MXPA00012173A - Process for preparing 1,4-dihydropyridine compounds - Google Patents

Abstract

A process for preparing a 1,4-dihydropyridine compound comprising contacting an enamine compound and a compound having a structure of wherein R<1-6>are as defined in the claims in the presence of a base;and treating the reaction mixture thus obtained in the presence of an acid or a combination of acids under mild reaction conditions. A resulting 1,4-dihydropyridine compound is useful as an anti-inflammatory agent or the like.

Description

PROCEDURE FOR THE PREPARATION OF 1, 4- DIHYDROPYRIDINE COMPOUNDS FIELD OF THE INVENTION This invention relates to a process for the preparation of 1,4-dihydropyridine compounds. Compounds with a 1,4-dihydropyridine structure are widely used in the pharmaceutical industry. The compounds have been used, for example, in the treatment or prevention of diseases such as cardiovascular diseases and inflammatory diseases.

ANTECEDENTS OF THE TECHNIQUE Nifedipine and amlodipine are 1,4-dihydropyridine compounds well known as calcium channel blockers. It has recently been discovered that certain 1,4-dihydropyridine compounds possess antagonistic bradykinin activity. For example, the PCT international patent publications WO 96/06082 and WO 97/30048 and the patent of E.U.A. 5,861, 402, describe 1,4-dihydropyridine compounds possessing bradykinin antagonistic activity which are useful in the treatment of diseases or symptoms, including an inflammatory disease, a cardiovascular disease and a trauma that produces pain. These bradykinin antagonist compounds are characterized by having, in their 2-position, a substituent comprising a moiety such as a carbonyl ester, amide or amide. Various methods of preparing 1,4-dihydripyridine have been described. For example, the Hantzsch synthesis has been widely used as a process for the preparation of 1,4-dihydro-2,6-dimethylpyridine. The process can be carried out by condensing two moles of β-dicarbonate with one mole of aldehyde in the presence of ammonia. J.B. Sainani reported the synthesis of a 1,4-dihydro-2,6-dimethyl-pyridine compound having asymmetric substituents at its 3 and 5 positions (Org. Chem. Incl. Med. Chem. (1994). , 33b, (6), 573-575).

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a process for preparing 1,4-dihydropyridine compounds comprising the steps of (a) contacting an enamine compound of structure / HN H2 H and a structure compound in the presence of a base; and (b) treating the reaction mixture thus obtained in the presence of an acid or a combination of acids. The present invention also provides a process for preparing a compound of formula (I): wherein R1 is selected from hydrogen and alkyl (C -? - C4); R2 is selected from nitrile, -SO3H, -SO2-alkyl (Ci-Cß), -SO-alkyl (Ci-Cß) -PO [Oalkyl (C? -C4)] 2, -C (= O) -R7, wherein R7 is selected from hydroxy or its salt, (C? -C6) -O-, amino, alkyl (C? -C6) -NH- and difalkyl (C? -C6)] - N-; R3 and R5 are independently selected from nitrile and alkoxy (d-C5) -C (= O) -; R is a mono-, di-, tri-, tetra- or pentasubstituted phenyl, substituents being independently selected from halo; alkyl (C? -C4) optionally substituted with one to three halo; (C 1 -C 4) alkoxy optionally substituted with one to three halo; nitro; Not me; monoalkyl (C? -C4) amino and difalkyl (C? -C4)] amino; R6 is selected from hydrogen; (C1-C10) alkyl; phenyl optionally substituted with one to two substituents independently selected from halo, (C1-C4) alkyl, trihaloalkyl (C -? - C4) and alkoxy (d-C4); and a 4- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms or heteroatom-containing moieties independently selected from -O-, -S-, -NH- and -N-CF (C? -C)], said ring being saturated, partially saturated or aromatic heterocyclic, and said heterocyclic ring being optionally substituted with a halo or (C? -C4) alkyl; and Y is selected from a covalent bond, methylene, oxygen and sulfur; the method comprising the steps of (a) addition reaction of an enamine compound of formula to a compound of formula 1 * ?. ^ Fi being R, R, R, R, R, R and Y as defined above, in the presence of a base under sufficient reaction conditions to couple the compounds; and (b) deletion of the compound resulting from step (a) in the presence of an acid catalyst selected from a protonic acid, and a combination of a protonic acid and a non-protonic Lewis acid. In the process described above, the compounds of formula (I) or (II) wherein R2 is a carboxyl group salt (ie R2 is -C (= O) -R7, where R7 is a hydroxy salt) are salts inorganic or organic carboxylic acid. Said salts are formed with a cation such as an alkali metal or alkaline earth metal (for example sodium, potassium, calcium and magnesium), hydroxide or alkoxide in water or an appropriate organic solvent, such as ethanol, isopropyl alcohol or a mixture thereof. According to the present invention, the desired 1,4-dihydropyridine compounds can be prepared in general under mild conditions in a container synthesis and in high yield. In the above process, the preferred substrates of formula (II) and the resulting compounds of formula (I) are those compounds of each formula in which R is hydrogen.

