KR100646670B1 - Improved Process for Preparing Lercanidipine hydrochloride - Google Patents

Abstract

The present invention relates to an improved process for the preparation of lercanidipine hydrogen chloride, more particularly 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine- Carboxylic acid group in carrying out the process for preparing lercanidipine by esterifying 3-carboxylic acid with 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol Is reacted with a carbonyl chloride compound to activate in the form of a mixed acid anhydride, followed by esterification to synthesize lercanidipine hydrogen chloride hydrate in a higher yield, and to synthesize the lercanidipine hydrogen chloride hydrate in a specific crystallization solvent. Improved preparation of lercanidipine, which comprises converting anhydrous lercanidipine hydrogen chloride, which is more stable under temperature and humidity conditions, by crystallization by selective use of Relate to.

Lercanidipine, 1,4-dihydropyridine hydrogen chloride, hydrate, anhydrous, activator of carboxylic acid group, carbonyl chloride compound

Description

Improved Process for Preparing Lercanidipine hydrochloride

1 is a DSC analysis graph of lercanidipine hydrochloride hydrate obtained by the method of Example 1, where the vertical axis represents heat flow (mV) and the horizontal axis represents temperature (° C).

Figure 2 is a DSC analysis graph of lercanidipine hydrochloride obtained by the method of Example 1, the vertical axis represents the heat flow (mV), the horizontal axis represents the temperature (° C).

The present invention relates to an improved process for the preparation of lercanidipine, more particularly 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3 In the process for preparing lercanidipine by esterifying a carboxylic acid with 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol, After reacting with a carbonyl chloride compound to activate a mixed acid anhydride form, an esterification reaction is performed to synthesize lercanidipine hydrogen chloride hydrate at a higher yield, and the synthesized lercanidipine hydrogen chloride hydrate is converted into a specific crystallization solvent. A method for the improved preparation of lercanidipine, which comprises converting anhydrous lercanidipine hydrogen chloride, which is more stable under temperature and humidity conditions, by crystallization by selective use. will be.

Lercanidipine has the compound name according to IUPAC nomenclature methyl 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6- Dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylate, which is represented by the following chemical formula:

Lercanidipine and its pharmaceutically acceptable salts are L-type calcium channel antagonists and are well known to be effective in the treatment of antihypertensives, maturities (such as throat tonsil inflammation), coronary artery disease, and the like.

Hydrochloric acid salts of lercanidipine may exist in the form of hydrate or anhydrous, depending on the method of preparation. Since lercanidipine hydrogen chloride is present in the anhydride form as compared to the hydrate form, It has been found to be more stable under conditions of water, moisture and temperature.

Lercanidipine As a representative prior art related to the production method of hydrogen chloride, the following production method is known.

U.S. Patent No. 4,705,797 discloses a method of preparing lercanidipine hydrogen chloride in the form of a hydrate by carrying out a preparation process as shown in Scheme 1 below.

However, in the known method according to Scheme 1, the Hantzsch cyclization reaction is carried out in the final preparation step for preparing lercanidipine hydrogen chloride, and in this cyclization reaction, various by-products are generated, so that the yield of the final target product is It is pointed out that there is a problem that is significantly reduced. In addition, it is pointed out that in order to remove by-products in the target product, a purification method unsuitable for industrial production such as column chromatography must be included. Due to this problem, the final stage yield is 35% and the overall process yield is very low, 23%. Therefore, it has been pointed out that there is a limit to applying the known method according to Scheme 1 as an industrial mass production method.

In addition, as a method for improving the manufacturing method according to Scheme 1, Korean Patent No. 395,441 discloses a method for preparing lercanidipine hydrogen chloride in the form of anhydrous by performing the manufacturing process as shown in the following Scheme 2. It is.

In the known method according to Scheme 2, lercanidipine hydrogen chloride is improved in comparison with the known method according to Scheme 1 in that anhydrous (anhydrous) form stable to light, temperature and moisture is obtained. However, since thionyl chloride (SOCl ₂ ) is used to activate the carboxylic acid derivative represented by Chemical Formula 2, thionyl chloride (SOCl ₂ ) is a substance causing environmental pollution, and thus cannot be an environmentally friendly synthesis method. In particular, there is a problem that the intermediate material produced by the reaction of thionyl chloride (SOCl ₂ ) is unstable and its handling is not easy.

