HK1039323A - Process for preparaing 1,4-dihydropyridine compounds - Google Patents

Description

Process for preparing 1, 4-dihydropyridine compounds

The present invention relates to a process for preparing 1, 4-dihydropyridine compounds. Compounds having the structure of 1, 4-dihydropyridines are widely used in the pharmaceutical industry. The compounds have been used, for example, to treat or prevent diseases such as cardiovascular disease or inflammation.

Nifedipine and amlodipine are well known 1, 4-dihydropyridine compounds as calcium channel blockers.

Recently, it has been found that certain 1, 4-dihydropyridine compounds have bradykinin antagonistic activity. For example, PCT International patent applications WO96/06082 and WO97/30048, and U.S. Pat. No. 5861402 disclose 1, 4-dihydropyridine compounds having bradykinin antagonistic activity which are useful in the treatment of diseases or syndromes including inflammation, cardiovascular disease and painful trauma. These bradykinin antagonist compounds are characterized by having a substituent at the 2-position which includes a moiety such as a carbonyl, ester, amide or imide moiety.

Various processes for preparing 1, 4-dihydropyridines have been disclosed. For example, the Hantzsch synthesis has been widely used as a method for preparing 1, 4-dihydro-2, 6-lutidine. The process may be carried out by condensing two moles of beta-dicarbonate with one mole of aldehyde in the presence of ammonia. Sainani reports the synthesis of 1, 4-dihydro-2, 6-lutidine compounds with asymmetric substituents at the 3-and 5-positions (including organic chemistry of pharmaceutical chemistry, org. chem. Incl. Med. chem. (1994),33b (6), 573-.

The present invention provides a process for preparing a 1, 4-dihydropyridine compound comprising the step of (a) an enamine of the formulaAnd compounds having the structureContacting in the presence of a base; (b) the resulting reaction mixture is treated in the presence of an acid or a combination of acids.

The invention also provides a process for preparing a compound of formula (I):wherein: r¹Selected from hydrogen and (C)₁-C₄) An alkyl group; r²Selected from nitriles; -SO₃H；-SO₂-(C₁-C₆) An alkyl group; -SO- (C)₁-C₆) An alkyl group; -PO [ O (C)₁-C₄) Alkyl radical]₂；-C(=O)-R⁷Wherein R is⁷Selected from hydroxy or its salt, (C)₁-C₆) alkyl-O-, amino, (C)₁-C₆) alkyl-NH-and di [ (C)₁-C₆) Alkyl radical]-N-；R³And R⁵Independently selected from nitrilesAnd (C)₁-C₅) alkoxy-C (= O) -; r⁴Is unsubstituted or mono-, di-, tri-, tetra-or penta-substituted phenyl, wherein the substituents are independently selected from halogen atoms; optionally substituted by one to three halogen atoms₁-C₄) An alkyl group; optionally substituted by one to three halogen atoms₁-C₄) An alkoxy group; a nitro group; an amino group; one (C)₁-C₄) Alkylamino and di [ (C)₁-C₄) Alkyl radical]An amino group; r⁶Selected from hydrogen; (C)₁-C₁₀) An alkyl group; optionally substituted by one to two independently selected halogen atoms, (C)₁-C₄) Alkyl, tri-halo (C)₁-C₄) Alkyl and (C)₁-C₄) Phenyl substituted with a substituent of alkoxy; and containing 1 to 4 heteroatoms or selected independently from-O-, -S-, -NH-and-N [ (C)₁-C₄) Alkyl radical]A 4-to 10-membered heterocycle containing a heteroatom moiety of (a), wherein said heterocycle is saturated, partially-saturated or aromatic, and said heterocycle is optionally substituted with a halogen atom or (C)₁-C₄) Alkyl substitution; and Y is selected from the group consisting of a covalent bond, methylene, oxygen and sulfur; the process comprises the step of (a) an enamine compound of the formulaWith a compound of the formulaWherein R is¹,R²,R³,R⁴,R⁵,R⁶And Y is as previously defined, in the presence of a base under conditions sufficient to couple the compounds; and (b) cyclizing the compound produced in step (a) in the presence of an acid catalyst selected from the group consisting of protic acids, and protic acids (protic acids) in combination with an aprotic Lewis acid.

In the above process, wherein R²Compounds of formula (I) or (II) which are salts of carboxyl groups (i.e. R)²Is wherein R is⁷Is a hydroxy salt of-C (= O) -R⁷) Are inorganic or organic salts of carboxylic acids. These salts are prepared by contacting the salt with a cation such as an alkali or alkaline earth metal (e.g., sodium, potassium, calcium, and magnesium), hydroxide or alkoxide in water or a suitable organic solvent such as ethyleneAlcohol, isopropanol or mixtures thereof.

