DD283607A5 - PROCESS FOR PREPARING 1,4-DIHYDRO-PYRIDINE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of the formula I According to the invention, this compound can be prepared, for example, by reacting a compound of the general formula II with methyl acetoacetate of the formula III and optionally with an amino compound of the formula IV in which the substituents are those described in US Pat have the meaning given in the description. Formula (I) to (IV) {1,4-Dihydro-pyridine derivatives; new manufacturing process; excellent yields; high purity; short reaction time; Use as a medicine}

Description

Field of application of the invention

The invention relates to a new and improved process for the preparation of 1,4-dihydro-pyridine derivatives; new intermediates that can be used in this process and a process for the preparation of said intermediates.

The invention relates to a new and improved process for the preparation of dimethyl 1,4-dihydro-2,6-dimethyl-4- (2'-nitrophenyl) pyridine-3,5-dicarboxylate (further referred to as "nifedipine").

Characteristic of the known state of the art

It is known that nifedipine is a valuable calcium antagonist and finds widespread use in the treatment of high blood pressure of all types and myocardial diseases (US Pat. No. 3,488,847).

For the preparation of nifedipine several methods have become known from the literature. A. Hantzsch (Justus Liebig: Annalen der Chemie 215,1 [1982]) described the reaction of aldehydes and 3-ketocarboxylic acid esters in the presence of an excess of ammonia. The process is described in Reaction Scheme A

R-CHO + 2 R ₁ -CO-CH ₂ -COOR ₂ + NH_ / excess /

I i

N H

Reaction scheme A

shown.

According to the method of A. Hantzsch-Bayer (C.Bayer Bersch Dtsch Chem.Ges.24, 1662 [1891]), an aldehyde is reacted with 2 equivalents of a 3-amino-carboxylic acid ester. The procedure is the reaction Scheme B

R-OHO

Reaction scheme B

illustrated.

E.Knoevenagel (Ber.Dtsch.Chem.Ges.31, 743 [1898]) reported the reaction of ylidenecarboxylic acid esters and enamino-carboxylic acid esters. The process is on Reaction Scheme C

s ^C0R l R _o 00C-ff \ C00R _p

R-CII = C + R ₁ -C = CH-COOR

COOR ₂ NH ₂

Reaction scheme C

seen.

H. H. Fox and coworkers (J. Org. Chem., 16, 125, 1951) studied the reaction of aldehydes, 3-keto-carboxylic acid esters, and enamino-carboxylic acid esters.

The process is described in Reaction Scheme D

R ^ J-COOR RpOO C-r K   "J

r-cho + r ₁ -co-ch ₂ -coor ₂ + r - ^, =

JI reaction scheme D

portrayed.

According to DOS No. 2,117,571, dihydropyridines are prepared in such a way that nitrophenyl benzylidene acetoacetate esters are reacted with β-aminocrotonic acid esters or ammonia and acetoacetic acid esters. The procedure is the reaction scheme E

COOR ₁ R-CH = C + CH ₃ -C =OH-COOR ₂ or CH ₃ -CO-CH ₂ -COO] I ₂ + JIiI ₃ -

N TmTT

R ₂ 00C-j <^ ^ y COOR ₂

Reaction scheme E

illustrated.

According to the literature, the above methods have also been applied to the production of nifedipine. According to DE-PS No. 1620827 nifedipine is prepared by reacting 2-nitro-benzaldehyde and methyl acetoacetate in methanol in the presence of an excess of ammonia. The disadvantage of this method is that the resulting nifedipine is contaminated by several by-products. In the HU-PS No. 192 546 the method described in DE-PS No. 1 620 827 is critically discussed. In this Hungarian patent, when reproducing Example 1, DE-PS No. 1620827 reports that the nifedipine obtained is contaminated with 7 by-products.

According to the HU-PS No. 192 546 an improved modification of the above-mentioned Knoevenagel synthesis for the preparation of

symmetrical 1,4-dihydro-pyridine-dicarboxylic esters, etc. Nifedipine described. After the first stage of the synthesis, 2-nitrobenzaldehyde is calculated with methyl acetoacetate in the presence of a catalytic amount -0.01-0.7 moles, per 1 mole of methyl acetoacetate - piperidine acetate with a very high yield of 97% for the 2nd -Nitro-benzylidenacetessigsäuremethylester reacted, after which this ester is reacted immediately or after isolation with 3-aminocrotonic acid methyl ester. The second stage yield is 87%, with the overall yield of the two stages being 84.4%. According to the teachings of the disclosure of this Hungarian patent, the thin-layer chromatogram (silica gel coated precoated plates, using a 3: 2: 5 mixture of chloroform, acetone and petroleum ether for development) of the resulting nifedipine shows no by-products.

