KR101369207B1 - Process for preparing (s)-(-)-felodipine - Google Patents

Abstract

In the present invention, S-(-)-ethylmethyl 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-, which is hereinafter referred to as "S-(-)-felodipine" The present invention relates to a method for preparing 3,5-pyridine-dicarboxylate, wherein a (S) -isomer is isolated by synthesizing a felodipine derivative including a chiral separation compound and then selectively transesterified with betahydroxyester. An efficient method for synthesizing S-(-)-felodipine is provided. The chiral separation material is synthesized by reaction of various nucleophiles with epoxides from (R) -glycidol or (S) -glycidol.

(R) -glycidol, (S) -glycidol, (S)-(-)-felodipine

Description

Process for producing (S)-(-)-felodipine {PROCESS FOR PREPARING (S)-(-)-FELODIPINE}

The present invention relates to a process for synthesizing S-(-)-felodipine using (R) -glycidol or (S) -glycidol as a starting material, and a derivative of 1-hydroxyethyl group as an intermediate. The present invention relates to an efficient synthetic process for synthesizing S-(-)-felodipine by synthesizing esters thereof to separate (S) -isomers and then selectively transesterifying from the (S) -isomers.

Pelodipine is a general name of ethylmethyl 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylate represented by the following formula (1), As a long-acting calcium channel blocker, it is well known to be useful for the treatment of cardiovascular diseases such as angina pectoris and hypertension.

As shown in Formula 1, felodipine is a chiral compound in which an asymmetric carbon is present. In general, the therapeutic effect as a drug on chiral compounds is better than pure isomeric compounds rather than isomeric mixtures, and may also show different pharmacological properties depending on the steric configuration of the isomeric compounds or their salt forms. In the case of felodipine, the S-(-)-isomer shows superior drug efficacy and pharmacokinetic properties compared to the R-(+) isomer (see PA Soon et al., Eur. J. Clin. Pharm. (1993) 44 113) . Therefore, there is a need for the development of a technique for synthesizing chiral compounds such as felodipine into optically pure isomers.

Development of the synthesis process of racemic felodipine is disclosed in Korean Patent No. 10-0488384. On the other hand, stereoselective synthesis of S-(-)-felodipine is synthesized by the separation of diastereomeric intermediates using chiral auxiliary (B. Lamm et al . Tetrahedon Lett. (1989) 30 6423), a method for synthesizing via optical splitting of an intermediate monocarboxylic acid (see WO 88/07524), and a method for stereoselectively synthesizing asymmetric reduction using a chiral auxiliary group from a pyridine compound (Molecules (ECHC) (1996) 16) is known, but it is known that there is a limit to the direct industrial application, and in addition to the above-mentioned method, to obtain optically pure S-(-)-felodipine to date or a synthetic method that can be applied industrially Is not known, and in the case of related derivative compounds, an optical splitting method using an enzyme (see K. Achiwa et al. , Curr. Org. Chem. 1999 3 , 77) is known, but the synthesis of S-(-)-felodipine It is not used for.

Among them, the synthesis method using chiral auxiliary groups is the most practical method so far, but the actual synthesis method is known in detail, but an electron withdrawing group capable of forming anion at the beta position of the chiral alcohol forming an ester with the chiral auxiliary group is required. Do.

In order to overcome the limitation of the selective hydrolysis reaction used in the conventional method for preparing (S)-(-)-felodipine, the present invention adopts a selective transesterification reaction using various chiral auxiliary groups as the central reaction.

The present invention relates to a method for synthesizing S-(-)-felodipine using chiral or an auxiliary group using cheap (R) -glycidol or (S) -glycidol as a starting material of a selective transesterification reaction. Compared to the conventional synthesis method, the process is simple and economical, and various intermediates can be secured, and thus, it can be applied to asymmetric synthesis of dihydropyridine compounds other than felodipine.

The present invention uses (R) -glycidol or (S) -glycidol as starting materials to synthesize chiral auxiliaries for the optical separation of felodipine, from which an intermediate of felodipine is synthesized, and two diastereo Separation of the mer and then directly treated with sodium methoxy provides a method for synthesizing S-(-)-felodipine through selective transesterification of betahydroxyester.

