KR100808281B1 - Method for the preparation of lercanidipine and acid addition salt thereof - Google Patents

Abstract

The present invention is an antihypertensive agent 1,1, N-trimethyl- (3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) An improved process for preparing pyridine-3,5-dicarboxylate (lercanidipine) or pharmaceutically acceptable acid addition salts thereof is provided. According to the present invention, 2, N-dimethyl-N- (3 Tertiary alcohol group of, 3-diphenylpropyl) -1-amino-2-propanol is made into a leaving group, and 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4- Substitution reaction of tertiary alcohol, which requires low yield and long reaction time by substitution reaction with metal salt of dihydropyridine-3-carboxylic acid, in short time and high yield in 1,1, N-trimethyl- ( 3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylate (lercanidipine) ) Or pharmaceutically acceptable acid addition salts thereof have.

Description

Method for preparing the lercanidipine and acid addition salts thereof

1 and 2 show the ¹ H nuclear magnetic resonance (NMR) spectrum of the compound obtained according to Example 3 of the present invention,

Figure 3 shows the ¹³ C nuclear magnetic resonance (NMR) spectrum of the compound obtained according to Example 3 of the present invention,

4 shows the mass spectrometry spectra of the compounds obtained according to Example 3 of the present invention.

The present invention relates to a method for producing lercanidipine and its acid addition salt, and more particularly, to a method for producing lercanidipine and its acid addition salt suitable for mass production because it is a more efficient and economical method.

Lercanidipine hydrochloride is a calcium channel blocker (L-type calcium channel antagonist) developed by Leccodati, Italy, and is used to treat antihypertensives and eye drops (such as inflammation of the tonsils of the throat) and coronary heart disease.

The first manufacturing method of recarnidipine may be synthesized as disclosed in Korean Patent Application No. 1985-0000888, but has a disadvantage in that the yield is low. Filed in No. 1997-7007905.

Scheme 1

The preparation method of Scheme 1 is a reaction to form lercanidipine by converting lercanidipine ring dihydropyridine carboxylic acid into a halide acid to perform esterification reaction with an alcohol group of aminoalcohol.

However, as is well known, esterification of tertiary alcohol is not usually used because of a long reaction time and low yield. This method, like the esterification of other tertiary alcohols, has a long reaction time and still shows low yields, although the yield is improved compared to the original preparation method.

In addition, the method of preparing compound (3) was carried out by reacting with 1-chloro-2-methyl-2-propanol using 2.5 equivalents of N-methyl-3,3-diphenylpropylamine in xylene, as shown in Scheme 2 below. Since N-methyl-3,3-diphenylpropylamine hydrochloride has to be separated, the N-methyl-3,3-diphenylpropylamine used in excess has problems in efficiency and economic efficiency of the reaction.

Scheme 2

In addition, there is a disadvantage in that recrystallization loss is severe due to recrystallization of crude lercanidipine obtained in the reaction in a protic solvent.

The technical problem to be achieved by the present invention is to improve the esterification reaction of the above-described conventional tertiary alcohol and to produce a new lercanidipine and its acid addition salt which can be mass-produced as a more efficient and economical production method, and the preparation thereof To provide a key intermediate.

In order to achieve the above technical problem, in the present invention, in the method for producing lercanidipine represented by the formula (1) or a pharmaceutically acceptable acid addition salt thereof,

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonylpyridine-3-carboxylic acid represented by the following Chemical Formula 2 and a compound of the following Chemical Formula 4 are semiprotic solvents: Provided is a method for preparing lercanidipine represented by the formula (1) or a pharmaceutically acceptable acid addition salt thereof, which is reacted with a base to produce lercanidipine under conditions.

[Formula 2]

[Formula 4]

Wherein R is AS (= 0) ₂ -O- or Cl,

A is an imidazolyl group.

[Formula 1]

Another technical problem of the present invention provides a compound represented by the following Chemical Formula 4, which is an intermediate for preparing lerica dipine of Chemical Formula 1.

[Formula 4]

Wherein R is AS (= 0) ₂ -O- or Cl,

A is an imidazolyl group.

Hereinafter, a method for preparing lercanidipine and its acid addition salt according to the present invention will be described in detail.

First, lercanidipine according to the present invention is 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonylpyridine-3-carboxyl represented by the following formula (2) The acid and the compound of formula 4 may be obtained by reacting with a base under aprotic solvent conditions.

