WO2007131759A1

WO2007131759A1 - A process for the preparation of amlodipine benzenesulfonate

Info

Publication number: WO2007131759A1
Application number: PCT/EP2007/004270
Authority: WO
Inventors: Borut Anzic; Janez Rzen; Boris Marolt; Borut Furlan
Original assignee: Lek Pharmaceuticals D.D.
Priority date: 2006-05-15
Filing date: 2007-05-14
Publication date: 2007-11-22

Abstract

The present invention relates to novel alkyl 2-(2-chlorobenzylidene)-4-(2- tritylaminoethoxy) acetoacetate, wherein alkyl represents C1C4 alkyl group, preferably ethyl 2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, as useful intermediate in the novel process for the preparation of amlodipine benzenesulfonate in high overall yield and high purity, containing substantially less then 0.1 Area % of 3,5-diethyl (±)-2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-1,4- dihydro-6-methyl-3,5-pyridinedicarboxylate as the single remaining impurity. No other impurities are contained in obtained pure crystalline amlodipine benzenesulfonate. Preferably, 2-chlorobenzaldehyde is contacted with ethyl-4-[2-(N- tritylamino)ethoxy]acetoacetate in an organic solvent, preferably ethanol, to form ethyl-2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, which is converted without isolation from the reaction mixture, preferably with methyl (E)-3- aminocrotonate to form 3-ethyl 5-methyl (±)-2-[2-(N-tritylamino)ethoxymethyl]-4-(2- chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate ('tritylamlodipine'), which is converted without isolation from the reaction mixture with benzenesulfonic acid in an organic solvent, preferably ethanol, followed by isolation and purification of amlodipine benzenesulfonate. C1-C4 alkyl alcohols, especially methanol, ethanol, isopropanol and mixtures thereof, are used as an organic solvent. Amlodipine benzenesulfonate (besylate) is useful as antiishemic and antihypertensive agent.

Description

A process for the preparation of amlodipine benzenesulfonate

Field of the invention

The present invention relates to novel intermediates useful in the synthesis of amlodipine benzenesulfonate as well as to process of making and using the same. According to the novel process of the invention amlodipine benzenesulfonate is obtained in high overall yield and high purity of 99.5 Area % and higher, containing single impurity of substantially less than 0.1 Area % (as determined by HPLC method). Amlodipine benzenesulfonate is an effective agent in blocking calcium canals and is useful as antiishemic and antihypertensive agent.

Technical problem

There is a constant need for preparing amlodipine benzenesulfonate in a simple process and with high overall yield and high purity, containing overall impurities as low as possible, which process would effectively remove undesired impurities, usually containing in commercially available drugs.

Prior art

Amlodipine is a generic name for 3-ethyl 5-methyl (±)-2-[(2-aminoethoxy)-methyl]-4- (2-chlorophenyl)-1 ,4-dihydro-6-methyl-3,5-pyridinedicarboxylate (see The Merck Index, 13^th Ed, (2001), under monographic number 491), and was disclosed as a novel substance in European patent EP-B1-0 089 167 as a useful antiishemic and antihipertensive agent. Also, pharmaceutically acceptable amlodipine acid addition salts were described, among which, maleate salt is particularly suitable. Amlodipine in the form of a free base may be prepared by the methods disclosed in European patent EP-B1 -0 089 167. According to these methods, amlodipine base is prepared from an amlodipine precursor, that is a 1 ,4-dihydropyridine derivative, which has an amino group in position 2, protected with selected amino-protecting groups, in such a manner that these amino protecting groups are removed from protected 1 ,4- dihydropyridine derivative. In case the amino group is protected with the benzyl group, the protecting group is removed by catalytic hydrogenation with a paladium catalyst in a dissolving agent, such as methanol and at room temperture. In a particularly suitable process, wherein the 1 ,4-dihydropyridine derivative amino protecting group is preferably phthaloyl protecting group, said protecting group is removed in alkaline medium with a) primary amine, e.g. methylamine, b) hydrazine hydrate or c) alkali metal hydroxide, followed by treatment with hydrochloric acid or sulfuric acid. The resulting amlodipine free base is, if desired, converted to a pharmaceutically acceptable acid addition salt thereof.