DETAILED DESCRIPTION OF THE INVENTION The term "(C 1 -C 4) alkyl", as used herein, unless otherwise indicated, means a straight or branched saturated monovalent hydrocarbon radical selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and tere-butyl. The term "(C? -C4) alkoxy", as used herein, unless otherwise indicated, means a linear or branched alkyl (C? -C4) -0- radical selected from methoxy, ethoxy, propoxy , isopropoxy, n-butoxy, sec-butoxy and tert-butoxy. The term "heterocyclic ring", as used herein, unless otherwise indicated, means a monocyclic or bicyclic hydrocarbon group having one or more heteroatoms in the ring, preferably having 6 to 9 carbon atoms and 1 to 4 heteroatoms or independently selected from -O-, -S-, -NH-, -N-N-alkyl (C? -C)], said heterocycle being saturated, partially saturated or aromatic. Examples of such groups include, but are not limited to, piperidino, morpholino, tiamorforino, pyrrolidino, pyrazolino, pirazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl , quinolyl and quinuclidinyl. The term "halo", as used herein, refers to F, Cl, Br or I, preferably to F or Cl. Preferred bases used in reaction step (a) of this invention include bases capable of promote a Michael type reaction. The preferred combination of "stage (a) base" and "step (b) acid catalyst" may be a "magnesium (II) base of step (a)" and a "protonic acid of step ( b) ". Preferably, the amount of base is equal to or greater than 1 equivalent.

Another preferred combination of "base of step (a)" and "acid catalyst of step (b)" may be "bases other than magnesium (II) bases (eg, alkylmagnesium halides, halomagnesium alkoxides and magnesium dialkoxides). ) that are capable of promoting a Michael-type reaction in step (a) "and" a combination of a protonic acid and a non-protonic Lewis acid ". Any non-protonic Lewis acid known to those skilled in the art, such as metal halides, metal triflates (i.e., metal trifluoromethanesulfonate) or the like, can be used in step (b). Examples of the Lewis acid include magnesium bromide, magnesium chloride, zinc bromide, zinc chloride, zinc iodide, tin (IV) chloride, titanium (IV) chloride, aluminum trichloride, ethylaluminum dichloride, chloride diethylaluminum, boron trifluoride, copper triflate (II), scandium triflate (lll), lanthanum triflate, ytterbium triflate, lanthanum chloride, cerium chloride (III) chloride and iron (lll). Acids individual Lewis preferred include magnesium bromide and its ether complexes such as diethyl magnesium bromide, magnesium chloride and its ether complexes such as diethyl magnesium chloride, zinc chloride, zinc bromide and scandium triflate (lll) Among the Lewis acids, preferred ones include magnesium (II) salts such as magnesium halides, magnesium bromides and their ether complexes such as magnesium bromide diethyletherate. Other preferred ones include magnesium (II) salts such as magnesium sulfate, magnesium acetate, halomagnesium acetate and halomagnesium sulfate.

