CN102381972A - Propofol hydroxy acid ester compound with ester constitutional terminal, preparation method for same and application thereof - Google Patents
Propofol hydroxy acid ester compound with ester constitutional terminal, preparation method for same and application thereof Download PDFInfo
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Abstract
Disclosed are a propofol hydroxy acid ester compound with an ester constitutional terminal, a preparation method for the same and application thereof. As shown in the constitutional formula (I) of the compound, Y refers to a C1-4 linear carbon chain, and R refers to acetyl or propiono. The propofol hydroxy acid ester compound can be prepared by utilizing corresponding propofol hydroxy acid ester as raw materials and is obtained by means of esterification reaction with corresponding acid anhydride. As experiments show, the compound is stable in vitro but capable of quickly releasing propofol with sedation and hypnogenesis and/or narcotism in blood plasma. Since hydroxy in propofol hydroxy butyric ester molecules is protected by means of shielding, heat stability of the propofol hydroxy acid ester compound is improved, and self-decomposition of the propofol hydroxy acid ester compound caused by lactonization is reduced.
Description
Technical field
The present invention relates to a kind of verivate of Propofol, specifically is a kind of terminal Propofol alcohol ester compounds of ester structure that has, with and preparation method thereof and application in pharmacy.
Background technology
Propofol (Propofol), chemical name are 2, the 6-diisopropyl phenol, be at present clinically the general anesthesia of widespread use induce, keep and the downern during Intensive Care Therapy, have rapid-action, the characteristics that the metabolism inactivation is fast.This compound progressively has been able to apply in worldwide since 1977 make clinical report first.Propofol also finds to have other many-sided pharmacological actions except the pharmacological action aspect anesthesia, like epilepsy, treatment migraine etc., therefore the research of oral propofol deutero-become the research focus.Because Propofol has very significant first pass effect, need modify to reduce first pass effect it.And the propofol derivative after modifying can't play the pharmacological action of expectation again if can not go out the former medicine of Propofol by snap-out release.Therefore, to research, be a present hot subject through the propofol derivative of various chemically modifieds.
Summary of the invention
In view of the foregoing, the present invention at first provides a kind of and has had the terminal Propofol alcohol ester compounds of ester structure, and the preparation method of this compound further is provided, and the application of this compound in pharmacy.
The present invention has the terminal Propofol alcohol ester compounds of ester structure, structure shown in formula I,
（Ⅰ）
Y in the formula is C
1 ~ 4The straight chain carbochain, R is ethanoyl or propionyl group.
The Y of above-mentioned formula I structure is preferably saturated carbon chains.Further more preferably Y is-CH
2-CH
2-or-CH
2-CH
2-CH
2-.
On the basis of said structure, the straight chain carbochain Y in the above-mentioned formula I structure also allows for and has a H on it at least by the substituted form of group that comprises methyl, ethyl, cyclopropyl, hydroxyl, sulfydryl, amino or substituted-amino.
The preparation that has the terminal Propofol alcohol ester compounds of ester structure of structure shown in the above-mentioned formula I of the present invention; The Propofol alcohol ester (II) that can use publication number CN101906039A to disclose is a raw material, obtains formula I structural object product with diacetyl oxide or propionic anhydride through esterification.Experiment shows that this esterification can both be carried out usually smoothly under 0 ℃ ~ 95 ℃ condition.According to different temperature of reaction, be reflected in 30 minutes to 24 hours and can accomplish.Wherein, the Y in the raw material formula II structure is C
1 ~ 4The straight chain carbochain.
（Ⅱ）
Because one of raw material that above-mentioned esterification is used is diacetyl oxide or propionic anhydride, so this esterification carries out under the condition that has the disacidify agent to exist, and obviously is more favourable.Wherein said disacidify agent can be selected by the usual manner of this type of reaction.The disacidify agent of recommend using among the present invention can be preferably and has more alkaline pyridine or comprise tertiary amine compounds such as triethylamine.
Experiment shows; The esterification of the above-mentioned preparation process of the present invention; Generally can be chosen in the similar esterification and carry out in the normally used reaction medium solvent, as selecting to comprise at least a in methylene dichloride, chloroform, tetracol phenixin, chlorobenzene, benzene, toluene, sherwood oil, hexanaphthene, normal hexane, acetonitrile, acetone, DMF, DMSO, THF, ether, triethylamine or the pyridine as reaction solvent.Wherein, preferred reaction solvent is doublely to do triethylamine or the pyridine that acid scavenger uses simultaneously.
