KR800001592B1 - Process for preparing 1,4-dihydro pyridine derivatives - Google Patents

Abstract

Title compds.(I; R1 = halogen, nitro or alkenyloxy substituted aryl or heterocycle; R2,R3 = esterified carboxyl; R3e = alkyl or hydroxy substituted alkyl; R5e = hydroxy, N,N'-dialkylamino or hydroxyalkylamino substituted lower alkyl; R'4b = alkyl or oxo substituted alkyl; R'5b = N' N'-dialkylamino or hydroxyalkylamino substituted lower alkyl) useful as vasodilators and antihypertensives, having lower toxicity than Nifedipine, were prepd. by reduction of compd.(II).

Description

Method for preparing 1,4-dihydropyridine derivative

The present invention relates to a 1,4-dihydropyridine derivative, in particular a method for preparing a 1,4-dihydropyridine derivative effective for vasodilatation and hypertension and pharmaceuticals effective in treating cardiovascular disease and hypertension It is about composition.

An object of the present invention is a method for preparing a new and useful 1,4-dihydropyridine derivative, and another object of the present invention is to prepare a useful pharmaceutical formulation of 1,4-dihydropyridine derivative which is effective in preventing vasodilation and hypertension A further object of the present invention is to provide a method for treating cardiovascular diseases such as coronary artery slack, angina pectoris or myocardial infarction and hypertension.

The 1,4-dihydropyridine derivative of the present invention is represented by the following general structural formula.

In the above structural formula

R ₁ is an aryl or heterocyclic group which may have one or more suitable substituents,

R ₂ and R ₃ are the same or different and are esterified carboxyl groups,

R ₄ and R ₅ are each hydrogen, cyano, lower alkyl, or substituted lower alkyl wherein the substituents are cyano, hydroxy, alkoxy, hydroxyimino, hydrazono, lower alkoxyimino, hydroxy (lower) alkyl. Mino, N'-or N ', N'-di (lower) alkylamino- (lower) alkylimino, hydrazino, hydroxy (lower) alkylamino, N'-or N', N'-di ( Lower) alkylamino- (lower) alkylamino, 5 or 6-angled saturated N-containing heterocyclic-1-yl (hydroxy, lower alkyl or hydroxy (lower) alkyl, or oxo, The carbonyl formed may be protected with a suitable protecting group), when one of R ₄ and R ₅ is hydrogen or a lower alkyl group, the other is always cyano or a substituted lower alkyl group, and R ₄ and R ₅ are hydrogen or If not lower alkyl, they are both cyano and one of the substituted lower alkyl groups.

Or R ₄ is hydrogen or a lower alkyl group,

R ₃ and R ₅ combine to form a group of the structure

In the above structural formula

R ₆ is hydrogen or methyl,

R ₇ is 2- (N, N-diethylamino) -ethyl or 2-hydroxy ethyl.

The words used in the definitions of the general structural formulas given in the specification and claims can be explained as follows.

The term "lower" means an alkylene, alkyl or alkenyl group having from 1 to 8 carbon atoms. The aryl and aryl moieties are such as phenyl, naphthyl, xylyl, toryl, mesityl, cumenyl, and may have one or more suitable substituents. Representatives of suitable substituents are hydrogen, nitro, hydroxy, halo (lower) alkyl, lower alkoxy and lower alkenyloxy. Halogen or halo moieties are fluorine, chlorine, bromine and iodine. Lower alkylene is a straight or branched chain and saturated divalent hydrocarbon, and examples thereof include methylene, ethylene, methylmethylene, trimethylene, propylene or tetramethylene. Lower and lower alkyl moieties consist of straight or branched and saturated hydrocarbons, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neo-pentyl, hexyl, heptyl or octyl.

Lower alkoxy and lower alkoxy moieties are methoxy, ethoxy, propoxy, isopropoxy, butyloxy, t-butoxy and pentyloxy. Halo (lower) alkyl is mono-halo (lower) alkyl (chloromethyl, bromomethyl or chloropropyl) or di-halo (lower) alkyl 1,2-dichloroethyl, 1,2-dibromoethyl or 2, 2-dichloroethyl) or tri-halo (lower) alkyl (trifluoromethyl or 1,2,2-trichloroethyl). Lower alkenyl and lower alkenyl moieties are vinyl, allyl, butenyl, butadienyl or penta-2,4-dienyl, consisting of straight or branched chain hydrocarbons and having one or more double bonds. Acyl and acyl moieties are lower alkanoyls such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl or substituted lower alkanoyl groups, for example carboxy (lower) Noyl, esterified carboxy (lower) alkanoyl (lower alkoxycarbonyl (lower) alkanoyl), N- or N, N-disubstituted amino (lower) alkanoyl (N-or N, N-di (lower) ) Alkylamino (lower) alkanoyl, i.e., N-methyl (or N, N-dimethyl) amino acetyl, 1 (or 2)-[N-ethyl N, N-diethyl) amino] propylonyl or 1 (or 2) )-[N-methyl-N-ethylamino] propylonyl) or N-lower alkyl-N-ar (lower) alkylamino (lower) alkanoyl, ie 1- (or 2)-[N-methyl-N- Benzylamino] propionyl or aryloxy (lower) alkanoyl, ie phenoxyacetyl, tolyloxyacetyl, 2 (or 3 or 4) -chlorophenoxyacetyl, 2- [2- (or 3 or 4) -chlorophenoxy ] -Propionyl, 2 Is 3 or 4) -nitrophenoxy acetyl or 2 (or 3 or 4) -methoxy-phenoxyacetyl), aroyl benzoyl, naphthoyl or toluoyl.

The heterocyclic group of R 'is an aliphatic heterocyclic group and includes heteroatoms such as one or more nitrogen atoms, sulfa atoms and oxygen atoms, for example thienyl, furyl, pyrrolyl, thiazolyl, thiadiazolyl , Tetrazolyl, pyridyl, pyrimidinyl, quinolyl, isoquinolyl, benzothienyl, indoryl or furinyl.

The esterified carboxy of R2 and R3 is lower alkoxy carbonyl (methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl): halo (lower) alkoxycarbonyl [ As halo-co-formers of the above-mentioned lower alkoxycarbonyls, for example 2-bromoethoxycarbonyl, 2-chloroethoxycarbonyl, 2 (or 3) -chloropropoxycarbonyl, 2 (or 3)- Bromopropoxycarbonyl, 2,2-dichloroethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl], hydroxy (lower) alkoxycarbonyl, 2-hydroxyethoxycarbonyl or 2 (Or 3) hydroxy propoxycarbonyl; Lower alkoxy (lower) alkoxycarbonyl, 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl or 9 (or 3) -methoxy (or ethoxy) propoxycarbonyl; Aryloxycarbonyl (phenoxycarbonyl, aryloxycarbonyl, xylyloxycarbonyl or P-chlorophenoxycarbonyl); Ar (lower) alkoxycarbonyloxy benzyloxycarbonyl, P-bromobenzyloxycarbonyl, 0-methoxy benzyloxycarbonyl or phenethyloxycarbonyl; Ar (lower) alkoxy (lower) alkoxycarbonyl (2- (benzyloxy) ethoxycarbonyl or 2 (or 3)-(benzineoxy) propoxycarbonyl), aryloxy (lower) alkoxycarbonyl (2- (Phenoxy) ethoxycarbonyl or 2 (or 3)-(phenoxy) propoxycarbonyl); N- or N, N- (di) -substituted amino (lower) alkoxycarbonyl, (N-or N, N- (di)-(lower) -alkylamino (lower) alkoxycarbonyl), for example 1 (or 2)-[N-methyl (or N, N-dimethyl) amino] ethoxycarbonyl, 1 (or 2)-[N-ethyl (or N, N-diethyl) amino] ethoxycarbonyl Or 1 (or 2)-[N-methyl-N-ethylamino] ethoxycarbonyl or N-lower alkyl-N-ar (lower) alkylamino (lower) -alkoxycarbonyl, for example 2- ( N-methyl-N-benzylamino-ethoxycarbonyl). On the other hand, R2 and R₃ are the same or different, and lower alkyl substituted with oxo includes lower alkane oil such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or pivaloyl. And lower alkanoyl (lower) alkyls such as formyl methyl, acetonyl, 2-formylethyl, 3-formylpropyl or butyrylmethyl and the like.

