CS249525B2 - Method of dihydropyridines production - Google Patents

Description

The present invention provides a process for the preparation of certain dihydropyridines, particularly certain 1,4-dihydropyridines bearing a heterocyclic residue in the side chain attached at the 2-position, which compounds are useful as anti-ischemic and anti-hypertensive agents.

The compounds of the invention inhibit the movement of calcium into cells and are thus capable of delaying or preventing cardiac contracts. Indeed, this contracture is believed to be caused by the accumulation of calcium inside cells under ischemic conditions. Excess calcium during ischemia can have a number of other deleterious effects that could further adversely affect the ischemic myocardium. These effects include the less efficient use of oxygen for ATP production, activation of mitochondrial fatty acid oxidation, and possibly promoting cellular necrosis.

Thus, the compounds of the invention are useful in the treatment or prevention of various cardiac conditions, such as angina, cardiac arrhythmias, heart attacks and cardiac hypertrophy. The disclosed compounds also exhibit vasodilatory activity as they can inhibit calcium entry into vascular tissue cells and are therefore useful

as antihypertensive agents and for the treatment of coronary artery spasm.

Accordingly, the invention provides a process for the preparation of the novel dihydropyridines of formula (I)

H a _n y S ^'R CQOFr ^0C? Y 3

N 1 C 3 H 2 O- (CH 3) 2 ^NHR (i) in which

R represents a phenyl group optionally substituted by one or two substituents independently selected from the group consisting of chlorine atoms and trifluoromethyl groups,

R @ ¹ and R @ ² are each independently C1 -C4 alkyl and

R ³ represents the radical CH 2

rze

Lo

NH _Z jr

NH, and pharmaceutically acceptable acid addition salts thereof.

Pharmaceutically acceptable acid addition salts of the compounds of formula (I) are those with non-toxic acid addition salt forms, such as:

hydrochlorides, hydrophoromides, sulfates or hydrogen sulfates, phosphates or hydrogen phosphates, acetates, citrates, fumarates, gluconates, lactates, maleates, succinates and tartrates.

Alkyl groups having three or four carbon atoms can be straight or branched.

In particular, the symbol R represents:

2-chlorophenyl,

2,3-dichlorophenyl or

2-chloro-3-trifluoromethyl, and most preferably

2,3-dichlorophenyl.

Preferably either R ¹ is methyl and R ^{2 is} ethyl, or R ¹ is ethyl and R ^{2 is} methyl. Most preferably R ¹ represents a methyl group and R ² ethyl.

In a preferred individual compound, R is 2,3-dichlorophenyl, R ¹ is methyl, R ² is ethyl, and R ³ is of formula

The compounds of formula I containing one or more centers of asymmetry exist in the form of one or more pairs of enantiomers and these pairs or individual isomers may be separated by physical methods, for example, traction crystallization of free bases or suitable salts, or free base chromatography. The invention includes both separated pairs and mixtures thereof, as racemic mixtures or as separated optically active isomeric forms.

In accordance with the invention, the compounds of the invention are prepared according to the following reaction scheme:

bl nzetfxyZ hyd.teL2Ltl

Jooc ČX

H h ₃ c

XOOR ²

N ~ CN

CH _Z O ~ (CH ~ _Z ^ NC y typhi / £ 7 OH (III)? CH ₂ O (CBT _{2) 2} ^N-CH 3 BL AA ^NH 2

In the formulas shown in this scheme, X is methylthio, methoxy or phenoxy.

The above-described reaction is usually carried out in a suitable organic solvent, such as methanol, ethanol, acetonitrile or tetrahydrofuran, if necessary with heating at up to 130 ³ C, preferably under heating to reflux. Heating of the reaction mixture is preferred when ethanol is used as the solvent. The reaction is generally complete in about 4 hours. The desired product can then be isolated and purified by conventional means.