Above-mentioned esterification can also be carried out under the condition of reactionless solvent except that can in said solvent medium, carrying out.
In as preparation The compounds of this invention raw material formula II compound; Though phenolic hydroxyl group in the Propofol and hydroxycarboxylic acid have obtained shielding after forming ester; Protected the first hydroxyl of being attacked in the elimination of crossing of Propofol; Reduced the ability of Propofol first pass metabolism, but compound (II) is not good in external stability, especially to thermo-responsive.In order to increase the thermostability of compound (II); Through a large amount of experiments and research; The present invention has designed the Propofol alcohol ester compounds that has the ester structure end of formula I structure formation; And proved Propofol alcohol ester that this formula I compound can not only effectively overcome formula II external to heat-labile shortcoming, improved its stability, and had in blood plasma and can discharge the characteristics that produce Propofol quickly with tranquilizing soporific and/or anaesthetic effect; And alcohol acid that discharges and corresponding esterification products do not have toxicity for human body yet.Thereby the compound of above-mentioned formula I structure formation is as prodrug of propofol; Be configured to pharmaceutically formulation such as acceptable emulsion; Outside vein or the vein approach of can be used as is used the maincenter suppressive drug that the animal or human produces tranquilizing soporific and/or anesthetic action, and can produce the ideal effect.
Below in conjunction with embodiment, foregoing of the present invention is remake further detailed description by the accompanying drawing illustrated embodiment.But should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following instance.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Description of drawings
Fig. 1 is the mass spectrum of the acetic ester of embodiment 1 Propofol butyric ester.
Fig. 2 is the mass spectrum of the propionic ester of embodiment 5 Propofol butyric esters.
Fig. 3 is the mass spectrum of the acetic ester of embodiment 9 Propofol hydroxyl valerates.
Fig. 4 is the mass spectrum of the propionic ester of embodiment 10 Propofol hydroxyl valerates.
Fig. 5 is the external rabbit plasma rate of decomposition of the ester compound graphic representation of the different Propofol alcohol esters of the present invention.
Embodiment
Embodiment 1
The preparation of the acetic ester of Propofol butyric ester:
4 g are dissolved in 20 ml methylene dichloride with the Propofol 4 hydroxybutyric acid ester that the mode of publication number CN101906039A prepares, add 10 ml acetic anhydride, be cooled to 0 ℃, drip 3 ml triethylamines; Keep temperature stirring reaction 24 h, after reaction finishes reaction solution is poured in the 100 ml water, stir 10 min; Standing demix is told organic layer, washs organic layer respectively once with saturated sodium carbonate solution and water; Tell organic layer, concentrating under reduced pressure is (elutriant (v/v, below all herewith): cyclohexane/ethyl acetate=95/5) after behind column chromatography for separation and the wash-out; The elutriant that contains product steams and desolventizes, and gets colorless oil 3.7 g, productive rate 79.7%.The structure detection result of product:
1) NMR: BRUKER 400M, with CDCl
3Be solvent, TMS is interior mark, and δ unit is ppm.
1 HNMR（δ）：1.187~1.204?(2s,?12H),?2.084(s,3H),2.090~2.144?(m,?2H),?2.709~2.747?(m,?2H),?2.846~2.914?(m,?2H),?4.181-4.212(m,2H),?7.143~7.249?(m,?3H)?。
2) NMR: BRUKER 400M, with CDCl
3Be solvent, TMS is interior mark, and δ unit is ppm.
13 CNMR（δ）：20.29,23.12,24.10,27.60,30.60,63.30,123.95,126.58,140.24,145.48,171.01,
171.46。
3) high resolution mass spectrum detects: mass spectrograph: the API3000 LC-Ms/Ms of American AB I company, ionization mode: EDI.
Ms + ：307.1917（C
18H
26O
6+H），329.1728（C
18H
26O
6+Na）。Collection of illustrative plates is as shown in Figure 1.