The above carbonyl group is protected with a suitable protecting group and the carbonyl group protected in the present invention means a carbonyl group protected by a conventional method for carbonyl. Suitable examples of such protected carbonyl groups are acetal, cyclic-acetal, thioacetal, cyclic-thioacetal, cyclic-monothioacetal, or acylyl groups. Lower alkyl groups containing such protected carbonyl groups are gem-di (lower) alkoxy (lower) alkyls (ie, dimethoxymethyl, 1,1-dimethoxyethyl, ethoxymethyl, dipropoxymethyl, 2,2-die Methoxyethyl or 2,2-diethoxypropyl); gem-lower alkylene dioxy (lower) alkyl (ie 1,3-dioxolan-2-yl, 2-methyl-1,3-dioxolane-2 -Yl, 4-methyl-1,3-dioxolan-2-yl, 4,5-dimethyl-1,3-dioxoran-2-yl, 1,3-dioxan-2-yl, 2- Methyl-1,3-dioxan-2-yl, 1,3-dioxolan-2-ylmethyl, 2-methyl-1,3-dioxoran-2-ylmethyl or 3- (1,3- Dioxoran-2-yl) propyl; gem-di- (lower) alkylthio (lower) -alkyl (zyl dimethylthiomethyl, 1,1-dimethyl thioethyl, diethylthiomethyl or 2,2-diethylthio Ethyl), gem-lower alkylenedithio (lower) alkyl (e.g., 1,3-dithioran-2-yl, 2-methyl-1,3-dithioran-2-yl, 4-methyl-1 , 3-dithioran-2-yl, 4,5-dimethyl-l, 3-dithioran-2-yl, 1,3-dithian-2-yl, 2-methyl-l, 3-dithiane-2 -Day, 1,3-diti Lan-2-ylmethyl, 2-methyl-1,3-dithioran-2-ylmethyl or 3- (1,3-dithioran-2-yl) propyl) and gem-di (lower) -alkanoyloxy (Lower) alkyl (e.g. diacetoxymethyl, 1,1-diacetoxy ethyl, dipropionyl oxymethyl or 2,2-dipropionyloxyethyl); 5 or 6-each saturated 1-oxa- 3-thioheterocyclic-1-yl- (lower) alkyl eg 1,3-oxathioran-2-yl, 2-methyl, 1,3-oxathioran-2-yl, 4-methyl- 1,3-oxathioran-2-yl, 4,5-dimethyl-1,3-oxathioran-2-yl, 1,3-oxotian-2-yl, 2-methyl-1,3-oxo Thian-2-yl, 1,3-oxothioran-2-ylmethyl, 2-methyl-1,3-oxathioran-2-ylmethyl or 3- (1,3-oxathioran-2-yl ) Profile.

5 or 6-angled saturated N-containing heterocyclic 1-yl groups include one or more heteroatoms selected from nitrogen, sulfur and oxygen atoms, which are optionally hydroxymethyl, 2-hydroxyethyl It may be substituted with a hydroxy, lower alkyl or hydroxy (lower) alkyl group, such as 2-hydroxypropyl or 3-hydroxypropyl.

Each lower alkoxyimino, ie N'- or N ', N'-di- (lower) alkylamino (lower) alkylimino, hydroxy (lower) alkylimino, N'- or N', N'-di- Definitions such as (lower) alkylamino (lower) alkylamino and hydroxy (lower) alkylamino may be clearly defined by applying the above examples.

According to the present invention, 1,4-dihydropyridine derivative (I) can be prepared by various methods, which are classified as follows.

(I. Composition of the Basic Structure)

1. Ring formation of 1,4-dihydropyridine nuclei

(II. Functional Group Conversion)

2. Hydrolysis to remove the protecting group of a protected carbonyl group

3. Condensation to form imino-functional groups

4. Dehydration

5. Reducing oxo or imino-functional groups

6. Acylation of hydroxy-functional groups

7. Oxidation of Alcohols with Carbonyl Compounds

8. Heat ring

9. Other transition

Each method will be described later in detail.

1. One of the ring-forming compounds (I) of the 1,4-dihydropyridine nucleus can be represented by the following structural formula (I-1).

In the above structural formula

R₁, R₂ and R₃ are as described above,

R ₄ a and R ₅ a are each a lower alkyl group substituted with hydrogen, lower alkyl or oxo, wherein the carbonyl group formed here is protected by a suitable protecting group, a lower group having one of R ₄ a and R ₅ a substituted with oxo Alkyl and the carbonyl group so formed is protected with a suitable protecting group)

The compound of formula (I-1) can be prepared by the following method.

(1) The compound of formula (II) is reacted with the amino compound of formula (III).

In the above structural formula, R ₁ , R ₂ , R ₃ , R ₄ a and R ₅ a are as described above.

(2) A mixture of an aldehyde compound of formula (II ′), a β-ketone acid of formula (II ″) and an amino compound of formula (III) is reacted.

R ₁ -CHO (II ′) R ₅ a-COCH ₂ -R ₃ (II ″)

R ₁ , R ₃ and R ₅ a in the above structural formula are as described above.

(3) The acetylene compound of formula III is reacted with ammonia or an ammonium salt with a compound of formula II.

R ₂ -C≡CR ₄ a (III ′)

R ₂ and R ₄ a in the above structural formula are as described above.

The starting compound (II) used in reactions (1) and (3) is new and prepared by reacting β-ketosan ester (II ″) with aldehyde (II ′), and the ammonium salt used in reaction (3) is the same inorganic. Ammonium salts and organic ammonium salts such as ammonium chloride or ammonium sulfaate, ammonium acetate.

The reaction (1), as the starting compound (2) and (3) (Ⅱ), (Ⅱ "), (Ⅲ) and (Ⅲ ') compound is used is R ₄ a and R ₅ a of these structural formulas of Change from case to case. Of course, both sides are changed when they are not the same group. In this case, not only when R ₄ a and R ₅ a are the same group, but also when R ₄ a and R ₅ a are different regardless of whether the groups R ₂ and R ₃ are the same.

Compound (II), the starting material used in reactions (1) and (2), contains geometric isomers such as cis-trans isomers due to intramolecular double bonds. Since these cis-trans isomers are in equilibrium distribution, the isomeric mixture of compound (II) can be applied to make the same target compound (I-1).

Reactions (1), (2) and (3) are suitable names at room temperature or warm, i.e. benzene, toluene, xylene, chloroform, carbon tetrachloride, methylene chloride, ethylene chloride, methanol, propanol, butanol, water or conventional It is performed with a phosphorus solvent.

