阅读说明：本技术 一种盐酸贝尼地平的制备方法 (Preparation method of benidipine hydrochloride ) 是由 邵长凯 胡来龙 娄焕军 于 2020-12-31 设计创作，主要内容包括：本发明属于药物的化学合成领域,具体而言,涉及一种降压药盐酸贝尼地平的制备方法。该方法包括如下步骤：起始原料3-硝基苯甲醛和乙酰乙酸甲酯在催化剂的存在下进行knoevenagel反应,Michael加成反应,成环,水解,再与氯化亚砜反应后,然后直接与1-苄基-3-羟基哌啶反应,经精制得到盐酸贝尼地平。本发明的盐酸贝尼地平的制备方法得到的盐酸贝尼地平的纯度较高,不需要柱层析分离,产品HPLC纯度在99.5％以上。且得到的盐酸贝尼地平的收率较高,收率可达68％以上。(The invention belongs to the field of chemical synthesis of medicines, and particularly relates to a preparation method of a hypotensor benidipine hydrochloride. The method comprises the following steps: the preparation method comprises the following steps of carrying out knoevenagel reaction on 3-nitrobenzaldehyde and methyl acetoacetate serving as starting raw materials in the presence of a catalyst, carrying out Michael addition reaction, cyclizing, hydrolyzing, reacting with thionyl chloride, directly reacting with 1-benzyl-3-hydroxypiperidine, and refining to obtain benidipine hydrochloride. The benidipine hydrochloride prepared by the preparation method of the benidipine hydrochloride has high purity, column chromatography separation is not needed, and the HPLC purity of the product is over 99.5 percent. And the yield of the benidipine hydrochloride is high and can reach more than 68 percent.)

1. A preparation method of benidipine hydrochloride comprises the following steps:

the preparation method comprises the following steps of carrying out knoevenagel reaction on 3-nitrobenzaldehyde and methyl acetoacetate serving as starting raw materials in the presence of a catalyst, carrying out Michael addition reaction, cyclizing, hydrolyzing, reacting with thionyl chloride, directly reacting with 1-benzyl-3-hydroxypiperidine, and refining to obtain benidipine hydrochloride.

2. The method for preparing benidipine hydrochloride according to claim 1, comprising the steps of:

(1) performing knoevenagel reaction on 3-nitrobenzaldehyde and methyl acetoacetate in the presence of a catalyst to generate 2- (3-nitrobenzylidene) -methyl acetoacetate;

(2) carrying out Michael addition and cyclization on 2- (3-nitrobenzylidene) -methyl acetoacetate and beta-amino methyl crotonate in absolute ethyl alcohol, methanol or isopropanol, evaporating the solvent under reduced pressure, cooling, crystallizing, filtering and drying to obtain 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylic acid dimethyl ester;

(3) carrying out hydrolysis reaction on 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylic acid dimethyl ester in sodium hydroxide solution and methanol to obtain 2, 6-dimethyl-4- (m-nitrophenyl) -1, 4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid; (4) and (3) carrying out chlorination reaction on 2, 6-dimethyl-4- (m-nitrophenyl) -1, 4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid and thionyl chloride or oxalyl chloride, then carrying out reaction on the obtained product and 1-benzyl-3-piperidinol, and refining and purifying the obtained product to obtain benidipine hydrochloride.

3. The method for preparing benidipine hydrochloride according to claim 2, wherein the catalyst in step (1) is one of concentrated sulfuric acid and acetic acid-piperidine.

4. The method for preparing benidipine hydrochloride according to claim 3, wherein the catalyst in step (1) is concentrated sulfuric acid.

5. The method for preparing benidipine hydrochloride according to claim 2, wherein the reaction solvent for the Michael addition and cyclization reaction in step (2) is one of absolute ethanol, methanol and isopropanol.

6. The method for preparing benidipine hydrochloride according to claim 5, wherein the reaction solvent for the Michael addition and cyclization reaction in step (2) is absolute ethanol.

7. The method for preparing benidipine hydrochloride according to claim 2, wherein the chlorinating reagent in the step (4) is one of thionyl chloride and oxalyl chloride.

8. The method for preparing benidipine hydrochloride according to claim 7, wherein the chlorinating reagent in the step (4) is thionyl chloride.

9. The method for preparing benidipine hydrochloride according to claim 2, wherein the refining solvent in the step (4) is preferably ethyl acetate-ethanol (1:4, V/V) or ethyl acetate-isopropanol (1:4, V/V).

