CN101298426A - Water-soluble derivate of 2,6-diisopropyl phenol and use thereof - Google Patents
Water-soluble derivate of 2,6-diisopropyl phenol and use thereof Download PDFInfo
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- CN101298426A CN101298426A CNA2008100169141A CN200810016914A CN101298426A CN 101298426 A CN101298426 A CN 101298426A CN A2008100169141 A CNA2008100169141 A CN A2008100169141A CN 200810016914 A CN200810016914 A CN 200810016914A CN 101298426 A CN101298426 A CN 101298426A
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Abstract
The invention relates to a 2, 6-diisopropyl phenol ester water-soluble compound and an application thereof. The representative general formula of the invention is [I], wherein, X refers to single bond, alkyl, amidocyanogen or substituted amino; Y refers to the amidocyanogen, the substituted amino, oxygen or the alkyl; R refers to polyhydroxyl alkyl; n is equal to 0 or 1. The 2, 6-diisopropyl phenol ester water-soluble compound of the invention has higher chemical stability outside a body, is easy to be dissolved into water and can be fast hydrolyzed to generate 2, 6-diisopropyl phenol under the action of ester hydrolytic ferment in the body to play the role of anesthesia.
Description
Technical field
The present invention relates to 2,6-diisopropyl benzene phenolic ester water-soluble cpds, particularly a kind of 2, the osamine yl carboxylic acid ester soluble derivative and the application thereof of 6-diisopropyl phenol.
Background technology
2, the 6-diisopropyl phenol is the fugitive general anesthetic of widespread use clinically, and its characteristics are rapid-action, does not have savings, and it is fast and complete to revive.Because it is insoluble in water, its injection liquid of clinical application is an emulsion.Because the emulsion characteristic, cause at present clinical commonly usedly 2,6-diisopropyl phenol injection poor stability can cause embolism in blood vessel, cause injection pain, mixes sedimentation with other injection generation easily, and also easy bacterium such as dyes at shortcoming.
World patent WO 2006017351 A1 and Chinese patent CN1744908 (publication number), 200480002967.8 (application number) discloses series 2, the derivative compound of 6-diisopropyl phenol amino acid soluble ester, these compounds substantially all are 2, the ester of 6-diisopropyl phenol and the sour salt that forms, have certain acidity. from chemical stability, band acid 2, the aqueous stability of 6-diisopropyl benzene phenolic ester is than neutral 2,6-diisopropyl benzene phenolic ester water-soluble cpds poor stability.
Summary of the invention
The present invention provides a kind of neutral to contain 2 of osamine base series matter in order to overcome the deficiency of above technology, the water-soluble cpds of 6-diisopropyl benzene phenolic ester, and it is good to have solvability, good stability.
Another object of the present invention is to the narcotic that the above-claimed cpd preparation is used for humans and animals is produced anesthetic action.
The present invention realizes by following measure:
The invention provides a kind of is 2 of representative with general formula for [I], 6-diisopropyl benzene phenolic ester water-soluble cpds:
Wherein X represents singly-bound, alkyl, amido or substituted amido;
Y represents amido, substituted amido, oxygen or alkyl;
R represents polyhydroxy alkyl;
N=0 or 1.
Of the present invention 2,6-diisopropyl benzene phenolic ester water-soluble cpds contains m crystal water, mark between the described m=1-10 or natural number.General formula is:
Of the present invention 2,6-diisopropyl benzene phenolic ester water-soluble cpds is characterized in that: described polyhydroxy alkyl is the polyhydroxy alkyl that carbohydrate structure derives, and the quantity of carbochain is 1-6, and the quantity of hydroxyl is 3-18.
Of the present invention 2,6-diisopropyl benzene phenolic ester water-soluble cpds is characterized in that: the substituted amido of described X representative be the quantity of carbochain be 1-8 alkyl for amido, the alkyl of described X representative is that the quantity of carbochain is 1-8 alkyl.
Of the present invention 2,6-diisopropyl benzene phenolic ester water-soluble cpds is characterized in that: the substituted amido of described Y representative be the quantity of carbochain be 1-12 alkyl for amido, the alkyl of described Y representative is that the quantity of carbochain is 1-12 alkyl.
The present invention is with aminosugar or sugared series matter and 2, and the 6-diisopropyl phenol synthesizes the neutral ester, and is stronger in external its chemical stability, water-soluble easily.In vivo, can be under the effect of ester hydrolase, hydrolysis produces 2 fast, and the 6-diisopropyl phenol plays anesthetic action.
The present invention is with aminosugar or sugar, and 2, the 6-diisopropyl phenol is a basic raw material, can prepare the compound of general formula [I] representative by following several method.
