FORM 2

THE PATENT ACT 1970,

(39 &1970)
THE PATENTS RULES, 2003
COMPLETE
Specification
(See section 10 and rule 13)
PROCESS FOR PRODUCING (S)-AMLODIPINE OF HIGH OPTICAL PURITY AND ITS PHARMACEUTICALLY USEFUL SALTS
EMCURE PHARMACEUTICALS LTD.,
an Indian Company
of Emcure House, T-184, M.I.D.C, Bhosari, Pune 411 026,
Maharashtra, India
FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:-


This invention relates to an improved process for producing optically active (S)-amlodipine of formula of figure 1 of the accompanying drawings in high optical purity and its pharmaceutically useful salts.
More particularly it relates to a process for preparation of (S)-amlodipine-L-(+)-hemi-tartarate as seen in figure 2 of the accompanying drawings from (RS)-amlodipine base using L-(+)-tartaric acid and the efficient separation and purification of salts in high optical purity.
Further it also relates to the process of converting (S)-amlodipine-L-(+)-hemi-tartarate and into its pharmaceutically acceptable salts such as besylate, maleate, fumarate, succinate, oxalate and the like with or without isolating free chiral amlodipine base.
BACKGROUND
Amlodipine and its salts are long lasting calcium channel blockers and are useful for the treatment of cardiovascular disorders. Racemic amlodipine is currently being used as its besylate or maleate salts in the treatment of angina, hypertension and congestive heart failure. Amlodipine has a chiral centre at position 4 of dihydropyridine ring and exists in two enantiomeric forms R and S. The two enantiomers of amlodipine and their salts have different pharmacological profiles. The S-isomer is the more potent calcium channel blocker while R-isomer has little or no calcium channel blocking activity. However, the R-isomer exhibits activity in the treatment or prevention of atherosclerosis.
PRIOR ART
Enantiomerically pure amlodipine isomers are prepared via separation of the diastereotopic azide esters of 2-methoxy-2-phenylethanol [J. E. Arrowsmith et al, J. Med. Chem. 29, 1696, 1986] R and S amlodipine isomers are also prepared by the resolution of intermediate racemic azido acid cinchonidine salts and eventually converted into enantiomerically pure amlodipine isomers [J. E. Arrowsmith et al, EP 0331315]. The resolution of racemic amlodipine base using L or D tartaric acid in organic solvent such as dimethyl sulphoxide has been described to give R-

amlodipine-L-(+)-hemitartarate and (S)-amlodipine-L-(+)-hemitartarate [US
6,046,338; WO 95/25722; US2003176706; EP 1348 697 ] [no Indian equivalents]. EP 1407773 and US 6608206 [no Indian equivalents] disclose the process for the preparation of (S)-Amlodipine besylate, which comprises reacting (S)-Amlodipine free base with benzene sulfonic acid in an organic solvent. Further, US 2003/0130321 and WO 03/035623 [no Indian equivalents] describe resolution of racemic amlodipine base using L or D tartaric acid in dimethylacetamide solvent. Yet another patent WO 2004/024689 [no Indian equivalent] describes resolution of racemic amlodipine base using L or D tartaric acid and DMSO as solvent.
The main disadvantages of the prior art are the use of expensive resolving agents or lack of suitability for industrial application.
The use of L-(+)-tartaric acid has been disclosed for the preparation of (S)-amlodipine-L-(+)-hemi-tartarate [see for example US 2003176706; EP 1348697 no Indian equivalents]. However, the enantiomeric purity of (S)-amlodipine obtained by this method is about 97% de. Moreover, this method involves use of total required quantity of tartaric acid (0.5 equivalent) in beginning of the reaction, subsequent isolation of precipitated (R)-amlodipine-L-(+)-hemitartarate followed by isolation of precipitated (S)-amlodipine-L-(+)-hemitartarate from filtrate by the sequential filtration. The time factor of the first filtration is very crucial in this method as after certain time (S)-amlodipine-L-(+)-hemitartarate also precipitates along with (R)-amlodipine-L-(+)-hemitartarate and leads to the inefficient separation of R and S isomers. Thus, the use of this method for the resolution of amlodipine base into its enantiomers on large scale gave unsatisfactory results in terms of both yield and enantiomeric purity.
OBJECTS OF THE INVENTION
The main object of the invention is to provide an industrially suitable method for the resolution of amlodipine base into its R and S isomers with high enantiomeric purity by using easily accessible natural L-(+)-tartaric acid as a resolving agent. Further objective of this invention is to provide a method for conversion of this chirally pure (S)-amlodipine base and its tartarate salt into pharmaceutically useful salts.