The reaction is promoted in the presence of an acid (eg acetic acid), a base (eg pyridine or piclin) or conventional buffer solution. These reagents act as reaction enhancers, while they are used as solvents when the reagents are liquid. The reaction accelerates when heated. Reaction conditions vary depending on the type of reactant used.

2. Hydrolysis to remove the protecting group protecting the carbonyl group The compound of formula (I-1) is hydrolyzed to form the compound of formula (I-2).

In the above structural formula

R ₁ , R ₂ and R ₃ are as described above

R ₄ b and R ₅ b are each (when R ₄ b, and one or more oxo-substituted lower alkyl group of R ₅ b) hydrogen, lower alkyl, oxo-lower alkyl group substituted by a

In this step, the protecting group of the carbonyl group of the R ₄ a and / or R ₅ a alkyl group of the compound (I-1) is removed by hydrolysis. Hydrolysis is carried out by conventional methods, for example the removal of protecting groups of acetal-type and cyclic acetal-type is preferably carried out by acid hydrolysis. That is, in combination with inorganic acids (eg hydrochloric acid or sulfuric acid) or organic acids (eg formic acid, acetic acid, trifluoroacetic acid or P-toluene sulfonic acid). The protecting group removal of thioacetal-type and cyclicthioacetal-type and cyclic monothioacetal-type is preferably carried out by hydrolysis in the presence of a heavy metal such as mercury chloride or copper chloride and the removal of the acetal-type protecting group is described above. Decomposition or base hydrolysis, i.e. inorganic bases (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) or organic bases (i.e. sodium meoxide, sodium ethoxide, potassium methoxide, potassium oxide, Preferably in the presence of pyridine or piclin). Such reactions of hydrolysis are suitable conventional methods such as water, acetone, methyl ethyl ketone, dioxane, ethanol, methanol, N, N-dimethylformamide, N-methylmorpholine or dimethylsulfoxide, any mixture of water or buffer, and the like. It is carried out in a solvent of phosphorus. The reaction temperature is not limited and the reaction usually takes place under cooling, room temperature and sometimes at elevated temperatures.

3. Condensation of Amino Functional Groups

Compounds of formula (I-3) are made by reacting compounds of formula (I-2) with amines of formula (IV).

From above

R ₁ , R ₂ and R ₃ are as described above,

R ₄ c and R ₅ c are each hydrogen, lower alkyl, or substituted lower alkyl (substituents are hydroxy amino, hydrazono, lower alkoxyimino, hydroxy (lower) alkylimino or N′- or N, N -Di- (lower) alkylamino (lower) alkylimino groups, provided that one of R ₄ c and R ₅ c is a lower alkyl group substituted as above

R ₁ , R ₂ , R ₃ , R ₄ b and R ₄ b are as described above.

R ₈ -NH ₂ (Ⅳ)

R ₈ is hydroxy, amino, lower alkoxy, hydroxy (lower) alkyl or N- or N, N-di (lower) alkylamino (lower) alkyl above.

In R ₄ b and / or R ₅ b of the starting compound (I-2) used according to the method, the oxo group is replaced by an amino group of NR ₈ (wherein R ₈ is as described above). Starting compound (I-2) is obtained by the above-mentioned hydrolysis method. The reaction is carried out in the usual way. For example, in the presence of a catalyst, i.e. acids (hydrochloric acid, hydrobromic acid, sulfonic acid, formic acid, acetinic acid, P-toluenesulfonic acid, borontrifluoride, silicon tetrachloride or titanium tetrachloride), basic conditions (amino -Using compound (IV)) or an acidic or basic conventional buffering solution and conventional solvents commonly used, such as water, dioxane, ethanol, methanol or dimethylformamide or mixtures of these and water.

The reaction temperature is usually carried out without cooling, at room temperature or at a constant elevated temperature. The amine (IV) is used as a reactant, and N'- or N ', N'-di- (lower) -alkylamino (lower) alkylamine, ie N'-methyl or N', N'-dimethylamino-ethylenediamine , N′-ethyl or N′N′-diethyl ethylenediamine, N′-methyl or N ′, N′-di-methylamino trimethylenediamine or N′-ethyl or N ′, N′-diethyl-amino Trimethylenediamine, hydroxy (lower) alkylamine (ethanol mamine or propane amine), hydroxylamine, hydrazine and lower alkoxy amine 0-methyl, 0-ethyl, 0-propyl or 0-isopropyl-hydroxyamine And the like. Such amines are used in the form of salts with acids such as inorganic acids (eg hydrochloric acid or sulfuric acid) or organic acids (eg acetic acid).

4. Dehydration

Compounds of formula (I-4) are prepared by treating compounds of formula (I-3 ') with a dehydrating agent.

From above

R ₁ , R ₂ and R ₃ are as described above,

R ₄ d and R ₅ d are each hydrogen, lower alkyl, cyano or W-cyano (lower) alkyl, and when one of R ₄ d and R ₅ d is hydrogen or lower alkyl the other is always cyano or W- cyano (lower) alkyl, R ₄ d and R ₅ d is more than this time is not a hydrogen or a lower alkyl group is one of a cyano or cyano-W- (lower) alkyl group, or R ₄ d is a small number, or Lower alkyl and R ₃ and R ₅ d combine to form the following structure:

In the above structural formula

R ₁ , R ₂ and R ₃ are as described above,

R ₅ d of R ₄ d are each hydrogen, lower alkyl or W-hydroxyimino (lower) alkyl, provided that one of R ′ ₄ c and R ′ ₅ c is a W-hydroxyamino (lower) alkyl group.

Starting compound (I-3 ') is obtained by the above-described concentration. Suitable examples of dehydrating agents are general organic or inorganic. Ie acids (e.g. sulfuric acid, phosphoric acid, polyphosphoric acid, formic acid, acetic acid, ethanesulfonic acid or P-toluenesulfonic acid), acid anhydrides (e.g. acetic anhydride, benzoic anhydride, or phthalic anhydride), acid halides (e.g. acetyl chloride , Benzoyl chloride, trichloroacetyl chloride, mesyl chloride, tosyl chloride, ethylchloroformate or phenylchloroformate), inorganic halogen compounds (e.g. thionylchloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, star Nickchloride or titanium tetrachloride), carbodiimide (e.g., N, N'-dicyclohexylcarbodiimide or N-cyclohexyl-N'-morpholinoethylcarbodiimide), N, N'-carbonyl Midazole, pentamethyleneketene-N-cyclohexylimine, ethoxyacetylene, 2-ethyl-7-hydroxyisoxazolium salt, other phosphorylation The same as water (i.e., force Potters pentoxide, polyphosphoric acid ethyl ester morpholine, triethyl phosphor benzoate or diphenyl phosphate). When the acid is used as a dehydrating agent, the reaction is conveniently conducted in the presence of alkali metal salts such as sodium or potassium salts. The reaction is usually carried out with conventional solvents. That is, ethyl ether, dimethylformamide, pyridine, acetic acid, formic acid, benzene, carbon tetrachloride, chloroform, methylene chloride, tetrahydropure, dioxane and the like are applied. The reaction is usually carried out at room temperature or under heating and the reaction temperature is carried out without limitation.

According to this process, the functional group-CH = N-OH in R ′ ₄ c and / or R ′ ₅ c of the starting compound (I-3 ′) is converted to the cyano functional group in the resulting compound (I-4) and further The compound of structural formula will be produced.