The starting materials of the formula III can be prepared from the compounds of the formula II (see European Patent Application Publication No. 0 089167) as follows:

N.CN

II N.CN χ_0_χ || ~ CH2O (CH2) 2 NH2 -----> CH2O- (CH2) 2-N-C-X

H isopropanol or methanol, room temperature, hours (II)

Acid addition salts of compounds of formula I may be prepared in a conventional manner, for example by reacting a solution of the free base in a suitable organic solvent and a solution of the desired acid in a suitable solvent and isolating the resulting salt either by filtration if precipitated from the solution or by evaporating the solution to dryness. .

The ability of the compounds of the invention to inhibit calcium entry into cells demonstrates their effectiveness in suppressing the response of isolated cardiac tissue to an increase in calcium ion concentration in vitro. This test is performed by fastening the spiral-cut strips of the rat aorta at one end and attaching it to the power transducer at the other end. The tissue is placed in a bath consisting of a physiological saline solution containing 45 mmol of potassium ions and 45 mmol of potassium ions and no calcium. Calcium chloride was then added to the bath by pipette until a final calcium ion concentration of 2 mmol. The change in tension caused by tissue contraction is recorded. Remove the bath, replace it with fresh saline, and repeat the test after 45 minutes with the test compound present in the lower solution. The concentration of this test compound needed to suppress responses by 50 percent (IC 50) is determined.

The results obtained with the individual compounds of the invention in this assay are summarized in the following table, where they are reported in IC 50 values. A 1M value means 1 grammol / liter. The lower the concentration, the more effective the compound is.

test substance IC50

the product of Example IB 2.00 X 10 “ ⁸ M the product of Example 2 2.29 X 10 ~ ⁹ M the product of Example 3B 6.02 X 10 ~ ⁹ M the product of Example 4 8.12 X 10 ~ ⁹ M the product of Example 5 3.02 X 10 ^-9 M

The antihyipertensive activity of the compounds of the invention can also be evaluated after oral administration by measuring the decrease in blood pressure of spontaneously hypertensive rats or renally hypertensive dogs.

For administration in human medicine for the curative or prophylactic treatment of cardiac disorders and hypertension, doses of the compounds of the invention when administered orally to an average adult patient (70 kg) will range from 5 to 100 mg per day, usually from 10 to 60 mg per day. Thus, an individual tablet or capsule to be administered to a typical adult patient may generally contain from 5 to 10 or 20 milligrams of active ingredient in combination with a suitable pharmaceutically acceptable carrier.

In the case of intravenous administration, the dosage for a single dose will usually be from 1 to 10 mg as needed. In practice, the appropriate dose, which will be most appropriate for each patient and will vary depending on the age, weight and response of the patient to the drug administered, will be determined by the attending physician.

The above dosage is only an example of an average case and, of course, there may be individual cases where higher or lower doses are required. All such cases are within the scope of the invention.

In human medicine, the compounds of formula (I) may be administered per se, but are generally administered in admixture with a pharmaceutical carrier selected taking into account the intended route of administration and standard pharmaceutical practice. For example, the compounds may be administered orally in the form of tablets containing, for example, starch or lactose as carriers, or in the form of capsules or ovules in which the disclosed compounds are contained either alone or in admixture with carriers and / or excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.

The active compounds according to the invention can also be administered by ipalareral injections, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, the disclosed compounds are most preferably used in the form of a sterile aqueous solution which may contain other substances, for example, glucose salts and isotonic treatment.

The invention is illustrated by the following non-limiting examples.

Example 1 (A) N- {2 - [(4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl) methoxy] ethyl} -N'-cyano -S-methyl-isothiourea

A mixture of 4.3 g of 2- (2-aminoethoxymethyl) -3-ethoxycarbonyl-4- (2-chlorophenyl) -5-methoxycarbonyl-6-methyl-1,4-dihydropyridine and 2 g of dimethyl N-cyanimidodithiocarbonate in 15 ml of isopropanol is allowed to stand at room temperature for 4 hours, then 30 ml of ether are added and the resulting mixture is allowed to stand overnight at room temperature. The crystalline precipitate was filtered off and dried after washing with ether.

