KR800001593B1 - 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; R4e = alkyl or hydroxy substituted alkyl; R5e = hydroxy, N, N'-dialkylamino or hydroxyalkylamino substituted lower alkyl; R'4b = alkyl or oxo substituted alkyl; R'4b = 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.

It is an object of the present invention to prepare 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 for 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) 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 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 a cyano or substituted lower alkyl group, and R ₄ and If R ₅ is not hydrogen or lower alkyl they are one of the substituted lower alkyl groups of cyano and electricity.

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-hydroxyethyl.

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, mesylyl, cumenyl, and may have one or more suitable substituents. Representatives of suitable substituents are hydrogen, nitro, hydroxy, halo (lower) alkyl, loweralkoxy and loweralkenyl oxy. 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 alkyl and lower alkyl moieties consist of straight or branched chain and saturated hydrocarbon chains 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, bromo methyl 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, butanedienyl or penta-2,4-dienyl, consisting of straight or branched 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, ie N-methyl (or N, N-dimethyl) amino acetyl, 1 (or 2)-[N-ethyl (or N, N-diethyl) amino] propionyl) Or 1 (or 2)-[N-methyl-ethylamino] propionyl) or N-lower alkyl-N-ar (lower) alkylamino (lower) alkanoyl, ie 1- (or 2)-[N-methyl -N-benzylamino] propionyl or aryloxy (lower) alkanoyl, phenoxyacetyl, tolyloxyacetyl, 2 (or 3 or 4) -chlorophenoxyacetyl, 2- [2- (or 3 or 4)- Chlorophenoxy] -acetyl or 2 (Or 3 or 4) -methoxy-phenoxyacetyl), aroyl, ie 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, thiadia Zolyl, tetrazolyl, pyrimidinyl, quinolyl, benzothienyl, indolyl or furinyl.

The esterified carboxy of R2 and R3 is lower alkoxy carbonyl (methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl): halo (lower) alkoxy carbonyl [above As halo-homologs of the lower alkoxy carbonyls mentioned, for example 2-bromoethoxycarbonyl, 2-chloroethoxycarbonyl, 2 (or 3) -chloropropoxycarbonyl, 2 (or 3) -bromorph Loxycarbonyl, 2,2-dichloroethoxycarbonyl or 2,22-trichloro ethoxycarbonyl], hydroxy (lower) alkoxycarbonyl, (2-hydroxyethoxycarbonyl or 2 (or 3) ) Hydroxy propoxycarbonyl; lower alkoxy (lower) alkoxycarbonyl 2-methoxyethoxycarbonyl, 2-ethoxycarbonyl or 9 (or 3) -methoxy (or ethoxy) propoxycarbonyl) ; Aryloxycarbonyl (phenoxycarbonyl, toryloxycarbonyl, xylyloxy carbonyl or P-chlorophenoxycarbonyl); Benzyloxy carbonyl P-brodobenzyloxycarbonyl, 0-methoxy benzyloxycarbonyl or phenethyloxycarbonyl as ar (lower) alkoxycarbonyl; Ar (lower) alkoxy (lower) alkoxycarbonyl (2- (benzyloxy) ethoxycarbonyl or 2 (or 3)-(benzyloxy) 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), eg 1 (Or 2)-[N-methyl) (or N, N-dimethyl) amino] ethoxycarbonyl, 1 (or 2)-[N-ethyl) (or N, N-diethyl) amino] ethoxycarbon Nil or 1 (or 2)-[N-methyl-N-ethylamino] ethoxycarbonyl or N-lower alkyl-N-ar (lower) alkylamino (lower) -alkoxycarbonyl, e.g. 2- Such as (N-methyl-N-benzylamino-ethoxycarbonyl). While R2 and R3 are the same or different, lower alkyl substituted with oxo includes lower alkanoyls such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or pivaloyl, etc. 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, thioacetyl, cyclic-thioacetal, cyclic-monothioacetal, or acylyl groups. Lower alkyl groups containing such protected carbonyl groups include gem-di (lower) alkoxy (lower) alkyl dimethoxymethyl, 1,1-dimethoxyethyl, diethoxymethyl, dipropoxymethyl, 2,2-diethoxyethyl or 2,2-diethoxypropyl; gem-lower alkylene dioxy (lower) alkyl (ie 1,3-dioxolan-2-yl, 2-methyl-1 3-dioxoran-2-yl, 4- Methyl-1,3-dioxolan-2-yl, 4,5-dimethyl-1,3-dioxoran-2-yl, 1,3-dioxan-2-yl, methyl-1,3-di Oxan-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 (dimethylthiomethyl, 1,1-dimethyl thioethyl, diethylthiomethyl or 2,2-diethylthioethyl), gem-lower alkyl Rendithio (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, l, 3-dithian-2-yl, 2-methyl-l, 3-ditian-2-yl, l, 3- Dithioran-2-ylme Yl, 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-horned 1-oxa-3-thiohetero Cyclic-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-oxotian-2- 1,3-oxothioran-2-ylmethyl, 2-methyl-1,3-oxathioran-2-ylmethyl or 3- (1,3-oxathioran-2-yl) propyl), etc. to be.

5 or 6-angled saturated N-containing heterocyclic 1-yl groups include one or more heteroatoms selected from nitrogen, sulfur, 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.

(The composition of I basic structure)

1. Ring formation of 1,4-dihydropyridine nuclei

(Change of Ⅱ functional group)

2. hydrolysis to remove protecting groups of protected carbonyl groups, 3. condensation to form already no-functional groups, 4. dehydration, 5. reduction of oxo or imino-functional groups, 6. acylation of hydroxy-functional groups , 7. oxidation of alcohols to carbonyl compounds, 8. heat ring, 9. other conversions.