According to the above-mentioned known methods - especially in the syntheses of the Hantzsch type - free ammonia is present during the entire reaction time, whereby undesirable side reactions take place and the end product contaminating by-products can be formed. Considering that the various pharmacopoeias are becoming increasingly demanding over the nifedipine to be used in therapy, there is a great need for the production of high-purity by-product-free nifedipine.

The implementation of the method described in the HU-PS No. 192 546 in operation has economic disadvantages. It is economically disadvantageous that the costly 3-amino-crotonsäuremethylester makes up half of the ester component used. Another disadvantage is the long overall reaction time. In the first stage, the formation of the 2-nitro-benzylidene-acetoacetate methyl ester takes 16 hours, in the second stage the said ylidene compound is converted to nifedipine with a reaction time of 36 hours. The total reaction time is thus 52 hours. The 3-aminocrotonic acid methyl ester used as starting material must be prepared in a separate step and this ester is relatively expensive.

Object of the invention

The aim of the invention is to provide a production method of nifedipine which is also economically feasible in operation, wherein the reaction time is shortened and a pure product free of impurities is obtained.

Explanation of the essence of the invention

The invention has for its object to find suitable starting compounds, reaction components and reaction conditions for the production of nifedipine.

The above object is achieved by means of the method according to the invention, wherein nifedipine is obtained in an economical way, in a pure state and also in operation with excellent yields.

The invention relates to a process for the preparation of the dimethyl-1,4-dihydro-2,6-dimethyl-4- (2'-nitrophenyl) -pyridine-3,5-dicarboxylate of the formula I,

H ₃ COOC

characterized in that

a) a compound of the general formula II

/ I /

CH = N-R

/ II /

(wherein η is the number 1 or 3; if η = 1, R is a group of the formula / a / or / b / 110,

/ A /

CH = N-CH ' \

/ B /

stands; and if η = 3, R is hydrogen) with methyl acetoacetate of the formula I.

CH 3 -CO-CH 2 -COOCH 3 and optionally with an amino compound of the general formula IV

/ ΗΛ _H

/ III /

/ IV /

(wherein Z is the group of formula / c / CH ₃ -C = CH-COOCH ₃

means k = 1 and the two symbols ρ are 0; or Z represents a straight or branched alkanoyloxy group containing 1-5 carbon atoms or a carbonate, hydrocarbon or hydroxide anion, k = 1 and the two symbols ρ are 1; ork = 0, one of the symbols ρ is 0 and the other is 1) in an inert solvent; or

b) reacting 2-nitro-benzaldehyde with methyl acetoacetate of the formula III and an aqueous ammonium hydroxide solution at a temperature of 101-120 ⁰ C, under a pressure of 2.0-6.0 bar, in one stage.

According to a variant of process a), the starting material used is the 1-methoxy-1 - (2'-nitro-phenyl) -N- (2'-nitro-phenyl) -methylene

methanamine of the formula II A

/HA/

CH = N - CH

NO,

used. This is the compound of general formula II wherein η = 1 and R represents the group of formula / a /. The reaction is carried out on Reaction Scheme F

OCH

+ 3CH 2 -CO-CH 2 -COOCH, + CH-J-C = CH-COOCH, -

O <C O O ι O

HH,

or

nh ₃ + ch ₃ -co-ch ₂ -cooch ₃

H ₃ COOC

CH ₃ OH

CH-

Reaction scheme F

illustrated. 1 mol of the compound of the formula HA is reacted with 3 moles of methyl acetoacetate and 1 mol of methyl 3-aminocrotonate. The 3-aminocrotonic acid methyl ester can also be prepared in situ from methyl acetoacetate and ammonia. For this purpose may advantageously be an aqueous ammonium hydroxide or

metanolic ammonia can be used. The reaction is carried out in an inert solvent or solvent mixture. Any inert organic solvent which does not react with the reactants under the reaction conditions used can be used as the reaction medium. It can polar protic solvents such as water; Alcohols (eg, methanol, ethanol, etc.); Amides (eg formamide, acetamide, etc.); or dipolar aprotic solvents (eg, acetonitrile, acetone, dimethyl sulfoxide, nitrobenzene, etc.). According to a particularly advantageous embodiment, methanol is used as the medium. The reaction temperature can be varied within wide limits. The temperature is generally between -10 ⁰ C and +120 ⁰ C, preferably 5-100 ° C, in particular 25-8O ⁰ C. The reaction time is dependent on the temperature about 12-60 hours, preferably 25-55 hours. The reaction generally proceeds within 36 hours in high yields.

It is advantageously possible to proceed by adding 3 moles of methyl acetoacetate and 1 mole of methyl 3-amino-crotonic acid to a suspension of 1 mole of the compound of the formula IIA formed with methanol. The reaction mixture is heated to boiling for 36 hours.