[Formula 2]

[Formula 4]

Wherein R is AS (= 0) ₂ -O- or Cl,

A is an imidazolyl group.

[Formula 1]

The reaction is preferably carried out in the presence of a catalyst, such a catalyst serves to shorten the reaction time and improve the yield, and non-limiting examples of the catalyst include potassium carbonate, sodium carbonate, cesium carbonate and the like. Herein, the content of the catalyst is 1.05 to 2.0 moles based on 1 mole of the compound of Formula 4. If the content of the catalyst is less than 1.0 mole, the reactivity is lowered, and if the content of the catalyst exceeds 2.0 mole, side reactions are caused, which is not preferable.

Examples of the semiprotic solvent include at least one selected from dimethylformamide, ethyl acetate, acetonitrile and acetone, and the content thereof is 300 to 1000 parts by weight based on 100 parts by weight of the compound of Formula 4 in terms of reactivity. desirable.

The content of the compound of Formula 2 is preferably 1.05 to 1.2 moles based on 1 mole of the compound of Formula 4, and when the content of the compound of Formula 2 is outside the above range, it is not preferable in terms of yield, reactivity, and the like.

Of the compound represented by Formula 4 and 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonylpyridine-3-carboxylic acid represented by Formula 2 below Reaction is represented by following Reaction Formula 3, This reaction temperature is preferably 60-160 degreeC. If the reaction temperature is less than 60 ℃ reaction time is delayed, if it exceeds 160 ℃ it causes undesirable side reaction.

Scheme 3

Wherein R is AS (= 0) ₂ -O- or Cl,

A is an imidazolyl group.

Compound represented by the formula (4) is not particularly limited to the synthesis method, but according to an embodiment of the present invention can be prepared according to the following method.

The compound of formula 4 is formed through the reaction of the compound represented by the following formula (3) with SO ₂ Cl ₂ , imidazole and a solvent or through the reaction of the compound represented by the formula (3), imidazolylsulfonyl chloride and a solvent Can be formed.

[Formula 3]

The content of the imidazole is preferably 2.0 to 5.0 moles based on 1 mole of the compound of Formula 3.

The content of SO ₂ Cl ₂ is preferably 1.05 to 2.0 moles based on 1 mole of the compound of Formula 3.

In addition, the content of the imidazolylsulfonyl chloride is preferably 1.05 to 2.0 moles based on 1 mole of the compound of Formula 3.

In the reaction, at least one selected from dichloromethane, ethyl acetate, and dimethylformamide is used as the solvent, and the content thereof is preferably 300 to 1000 parts by weight based on 100 parts by weight of the compound of Formula 3.

The reaction is carried out by converting the hydroxy group of the compound of formula 3 to leaving group, chlorine group, etc. as shown in Scheme 4 below, and carrying out the nucleophilic substitution reaction of the carboxylic acid to effect esterification of the lower reactivity tertiary alcohol. It is improved by more efficient and high yield reaction. It is preferable that this reaction temperature is -20-10 degreeC. If the reaction temperature is less than -20 ℃, there is a delay in the reaction time, but does not affect the reaction, but it is not desirable to have a separate equipment for mass production, and if it exceeds 10 ℃ it is undesirable because it causes side reactions Can not do it.

Scheme 4

Wherein R is AS (= 0) ₂ -O- or Cl,

A is an imidazolyl group.

According to one embodiment of the present invention, when the compound represented by the following Chemical Formula 3, SO ₂ Cl ₂ , imidazole is reacted, a compound represented by the following Chemical Formula 4a is obtained. The compound represented by the formula (4a) is converted to the compound represented by the following formula (4b) in a work-up process or a standing process. Herein, the compound represented by the formula (4a) or (4b) is one example of the compound represented by the formula (4).

[Formula 4a]

[Formula 4b]

The amino alcohol of Formula 3 is a tertiary alcohol having low reactivity with a carboxylic acid or a corresponding halide acid, and thus has a long reaction time, and thus, halide acid decomposes before reaction proceeds in a reaction with an unstable halide acid to act as an unreacted substance. There is this. However, the reactivity of the carboxylic acid of Formula 2 and the compound of Formula 4, particularly the sulfonyl derivative of Formula 4a, provided in the present invention is very excellent, and thus lercanidipine can be prepared in a high yield of 80% or more in a relatively short reaction time.