5.0 g of the title compound of melting point 177-179 ° C is obtained.

For G23H27ClN4O5S, calculated:

C 54.5%, H 5.4%, N 11.05%; found:

% C, 54.35;% H, 5.4%; N. 11.2%.

(B) 2- [2- (3-amino-1H-1,2,4-triazol-5-ylamino) ethoxymethyl] -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl 1,4-dihydropyridine

AND

0.4 g of N- {2 - [(4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl) methoxy] ethyl [-N'-cyano -S-methylisothiourea and 0.15 ml of hydrazine hydrate were dissolved in 20 ml of ethanol and refluxed for 3 hours. The solvent was evaporated, toluene (10 ml) was added and the solution was evaporated again to dryness. The residue was subjected to silica gel column chromatography using 2% methanol in methylene chloride as eluent. A beige-colored solid is obtained which, after recrystallization from ethyl acetate with a trace amount of ether, yields, in a yield of 0.1 g, the title compound, melting at 137-138 ° C.

Analysis: for C22H27CIN6O5 found:

% C, 53.45;% H, 5.5%; N. 17.2%.

The procedure described in Part (A) was repeated using dimethyl N-cyanimidocarbonate instead of dimethyl N-cyanimidodithiocarbonate, otherwise the reaction was carried out under the same reaction conditions. hydrazine hydrate is converted to the title compound (B).

Example 2

2- [2- (3-amino-1H-1,2,4-triazol-5-ylamino) ethoxymethyl] -4- (2-chloro-3-trifluoromethylphenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6 -methyl-1,4-dihydropyridine calculated:

C 53.8%, H 5.55, N 17.1%;

1) (MeS) ₂ C = N · CN / 1 PA

--_—->

2) N 2 / EtOH

NH ₂

nh ₂

A mixture of 0.5 g of 2- (2-aminoethoxymethyl) -4- (2-chloro-3-trifluoromethylphenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine and 0.16 g of dimethyl N The cyanimidodithiocarbonate in 5 ml of isopropanol is stirred at room temperature for 4 hours, then 10 ml of ether is added and the resulting mixture is stirred for a further 2 hours.The precipitated isothiourea is filtered off, washed with dry ether and dried directly without further purification.

The above solid product was dissolved in ethanol (vmL) and 0.2 mL of hydrazine hydrate was added in 3 portions while heating to reflux. After refluxing for 3 hours, the reaction solution was evaporated to dryness and the residue was recrystallized from ethyl acetate. 144-145 ° C.

For C23H26ClF3N6O5 calculated:

C, 49.6; H, 4.7; N, 15.0; found:

C 49.4%, H 4.7%, N. 15.0%

EXAMPLE 3 (A) In a manner analogous to Example 1 (A), the following compound was obtained using the corresponding 4- (2,3-dichlorophenyl) -1,4-dihydropyridyl derivative, melting at 215-217 ° C.

Calcd for C23H26Cl2N4O5S:

% C, 51.02;% H, 4.85;

τι πΙρι / ΑΠΠ '

H, 5.05; N, 10.1%.

(The above compound was reacted with hydrazine hydrate using the procedure described in Example 1 (B) to give the following product, m.p. 195-196 ° C.

Analysis: for C22H26Cl2N6O5. See C 4 H 8 O 2 Example 4 calculated: In a similar manner as in the example

% C, 50.45;% H, 5.15;% N, 15.35; 1 (B), but using methylhydrazine, the following compound was prepared with a melting point of 110-111 ° C.

H, 5.35; N, 15.6.

.1 / 2 H ₂ O

Analysis for C 23 H 29 ClN 6 O 5. V2 H2O

Example 5 calculated:

C 53.7%, H 5.9%, N 16.36%;

found:

H, 5.8%; N, 16.3%.

Analogous to Example 3 (B) but using methylhydrazine, the following compound was prepared, m.p. 118-120.5 ° C.

