CN102260184B - Propofol derivative as well as preparation method thereof and application thereof - Google Patents
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Abstract
The invention relates to a propofol derivative as well as a preparation method thereof and an application thereof. The propofol derivative is shown by the following general formula (a), wherein R is -NH2R1, -SO3R2 or -COOR2; R1 represents a pharmaceutical acid; and R2 represents an alkaline metal ion. Because a hydrophilic group is introduced into the propofol derivative provided by the invention, the water solubility is enhanced; the preparation can be prepared by using water as a solvent so that the side effect during clinical application is reduced; and the propofol derivative can stably exist in the water without being hydrolyzed into propofol. In addition, the propofol derivative provided by the invention has the advantages of simple and convenient preparation method and easiness in industrial production.
Description
Technical field
The present invention relates to propofol derivative and its preparation method and application, particularly water-soluble phenylformic acid (2,6-di-isopropyl) phenol ester derivatives and its preparation method and application.
Background technology
Disoprofol (propofol, 2,6-Bis(1-methylethyl)phenol) is a kind of intravenous anaesthetic.Within 1974, synthesize first successfully in the world, the people such as James in 1980 find that in experimentation on animals it has anaesthetic effect, within 1981, AstraZeneca pharmaceutical Co. Ltd (Italy) use soybean oil is as vehicle, developed micro-emulsion propofol injection, 1989 by U.S. FDA and recommend clinical use.Enter Chinese Medicine market through Chinese SFDA approval in December, 1993.Propofol injection is used for the induction of general anesthesia and maintains.Due to its pharmacokinetic characteristics, Disoprofol is very short action time, after using even long-time in organ still without accumulating.Therefore propofol is not only easily controlled, and clear-headed still fast than other narcotics after prolonged operations.In addition, Disoprofol also goes through as the long-term tranquilizer of strengthening monitor patients.
Disoprofol belongs to fat-soluble cpds, and poorly water-soluble need add vehicle to be applied to clinical.At present commercially available propofol injection is that the form of the oil-in-water emulsion to be formed as vehicle and water for injection by 10% soybean oil, 1.2% lecithin and 2.2% glycerine is applied to clinical.This emulsion likely causes patient's hyperlipidaemia in the time of intravenously administrable, and especially for the patient of long-term acceptance transfusion, the probability of suffering from hyperlipidaemia increases.In addition, this emulsion preservation period is shorter, and to bacterium and fungal contamination sensitivity.
Chinese patent application CN1357000A discloses the water-soluble propofol prodrugs that following formula represents.
Wherein, Z
+represent hydrogen, alkalimetal ion or amine.This water-soluble propofol prodrugs is take 2,6-Bis(1-methylethyl)phenol as raw material, carries out methylation reaction with chloromethyl dimethyl sulfide, then after SULPHURYL CHLORIDE chlorination, obtains intermediate O-(chloromethyl)-2,6 diisopropyl phenol.Then with the condensation of dibenzyl phosphate silver salt, obtain propofol, phosphate salt through steps such as hydrogenating reduction, deprotection and neutralizations.The step such as protecting group that experiences the condensation of dibenzyl phosphate silver salt in reaction and take off phosphono, so cost increases, is unsuitable for suitability for industrialized production.
Summary of the invention
In view of the above-mentioned problems in the prior art, the object of the present invention is to provide a kind of side effect when clinical application can be reduced, and be suitable for the propofol derivative of suitability for industrialized production, the inventor, through further investigation, provides the propofol derivative of following general formula (a) expression:
Wherein, R is-NH
2r
1,-SO
3r
2or-COOR
2, preferably R is positioned at ortho position or contraposition, is more preferably positioned at contraposition.R
1representing medicinal acid, for example, is hydrochloric acid or sulfuric acid, R
2representing alkalimetal ion, for example, is sodium ion or potassium ion.
Propofol derivative of the present invention is preferably PABA (2; 6-di-isopropyl) phenol ester hydrochloride, 4-[(2; 6-di-isopropyl) phenyl-oxygen base formyl radical] benzene sulfonic acid sodium salt or 4-[(2,6-di-isopropyl) phenyl-oxygen base formyl radical] Sodium Benzoate.