The method of preparing the compound of Formula 3 is not particularly limited, but according to one embodiment, N-methyl-3,3-diphenylpropylamine represented by Formula 5 and 1-chloro-2 represented by Formula 6 -Methyl-2-propanol can be obtained by reaction in the presence of a protic solvent or a semiprotic polar solvent base.

[Formula 5]

[Formula 6]

Examples of the protic or semiprotic polar solvent include at least one selected from ethanol, dimethylformamide, ethyl acetate, acetonitrile, and the content thereof is 100 to 500 parts by weight based on 100 parts by weight of the compound of Formula 5. do. As the base, sodium hydroxide, potassium hydroxide, a mixture thereof, and the like are used, and the content thereof is 1.05 to 1.5 moles based on 1 mole of the compound of Formula 5.

The content of the compound of Formula 6 is 1.05 to 1.3 moles based on 1 mole of the compound of Formula 5, the reaction of the compound of Formula 5 and the compound of Formula 6 may be carried out at 60 ~ 120 ℃. If the reaction temperature is less than 60 ℃ is not preferable because the reaction time is delayed, and if the reaction temperature exceeds 120 ℃ can increase the production cost in mass production is not preferred.

In the case of using the compound of formula 5 according to the preparation method according to the prior art, that is, the reaction scheme 2 described above, the use of 2.5 equivalents of excess leads to the use of relatively expensive raw materials, which is uneconomical and the separation of unreacted materials according to the excessive use It is difficult to obtain a high purity amino alcohol of the general formula (3) because it is not perfect.

However, in the present invention, by reacting a relatively low amount of chloroalcohol of the general formula (6) in a small amount of 1.05 to 1.3 equivalents, the unreacted compound of the general formula (5) does not exist, and by completely removing the chloroalcohol of the formula (6) by extraction, high purity and An aminoalcohol compound represented by Formula 3 can be prepared in high yield.

According to the preparation method it is possible to synthesize lercanidipine represented by the formula (1). Looking at the acid addition salt, for example, the method for preparing lercanidipine hydrochloride from it as follows.

Lercanidipine represented by Formula 1 may be separated into anhydrous lercanidipine by crystallization reaction. This crystallization reaction comprises the steps of preparing lercanidipine hydrochloride from lercanidipine using a mixed solvent of an aqueous hydrochloric acid solution, a protic solvent, and a semiprotic solvent, and purifying lercanidipine hydrochloride from a mixed solvent of a protic solvent and a semiprotic solvent. It is carried out through the steps.

The protic solvent is at least one selected from water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, s-butanol and t-butanol, and the aprotic solvent is ethyl acetate, acetone, methyl acetate, n At least one selected from the group consisting of -hexane, toluene and acetonitrile, and the mixing volume ratio of the protic solvent and the semiprotic solvent is from 5:95 to 50:50.

Lercanidipine and the pharmaceutically acceptable acid addition salts obtained according to the present invention have antihypertensive activity and are also effective against coronary heart disease. Accordingly, the present invention may further prepare a pharmaceutical composition by adding a pharmaceutically acceptable diluent or carrier in addition to lercanidipine and a pharmaceutically acceptable acid addition salt thereof.

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

Example  1.2, N-dimethyl-N- (3,3- Diphenylpropyl ) -1-amino-2- Propanol  synthesis

55 g of N-methyl-3,3-diphenylpropylamine and 35.18 g of 1-chloro-2-methyl-2-propanol were placed in a 1 L reactor, dissolved in 150 mL of dimethylformamide, and 13.18 g of sodium hydroxide was added thereto. After all the sodium hydroxide was added and the reaction solution was heated to 80 ~ 85 ℃ and stirred for 5 hours, the reaction solution was cooled to 25 ~ 30 ℃, ethyl acetate and water was extracted. Take an ethyl acetate layer, and add an aqueous hydrochloric acid solution and toluene to it, extract it again, take an aqueous hydrochloric acid layer, add ethyl acetate to it, neutralize it with an aqueous sodium hydroxide solution, and extract and dehydrate the ethyl acetate layer with manganese. Concentration under reduced pressure afforded 71.6 g (yield 97%) of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol as a residue.

