CN111072552B - Preparation method of cilnidipine - Google Patents
Preparation method of cilnidipine Download PDFInfo
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- CN111072552B CN111072552B CN201911251755.8A CN201911251755A CN111072552B CN 111072552 B CN111072552 B CN 111072552B CN 201911251755 A CN201911251755 A CN 201911251755A CN 111072552 B CN111072552 B CN 111072552B
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention discloses a preparation method of high-purity cilnidipine, wherein methoxyethyl acetoacetate and m-nitrobenzaldehyde react to generate 2- (3-nitrobenzylidene) methoxyethyl acetoacetate, and 2- (3-nitrobenzylidene) methoxyethyl acetoacetate and 3-aminocrotonic acid cinnamyl ester react to generate cilnidipine. The invention has the advantages of simple synthesis process, complete reaction, high yield and low cost, and is very suitable for industrial production.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method and application of a high-purity cilnidipine compound.
Background
Cilnidipine (cilnidipine), chemical name: 1, 4-dihydro-2, 6-dimethyl-4- (3-nitrophenyl) -3, 5-pyridinedicarboxylic acid 2-methoxyethyl cinnamyl alcohol ester, CAS No.: 132203-70-4, molecular formula is C27H28N2O7, molecular weight is 492.52, structural formula of cilnidipine is as follows:
cilnidipine is a dihydropyridine calcium antagonist and was first marketed in japan in 1995, by fuji corporation of japan. Cilnidipine can bind with dihydropyridine site of L-type calcium channel on vascular smooth muscle cell membrane to inhibit Ca2+Through transmembrane inflow of L-type calcium channel, the blood vessel smooth muscle is relaxed and dilated to reduce blood pressure, and it can also inhibit Ca2+The release of norepinephrine from sympathetic nerve terminals and sympathetic nerve activity is inhibited by transmembrane influx of N-type calcium channels on the sympathetic nerve cell membrane. The traditional Chinese medicine composition is mainly used for treating various types of hypertension, and has the characteristics of lasting, safe and mild antihypertensive effect, no accumulation after long-term use, definite curative effect and the like.
A great deal of research is carried out on the synthesis of cilnidipine at home and abroad, and two synthesis modes which are commonly used at present are mainly adopted, namely firstly, the methoxy ethyl acetoacetate reacts with m-nitrobenzaldehyde to generate 2- (3-nitrobenzylidene) acetoacetyl methoxy ethyl ester, and the 2- (3-nitrobenzylidene) acetoacetyl methoxy ethyl ester reacts with 3-aminocrotonic acid cinnamyl ester to generate cilnidipine; secondly, the reaction of the cinnamyl acetoacetate and m-nitrobenzaldehyde generates 2- (3-nitrobenzylidene) -cinnamyl acetoacetate, and the reaction of the 2- (3-nitrobenzylidene) -cinnamyl acetoacetate and 3-methoxy ethyl aminocrotonate generates cilnidipine.
The synthesis method of cilnidipine is researched by cinnarizine and the like, and the first synthesis method is used, wherein the preparation method of the 2- (3-nitrobenzylidene) acetoacetoxyethyl is that methoxyethyl acetoacetate is added into a reaction bottle, the temperature is reduced to 0-5 ℃, concentrated sulfuric acid is dropwise added at the temperature, and then m-nitrobenzaldehyde is added for room temperature reaction. Dissolving the reaction product in absolute ethyl alcohol, stirring uniformly, and filtering to obtain the product. The process has the advantage that the reactants are more viscous as the reaction progresses, so that the stirring is difficult, the reaction is incomplete, and the yield of the reaction is 58.6%.
CN105384682A discloses a preparation method of cilnidipine, which takes 2- (3-nitrobenzylidene) acetoacetic acid methoxy ethyl ester and 3-amino-2-butenoic acid cinnamyl ester as reaction raw materials, and the reaction is carried out under the catalysis of concentrated hydrochloric acid to generate cilnidipine. The reaction introduces concentrated hydrochloric acid, has complex operation steps, introduces new compounds, and is not beneficial to the refining of raw material medicaments.
