CH633266A5 - Process for preparing 1,4-dihydropyridine compounds - Google Patents

Description

The invention relates to processes for the preparation of new 1,4-dihydropyridine compounds which have a vasodilating and hypotensive effect and are therefore suitable for the therapeutic treatment of cardiovascular diseases and high blood pressure in humans.

The following 1,4-dihydropyridine compound is already known from US Pat. No. 3,485,847:

no cooch ch

3rd

ch

The aim of the present invention is to produce new, useful 1,4-dihydropyridine compounds by suitable processes so that the new compounds, preferably in the form of a vasodilator and antihypertensive agent, for the treatment of cardiovascular diseases such as coronary insufficiency, angina pectoris, myocardial infarction and hypertension, can be used therapeutically.

The new 1,4-dihydropyridine compounds obtainable according to the invention are represented by the following general formula:

It means R1 cyano or lower alkoxycarbonyl, R2 and R3 each esterified carboxy and R4 lower alkyl.

The compounds of formula (I) above, of course, also include one or more optical isomers that may occur as a result of the presence of one or more asymmetric carbon atoms in the molecule, and these isomers are also within the scope of the present invention.

The methods according to the invention are defined in claims 1 and 4.

The preparation of the starting products required for these processes is described below.

5

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65

Procedure 1

3rd

633266

/ ■ V-CH ^ C-CO-R5 \ = J U a

R *

R4-C = CH-R2

NH,

(II)

(III)

R

R

■ R

[i y

N-H

(1-1)

1 row

R [

a wherein R1, R2, R3 and R4 each have the meanings given above and R5a is methyl which carries a substituent selected from lower alkoxy, lower alkanoyloxy and lower alkylenedioxy.

Procedure 2

20th

Hydrolysis agent 2

3? R

R

wherein R1, R2, R3 and R4 each have the meanings given above and R5'a is methyl which carries a substituent selected from gem-di (lower) alkoxy, gem-di (lower) alkanoyloxy and gem-lower alkylenedioxy

Procedure 3

40

(1-2)

H

(1-2)

(1-3)

Procedure 4

1

55

R

R

R dehydrating agent ch = no

(1-3 ')

633266

wherein R1, R2, R3 and R4 each have the meanings given above.

The definitions used here are explained in more detail below and suitable examples are given.

The term "lower or lower" used here in connection with all alkane residues is understood to mean residues with 1 to 8, preferably 1 to 6, in particular 1 to 4 carbon atoms.

The "lower alkoxycarbonyl" radical which represents R1 can also be represented by the formula -C0-0- (lower) alkyl, in which the lower alkyl group comprises a monovalent radical of straight-chain (unbranched) and branched-chain lower alkanes. A suitable lower alkoxy-carbonyl group can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl and the like.

"Esterified carboxy", which represents R2 and R3, may include a substituted or unsubstituted alkoxycarbonyl group, e.g. those as stated in the explanation of the group representing R1, such as halogen (lower rig) alkoxycarbonyl (for example 2-bromoethoxycarbonyl, 2-chloroethoxycarbonyl, 2- (or 3) -chloropropoxycarbonyl, 2- (or 3rd ) - Bromopropoxycarbonyl, 2,2-dichloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and the like.); Hydroxy (low) alkoxycarbonyl (e.g. 2-hydroxyethoxycarbonyl, 2- (or 3) -hydroxy-propoxycarbonyl and the like), lower alkoxy (low) alkoxycarbonyl (e.g. 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl, 2- (or 3) methoxy (or ethoxy) propoxycarbonyl and the like); substituted or unsubstituted ar (lower) alk-oxycarbonyl (e.g. benzyloxycarbonyl, p-bromobenzyloxycarbonyl, o-methoxybenzyloxycarbonyl, phenethyloxycarbonyl and the like); Ar (low) alkoxy (low) alkoxycarbonyl (e.g. 2-benzyloxyethoxycarbonyl, 2- (or 3) -benzyloxypropoxy-carbonyl and the like); Aryloxy (lower) alkoxycarbonyl (e.g. 2-phenoxyethoxycarbonyl, 2- (or 3) -phenoxypropoxycarbonyl and the like); N- or N, N- (di) substituted amino (lower rig) alkoxycarbonyl, such as N- or N, N- (di) (lower) alkylamino-no (lower) alkoxycarbonyl [e.g. l- (or 2) - [N-methyl (or -N, N-dimethyl) amino] ethoxycarbonyl, 3- (or 2) - (N, N-dimethylaminopropoxycarbonyl), l- (or 2) - [N -Ethyl (or -N, N-diethyl) amino] ethoxycarbonyl or 1- (or 2) -N-methyl-N-ethylamino) ethoxycarbonyl and the like] or N-lower alkyl-N-ar (low) alkylamino (lower) alkoxycarbonyl (e.g. N-methyl-N-benzylaminoethoxycarbonyl and the like), substituted or unsubstituted aryloxycarbonyl (e.g. phenoxycarbonyl, tolyloxycarbonyl, xylyloxycarbonyl, p-chlorophenoxycarbonyl and the like) and the like, and in addition be on it noted that R2 and R3 may be the same or different.

The term "lower alkyl" can include a monovalent radical of straight-chain (unbranched) and branched-chain lower alkanes, and suitable lower alkyl groups can preferably be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, Hexyl, heptyl, octyl and the like, especially those of the Cj-C ^ alkyl groups and particularly preferably methyl.

The term "lower alkanoyl" can include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like, among which formyl is most preferred.

"Methyl which carries lower alkoxy" which stands for R5a,

may include mono-lower alkoxymethyl such as methoxymethyl, ethoxymethyl and the like, preferably di-lower alkoxymethyl such as gem-di (lower) alkoxymethyl such as di-methoxymethyl, diethoxymethyl, dipropoxymethyl and the like, including l, l-gem -Di (low) alkoxymethyl is particularly preferred.