The photoactive intermediate used above is a method that can be produced directly from the intermediate without undergoing the selective hydrolysis of the ester and the synthesis of the methyl ester. This method has the advantage that the process can be reduced by one step and the chiral brace can be recovered and reused compared to the existing method.

When explaining the invention in more detail as follows.

The present invention consists of two types of chiral auxiliaries for distinguishing the optical isomers of felodipine and the synthesis of S-(-) felodipine using the same.

The chiral adjuvant first contains an acid catalyst such as (R) -glycidol or (S) -glycidol and dihydropyran as shown in Scheme 1, for example pyridium paratoluene sulfonates (PPTs), p -toluenesulfonic acid (TsOH), camphoresulfonic acid (camphoresulfonic acid) and the like to the compound obtained by the addition reaction using a variety of nucleophiles. The nucleophile (Nu) used at this time can react with epoxide as well as R ₁ SH, R ₁ R ₂ NH, R ₁ OH, RR ₂ R ₃ CH, and its counterbase, that is, in the form of having removed hydrogen ions. And all nucleophiles, wherein R and R ₃ are H, R ₁ is phenyl, R ₂ is toluenesulfonate (Ts) and the like.

Synthesis of the felodipine intermediate using the chiral adjuvants thus obtained was carried out by reacting the ketoster obtained in the reaction with dichitin with 2,3-dichlorobenzaldehyde as shown in Scheme 2, and then using ethyl 3-amino-2-butenoate. It is prepared through the reaction of.

Preparation of S-(-)-felodipine is performed by treating the mixture of diastereomers obtained in the above reaction scheme with an acid such as p -toluenesulfonic acid, camphorsulfonic acid, pyridinium tosylate and acetic acid, as in Scheme 3, to form a hydroxyl group. Isomers are separated by recrystallization or chromatography using silica gel.

When the isolated isomers are reacted with a methoxy salt such as methoxy sodium (NaOMe), only beta hydroxy ester is selectively transesterified to directly prepare S-(-)-felodipine.

The chiral adjuvant recovered during the preparation of S-(-)-felodipine can be reused through selective reaction by known methods as in Scheme 4 (see AT Khan et al. , EJ Org. Chem. (2005) 4891). have.

Hereinafter, the present invention will be described by way of preferred embodiments of the present invention. However, the present invention is not limited to the embodiments described below, and it is apparent to those skilled in the art that many modifications can be made without departing from the technical spirit of the present invention.

Example 1 (Nu = PhSH)

Course 1.

6 g (80.99 mmol) of (R) -glycidol was dissolved in a solvent of 70 ml (1.1 M) of methylene chloride (CH ₂ Cl ₂ ), followed by 11.3 ml (1.5 eq) of 3,4-dihydropyran (DHP). ) And 1 g (0.05 eq) of pyridinium paratoluenesulfonate (PPTs) are added. After reacting for 6 hours at room temperature, 15-20 ml of water is added. 20-30 ml of sodium bicarbonate (NaHCO ₃ ) is neutralized, and then extracted three times with 100 ml of ether. Anhydrous sodium sulfate (Na ₂ SO ₄ ) was added thereto, followed by dehydration. The solvent was concentrated under reduced pressure to obtain 8.8 g (55 mmol, yield 69.1%).

Course 2.

2.65 g (1.2 eq) of sodium hydride (NaH) is dissolved in 40 ml of tetrahydrofuran (THF), and then 6.87 ml (1.2 eq) of benzene thiol is slowly added at 0 ° C. After mixing the reaction for 30 minutes, 8.8 g (55 mmol) of the product obtained in Step 1 are dissolved in 20 ml of tetrahydrofuran and added to the resulting sodium benzenethiol salt. The reaction mixture is reacted at room temperature for 12 hours. 10-15 ml of water is added, 30-40 ml of ammonium chloride (NH ₄ Cl) is neutralized, and extracted three times with 80 ml of ethyl acetate (EA). Anhydrous sodium sulfate (Na ₂ SO ₄₎ was added thereto, followed by dehydration. The solvent was concentrated under reduced pressure to obtain 14.23 g (53 mmol, 96% yield) of the product.

Course 3.

Dissolve 1.77 g (6.59 mmol) of the product of step 2 in 15 ml (0.44 M) of acetone, add 606 μl (1.2 eq) of dikytin and 107 μl (0.2 eq) of pyridine, and stir at reflux for 4 hours, followed by solvent. The reaction mixture was concentrated under reduced pressure, and purified through a column using a developing solvent in which the ratio of ethyl acetate and nucleic acid (EA: Hx) is 1: 5 to obtain 1.7 g (4.823 mmol, 73.1%) of product.