Propofol derivative of the present invention can be prepared as follows.
(1) R is-NH
2r
1time general formula (a) preparation method of propofol derivative that represents
Step 1: make nitrobenzoyl chloride react 2~4 hours to obtain product 1 with 2,6-Bis(1-methylethyl)phenol under alkaline condition.
Described alkaline condition refers to the environment that acid binding agent exists.Described acid binding agent is the acid generating in can absorption reaction system, and the alkaline matter not reacting with raw material, for example, be sodium bicarbonate, sodium carbonate; The tertiary amine such as triethylamine, Trimethylamine 99.
In step 1, solvent for use can be the organic solvents such as toluene, dimethylbenzene, methylene dichloride, trichloromethane.Temperature of reaction is preferably no more than 50 ℃.
Step 2: reduce above-mentioned product 1, generate benzaminic acid-(2,6-di-isopropyl) phenol ester.
Can, by utilizing iron powder, zinc powder, radium Buddhist nun nickel, palladium charcoal etc. to carry out reduction reaction as reductive agent in alcoholic solvent, preferably use iron powder as reductive agent.Temperature of reaction can be 35 ℃~65 ℃, is preferably 45 ℃~55 ℃, and preferred reaction 0.5~1.5 hour.
Step 3: benzaminic acid obtained above-(2,6-di-isopropyl) phenol ester is further generated to corresponding ammonium salt with acid-respons.Described acid is medicinal acid, for example, be hydrochloric acid, sulfuric acid etc.
(2) R is-SO
3r
2time general formula (a) preparation method of propofol derivative that represents
Take the product 1 for preparing in above-mentioned steps 1 as raw material, in the alcoholic solvent such as ethanol, Virahol, with the monovalent base aqueous metal salt back flow reaction of sulfurous acid 4~6 hours, prepare R for-SO
3r
2time general formula (a) represent propofol derivative.The monovalent base metal-salt of described sulfurous acid is for example sodium bisulfite or Potassium hydrogen sulfite.
(3) R is-COOR
2time general formula (a) preparation method of propofol derivative that represents
Step 1: cyano-benzoyl chloride is reacted 2~4 hours with 2,6-Bis(1-methylethyl)phenol under alkaline condition, prepare product 2.
Step 2: the product 2 that makes in step 1 preparation in alcoholic solvent and aqueous acid back flow reaction 8~12 hours at 60 ℃~110 ℃, prepares product 3.
Step 3: make in step 2 product 3 of preparation react with alkali metal hydroxide, obtain R and be-COOR
2time general formula (a) represent propofol derivative.Described alkali metal hydroxide can be sodium hydroxide or potassium hydroxide.
The present invention also provides a kind of pharmaceutical composition, and the effective constituent of described composition is propofol derivative of the present invention.Described pharmaceutical composition can be injection, lyophilized injectable powder or oral preparations.
Above-mentioned injection, lyophilized injectable powder or oral preparations can obtain by the normally used preparation method in this area.For example can be prepared as follows injection.
Take propofol derivative of the present invention and the sodium-chlor of recipe quantity, joined in appropriate water for injection, stir and make it to dissolve.Gained liquid is diluted to cumulative volume with water for injection, adds charcoal absorption, filter decarburization.Content, pH value are surveyed in sampling, after to be tested conforming with the regulations, filter with φ 0.45 μ m millipore filter, then filtrate are carried out to visible foreign matters inspection.After qualified on inspection, embedding, sterilizing, obtains injection.
In addition, the present invention also provides above-mentioned propofol derivative in the application of preparing in anaesthetic.Described anaesthetic can be injection, lyophilized injectable powder or oral preparations.
Propofol derivative of the present invention is owing to having introduced hydrophilic radical, so water-soluble increase can be carried out take water as solvent preparation, thereby reduces side effect when clinical application, and can be in water stable existence, and be not hydrolyzed into Disoprofol.In addition, propofol derivative preparation method of the present invention is easy, is easy to suitability for industrialized production.