“Methyl carrying lower alkylenedioxy” which stands for R5a can preferably comprise gem-Niederalkylenendioxy-

methyl, e.g. l, 3-dioxolan-2-yl, 4-methyl-l, 3-dioxolan-2-yl, 4,5-dimethyl-l, 3-dioxolan-2-yl and the like.

“Methyl which carries lower alkanoyloxy” which stands for R5a, where the lower alkanoyl radical has the same meaning

5 gene as indicated above may preferably include gem-di (lower) alkanoyloxymethyl such as diacetoxymethyl, dipropionyloxymethyl and the like.

The starting compounds to be used according to the invention include known and new compounds and they can be prepared as follows:

The starting compound (II) used in Process 1 can be prepared by reacting the 4-substituted acetoacetate (IIA) and an aldehyde (IIB) as shown in the following reaction scheme:

15

R ^ C0CH2-R3 + R ■ "* Ra" C0 | j "R3

CHO CH

Ò "r1

(iia) (iib) or

25 wherein R1, R3 and R5a each have the meanings given above.

The other starting compound (III) used in the method 1 can be prepared from an acetylene compound (IIIA) and ammonia or a salt thereof or

30 from a 4-substituted acetoacetate compound (IIIB) and ammonia or a salt thereof, as indicated in the following reaction scheme:

35 © R4-C'CH-R2 + NH3 + R4-C = CH-R2

Ah2

(iiia) (hd

40 wherein R2 and R4 each have the meanings given above;

© R4-C-CH7R2 + NH. R4-C = CH-R2

w Ii 2 3 j

45 0 nh2

(iiib) (iii)

wherein R2 and R4 each have the meanings given above

Have 50.

Processes for the preparation of 1,4-dihydropyridine compounds (I) are explained in more detail below.

Procedure 1

55 This process relates to the preparation of a compound (1-1) by reacting a compound (II) with an amino compound (III).

Each of the starting compounds (II) and (III) also includes the cis-trans isomers as a result of the double bond and

Both eis and trans isomers are equivalent to one another with regard to compounds (1-1) and therefore any isomer and any mixture of the isomers of these starting compounds (II) and (III) fall within the scope of this process.

65 The reaction can be carried out at ambient temperature or with heating or with heating. The reaction can also be carried out in the absence of a solvent, but it is usually carried out in one

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suitable solvents, such as benzene, toluene, xylene, chloroform, carbon tetrachloride, methylene chloride, ethylene chloride, methanol, propanol, butanol, water or in other conventional solvents. The reactions can usually be carried out in the presence of an agent such as e.g. an acid (such as acetic acid), a base (such as pyridine or picoline) or in a conventional buffer solution. These agents act as reaction accelerators and can be used as solvents if they are liquid. The reactions can also be accelerated by heating. The reaction conditions can vary depending on the type of reactants used.

Regarding the type of reaction of this method, it should be noted that the method can be carried out, for example, by reacting a mixture of the 4-sub-substituted acetoacetate (IIA), the aldehyde (1IB) and the amino compound (III) or alternatively by reacting the Ace -tylene compound (IIIA) first with ammonia or a salt thereof and then with compound (II).

The ammonia salt used in the above reaction may include an inorganic ammonium salt such as ammonium chloride or ammonium sulfate and an organic ammonium salt such as ammonium acetate.

Procedure 2

This method relates to the preparation of a compound (1-2) by hydrolysis of a compound (1-1 ').

The compound (1-1 ') can be prepared as explained in the above method 1. In this process, the gem-di (lower) alkoxy, gem-di (lower) alkanoyloxy and gem-lower alkylenedioxy groups for which R4, a or R5'a in compound (1-1 ') stand , converted into the oxo group by hydrolysis.

The hydrolysis can be carried out in a conventional manner, as is usually used for the saponification (cleavage) of the so-called acetal, ketal or acylal function in the corresponding carbonyl function. In particular, hydrolysis for a gem-di (lower) alkoxy and gem-lower alkylenedioxy group e.g. preferably using acidic hydrolysis, i.e. in the presence of an acid, e.g. an inorganic acid (such as hydrochloric acid, sulfuric acid and the like) or an organic acid (such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and the like), and hydrolysis for a gem-di (lower) alkanoyloxy group is preferred using the above acid hydrolysis or alternatively using basic hydrolysis, ie in the presence of a base, e.g. an inorganic base (such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like) or an organic base (such as sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, pyridine, picoline and the like).

The hydrolysis can be carried out in a suitable conventional solvent such as water, acetone, methyl ethyl ketone, di-oxane, ethanol, methanol, N, N-dimethylformamide, N-methylmorpholine or dimethyl sulfoxide, in any mixture thereof or in a buffer solution thereof . The reaction temperature is not subject to any restrictions and the reaction is usually carried out under cooling, at room temperature or at a slightly elevated temperature.

Procedure 3

This method relates to the preparation of a compound (1-3) by reacting the compound (1-2) with hydroxylamine or a salt thereof.

In this process, the formyl group of the starting compound (1-2) is converted into the hydroxyiminomethyl group. The compound (1-2) can be prepared by the method 2 described above.

5 The preferred hydroxylamine salt can be a salt with an acid, e.g. an inorganic acid (such as hydrochloric acid, sulfuric acid and the like) or an organic acid (such as acetic acid and the like).

The reaction is carried out in the usual way, e.g. io in the presence of a catalyst, e.g. an acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, p-toluenesulfonic acid, boron trifluoride, silicon tetrafluoride or titanium tetrachloride), in a basic state, which is generated by using free hydroxyl-15 amine, or in an acidic or basic conventional buffer solution , and usually it is carried out in a suitable conventional solvent such as water, di-oxane, ethanol, methanol or dimethylformamide or in any mixture thereof.

The reaction temperature is not subject to any restrictions and the reaction is usually carried out under cooling, at room temperature or at a slightly elevated temperature.

Procedure 4

This process relates to the preparation of a compound (1-4) by reacting the compound (1-3 ') with a dehydrating agent. The oxime compound (1-3 ') can be produced according to method 3 described above.