CN104557679A discloses a synthesis method of cilnidipine, which comprises the steps of taking 2- (3-nitrobenzylidene) methoxy ethyl acetoacetate and 3-aminocrotonic acid cinnamyl ester as reaction raw materials, adding isobutanol solvent and an aluminum isobutoxide catalyst under the protection of nitrogen, and carrying out reflux reaction to obtain cilnidipine. The reaction needs to be protected by introducing nitrogen, and the requirement on equipment for industrial production is higher.
Therefore, the existing synthesis method of cilnidipine has the problems of low yield, complex operation and incapability of being effectively suitable for industrial production, and the method for industrially producing cilnidipine, which is simple in synthesis process, high in yield, low in cost and high in purity, is developed to be very significant.
Disclosure of Invention
The main purpose of the application is to provide a method for synthesizing high-purity cilnidipine.
In order to achieve the above purpose and solve the problems in the synthesis of cilnidipine, the following technical scheme is adopted in the application:
the method mainly comprises four steps:
the first step is as follows: synthesis of 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product
Under the catalysis of concentrated sulfuric acid, acetic anhydride is used as a solvent for condensation reaction of the methoxy ethyl acetoacetate and m-nitrobenzaldehyde, after the reaction is finished, ethanol is added, and a crude product of the 2- (3-nitrobenzylidene) methoxy ethyl acetoacetate is obtained by stirring and filtering;
wherein the ratio of acetoacetic acid methoxy ethyl ester: m-nitrobenzaldehyde: acetic anhydride: the molar ratio of the concentrated sulfuric acid is
1.0-1.5:1:0.9-1.2:0.1-0.3；
Wherein the temperature is kept between 0 and 5 ℃ when the reactants are added; the reaction temperature is 25-30 ℃, and the reaction time is 1-12 h.
In the prior art, methoxy ethyl acetoacetate and m-nitrobenzaldehyde react under the catalysis of concentrated sulfuric acid to generate 2- (3-nitrobenzylidene) methoxy ethyl acetoacetate, so that the problems of inconvenient reaction operation, low yield and the like are solved.
The second step is that: refining a 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product;
completely dissolving the 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product by using a water-insoluble organic solvent, stirring by using an alkali solution, standing for layering, discarding the water phase, adding pure water into the organic phase, stirring, standing for layering, discarding the water phase, and evaporating the water-insoluble organic solvent in the organic layer.
Wherein the insoluble organic solvent is one or more of dichloromethane, toluene, chloroform and ethyl acetate, preferably dichloromethane;
wherein the alkali solution is one or more of sodium bicarbonate, sodium carbonate and potassium carbonate solution, preferably sodium bicarbonate solution;
according to the synthesis method of cilnidipine, when the synthesis of cilnidipine is continued under the condition that 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester is not refined, a hydrolysis byproduct of cilnidipine appears in a product of cilnidipine, and the byproduct is difficult to remove in the refining process of cilnidipine, so that the quality of the cilnidipine bulk drug is seriously influenced.
The third step: synthesis of cilnidipine
Refined 2- (3-nitrobenzylidene) acetoacetic acid methoxy ethyl ester and 3-aminocrotonic acid cinnamyl ester react in an absolute ethyl alcohol solvent, and after reaction, a cilnidipine crude product is obtained through treatment;
the post-reaction treatment is to add absolute ethyl alcohol and active carbon into a reaction system, reflux and stir, filter the mixture while the mixture is hot, and slowly cool the filtrate, stir and crystallize the mixture.
Wherein the molar ratio of the 2- (3-nitrobenzylidene) acetoacetic acid methoxy ethyl ester to the 3-aminocrotonic acid cinnamyl ester is 1:0.8-1.2, the reaction temperature is 60-78 ℃, and the reaction time is 10-24 h. The reaction temperature is preferably 60-65 ℃ and the reaction time is 22 h.
Wherein the reflux temperature in the post-treatment is 60-78 deg.C, preferably 60-65 deg.C.
The fourth step: refining of cilnidipine
Adding absolute ethyl alcohol into the crude product of cilnidipine, heating and stirring, cooling and crystallizing to obtain refined cilnidipine;
wherein the molar ratio of the crude cilnidipine to the absolute ethyl alcohol is 1:20-40, preferably 1: 30; the heating and stirring temperature is 60-78 ℃, the crystallization temperature is 35-40 ℃, and the optimal temperature is 38 ℃.
