KR101088488B1 - Method for preparing an optically active amlodipine - Google Patents

Abstract

The present invention relates to a method for preparing S-amlodipine or R-amlodipine from racemic amlodipine using chiral camphoric acid as a light splitting agent.

Description

Method for producing amlodipine having optical activity {METHOD FOR PREPARING AN OPTICALLY ACTIVE AMLODIPINE}

The present invention relates to a method for preparing amlodipine having optical activity, ie S-amlodipine or R-amlodipine. More specifically, the present invention relates to a method for preparing S-amlodipine or R-amlodipine from racemic amlodipine using chiral camphoric acid as a light splitting agent.

Amlodipine is widely used as a calcium channel blocker to treat cardiovascular diseases such as hypertension and angina (US Pat. No. 4,572,909). There are two stereoisomers of amlodipine. The pharmacological activity of blocking calcium channels is mainly due to S-amlodipine [ J. Med . Chem ., 29 , 1696 (1986); J. Med . Chem ., 35 , 3341 (1992)], R-amlodipine shows little activity as a calcium channel blocker but is known as a potent inhibitor of smooth muscle migration as another pharmacological agent (US Pat. No. 6,080,761).

As a method for preparing S-amlodipine or R-amlodipine having optical activity, J. Med . Chem., 29, 1696 (1986 ) is a diastereomer of ah map ester compound has been prepared by the techniques how to remove the chromatography method to (a compound (b) of formula 1), J. Med . Chem ., 35 , 3341 (1992) describe a method for preparing an amide compound (compound (d) of Formula 1) which is a diastereomer and separating it by chromatography. However, the method of separating the diastereomer compound by chromatography has a disadvantage in that it is not suitable for mass production. In addition, European Patent No. 331,315 uses a synonydine to racemic azido acid compound (Compound (c) of Formula 1) to prepare a diastereomeric synconidine salt, and then crystallizes and multistage chemical reactions. It describes a method for producing S- amlodipine via, but the reaction step is multi-stage and complex, which is not suitable for mass production.

Formula 1

(a) R = CH ₂ CH ₃ , X = NH ₂ (b) R = CH ₂ CH (OCH ₃ ) Ph- (S), X = N ₃

(c) R = H, X = N ₃ (d) R = CH ₂ CH ₃ , X = (1S) -campanoylamino

On the other hand, as a manufacturing method suitable for mass production, the salt of diastereomer-type S-amlodipine and tartaric acid is crystallized by crystallization using D-tartaric acid or L-tartaric acid as a light splitting agent to racemic amlodipine which can be easily manufactured or purchased. In addition, a method for preparing S-amlodipine has been reported (International Patent WO 95/25722; International Patent WO 2003/035623; International Patent WO 2006/043148; United States Patent Publication 2003 / 0176706A; International Patent WO 2004/024689) .

Although the above-mentioned manufacturing method is a method suitable for mass production compared to the existing technology, it has a disadvantage in that it is difficult to recover due to the high water solubility of D-tartaric acid or L-tartaric acid as a light splitting agent.

Accordingly, the present inventors have searched for the light splitting effect of racemic amlodipine using several kinds of chiral organic acids as a light splitting agent, and in particular, the chiral camphoric acid has a very excellent light splitting effect after light splitting. It was found that the recovery of the Jane chiral camphor acid is also very easy. The present invention is based on these unique experimental results and provides a method for producing amlodipine having optical activity that is economical and suitable for mass production. That is, in the present invention, it is an economical manufacturing method capable of producing a large amount of S-Amlodipine or R-Amlodipine through the process of light splitting using chiral camphor acid as a light splitting agent to racemic amlodipine which is easy to manufacture and purchase. .

Technical Challenge

An object of the present invention is to use S- amlodipine or R- amlodipine by light-dividing racemic amlodipine by using chiral camphor acid, which is easy to recover, and easy to recover, in order to solve the problems of known manufacturing methods. It is to provide a method of manufacturing.

Technical solution

In order to achieve the object of the invention as described above, the present invention is a racemic amlodipine represented by the following formula (2) and (1R, 3S) -camphor acid or (1S, 3R)-camphoric acid represented by the formula (3) By reacting to prepare a salt of the diastereomer type and then hydrolyzed it to provide a method for producing S- amlodipine or R- amlodipine having optical activity.

Formula 2

Formula 3

Favorable effect

The present invention provides an economical manufacturing method capable of producing a large amount of S- amlodipine or R- amlodipine through the process of light-dividing the racemic amlodipine which is easy to manufacture and purchase with chiral camphor acid as a light splitting agent.