In the above structural formula

R ₁ and R ₂ are as described above,

R ″ ₄ c is hydrogen or lower alkyl group (when starting material (I-3 ′) in which R ′ ₅ c is hydroxyiminomethyl is treated in strong acidity)

Compound (I-4 ') and its preparation are within the scope of the present invention. This dehydration process can be carried out successfully without separation of compound (I-3 ') in a pre-condensation step, which is also within the scope of the present invention.

5. Reduction of oxo or imino functional groups

The compound of formula (I-5) is prepared by reducing the compound of formula (I-2 ').

In the above structural formula

R ₁ , R ₂ and R ₃ are as described above,

R ₄ e and R ₅ e are each hydrogen, lower alkyl or substituted lower alkyl (substituents are hydroxy, hydrazino, hydroxy (lower) -alkylamino or N′- or N ′, N′-di (lower) Alkylamino (lower) -alkylamino, provided that one of R ₄ e and R ₅ e is a substituted lower alkyl group or R ₄ e is hydrogen or a lower alkyl group, and R ₃ and R ₅ e are

Combine with each other (R ₆ and R ₇ are each defined above).

In the above structural formula

R ₁ , R ₂ and R ₃ are as described above,

R _'4 and R b' ₅ b are each hydrogen, lower alkyl or substituted lower alkyl group (the substituent is oxo, hydroxy rajo furnace, hydroxy (lower) -alkyl or the unexposed N'- or N'N'- di ( lower) alkylamino (lower) - one of alkylamino, with the proviso that R _'4 b and R' b ₅ is an electric-substituted lower alkyl group).

Starting compounds (I-2 ') are prepared by the above hydrolysis or condensation. Reduction is carried out by conventional methods of reducing oxo or imino to hydroxy or amino.

Reducing agents include alkali metal hydrides (eg lithium borohydride, sodium borohydride) or catalysts for catalytic reduction such as palladium carbon, palladium chloride or rhodium carbon. The solvent is such as water, methanol, ethanol, isopropanol, dimethylformamide. The reaction temperature is not limited and the reaction is usually carried out under cooling, room temperature or any elevated temperature. The method of reduction is arbitrarily selected according to the kind of starting compound (I-2 ').

According to this process, the oxo or imino functional groups in the starting compound (I-2 ′) are converted to hydroxy or amino-functional groups, respectively, to give compound (I-5). Meanwhile, the compound of formula (I-5-1) and the compound of formula (I-5-2) may be simultaneously generated from compound (I-5).

In the above structural formula

R ₆ is defined above,

R ₄ e is hydrogen or a lower alkyl group.

In the above structural formula

R ₇ is defined above,

R ₄ e is hydrogen or a lower alkyl group.

In the compound (I-5) used at this time

R ₅ e is hydroxy methyl (when R ₆ is hydrogen), 1-hydroxyethyl (when R ₆ is methyl), 2- (N, N-diethylamino) ethyl aminomethyl (R ₇ is 2- N, N-diethylamino) ethyl or 2-hydroxyethylaminomethyl (when R ₇ is 2-hydroxyethyl) group. Such cases also belong to the scope of the present invention.

6. Acylation of hydroxy functional groups

Compounds of formula (I-6) are prepared by reacting a compound of formula (I-5 ') with an acylating agent of formula (V).

In the above structural formula

R ₁ , ₂ R ₃ and R ₄ f are each defined above,

R ₄ f and R ₅ f are each hydrogen, lower alkyl or acyloxy (lower) alkyl (where R ₅ and R f ₁ is at least one of acyloxy (lower) alkyl group) is.

In the above structural formula

R ₁ , R ₂ and R ₃ are each defined above,

R ′ ₄ e and R ′ ₅ e are each a hydrogen, lower alkyl or hydroxy (lower) alkyl group, provided that at least one of R ′ ₄ e and R ′ ₅ e is a hydroxy (lower) alkyl group.

R ₉ -OH (Ⅴ)

In the above general formula

R ₉ is acyl or a reaction derivative thereof.

Starting compounds (I-5 ') can be prepared by the above-mentioned reduction method. Suitable as the alkyl group of R ₉ are lower alkyloils which are substituted with carboxy, esterified carboxy, N- or N, N-di-substituted amino or artyloxy, aroyl groups and the like. Suitable acylating agents (V) include lower alkanoic acid (formic acid, acetic acid, propionic acid, butyric acid, isobutyl acid, valeric acid, isovaleric acid or pivalic acid) or carboxy (lower) alkanophosphoric acid, (di- or polybasic) Dicarboxylic acids, i.e., lower alkyl esters such as malophosphoric acid, succinic acid, adapic acid, glutamic acid, pimeric acid, or serveric acid), esterified carboxyl (lower) alkanophosphoric acid (methyl esters, ethyl esters or propyl esters) Or partial esters of polybasic carboxylic acids), N- or N, N-di-substituted amino (lower) alkanoic acid (N- or N, N-di (lower) -alkylamino (lower) alkanoic acid) For example N-methyl (or N, N-dimethyl) amino-acetic acid, 1 (or 2)-[N-ethyl (or N, N-dimethyl) amino] propionic acid or 1 (or 2)-[N -Methyl-N-ethylamino] propionic acid, or N-lower alkyl-N-art (lower) alkylamino (lower) alkanoic acid, for example 1 (or 2)-[N-methyl-N-benzylamino] propionic acid, atyloxy (lower) alkanoic acid (phenoxyacetic acid, toryloxy acetic acid, 2 (or 3 or 4) -chlorophenoxypropanoic acid, 2- [2 (Or 3 or 4) -chlorophenoxy] propionic acid, 2 (or 3 or 4) nitrophenoxy acetic acid or 2- (or 3 or 4) -methoxy-phenoxy acetic acid) and aromatic carboxylic acid (benzophosphoric acid, naphtho) Phosphoric acid, toluic acid), etc. The reaction derivatives of the carboxyl groups of the compound (V) are acid halides such as acid chlorides, acid anhydrides, active ammite, azide or reactive esters (methyl esters, ethyl epiteres, cyanomethyl esters, P-nitrophenyl ester or pyranyl ester).

The reaction is carried out using generic drugs. Ie inorganic bases (e.g. sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate) or organic bases (e.g. N-methylpiperidine, triethylamine, pyridine, N -Methylmorpholine or N, N-dimethylaniline) and general solvents (pyridine, ether, dioxane, acetone, chloroform, methylene, chloride, tetrahydroputane, dimethylformamide, benzene or water) and the like are used. The reaction temperature is not limited and the reaction is usually carried out under cooling, room temperature or any elevated temperature.

If necessary condensation may also be used. Alkoxyacetylene if phosphorus oxychloride, thionyl chloride, N, N'-dicyclohexyl carbodiimide, N-cyclohexyl-N'-morpholino ethylcarbodiimide, penta methylene ketene-N-cyclohexyl , 2-ethyl-7-hydroxyisoxazolium salt, 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide or 6-chloro-1-tosyloxybenzotriazole and the like are used.

7. Oxidation of Aldehyde Alkles

The compound of formula (I-7) is prepared by oxidizing the compound of formula (I-5 ″).