Also, a process for preparing amlodipine base from amlodipine precursors, e.g. the azidoamlodipine (the explosive compound), which is reduced to amlodipin base, is disclosed in said European patent, and gives low yields.

The yields of said phthaloil amlodipine precursor (known also as "phthalimidoamlodipine"), which may be prepared according to the well known Hantzsch method for preparing asymmetric 1 ,4-dihydropyridine diesters, are relatively low. The process where phthaloyl amino protecting group may be used, require the use of toxic agents, e.g. methylamine, or cancerogenic hydrazine hydrate (see The Merck Index, 13^th Ed, (2001 ), an Enzyclopedia of Chemicals, Drugs, and Biologicals, monographic numbers 6044 and 4789).

Patent EP-B1 -0 244 944 discloses a novel amlodipine benzenesulfonate (besylate) salt and pharmaceutical forms thereof. Said salt is particularly suitable for preparing pharmaceutical dosage forms because of its good water solubility, high stability, non- hygroscopicity and good properties for manufacturing of said dosage forms. In accordance with the description is amlodipine benzenesulfonate prepared by conversion of amlodipine free base with benzenesulfonic acid or with ammonium benzenesulfonate in an inert solvent, e.g. industrial methylated spirit.

Patent EP-B1-0 599 220 discloses a process for preparing amlodipine benzenesulfonate by conversion of 3-ethyl 5-methyl (±) 2-[2-(N-tritylamino)- ethoxymethyl]-4-(2-chlorophenyl)-1 ,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, prepared by means of Hantzsch method, with benzenesulfonic acid in methanolic or aqueous methanolic medium, at a temperature between 20° and reflux temperature, followed by isolation and purification of amlodipine benzenesulfonate. The process gives good overall yields and avoids the use of some toxic and cancerous chemicals.

International patent application, publication number WO 03/004025 discloses improved process for the preparation of amlodipine benzenesulfonate as described in EP-B1 -0 599 220, wherein the reaction is carried out in ethanolic medium, what gives higher overall yields. The desired product is also purified with recrystallisation from water, whereat crystalline amlodipine benzenesulfonate monohydrate is formed intermediary.

International patent application, publication number WO 02/053535 relates to alkyl 2- (o-chlorobenzylidene)-4-(2-phthalimidoethoxy) acetoacetates as useful intermediates in the synthesis of amlodipine base and pharmaceutically acceptable acid addition salts thereof, e.g. amlodipine benzenesulfonate, with a good yield and purity.

Description of the invention

The object of the present invention is to find a novel process for preparing amlodipine benzenesulfonate in an easily feasible way, which would afford the desired substance in high overall yield and high purity of 99.5 Area % and higher, containing single impurity of substantially less then 0.1 Area % (as determined by HPLC method).

The problem has been solved by the present invention which relates to novel compound, alkyl 2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate as useful intermediate in the novel process for the preparation of amlodipine benzenesulfonate of formula (1 )

(1 ) wherein R₁ represents methyl group and R₂ represents ethyl group. In a first embodiment, the present invention relates to novel compound, alkyl 2-(2- chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate of formula (3)

(3) wherein R₂ represents a CrC₄ alkyl group and it preferebly represents an ethyl group, a methyl group and an isopropyl group.

In a second embodiment, the present invention relates to the use of said novel compound as intermediate in the novel process for the preparation of amlodipine benzenesulfonate.

The present invention also provides a process for preparing the novel intermediate of formula (3), comprising reacting 2-chlorobenzaldehyde of formula (A) with alkyl 4- [2-(N-tritylaminoethoxy)] acetoacetate of formula (C), preferably ethyl-4-[2-(N- tritylamino)ethoxy]acetoacetate, wherein R₂ represents a C_rC₄ alkyl group, as shown below.

