WO2012123966A1

WO2012123966A1 - Process for the preparation of 4 -substituted -1, 4-dihydropyridines

Info

Publication number: WO2012123966A1
Application number: PCT/IN2012/000138
Authority: WO
Inventors: Sachin Ulhas SONAVANE; Rohan Ashok NIKAM; Kamlesh Jayantilal Ranbhan; Arun Kanti Mandal; Ganesh Gurpur Pai
Original assignee: Arch Pharmalabs Limited
Priority date: 2011-03-04
Filing date: 2012-02-29
Publication date: 2012-09-20

Abstract

4-Substituted-l,4-dihydropyridines of formula I are prepared by a cycloaddition reaction in which the cyclization is driven to completion at ambient temperature optionally in water without any catalyst. For exemplary purposes, the invention is described in particular detail with respect to the preparation of felodipine of formula II. Felodipine, a vasodilator, is prepared by a cycloaddition reaction of alkyl 3- aminocrotonate with dichlorobenzylidene under reaction conditions whereby the product crystallizes out of the reaction solution and may be directly isolated by filtration.

Description

TITLE: PROCESS FOR THE PREPARATION OF 4- SUBSTITUTED- 1, 4 -DIHYDROPYRIDINES

Formula I

wherein Ar, R_b R₂, R₃, R4 are as defined hereinbelow.

FIELD OF THE TECHNOLOGY: The present invention relates to a novel, economical and eco-friendly process for the preparation of 4- substituted-l,4-dihydropyridine compounds represented by formula I. The process to prepare 4-substituted-l,4-dihydropyridine comprises contacting substituted benzaldehyde with alkyl acetoacetate optionally in the presence of a catalyst to form corresponding benzylidene intermediate of Formula III. The benzylidene intermediate of formula III is sequentially contacted with alkyl aminocrotonate also termed as enamine or alkyl ester of aminocrotonic acid of formula IV to form corresponding 4-substituted-l,4-dihydropyridine in neat without any solvent . The present invention is not only economical but also eco-friendly as reaction takes place in neat i.e. without use of external solvent thereby making it safe and eco friendly.

A Few examples of 4-substituted-l,4-dihydropyridine compounds which comprises benzylidene compound of formula III as an intermediate are amlodipine, Phthaloyl Amlodipine, cronidipine, diperdipine, furaldipine, isradipine, lacidipine, manidipine, mepirodipine, nifedipine, nivaldipine, nimodipine, nisoldipine, nitendipine, sagandipine and taludipine, clevidipine and the like. For exemplary purposes, the invention is described in particular details with respect to the process for the preparation of felodipine of formula II. It is understood by those skilled in the art that a similar procedure may be employed for other molecules of formula I. For preparation of compounds other than felodipine, the respective starting materials aldehyde compounds are employed.

formula II

Formula III

wherein Ar, R³and R²are as defined hereinabelow

Formula IV

wherein defined herein below

Formula IIIA

wherein R represents C1-C4 alkyl group

Formula IV A

Wherein R' is ethyl

A: wherein Ar is selected from

Ri is selected from:

o

a) C II— OFV

C) CN d) COOH

Rjfrom (a) as mentioned above and R₂ from formula I are independently selected from

a) C_rC₆ -alkyl group,

b) C3- 8- cycloalkyl,

c) C₂-C5- alkenyl

d) C_rC₄- aralkyl

e) C₂-C₄ -aralkenyl

f) C C₅-alkylNR₈R₉ g) C C₄ alkyl-0-C_rC₄-alkyl h) C_rC₄-alkylON0₂

j) -(CH₂)n-N NR¹¹

m) (CH₂)n— C— CH₃

and

s)— (CH₂)mC₃-C₆-cycloalkyl

R is selected from:

a) CpCg -alkyl

b) C₃-C₈-cycloalkyl c) (CH₂)_n-R₁₂ and

d) Hydrogen

R⁴ is selected from:

a) C,-C₈ -alkyl

b) C₃-C8-cycloalkyl

c) (CH₂)_n-R₁₂ and

d) Hydrogen

R₅, R6 and R₇ are independently selected from a) hydrogen

b) halogen

c) Nitro

o

d) C=CH— O— C II 1— Bu

' H

e) CF₃

f) Q-Qralkyl

g) C₃-C8-cycloalkyl

h) ethynyl,

i) -(CH₂)_n-R₁₂

and

k) -0-(CH₂)_n-NH-CH₂-CH(OH)CH₂-0(C₆H₅)

Rs and R₉ are independently selected from: a) C_rC₈ -alkyl

b) C₃-Cg-cycloalkyl

c) aralkyl as defined herein above and d) hydrogen

Rio is selected from a) hydrogen

b) Cj-C₈ -alkyl

c) C₃-C₈-cycloalkyl

d) d-C₄-aralkyl R] I is selected from:

a) hydrogen

b) Ci-C₄-aralkyl

c) dichlorophenyl

d) C,-C₈ -alkyl

e) C₃-C₈-cycloalkyl

Ri2 is selected from a) halogen,

b) NR₈R₉

c) NHC(0)-C_rC₈ alkyl d) SR₈

e) S0₂-pyridyl

f) OR₈

g) COOR₈

R₁₃ is selected from a) (CH₂)_n-NHR₁₄

b) -C(0)NH₂

H₂C(0)NH₂

R₁₄ is selected from

Ri5 is selected from a) -NR₈R₉

b) 1-piperdinyl x is O, S or N ₆

m is 0 to 2

n is 0 to 3 BACKGROUND OF THE INVENTION:

The present invention relates to a novel, economical and eco friendly process for the preparation of 4-substituted-l,4-dihydropyridine compounds represented by formula I which are known for their use in making a wide range of medicaments. Felodipine, the compound of Formula II, is a known vasodilator (Merck Index 11, 3895 and references cited therein). US4220649, US4705797, US4769374, US4806544, US4874773, EP0089167A, EP0063365 and EP0342182 disclose phenyl- 1,4-dihydro- pyridine compounds which have therapeutic activity in the treatment of heart disease .

