WO2008026838A1

WO2008026838A1 - Method for preparing an optically active amlodipine

Info

Publication number: WO2008026838A1
Application number: PCT/KR2007/003894
Authority: WO
Inventors: Il Suk Byun; Young Youn Kim; Wan Joo Kim
Original assignee: Chemtech Research Inc
Current assignee: Chemtech Research Inc
Priority date: 2006-08-30
Filing date: 2007-08-14
Publication date: 2008-03-06
Anticipated expiration: 2009-02-28
Also published as: KR101088488B1; KR20090026794A

Abstract

The present invention provides a method for preparing S-amlodipine or R-amlodipine from racemic amlodipine using camphoric acid as an optical resolving agent.

Description

METHOD FOR PREPARING AN OPTICALLY ACTIVE

AMLODIPINE

Technical Field

[1] The present invention relates to a method for preparing an optically active amlodipine, i.e. S-amlodipine or R-amlodipine. More particularly, the present invention relates to a method for preparing S-amlodipine or R-amlodipine from racemic amlodipine using a chiral camphoric acid as an optical resolving agent. Background Art

[2] Amlodipine is a calcium channel blocker, and is widely used for the treatment of cardiovascular disorders, such as hypertension and angina, as disclosed in U. S. Patent No. 4,572,909. Amlodipine has two enantiomers, i.e. S-amlodipine and R-amlodipine, and the S-amlodipine has more potent pharmacological activity as a calcium channel blocker, as described in J. Med. Chem., 29, 1696 (1986) and J. Med. Chem., 35, 3341 (1992). The R-amlodipine is known as a potent inhibitor of smooth muscle cell migration despite its lack of calcium channel-blocking activity, as disclosed in U. S. Patent No. 6,080,761.

[3] J. Med. Chem., 29, 1696 (1986) describes a preparation of an optically active S- amlodipine or R-amlodipine by preparing diastereotopic azido esters having the following formula l(b) and separating the same by chromatography. Furthermore, J. Med. Chem., 35, 3341 (1992) describes a chromatographic separation of di- astereomeric amide isomers having the following formula l(d). However, none of the methods for separating diastereomers through a chromatographic process are suitable for a preparation process to obtain the product in a high yield. In addition, EP 0 331 315 B discloses a method of preparing S-amlodipine via the preparation of cin- chonidine salts as diastereomers using cinchonidine with a racemic azido acid compound having the following formula l(c), followed by a resolution of the intermediate diastereomers through crystallization and multi-step chemical reactions. However, the preparation method disclosed in EP 0 331 315 B is also unsuitable to obtain the product in a high yield due to its multi-step reaction mechanism and the complexity of the reaction process.

[4] Formula 1

[5]

[6] (a) R = CH CH , X = NH ;

[7] (b) R = CH₂CH(OCH₃)Ph-(S), X = N₃;

[8] (c) R = H, X = N₃;

[9] (d) R = CH₂CH₃, X = (lS)-camphanoylamino

[10] Meanwhile, as preparation processes suitable for a high yield preparation process, there have been reported methods of preparing S-amlodipine via the resolution of di- astereomers of S-amlodipine and their salts of tartaric acid using crystallization by applying D-tartaric acid or L-tartaric acid as an optical resolving agent to easily prepared or commercially available racemic amlodipine, as disclosed in WO 95/25722, WO 2003/035623, WO 2006/043148, U.S. Patent Published Application 2 003/0176706A, and WO 2004/024689.

[11] While said preparation methods are relatively suitable for a high yield preparation process compared to existing methods, they still have disadvantages from the standpoint of collection efficiency, which is presumably because D-tartaric acid or L- tartaric acid used as an optical resolving agent is highly water-soluble.