Therefore, it is pointed out that the manufacturing method of lercanidipine which is known so far has room for improvement.

The present inventors have attempted to solve the problems pointed out in the synthesis method of anhydrous lercanidipine hydrogen chloride known from Korean Patent No. 395,441, and to develop an improved synthesis method useful for industrial mass production of lercanidipine. I tried.

As a result, a more stable reaction intermediate was synthesized using a carbonyl chloride compound represented by RC (O) -Cl as a reagent for activating the carboxylic acid group of the carboxylic acid derivative represented by Chemical Formula 2, and also with an aminopropyl alcohol compound. The hydrate of lercanidipine hydrogen chloride produced after the reaction of was crystallized with a specific mixed organic solvent, and thus, the present invention was completed by developing an improved preparation method for synthesizing anhydrous lercanidipine hydrogen chloride with higher purity and higher yield. .

It is therefore an object of the present invention to provide an improved process for the production of lercanidipine of the present invention that is useful for industrial mass production.

The present invention provides a method for preparing lercanidipine represented by the following formula (1) by reacting a carboxylic acid derivative represented by the following formula (2) with an aminopropyl alcohol compound represented by the following formula (3),

Ⅰ) exists under the following organic amine to carboxylic acid derivatives RC (O) -Cl (this time represented by the following formula (2) of a base, R is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, an aryl group, or an aryl group Reacting with an activator represented by oxy) to activate the carboxylic acid group, and then reacting with an aminopropyl alcohol compound represented by the following Chemical Formula 3 to prepare lercanidipine hydrogen chloride hydrate represented by the following Chemical Formula 1a;

Ii) crystallizing lercanidipine hydrogen chloride hydrate in the reaction mixture from a mixture of ethyl acetate / water / hexane; And

Iii) lercanidipine hydrogen chloride hydrate obtained by the above crystallization is crystallized with a mixed solution of ethyl acetate / methyl isobutyl ketone or a mixed solution of ethyl acetate / isopropyl acetate, anhydrous represented by the following formula (1b) Characterized in that the manufacturing method comprises the step of converting the form of lercanidipine hydrogen chloride.

The preparation method of the present invention according to Scheme 3 will be described in more detail for each preparation step as follows.

First, carboxylic acid derivatives represented by a RC (O) -Cl (wherein, R is an alkoxy group, an aryl group, or aryloxy C ₁ -C ₆ alkyl group, a C ₁ -C ₆₎ represented by the above formula (2) The compound is reacted to prepare an acid anhydride derivative represented by Chemical Formula 4, in which a carboxylic acid group is activated.

The activator represented by RC (O) -Cl used to activate the carboxylic acid group is specifically trimethyl acetylchloride, benzoyl chloride, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, phenyl chloroformate. Mate and the like. The activation reaction of the carboxylic acid group is carried out in a low temperature range of less than 0 ℃ in the presence of a base, preferably in the temperature range of -30 ℃ to 0 ℃. At this time, the base uses an organic amine generally applied in the art, and more specifically, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, and moreporin may be used. As the reaction solvent, a mixed solution obtained by mixing an organic solvent containing methylene chloride, chloroform, ethyl acetate, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, acetonitrile, acetone, etc. alone or in an appropriate mixing ratio may be used. In particular, when ethyl acetate is used as a reaction solvent, ethyl acetate may be used as a reaction solvent and a crystallization solvent, thus eliminating the process of removing the reaction solvent in the crystallization process of lercanidipine hydrogen chloride hydrate represented by Formula 1a. In this state, since the target substance can be directly crystallized and separated from the reaction solution, the synthesis and purification processes can be simplified.