- 1/2 H ₂ 0

Analysis: for C23H28Cl2N6O5. V2 H2O

Example 6 calculated:

H, 5.3%; N, 15.3%; found:

H, 5.3%; N, 15.0%.

Following the procedure of Example 1, the following product was prepared from the appropriate starting materials:

Nhh

The free base hemihydrate product melts at 173-175 ° C.

Analysis:

calculated:

C, 49.4; H, 5.1; N, 15.7; found:

H, 5.05; N, 15.5.

The following preparations illustrate the preparation of some starting materials.

Preparation 1

Preparation of 2 - [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrldine maleate

Suspension 103 g of 2- (2-azidoethoxymethyl) -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine in

2.5 liters of ethanol were stirred at room temperature in a hydrogen atmosphere at 50 psi for 16 hours in the presence of 40 g of 5% palladium on calcium carbonate. The reaction mixture was filtered, evaporated and a solution of 22 g of maleic acid in 100 ml of ethanol was added to the residue. The reaction mixture was stirred at room temperature for 2 hours, the resulting solid product was collected and dried after washing with ethanol. 100 g of the title compound of melting point 169-170.5 ° C are obtained. Calcd for C24H29ClN2O9:

% C, 54.91;% H, 5.57;% N, 5.34;

pi q found 54.82% c, 5.62% H, 5.46% N. Preparation 2

2- (2-Aminoethoxymethyl) -4- (2,3-dichlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine of melting point 171 was prepared in an analogous manner to the corresponding azido compound. to 173 ° C, characterized as hemifumarate hemihydrate.

Analysis: for

C20H24Cl2N2O5. V2 C4H4O4. V2 H2O calculated:

C 51.8%, H 5.3%, N 5.5%; found:

C 51.7%, H 5.3%, N 5.5%

The hemifumarate is neutralized to the appropriate free base, m.p. 120-122 ° C. Preparation 3

2- (2-azidoethoxymethyl) -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine

To a suspension of sodium hydride (114 g; 80% dispersion in oil) in 500 mL of tetrahydrofuran was added a solution of 160 g of 2-azidoethanol in 300 mL of tetrahydrofuran over 40 minutes. After stirring at room temperature for 1 hour, a solution of ethyl 4-chloroacetoacetate (276 g) in tetrahydrofuran (250 ml) was added dropwise with ice-cooling over 2 hours. The reaction mixture was stirred at room temperature for 16 hours, diluted with 150 mL of ethanol and adjusted to pH 6-7 with 4M hydrochloric acid.

The solid material present is dissolved by adding water, the layers are separated, the organic layer is evaporated, the residue is diluted with 600 ml of water and evaporated. The residue was partitioned between ethyl acetate and water and the aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4) and evaporated to give ethyl 4- (2-azidoethoxy) acetoacetate as a brown oil which was 73% pure by gas chromatography.

A mixture of this crude product and 92.3 g of ammonium acetate in 600 ml of ethanol was heated at reflux for 1 hour, then allowed to cool to room temperature and 286.6 g of methyl 2- (2-chlorobenzylidene) was added. acetoacetate. The resulting mixture was heated at reflux for 5.5 hours, then evaporated, the residue was stirred with 1.5 liters of methanol for 1 hour. The resulting solid was collected, washed twice with methanol and recrystallized from methanol after drying. This gives 78 g of the title compound, m.p. 145-146 ° C.

Calcd for C20H23ClN4O5:

H, 5.33; N, 12.88; found:

H, 5.37; N, 13.01. Preparation 4

Following the procedure described in Preparation 3, 2- (2-azidoethoxy) methyl-4- (2,3-dichlorophenyl) was prepared using methyl 2- (2,3-dichlorobenzylidene) acetonitrile instead of methyl 2- (2-chlorobenzylidene) acetoacetate. M.p. 141 ° C) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine.

