CN101298426B - 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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- CN101298426B CN101298426B CN2008100169141A CN200810016914A CN101298426B CN 101298426 B CN101298426 B CN 101298426B CN 2008100169141 A CN2008100169141 A CN 2008100169141A CN 200810016914 A CN200810016914 A CN 200810016914A CN 101298426 B CN101298426 B CN 101298426B
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- diisopropyl phenol
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- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical class CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 title abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- -1 2, 6-diisopropyl phenol ester Chemical class 0.000 claims abstract description 11
- 239000013078 crystal Substances 0.000 claims description 7
- 230000003444 anaesthetic effect Effects 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 230000003533 narcotic effect Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 125000000837 carbohydrate group Chemical group 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 5
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 abstract 2
- 206010002091 Anaesthesia Diseases 0.000 abstract 1
- YLFIGGHWWPSIEG-UHFFFAOYSA-N aminoxyl Chemical class [O]N YLFIGGHWWPSIEG-UHFFFAOYSA-N 0.000 abstract 1
- 230000037005 anaesthesia Effects 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 125000003368 amide group Chemical group 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- 230000004580 weight loss Effects 0.000 description 5
- CBOJBBMQJBVCMW-BTVCFUMJSA-N (2r,3r,4s,5r)-2-amino-3,4,5,6-tetrahydroxyhexanal;hydrochloride Chemical compound Cl.O=C[C@H](N)[C@@H](O)[C@H](O)[C@H](O)CO CBOJBBMQJBVCMW-BTVCFUMJSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229960001911 glucosamine hydrochloride Drugs 0.000 description 4
- 150000002337 glycosamines Chemical class 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- SDOFMBGMRVAJNF-UHFFFAOYSA-N 6-aminohexane-1,2,3,4,5-pentol Chemical compound NCC(O)C(O)C(O)C(O)CO SDOFMBGMRVAJNF-UHFFFAOYSA-N 0.000 description 2
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- PXOIIZOTNBIMPZ-UHFFFAOYSA-N dichloromethane;oxalyl dichloride Chemical compound ClCCl.ClC(=O)C(Cl)=O PXOIIZOTNBIMPZ-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
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 basically all are 2, the ester of 6-diisopropyl phenol and the sour salt that forms; Have certain acidity. from chemicalstability; Band is acid 2, and 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 through 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 carbochain quantity of the substituted amido of described X representative is 1---8, and the carbochain quantity of the alkyl of described X representative is 1---12.
Of the present invention 2,6-diisopropyl benzene phenolic ester water-soluble cpds is characterized in that: the carbochain quantity of the substituted amido of described Y representative is 1---12, and the carbochain quantity of the alkyl of described Y representative is 1---12.
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 chemicalstability, 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 through following several method.