Kirchner, Ber. 25, 2786 (1892) describes the reaction of aldehydes with 3- ketocarboxylic esters and ammonia in accordance with the reaction given below in Scheme-I:

Scheme I:

Aldehyde 3-keto carboxylic acid ester . . ... . . . . ... .

4 substituted-l,4-dihydro

pyridine

wherein R is optionally substituted aromatic group e.g. phenyl

R_j and R₂ are same or different groups and each represents C_]-C₅ alkyl group

Fox et al. J. Org. Chem. 16, 1259 (1951) describes the reaction of aldehydes with 3 -ketocarboxylic esters and enaminocarboxylic esters in accordance with the reaction given below in Scheme-II:

Scheme II

Aldehyde 3-keto carboxylic acid ester Enaminc carboxylic acid ester 4 substituted-1,4- dihydro pyridine

wherein R is optionally substituted aromatic group e.g. phenyl

R_| and R₂ are same or different groups and each represents C C₅ alkyl group Knoevenagel, Ber. 31, 743 (1898) describes the reaction of ylidene-3- ketocarboxylic acid esters (benzylidene) with enaminocarboxylic acid esters (enamine) in accordance with the reaction given below in scheme-Ill:

benzylidene-3-keto carboxylic enamine carboxylic 4 substituted 1,4- acid ester acid ester dihydropyridine

wherein R is optionally substituted aromatic group e.g. phenyl

Ri and R₂ are same or different groups and each represents C₁-C5 alkyl group

In general the preparation of 4- Substituted- 1, 4-dihydropyridines of formula I comprises a two step synthesis, the last step of which comprises formation of the dihydropyridine ring. Formation of the 4-aryldihydropyridines has been accomplished by:

1) Simultaneous reaction of an aromatic aldehyde, an acetoacetate ester and 3-aminocrotonic acid ester (as described above in scheme II) in a single step;

2) A stepwise procedure comprising contacting an aromatic aldehyde with an acetoacetate ester and then reacting the resulting benzylidene compound with a 3-aminocrotonic acid ester (as described above in scheme III). Regardless of whether the sequence of reactions is a single step or two steps, the disclosed cycloaddition has always been thermally driven to completion. Thermal cycloaddition reactions have also been described which are carried out in the presence of an organic base or the acetic acid salt of an organic base.

US4264611 (hereinafter referred as '611) discloses both the procedures, one step process comprising simultaneous reaction of an aromatic aldehyde, an acetoacetate ester and 3-aminocrotonic acid ester in an alcohol solvent. Two steps process comprising the reaction of an aromatic aldehyde with an acetoacetate ester and then reacting the resulting benzylidene with a 3 -amino crotonic acid ester in an alcoholic solvent. Example 1 of the '611 discloses the preparation of felodipine comprising the reaction of 2,3- dichlorobenzylideneacetyl acetic acid methyl ester and 3-aminocrotonic acid ethyl ester in tert butanol and the contents were kept at ambient temperature for four days. There is no indication about the purity.

Example 2 of '611 describes one step reaction comprising of 2,3- dichlorobenzaldehyde, 3-aminocrotonic acid ethyl ester and acetyl acetic acid 2-methoxyethyl ester in ethanol at reflux to form corresponding dihydro pyridine with only 36% yield without mentioning the purity of the product. The drawback associated with '61 1 is the time required for the completion of the reaction (four days as described in Example 1 and lower yield as described in Example 2.

US5310917 discloses the preparation of 4-substituted-l,4-dihydropyridines by a cycloaddition reaction wherein cyclization is driven to completion, after thermal reaction, by addition of an acid. Felodipine, a vasodilator, is prepared by a cycloaddition reaction of ethyl 3-aminocrotonate with a suitably substituted dichlorobenzylidene under reaction conditions whereby the product crystallizes out of the reaction solution and may be directly isolated by filtration. It discloses a process comprising heating a mixture of a benzylidene with an aminocrotonate ester in the presence of a strong acid. Use of the acid not only accelerates the reaction rate but also minimizes the impurity formation by reducing span of thermal reaction thereby enhancing the purity of felodipine. As per the findings of the said patent the ring closure in the cycloaddition reaction of substituted 3-1iminocrotonate and substituted benzylidene is not only thermally driven to completion; rather, a strong acid is also required to be added to reduce heating period and to catalyze and facilitate the complete cyclization to provide the 4-substituted- 1 ,4-dihydropyridine.

US4600778 discloses preparation of felodipine comprising cycloaddition reaction of ethyl 3-aminocrotonate and 2,3-dichlorobenzylidene compound in isopropanol by refluxing for 24 hours without mentioning the purity (Example 3). Drawback of this patent is the lengthy thermal reaction that will be contributing towards impurity formation as stated in US5310917.

EP0370974 discloses preparation of the 4-substituted-l,4-dihydropyridine comprising cycloaddition reaction of ethyl 3-aminocrotonate and benzylidene compound in isopropanol using a organic base like triethylamine.