(C) (A)

The reaction is carried out in a reaction solvent, preferably in an organic solvent such as C₁-C₄ alkyl alcohol, especially methanol, ethanol, isopropanol and mixtures thereof or in a hydrocarbon such as benzen, toluene, advantageusly in a presence of an organic base as a catalyst, such as piperidine, piperazine, N-methyl piperazine, morpholine, pyrrolidine or secondary amines of the formula FVNH-R₄, wherein R₃ and R₄ each independently represent CrC₄ alkyl group, such as a methyl, an ethyl, or an isopropyl group. The reaction may be performed at temperatures from about 2O⁰C to reflux temperature. The obtained compound of formula (3) , preferably ethyl 2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, may be used directly in the next synthetic step without isolation from the crude reaction mixture.

The obtained compound of formula (3) (in the form of a mixture of cis and trans isomers) in the crude reaction mixture may be further used to produce a trityl- protected precursor of formula (2),

(2) wherein Ri and R₂ each independently represent a C₁-C₄ alkyl group, preferably 3-ethyl 5-methyl (±) 2-[2-(N-tritylamino)-ethoxymethyl]-4-(2-chlorophenyl)- 1 ,4-dihydro-6-methyl-3,5-pyridinedicarboxylate (hereinafter referred as "tritylamlodipin"), in the next reaction step by reacting the novel intermediate of formula (3), preferabyl ethyl 2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, with an alkyl 3-aminocrotonate of formula (B), wherein Ri represents a CrC₄ alkyl group, preferably methyl 3-aminocrotonate, as shown below.

(3) (B)

The reaction between compounds of formula (3) and (B) may be performed in a suitable organic solvent, such as CrC₄ alkyl alcohol, especially methanol, ethanol, isopropanol and mixtures thereof, at temperatures from about 20° to reflux temperature.

The obtained compound of formula (2) , preferably "tritylamlodipine", may be used in the further reaction step without isolation from the crude reaction mixture by reacting the compound of formula (2) with benzenesulfonic acid in the same reaction solvent, e.g. CrC₄ alkyl alcohol, especially methanol, ethanol, isopropanol and mixtures thereof, at a temperature between about 2O⁰C and reflux temperature, to obtain amlodipine benzenesulfonate.

In order to remove the triphenylmethyl CrC₄ alkyl ether, e.g. triphenylmethyl ethyl ether, as by-product, from the reaction mixture, stirring at a temperature below 0⁰C, preferably at about -10⁰C, is necessary. From the crude reaction mixture, which is in the form of a slurry residue, amlodipine benzenesulfonate may be isolated by extraction of said slurry residue using a mixture of toluene, n-heptane, and water as three-phase system, whereat polar and non-polar admixtures are removed. In order to effectively remove diethyl-2,6-bis [2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1 ,4- dihydro-6-methyl-3,5-pyridinedicarboxylate of the formula:

H₂NC

as the most difficult removable undesired impurity, amlodipine benzenesulfonate is recrystallized from ethyl acetate and from water. Recrystallisation of amlodipine benzenesulfonate from water effectively remove completely said undesired impurity.

By the process of recrystallisation of amlodipine benzenesulfonate from water it is intermediary formed crystalline amlodipine benzenesulfonate monohydrate, which compound after drying converts to dry crystalline amlodipine benzenesulfonate. Said product is finally purified by recrystallisation from an appropriate organic solvent, such as methanol, to obtain white crystals of high purity of amlodipine benzenesulfonate of 99.5 Area % and higher, containing one and only impurity of substantially less than 0.1 Area % (as determined by HPLC method). By the term substantially less then 0.1 Area % is meant that the single remaining impurity in pure crystalline amlodipine benzensulfonate amounts less then 0.1 Area % of 3,5-diethyl (±)-2-[(2-aminoethoxy)-methyl]-4-(2-chtorophenyl)-1 ,4-dihydro-6-methyl-3,5-pyridine dicarboxylate of the formula:

No other detectable impurities are contained in the obtained pure crystalline amlodipine benzenesulfonate according to the present invention.

