CN101781330B - Propofol, phosphate and amino acid double salt and preparation method and application thereof - Google Patents
Propofol, phosphate and amino acid double salt and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses propofol, phosphate and amino acid double salt and a preparation method and application thereof. The method comprises the following steps of: reacting propofol as a raw material with a phosphorylating reagent under a basic condition to obtain a phosphorus oxychloride intermediate; hydrolyzing the phosphorus oxychloride intermediate to obtain propofol ethyl phosphoric acid;then salifying with basic amino acid and concentrating to obtain a crude product; and recrystallizing and purifying the crude product to obtain the propofol, phosphate and amino acid double salt witha structure formula shown as (1), wherein R is the basic amino acid. The medical double salt has favorable water solubility and stability and can be prepared into injections, oral solutions, capsules, tablets and the like after mixing with necessary auxiliary materials. The invention obviously improves the water solubility and the bioavailability of the propofol, reduces irritation and increases therapeutic cooperativity. The synthesis method has the advantages of simple operation, easy obtainment of the raw material, low cost and high yield.
Description
Technical field
The present invention relates to field of medicine and chemical technology, particularly a kind of water-soluble prodrug---propofol, phosphate, its preparation method and the application in preparation tranquilizing soporific and anesthetic action medicine.
Background technology
Disoprofol (Propofol, formula (2) has another name called propofol, Diprivan, chemistry 2,6-Bis(1-methylethyl)phenol by name) is the quiet notes narcotic of a kind of widely used whole body.It has, and onset is rapid, and action time is short, revives rapidly fully, and untoward reaction is few, does not stay sequela, and (can be used for anesthesia induction, keep and epidural anesthesia assisted) applied widely, dosage is easy to the good characteristics such as grasp.But because Disoprofol is fat-soluble cpds, be insoluble in water, thereby its pharmacokinetic property is not good.At present the main dosage form of lipomul that adopts carries out intravenously administrable, and this lipomul has certain side effect, as causes the generation etc. of injection pain, lipid metabolism disorders and hyperlipidemia, Digestive tract adverse events and infection.
Carry out precursor by the Phosphation method and derive and significantly to improve the water-soluble of Disoprofol, thereby more be fit to clinical application.The propofol, phosphate prodrug has phosphorus propofol sodium (Fospropofol Disodium, formula (5)) and the direct-connected propofol organic phosphate disodium salt (PropofolPhosphate, formula 6) that connects through methylene radical at present.These two kinds of Phosphation transformations all can improve Disoprofol water-soluble, improve pharmacokinetic property, but they all belong to monistic propofol, phosphate salt, and, the compound of formula (5) will discharge formaldehyde (the European Journal of PharmaceuticalSciences of a part in vivo in the metabolic process, 2008,34:110-117), comparatively unfavorable aspect drug safety.
Basic aminoacids such as L-arginine, 1B, L-Histidine are needed by human or semi-dispensable amino acid, and growth and the growth of human body had extremely important physiological significance.L-arginine has unique adjusting blood sugar, protection liver, strengthens body immunity, delays senility, the promotion functions antifatigue, promote wound healing, promote the effects such as infant physical growth; 1B then has the calcium absorption of raising and the effects such as accumulation in vivo, acceleration bone growth thereof, can generate salt with acidic drug (such as Whitfield's ointment etc.) and alleviate untoward reaction, also can be used as the ancillary drug of diuretic(s), share then with methionine(Met) and can treat severe hypertension etc.; L-Histidine is even more important for the growth of infant and animal, and can be used as biochemical reagents and medicament, also can be used for treating heart trouble, anaemia, the medicine of rheumatic arthritis etc.
Summary of the invention
Purpose of the present invention aims to provide a kind of new Disoprofol water-soluble prodrug---propofol, phosphate (Propofol Phosphate Diamino Acid Salts, chemical name: 2,6-diisopropyl phenyl-1-oxo phosphoric acid ester diamino acid double salt).
Another object of the present invention is to provide the preparation method of above-mentioned propofol, phosphate.
