CN101781330A - 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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- CN101781330A CN101781330A CN 201010108941 CN201010108941A CN101781330A CN 101781330 A CN101781330 A CN 101781330A CN 201010108941 CN201010108941 CN 201010108941 CN 201010108941 A CN201010108941 A CN 201010108941A CN 101781330 A CN101781330 A CN 101781330A
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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 with a 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 amino acid double salt, 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 is called 2, the 6-diisopropyl phenol), be 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 good characteristics such as grasp.But, be insoluble in water, thereby its pharmacokinetic property is not good because Disoprofol is a fat-soluble cpds.At present mainly adopt the dosage form of lipomul to carry out intravenously administrable, this lipomul has certain side effect, as causes injecting the generation etc. of pain, lipid metabolism disorders and hyperlipidemia, Digestive tract adverse events and infection.
Carry out precursorization by the Phosphation method and derive and significantly to improve the water-soluble of Disoprofol, thereby be fit to clinical application more.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, L-Methionin, L-Histidine are needed by human or semi-dispensable amino acid, and the growth and the growth of human body had extremely important physiological significance.The L-arginine has unique blood sugar regulation, protection liver, enhancing body immunity, delays senility, promotes effects such as function antifatigue, promotion wound healing, promotion infant physical growth; L-Methionin then has the calcium absorption of raising and effects such as accumulation in vivo, acceleration bone growth thereof, can generate salt with acidic drug (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.; The 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 amino acid double salt (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 amino acid double salt.
Further purpose of the present invention provides the application of above-mentioned propofol, phosphate amino acid double salt
Purpose of the present invention realizes by following technical scheme:
The present invention at first provides a kind of structure propofol, phosphate amino acid double salt as the formula (1):
Wherein, R can be the basic aminoacids that comprises L-arginine or L-Methionin or L-Histidine.The present invention also provides the preparation method of the propofol, phosphate amino acid double salt of said structure, may further comprise the steps:
(1), structure in alkaline condition and organic solvent, under 0～50 ℃, obtains the Disoprofol phosphoryl chloride intermediate of structure suc as formula (3) with the phosphorylation agent phosphorus oxychloride reaction suc as formula the Disoprofol (2, the 6-diisopropyl phenol) of (2) after 2～10 hours:
(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 the Disoprofol dihydrogen phosphate of structure suc as 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 promptly gets the propofol, phosphate amino acid double salt (2,6-diisopropyl phenyl-1-oxo phosphoric acid ester diamino acid double salt) of structure suc as formula (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 is meant 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 is meant the pharmaceutical carrier of pharmaceutical field routine, as vehicle, disintegrating agent, tackiness agent, lubricant, antioxidant, Drug coating, tinting material, perfume compound, tensio-active agent etc.
Above-mentioned propofol, phosphate amino acid double salt or aforementioned pharmaceutical compositions can be used to prepare the medicine 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 condition of storage.
(2), the used basic aminoacids of the present invention is the necessary for human body nutritive ingredient, when the compound of described formula (1) is brought into play effect such as the tranquilizing soporific of Disoprofol and anesthesia in vivo, the amino acid that is discharged can be human body and utilizes, play the Synergistic treatment effect, help patient's recovery.
(3), reaction conditions gentleness of the present invention, easy and simple to handle, raw materials used cheap, environmental pollution is little.
Description of drawings
Fig. 1 is propofol, phosphate two arginine double salt
1The HNMR spectrum.
Fig. 2 is the ESI-MS spectrum of propofol, phosphate two arginine double salt.
Fig. 3 is propofol, phosphate two arginine double salt
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 thereto.
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 following stirring reactions of methylene dichloride 10ml 0.5 hour, dropwise slowly add phosphorus oxychloride 2.30g (0.015mol), dropwise about 1 hour, dropwise the back dropping funnel once with dichloromethane rinse, 25 ℃ were down continued stirring reaction 3 hours, and reaction finishes, and added the water hydrolysis under 25 ℃, the control reaction solution is always acid, stirring reaction 2 hours, reaction finishes, and water washing is colourless substantially to water layer, use the dichloromethane extraction water layer, merge organic layer, be spin-dried for, get the reddish-brown viscous liquid, purified again Disoprofol dihydrogen phosphate white crystal 2.01g, the yield: 77.9% of promptly getting.
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 following stirring reaction of methylene dichloride 10ml 0.5 hour, dropwise slowly add phosphorus oxychloride 2.30g (0.015mol), dropwise about 1 hour, dropwise the back dropping funnel once with dichloromethane rinse, 0 ℃ was down continued stirring reaction 10 hours, and reaction finishes, and added the water hydrolysis under 0 ℃, the control reaction solution is always acid, stirring reaction 4 hours, reaction finishes, and water washing is colourless substantially to water layer, use the dichloromethane extraction water layer, merge organic layer, be spin-dried for, get the reddish-brown viscous liquid, purified again Disoprofol dihydrogen phosphate white crystal 1.53g, the yield: 59.3% of promptly getting.