10. The method for preparing benidipine hydrochloride according to claim 9, wherein the refining solvent in the step (4) is preferably ethyl acetate-ethanol (1:4, V/V).

Technical Field

The invention belongs to the field of chemical synthesis of medicines, and particularly relates to a preparation method of a hypotensor benidipine hydrochloride.

Background

Hypertension has now become an important disease that seriously affects human health. The serious complications such as cerebral apoplexy, myocardial infarction, heart failure, renal insufficiency and the like caused by hypertension have high disability and fatality rate, so that the patient is burdened with individuals, families and society of the patient, and medical and social resources are seriously consumed. At present, the prevalence rate of hypertension of people in China is in an increasing situation, statistics shows that the prevalence rate of hypertension patients in China reaches 2.5 hundred million, the prevalence rate of hypertension of adults is 25% -30%, 350 ten thousand people die of cardiovascular and cerebrovascular diseases every year, and more than half of the deaths are related to hypertension.

The calcium channel blocker is a main medicine for treating hypertension, can be used as a first-line medicine for treating hypertension alone, and can also be used together with other antihypertensive medicines. The antihypertensive effect is characterized in that: has better effect on low renin (including the elderly) hypertension; the blood pressure reducing effect is rapid, and particularly, the selectivity of the blood vessel expanding effect is high in dihydropyridines; has no obvious influence on metabolism, and the benidipine hydrochloride can strongly inhibit calcium channels, block calcium ion inflow, selectively act on blood vessels, relax the blood vessels and reduce the resistance of the blood vessels, thereby playing a role in reducing blood pressure.

Benidipine hydrochloride second-generation dihydropyridine calcium antagonist is a long-acting and strong antihypertensive drug developed by Nippon synergy fermentation industry Co. This product was marketed in Japan in 1991 and was developed and sold in Europe by the German Integrated chemical company Calikemi. The English name is Benidipine Hydrochloride, and the Chinese cultural name is: (R, R) - (+/-) -2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydro-3, 5-pyridinedicarboxylic acid methyl- (R) -1-benzyl-3-piperidyl ester hydrochloride, Chemical Abstract (CAS): 91599-74-5, the structure of the benidipine hydrochloride compound of formula (IV) is as follows:

the molecular formula is as follows: c₂₈H₃₂ ClN₃ O₆

Molecular weight: 542.03

The benidipine hydrochloride is a safe and effective calcium ion antagonist, has very wide application prospect and great market potential. At present, the traditional and more classical synthesis methods of the medicine mainly comprise the following types:

1. the reaction route of the Chinese compound patent CN103641774B is as follows:

the preparation process comprises the steps of reacting 2, 6-dimethyl-4- (m-nitrophenyl) -1, 4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid with chlorophosphate under an alkaline condition to generate mixed anhydride; and carrying out reflux reaction on the mixed anhydride and N-benzyl-3-hydroxypiperidine to generate a benidipine crude product. And salifying the benidipine crude product to obtain a benidipine hydrochloride crude product, and stirring and crystallizing the benidipine hydrochloride crude product in an ethanol-acetone mixed solution to obtain the benidipine hydrochloride. The crystallization time of the route is longer, and the product is not purified well. The yield of the route is not high, the yield is only 40.1-49.2%, and the post-treatment is complicated, so that the method is not beneficial to industrial mass production.

2. The reaction scheme of patent EP 0063365 is as follows:

scheme 1 is as follows:

the preparation process of the reaction route is that methyl-3-nitrobenzal acetoacetate and N-benzyl-3-piperidyl-3-aminocrotonate are refluxed and cyclized in isopropanol or methanol to obtain benidipine. The starting materials used in the method, namely methyl-3-nitrobenzal acetoacetate and N-benzyl-3-piperidyl-3-aminocrotonate, are not easy to obtain, and the synthesis of the N-benzyl-3-piperidyl-3-aminocrotonate needs to use raw materials with polymerization explosion risks, so that the method is high in operation risk and not environment-friendly.

The reaction scheme 2 reported in this patent is as follows:

the route is that 3-nitrobenzaldehyde, 3-amino methyl crotonate and N-benzyl-3-piperidyl acetoacetate are refluxed and cyclized in organic solvent tetrahydrofuran to obtain benidipine hydrochloride. The reaction time of the route is long, the yield is low, raw materials with polymerization explosion risks are needed for synthesizing the N-benzyl-3-piperidyl acetoacetate, the operation risk is high, the route is not environment-friendly, the operation is complicated, and the route is not suitable for industrial production.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a novel preparation method of benidipine hydrochloride for treating hypertension.