Starting compounds 2-chlorobenzaldehyde and methyl (E)-3-aminocrotonate are commercially available, while ethyl 4-[2-(N-tritylamino)-ethoxy]acetoacetate and other lower alkyl derivatives thereof may be prepared according to the description as disclosed in European patent EP-B-O 599 220 (see Examples 1 to 4).

The invention is illustrated by the following Example:

EXAMPLE

Ethyl-4-[2-(N-tritylamino)ethoxy]acetoacetate (78.5 g, 0.16 moles), 2- chlorobenzaldehyde (20 mL, 0.18 moles) and absolute ethanol (80 ml_) are heated and stirred at 35⁰C and then 4/5 parts of previously prepared solution of piperidine (1.28 mL, 0.01 moles) in absolute ethanol (7.1 mL) is slowly added during 2 hours at the same temeperature. The reaction mixture is then heated at 55⁰C and 1/5 parts of the rest of previously prepared ethanolic solution of piperidine is added during 30 minutes and the reaction mixture is further stirred for 1 hour at said temperature. The reaction mixture is then acidified with 0.74 ml (0.01 moles) of acetic acid. To the obtained crude ethanolic solution of ethyl-2-(2-chlorobenzylidene)-4-(2- tritylaminoethoxy)acetoacetate (as the mixture of cis and trans isomers) is methyl-3- aminocrotonate (17.75 g, 0.15 moles) slowly added during 1 hour at 55⁰C. After methyl-3-aminocrotonate is added the obtained reaction mixture is further stirred at the same temperature for 1 hour. To the obtained crude solution of 3-ethyl 5-methyl (±) 2-[2-(N-tritylamino)-ethoxymethyl]-4-(2-chlorophenyl)-1 ,4-dihydro-6-methyl-3,5- pyridinedicarboxylate (= tritylamlodipine) in ethanol, heated to the reflux temperature, a solution of benzenesulfonic acid (24.39 g, 100%) in absolute ethanol (30 ml_) is slowly added with stirring during 4 hours. Reaction mixture is further stirred at reflux temperature for 40 minutes, then slowly cooled to a temperature of -1 O⁰C and stirred at this temperature for 12 hours. The precipitate of triphenylmethyl ethyl ether, which separated, is filtered off and washed with ethanol. The obtained filtrate is concentrated in vacuo, whereat a 121 .8 g of slurry residue is obtained. Said slurry residue is transferred into 250 ml_ erlenmayer flask, demineralized water is added to the top of the flask and heated said flask on the oil bath, previously heated to 51 ⁰C, for 1 hour. Extraction of obtained slurry mixture is performed with a mixture of toluene and n-heptane (960 ml_, 1 :1 ; V/V) under slowly stirring for 16 hours and a flow rate of 1 mL/minute.