One specific embodiment of the invention is:
the first step is as follows: synthesis of 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product
Adding 3.0kg of methoxy ethyl acetoacetate and 1.5kg of acetic anhydride into a 10L reaction kettle, heating the internal temperature to 0-5 ℃, dropwise adding 300g of concentrated sulfuric acid at the internal temperature of 0-5 ℃, keeping the temperature after dropwise adding, adding 2.0kg of m-nitrobenzaldehyde, heating to 25-30 ℃, and reacting for 6-7h to terminate the reaction. Adding 95% ethanol, filtering, and vacuum drying at 45 deg.C for 10 hr to obtain light yellow solid.
The second step is that: refining of 2- (3-nitrobenzylidene) methoxyethyl acetoacetate
Placing the 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product in a 30L reaction kettle, adding 10kg of dichloromethane for dissolving, then adding sodium bicarbonate saturated solution, stirring for 30min at room temperature, standing for layering, adding pure water into the organic phase, stirring for 30min at room temperature, standing for layering, and removing dichloromethane in the organic layer through reduced pressure distillation.
The third step: synthesis of cilnidipine
Adding 2.5kg of 3-aminocrotonic acid cinnamyl ester and 11.6kg of absolute ethyl alcohol into the solution obtained in the step (2), and carrying out reflux reaction for 22 hours. Adding absolute ethyl alcohol and active carbon into the reaction system, and refluxing and stirring for 30 min. Filtering while the solution is hot, and slowly cooling, stirring and crystallizing the filtrate. Filtering, and vacuum-drying the filter cake at 60 ℃ for 10h to obtain the cilnidipine.
The fourth step: refining of cilnidipine
Placing the crude product of cilnidipine in a 30L reaction kettle, adding 15kg of absolute ethyl alcohol, heating to the internal temperature of 65 ℃, stirring to dissolve, slowly cooling to 35-40 ℃, filtering, vacuum-drying a filter cake at 60 ℃ for 10h to obtain a white to light yellow powdery solid, and detecting the cilnidipine by adopting a high performance liquid chromatography, wherein the total yield is 70.0%, and the HPLC purity is 99.92%.
The application also comprises an intermediate product and a finished product of cilnidipine prepared by the synthesis method.
The synthesis method also comprises the application of the synthesis method in the preparation of medicines.
In the prior art, a plurality of methods for synthesizing cilnidipine exist, but most of the methods have the problems of low yield and many impurities. Aiming at the synthetic route of our part, in the process of research and development, the technicians of our part find that under the condition that 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester is not refined, a hydrolysis byproduct of cilnidipine appears in a product of the cilnidipine, and the byproduct is difficult to remove in the refining process of the cilnidipine.
The reason for the above phenomenon is that a large amount of acetic acid is generated in the synthesis process of 2- (3-nitrobenzylidene) methoxyethyl acetoacetate, and a large amount of sulfuric acid or hydrochloric acid is also used in the reaction process in the prior art, so that a certain amount of acid residue is generated in the crude product of 2- (3-nitrobenzylidene) methoxyethyl acetoacetate, while a certain amount of reaction water is generated in the synthesis process of cilnidipine, and the hydrolysis of ester bonds in cilnidipine molecules can occur at a high temperature for a long time under acidic conditions, so that a hydrolysis byproduct of cilnidipine is generated. According to the invention, the reaction intermediate 2- (3-nitrobenzylidene) acetoacetoxyethyl ester is refined, so that the acid residue is removed, and the generation of hydrolysis byproducts is reduced.
Due to the adoption of the technical scheme, the beneficial effects of the application are as follows:
(1) the method solves the problem that part of impurities are difficult to remove in the synthesis process of the cilnidipine bulk drug by adding an intermediate refining step, and the subsequent refining process of cilnidipine is simpler and the purity of the finished product is high.
(2) The method for preparing cilnidipine has the advantages of simple synthesis process, complete reaction, high yield and low cost, and is very suitable for industrial production.