A preparation method of benidipine hydrochloride comprises the following steps:

the preparation method comprises the following steps of carrying out knoevenagel reaction on 3-nitrobenzaldehyde and methyl acetoacetate serving as starting raw materials in the presence of a catalyst, carrying out Michael addition reaction, cyclizing, hydrolyzing, reacting with thionyl chloride, directly reacting with 1-benzyl-3-hydroxypiperidine, and refining to obtain benidipine hydrochloride.

The reaction route is as follows:

the preparation method of the benidipine hydrochloride comprises the following steps:

(1) performing knoevenagel reaction on 3-nitrobenzaldehyde and methyl acetoacetate in the presence of a catalyst to generate 2- (3-nitrobenzylidene) -methyl acetoacetate;

(2) carrying out Michael addition and cyclization on 2- (3-nitrobenzylidene) -methyl acetoacetate and beta-amino methyl crotonate in absolute ethyl alcohol, methanol or isopropanol, evaporating the solvent under reduced pressure, cooling, crystallizing, filtering and drying to obtain 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylic acid dimethyl ester;

(3) carrying out hydrolysis reaction on 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylic acid dimethyl ester in sodium hydroxide solution and methanol to obtain 2, 6-dimethyl-4- (m-nitrophenyl) -1, 4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid;

(4) and (3) carrying out chlorination reaction on 2, 6-dimethyl-4- (m-nitrophenyl) -1, 4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid and thionyl chloride or oxalyl chloride, then carrying out reaction on the obtained product and 1-benzyl-3-piperidinol, and refining and purifying the obtained product to obtain benidipine hydrochloride.

The catalyst in the step (1) is one of concentrated sulfuric acid and acetic acid-piperidine. Preferably concentrated sulfuric acid.

The reaction solvent of the Michael addition and cyclization reaction in the step (2) is one of absolute ethyl alcohol, methanol and isopropanol. Preferably anhydrous ethanol.

And (3) the chlorinating reagent in the step (4) is one of thionyl chloride and oxalyl chloride. Thionyl chloride is preferred.

The refining solvent in the step (4) is preferably ethyl acetate-ethanol (1:4, V/V) or ethyl acetate-isopropanol (1:4, V/V). Preferably ethyl acetate-ethanol (1:4, V/V).

Compared with the prior art, the method of the invention has the following advantages and beneficial effects:

1. in the preparation method of benidipine hydrochloride, the used starting materials are easy to purchase, raw materials and reagents with explosion risks are avoided, the reagents used in the reaction do not pollute the environment, the cost is low, and the method is suitable for industrial production.

2. The preparation method of benidipine hydrochloride has short reaction steps and simple operation and post-treatment;

3. the benidipine hydrochloride prepared by the preparation method of the benidipine hydrochloride has high purity, column chromatography separation is not needed, and the HPLC purity of the product is over 99.5 percent. And the yield of the benidipine hydrochloride is high and can reach more than 68 percent. The reaction process has mild conditions and is suitable for industrial production.

Drawings

FIG. 1 is an HPLC chromatogram of the intermediate methyl 2- (3-nitrobenzylidene) -acetoacetate (I) prepared in example 1 of this invention;

FIG. 2 is an HPLC chromatogram of the intermediate methyl 2- (3-nitrobenzylidene) -acetoacetate (I) prepared in example 2 of this invention;

FIG. 3 is an HPLC chromatogram of intermediate dimethyl 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylate (II) prepared in example 3 according to the present invention;

FIG. 4 is an HPLC chromatogram of intermediate dimethyl 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylate (II) prepared in example 4 of the present invention;

FIG. 5 is an HPLC chromatogram of intermediate 2, 6-dimethyl-4- (m-nitrophenyl) -1, 4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid (III), prepared in example 5 of the present invention;

FIG. 6 is an HPLC chromatogram of benidipine hydrochloride (IV) prepared in example 6 of the present invention;

FIG. 7 is an HPLC chromatogram of benidipine hydrochloride (IV) prepared in example 7 of the present invention;

FIG. 8 is an HPLC chromatogram of benidipine hydrochloride (IV) prepared in example 8 of the present invention.

Detailed Description

The invention will be further described with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand the invention without limiting the invention thereto, and that various modifications or improvements can be made by those skilled in the art without departing from the basic idea of the invention.

The invention uses 3-nitrobenzaldehyde and methyl acetoacetate aldol to condense the obtained product and beta-amino methyl crotonate to react in solvent to obtain 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylic acid dimethyl ester.