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) The aldehyde compound of formula (II) is reacted with the β-ketone acid of formula (II ″) and the amino compound of formula (III).

R ₁ -CHO (II ′) R ₅ a-COH 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 an ammonia or 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-keroic acid ester (II ') with aldehyde (II'). 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.

As starting starting materials in the reactions (1), (2) and (3), compounds of (II), (II ″), (III) and (III ′) are used, and R ₄ a and R ₅ a in these structural formulas are used. Are interchangeable in some cases. Of course, both the (also not groups such there is changes this case, R ₄ a and R ₅ a is date time, as well as R ₂ and, regardless of the same whether the R ₃ group R ₄ a and R ₅ a is changed when different such .

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 solvents at room temperature or warm, i.e. benzene, toluene, xylene, chloroform, carbon tetrachloride, methylene chloride, ethylene chloride, methanol, propanol, butanol, water or conventional Perform with 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 a lower alkyl group substituted by hydrogen, lower alkyl or oxo (R ₄ b and R

_When at least one of ₅ b is an oxo substituted lower alkyl group.

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 in a conventional manner, for example the removal of protecting groups of acetyl-type and cyclic acetyl-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, trifluoroacetic acid or P-toluene sulfonic acid). The protecting group removal of thioacetal- and cyclicthioacetyl-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 (eg sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) or organic bases (ie sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, In the presence of pyridine or picoline). 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 formation of imino 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 imino, 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 ₅ 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.

R ₄ b and / or oxo group on R ₅ b of the starting compound (Ⅰ-2) used in accordance with the present method is replaced with the imino group of = NR _8. (On R ₈ are 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-compound (IV)), or conventional buffer solutions of acid or basic and conventional solvents commonly used, such as water, dioxane, ethanol, methanol or dimethylformamide or any mixture 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′-dimethylamino trimethylenediamine or N′-ethyl or N ′, N′-diethylaminotrimethylene Such as diamines, hydroxy (lower) alkylamines (ethanol amines or propanol amines), hydroxylamines, hydrazines and lower alkoxy amines (0-methyl, 0-ethyl, 0-propyl or 0-isopropyl-hydroxyamines) will be. 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 ω-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 ω- 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 ω- cyano or cyano (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 ₄ d and R ₅ d are each hydrogen, lower alkyl or ω- hydroxyimino (lower) alkyl, (only one of R _'4 and R c' is ₅ c being ω- hydroxy amino (lower) alkyl group).

Starting compound (I-3 ') is obtained by the above-described concentration. Suitable examples of dehydrating agents are general organic and inorganic. That is, acids (e.g. sulfuric acid, phosphoric acid, polyphosphoric acid, formic acid, acetic acid, ethanesulfonic acid or P-toluenesulfonic acid), acid anhydrides (e.g., acetic acid inorganic, 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. thionyl chloride, 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 phosphorus The same as compound (i.e., phosphorus 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 salts 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, tetrahydrofuran, dioxane and the like are applied. The reaction is usually carried out at room temperature or under salting 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 in form (R ₆ and R ₇ 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) alkyl is one of the unexposed, 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 (e.g. lithium borohydride, sodium borohydride, potassium borohydride) or sodium cyanoborohydride) or palladium carbon, palladium chloride or rhodium carbon as catalysts for catalytic reduction Etc. are used with the solvent. 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-dimethylamino) ethyl) or 2-hydroxyethylaminomethyl (when R ₇ is 2-hydroxyethyl).

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 , R ₂ and R ₃ are each defined above,

R ₄ f and R ₅ f are each hydrogen, lower alkyl or acyloxy (lower) alkyl group (where R ₄ f and R ₅ f, at least one is an 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 hydrogen, lower alkyl or hydroxy (lower) alkyl groups, provided that R ′ ₄

at least one of 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 acyl groups of R ₉ are lower alkanoyl groups substituted with carboxy, esterified carboxy, N- or N, N-di-substituted amino or aryloxy, 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) Di or poly carboxylic acids such as malophosphoric acid, succinic acid, adipic acid, glutamic acid, pimeric acid or serveric acid), esterified carboxy (lower) alkanoic acid (lower alkyl esters such as methyl esters, ethyl esters or propyl esters) Partial esters of base carboxylic acids), N- or N, N-di-substituted amino (lower) alkanoic acid (N- or N, N-di- (lower) -alkylamino (lower) alkanophosphoric 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-ar (lower) alkylamino (lower) alkanoic acid, for example 1 (or 2)-[N-methyl-N-benzylamino] propionic acid, aryloxy (lower) alkanoic acid (phenoxyacetic acid, toryloxy acetic acid, 2 (or 3 or 4) -chlorophenoxyacetic 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 anhydride active amides, azides or reaction esters (methyl esters, ethyl esters, cyanomethyl esters, P-nitro). Phenyl ester or pyranyl ester).

The reaction is carried out using generic drugs. Namely inorganic bases (e.g. sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate) or organic bases (e.g. N-methylpiperidine, triethylimine, pyridine, N -Methylmorpholine or N, N-dimethylaniline) and general solvents (pyridine, ether, dioxane, acetone, chloroform, methylene chloride, tetrahydrofuran, 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. Phosphorous oxychloride, thionyl chloride, N, N'-dicyclohexyl carbodiimide, N-cyclohexyl-N'-morpholino ethylcarbodiimide, pentamethylene ketene-N-cyclohexylimine, alkoxyacetylene, 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 Alcohols

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 as defined above,

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

If R ₄ g and R _5g are not hydrogen or lower alkyl they are groups selected from formyl and W-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 ω-hydroxy (lower) alkyl group, provided that one of R ″ ₄ e and R ″ ₅ e is an ω-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 a corresponding formyl functional group without conducting influence on other parts of the compound (I-5 ″). Preferred oxidation is the reaction of the organosulfonic acid or its reaction derivatives 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 and R ₅ e is a hydroxymethyl group.