Example  2. 2, N-dimethyl-N- (3,3- Diphenylpropyl ) -1-amino-2- Propanol  synthesis

55 g of N-methyl-3,3-diphenylpropylamine and 35.18 g of 1-chloro-2-methyl-2-propanol were placed in a 1 L reactor, dissolved in 150 mL of ethanol, and 13.18 g of sodium hydroxide was added thereto. After all the sodium hydroxide was added and the reaction solution was heated to 80 ~ 85 ℃ and stirred for 5 hours, the reaction solution was cooled to 25 ~ 30 ℃, ethyl acetate and water was extracted. Take an ethyl acetate layer, and add an aqueous hydrochloric acid solution and toluene, and extract it again, take an aqueous hydrochloric acid layer, add ethyl acetate to it, neutralize it with an aqueous sodium hydroxide solution, and extract and dehydrate the ethyl acetate layer with manganese. Concentration under reduced pressure afforded 67.88 g (yield 92%) of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol as a residue.

Example  3. 2, N-dimethyl-N- (3,3- Diphenylpropyl ) -1-amino-2- Propylchloride  synthesis

50 g of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol was added to a 1 L reactor, dissolved in 400 mL of dichloromethane, and the internal temperature was cooled to -5 to 0 ° C. 34 g of sulfonyl chloride was slowly added dropwise so as not to exceed −5 to 0 ° C. After the addition was completed, the mixture was stirred at the same temperature for 1 hour. After stirring for one hour, while maintaining the same temperature, 28.7 g of imidazole was dissolved in 90 mL of dichloromethane and slowly added dropwise so that the temperature of the reaction solution did not exceed -5 to 0 ° C. After completion of the dropwise addition, the reaction solution was heated to 20-25 ° C., stirred for 3 hours, extracted twice with aqueous hydrochloric acid solution, washed with dichloromethane layer, extracted again with 1N aqueous sodium hydroxide solution, and taken up with dichloromethane layer. The dichloromethane layer extracted with water was dehydrated with forget-me-not, and then distilled under reduced pressure to give a sticky liquid product 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propylchloride (89%). 47.4 g was obtained in yield.

The structure of the compound was confirmed by the NMR of FIGS. 1 to 3 and the MASS spectrum of FIG. 4.

Example  4

67.88 g of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol was dissolved in 120 mL of dimethylformamide and 120 mL of ethyl acetate, placed in a 1L reactor, and cooled to -5 to 0 ° C. Then, 46.2 g of sulfonyl chloride was slowly added dropwise so as not to exceed −5 to 0 ° C. After the addition was completed, the mixture was stirred at the same temperature for 1 hour.

After stirring for one hour, 38..84 g of imidazole was dissolved in 75 mL of dimethylformamide while maintaining the same temperature, and slowly added dropwise so that the temperature of the reaction solution did not exceed -5 to 0 ° C. The reaction solution was stirred for 3 hours and then extracted three times with aqueous hydrochloric acid solution to wash the ethyl acetate layer. The mixture was again extracted with 1N aqueous sodium hydroxide solution to obtain an etheracetate layer. The water was removed with ethyl acetate, and then the product 2, The ethyl acetate layer obtained by extracting N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propylchloride was used for the next reaction as it was.

Example  5. 2, N-dimethyl-N- (3,3- Diphenylpropyl ) -1-amino-2- With propylchloride from Lercanidipine Of the crude product  synthesis

55 g of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonylpyridine-3-carboxylic acid was added to the ethyl acetate layer obtained in Example 4, followed by dimethylform. 50 mL of amide was added thereto, and 42.6 g of potassium carbonate was added thereto, and the mixture was heated and reacted under reflux for 6 hours. The reaction solution was extracted three times with water, the ethyl acetate layer was washed, dehydrated with forget-me-not and concentrated under reduced pressure to give 88.1 g (yield 87%) of lecanidipine crude product as a residue.

Example  6. In aqueous hydrochloric acid solution, ethanol, ethyl acetate and toluene Hydrochloric acid Nidipin Crude  synthesis

88.1 g of the crude lercanidipine product obtained in Example 5 was dissolved in 90 mL of 2N hydrochloric acid and 135 mL of ethanol, and stirred at 20 to 25 ° C. for 2 hours. 300 mL of ethyl acetate and 150 mL of toluene were added thereto, and the reaction solution was again After cooling to 0-5 [deg.] C., the mixture was stirred for 12 hours. The resulting crystals were filtered, washed with a mixture of ethyl acetate and toluene, and dried at 80 ° C. for 12 hours to give 88.6 g of crude lercanidipine (yield 95%) with a purity of 99.2% (HPLC). 135 ℃)

Example  7. Aqueous hydrochloric acid solution, methanol, ethyl acetate and n- In hexane  Hydrochloric acid Ler  Canidipine Crude product  synthesis