Course 4.

After dissolving 1.7 g (4.823 mmol) of the product in step 3 in 12 ml (0.4 M) of benzene, 1.02 g (1.2 eq) of 2,3-dichlorobenzenealdehyde, 96 μl of piperidine (0.3 eq) and 55 μl of acetic acid (0.3eq) is added. After refluxing for 2 hours, water was added, extraction was performed with ethyl acetate, and the product was purified through a column using a developing solvent having a ratio of ethyl acetate and nucleic acid (EA: Hx) of 1: 5. The product was 1.9 g (3.737 mmol, yield 77.4). %) Was obtained.

Course 5.

10 ml of pyridine was added to 1.9 g (3.737 mmol) of the product in step 4, 520 μl of ethyl-3-aminocrotonate (1.1 eq) was added thereto, and the mixture was stirred under reflux for 4 hours, and then cooled to room temperature. Concentrate and remove. Then, the product was purified through a column using a developing solvent having a ratio of ethyl acetate and nucleic acid 1: 3 to obtain 1.67 g (2.69 mmol, 72% yield) of the product.

Course 6.

After dissolving 644 mg (1.038 mmol) of the product in Step 5 in 4 ml (0.25 M) of ethanol, 394 mg (2 eq) of para-toluenesulfonic acid ( p -TsOH) was added thereto and reacted at room temperature for 4 hours. Add water and extract with ethyl acetate. Purification was carried out through a column using a solvent having a ratio of ethyl acetate and nucleic acid 1: 1 to obtain 412 mg (0.768 mmol, yield 74%) of the product.

Course 7.

= -7.13° C=1, 메탄올 (TL paper reference ;

= -7.3° C=1, 메탄올)과 같은 조건 하에 비선광도를 측정한 결과, 97.6 %의 (S)-형태 에난시오머 접근율(Enantiomeric excess)을 얻었다. 5 mg (1.1 eq) of sodium is dissolved in 0.5 ml (0.4 M) of methanol, and then slowly added to 107 mg (0.1995 mmol) of the product of Step 6, followed by stirring at reflux for 70 hours at 70 ° C. The solvents were concentrated under reduced pressure, added with water, treated with ammonium chloride (aq.), Extracted with ethyl acetate, and purified through a column using a developing solvent in which the ratio of ethyl acetate and nucleic acid was 1: 1 (S)-( 61.3 mg (0.1596 mmol, yield 80%) of-)-felodipine were obtained, and 19 mg (51% yield) of chiral adjuvants without protecting groups were obtained.

= -7.13 ° C = 1, methanol (TL paper reference;

= -7.3 ° C = 1, methanol) and the specific light was measured under conditions such as (S) -form enantiomeric excess (Enantiomeric excess) of 97.6%.

Example 2 (Nu = PhOH)

Course 1.

Dissolve 1 g (6.32 mmol) of product 1 and 320 mg (8.00 mmol) of sodium hydroxide in 6 ml (1 M) of distilled water in Example 1 of Example 1, react for 8 hours at 100 ° C, and neutralize with 8 ml of 1N hydrochloric acid. After extraction, the mixture was extracted three times with 10 ml of ethyl acetate. This was added to anhydrous sodium sulfate, dehydrated, and the solvent was concentrated under reduced pressure, and purified through a column using a developing solvent in which the ratio of ethyl acetate and nucleic acid was 1: 3 to obtain 1.35 g (5.35 mmol, yield 84.7%) of the product.

Course 2.

Dissolve 1.35 g (5.35 mmol) of the product in Process 1 in 10 ml (0.5 M) of acetone, add 0.5 ml (1.2 eq) of dichitin and 90 µl (0.2 eq) of pyridine, and stir at reflux for 4 hours. (10ml) was added and extracted three times with 20 ml of ethyl acetate. Anhydrous sodium sulfate was added thereto to dehydrate the solvent, and the solvent was concentrated under reduced pressure to obtain 1.71 g (5.08 mmol, yield 95.0%) of the product.

Course 3.