Suitable dehydrating agents include conventional organic or inorganic dehydrating agents such as e.g. an inorganic acid (such as sulfuric acid, phosphoric acid, polyphosphoric acid and the like), an organic acid (such as formic acid, acetic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like), an organic acid anhydride (such as acetic anhydride, benzoic anhydride, phthalic anhydride and the like) , an organic acid halide (such as acetyl chloride, benzoyl chloride, trichloroacetyl chloride, mesyl chloride, tosyl chloride, ethyl chloroformate, phenyl chloroformate and the like); an inorganic halogen compound (e.g. thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, tin (IV) chloride, titanium tetrachloride and the like); a carbodiimide (e.g. N, N'-dicyclohexylcarbodiimide, N-cyclo-hexyl-N'-morpholinoethylcarbodiimide and the like), N, N'-carbonyldiimidazole; Pentamethylene ketene-N-cyclohexylimine; Ethoxyacetylene; 2-ethyl-7-hydroxyisoxazoium salt; another phosphorus compound (e.g. phosphorus pentoxide, polyphosphoric acid ethyl ester, triethyl phosphate or phenyl phosphate) and the like, or a mixture thereof. If an acid is used as the dehydrating agent, the reaction can also be carried out in the presence of its salt, e.g. their alkali metal salt (such as sodium or potassium salt) or the like.

The reaction is usually carried out in a conventional solvent such as diethyl ether, dimethylformamide, pyridine, acetic acid, formic acid, benzene, carbon tetrachloride, chloroform, methylene chloride, tetrahydrofuran, di-oxane and the like, and is usually carried out at room temperature or below Heating performed and the reaction temperature is not restricted.

This dehydration process can also be carried out according to the condensation process described above without isolation of the oxime (1-3 '). This case also falls within the scope of the present invention.

The reaction product can be separated from the reaction mixture and isolated and, for example, by extraction with a suitable solvent, by chromatography,

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6

Precipitation, recrystallization and the like can be cleaned.

The compound (I) obtained often comprises at least one pair of optical isomers due to the presence of an asymmetric carbon atom in the 4-position of the 1,4-dihydropyridine nucleus, and can be in the form of any optical isomer or in the form of a racemic mixture . The racemic compound can be separated into its respective optical isomers by a conventional method for resolving a racemic mixture, for example, by chemically decomposing the salts of the diastereoisomer with a conventional optically active acid (such as tartaric acid or camphor sulfonic acid and the like).

Regarding the usability of the compound (I) prepared by the process described above, it should be noted that the compound (I) has a vasodilatory effect and that it is suitable for the therapeutic treatment of high blood pressure (hypertension) and cardiovascular diseases such as coronary insufficiency, angina pectoris or Myocardial infarction.

For therapeutic purposes, the 1,4-dihydropyridine compounds (I) can be administered orally in a daily dose of 0.1 to 500 mg, preferably 1 to 50 mg.

They are preferably administered in the form of a medicament which contains the 1,4-dihydropyridine compounds (I) as an active ingredient in an amount of 0.01 to 500 mg, preferably 0.1 to 250 mg, per dose unit for the oral route and contains parenteral use.

When determining the amount of the active ingredient in the dosage unit form, the activity of the active ingredient and the size of the patient must be taken into account. For the administration of this drug, the active ingredients can usually be in the form of a tablet, a granule, a powder, a capsule, a suppository, a suspension, a solution and the like. Pharmaceutical carriers or diluents that can be used include solid or liquid non-toxic, pharmaceutically acceptable substances. Examples of solid or liquid carriers or diluents are lactose, magnesium stearate, kaolin, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, acacia, peanut oil, olive oil or sesame oil, cocoa butter or other conventional materials. Similarly, the carrier or diluent can also be a time delay material such as e.g. a glyceryi monostearate, glyceryl distearate, a wax and the like.

A wide variety of pharmaceutical preparations can be used. If a solid carrier is used, the preparation can be tableted, embedded in a hard gelatin capsule or used in the form of a pill or lozenge.

In order to explain the usefulness of the compound (I), pharmaceutical tests were carried out on the following compounds. The test results obtained are also shown below.

The pharmacological activity of the 1,4-dihydropyridine compounds of formula (I) was determined by standard methods, i.e. by intravenous administration of the 1,4-di-hydropyridine compounds to dogs anesthetized with pentobarbital and recording of the coronary blood flow.

Compound A: Dimethyl-2,6-dimethyl-4- (2-nitrophenyl) -3,5-dicarboxylate

Compound B: Dimethyl-2-methyl-4- (2-cyanophenyl) -6-cyano-3,5-dicarboxylate.

TABLE

Coronary Blood Flow Increase (%)

The values given in% were compared with the

Control value [29.5 ± 5.5 ml / min.]

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15

Dose [ig / kg

tested connection

64

250

1000

A

169

118

dead

B

173

159

156

The compound A is known under the generic name “Nifedi-pine” and is already on the market as a coronary vasodilator.

The invention is illustrated by the following examples, in which the syntheses of some specific compounds are described, but is not limited thereto.

Production of the starting products

25th

example 1

1-i) 80.5 g of sodium metal was dissolved in 960 ml of methanol and then concentrated to produce 470 ml of a suspension of sodium methylate in methanol. To this suspension, 129 g of 2,2-dichloroacetic acid was added dropwise at such a rate that the solvent was refluxed with weak exothermic boiling, and the mixture was refluxed with stirring for 3.5 hours. After the resulting solution was cooled to below 10 ° C, a mixture of 200 ml of methanol and 100 g of anhydrous hydrogen chloride was added dropwise over a period of% h below 10 ° C, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was neutralized with cooling down to below 10 ° C. by treatment with a methanolic solution of sodium methylate, which had been prepared from 32 g of sodium metal and 400 ml of methanol, and the precipitates were washed with 150 ml of methanol. The filtrate and the washing water were combined and evaporated to dryness at 30 ° C. under reduced pressure. The residue was extracted by decanting with benzene (once with 200 ml and additionally twice with 100 ml portions). The benzene extracts were combined and evaporated to dryness under reduced pressure and the residue was fractionated by distillation under reduced pressure to give 89.5 g of an oily methyl 2,2-dimethoxy acetate, bp 68 to 69 ° C / 20 mmHg.