The preparation of the acetic ester of Propofol butyric ester:
5 g Propofol 4 hydroxybutyric acid esters are dissolved in 15 ml acetic anhydride, drip 3 ml triethylamines, stirring at room is reacted 3 h, after reaction finishes reaction solution is poured in the 100 ml water; Add 50 ml ETHYLE ACETATE, stir 10 min, standing demix is told organic layer; Wash organic layer respectively once with saturated sodium carbonate solution and water, tell organic layer, concentrating under reduced pressure is after the column chromatography wash-out; After the elutriant that contains product removes solvent under reduced pressure, colorless oil 4.84 g, productive rate 83.5%.
The preparation of the acetic ester of Propofol butyric ester:
5 g Propofol 4 hydroxybutyric acid esters are dissolved in 15 ml acetic anhydride, drip 3 ml triethylamines,, after reaction finishes reaction solution is poured in the 100 ml water in 50 ℃ of stirring reaction 1 h; Add 50 ml ETHYLE ACETATE, stir 10 min, standing demix is told organic layer; Wash organic layer respectively once with saturated sodium carbonate solution and water, tell organic layer, concentrating under reduced pressure is after the column chromatography wash-out; After the elutriant that contains product removes solvent under reduced pressure, colorless oil 4.25 g, productive rate 73.3%.
The preparation of the acetic ester of Propofol butyric ester:
5 g Propofol 4 hydroxybutyric acid esters are dissolved in 15 ml acetic anhydride, drip 3 ml triethylamines,, be cooled to room temperature in 95 ℃ of stirring reaction 30 min; Reaction solution is poured in the 100 ml water, added 50 ml ETHYLE ACETATE, stir 10 min, standing demix; Tell organic layer, wash organic layer respectively once with saturated sodium carbonate solution and water, tell organic layer, concentrating under reduced pressure is after the column chromatography wash-out; After the elutriant that contains product removes solvent under reduced pressure, colorless oil 3.14 g, productive rate 54.1%.
Embodiment 5
The preparation of the propionic ester of Propofol butyric ester:
2 g Propofol 4 hydroxybutyric acid esters are dissolved in 20 ml methylene dichloride, add 10 ml propionic anhydrides, be cooled to 0 ℃; Drip 3 ml triethylamines, keep temperature stirring reaction 24 h, after reaction finishes reaction solution is poured in the 100 ml water; Stir 10 min, standing demix is told organic layer; Wash organic layer respectively once with saturated sodium carbonate solution and water, tell organic layer, concentrating under reduced pressure is (elutriant: cyclohexane/ethyl acetate (v/v)=95/5) wash-out (following all herewith) after column chromatography; After the elutriant that contains product removes solvent under reduced pressure, colorless oil 1.83 g, productive rate 75.4%.The structure detection result of product:
1) NMR: BRUKER 400M, with CDCl
3Be solvent, TMS is interior mark, and δ unit is ppm.
1 HNMR（δ）：1.153~1.205?(m,?15H),?2.098~2.167(m,2H),2.322~2.402?(m,?2H),?2.711~2.7478(m,?2H),?2.844~2.913?(m,?2H),?4.195-4.227(m,2H),?7.146~7.260?(m,?3H)?。
2) NMR: BRUKER 400M, with CDCl
3Be solvent, TMS is interior mark, and δ unit is ppm.
13 CNMR（δ）：?9.15,23.31,24.15,27.54,30.59,63.12,123.94,126.57,140.24,145.47,171.47,
174.42。
3) high resolution mass spectrum: mass spectrograph: the API3000 LC-Ms/Ms of American AB I company, ionization mode: EDI.
Ms + ：321.2065(C
19H
28O
4+H)，343.1886(C
19H
28O
4+Na)。Collection of illustrative plates is as shown in Figure 2.
Embodiment 6
The preparation of the propionic ester of Propofol butyric ester:
2 g Propofol 4 hydroxybutyric acid esters are dissolved in 10 ml propionic anhydrides, drip 3 ml triethylamines, stirring at room is reacted 3 h, after reaction finishes reaction solution is poured in the 100 ml water; Add 50 ml ETHYLE ACETATE, stir 10 min, standing demix is told organic layer; Wash organic layer respectively once with saturated sodium carbonate solution and water, tell organic layer, concentrating under reduced pressure is after the column chromatography wash-out; After the elutriant that contains product removes solvent under reduced pressure, colorless oil 1.89 g, productive rate 77.1%.
