CN1882543A - Process for preparation of chiral amlodipine salts - Google Patents

Abstract

The invention discloses a method for preparing chiral amlodipine, that is, pharmaceutically acceptable salts of S(-) amlodipine and R(+) amlodipine without separation of chiral free bases, wherein the obtained product has 96-99 % optical purity. The method involves resolution of RS amlodipine base with L(+) or D(-) tartaric acid, followed by reaction of the isolated tartrate salt with an organic acid to obtain all compounds of 96-99% ee corresponding to the acid used. Said salt.

Description

The method for preparing chiral amlodipine salt

field of invention

The present invention relates to an improved process for the preparation of chiral amlodipine salts. More particularly, the present invention relates to the preparation of S(-) amlodipine having the structure of formula (1) and R(+) ammonia having the structure of formula (2) as shown below in the presence of dimethylsulfoxide Pharmaceutically acceptable salts of lodipine, and methods for their direct conversion into besylate salts without isolation of the free base, wherein R=benzenesulfonic acid, succinic acid, maleic acid, oxalic acid, p-toluenesulfonic acid acid.

Formula-1 Formula-2

Background of the invention

Among all the above-mentioned S(-) amlodipine salts, S(-) amlodipine besylate (4-S)-2-{[(2-aminoethyl)oxy]methyl}-4-(2 -Chlorophenyl)6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulfonate is of commercial importance as a potent long-acting calcium channel blocker.

R(+) amlodipine has been reported to be a potent inhibitor of smooth muscle cell migration (see PCT/EP-94/02697). (R, S) Amlodipine and its salts are long-acting calcium channel blockers and are used in the treatment of cardiovascular disorders. Racemic amlodipine is currently used in the form of the besylate salt for the treatment of hypertension and angina. The preparation of racemic compounds is disclosed in European Patent No. EP 0089167. Amlodipine is a racemic compound and has a chiral center at the 4-position of the dihydropyridine ring. The S(-) isomer has calcium channel blocker activity, while the R(+) isomer is a potent inhibitor of smooth muscle cell migration. The prior art for the preparation of the R and S enantiomers is a) resolution of amlodipine azide ester with optically active 2-methoxy-2-phenylethanol (see J.Med.Chem.29 , 1696,1986, European Application No. 0331315A), or b) resolution of amlodipine base with optically active camphoric acid (seeing J.Med.Chem.35,3341,1992), c) in the organic solvent DMSO, Use L (+) or D (-) tartaric acid to resolve RS amlodipine base respectively (see US Patent 6,046,338 (2000) PCT95/25722 1995), d) use cinchonidine to resolve the secondary terminal azide of amlodipine Ester precursors (see US Patent 6,291,490 (2001), ChemPharm Bull. 28(9), 2809-2812, 1980).

The preparation of S(-) amlodipine besylate was disclosed in the publication, (see J.Chem.B., 693, 1997, 367-375), followed by co-pending patent application No. NF347/02 described in detail and claimed in , which patent application No. NF347/02 relates to a process for the preparation of pharmaceutically acceptable salts of S(-) amlodipine, such as besylate, succinic acid, from S(-) amlodipine salt, maleate, oxalate and tosylate.

The main disadvantages of the prior art are:

1. Use expensive resolution reagents such as camphoric acid, 2-methoxy-2-phenylethanol, cinchonidine.

2. Use 0.5 mole of L (+) or D (-) tartaric acid, which increases the workload of reclaiming tartaric acid.

3. A smaller amount of resolution reagent is used, so that the yield of the separated resolution salt is low.

4. Use a large amount of solvent (1:10).

5. Isolation of the free chiral base from the salt and treatment with benzenesulfonic acid to obtain the benzenesulfonate salt.

purpose of invention

The object of the present invention is to provide a method for preparing S(-) and R(+) amlodipine besylate from racemic amlodipine using D or L tartaric acid without separating free amlodipine base.

Summary of the invention

Accordingly, the present invention provides an improved process for the preparation of pharmaceutically acceptable chiral salts of amlodipine, namely the S(-) amlodipine salt having the structure of formula (1) and the R(+) salt having the structure of formula (2) Amlodipine salt.