According to the present invention, in general, the desired 1, 4-dihydropyridine compound can be prepared in a one-pot synthesis under mild conditions and in high yield.

In the above process, the preferred substrate of formula (II) and the resulting compound of formula (I) are those wherein R is¹Are compounds of the formula hydrogen.

The term "(C) as used herein₁-C₄) Alkyl ", unless otherwise indicated, means a straight or branched chain saturated monovalent hydrocarbon radical selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.

The term "(C) as used herein₁-C₄) Alkoxy ", unless otherwise stated, means a straight or branched chain (C) selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy₁-C₄) An alkyl-O group.

The term "heterocycle" as used herein, unless otherwise indicated, means a monocyclic or bicyclic hydrocarbon group having one or more heteroatoms in the ring, preferably 6 to 9 carbon atoms and 1 to 4 heteroatoms or independently selected from-O-, -S-, -NH-, and-N [ (C)₁-C₄) Alkyl radical]-, wherein said heterocyclic ring is saturated, partially saturated or aromatic. Examples of such groups include, but are not limited to, piperidino, morpholino, thiomorpholino, pyrrolidino, pyrazolinyl, pyrazolidino, pyrazolyl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl, and quinuclidinyl.

The term "halogen atom" as used herein means F, Cl, Br or I, preferably F or Cl.

Preferred bases for use in reaction step (a) of the present invention include bases capable of promoting a Michael type reaction.

A preferred combination of "base in step (a)" and "acid catalyst in step (b)" may be "magnesium (II) base in step (a)" and "protic acid in step (b)".

Preferably, the amount of base is equal to or greater than 1 equivalent.

Other preferred combinations of "base in step (a)" and "acid catalyst in step (b)" may be "base in step (a) other than magnesium (ii) base capable of promoting Michael type reaction (e.g., alkyl-magnesium halide, halogen-magnesium-alkoxide and magnesium-dialkoxide)" and "combination of protic acid and aprotic Lewis acid". Any aprotic Lewis acid known to those skilled in the art such as metal halides, metal triflates (i.e., metal triflates), and the like may be used in step (b). Examples of Lewis acids include magnesium bromide, magnesium chloride, zinc bromide, zinc chloride, zinc iodide, tin (IV) chloride, titanium (IV) chloride, aluminum trichloride, ethylaluminum dichloride, diethylaluminum chloride, boron trifluoride, copper (II) trifluoromethanesulfonate, scandium (III) trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, lanthanum chloride, cerium (III) chloride and iron (III) chloride. Preferred individual Lewis acids include magnesium bromide and its ether complexes such as magnesium bromide diethyl ether, magnesium chloride and its ether complexes such as magnesium chloride diethyl ether, zinc chloride, zinc bromide and scandium (iii) trifluoromethanesulfonate. Among the Lewis acids, preferred acids include magnesium (II) salts such as magnesium halides, magnesium bromide and ether complexes thereof such as magnesium bromide diethyl ether. Another preferred acid includes magnesium (II) salts such as magnesium sulfate, magnesium acetate, magnesium halide acetate and magnesium halide sulfate.

Aprotic Lewis acids such as MgCl₂May be previously added in step (a).

When the starting compound contains Lewis basic atoms such as N and O, the amount of Lewis acid added may be increased for the success of step (b).

Preferably, the process of the present invention may be carried out in a reaction in which the reaction step (a) is carried out in a reaction inert solvent at a temperature ranging from-150 ℃ to the reflux temperature of the reaction mixture for 3 minutes to 2 days; the reaction step (b) is carried out in a reaction inert solvent at a temperature ranging from-150 ℃ to the reflux temperature of the reaction mixture for 1 second to 5 days.

More preferably, the process of the present invention may be carried out in which the reaction step (a) is carried out in a reaction inert solvent at a temperature ranging from-40 ℃ to 80 ℃ for 1 minute to 2 days; the reaction step (b) is carried out in a reaction inert solvent at a temperature ranging from-40 ℃ to 80 ℃ for 1 minute to 5 days.

Preferred bases for use in step (a) of the present invention include (C)₁-C₄) Alkyl lithium, halogenated (C)₁-C₄) Magnesium alkoxide (C)₁-C₄) alkoxide), halogenated (C)₁-C₆) Alkyl magnesium, metal hydride, metal (C)₁-C₃) Alkoxides, metal-n-butoxide, metal-sec-butoxide, metal-tert-butoxide, metal carbonates and metal fluorides.