Embodiment 7
The preparation of the propionic ester of Propofol butyric ester:
2 g Propofol 4 hydroxybutyric acid esters are dissolved in 10 ml propionic anhydrides, drip 3 ml triethylamines,, after reaction finishes reaction solution is poured in the 100 ml water in 50 ℃ of stirring reaction 1 h; Add 50 ml ETHYLE ACETATE, stir 10 min, standing demix is told organic layer; Wash organic layer respectively once with saturated sodium carbonate solution and water, tell organic layer, concentrating under reduced pressure is after the column chromatography wash-out; After the elutriant that contains product removes solvent under reduced pressure, colorless oil 1.77 g, productive rate 72.9%.
Embodiment 8
The preparation of the propionic ester of Propofol butyric ester:
2 g Propofol 4 hydroxybutyric acid esters are dissolved in 10 ml propionic anhydrides, drip 3 ml triethylamines,, be cooled to room temperature in 95 ℃ of stirring reaction 30 min; Reaction solution is poured in the 100 ml water, added 50 ml ETHYLE ACETATE, stir 10 min, standing demix; Tell organic layer, wash organic layer respectively once with saturated sodium carbonate solution and water, tell organic layer, concentrating under reduced pressure is after the column chromatography wash-out; After the elutriant that contains product removes solvent under reduced pressure, colorless oil 1.04 g, productive rate 43.1%.
Embodiment 9
The preparation of the acetic ester of Propofol hydroxyl valerate:
2 g Propofol 5-hydroxyl valerates are dissolved in 10 ml acetic anhydride, drip 3 ml triethylamines, stirring at room is reacted 3 h, after reaction finishes reaction solution is poured in the 100 ml water; Add 50 ml ETHYLE ACETATE, stir 10 min, standing demix is told organic layer; Wash organic layer respectively once with saturated sodium carbonate solution and water, tell organic layer, concentrating under reduced pressure is after the column chromatography wash-out; After the elutriant that contains product removes solvent under reduced pressure, colorless oil 1.72 g, productive rate 74.9%.The structure detection result of product:
1) NMR: BRUKER 400M, with CDCl
3Be solvent, TMS is interior mark, and δ unit is ppm.
1 HNMR（δ）：?1.190~1.202?(2s,?12H),?1.774~1.810(2m,4H),2.069?(s,?3H),?2.658~2.683?(m,?2H),?2.861~2.907?(m,?2H),?4.127~4.148(m,2H),7.150~7.258?(m,?3H)。
2) NMR: BRUKER 400M, with CDCl
3Be solvent, TMS is interior mark, and δ unit is ppm.
13 CNMR（δ）：20.97,20.99,21.59,27.56,28.16,33.64,63.94,123.92,126.51,140.25,145.50,
171.16,171.86。
3) high resolution mass spectrum: mass spectrograph: the API3000 LC-Ms/Ms of American AB I company, ionization mode: EDI.
Ms + ：321.2069(C
19H
28O
4+H)，343.1881(C
19H
28O
4+Na)。Collection of illustrative plates is as shown in Figure 3.
The preparation of the propionic ester of Propofol hydroxyl valerate:
2 g Propofol 5-butyric esters are dissolved in 10 ml propionic anhydrides, drip 3 ml triethylamines, react 1 h, after reaction finishes reaction solution is poured in the 100 ml water in stirring at room; Add 50 ml ETHYLE ACETATE, stir 10 min, standing demix is told organic layer; Wash organic layer respectively once with saturated sodium carbonate solution and water, tell organic layer, concentrating under reduced pressure is after the column chromatography wash-out; After the elutriant that contains product removes solvent under reduced pressure, colorless oil 1.68 g, productive rate 69.9%.The structure detection result of product:
1) NMR: BRUKER 400M, with CDCl
3Be solvent, TMS is interior mark, and δ unit is ppm.
1 HNMR（δ）：?1.149~1.199?(m,?15H),?1.674~1.887(2m,4H),2.340~2.363?(m,?2H),?2.670~2.680?(m,?2H),?2.884~2.894?(m,?2H),?4.097~4.157(m,2H),7.160~7.255?(m,?3H)。
2) NMR: BRUKER 400M, with CDCl
3Be solvent, TMS is interior mark, and δ unit is ppm.