The formed compound of the formula IIA can also be converted into nifedipine without isolation in the same apparatus. After the course of the reaction, the nifedipine formed can be isolated from the reaction mixture by very simple methods. After cooling the reaction mixture, the precipitated nifedipine is filtered, dissolved in acetic acid with heating, precipitated with water, filtered, washed and dried. The product obtained complies with the criteria of pharmacopoeia without further recrystallization or other purification.

According to another variant of process a), the starting material is 1- (2'-nitrophenyl) -N, N'-bis (2'-nitro-phenyl) -methylene-methanediamine of the formula II B

CH = N - CH - N = CH

/ MB /

used. This is a compound of general formula II, wherein η = 1 and R is the group of formula IbI (see Scheme G).

5 CH -CO-CH, -, - COOCH., + CH - C = CH-COOCH_

ΝΗ _Λ

or

NH "+ CH -CC-CH ₀ -COOCH

5 3 <L

H COOC

Reaction scheme G

1 mol of the compound of formula II B is reacted with 5 moles of methyl acetoacetate and 1 mol of 3-amino-crotonsäuremethylester; this is a compound of general formula IV wherein Z is the group of formula (c); k = 1 and the two symbols ρ stand for 0. The latter ester can also be formed in situ from methyl acetoacetate and ammonia. For this purpose, aqueous ammonium hydroxide or methanolic ammonia can be used. The reaction can be carried out in an inert solvent or solvent mixture. The reaction medium used may be inert solvents which do not react with the starting materials under the given reaction conditions. The same solvents can be used as reaction medium, which in connection with the use of the

Starting material of the formula II A were enumerated. It is particularly advantageous to work in methanol as a medium. The reaction can be completed over a wide temperature range. Generally can be at a temperature between -1O ⁰ C and +120 ⁰ C, advantageously operate at 5-100 ⁰ C, in particular at 25-8O ⁰ C. The reaction lasts - depending on the temperature - about 12-60 hours, advantageously 25-55 hours. The reaction generally proceeds within 36-40 hours with good yields.

The compound of the formula HB can also be converted to nifedipine without isolation in the same apparatus. After completion of the reaction, the nifedipine can be isolated from the reaction mixture by simple methods. According to one method, the precipitated after cooling nifedipine is filtered, washed and dried. According to an advantageous manner of work-up, the precipitated nifedipine is separated off, dissolved in acetic acid with heating and precipitated with water. The nifedipine thus obtained corresponds to the requirements of the pharmacopoeias and requires no further recrystallization

 According to a further variant of the process a), the trimeric 2-nitro-benzaldimine of the formula II C is used as starting material

H = NH

(NC)

used. This is a compound of general formula II, wherein η = 3 and R is hydrogen. The process is described in Reaction Scheme H

6 CH ₃ -CO-CH ₂ -COOCHy

H ₃ COOC

COOCH.

Reaction scheme H

portrayed. 1 mole of the compound of formula HC is reacted with 6 moles of methyl acetoacetate. The reaction is carried out in an inert solvent or solvent mixture. As the reaction medium, any inert solvents can be used which do not react with the starting materials under the reaction conditions used. The solvents listed in connection with the use of the starting material of the formula NA can be used. The methanol has proven to be a particularly advantageous reaction medium. The temperature can vary within wide limits. In general, can operate at a temperature between -10 ° C and +120 ⁰ C, preferably at 5-100 ⁰ C, especially at 25-80 ⁰ C. The reaction time depends on the temperature and is 12-60 hours, advantageously about 25-55 hours, preferably about 36-50 hours.

The compound of the formula MC can also be converted to nifedipine without isolation in the same apparatus.

The nifedipine thus obtained can be easily isolated from the Reaktinsgemisch. The product can be cooled, filtered

or centrifuging or dissolving in acetic acid with heating, precipitation with water, washing and drying, and isolation. The resulting nifedipine meets the criteria of Pharamkopöen and does not require recrystallization.

The compounds used as starting material of the general formula II are novel, not described in the literature derivatives.

The invention further relates to the compounds of general formula II and a process for the preparation thereof.