On the other hand, 18.28 g of sodium metal was dissolved in 300 ml of 55 methanol, and the methanol was removed by evaporation under reduced pressure. The residue was suspended in about 700 ml of anhydrous toluene and the suspension was concentrated to 200 ml under atmospheric pressure to give a methanol-free suspension of 200 ml of Na-60 trium methylate in toluene. To this suspension was added a mixture of 88.8 g of methyl 2,2-dimethoxyacetate prepared above and 58.8 g of methyl acetate at 50 to 60 ° C over a period of about 50 minutes, after which the mixture heated to reflux with stirring for 2.5 hours. After cooling, the reaction mixture was poured into a mixture of acetic acid and ice water, and then the acidic mixture was stirred for a while. The organic layer was collected using

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an aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue was distilled under reduced pressure to give 82.27 g of oily methyl 4,4-dimethoxyacetoacetate, bp 88-91 ° C / 5 mmHg.

1-ii) Yi a solution of 390 mg of piperidine in 5 ml of benzene was added in portions to a mixture of 5.0 g of 2-cyanobenzaldehyde, 7.39 g of methyl 4,4-dimethoxyacetoacetate and 0.458 g of acetic acid in 15 ml of benzene added over a period of 20 min each. The mixture was refluxed for 2 hours and the water formed was removed azeotropically during the course of the reaction. After cooling, the reaction mixture was shaken with a mixture of 50 ml of benzene and 30 ml of water, and the organic layer was separated and washed with a dilute aqueous sodium bicarbonate solution and water. The aqueous washings were extracted with 30 ml of benzene. The benzene extract was combined with the above organic layer, washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue (14.8 g) was chromatographed on a silica gel column (200 g) and eluted with a benzene / ethyl acetate (vol. Ratio 25: 1), whereby 6.90 g of oily methyl-2- (2 - cyanobenzylidene) -4,4-dimethoxyacetoacetate. The thin layer chromatogram and the NMR spectrum of this product showed that it was a mixture of two stereoisomers.

NMR spectrum: 5 ppm (CDC13):

3.4 (3H, s); 3.48 (3H, s); 3.78 and 3.90 (3H, each s); 4.82 and 5.09 (1H, each s); 7.43 to 7.8 (4H, m); 8.0 and 8.15 (1H, each s).

1-ii), another example

(1) A solution of 6.56 g of 2-cyanobenzaldehyde, 7.93 g of 4,4-dimethoxyacetoacetic acid, methyl ester, 0.18 g of acetic acid and 0.17 g of piperidine in 40 ml of benzene is stirred for 5 hours with azeotropic removal of the water heated to boiling at reflux. After cooling, the reaction mixture is diluted with benzene, then washed first with water and then with an aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent is removed under reduced pressure and the remaining oil (13.75 g) is chromatographed on a column of 420 g of silica gel with a mixture (20: 1 v / v) of benzene and ethyl acetate as the eluent. The fractions containing the desired compound are combined and the solvent is distilled off under reduced pressure, 10.11 g of methyl 2- (2-cyanobenzylidene) -4,4-di-methoxyacetoacetate (mixture of the ice and trans isomers) in Form of a yellowish oil can be obtained. NMR spectrum:

5 ppm (CDCI3): 3.41 (s)) 3.79 (s))

(6H), (3H),

3.49 (s) 3.92 (s)

4.83 (s)

5.11 (s) 8.07 (s)

8.16 (s)

(1H), 7.5 to 8.0 (4H, m),

(1H)

The following starting products are obtained in the same way:

(2) 2- (2-Methoxycarbonylbenzylidene) -4,4-dimethoxyacet-acetic acid methyl ester (mixture of the ice and trans isomers).

NMR spectrum:

6 ppm (CDC13): 3.26 (s)

3.43 (s)

(6H)

3.56 (s) 3.83 (s) 3.87 (s) 3.89 (s)

4.67 (s)

(6H)

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15

(1H)

5.13 (s) J

7.2 to 8.1 (4H, m), 8.39 (s) 8.46 (s)

(1H)

(3) 2-chloroethyl ester of 2- (2-cyanobenzylidene) -acetes-acetic acid (mixture of the ice and trans isomers). NMR spectrum:

6 ppm (CDCI3): 2.34 (s) j 20 i (3H)

2.50 (s))

3.6 to 3.9 (2H, m), 4.3 to 4.6 (2H, m), 7.25 to 7.9 (4H, m),

25th

8.00 (s) 7.88 (s)

(1H)

30 (4) 2-ethoxyethyl ester of 2- (2-cyanobenzylidene) -acetic acetic acid (mixture of the ice and trans isomers). NMR spectrum:

S ppm (CDCI3): 1.15 (t, J = 6.5 Hz))

(3H),

35 1.23 (t, J = 6.5 Hz) J

2.35 (s))

(3H)

2.48 (s)

40

45

3.58 (2H, q, J = 6.5 Hz), 3.7 to 3.8 (2H, m),

4.3 to 4.5 (2H, m), 7.30 to 8.05 (4H, m),

7.95 (s) 7.91 (s)

(1H)

50 (5) 2-phenoxyethyl ester of 2- (2-cyanobenzylidene) -acetic acetic acid (one of the ice and trans isomers), mp. 102.5 to 104 ° C.

(6) 2-Benzyloxyethyl ester of 2- (2-cyanobenzylidene) -acetic acetic acid (mixture of the ice and trans isomers). 55 NMR spectrum:

§ ppm (CDCI3): 2.29 (s) I

(3H),

2.43 (s)

60

65

3.50 to 3.85 (2H, m), 4.20 to 4.60 (2H, m),

4.55 (s)!

