CN108250093B - Compound Dahpe and preparation method and application thereof - Google Patents
Compound Dahpe and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of chemical medicine, and particularly relates to a compound Dahpe, and a preparation method and application thereof. The molecular structural formula of the compound Dahpe is shown in formula I in the specification. The preparation method of the compound Dahpe comprises the following steps: obtaining three raw materials of 5-heptyloxy-1-pentanol, 2-chloropropionyl chloride and diethylamine alcohol; acylating the 5-heptyloxy-1-pentanol and the 2-chloropropionyl chloride to prepare an intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester; and (3) carrying out dechlorination amination reaction on the intermediate 2-chloropropionic acid-5-heptyloxy-1-amyl ester and the diethylamine alcohol to obtain the compound Dahpe. The compound Dahpe can be applied to a cardiovascular and cerebrovascular drug transdermal preparation, remarkably promotes the percutaneous absorption of cardiovascular and cerebrovascular drugs, enhances the drug effect of the drugs, and has the percutaneous permeation promoting activity which is remarkably superior to that of the prior art.
Description
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to a compound Dahpe, and a preparation method and application thereof.
Background
Transdermal Drug Delivery Systems (TDDS) are controlled release preparations that are administered transdermally to provide systemic therapeutic effects, do not have the "first pass effect" of the liver, are not damaged by gastrointestinal digestive enzymes, and have the advantages of long action time, few toxic and side effects and adverse reactions, and high efficacy. Due to the barrier action of the skin and the physicochemical properties of the drugs, the permeability of some drugs through the skin is low, and the drugs reaching the body through the skin are difficult to reach effective treatment concentration, so how to enhance the transdermal absorption of the drugs is a research hotspot at present. At present, the common means include adding a percutaneous absorption enhancer, physical methods (such as an ion introduction method and an ultrasonic method), preparation methods (such as preparing into liposome), and the like, and the more studied method is adding the percutaneous absorption enhancer.
It has been reported that 2- (N, N-dimethyl) alanine lauryl alcohol ester (DDAIP) has transdermal penetration promoting activity to medicines such as indomethacin, pentafluorouracil, clonidine and hydrocortisone, wherein the transdermal penetration promoting activity of DDAIP to pentafluorouracil and indomethacin is 3-4 times that of a common transdermal absorption promoter Azone (chemical name: 1-N-dodecyl azepinone-2); DDAIP had a slightly poorer penetration enhancing effect on clonidine and hydrocortisone. The current preparation methods of DDAIP mainly comprise the following two methods: (1) 2-halogenated propionic acid is acylated and esterified to synthesize 2-halogenated propionic acid lauryl alcohol ester, and then nucleophilic substitution reaction is carried out on the 2-halogenated propionic acid lauryl alcohol ester and dimethylamine to synthesize a target molecule; the method belongs to multi-step reaction, has more side reaction and lower yield (59.7-74.8%). (2) Carrying out ester exchange reaction on ethyl 2- (N, N-dimethylamino) propionate and lauryl alcohol to synthesize a target molecule; the method needs to prepare ethyl 2- (N, N-dimethylamino) propionate firstly, and the ester exchange reaction is a reversible reaction which needs sodium methoxide as a catalyst and toluene which is a harmful solvent to the environment. In the prior art, the 2- (N, N-dihydroxyethyl) alanine ester compound not only has low preparation method yield, but also has no record on the application of the cardiovascular and cerebrovascular drug transdermal preparation, and the development of the transdermal preparation is urgently needed clinically.
Disclosure of Invention
The invention aims to solve the defects of the prior art, provides a brand-new compound Dahpe, and a preparation method and application thereof, and aims to solve the problems that the application of the existing transdermal absorption enhancer in clinical cardiovascular and cerebrovascular drug transdermal preparations is limited, and the yield of the preparation method of the 2- (N, N-dihydroxyethyl) alanine ester compound is low.