The compounds of general formula II can be prepared by the process according to the invention so that

A) for the preparation of the compound of formula II, wherein π = 1 and R is the group of the formula / a /, 2-nitro-benzaldehyde with an ammonium salt of the general formula Ri-COONH ₄ (wherein Ri is hydrogen or C ₁ ^ alkyl represents) and converts methanol; or

B) for the preparation of the compound of general formula II, wherein η = 1 and R is the group of formula (b), 2-nitrobenzaldehyde with an ammonium salt of the general formula Ri-COONH ₄ or reacted with ammonium hydroxide; or

C) for the preparation of the compound of general formula II, wherein η = 3 and R is hydrogen, reacting 2-nitro-benzaldehyde with ammonia in an inert solvent;

and, if desired, isolating the resulting compound of general formula II from the reaction mixture. According to the above process A), the compound of the formula IIA is prepared by reacting 2-nitrobenzaldehyde and an ammonium salt of the general formula Ri-COONH ₄ (in which Ri is hydrogen or a straight-chain or branched alkyl group having 1-4 carbon atoms) and methanol manufactured. The C ₁ ^ alkyl group may be, for example, methyl, ethyl, n-propyl, isopropyl, η-butyl. As the ammonium salt of the general formula R1-COONH4, ammonium acetate may preferably be used. The methanol used as the reaction component can also be used in excess, wherein it also serves as the reaction medium. The reaction temperature can vary within wide limits and is generally between -1O ⁰ C and +180 ⁰ C, preferably 15-4sO ° C. The reaction proceeds relatively quickly (1.5-7 hours) and the desired compound of formula IIA can be obtained with an excellent yield within about 7 hours. If desired, the reaction can also be carried out in other inert solvents which do not react with the starting materials.

The resulting compound of the formula IIA can be isolated from the reaction mixture by known methods. The product can be isolated simply by cooling the reaction mixture, separating the solid reaction product by filtration or centrifugation, and then washing and drying. It is also possible to proceed by directly converting the compound of formula HA in the same apparatus without isolation to nifedipine. According to the above method B), the compound of formula II B is prepared by reacting 2-nitro-benzaldehyde in an inert solvent with an ammonium salt of the general formula Ri COONH ₄ or ammonium hydroxide. The ammonium salt of the formula Ri-COONH ₄ is particularly suitable ammonium acetate. The reaction between 2-nitrobenzaldehyde and the ammonium salt of the general formula Ri-COONH ₄ -advantageously ammonium acetate-can be carried out in an inert organic solvent. For this purpose, inert, with the starting materials used under the specified reaction conditions unreacted solvent, namely polar protic solvents such as water; at least two carbon atoms containing aliphatic alcohols (eg., Ethanol, isopropanol), amides (eg, formamide, acetamide) or dipolar aprotic solvents (eg, acetonitrile, acetone, dimethyl sulfoxide, nitrobenzene, etc.). It is particularly advantageous to work in isopropanol as the reaction medium. According to another variant of the method B) 2-nitro-benzaldehyde is reacted with ammonium hydroxide. As the reaction medium, methanol may preferably be used.

The reaction B) can be carried out within a wide temperature interval. One can, in general, at a temperature between -10 ° C and + 80 ° C, especially at 15-40 ⁰ C, working. The reaction is relatively fast. The reaction generally takes about 6-7 hours and the desired compound of formula HB can be obtained after 7 hours of reaction in excellent yield.

The formed compound of formula MB can be prepared by simple methods, e.g. as shown in the method A) -isolated. However, it is also possible to proceed by converting the formed compound of the formula IIB into nifedipine without isolation in the same apparatus.

According to the above process C), the compound of formula MC, which is in both monomeric and intrinsic form, is prepared by reacting 2-nitrobenzaldehyde in an inert solvent with ammonia. According to an advantageous embodiment of this method, a solution of 2-nitro-benzaldehyde and methanol is reacted with methanolic ammonia. The reaction can also be carried out in the presence of inert solvents which do not react with the starting materials used under the reaction conditions indicated. Suitable reaction media are the solvents listed in process B).

The reaction temperature can vary within wide limits. It can be advantageous at a temperature between -10 ⁰ C and + 8O ⁰ C, preferably at 15-40 ⁰ C, work. The reaction time is generally about 5-25 hours. The resulting compound of formula II can be easily isolated by known methods. For example as described in the method A). However, the formed compound of the formula HC can also be converted to nifedipine without isolation in the same apparatus.

It has been found that the compounds of the general formula II are formed in excellent yields and in such a pure state that these can be converted directly to nifedipine corresponding to the requirements of the Pharamkopöen without recrystallization.

It has surprisingly been found that, if 2-nitro-benzaldehyde in the same organic solvent-methanol - treated with various sources of ammonia, depending on the source of ammonia various compounds of general formula II are formed. The relationship between the chemical structure of the compound of general formula II formed and the source of ammonia used is shown in Table I.

Ammonia source Chemical formula Yield

Ammonium acetate MA 98%

Ammonium hydroxide MB 92%

Anhydrous ammonia HC 75%

The starting materials used (2-nitro-benzaldehyde, ammonium salts of the general formula Ri-COONH ₄ , ammonium hydroxide, methanol) are commercial products.

According to process b) nifedipine is prepared by reacting 2-nitrobenzaldehyde and methyl acetoacetate of the formula III of an aqueous ammonium hydroxide solution, in the presence of an inert solvent, at a temperature of 101-120 ° C, under a pressure of 2.0- 6.0 bar in one stage.