Formula-1 Formula-2

Wherein R is selected from benzenesulfonic acid, succinic acid, maleic acid, oxalic acid and p-toluenesulfonic acid, wherein the separation of free base is not required to prepare the salts of formula 1 and formula 2 with an optical purity of 96-99%, the method include:

(a) At a temperature of 20-35°C, react a solution of RS amlodipine base in an organic solvent with L(+) or D(-) tartaric acid in an organic solvent for 16-24 hours to obtain amlodipine-containing tartaric acid salt solvates;

(b) isolating and reacting said amlodipine tartrate from step (a) with an aqueous acid solution at a temperature of 20-40° C., optionally in the presence of an organic solvent;

(c) adding water to the reaction mixture of step (b) to obtain the salt of formula 1 or formula 2, separating the salt of formula 1 or formula 2 and drying to obtain the acid used in step (2) The corresponding 96-99% ee salt.

In an embodiment of the present invention, the solvent used in step (a) is DMSO.

In another embodiment of the present invention, the concentration of RS amlodipine base to solvent (DMSO) is 0.16-0.40 g/ml.

In another embodiment of the present invention, the L(+) tartaric acid or D(-) tartaric acid used is 0.25 molar equivalent of the amlodipine base.

In another embodiment of the present invention, said solvate obtained from step (a) is a solvate comprising S(-) amlodipine hemi-D(-) tartrate monoDMSO solvate or R(+) amlodipine hemi-L (+) Precipitation of tartrate monoDMSO solvate.

In another embodiment of the present invention, said solvent used for salt formation in step (b) is selected from dimethylsulfoxide, isopropanol and ethanol.

In another embodiment of the present invention, the cumulative ratio of water to solvent used in steps (b) and (c) is 5:1-8:1.

In another embodiment of the present invention, the acid used in step (b) is selected from benzenesulfonic acid, maleic acid, oxalic acid and p-toluenesulfonic acid.

In another embodiment of the present invention, the ratio of amlodipine tartrate to organic solvent in step (b) is 1:1-1:5.

In another embodiment of the present invention, the molar equivalent of benzenesulfonic acid used is 0.9-1.

In another embodiment of the present invention, the optical purity of R(+) amlodipine besylate or S(-) amlodipine besylate is increased from 95% to 99%.

Detailed Description of the Invention

The invention provides a preparation method of pharmaceutically acceptable chiral amlodipine salt comprising S(-) amlodipine salt having the structure of formula (1) and R(+) amlodipine salt having the structure of formula (2) .

Formula-1 Formula-2

In the above formula 1 and formula 2, R is selected from benzenesulfonic acid, succinic acid, maleic acid, oxalic acid and p-toluenesulfonic acid. The salts of Formula 1 and Formula 2 were prepared with an optical purity of 96-99% without isolation of the free base.

The method of the present invention comprises:

(a) reacting a solution of RS amlodipine base in an organic solvent with a solution of L(+) or D(-) tartaric acid in an organic solvent at a temperature of 20-35° C. for 16-24 hours.

(b) isolating said tartrate salt obtained from step (a) and reacting said salt with an aqueous acid solution at a temperature of 20-40° C., optionally in the presence of an organic solvent.

(c) adding water to said reaction mixture from step (b) to obtain said salt, which is isolated and dried to obtain a salt having 96-99% ee corresponding to the acid used in step (b) .

The solvent used in step (a) is preferably dimethyl sulfoxide (DMSO), and the concentration of the RS amlodipine base-to-solvent (DMSO) is 0.16-0.40 g/ml. The L(+) tartaric acid or D(-) tartaric acid used in step (a) is 0.25 molar equivalents to the base. Preferably said tartrate is obtained by precipitation and the solvate precipitated is S(-) amlodipine hemi-D(-) tartrate monoDMSO solvate or R(+) amlodipine hemi-L(+) tartrate Mono DMSO solvate. The solvent used for salt formation in step (b) is selected from dimethylsulfoxide, isopropanol or ethanol. The ratio of amlodipine salt to organic solvent used for salt formation in step (b) is 1:1-1:5. In step (b) and step (c), the ratio of water to solvent used cumulatively is 5:1-8:1. The acid used in step (b) is selected from benzenesulfonic acid, maleic acid, oxalic acid and p-toluenesulfonic acid. The molar equivalent of the used benzenesulfonic acid is 0.9-1.

The optical purity of R(+) amlodipine besylate or S(-) amlodipine besylate increased from 95% to 99%.

The uniqueness of the present invention is that, with good yield (87-92%), produce S(-) amlodipine or R(+) amlodipine salt. R, the resolution process of S amlodipine and the formation process of besylate are as follows:

The method of the present invention is described herein by reference to the following examples, which are merely illustrative of the present invention and should not be construed as limiting the scope of the present invention in any way.