Preferred acids for use in step (b) of the present invention include hydrochloric acid, toluene (p-, m-or o-toluene) sulfonic acid, phosphoric acid, sulfuric acid, nitric acid and (C)₁-C₆) An alkanoic acid.

Preferred methods of the invention include compounds of formula (I): wherein R is¹Selected from hydrogen, methyl and ethyl; r²Is selected from-C (= O) -R⁷Wherein R is⁷Selected from hydroxy or its salt, (C)₁-C₆) alkyl-O-, amino, (C)₁-C₆) alkyl-NH-and di [ (C)₁-C₆) Alkyl radical]-N-；R³And R⁵Independently selected from (C)₁-C₃) alkoxy-C (= O) -; r⁴Is a di-substituted phenyl group wherein the substituents are independently selected from halogen atoms; optionally substituted by one or two halogen atoms₁-C₄) Alkyl and nitro; r⁶Selected from hydrogen; (C)₁-C₅) An alkyl group; optionally substituted by one to two independently selected halogen atoms, (C)₁-C₄) Alkyl radical, CF₃And (C)₁-C₄) Phenyl substituted with a substituent of alkoxy; and is selected from piperidino, morpholino, thiomorpholino, pyrrolidino, pyrazolino, pyrazolidino, pyrazolyl(pyrazoryl), piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl and quinuclidinyl 4-to 10-membered heterocycle, wherein said heterocycle is optionally substituted by a halogen atom or (C)₁-C₄) Alkyl substitution; and Y is selected from the group consisting of a covalent bond, methylene, oxygen and sulfur.

Preferred methods of the invention include compounds of formula (I): wherein R is¹Is hydrogen; r²Is COOH, COOCH₃Or COOC₂H₅；R³And R⁵Independently of one another is COOH, COOCH₃Or COOC₂H₅；；R⁴Is mono-or di-substituted phenyl, wherein the substituents are independently selected from fluoro, chloro and nitro; r⁶Selected from hydrogen; (C)₁-C₃) An alkyl group; optionally substituted by one to two independently selected halogen atoms, (C)₁-C₃) Alkyl radical, CF₃And (C)₁-C₃) Phenyl substituted with a substituent of alkoxy; and a 4-to 10-membered heterocyclic ring selected from piperidino, morpholino, thiomorpholino, pyrrolidino, pyrazolino, pyrazolidino, pyrazolyl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl and quinuclidinyl, wherein said heterocyclic ring is optionally substituted with a halogen atom or (C)₁-C₃) Alkyl substitution; and Y is a covalent bond or methylene.

The following reaction schemes and discussions illustrate the preparation of the present invention for the preparation of compounds of formula (I). Unless otherwise indicated, R¹To R⁸Y, and p, q and r are as previously defined in the reaction schemes and discussion below. In each of the reactions described below, unless otherwise indicated, the reaction pressure is not critical. Generally, the reaction will be carried out at about 1 to about 3 atmospheres, preferably atmospheric (about 1 atmosphere). Also, unless otherwise noted, the reaction is at about room temperature (i.e., about 20 ℃ to 25 ℃).

The compounds of formula (i) may be prepared by the process of the invention according to scheme 1.

Scheme 1

Scheme 1 illustrates a process of the invention for the preparation of a compound of formula (i) comprising the step (a): addition of an enamine compound of formula (II) to an alkylene compound of formula (III) followed by acid-catalyzed cyclization of the compound obtained in step (b) step (a).