The non-protonic Lewis acid, such as MgCl 2, can be added in step (a) in advance. When the starting compounds contain basic Lewis atom (s), such as N and O, the amount of Lewis acid added can be increased to achieve step (b). The process of this invention can be carried out preferably under reaction conditions in which step (a) is carried out in a solvent inert to the reaction at a temperature in the range of -150 ° C to the reflux temperature of the reaction mixture for 3 minutes to 2 days; and the reaction step (b) is carried out in a solvent inert to the reaction at a temperature in the range of -150 ° C to the reflux temperature of the reaction mixture for 1 second to 5 days. More preferably, the process of this invention can be carried out under reaction conditions in which the reaction step (a) is carried out in a solvent inert to the reaction at a temperature in the range of -40 ° C to 80 ° C. ° C for 1 minute to 40 hours; and the reaction step (b) is carried out in a solvent inert to the reaction at a temperature in the range of -40 ° C to 80 ° C for 1 minute to 5 days. Preferred bases used in the reaction step (a) of this invention include alkyl lithium (C 1 -C 4), alkoxides (C 1 -C 4) of halomagnesium, alkylmagnesium (C 1 -C 6) halides, metal hydrides, alkoxides (C 1). -C3) metals, metal n-butoxides, metal sec-butoxides, metal tert-butoxides, metal carbonates and metal fluorides. Preferred acids used in reaction step (b) of this invention include hydrochloric acid, toluene (p-, m- or o-toluene) sulfonic acid, phosphoric acid, sulfuric acid, nitric acid and alkanoic acid (C? -C6) ). Preferred methods of this invention include a compound of formula (I) wherein: R1 is selected from hydrogen, methyl and ethyl; R2 is selected from -C (= O) -R7, wherein R7 is selected from hydroxy or its salt, alkyl (C? -C6) -0-, amino, alkyl (C? -Cd) -NH- and difalkyl (C? -C6)] - N- R3 and R5 are independently selected from (C1-C3) alkoxy-C (= O) -; R 4 is a disubstituted phenyl, substituents being independently selected from halo, (C 1 -C 4) alkyl optionally substituted by one to two halo and nitro; R is selected from hydrogen; (C1-C5) alkyl; phenyl optionally substituted with one to two substituents independently selected from halo, (C? -C4) alkyl, CF3 and (C1-C4) alkoxy; and a 4- to 10-membered heterocyclic ring selected from piperidino, morpholino, thiamorforin, pyrrolidino, pyrazolidine, pyrazolidin, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolyl and quinuclidinyl, and said heterocyclic ring being optionally substituted with a halo or alkyl (C? -C); and Y is selected from a covalent bond, methylene, oxygen and sulfur. A preferred process of this invention includes a compound of formula (I) wherein R 1 is hydrogen; R2 is COOH, COOCH3 or COOC2H5; R3 and R5 are independently COOH, COOCH3 or COOC2H5; R 4 is a mono, or disubstituted phenyl, the substituents being independently selected from fluoro, chloro and nitro; R6 is selected from hydrogen; alkyl (C? -C3), phenyl optionally substituted with one to two substituents independently selected from halo, (C? -C3) alkyl, CF3 and (dC3) alkoxy; and a 4- to 10-membered heterocyclic ring selected from piperidino, morpholino, thiamorforino, pyrrolidino, pyrazolidine, pyrazolidin, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, midazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolyl and quinuclidinyl, and said heterocyclic ring being optionally substituted with a halo or (C? -C3) alkyl; and Y is a covalent bond or methylene. The following reaction schemes and discussions illustrate the preparation process of the present invention for preparing a compound of formula (I). Unless otherwise indicated, from R1 to R8, Y, p, q and r in the reaction schemes and in the discussion that follows are defined above. In each reaction described below, unless otherwise indicated, the reaction pressure is not critical. Generally, the reactions will be carried out at a pressure of about one to about three atmospheres, preferably at ambient pressure (about 1 atmosphere). In addition, unless otherwise indicated, the reactions are carried out at about room temperature (i.e., about 20 to 25 ° C). The compounds of formula (I) can be prepared by a process of this invention according to scheme 1.