After the extraction has been completed, 30 mL of chloroform is added to the combined organic phase of toluene / n-heptane and aqueous phase, and the organic phase is separated from the aqueous phase. Obtained organic phase is concentrated in vacuo, whereat a 85.4 g of slurry residue is obtained. Said slurry residue is recrystallized from a mixture of 200 mL of ethyl acetate and 10 mL of water. 35.72 g of wet precipitate of amlodipine benzenesulfonate is obtained, which is dried at temperature up to 70 °C and reduced pressure (400 mbar) for 24 hours. 23.52 g of dry amlodipine benzensulfonate is obtained, which is suspended in 240 mL of demineralized water and 2 mL of ethyl acetate and the obtained suspension is heated to 80⁰C until the clear solution is formed. Obtained clear solution is cooled slowly with stirring for 24 hours at room temperature, whereat amlodipine benzenesulfonate monohydrate crystallize. The obtained crystalline amlodipine benzenesulfonate monohydrate is filtered off, washed with demineralized water and the obtained 39.02 g of wet precipitate of crystalline amlodipine benzenesulfonate monohydrate is dried at temperature up to 80⁰C and reduced pressure (400 mbar) for 4 hours. After drying 18.83 g of crystalline amlodipine benzensulfonate is obtained. 18.83 g of crystalline amlodipine benzenesulfonate is suspended in 175 mL of demineralized water and the obtained suspension is heated to 83⁰C until a clear solution is formed. Ethyl acetate is evaporated in vacuo and suspension cooled to room temperature. After 5 hours the suspension is filtered, washed with demineralized water, resulting 32.93 g of wet precipitate of amlodipine benzenesulfonate, which is dried at 5O⁰C and reduced pressure (400 mbar). After drying 17.09 g of dry amlodipine benezensulfonate is obtained.

17.09 g of amlodipine benzenesulfonate is recrystallized from methanol (25 mL). Obtained suspension of amlodipine benzenesulfonate in methanol is heated to 80⁰C to dissolve completely all of amlodipine benensulfonate. Resulting solution is cooled slowly to the temperature of about 20⁰C and then allowed the product to crystallize for 18 hours. The resulting suspension is then cooled slowly to about -10°C for 2 hours. The resulting crystals of amlodipine benzenesulfonate are filtered off and the precipitate washed with 5 mL of methanol (mother liquors are kept for later isolation of additional quantity of crystalline amlodipine benzenesulfonate to improve the overall yield). Obtained 17.23 g of methanol wet precipitate of amlodipine benzenesulfonate is dried at temperature up to 80 °C and reduced pressure (under 400 mbar) for 1 hour. Thus, 16.57 g dry crystalls of amlodipine benzenesulfonate are obtained.

Obtained 16.57 g dry crystalline amlodipine benzenesulfonate is recrystallized again from methanol (25 mL) Obtained suspension of amlodipine benzenesulfonate in methanol is heated to 80 °C to dissolve completely all of amlodipine benzenesulfonate. The resulting solution is cooled slowly at 20⁰C for 18 hours and the obtained solution is then cooled to -10⁰C for 2 hours. After completing of the crystallization, the product is filtered off, washed with methanol (5 mL), whereat 16.12 g of methanol wet precipitate of amlodipine benzenesulfonate is dried at temperature up to 80 °C and reduced pressure (under 400 mbar) for 1 hour. Thus, 15.12 g of dry white crystalls of amlodipine benzenesulfonate of high purity, m.p. 201.0⁰C, are obtained. Assay (determined by HPLC method):

Amlodipine benzenesulfonate: 99.53 Area %

3,5-diethyl (±) 2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-1 ,4-dihydro-6-methyl-

3,5-pyridinedicarboxylate: 0.07 Area %

Isolation od additional quantities of white crystalls of amlodipine benzenesulfonate of high purity from mother liquors

Combined mother liquors obtained after recrystallisation of amlodipine benzenesulfonate from methanol are concentrated in vacuo to about 30 vol. % of starting above combined mother liquors. The resulting concentrate is cooled on the ice bath slowly at about -1 O⁰C for 2 hours to crystallize amlodipine benzenesulfonate, which is filtered off, washed with methanol and used for recrystallisation from methanol according to above described procedure.

Claims

1. A compound of the formula (3) :

(3) wherein R₂ represents a CrC₄ alkyl group.

2. The compound according to claim 1 , wherein said compound is in the form of a mixture of cis and trans isomers.

3. The compound according to claim 1 , wherein R₂ is a methyl group, an ethyl group, or an isopropyl group.

4. The compound according to claim 1 , wherein R₂ is an ethyl group.

5. A process for the preparation of alkyl 2-(2-chlorobenzylidene)-4-(2- tritylaminoethoxy) acetoacetate according to claim 1 , which comprises reacting 2- chlorobenzaldehyde with a compound of formula (C)

(C) wherein R₂ represents a CrC₄ alkyl group, to form a compound of formula (3)

(3) wherein R₂ represents a CrC₄ alkyl group.