26.5 g of the crude lercanidipine crude product obtained in Example 5 was dissolved in 90 mL of 2N hydrochloric acid and 135 mL of methanol, stirred at 20 to 25 ° C. for 2 hours, and 300 mL of ethyl acetate and 70 mL of n-hexane were added thereto. It was cooled again to 0 ~ 5 ℃ and stirred for 12 hours. The resulting crystals were filtered, washed with ethyl acetate and toluene mixed solvent and dried at 80 ° C. for 12 hours to give 26.1 g (93%) of crude lercanidipine hydrochloride with a purity of 99.3% (HPLC) (melting point 132). 135 ° C)

Example  8. Hydrochloric Acid with Ethyl Acetate Lercanidipine  refine

76.9 g of crude crude lercanidipine was added to a 1 L reactor, and 10 mL of water, 15 mL of ethanol, and 320 mL of ethyl acetate were added thereto, and the resulting mixture was dissolved by heating to 80 ° C. , 100 mg of lercanidipine hydrochloride standard was seeded and stirred for 24 hours.

The resulting crystals were filtered and dried at 70 ° C. for 24 hours to obtain 71.5 g of lercanidipine hydrochloride with a purity of 99.8%. (Melting point 186-189 ° C.)

Example  9. Hydrochloric Acid with Acetone Lercanidipine  refine

93 g of crude lercanidipine hydrochloride was added to a 1 L reactor, 12 mL of water, 18 mL of ethanol, and 280 mL of acetone were added. The mixture was heated to 60 DEG C and refluxed until dissolved. After cooling, 100 mg of lercanidipine hydrochloride standard was added, seeded, and stirred for 24 hours. The resulting crystals were filtered and dried at 70 ° C. for 24 hours to obtain 86.5 g of lercanidipine hydrochloride with a purity of 99.8%. (Melting point 186-189 ° C.)

Example  10. Acetonitrile  Hydrochloric acid Lercanidipine  refine

100 g of crude lercanidipine hydrochloride was added to a 1 L reactor, 10 mL of water and 200 mL of acetonitrile were added, and the mixture was heated to 70 ° C and stirred until it dissolved. 50 mg of candipine standard was added, seeded, and stirred for 24 hours. The resulting crystals were filtered and dried at 70 ° C. for 24 hours to obtain 92.5 g of lercanidipine hydrochloride with a purity of 99.8%. (Melting point 186-189 ° C.)

Comparative example . One

11.6 g of 2,6-dimethyl-5-methoxycarbonyl-4 (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid was maintained at -4 ° C to + 1 ° C under nitrogen. To 65 mL of ethane chloride and 16 mL of anhydrous dimethylformamide, 4.58 g of thionyl chloride was added dropwise to the stirring mixture over 15 minutes. The mixture is stirred for 1 hour in the same temperature range. 10.4 g of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol is diluted with 10 mL of anhydrous dichloromethane and added dropwise at -10 to 0 占 폚 over 15 minutes. After stirring at 0 ° C. for 3 hours, the mixture was reacted at room temperature for 18 hours, distilled under reduced pressure not to exceed 25 ° C., and the solvent was geometrically dissolved in 350 mL of ethyl acetate. The ethyl acetate layer was extracted once with 70 mL of saturated sodium chloride solution, 5 times with 70 mL of 10% sodium carbonate solution, 70 mL of saturated sodium chloride solution, 5 times with 70 mL of 1N HCl, and once with 70 mL of saturated sodium chloride solution, and then the organic layer was dried over anhydrous sodium sulfate. Dried over filtrate, concentrated the organic layer to 100 mL under reduced pressure, seeded with 50 mg of lercanidipine hydrochloride with stirring at 0-5 ° C. and left for one day, filtered and dried for 12 hours at 70 ° C., purity 99.1 Obtained in 12.7 g (63.5% yield) of crude lercanidipine hydrochloride. (Melting point 128-131 degreeC)

12.7 g of lercanidipine hydrochloride crude product was dissolved in 25 mL of pure ethanol, cooled to room temperature, seeded with 20 mg of lercanidipine hydrochloride, stirred for 24 hours, and the resulting solid was filtered and dried at 70 ° C. for 24 hours. To obtain 9.9 g (yield 78%) of lercanidipine hydrochloride having a purity of 99.76%. (Melting point 186 to 188 ° C)

When synthesized lercanidipine hydrochloride according to Example 5-6 and Comparative Example 1, it is shown in Table 1 by comparing the yield and purity. Here, the reaction yield of Table 1 is obtained by examining the yield from the compound of Formula 2 to the crude product of lercanidipine hydrochloride, and the recrystallization yield is evaluated using Example 10 and Comparative Example 1.