Meanwhile, the acid anhydride derivative represented by Chemical Formula 4 prepared above is reacted with the aminopropyl alcohol compound represented by Chemical Formula 3 to prepare lercanidipine hydrogen chloride hydrate represented by Chemical Formula 1a. Is carried out by maintaining a low temperature of less than 0 ℃, preferably a temperature range of -30 ℃ to 0 ℃.

Then, in order to separate and purify the lercanidipine hydrogen chloride hydrate from the reaction mixture, the solvent crystallization method was applied in the present invention, wherein the mixed solution of ethyl acetate / water / hexane is selected as the resulting purification solvent do. The mixing ratio of the mixed solution of ethyl acetate / water / hexane as the crystallization solvent is to maintain the volume ratio of 1/1/1 to 1/7/7, and the yield of lercanidipine hydrogen chloride hydrate in accordance with the change of the mixing ratio of these mixed solutions There may be differences.

Then, a solvent crystallization method is applied to convert the lercanidipine hydrogen chloride hydrate represented by Chemical Formula 1a to the anhydrous form as represented by Chemical Formula 1b. As a crystallization solvent for conversion to anhydride, a mixed solution of ethyl acetate (EtOAc) and methyl isobutyl ketone (MIBK) or a mixed solution of ethyl acetate (EtOAc) and isopropyl acetate (i-PrOAc) can be used. In the case of the mixed solution of ethyl acetate / methyl isobutyl ketone or the mixed solution of ethyl acetate / isopropyl acetate, the mixing ratio of these mixed solutions is 1/5 to 5/1 by volume (more preferably 1/3 to 3/1 by volume) ) To maintain the range. In addition, the above-mentioned mixed solution may be used within the range of 3 to 10 mL (more preferably, 4 to 7 mL) with respect to 1 g of lercanidipine hydrogen chloride hydrate to obtain more preferable results in terms of yield and purity. Can be. The lercanidipine hydrogen chloride obtained by using the above-mentioned crystallization solvent is included in the characteristic properties of anhydrous (melting point = 185 to 190 ° C), and pure anhydride having a high purity of 98% or more. It was confirmed that the compound in the form.

As described above, according to the production method according to the present invention, the desired anhydrous lercanidipine could be easily synthesized by the selective use of an activator of carboxylic acid, and a high purity target was synthesized by a simple crystallization. can do.

Such a present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1 Preparation of Lercanidipine Hydrogen Chloride

20 g (0.060 mol) of 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid 150 mL of ethyl acetate and dimethyl acetamide 50 mL was added and 7.89 g of triethylamine was added. The reaction mixture was cooled to −5 ° C., 9.07 g (0.075 mol) of trimethylacetyl chloride was added, followed by stirring at the same temperature for 3 hours, whereby 5-t-butylcarbonyloxycarbonyl-2,6-dimethyl- was used as the active compound. 4- (3-nitro-phenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester was formed in the reaction vessel.

Subsequently, 19.63 g (0.066 mol) of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol was mixed with 40 mL of ethyl acetate in the reaction solution. It was slowly added dropwise while maintaining and stirred for 3 hours. Upon completion of the reaction, 600 mL of water was added, stirred for 10 minutes, allowed to stand, and the layers separated. The organic layer was washed sequentially with 10% aqueous NaCl solution (300 mL), 5% aqueous KHCO ₃ solution (300 mL × 3), 1N-HCl aqueous solution (400 mL × 3), and 20 g of alumina was added to the organic layer. Stir for minutes and then filter.

The filtered ethyl acetate filtrate was adjusted to a volume of about 200 mL, 800 mL of water and 200 mL of hexane were added thereto, 1.0 mL of hydrochloric acid was added thereto, and vigorous stirring was performed at 0 to 5 ° C. to precipitate crystals. The precipitated crystals were filtered, and the filtered crystals were again added to 600 mL of water, 3.00 mL of hydrochloric acid was added, followed by stirring for 2-3 hours, filtered and dried to give about 36.7 g of yellow lercanidipine hydrogen chloride hydrate (yield 92.8%). And purity 97.2%). The obtained lercanidipine hydrogen chloride hydrate had a water content of 1.98% as measured by a Kaal-Fisher moisture meter and a melting point (mp) of 118 to 123 ° C. In addition, the result of differential scanning calorimetry of the obtained lercanidipine hydrogen chloride hydrate was attached to FIG.