Further purpose of the present invention provides the application of above-mentioned propofol, phosphate
Purpose of the present invention realizes by following technical scheme:
The present invention at first provides a kind of structure suc as formula the propofol, phosphate shown in (1):
Wherein, R can be the basic aminoacids that comprises L-arginine or 1B or L-Histidine.The present invention also provides the preparation method of the propofol, phosphate of said structure, may further comprise the steps:
(1), structure is suc as formula the Disoprofol (2 of (2), the 6-diisopropyl phenol) in alkaline condition and organic solvent, under 0～50 ℃, obtain structure after 2～10 hours suc as formula the Disoprofol phosphoryl chloride intermediate of (3) with the phosphorylation agent phosphorus oxychloride reaction:
(2), structure suc as formula the Disoprofol phosphoryl chloride of (3) 0～50 ℃ through acid hydrolytic reaction 1～4 hour, be spin-dried for solvent after the washing separation and purification, obtain structure suc as formula the Disoprofol dihydrogen phosphate of (4):
(3), structure suc as formula the Disoprofol dihydrogen phosphate of (4) under 0～60 ℃ of condition, add organic dissolution with solvents, add the basic aminoacids aqueous solution, reacted 1～4 hour, be spin-dried for solvent, the gained solid crude product namely gets structure suc as formula the propofol, phosphate (2,6-diisopropyl phenyl-1-oxo phosphoric acid ester diamino acid double salt) of (1) through separation and purification.
As preferably, in the step (1), alkali is triethylamine or diethylamine, more preferably triethylamine in the described alkaline condition; The mol ratio of Disoprofol and alkali is 1: 1～1: 5, more preferably 1: 1.5; More preferably 20～30 ℃ of temperature, in more preferably 3～5 hours reaction times, the mol ratio of Disoprofol and phosphorylation agent phosphorus oxychloride is 1: 1～1: 5, more preferably 1: 1.5; Organic solvent is methylene dichloride or trichloromethane, more preferably methylene dichloride.
As preferably, in the step (2), the acid in the described acidic hydrolysis is hydrochloric acid, phosphoric acid or sulfuric acid, and more preferably hydrochloric acid is operating as and directly adds the water acidolysis; More preferably 20～30 ℃ of temperature of reaction, more preferably 2～3 hours reaction times; Washing separation and purification operation is to wash with water, and the water layer of washing is stripped with organic solvent, merges organic layer.
As preferably, in the step (3), described organic solvent is methyl alcohol or ethanol, more preferably ethanol; More preferably 20～40 ℃ of temperature of reaction, more preferably 2～3 hours reaction times; The mol ratio of basic aminoacids and Disoprofol is 1: 2～1: 3, more preferably 1: 2; Separation and purification recrystallization operation refers to that product is with acetone or acetone-water recrystallization, more preferably acetone-water.
The chemical equation of preferred synthesis step is as follows:
The present invention also provides a kind of pharmaceutical composition, contains the compound formula (1) for the treatment of significant quantity and is activeconstituents, can contain one or more pharmaceutically acceptable carriers.Described pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, such as vehicle, disintegrating agent, tackiness agent, lubricant, antioxidant, Drug coating, tinting material, perfume compound, tensio-active agent etc.
Above-mentioned propofol, phosphate or aforementioned pharmaceutical compositions can be for the preparation of the medicines with tranquilizing soporific and anesthetic action.
In the practical application, above-claimed cpd or pharmaceutical composition can be made required formulation, for example non-oral injection, ophthalmic preparation, dentistry preparation; Or tablet of oral administration, capsule, granule etc.
The present invention compared with prior art has following advantage and effect:
(1), the present invention significantly improved Disoprofol water-soluble and bioavailability, reduced pungency.And the compound of described formula (1) is stable in properties under room temperature and conventional storage condition.
(2), the used basic aminoacids of the present invention is the necessary nutritive ingredient of human body, when the compound of described formula (1) is brought into play the effect such as the tranquilizing soporific of Disoprofol and anesthesia in vivo, the amino acid that discharges can be human body and utilizes, play the Synergistic treatment effect, be conducive to patient's recovery.
(3), reaction conditions of the present invention is gentle, easy and simple to handle, raw materials used cheap, environmental pollution is little.
Description of drawings
Fig. 1 is propofol, phosphate two Arginine Salts
1The HNMR spectrum.
Fig. 2 is the ESI-MS spectrum of propofol, phosphate two Arginine Salts.
Fig. 3 is propofol, phosphate two Arginine Salts
31The PNMR spectrum.
Fig. 4 is propofol, phosphate two Methionin double salt
1The HNMR spectrum.
Fig. 5 is the ESI-MS spectrum of propofol, phosphate two Methionin double salt.
Fig. 6 is propofol, phosphate two Histidine double salt
1The HNMR spectrum.
Fig. 7 is the ESI-MS spectrum of propofol, phosphate two Histidine double salt.
Embodiment
Below in conjunction with embodiment the present invention is done further detailed description, but embodiments of the present invention are not limited to this.