13 CNMR（δ）：9.15,21.61,22.78,27.56,28.20,33.65,63.75,123.90,126.50,140.24,145.50,
171.86,174.54。
3) high resolution mass spectrum: mass spectrograph: the API3000 LC-Ms/Ms of American AB I company, ionization mode: EDI.
Ms + ：335.2216(C
20H
30O
4+H)，357.2028(C
20H
30O
4+Na)。Collection of illustrative plates is as shown in Figure 4.
Embodiment 11
The preparation of the propionic ester of Propofol butyric ester:
2 g Propofol 4 hydroxybutyric acid esters are dissolved in 10 ml propionic anhydrides, drip 3 ml pyridines,, after reaction finishes reaction solution is poured in the 100 ml water in 50 ℃ of stirring reaction 1 h; Add 50 ml ETHYLE ACETATE, stir 10 min, standing demix; Tell organic layer, wash organic layer respectively once, tell organic layer with saturated sodium carbonate solution and water; Concentrating under reduced pressure is after the column chromatography wash-out, the elutriant that contains product remove under reduced pressure behind the solvent colorless oil 1.65 g, productive rate 67.9%.
2 g Propofol 5-hydroxyl valerates are dissolved the 20ml chloroform, add 10 ml acetic anhydride, drip 3 ml triethylamines, stirring at room is reacted 3 h; After reaction finishes reaction solution is poured in the 100 ml water, added 50 ml chloroforms, stir 10 min, standing demix; Tell organic layer, wash organic layer respectively once with saturated sodium carbonate solution and water, tell organic layer, concentrating under reduced pressure is after the column chromatography wash-out; The elutriant that contains product removes solvent under reduced pressure, gets colorless oil 1.71 g, productive rate 74.7%.
Embodiment 12
Respectively three parts of concentration of each parallel preparation be 30 mg/ml the foregoing description 1 the Propofol butyric ester acetic ester, embodiment 5 the Propofol butyric ester propionic ester, embodiment 9 the Propofol hydroxyl valerate acetic ester and
4.The propionic ester solution of the Propofol hydroxyl valerate of embodiment 10 adds the rabbit plasma place water bath (37 ℃) in advance, mix, under 37 ℃ of conditions respectively at 0 min; 1 min, 3 min, 5 min; 7 min, 10 min, 20 min; 30 min, 1 h, 2 h; Get above-mentioned 100 μ l pastille blood plasma when 3 h and 4 h, the HPLC method is measured the concentration of actives Propofol, and the result shows that the acetic ester of Propofol butyric ester, the propionic ester of Propofol butyric ester, the acetic ester of Propofol hydroxyl valerate and the propionic ester of Propofol hydroxyl valerate can be decomposed into the actives Propofol rapidly in blood plasma.The external rabbit plasma rate of decomposition curve of the ester compound of multi-form Propofol alcohol ester is as shown in Figure 5
Embodiment 13
Heat stability test: each 0.5 g of propionic ester of Propofol hydroxyl valerate of acetic ester, embodiment 10 of Propofol hydroxyl valerate of propionic ester, embodiment 9 of Propofol butyric ester that gets acetic ester, the embodiment 5 of the Propofol butyric ester of Propofol butyric ester (reference substance 1), Propofol hydroxyl valerate (reference substance 2) and the foregoing description 1; In the clean container of opening; 60 ℃ of held 10 days; Respectively at the 5th day and sampling in the tenth day, detect each compounds content.Experimental result shows; The good thermal stability of the propionic ester of the acetic ester of the propionic ester of the acetic ester of Propofol butyric ester, Propofol butyric ester, Propofol hydroxyl valerate, Propofol hydroxyl valerate, and do not have Propofol butyric ester, Propofol hydroxyl valerate thermally-stabilised relatively poor of esterification.The result is as shown in table 1.
The experiment of the phenol hydroxy acid ester substituted ester compound thermostability of table 1 (60 ℃
)
| Compound (content wt%) | The 5th day content | The tenth day content |
| Reference substance 1 (96%) | 43% | 21% |
| Reference substance 2 (96%) | 64% | 40% |
| Embodiment 1 (98%) | 96% | 95% |
| Embodiment 5 (98%) | 97% | 95% |
| Embodiment 9 (98%) | 97% | 96% |
| Embodiment 10 (98%) | 98% | 98% |
Claims (10)
1. have the terminal Propofol alcohol ester compounds of ester structure, structure shown in formula I,
（Ⅰ）
Y in the formula is C
1 ~ 4The straight chain carbochain, R is ethanoyl or propionyl group.