The preceding addition step (a) may be carried out under the conditions used for the nucleophilic addition reaction, using a suitable base in a reaction-inert solvent. More preferably, the reaction can be carried out under conditions commonly used for Michael-type addition. Preferred bases for this reaction are those used in the Michael-type reaction. Examples of preferred bases include alkyl magnesium halides and alkyl magnesium halides known as Grignard reagents. More preferred bases include brominated (C)₁-C₆) Alkyl magnesium and tert-butoxy magnesium bromide. Preferred solvents for the reaction include (C)₁-C₄) Alkanols, Tetrahydrofuran (THF), diethyl ether, dioxane, hexane, toluene, 1, 2-Dimethoxyethane (DME), and the like. The reaction may be carried out at a temperature of about-150 ℃ to reflux, preferably about-100 ℃ to 100 ℃. Conveniently, the reaction may be carried out at room temperature using, for example, halogenation (C)₁-C₄) Magnesium alkoxide, halo (C)₁-C₆) Alkyl magnesium, metal hydride, metal (C)₁-C₃) Alkoxide of magnesium-bis [ (C)₁-C₃) Alkoxide of alkane]Metal-n-butoxide, metal-sec-butoxide, metal-tert-butoxide, metal carbonates such as potassium carbonate, or metal amides such as those in which R is C_1-4Alkyl or-Si (C)_1-3Alkyl radical)₃R of (A) to (B)₂N-M, M is Li, Na, Mg or K (preferably halogenated (C)₁-C₄) Magnesium alkoxide, halo (C)₁-C₆) Magnesium alkyl). In the case where the base is potassium carbonate, the reaction is effectively carried out in THF. In the case where the base is CsF or KF, the reaction is effectively carried out in THF or methanol (MeOH) at elevated temperatures, e.g., 60 ℃. In the case of butyl lithium (BuLi), the reaction is effectively carried out in THF,at about-78 ℃ to about-30 ℃. In the presence of halogenation (C)₁-C₄) Magnesium alkoxides or halides (C)₁-C₆) In the case of magnesium alkyls, the preferred solvent is THF. Suitable reaction times range from about 3 minutes to 2 days, preferably from about 30 minutes to about 40 hours.

The subsequent cyclisation process step (b) may be carried out in the presence of a protic acid. Suitable protic acids include (C)₁-C₆) Alkanoic acids such as acetic acid, hydrochloric acid (HCl) and sulfonic acids such as p-toluenesulfonic acid. When the base used in step (a) is not a magnesium (II) base, an aprotic Lewis acid is preferably added to the reaction mixture in combination with the protic acid. The reaction may be carried out at a temperature of about-150 ℃ to reflux, preferably about-100 ℃ to 100 ℃. The reaction time ranges from about 1 second to 5 days, preferably from 5 minutes to 20 hours.

In general, the reaction illustrated in scheme 1 can be carried out at about-78 ℃ with dry ice/acetone or dry ice/methanol, about 0 ℃ with an ice bath, room temperature or 100 ℃, preferably about 0 ℃ to about room temperature.

The reaction steps (a) and (b) are carried out in the same reaction vessel under mild reaction conditions and in high yield.

The enamine compounds of formula (II) may be prepared according to processes known to those skilled in the art, as illustrated in scheme 2.

Scheme 2

Typically, the beta-keto ester compound of formula (IV) can be converted to a compound in which R is²And R³A compound of formula (ii) as hereinbefore defined. The reduction may be carried out in an inert solvent that dissolves ammonia gas, at a temperature in the range of about 0 ℃ to 60 ℃. Suitable reaction inert solvents include lower alkanols such as methanol and ethanol. Alternatively, the ammonia-containing gas solution given above may be added to the solution containing the β -keto ester (IV). The mixture is reacted at a temperature ranging from about 0 ℃ to 60 ℃ to give an enamine compound (II).

The alkylene compound of formula (iii) may be prepared according to procedures known in the art. Scheme 3 illustrates the scheme of the preparation method.

Scheme 3

The carbonyl compound of formula (V) may be coupled with the aldehyde compound of formula (VI) according to known procedures to give the alkylene compound of formula (III). For example, wherein R⁶-Y-is optionally substituted heterocycle- (CH)₂)₂The compound of formula (V) may be reacted with a compound of formula (VI) according to the process reported by L.Tietz et al, Liebigs Ann.Chem., pp.321-329,1988. The reaction may be carried out in a suitable reaction-inert solvent such as aromatic hydrocarbons, e.g. benzene, toluene and xylene, alcohols, e.g. methanol, ethanol, propanol and butanol, ethers, e.g. diethyl ether, dioxane and Tetrahydrofuran (THF), halogenated hydrocarbons, e.g. dichloromethane, chloroform and dichloroethane, amides, e.g. N, N-dimethylformamide, nitriles, e.g. acetonitrile. The reaction may be carried out at about 0 ℃ to the reflux temperature of the reaction mixture, preferably 80 ℃ to 120 ℃ for about 30 minutes to 24 hours, preferably 30 minutes to 6 hours. The reaction may conveniently be carried out in the presence of a base or acid catalyst. Suitable base catalysts are piperidines, pyridines and alkoxides, while suitable acid catalysts are acetic acid, TiCl₄And p-toluenesulfonic acid.