Thermometer is being housed, add Disoprofol 1.78g (0.01mol) in the 50ml three-necked flask of constant pressure funnel and reflux condensing tube, triethylamine 1.52g (0.015mol), 25 ℃ of lower stirring reactions of methylene dichloride 10ml 0.5 hour, dropwise slowly add phosphorus oxychloride 2.30g (0.015mol), dropwise about 1 hour, dropwise rear dropping funnel with dichloromethane rinse once, 25 ℃ lower continued stirring reaction 3 hours, react complete, added water under 25 ℃ to be hydrolyzed, the control reaction solution is always acid, stirring reaction 2 hours reacts complete, and water washing is substantially colourless to water layer, use the dichloromethane extraction water layer, merge organic layer, be spin-dried for, get the reddish-brown viscous liquid, purified Disoprofol dihydrogen phosphate white crystal 2.01g, the yield: 77.9% of namely getting again.
Thermometer is being housed, add Disoprofol 1.78g (0.01mol) in the 50ml three-necked flask of constant pressure funnel and reflux condensing tube, triethylamine 1.52g (0.015mol), 0 ℃ of lower stirring reaction of methylene dichloride 10ml 0.5 hour, dropwise slowly add phosphorus oxychloride 2.30g (0.015mol), dropwise about 1 hour, dropwise rear dropping funnel with dichloromethane rinse once, 0 ℃ lower continued stirring reaction 10 hours, react complete, added water under 0 ℃ to be hydrolyzed, the control reaction solution is always acid, stirring reaction 4 hours reacts complete, and water washing is substantially colourless to water layer, use the dichloromethane extraction water layer, merge organic layer, be spin-dried for, get the reddish-brown viscous liquid, purified Disoprofol dihydrogen phosphate white crystal 1.53g, the yield: 59.3% of namely getting again.
Thermometer is being housed, add Disoprofol 1.78g (0.01mol) in the 50ml three-necked flask of constant pressure funnel and reflux condensing tube, triethylamine 1.52g (0.015mol), 25 ℃ of lower stirring reactions of methylene dichloride 10ml 0.5 hour, dropwise slowly add phosphorus oxychloride 2.30g (0.015mol), dropwise about 1 hour, dropwise rear dropping funnel with dichloromethane rinse once, 50 ℃ lower continued stirring reaction 2 hours, react complete, added water under 50 ℃ to be hydrolyzed, the control reaction solution is always acid, stirring reaction 1 hour reacts complete, and water washing is substantially colourless to water layer, use the dichloromethane extraction water layer, merge organic layer, be spin-dried for, get the reddish-brown viscous liquid, purified Disoprofol dihydrogen phosphate white crystal 1.89g, the yield: 73.2% of namely getting again.
With Disoprofol dihydrogen phosphate (1.29g, 0.005mol) add an amount of dissolve with ethanol, drip L-arginine (1.74g under the room temperature, 0.010mol) the aqueous solution, dropwise and continued stirring reaction 2 hours, react complete, vacuum is spin-dried for desolventizing, get propofol, phosphate two arginic acid salt crude products, crude product gets white solid 2.68g through recrystallization purifying, yield: 88.4%.
With Disoprofol dihydrogen phosphate (1.29g, 0.005mol) add an amount of dissolve with ethanol, drip L-Histidine (1.55g under the room temperature, 0.010mol) the aqueous solution, dropwise and continued stirring reaction 2 hours, react complete, vacuum is spin-dried for desolventizing, get propofol, phosphate two Histidine salt crude products, crude product namely gets white solid 2.37g through recrystallization purifying, yield: 83.4%.
With Disoprofol dihydrogen phosphate (1.29g, 0.005mol) add an amount of dissolve with ethanol, drip 1B (1.46g under the room temperature, 0.010mol) the aqueous solution, dropwise and continued stirring reaction 2 hours, react complete, vacuum is spin-dried for desolventizing, get propofol, phosphate two lysine salt crude products, crude product namely gets white solid 2.21g through recrystallization purifying, yield: 80.3%.
The structure spectrogram of each embodiment gained compound is shown in Fig. 1-7, and structural formula and the spectroscopic data of gained compound are as follows:
1, embodiment 1-3 Disoprofol dihydrogen phosphate (2,6-diisopropyl phenyl-1-oxo dihydrogen phosphate)
Fusing point and the spectroscopic data of Disoprofol dihydrogen phosphate are as follows: Mp:168～171 ℃;
1HNMR (400MHz, CD
3COCD
3, δ/ppm, J/Hz): 1.15 (d, 12H, J=7.2), 3.51～3.58 (m, 2H, J=7.2), 7.14 (m, 3H), 10.34 (s ,-OH, D
2O, exchangeable).
