WO2012123966A1 - Procédé pour la préparation de 1,4-dihydropyridines substituées en position 4 - Google Patents

Procédé pour la préparation de 1,4-dihydropyridines substituées en position 4 Download PDF

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WO2012123966A1
WO2012123966A1 PCT/IN2012/000138 IN2012000138W WO2012123966A1 WO 2012123966 A1 WO2012123966 A1 WO 2012123966A1 IN 2012000138 W IN2012000138 W IN 2012000138W WO 2012123966 A1 WO2012123966 A1 WO 2012123966A1
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formula
reaction
solvent
alkyl
cycloalkyl
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PCT/IN2012/000138
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Sachin Ulhas SONAVANE
Rohan Ashok NIKAM
Kamlesh Jayantilal Ranbhan
Arun Kanti Mandal
Ganesh Gurpur Pai
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Arch Pharmalabs Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • TITLE PROCESS FOR THE PREPARATION OF 4- SUBSTITUTED- 1, 4 -DIHYDROPYRIDINES
  • 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.
  • 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.
  • 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.
  • the respective starting materials aldehyde compounds are employed.
  • R represents C1-C4 alkyl group
  • R' is ethyl
  • Ri is selected from:
  • Rjfrom (a) as mentioned above and R 2 from formula I are independently selected from
  • R is selected from:
  • R 4 is selected from:
  • R 5 , R6 and R 7 are independently selected from a) hydrogen
  • Rs and R 9 are independently selected from: a) C r C 8 -alkyl
  • Ri2 is selected from a) halogen
  • R 13 is selected from a) (CH 2 ) n -NHR 14
  • R 14 is selected from
  • Ri5 is selected from a) -NR 8 R 9
  • n 0 to 2
  • n 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 .
  • R is optionally substituted aromatic group e.g. phenyl
  • R j and R 2 are same or different groups and each represents C ] -C 5 alkyl group
  • R is optionally substituted aromatic group e.g. phenyl
  • and R 2 are same or different groups and each represents C C 5 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:
  • R is optionally substituted aromatic group e.g. phenyl
  • Ri and R 2 are same or different groups and each represents C 1 -C5 alkyl group
  • 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:
  • US4264611 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.
  • 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 discloses reaction of benzylidene intermediate with alkyl or alkylaryl aminocrotonate, e.g., ethyl aminocrotonate, methylaminocrotonate, using C C 6 alcohol.
  • alkyl or alkylaryl aminocrotonate e.g., ethyl aminocrotonate, methylaminocrotonate
  • the 2,3- dichloro benzylidene intermediate is condensed with a suitably substituted enamine, such as, ethylami fluxing alcoholic solvent.
  • felodipine reaction is sensitive to the amount of ethylaminocrotonate charged during coupling reaction.
  • 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.
  • 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,
  • 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 ⁇ -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.
  • 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 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.
  • 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
  • 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.
  • the term "Thermal reactions” defined herein above and herein below means the reaction that requires additional heat for progression and completion of the reaction.
  • 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.
  • IP A isopropyl alcohol
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • scheme-VII illustrates the preparation of the compound of formula I.
  • R l5 R , R 3 , 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.
  • 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.
  • 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.
  • Felodipine is filtered off and dried under the vacuum.
  • 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.
  • 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, " 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.
  • solvent is toluene and antisolvent is heptane.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 NaHC0 3 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%.

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Abstract

L'invention concerne des 1,4-dihydropyridines substituées en position 4 de formule I qui sont préparées par une réaction de cycloaddition dans laquelle la cyclisation est conduite à achèvement à la température ambiante éventuellement dans de l'eau sans aucun catalyseur. A des fins d'illustration par des exemples, l'invention est décrite plus en détail en ce qui concerne la préparation de félodipine de formule II. La félodipine, un vasodilatateur, est préparée par une réaction de cycloaddition de 3-aminocrotonate d'alkyle avec du dichlorobenzylidène dans des conditions de réaction dans lesquelles le produit cristallise à partir de la solution réactionnelle et peut être directement isolé par filtration.
PCT/IN2012/000138 2011-03-04 2012-02-29 Procédé pour la préparation de 1,4-dihydropyridines substituées en position 4 WO2012123966A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104177286A (zh) * 2014-08-11 2014-12-03 广东东阳光药业有限公司 一种地平类药物的制备方法

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US4264611A (en) 1978-06-30 1981-04-28 Aktiebolaget Hassle 2,6-Dimethyl-4-2,3-disubstituted phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid-3,5-asymmetric diesters having hypotensive properties, as well as method for treating hypertensive conditions and pharmaceutical preparations containing same
EP0063365A1 (fr) 1981-04-17 1982-10-27 Kyowa Hakko Kogyo Co., Ltd. Dérivés de 1,4-dihydropyridine et les compositions pharmaceutiques les contenant
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