From above

R ₁ , R ₂ and R ₃ are the same as defined above

R ₄ g and R ₅ g are each hydrogen, lower alkyl, formyl or ω-formyl (lower) alkyl (when one of R ₄ g and R ₅ g is hydrogen or lower alkyl, the other is always formyl or ω-formyl (lower) alkyl,

If R ₄ g and R ₅ g are not hydrogen or lower alkyl they are a group selected from formyl and ω-formyl (lower) alkyl)

In the above structural formula

R ₁ , R ₂ and R ₃ are as defined above,

R ″ ₄ e and R ″ ₅ e are each hydrogen, lower alkyl, or w-hydroxy (lower) alkyl group, provided that one of R ″ ₄ e and R ″ ₅ e is a w-hydroxy (lower) -alkyl group .

Starting compounds (I-5 ") can be prepared by the abovementioned reduction methods. Oxidation is carried out by conventional methods and optionally by oxidizing the primary alcohol functional group to the corresponding formyl functional group without conducting influence on other parts of the compound (1-5 ″). Preferred oxidation is the reaction of the organic sulfonic acid or its reaction derivative with the starting compound (I-5 "), preferably warming and optionally carried out with a solvent in the presence of a base.

This reaction proceeds via an organic sulfonic acid ester of compound (I-5 ″) as an intermediate. Preferred organosulfonic acids are methanesulfonic acid, P-toluenesulfonic acid, P-nitrophenylsulfonic acids and reaction derivatives thereof and bases are those with respect to compound (V) mentioned in the preacylation process.

8. Pyrrolidine Ring Lung

The compound of formula (I-8) can be prepared by heating compound (I-5) or compound (I-3) in a general solvent.

In the above structural formula R ₁ and R ₂ are as described above,

R ₄ h is hydrogen or lower alkyl, R ₃ and R ₅ h are joined to form a group of the structure

From above

R ₆ is as defined above.

In compound (I-5) R ₄ e is hydrogen or lower alkyl,

R ₅ e is a hydroxymethyl group.

R ₄ c in Compound (I-3) is hydrogen or a lower alkyl group,

R ₅ c is a hydroxy group rajo furnace.

Suitable solvents are water, methanol, ethanol, isopropanol, butanol, dioxane, benzene, toluene, dimethylformamide, tetrahydrofuran, or conventional buffer solutions and the like.

The reaction can be accelerated by the addition of a significant amount of organic or inorganic bases or catalysts such as trialkylamines such as trimethylamine or triethylamine. Ie pyridine, alkali metal compounds (e.g. sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate) and organic or organic acids (acetic acid, P-toluenesulfonic acid, hydrochloric acid, sulfuric acid, borontrifluoride) , Silicon tetrachloride, titanium tetrachloride, etc. The reaction temperature is preferably performed without limitation warming or heating.

9. Other transition

1) Compound (I) can be prepared by halogenating the hydroxyl group of Compound (I-5 '). In compound (I), R ₁ , R ₂ and R ₃ are as defined above and R ₄ and R ₅ are each hydrogen, lower alkyl or 5 or 6-angled saturated N-containing heterocyclic-1-yl, ( A lower alkyl group substituted with a hydroxy lower alkyl or a hydroxy lower alkyl group. At least one of hydrogen, lower alkyl or hydroxy (lower) alkyl, provided that one of R ₄ and R ₅ is substituted lower alkyl. Prepared by substitution reaction with halo-compound 5 or 6-each saturated imino-containing heterocyclic compound. The first halogenation reaction is carried out with a halogenation reagent. Halogenating agents are conventional compositions (e.g. thionyl chloride, phosphorus stevetomide, phosphorus pentachloride or phosgene) and other phosphorus compounds, ie triphenylphosphine or tri (lower) alkylphosphite ( Examples are trimethyl phosphite or triethyl phosphite) and polyhalo (lower) alkanes (carbon tetrachloride or carbon tetrabromide in solvent).

As the solvent, carbon detrachloride, chloroform, methylene-chloride, benzene and the like are used. This reaction is carried out in a neutral state, with the latter combination being preferred. On the other hand, when using the former general chemicals, the reaction is neutralized with a base or an acidic substance generated from a halogenating agent during the reaction generation period. The reaction temperature usually depends on the type of halogenating agent, but the latter combinations are efficiently carried out at milder temperatures (cold or warm) and anhydrous in the case of the former general agents which are preferably carried out at elevated temperatures.

Secondary substitutions are optionally carried out with bases, similar to the acylation methods described above. The reaction is carried out in a suitable solvent such as chloroform, methylene chloride, benzene, acetone, ether, tetrahydroputane, dimethylformamide, methanol, ethanol or propanol. The reaction temperature is not limited and the reaction is usually carried out at room temperature or at elevated temperatures (warm or under heating) according to the method hydroxy of R ′ ₄ e and / or R ′ ₅ e of compound (I-5 ′). (Lower) alkyl is first converted to a halo (lower) alkyl group and then to a 5 or 6-angled saturated N-containing heterocyclic-1-yl group in R ₄ and / or R ₅ of compound (I). Convert to saturated lower alkyl.

2) Compound (I) (amino (lower) alkoxycarbonyl in which one of R ₂ and R ₃ is N- or N, N-di-substituted) corresponds to at least one of the corresponding compound (I) (where R ₂ and R ₃ One can be prepared by reacting an N- or N, N-di-substituted amine with a halo (lower) alkoxycarbonyl group) according to the method mentioned in 1).

3) The compound (Ⅰ) (R ₂ and R ₃ of Foe also one hydroxy (lower) alkoxycarbonyl) is a corresponding compound (at least one of Ⅰ) (R ₂ and R ₃ is halo (lower) alkoxycarbonyl ) May be prepared by hydrolysis by the above-described hydrolysis method.

4) Compound (I) [R ₁ , R ₂ and R ₃ are each defined by the source and R ₄ and R ₅ are each hydrogen, lower alkyl or gem-di- (lower) alkoxy (lower) alkyl, gem-loweralkyl Rendoxy (lower) alkyl; Substituted lower alkyl selected from gem-di- (lower) alkylio (lower) alkyl and gem- (lower) alkylene-dithio- (lower) alkyl, provided that at least one of R ₄ and R ₅ is substituted lower alkyl )] Is a lower alkanol (i.e. methanol, ethanol or propanol) or lower alkanethiol (e.g. ethylene glycol, propylene glycol, 2,3-butanediol or 1,3-propanediol), thiols such as lower alkanthiol And hydroxy compounds such as ethanethiol) lower alkanedithiol (ethanedithiol, 1,2-propanedithiol, 2,3-butanedithiol or 1,3-propane dithiol) (I-2 ) Can be prepared by reacting. The reaction is preferably carried out in the presence of a catalytic amount of organic or inorganic acid, ie hydrochloric acid, sulfuric acid, acetoic acid, borontofloride, zinc chloride or P-toluenesulfonic acid.

5) Compound (I) (R ₁ , R ₂ and R ₃ are mentioned above and R ₄ and R ₅ are each hydrogen, lower alkyl or cyano (lower) alkyl group, provided that at least one of R ₄ and R ₅ is Cyano (lower) alkyl pneumatic) can be prepared by reacting the halo compound obtained in the above-described conversion 1) with a compound of the formula R ₁₀ -CN (R ₁₀ is hydrogen or a metal atom). Preferred metals for R ₁₀ are alkali metals such as sodium or potassium, alkali metals such as magnesium or calcium, heavy metals such as mercury or silver. The reaction is carried out in a preferred solvent such as water, methanol, ethanol, butanol, chloroform, benzene, toluene, N, N-dimethylformamide, dimethylsulfoxide, N-methylmoline, pyridine or a conventional solvent at room temperature or while heating.