Method A: in the methylene dichloride saturated solution of phosgene, quantitatively add 2, the solution of 6-diisopropyl phenol, with the GS reaction, it represents reaction formula is scheme 1 (Scheme1) again:
Scheme?1
Method B: available TRIPHOSGENE 99.5 replaces phosgene, and it represents reaction formula is scheme 2 (Scheme 2):
Scheme?2
Method C: available oxalyl chloride replaces phosgene, and it represents reaction formula is scheme 3 (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):
Scheme4
Method E: replace aminosugar with monose or polysaccharide (like glucose), it represents reaction formula is scheme 5 (Scheme 5):
Scheme?5
Method E: available other polyhydroxy amines replace aminosugar, and it represents reaction formula is scheme 6 (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 chemicalstability, 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
To the dichloromethane solution of phosgene (10%, 10mL), under the frozen water cooling and stirring; Slowly be added dropwise to 2, and the dichloromethane solution of 6-diisopropyl phenol (1.78g/10mL, 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, and underpressure distillation removes and desolvates again. and resistates is dissolved in 20 milliliters anhydrous glycol dimethyl ether; Under the frozen water cooling and stirring; Slowly dripping 20 milliliters of the glycol dimethyl ether mixing solutionss (containing glucosamine hydrochloride 2.16 grams, 2.8 milliliters of triethylamines) of glucosamine hydrochloride and triethylamine. 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; Solid is dissolved in 100 ml waters again, and 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
(2.65g 0.01mol) is dissolved in 100 milliliters the anhydrous methylene chloride, under 0 ℃, slowly drips 2 with TRIPHOSGENE 99.5; (1.80g, 10 milliliters of anhydrous methylene chloride solution 0.01mol) after adding, stirred 30 minutes in 5 ℃ the 6-diisopropyl phenol; Under keeping 0-5 ℃, and glycamine (glucamine 7) (1.8g, 5 milliliters of anhydrous ethylene glycol dimethyl ether solutions 0.01mol) are after adding; In stirring at room 1 hour, reducing pressure in desolventizing less than 30 ℃ of steamings. remnants are dissolved in 100 ml waters, cross to 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
(1M, 0.01mol) is cooled to 0 ℃ by 10 milliliters will to contain the dichloromethane solution of oxalyl chloride; Slowly drip and contain 2,6-diisopropyl phenol (1.80g, 10 milliliters of anhydrous methylene chloride solution 0.01mol); 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) with 2, the 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; In 0 ℃ add glycamine (glucamine 7) (1.8g, 5 milliliters of anhydrous ethylene glycol dimethyl ether solutions 0.01mol) are after adding; In stirring at room 24 hours. add 2 milliliters of Virahols, stirred 3 hours, filtration; Filtrate decompression is in less than 30 ℃ of solvent evaporated, and remnants are dissolved in 100 ml waters, crosses to 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
To contain oxalyl chloride dichloromethane solution (1M, 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, reducing pressure in desolventizing less than 30 ℃ of steamings. remnants are dissolved in 100 ml waters, cross to filter clear liquor; Lyophilize gets compound 15 (4.20g, 93%). and 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 result sees table 1.
| ? | Compound 4 | Compound 10 | Compound 12 | 2, the 6-diisopropyl phenol |
| Solubleness | 250mg/mL | 198mg/mL | 150mg/mL | ＜2mg/mL |
Claims (4)
- General formula be [I] 2,6-diisopropyl benzene phenolic ester water-soluble cpds:Wherein to represent singly-bound, carbonatoms be the alkyl of 1---8 to X;Y represents secondary amine, Sauerstoffatom;R represents polyhydroxy alkyl, carbochain amount of carbon atom be 1-12, the quantity of hydroxyl is 3-18;N=0 or 1.
- 2. according to claim 12,6-diisopropyl benzene phenolic ester water-soluble cpds is characterized in that: described polyhydroxy alkyl is the polyhydroxy alkyl that carbohydrate structure derives.
- 3. the said general formula of claim 1 is the hydrate of the compound of [I], contains m crystal water, mark between the described m=1-10 or natural number.
- 4. the said compound of claim 1 is used for the 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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| CN101298426B true CN101298426B (en) | 2012-08-22 |
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| US9023813B2 (en) * | 2011-04-13 | 2015-05-05 | NuTek Pharma Ltd. | Synthesis and use of glycoside derivatives of propofol |
| CN108558685B (en) * | 2017-06-08 | 2020-11-20 | 西安力邦制药有限公司 | 2, 6-disubstituted phenol meglumine derivative and application thereof |
| CN118084755B (en) * | 2024-04-22 | 2024-08-02 | 潍坊富邦药业有限公司 | Astaxanthin derivative with high water solubility and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1744908A (en) * | 2003-01-28 | 2006-03-08 | 什诺波特有限公司 | Amino acid-derived propofol prodrugs, compositions and applications thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1744908A (en) * | 2003-01-28 | 2006-03-08 | 什诺波特有限公司 | Amino acid-derived propofol prodrugs, compositions and applications thereof |
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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 |