Calcd for C20H33Cl2N4O5:

% C, 51.18;% H, 4.73;% N, 11.94; found:

% C, 50.88;% H, 4.78;% 11.73. Preparation 5 (i) Preparation of ethyl 4- (2-phthalimidoethoxy) acetoacetate

NaH

O CHgCl ⁺ hocw _from ch ₂ n

tetrah-ydro fu.r3.r2 ⁰

CO ₂ E ₁ CH ₂ O-CH ₂ H ₂ O

To a suspension of sodium hydride (57% dispersion in oil, 66.1 g 1.57 mol) in 500 ml tetrahydrofuran, cooled to 0 ° C, was added 150 g (0.785 mol) of 2-phthalimidoethanol and then 129 g under nitrogen over 1 hour. (0.785 mol) of ethyl 4-chloroacetoacetate in 250 ml of tetrahydrofuran, the mixture was stirred at room temperature overnight and then poured into a mixture of 800 ml of 1M hydrochloric acid and 750 ml of ethyl acetate. The residue was divided into 2 layers and the upper layer of mineral oil was removed to give 243 g of crude title compound as a residue which was used without further purification.

(iij Preparation of 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- [2-phthalimidoethoxymethyl] -1,4-dihydropyridine

To a solution of 200 g (0.627 mol) of ethyl 4- (2-phthalimidoethoxy) acetoacetate in 1 liter of isopropanol was added 72.2 g (0.627 mol) of methyl -3-aminocrotonate and 88.1 g (0.627 mol) of 2-chlorobenzaldehyde. The isopropanol was evaporated under reduced pressure and replaced with 1 liter of acetic acid The solid product was allowed to agglomerate at 10 degrees Celsius, then collected and suspended in 300 ml of methanol. and dried under vacuum at 50 ° C to give the title compound (84.4 g), m.p. 146-147 ° C.

Calcd for C28H27ClN2O7:

62.4% C, 5.05% H, 5.2% N; found:

62.2% C, 5.0% H, 5.2% N.

Preparation 6

Following the same procedure as in the previous preparation, but using the corresponding 2,3-dichlorobenzaldehyde as the starting material, the following compound was prepared, m.p. The reaction time is the same.

Analysis: for C28H2GCl2N2O7

Preparation 7 calculated:

C 58.6%, H 4.6%, N 4.9%;

found:

58.7% C, 4.5% H, 5.0% N.

Preparation of 2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine maleate

MeO _from C

*

400 g of the intermediate phthalimide derivative of Preparation 5 are suspended in 6 liters of ethanol containing 111 g of hydrazine hydrate. The reaction mixture was refluxed for 2 hours, cooled, filtered and evaporated to a yellow oil. The oily material is taken up in 6.5 l of methylene chloride, the organic solution is washed with water and, after drying over magnesium sulfate, evaporated. The residue is taken up with 1.2 liters of methanol-denatured hot ethanol and diluted with 400 ml of methanol-denatured hot ethanol containing 86 g of maleic acid. After cooling, the title compound crystallizes out of solution as the maleic acid salt. The yield of the product melting at 169-171 ° C is 303 g. Analysis: for C 20 H 25 ClN 2 O 5. C4H4O4 calculated:

C, 54.9; H, 5.6; N, 5.3; found:

H, 5.55; N, 5.3%. Preparation 8

In a similar manner as in the foregoing preparation, the following compound was obtained from the corresponding 2,3-dichlorophenyl derivative, m.p. 171-173 ° C.

fumarat * 7/2

Analysis: for

C20H24Cl2N2O5. C4H4O4.1 / 2 H2O calculated:

C 51.5%, H 5.05%, N 5.0%; found:

% C, 51.55;% H, 5.3%;

Preparation 9

In a similar manner to Preparation 5, but using the corresponding 2-chloro-3-trifluoromethylbenzaldehyde in step (ii), the following compound was obtained, melting at 179 ° C. The same reaction time as in Preparation 5 was used.

Analysis: for C29H26ClF3N2O7

Preparation 10 calculated ·:

H, 4.3; N, 4.6;

found:

57.2% C, 4.45% H, 4.8% N.