The intermediate compounds of formula (v) may be prepared from known compounds according to procedures known to those skilled in the art. For example, wherein R⁶Is an optionally substituted heterocycle (including heteroaryl) as previously defined, and R³Is (C)₁-C₅) The compound of formula (v) of alkoxy-C (= O) -may be prepared according to the procedure described in scheme 4.

Scheme 4

Wherein R is⁶The aldehyde compound of formula (VII) as defined above is reacted with malonic acid under basic conditions. For example, the reaction is carried out in the presence of a weak base such as piperidine in a reaction-inert solvent such as pyridineTo give a carboxylic acid compound of the formula (VIII). The resulting compound of formula (VIII) may be subjected to an aliphatic nucleophilic substitution reaction in the presence of a coupling agent to give a pentenoate compound of formula (IX). The reaction may conveniently be carried out by first treating the compound of formula (VII) with a coupling agent such as N, N' -carbonyldiimidazole in a reaction inert solvent such as dimethylformamide and then with a nucleophile such as CH₃O₂CCH₂K is carried out in the presence of a Lewis acid such as magnesium chloride. The foregoing treatment may be carried out at a temperature of about 0 ℃ to about 60 ℃, preferably room temperature, for about 1 minute to 12 hours. The latter reaction may be carried out at a temperature of about 0 ℃ to 100 ℃, preferably about room temperature to 60 ℃ for about 1 minute to 12 hours. The compound of formula (IX) may be reduced with a metal catalyst in a hydrogen atmosphere according to known procedures to give the compound of formula (V). Suitable catalysts are Raney nickel catalysts and noble metal catalysts including Pd/C and palladium hydroxide. The reaction may be carried out in a reaction inert solvent such as methanol at about room temperature in hydrogen at a suitable pressure, for example, with a balloon, for about 1 minute to 12 hours.

The keto compounds of formula (V) and substituted benzaldehyde compounds of formula (VI) may also be prepared according to known methods (e.g., (1) D.Scherling, J.Labelled compds.radiopharm., Vol.27, pp.599-,1989, (2) C.R.Holmqquist et al, J.Org.Chem., Vol.54, pp.3528-,1989, (3) S.N.Huckin et al, J.Am.Chem.Soc., Vol.96, pp.1082-,1974, (4) J.C.S.PerkinI, pp.529-,1970, (5) Synthesis pp.37,1986, and (6) J.C.S.Chem.Commum, pp.932-, 7).

The compounds of formula (I) have chiral centers and, if desired, mixtures of the enantiomers of the compounds can be separated by methods known to those skilled in the art, for example by HPLC or fractional crystallization. Furthermore, enantiomeric mixtures of the compounds of formula (III) can also be optically separated in a similar manner before carrying out the preparation process of the invention.

The compound of formula (I) prepared according to the above-mentioned method can be isolated and purified by a common technique such as recrystallization or chromatographic purification.

The resulting compound of formula (I) may be further subjected toThe desired reaction. For example, wherein R²The compound which is-COOH can be subjected to a coupling reaction with a desired amine or imine compound to give a compound as disclosed in WO96/06082, WO97/30048, U.S. Pat. No. 5861402 and the like.

By the process of the present invention, 1, 4-dihydropyridine compounds can be efficiently prepared under mild conditions. In particular, 1, 4-dihydropyridine compounds, which are difficult to synthesize by the Hantzsch process (without mild conditions), can also be synthesized because of the mild conditions of the present invention.

Examples

The invention is illustrated by the following non-limiting examples in which, unless otherwise stated: all operations were carried out at room temperature, i.e. 18-25 ℃; evaporation of the solvent was carried out under reduced pressure with a rotary evaporator at a bath temperature of up to 60 ℃; the reaction was monitored by Thin Layer Chromatography (TLC), reaction time was used for illustration only; the melting points given (m.p.) are uncorrected (polymorphism will result in different melting points); all isolated compound structures and purities were determined by at least one of the following techniques: tlc (Merck silica gel 60F)₂₅₄Prefabricated TLC plates or Merck NH₂ F_254sPreformed HPLC plate), mass spectrometry, Nuclear Magnetic Resonance (NMR), infrared absorption spectroscopy (IR) or microanalysis. The yields are given for illustration only. Flash column chromatography was performed on Merck silica gel 60(230-400 mesh ASTM) or Fuji Silysia chromatex^DU3050 (amino form, 30-50 μm). Low-resolution mass spectral data (EI) were obtained on an automated 120(JEOL) mass spectrometer. Low resolution mass spectral data (ESI) were obtained on a Quattro II (Micromass) mass spectrometer. Unless otherwise stated, NMR data were measured in parts per million (ppm) on a 270 Mhz (JEOL JNM-LA 270 spectrometer) relative to Tetramethylsilane (TMS) as an internal standard using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent; the conventional abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, and so on. The IR spectrum was measured by Shimazu infrared spectrometer (IR-470). Optical rotation was measured by JASCO DIP-370 Digital Polarimeter (Japan Spectrosco)pic CO, Ltd.) measurements. Chemical symbols have their usual meaning; b.p. (boiling point), m.p. (melting point), 1 (l), ml (ml), g (g), mg (mg), mol (mol), mmol (mmol), eq (eq). Methyl 3-oxo-5- (1, 3-thiazol-2-yl) -4-pentenoate:

methyl 3-oxo-5- (1, 3-thiazol-2-yl) -4-pentenoate was prepared from 3- (1, 3-thiazol-2-yl) -2-pentenoic acid (Bull. chem. Soc. Jap.1974,47,151.) according to literature procedures (Heterocycles 1994,38, 751.). To a solution of 3- (1, 3-thiazol-2-yl) -2-pentenoic acid (100.0g,644.4mmol) in DMF (1000ml) was added 1, 1' -carbonyldiimidazole (115.0g,708.9mmol) in small portions with stirring. After stirring at room temperature for 5 hours, anhydrous magnesium chloride (73.6g,773.0mmol) and potassium monomethyl malonate salt (120.8g,773.0mmol) were added to the reaction mixture. The resulting suspension was heated and stirred at 55 ℃ for 14 hours. After cooling to room temperature, the reaction mixture was poured into 1500ml of 2N hydrochloric acid, and extracted with a mixture of ethyl acetate (1500ml) and toluene (500 ml). The organic phase was separated off and the aqueous phase was extracted with a 3: 1 mixture (2000ml) of ethyl acetate and toluene. The combined organic phases were washed with water (1000ml) and brine (1000ml), dried (sodium sulphate) and evaporated, giving 132.0g of methyl 3-oxo-5- (1, 3-thiazol-2-yl) -4-pentenoate (1/2 keto/enol form)¹H NMR(CDCl₃) δ:11.77(s,2/3H),7.97(d, J =3.1Hz,1/3H),7.90(d, J =3.1Hz,2/3H),7.72(d, J =16.0Hz,1/3H),7.55(d, J =15.6Hz,2/3H),7.51(d, J =3.1Hz,1/3H),7.39(d, J =3.1Hz,2/3H),7.06(d, J =16.0Hz,1/3H),6.80(d, J =15.6Hz,2/3H),5.28(s,2/3H),3.79(s,3 × 2/3H),3.77(s,3 × 1/3H),3.45(s,2 × 1/3H). 3-oxo-5- (1, 3-thiazol-2-yl) -4-pentanoic acid methyl ester:

a mixture of methyl 3-oxo-5- (1, 3-thiazol-2-yl) -4-pentenoate (132.0g) and palladium hydroxide (20 wt% (13g) on carbon) in methanol (2600ml) was stirred by balloon under an atmosphere of hydrogen at room temperature for 4 hours. The catalyst was filtered off and the filtrate was evaporated to give 130.0g of methyl 3-oxo-5- (1, 3-thiazol-2-yl) -4-pentanoate as a brown liquid.¹H NMR(CDCl₃) δ:7.65(d, J =3.3Hz,1H),7.20(d, J =3.3Hz,1H),3.73(s,3H),3.53(s,2H),3.33(t, J =6.9Hz,2H),3.13(t, J =6.9Hz, 2H). 3- (2, 6-dichlorophenyl) -2- [ (1, 3-thiazol-2-yl) propanoyl]-2-pentanMethyl enoate:

to a solution of methyl 3-oxo-5- (1, 3-thiazol-2-yl) -4-pentanoate (130g) in toluene (600ml) were added 2, 6-dichlorobenzaldehyde (113.0g,644mmol), acetic acid (5ml) and piperidine (5 ml). The mixture was distilled to remove the initial distillate (about 100ml) and then the distillation apparatus was changed to a Dean-Stark trap and heated at reflux temperature for 4 hours with azeotropic removal of water. The mixture was washed with water (200ml) and brine (200ml), dried (sodium sulphate) and evaporated to give a crude mixture. It was purified by silica gel column chromatography (1800g, hexane/ethyl acetate =3/1 as eluent) to give 165.3g (69%, 3 steps) of 3- (2, 6-dichlorophenyl) -2- [ (1, 3-thiazol-2-yl) propanoyl]-methyl 2-pentenoate as a brown oil. This is a 1: 1 mixture of double bond isomers.¹H NMR(CDCl₃) δ:7.70-7.15(m,6H),3.91 and 3.66 (apparently two singlet) 3H),3.44 and 3.28 (apparently two singlet, 4H). 4- (2, 6-dichlorophenyl) -2- (2-methoxy-2-oxoethyl) -6- [2- (1, 3-thiazol-2-yl) ethyl]-dimethyl 1, 4-dihydropyridine-3, 5-dicarboxylate:

A1.0M solution of EtMgBr in THF (1192ml,1192 mmol; 2.0eq.) was added slowly dropwise over a period of 2 hours to a stirred solution of 2-methyl-2-propanol (92.8g,1252 mmol; 2.1eq.) in anhydrous THF (1100ml) at 0 ℃ under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 1 hour. The mixture was then added slowly dropwise to a solution of dimethyl 3-amino-2-pentenedioate (113.5g,655 mmol; 1.1eq.) in dry THF (550ml) at 0 ℃ over 20 minutes. The resulting pale yellow solution was stirred at the same temperature for 1 hour, and then 3- (2, 6-dichlorophenyl) -2- [ (1, 3-thiazol-2-yl) propionyl group was added at 0 ℃ over 30 minutes]-methyl 2-pentenoate (219.9g,594 mmol' 1.0eq.) in anhydrous THF (550 ml). The reaction mixture was stirred at room temperature under nitrogen for 16 hours, then acetic acid (170 ml; 5.0eq.) was added at 0 ℃. The resulting mixture was stirred at room temperature for 6 hours. The mixture was poured into a 2N aqueous solution (1000ml) of sodium hydroxide, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2000 ml). The combined organic phases were washed with water (1000ml) and brine (1000ml), dried (sodium sulphate) and concentrated to give a crude mixture. Purification by column chromatography on silica gel (3 times 1700g) with hexane/ethyl acetateThe ester (2/1 to 1/2) gave 246.0g (85%) of 4- (2, 6-dichlorophenyl) -2- (2-methoxy-2-oxoethyl) -6- [2- (1, 3-thiazol-2-yl) ethyl]Dimethyl (E) -1, 4-dihydropyridine-3, 5-dicarboxylate as a brown oil.¹H NMR(CDCl₃)δ:8.33(s,1H),7.67(d,J=3.3Hz,1H),7.24(t,J=8.0Hz,2H),7.24(d,J=3.3Hz,1H),6.98(dd,J=8.0,8.0Hz,1H),5.99(s,1H),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,1H)。

In step D of the above example, the coupling in the presence of magnesium base and the subsequent cyclization in the presence of acidic acid is a one-pot synthesis.

Claims (13)

1. A process for preparing a 1, 4-dihydropyridine compound comprising the step of (a) an enamine of the formulaAnd compounds having the structureContacting in the presence of a base; (b) the resulting reaction mixture is treated in the presence of an acid or a combination of acids.

2. A process according to claim 1 for the preparation ofPreparing a compound of formula (I):wherein: r¹Selected from hydrogen and (C)₁-C₄) An alkyl group; r²Selected from nitriles; -SO₃H；-SO₂-(C₁-C₆) An alkyl group; -SO- (C)₁-C₆) An alkyl group; -PO [ O (C)₁-C₄) Alkyl radical]₂；-C(=O)-R⁷Wherein R is⁷Selected from hydroxy or its salt, (C)₁-C₆) alkyl-O-, amino, (C)₁-C₆) alkyl-NH-and di [ (C)₁-C₆) Alkyl radical]-N-；R³And R⁵Independently selected from the group consisting of nitrile and (C)₁-C₅) alkoxy-C (= O) -; r⁴Is unsubstituted or mono-, di-, tri-, tetra-or penta-substituted phenyl, wherein the substituents are independently selected from halogen atoms; optionally substituted by one to three halogen atoms₁-C₄) An alkyl group; optionally substituted by one to three halogen atoms₁-C₄) An alkoxy group; a nitro group; an amino group; one (C)₁-C₄) Alkylamino and di [ (C)₁-C₄) Alkyl radical]An amino group; r⁶Selected from hydrogen; (C)₁-C₁₀) An alkyl group; optionally substituted by one to two independently selected halogen atoms, (C)₁-C₄) Alkyl, tri-halo (C)₁-C₄) Alkyl and (C)₁-C₄) Phenyl substituted with a substituent of alkoxy; and containing 1 to 4 heteroatoms or selected independently from-O-, -S-, -NH-and-N [ (C)₁-C₄) Alkyl radical]A 4-to 10-membered heterocycle containing a heteroatom moiety of (a), wherein said heterocycle is saturated, partially-saturated or aromatic, and said heterocycle is optionally substituted with a halogen atom or (C)₁-C₄) Alkyl substitution; and Y is selected from the group consisting of a covalent bond, methylene, oxygen and sulfur; the process comprises the step of (a) an enamine compound of the formulaWith a compound of the formulaWherein R is¹,R²,R³,R⁴,R⁵,R⁶And Y is as previously defined, in the presence of a base under reaction conditions sufficient for addition reaction of the compound; and (b) cyclizing the compound produced in step (a) in the presence of an acid catalyst selected from the group consisting of a protic acid, and a combination of a protic acid and an aprotic Lewis acid.