Drawings
FIG. 1 is a diagram of high performance liquid chromatography of cilnidipine of comparative example 1;
FIG. 2 is a graphic representation of high performance liquid chromatography of cilnidipine of example 1;
FIG. 3 is a graphic representation of high performance liquid chromatography of cilnidipine of example 2;
FIG. 4 is a graphic representation of high performance liquid chromatography of cilnidipine of example 3;
Detailed Description
The present application is described in further detail below with reference to specific embodiments and the attached drawings. The following examples are intended to be illustrative of the present application only and should not be construed as limiting the present application.
Comparative example 1
(1) Synthesis of 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product
Adding 2.4kg of methoxy ethyl acetoacetate and 1.6kg of acetic anhydride into a 10L reaction kettle, heating the internal temperature to 0-5 ℃, dropwise adding 136g of concentrated sulfuric acid at the internal temperature of 0-5 ℃, keeping the temperature after dropwise adding, adding 2.1kg of m-nitrobenzaldehyde, heating to 25-30 ℃, reacting for 6-7h, and stopping the reaction. Adding 95% ethanol, filtering, and vacuum drying at 45 deg.C for 10 hr to obtain light yellow solid.
(2) Synthesis of cilnidipine
Putting the 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product into a 30L reaction kettle, and adding 2.70kg of 3-aminocrotonic acid cinnamyl ester; anhydrous ethanol (11.6kg) was refluxed for 22 hours. Adding absolute ethyl alcohol and active carbon into the reaction system, and refluxing and stirring for 30 min. Filtering while the solution is hot, slowly cooling the filtrate to 15-20 ℃, filtering, and vacuum-drying the filter cake for 10h at 60 ℃ to obtain the cilnidipine.
(3) Refining of cilnidipine
Placing the crude product of cilnidipine in a 30L reaction kettle, adding absolute ethyl alcohol, heating to an internal temperature of 65 ℃, stirring to dissolve, slowly cooling to 35-40 ℃, filtering, vacuum-drying a filter cake at 60 ℃ for 10 hours to obtain a white to light yellow powdery solid, and detecting cilnidipine by adopting a high performance liquid chromatography, wherein the result is shown in figure 1, the yield is 60.0%, and the HPLC purity is 93.93%.
As can be seen from the figure of comparative example 1, according to the synthesis method disclosed by the invention, when 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester is not subjected to a refining step, an obvious impurity peak appears in a cilnidipine bulk drug, and the purity of cilnidipine is low, so that the medicinal requirement cannot be met.
Table 1: FIG. 1 related parameters of detection map
| Peak number | Retention time | Area of | % area | Theoretical plate number (USP) | Degree of separation (USP) | |
| 1 | 5.148 | 7687 | 0.030 | 5779.480 | / | 763 |
| 2 | 6.227 | 105719 | 0.411 | 6830.023 | 3.771 | 9118 |
| 3 | 7.760 | 173524 | 0.675 | 5534.438 | 4.267 | 10647 |
| 4 | 8.307 | 361803 | 1.407 | 6788.954 | 1.334 | 26906 |
| 5 | 8.625 | 486236 | 1.891 | 6724.793 | 0.771 | 32102 |
| 6 | 9.425 | 245726 | 0.965 | 9423.075 | 1.979 | 16346 |
| 7 | 10.777 | 25159 | 9.098 | 5402.039 | 2.774 | 1025 |
| 8 | 11.427 | 30482 | 0.119 | 5739.008 | 1.092 | 1334 |
| 9 | 15.216 | 17758 | 0.069 | 8390.426 | 5.978 | 811 |
| 10 | 15.677 | 14598 | 0.057 | 7077.383 | 0.654 | 662 |
| 11 | 19.274 | 24152118 | 93.930 | 11387.590 | 4.901 | 870959 |
| 12 | 21.970 | 19325 | 0.075 | 16021.837 | 3.805 | 765 |
| 13 | 25.561 | 11357 | 0.044 | 14012.303 | 4.610 | 366 |
| 14 | 27.658 | 61272 | 0.238 | 14584.093 | 2.357 | 1821 |
Example 1
(1) Synthesis of 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product
Adding 2.4kg of methoxy ethyl acetoacetate and 1.6kg of acetic anhydride into a 10L reaction kettle, heating the internal temperature to 0-5 ℃, dropwise adding 136g of concentrated sulfuric acid at the internal temperature of 0-5 ℃, keeping the temperature after dropwise adding, adding 2.1kg of m-nitrobenzaldehyde, heating to 25-30 ℃, reacting for 6-7h, and stopping the reaction. Adding 95% ethanol, filtering, and vacuum drying at 45 deg.C for 10 hr to obtain light yellow solid.