It has been found according to the invention that if the reaction is carried out under the above conditions, the reaction takes place within a very short time and a highly pure, the criteria of the Pharamkopöen without further purification corresponding product is obtained.

It was not to be expected on the basis of the teaching of the specialist literature that the implementation of the reaction with ammonia under pressure at a temperature of 101-120 ⁰ C provides such a nifedipine pure. It has been found according to the invention that, if the temperature is raised to the interval of 101-120 ° C, the main reaction leading to nifedipine proceeds at a very high rate, the rate of side reactions leading to the formation of undesired by-products not increasing, and these side reactions do not even occur within the short reaction time used. It is particularly surprising that by-products of the so-called diamide and monoamide structure are not formed in the presence of ammonia, even in the presence of a large excess of ammonia (2.0 moles).

According to process b) are advantageously 2-4 moles of methyl acetoacetate and 1-3 moles of aqueous ammonium hydroxide, calculated to 1 mole of 2-nitro-benzaldehyde used. The particularly advantageous molar ratios are 2.2-3.5 moles of methyl acetoacetate and 1.04-2.00 moles of ammonia (in the form of an aqueous ammonium hydroxide solution), calculated to 1 mole of 2-nitro-benzaldehyde. The concentration of the ammonium hydroxide solution is 20-30% by weight, preferably 25% by weight.

Process b) is a one-step process and the preparation of the 3-aminocrotonic acid methyl ester used as starting material in the known processes is superfluous. The reaction is carried out in the presence of an inert solvent. Suitable reaction medium are advantageously lower aliphatic alcohols, in particular methanol.

According to an advantageous embodiment of process b), a mixture of 2-nitrobenzaldehyde, methyl acetoacetate, an aqueous ammonium hydroxide solution and an inert organic solvent, preferably methanol, is heated to 101-120 ° C. under pressure. The reaction pressure is 2.0-6.0 bar, advantageously 2.0-2.3 bar. The reaction is very fast, the reaction time is about 2-5 hours.

The workup of the reaction mixture is done by simple methods. After completion of the reaction carried out at 101-12O ⁰ C for a few hours, the reaction mixture is cooled-generally to 0-5 ⁰ C-, the precipitated nifedipine is separated by filtration or centrifugation and washed with methanol.

The product obtained meets the criteria of the Phakakopoen and requires no further purification.

The advantages of the process according to the invention can be summarized below as follows:

Method a)

In the known methods which do not belong to the Hantzsch type (i.e., more expensive enamino-carboxylic acid esters are used in addition to the β-keto-carboxylic acid esters), said expensive enamino-carboxylic acid ester constitutes half of the total amount of the ester component. According to the method described in the HU-PS No. 192,546 1 mole of 3-amino-crotonsäuremethylester, calculated to 1 mole of methyl acetoacetate, is used.

In contrast, according to the inventive method a) enamino-carboxylic acid ester (3-amino-crotonsäuremethylester) either not used (in the application of the starting material of the formula II C) or its amount is only one sixth (starting material of the formula II B) or a Quarter (starting material of formula Il A) of the total amount of ester component used as starting material.

The reaction time is shorter than in the method described in HU-PS No. 192546. In the first stage of the known synthesis, the formation of the ylidene derivative takes 16 hours, whereas in the first stage of the process a) the starting materials of the general formula II are formed more rapidly, within about 7 hours (see FIG.

especially reaction schemes G and F). The conversion of the starting materials of the general formula II to nifedipine takes about as long as the second step of the known method (conversion of the ylide derivative into nifedipine).

It is surprising and was not foreseeable that despite the complicated reaction mechanism, the process a) nifedipine with excellent yields in such a pure form that it is suitable for pharmaceutical purposes without further purification

Method b)

- one-step process;

- very short reaction time (a few hours);

- the use of 3-amino-crotonsäuremethylester is avoided;

- very good yield;

- great purity.

It was not foreseen that under the reaction conditions used, the ammonia present does not cause any undesirable side reactions and no by-products of the diamide or monoamide structure are formed. The mentioned side reactions are also suppressed if the reaction is carried out in the presence of a large excess of ammonia (2 moles).