[12] To address these disadvantages the present inventors have explored the optically resolving effect of racemic amlodipine using a variety of different chiral organic acids as optical resolving agents. Unexpectedly, the present inventors discovered that chiral camphoric acid had an exceptionally high resolving effect and that the chiral camphoric acid used as an optical resolving agent was easily collected. Based on these unique findings, the present invention provides a method of preparing optically active amlodipine which is cost-effective and suitable for a high yield preparation process. In other words, the present invention provides an efficient and economic method of preparing S-amlodipine or R-amlodipine via the resolution of racemic amlodipine, which is easily prepared and commercially available, using chiral camphoric acid as an optical resolving agent. Disclosure of Invention

Technical Problem

[13] To solve the problems with the conventional preparation methods, the present invention provides a method of preparing S (-) amlodipine or R-amlodipine by optically resolving racemic amlodipine using as an optical resolving agent chiral camphoric acid that is easily collected while having excellent resolving efficacy. Technical Solution

[14] To accomplish the above objective of the present invention, there is provided a method of preparing optically active S(-)amlodipine or R-amlodipine including preparing a diastereomeric salt by reacting racemic amlodipine represented by the formula 2 with (IR, 3S)-camphoric acid or (IS, 3R)-camphoric acid represented by the formula 3, and hydrolyzing the diastereomeric salt:

[15] Formula 2

[16]

[17] Formula 3

[18]

(1 R₁ 3S)-camphoric acid (1 S, 3R)-caιmphoric acid Advantageous Effects

[19] The present invention provides a cost-effective method of preparing S-amlodipine or R-amlodipine in a high yield by optically resolving racemic amlodipine, which is easily prepared and commercially available, using chiral camphoric acid as an optical resolving agent. Best Mode for Carrying Out the Invention

[20] The present invention provides a method of preparing optically active amlodipine by reacting racemic amlodipine with a chiral camphoric acid, (IR, 3S)-camphoric acid or (IS, 3R)-camphoric acid. The process of preparing S-amlodipine is shown in the reaction scheme below:

[21] Reaction Scheme 1

[22] S-amlodipine-

(1 R.3S Vcamphoric acid salt

in a molar ration of 2:1

Racernϊc arn!odipine(2) (1 R, 3$)-caiϊipfioric 3cid(3)

(hydrolysis)

S-amlodipine

[23] Meanwhile, R-amlodipine can be easily prepared using (IS, 3R)-camphoric acid instead of (IR, 3S)-camphoric acid in Reaction Scheme 1.

[24] In the present invention, the chiral camphoric acid is preferably used in an amount of not more than 2 equivalents, more preferably 0.2 to 1.0 equivalent, per mole of racemic amlodipine.

[25] The obtained diastereomeric salt is (IR, 3S)-camphoric acid salt of S-amlodipine or

(IS, 3R)-camphoric acid salt of R-amlodipine. In the obtained salt, the molar ratio of amlodipine to camphoric acid is 2:1. This is presumably because camphoric acid having two acidic groups reacts with two enantiomers of amlodipine to form salts.

[26] The process of hydrolyzing the salt of amlodipine and camphoric acid may be carried out using various well-known methods for preparing S-amlodipine from diastereomeric salts, for example, a conventional extraction process. The obtained diastereomeric salts are extracted in an immiscible two-phase solvent of dichloromethane and a sodium hydroxide solution to obtain S-amlodipine and camphoric acid, which are dissolved in a dichloromethane layer and a sodium hydroxide solution layer, respectively. These layers are acidified using hydrochloric acid and extracted using ethyl acetate, thereby easily collecting camphoric acid for recycling. The optical purity of the resulting amlodipine can be easily determined by analysing N-Boc-amlodipine obtained by reacting the amlodipine with di-t-butyl pyrocarbonate using a Chiralcel OD column, as reported in J. Med. Chem., 35, 3341 (1992). Mode for the Invention

[27] The present invention is not restricted to the following embodiments, and many variations are possible within the spirit and scope of the present invention.