Dissolve 1.71 g (5.08 mmol) of the product from Process 2 in 10 ml (0.5 M) of benzene, then 1.07 g (1.2 eq) of 2,3-dichlorobenzaldehyde, 150 μl of piperidine (0.3 eq) and 87 μl of acetic acid ( 0.3 eq). After refluxing for 2 hours, water was added, extraction was performed with ethyl acetate, and the product was purified through a column using a developing solvent having a ratio of ethyl acetate and nucleic acid 1: 5 to obtain 1.88 g (3.81 mmol, yield 75.0%) of the product.

Course 4.

8 ml (0.5 M) of pyridine was added to 1.88 g (3.81 mmol) of the product obtained in Step 3, followed by 0.6 ml (1.2 eq) of ethyl-3-aminocrotonate, and the mixture was stirred under reflux for 4 hours. After lowering, the pyridine is concentrated to remove. Then, the resultant was purified through a column using a developing solvent having a ratio of ethyl acetate to nucleic acid of 1: 2 to obtain 1.73 g (2.86 mmol, yield 75.1%) of the product.

Course 5.

Dissolve 1.73 g (2.86 mmol) of the product in step 4 in 10 ml (0.29 M) of ethanol, add 1.1 g (2 eq) of paratoluenesulfonic acid and react for 4 hours at room temperature. Add water and extract with ethyl acetate. Purification was carried out through a column using a developing solvent in which the ratio of ethyl acetate and nucleic acid was 1: 2 to obtain 1.19 g (2.29 mmol, 80% yield) of the product.

Course 6.

5.3 mg (1.2 eq) of sodium are dissolved in 1 ml (0.19 M) of methanol, and then slowly added to 100 mg (0.191 mmol) of the product of Step 5, followed by stirring under reflux at 70 ° C. for 2 hours. The solvents were concentrated under reduced pressure, added with water, treated with ammonium chloride (aq.), Extracted with ethyl acetate, and purified through a column using a developing solvent in which the ratio of ethyl acetate and nucleic acid was 1: 1. 7) mg (0.153 mmol, yield 80%) were obtained.

Example 3 (Nu = MeSO ₂ Ph)

Course 1.

Dissolve 1.18 g (7.55 mmol) of methylphenylsulfone in 80 ml of anhydrous tetrahydrofuran and add 12.1 ml (1.6 M) of normal-butyllithium (n-BuLi) at -78 ° C. After stirring at this temperature for 30 minutes, 1 g (6.32 mmol) of the product in Example 1 was added 5 ml of tetrahydrofuran, and then slowly raised to room temperature and reacted at room temperature for 2 hours, followed by ammonium chloride. After neutralizing 100 ml of 100 ml of ethyl acetate extracted three times. This was added to anhydrous sodium sulfate and dehydrated. The solvent was concentrated under reduced pressure, and the product was obtained through a column using a developing solvent having a ratio of ethyl acetate and nucleic acid of 1: 3 to obtain 1.85 g (yield 93%) of the product.

Course 2.

Dissolve 1.85 g (5.88 mmol) of the product obtained in step 1 in 10 ml (0.6 M) of acetone, add 0.54 ml (1.2 eq) of dichitin and 97 μl (0.2 eq) of pyridine, and reflux and reflux for 4 hours, followed by water 10 Put ml and extract 3 times with 20 ml of ethyl acetate. Anhydrous sodium sulfate was added thereto, followed by dehydration. The solvent was concentrated under reduced pressure to obtain 2.11 g (5.29 mmol, yield 90.0%) of the product.

Course 3.

2.11 g (5.29 mmol) of the product from Process 2 was dissolved in 10 ml (0.5 M) of benzene, followed by 1.11 g (1.2 eq) of 2,3-dichlorobenzaldehyde, 160 μl of piperidine (0.3 eq) and 90 μl of acetic acid ( 0.3 eq). After refluxing for 2 hours, water was added, extraction was performed with ethyl acetate, and the product was purified through a column using a developing solvent in which the ratio of ethyl acetate and nucleic acid is 1: 5 to obtain 2.06 g (3.71 mmol, yield 70.1%) of the product.

Course 4.