Further details of the present invention can be found in the following examples, without limiting the scope of protection to these examples.

embodiment

The invention is explained in more detail below with reference to some examples.

example 1

A suspension of 315.3 g (1 mol) of 1-methoxy-1- (2'-nitro-phenyl) -N- (2'-nitrophenyl) methylene-methanamine and 1 liter of methanol are initially charged with 348.3 g ( 3 moles) of methyl acetoacetate and then 115.1 g (1 mol) of methyl 3-amino-crotonate added with stirring. The reaction mixture is boiled for 36 hours and then cooled. The precipitated product is filtered, sucked to dryness, dissolved in acetic acid with heating and precipitated with water. The product obtained is filtered, washed with methanol and dried. 572 g of nifedipine are obtained, yield 82.6%, F .: 172-174T. The product obtained is dissolved in chloroform. The thin-layer chromatogram developed in a diisopropyl ether-containing bath on HPTLC Kieselgel 60 thin-layer plates shows no foreign stains. The starting material is prepared as follows:

151.1 g (1 mol) of 2-nitro-benzaldehyde are dissolved in 250 ml of methanol, whereupon 80 g (1.04 mol) of ammonium acetate are added with stirring. The reaction mixture is stirred first at 40 ^° C. for 15 minutes and then at room temperature for 7 hours. After cooling, the precipitated product is filtered, washed with water and dried. It wrden 154.5 g of 1-methoxy-1- (2'-nitro-phenyl) -N- obtain (2'-nitro-phenyl) -methylene-methane amine, yield 98%, m.p. = 117-118 ⁰ C.

Example 2

31.5 g (0.1 mol) of 1-methoxy-1- (2'-nitro-phenyl) -N- (2'-nitro-phenyl) -methylene-methanamine are suspended in 100 ml of methanol. To the suspension are added 46.45 g (0.4 mole) of methyl acetoacetate with stirring, after which an equivalent amount of ammonia-containing ammonium hydroxide is added dropwise. The reaction mixture is boiled for 14 hours and then cooled. The precipitated product is filtered, washed with cold methanol and water and dried. 49.2 g of nifedipine are obtained. Yield 71%, m.p .: 170-172 ⁰ C.

Example 3

To a mixture of 31.5 g (0.1 mole) of 1-methoxy-1- (2'-nitro-phenyl) -N- (2'-nitrophenyl) -methylene-methanamine and 68 ml of methanol are added 46.45 g with stirring (0.4 mole of methyl acetoacetate is added, then a methanolic ammonia solution containing ammonia of 1.7 g (0.1 mole) is added dropwise.) The reaction mixture is boiled for 36 hours and then cooled, and the precipitated product is filtered , sucked to dryness, dissolved in acetic acid under heating, precipitated with water and dried. There are obtained 51,2g nifedipine, yield 74%, m.p .: 171-173 ⁰ C.

Example 4

A suspension of 433.4 g (1 mol) of 1- (2'-nitrophenyl) -N, N'-bis (2'-nitrophenyl) methylene-methanediamine and 1.5 liters of methanol are stirred 580, 6g (5 mol) of methyl acetoacetate and 115.1 g (1 mol) of methyl 3-amino-crotonate were added. The reaction mixture is heated to boiling for 46 hours, then cooled. The precipitated product is filtered, sucked to dryness, dissolved in acetic acid with heating and precipitated with water. The precipitated product is filtered and dried. This gives 810,2g of nifedipine, yield 78.5%, F .: 173-174 ⁰ C. The starting material is prepared as follows:

a) 151.1 g (1 mol) of 2-nitrobenzaldehyde and then 80 g (0.14 mol) of ammonium acetate are added with stirring to 500 ml of isopropanol first. The reaction mixture is stirred for 15 minutes at 40 ⁰ C and then for 7 hours at room temperature. The precipitated product is filtered, washed with water and dried. There are 141.6 g of 1- (2'-nitro-phenyl) -N, N'-bis (2'-nitro-phenyl) -methylen-methanediamine obtained, yield 98%, F.: 124-127 ⁰ C. ,

b) To a solution of 15.1 g (0.1 mol) of 2-nitrobenzaldehyde and 40 ml of methanol, an ammonium hydroxide solution having an ammonia content of 1.7 g (0.1 mol) is added dropwise with stirring. The solution is stirred for 25 hours at room temperature, then cooled, whereupon the precipitated product is filtered, washed with methanol and dried. There are 13.3 g of 1- (2'-nitro-phenyl) -N, N'-bis (2'-nitro-phenyl) -methylene-diamine, yield 92%, F.: 123-126 ⁰ C. ,

Example 5

A suspension of 43.3 g (0.1 mol) of 1- (2'-nitrophenyl) -N, N'-bis (2'-nitrophenyl) methylene-methanediamine and 140 ml of methanol are added with stirring 69, 7g (0.6 mol) of methyl acetoacetate and 8.7 ml of a 25% ammonium hydroxide solution. The reaction mixture is stirred for 42 hours at 45 ⁰ C and cooled. The precipitated product is filtered, dissolved in acetic acid with heating, washed with water and dried. There are obtained 79.0 g of nifedipine, yield 76%, mp.: 172-173 ⁰ C.