TABLE 1

 Yield of reaction (yield from formula 2 to crude product)  Crude product purity  Recrystallization yield  Recrystallization purity Examples 5-6 83% 99.4% 94% 99.8% Comparative Example 1 63% 99.2% 78% 99.76%

As can be seen from Table 1, according to Examples 5 and 6 it was confirmed that the purity and yield in the synthesis of lercanidipine hydrochloride compared to the case of Comparative Example 1. In addition, the production cost can be reduced by reducing the reaction time.

As described above, the present invention provides a compound of Formula 4, which is a new intermediate, and can be synthesized in high yield and high efficiency by solving the problem of esterification of tertiary alcohol through synthesis using the compound. . In addition, high purity lercanidipine hydrochloride can be obtained by recrystallization of the acid addition salt of lercanidipine using an aprotic solvent.

Claims (9)

In the method for preparing lercanidipine represented by the formula (1) or a pharmaceutically acceptable acid addition salt thereof, 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonylpyridine-3-carboxylic acid represented by the following Chemical Formula 2 and a compound of the following Chemical Formula 4 are semiprotic solvents: Lercanidipine is prepared by reaction with a base under conditions; Compound represented by the formula (4), It is formed through the reaction of a compound represented by the formula (3), SO ₂ Cl ₂ , imidazole and a solvent or is formed through the reaction of a compound represented by the formula (3) with an imidazolylsulfonyl chloride and a solvent, Compound represented by the formula (3), Lercanidipine represented by the formula (1) or a pharmaceutically acceptable compound thereof, which is obtained by reacting a compound represented by the following formula (5) with a compound represented by the following formula (6) in a protic solvent or aprotic solvent and in the presence of a base Method for preparing acid addition salt.  [Formula 2]

[Formula 4]

Wherein R is AS (= 0) ₂ -O- or Cl, A is an imidazolyl group, [Formula 1]

[Formula 5]

[Formula 6]

According to claim 1, 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonylpyridine-3-carboxylic acid represented by the formula (2) and the formula (4) The semiprotic solvent used in the reaction of the compound of At least one selected from the group consisting of dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetonitrile, ethyl acetate, dioxane, toluene and xylene, Said base is at least one selected from the group consisting of potassium carbonate, sodium carbonate and cesium carbonate, lercanidipine represented by the formula (1) or a pharmaceutically acceptable acid addition salt thereof. delete delete The method of claim 1, wherein the protic solvent or semiprotic solvent used in the reaction of the compound represented by Formula 5 and the compound represented by Formula 6, At least one selected from the group consisting of methanol, ethanol, propanol, butanol, dimethylformamide, dimethylsulfoxide, dimethylacetamide, acetonitrile, ethyl acetate and dioxane, A method for producing lercanidipine represented by the formula (1) or a pharmaceutically acceptable acid addition salt thereof, wherein the base is at least one selected from sodium hydroxide and potassium hydroxide. The method according to claim 1, further comprising the step of separating the lercanidipine represented by the formula (1) to lercanidipine hydrochloride by a crystallization reaction, or the lercanidipine represented by the formula (1) Method for producing acid addition salt thereof. The method of claim 6, wherein the crystallization reaction, Preparing lercanidipine hydrochloride from lercanidipine using a mixed solvent of an aqueous hydrochloric acid solution and a protic solvent and an aprotic solvent; And A process for preparing lercanidipine represented by the formula (1) or a pharmaceutically acceptable acid addition salt thereof, comprising the step of purifying lercanidipine hydrochloride from a mixed solvent of a protic solvent and a semiprotic solvent. The method according to claim 7, wherein the protic solvent is at least one selected from water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, s-butanol and t-butanol, The aprotic solvent is at least one selected from the group consisting of ethyl acetate, acetone, methyl acetate, n-hexane, toluene and acetonitrile, A method for producing lercanidipine represented by the formula (1) or a pharmaceutically acceptable acid addition salt thereof, wherein the mixing volume ratio of the protic solvent and the semiprotic solvent is 5: 95-50: 50. A compound represented by the following formula (4). [Formula 4]

Wherein R is AS (= 0) ₂ -O- or Cl, A is an imidazolyl group.

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