(2) Refining of 2- (3-nitrobenzylidene) methoxyethyl acetoacetate
Placing the 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product in a 30L reaction kettle, adding 10kg of dichloromethane for dissolving, then adding sodium bicarbonate saturated solution, stirring for 30min at room temperature, standing for layering, adding pure water into the organic phase, stirring for 30min at room temperature, standing for layering, and distilling off dichloromethane in the organic layer under reduced pressure.
(3) Synthesis of cilnidipine
Adding 2.70kg of 3-aminocrotonic acid cinnamyl ester and 11.6kg of absolute ethyl alcohol into the solution obtained in the step (2), and carrying out reflux reaction for 22 hours. Adding absolute ethyl alcohol and active carbon into the reaction system, and refluxing and stirring for 30 min. Filtering while the solution is hot, slowly cooling the filtrate to 15-20 ℃, filtering, and vacuum-drying the filter cake for 10h at 60 ℃ to obtain the cilnidipine.
(4) Refining of cilnidipine
Placing the crude product of cilnidipine in a 30L reaction kettle, adding anhydrous ethanol (14.5kg), heating to an internal temperature of 65 ℃, stirring to dissolve, slowly cooling to 35-40 ℃, filtering, vacuum-drying a filter cake at 60 ℃ for 10h to obtain a white to light yellow powdery solid, and detecting the cilnidipine by adopting a high performance liquid chromatography, wherein the result is shown in figure 2, the total yield is 70.0%, and the HPLC purity is 99.92%.
Table 2: FIG. 2 related parameters of detection spectra
| Peak number | Retention time | Area of | % area | Theoretical plate number (USP) | Degree of separation (USP) | |
| 1 | 8.032 | 0.2457 | 0.05 | 9221 | 19.575 | 1.14 |
| 2 | 18.962 | 542.9415 | 99.92 | 9331 | 6.270 | 1075.144 |
| 3 | 24.805 | 0.1264 | 0.02 | 8382 | 4.848 | 0.186 |
| 4 | 30.833 | 0.0723 | 0.01 | 7653 | n.a. | 0.082 |
Example 2
(1) Synthesis of 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product
Adding 2.2kg of methoxy ethyl acetoacetate and 1.3kg of acetic anhydride into a 10L reaction kettle, heating the internal temperature to 0-5 ℃, dropwise adding 136g of concentrated sulfuric acid at the internal temperature of 0-5 ℃, keeping the temperature after dropwise adding, adding 2.1kg of m-nitrobenzaldehyde, heating to 25-30 ℃, reacting for 2-3h, and stopping the reaction. Adding 95% ethanol, filtering, and vacuum drying at 45 deg.C for 10 hr to obtain light yellow solid.
(2) Refining of 2- (3-nitrobenzylidene) methoxyethyl acetoacetate
Putting the 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product into a 30L reaction kettle, adding 9.9kg of ethyl acetate to dissolve the ethyl acetate, adding sodium carbonate saturated solution, stirring for 30min at room temperature, standing for layering, adding pure water into the organic phase, stirring for 30min at room temperature, standing for layering, and removing the ethyl acetate in the organic layer by reduced pressure distillation.
(3) Synthesis of cilnidipine
And (3) adding 1.96kg of 3-aminocrotonic acid cinnamyl ester and 11.6kg of absolute ethyl alcohol into the solution obtained in the step (2), and carrying out reflux reaction for 22 hours. Adding absolute ethyl alcohol and active carbon into the reaction system, and refluxing and stirring for 30 min. Filtering while the solution is hot, slowly cooling the filtrate to 15-20 ℃, filtering, and vacuum-drying the filter cake for 10h at 60 ℃ to obtain the cilnidipine.