In order to achieve the above object, according to one aspect of the present invention, there is provided a compound Dahpe. The chemical structural formula of the compound Dahpe is shown as the following formula I:
the compound Dahpe provided by the invention can be used as a transdermal absorption enhancer for cardiovascular and cerebrovascular drug transdermal preparations; in the preparation, the percutaneous absorption of the cardiovascular and cerebrovascular medicines can be promoted, the drug effect of the medicines is enhanced, and the percutaneous permeation promoting activity of the preparation is obviously superior to that of the prior art.
As another aspect of the present invention, there is provided a process for preparing the above compound Dahpe (formula I). The method comprises the following steps:
obtaining three raw materials of 5-heptyloxy-1-pentanol, 2-chloropropionyl chloride and diethylamine alcohol;
acylating the 5-heptyloxy-1-pentanol and the 2-chloropropionyl chloride to prepare an intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester;
dechlorinating and aminating the intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester and the diethylamine alcohol to obtain the compound Dahpe of claim 1.
The preparation method of the compound Dahpe provided by the invention has the advantages of simple process, easy operation and low cost, and no pollution to the environment in the preparation process, and compared with the preparation method of the 2- (N, N-dihydroxyethyl) alanine ester compound in the prior art, the yield is obviously improved and reaches more than 90.2%.
Finally, the invention also provides an application of the compound Dahpe and/or the compound Dahpe prepared by the preparation method of the compound Dahpe in a cardiovascular and cerebrovascular drug transdermal preparation.
In the application provided by the invention, the compound Dahpe can promote percutaneous absorption of cardiovascular and cerebrovascular medicines and enhance the treatment efficacy of the medicines, and the percutaneous permeation promoting activity of the compound Dahpe is obviously superior to that of the prior art. Therefore, the selection range of the transdermal absorption enhancer in the clinical cardiovascular and cerebrovascular drug transdermal preparation can be further improved, and the medical health of people is guaranteed.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In one aspect, embodiments of the present invention provide a compound having the chemical name: 2- (N, N-dihydroxyethyl) alanine-5-heptyloxy-1-pentyl ester, the chemical structural formula of which is shown in the following formula I:
to distinguish from the existing compounds, the inventors defined the above compounds as Dahpe. The compound Dahpe is used as one of 2- (N, N-dihydroxyethyl) alanine esters, and can be used as a transdermal absorption enhancer in cardiovascular and cerebrovascular drug transdermal preparations; in the preparation, the percutaneous absorption of the cardiovascular and cerebrovascular medicines can be obviously promoted, the drug effect of the medicines is enhanced, and the percutaneous permeation promoting activity of the preparation is obviously superior to that of the prior art.
On the other hand, the embodiment of the invention also provides a preparation method of the compound Dahpe, which comprises the following steps:
s01: obtaining three raw materials of 5-heptyloxy-1-pentanol, 2-chloropropionyl chloride and diethylamine alcohol;
s02: acylating the 5-heptyloxy-1-pentanol and the 2-chloropropionyl chloride in the step S01 to obtain an intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester;
s03: the intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester in the step S02 and the diethylamine alcohol in the step S01 are subjected to a dechlorination amination reaction to prepare the compound Dahpe of the invention example.
The reaction process of the above preparation method is as follows. The preparation method has the advantages of simple process, easy operation and low cost, and has no pollution to the environment in the preparation process, and compared with the preparation method of the 2- (N, N-dihydroxyethyl) alanine ester compound in the prior art, the target yield is obviously improved and reaches more than 90.2 percent.
Specifically, in the above step S02, the acylation reaction process is:
s021: mixing and stirring the 5-heptyloxy-1-pentanol and the 2-chloropropionyl chloride in the step S01 for 6-10 hours, and adjusting to be alkaline to obtain an organic layer and a water layer;
s022: extracting the water layer in the step S021 by using ether or ethyl acetate, mixing the water layer with the organic layer, washing with water, and drying to obtain a solution;
s023: and (4) concentrating the solution in the step (S022), and performing column chromatography to obtain an intermediate 2-chloropropionic acid-5-heptyloxy-1-amyl ester.