Another object of this invention is to resolve an amlodipine base into its R and S isomer having a purity of over 99 per cent.
SUMMARY OF THE INVENTION
The process described herein is a simple, economically viable and efficient process for preparing both the enantiomers of amlodipine and their pharmaceutical acceptable salts in good yield with very high enantiomeric purity (>99 % ee). Accordingly, the invention provides an excellent tool for industrial production of S-amlodipine salts.
Accordingly, (RS)-amlodipine base is treated with 0.25 to 0.3 equivalent of L-(+)-tartaric acid in aprotic solvents, selected from a group consisting of dimethyl sulphoxide (DMSO), N-methylpyrrolidinone (NMP), N,N-dimethylacetamide (DMA) or mixtures thereof.
However, use of DMSO as a solvent is preferred. Addition of 0.25 to 0.3 equivalent of L-(+)-tartaric acid ensures that only (R)-amlodipine-L-(+)-hemi-tartarate-aprotic solvent solvate is formed preferentially. The chiral purity of (R)-amlodipine-L-(+)-hemi- tartarate is found to be >97% de. The mother liquor thus gets enriched with S-isomer, from which is isolated (S)-amlodipine-L-(+)-hemi-tartarate-aprotic solvent solvate salt (90% de) by additional use of 0.2 to 0.25 equivalent of L-(+)-tartaric acid. The high diasteromeric purity (>99 % de) of S-amlodipine-L-(+)-hemi-tartarate is achieved by temperature dependent sequential crystallization of S- enriched hemi-tartarate aprotic solvent solvate from alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol and mixture thereof etc. preferably methanol and/or ethanol. (RS)-Amlodipine-L-(+)-hemi-tartarate precipitates out at 25-45 °C, preferably at 30 to 40 °C and more preferably at 30 to 35 °C during crystallisation of S-enriched hemi-tartarate as an aprotic solvent solvate, is removed by filtration and recycled. Highly pure (S)-amlodipine-L-(+)-hemitartarate (>99% de) is isolated on cooling the mother liquor to 0 - 30 °C followed by filtration, more preferably at 5-10 °C. The chirally pure R and S amlodipine-L-(+)-hemi-tartarate salts can optionally be converted into their respective free bases by the treatment of bases such as aq. ammonia solution, and alkali metal hydroxides such as NaOH, KOH at 20-35 °C. The

pharmaceutically useful salts of R and S amlodipine are prepared either from their respective tartarate salts or their free bases with acids, such as benzene sulphonic acid, nicotinic acid, succinic acid, maleic acid, fumaric acid, oxalic acid, camphor-10-sulphonic acid, etc.
According to this invention therefore there is provided a process for the preparation of chirally pure (S)-amlodipine salts, which comprises the steps of (i) adding firstly 0.25 to 0.3 molar equivalent of L-(+)-tartaric acid into the solution of (RS)-amlodipine in an aprotic solvent (ii) filtering the solution obtained of (R)-amlodipine-L-(+)-hemi-tartarate-aprotic solvent -solvate leaving behind a mother liquor; (iii) adding 0.20 to 0.249 molar equivalent of L-(+)-tartaric acid to the mother liquor to precipitate (S)-amlodipine-L-(+)-hemi-tartarate aprotic solvent-solute; (iv) filtering the said (S)-amlodipine-L-(+)-hemi-tartarate-solute; (v) isolating (S)-amlodipine-L-(+)-hemi-tartarate by crystallization of the said solute using an alcoholic solvent and (vi) converting the isolated solute obtained from step (v) to optionally a pharmaceutically acceptable (S)-amlodipine or its salt.
The main advantages of this invention are:
1. Initial addition of 0.25 to 0.3 equivalents L-(+)-tartaric acid preferentially precipitates the unwanted R-isomer, the mother liquor on subsequent treatment of 0.20 to 0.249 equivalents of tartaric acid offers enantiomerically pure (S)-isomer.
2. Thus, sequential addition makes this process rugged and it is not a function of time factor, unlike the process described in prior art [US 2003176706; EP 1348697].
3. The purification process described in this invention offers enantiomerically highly pure S-isomer in a single crystallisation.
4. This process offers separation of both the stereoisomers (R and S) in high chiral purity.
5. The isolated RS-amlodipine tartarate obtained during crystallization is recycled and reused after converting it to its free base, making process cost effective.
6. The aprotic solvent mother liquor being free from any of the isomers can be recycled conveniently, which makes the process eco-friendly.