SCHEME 1 Scheme 1 exemplifies a process of this invention for preparing a compound of formula (I) comprising step (s): adding an enamine compound of formula (II) to an alkylene compound of formula (III) followed by step (b) of acid catalyzed deletion reaction of the resulting compound in step (a). The above step (a) of addition can be carried out under the conditions applied to the nucleophilic addition reactions, using a suitable base in a solvent inert to the reaction. More preferably, the reaction can be carried out under the conditions commonly used in Michael type additions. The preferred bases for this reaction are those used in Michael type reactions. Examples of preferred bases include alkylmagnesium halides known as Grignard reagents and halomagnesium alkoxides. Most preferred bases include alkyl (C6C6) magnesium bromide and tert-butoxymagnesium bromide. Preferred solvents used in this reaction include alkanol (C? -C4), tetrahydrofuran (THF), diethyl ether, dioxane, hexane, toluene, 1,2-dimethoxyethane (DME) and the like. This reaction can be carried out at a temperature of about -150 ° C at reflux, preferably from about -100 ° C to 100 ° C. According to convenience, this reaction can be carried out at about room temperature using, for example halomagnesium alkoxides (Ci-C4), alkyl halides (Ci-Cejmagnesium, metal hydrides, metal alkoxides (C? -C3), difalkoxides (C ? -C3)] of magnesium, metal n-butoxides, metal sec-butoxides, metal tert-butoxides, a metal carbonate such as K2CO3, or metallamides such as R2N-M, where R is alkyl Co -Si (C? -3 alkyl)? )3; and being M Li, Na, Mg or K (preferably alkoxides (d-C) of halomagnesium or halides of alkylmagnesium (Ci-Cß)). In case the base is K2CO3, the reaction is carried out efficiently in THF. In case the base is CsF or KF, the reaction is carried out efficiently in THF or methanol (MeOH) at an elevated temperature such as about 60 ° C. In case of using butyl lithium (BuLi), the reaction is carried out efficiently in THF at from about -78 ° C to about -30 ° C. In case of using halomagnesium alkoxides (C? -C4) or alkylmagnesium halides (C1-C6), a preferred solvent is THF. Suitable reaction times are in the range from about 3 minutes to about 2 days, preferably from about 30 minutes to about 40 hours. The subsequent step (b) of the cyclization process can be carried out in the presence of a protonic acid. Suitable protonic acids include (C 1 -C 6) alkanoic acids such as acetic acid, hydrochloric acid (HCl) and sulfonic acids such as p-toluenesulfonic acid. It is preferred to add a non-protonic Lewis acid to the reaction mixture in combination with the protonic acid when the base used in step (a) is different from magnesium (II) bases. This reaction can be carried out at temperature from about -150 ° C to reflux, preferably from about -100 ° C to 100 ° C. The reaction time is in the range between about 1 second to 5 days, preferably 5 minutes to 20 hours. Generally, the reactions illustrated in scheme 1 can be carried out at about -78 ° C using dry ice / acetone or dry ice / methanol, at about 0 ° C, using an ice bath, at room temperature or at 100 ° C, preferably at about 0 ° C or about room temperature. The reaction steps (a) and (b) are carried out in the same reaction vessel under mild conditions with high yield. An enamine compound of formula (II) can be prepared according to procedures known to those skilled in the art, such as those illustrated in scheme 2.

SCHEME 2 Typically, a beta-ketoester compound of formula (IV) can be transformed into a compound of formula (II), R2 and R3 being as defined above. This reduction can be carried out in a solvent inert to the reaction by redissolving gaseous ammonia at a temperature in the range from about 0 ° C to 60 ° C. Suitable inert reaction solvents include lower alkanols such as methanol and ethanol. Alternatively, the gaseous ammonia-containing solution given above can be added to a solution containing a beta-ketoester (IV). The mixture is reacted at a temperature in the range of about 0 ° C to 60 ° C to provide the enamine compound (II). An alkylene compound of formula (III) can be prepared according to procedures known to those skilled in the art. Scheme 3 illustrates an embodiment of the preparation process. RXy R¡ (v) o HO (VI) SCHEME 3 A carbonyl compound of formula (V) can be subjected to a coupling reaction with an aldehyde compound of formula (VI) to provide the alkylene compound of formula (III) according to a known method. For example, a compound of formula (V) can be reacted with R -Y- being an optionally substituted heterocycle - (CH2) 2- with a compound of formula (VI) according to a process outlined by L.

Tietze et al., Liebigs, Ann. Chem., P. 321-329, 1988. This reaction can be carried out in a solvent inert to the suitable reaction, for example an aromatic hydrocarbon such as benzene, toluene and xylene, an alcohol such as methanol, ethanol, propanol and butanol, an ether such as diethyl ether, dioxane and tetrahydrofuran (THF), a halogenated hydrocarbon such as methylene chloride, chloroform and dichloroethane, an amide such as N, N-dimethylformamide, and a nitrile such as acetonitrile. This reaction can be carried out at a temperature in the range from about 0 ° C to the reflux temperature of the reaction mixture, preferably from about 80 ° C to 120 ° C for from about 30 minutes to 24 hours, preferably from 30 minutes to 6 hours. This reaction can be carried out suitably in the presence of an acid or basic catalyst. Suitable basic catalysts are those such as piperidine, pyridine and alkoxides, and suitable acid catalysts are those such as acetic acid, TiCl 4 and p-toluenesulfonic acid. An intermediate of formula (V) can be prepared starting with a known compound according to a method known to those skilled in the art. For example, a compound of formula (V) can be prepared, R being an optionally substituted heterocycle (including heteroaryl) defined as above, and R3 being a (C? -C5) -C (= 0) - alkoxy, according to the process described in scheme 4.