In compound (I-3), R ₄ C is hydrogen or a lower alkyl group, and C ₅ C is a hydrazono methyl group.

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

The reaction can be accelerated by the addition of a significant amount of organic or inorganic bases or catalysts such as trialkylamines (eg 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, ( Lower alkyl group substituted with hydroxy lower alkyl or hydroxy lower alcohol 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 tribromide, phosphorus pentachloride or phosgene) and other phosphorus compounds, ie triphenylphosphine or tri (lower) alkylphosphites (e.g. trimethylphosphate). Pit or triethyl phosphite) and polyhalo (lower) alkanes (carbon tetrachloride or carbon tetrabromide in a solvent) and the like.

As the solvent, carbon tetrachloride, 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, tetrahydrofuran, 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 hydroxide 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 is the corresponding compound (at least one of Ⅰ) (R ₂ and R ₃ is halo (lower) alkoxycarbonyl (Ⅰ) (R ₂ and R _3, at least one hydroxy (lower one) alkoxycarbonyl)) Can be prepared by hydrolysis by the above-described hydrolysis method.

4) Compound (I) [R ₁ , R ₂ and R ₃ are respectively defined above and R ₄ and R ₅ are each hydrogen, lower alkyl or gem-di (lower) alkoxy (lower) alkyl, gem-lower alkylenedioxy (Lower) alkyl; Substituted lower alkyl selected from gem-di- (lower) alkylthio (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), or a thiol such as lower alkanthiol (methanethiol) Compounds corresponding to hydroxy compounds such as ethanethiol) lower alkanedithiol (ethanedithiol, 1,2-propanethiol, 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 sulfuric acid, acetic acid, borontrifluoride, zinc chloride or P-toluenesulfonic acid.

5) Compound (1) (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-mentioned conversion 1) with a compound of the general 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-methyldolporin, pyridine or conventional solvents at room temperature or while heating. .

The product obtained in the reaction according to the invention is separated from the reaction mixture in a conventional manner, isolated and purified by conventional purification methods, usually recrystallized from a solvent or a mixture of such solvents. In the obtained compound (I), R ₂ and R ₃ or R ₄ and R ₅ are not the same as each other 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. The racemic mixture is dissolved into each optical isomer by conventional methods for racemic separation.

That is, the fraction of the racemic compound can be separated by 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 500 mg of 1,4-dihydropyridine derivative (I) as the active ingredient, preferably about 25 mg to 250 mg (dosage unit). One skilled in the art will be able to determine the amount of active ingredient in the dosage unit claimed and the activity of the ingredient is considered depending on the size of the test animal. It is based on mg / kg and the amount of active ingredient in the composition is 1 μg / kg to 10 mg / kg and 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 substances, and examples of solid or liquid carriers or diluents include lactose, magnesium stearate, terra alba, sucrose, cornstarch, talc, stearic acid, gelatin, a Garlic, pectin, acacia, peanut oil, olive oil, sesame oil, cacao butter.

Meanwhile, the carrier or diluent includes a retardant 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 troches or lozenges.

In order to suggest the pharmaceutical activity of 1,4-dihydropyridine of formula (I) by standard method, the blood flow of coronary artery is recorded by intravenous injection of 1,4-dihydropyridine in dogs anesthetized with pentobarbital.

The test results are described below.

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

The following examples are illustrative of the description of synthesizing the target compounds of the present invention and do not limit the method.

Example 1

1) Diethyl 2,6-diformyl-4- (2-chlorophenyl) -1,4-dihydro pyridine-3,5-dicarboxylate (272.mg) was added to 99% ethanol (7 ml). To one solution sodium borohydride (52.7 mg) is added under about 5 ° C. stirring and the resulting mixture is further stirred at 5 ° C. for 10 minutes. The resulting solution is neutralized with dilute hydrochloric acid and ethanol and removed at room temperature under reduced pressure. Water was added to the residue and the precipitate was collected by filtration and dried to diethyl 2,6-dihydroxymethyl-4- (2-chloro-phenyl) -1,4-dihydropyridine-3,5- Pale yellow crumb crystals (261.0 mg) of dicarboxylate are obtained. The debris crystals are recrystallized from a mixture of ethanol and diethyl ether to give pure pale yellow acicular crystals with a melting point of 190 to 191 ° C.

2) Diethyl 2-methyl-4- (2-chlorophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.g) was added to ethanol (30 ml). To the application is added sodium borohydride (155 mg) under reduced pressure and the compound is further stirred at room temperature for about 2 hours.

The resulting mixture is acidified with dilute hydrochloric acid and the solvent is removed. Water is added to the residue and the mixture is extracted twice with ethyl acetate. The extract is washed with water and dried, and the solvent is removed from the extract under reduced pressure to give a red oil (1.3525 g). The oil is dissolved in diethyl ether and left at room temperature. The filtrate is left after insoluble product is removed by filtration. Slowly precipitated crystals were collected by filtration and recrystallized from a mixture of diethyl ether and n-hexane to diethyl 2-methyl-4- (2-chlorophenyl) -6-hydroxy methyl-1 having a melting point of 143 ° C. Obtained pure crystals (92.0 mg) of, 4-dihydropyridine-3,5-dicarboxylate. The insoluble product obtained above was collected by filtration and recrystallized from ethyl acetate to give ethyl 2-methyl-4- (2-chlorophenyl) -5-oxo-1,4,5,7- having a melting point of 211 to 212 캜. Tetrahydroper affords a colorless prism (241.5 mg) of [, 4-b] pyridine-3-carboxylate.