The product obtained in the reaction according to the invention is isolated and isolated from the reaction mixture in a conventional manner and is recrystallized from a common solvent or a mixture of such solvents for purification by conventional purification methods. In the obtained compound (I), R ₂ and R ₃ or R ₄ and R ₅ are not mutually different and are mutual stereoisomers and optically because of at least one asymmetric carbon atom present at 4 position of 1,4-dihydropyridine nucleus. It can also exist as isomers or racemic mixtures. Moreover, when compound (I) has two or more asymmetric carbon atoms in a molecule, each of a colon or a mixture may be present. The mixture of colon is separated into racemic compounds by conventional methods such as chromatography or fractional recrystallization. Racemic mixtures are dissolved into their respective optical isomers by a conventional method for racemic separation. That is, it can be separated by fractional recrystallization of the salt of the racemic compound with optically active acid (tataric acid or camphorsulfonic acid). Compound (I) has vasodilator activity and is useful for treating heart diseases such as hypertension and coronary insufficiency, angina pectoris or cardiomyopathy.

The composition of the present invention is about 5 mg to 590 mg, preferably about 25 mg to 250 mg (dosage unit) of 1,4-dihydropyridine derivative (I) as an active ingredient. One skilled in the art will be able to determine the amount of active ingredient in the claimed dosage unit. Depending on the size of the test animal, the activity of the component is considered. It is based on mg / kg and the amount of active ingredient in the composition is 1 μg / kg to 10 mg / kg, more preferably about 0.5 mg / kg to 5 mg / kg.

Depending on the purpose of administration of the present pharmaceutical composition, the active ingredient is conventionally prepared as tablets, granules, powders, suppositories, suspensions, solutions. Pharmaceutical carriers or diluents are solid or liquid pharmaceutically non-toxic acceptable materials and examples of solid or liquid carriers or diluents include lactose, magnesium stearate, terra alba, sucrose, corn starch, talc, stearic acid, gelatin, Agar, pectin, acacia, peanut, olive, sesame and cacao bitter.

On the other hand, the carrier or diluent contains a time-lag substance such as glyceryl monostearate or glyceryl distearate or wax. A wide variety of pharmaceutical forms are applied. When solid carriers are used, they are prepared in tablet form and in the form of hard gelatin capsules or torch or lozenges.

In suggesting the pharmaceutical activity of 1,4-dihydropyridine of formula (I) by standard methods, the blood flow of coronary blood was recorded by intravenous injection of 1,4-dihydropyridine in dogs anesthetized with pentobarbital. The test results are described below.

[table]

Compound A is known under the generic name “nifedipine” and is already marketed as a coronary vasodilator.

The following examples illustrate the synthesis of the target compounds of the present invention but do not limit the method.

Example 1

1) To a solution in which diethyl 2.6-bis (diethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylate (1.7 g) was added to acetone (17 ml). 6N-hydrochloric acid (1.5 ml) is added and stirred at room temperature for 3 hours. After removal of the solvent, the residue is extracted with diethyl ether and the extract is washed with water and dried. The solvent is removed from the extract to give diethyl 2,6-diformyl-4- (2-chlorophenyl) -1,4-dihydro-pyridine-3,5-dicarboxylate (1.35 g). The product is recrystallized from diethyl ether to give pure yellow particles having a melting point of 85 to 86 ° C.

2) To acetone (5 ml) was added diethyl 2-methyl-4- (2-chlorophenyl) -6-diethoxymethyl-1,4-dihadropyridine-3,5-dicarboxylate (452 ml). To the solution is added 6N-hydrochloric acid (0.2-0.3 ml) and stirred at room temperature for 1 hour. After removing acetone, the residue is extracted twice with ethyl acetate and the extract is washed with water and dried.

The solvent is removed from the extract to give diethyl 2-methyl-4- (2-chlorophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate and the product is n-hexane and Recrystallization from a diethyl ether mixture yields a pure product having a melting point of 62 to 63 ° C.

3) 6N in a solution of dimethyl 2-methyl-4- (2-chlorophenyl) -6- (1-dimethoxyethyl) -1,4-dihydropyridine-3,5-dicarboxylate in acetone (5 ml) Hydrochloric acid (0.5 ml) is added and added at room temperature for 17 minutes. The reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate and the solvent is distilled off under reduced pressure. Water is added to the residue and the mixture is left to afford crystals. The crystals are collected by filtration and dried to give crystals (350.2 mg). These crystals were recrystallized from a mixture of n-hexane and ethyl acetate to give dimethyl 2-methyl-4- (2-chlorophenyl) -6-acetyl-1,4-dihydropyridine-3,5 having a melting point of 161 to 162 캜. Yellow particles of dicarboxylate are obtained.

4) Add diethyl 2-methyl-4- (2-nitrophenyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1,1563 g) to acetone (10 ml) To one solution is added 6N-hydrochloric acid (2.5 ml) and stirred at room temperature for 30 minutes. After removal of acetone, water is added to the residue and neutralized with an aqueous solution of sodium bicarbonate. The precipitated solid was collected by filtration, washed with water and dried to give diethyl 2-methyl-4- (2-nitophenyl) -6-formyl-1,4-dihydropiperidine-3,5- A yellow powder of dicarboxylate (0.947 g) is obtained, and the product is recrystallized from a mixture of ethanol and n-hexane to give a pure product having a melting point of 101 to 103 ° C.

5) Diethyl 2-methyl-4- (3-nitrophenyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (462.5 ml) was added to acetone (4 ml). 6N-chloric acid (0.4 ml) is added to the solution and stirred for 1 hour at room temperature. After the reaction, the solvent is removed from the resulting solution. Water is added to the residue and the residue is triturated. The powder was collected by filtration and washed with water to dryness, diethyl 2-methyl-4- (3-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dica having a melting point of 130 to 133 캜. Compound 8 (360 mg) is obtained.

6) Diethyl 2-methyl-4- (2-trifluoromethylphenyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.2 g) was added to acetone (5 ml). To the added solution is added 6N-hydrochloric acid (5 ml) and stirred at room temperature for about 1.5 hours. After removing acetone, water was added to the residue, the resulting aqueous solution was extracted twice with ethyl acetate, the extract was washed with water and dried, and the solvent was removed from the extract to remove diethyl 2-methyl-4- (2-trifluoromethylphenyl). A red oil (4.2 g) of -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate is obtained.

I.R spectrum (nusol)

ν (cm ^-1 : 3350,1700,1640,1605,1480,1200,1100,1035,950,763

NMR: Spectrum (δ: CDCl ₃ + D ₂ O)

pgm: 1.2 (6H, t, J = 7Hz), 2.4 (3H, S), 3.92-4.38 (H, m), 5.72 (1H, S), 7.06 (1H.S), 7,24-7.62 (4H , m).

7) Diethyl 2-methyl-4- (2-methoxy-phenyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (447.5 mg) in acetone (7.ml) 6N-hydrochloric acid (0.ml) is added to the added solution and stirred for 1 hour at room temperature. The resulting mixture was treated in the same manner as in Example 2-4) to diethyl 2-methyl-4- (2-methoxyphenyl) -6-formyl-1,4-dihydropyridine-3,5-dica Red yellow crystals of carboxylate (372.2 mg) are obtained. The product is recrystallized from a diethyl ether and n-hexane mixture to give a pure product having a melting point of 111 to 112 ° C.