Embodiment
Illustrate the preparation method of water-soluble propofol derivative of the present invention below, but the present invention is not limited to following specific embodiment.
The preparation of embodiment 1 PABA (2,6-di-isopropyl) phenol ester hydrochloride
The preparation of 1.1 PABAs (2,6-di-isopropyl) phenol ester
Method 1
178g 2,6-Bis(1-methylethyl)phenol is dissolved in 300ml methylene dichloride, and adds wherein 105g triethylamine, stir, make mixed solution.Then in ice bath to the dichloromethane solution (185g paranitrobenzoyl chloride is dissolved in 300ml methylene dichloride) that drips paranitrobenzoyl chloride in this mixed solution, control rate of addition, make the temperature of reaction system be no more than 50 ℃.After dropping finishes, at room temperature stir 4 hours.Then organic layer is washed to neutrality, separates and obtain organic layer, and organic layer is carried out to underpressure distillation, remove organic solvent.In distillation residue, add methyl alcohol 400ml, heating makes its dissolving.Then cooling its crystallize out that makes, filters and is dried, and obtains 243g white solid a, i.e. product 1.
Get 163.5g white solid a, join in 400ml 95% ethanol, be heated to 45 ℃~50 ℃, be stirred to white solid a and dissolve completely.Then add wherein 60~100 object iron filings 84g, and drip the hydrochloric acid 100ml of 0.1mol/l.At 45 ℃~50 ℃, be incubated 1 hour.Then add 10g diatomite, filtered while hot after stirring.Concentrate filtrate to 150ml, be then cooled to room temperature and filter, and filter cake is joined in 500ml water.Hydrochloric acid with 0.1mol/l under whipped state regulates PH=3~4.Next use dichloromethane extraction, each 100ml, extracts 2~3 times.Then with saturated sodium bicarbonate aqueous solution, water layer pH value is adjusted to 10 left and right, separates out solid, filter and be dried, obtain 117g solid, be i.e. PABA (2,6-di-isopropyl) phenol ester.
1H NMR(300MHz,CDCl
3):δ1.32(d,J=6.9Hz,12H),2.95(q,J=6.8Hz,2H),3.92(s,2H),6.60-6.63(dd,2H),6.87-7.01(m,3H),7.75-7.78(dd,2H)
Method 2
Get 32.7g white solid a and join in 200ml methyl alcohol, add Pd-C (palladium/charcoal) catalyzer 3.3g, pass into hydrogen, and keep pressure at 0.1~0.3MPa, at 45 ℃~50 ℃, stir 20~30min.Then add 5g diatomite, filter, by filtrate decompression concentrate drying.In enriched material, add water 100ml, with hydrochloric acid adjusting PH=3~4 of 0.1mol/l, then use dichloromethane extraction 2~3 times, and with about saturated sodium bicarbonate solution adjusting water layer PH=10, separate out solid, filter and be dried, obtain 26.7g white solid, it is PABA (2,6-di-isopropyl) phenol ester.
1H NMR(300MHz,CDCl
3):δ1.32(d,J=6.9Hz,12H),2.95(q,J=6.8Hz,2H),3.92(s,2H),6.60-6.63(dd,2H),6.87-7.01(m,3H),7.75-7.78(dd,2H)
The preparation of 1.2 PABAs (2,6-di-isopropyl) phenol ester hydrochloride
By PABA (2,6-di-isopropyl) phenol ester 89g joins in 300ml acetone, be heated to 55~60 ℃, after stirring and dissolving, add wherein the hydrochloric acid soln 100ml of 3mol/l, stir 30min, in cooling backward system, slowly add ethyl acetate, stir simultaneously, until there is solid to separate out, filters and be dried, obtain PABA (2,6-di-isopropyl) phenol ester hydrochloride 83g.