2. compound as claimed in claim 1, the Y that it is characterized in that said formula I structure is a saturated carbon chains.
3. compound as claimed in claim 2 is characterized in that the Y of said formula I structure is-CH
2-CH
2-or-CH
2-CH
2-CH
2-.
4. like the described compound of one of claim 1 to 3, it is characterized in that having at least a H to replace on the straight chain carbochain Y in the said formula I structure by the group that comprises methyl, ethyl, cyclopropyl, hydroxyl, sulfydryl, amino or substituted-amino.
5. the preparation method of the said formula I structural compounds of one of claim 1 to 4; It is characterized in that with Propofol alcohol ester (II) be raw material; Obtain formula I structural object product with diacetyl oxide or propionic anhydride through esterification, the Y in the raw material formula II structure is C
1 ~ 4The straight chain carbochain,
（Ⅱ） 。
6. preparation method as claimed in claim 5 is characterized in that said esterification carries out under the condition that has the disacidify agent to exist.
7. preparation method as claimed in claim 6 is characterized in that said disacidify agent is pyridine or tertiary amine compounds.
8. like the described preparation method of one of claim 5 to 7; It is characterized in that said esterification carries out in reaction solvent, reaction solvent is to comprise at least a in methylene dichloride, chloroform, tetracol phenixin, chlorobenzene, benzene, toluene, sherwood oil, hexanaphthene, normal hexane, acetonitrile, acetone, DMF, DMSO, THF, ether, triethylamine or the pyridine.
9. like the described preparation method of one of claim 5 to 7, it is characterized in that said esterification carries out under the condition of reactionless solvent.
10. the application of the compound of the said formula I structure of one of claim 1 to 4 in the maincenter suppressive drug that the animal or human is produced tranquilizing soporific and/or anesthetic action as approach outside vein or vein.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108164419A (en) * | 2017-12-25 | 2018-06-15 | 武汉大学 | The preparation and application of the propofol prodrugs of monodisperse poly glycol monomethyl ether modification |
| CN114105808A (en) * | 2021-11-19 | 2022-03-01 | 深圳市爱卫德为生物科技有限公司 | Propofol compound and preparation method and application thereof |
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| US20050004381A1 (en) * | 2003-01-28 | 2005-01-06 | Gallop Mark A. | Amino acid derived prodrugs of propofol, compositions and uses thereof |
| CN101633671A (en) * | 2009-07-13 | 2010-01-27 | 杭州奥默医药技术有限公司 | Phosphoryl carboxylic acid propofol ester derivative and preparation method thereof |
| CN101885735A (en) * | 2010-06-23 | 2010-11-17 | 四川大学华西医院 | Phenol hydroxy acid ester substituted phosphate compound, preparation method and application in medicines |
| CN101906039A (en) * | 2010-06-23 | 2010-12-08 | 四川大学华西医院 | Hydroxyl acid ester compound of substituted phenol, preparation method and application in drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050004381A1 (en) * | 2003-01-28 | 2005-01-06 | Gallop Mark A. | Amino acid derived prodrugs of propofol, compositions and uses thereof |
| CN101633671A (en) * | 2009-07-13 | 2010-01-27 | 杭州奥默医药技术有限公司 | Phosphoryl carboxylic acid propofol ester derivative and preparation method thereof |
| CN101885735A (en) * | 2010-06-23 | 2010-11-17 | 四川大学华西医院 | Phenol hydroxy acid ester substituted phosphate compound, preparation method and application in medicines |
| CN101906039A (en) * | 2010-06-23 | 2010-12-08 | 四川大学华西医院 | Hydroxyl acid ester compound of substituted phenol, preparation method and application in drug |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108164419A (en) * | 2017-12-25 | 2018-06-15 | 武汉大学 | The preparation and application of the propofol prodrugs of monodisperse poly glycol monomethyl ether modification |
| CN114105808A (en) * | 2021-11-19 | 2022-03-01 | 深圳市爱卫德为生物科技有限公司 | Propofol compound and preparation method and application thereof |
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