CN85107087A - The preparation technology of Hete rocyclic derivatives - Google Patents

Abstract

Compound provided by the present invention is described by following structural formula: In the formula: R ₁, R ₂, R ₃, R ₄And R ₅As what defined at specification sheets and claims.

This compounds can limit the calcium ion injection rate of permeates cell membranes, thereby reduces the concentration of intracellular calcium; Thereby can be used to treat cardiovascular disorder, for example vascular hypertension.

Description

The preparation technology of Hete rocyclic derivatives

The present invention has narrated can influence the new type heterocycle derivative that permeates cell membranes enters the calcium ion amount of heart cell and smooth muscle cell.Narrate its preparation technology, contain pharmaceutical preparation and their application aspect treatment of this analog derivative.

Intracellular calcium is well-known to control heart and unstriated muscle pinch system role.In addition, confirmed that all energy stop or the amount that cytolemma enters the calcium ion in heart and the smooth muscle contraction system cells tissue is passed in minimizing, thereby the compound of calcium ion concn all can be used for treating cardiovascular disorder in the restrictive cell.

We have now found that one group of new compound.They can limit the calcium ion amount that cytolemma enters cell of passing, thereby reduce the concentration of intracellular calcium, therefore can be used for treating cardiovascular disorder, such as hypertension, stenocardia, myocardial ischemia, congested heart failure and the disease of the cerebrovascular and surrounding tissue thereof.

For this reason, the invention provides its general structure by (I) represented compound:

In the formula:

R ₁And R ₄Represent C ₁-C ₄In arbitrary alkyl;

R ₂And R ₃Representative can be by the C of Sauerstoffatom partition ₁-C ₆In arbitrary straight or branched alkyl chain;

R ₅Represent a C ₁-C ₁₃The straight or branched alkyl, or one can be by C ₁-C ₃The C that alkyl substituent replaced ₅-C ₈Cycloalkyl;

The compound that the structure formula I is described can exist with the form of some kinds of isomer and/or enantiomorph.Present invention includes all these isomer, enantiomorph and their mixture.In compound with structure formula I ,-CH=CHCO ₂R ₅Group can exist with cis (Z) configuration or trans (E) configuration.Present invention includes this two kinds of isomer and their mixture.

Containing suitable R ₂With R ₃In the examples of groups, R ₂With R ₃Represent any C ₁-C ₄In the alkyl of straight or branched, as methyl, ethyl, sec.-propyl, isobutyl-and the tertiary butyl; Or by C ₁-C ₃The C that alkoxyl group (as: methoxyl group or propoxy-) is replaced ₁-C ₄Alkyl (as: methyl, ethyl or n-propyl).

Work as R ₅That group is represented is C ₁-C ₁₃Alkyl the time, it can comprise such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl, 2 so, 6-dimethyl-4-heptyl, octyl group and tridecyl.If R ₅Represent a cycloalkyl, it generally is to represent cyclopentyl, cyclohexyl and suberyl so.Above-mentioned cycloalkyl can be by C ₁-C ₃Alkyl (as methyl) replacement.

In the represented compound of structure formula I, its

-CH=CH-CO ₂R ₅Group is preferable with those compounds properties of trans (E) configuration existence.

R ₁With R ₄In the group, being preferably ethyl, is good with methyl especially.

R ₂And R ₃C preferably ₁-C ₄In arbitrary alkyl; For example methyl, ethyl, sec.-propyl or isobutyl-; Or by C ₁-C ₃The ethyl that alkoxyl group (as methoxyl group or propoxy-) is replaced.

R ₅C preferably ₃-C ₉The straight or branched alkyl, for example sec.-propyl, the tertiary butyl, 2,6-dimethyl-4-heptyl or octyl group, or C ₅-C ₇Cycloalkyl, for example can be by cyclopentyl or the cyclohexyl that methyl replaced.

One compounds of special recommendation of the present invention is in its structure formula I, R ₁And R ₄Be methyl, R ₂And R ₃Difference represent methylidene, ethyl, sec.-propyl, isobutyl-, propoxy-ethyl or methoxy ethyl, and R ₅Represent C ₃-C ₉Alkyl, especially sec.-propyl, the tertiary butyl, 2,6-dimethyl-4-heptyl or octyl group is advisable or the cyclohexyl that can be replaced by monomethyl.

In the compound of above-mentioned special recommendation, R ₅For those compounds of the tertiary butyl are subjected to special attention.

A kind of compound of special recommendation of the present invention is 4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester; Especially the trans-isomer(ide) with it is good.

Other compound that the present invention recommends has:

4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid 3-methyl ester, 5-(2-methyl-propyl) ester;

4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid dimethyl ester;

4-(2-(3-(1,1-dimethyl oxyethyl group) 3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid, 3-methyl ester 5-ethyl ester;

In above-mentioned each compound especially the trans-isomer(ide) with them be good.

All cpds among the present invention comes ionic concn in the restrictive cell by the calcium ion amount that stops or reduce permeates cell membranes to enter cell.Thereby these compounds will limit or suppress the influence of calcium ion to the vascular smooth muscle normal condition of degenerate (depolarised).

Verified by the experiment of the male wister rat of suffering from spontaneously hypertensive disease being carried out intravenous injection and/or oral dispenser, all cpds among the present invention all has antihypertensive active.Have found that at all cpds of the present invention, particularly above-mentioned several unique compounds have good especially activity; And the relatively long property of medicine continuous action time.