8 ml (0.5 M) of pyridine was added to 2.06 g (3.71 mmol) of the product of step 3, followed by 0.6 ml (1.2 eq) of ethyl-3-aminocrotonate, and the mixture was stirred under reflux for 4 hours, and then the temperature was returned to room temperature. After lowering, the pyridine is concentrated to remove. Then, the product was purified through a column using a developing solvent having a ratio of ethyl acetate and nucleic acid 1: 2 to obtain 1.73 g (2.60 mmol, yield 70.1%) of the product.

Course 5.

Dissolve 1.73 g (2.60 mmol) of the product in step 4 in 10 ml (0.26 M) of ethanol, add 1.0 g (2 eq) of para-toluenesulfonic acid and react at room temperature for 4 hours. Add water and extract with ethyl acetate. Purification was carried out through a column using a developing solvent in which the ratio of ethyl acetate and nucleic acid was 1: 2 to obtain 1.29 g (yield 85%) of the product.

Course 6.

4.7 mg (1.2 eq) of sodium is dissolved in 1 ml (0.17 M) of methanol, and then slowly added to 100 mg (0.172 mmol) of the product of Step 5, followed by stirring under reflux at 70 ° C. for 2 hours. The solvents were concentrated under reduced pressure, added with water, treated with sodium chloride (aq.), Extracted with ethyl acetate, and purified through a column using a developing solvent in which the ratio of ethyl acetate and nucleic acid was 1: 1. 53 mg (0.137 mmol, yield 80%) were obtained.

Example 4 (Nu = PhNHTs)

Course 1.

1 g (6.32 mmol) of the product of Example 1 of Example 1 was dissolved in 6 ml (1 M) of 1,4-dioxane, followed by 88 mg (0.1 eq) of potassium carbonate (K ₂ CO ₃ ). Add 144 mg (0.1 eq) of triethylbenzylammonium chloride (TEBA) and 1.72 g (1.1 eq) of p- toluenesulfonanilide. After reacting at 120 ° C. for 8 hours, 3-4 ml of water is added thereto. 4 to 5 ml of ammonium chloride was added to neutralize and extracted three times with 10 ml of ethyl acetate. Anhydrous sodium sulfate was added thereto to dehydrate the solvent, and the solvent was concentrated under reduced pressure. The product was purified through a column using a developing solvent in which the ratio of ethyl acetate and nucleic acid was 1: 3 to obtain 2 g of a product (4.93 mmol, yield 78%).

Course 2.

Dissolve 1.23 g (3.03 mmol) of the product in step 1 in 6 ml (0.5 M) of acetone, add 280 μl (1.2 eq) of dichitin and 50 μl (0.2 eq) of pyridine, and reflux and stir for 4 hours. Put 3 to 4 ml and extract three times with 10 ml of ethyl acetate. Anhydrous sodium sulfate was added thereto to dehydrate the solvent, and the solvent was concentrated under reduced pressure to obtain 1.46 g (2.982 mmol, yield 98.4%) of the product.

Course 3.

1.46 g (2.982 mmol) of the product in reaction 2 was dissolved in 7.5 ml (0.4 M) of benzene, followed by 626 mg (1.2 eq) of 2,3-dichlorobenzaldehyde, 88 μl of piperidine (0.3 eq) and 51 μl of acetic acid ( 0.3 eq). After stirring under reflux for 2 hours, water was added, extraction was performed with ethyl acetate, and the product was obtained by 1.43 g (2.212 mmol, 74.2%) of the product through a column using a developing solvent having a ratio of ethyl acetate and nucleic acid 1: 5.

Course 4.

5 ml (0.44 M) of pyridine was added to 1.43 g (2.212 mmol) of the product obtained in Step 3, 308 μl of ethyl-3-aminocrotonate (1.1 eq) was added thereto, and the mixture was stirred under reflux for 4 hours. After lowering, the pyridine is concentrated to remove. Then, the product was purified through a column using a developing solvent having a ratio of ethyl acetate and nucleic acid 1: 2 to obtain 1.34 g (1.769 mmol, 80% yield) of the product.

Course 5.

After dissolving 520 mg (0.686 mmol) of the product in step 4 in 2.5 ml (0.27 M) of ethanol, 262 mg (2 eq) of paratoluenesulfonic acid was added thereto and reacted at room temperature for 4 hours. Add water and extract with ethyl acetate. Purification was carried out through a column using a developing solvent having a ratio of ethyl acetate and nucleic acid 1: 2 to obtain 300 mg (yield 65%) of the product.

Course 6.