US6858747B2 discloses the process for the preparation of felodipine and nitrendipine comprising contacting appropriate benzylidene intermediate having the high purity (nitrendipine benzylidene in case of nitrinedipine) with ethyl aminocrotonate in an alcoholic solvent under reflux temperature for 10-30 hours. The solvent is removed and an anti-solvent is added. The product is then filtered and washed with an additional amount of solvent to obtain Felodipine.

US5977369A (hereinafter referred as '369) discloses reaction of benzylidene intermediate with alkyl or alkylaryl aminocrotonate, e.g., ethyl aminocrotonate, methylaminocrotonate, using C C₆ alcohol. The 2,3- dichloro benzylidene intermediate is condensed with a suitably substituted enamine, such as, ethylami fluxing alcoholic solvent.

'369 discloses that felodipine reaction is sensitive to the amount of ethylaminocrotonate charged during coupling reaction. When ethyl aminocrotonate charged exceeds about 1 equivalent (per benzylidene intermediate), symmetrical diesters of formulae B and/or C are produced, especially the diethyl ester (C). These ester impurities are difficult to remove in subsequent purification process. In addition to the ethylaminocrotonate charging sensitivity, the felodipine reaction of coupling is also sensitive to reaction time. The amount of symmetrical diesters of formulae B and/or C increases with time at the expense of the felodipine product.

EP0371492 discloses reaction between the compound of 2-haloethyl 2- benzylidene-3-oxobutanoate and the compound selected from methyl 3- aminocrotonate, ethyl 3-aminocrotonate, isopropyl 3-aminocrotonate, n- propyl-3-aminocrotonate, isobutyl-3-aminocrotonate, n-butyl-3- aminocrotonate, sec-butyl 3-aminocrotonate, tert-butyl 3-aminocrotonate, 2- methoxy ethyl 3-aminocrotonate, methoxypropyl 3-aminocrotonate, ethoxyethyl 3-aminocrotonate, or the like, at a reaction temperature of 0°C to 150°C and a reaction time of one hour to three days in a reaction medium such as methanol, ethanol, isopropyl alcohol, n-butyl alcohol, toluene, benzene, cyclohexane alone or in combination in presence of dehydrating agent selected from anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieve 4A, molecular sieve 3 A or the like.

EP0534520 discloses the process for the preparation of dihydropyridines by heating the mixture of the benzylidene compound of the formula III and suitably substituted enamine of the formula IV in water miscible solvent at elevated temperature, followed by the addition of strong acid. The reaction product is then isolated by extractive workup with a suitable organic solvent such as methylene chloride and ethyl acetate. The benzylidene compound of the formula III as described hereinabove is obtained comprising reaction of suitably substituted benzaldehyde selected from 3-nitrobenzaldehyde, 2- nitrobenzaldehyde, and 2,3-dichlorobenzaldehyde with a suitably substituted β-keto acid ester selected from ethyl acetoacetate, methyl acetoacetate, and cyclopropyl acetoacetate, in the presence of a catalyst, selected from acetic acid, piperidine, a mixture of acetic acid and piperidine.

CN101613314 discloses a process for the preparation of Felodipine comprising cycloaddition of methyl 2-(2,3-dichlorobenzylidene)acetoacetate with ethyl 3-aminocrotonate in alcohol solvent in the presence of a strong acidic cation exchange resin. IN2006MU00669 discloses a process for the preparation of 4-substituted 1,4-dihydro pyridines comprising contacting a benzylidene compound with 3-aminocrotonate, in presence of an organic solvent, wherein the reaction is characterized by the fact that the said organic solvent is continuously distilled from the reaction mass so as to facilitate removal of water.

US5942624 (hereinafter referred as '624) discloses a process for the preparation of felodipine by cyclization of dichlorobenzylidene intermediate with ethyl 3-aminocrotonate using pyridine as catalyst in alcohol solvent. The product was crystallized from acetone to give felodipine. '624 does not indicate about the purity of product.

EP08793707 discloses a process for the preparation of S-felodipine obtained from asymmetric synthesis comprising the formation of benzylidene intermediate of formula C followed by its cycloaddition with as depicted in scheme-IV given herein below.

As per the pharmacopeia the impurities present in felodipine are as follows:

imp Λ

Ethyl ylpyridine-3,5-dicarboxylate

Imp B

D ridine-3,5-dicarbo]iylate

Imp C

Diethyl 4-(2 3-dichlorophenyl)-2,6-dimethyl-l,4-dihydropyridine-3,5-dicarboxylate

Disadvantages associated with the prior art are:

1) Difficulty in isolation of 4-substituted 1,4-dihydropyridines if impure benzylidene intermediate is used as such for the cycloaddition reaction, resulting into extractive work-up and lower yield.

2) Long duration of thermal reaction of cycloaddition and its impact on formation of symmetrical impurities of formulae B and/or C.

3) Thermal driven cycloaddition of benzylidene intermediate of formula III and enamine of formula IV at reflux temperature e.g. reaction at about 80°C when isopropanol as solvent generating impurities of formulae B and C.

4) Use of alcohols as solvents may results in formation of impurities due to trans-esterification. Felodipine being unsymmetrical ester trans-esterified impurities gets formed.

5) Use of acid as a catalyst during the reaction of cycloaddition of benzylidene intermediate of formula III and enamine of formula IV after thermal reaction in order to take it for completion. 6) Use of strong acidic cation exchange resin.

7) Azeotropic removal of water using simultaneous distillation of solvent resulting into excessive consumption of solvent.

8) Use of foul smelling pyridine as a catalyst during cycloaddition of benzylidene intermediate of formula III and enamine of formula IV in alcohol solvent.