[28] EXAMPLES

[29] Example 1: Preparation of S-amlodipine from racemic amlodipine

[30] 10 g of racemic amlodipine and 3.7 g of (lR,3S)-camphoric acid were added to 100 mL of isopropanol and heated to be dissolved, followed by slowly cooling down the resultant solution to room temperature. The solution was allowed to stand undisturbed at room temperature for 20 hours to precipitate crystals. The precipitated crystals were extracted, collected, and dried under reduced pressure, to yield 2.8 g of (lR,3S)-camphoric acid salt of S-amlodipine. The obtained (lR,3S)-camphoric acid salt of S-amlodipine had a 2 : 1 molar ratio of S-amlodipine to (lR,3S)-camphoric acid, as confirmed by H NMR spectral analysis:

[31] ¹U NMR (CD OD, 300 MHz) 0.90 (s, 3H), 1.15 (m, 9H), 1.27 (s, 3H), 1.40(m,

IH), 1.71 (m, IH), 2.10 (m, IH), 2.32 (s, 6H), 2.50(m, IH), 2.71 (m, IH), 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)

[32] 2.8 g of the obtained (lR,3S)-camphoric acid salt of S-amlodipine was added to 30 mL of dichloromethane and 30 mL of a 2N sodium hydroxide solution, stirred and allowed to stand to isolate a dichloromethane layer. 30 mL of dichloromethane was further added to the aqueous solution, stirred and allowed to stand to further isolate a dichloromethane layer. The obtained dichloromethane solution was dried using magnesium sulfate and concentrated under reduced pressure to yield 2.1 g of S- amlodipine.

[33] ¹H NMR (CD₃OD, 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, IH)

[34] Optical purity: S-amlodipine/R-amlodipine = 98.6/1.4

[35] The solution was acidified using a 2N hydrochloric solution, and an organic layer was extracted twice from the solution using 100 mL of ethylacetate. The extracted organic layer was dried using magnesium sulfate and concentrated under reduced pressure to collect 0.49 g of (lR,3S)-camphoric acid. [36] ¹U NMR (DMSO-d6, 300 MHz) 0.75 (s, 3H), 1.12 (s, 3H), 1.18 (s, 3H), 1.36 (m,

IH), 1.72 (m, IH), 1.96 (m, IH), 2.36 (m, IH), 2.72 (m, IH), 12.1 (s, 2H) [37] Example 2: Preparation (1) of diastereomeric salt from racemic amlodipine

[38] 6.0 g of racemic amlodipine and 2.94 g of (lR,3S)-camphoric acid were added to 65 mL of isopropanol and heated to be dissolved, followed by slowly cooling down the resultant solution to room temperature. The solution was allowed to stand undisturbed at room temperature for 22 hours to precipitate crystals. The precipitated crystals were extracted, collected, and dried under reduced pressure, to yield 1.51 g of (lR,3S)-camphoric acid salt of S-amlodipine. [39] Optical purity: S-amlodipine/R-amlodipine = 99.0/1.0

[40] Example 3: Preparation (2) of diastereomeric salt from racemic amlodipine

[41] 8.0 g of racemic amlodipine and 1.9 g of (lR,3S)-camphoric acid were added to 80 mL of isopropanol and heated to be dissolved, followed by slowly cooling down the resultant solution to room temperature. The solution was allowed to stand undisturbed at room temperature for 17 hours to precipitate crystals. The precipitated crystals were extracted, collected, and dried under reduced pressure, to yield 2.36 g of (lR,3S)-camphoric acid salt of S-amlodipine. [42] Optical purity: S-amlodipine/R-amlodipine = 97.9/2.1

[43] Example 4: Preparation (3) of diastereomeric salt from racemic amlodipine

[44] 3.0 g of racemic amlodipine and 1.11 g of (lS,3R)-camphoric acid were added to 30 mL of isopropanol and heated to be dissolved, followed by slowly cooling down the resultant solution to room temperature. The solution was allowed to stand undisturbed at room temperature for 21 hours to precipitate crystals. The precipitated crystals were extracted, collected, and dried under reduced pressure, to yield 0.81 g of (lS,3R)-camphoric acid salt of S-amlodipine. [45] Optical purity: S-amlodipine/R-amlodipine = 1.5/98.5