8) acetone (54.15 ml) in diethyl 2-methyl-4- (2-chloro-5-nitrophenyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (9.45 To the solution added g) 6N hydrochloric acid (5 ml) is added and the resulting mixture is stirred at room temperature for 1.5 hours. After removing acetone from the reaction mixture, water is added to the residue and the mixture is left for 15 minutes. The precipitated crystals are collected by filtration and washed with water to give crystals (4.2 g). The obtained crystals (500 mg) were recrystallized from n-hexane and ethyl acetate and diethyl 2-methyl-4- (2-chloro-5-nitrophenyl) -6-formyl-1,4 having a melting point of 172 to 173 ° C. Crystals (347 mg) of -dihydropyridine-3,5-dicarboxylate are obtained.

9) A solution of diethyl 2-methyl-4- (2-thienyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (424 mg) added to acetone (15 mg) To 6N-hydrochloric acid (0.2 ml) is added and the solution is stirred at room temperature for 1 hour. The resulting solution is concentrated and the residue is extracted with diethyl ether. The extract was washed with water, dried and then the solvent was removed to give a yellow oil of diethyl 2-methyl-4- (2-thienyl) -6-formyl-1,4-dihydro-pyridine-3,5-dicarboxylate. To obtain. The obtained product was immediately determined and the product was recrystallized from a mixture of n-hexane and diethyl ether to give a pure product (247.7 mg) having a melting point of 67 to 68.5 ° C.

10) A solution of diethyl 2-methyl-4- (2-pertyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (6.6 g) added to acetone (66 ml) To 6N hydrochloric acid (6.6 ml) is added and the product is stirred at room temperature for 1 hour and 3/4 hours. After removal of acetone from the reaction mixture, the residue is extracted from ethyl acetate. The extract is washed with water, dried and concentrated. The production day (6.1 g) was purified by column chromatography of silica gel eluate (20 parts of chloroform and 1 part volume of ethyl acetate). Fraction concentrate (day of the week, 2.4 g) of the eluate is shown as a point in the bacterium chromatography, crystals (1.79 g) are obtained, and fraction concentrate (700 mg) of the eluate is shown as several points in the bacterium chromatography and the crystals (410 mg). ) Is obtained. These crystals are linked together and recrystallized from n-hexane to diethyl 2-methyl-4- (2-peryl) -6-formyl-1,4-dihydropyridine-3,5 having a melting point of 78 to 79.5 ° C. Needle crystals of dicarboxylate (400 mg) are obtained.

11) 2-Ethoxyethyl 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4 in acetone (19 ml) and 6N hydrochloric acid (1.9 ml) Example 2- (1) 2-ethoxyethyl 2-methyl-4- having a melting point of 107 to 108 ° C in the same manner as a starting material, using a mixture of -dihydropyridine-3-carboxylate (1.9 g) as a starting material. Crystals of (2-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate are obtained (recrystallized from diisopropyl ether).

12) 2-hydroxyethyl 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate in acetone (30 ml) 6N hydrochloric acid (1 ml) was added to the solution to which (2.5 g) was added, followed by treatment in the same manner as in Example 2- (6) to 2-hydroxyethyl 2-methyl-4- (2-nitrophenyl)- A viscous day (2.10 g) of 5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate is obtained.

NMR Spectrum (δ, COCl ₃ )

ppm: 6.07 (1H, S), 10.43 (1H, S)

13) Benzyl 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydro in acetone (15 ml) and 6N hydrochloric acid (1.5 ml) The mixture of pyridine-3-carboxylate (1.5 g) was treated in the same manner as in Example 2- (6) to give a reddish brown oil which crystallized the product and washed with n-hexane to give benzyl 2-methyl-4- (2 A crystal (1.30 g) of -nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate is obtained.

I.R spectrum (nusol)

ν (cm-1): 3400,1699, 1673, 1608, 1530, 1490, 1380, 1355, 1220, 1110, 1030, 835, 795

NMR spectrum (ω, CDCl ₃ )

pgm: 1.21 (3H, t, J = 7Hz), 2.38 (3H, S), 4-4.42 (2H, m), 5.07 (2H, S), 6.01 (1H, S), 6.9 (1H, wide S) , 7.25-7.8 (9H, m), 10.33 (1H, S).

14) 2-benzyloxyethyl 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1 in acetone (25 ml) and 6-N hydrochloric acid (2 ml); Benzyloxyethyl 2-methyl-4- (2-nitrophenyl) -5 was treated in the same manner as in Example 2-6 using an oil (2.5 g) mixture of 4-dihydropyridine-3-carboxylate as a starting material. A red oil (2.05 g) of -ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate is obtained.

I.R Spectrum (Film)

ν (cm ^-1 ): 3380, 1695, 1532, 1485, 1277, 1210, 1100, 1040, 860, 750

NMR Spectrum (δ CDCl ₃ )

ppm: 2.40 (3H, S), 4.48 (2H, S), 6.08 (1H, S), 10.40 (1H, S).

15) 2-phenoxyethyl 2-methyl-4 (2-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1 in acetone (12 ml) and 6-N-hydrochloric acid (1.2 ml) A mixture of 2,4-dihydropyridine-3-carboxylate (1.24 g) added as a starting material was treated in the same manner as in Example 2-6) to 2-phenoxyethyl 2-methyl-4- (2- An oil (1.1 g) of nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate is obtained.

I.R. Spectrum (Film)

ν (cm ^-1 ): 3400, 1700, 1640, 1600, 1530, 1480, 1350, 1240, 1200, 1100, 860, 785, 755, 992

NMR Spectrum (δ, CDCl ₃ )

ppm: 1.2 (3H, t, J Hz), 2.4 (3H, S), 3.98-4.46 (6H, m), 6.03 (1H, S), 6.71-7.76 (9H, m), 10.4 (1H, S)

16) 2-Ethoxyethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate in acetone (60 ml) (5.85 g) to 6N hydrochloric acid (3 ml) is added and the resulting mixture is stirred at room temperature for about 2 hours. The solvent is distilled off under reduced pressure and water is added to the residue. The mixture is extracted twice with ethyl acetate and the extract is washed with aqueous sodium chloride and dried. The solvent was distilled off to give a red oil (5.7 g) which turned into crystals. The crystals were triturated with η-hexane and diethyl ether, and the resulting powder (4.81 g) was collected by filtration, and the powder (1.81 g) was recrystallized from diethyl ether and ethyl acetate to have a melting point of 100 to 101 ° C. Obtained yellowish orange particles (1.2 g) of methoxy ethyl 2-methyl-4- (2-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate .

17) 2- (N-methyl-N-benzylamino) -ethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4 in acetone (70 ml) To the solution to which -dihydropyridine-3-carboxylate (25 g) is added 6N-hydrochloric acid (7 ml) is added and the resulting mixture is stirred at room temperature for 3 hours. When the solvent is distilled off under reduced pressure and water is added to the residue, an oily substance appears. To the aqueous mixture is added alkaline powder of sodium bicarbonate, which is then extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off under reduced pressure to thereby remove 2- (N-methyl-N-benzeneamino) -ethyl-2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6 Obtain red oil (5.8 g) of -formyl-1,4-dihydropyridine-3-carboxylate.

N.M.R. Spectrum (δ: CDCl)

ppm: 1.29 (3H, t, J = 7Hz), 2.21 (3H, S), 2.45 (3H, S), 2.63 (2H, t, J = 6Hz), 3.51 (2H, S), 3.95-4.42 (2H , t), 3.95-4.42 (2H, q), 5.28 (1H, S), 7.08 (1H, S), 7.28-8.12 (4H, m), 10.54 (1H, S).