Method A: in the methylene dichloride saturated solution of phosgene, quantitatively add 2, the solution of 6-diisopropyl phenol, with the glucosamine reaction, it represents reaction formula is scheme 1 (Scheme 1) again:
Method B: available triphosgene replaces phosgene, and it represents reaction formula is scheme 2 (Scheme 2):
Method C: available oxalyl chloride replaces phosgene, and it represents reaction formula is scheme 3 (Scheme 3):
Method D: other acid anhydrides such as available Succinic anhydried replace phosgene, and it represents reaction formula is scheme 4 (Scheme 4):
Method E: replace aminosugar with monose or polysaccharide (as glucose), it represents reaction formula is scheme 5 (Scheme 5):
Method E: available other polyhydroxy amines replace aminosugar, and it represents reaction formula is scheme 6 (Scheme 6):
Of the present invention 2,6-diisopropyl benzene phenolic ester water-soluble cpds is by 2, and the 6-diisopropyl phenol synthesizes the neutral ester, and is stronger in external its chemical stability, water-soluble easily.In vivo, can be under the effect of ester hydrolase, hydrolysis produces 2 fast, and the 6-diisopropyl phenol plays anesthetic action.
Embodiment
Embodiment 1: compound 4 or 5 synthetic
Dichloromethane solution (10% to phosgene, 10mL), under the frozen water cooling and stirring, slowly be added dropwise to 2, dichloromethane solution (the 1.78g/10mL of 6-diisopropyl phenol, 0.01mol). after adding, continue to stir 30 minutes, decompression is distilled down to remove and is desolvated. and remnants are dissolved in 10 milliliters of methylene dichloride again, underpressure distillation removes and desolvates again. and resistates is dissolved in 20 milliliters anhydrous glycol dimethyl ether, under the frozen water cooling and stirring, the glycol dimethyl ether mixing solutions that slowly drips glucosamine hydrochloride and triethylamine (contains glucosamine hydrochloride 2.16 grams for 20 milliliters, 2.8 milliliters of triethylamines). mixture stirred 1 hour naturally, evaporated under reduced pressure solvent (heating is less than 30 ℃), residual solid is removed impurity salt with washed with dichloromethane, and solid is dissolved in 100 ml waters again, lyophilize gets white solid compound 4 or 5 (3.21g, 75%). and the weight loss on drying analysis is for containing 2.5 crystal water. mass spectrum (ESI) 384 (M+1).
Embodiment 2: compound 8 synthetic
With triphosgene (2.65g, 0.01mol) be dissolved in 100 milliliters the anhydrous methylene chloride, under 0 ℃, slowly drip 2,6-diisopropyl phenol (1.80g, 10 milliliters of anhydrous methylene chloride solution 0.01mol), after adding, stirred 30 minutes in 5 ℃, keep 0-5 ℃ under, glucosamine (glucamine 7) (1.8g, 0.01mol) 5 milliliters of anhydrous ethylene glycol dimethyl ether solutions, after adding,, reducing pressure in desolventizing less than 30 ℃ of steamings in stirring at room 1 hour. remnants are dissolved in 100 ml waters, filter clear liquor, lyophilize gets compound 8 (3.65g, 95%). and the weight loss on drying analysis is for containing 2 crystal water. mass spectrum (ESI) 386.5 (M+1).
Embodiment 3: compound 10 synthetic
Dichloromethane solution (the 1M that will contain oxalyl chloride, 10 milliliters, 0.01mol) be cooled to 0 ℃, slowly drip and contain 2,6-diisopropyl phenol (1.80g, 0.01mol) 10 milliliters of anhydrous methylene chloride solution, continue to stir 30 minutes, under the frozen water cooling and stirring, the glycol dimethyl ether mixing solutions that slowly drips glucosamine hydrochloride and triethylamine (contains glucosamine hydrochloride 2.16 grams for 20 milliliters, 4.5 milliliters of triethylamines). mixture stirred 1 hour naturally, evaporated under reduced pressure solvent (heating is less than 30 ℃), residual solid is removed impurity salt with washed with dichloromethane, and solid is dissolved in 100 ml waters again, lyophilize gets white solid compound 10 (3.71g, 81%). and the weight loss on drying analysis is for containing 2.5 crystal water. mass spectrum (ESI) 412.4 (M+1).
Embodiment 4: compound 12 synthetic
With Succinic anhydried (1g, 0.01mol) and 2,6-diisopropyl phenol (1.80g, 0.01mol) mixed dissolution is in 100 milliliters anhydrous methylene chloride, disappear in stirring at room 3 hours to reaction raw materials. be cooled to 5 ℃, (2.26g 0.011mol), stirs after 10 minutes disposable adding DCC, add glucosamine (glucamine 7) (1.8g in 0 ℃, 0.01mol) 5 milliliters of anhydrous ethylene glycol dimethyl ether solutions, after adding, in stirring at room 24 hours. add 2 milliliters of Virahols, stirred 3 hours, filter, filtrate decompression is in less than 30 ℃ of solvent evaporated, and remnants are dissolved in 100 ml waters, filter clear liquor, lyophilize gets compound 12 (3.98g, 85%). and the weight loss on drying analysis is for containing 1.5 crystal water. mass spectrum (ESI) 442.2 (M+1).