R6- CHO (Vil) SCHEME 4 An aldehyde compound (Vil) is reacted, with R6 being as defined above, with malonic acid under basic conditions. For example, this reaction can be carried out in the presence of a weak base such as piperidine in a reaction-inert solvent such as pyridine, to provide a carboxylic acid compound of formula (VIII). The compound (VIII) thus obtained can be subjected to an aliphatic nucleophilic substitution reaction in the presence of a coupling agent, yielding a pentanoate compound of formula (IX). This reaction can be conveniently carried out firstly by treating the compound of formula (VII) with a coupling agent such as N, N'-carbonyldiimidazole in a reaction-inert solvent such as dimethylformamide, then reacting it with a nucleophilic reagent such as CH3O2CCH2K in the presence of a Lewis acid such as magnesium chloride. The above treatment can be carried out at a temperature in the range from about 0 ° C to about 60 ° C, preferably at about room temperature for from about 1 minute to 12 hours. This latter reaction can be carried out at a temperature in the range from about 0 ° C to 100 ° C, preferably from about room temperature to 60 ° C for about 1 minute to 12 hours. The compound of formula (IX) can be reduced on a metal catalyst under a hydrogen atmosphere to provide the compound of formula (V) according to a known process. Suitable catalysts are those such as Raney nickel catalyst and noble metal catalysts, including palladium on carbon and palladium hydroxide. This reaction can be carried out in a reaction-inert solvent such as methanol, at about room temperature under a hydrogen atmosphere at an appropriate pressure, for example using a balloon, for from about 1 minute to 12 hours. A ketone compound of the formula (V) and a substituted benzaldehyde compound of the formula (VI) can also be prepared according to known methods (for example, (1) D. Scherling, J. Labelled Compds, Radiopharm., Vol 27. p. 599-, 1989, (2) CR Holmquist et al., J. Org. Chem., Vol 54, pp. 3528-, 1989, (3) SN Huckin et al., J. Am. Chem. Soc, vol 96, p.1082-, 1974, (4) JCS Perkin I, p.529-, 1979, (5) Synthesis, p.37, 1986 and (6) JCS Chem. Commun., p.932-, 1977).

The compounds of formula (I) have a chiral center and, if necessary, an enantiomeric mixture of the compounds can be separated by procedures known to those skilled in the art (e.g., using HPLC or fractional crystallization). In addition, an enantiomeric mixture of compounds of formula (III) can be optically separated by similar procedures before subjecting them to the preparation methods of this invention. The compounds of formula (I) prepared according to the methods described above can be isolated and purified by conventional procedures such as recrystallization or chromatographic purification. The compounds of formula (I) thus obtained can be further subjected to the desired reactions. For example, compounds in which R 2 is -COOH, can be subjected to coupling reactions with desired amino or metal compounds, provided with compounds such as those described in WO 96/06082, WO 97/30048, patent of USA 5,861, 402 or the like. With the methods of the present invention, 1,4-dihydropyridine compounds can be efficiently prepared under mild conditions. Especially, the 1,4-dihydropyridine compounds which are difficult to synthesize by the Hantzsch method (under non-mild conditions) can be synthesized due to the mild conditions of the present invention.

EXAMPLE The invention is illustrated by the following non-limiting example in which, unless otherwise indicated; all operations were carried out at room temperature, that is, in the range of 18-25 ° C; the evaporation of the solvent was carried out using a rotary evaporator under reduced pressure with a bath temperature of up to 60 ° C; the reactions were controlled by thin layer chromatography (tic) and the reaction times are given only for illustration; the given melting points (p.f.) are not corrected (the polymorphism can result in different melting points); the structure and purity of all isolated compounds were ensured by at least one of the following techniques: tic (TLC plates pre-coated with Merck F254 silica gel 60 or HPTLC plates precoated with Merck NH2 F254s), mass spectrometry, nuclear magnetic resonance (NMR), infrared absorption (IR) spectra or microanalysis. The returns were given for illustrative purposes only. Flash column chromatography was carried out using Merck silica gel 60 (230-400 mesh ASTM) or DU3050 from Fuji Silysia Chromatorex (R) (amino type, 30-50 μm). The low resolution mass spectral data (El) were obtained in an Automass 120 mass spectrometer (JEOL). The low resolution mass spectral data (ESI) were obtained in a Quattro II mass spectrometer (Micromass). The NMR data were determined at 270 MHz (JEOL JNM-LA 270 spectrometer) using chloroform (99.8% D) or dimethylsulfoxide (99.9% D) deuterated as solvent unless otherwise indicated, relative to trimethylsilane (TMS) as an internal standard in parts per million (ppm); The conventional abbreviations used are: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, br = width, etc. The IR spectra were measured using a Shimazu infrared spectrometer (IR-470). Optical rotations were measured using a DAS-370 digital polarimeter from JASCO (Japan Spectroscopic CO, Ltd.). Chemical symbols have their usual meanings: e.g. (boiling point), m.p. (melting point), I (liter (s)), ml (milliliter (s)), g (gram (s)), mg (milligram (s)), mol (moles), mmol (millimoles), eq. (equivalent (s)).

