adding, continue to stir 2-3 hour, filter under whipped state, filtrate again essence filter once, lyophilize obtains object compound (I);
Reaction formula is:
。
3. the preparation method of the anesthesiophore hydroxybenzoate magnesium salts of a kind of tool according to claim 2, is characterized in that, described compound (II) with the mol ratio of magnesium hydroxide is: as n=1, compound (II): magnesium hydroxide=1:1; As n=2, compound (II): magnesium hydroxide=2:1;
4. the application in anaesthetic prepared by the anesthesiophore hydroxybenzoate magnesium salts of a kind of tool according to claim 1.
5. application according to claim 4, is characterized in that, described medicine is water soluble parenteral solution.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101633671A (en) * 2009-07-13 2010-01-27 杭州奥默医药技术有限公司 Phosphoryl carboxylic acid propofol ester derivative and preparation method thereof
CN101863918A (en) * 2010-06-12 2010-10-20 李世系 Water-soluble dipropofol and preparation method thereof
CN102260184A (en) * 2011-06-09 2011-11-30 浙江九旭药业有限公司 Propofol derivative as well as preparation method thereof and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101633671A (en) * 2009-07-13 2010-01-27 杭州奥默医药技术有限公司 Phosphoryl carboxylic acid propofol ester derivative and preparation method thereof
CN101863918A (en) * 2010-06-12 2010-10-20 李世系 Water-soluble dipropofol and preparation method thereof
CN102260184A (en) * 2011-06-09 2011-11-30 浙江九旭药业有限公司 Propofol derivative as well as preparation method thereof and application thereof

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