(2H)

4.44 (s) j 7.15 to 7.85 (9H, m), 7.96 (s)

7.83 (s)

(1H)

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1-iii) A mixture of 6.8 g of the methyl 2- (2-cyanobenzylidene) -4,4-dimethoxyacetoacetate obtained above and 2.98 g of methyl 3-aminocrotonate was stirred at about 60 ° C for 2 hours stirred with heating and then the temperature was gradually raised and held at 100 to 103 ° C for 10 hours. During the course of the reaction, 3 ml of n-propyl alcohol was added to the reaction mixture to dissolve the crystalline mass thereby obtained. The reaction mixture was dissolved in a mixture of 9 ml of isopropyl ether and 3 ml of methanol and allowed to stand for a while, whereby 6.39 g of pale brown fine crystals of dimethyl-2-methyl-4- (2-cyanophenyl) -6-dimethoxymethyl-1 , 4-dihydro-pyridine-3,5-dicarboxylate; an aliquot of it was recrystallized from a diisopropyl ether / methanol (volume ratio 1: 1) mixture to give the pure crystals, mp 133 to 134.5 ° C.

NMR spectrum: S ppm (CDC13):

3.4 (3H), s); 3.48 (3H, s), 3.78 and 3.9 (3H, s), 4.83 and 5.09 (1H, s), 7.43 to 7.8 (4H, m), 8, 0 and 8.5 (1H, s).

2-i) Yi of a solution of 306 mg was added in portions to a mixture of 4.92 g of methyl 2-formyl benzoate, 7.2 g of ethyl 4,4-diethoxyacetoacetate and 0.36 g of acetic acid in 15 ml of benzene Piperidine in 5 ml of benzene was added over a period of 20 minutes each and the mixture was heated under reflux for 3 hours, the water formed being removed azeotropically. After cooling, the reaction mixture was diluted with a further 25 ml of benzene, washed 3 times with water and successively with a dilute aqueous sodium bicarbonate solution, water and a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 12.7 g of a reddish oil of crude ethyl 2- (2-methoxycarbonylbenzylidene) -4,4-diethoxyacetoacetate, which was used in the following reaction without further purification.

2-ii) A mixture of 12.7 g of ethyl 2- (2-methoxycar-bonylbenzylidene) -4,4-diethoxyacetoacetate and 5.03 g of ethyl 3-aminocrotonate was stirred at about 60 to 70 for 1.5 hours ° C with stirring and then the temperature was gradually raised to hold it at 90 ° C for 3.5 hours and finally at 110 ° C for 4.5 hours. After cooling, the reaction mixture was dissolved in 50 ml of ethyl acetate, washed twice with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 12.8 g of a reddish-brown oily residue. The oil was treated with an isopropyl ether / n-hexane (vol. Ratio 1:10) mixture, whereby 3.5 g of a light brown crystalline powder of diethyl-2-methyl-4- (2-methoxycarbonylphenyl) - 6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarb-oxylate was obtained. An additional batch of 0.33 g was recovered from the mother liquor and another batch of 1.6 g was recovered from the total mother liquor by subjecting the remaining oil (8.0 g) to silica gel column chromatography (240 g) and with a benzene / ethyl acetate (volume ratio 15: 1 and 10: 1) mixture eluted (total yield 5.43 g). A 300 mg portion of the first batch was recrystallized from 3 ml of n-hexane to give 290 mg of pure crystals, mp 94 to 95 ° C.

NMR spectrum: 5 ppm (CDC13):

1.25 (6H, t, J = 7Hz), 1.15 (6H, t, J = 7Hz), 2.33 (3H, s), 3.92 (3H, s), 3.42 to 4, 23 (8H, m), 6.04 (1H, s), 6.11 (1H, s), 6.6 (1H, broad s), 7.0 to 7.8 (4H, m).

Example 2

(1) To a solution of 6.0 g of dimethyl-2-methyl-4- (2-cyanophenyl) -6-dimethoxymethyl-1,4-dihydropyridine-3,5-di-carboxylate in 60 ml of acetone was added 6 ml 6N hydrochloric acid was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 30 ml of water and adjusted to pH 7.5 with an aqueous sodium bicarbonate solution, and the Ace-5 ton was distilled off under reduced pressure. The crystalline mass obtained was comminuted as finely as possible with a glass rod, washed with a further 100 ml of water, collected by filtration, further washed thoroughly with water and dried in air, 5.19 g of a crystalline powder of dimethyl 2-methyl-4- (2-cyanophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate.

NMR spectrum: 5 ppm (CDC13):

2.41 (3H, s), 3.65 (3H, s), 3.75 (3H, s), 5.5 (1H, s), 7.0 15 (1H, s), 7.25 to 7.66 (4H, m), 10.53 (1H, s).

(2) To a solution of 5.03 g of diethyl 2-methyl-4- (2-methoxycarbonylphenyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate in 50 ml of acetone was added 5 ml 6N chloro-20 hydrochloric acid was added and the mixture was stirred at room temperature for 2 hours. After the addition of 30 ml of water, the reaction mixture was neutralized with an aqueous sodium bicarbonate solution and the acetone was distilled off under reduced pressure. The resulting 25 oily precipitates were extracted with ethyl acetate. The ethyl acetate extracts were washed with water and with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure, giving 4.26 g of a reddish oil 30 from crude diethyl-2-methyl-4- (2-methoxycarbonylphenyl) - -6-formyl-l, 4-dihydropyridine-3,5-dicarboxylate, which was used in the subsequent reaction without further purification.

NMR spectrum: 5 ppm (CDC13):

35 1.1 (3H, t, J = 7Hz), 1.8 (3H, t, J = 7Hz), 2.37 (3H, s),

3.93 (3H, s), 3.9 to 4.28 (4H, m), 6.2 (1H, s), 6.98 (1H, s), 7.1 to 7.8 (4H, m), 10.2 (1H, s).

Example 3

40 isopropyl-2-methyl-4- (2-methoxycarbonylphenyl) -5-meth-oxycarbonyl-6-ethylenedioxymethyl-1,4-dihydropyridine-3-carboxylate was prepared by the reaction of methyl 2- (2-methoxycarbonylbenzylidene) -4,4-ethylenedioxyacetoacetate with isopropyl-3-aminocrotonate in practically the same manner as described in Example 1 (2-ii). F. 129 to 129.5 ° C.