3. The process according to claim 1, wherein the base in step (a) is a base capable of promoting a Michael-type reaction.

4. The process of claim 1 wherein the base in reaction step (a) is a magnesium (II) base and the acid catalyst in reaction step (b) is a protic acid.

5. The process of claim 1 wherein the base in step (a) is not a magnesium (ii) base and the acid catalyst in step (b) is a combination of a protic acid and an aprotic Lewis acid.

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

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

8. The process according to claim 1, wherein the base in step (a) is selected from (C)₁-C₄) Alkyl lithium, halogenated (C)₁-C₄) Magnesium alkoxide, halo (C)₁-C₆) Alkyl magnesium, metal hydride, metal (C)₁-C₃) Alkoxide of magnesium-bis [ (C)₁-C₃) AlkanolsSalt (salt)]Metal-n-butoxide, metal-sec-butoxide, metal-tert-butoxide, metal carbonates and metal fluorides.

9. The process according to claim 1, wherein the acid catalyst used in the reaction step (b) is selected from the group consisting of hydrochloric acid, p-toluenesulfonic acid, phosphoric acid, sulfuric acid, nitric acid and (C)₁-C₆) An alkanoic acid.

10. The method according to claim 2, wherein R¹Selected from hydrogen, methyl and ethyl; r²Is selected from-C (= O) -R⁷Wherein R is⁷Selected from hydroxy or its salt, (C)₁-C₆) alkyl-O-, amino, (C)₁-C₆) alkyl-NH-and di [ (C)₁-C₆) Alkyl radical]-N-；R³And R⁵Independently selected from (C)₁-C₃) alkoxy-C (= O) -; r⁴Is a di-substituted phenyl group wherein the substituents are independently selected from halogen atoms; optionally substituted by one or two halogen atoms₁-C₄) Alkyl and nitro; r⁶Selected from hydrogen; (C)₁-C₅) An alkyl group; optionally substituted by one to two independently selected halogen atoms, (C)₁-C₄) Alkyl radical, CF₃And (C)₁-C₄) Phenyl substituted with a substituent of alkoxy; and a 4-to 10-membered heterocyclic ring selected from the group consisting of piperidino, morpholino, thiomorpholino, pyrrolidino, pyrazolidino, pyrazolyl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl and quinuclidinyl, said heterocyclic ring optionally being substituted with a halogen atom or (C)₁-C₄) Alkyl substitution; and Y is selected from the group consisting of a covalent bond, methylene, oxygen and sulfur.

11. The method according to claim 11, wherein R¹Is hydrogen; r²Is COOH, COOCH₃Or COOC₂H₅；R³And R⁵Independently of one another is COOH, COOCH₃Or COOC₂H₅；R⁴Is mono-or di-substituted phenyl, wherein the substituents are independently selected from fluoro, chloro and nitro; r⁶Selected from hydrogen; (C)₁-C₃) An alkyl group; optionally substituted by one to two independently selected halogen atoms, (C)₁-C₃) Alkyl radical, CF₃And (C)₁-C₃) Phenyl substituted with a substituent of alkoxy; and a 4-to 10-membered heterocyclic ring selected from the group consisting of piperidino, morpholino, thiomorpholino, pyrrolidino, pyrazolidino, pyrazolyl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolinyl and quinuclidinyl, wherein said heterocyclic ring is optionally substituted with a halogen atom or (C)₁-C₃) Alkyl substitution; and Y is a covalent bond or methylene.

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

13. A process according to claim 5, the aprotic Lewis acid is a magnesium (II) salt.