I.R. Spectrum (Film)

ν (cm ⁻¹ ): 3350, 1735, 1700, 1690, 1635, 1600, 1525, 1480, 1350, 1279, 1215, 1100, 1030, 735.

18) 2- (N, N-diethylamino) ethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4- in acetone (24.6 ml) To the mixture to which brown oil (2.46 g) of dihydropyridine-3-carboxylate was added was added 6N hydrochloric acid (2.46 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture is adjusted to pH 7 with an aqueous solution of sodium bicarbonate and the acetone is distilled off. The residue was extracted with ethyl acetate and the extract was washed with water, dried and concentrated to give 2- (N, N-diethylamino) ethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6- An oil (1.81 g) of formyl-1,4-dihydropyridine-3-carboxylate is obtained.

NMR Spectrum (δ, CDCl ₃ )

ppm: 2.03 (3H, S), 5.3 (1H, S), 10.47 (1H, S)

19) Add diethyl 2-methyl-4- (3-hydroxyphenyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.16 g) to acetone (10 ml) To one mixture 6N hydrochloric acid (1 ml) is added and the mixture is stirred for 1.5 hours at room temperature. The solvent is distilled off under reduced pressure, water is added to the residue and triturated. The resulting suspension is extracted with ethyl acetate and the extract is washed with water and dried over magnesium sulfaate. The solvent is distilled off under reduced pressure and the residue is treated with diethyl ether to give a crystal (0.8 g). Crystalline (200 mg) was recrystallized from a mixture of η-hexane and diethyl ether to give diethyl2-methyl-4- (3-hydroxyphenyl) -6-formyl-1,4-di having a melting point of 141.5 to 142.5 ° C. Obtain pure crystals (130 mg) of hydropyridine-3,5-dicarboxylate.

20) Add yellow oil (360 m) of methyl 4- (2-chlorophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate to acetone (10 ml) To one mixture 6N hydrochloric acid (0.3 ml) is added and the resulting mixture is stirred at room temperature for 1.5 hours and acetone is removed. Water is added to the residue and the mixture is extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated. The resulting orange oil (0.26 g) was crystallized and the crystals washed with η-hexane to give methyl 4- (2-chlorophenyl) -5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3 A pale yellow powder (80.7 mg) of carboxylate is obtained.

I.R. Spectrum (Nuzol)

ν (cm ^-1 ): 3300, 1690, 1675, 1491, 1442, 1376, 1303, 1221, 1186, 1060, 831, 757

N.M.R. Spectrum (δ, CDCl)

ppm: 1.10 (3H, t, J = 7Hz), 3.68 (3H, S), 4.18 (2H, q, J = 7Hz), 5.56 (1H, S), 7-7.6 (6H, m), 10.44 (1H , S).

Example 2

1) A solution of 10.68 g of dimethyl 2-methyl-4- (2-nitrophenyl) -6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate in 110 ml of acetone and 10 ml of 6N hydrochloric acid The mixture is stirred at 25 ° C. for 3 hours, neutralized with aqueous sodium bicarbonate solution, and the acetone is distilled off under reduced pressure. The resulting reddish yellow oily precipitate is solidified, finely ground, filtered, collected, washed with water and dehydrated overnight to give dimethyl 2-methyl-4- (2-nitrophenyl) -6-formyl-1,4 as an impure crystal. 9.33 g of -dihydropyridine-3,5-dicarboxylate are obtained.

NMR Sppm (CDCl ₃ )

2.41 (3H, S), 3.58 (3H, S), 3.71 (3H, S), 5.88 (1H, S), 7.10 (1H, wide S), 7.2-7.9 (4H, m), 10.43 (1H, S ).

2) Isopropyl 2-methyl-4- (2-nitrophenyl) -5-methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (10.5 g) To a solution dissolved in acetone (105 ml) is added 6N hydrochloric acid (15.5 ml) and the mixture is stirred at 25 ° C. for 2 hours. After removing acetone, the resulting solution is diluted with water (50 ml), alkalized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate extract was washed twice with saturated aqueous sodium chloride solution, dehydrated on magnesium sulfate and evaporated to dryness under reduced pressure. A yellowish yellow oily residue (11.08 g) was triturated with a mixture of diethyl ether and η-hexane to yield a yellow crystalline powder of isopropyl 2-methyl-4- (2-nitrophenyl) -5-methoxy-carbo Yield-6-formyl-1,4-dihydropyridine-3-carboxylate (8.94 g) is obtained.

NMR δ ppm (CDCl ₃ )

0.97 (3H, d, J = 6 Hz), 1.21 (3H, d, J = 6 Hz) 2.43 (3H, S), 4.97 (1H, het, J = 6 Hz), 6.00 (1H, S), 6.95 (1H, Wide S), 1.2 to 7.9 (4H, m), 10.38 (1H, S)

3) Dimethyl 2-methyl-4- (3-nitrophenyl) -6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (7.5 g) in a solution of acetone (75 ml) 6N hydrochloric acid (7.5 ml) is added and the mixture is stirred for 6 hours at room temperature. The precipitated filtration collected during the reaction was collected by dimethyl 2-methyl-4- (3-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.26 g). Obtained as yellow crystals. The filtrate was adjusted to a pH of 7.5 to 8 with aqueous sodium bicarbonate solution and acetone was distilled off under reduced pressure to give the same product as an orange crystal (3.84 g). (Total yield: 6.1 g). The first product is pure crystals when recrystallized from methanol. Melting Point: 157 ~ 157.5 ℃

NMR δ ppm (CDCl ₃ )

2.48 (3H, S), 3.7 (3H, S), 5.3 (1H, S), 7.13 to 8.17 (5H, m), 10.5 (1H, S).

4) 2-benzyloxyethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (6.0 g) To 6 N hydrochloric acid (6 ml) was added to a solution of acetone (60 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture is adjusted to pH 7 to 7.5 with aqueous sodium bicarbonate solution and distilled off acetone under reduced pressure. The resulting solution was diluted with water (150 ml) to separate the oily phase precipitate and washed twice with ethyl acetate (100 ml and 500 ml, respectively). The organic layer was washed with water, dehydrated on magnesium sulfate, and evaporated to dryness under reduced pressure to give 2-benzyloxyethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-6-formyl-1, as an oil. 4-dihydropyridine-3-carboxylate (5.02 g) is obtained.

NMR δ pdm (CDCl ₃ )

1.25 (3H, t, J = 7 Hz), 2.41 (3H, S), 4.5 (4H, S), 3.5 to 4.4 (6H, m), 5.29 (1H, S), 7.3 to 8.15 (10H, m), 10.45 (1 H, S).

Claims (1)

A process for preparing the compound of formula (I), characterized by hydrolysis of the compound of formula (II).

Wherein R ₁ is an aryl or heterocyclic group which may have one or more suitable substituents selected from halogen, nitro, hydroxy, halo (s) alkyl, lower alkoxy or lower alkenyloxy and R ₂ and R ₃ are The same or different and esterified carboxy, R ₄ b is lower alkyl substituted with hydrogen, lower alkyl or oxo, R ₅ b is lower alkyl substituted with oxo and R ₄ a is lower alkyl substituted with hydrogen, lower alkyl or oxo (Carbonyl group formed here is protected with a suitable protecting group) and R ₅ a is lower alkyl substituted with oxo (carbonyl group formed here is protected with a suitable protecting group).