So all cpds of the present invention is being significant aspect the treatment hypertension.They also may be used for the treatment of other cardiovascular diseases, comprise the disease of stenocardia, myocardial ischemia, congestive heart failure and the cerebrovascular and surrounding tissue thereof.These compounds can be routinely method, adopt a kind of or several pharmaceutical carriers, produce reagent combination.

Therefore, content of the present invention also comprises and is used for oral, hypogloeeis, various medicinal preparationss subcutaneous, that made by compound shown in the structure formula I without enteron aisle dispenser and internal rectum dispenser etc. by formulation.

Oral medicinal products can be made tablet (can coated with glued membrane or sugar-coat), capsule, pulvis, granular preparation, contain syrupy solution or adopt harmless vehicle to make suspension according to ordinary method.The goods of hypogloeeis dispenser can method routinely be made tablet or lozenge according to prescription.

The compound of structure formula I can be made blob of viscose annotate to press agent (bolus injec-tion) or the mode by continous pouring to be used for without enteron aisle dispenser process.Medicinal constituent can be made into suspension, solution or the emulsion in oily or water-bearing media; Can contain such as preparations such as suspension agent, stablizer and/or dispersion agents.In order to adopt the injection dispenser, these preparations can be made with the form of disposable dosage or the form of multidose, preferably add sanitas simultaneously.

In addition, be used for parenteral dispenser method, its effective constituent can also be powdered, so that use a kind of suitable medium to prepare again.

Structural formula can be made ointment or water slurry for all cpds of (I), for use in the dispenser method of permeating via skin.Also can make suppository or be detained enema for use in the rectum dispenser.

Active compound of the present invention is used for the treatment of the suggestion per daily dose of the usefulness of being grown up in 0.005 milligram to 50 milligrams scope, for example in 0.01 milligram to 20 milligrams scope.This dosage can be easily once or divide and use several times.The exact dosage desired that is adopted should be decided according to year the making of patient, healthy state and application method.

When oral, can adopt the dosage of 0.01-50 milligram/day, easily patient be imposed compound of the present invention.Employing is during without enteron aisle dispenser method, with the dosage of 0.005-1 milligram/day (recommending to adopt 0.01-0.5 milligram/day) easily to patient to compound of the present invention.

When oral, the application times of advising this compound is 2 times/day, in particular cases 1 time/day.

The preparation method of all cpds shown in the following narrative structure formula I.In the various intermediates hereinafter, R ₁, R ₂, R ₃, R ₄And R ₅Implication clear and definite when all cpds of definition structure formula I above, or be in above group under the protection form.

The compound of structure formula I, particularly their trans (E) isomer can utilize alpha, beta-unsaturated ketone (II) and amino ester (III) to react and prepare.This is reflected in the solvent of Fatty Alcohol(C12-C14 and C12-C18) (as an ethanol or Virahol) class and is easy to carry out.Proposal reactions is carried out under heating condition (for example 40-150 ℃).

Alpha, beta-unsaturated ketone (II) can react in the solvent of Fatty Alcohol(C12-C14 and C12-C18) (as an ethanol or Virahol) class by aldehyde (IV) and ketone ester (V) and prepare, and is preferably under heating (for example 40-150 ℃) condition and carries out.Under the condition that the catalyzer just like Piperidineacetic acid ester one class exists, reaction is easy to carry out.

In the improvement technology of the compound of a preparation structure formula I, can make the mixture of aldehyde (IV) and amino ester (III) and ketone ester (V), the reaction conditions according to aforementioned alpha, beta-unsaturated ketone (II) and amino ester (III) reacts.

The compound of structure formula I, especially R ₁And R ₄Identical, R ₂And R ₃Identical trans-isomer(ide) can pass through aldehyde (IV) in the presence of suitable acid catalyst, reacts with amino ester (III) and makes.The acid catalyst that is suitable for comprises as the organic acid (as acetic acid) of oxalic acid, paraffinic acid one class or as the halogenated-chain acid of trichoroacetic acid(TCA), trifluoroacetic acid or their pyridinium salt one class; Or as the sulfonic acid of an alkyl group sulfonic acid (for example methylsulphonic acid) or aryl sulfonic acid (for example Phenylsulfonic acid or tosic acid) class; Or as tetrafluoro for four halo boronic acid compounds the boric acid.Suggestion is having that solvent exists, is reacting under the condition of temperature range for-70-30 ℃ (recommendation-30-10 ℃).React adoptable solvent and comprise the such aprotic solvent of hydro carbons (for example normal hexane, hexanaphthene and acetonitrile); Or t-butyl methyl ether, diox or the such ethers of tetrahydrofuran (THF); Or the protonic solvent as alkanol (for example methyl alcohol, ethanol, propyl alcohol, Virahol or butanols).

R ₁With R ₄Identical, R ₂With R ₃Its identical structural formula is the compound shown in (I) formula, and its trans (E) isomer especially can also react with ketone ester (V) and ammonium acetate by aldehyde (IV) and makes.This is reflected in the solvent of pyridine one class and is heated to 50-120 ℃, is easy to carry out under refluxing.