The process of present invention is described herein below with reference to examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 the optically active (S)-amlodipine
Figure 2 is the structural formula of (S)-amlodipine-L-(+)-hemi-tartarate
Figure 3 is the structural formula of (R)-amlodipine-L-(+)-hemi-tartarate; and
Fig.4 is the graphical representation showing HPLC chromatogram report indicating
the chemical purity of the (S)-amlodipine besylate made in accordance with this
invention .
Example 1
(R) -Amlodipine-L-(+)-hemi tartarate
7 Kg (17.13 moles) of (±) amlodipine free base was dissolve in 24 Lit. of dimethyl
sulphoxide (DMSO). To this solution, were charged 770 grams (5.13 moles) of L-(+)
tartaric acid in 5.2 liters of DMSO. Reaction mass was stirred for 80 min. Precipitated
(R)-Amlodipine -L-(+)-hemitartarate-DMSO-solvate was separated by centrifugation.
The product was washed with 1.5 Lit. of DMSO, followed by 1 Lit. of acetone.
(R)-Amlodipine -L-(+)-hemitartarate as a DMSO solvate was dried at 50 °C in vacco.
Yield: 4 Kg.
The dry product was dissolved in 20 Lit. of methanol, by heating to reflux for 2 hrs.
Heating was then discontinued and reaction mixture was gradually cooled to room
temperature
(R)-Amlodipine -L-(+)-hemitartarate precipitated was centrifuged and washed with 2
Lit. of methanol. Dried at 50 °C in vacco.
Yield: 3.8 Kg.
R-contents by Chiral HPLC: 99.08%.

Example 2
(S) -Amlodipine -L -(+) -hemitartarate- DMSO solvate
DMSO mother liquor of Example 1 was charged to the reactor. To this solution, 520
grams (3.46 moles) of L-(+) tartaric acid in 3.5 Lit. of DMSO were added drop wise
in 2.5 hrs.
Reaction mixture was stirred for 18 hrs during which, (S)-Amlodipine-L-(+)-
hemitartarate precipitated as DMSO solvate. The product was separated by
centrifugation. Washed with 2 Lit. of acetone and dried in vacco at 35 °C.
Yield: 3.29 Kg
S-contents by chiral HPLC: 90 %
Example 3
(S)-Amlodipine -L -(+)-hemitartarate Pure
Product obtained in example 2 was refluxed with 40 Lit. of methanol to dissolve.
After complete dissolution, reaction mixture was cooled to 30 °C by means of external
circulation of chilled water through reactor jacket in one hour.
(RS)-Amlodipine-L-(+)-hemitartarate precipitated out at this temperature, which was
filtered. (Yield: 976 grams, R contents 57 %, S Contents 43 %)
Mother liquor was charged back to the reactor and cooled to 5 °C and precipitated
pure (S)-amlodipine-L-(+)-hemitartarate was separated by centrifugation. Product
washed with 2 Lit. methanol and dried in vacuo at 35 °C
Yield: 3.25 Kg.
S-Contents By chiral HPLC: 99.6 %
Example 4
(R) -Amlodipine free base