3) To a mixture of dimethyl 2-methyl-4- (2-chlorophenyl) -6-acetyl-1,4-dihydropyridine-3,5-dicarboxylate (450 mg) to methanol (15 ml) was added sodium borohydride. High dry (46.8 mg) is added gradually (with stirring under cooling). The solution is neutralized with 2N-hydrochloric acid under cooling and the solvent is distilled off under reduced pressure of water bath below 30 ° C. Water is added to the residue and adjusted to pH 7-8 with a small amount of aqueous sodium bicarbonate. The resulting mixture was left to yield a white powder, and the powder was collected by filtration and dried to give a powder (395.0 mg).

Diethyl ether (20 ml) is added to the present invention and the mixture is stirred at room temperature for 30 minutes. Insoluble white powder is collected by filtration and washed with ethyl acetate. The filtrate and the washings are mixed with each other and the solvent is distilled off at a relatively low temperature so that the dimethyl 2-methyl-4- (2-chlorophenyl) -6- (1-hydroxyethyl) -1, Crude crystals (100.5 g) of 4-dihydropyridine-3,5-dicarboxylate are obtained.

The white powder obtained above was collected by filtration and washed with diethyl ether to obtain methyl 2-methyl-4- (2-chlorophenyl) -5-oxo-7-methyl-1,4, having a melting point of 228 to 233 ° C. 5,7-Tetrahydroper gives crumb white powder (264.2 mg) of [3,4-b] pyridine-3-carboxylate.

4) Diethyl 2-methyl-4- (2-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.0881 g) was added to ethanol (20 ml). Sodium borohydride (0.1892 g) is gradually added to the solution under stirring and the resulting mixture is further stirred at room temperature for 1 hour. The solution is acidified with dilute hydrochloric acid, stirred at room temperature for 30 minutes, the resulting solution is filtered, concentrated under reduced pressure and extracted with methyl acetate. The extract was washed with water, dried and the solvent was removed to remove the orange of diethyl 2-methyl-4- (2-nitrophenyl) -6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate Obtain oil (1.8596 g). After the debris product is dissolved in ethanol, the solution is filtered, the filtrate is concentrated under reduced pressure and the oily residue is left for 3 days. The crystals thus obtained are recrystallized with ether to give a pure product having a melting point of 112 to 113 ° C.

The insoluble product obtained by filtration of the resulting solution was recrystallized from ethanol to ethyl 2-methyl-4- (2-nitrophenyl) -5-oxo-1,4,5,7- having a melting point of 220 to 222 캜. Tetrahydroper affords a pale yellow flake (455.1 mg) of [3,4-b] pyridine-3-carboxylate. The product is further refined with ethyl acetate to give pure crystals having a melting point of 221 to 223 ° C.

5) Suspension in which diethyl 2-methyl-4- (3-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (233 mg) was added to ethanol (10 ml). To the solution is added sodium borohydride (22.7 mg) at 0 ° to 5 ° C. under stirring and the mixture is further stirred at about 5 ° C. for 1 hour and 10 minutes. After the reaction, the mixture is adjusted to pH 4-5 with 0.1 N-hydrochloric acid and the solvent is removed under reduced pressure. The residue is extracted with ethyl acetate and the extract is washed with water and dried over magnesium sulfaate. The extract was concentrated under reduced pressure, the residue was crystallized by treatment with a mixture of diethyl ether and n-hexane, and the precipitated crystals were collected by filtration, dried and recrystallized from a mixture of diethyl ether and n-hexane to give a melting point of 141. A crystal of diethyl 2-methyl-4- (3-nitrophenyl) -6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (152 mg) is obtained at from 142.5 占 폚.

6) Diethyl 2-methyl-4- (2-trifluoromethyl-phenyl) -6-formyl-1,4-dihydropyridine-2,5-dicarboxylate (1.0 g) in ethanol (20 ml) To the solution to which sodium borohydride (92 mg) was gradually added under stirring and cooling, the resulting mixture was further stirred for 25 minutes. The resulting mixture is adjusted to pH 4-5 with 0.1 hydrochloric acid, ethanol is removed without much heating under reduced pressure and water is added to the residue to afford crystals. The crystals are collected by filtration to give debris crystals (1.2 g). The crystals were recrystallized from a mixture of diethyl ether and n-hexane to diethyl 2-methyl-4- (2-trifluoro methylphenyl) -6-hydroxy-methyl-1,4- having a melting point of 147 to 148.5 ° C. Pure crystals of dihydropyridine-3,5-dicarboxylate are obtained.

7) Diethyl 2-methyl-4- (2-methoxy-phenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1320 g) was added to ethanol (30 ml). To the added solution is gradually added sodium borohydride (114 mg) under stirring and the resulting mixture is further stirred at room temperature for 1 hour. The resulting mixture is acidified with dilute hydrochloric acid, ethanol is removed from the mixture, water is added to the residue and solidified. The solid is collected by filtration, dried and washed with ethyl ether.

The diethyl ether washings were concentrated to a volume of about 10 ml and left at room temperature to diethyl 2-methyl-4- (2-methoxyphenyl) -6-hydroxymethyl-1,4-di having a melting point of 125 to 126 ° C. A pale yellow particle (372.5 mg) of hydropyridine-3,5-dicarboxylate is obtained. Alternatively, the solid obtained above is collected by filtration, washed with diethyl ether, and a mixed solution of P-toluenesulfonic acid (catalyst amount) is added to ethanol (5 ml) and the mixture is refluxed for one hour.

After removal of the ethanol the residue is triturated with diethyl ether and collected by filtration. The powder was recrystallized from a mixture of acetone and ethyl acetate, followed by ethyl 2-methyl-4- (2-methoxyphenyl) -5-oxo-1,4,5,7-tetrahydroper having a melting point of 219 to 220 캜 [3. , 4-b] to give a colorless particle (114.8 mg) of pyridine-3-carboxylate.