Next step preparation technology of the present invention adopts structural formula to be (I) R wherein ₅For the respective acids of the compound of hydrogen by esterification method, all cpds of preparation structure formula I.Like this, this technology example just is to use alkylating agent R ₅X Processing Structure formula is (I) and R wherein ₅Represent the compound of hydrogen, prepare all cpds of structure formula I.At R ₅Among the X, R ₅Definition identical with regulation in the structure formula I; X then represents the leavings group as muriate, bromide, iodide or sulfonyloxy methyl salt etc.In the presence of alkaline matter, be easy to carry out no matter whether heat this reaction.For example, this reaction can be carried out in 10-100 ℃ temperature range.The alkaline matter that uses has the carbonate of alkali or alkaline-earth metal, and for example being dissolved in is salt of wormwood in the such polar aprotic solvent of DIMETHYL FORMAMIDE or methyl-sulphoxide.

The next example of the present invention is to be (I) R wherein by structural formula ₅For the corresponding carboxylic acid of hydrogen prepares all cpds of the present invention.Derivative (as mixed acid anhydride) that can activate and corresponding pure R by its one ₅OH or alkoxide react and prepare.At R ₅R among the OH ₅Definition and structure formula I in identical.

Structural formula is (I) and R wherein ₅Representing all cpds of hydrogen, can be (I) R wherein by the hydrolysis structural formula ₅For the method for the compound of the tertiary butyl makes.Hydrolytic process can use the hydrogen bromide that is dissolved in the acetate to carry out under the condition that has solvent (as methylene dichloride) to exist.Reaction is carried out better at low temperatures, for example-and 78-35 ℃.

In another kind of preparation technology of the present invention, trans (E) isomer of structure formula I compound can make by the compound of Processing Structure formula VI.

(Hal represents a bromine atoms or iodine atom in the formula)

This process is to use acrylate CH ₂=CHCO ₂R ₅(VII) handles that compound (VI) realizes in the presence of the palladium salt (as palladium) of catalytic amount and a kind of suitable organic bases as trihydroxy-amine (as triethylamine or tri-n-butylamine).This has been reflected at triaryl phosphine (as three-ortho position-tolylphosphine) and exists down and also can carry out smoothly, carries out more smoothly and the condition that exists at triphenylphosphine is next.

Reaction can be carried out in a kind of suitable solvent (for example dimethylbenzene or tertiary butyl acetate) smoothly; And in DIMETHYL FORMAMIDE or certain solvent mixture (for example mixture of dimethylbenzene and DIMETHYL FORMAMIDE), reaction can more successfully be carried out.Heat during proposal reactions.The heated perimeter of recommendation response mixture is 80-150 ℃, but is good with 100-110 ℃.

Structural formula is (I) wherein R ₅The various carboxylic acids of representing hydrogen are the new compounds of a class, are the useful chemical intermediate of preparation structural formula for all cpds of (I).It has embodied another characteristics of the present invention.

The all cpds of structure formula IV can prepare with triphenylphosphine (IX) and dialdehyde (VIII) reaction in solvent (for example methylene dichloride or toluene).

The all cpds of structure formula IV also can obtain with 2-halogeno-benzene formaldehyde (X) reaction with acrylate (VII).

(in the formula, Hal represents a bromine atoms or iodine atom)

The condition of this reaction is identical with acrylate (VII) reaction part with the compound of said structure formula VI.

The all cpds of structure formula VI can make with 2-halogeno-benzene formaldehyde (X) reaction with amino ester (III) and/or ketone ester (V).Reaction conditions can be by the compound of said structure formula IV and the reaction conditions between amino ester (III) and/or the ketone ester (V) and is decided.

Structure formula III, (V), (VII), (VIII), (IX) and compound or compound known such as (X), or the compound that can prepare with the similarity method of preparation known compound.

Structural formula is (I) and wherein-CH=CHCO ₂R ₅Group is all cpds of cis (Z) configuration, can prepare with the method for its trans accordingly (E) isomer solution of irradiation.Therefore, in nitrogen, use sun exposure, just can obtain cis (Z) and trans (E) mixture of isomers when the dichloromethane solution of trans (E) isomer.This mixture can adopt such as routine techniquess such as fractional crystallization and/or chromatographic separation separately.

The all cpds of structure formula I also can prepare with the phosphorane and compound (XI) reaction that are dissolved in the appropriate solvent (as methylene dichloride, tetrahydrofuran (THF) or toluene).Proposal reactions is carried out under heating (for example 40-120 ℃) condition, and is next more convenient in backflow.

Intermediate (XI) can prepare with the corresponding acetal of aqueous acid hydrolysis (XII).(in (XII) formula, R ₆The expression alkyl).

Structural formula makes for the compound of (XII) can react with the compound of aldehyde (X III) and structure formula III and/or (V).Reaction conditions is identical with the reaction conditions of above-mentioned all cpds by intermediate (IV) preparation structure formula I.Intermediate (X III) can be by reacting with bromobenzene derivative (X IV) and butyllithium in solvent, adds the method for DIMETHYL FORMAMIDE then and obtain.

The present invention is illustrated in the T.L.C. that is mentioned in all examples with following example and refers to thin-layer chromatography on Merck silica gel 60F-254; All temperature are ℃.

Intermediate 1

(1a) (E)-3-(2-formyl radical phenyl)-2-vinylformic acid, 1,1-dimethyl ethyl ester.

Contain 54.7 gram triphen phosphinidene acetate 1 in 100 milliliters, the universe dichloromethane solution of 1-dimethyl ethyl ester added in 15 minutes in the universe dichloromethane solution that contains 19.3 gram Phthalyldicarboxaldehydes at 0 ℃.After evaporation removes and desolvates, oily matter ether extracting; The triphenylphosphine oxidation thing of solids removed by filtration; With ether filter wash cake; Evaporate to dryness filtrate obtains 36 gram xanchromatic oily matter.With its wash-out (petroleum ether/ethyl ether, 7: 3) on silicagel column.Obtain this title compound of 21.4 gram colorless oil.