[46] Example 5: Preparation of S-amlodipine from racemic amlodipine

[47] 10 g of racemic amlodipine and 1.23 g of (lR,3S)-camphoric acid were added to 70 mL of ethyl acetate and heated to be dissolved, followed by slowly cooling down the resultant solution to room temperature. The solution was allowed to stand undisturbed at room temperature for 21 hours to precipitate crystals. The precipitated crystals were extracted, collected, and dried under reduced pressure, to yield 4.7 g of (lR,3S)-camphoric acid salt of S-amlodipine. [48] Optical purity: S-amlodipine/R-amlodipine = 98.9/1.1

[49] Example 6: Preparation of S-amlodipine from racemic amlodipine

[50] 10 g of racemic amlodipine and 1.23 g of (lR,3S)-camphoric acid were added to 75 mL of acetonitrile and heated to be dissolved, followed by slowly cooling down the resultant solution to room temperature. The solution was allowed to stand undisturbed at room temperature for 23 hours to precipitate crystals. The precipitated crystals were extracted, collected, and dried under reduced pressure, to yield 5.5 g of (lR,3S)-camphoric acid salt of S-amlodipine. [51] Optical purity: S-amlodipine/R-amlodipine = 97.8/2.2

[52] Example 7: Preparation of S-amlodipine from racemic amlodipine

[53] 20 g of racemic amlodipine and 2.47 g of (lR,3S)-camphoric acid were added to

160 mL of acetonitrile and heated to be dissolved, followed by slowly cooling down the resultant solution to room temperature. The solution was allowed to stand undisturbed at room temperature for 19 hours to precipitate crystals. The precipitated crystals were extracted to collect crystals. The collected crystals were added to 120 mL of acetonitrile to be dissolved, followed by slowly cooling down the resultant solution to room temperature. The solution was allowed to stand undisturbed at room temperature for 20 hours to precipitate crystals. The precipitated crystals were extracted, collected, and dried under reduced pressure, to yield 9.7 g of (lR,3S)-camphoric acid salt of S-amlodipine. [54] Optical purity: S-amlodipine/R-amlodipine = 99.98/0.02

Industrial Applicability [55] As described above, the present invention provides a method for preparing an optically active amlodipine using a chiral camphoric acid as an optical resolving agent that can be easily collected and has an excellent resolving efficacy. The method according to the present invention is cost-effective and suitable to obtain the product in a high yield,

Claims

[1] A method for preparing an optically active amlodipine by reacting racemic amlodipine with a chiral camphoric acid. [2] The method of claim 1, wherein said chiral camphoric acid is (IR,

3S)-camphoric acid or (IS, 3R)-camphoric acid. [3] The method of claim 1, wherein said chiral camphoric acid is used in an amount of not more than 2 equivalents per mole of racemic amlodipine. [4] The method of claim 3, wherein said chiral camphoric acid is used in an amount ranging from 0.2 to 1.0 equivalent per mole of racemic amlodipine. [5] The method of claim 1 or 2, wherein said optically active amlodipine, S- amlodipine or R-amlodipine, is prepared by reacting racemic amlodipine with the chiral camphoric acid to obtain a diastereomeric salt of (lR,3S)-camphoric acid and S-amlodipine or a diastereomeric salt of (lS,3R)-camphoric acid and R- amlodipine, and then hydrolyzing the diastereomeric salt through a conventional extraction process. [6] (lR,3S)-camphoric acid salt of S-amlodipine, wherein the molar ratio of S- amlodipine to (IR, 3S)-camphoric acid is 2:1. [7] (lS,3R)-camphoric acid salt of R-amlodipine, wherein the molar ratio of R- amlodipine to (IS, 3R)-camphoric acid is 2:1.