阅读说明：本技术 两种高纯度丁酸氯维地平杂质的制备方法 (Preparation method of two high-purity clevidipine butyrate impurities ) 是由 任业明 段崇刚 赵思太 鲜婧 孙谦 刘宜辉 龚艳艳 樊志萍 于 2020-03-11 设计创作，主要内容包括：本发明涉及两种丁酸氯维地平杂质4-(2,4-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸甲酯丁酰氧基甲酯(I)和4-(3,4-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸甲酯丁酰氧基甲酯(II)的制备方法。通过对丁酸氯维地平杂质的制备,为丁酸氯维地平的质量研究提供杂质对照品。<Image he="457" wi="698" file="DDA0002407484740000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>I：R1＝Cl,R2＝H；II：R1＝H,R2＝Cl。(The invention relates to a preparation method of two clevidipine butyrate impurities, namely 4- (2, 4-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylic acid methyl ester butyryloxymethyl ester (I) and 4- (3, 4-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylic acid methyl ester butyryloxymethyl ester (II). The impurity reference substance is provided for the quality research of the clevidipine butyrate through the preparation of the clevidipine butyrate impurity.)

1. Two preparation methods of clevidipine butyrate impurities (I) and (II) are characterized by comprising the following steps of:

the first step is as follows: carrying out Knoevenagel condensation reaction on a compound (2, 4-dichlorobenzaldehyde or 3, 4-dichlorobenzaldehyde) and methyl acetoacetate (shown in the formula (1) in a mixed solution of isopropanol, acetic acid and piperidine to generate a compound (2) (methyl 2- (2, 4-dichlorobenzylidene) -acetoacetate or methyl 2- (3, 4-dichlorobenzylidene) -acetoacetate ];

the second step is that: michael cyclization of a compound of formula (2) and cyanoethyl 3-amino-crotonate in ethanol to produce a compound of formula (3) [ cyanoethyl 4- (2, 4-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylate or cyanoethyl 4- (3, 4-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylate ];

the third step: selectively hydrolyzing the compound shown in the formula (3) in sodium hydroxide and acetone to generate a compound shown in the formula (4) [4- (2, 4-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylic acid monomethyl ester or 4- (3, 4-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylic acid monomethyl ester ];

the fourth step: the compound of the formula (4) and chloromethyl butyrate generate esterification reaction in a mixed solution of acetonitrile and potassium carbonate to generate a target compound (I, II);

the fifth step: and (3) refluxing and dissolving the crude product of the clevidipine butyrate impurity (I, II) by using a mixed solvent of alcohol solvents such as methanol, ethanol, isopropanol and the like and acetone, decoloring by using activated carbon, and cooling to 0 ℃ for crystallization for 1 hour to obtain a pure clevidipine butyrate impurity (I, II).

2. A method of producing clevidipine butyrate impurity (I, II) according to claim 1, wherein the method comprises the steps of:

the first step is as follows: condensation reaction, namely heating the compound of the formula (1) and methyl acetoacetate to 40 ℃ in isopropanol solvent by using acetic acid and piperidine as catalysts, reacting for 5 hours, cooling to 10 ℃, stirring, crystallizing for 1 hour, filtering, and washing with cold isopropanol to obtain a white solid compound of the formula (2);

the second step is that: performing cyclization reaction, performing reflux reaction on the compound of the formula (2) and 3-aminocrotonic acid cyanoethyl ester by taking ethanol as a solvent for 9 hours, adding activated carbon for decoloring for 15 minutes, performing hot filtration, and performing cold crystallization to obtain a light yellow solid compound of the formula (3);

the third step: performing hydrolysis reaction, namely reacting the compound of the formula (3) in acetone and sodium hydroxide aqueous solution at 20-30 ℃ for 4.5h, adding water to dilute the reaction solution, washing with dichloromethane, dropwise adding hydrochloric acid solution to adjust the pH to 5-6 under the cooling of ice water, stirring for half an hour, and filtering to obtain a light yellow solid compound of the formula (4);

the fourth step: performing esterification reaction, performing reflux reaction on the compound shown in the formula (4) and chloromethyl butyrate in anhydrous potassium carbonate and acetonitrile for 6 hours, performing heat filtration to remove inorganic salts, adding ethanol/water into filtrate, reacting at room temperature for 8 hours, filtering, and washing a filter cake by using an isopropanol/water mixed solution to obtain a white solid clevidipine butyrate impurity (I, II) crude product;

the fifth step: heating, refluxing and dissolving the crude product of the clevidipine butyrate impurity (I, II) by using an ethanol/acetone (2:1) mixed solvent, cooling to 0 ℃, stirring for 30 minutes, and separating out a white solid clevidipine butyrate impurity (I, II) pure product.