Embodiment 5: compound 15 synthetic
Dichloromethane solution (the 1M that will contain oxalyl chloride, 10 milliliters, 0.01mol) be cooled to 0 ℃, slowly drip and contain 2, (1.80g, 10 milliliters of anhydrous methylene chloride solution 0.01mol) continue to stir 30 minutes the 6-diisopropyl phenol, under the frozen water cooling and stirring, adding glucose (glucose 13) (1.8g, 5 milliliters of anhydrous ethylene glycol dimethyl ether solutions 0.01mol) are after adding, in stirring at room 3 hours, reduce pressure in desolventizing less than 30 ℃ of steamings. remnants are dissolved in 100 ml waters, filter clear liquor, lyophilize, getting compound 15 (4.20g, 93%). the weight loss on drying analysis is for containing 2.5 crystal water. mass spectrum (ESI) 413 (M+1).
The solubleness test:
Get that compound 1,2,3 is dissolved in water (25 ℃ of room temperatures) in right amount in the embodiments of the invention, measure solubleness respectively, the results are shown in Table 1.
| Compound 4 | Compound 10 | Compound 12 | 2, the 6-diisopropyl phenol | |
| Solubleness | 250mg/mL | 198mg/mL | 150mg/mL | ＜2mg/mL |
Claims (6)
1. be that [I] is 2 of representative with general formula, 6-diisopropyl benzene phenolic ester water-soluble cpds:
Wherein X represents singly-bound, alkyl, amido or substituted amido;
Y represents amido, substituted amido, oxygen or alkyl;
R represents polyhydroxy alkyl;
N=0 or 1.
2. according to claim 12,6-diisopropyl benzene phenolic ester water-soluble cpds is characterized in that: contain m crystal water, mark between the described m=1-10 or natural number.
3. according to claim 1 and 22,6-diisopropyl benzene phenolic ester water-soluble cpds is characterized in that: described polyhydroxy alkyl is the polyhydroxy alkyl that carbohydrate structure derives, and the quantity of carbochain is 1-12, and the quantity of hydroxyl is 3-18.
4. according to claim 32,6-diisopropyl benzene phenolic ester water-soluble cpds is characterized in that: the substituted amido of described X representative for carbochain quantity be 1-8 alkyl for amido, the alkyl of described X representative is 1-8 alkyl for carbochain quantity.
5. according to claim 32,6-diisopropyl benzene phenolic ester water-soluble cpds is characterized in that: the substituted amido of described Y representative for carbochain quantity be 1-12 alkyl for amido, the alkyl of described Y representative is 1-12 alkyl for carbochain quantity.
6. the described compound of claim 1 is used for application on the narcotic that humans and animals produces anesthetic action in preparation.
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| CN2008100169141A CN101298426B (en) | 2008-06-17 | 2008-06-17 | Water-soluble derivate of 2,6-diisopropyl phenol and use thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120264702A1 (en) * | 2011-04-13 | 2012-10-18 | NuTek Pharma Ltd. | Synthesis And Use Of Glycoside Derivatives of Propofol |
| CN108558685A (en) * | 2017-06-08 | 2018-09-21 | 西安力邦制药有限公司 | 2,6- disubstituted benzenes phenol meglumine analog derivative and application |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA200504940B (en) * | 2003-01-28 | 2006-09-27 | Xenoport Inc | Amino acid derived prodrugs of propofol, compositions and uses thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120264702A1 (en) * | 2011-04-13 | 2012-10-18 | NuTek Pharma Ltd. | Synthesis And Use Of Glycoside Derivatives of Propofol |
| US9023813B2 (en) * | 2011-04-13 | 2015-05-05 | NuTek Pharma Ltd. | Synthesis and use of glycoside derivatives of propofol |
| CN108558685A (en) * | 2017-06-08 | 2018-09-21 | 西安力邦制药有限公司 | 2,6- disubstituted benzenes phenol meglumine analog derivative and application |
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| CN101298426B (en) | 2012-08-22 |
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Effective date of registration: 20191030 Address after: 046000 12-2, yunhaiyuan, Shennong, Changzhi City, Shanxi Province Patentee after: Li Xiangyi Address before: 250014 Lixia District, Shandong City, Ji'nan Province, No. ten, No. 4, Quancheng Patent Office Patentee before: Jin Guangyi |
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