Example 4

(1) A mixture of 10.1 g of (2-cyanobenzylidene) -4,4-di-methoxyacetoacetic acid methyl ester and 5.51 g of 3-aminocroton-50 acid isopropyl ester is heated to 78 ° C for 40 minutes and 120 ° for 5% hours C heated with stirring, whereupon heating was continued for 1 hour at 125 ° C without stirring. The reaction mixture is left to stand overnight and then dissolved in ethyl acetate. The solution is washed once with water, dried and evaporated to dryness under reduced pressure: a residue remains which is recrystallized from ethyl ether. The crystals are collected by filtration and washed with a small amount of ethyl ether; 8.96 g of iso-60 propyl ester of 4- (2-cyanophenyl) -5-methoxycarbonyl-6-di-methoxymethyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid are obtained in the form of a crude powder. A further 0.77 g of crude product are recovered from the filtrate. 0.5 g of crude product is recrystallized from isopropyl ether, giving 0.37 g of pure 65 t white powder; the compound melts at 171 to 172.5 ° C.

Following the same procedure, the following connection is also obtained:

9

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(2) Isopropyl ester of 5-methoxycarbonyl-4- (2-methoxy-carbonylphenyl) -6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

NMR spectrum: 5 ppm (CDC13):

0.95 (3H, d, J = 7Hz), 1.19 (3H, d, J = 7Hz), 2.37 (3H, s), 3.40 (3H, s), 3.46 (3H, s), 3.61 (3H, s), 3.97 (3H, s), 4.97 (1H, Heptet, J = 7Hz), 5.93 (1H, s), 6.05 (1H, s ), 6.59 (1H, broad singlet), 7.0 to 7.9 (4H, m).

Example 5

(1) A mixture of 4.72 g of the 2-chloroethyl ester of 2- (2-cyanobenzylidene) -acetoacetic acid and 4.06 g of 3-amino-4,4-diethoxycrotonic acid ethyl ester is brought to 100-105 ° C. over 3 hours Stir heated. After cooling, the reaction mixture is dissolved in ethyl acetate and the solution is washed twice with an aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent is removed under reduced pressure and the remaining oil is chromatographed on silica gel with a mixture (5: 1, v / v) of benzene and ethyl acetate; 5.81 g of 2-chloroethyl ester of 4- (2-cyano-phenyl) -5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid are obtained.

NMR spectrum: 5 ppm (CDC13):

1.1 to 1.4 (9H, m), 2.37 (3H, s), 3.4 to 3.95 (6H, m),

4.0 to 4.4 (4H, m), 5.39 (1H, s), 6.24 (1H, s), 6.90 (1H, broad singlet), 7.1 to 7.6 (4H, m ).

The following connections are obtained in the same way:

(2) 2- (N-Benzyl-N-methylamino) ethyl ester of 4- (2-cyano-phenyl) -5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

NMR spectrum: 5 ppm (CDC13):

1.1 to 1.5 (9H, m), 2.21 (3H, s), 2.40 (3H, s), 2.72 (2H, t, J = 6Hz), 3.53 (2H, s) , 3.5 to 4.5 (8H, m), 5.44 (1H, s), 6.30 (1H, s), 6.87 (1H, broad singlet), 7.2 to 7.8 ( 9H, m).

(3) 2-ethoxyethyl ester of 4- (2-cyanophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

NMR spectrum: 8 ppm (CDC13):

1.0 to 1.5 (12H, m), 2.42 (3H, s), 3.3 to 4.4 (12H, m), 5.45 (1H, s), 6.30 (1H, s), 6.87 (1H, s), 7.1 to 7.7 (4H, m).

(4) 2-phenoxyethyl ester of 4- (2-cyanophenyl) -5-ethoxy-carbonyl-6-diethoxymethyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, mp. 94 to 95 ° C.

(5) 2-Benzyloxyethyl ester of 4- (2-cyanophenyl) -5-ether-oxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine - 3-carboxylic acid, mp. 97.5 to 98.5 ° C.

Example 6

(1) A solution of 9.32 g of isopropyl ester of 4- (2-cyano-phenyl) -5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid in 11 ml of 6-normal Hydrochloric acid and 95 ml acetone is stirred for 5 hours at room temperature. The reaction mixture is neutralized with sodium hydrogen carbonate and then the acetone is removed by distillation. The remaining solution is mixed with water and ethyl acetate, the ethyl acetate layer is separated off, washed with water and an aqueous sodium chloride solution and finally dried over magnesium sulfate. The ethyl acetate is distilled off under reduced pressure and the remaining solid is washed with a mixture of ethyl ether and hexane; you get

7.45 g of isopropyl ester of 4- (2-cyanophenyl) -6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid in the form of a crude yellow-orange powder. By recrystallizing 0.5 g of this powder from isopropyl ether, 0.34 g of pure product with a melting point of 132 ° to 134 ° C. is obtained in the form of a yellow-orange powder.

The following connections are obtained in the same way:

(2) Isopropyl ester of 6-formyl-5-methoxycarbonyl-4- (2-methoxycarbonylphenyl) -2-methyl-1,4-dihydropyridine-3-carbonic acid.

NMR spectrum:

S ppm (CDCl3): 0.94 (d, J = 6.5 Hz) \

(6H),

1.19 (d, J = 6.5 Hz) J 2.41 (3H, s), 3.70 (3H, s), 3.97 (3H, s), 4.96 (1H, Heptet, J = 6.5 Hz), 6.21 (1H, s), 6.82 (1H, broad singlet), 7.0 to 7.9 (4H, m), 10.23 (1H, s).

(3) 2- (N-Benzyl-N-methylamino) ethyl ester of 4- (2-cyano-phenyl) -5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydro-pyridine-3-carboxylic acid.