Example 6

9 g (0.02 mol) of trimeric 2-nitro-benzaldehyde-imine and 14 g (0.12 mol) of methyl acetoacetate are dissolved in 25 ml of methanol. The reaction mixture is heated to boiling for 25 hours, then cooled. The precipitated crystals are filtered, dissolved in acetic acid with heating, precipitated with water, the solution is cooled, filtered, washed with water and methanol and dried. There are obtained 12.4 g of nifedipine, yield 60%, m.p .: 170-173 ⁰ C. The starting material is prepared as follows:

To a solution of 15.1 g (0.1 mol) of 2-nitro-benzaldehyde and 40 ml of methanol, a methanolic ammonia solution with an ammonia content of 1.7 g (0.1 mol) is added dropwise with stirring. The reaction mixture is stirred at room temperature for 20 hours, then cooled. The precipitated product is filtered, washed with methanol and dried. 11.3 g of destrimeric 2-nitrobenzaldimine are obtained, yield 75.3%, mp 117-119 ° C.

Example 7

60.4 g (0.4 mol) of 2-nitrobenzaldehyde, 102.1 g (0.88 mol) of methyl acetoacetate, 28.25 g (0.415 mol) of a 25% strength aqueous ammonium hydroxide solution and 150 ml of methanol are weighed into a glass reactor , The reactor is closed and the reaction mixture heated with stirring at a temperature of 101-103 ° C, under a pressure of 2.0-2.2 bar for 5 hours. After cooling to 0-5 ⁰ C, the precipitated product is filtered and washed with methanol. There are obtained 110.5 g of nifedipine, yield 79.8%, mp .: 171.5-175 ° C.

After thin layer chromatography, the product is uniform. Thin-layer chromatograms (Merck plates coated with silica gel, using a 3: 2: 5 mixture of chloroform, acetone and petroleum ether for development) can not detect byproducts. According to modern HPLC analysis (USPXXI, Supplement 3, page 2018, valid from January 1, 1986), the nifedipine content of the product is 98.39%. The product thus obtained meets the criteria of the above pharmacopoeias without further purification.

Example 8

The procedure is as in Example 7, with the difference that the reaction is carried out at a temperature of 120 ⁰ C, under a pressure of 6.0 bar for 3 hours. There are obtained 110.7 g of nifedipine, yield 80.0%. The product complies with USPXXI criteria without purification, F: 172-175 ° C.

Example 9

The procedure is as in Example 7, with the difference that one uses 0.4 mol of 2-nitro-benzaldehyde, 0.8 mol of a 25% aqueous ammonium hydroxide solution and 0.88 mol of methyl acetoacetate. There are obtained 111.4 g of nifedipine, yield 80.5%. The product meets the criteria of USPXXI without further purification. F .: 172-175 ° C.

Example 10

The procedure is as in Example 7, with the difference that one uses 0.4 mol of 2-nitro-benzaldehyde, 0.415 mol of a 25% aqueous ammonium hydroxide solution and 1.40 mol of methyl acetoacetate. There are obtained 112.1 g of nifedipine, yield 81%, m.p .: 172-175 ⁰ C.

 The product meets the criteria of USPXXI without further purification.

Example 11

Into a 250-liter enamelled autoclave are weighed 25 kg (0.165 KMoI) of 2-nitro-benzaldehyde, 53 kg (0.456 KMoI) of methyl acetoacetate, 16 kg (0.235 KMoI) of a 25% ammonium hydroxide solution and 80 liters of methanol. The apparatus is closed and stirred at a temperature of 101-103 ⁰ C, under a pressure of 2.0-2.2 bar for 5 hours. The reaction mixture is cooled to 0-5 ⁰ C, the precipitated Nifedipin filtered and washed with methanol. There will be 44.4kg nifedipine, yield 77.5%. After thin layer chromatography, the product is uniform, according to HPLC, the nifedipine content is 98.24%. The quality of the product meets the criteria of USPXXI without further purification, F .: 171.5-175 ⁰ C.

Claims (29)