None of the prior art teaches or motivates or a person of ordinary skill to anticipate about carrying out the reaction with out using any solvent for cycloaddition reaction between benzylidene intermediate of formula III and alkyl aminocrotonate of formula IV for the preparation of compound of formula I in excellent yield and purity thus making it eco friendly and economically beneficial and viable at plant scale.

In view of above there is a dire need for an efficient, industrially viable, economical and eco-friendly process for the preparation of substantially pure 4-substituted 1,4-dihydropyridines of Formula I in high yield overcoming deficiencies associated with the processes disclosed therein in the prior art for the preparation of 4-substituted 1,4-dihydropyridines. Disclosed herein is an efficient, ecofriendly, economical and industrially viable process for the preparation of 4-substituted- 1,4-dihydropyridines of formula I which overcomes the shortcomings associated with the processes disclosed therein in the prior art. In a preferred embodiment a process for the preparation of felodipine is disclosed.

The present invention discloses cycloaddition reaction comprising contacting benzylidene intermediate of formula III and enamine of formula IV to obtain 4-substituted 1,4-dihydropyridines as depicted in the following scheme V Scheme V

wherin Ar,R\R²,R³ and R⁴ are defined as above

The novelty and inventive features of the present invention are:

1) The present invention is not only improvement over the prior art processes but also provides an economical, eco-friendly and industrially viable process hence beneficial to the industry and environment.

2) The cycloaddition reaction between benzylidene intermediate of formula III and alkyl aminocrotonate of formula IV for the preparation of compound of formula I is conducted neat without any solvent. This aspect is neither previously disclosed nor there is any teaching or indication in the prior art nor a person skilled in the art can anticipate from the processes disclosed therein in the prior art.

3) Avoids use of acid or strong acidic cation exchange resin for the completion of cycloaddition reaction as reported therein in the prior art.

4) The cycloaddition comprising reacting compound of formulae III with compound of formula IV in neat without any solvent is also conducted at room temperature (25-30°C) which is contrary to the concept disclosed therein in the prior art wherein it has been described that thermal driven reaction criteria is necessary for driving such reaction towards completion. The said reaction gets takes longer duration when (about 11 hrs) carried out at room temperature (25-30°C) with improved impurity profile. However, when the same reaction is carried out in neat without using any solvent at 55-60°C the reaction gets completed in a shorter time about 4 Hrs with still better impurity profile.

5) Ease of isolation avoiding extracting operational procedures. 6) Providing the compound of formula I especially felodipine of formula II having no impurity of formula A and minimized or nil amount of symmetrical diester impurities of formulae B (dimethyl) and/or C (Diethyl).

7) Eliminating use of dehydrating agent as reported in the prior art

10) Eliminating azeotropic distillation of solvent for the removal of water as reported in the prior art.

11) Eliminating use of pyridine as a catalyst as reported in the prior art.

12) Short duration required for the completion of the reaction at ambient temperature than reported in the prior art.

The term "Thermal reactions" defined herein above and herein below means the reaction that requires additional heat for progression and completion of the reaction.

It has been observed by the inventors of the present invention that the ring closure by the cycloaddition reaction of substituted benzylidene of formula III and substituted 3-aminocrotonate of formula IV is neither a necessarily thermally driven reaction nor requires use of a strong acid to catalyze and facilitate the complete cyclization to provide the 4-substituted-l,4- dihydropyridine of formula I.

Prior art discloses use of alcohol preferably isopropyl alcohol (isopropanol) (IP A) as a solvent for the preparation of felodipine of the formula II comprising the condensation of benzylidene compound of formula III and enamine of compound of formula IV. US5977369A discloses the process for the preparation of Felodipine comprising the reaction between dichlorobenzylidene intermediate of formula Ilia and ethyl-3- aminocrotonate of formula IVA using alcohol preferably IPA as a solvent. The inventors of the present invention observed that the said process resulted into the formation of symmetrical impurities of the formulae B and C upto 16% and 10% respectively when IPA is used as a solvent. When ethyl alcohol is used as a solvent, symmetrical impurities of the formulae B and C are upto 16% and 4.2% respectively. Therefore, it has been observed that alcohols are not appropriate solvents for conducting the said cycloaddition reaction. Reaction results are described in table I. Furthermore, processes disclosed in the prior art for the preparation of 4-substituted 1,4- dihydropyridines preferably felodipine comprises using dehydrating agent or continuous distillation of the solvent during the reaction to remove water formed as a byproduct during the reaction indicating that the presence of water hinders the reaction. Prior art in a vivid manner teaches that the water should not be present or the reaction has to be carried out in the absence of water and particularly that in no way water can be used as a solvent for the said reaction. However, the inventors of the present invention have carried out the same reaction in water alone or in combination with water miscible solvents resulting into the formation of product indicating that the traces of water generated during the reaction of compound of benzylidene compound of formula III with 3-aminocrotonate (also referred as enamine) of formula IV should neither hinder nor inhibit the progress of the reaction. Results described in Table III validates the scope of the present invention that water in traces present in reaction medium is not a hurdle which permits to avoid the use of dehydrating agent or azeotropic distillation which makes the process non-economical and industrially unviable as the azeotropic distillation and dehydrating agent operational steps use large volume of solvent. Inventors of the present inventions have also observed that preparation of 1,4-dihydropyridines comprising contacting benzylidene compound of formula III with enamine compound of formula IV in a biphasic system comprising water and water immiscible solvent optionally in presence of a phase transfer catalyst is not an ideal reaction medium to achieve the optimized results. Similarly use of Lewis catalyst, use of PTC with water as solvent or in neat does not provide the satisfactory results as described in table III compared to results obtained when the said reaction is carried out in neat with out using any solvent.