Through the process of the step S02, the intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester is finally obtained, and the yield of the 2- (N, N-dihydroxyethyl) alanine-5-heptyloxy-1-pentyl ester is finally improved through the intermediate and the combination with the subsequent steps.
More specifically, the molar ratio of 5-heptyloxy-1-pentanol to 2-chloropropionyl chloride in the above step S021 is (1: 1) - (1: 1.5), preferably 1: 1.2. Within the range of the molar ratio, the acylation reaction is more sufficient, and the yield of the intermediate 2-chloropropionic acid-5-heptyloxy-1-amyl ester is finally improved.
More specifically, the washing process in the above step S022 is performed using saturated saline washing, and the drying process is performed using anhydrous sodium sulfate or anhydrous magnesium sulfate. Therefore, the purity of the solution is easier to improve, and the yield of the intermediate 2-chloropropionic acid-5-heptyloxy-1-amyl ester is easier to improve through column chromatography after concentration.
Specifically, in the above step S03, the dechlorination amination process is:
s031: mixing the intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester in the step S02 and the diethylamine alcohol in the step S01, adding acetone and potassium iodide, stirring for 5-8 hours, and filtering to obtain a filtrate;
s032: and concentrating the filtrate obtained in the step S031, and performing column chromatography to obtain the compound Dahpe of the embodiment.
Through the process of step S03, the yield of the compound Dahpe of the present invention is finally obtained to be more than 90.2%.
More specifically, the molar ratio of the intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester and the diethylamino alcohol in the above step S031 is (1: 2) - (1: 2.5), preferably 1: 2.2. Within this molar ratio range, the dehydrochlorination-amination reaction is more complete, and the yield of the compound Dahpe is finally improved.
More specifically, potassium iodide in the above step S031 is a solid powder. The solid powder can easily ensure that the intermediate 2-chloropropionic acid-5-heptyloxy-1-amyl ester and the diethylamine alcohol fully react, and the filtrate after filtration is concentrated and can easily pass through column chromatography, thereby finally improving the yield of Dahpe.
Finally, the embodiment of the invention also provides the application of the compound Dahpe and/or the compound Dahpe prepared by the preparation method of the compound Dahpe in the cardiovascular and cerebrovascular drug transdermal preparation.
The compound Dahpe provided by the embodiment can promote percutaneous absorption of cardiovascular and cerebrovascular medicines, enhances the treatment efficacy of the medicines, and has percutaneous permeation-promoting activity which is obviously superior to that of the prior art. Therefore, the selection range of the transdermal absorption enhancer in the clinical cardiovascular and cerebrovascular drug transdermal preparation can be further improved, and the medical health of people is guaranteed.
Specifically, the cardiovascular and cerebrovascular medicine is at least one of nimodipine, amlodipine, bisoprolol fumarate, benazepril, metoprolol tartrate and captopril.
In the embodiment of the invention, the cardiovascular and cerebrovascular medicines are used as medicine models, rat skin is used as a biomembrane model, a percutaneous permeation-promoting activity contrast test of the compound Dahpe on the medicines is carried out, and nimodipine and amlodipine are specifically selected. The experimental results show that: the compound Dahpe containing w ═ 2.5% has good transdermal penetration-promoting activity on the medicine, and the transdermal penetration-promoting effect of the compound Dahpe is 6-10 times that of a blank control group (P is less than 0.05), and is obviously superior to that of Azone. Therefore, the transdermal drug delivery system can remarkably promote the transdermal absorption of drugs in the cardiovascular and cerebrovascular drug transdermal preparation and enhance the curative effect of the drugs.
The invention is described in further detail with reference to a part of the test results, which are described in detail below with reference to specific examples.
Example 1
This example provides a compound, Dahpe, having the chemical name: 2- (N, N-dihydroxyethyl) alanine-5-heptyloxy-1-pentyl ester; the structural formula is shown as the formula I.