Then, 110 mL of ethyl acetate and 140 mL of methyl isobutyl ketone were added to 37 g of the hydrate obtained above, stirred for 30 minutes while heating to reflux, cooled to room temperature, stirred for 30 hours, and the resulting crystals were filtered and dried. And 33.54 g (yield 86%, purity 98.8%) of anhydrous lercanidipine hydrogen chloride (theoretical yield = 39.01 g) were obtained. The obtained lercanidipine hydrogen chloride had a melting point (mp) of 185.7 to 189.7 ° C.

In addition, the result of differential scanning calorimetry (DSC) of the obtained anhydrous lercanidipine hydrogen chloride hydrate was attached to FIG.

Example 2 Preparation of Lercanidipine Hydrogen Chloride

150 mL of ethyl acetate and dimethyl acetate in 20 g (0.060 mol) of 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid 50 mL of amide was added and 7.89 g of triethylamine was added. The reaction mixture was cooled to −5 ° C., 8.03 g (0.074 mol) of ethyl chloroformate was added, followed by stirring at the same temperature for 4 hours, whereby 5-ethoxycarbonyloxycarbonyl-2,6-dimethyl was used as the active compound. 4- (3-nitro-phenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester was formed in the reaction vessel.

Subsequently, 19.63 g (0.066 mol) of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol was mixed with 40 mL of ethyl acetate in the reaction solution. It was slowly added dropwise while maintaining and stirred for 3 hours. When the reaction was completed, 600 mL of water was added, stirred for 10 minutes, allowed to stand, and layers were separated. The organic layer was washed sequentially with 10% aqueous NaCl solution (300 mL), 5% aqueous KHCO ₃ solution (300 mL × 3), and 1N HCl aqueous solution (400 mL × 3), and 20 g of alumina was added to the organic layer for 30 minutes. Stir for and filter.

The filtered ethyl acetate filtrate was adjusted to a volume of about 200 mL, to which 300 mL of hexane and 900 mL of water were added. Then, 1.6 mL of hydrochloric acid was added and vigorously stirred at 0 to 5 ° C to precipitate crystals. The precipitated crystals were filtered, and the filtered crystals were again added to 600 mL of water, 3.00 mL of hydrochloric acid was added, followed by stirring for 2-3 hours, filtered and dried to give about 35.6 g of yellow lercanidipine hydrogen chloride hydrate (yield 90.0%). Purity 97.7%). The obtained lercanidipine hydrogen chloride hydrate had a water content of 2.01% as measured by a Kaal-Fisher moisture meter and a melting point (mp) was 118 to 124 ° C. Then, 120 mL of ethyl acetate and 150 mL of isopropyl acetate were added to 35.6 g of the hydrate obtained above, and the mixture was stirred under reflux for 30 minutes, cooled to room temperature, stirred for 30 hours, and the resulting crystals were filtered and dried, Type lercanidipine hydrogen chloride 32.38 g (yield 83%, purity 98.3%) were obtained. mp = 185.7-188.9 ° C.

Comparative example. Preparation of Lercanidipine Hydrogen Chloride Illustrated in Korean Patent No. 395,441