During the optimization of the process of the present invention, cycloaddition reaction comprising neat reaction without any solvent between dichlorobenzylidene intermediate of formula Ilia and alkyl 3-aminocoronate of formula IVA without using any solvent has been studied at various temperature ranges of about 5°C to about 120°C and the results of the same have been summarized in table III. The results indicate that the preferable temperature range is about 55-60°C that gives best results in respect of yield, purity and impurities profile.

Another important feature of the present invention is that the cycloaddition reaction of substituted benzylidene of formula III and substituted 3- aminocrotonate of formula IV when conducted in neat without using any solvent results in the formation of 4-substituted 1,4-dihydropyridines having higher purity, better yield and with no impurity of formula A and nil or negligible impurities of formulae B and C. Another remarkable feature of the present invention is that the reaction gets completed at room temperature compared to reflux temperature as disclosed in the prior art eliminating the formation of some impurities and eliminating or minimizing the formation of some which are formed in substantial amount when reaction is carried out in accordance with the process disclosed in therein in the prior art comprising thermal driven reaction and use of alcoholic solvents at reflux temperature.

Process disclosed therein in the prior art demonstrates that during the reaction between benzylidene of formula III and enamine compound of formula IV a molecule of water is liberated which needs to be removed from the reaction mixture to facilitate the reaction to proceed in forward direction in a shorter time. However, inventors of the present invention while working on the invention have observed that the said reaction takes place even in water as a solvent; proving that traces of water that gets generated during the condensation of the compound of formula III with compound of formula IV is not a hurdle. This avoids the use of dehydrating agent or azeotropic distillation which intern avoids excessive consumption of the solvent.

Yet another feature of the present invention is to optimize the ideal molar ratio of the reactants for the best results in respect of yield, purity and impurities profile. Inventors of the present invention have studied the various neat reactions without using any solvent by varying molar ratios of the reactants and the results are summarized in TABLE IV. Best results are obtained when compounds of formulae III and IV are used in the ratio of 1 : 1 at temperature of about 55-60°C in about 4 hours duration thus avoiding the formation of impurities.

TABLE I

INDICATING THE FORMATION OF IMPURITIES A AND B WHEN ALCOHOLS ARE USED

AS SOLVENT

TABLE II

INDICATING WATER WITH WATER MISCIBLE SOLVENTS, BIPHASIC AND USE OF

LEWIS CATALYST AS NON -FAVOURABLE PARAMETERS

TABLE III

INDICATING NEAT REACTION AS IDEAL MODE FOR THE REACTION AND REACTION CAN PROCEED IN WATER RATHER THAN IT IS A HURDLE

TABLE IV

INDICATING STUDIES AT VARIOUS MOLR RATIOS OF COMPOUNDS OF FORMULAE III

AND IV

OBJECTS OF THE INVENTION:

First aspect of the present invention is to provide an improved process for the preparation of 4-substituted-l,4-dihydropyridines of formula I.

Second aspect of the present invention is to provide a process for the preparation of 4-substituted-l,4-dihydropyridines comprising contacting benzylidene compound of formula III with enamine compound of formula IV without using any solvent thereby conducting the reaction in neat to obtain substantially pure product in higher yield. Third aspect of the present invention is to provide a process for the preparation of 4-substituted-l,4-dihydropyridines at ambient temperature which is contrary to the concept reported in the prior art that the cyclization to the completion is a thermal driven reaction as it is carried out at elevated solvent reflux temperature i.e. the reaction requires external heating to proceed at a reasonable rate.

Fourth aspect of the present invention is to provide a process for the preparation of 4-substituted-l, 4-dihydropyridines comprising contacting benzylidene compound of formula III with enamine compound of formula IV in water as solvent.

Fifth aspect of the present invention is to provide a process for the preparation of 4-substituted-l, 4-dihydropyridines comprising contacting benzylidene compound of formula III with enamine compound of formula IV wherein 4-substituted-l, 4-dihydropyridine is isolated by filtration of the reaction mixture, thereby eliminating the need for a more expensive and time consuming extractive isolation procedure which also employs environmentally harmful halogenated solvents in large volumes.

Sixth aspect of the present invention is to provide a process for the preparation of felodipine appreciably free from the impurities of formula A, B and C.

Seventh aspect of the present invention is to provide a process for the preparation of felodipine complying the specifications comprising contacting benzylidene compound of formula IIIA with enamine compound of formula IVA in neat without solvent.

Eighth aspect of the present invention is to provide a process for the preparation of felodipine comprising contacting 2,3-dichloro benzylidene compound of formula IIIA with ethyl 3-aminocrotonate of compound of formula IVA wherein felodipine is isolated by filtration of the reaction mixture, thereby eliminating the need for a more expensive and time consuming extractive isolation procedure which may employ environmentally harmful halogenated solvents in large volumes. Ninth aspect of the present invention is to provide an improved process for the preparation of felodipine having higher yield with higher purity compared to product obtained in accordance with the processes disclosed in the prior art.

SUMMARY OF THE INVENTION:

The present invention relates to a novel, eco friendly, industrially viable and economical process for the preparation of 4-substituted-l,4-dihydropyridine compounds of formula I and analogs thereof. For exemplary purposes, the invention is described in particular detail with respect to the preparation of felodipine of formula II. The process to prepare 4-substituted-l,4- dihydropyridine comprises a two step procedure comprising contacting substituted benzaldehyde with alkyl acetoacetate optionally in the presence of a catalyst to obtain benzylidene intermediate of Formula III. The said benzylidene intermediate is sequentially contacted with alkyl aminocrotonate also termed as enamine or alkyl ester of amino crotonic acid of formula IV in neat without using any solvent or using water as a solvent to provide 4-substituted-l,4-dihydropyridine of formula I.