The preparation method of the compound Dahpe is as follows:
s11: obtaining three raw materials of 5-heptyloxy-1-pentanol, 2-chloropropionyl chloride and diethylamine alcohol;
s12: acylating 5-heptyloxy-1-pentanol and 2-chloropropionyl chloride to obtain intermediate 2-chloropropionic acid-5-heptyloxy-1-pentanoate;
s13: the intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester and diethylamine alcohol are subjected to dechlorination amination reaction to prepare the compound Dahpe of the invention example.
In the step S12, the acylation reaction is carried out, and the synthetic process of the intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester is as follows:
s121: in a 50mL three-necked flask, 9.47g (46.8mmol) of 5-heptyloxy-1-pentanol was placed, and 5mL (51.5mmol) of 2-chloropropionyl chloride was added dropwise under stirring at room temperature, and after completion of the addition, stirring was continued at room temperature for 6 hours. Saturated NaHCO is used for reaction liquid3Adjusting the solution to be alkalescent to obtain an organic layer and a water layer.
S122: extracting the aqueous layer with diethyl ether or ethyl acetate, mixing the organic layers, washing with saturated sodium chloride, and extracting with anhydrous Na2SO4Or anhydrous MgSO4Dry overnight.
S123: and (3) evaporating the solvent of the overnight solution, performing column chromatography (silica gel is 100-300 meshes), and evaporating the eluent by using chloroform as the eluent to obtain 11.69g of colorless liquid, wherein the yield is 85.3%.
The product is an intermediate 2-chloropropionic acid-5-heptyloxy-1-amyl ester, and the infrared spectrum data thereof are as follows: ir (kbr) v: 2928,2856,2783,1772,1149,735cm-1。
Specifically, in the step S13 of dechlorination and amination reaction, the process for synthesizing the compound Dahpe is as follows:
s131: to 14.64g (50.0mmol) of intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester were added 10mL of acetone, 11.04g (105.0mmol) of diethanolamine and a small amount of KI solid powder, and the reaction was stirred at room temperature for 5 hours.
S132: filtering the mixed solution after the stirring reaction, evaporating the solvent from the filtrate under reduced pressure, taking ethyl acetate as an eluent, and carrying out column chromatography on the residue (silica gel is 100-300 meshes) to obtain 16.30g of colorless liquid, wherein the yield is 90.2%.
This product was Dahpe, a compound described above in this example. The IR of the mixture,1The results of H NMR, ESI-MS and elemental analysis are as follows: ir (kbr) v: 3538,2938,2874,1754,1468,1280,1147cm-1；1H NMR(500MHz,CDCl3) δ: 0.90(t,3H), 1.28-1.32 (m,8H), 1.33-1.40 (m,5H), 1.55-1.61 (m,4H), 1.64-1.69 (m,2H),2.57(t,4H),3.19(q,1H),3.30(t,4H),3.39(t,4H),4.14(t,2H), wherein two active hydrogens are deuterated; ESI-MS, m/z: 362[ M + H ]]+Theoretical value of elemental analysis: c19H39NO5: c63.12, H10.87, N3.87; actual measured values: c63.03, H10.90, N3.86.
Example 2
This example provides a compound, Dahpe, having the chemical name: 2- (N, N-dihydroxyethyl) alanine-5-heptyloxy-1-pentyl ester; the structural formula is shown as the formula I.
The preparation method of the compound Dahpe is as follows:
s21: obtaining three raw materials of 5-heptyloxy-1-pentanol, 2-chloropropionyl chloride and diethylamine alcohol;
s22: acylating 5-heptyloxy-1-pentanol and 2-chloropropionyl chloride to obtain intermediate 2-chloropropionic acid-5-heptyloxy-1-pentanoate;
s23: the intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester and diethylamine alcohol are subjected to dechlorination amination reaction to prepare the compound Dahpe of the invention example.
In the step S22, the acylation reaction is carried out, and the synthetic process of the intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester is as follows:
s221: in a 50mL three-necked flask, 8.68g (42.9mmol) of 5-heptyloxy-1-pentanol was placed, and 5mL (51.5mmol) of 2-chloropropionyl chloride was added dropwise under stirring at room temperature, and after completion of the addition, stirring was continued at room temperature for 8 hours. Saturated NaHCO is used for reaction liquid3Adjusting the solution to be alkalescent to obtain an organic layer and a water layer.