(4) Refining of cilnidipine
Placing the crude product of cilnidipine in a 30L reaction kettle, adding anhydrous ethanol (14.26kg), heating to an internal temperature of 65 ℃, stirring to dissolve, slowly cooling to 35-40 ℃, filtering, vacuum-drying a filter cake at 60 ℃ for 10h to obtain a white to light yellow powdery solid, and detecting cilnidipine by adopting a high performance liquid chromatography, wherein the result is shown in figure 3, the total yield is 69.0%, and the HPLC purity is 99.91%.
Table 3: FIG. 3 related parameters of detection spectra
| Peak number | Retention time | Area of | % area | Theoretical plate number (USP) | Degree of separation (USP) | |
| 1 | 3.557 | 0.0515 | 0.01 | 7461 | 2.626 | 0.397 |
| 2 | 4.073 | 0.0633 | 0.01 | 5089 | 3.336 | 0.390 |
| 3 | 4.872 | 0.0091 | 0.00 | 6002 | 11.647 | 0.060 |
| 4 | 8.290 | 0.2462 | 0.04 | 9682 | 8.383 | 1.145 |
| 5 | 11.597 | 0.0268 | 0.00 | 10439 | 13.415 | 0.092 |
| 6 | 19.997 | 566.4176 | 99.91 | 9956 | 7.127 | 1095.770 |
| 7 | 26.345 | 0.1011 | 0.02 | 11455 | n.a. | 0.170 |
Example 3
(1) Synthesis of 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product
Adding 3.3kg of methoxy ethyl acetoacetate and 1.68kg of acetic anhydride into a 10L reaction kettle, heating the internal temperature to 0-5 ℃, dropwise adding 409g of concentrated sulfuric acid at the internal temperature of 0-5 ℃, keeping the temperature after dropwise adding, adding 2.1kg of m-nitrobenzaldehyde, heating to 25-30 ℃, reacting for 11-12h, and stopping the reaction. Adding 95% ethanol, filtering, and vacuum drying at 45 deg.C for 10 hr to obtain light yellow solid.
(2) Refining of 2- (3-nitrobenzylidene) methoxyethyl acetoacetate
Placing the 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product in a 30L reaction kettle, adding 9.6kg of chloroform for dissolving, then adding potassium carbonate saturated solution, stirring for 30min at room temperature, standing for layering, adding pure water into the organic phase, stirring for 30min at room temperature, standing for layering, and removing the chloroform in the organic layer by reduced pressure distillation.
(3) Synthesis of cilnidipine
Adding 2.84kg of 3-aminocrotonic acid cinnamyl ester and 11.2kg of absolute ethyl alcohol into the solution obtained in the step (2), and carrying out reflux reaction for 22 hours. Adding absolute ethyl alcohol and active carbon into the reaction system, and refluxing and stirring for 30 min. And slowly cooling the filtrate to 15-20 ℃, filtering, and vacuum-drying the filter cake for 10 hours at 60 ℃ to obtain the cilnidipine.
(4) Refining of cilnidipine
Placing the crude product of cilnidipine in a 30L reaction kettle, adding anhydrous ethanol (14.05kg), heating to the internal temperature of 65 ℃, stirring to dissolve, slowly cooling to 35-40 ℃, filtering, vacuum-drying a filter cake at 60 ℃ for 10h to obtain a white to light yellow powdery solid, and detecting the cilnidipine by adopting a high performance liquid chromatography, wherein the result is shown in figure 4, the total yield is 68.0%, and the HPLC purity is 99.90%.
Table 4: FIG. 4 related parameters of detection spectra
According to the experimental results, the peak with retention time 19.274min in fig. 1 is cilnidipine, the peak with retention time 18.962min in fig. 2 is the peak with cilnidipine, the peak with retention time 19.997min in fig. 3 is the peak with cilnidipine, the peak with retention time 20.430min in fig. 4 is the peak with cilnidipine, and the peak with retention time 8.625min in fig. 1 is the peak with hydrolysis by-product of cilnidipine. No byproduct impurity peaks were detected in fig. 2, 3 and 4.