For synthesizing benidipine hydrochloride, the invention hydrolyzes 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylic acid dimethyl ester, reacts with thionyl chloride or oxalyl chloride, reacts with 1-benzyl-3-hydroxypiperidine, forms salt, and is refined and purified to obtain benidipine hydrochloride.

Example 1: preparation of intermediate 2- (3-nitrobenzylidene) -methyl acetoacetate (I)

Adding 34.8g (0.3mol) of methyl acetoacetate and 5.0ml of glacial acetic acid into a reaction bottle, then slowly adding 5.0ml of concentrated sulfuric acid at 0-10 ℃, stirring for 15 minutes, then slowly adding 30.2g (0.2mol) of 3-nitrobenzaldehyde at 0-10 ℃, controlling the temperature of the mixture to be 20-30 ℃, stirring and reacting for 1-2 hours, then adding 20ml of absolute ethyl alcohol, stirring for 30 minutes, generating a large amount of solid crystals, filtering, washing a filter cake by 10ml of absolute ethyl alcohol, and drying the solid by blowing at 60-70 ℃ for 8 hours to obtain 43.0g of white solid, wherein the yield is 86.3%, and the HPLC purity (area normalization): 98.855%, HPLC results are shown in FIG. 1.

Example 2: preparation of intermediate 2- (3-nitrobenzylidene) -methyl acetoacetate (I)

Adding 34.8g (0.3mol) of methyl acetoacetate and 5.0ml of glacial acetic acid into a reaction bottle, then slowly adding 5.0ml of piperidine at 0-10 ℃, stirring for 15 minutes, then slowly adding 30.2g (0.2mol) of 3-nitrobenzaldehyde at 0-10 ℃, controlling the temperature of the mixture to be 20-30 ℃, stirring and reacting for 1-2 hours, then adding 20ml of absolute ethyl alcohol, stirring for 30 minutes, generating a large amount of solid crystals, filtering, washing a filter cake with 10ml of absolute ethyl alcohol, and drying the solid by blowing at 60-70 ℃ for 8 hours to obtain 41.0g of white solid, wherein the yield is 82.2%, and the HPLC purity (area normalization): 98.689%, HPLC results are shown in FIG. 2.

Example 3: preparation of intermediate 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylic acid dimethyl ester (II)

Adding 20.0g (0.08mol) of 2- (3-nitrobenzylidene) -methyl acetoacetate, 11.5g (0.1mol) of beta-aminocrotonic acid methyl ester and 150ml of absolute ethyl alcohol into a reaction bottle, controlling the temperature of the mixture to be 40-50 ℃, stirring and reacting for 2-4 hours, after the reaction is finished, placing the mixture in an ice water bath to be cooled and crystallized at the temperature of 0-10 ℃. Stirring for 1 hour until white-like crystals precipitate, filtering, and air-drying the solid at 50-60 deg.C for 8 hr to obtain light yellow solid 24.2g, yield 87.3%, and HPLC purity (area normalization): 99.868%, HPLC results are shown in FIG. 3.

Example 4: preparation of intermediate 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylic acid dimethyl ester (II)

Adding 20.0g (0.08mol) of 2- (3-nitrobenzylidene) -methyl acetoacetate, 11.5g (0.1mol) of beta-aminocrotonic acid methyl ester and 150ml of methanol into a reaction bottle, controlling the temperature of the mixture to be 40-50 ℃, stirring and reacting for 2-4 hours, and after the reaction is finished, placing the mixture in an ice water bath to be cooled and crystallized at the temperature of 0-10 ℃. Stirring for 1 hour until white crystals precipitate, filtering, and air-drying the solid at 50-60 deg.C for 8 hr to obtain light yellow solid 23.7g, yield 85.4%, and HPLC purity (area normalization): 99.854%, HPLC results are shown in FIG. 4.

Example 5: preparation of intermediate 2, 6-dimethyl-4- (m-nitrophenyl) -1, 4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid (III)

Adding 20.0g (0.058mol) of intermediate 1, 4-dihydro-2, 6-dimethyl-4- (m-nitrophenyl) -3, 5-pyridinedicarboxylic acid dimethyl ester (III) and 200ml of methanol into a reaction bottle, adding 100ml of 10% sodium hydroxide aqueous solution under stirring, heating to 40-60 ℃, preserving heat for reacting for 3-4 hours, evaporating the methanol under reduced pressure, then slowly adding 200ml of purified water, stirring for 30 minutes, filtering the mixture, acidifying the filtrate to pH of 2.0 by using 1mol/L hydrochloric acid, separating out a solid, filtering, washing by using purified water, drying the solid by blowing at 70-80 ℃ for 8 hours to obtain 16.3g of white-like solid, wherein the yield is 84.5%, and the HPLC purity (area normalization): 98.451%, HPLC results are shown in FIG. 5.