6. The process according to claim 5, wherein R₂ in formula (3) represents a methyl, an ethyl or an isopropyl group.

7. The process according to claims 5 or 6, wherein R₂ in formula (3) represents an ethyl group.

8. The process according to any of the preceding claims 5 to 7, wherein said reaction is carried out in an organic solvent.

9. The process according to claim 8, wherein said solvent comprise methanol, ethanol, isopropanol and mixtures thereof.

10. The process according to claims 5 to 9, wherein compound of formula (3) is used in the next reaction step without isolation from the reaction mixture.

1 1 . A process for the preparation of 3-ethyl 5-methyl (±) 2-[(2-aminoethoxy)-methyl]- 4-(2-chlorophenyl)-1 ,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate (amlodipine benzenesulfonate), which comprises reacting a compound of formula (3)

(3) wherein R₂ represents ethyl group, without its isolation from the reaction mixture obtained according to claims 5 to 0, with an alkyl 3-aminocrotonate of formula (B)

wherein Ri represents methyl group, to form a compound of formula (2)

(2) wherein Ri represents a methyl group and R2 represents an ethyl group, wherein said compound is reacting without its isolation from the reaction mixture with benzenesulfonic acid in an organic solvent, at a temperature between 20⁰C and reflux temperature, followed by isolation and purification of amlodipine benzenesulfonate.

12. The process according to claim 1 1 , wherein said reaction is carried out in an organic solvent.

13. The process according to claims 11 and 12, wherein said solvent comprises methanol, ethanol, isopropanol and mixtures thereof.

14. The process according to claim 13, wherein an organic solvent is ethanol.

15. The process according to claim 11 , wherein the steps of isolating and purifying of amlodipine benzenesulfonate further comprise stirring at a temperature below about 0⁰C to remove any triphenylmethyl ethyl ether from the reaction mixture.

16. The process according to claim 15, wherein the stirring comprises stirring at a temperature of about -10⁰C.

17. The process according to claim 11 , wherein amlodipine benzenesulfonate is isolated from the reaction mixture by extraction of slurry residue using a mixture comprising toluene, n-heptane, and water, whereafter amlodipine benzenesulfonate is obtained.

18. The process according to claim 11 and 17, wherein obtained amlodipine benzenesulfonate is recrystallised from ethyl acetate and from water and further from methanol to obtain pure amlodipine benzenesulfonate having a purity of 99.5 Area % (HPLC) and higher, containing impurities substantially less then 0.1 Area %.

19. The process according to claim 1 1 , which further comprises reacting 2- chlorobenzaldehyde with ethyl-4-[2-(N-tritylamino)ethoxy]acetoacetate in an organic solvent to form ethyl-2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate in a crude reaction mixture.

20. The process according to claims 1 1 and 19, wherein said reaction is carried out in methanol, ethanol, isopropanol and mixtures thereof as organic solvent.

21 . The process according to claims 19 and 20, wherein said solvent is ethanol.

22. Amlodipine benzenesulfonate obtained according to any of the preceding claims, wherein said compound has a purity of 99.5 Area % (HPLC) and higher, with contents of impurities substantially less then 0.1 Area %.

23. Amlodipine benzenesulfonate according to claim 22, wherein it contains substantially less than 0.1 Area % of 3,5-diethyl (±) 2-[(2-aminoethoxy)-methyl]-4- (2-chlorophenyl)-1 ,4-dihydro-6-methyl-3,5-pyridinedicarboxylate as the single impurity.

24. Amlodipine benzenesulfonate according to claims 22 and 23 in the crystalline form.