The T.L.C.(petroleum ether/ethyl ether, 1: 1) the Rf=0.45(Rf value).

(1b) uses the same method, and makes 12 gram (E)-3-(2-formyl radical phenyl by 13.4 gram Phthalyldicarboxaldehydes and 34.8 gram triphen phosphinidene ethyl acetate)-the 2-ethyl propenoate.

The T.L.C.(petroleum ether/ethyl ether, 1: 1) Rf=0.40.

Intermediate 2

The 2-(diethoxymethyl) bromobenzene

To contain 33.2 gram 2-bromobenzaldehydes in 30 milliliters of ethanol, the mixture of 29 gram triethyl ortho-formiates and the Powdered ammonium chloride of 0.379 gram at room temperature stirred 8 hours.Filter this suspension; Evaporated filtrate; The yellow oil that distillation under reduced pressure obtains obtains 31 these title compounds of gram.

Boiling point: 63 ℃/0.3 mmhg;

T.L.C.(gasoline/ether, 6: 1) Rf=0.6

Intermediate 3

The 2-(diethoxymethyl) phenyl aldehyde

The hexane solution of the butyllithium of 160 milliliters of 1.2M is added in the solution of being made up of 250 milliliters of tetrahydrofuran (THF)s and 250 millimeters ether; Under agitation, it is cooled to-70 ℃, makes temperature maintenance then, under this temperature, in mixture, slowly splash into one by 75 milliliters of tetrahydrofuran (THF)s and 165 milliliters of solution that DIMETHYL FORMAMIDE is formed at-65 ℃.Then add 150 milliliters of saturated aqueous ammonium chlorides again; Tell organic phase, with extracted with diethyl ether water (2 * 70 milliliters); Merge organic phase; Use MgSO ₄After the drying, evaporation removes and desolvates, and obtains a brown oily matter.This oily matter underpressure distillation is just obtained this title compound of 30 gram white waxy solid.Boiling point: 87 ℃/0.9 mmhg T.L.C.(gasoline/ether, 7: 3) Rf=0.6.

Intermediate 4

4-(2-formyl radical phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine carboxylic acid diethyl ester

Under 0 ℃ and agitation condition, 5 gram intermediates 3 are dropped in the solution of being made up of 5 milliliters of Glacial acetic acid and 9.3 gram Ethyl-3-Amino Crotonates.With in 100 milliliters of ethyl acetate of reactant impouring, the hydrochloric acid of adding 10% shakes after two hours; Tell organic phase; Use MgSO ₄The evaporation of dry back.Remaining brown oil is made with extra care (silica gel with chromatographic column; Dichloromethane/ethyl acetate, 7: 3); Use the ether crystallization then; Obtain 0.200 this title compound of gram yellow solid shape.Fusing point: 172-173 ℃

T.L.C.(gasoline/ethyl acetate, 7: 3) Rf=0.4

Intermediate 5

The 4-(2-(2-carboxyl vinyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

Under-78 ℃, with 70 milliliter 33% HB _r/ CH ₃The dichloromethane solution of COOH is added in 70 milliliters of dichloromethane solutions that contain 10 gram examples 1 compounds at leisure.This mixture is warming up to-35 ℃ then; Be poured in the frozen water after 10 minutes.PH value is transferred to 6, uses this mixture of ethyl acetate extraction then; Use Na after the washing ₂SO ₄Dry; Evaporation removes and desolvates, again with solid petrol ether/ethyl acetate (1: 1) the solution weight crystallization that obtains, so obtain 6.5 these title compounds of gram white solid.T.L.C.（CH ₂Cl ₂/CH ₃CO ₂C ₂H ₅/CH ₃COOH，8∶2∶1）Rf＝0.4。Fusing point: 175～178 ℃

Intermediate 6

(6a) 2,6-dimethyl-4-heptyl methanesulfonates

At 0 ℃, the diethyl ether solution of Methanesulfonyl chloride is added drop-wise to 2, in the diethyl ether solution of 6-2,6-dimethyl-4-heptanol and triethylamine.Mixture at room temperature stirred 2 hours, then with in its impouring water; Use extracted with diethyl ether; Use dilute hydrochloric acid and water washing organic phase successively, use Na ₂SO ₄Dry; After the evaporating solvent, just obtain this title compound of 2.6 gram colorless oil.

T.L.C.(ethyl acetate/hexanaphthene, 4: 6) Rf=0.55.

(6b) 2-methylcyclohexyl methanesulfonates

Make by Methanesulfonyl chloride and 2-methylcyclohexane.

The T.L.C(dichloromethane/ethyl acetate, 7: 3) Rf=0.75.