A. Methyl 3-oxo-5- (1, 3-thiazol-2-yl) -4-pentenoate: 3-Oxo-5- (1,3-thiazol-2-yl) -4-pentenoate was prepared from methyl from 3- (1, 3-thiazol-2-yl) -2-propenoic acid (Bull, Chem. Soc. Jap, 1974, 47, 151) according to the procedure of the literature (Heterocycles 1994, 38, 751 ). It was added to a stirred solution of 3- (1) acid, 3-thiazol-2-yl) -2-propenoic acid (100.0 g, 644.4 mmol) in DMF (100 ml) 1, r-carbonyldimidazole (115.0 g, 708.9 mmol) in small portions. After stirring at room temperature for 5 hours, anhydrous magnesium chloride (73.6 g, 773.0 mmol) and the potassium salt of monomethyl malonate (120.8 g, 773.0 mmol) were added to the reaction mixture. The resulting suspension was heated at 55 ° C with stirring for 14 hours. After cooling to room temperature, the reaction mixture was poured into 1500 ml of 2 N HCl and extracted with a mixture of EtOAc (1500 ml) and toluene (500 ml). The organic phase was separated and the aqueous phase was extracted with a 3: 1 mixture of EtOAc and toluene (2000 ml). The combined organic phase was washed with H20 (1000 ml) and brine (1000 ml), dried (Na2SO) and evaporated, yielding 132.0 g of 3-oxo-5- (1,3-thiazole-2-yl) -4-methyl pentenoate (1/2 keto / enol form). 1H-NMR (CDCI) d: 11.77 (s, 2 / 3H), 7.97 (d, J = 3.1 Hz, 1 / 3H), 7.90 (d, J = 3.1 Hz, 2 / 3H), 7.72 (d, J = 16.0 Hz, 1 / 3H), 7.55 (d, J = 15.6 Hz, 2 / 3H), 7.51 (d, J = 3.1 Hz, 1 / 3H), 7.39 (d, J = 3.1 Hz, 2 / 3H), 7.06 (d, J = 16.0 Hz, 1 / 3H), 6.80 (d, J = 15.6 Hz, 2 / 3H), 5.28 (s, 2 / 3H), 3.79 (s, 3 x 2 / 3H), 3.77 (s, 3 x 1 / 3H), 3.45 (s, 2 x 1 / 3H).

B. Methyl 3-oxo-5- (1, 3-thiazol-2-yl) pentanoate: A mixture of 3-oxo-5- (1,3-thiazol-2-yl) -4-pentenoate was stirred. methyl (132.0 g) and 20% by weight palladium hydroxide on carbon (13 g) in MeOH (2600 ml) under a hydrogen atmosphere per balloon at room temperature for 4 hours. The catalyst was removed by filtration and the filtrate was dried by evaporation to give 130.0 g of methyl 3-oxo-5- (1, 3-thiazol-2-yl) pentanoate as a brown liquid. 1H-NMR (CDC) d: 7.65 (d, J = 3.3 Hz, 1 H), 7.20 (d, J = 3.3 Hz, 1 H), 3.73 (s, 3H), 3.53 (s, 2H), 3.33 ( t, J = 6.9 Hz, 2H), 3.13 (t, J = 6.9 Hz, 2H).

C. 3- (2,6-Dichlorophenyl) -2 - [(113-thiazol-2-yl) propanoylf-2-propanoate methyl: 2,6-dichlorobenzaldehyde (113.0 g, 644 mmol), acetic acid ( 5 ml) and piperidine (5 ml) were added to a solution of methyl 3-oxo-5- (1, 3-thiazol-2-yl) pentanotao (130 g) in toluene (600 ml). This mixture was distilled to remove the initial distillate (approximately 100 ml), then the distillation apparatus was replaced by a Dean-Stark trap and heated to reflux temperature with azeotropic removal of H20 for 4 hours. The mixture was washed with H20 (200 ml) and brine (200 ml), dried (Na2SO) and evaporated to give a crude mixture. This was purified by column chromatography on silica gel (1800 g, hexane / EtOAc = 3/1 as eluent) to give 165.3 g (69% in 3 steps) of 3- (2,6-dichlorophenyl) -2-f1, Methyl 3-thiazol-2-yl) propanoyl] -2-propenoate in the form of a brown oil. This is a 1: 1 mixture of the double bond isomers. 1H NMR (CDCl3) d: 7.70-7.15 (m, 6H), 3.91 and 3.66 (apparently two singles, 3H), 3.44 and 3.28 (apparently two singles, 4H).