claims: (where η is the number 1 or 3; if η = 1, R is a group of the formula / a / or / b / CH = N-CH / a / / b / stands; and if η = 3, R is hydrogen) with methyl acetoacetate of the formula III Ch ₃ -CO-CH ₂ -COOCH ₃ / III / and optionally with an amino compound of general formula IV Z / ^{/ H /} P / IV / (wherein Z is the group of formula IcI CH ₃ -C = CH-COOCH ₃ IcI means k = 1 and the two symbols ρ stand for O; or Z represents a straight-chain or branched alkanoyloxy group containing 1-5 carbon atoms or a carbonate, hydrocarbonate or hydroxide anion, k = 1 and the two symbols ρ represent 1; ork = 0, one of the symbols is O and the other is 1) in an inert solvent; or b) reacting 2-nitro-benzaldehyde with methyl acetoacetate of the formula III and an aqueous ammonium hydroxide solution at a temperature of 101-120 ° C, under a pressure of 2.0-6.0 bar, in one stage. 2. The method according Anspruch1 a), characterized in that the starting material is the 1-methoxy-1- (2'-nitro-phenyl) -N- (2'-nitro-phenyl) -methylen-methanamine of the formula II A OCIL CH = N - CII /HA/ i.e. a compound of general formula II, where n = 1 and R is the group of formula / a /. 3. The method according to claim 2, characterized in that 1 mol of the compound of formula II A with 3Molen methyl acetoacetate and 1 mole of 3-amino-crotonsäuremethylester (compound of general formula IV, wherein Z is the group of formula IcI , k = 1 and ρ = 0). 4. The method according to claim 3, characterized in that forming the 3-amino-crotonsäuremethylester from methyl acetoacetate and ammonia in situ. 5. The method according to claim 4, characterized in that one uses aqueous ammonium hydroxide or methanolic ammonia. 6. The method according to claim 2, characterized in that reacting the compound of formula II A with the methyl acetoacetate and the 3-amino-crotonic acid methyl ester without isolation. 7. The method according to any one of claims 1-6, characterized in that one carries out the reaction in methanol as a medium. 8. The method according to any one of claims 2-7, characterized in that one carries out the reaction at a temperature between -10 ° C and 120 ⁰ C. 9. The method of claim 8, characterized in that C-the reaction is conducted at 5-100 ° C, preferably at 25-8O ^0th 10. The method according to claim 1 a), characterized in that the starting material is 1- (2'-nitro-phenyl) -N, N'-bis (2'-nitro-phenyl) -methyl-methanediamine of the formula II B CH = N - CH - N a CH- so - '-' ^{/ IIB /} - d. H. a compound of the general formula II in which η is - 1 and R is the group of the formula / b - used. 11. The method according to claim 10, characterized in that reacting 1 mol of the compound of formula II B with 5 moles of methyl acetoacetate and 1 mole of 3-amino-crotonic acid methyl ester of formula IV. 12. The method according to claim 11, characterized in that the 3-aminocrotonic acid methyl ester of methyl acetoacetate and ammonia forms in situ. 13. The method according to claim 12, characterized in that one uses aqueous ammonium hydroxide or methanolic ammonia. 14. The method according to claim 10, characterized in that reacting the compound of formula HB with the methyl acetoacetate and the 3-amino-crotonsäuremethylester without isolation. 15. The method according to any one of claims 10-14, characterized in that one carries out the reaction in a lower aliphatic alcohol, preferably methanol or isopropanol. 16. The method according to any one of claims 10-15, characterized in that one carries out the reaction at a temperature between -10 ⁰ C and +120 ⁰ C. 17. The method according to claim 16, characterized in that one carries out the reaction at 5-100 ⁰ C, preferably at 25-80 ⁰ C, performs. 18. The method according to claim 1 a), characterized in that as starting material, the trimeric 2-nitro-benzaldimine of the formula HC CH = NH / Nc / d. H. a combination of the general forms! II, wherein η = 3 and R is hydrogen. 19. The method according to claim 18, characterized in that reacting 1 mol of the compound of the formula MC with 6 moles of methyl acetoacetate. 20. The method according to claim 19, characterized in that one carries out the reaction in methanol as a medium. 21. The method according to any one of claims 18 to 20, characterized in that reacting the compound of formula II C with the methyl acetoacetate without Isolieurung. 22. The method according to any one of claims 18 to 21, characterized in that one carries out the reaction at a temperature between -10 ⁰ C and + 12O ⁰ C. 23. The method according to claim 22, characterized in that one carries out the reaction at 5 to 100 ⁰ C, preferably at 25 to 80 ⁰ C, performs. 24. The method according to claim 1 b, characterized in that one carries out the reaction at a temperature of 100-105 ° C, under a pressure of 2.0-2.5 bar. 25. The method according to claim 24, characterized in that one uses a 20-30gew .-% aqueous ammonium hydroxide solution. 26. The method according to claim 25, characterized in that one uses a 25gew .-% aqueous ammonium hydroxide solution. 27. The method according to any one of claims 24-26, characterized in that 2-4 moles of methyl acetoacetate and 1-3 moles of an aqueous ammonium hydroxide solution, calculated to 1 mole of 2-nitro-benzaldehyde used. 28. The method according to claim 27, characterized in that 2.2-2.5 moles of methyl acetoacetate and 1.04-2.00 moles of an aqueous ammonium hydroxide, calculated to 1 mole of 2-nitro-benzaldehyde used. 29. The method according to any one of claims 24-28, characterized in that one carries out the reaction for 2-5 hours.