Optical purity (enantiomeric excess e.e.) was determined using a chiral HPLC column: chiral Chrompak 15 cm, waveguide coupled cross-field amplifier tube (ultron). The mobile phase uses disodium hydrogen phosphate buffer of pH 6.9: acetonitrile (80:20), the flow rate is 1ml/min, Rt-R=6.1min., S=7.3min at 360nm.

Example 1: Preparation of R(+) amlodipine hemi-L(+) tartrate monoDMSO solvate from RS amlodipine

To a stirred solution of 10.50 g (0.0256 mole) RS amlodipine in 30 ml DMSO was added a solution of 1.93 g (0.0128 moles, 0.5 equivalent (eq.)) L(+) tartaric acid in 30 ml DMSO. Within 5-10 minutes, solids began to separate from the clear solution. The reaction was stirred for 3 hours and the solid was filtered off, washed with acetone and dried to afford 6.66 g (46.2%) of R(+) amlodipine hemi L(+) tartrate monoDMSO solvate. Melting point (mp.) 160-162°C, determined by chiral HPLC to be 95.2%d.e. M. Kremser.].

Example 2: Preparation of R(+) amlodipine hemi-L(+) tartrate monoDMSO solvate from RS amlodipine

To a stirred solution of 100 g (0.245 mole) RS amlodipine in 300 ml DMSO was added a solution of 9.2 g (0.06 mole, 0.25 equivalent (eq.)) L(+) tartaric acid in 300 ml DMSO. Within 5-10 minutes, solids began to separate from the clear solution. The reaction was stirred for 3 hours and the solid was filtered off, washed with acetone and dried to yield 52.3 g (36.2%) of R(+) amlodipine hemi-L(+) tartrate monoDMSO solvate. Melting point (mp.) 160-162°C, 98.2% d.e. by chiral HPLC.

Example 3: Preparation of R(+) amlodipine hemi-L(+) tartrate monoDMSO solvate from RS amlodipine

To a stirred solution of 100 g (0.245 mole) RS amlodipine in 150 ml DMSO was added a solution of 9.2 g (0.06 mole, 0.25 equivalent (eq.)) L(+) tartaric acid in 100 ml DMSO. Within 5-10 minutes, solids began to separate from the clear solution. The reaction was stirred for 3 hours and the solid was filtered off, washed with acetone and dried to yield 58.6 g (40.5%) of R(+) amlodipine hemi L(+) tartrate monoDMSO solvate. Melting point (mp.) 160-162°C, 96.8% d.e. by chiral HPLC.

Example 4: Preparation of S(-) amlodipine hemi-D(-) tartrate monoDMSO solvate from RS amlodipine

To a stirred solution of 100 g (0.245 mole) RS amlodipine in 500 ml DMSO was added a solution of 9.2 g (0.06 mole, 0.25 equivalent (eq.)) D(-) tartaric acid in 500 ml DMSO. Within 5-10 minutes, solids began to separate from the clear solution. The reaction was stirred overnight at room temperature and the solid was filtered off, washed with acetone and dried to afford 47.5 g (34.6%) of S(-) amlodipine hemi-D(-) tartrate monoDMSO solvate. Melting point (mp.) 159-161°C, 99.5% d.e. by chiral HPLC.

Example 5: Preparation of S(-) amlodipine hemi-D(-)tartrate monoDMSO solvate from RS amlodipine

To a stirred solution of 100 g (0.245 mole) RS amlodipine in 250 ml DMSO was added a solution of 9.2 g (0.06 mole, 0.25 equivalent (eq.)) D(-) tartaric acid in 250 ml DMSO. Within 5-10 minutes, solids began to separate from the clear solution. The reaction was stirred overnight at room temperature and the solid was filtered off, washed with acetone and dried to yield 56.2 g (40.8%) of S(-) amlodipine hemi-D(-) tartrate monoDMSO solvate. Melting point (mp.) 159-161°C, 98.4% d.e. by chiral HPLC.

Example 6: Preparation of R(+) Amlodipine Besylate from R(+) Amlodipine Semi-L(+) Tartrate MonoDMSO Solvate

68.8g (0.122mole, 95.2%de) R(+) amlodipine hemi-L(+) tartrate monoDMSO solvate prepared according to Example 2 was suspended in aqueous isopropanol (70ml IPA: 250ml distilled water ), and a solution of benzenesulfonic acid (19.35 g of 90% technical grade, 0.110 mole) in 150 ml of water was added. The reaction mixture was stirred for 2 hours and the resulting mud was filtered, washed with distilled water and hexane, and the solid was dried under vacuum at 40° C. to constant weight to obtain R (+) amlodipine besylate (63.4 g, yield 84.6%) ), determined by chiral HPLC to be 99.3ee.