8) Suspension in which diethyl 2-methyl-4- (3-hydroxyphenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (600 mg) was added to ethanol (15 ml). To sodium borohydride (6.3 mg) is added (under stirring at 0 ° C.) and the resulting mixture is further stirred for 1 hour. The resulting mixture is adjusted to pH 3-4 with 0.1 N hydrochloric acid under cooling, ethanol is distilled off under reduced pressure and the residue is extracted with ethyl acetate.

The extract was washed twice with water and then with aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to give a crystal (600 mg).

The crystals were recrystallized from a mixture of ethyl acetate and diethyl ether to give diethyl 2-methyl-4- (3-hydroxy phenyl) -6-hydroxy methyl-1,4-di having a melting point of 161.5 ° C. to 163 ° C. Obtain pure crystals (350 mg) of hydro pyridine-3,5-dicarboxylate.

9) Diethyl 2-methyl-4- (2-thienyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (940.68 mg) in 99% ethanol (30 ml). To the added solution is gradually added sodium borohydride (113.5 mg) under stirring and further stirred at room temperature for 2 hours. After ethanol removal, the residue is extracted with ethyl acetate and the extract is washed twice with water and dried. The solvent is removed from the extract to yield a pale yellow oil. The oil is powdered with η-hexane and the powder is dissolved in ethyl acetate.

After collection by filtration of the insoluble product, n-hex salt is added to the filtrate and the mixture is left in the cooler. The crystals shown were collected by filtration to diethyl 2-methyl-4- (2-thienyl) -6-hydroxy methyl-1,4-dihydro pyridine-3,5-dicarboxyl having a melting point of 125 to 126 ° C. A pale yellow particle (857.2 mg) of eight is obtained.

The insoluble product obtained above was purified by filtration to give ethyl 2-methyl-4- (2-thienyl) -5-oxo-1,4,5,7-tetridelopiro [3,4- with a melting point of 232 ° C. b] to obtain a powder of pyridine-3-carboxylate (33.3 mg).

10) 2-hydroxy ethyl 2-methyl-4- (2-nitrophenyl-5-ethoxycarbonyl-6-formyl-1,4-dihydro pyridine-3-carboxylate (2.0 g) in ethanol (40 ml) To the solution was added sodium borohydride (113.5 mg) in small portions under stirring at 5 ° C. The mixture was further stirred at 5 ° C. for 30 minutes and slightly acidified with 50% acetic acid After ethanol removal, water was added to the residue. The mixture is weakly alkalined with an aqueous solution of sodium bicarbonate, left to stand and filtered.

The precipitate (1.58 g) was collected by filtration and recrystallized from a mixture of ethanol and diisopropyl ether to give 2-hydroxy ethyl 2-methyl-4- (2-nitrophenyl) -5- having a melting point of 167-169 ° C. Pale yellow particles (0.99 g) of ethoxy carbonyl-6-hydroxy methyl-1,4-dihydro pyridine-3-carboxylate are obtained.

11) Benzyl 2-methyl-4- (2-nitrophenyl) -5-ethoxy carbonyl-6-formyl-1,4-dihydro pyridine-3-carboxylate (1,2 g) in ethanol (20 mg) To this suspension solution was added sodium borohydride (60.6 mg) under ice-cooling and stirred, further stirred at 0 ° C. for 1 hour and stirred at 30 ° C. for 1 hour.

Water is added to the reaction mixture, the resulting mixture is adjusted to pH 6-7 with 2N hydrochloric acid and the solvent is distilled off. The residue is extracted with ethyl acetate, washed with water and dried. After removal of the solvent, the resulting oil (1.3 g) was purified by column chromatography of silica gel eluate (10 parts of benzene and 1 part of ethyl acetate volume) to obtain an oil, which immediately crystallized. The resulting crystals are recrystallized from a mixture of diethyl ether and η-hexane and dissolved in benzene. Benzene solution was purified five times by azeotropic process to benzyl 2-methyl-4- (2-nitrophenyl) -5-ethoxy carbonyl-6-hydroxy methyl-1,4-dihydropyridine having a melting point of 51 to 57 ° C. Obtain pure crystals of -3-carboxylate.

12) 2-Ethoxy ethyl-2-methyl-4- (3-nitrophenyl) -5-ethoxy carbonyl-6-formyl-1,4-dihydro pyridine-3-carboxylate in ethanol (15 ml) (1.13 g) was added sodium borohydride (80 mg) with stirring under ice cooling and the compound was further stirred for 1 hour at the same temperature.

The reaction mixture is diluted with hydrochloric acid to pH 6 under ice-cooling and the solvent is distilled off. Water is added to the residue and the aqueous mixture is extracted with ethyl ether. The extract is washed with water and dried over magnesium sulfaate. Oil is obtained after solvent removal. The oil was crystallized by treating with η-hexane and the crystallized by recrystallization with a mixture of diethyl ether and η-hexane to give 2-ethoxy ethyl 2-methyl-4- (3-nitrophenyl)-having a melting point of 99 to 100 ° C. Pure crystals (900 mg) of 5-ethoxy carbonyl-6-hydroxy methyl-1,4-dihydro pyridine-3-carboxylate are obtained.

13) 2- (N-methyl-N-benzylamino) ethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxy carbonyl-6-formyl-1,4-di in ethanol (15 ml) To the solution to which hydropyridine-3-carboxylate (1.5 g) was added was added sodium borohydride (112 mg) under stirring and ice cooling, and the mixture was further stirred at the same temperature for 20 minutes.

The reaction mixture is adjusted to pH 6-7 with 0.1N hydrochloric acid under ice cooling and concentrated under reduced pressure. Ethyl acetate and water are added to the residue and the aqueous layer is further washed twice with ethyl acetate.