Best Mode for Carrying Out the Invention

In the present invention, racemic amlodipine is reacted with chiral camphor acid (1R, 3S) -camphor acid or (1S, 3R) -camphor acid to prepare amlodipine with optical activity. A schematic representation of the process for preparing S-amlodipine is as follows:

Scheme 1

Meanwhile, R-amlodipine can be easily prepared by using (1S, 3R) -camphor acid instead of (1R, 3S) -camphor acid in Scheme 1.

In the present invention, chiral camphor acid is preferably used in an amount of 2 equivalents or less based on racemic amlodipine, more preferably 0.2 equivalent to 1.0 equivalent. The resulting diastereomeric salt is the (1R, 3S) -camphor salt of S-Amlodipine or the (1S, 3R) -camphor salt of R-Amlodipine, wherein the salt has a molar ratio of amlodipine and camphoric acid 2: 1. Obtained with phosphorus salts. This is because camphoric acid has two acidic groups, forming two salts with amlodipine.

Hydrolysis of the salts of amlodipine and camphor acid can employ a variety of methods known to obtain S-amlodipine in the salt of the diastereomeric form. As a specific example, a general extraction process can be used. The obtained diastereomer-type salt is extracted in a two-phase solvent in which dichloromethane and sodium hydroxide are mixed, so that the dichloromethane layer and the sodium hydroxide solution layer are respectively applied. Dissolved S-amlodipine and camphor acid can be obtained. These layers are acidified with hydrochloric acid and then extracted with ethyl acetate to easily recover and reuse camphoric acid. The optical purity of the obtained amlodipine is J. Med . According to the method reported in Chem ., 35 , 3341 (1992), N-Boc-amlodipine obtained by reaction with di-t-butyl pyrocarbonate can be easily analyzed using a Chiralcel OD column.

DETAILED DESCRIPTION OF THE INVENTION

The invention is further elaborated by the following examples, which do not limit the scope of the invention.

Example 1 Preparation of S-Amlodipine from Racemic Amlodipine

Racemic amlodipine (10 g) and (1R, 3S) -camphor acid (3.7 g) are added to isopropanol (100 mL), dissolved by heating, and slowly cooled to room temperature. The solution was allowed to stand at room temperature for 20 hours, and the precipitated crystals were filtered out and dried under reduced pressure to obtain (1R, 3S) -camphor acid salt (2.8 g) of S-amlodipine.

The obtained (1R, 3S) -camphor acid salt of S-amlodipine was confirmed to have a molar ratio of S-amlodipine and (1R, 3S) -camphor acid by 2: 1 through the following NMR analysis data.

¹ H NMR (CD ₃ OD, 300 MHz) 0.90 (s, 3H), 1.15 (m, 9H), 1.27 (s, 3H), 1.40 (m, 1H), 1.71 (m, 1H), 2.10 (m, 1H), 2.32 (s, 6H), 2.50 (m, 1H), 2.71 (m, 1H), 3.09 (m, 4H), 3.57 (s, 6H), 3.70 (m, 4H), 4.03 (m, 4H ), 4.69 (q, 4H), 5.40 (s, 2H), 7.14 (m, 6H), 7.38 (m, 2H)

The (1R, 3S) -camphor salt (2.8 g) of S-amlodipine obtained in the above experiment was added to dichloromethane (30 mL) and 2N aqueous sodium hydroxide solution (30 mL), stirred and left to stand, and a dichloromethane layer was obtained. Dichloromethane (30 mL) was further added to the aqueous solution, stirred and left to stand, and then the dichloromethane layer was separated. The resulting dichloromethane solution was dried over magnesium sulfate and concentrated under reduced pressure to obtain S-amlodipine (2.1 g).

¹ H NMR (CD ₃ OD, 300 MHz) 1.15 (t, 3H), 2.32 (s, 3H), 2.86 (t, 2H), 3.57 (m, 5H), 4.05 (m, 2H), 4.67 (q, 2H), 5.39 (s, 2H), 7.14 (m, 3H), 7.38 (m, 1H)

Optical Purity: S-Amlodipine / R-Amlodipine = 98.6 / 1.4

The aqueous solution was acidified with 2N aqueous hydrochloric acid solution and extracted twice with ethyl acetate (100 mL). The extracted organic layer was dried over magnesium sulfate and concentrated under reduced pressure to recover (1R, 3S) -camphor acid (0.49 g).

¹ H NMR (DMSO-d6, 300 MHz) 0.75 (s, 3H), 1.12 (s, 3H), 1.18 (s, 3H), 1.36 (m, 1H), 1.72 (m, 1H), 1.96 (m, 1H), 2.36 (m, 1H), 2.72 (m, 1H), 12.1 (s, 2H)

Example 2 Preparation of Salts in Diastereomeric Form from Racemic Amlodipine 1

Racemic amlodipine (6.0 g) and (1R, 3S) -camphor acid (2.94 g) were added to isopropanol (65 mL), dissolved in heating, and slowly cooled to room temperature. The solution was allowed to stand at room temperature for 22 hours, and the precipitated crystals were filtered out and dried under reduced pressure to obtain (1R, 3S) -camphor acid salt of S-amlodipine (1.51 g).