Microanalysis: C 51.33%, H 6.13%, N 4.62%, S 5.51 The calculated C ₂₀ H ₂₄ O ₅ N ₂ ClC ₆ H ₆ O ₃ S.2.5 (H ₂ O) theoretical value is C 51.1%, H 5.7 %, N 4.58%, S 5.24%.

Example 7: Preparation of R(+) Amlodipine Besylate from R(+) Amlodipine Semi-L(+) Tartrate MonoDMSO Solvate

68.8g (0.122mole, 95.2%de) R(+) amlodipine hemi-L(+) tartrate monoDMSO solvate prepared according to Example 2 was suspended in aqueous isopropanol (70ml IPA: 250ml distilled water ), and a solution of benzenesulfonic acid (90% technical grade, 21.28 g, 0.122 mole) in 150 ml of water was added. The reaction mixture was stirred for 2 hours and the resulting mud was filtered, washed with distilled water and hexane, and dried under vacuum at 40°C to a constant weight to obtain R(+) amlodipine besylate (66.74g, yield 89.1%) ), determined by chiral HPLC to be 98.7ee.

Example 8: Preparation of S(-) Amlodipine Besylate from S(-) Amlodipine Semi-D(-) Tartrate MonoDMSO Solvate

50g (0.089mole) S (-) amlodipine semi-D (-) tartrate monoDMSO solvate prepared according to Example 4 was suspended in aqueous isopropanol (70ml IPA: 150ml distilled water), and 100ml Benzenesulfonic acid (90% technical grade 14.1 g, 0.081 mole) solution in water. The reaction mixture was stirred for 2 hours and the resulting mud was filtered, washed with distilled water and hexane, and the solid was dried under vacuum at 40°C to constant weight to obtain S(-) amlodipine besylate (47.5g, yield 87.2% ), determined by chiral HPLC to be 99.5ee.

Microanalysis: C 50.91%, H 6.3%, N 4.67%, S 5.91 The calculated C ₂₀ H ₂₄ O ₅ N ₂ ClC ₆ H ₆ O ₃ S.2.5 (H ₂ O) theoretical value is C 51.1%, H 5.7 %, N 4.58%, S 5.24%.

Example 9: Preparation of S (-) Amlodipine Besylate from S (-) Amlodipine Semi-D (-) Tartrate Mono-DMSO Solvate

50g (0.089mole) S (-) amlodipine semi-D (-) tartrate monoDMSO solvate prepared according to Example 4 was suspended in aqueous isopropanol (70ml IPA: 150ml distilled water), and added A solution of benzenesulfonic acid (90% technical grade, 15.47 g, 0.089 mole) in 100 ml of water. The reaction mixture was stirred for 2 hours and the resulting mud was filtered, washed with distilled water and hexane, and the solid was dried under vacuum at 40° C. to constant weight to obtain S(-) amlodipine besylate (50.1 g, yield 92.1%) ), determined by chiral HPLC to be 99.3ee.

Example 10: Preparation of S(-) Amlodipine Besylate from S(-) Amlodipine Semi-D(-) Tartrate MonoDMSO Solvate

50g (0.089mole) S (-) amlodipine semi-D (-) tartrate monoDMSO solvate prepared according to embodiment 4 is placed in 200ml distilled water and adjusted to mud, and add benzenesulfonic acid (90% Industrial grade 15.47g, 0.089mole) solution. The reaction mixture was stirred for 2 hours and the resulting mud was filtered, washed with distilled water and hexane, and the solid was dried under vacuum at 40° C. to constant weight to obtain S(-) amlodipine besylate (50.1 g, yield 92.1%) ), determined by chiral HPLC to be 99.3ee.

Example 11: Preparation of R(+) amlodipine besylate from R(+) amlodipine hemi-L(+) tartrate monoDMSO solvate

68.8 g (0.122 mole, 95.2% de) R (+) amlodipine semi-L (+) tartrate monoDMSO solvate prepared according to Example 1 was suspended in aqueous isopropanol (90 ml IPA: 250 ml distilled water ), and a solution of benzenesulfonic acid (19.35 g of 90% technical grade, 0.110 mole) in 150 ml of water was added. The reaction mixture was stirred for 2 hours and the resulting mud was filtered, washed with distilled water and hexane, and the solid was dried under vacuum at 40° C. to constant weight to obtain R (+) amlodipine besylate (51.6 g, yield 69.4%) ), determined by chiral HPLC to be 99.3ee.