1H NMR(300MHz,D
2O):δ1.21(d,J=7.0Hz,12H),2.93(q,J=6.9Hz,2H),4.28(s,2H),6.59-6.62(dd,2H),6.93-7.07(m,3H),7.73-7.76(dd,2H)
Embodiment 2 4-[(2,6-di-isopropyl) phenyl-oxygen base formyl radical] preparation of benzene sulfonic acid sodium salt
Take 32.7g white solid a and be dissolved in 300ml ethanol, heated and stirred makes its dissolving.Then drip 30% aqueous solution of sodium bisulfite 40ml, dropping finishes rear backflow 4~6 hours, concentrating under reduced pressure reaction solution is to dry, in enriched material, add with the acetone 100ml after molecular sieve dehydration, reflux also stirs 30min, filtering insolubles while hot, and filtrate is carried out to cooling, stirring, separate out solid.Filter and be dried, obtain 4-[(2,6-di-isopropyl) phenyl-oxygen base formyl radical] benzene sulfonic acid sodium salt crude product 30.1g.It is further purified with acetone recrystallization, obtains crystallization 23.5g.
1H NMR(300MHz,D
2O):δ1.19(d,J=7.1Hz,12H),2.93(q,J=6.8,2H),7.04-7.11(m,3H),7.18-7.21(m,2H),7.96-8.01(m,2H)
Embodiment 3 4-[(2,6-di-isopropyl) phenyl-oxygen base formyl radical] preparation of Sodium Benzoate
The preparation of 3.1 products 3
Method 1
By 2,6-diisopropyl phenol 53.4g joins in 900ml toluene, under ice bath is cooling, stir, in the time that reaching below 10 ℃, temperature starts to drip the toluene solution (hiding to below 10 ℃ in refrigerator and cooled 51g is dissolved in 150ml toluene to cyano-benzoyl chloride after) to cyano-benzoyl chloride, control rate of addition and make the temperature of reaction system be no more than 30 ℃, after dropping finishes, under room temperature, stir 2~4 hours.Then wash with water 2 times, each 500ml, isolates oil reservoir, and by oil reservoir concentrating under reduced pressure.To adding methyl alcohol in enriched material: acetone=3: the mixed solvent 450ml of 1 (volume ratio), after heating for dissolving, stir on cooling limit, limit, and crystallization obtains 61.8g solid b, i.e. product 2.
Get 30.7g solid b, join in 300ml ethanol, be heated to reflux, drip wherein 30% aqueous sulfuric acid 65ml, drip and finish rear continuation backflow 8~12 hours.Reaction solution is evaporated to without alcohol taste, then adds 200ml water and 200ml ethyl acetate, stir 30min, isolate organic phase.By ethyl acetate (50ml/ time) aqueous phase extracted twice, merge organic phase.Concentrating under reduced pressure organic phase is extremely dry, then adds 10% aqueous sodium hydroxide solution 40ml, stirs after 30min, gets its supernatant liquor, adds dilute hydrochloric acid and regulates PH=3~4, filters, and filter cake obtains 11.2g solid c, i.e. product 3 after draining.
Method 2
Get 30.7g solid b, 0.5g itrile group lytic enzyme, join in 250ml water and stir, controlling temperature of reaction is 45 ℃~55 ℃, and is 9 left and right with saturated sodium bicarbonate aqueous solution maintenance system pH value in reaction process.After reaction system clarification, stop heating, regulate PH=3~4 of reaction solution with dilute hydrochloric acid, separate out solid, filter, filter cake obtains 31.5g solid d, i.e. product 3 after draining.
3.2 4-[(2,6-di-isopropyl) phenyl-oxygen base formyl radical] preparation of Sodium Benzoate
16.3g solid c or solid d are joined in 150ml acetone, be heated to 50 ℃~55 ℃, slowly drip aqueous sodium hydroxide solution (by 20g dissolution of sodium hydroxide in 40ml water), stir 30min~60min, then, stir on cooling limit, limit, spends the night after separating out solid in refrigerator cold-storage.Then filter, with acetone: methyl alcohol=3: the mixed solvent of 1 (volume ratio) carries out recrystallization to filter cake, vacuum-drying, obtains white solid, i.e. 4-[(2,6-di-isopropyl) phenyl-oxygen base formyl radical] Sodium Benzoate 10.3g.