S222: extracting the aqueous layer with diethyl ether or ethyl acetate, mixing the organic layers, washing with saturated sodium chloride, and extracting with anhydrous Na2SO4Or anhydrous MgSO4Dry overnight.
S223: and (3) evaporating the overnight solution to remove the solvent, performing column chromatography (silica gel is 100-300 meshes), and evaporating to remove the eluent by using chloroform as the eluent to obtain 11.73g of colorless liquid, wherein the yield is 93.4%.
The product was intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester and its infrared spectroscopic data as described in example 1.
The synthesis process of the dechlorination amination compound Dahpe in the step S23 comprises the following steps:
s231: to 14.64g (50.0mmol) of intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester were added 10mL of acetone, 11.57g (110.0mmol) of diethanolamine and a small amount of KI as a solid powder, and the reaction was stirred at room temperature for 8 hours.
S232: filtering the mixed solution after the reaction, evaporating the solvent from the filtrate under reduced pressure, using ethyl acetate as an eluent, and performing column chromatography (silica gel is 100-300 meshes) on the residue to obtain 17.19g of colorless liquid, wherein the yield is 95.1%.
This product was Dahpe, a compound described above in this example. The IR of the mixture,1The results of H NMR, ESI-MS and elemental analysis are as described in example 1.
Example 3
In this example, the effect of the compound Dahpe on the transdermal penetration promoting activity of the drug in the cardiovascular and cerebrovascular drug nimodipine transdermal preparation is verified through a drug model, and the process is as follows.
(1) Nimodipine standard curve
First, 2g of nimodipine and 0.5g of polyethylene glycol 400 are mixed uniformly, then the mixture is dissolved in 100mL of 70% ethanol, and the dissolved solution is diluted into standard solutions with the concentrations C of 30 mu g/mL, 25 mu g/mL, 20 mu g/mL, 15 mu g/mL, 10 mu g/mL, 5 mu g/mL and 2.5 mu g/mL by phosphate buffer solution with the pH value of 7.4. Measuring the absorbance A of the standard solution at 237nm by using an ultraviolet spectrophotometer to obtain a regression equation: c (μ g/mL) ═ 0.0876A +0.0378, and r ═ 0.9995.
(2) 1% nimodipine solution
Nimodipine-ethanol solution containing w ═ 1% is prepared from 2g of nimodipine, 0.5g of polyethylene glycol 400 and 70% ethanol.
(3) Nimodipine solution containing compound Dahpe
Nimodipine-ethanol solution with the content of the nimodipine w-1% is mixed with the compound Dahpe to prepare the nimodipine-ethanol solution with the content of the compound Dahpe w-2.5%.
(4) Preparation of isolated mouse skin
And (3) obtaining the complete skin of the hairy rat at the abdomen, removing subcutaneous tissues, and washing with physiological saline for 2-3 times for later use.
(5) In vitro drug transdermal absorption test
The drug transdermal absorption test is carried out on a TT-18 type transdermal meter. Mouse is connected with a mouseThe stratum corneum layer is fixed between the supply chamber and the receiving chamber towards the supply chamber, and the effective penetration area of the skin is 2.55cm25mL of a phosphate buffer solution having a pH of 7.4 was added as a receiving solution to the receiving chamber, and the receiving chamber was placed in a circulating water bath at (37. + -. 0.1). degree.C.and magnetically stirred. 1mL of the release solution was added to the feeding chamber. Within 12h, 50 μ L of the receiving solution was quantitatively taken out from the receiving chamber at different time intervals while an equal amount of phosphate buffer solution having a pH of 7.4 was replenished to the receiving chamber, and the taken-out receiving solution was measured for its absorbance at 237nm with an ultraviolet spectrophotometer, and the cumulative permeation amount per unit area was calculated, and nimodipine percutaneous absorption parameters, such as nimodipine percutaneous absorption parameters in table 1 below (n-4,
) As shown.