Intermediate 7

The 4-(2-bromophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine carboxylic acid diethyl ester

(a) under agitation with the ethanol solution that contains 83.7 gram 2-bromobenzaldehydes in 1350 milliliters, be cooled to-10 ℃ after, rapidly 108 gram trifluoroacetic acids are joined in this solution; Then in 1 hour, splash into 750 milliliters of ethanolic solns that contain 146 gram ethyl 3-amino-butenates.Continue down to stir 1 hour at-10 ℃, then under brute force stirs, this mixture dropped in 7000 milliliter 0.3% the hydrochloric acid soln.Solid collected by filtration, water and petroleum ether and then 60 ℃ of following vacuum-dryings.Obtain 156 these title compounds of gram.Fusing point: 142-143 ℃ of T.L.C(ethyl acetate/petroleum ether, 8: 2) Rf=0.5

(b) the ethanol solution reflux 15 hours of 10.8 gram 2-bromobenzaldehydes, 9.36 gram ethyl 3-amino-butenates and 9.12 gram ethyl acetoacetic esters will be contained in 50 milliliters.After this mixture cooling, with 250 milliliters of dehydrated alcohol dilutions; Under brute force stirs, it is added drop-wise to then in 2000 milliliter 0.2% the hydrochloric acid soln.Solid collected by filtration; With carrying out vacuum-drying after 150 milliliters of petroleum ether, obtain 19.3 these title compounds of gram.Fusing point: 142-143 ℃

Intermediate 8

The 4-(2-iodophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine carboxylic acid diethyl ester

According to intermediate 7(a) preparation method, make 54.8 these title compounds of gram by 46.4 gram 2-benzaldehyde iodines and 73 gram ethyl 3-amino-butenates.Fusing point: 178 ℃ of T.L.C.(dichloromethane/ethyl acetate, 9: 1) Rf=0.5

Intermediate 9

2-2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-methylene-3-oxo-methyl-butyrate

1 milliliter of aqueous isopropanol that contains 0.11 gram piperidines and 0.078 gram acetate is added to 15 milliliters contains 5.2 gram 3-(2-formylphenyls) vinylformic acid 1, in the aqueous isopropanol of 1-dimethyl ethyl ester and 2.55 gram methyl-acetoacetic esters.Mixture was stirred 1 hour down at 60 ℃, and evaporation removes and desolvates; Residue is with 100 milliliters of ether extractings.This extracting solution is washed through Na after using HCl, water and the saturated bicarbonate washing of 1N successively again ₂SO ₄Drying, evaporation obtains an oil after removing and desolvating, should oil with chromatographic column refining (gasoline/ether gradient, 7: 3-1: 1) just obtain the trans/cis mixture of isomers of light this title compound of buttery of 4.2 grams.

Example 1

(E)-and 4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

24 gram ethyl 3-amino-butenates at room temperature are added in the ethanolic soln that contains 21.4 gram intermediate 1a.This red solution at room temperature stirred 5 hours; Then with in its impouring water; Use ethyl acetate extraction.Use the aqueous solution and the water washing organic phase of 5% sodium bicarbonate successively, use Na then ₂SO ₄Dry; Evaporation removes to desolvate and obtains the oil of a dark color.This oil is carried out elution (CH on a silicagel column ₂Cl ₂/ ethyl acetate, 9: 1) and just obtain this title compounds of 3.6 gram white solid through re-crystallizing in ethyl acetate.Fusing point: 173-175 ℃

The T.L.C.(dichloromethane/ethyl acetate, 9: 1) Rf=0.4

Example 2

4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

At room temperature, contain 0.1 gram triphen phosphinidene acetate 1 in 0.5 milliliter, the dichloromethane solution of 1-dimethyl ethyl ester is added in 0.5 milliliter of dichloromethane solution that contains 0.1 gram intermediate 4; After in methylene dichloride, refluxing 12 hours, add tetrahydrofuran (THF) and continue to reflux 12 hours; And then adding toluene refluxed mixture again 5 hours.Evaporate this mixture; Residue is refining with chromatographic column, uses the gasoline crystallization then, obtains the cis of 120 milligrams of these title compounds and the mixture of trans-isomer(ide).

Example 3

(E)-and 4-(2-(3-oxyethyl group-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

At room temperature, contain in the acetic acid solution of 10.2 gram intermediate 1b in being added to 13 gram ethyl 3-amino-butenates in 150 milliliters.This red solution was at room temperature stirred 3 hours, then with in its impouring water and use ethyl acetate extraction.Organic phase is used 5% aqueous sodium carbonate and water washing successively; Through Na ₂SO ₄Drying, and obtain the dark oil of 20 grams after boiling off solvent.With this oil elution (CH on silicagel column ₂Cl ₂/ ethyl acetate, 7: 3) just obtain 4.5 these title compounds of gram white solid through petroleum ether/ethyl ether (9: 1) recrystallization.Fusing point: 130-131 ℃ of T.L.C.(dichloromethane/ethyl acetate, 8: 2) Rf=0.50

Example 4

(4a) (E)-4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid 3-methyl esters, 5-ethyl ester

The mixture that is contained in the gram of 0.5 in ethanol intermediate 1a, 0.27 gram ethyl 3-amino-butenate and 0.24 gram methyl-acetoacetic ester was refluxed 14 hours, evaporation removes and desolvates then, slightly oil elution on silicagel column (ether/sherwood oil, 7: 3) obtains this title compound of 0.25 gram yellow solid shape.Fusing point: 165-167 ℃ of (sherwood oil) T.L.C.(ether/sherwood oil, 9: 1) Rf=0.3

With compound be with the quadrat method preparation:

(4b) (E)-4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid 3-methyl esters, 5-(2-methyl-propyl) ester

By intermediate 1a, methyl 3-amino-butenate and 2-methyl-propyl acetylacetic ester make.Fusing point: 147-149 ℃ of (sherwood oil) T.L.C.(petrol ether/ethyl acetate, 6: 4) Rf=0.35