Example 6: preparation of benidipine hydrochloride (IV)

Adding 5.0g (0.015mol) of 2, 6-dimethyl-4- (m-nitrophenyl) -1, 4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid, 30ml of dichloromethane and 10ml of N, N-dimethylformamide into a reaction flask, dropwise adding 2.4g (0.02mol) of thionyl chloride under ice bath, stirring to react for 1 hour, then heating to 20-30 ℃, adding 3.5g (0.018mol) of 1-benzyl-3-piperidinol, continuing to react for 1 hour, after the reaction is finished, respectively washing the reaction liquid with 40ml of purified water and 40ml of 4% sodium carbonate solution, adding 50ml of dichloromethane, adding 40ml of 3mol/L hydrochloric acid solution at normal temperature, stirring for 1 hour, washing with 40ml of purified water, and drying the organic layer with anhydrous sodium sulfate. Evaporating the solvent under reduced pressure, adding 20ml of ethyl acetate-ethanol (1:4, V/V) mixed solution into the concentrate, heating and stirring for 30 minutes at 40-50 ℃, then cooling to 0-10 ℃, crystallizing and stirring for 30 minutes, filtering, and drying the solid by air blowing at 70-80 ℃ for 8 hours to obtain 5.73g of light yellow solid, wherein the yield is 70.5%, and the HPLC purity (area normalization method): 99.903%, HPLC results are shown in FIG. 6.

Example 7: preparation of benidipine hydrochloride (IV)

Adding 5.0g (0.015mol) of 2, 6-dimethyl-4- (m-nitrophenyl) -1, 4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid, 30ml of dichloromethane and 10ml of N, N-dimethylformamide into a reaction flask, dropwise adding 2.4g (0.02mol) of thionyl chloride under ice bath, stirring for reaction for 1 hour, heating to 20-30 ℃, adding 3.5g (0.018mol) of 1-benzyl-3-piperidinol, continuing to react for 1 hour, after the reaction is finished, respectively washing the reaction liquid with 40ml of purified water and 40ml of 4% sodium carbonate solution, adding 50ml of dichloromethane, adding 40ml of 3mol/L hydrochloric acid solution at normal temperature, stirring for 1 hour, washing with 40ml of purified water, and drying the organic layer with anhydrous sodium sulfate. And (2) evaporating the solvent under reduced pressure, adding 20ml of ethyl acetate-isopropanol (1:4, V/V) mixed solution into the concentrate, heating and stirring at 40-50 ℃ for 30 minutes, then cooling to 0-10 ℃, crystallizing and stirring for 30 minutes, filtering, and drying the solid by blowing at 70-80 ℃ for 8 hours to obtain 5.62g of light yellow solid, wherein the yield is 69.1%, and the HPLC purity (area normalization method): 99.75% and HPLC results are shown in FIG. 7.

Example 8: preparation of benidipine hydrochloride (IV)

5.0g (0.015mol) of 2, 6-dimethyl-4- (m-nitrophenyl) -1, 4-dihydropyridine-5-carboxylic acid methyl ester-3-carboxylic acid, 30ml of dichloromethane and 10ml of N, N-dimethylformamide are added to a reaction flask, 2.54g (0.02mol) of oxalyl chloride is added dropwise in an ice bath, after stirring and reacting for 1 hour, the temperature is raised to 20-30 ℃, 3.5g (0.018mol) of 1-benzyl-3-piperidinol is added, the reaction is continued for 1 hour, after the reaction is finished, the reaction solution is respectively washed by 40ml of purified water and 40ml of 4% sodium carbonate solution, after 50ml of dichloromethane is added, 40ml of 3mol/L hydrochloric acid solution is added at normal temperature, stirring is carried out for 1 hour, washing by 40ml of purified water, and the organic layer is vigorously dried by anhydrous sodium sulfate. Evaporating the solvent under reduced pressure, adding 20ml of ethyl acetate-ethanol (1:4, V/V) mixed solution into the concentrate, heating and stirring for 30 minutes at 40-50 ℃, then cooling to 0-10 ℃, crystallizing and stirring for 30 minutes, filtering, and drying the solid by air blowing at 70-80 ℃ for 8 hours to obtain 5.53g of light yellow solid, wherein the yield is 68.0%, and the HPLC purity (area normalization method): 99.88% and HPLC results are shown in FIG. 8.