2, embodiment 4 propofol, phosphates two arginic acid salts
The spectroscopic data of propofol, phosphate two arginic acid salts (2,6-diisopropyl phenyl-1-oxo phosphoric acid ester two arginic acid salts) is as follows:
1HNMR (400MHz, D
2O, δ/ppm, J/Hz): 1.02 (d, 12H, J=7.2), 1.49～1.58 (m, 4H), 1.69～1.74 (m, 4H), 3.08 (t, 4H, J=6.4), 3.52 (t, 2H, J=6.4), 3.57～3.60 (m, 2H, J=7.2), 7.051 (m, 3H);
31PNMR (400MHz, D
2O, δ/ppm, 85%H
3PO
4): 1.25; ESI-MS (m/z): [M+1]
+605,258,174.
3, embodiment 5 propofol, phosphates two Histidine salt
The spectroscopic data of propofol, phosphate two Histidine salt (2,6-diisopropyl phenyl-1-oxo phosphoric acid ester two Histidine salt) is as follows:
1HNMR (400MHz, D
2O, δ/ppm, J/Hz): 1.05 (d, 12H, J=6.8), 3.06～3.19 (m, 4H), 3.41～3.48 (m, 2H, J=6.8), 3.86～3.89 (dd, 2H, J=5.6), (7.04 m, 2H), 7.07～7.11 (m, 2H), 8.03 (s, 2H); ESI-MS (m/z): [M+1]
+569,258,155.
4, embodiment 6 propofol, phosphates two lysine salts
The spectroscopic data of propofol, phosphate two lysine salts (2,6-diisopropyl phenyl-1-oxo phosphoric acid ester two lysine salts) is as follows:
1HNMR (400MHz, D
2O, δ/ppm, J/Hz): 1.07 (d, 12H, J=6.8), 1.38～1.43 (m, 4H), 1.58～1.66 (m, 4H), 1.81～1.89 (m, 4H), 2.90 (t, 2H, J=7.6), 3.39～3.44 (m, 2H), 3.84 (t, 2H, J=6.0), 7.08～7.14 (m, 3H); ESI-MS (m/z): [M+1]
+551,258,146.
Example of formulations 1: injection
Propofol, phosphate two arginic acid salts of getting 50.0mg are added among 15～20 ℃ the 5% glucose solution 20ml, behind the stirred solution, add the 10mg needle-use activated carbon, stir the filtration decarburization 10 minutes; With 0.45 μ m membrane filtration, use again 0.22 μ m membrane filtration, adding 5% glucose solution total amount is 100ml, measures content, checks clarity, is filled in the 100ml infusion bottle, aluminium lid is rolled in tamponade, 121 ℃ of sterilization 20min.
Example of formulations 2: injection
35～40 ℃ of vacuum-dryings of gained solid among the embodiment 4～6 are got sterilized powder, under aseptic condition, be distributed into the 25mg/ bottle, the 50mg/ bottle, the 75mg/ bottle, the 100mg/ bottle gets the sterilized powder injection formulations of propofol, phosphate.
Example of formulations 3: capsule
The propofol, phosphate two arginic acid salt pressed powders of 50.0mg are mixed fully with the 30.0mg lactose, mixture is inserted capsule to obtain oral capsule with the amount of 80.0mg/ capsule.
Example of formulations 4 tablets
The propofol, phosphate two arginic acid salt pressed powders of 50.0mg are mixed mutually with 1g glucose, 10g W-Gum and 1.5g 5% corn starch paste, make mixture forming particle with wet grain method.Then add the 1g Magnesium Stearate, obtain oral preparation by pressed disc method.
Example of formulations 5 granules
Get 50.0mg propofol, phosphate two arginic acid salts, 40mg dextrin and 80mg sucrose mixing, with wet granulation, put 60 ℃ lower fully dry, packing and get final product.
Water-soluble mensuration:
Take by weighing respectively each 0.1mg of propofol, phosphate under the normal temperature and pressure and place three in vitro, in vitro adding one by one 1 μ l distilled water, the limit edged jolts respectively, the volume of recording the water that adds when compound dissolves fully to be seen.Recording the water-soluble of propofol, phosphate is greatly improved, its solubleness is respectively: propofol, phosphate two arginic acid salt 0.031g/ml, propofol, phosphate two Histidine salt 0.029g/ml, propofol, phosphate two lysine salt 0.025g/ml (solubleness of Disoprofol in pure water only is 146mg/L).
Stability Determination in the aqueous solution:
Prepare respectively the 5mg/ml propofol, phosphate aqueous solution, under the room temperature, lucifuge left standstill 28 days, carried out tracking and measuring through TLC and NMR again, did not find that it has hydrolysate or other degradation productions.