The extracts and washes obtained above were mixed with each other, washed with water, dried over magnesium sulfaate and concentrated under reduced pressure to afford 2- (N-methyl-N-benzylamino) -ethyl-2-methyl-4- (3-nitro). Obtain an oil (1.48 g) of phenyl) -5-ethoxy carbonyl-6-hydroxy methyl-1,4-dihydro pyridine-3-carboxylate.

I.R. Spectrum (Film)

ν (cm ^-1 ): 3390, 1730, 1680, 1650, 1600, 1520, 1460, 1345, 1200, 1100, 1025, 900, 780, 740, 700

NMR Spectrum (δ: CDCl ₃ + D ₂ O)

ppm: 1.2 (3H, t, J = 7Hz), 2.2 (3H, S), 2.66 (2H, t, J = 6Hz), 3.53 (2H, S), 3.97-4.26 (4H, m) 5.14 (1H, S), 7.28-8.15 (10H, m)

The oil thus obtained was dissolved in diethyl ether, 21% ethanol hydrochloric acid (225 mg) was added to the solution, and the precipitated oil was left alone, washed several times with diethyl ether and powdered to obtain 2- (N-methyl- N-benzylamino) Powder of ethyl 2-methyl-4- (3-nitrophenyl) -5-ethoxy carbonyl-6-hydroxy methyl-1,4-dihydropyridine-3-carboxylate hydrochloride (540 mg) ). (Decomposes to brown at 89 ° C.).

I.R. Spectrum (Nuzol)

ν (cm ^-1 ): 3300, 2600, 1680, 1525, 1375, 1350, 1200, 1095, 740, 700

14) Mixture of ethanol (10 ml) with a powder of methyl 4- (2-chlorophenyl) -5-ethoxy carbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (329 mg) added To this is added sodium borohydride (25.11 mg) under ice cooling. After further stirring for 50 minutes, the mixture is adjusted to pH 4-5 with dilute hydrochloric acid. After ethanol removal, the residue is added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried, and the remaining crystals (about 280 mg) were dissolved in a mixture of diethyl ether and η-hexane and stored in a cooler, methyl 4- (2-chlorophenyl) -5-, having a melting point of 187 to 188 ° C. Pure crystals (184 mg) of methoxy carbonyl-6-hydroxy methyl-1,4-dihydro pyridine-3-carboxylate are obtained.

15) Diethyl 2-methyl-4- (2-nitrophenyl) -6- [2- (N, N-diethylamino) ethyl] iminomethyl-1,4-dihydropyridine-3 in 99% ethanol To the solution to which, 5-dicarboxylate (1.1 g) was added was added sodium borohydride (115 mg) under stirring and the mixture was further stirred at room temperature for 5 hours. The resulting mixture is acidified with dilute hydrochloric acid, after ethanol removal, water is added to the residue and the mixture is washed with diethyl erler. The aqueous layer is alkaline with an aqueous solution of sodium bicarbonate, extracted with ethyl acetate, and the solvent is removed from the extract to remove diethyl 2-methyl-4- (2-nitrophenyl) -6- [2-N, N-diethylamino ) -Ethyl] aminomethyl-1,4-dihydropyridine-3,5-dicarboxylate (1 part) and ethyl 2-methyl-4- (2-nitrophenyl) -5-oxo- [2- (N , N-diethyl amino) -ethyl] -1,4,5,7-tetra hydropyriro- (3,4-b) pyridine-3-carboxylate (1 part) 0.8087 g) is obtained. After the mixture was dissolved in ethanol, the solution was refluxed for 5 hours and the solvent was removed to obtain a crystal. The crystals were recrystallized from ethanol to make ethyl 2-methyl-4- (2-nitrophenyl) -5-oxo-6- (N, N-diethylamino) -ethyl] -1,4 having a melting point of 187 to 188 ° C. Obtained yellow needles (729.9 mg) of, 5,7-tetra hydropyriro- (3,4-b) -pyridine-3-carboxylate.

16) Diethyl 2-methyl-4- (2-nitrophenyl) -6- (2-hydroxyethyl) imino methyl-1,4-dihydro pyridine-3,5-dica in 95% ethanol (15 ml) Sodium borohydride (115 mg) is added to the solution to which carboxylate (1.gg) is added and stirred overnight at room temperature. The resulting mixture is slightly acidified with dilute hydrochloric acid and ethanol is removed from the mixture. The residue is alkaline with an aqueous solution of sodium bicarboate and extracted with ethyl acetate. The extract is washed and dried over magnesium sulfaate. The solvent was distilled off to give an oil of diethyl 2-methyl-4- (2-nitrophenyl) -6- (2-hydroxy ethyl) -amino methyl-1,4-dihydro pyridine-3,5-dicarboxylate To obtain. The oil is dissolved in 95% ethanol (15 ml) and the solution is refluxed for 3 hours. The ethanol was removed from the solution to give a red oil which was powdered and recrystallized from a mixture of ethanol and diethyl ether to ethyl 2-methyl-4- (2-nitrophenyl) -5-oxo-6- (2- Obtain orange crystals (0.5998 g) of hydroxy ethyl-1,4,5,7-terra hydro pyriro- [3,4-b] pyridine-3-carboxylate.The product is ethanol and diethyl ether. Recrystallization with a mixture of yielded pure pale orange particles having a melting point of 210 to 211 ° C.

Example 2

Diethyl 2-methyl-4- (2-allyloxyphenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (4.70 g) was added to ethanol (100 ml). To borohydride (445.2 ml) was added gradually at 40 ° C. and the resulting mixture was stirred at 4 ° C. for 1.5 hours under ice cooling. The reaction mixture is acidified with 50% acetic acid and ethanol is removed. Water is added to the residue and the aqueous mixture is stirred for 10 minutes, the powder is collected by filtration, washed with water and crumb crystals (4.49 g) are obtained. The crystals were recrystallized from methanol to give diethyl 2-methyl-4- (2-allyloxyphenyl) -6-hydroxy methyl-1,4-dihydro pyridine-3,5-dicarboxyl having a melting point of 124 to 126 ° C. Yields yellow crystals of eight.