Embodiment 3
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 following stirring reactions of methylene dichloride 10ml 0.5 hour, dropwise slowly add phosphorus oxychloride 2.30g (0.015mol), dropwise about 1 hour, dropwise the back dropping funnel once with dichloromethane rinse, 50 ℃ were down continued stirring reaction 2 hours, and reaction finishes, and added the water hydrolysis under 50 ℃, the control reaction solution is always acid, stirring reaction 1 hour, reaction finishes, and water washing is colourless substantially to water layer, use the dichloromethane extraction water layer, merge organic layer, be spin-dried for, get the reddish-brown viscous liquid, purified again Disoprofol dihydrogen phosphate white crystal 1.89g, the yield: 73.2% of promptly getting.
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, reaction finishes, vacuum is spin-dried for to remove and desolvates, 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, reaction finishes, vacuum is spin-dried for to remove and desolvates, get propofol, phosphate two Histidine salt crude products, crude product promptly 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 L-Methionin (1.46g under the room temperature, 0.010mol) the aqueous solution, dropwise and continued stirring reaction 2 hours, reaction finishes, vacuum is spin-dried for to remove and desolvates, get propofol, phosphate two lysine salt crude products, crude product promptly 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 the 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)
The 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 0.22 μ m membrane filtration again, 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, are distributed into the 25mg/ bottle, the 50mg/ bottle, the 75mg/ bottle, the 100mg/ bottle, the sterilized powder injection formulations of propofol, phosphate amino acid double salt.
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 capsular amount of 80.0mg/.
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.Add the 1g Magnesium Stearate then, 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 ℃ of following thorough dryings, packing promptly.
Water-soluble mensuration:
Take by weighing each 0.1mg of propofol, phosphate amino acid double salt under the normal temperature and pressure respectively and place three in vitro, add 1 μ l distilled water one by one in vitro respectively, the limit edged jolts, and waits to note when observing compound dissolves fully the volume of the water that is added.Recording the water-soluble of propofol, phosphate amino acid double salt 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 is measured in the aqueous solution:
Prepare the 5mg/ml propofol, phosphate amino acid double salt aqueous solution respectively, 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
The propofol, phosphate amino acid double salt 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 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 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.
The foregoing description is a preferred implementation 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 (10)
1. a structure is suc as formula the propofol, phosphate amino acid double salt of (1):
Wherein, R is a basic aminoacids.
2. according to the described propofol, phosphate amino acid double salt of claim 1, it is characterized in that: described L-arginine, L-Methionin or L-Histidine.
3. according to the preparation method of claim 1 or 2 described propofol, phosphate amino acid double salts, it is characterized in that may further comprise the steps:
(1), structure under alkaline condition and in the organic solvent, down with phosphorus oxychloride reaction 2～10 hour after obtains structure Disoprofol phosphoryl chloride suc as formula (3) in 0～50 ℃ suc as formula the Disoprofol of (2):
(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 the Disoprofol dihydrogen phosphate of structure suc as formula (4):
(3), structure under 0～60 ℃ of condition, adds organic dissolution with solvents suc as formula the Disoprofol dihydrogen phosphate of (4), adds the basic aminoacids aqueous solution, reacted 1～4 hour, be spin-dried for solvent, the gained solid crude product promptly gets the propofol, phosphate amino acid double salt of structure suc as formula (1) through recrystallization purifying.
4. preparation method according to claim 3 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.
5. preparation method according to claim 3 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.
6. preparation method according to claim 3 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, merges organic layer then.
7. preparation method according to claim 3 is characterized in that: in the step (3), described organic solvent is methyl alcohol or ethanol; Described recrystallization purifying is meant that product is with acetone or acetone-water recrystallization.
8. the preparation method of water-soluble prodrug propofol, phosphate amino acid double salt according to claim 3 is characterized in that: in the step (3), the mol ratio of described Disoprofol dihydrogen phosphate and basic aminoacids is 1: 2～3.
9. pharmaceutical composition with tranquilizing soporific and anesthetic action is characterized in that: contain the claim 1 of significant quantity or 2 described propofol, phosphate amino acid double salts as activeconstituents, and contain one or more pharmaceutically acceptable pharmaceutical carriers.
10. claim 1 or the 2 described propofol, phosphate amino acid double salts application in preparation tranquilizing soporific and anaesthetic.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102603613A (en) * | 2012-03-13 | 2012-07-25 | 四川大学华西医院 | 4-(methoxycarbonyl)-4-(N- phenylpropionamido)- piperidine-1-substituted compound, preparation method and pharmaceutical application |
| CN109456360A (en) * | 2018-12-17 | 2019-03-12 | 河南中医药大学 | A kind of preparation method of phosphorus propofol sodium |
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| CN101575349B (en) * | 2009-06-11 | 2011-07-20 | 中国科学院广州化学研究所 | Method for preparing propofol organic phosphate disodium salt |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603613A (en) * | 2012-03-13 | 2012-07-25 | 四川大学华西医院 | 4-(methoxycarbonyl)-4-(N- phenylpropionamido)- piperidine-1-substituted compound, preparation method and pharmaceutical application |
| CN102603613B (en) * | 2012-03-13 | 2014-10-15 | 四川大学华西医院 | 4-(methoxycarbonyl)-4-(N- phenylpropionamido)- piperidine-1-substituted compound, preparation method and pharmaceutical application |
| CN109456360A (en) * | 2018-12-17 | 2019-03-12 | 河南中医药大学 | A kind of preparation method of phosphorus propofol sodium |
| CN109456360B (en) * | 2018-12-17 | 2021-05-14 | 河南中医药大学 | Preparation method of fospropofol disodium |
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