Contacting or contacted in the specifications means reacting, stirring, mixing, refluxing, condensing and the like.

The term "neat" used in the specification means there is no solvent used for the reaction. Reaction comprises reaction of only reactants.

DETAILED DESCREPTION OF THE INVENTION:

Reference will now be made in detail to the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In addition, and as will be appreciated by one skilled in the art, the invention may be embodied as a method, system or process.

The present invention relates to an improvement in the process for the preparation of the compound of formula I to overcome the shortcomings in the processes disclosed therein in the prior art. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. Optimum temperature chosen should neither inhibit the reaction nor form the unwanted impurities.

The time required for the reaction also varies widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period of about 2 to about 15 hours suffices.

The reaction can also be performed in a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved.

The reagents employed in the synthetic scheme are well known in the art and are all readily commercially available. The compound of the formula III can be prepared for the purpose of the present invention by any of the methods known in the literature. For example process for the preparation of 2,3- dichloro benzylidene of formula Ilia is given in scheme- VI comprising contacting 2,3-dichlorobenzaldehyde with methyl acetoacetate, in the presence of a catalyst selected from piperidine, acetic acid, and a mixture thereof to provide after aqueous workup the dichlorobenzylidene of formula Ilia.

Efficient, industrially viable and economical processes for the preparation of compound of formula I are illustrated herein below in various embodiments within the scope of the present invention.

In a general embodiment benzylidene intermediate of formula III is contacted with enamine compound of formula IV in a suitable stochiometric ratio in neat without using any solvent at suitable temperature as specified in table-IV hereinabove till the completion of the reaction. After the completion of the reaction solvent is added to the reaction mass at about the same temperature and heat if required to get a clear solution followed by addition of an antisolvent followed by cooling the reaction mass to separate the product as a solid mass. Product is filtered off and dried under the vacuum. The following scheme-VII illustrates the preparation of the compound of formula I.

Scheme-VII

III acid ester IV ormu a

wherin A^R'.R²,!*³ and R⁴ are defined as above

wherein R_l5 R , R₃, R4 are as defined under subheading A

The preferred stoichometric ratio of compounds of formulae III and IV is about 1 :1. The preferred suitable temperature is about 55-60°C. Solvent is selected from the group comprising hydrocarbons, halogenated hydrocarbons and ethers or mixture thereof.

Hydrocarbon solvent is selected from the group comprising toluenes, xylenes, chlorobenzene, o-dichlorobenzene or mixture thereof and the like. Halogenated solvent is selected from the group comprising chloroform, methylene chloride or mixture thereof and the like. Ethereal solvents are selected from the group comprising dimethyl ether, diethyl ether, diisopropyl ether, methyl tert butyl ether mixture thereof and the like.

Anti solvent used in the embodiment is selected from the group comprising water immiscible solvents comprising aliphatic and aromatic hydrocarbons, ethereal solvents, halogenated solvents or the mixture thereof and the like.

Aliphatic hydrocarbon antisolvent is selected from the group comprising straight chain or branched acyclic hydrocarbons or cyclic hydrocarbons selected from the group comprising hexane (commercial or normal), heptane (commercial or normal), 2,2,4-trimethylpentane, or mixture thereof and the like. Ethereal solvent is selected from the group comprising dimethyl ether, diethyl ether, diisopropyl ether, methyl tert butyl ether or mixture thereof and the like. Aromatic hydrocarbon is selected from the group comprising benzene, toluene, xylenes, chlorobenzene, o-dichlorobenzene or mixture thereof and the like. Halogenated solvent is selected from chloroform, methylene chloride or mixture thereof and the like.

In a preferred embodiment ethyl ester of 2,3- dichlorobenzylidene of formula IIIA is contacted with enamine represented by methyl-3- aminocrotonate of formula IVA in the stochiometric ratio as specified in Table-IV hereinabove under the neat condition without using any solvent at suitable temperature as specified in table-IV hereinabove till the completion of the reaction. After the completion of the reaction solvent is added to the reaction mass and contents are heated to get clear solution followed by adding antisolvent and cooling the reaction mass for the complete separation of the product as a solid. Felodipine is filtered off and dried under the vacuum.

Scheme-VIII

2,3-dichloro benzylidene int methyl 3-amino crotonate Felodipine

The term "neat" used in the specification means there is no solvent used for the reaction.

The preferred stochiometric ratio of compounds of formulae IIIA and IVA is about 1 : 1. The preferred suitable temperature is about 55-60°C.

Solvent is selected from the group comprising hydrocarbons, halogenated hydrocarbons and ethers or mixture thereof.

Aliphatic hydrocarbon antisolvent is selected from the group comprising straight chain or branched acyclic hydrocarbons, ^" cyclic hydrocarbons selected from hexane (commercial or normal), heptane (commercial or normal), 2,2,4-trimethylpentane, or mixture thereof and the like. Ethereal solvent is selected from the group comprising dimethyl ether, diethyl ether, diisopropyl ether, methyl tert butyl ether or mixture thereof and the like. Aromatic hydrocarbon is selected from the group comprising benzene, toluene, xylenes, chlorobenzene, o-dichlorobenzene or mixture thereof and the like. Halogenated solvent is selected from chloroform, methylene chloride or mixture thereof and the like.

Preferably solvent is toluene and antisolvent is heptane.