Optical Purity: S-Amlodipine / R-Amlodipine = 99.0 / 1.0

Example 3 Preparation of Diastereomeric Salts from Racemic Amlodipine 2

Racemic amlodipine (8.0 g) and (1R, 3S) -camphor acid (1.9 g) were added to isopropanol (80 mL), dissolved by heating, and slowly cooled to room temperature. The solution was allowed to stand at room temperature for 17 hours, and the precipitated crystals were filtered out and dried under reduced pressure to obtain (1R, 3S) -camphor acid salt (2.36 g) of S-amlodipine.

Optical Purity: S-Amlodipine / R-Amlodipine = 97.9 / 2.1

Example 4 Preparation of Diastereomeric Salts from Racemic Amlodipine 3

Racemic amlodipine (3.0 g) and (1S, 3R) -camphor acid (1.11 g) were added to isopropanol (30 mL), dissolved by heating, and slowly cooled to room temperature. The solution was allowed to stand at room temperature for 21 hours, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain (1S, 3R) -camphor acid salt (0.81 g) of R-amlodipine.

Optical Purity: S-Amlodipine / R-Amlodipine = 1.5 / 98.5

Example 5 Preparation of S-Amlodipine from Racemic Amlodipine

Racemic amlodipine (10 g) and (1R, 3S) -camphor acid (1.23 g) were added to ethyl acetate (70 mL), dissolved by heating, and slowly cooled to room temperature. The solution was allowed to stand at room temperature for 21 hours, and the precipitated crystals were filtered out and dried under reduced pressure to obtain (1R, 3S) -camphor salt of S-amlodipine (4.7 g).

Optical Purity: S-Amlodipine / R-Amlodipine = 98.9 / 1.1

Example 6: Preparation of S-Amlodipine from Racemic Amlodipine

Racemic amlodipine (10 g) and (1R, 3S) -camphor acid (1.23 g) were added to acetonitrile (75 mL), dissolved by heating, and slowly cooled to room temperature. The solution was allowed to stand at room temperature for 23 hours, and the precipitated crystals were filtered out and dried under reduced pressure to obtain (1R, 3S) -camphor acid salt (5.5 g) of S-amlodipine.

Optical Purity: S-Amlodipine / R-Amlodipine = 97.8 / 2.2

Example 7 Preparation of S-Amlodipine from Racemic Amlodipine

Racemic amlodipine (20 g) and (1R, 3S) -camphor acid (2.47 g) are added to acetonitrile (160 mL), dissolved by heating, and slowly cooled to room temperature. The solution was allowed to stand at room temperature for 19 hours, and the precipitated crystals were obtained by filtration. The obtained crystals were heated and dissolved in acetonitrile (120 mL), and then slowly cooled to room temperature. The solution was allowed to stand at room temperature for 20 hours, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain (1R, 3S) -camphor acid salt (9.7 g) of S-amlodipine.

Optical Purity: S-Amlodipine / R-Amlodipine = 99.98 / 0.02

The method for producing amlodipine according to the present invention provides an economical and suitable method for mass production by using chiral camphor acid, which has an excellent light splitting effect and is easily recoverable, as a light splitting agent.

Claims (7)

A method for producing amlodipine having optical activity by reacting racemic amlodipine with chiral camphor acid. The method of claim 1, wherein the chiral camphor acid is (1R, 3S) -camphor acid or (1S, 3R) -camphor acid. The method according to claim 1, wherein the chiral camphor acid is used in the amount of 0.2 to 2.0 equivalents based on racemic amlodipine. The method according to claim 3, wherein the chiral camphor acid is used in an amount of 0.2 to 1.0 equivalents based on racemic amlodipine. The (1R, 3S) -camphor acid salt of S-Amlodipine or (1S, 3R) -camphor acid salt of R-Amlodipine, according to claim 1 or 2, wherein the racemic amlodipine is reacted with chiral camphoric acid. A method for producing S-Amlodipine or R-Amlodipine having optical activity by hydrolysis through an extraction process. (1R, 3S) -camphor salt of S-amlodipine with a molar ratio of S-amlodipine and (1R, 3S) -camphor acid 2: 1. (1S, 3R) -camphor salt of R-amlodipine with a molar ratio of R-amlodipine and (1S, 3R) -camphor acid 2: 1.