(4C) (E)-4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid 3-(1-methylethyl) ester, the 5-(2-methoxy ethyl) ester

By intermediate 1a, 1-methylethyl 3-amino-butenate and 2-methoxy ethyl acetylacetic ester make.Fusing point: 156-157 ℃ of (sherwood oil) T.L.C.(ethyl acetate/hexanaphthene, 1: 1) Rf=0.35

(4d) (E)-4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid dimethyl ester

By intermediate 1a, methyl 3-amino-butenate and methyl-acetoacetic ester make.Fusing point: 158-162 ℃ of (petroleum ether/ethyl ether, 100: 1) T.L.C.(gasoline/ethyl acetate, 6: 4) Rf=0.25

(4e) (E)-4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3, the 5-pyridine dicarboxylic acid is two-2-just-the propoxy-ethyl ester

By intermediate 1a, just-propoxy-ethyl 3-amino-butenate and just-propoxy-ethyl acetoacetic ester makes.

Fusing point: 115-116 ℃ (gasoline/ether)

T.L.C.(ethyl acetate/hexanaphthene, 1: 1) Rf=0.40

(4f) (E)-4-(2-(3-oxyethyl group-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid ethyl (1, the 1-dimethyl) ethyl ester

By intermediate 1b, ethyl 3-oxobutanoate and 3-aminobutene acid 1,1-dimethyl ethyl ester makes.

Example 5

(5a) (E)-4-(2-(3-octyloxy-3-oxo-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3 ,-pyridine dicarboxylic acid diethyl ester

After the suspensoids of 0.5 gram intermediate 5,0.38 gram n-octyl bromide and 10 gram salt of wormwood are at room temperature stirred 20 hours, in its impouring water, use ethyl acetate extraction; Use Na behind the water thorough washing ₂SO ₄Dry; Evaporation removes and desolvates, and with sherwood oil it is developed into a kind of oily matter, uses the sherwood oil recrystallization then, obtains this title compound of 0.3 gram white solid.

Fusing point: 110-112 ℃.The T.L.C.(dichloromethane/ethyl acetate, 9: 1) Rf=0.5

(5b) (E)-4-(2-(3-methoxyl group-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

Make by intermediate 5 and monobromethane.

Fusing point: 138-140 ℃ of (sherwood oil) T.L.C.(dichloromethane/ethyl acetate, 8: 2) Rf=0.40

(5C) (E)-4-(2-(3-(1-methyl ethoxy)-and 3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

Make by intermediate 5 and 1-methylethyl bromine.

Fusing point: 145-147 ℃ (sherwood oil)

The T.L.C.(dichloromethane/ethyl acetate, 8: 2) Rf=0.45

(5d) (E)-4-(2-(3-(2-methyl propoxy-)-3-ization generation-1-propenyl) phenyl (1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

Make by intermediate 5 and 2-methyl-propyl bromine.

Fusing point: 172-174 ℃ of (sherwood oil) T.L.C.(dichloromethane/ethyl acetate, 8: 2) Rf=0.55

(5e) (E)-4-(2-(3-cyclohexyloxy-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

Make by intermediate 5 and cyclohexyl bromide.

Fusing point: 175-177 ℃ of (sherwood oil) T.L.C.(dichloromethane/ethyl acetate, 9: 1) Rf=0.40

(5f) (E)-4-(2-(3-tridecane oxygen base-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

At room temperature react by intermediate 5 and tridecyl bromine and to make.Fusing point: 87-89 ℃ of T.L.C.(petrol ether/ethyl acetate, 6: 4) Rf=0.40

(5g) (E)-4-(2-(3-ring oxygen base in heptan-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

Make by intermediate 5 and suberyl bromine.Fusing point: 192-194 ℃ of T.L.C.(dichloromethane/ethyl acetate, 8: 2) Rf=0.45

(5h) (E)-4-(2-(3-cyclopentyloxy-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

Make by intermediate 5 and cyclopentyl bromide.Fusing point: 182-184 ℃ of T.L.C.(ethyl acetate/hexanaphthene, 1: 1) Rf=0.42

Example 6

(E)-and 4-(2-(3-octyloxy-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

To in 5 milliliters of DIMETHYL FORMAMIDE, contain the suspension of 0.1 gram intermediate, 5,0.077 gram octyl group methanesulfonates and 2 gram salt of wormwood, at room temperature stir 20 hours, then with in the mixture impouring water; Use ethyl acetate extraction, behind the water thorough washing, at Na ₂SO ₄Last dry; Evaporation removes and desolvates, and with sherwood oil its mill is loose and makes a kind of oily matter, just obtains this title compound of 0.04 gram white solid then with the sherwood oil recrystallization.Fusing point: 110-112 ℃ of T.L.C.(dichloromethane/ethyl acetate, 9: 1) Rf=0.5

Example 7

(E)-and 4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

With 5 milliliters of N that contain 0.2 gram intermediate 5 and 0.07 gram salt of wormwood, the suspension of N-DIMETHYL FORMAMIDE is handled and was at room temperature stirred 20 hours with 0.14 gram tert.-butyl bromide.In mixture impouring water, use ethyl acetate extraction; Fully washing is through Na ₂SO ₄Dry, evaporation obtains an oily matter after removing and desolvating, and it is just obtained this title compound of 0.005 gram white solid with the sherwood oil crystallization.Fusing point: 173-175 ℃