D: 4- (2,6-Dichlorophenyl) -2- (2-methoxy-2-oxoethyl) -6-r 2 - (1,3-thiazol-2-yl) ethyl-1,4-dihydropyridine-3,5 dimethyl carboxylate: A solution of EtMgBr 1.0 M in THF (1192 ml, 1192 mmol) dropwise slowly at 0 ° C, under nitrogen, and for a period of 2 hours to a stirred solution of 2-methyl-2-propanol (92.8 g, 1252 mmol, 2.1 eq.) In anhydrous THF (1100 ml). The resulting solution was stirred at room temperature for 1 hour. Then a solution of dimethyl 3-amino-2-pentenedioate (113.5 g, 655 mmol, 1.1 eq.) In anhydrous THF (550 ml) was added dropwise to the mixture slowly at 0 ° C for 20 minutes. The resulting pale yellow solution was stirred at the same temperature for 1 hour, then a solution of 3- (2,6-dichlorophenyl) -2 - [(1,3-thiazol-2-yl) propanoyl] -2- was added. Methyl propenoate (219.9 g, 594 mmol, 1.0 eq.) in anhydrous THF (550 mL) at 0aC for 30 minutes. The reaction mixture was stirred at room temperature for 16 hours under nitrogen, then acetic acid (170 ml, 5.0 eq.) Was added at 0 ° C. The resulting mixture was stirred at room temperature for 6 hours. The mixture was poured over aq. NaOH. 2 N (1000 ml), the organic phase was separated and the aqueous phase was extracted with EtOAc (2000 ml). The combined organic phase was washed with H2O (1000 ml) and brine (1000 ml), dried (Na2SO4) and concentrated to give a crude mixture. Purification by column chromatography with silica gel (3 times, 1700 g) eluted with hexane / EtOAc (2/1 to 1/2) to provide 246.0 g (85%) of 4- (2,6-dichlorophenyl) -2 Dimethyl (2-methoxy-2-oxoethyl) -6- [2- (1, 3-thiazol-2-yl) ethyl] -1,4-dihydropyridine-3,5-dicarboxylate in the form of a brown oil. 1 H-NMR (CDCl 3) d: 8.33 (s, 1 H), 7.67 (d, J = 3.3 Hz, 1 H), 7.24 (t, J = 8.0 Hz, 2 H), 7.24 (d, J = 3.3 Hz, 1 H), 6.98 (dd, J = 8.0, 8.0 Hz, 1 H), 5.99 (s, 1 H), 3.86-3.65 (m, 5H), 3.51 (s, 3H), 3.54 (s, 3H), 3.45-3.25 (m, 3H), 3.14-2.96 (m, 1 H).

In step D of the above working example, the coupling in the presence of a magnesium base and the subsequent deletion in the presence of an acidic acid took place in the form of synthesis in a container.

Claims (13)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for preparing 1,4-dihydropyridine compounds comprising the steps of (a) contacting an enamine compound of structure

/ HN -c C H2 H and a structure compound

CN CN CN "" "" "" alquilo alquilo C1 alquilo alquilo alquilo o o in the presence of a base; and (b) treating the reaction mixture thus obtained in the presence of an acid or a combination of acids. 2. A process according to claim 1 for preparing a compound of formula (I): wherein R1 is selected from hydrogen and alkyl (C? -C); R2 is selected from nitrile, -SO3H, -S02-alkyl (C? -C6), -SO-alkyl (C? -C6) -POfOalkyl (C? -C4)] 2, -C (= 0) -R, wherein R is selected from hydroxy or its salt, alkyl (C? -Ce) -O-, amino, alkyl (d-C6) -NH- and difalkyl (C? -C6)] - N-; R3 and R5 are independently selected from nitrile and (C? -C5) -C (= O) - alkoxy; R 4 is a mono-, di-, tri-, tetra- or pentasubstituted phenyl, substituents being independently selected from halo; alkyl (C? -C4) optionally substituted with one to three halo; alkoxy (CrC) optionally substituted with one to three halo; nitro; Not me; monoalkyl (C? -C) amino and difalkyl (C? -C4)] amino; R is selected from hydrogen; (C1-C10) alkyl; phenyl optionally substituted with one to two substituents independently selected from halo, alkyl (C -? - C), trihaloalkyl (C? - C) and (C? -C4) alkoxy; and a 4- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms or heteroatom-containing moieties independently selected from -O-, -S-, -NH- and -N-alkyl (C? -C)], said ring being saturated, partially saturated or aromatic heterocyclic, and said heterocyclic ring being optionally substituted with a halo or alkyl (C? -C); and Y is selected from a covalent bond, methylene, oxygen and sulfur; the method comprising the steps of (a) addition reaction of an enamine compound of formula