1H NMR(300MHz,D
2O):δ1.24(d,J=6.9Hz,12H),2.90(q,J=7.1Hz,2H),6.89-7.04(m,3H),8.19-8.22(m,4H)
Solubility test
According to 2010 editions " pharmacopeia " note on the use Article 15 methods, the compound of preparation in embodiment 1~3 is carried out to solubility test.
Accurately take PABA-(2; 6-di-isopropyl) phenol ester hydrochloride, 4-[(2; 6-di-isopropyl) phenyl-oxygen base formyl radical] benzene sulfonic acid sodium salt, 4-[(2; 6-di-isopropyl) phenyl-oxygen base formyl radical] the each 1g of Sodium Benzoate left and right; add after purified water at every turn; 30 seconds of powerful jolting every 5 minutes, and observe, if be considered as dissolving completely without macroscopic particles of solute in 30 minutes.The results are shown in Table 1.
Table 1
Propofol derivative | Sample size (g) | Purified water (ml) |
PABA-(2,6-di-isopropyl) phenol ester hydrochloride | 1.023 | <1 |
4-[(2,6-di-isopropyl) phenyl-oxygen base formyl radical] benzene sulfonic acid sodium salt | 1.048 | <1 |
4-[(2,6-di-isopropyl) phenyl-oxygen base formyl radical] Sodium Benzoate | 0.998 | <1 |
As shown in Table 1, the propofol derivative preparing in embodiment 1~3 all can dissolve in the water that is less than 1ml, dissolves so all belong to very easily.
Water stability testing
Respectively the propofol derivative preparing in embodiment 1~3 is made to the aqueous solution that concentration is 25mg/ml, and this aqueous solution is respectively charged in 10ml cillin bottle (substantially impermeable oxygen) and 10ml polyethylene bottle (easily oxygen permeable), deposit at room temperature.Sample respectively at the 1st, 2,4,6 days, with reference to the detection method of Disoprofol raw material, utilize high performance liquid chromatography to detect whether there is free Disoprofol, the results are shown in Table 2.
High performance liquid chromatography testing conditions is as follows:
Instrument: the high performance liquid chromatograph LC-2010A processed of Shimadzu Seisakusho Ltd.
Detector: UV-detector
(4.6 × 250mm, 5 μ m) for chromatographic column: VP-ODS
Moving phase: methyl alcohol: acetonitrile: water=60: 15: 25, and contain 0.01% triethylamine
Flow velocity: 1.0ml/min
Detect wavelength: 280nm
Table 2
From the detected result of table 2, the propofol derivative of embodiment 1~3 preparation can be in water stable existence, and can not be hydrolyzed into Disoprofol.
Animal experiment
Get 12 healthy mices, body weight, between 20~25g, is divided into four groups at random.Before test and in the observation period, all raise by normal raising condition.By the propofol derivative of embodiment 1~3 preparation, i.e. compound PABA-(2; 6-di-isopropyl) phenol ester hydrochloride, 4-[(2; 6-di-isopropyl) phenyl-oxygen base formyl radical]) benzene sulfonic acid sodium salt, 4-[(2; 6-di-isopropyl) phenyl-oxygen base formyl radical] Sodium Benzoate is dissolved in respectively in physiological saline, take commercially available propofol emulsion as reference substance.Dosage all measures by the effective dose 10mg/kg of Disoprofol.
The injection of employing tail vein, observes mouse immediately, whether occurs anesthesia reaction.The judgement criteria of anesthesia reaction: animal general weakness, of flaccid muscles, righting response disappears, and pain stimulation loss for reaction to external world, breathes smooth-going.Test-results is in table 3.