Example 8

(Z)-and 4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

250 milliliters of dichloromethane solutions that contain 1 gram example, 1 compound with nitrogen gas stream deoxidation 3 minutes, in nitrogen environment, were left standstill for two weeks then in the sun.Evaporate this solution, the solid that obtains obtains 0.2 gram white solid with gasoline/ether recrystallization twice of 9: 1; This solid is used methylene dichloride elution 5 times on a silica-gel plate; Obtain a colourless oil,, just obtain this title compound of 0.05 gram white solid again with its petroleum ether/ethyl ether crystallization with 9: 1.Fusing point: 143-145 ℃ of T.L.C.(dichloromethane/ethyl acetate, 9: 1) Rf=0.40

Example 9

(9a) (E)-4-(2-(3-(2,6-dimethyl-4-oxygen in heptan base)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

Will be by 30 milliliters of DIMETHYL FORMAMIDE and 2 gram intermediates, 5,1.6 grams 2, the suspension that 6-dimethyl-4-heptyl methanesulfonates and 40 gram salt of wormwood are formed is after stirring 12 hours under 60 ℃, in the impouring water; Use ethyl acetate extraction.The water thorough washing is at Na ₂SO ₄Last dry; Evaporation removes to desolvate and obtains the thick oil of 3 grams; With this oil on silicagel column with ether/sherwood oil elution of 8: 2, obtain 0.66 the gram white solid this title compound.Fusing point: 49-52 ℃ of T.L.C.(petrol ether/ethyl acetate, 6: 4) Rf=0.45

Preparation is equally:

(9b) (E)-4-(2-(3-(2-methyl cyclohexane oxygen base)-and 3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

Make by intermediate 5 and 2-methylcyclohexyl methanesulfonates.Fusing point: 165-166 ℃ of T.L.C.(dichloromethane/ethyl acetate, 8: 2) Rf=0.55

Example 10

(E)-and 4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-diethyl-3,5-pyridine dicarboxylic acid diethyl ester

After 25 milliliters of ethanolic solns that are dissolved with 3.2 gram intermediate 1a are cooled to 0 ℃, adds 2 milliliters of trifluoroacetic acids, add again and contain 10 ethanolic solns that restrain Ethyl-3-Amino Crotonates in 25 milliliters.This mixture stirred 1 hour at 0 ℃, and in the impouring water, ethyl acetate extraction is used in the sodium bicarbonate neutralization with 10% more then.Organic phase is used 10% hydrochloric acid and water washing successively, through Na ₂SO ₄Dry and boil off solvent after obtain an oil, with its elution on silicagel column (gradient of ether/gasoline, 3: 7-7: 3) just obtain this title compounds of 2 gram light yellow solid shapes.Fusing point: 154-155 ℃ of T.L.C.(petrol ether/ethyl acetate, 1: 1) Rf=0.65

Example 11

(E)-and 4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

(a) will in 200 milliliters of DIMETHYL FORMAMIDE, contain the mixture that 171.5 gram intermediates, 7,67.0 gram tertiary butyl acrylate, 97.6 restrain Tributylamines, 0.94 gram palladium and 4.4 gram triphenylphosphines, in nitrogen environment, under 110 ℃, heated 24 hours.Cool off this mixture then, remove by filter catalyzer after, the evaporate to dryness organic solvent; Residue is dissolved in 700 milliliters of acetone, under brute force stirs, this drips of solution is added in 8000 milliliter 0.5% the hydrochloric acid soln.Solid collected by filtration, water and petroleum ether successively are 60 ℃ of following vacuum-dryings.Obtain a yellow solid, with this solid with twice recrystallization of 500 milliliters of ethyl acetate.Obtain 100 gram title compounds.Fusing point: 174-175 ℃ of T.L.C.(dichloromethane/ethyl acetate, 8: 2) Rf=0.48

(b) in kind, make 46 these title compounds of gram by 91 gram intermediates 8 and 33 gram tertiary butyl acrylate.

Example 12

(E)-and 4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester

With 75 milliliters of ethanol solutions that contain 19.5 gram ethyl 3-amino-butenates, in-10～0 ℃ temperature range, be added in the mixture of 90 milliliters of dehydrated alcohols of oil and 11.6 gram (E)-tertiary butyl-2-formyl radical-laurates and 11.4 gram trifluoroacetic acids compositions; Allow this mixture in this temperature range, wear out 1.5 hours, add 150 milliliter 8% sodium bicarbonate aqueous solution then.Product extracts (3 * 200 milliliters) with t-butyl methyl ether; Close the And extraction liquid, wash (2 * 150 milliliters) with water after, use MgSO ₄Dry.Filter, boil off solvent after, make the oiliness thing that a usefulness 50 milliliters of sherwood oils mills have loose, refilter and just obtain a kind of granular solids, with 30 milliliters of ethyl acetate crystallizations, just obtain 8.5 and restrain these title compounds.Fusing point: 174-175 ℃

Example 13

(E)-and 4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid methylethyl ester

With 20 milliliters of ethanolic solns that contain 1.13 gram ethyl 3-amino-butenates and 2.9 gram intermediates 9, reflux 13 hours.After boiling off solvent, residual oil is with chromatographic column refining (gradient of gasoline/ethyl acetate, 7: 3-1: 1) obtain this title compound of 0.42 gram white solid.Fusing point: 165-167 ℃

Example 14

Medicine is formed

(a) tablet

（Ⅰ）

^*B _o.P. be British Pharmacopoeia (annotation of translation)

This medicament is configured as granular with the ethanolic soln of polyvinylpyrrolidone, mix vehicle then and be pressed into suitable sheet with stamping machine.