In one more specific embodiment of the invention methyl ester of 2,3- dichloro-benzylidiene intermediate of formula IIIA is contacted with ethyl- 3 -amino crotonate of formula IVA in suitable stochiometric ratio in a water at suitable temperature as specified in table-IV given hereinabove. Reaction mass is stirred at same temperature till the reaction is complete. After the reaction is complete water is removed under the reduced pressure. The residue obtained is then charged with antisolvent under stirring. Contents are cooled for complete separation of the product in solid form. Felodipine so obtained is filtered off washed with mixture of methyl tert-butyl ether and heptanes. Felodipine is dried under vacuum.

Anti solvent is selected from the groups comprising aliphatic hydrocarbons, ethers, aromatic hydrocarbons, halogenated solvents or mixture thereof.

Antisolvent is selected from the group comprising straight chain or branched chain acyclic , cyclic hydrocarbons selected from hexane (commercial or normal), heptanes (commercial or normal), 2,2,4-trimethylpentane, cyclohexane or mixture thereof and the like. Ethereal solvent is selected from the group comprising dimethyl ether, diethyl ether, diisopropyl ether, methyl tert butyl ether or mixture thereof and the like. Aromatic- hydrocarbon is selected from benzene, toluenes, xylenes, chlorobenzene, o- dichlorobenzene or mixture thereof and the like. Halogenated solvent is selected from the group comprising chloroform, methylene chloride or mixture thereof and the like.

The term "preferable and suitable temperature pertains to 55°C to about 60°C" in the context of which inventors wish to state that reaction is studied at different temperature parameters ranging from about 10 to about 100°C but the process is optimized at about 55 to about 60°C as the said temperature range results into the product in good yield having high purity and ideal impurity profile minimising or eliminating formation of impurities of formulae B, C and A.

The reaction mass after the addition of antisolvent is cooled to preferred temperature of 10-15°C for the complete separation of product in solid form.

The term "room temperature" used herein above and herein below is the temperature in the range of about 25 to about 30°C which is very much possible in countries like India.

The present invention can be best illustrated by the following examples.

Step 1: Preparation of Methyl ester of 2,3-dichloro-benzylidiene intermediate

Example 1 : 2, 3-dichlorobenzaldehyde (50.0g, 0.28 mol) reacts with methyl acetoacetate (33.17g, 0.28 mol) in the presence of acetic acid (17.14 gm, 0.28 mol) and piperidine (5.95g, 0.07 mol) in an alcoholic solvent at temperature of 30-60°C. The reaction was maintained for 4-10 hrs and monitor on TLC till completion. After distillation of alcoholic solvent, MDC was added and it was washed with NaHC0₃ solution. MDC layer was distilled out under reduced pressure; the resultant product was isolated by addition of mixture of IPA and heptane. The solids were filtered and washed with mixture of IP A/heptane. The solid was dried under vacuum to provide methyl benzylidene in a yield of about 75-80% with HPLC purity NLT 99.0%. Step 2: Preparation of Felodipine:

Example 2: Methyl ester of 2,3-dichloro-benzylidiene intermediate (50.0 g, 0.18 mol) was charged in a well equipped reaction assembly followed by the addition of ethyl-3-amino crotonate (28.5 g, 0.22 mol) at 25- 30°C.Reacton mass was stirred at same temperature with simultaneous monitoring of the reaction for 11 hours. This reaction mass was then charged with (150 ml toluene) and 150 ml of heptane under stirring at 25-30°C. Contents were cooled to 10-15°C for another 30 minutes. Felodipine so obtained was filtered off washed with mixture of methyl tert-butyl ether and heptanes. Felodipine was dried under vacuum. Yield obtained was: 58 g with HPLC purity of 98.5%.

Example 3: Methyl ester of 2,3-dichloro-benzylidiene intermediate (50.0 g, 0.18 mol) was charged in a well equipped reaction assembly followed by the addition of 150 ml water and ethyl-3-amino crotonate (28.5 g, 0.22 mol) at 25-30°C.Reacton mass was stirred at same temperature with simultaneous monitoring of the reaction for 14 hours. Water was removed under the reduced pressure. The residue obtained was then charged with (150 ml toluene) and 150 ml of heptane under stirring at 25-30°C. Contents were cooled to 10-15°C for another 30 minutes. Felodipine so obtained was filtered off washed with mixture of methyl tert-butyl ether and heptanes. Felodipine was dried under vacuum. Yield obtained was: 52 g with HPLC purity of 78%.

Example 4 using Benzylidene intermediate: EAC ratio 1 : 1 :

The cycloaddition reaction between methyl benzylidene (25.0 gm. 0.091 mol) and ethyl 3-amino crotonate (11.80 gm, 0.091mol) was carried out under solvent-free (in neat) condition. The reaction mixture was heated in temperature ranges between 55-60°C for 4 hrs. After completion of reaction, added toluene and heated to 65-70°C to get clear solution. The solid was precipitated by addition of heptane. After drying felodipine was obtained as pale yellow solid with HPLC purity of 99.2% and yield 79% Example 5 using Benzylidene intermediate: EAC ratio 1 :1.5:

The cycloaddition reaction between methyl benzylidene (25.0 gm. 0.091 mol) and ethyl 3-amino crotonate (17.72 gm, 0.136mol) was carried out under solvent-free (in neat) condition. The reaction mixture was heated in temperature ranges between 55-60°C for 3 hrs. After completion of reaction, added toluene and heated to 65-70°C to get clear solution. The solid was precipitated by addition of heptane. After drying felodipine was obtained as pale yellow solid with HPLC purity of 98.8% and yield 74%.