TABLE 1
aThe steady state flow rate is the slope of the cumulative permeation per unit area of the drug versus time curve;
bosmotic coefficient of the drug is stable flow/C0，C0Providing the diffusion cell with an initial concentration of the drug in the chamber;
cincrease of permeability ER1Is the ratio of the permeability coefficients of the penetration enhancer group and the blank control group;
dincrease of permeability ER2Is the ratio of the permeability coefficients of the penetration enhancer group and the Azone group;
ecompared with a blank control group, the compound Dahpe has a statistically significant difference (P) in the effect of promoting the percutaneous absorption of the medicine<0.05)。
From the data in table 1, it can be seen that when the content of the compound Dahpe is w ═ 2.5%, nimodipine has good transdermal penetration promoting activity for cardiovascular and cerebrovascular drugs, and the transdermal absorption of the promoted drugs is significantly better than that of the prior art.
Example 4
In this example, the effect of compound Dahpe on the transdermal permeation promoting activity of the drug in the cardiovascular and cerebrovascular drug amlodipine transdermal preparation is verified through a drug model, and the process is as follows.
(1) Standard curve of amlodipine
2g of amlodipine and 0.5g of polyethylene glycol 400 are mixed uniformly, the mixture is dissolved in 100mL of 70% ethanol, and the dissolved solution is diluted into standard solutions with the concentrations C of 30. mu.g/mL, 25. mu.g/mL, 20. mu.g/mL, 15. mu.g/mL, 10. mu.g/mL, 5. mu.g/mL and 2.5. mu.g/mL by using a phosphate buffer solution with the pH value of 7.4. Measuring the absorbance A of the standard solution at 365nm by using an ultraviolet spectrophotometer to obtain a regression equation: c (μ g/mL) ═ 0.0436A +0.258, and r ═ 0.9983.
(2) 1% amlodipine solution
2g of amlodipine, 0.5g of polyethylene glycol 400 and 70% ethanol are prepared into an amlodipine-ethanol solution containing w ═ 1%.
(3) Amlodipine solution containing compound Dahpe
The amlodipine-ethanol solution with the content of the amlodipine w ═ 1% is mixed with the compound Dahpe to prepare the amlodipine-ethanol solution with the content of the compound Dahpe of w ═ 2.5%.
(4) Preparation of isolated mouse skin
And (3) obtaining the complete skin of the hairy rat at the abdomen, removing subcutaneous tissues, and washing with physiological saline for 2-3 times for later use.
(5) In vitro drug transdermal absorption test
The drug transdermal absorption test is carried out on a TT-18 type transdermal meter. Fixing the stratum corneum of mouse skin between the supply chamber and the receiving chamber toward the supply chamber, and the effective penetration area of skin is 2.55cm25mL of a phosphate buffer solution having a pH of 7.4 was added as a receiving solution to the receiving chamber, and the receiving chamber was placed in a circulating water bath at (37. + -. 0.1). degree.C.and magnetically stirred. 1mL of the release solution was added to the feeding chamber. Quantitatively taking out 50 μ L of the receiving solution from the receiving chamber at different time intervals within 12h, simultaneously supplementing the receiving chamber with equal amount of phosphate buffer solution with pH of 7.4, measuring absorbance of the taken-out receiving solution at 365nm with ultraviolet spectrophotometer, and calculating cumulative permeation amount per unit areaAnd the transdermal amlodipine absorption parameter, which is shown in table 2 below (n-4,
) As shown.