Example 12: Preparation of S(-) Amlodipine Maleate from S(-) Amlodipine Hemi-D(-) Tartrate MonoDMSO Solvate

S (-) amlodipine hemi-D (-) tartrate monoDMSO solvate (6.8 g, 0.012 mole) was dissolved in ethanol (10 ml), and maleic acid (1.42 g, 0.012 mole) in 70 ml of water was added under stirring. mole). The precipitated solid was filtered, washed with cold water, hexane and dried under vacuum to obtain 5.32g (82.88%) S (-) amlodipine maleate, melting point (mp.) 176-177 ° C, optical rotation: [α ] ^t D = -25.10 (c = 1, MeOH) 98.31 ee.

Example 13: Preparation of S(-) amlodipine oxalate from S(-) amlodipine hemi-D(-) tartrate monoDMSO solvate

Dissolve S(-) amlodipine hemi-D(-) tartrate monoDMSO solvate (6.8 g, 0.012 moles) in ethanol (10 ml) and add oxalic acid (1.54 g, 0.012 moles) in 70 ml of water with stirring . The precipitated solid was filtered, washed with cold water, hexane and dried under vacuum to obtain 5.80 g (89.2%) of S(-) amlodipine oxalate, melting point (mp.) 201-203° C., optical rotation: [α] ^t D = -27.95 (c = 1, MeOH) 98.41ee.

Advantages of the present invention:

1. Avoid expensive resolution reagents such as camphoric acid, 2-methoxy-2-phenylethanol, cinchonidine.

2. Avoid increasing the workload of reclaiming tartaric acid due to the use of 0.5 moles of L (+) or D (-) tartaric acid.

3. A smaller amount of resolution reagent is used, and the yield of the separated resolution salt is high.

4. Avoid using a large amount of solvent (1:10).

5. Avoid isolation of the free chiral base from the salt and treatment with benzenesulfonic acid to obtain the benzenesulfonate.

Claims (11)

1. the method for the acceptable chirality salt of medicine of preparation amlodipine promptly has S (-) Amlodipine of formula (1) structure and R (+) Amlodipine with formula (2) structure,

Formula-1 formula-2

Wherein R is selected from Phenylsulfonic acid, succsinic acid, toxilic acid, oxalic acid and tosic acid, and the salt that wherein prepares described formula 1 and formula 2 need not separated free alkali, and the salt of described formula 1 and formula 2 has 96% to 99% optical purity, and described method comprises:

(a) under 20-35 ℃ temperature, with L (+) in the solution of RS amlodipine base in the organic solvent and the organic solvent or the tartaric solution reaction 16-24 of D (-) hour, to obtain to comprise the solvate of amlodipine tartarate salt;

(b) separate and in 20-40 ℃ temperature, choose wantonly in the presence of organic solvent, described amlodipine tartarate salt and the aqueous acid that obtains in the step (a) reacted;

(c) water is joined in the described reaction mixture of step (b) to obtain the salt of described formula 1 and formula 2, separate described formula 1 and and 2 salt and dry, obtain with step (2) in the salt of the corresponding 96-99%ee of described acid that uses.

2. the method for claim 1, wherein the described solvent that uses in the step (a) is DMSO.

3. the method for claim 1, wherein said RS amlodipine base is 0.16g/ml to 0.40g/ml to the concentration of solvent (DMSO).

4. the method for claim 1, wherein employed described L (+) tartrate or D (-) tartrate are 0.25 molar equivalent of described amlodipine base.

5. the method for claim 1, wherein the described solvate that obtains in step (a) is the precipitation that comprises S (-) amlodipine half D (-) tartrate list DMSO solvate or R (+) amlodipine half L (+) tartrate list DMSO solvate.

6. the method for claim 1, the described solvent that wherein is used for salt formation in step (b) is selected from dimethyl sulfoxide (DMSO), Virahol and ethanol.

7. the method for claim 1, wherein in step (b) and the accumulative total ratio of water (c) and solvent be 5: 1 to 8: 1.

8. the method for claim 1, wherein the described acid of using in step (b) is selected from Phenylsulfonic acid, toxilic acid, oxalic acid and tosic acid.

9. the method for claim 1, wherein the ratio of amlodipine tartarate salt and organic solvent is 1: 1 to 1: 5 in step (b).

10. method as claimed in claim 8, wherein the molar equivalent of employed Phenylsulfonic acid is 0.9 to 1.

11. the method for claim 1, the optical purity of wherein said R (+) amlodipine besylate or S (-) amlodipine besylate brings up to 99% from 95%.