Example 6 using Benzylidene: EAC ratio 1 :2.0:

The cycloaddition reaction between methyl benzylidene (25.0 gm. 0.091 mol) and ethyl 3-amino crotonate (23.62 gm, 0.183mol) was carried out under solvent-free condition. The reaction mixture was heated in temperature ranges between 55-60°C for 2 hrs. After completion of reaction, added toluene and heated to 65-70°C to get clear solution. The solid was precipitated by addition of heptane. Crystallization using toluene heptane mixture after drying felodipine was obtained as pale yellow solid with HPLC purity of 98.5% and yield-72%.

Example 7 using Benzylidene: EAC ratio 1 : 1 at 80-85°C

The cycloaddition reaction between methyl benzylidene (25.0 gm. 0.091 mol) and ethyl 3-amino crotonate (11.80 gm, 0.091mol) was carried out under solvent-free condition. The reaction mixture was heated in temperature ranges between 80-85°C for 2.5 hrs. After completion of reaction, added toluene and heated to 65-70°C to get clear solution. The solid was precipitated by addition of heptane. After drying felodipine was obtained as pale yellow solid with HPLC purity of 92% and yield-63%.

Claims

CLAIMS: We claim:

1. A process for the preparation of 4-substituted 1 ,4-dihydro pyridine of the formula I

Formula I

A: wherein Ar is selected from

i is selected from: O

a) -OR,

^!R⁹RNC

C) CN

d) COOH

Rl 'from (a) as mentioned above and R₂ from formula I are independently selected from

a) Ci-C₆ -alkyl group,

b) C₃-C₈- cycloalkyl,

c) C₂-C₅- alkenyl

d) C_rC₄- aralkyl

e) C₂-C₄ -aralkenyl

f) C C₅-alkylNR₈R₉

g) C C₄ alkyl-0-C C₄-alkyl

h) C C₄-alkylON0₂

O

m)— (CH₂)n— C— CH₃

nd

s)— (CH₂)mC₃-C₆-cycloalkyl

R³ is selected from:

a) C_rC₈ -alkyl

b) C₃-C₈-cycloalkyl

c) (CH₂)_n-R₁₂ and

d) Hydrogen

R⁴ is selected from:

a) Ci-Cg -alkyl

b) C₃-C₈-cycloalkyl

c) (CH₂)_n-R₁₂ and

d) Hydrogen

R₅, R6 and R₇ are independently selected a) hydrogen

b) halogen

c) Nitro

o

II

d) C=CH— O— C 1— Bu

' H

e) CF₃

f) C Qs-alkyl

g) C₃-C₈-cycloalkyl

h) ethynyl,

and

k) -0-(CH₂)_n-NH-CH₂-CH(OH)CH₂-0(C₆H₅)

R₈ and R₉ are independently selected from: a) C_rC₈ -alkyl

b) C₃-C₈-cycloalkyl

c) aralkyl as defined herein above and d) hydrogen

R₁₀ is selected from a) hydrogen

b) C C₈ -alkyl

c) C₃-C₈-cycloalkyl

d) C_rC₄-aralkyl

Rn is selected from:

a) hydrogen

b) C_rC₄-aralkyl

c) dichlorophenyl

d) C_rC₈ -alkyl

e) C₃-C₈-cycloalkyl

R₁₂ is selected from

a) halogen,

b) NR₈R₉

c) NHC(0)-C_rC₈ alkyl

d) SR₈

e) S0₂-pyridyl

f) OR₈

g) CQOR₈

R_]3 is selected from

a) (CH₂)„- HR₁₄

b) -C(0)NH₂

c) -(CH₂)_n-NHCH₂C(0)NH₂

R]₄ is selected from

a) hydrogen,

R₁₅ is selected from

a) -NR₈R₉

b) 1-piperdinyl x is O, S or NR₆

m is 0 to 2

n is 0 to 3 comprising the steps of:

a) contacting benzylidine compound of the formula III with enamine compound of formula IV in neat without solvent till completion of reaction;

Formula III

wher R²are as defined hereinaabove

Formula IV

wherein R₄ and Rj are defined herein above b) adding solvent to the reaction mass of step a);

c) optionally heating the reaction mass of step b) to obtain a clear solution; d) adding an anti solvent to the reaction mass of step c) to obtain compound of formula I in solid form; e) optionally cooling the contents of step d) to induce complete precipitation/ crystallization;

f) collecting the compound of formula I by filtration.

2. A process of claim lb, wherein solvent is selected from the group comprising water immiscible solvents selected from aliphatic and aromatic hydrocarbons, ethers and halogenated solvents.

3. A process of claim Id wherein antisolvent is selected from the group comprising water immiscible non-polar solvents selected from the aliphatic hydrocarbons, ethereal solvents.

4. A process for the preparation of felodipine of the formula II

comprising:

a) contacting methyl ester of 2,3-dichloro-benzylidiene of formula Ilia with enamine of the formula IVa in neat without solvent till completion of reaction;

b) adding solvent to the reaction mass of step a);

c) optionally heating the reaction contents of step b) to obtain a solution; d) adding an anti solvent to the solution obtained in step c) to obtain compound of formula III in solid form;

e) optionally cooling the contents of step d) to induce complete precipitation/crystallization;

f) collecting the felodipine by filtration.

Formula IIIA

wherein R represents C_rC₄ alkyl group

Formula IV A>

R and R* are same or different

and each represents C1-C5 alkyl

group

5. A process of claim 6b wherein solvent is selected from the group comprising water immiscible solvents selected from aromatic hydrocarbons, ethers and halogenated solvents.

6. A process of claim 6d wherein antisolvent is selected from the group comprising water immiscible non-polar solvents selected from the aliphatic hydrocarbons, ethereal solvents.