NMR spectrum: 6 ppm (CDC13):

1.29 (3H, t, J = 7.5 Hz), 2.21 (3H, s), 2.44 (3H, s), 2.71 (2H, t, J = 6 Hz), 3, 51 (2H, s), 4.1 to 4.4 (4H, m), 5.51 (1H, s), 7.04 (1H, broad singlet), 7.2 to 7.75 (9H, m ), 10.57 (1H, s).

(4) 2-ethoxyethyl ester of 4- (2-cyanophenyl) -5-ethoxy-carbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp. 115 to 116 ° C.

(5) 2-phenoxyethyl ester of 4- (2-cyanophenyl) -5-ethoxycarbonyl-6-formyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, mp. 104 to 105 ° C.

(6) 2-Benzyloxyethyl ester of 4- (2-cyanophenyl) -5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

NMR spectrum: 5 ppm (CDC13):

1.28 (3H, t, J = 7 Hz), 2.41 (3H, s), 3.5 to 3.8 (2H, m), 4.0 to 4.5 (4H, m), 4 , 48 (2H, s), 5.48 (1H, s), 6.9 to 7.5 (10H, m), 10.51 (lHs).

Procedural examples

Example I

(1) A mixture of 2.4 g of dimethyl-2-methyl-4- (2-cyanophenyl) -6-formyl-l, 4-dihydropyridine-3,5-dicarboxylate, 539.3 mg of hydroxylamine hydrochloride and 752.3 mg of sodium acetate in 15 ml of acetic acid was stirred at room temperature for 55 minutes to form dimethyl 2-methyl-4- (2-cyanophenyl) 6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate. 2.375 g of acetic anhydride was added to the reaction mixture, and the mixture was heated at 110 ° C. for 4 hours with stirring. The reaction mixture was concentrated and treated with 30 ml of water. The acidic solution obtained was adjusted to pH 7.5 to 8 with an aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layer was washed with water and with a saturated aqueous sodium chloride solution and evaporated to dryness under reduced pressure. The residue obtained was kept in a refrigerator overnight to cause crystallization. The crystals thus obtained were collected by filtration and washed with a small portion of cold methanol, whereby 1.71 g of crystals of dimethyl-2-methyl-4 - (2-cyanophenyl) -6-cyano-l, 4-dihydropyridine- 3,5-dicarboxylate

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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10th

received. Another batch (0.9 g) was obtained from the mother liquor. The combined crystals (2.61 g) were recrystallized from methanol to give 1.2 g of pure crystals (mp 166 to 166.5 ° C).

NMR spectrum: S ppm (CDC13):

2.4 (3H, s), 3.67 (3H, s), 3.75 (3H, s), 5.42 (1H, s), 7.2 to 7.62 (4H, m), 7 , 9 (1H, s).

(2) A mixture of 2.6 g of diethyl 2-methyl-4- (2-meth-oxycarbonylphenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxoxide, 495 mg of hydroxylamine hydrochloride and 691 mg Sodium acetate in 20 ml of acetic acid was stirred at room temperature for 1 hour to form diethyl 2-methyl-4- (4-methoxycarbonylphenyl) -6-hydroxyiminomethyl-1,4-dihy dropyridine - 3,5-dicarboxylate has been. 2.18 g of acetic anhydride was added to the reaction mixture, and the mixture was heated to 110 ° C with stirring for 3.5 hours. The acetic acid was distilled off from the reaction mixture under reduced pressure, and the residue thereby obtained was adjusted to pH 8 with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate extracts were washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness. The resulting oil (2.88 g) was chromatographed on a silica gel column (72 g) and eluted with a benzene / ethyl acetate (v / v ratio 10: 1) to give 1.6 g of an oil containing 3 ml of isoprppyl ether was triturated to form 1.3 g of crystalline powder. After recrystallization from 20 ml of a diisopropyl ether / ethanol (vol. Ratio 15: 1 J mixture, 1.03 g of pure crystals of diethyl-2-methyl-4- (2-methoxycarbonylphenyl) -6- cyano - 1,4-dihydropyridine-3,5-dicarboxylate, m.p. 126 to 127 ° C. NMR spectrum: 5 ppm (CDC13):

1.15 (3H, t, J = 7Hz), 1.24 (3H, t, J = 7Hz), 2.33 (3H, s), 3.98 (3H, s), 3.90 to 4, 38 (4H, q, J = 7Hz), 6.22 (1H, s), 7.2 to 7.88 (4H, m).

Example II

(1) A solution of 3.90 g of isopropyl ester of 4- (2-cyano-phenyl) -6-formyl-5-methoxycarbonyl-2-methyl-l, 4-dihydro-pyridine-3-carboxylic acid in 20 ml of acetic acid 0.88 g of hydroxylamine hydrochloride and 1.30 g of sodium acetate are added and the mixture is stirred at room temperature for 1 hour. 3.97 g of acetic anhydride are added to the reaction mixture with stirring and the stirring is continued during

Continue for 1 hour at room temperature and for a further 4 hours at 95 to 100 ° C. The reaction mixture is left to cool to room temperature and the acetic acid is then evaporated under reduced pressure. The residue is diluted with water, neutralized with an aqueous sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic phases are combined, washed twice with water and then dried and the solvent is distilled off under reduced pressure; an oil is obtained which is left to stand overnight and then triturated with a small amount of ethyl ether to give a powder. The powder is washed with isopropyl ether and recrystallized from methanol; 1.99 g of isopropyl ester of 6-cyano-4- (2-cyanophenyl) -5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carbon acid of mp 198 to 200 ° C. are obtained in the form of yellowish-orange crystals.

The following connections are obtained in the same way:

(2) isopropyl ester of 6-cyano-5-methoxycarbonyl-4- (2-

-methoxycarbonylphenyl) -2-methyl-l, 4-dihydropyridine-carboxylic acid, mp. 121.5 to 123 ° C.