TABLE 2
aThe steady state flow rate is the slope of the cumulative permeation per unit area of the drug versus time curve;
bosmotic coefficient of the drug is stable flow/C0，C0Providing the diffusion cell with an initial concentration of the drug in the chamber;
cincrease of permeability ER1Is the ratio of the permeability coefficients of the penetration enhancer group and the blank control group;
dincrease of permeability ER2Is the ratio of the permeability coefficients of the penetration enhancer group and the Azone group;
ecompared with a blank control group, the compound Dahpe has a statistically significant difference (P) in the effect of promoting the percutaneous absorption of the medicine<0.05)。
As can be seen from the data in table 2, when the content of the compound Dahpe is w ═ 2.5%, the cardiovascular and cerebrovascular drug amlodipine has good percutaneous permeation promoting activity, and the percutaneous absorption of the drug is significantly better than that of the prior art.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A compound Dahpe, the molecular structural formula of which is shown as the following formula I:
2. a preparation method of a compound Dahpe is characterized by comprising the following steps:
obtaining three raw materials of 5-heptyloxy-1-pentanol, 2-chloropropionyl chloride and diethylamine alcohol;
acylating the 5-heptyloxy-1-pentanol and the 2-chloropropionyl chloride to prepare an intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester;
dechlorinating and aminating the intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester and the diethylamine alcohol to obtain the compound Dahpe of claim 1.
3. The process for the preparation of the compound Dahpe according to claim 2, wherein the acylation reaction is carried out by:
mixing and stirring the 5-heptyloxy-1-pentanol and the 2-chloropropionyl chloride for 6-10 hours, and adjusting to be alkaline to obtain an organic layer and a water layer;
extracting the water layer with diethyl ether or ethyl acetate, mixing with the organic layer, washing with water, and drying to obtain solution;
and concentrating the solution, and performing column chromatography to obtain the intermediate 2-chloropropionic acid-5-heptyloxy-1-amyl ester.
4. The method for preparing the compound Dahpe according to claim 3, wherein the washing process uses a saturated saline solution for washing, and the drying process uses anhydrous sodium sulfate or anhydrous magnesium sulfate for drying.
5. The process for the preparation of the compound Dahpe according to claim 2, wherein the dehydrochlorination amination process is:
mixing the intermediate 2-chloropropionic acid-5-heptyloxy-1-amyl ester and the diethylamine alcohol, adding acetone and potassium iodide, stirring for 5-8 hours, and filtering to obtain a filtrate;
and concentrating the filtrate, and performing column chromatography to obtain the compound Dahpe.
6. The method for preparing the compound Dahpe according to claim 5, wherein the potassium iodide is a solid powder.
7. The process for the preparation of the compound Dahpe according to any one of claims 2 to 4, wherein the molar ratio of 5-heptyloxy-1-pentanol to 2-chloropropionyl chloride is (1: 1) - (1: 1.5).
8. The process for the preparation of the compound Dahpe according to any one of claims 2 or 5 to 6, wherein the molar ratio of the intermediate 2-chloropropionic acid-5-heptyloxy-1-pentyl ester and the diethylamino alcohol is (1: 2) - (1: 2.5).
9. Use of the compound Dahpe according to claim 1 and/or the compound Dahpe prepared by the method for preparing the compound Dahpe according to any one of claims 2 to 8 in the preparation of a cardiovascular and cerebrovascular drug transdermal preparation.
10. The use of the compound Dahpe of claim 9 in the preparation of a cardiovascular transdermal drug delivery formulation, wherein the cardiovascular drug is at least one of nimodipine, amlodipine, bisoprolol fumarate, benazepril, metoprolol tartrate, and captopril.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4980378A (en) * | 1988-06-01 | 1990-12-25 | Odontex, Inc. | Biodegradable absorption enhancers |
| CN1850785A (en) * | 2006-06-01 | 2006-10-25 | 汕头大学 | N,N-dibasic glycine 3,7-dimethyl n-octyl ester, and its preparing method and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4980378A (en) * | 1988-06-01 | 1990-12-25 | Odontex, Inc. | Biodegradable absorption enhancers |
| CN1850785A (en) * | 2006-06-01 | 2006-10-25 | 汕头大学 | N,N-dibasic glycine 3,7-dimethyl n-octyl ester, and its preparing method and use |
Non-Patent Citations (1)
| Title |
|---|
| N,N-二取代甘氨酸酯的合成及其经皮促渗活性;李伟杰等;《化学研究与应用》;20051231;第17卷(第6期);762-765 * |
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