116.2 g (0.35 mol) of 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid was dried with 645 mL of anhydrous methane dichloride and anhydrous. To a mixed solution of 160 mL of dimethylformamide, 45.8 g (0.385 mol) of thionyl chloride (SOCl ₂ ) was slowly added dropwise for 15 minutes while maintaining at -4 ° C to 1 ° C under a nitrogen stream, followed by stirring at the same temperature range. It was. Then, 104.1 g (0.35 mol) of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol was maintained while maintaining the temperature of the reaction solution at -10 ° C to 0 ° C. Add dropwise over 15 minutes. After stirring for 3 hours at 0 ° C., it was left at room temperature for 18-20 hours, the solvent was distilled under vacuum and the residue was dissolved in 3500 mL of ethyl acetate. The organic layer was diluted with aqueous NaCl solution (700 mL), 10% Na ₂ CO ₃ solution (700 mL × 5), saturated NaCl solution (700 mL), 1N HCl solution (700 mL × 5), and saturated NaCl solution (700 mL). Washed sequentially. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ for 30 minutes, filtered and treated with activated carbon (23 g) and filtered. The filtrate was concentrated to about 1 L in volume, sprayed with lercanidipine hydrogen chloride seed and left at 0 ° C. to 5 ° C. for one day. The resulting solid was filtered and then recrystallized with anhydrous ethanol to give 179.5 g (76% yield) of anhydrous lercanidipine hydrogen chloride. mp = 186 to 188 ° C

As described above, the preparation method according to the present invention is lercanidipine represented by the formula (1) by the esterification reaction of the carboxylic acid derivative represented by the formula (2) and the aminopropyl alcohol compound represented by the formula (3) In preparing the above, the carboxylic acid derivative represented by Chemical Formula 2 is activated with a carbonyl chloride compound to synthesize an intermediate represented by Chemical Formula 4 in the form of an acid anhydride, and then ester with an aminopropyl alcohol compound represented by Chemical Formula 3. By carrying out the oxidization reaction, it was possible to maximize the reaction efficiency by synthesizing the stable reaction intermediates and to greatly improve the production yield. Also, the lercanidipine hydrogen chloride hydrate produced by the esterification reaction was high due to the selective use of a specific crystallization solvent. Purity Anhydrous Lercany The effect of converting to dipine hydrogen chloride is obtained.

Therefore, the manufacturing method according to the present invention can be usefully applied to the industrial mass production of lercanidipine.

Claims (7)

In the method for preparing lercanidipine represented by the following formula (1) by reacting the carboxylic acid derivative represented by the following formula (2) and the aminopropyl alcohol compound represented by the following formula (3), Iii) in the presence of an organic amine base selected from triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine and moorporin, the carboxylic acid derivative represented by the following formula (2) is represented by RC (O) -Cl (where R is an alkoxy group, a phenyl group, or by reacting with an activator represented by a phenoxy group), after activating the carboxylic acid group, aminopropyl represented by the following formula (3) an alcohol compound of the group of _{C 1 -C 6, C 1 -C} 6 and Reacting to prepare lercanidipine hydrogen chloride hydrate represented by Formula 1a; Ii) crystallizing lercanidipine hydrogen chloride hydrate in the reaction mixture from a mixture of ethyl acetate / water / hexane; And Iii) lercanidipine hydrogen chloride hydrate obtained by the above crystallization is crystallized with a mixed solution of ethyl acetate / methyl isobutyl ketone or a mixed solution of ethyl acetate / isopropyl acetate, anhydrous represented by the following formula (1b) Method for producing a lercanidipine hydrogen chloride in the form of a process comprising:

delete According to claim 1, wherein the activator represented by RC (O) -Cl is selected from trimethyl acetyl chloride, benzoyl chloride, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate and phenyl chloroformate Characterized in the manufacturing method. According to claim 1, wherein the solvent for crystallizing lercanidipine hydrogen chloride hydrate (ii) in the reaction mixture is a mixed solution of ethyl acetate / water / hexane of 1/1 / 1 to 1/7/7 volume ratio Manufacturing method characterized by using. 2. The mixed solution according to claim 1, wherein ethyl acetate / methyl isobutyl ketone is mixed at a volume ratio of 1: 3 to 3: 1 as a crystallization solvent for converting lercanidipine hydrogen chloride hydrate to anhydrous. Or ethyl acetate / isopropyl acetate using a mixed solution mixed at a volume ratio of 1: 3 to 3: 1. The method according to claim 5, wherein the mixed solution is used in the range of 3 to 10 mL based on 1 g of lercanidipine hydrogen chloride hydrate. The method according to claim 6, wherein the mixed solution is used in the range of 4 to 7 mL based on 1 g of lercanidipine hydrogen chloride hydrate.

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