1 kg of (R)-Amlodipine -L -(+)-hemitartarate obtained in example 1 was charged to the reaction flask containing 3.5 Lit of dichloro methane. Contents were stirred to dissolve. To this were charged 4.5 Lit of water and 500 ml 10% ammonium hydroxide. Stirred for 2 hrs and dichloro methane layer was separated. Aqueous layer was extracted with 500 ml dichloromethane and combined dichloromethane layer was washed with water 4X500 ml.
Dichloromethane extract was dried over anhydrous sodium sulphate and concentrated till 90% of the solvent was recovered. 5 Lit Pet ether was added to the thick mass under vigorous stirring. (R)-Amlodipine free base was separated by filtration and dried in vacco at 40 °C Yield: 673 gm. Chiral Purity by HPLC: - 99.23% R isomer
Example 5
(S)-Amlodipine free base
Process described in Example 4 was carried out using (S)-Amlodipine -L -(+)-
hemitartarate obtained in example 3.
Yield: 697 gm.
Chiral Purity by HPLC: 99.68 % S isomer
Example 6 (S)-Amlodipine Oxalate (anhydrous)
(S)-Amlodipine free base (10gm) dissolved in methanol (30 ml). Oxalic acid (1.125 gm) was dissolved in 20 ml methanol. Oxalic acid solution was charged to (S)-Amlodipine free base solution in methanol under stirring at room temperature. Stirring was continued for 4 hrs. Concentrated the reaction mass to sticky yellow solid. This was dissolved in 25ml. chloroform and concentrated to remove traces of water and methanol if any. To the sticky yellow semisolid, were added 50 ml of hexane and allowed to stir for 4-5 hrs (till sticky product becomes free flowing)

during which hexane layer was decanted and equal amount of fresh hexane was added twice. Filtered the product and suck dried at room temperature. Yield: 8.2 gm
Example 7
(S)-Amlodipine Oxalate (Hydrate)
Amlodipine free base (10 gm) was dissolved in methanol (30 ml).Oxalic acid (1.125) was dissolved in 20 ml methanol. Oxalic acid solution was charged to (S)-Amlodipine free base solution in methanol under stirring at room temperature. Stirring was continued for 4 hrs. Reaction mixture was poured in 250 ml demineralized water and stirred for 18 hrs. (till sticky product turns free flowing) Filtered the product, washed with n-Hexane (25 ml.), and suck dried at room temperature. Yield: 10.162 gm
Example 8 (S)-Amlodipine Fumarate
Amlodipine free base(10 gm) was dissolved in methanol (30 ml). Fumaric acid (1.45gm) was dissolved in 20 ml methanol. Fumaric acid solution was charged to (S)-Amlodipine freebase solution in methanol under stirring at room temperature. Stirring was continued for 4 hrs. Concentrated the reaction mass to sticky yellow solid. To the sticky yellow semisolid, were added 50 ml of hexane and allowed to stir. Sticky product becomes free flowing within few minutes. Filtered the product and suck dried at room temperature. Yield: 10.36 gm
Example 9 (S)-Amlodipine maleate
Amlodipine free base (10gm.) was dissolved in methanol (30 ml). Maleic acid (1.45 gm) was dissolved in 20 ml methanol. Maleic acid solution was charged to (S)-Amlodipine free base solution in methanol under stirring at room temperature. Stirring was continued for 4 Hrs. Concentrated the reaction mass to sticky yellow

solid. This was dissolved in 25ml. chloroform and concentrated to remove traces of water and methanol if any. To the sticky yellow semisolid, were added 50 ml of hexane and allowed to stir for 4-5 hrs (till sticky product becomes free flowing) during which hexane layer was decanted and equal amount of fresh hexane was added twice. Filtered the product and suck dried at room temperature. Yield: 10.62 gm
Example 10
(S)-Amlodipine nicotinate
Nicotinic acid (3.02gm) was dispersed in 20 ml chloroform. (S)-Amlodipine free base (10 gm) was dissolved in 30 ml chloroform. Solution of (S)-amlodipine free base was charged to dispersion of nicotinic acid in the reaction flask. Reaction mixture becomes uniform immediately after addition. Stirring was continued further. Nicotinate salt precipitates slowly within few minutes. Reaction mixture was stirred for 2 hrs and further heated to 50 °C for 30 min. to ensure completion of reaction. Cooled the reaction mixture to room temperature and filtered. Washed with 25 ml chloroform. Dried at room temperature. Yield: 8.07 gm
Example 11
(S)-Amlodipine-D-l0-Camphor sulphonate
D-10-camphor sulphonic acid (6.1gm) was dissolved in 15 ml water. (S)-Amlodipine free base (10 gm) was dissolved in 30 ml methanol. D-10-camphor sulphonic acid solution was charged to the methanol solution of (S)-amlodipine free base. Reaction mixture was stirred for 4 hrs. and 15 ml water was added. D-10-camphor sulphonate precipitated was filtered and washed with 25 ml water and 25 ml n-hexane. Dried at room temperature. Yield: 15.0 gm
Example 12 (S)-Amlodipine-Besylate
Benzene sulphonic acid (14.8gm) was dissolved in 25ml water. (S)-Amlodipine tartarate (46 gm) was suspended in 252 ml water + 46 ml isopropanol. Benzene