Example 3

1) Cool a solution of 3.60 g of dimethyl-4- (2-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate in (72 ml) methanol (0.2271 g) of natchal borohydride is added little by little with stirring under cooling.

The mixture is stirred at 0 ° C. for 15 minutes. The reaction mixture is adjusted to a pH of about 6 with 50% acetic acid and methanol is removed by distillation under reduced pressure at 30 占 폚 or lower. The remaining solution (100 ml) was diluted with water and extracted with ethyl acetate. The extract is washed sequentially with water, sodium bicarbonate solution and water, then dried over magnesium sulfate and evaporated to dryness. Residual oil (3.70 g) was treated with diisopropyl ether to crystallize to give crude crystals (2.74 g), first crystallized from methanol (8 ml) and then from ethyl acetate (10 ml) to dimethyl 2-methyl-4 with a melting point of 164.5 to 165 ° C. Obtain-(2-nitrophenyl) -6-hydroxy methyl-1,4-dihydro pyridine-3,5-dicarboxylate pure crystals (770 mg). Combine the whole mother liquors of the recrystallization together and concentrate. The crystalline residue is collected by filtration and washed with methanol (5 ml) to give more crystals (1.72 g) which is recrystallized from ethyl acetate to give a further pure sample (840 mg) of the same product as obtained above. (Melting point: 164.5-165 degreeC)

Total yield 1.61 g

NMM δ ppm (CDCl ₃ )

2.33 (3H, S), 3.56 (3H, S), 3.58 (3H, S), 4.76 (2H, S), 5.75 (1H, S), 7.5 to 5.75 (4H, m)

2) A solution of isopropyl 2-methyl-4- (2-nitrophenyl) -5-methoxycarbonyl-6-formyl-1,4-dihydro pyridine-3-carboxylate (3.88 g) in 70 ml of methanol Cool down to -3 ° C and add sodium borohydride (0.2082 g) little by little with stirring. After stirring at −2 ° C. for 30 min, the mixture is acidified with 50% acetic acid and methanol is removed under reduced pressure. The resulting mixture is diluted with water and extracted with ethyl acetate.

The extract was washed successively with water, rare water-soluble sodium bicarbonate solution and again water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (4.37 g) to give a pale pink viscous oil, which was treated with a mixture of diethyl ether and n-hexane. To give a yellowish crystalline powder (3.75 g). Recrystallization from methanol (10 ml) yields a pressurization of isopropyl 2-methyl-4- (2-nitrophenyl) -5-methoxy carbonyl-6-hydroxy methyl-1,4-dihydropyridine-3-carboxylate One granule (2.38 g) is obtained (melting point 135 to 137 ° C). Further recrystallization from ethyl acetate (5 ml) gave a pure sample (1.08 g) with a melting point of 136.5 ° C. to 138 ° C.

NMR δ ppm (CDCl ₃ )

0.96 (3H, d, J = 6HZ), 1.22 (3H, d, J = 6HZ), 2.38 (3H, S), 3.53 (3H, S), 4.70 (2H, S), 4.94 (1H, hept, J = 6 HZ), 5.83 (H, S), about 7.0 to 8.0 (5H, m)

3) 2-benzyloxyethyl 2-methyl-4- (2-nitrophenyl) -5-ethoxy carbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate in (36 ml) ethanol ( To the 1.8 g) cold mixture, sodium borohydride (75.mg) is added below -3 ° C and the resulting mixture is stirred at -3 ° to -5 ° for 40 minutes. The half mixture is adjusted to pH 5-6 with 50% acetic acid and ethanol is distilled off under reduced pressure. The residue is diluted with water (100 ml) to separate the crystalline mass, powdered and collected by filtration.

Crystals (1.57 g) are recrystallized from diethyl ether and n-hexane mixtures. The obtained crystals (910 mg) are not pure enough to be analyzed and are then combined again with the filtrate and purified by passing through column chromatography them on a silica gel column, eluting with a mixture of benzene and ethyl acetate (10: 1 v / v) to give an oil (1 g). ) And crystallized and recrystallized from diisopropyl ether and ethanol mixture to 2-benzyloxyethyl 2-methyl-4- (2-nitrophenyl) -5-ethoxy carbonyl-6- having a melting point of 96-97 ° C. Pure crystals (530 mg) of hydroxy methyl-1,4-dihydro pyridine-3-carboxylate are obtained.

NMR δ ppm (CDCl ₃ )

1.10 (3H, t, J = 7HZ), 2.30 (3H, S), 4.47 (2H, S), 3.50-4.33 (6H, m), 4.73 (2H, d, J = 5HZ) 7.05-7.75 (9H, m).

4) Dimethyl 2-methyl-4- (3-nitrophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (3.84 g) was suspended in methanol (76 ml) and cooled. To the solution is added sodium borohydride (221.8 mg) little by little with stirring over 7 minutes at -7 ° C. Sodium borohydride (40 mg) is added to the reaction mixture with stirring for 5.5 hours. The reaction mixture is diluted with water (50 ml), acidified by addition of 50% aqueous acetic acid, and a small amount of the insoluble material is filtered off. The filtrate is evaporated and the remaining mixture of solid and oily substances is washed with 10 ml of diisopropyl ether to give a solid product (2.7 g). The solid product was recrystallized once with a mixture of methanol and diisopropyl ether (20 ml) (yield 1.76 g) and recrystallized with methanol (6 ml) to give dimethyl 2-methyl-4- (3- Nitrophenyl) -6-hydroxy methyl-1,4-dihydro pyridine-3,5-dicarboxylate (1.48 g) is obtained as pure crystals. The solvent is evaporated and treated with methanol to obtain by-product (330 mg) from the first recrystallized mother liquor.