Pharmacodynamics test
Propofol, phosphate is made into the aqueous solution of equal portions, behind 0.2 μ m non-velum filteration, is used for the animal injection.
One, the pharmacodynamics test of propofol, phosphate two Arginine Salts:
Rat be studies show that through the tail vein injection, dosage is respectively 200,300, during 400mg/kg, begin to produce that the anesthetic action required time is respectively 12.5 ± 3.5,8.4 ± 2.4,6.1 ± 1.9min, lasting effective drug duration is respectively 7.2 ± 4.6,11.3 ± 8.7,15.7 ± 10.1min.
Mouse be studies show that through the tail vein injection, dosage is respectively 50,100, during 150mg/kg, begin to produce that the anesthetic action required time is respectively 7.4 ± 2.2,5.1 ± 1.7,2.9 ± 1.8min, lasting effective drug duration is respectively 12.7 ± 2.9,22.8 ± 4.8,39.1 ± 7.3min.
Two, the pharmacodynamics test of propofol, phosphate two Histidine double salt:
Rat be studies show that through the tail vein injection, dosage is respectively 200,300, during 400mg/kg, begin to produce that the anesthetic action required time is respectively 13.7 ± 3.1,9.4 ± 2.5,6.5 ± 1.3min, lasting effective drug duration is respectively 6.1 ± 3.1,10.9 ± 6.1,14.1 ± 11.6min.
Mouse be studies show that through the tail vein injection, dosage is respectively 50,100, during 150mg/kg, begin to produce that the anesthetic action required time is respectively 9.1 ± 2.9,6.3 ± 2.1,3.6 ± 1.4min, lasting effective drug duration is respectively 10.7 ± 3.9,21.1 ± 5.1,37.3 ± 7.9min.
Above-described embodiment is the better embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (9)
1. a structure is suc as formula the propofol, phosphate of (1):
Formula (1)
Wherein, R is basic aminoacids; Described basic aminoacids is L-arginine, 1B or L-Histidine.
2. the preparation method of described propofol, phosphate according to claim 1 is characterized in that may further comprise the steps:
(1), structure under alkaline condition and in the organic solvent, 2～10 hour after obtains structure suc as formula the Disoprofol phosphoryl chloride of (3) in 0～50 ℃ of lower and phosphorus oxychloride reaction suc as formula the Disoprofol of (2):
Formula (2) formula (3)
(2), structure under 0～50 ℃, through acid hydrolytic reaction 1～4 hour, is spin-dried for solvent after the washing separation and purification suc as formula the Disoprofol phosphoryl chloride of (3), obtains structure suc as formula the Disoprofol dihydrogen phosphate of (4):
Formula (4)
(3), structure suc as formula the Disoprofol dihydrogen phosphate of (4) under 0～60 ℃ of condition, add organic dissolution with solvents, add the basic aminoacids aqueous solution, reacted 1～4 hour, be spin-dried for solvent, the gained solid crude product namely gets structure suc as formula the propofol, phosphate of (1) through recrystallization purifying.
3. preparation method according to claim 2, it is characterized in that: in the step (1), alkali is triethylamine or diethylamine in the described alkaline condition; Described organic solvent is methylene dichloride or trichloromethane.
4. preparation method according to claim 2, it is characterized in that: in the step (1), the mol ratio of described Disoprofol and alkali is 1: 1～5; The mol ratio of described Disoprofol and phosphorus oxychloride is 1: 1.5.
5. preparation method according to claim 2, it is characterized in that: in the step (2), the acid in the described acidic hydrolysis is hydrochloric acid, phosphoric acid or sulfuric acid, is operating as directly to add the water acidolysis; Described washing lock out operation is to wash with water, and the water layer of washing is stripped with organic solvent again, then merges organic layer.
6. preparation method according to claim 2, it is characterized in that: in the step (3), described organic solvent is methyl alcohol or ethanol; Described recrystallization purifying refers to that product is with acetone or acetone-water recrystallization.
7. the preparation method of propofol, phosphate according to claim 2, it is characterized in that: in the step (3), the mol ratio of described Disoprofol dihydrogen phosphate and basic aminoacids is 1: 2～3.
8. the pharmaceutical composition with tranquilizing soporific and anesthetic action is characterized in that: contain the propofol, phosphate claimed in claim 1 of significant quantity as activeconstituents, and contain one or more pharmaceutically acceptable pharmaceutical carriers.
9. the application of propofol, phosphate claimed in claim 1 in preparation tranquilizing soporific and anaesthetic.
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