Preparation of 2- (2-azidoethoxymethyl) -4- (2-chloro-3-trifluoromethylphenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine

The title compound, melting at 143-145 ° C, was prepared in an analogous manner to Preparation 3 using the corresponding 2-chloro-3-trifluoromethylbenzaldehyde as the starting material. The reaction time is the same as in Preparation 3.

For C21H22ClF3N4O5 calculated:

% C, 50.15;% H, 11.1%;

found:

50.2% C, 4.4% H, 11.3% N. Prepar

Preparation of 2- (2-aminoethoxymethyl) -4- (2-chloro-3-trifluoromethylphenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine.

The title compound was prepared by catalytic hydrogenation of the azido compound of Preparation 10 as described in Preparation

1. This compound is identical to the product of Preparation 13 by NMR and IR spectroscopy.

Preparation 12

Preparation of 2- (2-azidoethoxymethyl) -4- (2,3-dichlorophenyl) -3-methoxycarbonyl-5-ethoxycarbonyl-6-methyl-1,4-dihydropyridine

Ct

COsCHt,

CH 1 R CH 2 O-CH 2 CH 3 N 5

The title compound, melting at 126 ° C, was prepared in an analogous manner to Preparation 3 but using methyl 4-bromoacetoacetate instead of ethyl 4-chloroacetoacetate to give methyl 4- (2-azidoethoxy) acetoacetate instead of ethyl 4 - (2-azidoethoxy) acetoacetate The other reaction conditions are the same.

For C20H22Cl2N4O5 calculated:

C 51.2%, H 4.7%, N 11.9%;

found:

H, 4.7; N, 12.1. Preparation 13

Preparation of 2- (2-aminoethoxymethyl) -4- (2-chloro-3-trifluoromethylphenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine

To 14 ml of 40% aqueous methylamine was added 2.8 g of the intermediate phthalimide derivative from Preparation 9, and the mixture was stirred at room temperature for 17 hours. The resulting solid is filtered off, redissolved in 50 ml of chloroform, dried over magnesium sulphate and evaporated. The yellow solid was crystallized from hexane to give the title compound, m.p. 122 ° C. Yield 1.0 g.

Analysis calculated for: C21H24ClF3N2O5:

52.9 O / o C, 5.1% H, 5.9% N;

found:

% C, 52.25;% H, 4.9;

Preparation

Preparation of 4- (3,3-dichlorophenyl) -5-ethoxycarbonyl-3-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxymethyl) -1,4-dihydropyridine

The title compound, melting at 1.65 ° C, was prepared in an analogous manner to Preparation 5 (ii) but using 2,3-dichlorobenzaldehyde, methyl 4- (2-phthalimidoethoxy) acetoacetate and ethyl 3-aminocrotonate. the same.

Calcd for C28H26Cl2N2O7:

C 58.65; H 4.6; N 4.9%;

η α 1 Ρ7οη π ’

58.5% C, 4.7% H, 5.0% N.

The starting acetoacetate was prepared in an analogous manner to Preparation 5 (i). Preparation 15

Preparation of 2- (2-aminoethoxymethyl) -4- (2,3-dlchlorophenyl) -5-ethoxycarbonyl-3-methoxycarbonyl-6-methyl-1,4-dihydropyridine

Whose

° 2 ° ^{C CO} 2. ^Ch 3

Ji Η np LI ^vH 3 H

The title compound, melting at 131-132 ° C, was prepared in an analogous manner to Preparation 13, but starting from Preparation 14.

Calcd for C20HZ4Cl2N2O5:

C, 54.2; H, 5.5; N, 6.3; found:

53.9% C, 5.5%. 6,4% N.