Table 3
Phenomenon after injection | Average onset time | On average hold time | |
Reference substance | There is anesthesia reaction | 40 seconds | 10.2 minutes |
Embodiment 1 | There is anesthesia reaction | 47 seconds | 11.5 minutes |
Embodiment 2 | There is anesthesia reaction | 52 seconds | 11.6 minutes |
Embodiment 3 | There is anesthesia reaction | 56 seconds | 12.0 minutes |
As shown in Table 3, the propofol derivative of embodiment 1~3 preparation has the anaesthetic effect similar to commercially available product propofol emulsion.
Obviously, those skilled in the art can carry out various changes and modification and not depart from the spirit and scope of the present invention the present invention.Like this, if within of the present invention these are revised and modification belongs to the scope of the claims in the present invention and equivalent technologies thereof, the present invention is also intended to comprise these changes and modification interior.
Claims (6)
1. propofol derivative, is characterized in that, described propofol derivative is:
PABA (2,6-di-isopropyl) phenol ester hydrochloride;
4-[(2,6-di-isopropyl) phenyl-oxygen base formyl radical] benzene sulfonic acid sodium salt;
4-[(2,6-di-isopropyl) phenyl-oxygen base formyl radical] Sodium Benzoate.
2. the method for preparation propofol derivative claimed in claim 1, is characterized in that, the method for preparing described PABA (2,6-di-isopropyl) phenol ester hydrochloride comprises the following steps:
(1) make paranitrobenzoyl chloride under alkaline condition, react and make product 1 with 2,6-Bis(1-methylethyl)phenol;
(2) reduce described product 1, obtain reduzate;
(3) reduzate described in acidifying.
3. a pharmaceutical composition, is characterized in that, the effective constituent of described composition is the propofol derivative described in claim 1.
4. pharmaceutical composition according to claim 3, is characterized in that, described pharmaceutical composition is injection or oral preparations.
5. propofol derivative claimed in claim 1 is in the application of preparing in anaesthetic.
6. application according to claim 5, is characterized in that, described anaesthetic is injection or oral preparations.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6362234B1 (en) * | 2000-08-15 | 2002-03-26 | Vyrex Corporation | Water-soluble prodrugs of propofol for treatment of migrane |
CN101781329A (en) * | 2010-01-25 | 2010-07-21 | 陕西合成药业有限公司 | Propofol derivative for therapy |
CN102020574A (en) * | 2009-09-14 | 2011-04-20 | 李勤耕 | diisopropylphenyl gamma-aminobutyrate derivatives and preparation methods thereof |
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Publication number | Priority date | Publication date | Assignee | Title |
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US6362234B1 (en) * | 2000-08-15 | 2002-03-26 | Vyrex Corporation | Water-soluble prodrugs of propofol for treatment of migrane |
CN102020574A (en) * | 2009-09-14 | 2011-04-20 | 李勤耕 | diisopropylphenyl gamma-aminobutyrate derivatives and preparation methods thereof |
CN101781329A (en) * | 2010-01-25 | 2010-07-21 | 陕西合成药业有限公司 | Propofol derivative for therapy |
Non-Patent Citations (2)
Title |
---|
Giuseppe Trapani et al..Propofol Analogues. Synthesis, Relationships between Structure and Affinity at GABAA Receptor in Rat Brain, and Differential Electrophysiological Profile at Recombinant Human GABAA Receptors.《Journal of Medicinal Chemistry》.1998,第41卷(第11期),第1846-1854页. |
Propofol Analogues. Synthesis, Relationships between Structure and Affinity at GABAA Receptor in Rat Brain, and Differential Electrophysiological Profile at Recombinant Human GABAA Receptors;Giuseppe Trapani et al.;《Journal of Medicinal Chemistry》;19980428;第41卷(第11期);第1846-1854页 * |
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Address after: 321016 Zhejiang city of Jinhua province Xian No. 398 North Street Patentee after: Zhejiang Shangyao Jiuxu Pharmaceutical Co.,Ltd. Address before: 321016 Zhejiang city of Jinhua province Xian No. 398 North Street Patentee before: ZHEJIANG JIUXU PHARMACEUTICAL Co.,Ltd. |
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