NMR δ ppm (CDCl ₃ )

2.40 (3H, S), 3.65 (6H, S), 4.81 (2H, d, J = 5HZ), 5.11 (1H, S), 7.25-8.10 (6H, m)

5) 2-benzyloxyethyl 2-methyl-4- (3-nitrophenyl) -6-ethoxycarboxy-6-formyl-1,4-dihydropyridine-3-carboxylate (2.0 g) was added to ethanol ( To the solution cooled by dissolving in 40 ml), sodium borohydride (84.1 g) is added little by little with stirring at -5 ° C over 3 minutes. After 35 minutes an additional portion of sodium borohydride (8.4 mg) is added and the mixture is further stirred at −6 ° C. for 10 minutes. The reaction mixture was added with 50% aqueous acetic acid to adjust the pH to 5-6 and ethanol was distilled off under reduced pressure.

The remaining mixture is diluted with water (100 ml) and extracted with ethyl acetate. The extract is washed with water, dehydrated on magnesium sulfate and evaporated to dryness under reduced pressure to obtain an oily form which is crystallized by standing overnight in a freezer. The crystals were washed with hexane to obtain crystals (1.6 g) which were recrystallized from a mixture of diisopropyl ether and ethanol (1: 1, v / v) (12 ml) to give 2-benzyloxy ethyl having a melting point of 114.5 to 115.5 ° C. 2-Methyl-4- (3-nitrophenyl) -5-ethoxy carbonyl-6-hydroxy phenyl-1,4-dihydro pyridine-3-carboxylate (860 mg) is obtained as pure crystals. By-products are recovered from the mother liquor in a conventional manner. (Yield: 220 mg, Melting point: 112-114 degreeC)

NMR δ ppm (CDCl ₃ )

1.20 (3H, t, J = 7HZ), 2.75 (3H, S), 3.65 (2H, t, J = 3HZ), 4.15 (2H, q, J = 7HZ), 4.24 (2H, t, J = 3HZ) , 4.51 (2H, S), 4.78 (2H, wide S), 5.13 (1H, S), 7.20-8.13 (9H, m)

Example 4

1) 6-formyl-5-methoxy carbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydro pyridine-3-carboxylate (4.2 g) dissolved in ethanol (85 ml) Then, sodium borohydride (0.409 g) was gradually added dropwise over 35 minutes while stirring with cooling to 0 ° C or below.

The reaction mixture is acidified with 50 $ acetic acid solution and then ethanol is removed under reduced pressure. The resulting aqueous suspension is diluted with water and the precipitated pale yellow powder is collected by filtration, washed with water and dried. This powder (3.89 g) was recrystallized from ethanol to give yellow powdered 6-hydroxymethyl-5-methoxy carbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3- Isopropyl ester of carboxylic acid (3.05 g) is obtained. Melting Point 164-166 deg.

In the same manner as in Example 15-1, the following compounds were prepared.

2) isopropyl ester of 6-hydroxy methyl-5-methoxy carbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid, melting point 132-133 ° C

3) Isopropyl ester of 6-hydroxy methyl-5-methoxy carbonyl-2-methyl-4- (2-tolyl) -1,4-dihydro pyridine-3-carboxylic acid, melting point 134-135.5 deg.

4) Isopropyl ester of 6-hydroxy methyl-5-methoxy carbonyl-2-methyl-4- (4-pyridyl) -1,4-dihydro pyridine-3-carboxylic acid, melting point 182-183 ° C. ( decomposition)

5) Isopropyl ester of 4- (2-trifluoro methylphenyl) -6-hydroxy methyl-5-methoxy carbonyl-2-methyl-1,4-dihydro pyridine-3-carboxylic acid, melting point 123-125 ℃

6) Dipropyl ester of 6-hydroxy methyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydro pyridine-3,5-dicarboxylic acid, melting point 118 to 120 ° C

7) 2-phenoxy ethyl ester of 5-ethoxy carbonyl-4- (2-trifluoro methylphenyl) -6-hydroxy methyl-2-methyl-1,4-dihydro pyridine-3-carboxylic acid, melting point 148 to 149 ° C

8) 2-ethoxy ethyl ester of 5-ethoxy carbonyl-4- (2-trifluoro methylphenyl) -6-hydroxy methyl-2-methyl-1,4-dihydro pyridine-3-carboxylic acid, melting point 65 to 66.5 ° C

9) 2-benzyloxy ethyl ester of 5-ethoxy carbonyl-4- (2-trifluoro methylphenyl) -6-hydroxy methyl-2-methyl-1,4-dihydro pyridine-3-carboxylic acid, melting point 104 to 106 ° C

Claims (1)

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

R ₁ in the above formula is an aryl or heterocyclic group which may have one or more suitable substituents selected from halogen, nitro, hydroxy, halo (lower) alkyl, lower alkoxy or lower alkenyloxy, and R ₂ and R ₃ Are the same or different and are esterified carboxy (wherein R ₃ is esterified carboxy) R ₄ e is lower alkyl or lower alkyl substituted with hydroxy and R ₅ e is hydroxy, N, N R ₃ and R ₅ if lower alkyl substituted with ′ -di (lower) alkylamino (lower) alkylamino or hydroxy (lower) alkylamino or R ₁ and R ₂ are as above and R ₄ e is lower alkyl e are joined together to form a group of the formula wherein R ₇ is 2- (2N, N-diethylamino) ethyl or 2-hydroxyethyl)

R _'4 b is lower alkyl and R ₅ b is oxo, N-substituted by lower alkyl or oxo', N'- di (lower) alkyl substituted with amino (lower) alkyl butylimino or hydroxy (lower) alkyl mino Lower alkyl.