HN R ^ ^ R (M) to a compound of formula

R1, R2, R3, R4, R5, R6 and Y being as defined above, in the presence of a base under sufficient reaction conditions for the addition reaction of the compounds; and (b) deletion of the compound resulting from step (a) in the presence of an acid catalyst selected from a protonic acid, and a combination of a protonic acid and a non-protonic Lewis acid. 3. The process of claim 1, wherein the base in the reaction step (a) is a base capable of promoting a Michael-type reaction. 4. The process of claim 1, wherein the base of the reaction step (a) is a magnesium base (II) and the acid catalyst of the reaction step (b) is a protonic acid. 5. The process of claim 1, wherein the base of process (a) is other than magnesium (II) and the acid catalyst of step (b) is a combination of a protonic acid and a non-Lewis acid. protonic.

6. The process of claim 1, wherein the reaction step (a) is carried out in a solvent inert to the reaction at a temperature in the range of -150 ° C at the reflux temperature of the mixture. of reaction, for 3 minutes to 2 days, and the reaction step (b) is carried out in a solvent inert to the reaction at a temperature in the range of -150 ° C at the reflux temperature of the reaction mixture. reaction for 1 second to 5 days.

7. The process of claim 6, wherein the reaction step (a) is carried out in a solvent inert to the reaction at a temperature in the range of -40 ° C to 80 ° C for 1 minute at 40 hours, and the reaction step (b) is carried out in a solvent inert to the reaction at a temperature in the range from -40 ° C to 80 ° C for 1 minute to 5 days.

8. The process of claim 1, wherein the base of the reaction step (a) is selected from alkyl lithiums (C? -C), alkoxides (C? -C) of halomagnesium, alkylmagnesium halides ( Ci-Cd), metal hydrides, metal alkoxides (C? -C3), magnesium difalcoxides (C? -C3)], metal n-butoxides, metal sec-butoxides, metal tert-butoxides, metal carbonates and metal fluorides.

9. The process of claim 1, wherein the acid catalyst of the reaction step (b) is selected from hydrochloric acid, toluene (p-, m- or o-toluene) sulfonic acid, phosphoric acid, sulfuric acid , nitric acid and alkanoic acid (Ci-Cß).

10. The process according to claim 2, wherein R1 is selected from hydrogen, methyl and ethyl; R2 is selected from -C (= 0) -R7, wherein R7 is selected from hydroxy or its salt, alkyl (Ci-CßJ-O-, amino, alkyl (CI-CT) -NH- and diphalkyl (C? -C6) ] -N-; R and R are independently selected from (Ci-C3) -C (= O) - alkoxy; R is a disubstituted phenyl, substituents being independently selected from halo, (C? -C) alkyl optionally substituted with one to two halo and nitro, R6 is selected from hydrogen, (C1-C5) alkyl, phenyl optionally substituted with one to two substituents independently selected from halo, (C? -C4) alkyl, CF3 and (C? -C) alkoxy and a 4- to 10-membered heterocyclic ring selected from piperidino, morpholino, thiamorforino, pyrrolidino, pyrazolidine, pyrazolidin, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolyl and quinuclidinyl, and said heterocyclic ring being optionally substituted with a halo or alkyl (C? -C4), and Y is selected ione of a covalent bond, methylene, oxygen and sulfur.

11. The process according to claim 11, wherein R1 is hydrogen; R2 is COOH, COOCH3 or COOC2H5; R3 and R5 are independently COOH; COOCH3 or COOC2Hs; R 4 is a mono- or disubstituted phenyl, substituents being independently selected from fluoro, chloro and nitro; R6 is selected from hydrogen, (C1-C3) alkyl, phenyl optionally substituted with one to two substituents independently selected from halo, (C? -C3) alkyl, CF3 and (C? -C3) alkoxy; and a 4- to 10-membered heterocyclic ring selected from piperidino, morpholino, thiamorforino, pyrrolidino, pyrazolidine, pyrazolidin, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolyl and quinuclidinyl, and said heterocyclic ring being optionally substituted with a halo or (C1-C3) alkyl; and Y is a covalent bond or methylene.

12. The process according to claim 5, wherein the non-protonic Lewis acid is a metal halide or metal triflate.

13. The process according to claim 5, wherein the non-protonic Lewis acid is a magnesium (II) salt.