High performance liquid phase detection method for cilnidipine in comparative examples and examples
High performance liquid chromatograph: waters Acquity Acr System
Chromatographic conditions are as follows: a chromatographic column: perfluorohexylpropylsilanized silica gel is used as a stationary phase;
mobile phase: methanol-buffered salt (1.36g/L of sodium acetate trihydrate solution adjusted to pH 5.5) - (60:40 with 1% acetic acid);
flow rate: adjusting the flow rate to about 20min of cilnidipine retention time;
column temperature: 25 ℃;
detection wavelength: 240nm
Sample introduction amount: 10 μ L
The detection method comprises the following steps: preparing system applicability: about 10mg of cilnidipine in the example exposed to fluorescence (15000lx · h) was taken, placed in a 20mL measuring flask, dissolved by adding 4mL of acetonitrile, diluted to the mark with mobile phase and shaken well as a system suitability solution.
Preparing a test solution: operating in dark place, taking about 50mg of the product, precisely weighing, placing in a 100mL measuring flask, adding 20mL of acetonitrile for dissolving, adding a mobile phase for diluting to a scale, and shaking up to obtain a test solution;
preparing a control solution: 1mL of the test solution is precisely measured, placed in a 200mL measuring flask, and diluted to the scale with the mobile phase to serve as a control solution.
The foregoing is a more detailed description of the present application in connection with specific embodiments thereof, and it is not intended that the present application be limited to the specific embodiments thereof. For those skilled in the art to which the present application pertains, several simple deductions or substitutions may be made without departing from the concept of the present application, and all should be considered as belonging to the protection scope of the present application.
Claims (8)
1. A preparation method of cilnidipine is characterized by comprising the following steps:
(1) carrying out condensation reaction on the methoxy ethyl acetoacetate and m-nitrobenzaldehyde under the catalysis of concentrated sulfuric acid by using acetic anhydride as a solvent, adding ethanol after the reaction is finished, stirring and filtering to obtain a 2- (3-nitrobenzylidene) methoxy ethyl acetoacetate crude product;
(2) refining a 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester crude product;
(3) refined 2- (3-nitrobenzylidene) acetoacetic acid methoxy ethyl ester and 3-aminocrotonic acid cinnamyl ester react in an ethanol solvent, and a cilnidipine crude product is obtained after the reaction and the treatment;
(4) adding absolute ethyl alcohol into the crude product of cilnidipine, heating and stirring until the product is clear, cooling and crystallizing to obtain refined cilnidipine;
the refining method in the step (2) is that the crude product of the 2- (3-nitrobenzylidene) acetoacetic acid methoxyethyl ester is completely dissolved by a water-insoluble organic solvent, stirred by an alkali solution, stood for layering, the water phase is discarded, the organic phase is added with pure water and stirred, stood for layering, the water phase is discarded, and the organic solvent in the organic layer is evaporated; the alkali solution is one or more of sodium bicarbonate, sodium carbonate and potassium carbonate solution.
2. The method according to claim 1, wherein in the step (2), the water-insoluble organic solvent is one or more of dichloromethane, chloroform, ethyl acetate and toluene;
3. the process of claim 1, wherein in step (1) the ratio of methoxyethyl acetoacetate: m-nitrobenzaldehyde: acetic anhydride: the molar ratio of the concentrated sulfuric acid is 1.0-1.5:1:0.9-1.2: 0.1-0.3.
4. The process according to claim 1, wherein the reaction temperature in step (1) is 25 to 30 ℃ and the reaction time is 1 to 12 hours.
5. The process of claim 1, wherein the molar ratio of methoxyethyl 2- (3-nitrobenzylidene) acetoacetate to cinnamyl 3-aminocrotonate in step (3) is 1:0.8 to 1.2, the reaction temperature is 60 to 78 ℃, and the reaction time is 10 to 24 hours.
6. The method according to claim 1, wherein the post-reaction treatment in the step (3) is that the reaction system is supplemented with absolute ethyl alcohol and activated carbon, the mixture is refluxed and stirred, the mixture is filtered while the mixture is hot, and the filtrate is slowly cooled and stirred for crystallization.
7. The method of claim 6, wherein the reflux temperature is 60-78 ℃.
8. The method of claim 1, wherein the molar ratio of the crude cilnidipine to the absolute ethanol in step (4) is 1:20-40 ℃, the heating and stirring temperature is 60-78 ℃, and the crystallization temperature is 35-40 ℃.
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