Preparation 16

Preparation of 2-chloro-3-trifluoromethylbenzaldehyde

54.15 g 2 of chloro-1-trifluoromethylbenzene are dissolved in 500 ml of dry tetrahydrofuran, the solution is stirred under a stream of dry nitrogen [complete reaction under a dry nitrogen atmosphere until the addition of distilled water] is cooled to -68 ° C and 180 ml of a 1.6 M n-butyllithium solution of hexane were added dropwise thereto below -60 ° C. After stirring at -68 ° C for 2 hours, a solution of 22 ml of dimethylformamide in 100 ml of dry tetrahydrofuran was added dropwise while maintaining the temperature below -60 ° C.

The reaction mixture was allowed to slowly warm to room temperature over 17 hours and then 200 mL of distilled water was added. The organic phase was separated and the aqueous phase was extracted with ether (100 ml). The ether extracts were combined with the organic phase, washed with saturated sodium chloride solution, and dried over magnesium sulfate, filtered and evaporated. 61.5 g of an orange oil are obtained, consisting of the crude title compound.

This oily material was added to a solution of 65 g of sodium bisulfite in 600 ml of distilled water and heated at 60 ° C for 0.5 h. The resulting solution is extracted three times with 100 ml of methylene chloride 249525 each, the aqueous phase is acidified with concentrated sulfuric acid to pH 1 and heated at 100 DEG C. for a further 0.5 hours. The resulting aqueous solution was extracted three times with 200 ml of methylene chloride each time, the combined organic extracts were dried over magnesium sulfate, filtered and evaporated. 42 g of a colorless solid which, after crystallization from hexane gives the title compound, melting at 43-44 ^& C.

Analysis: calculated for CelMbClO:

C, 46.1; H, 2.0;

found:

45.9% C, 2.0% H.

Preparation 17

Preparation of 2,3-dichlorobenzaldehyde

A procedure similar to that described in the preceding preparation, starting from 1,2-dichlorobenzene, has been shown to be the best method of preparing the title compound, melting at 62 ° C.

Calcd for C7H4Cl2O:

% C, 48.04;% H, 2.30;

found:

47.62

C, 2.38 θ / ο H.

The following abbreviations are used in the above formulas and tables:

Methyl group

Et = ethyl

Pr = propyl group iPr = isopropyl group

Bu = butyl

Ac = acetyl

IPA = isopropanol

Claims (5)

A process for the preparation of dihydropyridines of the general formula I R ^ OOC COOR CH ₃ H (I) wherein R represents a phenyl group optionally substituted by one or two substituents independently selected from the group consisting of chlorine atoms and trifluoromethyl groups, R @ ¹ and R @ ² are each independently C1 -C4 alkyl and R ³ represents a residue NH .CH, or OF. NH, ο their pharmaceutically acceptable acid addition salts, characterized in that the compound of formula III HR 9 _R W ^X Y H a-O-CCH 2 NCX H C) in c: which R, R ¹ and R ² are as defined above and X is methylthio, methoxy or phenoxy, reacted with hydrazine, hydrazine hydrate or methylhydrazine, and the resulting product is optionally converted by treatment with a suitable acid into its pharmaceutically acceptable acid addition salt. 2. The process according to claim 1, wherein the starting materials are compounds of the above formula III, wherein X is methylthio or methoxy and the remaining general symbols are as in point 1. 3. Process according to claim 1 or 2, characterized in that the corresponding starting materials are used to form the compounds of Formula 1 in which either R ¹ represents a methyl group and R ² ethyl group, or R ¹ is ethyl and R ² and R is 2-chlorophenyl, 2,3-dichlorophenyl or 2-chloro-3-trifluoromethyl. 4. Method according to claim 1, characterized in that starting materials are used the above formula III wherein X is methylthio and R, R ¹ and R ² are defined as in point 1. 5. A process according to claim 4, wherein R is 2,3-dichlorophenyl, R @ ¹ is methyl, R @ ² is ethyl, and X is methylthio, wherein the compound of formula III is reacted with hydrazine hydrate to give 2- [2- (3-amino-1H-1,2,4-triazol-5-ylamino) ethoxymethyl] -4- (2,3-dichlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, which is optionally converted into its pharmaceutically acceptable acid addition salt by reaction with a suitable acid.