（Ⅱ）

^*BPC is bpc book (annotation of translation)

This medicament mixes vehicle after sieving by suitable screen cloth earlier, is pressed into suitable sheet with stamping machine.

Change weight of formulation and strike out the tablet that suitable shape can prepare the multiple efficacy of a drug.This tablet also can use routine techniques, and with suitable film forming material for example: methylcellulose gum, ethyl cellulose or Vltra tears etc. are covered with film or wrap sugar-coat.

(b) soft capsule

Under agitation condition, in poly(oxyethylene glycol) 400, use suitable packing machine that this mixture is inserted soft capsule then medicine dissolution.Change loading level and just can prepare the different various capsules of dosage.Also can change capsular specification if necessary to adapt to the variation of fill-up.

In the superincumbent exemplary drugs, active principle refers to one or more compounds of general structure (I); But that best is 4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester; Especially its trans-isomer(ide).

Claims (12)

1, the preparation technology of the compound of structure formula I

In the formula:

R ₁And R ₄Represent C ₁-C ₄In arbitrary alkyl;

R ₂And R ₃Representative can be by the C of Sauerstoffatom partition ₁-C ₆In the alkyl of arbitrary straight or branched;

R ₅Represent a C ₁-C ₁₃The straight or branched alkyl; Or one can be by C ₁-C ₃The C that alkyl substituent replaces ₅-C ₈Cycloalkyl;

Comprise:

(a) the same amino ester of the compound of structure formula II (III) (R in the formula ₁, R ₂, R ₅R ₃, and R ₄Definition and structure formula I in identical) reaction carried out.

(b) reaction that keto esters carried out of the amino ester of the aldehyde isostructure formula III of structure formula IV and structural formula (V).(R in the formula ₅R ₄, R ₃R ₂And R ₁Definition and structure formula I in identical)

(c) by the aldehyde of structure formula IV with the amino ester of 1. structure formula III or 2. in the presence of ammonium salt the keto esters of isostructure formula (V) react preparation R ₁And R ₄Identical; R ₂And R ₃Identical compound with structure formula I.

(d) structural formula is (I) and R wherein ₅Represent the esterification of the respective acids of hydrogen.

(e) in the presence of palladium salt and organic bases, by the compound (R in the formula of structure formula VI ₁, R ₂, R ₃And R ₄Definition and structure formula I in identical; Hal represents bromine or iodine) with acrylate CH ₂=CHCO ₂R ₅(VII) (R in the formula ₅Definition and structure formula I in identical) reaction, to the preparation of trans-isomer(ide) with structure formula I compound.

(f) compound (R in the formula of structural formula (XI) ₁, R ₂, R ₃And R ₄Definition and structure formula I in identical) same triphenylphosphine (IX) (R in the formula ₅Definition and structure formula I in identical) react.

(g), prepare the cis-isomeride of structure formula I compound with the trans-isomerism liquid solution of light irradiating structure formula I compound.

2,, prepare in its structural formula R according to claim 1 ₁And R ₄The technology of the compound of any represent methylidene or ethyl.

3,, prepare R in its structural formula according to claim 1 or 2 ₁And R ₄Technology of the compound of represent methylidene all.

4, according to claim 1 to 3 each, prepare R in its structural formula ₂And R ₃Represent any one can be by C ₁-C ₃The C that alkoxyl group replaces ₁-C ₄The technology of the compound of alkyl.

5, according to claim 1 to 4 each, prepare R in its structural formula ₂And R ₃Represent the technology of the compound of arbitrary group of from methyl, ethyl, sec.-propyl, isobutyl-, tert-butyl, methoxy ethyl or propoxy-ethyl, selecting.

6, according to claim 1 to 5 each, prepare R in its structural formula ₅Represent C ₃-C ₉The alkyl of straight or branched; Perhaps representative can be by C ₁-C ₃The C that alkyl replaces ₅-C ₇The technology of the compound of cycloalkyl.

7, according to claim 1 to 6 each, prepare R in its structural formula ₅Represent sec.-propyl, the tertiary butyl, 2,6-dimethyl-4-heptyl, octyl group or cyclohexyl groups; Perhaps represent one by methyl substituted the technology of compound of cyclohexyl.

8, according to claim 1 to 7 each, prepare R in its structural formula ₁And R ₄Represent methylidene; R ₂And R ₃Any represent methylidene, ethyl, sec.-propyl, isobutyl-, propoxy-ethyl or methoxy ethyl group; And, R ₅Represent sec.-propyl, tertiary butyl, 2,6-dimethyl-4-heptyl, octyl group or cyclohexyl groups, perhaps represent one by methyl substituted the technology of compound of cyclohexyl.

9, according to claim 1 to 8 each, prepare R in its structural formula ₅Represent the technology of the compound of the tertiary butyl.

10, according to claim 1 to 9, preparation 4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3, the technology of 5-pyridine dicarboxylic acid diethyl ester.

11, according to claim 1 to 9, the technology of one of preparation following compounds:

4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid 3-methyl esters, 5-(2-methyl-propyl) ester;

4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid dimethyl ester;

4-(2-(3-(1,1-dimethyl oxyethyl group)-3-oxo-1-propenyl) phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid 3-methyl esters 5-ethyl ester;

12, according to claim 1 to 11, the technology of the trans-isomer(ide) of the compound of preparation structure formula I.