(3) 2- (N-benzyl-N-methylamino) ethyl ester of 6-cyano - 4- (2-cyanophenyl) -5-ethoxycarbonyl-2-methyl-1,4-dihydro-

5 pyridine-3-carboxylic acid hydrochloride, mp. 230 ° C (dec.).

(4) 2-ethoxyethyl ester of 6-cyano-4- (2-cyanophenyI) -5 - ethoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carboxylic acid, mp. 135 to 136 ° C.

(5) 2-phenoxyethyl ester of 6-cyano-4- (2-cyanophenyl) -io -5-ethoxycarbonyl-2-methyl-l, 4-dihydropyridine-3-carbon-

acid, mp. 170.5 to 172 ° C.

(6) 2-Benzyloxyethyl ester of 6-cyano-4- (2-cyanophenyl) -5-ethoxycarbonyl-2-methyl-l, 4-dihydropyridin-3-carboxylic acid, mp. 132 to 133 ° C.

15

Example III

A mixture of 4.29 g of 6-formyl-2-methyl-4- (2-cyano-phenyl) -5-methoxycarbonyl-l, 4-dihydropyridine-3-carbon-20 acid-n-propyl ester, 0.87 g Hydroxylamine hydrochloride, 1.13 g sodium acetate and 26 ml acetic acid is stirred for 5 hours at room temperature. 5 g of acetic anhydride are added to the mixture, followed by stirring for 80 minutes at room temperature, then for 2 ^ 25 hours at 85 ° C. and finally for a further 9% hours at 93 ° C. After cooling, the solvent is reduced under reduced pressure Pressure is removed from the reaction mixture * and the residue is mixed with an aqueous sodium bicarbonate solution and with methylene chloride The organic phase is separated off, washed with water, dried and evaporated to dryness, leaving 3.42 g of residue, which is 100 g Chromatograph silica gel eluting with methylene chloride, combining the desired fractions and evaporating, and the residue which remains is recrystallized twice from a mixture of methanol and water and then from methylene chloride to give 2.29 g of pure crystals of 6-cyano-2 - methyl-4- (2-cyanophenyl) -5-methoxycarbonyl-l, 4-dihydropyridine-3-carboxylic acid n-propyl ester of mp 150.0 to 40 151, 5 ° C.

NMR spectrum: 5 ppm (CDC13):

0.77 (3H, triplet, H = 7Hz), 1.59 (2H, Sixtett, J = 7Hz),

2.37 (3H, singlet), 3.74 (3H, singlet), 3.98 (2H, triplet, J = 7Hz), 5.38 (1H, singlet), 6.85 (1H, multiplet), 45 7.0-7.7 (4H, multiplet).

Example IV

1.81 g of 6-cyano-2-methyl-4- (2-cyanophenyl) -5-methoxy-carbonyl-l, 4-dihydropyridine-3-carboxylic acid isobutyl ester are reacted with 3.39 g of 6-formyl Isobutyl 2-methyl-4- (2-cyano-phenyl) -5-methoxycarbonyl-1,4-dihydropyridine-3-carbonate with 0.89 g hydroxylamine hydrochloride, 55 1.12 g sodium acetate, 25 ml acetic acid and 6.24 g of acetic anhydride obtained by the procedure similar to that of Example III; M.p. 196.0 to 197.5 ° C.

NMR spectrum: § ppm (CDC13):

0.75 (3H, doublet, J = 7Hz), 0.81 (3H, doublet, J = 7Hz), 60 1.97 (1H, multiplet), 2.40 (3H, singlet), 3.78 (3H , Singlet), 3.85 (2H, doublet, J = 7Hz), 5.41 (1H, singlet), 7.02 (1H, multiplet), 7.19-7.68 (4H, multiplet).

65 Example V

1.69 g of 6-cyano-2-methyl-4- (2-cyanophenyl) -5-methoxycarbonyl-l, 4-dihydropyridine-3-carboxylic acid neopentyl ester are reacted with 3.78 g of 6-formyl-2 -methyl-4- (2-

-cyanophenyl) -5-methoxycarbonyl-l, 4-dihydropyridine-3-carbonic acid neopentyl ester with 0.97 g of hydroxylamine hydrochloride, 1.19 sodium acetate, 25 ml of acetic acid and 6.4 g of acetic anhydride in that of Example III more similar Get working style; Mp 173.0 to 174.0 ° C. j

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NMR spectrum: S ppm (CDC13):

0.87 (9H, singlet), 2.41 (3H. Singlet), 3.79 (3H, singlet), 3.84 (2H, singlet), 5.44 (1H, singlet), 6.85 (1H , Multiplet), 7.2-7.8 (4H, multiplet).

Claims (6)

633266 2nd R 2. The method according to claim 1, characterized in that in formula I the lower alkoxycarbonyl R1 and / or the esterified carboxy R2 and R3 is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or t-butoxycarbonyl. 2nd PATENT CLAIMS 1. Process for the preparation of 1,4-dihydropyridine compounds of the formula: R wherein R1 is cyano or lower alkoxycarbonyl, R2 and R3 are each esterified carboxy and R4 is lower alkyl, characterized in that a compound of the formula: R h = no R wherein R1, R2, R3 and R4 each have the meanings given above, treated with a water-releasing agent. 3. The method according to claim 1, characterized in that the dimethyl-2-methyl-4- (2-cyanophenyl) -6-cyano-l, 4 - dihydropyridine-3,5-dicarboxylate is prepared. 4th R ch = no H implemented and treated the latter with a water-releasing agent. 4. A process for the preparation of 1,4-dihydropyridine compounds of the formula I defined in claim 1, characterized in that a compound of the formula: cho wherein R1, R2, R3 and R4 have the meanings given in claim 1, with hydroxylamine or a salt thereof to give a compound of the formula: 5. The method according to claim 4, characterized in that in formula I the lower alkoxycarbonyl R1 and / or the esterified carboxy Rz and R3 is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or t-butoxycarbonyl. 6. The method according to claim 4, characterized in that the dimethyl-2-methyl-4- (2-cyanophenyI) -6-cyano = 1,4 - dihydropyridine-3,5-dicarboxylate is prepared.