3.8 mg (1.2 eq) of sodium is dissolved in 1 ml (0.13 M) of methanol, and then slowly added to 93 mg (0.138 mmol) of the product in Reaction 5, followed by stirring under reflux at 70 ° C. for 2 hours. The solvents were concentrated under reduced pressure, added with water, treated with ammonium chloride (aq.), Extracted with ethyl acetate, and purified through a column using a developing solvent in which the ratio of ethyl acetate and nucleic acid was 1: 1. 44.5 mg (0.116 mmol, yield 84%) of (-)-felodipine were obtained.

Example 5 Synthesis of Pelodipine Using (S) -Glycidol as Starting Material

Course 1.

(R, S) -3-ethyl 5-((S) -1-hydroxy-3- (phenylthio) via the same reactions as in Example 1 using 60 g (0.8 mol) of (S) -glycidol ) Propan-2-yl) 4- (2,3-dichlorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 5 g (9.3 mmol) was obtained. The diastereomer mixture was poured into a solvent of 8 ml of benzene and ethyl acetate in a ratio of 2: 1, heated to form a solution, and crystallized at room temperature to be filtered to obtain pure (R) -3-ethyl 5-((S) -1-hydroxy-3- (phenylthio) propan-2-yl) 4- (2,3-dichlorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxyl Yield 1.75 g (3.3 mmol).

Course 2.

= -7.25° C=1,메탄올 (TL paper reference;

= -7.3° C=1, 메탄올)과 같은 조건 하에 비선광도를 측정한 결과, 99.3 %의 (S)-형태 에난시오머 접근율을 얻었다. The product in Procedure 1 was reacted with sodium methoxy as in Example 1 to afford (S)-(-)-felodipine.

= -7.25 ° C = 1, methanol (TL paper reference;

= -7.3 ° C = 1, methanol), the specific light was measured under the conditions (9)% of (S) -form enantiomer access.

In order to overcome the limitation of the selective hydrolysis reaction conventionally used in the preparation of (S)-(-)-felodipine, the present invention utilizes a selective transesterification reaction using various chiral auxiliaries (S)-( -)-The method of synthesizing felodipine, which is economical and secures various intermediates using (R)-or (S) -glycidol, which is a simpler process and cheaper starting material than conventional synthesis. It can also be applied to asymmetric synthesis of dihydropyridine compounds other than felodipine.

Claims (6)

(a) reacting (R) -glycidol or (S) -glycidol of formula (2) with dihydropyran (DHP) and then adding a nucleophile (Nu) to obtain a compound of formula (3);

(b) reacting the compound of Formula 3 with dichitin of Formula 4 to obtain a compound of Formula 5;

(c) reacting the compound of Formula 5 with 2,3-dichlorobenzaldehyde of Formula 6 to obtain a compound of Formula 7;

(d) reacting the compound of Formula 7 with 3-amino-2-butenoate of Formula 8 to obtain a felodipine intermediate of Formula 9;

(e) treating the felodipine intermediate of Formula 9 with an acid and then separating the (S) -isomer; And (f) selective transesterification of the (S) -isomer with a methoxy salt to obtain (S)-(-)-felodipine of formula (1): Manufacturing method. Formula 1

The method of claim 1, The method further comprises the step of converting the chiral auxiliary group of Formula 10 recovered after the preparation of (S)-(-)-felodipine with dihydropyran (DHP) to the compound of Formula 3 again. , (S)-(-)-felodipine production method.

The method according to claim 1 or 2, The nucleophile (Nu) is R ₁ SH, R ₁ R ₂ NH, R ₁ OH, RR ₂ R ₃ CH (wherein R and R ₃ is H, R ₁ is phenyl, R ₂ is tosylate) and A method for producing (S)-(-)-felodipine, which is selected from the group consisting of nucleophiles capable of reacting with epoxides containing these bases. The method according to claim 1 or 2, The acid is any one selected from the group consisting of p -toluenesulfonic acid, camphoresulfonic acid, pyridinium tosylate and acetic acid, (S)-(-)-felodipine. The method according to claim 1 or 2, The methoxy salt is sodium methoxy sodium, characterized in that, (S)-(-)-felodipine production method. The method according to claim 1 or 2, The step (e) is characterized in that the isomers are separated by chromatography using recrystallization or silica gel, (S)-(-)-felodipine production method.