3. A method of producing clevidipine butyrate impurity (I, II) according to claim 1, comprising the steps of:

taking a compound (2, 4-dichlorobenzaldehyde or 3, 4-dichlorobenzaldehyde) shown as a formula (1) as a starting material, adding the compound (57.8g) into a 250ml reaction bottle, adding isopropanol (100ml) for dissolving, then respectively adding methyl acetoacetate (38.3g), acetic acid (1.1g) and piperidine (1.7g), after the addition is finished, heating the mixed solution to 40 ℃, stirring for 5 hours, cooling to 10 ℃, generating a large amount of solid, stirring for crystallization for 1 hour, filtering, and washing with cold isopropanol to obtain a white solid compound shown as a formula (2): 60.3 g;

adding the compound of the formula (2) obtained in the previous step into a 500ml reaction bottle, adding ethanol (200ml) for dissolving, adding 3-aminocrotonic acid cyanoethyl ester (34g), heating to reflux reaction for 9h, adding activated carbon for decoloring for 15 min, performing hot filtration, cooling the filtrate to 0 ℃ and crystallizing to obtain a light yellow solid compound of the formula (3): 58.7 g;

adding the compound of the formula (3) obtained in the previous step into a 3000ml reaction bottle, adding acetone (500ml), cooling to 10-20 ℃, dropwise adding a sodium hydroxide aqueous solution (17g/350ml), reacting at 20-30 ℃ for 4.5h after dropwise adding, adding water (1000ml) to dilute the reaction solution, washing with dichloromethane (200ml), dropwise adding a hydrochloric acid solution into the aqueous solution under ice water cooling to adjust the pH value to 5-6, stirring for 30 min, and filtering to obtain a light yellow solid compound of the formula (4) of 48.2 g;

adding acetonitrile (288ml) into a 1000ml reaction bottle of the compound of the formula (4) obtained in the previous step for dissolving, then adding anhydrous potassium carbonate (18gl) and chloromethyl butyrate (27g), heating and refluxing for 6h, filtering, diluting filtrate with ethanol/water (100ml/200ml), stirring for 8h at room temperature, filtering, washing filter cakes with ethanol/water (50ml/150ml), and obtaining 39.5g of crude clevidipine butyrate impurity (I, II);

adding the crude clevidipine butyrate impurity (I, II) into a 250ml reaction bottle, adding an ethanol/acetone mixed solvent (2:1, 117ml), heating, refluxing and dissolving, decoloring with activated carbon for 15 minutes, cooling to 0 ℃, and crystallizing for 30 minutes to separate out 35.1g of a white solid clevidipine butyrate impurity (I, II) pure product.

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of impurity 4- (2, 4-dichlorophenyl) -2, 6-dimethyl-3, 5-pyridinedicarboxylic acid methyl ester butyryloxymethyl ester and 4- (3, 4-dichlorophenyl) -2, 6-dimethyl-3, 5-pyridinedicarboxylic acid methyl ester butyryloxymethyl ester in the preparation process of two kinds of clevidipine butyrate.

Background

Clevidipine butyrate (clevidinebutyrate) is a novel dihydropyridine calcium channel blocker for meridian injection and is used for selectively inhibiting calcium ion inflow outside arterial vascular smooth muscle cells. The emulsion is prepared by Medicines Company and is approved by the FDA of the United states to be marketed at 8.1.2008, and the dosage form is injection emulsion. The chemical name of the product is 4- (2, 3-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylic acid methyl (1-butyryloxy) methyl ester, the structural formula is as follows, the product has quick effect, quick elimination, no accumulation in vivo and small toxic and side effects, and is different from the hypertension of kidney and (or) liver metabolism after being injected into the channels at present, and the product is mainly used for treating the serious hypertension which is ineffective or difficult to be orally taken, and the blood pressure control after the operations such as the cardiac operation, percutaneous coronary artery interventional therapy and the like. Clevidipine butyrate has the following structure:

at present, the synthetic process routes of clevidipine butyrate reported in China are many, and researches on the synthetic literature of clevidipine butyrate, the synthesis of clevidipine butyrate published in the journal of the Chinese medical industry in 2010 from Cao Xiu Zhi, the synthesis of clevidipine butyrate published in the journal of Chinese new medicine in 2012 in Chen, the synthesis research of clevidipine butyrate as an antihypertensive drug in a fine chemical intermediate in 2013 from Zhawa Huatang find that no matter which synthetic process route is adopted, 2, 3-dichlorobenzaldehyde is used as a starting material, 2, 3-dichlorobenzaldehyde contains two impurities of 2, 4-dichlorobenzaldehyde and 3, 4-dichlorobenzaldehyde, and 4- (2, 4-dichlorophenyl) -2, 6-dimethyl-3, 5-pyridinedicarboxylic acid methyl ester butyryloxymethyl ester and 4- (3) can be respectively generated in subsequent reactions, 4-dichlorophenyl) -2, 6-dimethyl-3, 5-pyridinedicarboxylic acid methyl ester butyryloxymethyl ester two impurities of clevidipine butyrate. Therefore, research on clevidipine butyrate impurity (I, II) is necessary. The results are shown below:

disclosure of Invention

In order to improve the quality of the clevidipine butyrate and reduce the risk of clinical medication, the invention provides two methods for preparing the high-purity clevidipine butyrate impurity, which make a contribution to the quality research of the clevidipine butyrate.

The invention provides two methods for preparing high-purity clevidipine butyrate impurities, which have the advantages that the raw materials and reagents adopted by the method are cheap and easy to obtain, the operation is simple, special requirements such as high temperature and high pressure are avoided, and the purity of the prepared clevidipine butyrate impurities (I, II) reaches more than 99.5%.

The invention provides two methods for preparing high-purity clevidipine butyrate impurity (I, II), which are characterized by comprising the following steps:

the first step is as follows: carrying out Knoevenagel condensation reaction on a compound (2, 4-dichlorobenzaldehyde or 3, 4-dichlorobenzaldehyde) and methyl acetoacetate (shown in the formula (1) in a mixed solution of isopropanol, acetic acid and piperidine to generate a compound (2) (methyl 2- (2, 4-dichlorobenzylidene) -acetoacetate or methyl 2- (3, 4-dichlorobenzylidene) -acetoacetate ];

the second step is that: michael cyclization of a compound of formula (2) and cyanoethyl 3-amino-crotonate in ethanol to produce a compound of formula (3) [ cyanoethyl 4- (2, 4-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylate or cyanoethyl 4- (3, 4-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylate ];

the third step: selectively hydrolyzing the compound shown in the formula (3) in sodium hydroxide and acetone to generate a compound shown in the formula (4) [4- (2, 4-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylic acid monomethyl ester or 4- (3, 4-dichlorophenyl) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylic acid monomethyl ester ];

the fourth step: the compound of the formula (4) and chloromethyl butyrate generate esterification reaction in a mixed solution of acetonitrile and potassium carbonate to generate a target compound (I, II);

the fifth step: and (3) refluxing and dissolving the crude product of the clevidipine butyrate impurity (I, II) by using a mixed solvent of alcohol solvents such as methanol, ethanol, isopropanol and the like and acetone, decoloring by using activated carbon, and cooling to 0 ℃ for crystallization for 1 hour to obtain a pure clevidipine butyrate impurity (I, II).

Further, the alcohol used in the first, second and fourth steps may be an alcohol solvent such as methanol, ethanol, isopropanol, etc.

Further, the washing solvent used in the third step may be selected from water-immiscible solvents such as dichloromethane, ethyl acetate, toluene, etc.

Furthermore, the proportion of ethanol and acetone has a large influence on recrystallization of the clevidipine butyrate impurity (I, II), and the investigation result shows that when the proportion of ethanol and acetone is 2:1, the purity of the clevidipine butyrate impurity (I, II) obtained by refining reaches more than 99.9%, and the yield is more than 90%.

Drawings

FIG. 1 is an HP L C map of clevidipine butyrate impurity I

FIG. 2 is an HP L C map of clevidipine butyrate impurity II

Detailed Description

The present invention will be further described with reference to the following specific examples, which are not intended to limit the scope of the present invention, and all techniques implemented based on the above-described contents of the present invention shall fall within the scope of the present invention.