sulphonic acid solution was charged to the above suspension. Reaction mixture was stirred for 5 min. and 45 ml water was added. Benzene sulphonate salt precipitated was stirred for 30 min filtered and washed with 3 X 46 ml water and 46 ml cyclohexane hexane. Dried at room temperature. Yield: 46.0 gm
Example 13 (S)-Amlodipine-Besylate
Benzene sulphonic acid (12.85 gms) was dissolved in 22ml water. (S)-Amlodipine
tartarate (40 gms) was suspended in a mixture of water (220 ml) and isopropanol (40
ml). Benzene sulphonic acid solution was charged to the above suspension. Reaction
mixture was stirred for 5 min. and 38 ml of water was added. The Benzene sulphonate
salt which was precipitated was stirred for 30 min and filtered . Wet cake was washed
with water (120 ml) and cyclohexane(40 ml) and dried at room temperature.
Yield : 40.0 gms
Chemical purity: 99.96% Optical purity : 100%

Claim:
1. A process for the preparation of chirally pure (S)-amlodipine salts, which comprises the steps of (i) adding firstly 0.25 to 0.3 molar equivalent of L-(+)-tartaric acid into the solution of (RS)-amlodipine in an aprotic solvent (ii) filtering the solution obtained of (R)-amlodipine-L-(+)-hemi-tartarate-aprotic solvent -solvate leaving behind a mother liquor; (iii) adding 0.20 to 0.249 molar equivalent of L-(+)-tartaric acid to the mother liquor to precipitate (S)-amlodipine-L-(+)-hemi-tartarate aprotic solvent-solute; (iv) filtering the said (S)-amlodipine-L-(+)-hemi-tartarate-solute; (v) isolating (S)-amlodipine-L-(+)-hemi-tartarate by crystallization of the said solute using an alcoholic solvent and (vi) converting the isolated solute obtained from step (v) to optionally a pharmaceutically acceptable (S)-amlodipine or its salt.
2. A process according to claim 1, wherein the aprotic solvent used is selected from a group consisting of dimethyl sulphoxide (DMSO), N-methylpyrrolidinone (NMP), N,N-dimethylacetamide (DMA) or mixtures thereof.
3. A process according to claim 1, wherein the aprotic solvent is dimethyl sulphoxide (DMSO).
4. A process according to claim 1, wherein the alcoholic solvent is selected from a group consisting of methanol, ethanol, isopropanol, n-propanol or their mixtures thereof.
5. A process according to claim 1, wherein addition of L-(+)-tartaric acid is done as solution of L-(+)-tartaric acid in an aprotic solvent.
6. A process according to claim 5, wherein the aprotic solvent is dimethyl sulphoxide (DMSO).

7. A process according to claim 1, wherein purification by crystallisation is
carried out by sequential isolation of the precipitated solute at different
temperatures.
8. A process according to claim 1, wherein isolation of the precipitated (S)-
amlodipine-L-(+)-hemi-tartarate is carried out from mother liquor by cooling it
below 30 °C.
9. A process according to claim 8, wherein (RS)-amlodipine-L-(+)-hemi-tartarate is precipitated and isolated by filtration or centrifugation from the mother liquor at temperature 30 to 40 °C during crystallisation and the aprotic solvent and/or the (RS)-amlodipine-L-(+)-hemi-tartarate are recycled.
10. A process according to claim 1 wherein the pharmaceutically acceptable salt is selected from a group comprising of benzene sulphonic acid, nicotinic acid, succinic acid, maleic acid, fumaric acid, oxalic acid, camphor-10-sulphonic acid.
11. An (S)-amlodipine salt of purity (>99%)de made in accordance with any one of the preceding claims.
Dated this 23rd day of February 2005.
MOHAN DEW AN
OF R.K.DEWAN & COMPANY
APPLICANTS' PATENT ATTORNEY