DD268941A1 - PROCESS FOR PREPARING PYRAZOLIDONE (3) -AZOMETHINIMINES - Google Patents

Abstract

The invention relates to a process for the preparation of pyrazolidone (3) azomethine imines. The aim of the invention is to obtain pyrazolidone (3) -azomethinimines under industrial conditions in a crystalline, reproducible and high yield without causing dimers of the pyrazolidone (3) azomethine imines. This eliminates the costly and lossy separation of previously uncontrollable and forcibly obtained dimers, which, unlike dimers of other azomethine imines do not react like 2 molecules of azomethine imine and are not reactive by-products or impurities of the pyrazolidone (3) azomethine imines. According erfindungsgemaess is by a novel combination of technically simple measures, namely addition of alkali metal bicarbonate to the reaction mixture of a pyrazolidone (3), an aldehyde and an inert solvent and continuous distillation of 1 mol of water per 1 mol of pyrazolidone (3) -azomethinimin Rückfüfuehrung of indifferent solvent reaches this goal. Although the formation of pyrazolidone (3) azomethine imines is an acid catalyzed reaction, surprisingly the process of the present invention gives high yields of pure pyrazolidone (3) azomethine imines, which are important intermediates for drugs, in short reaction times.

Description

Hi-.

in the

R ² and R ^{3 have} the meanings given above

with an aldehyde of the general formula III,

R ¹ -CHO III

in the

R ^{1 has} the meaning given above,

characterized in that in an inert solvent to the reaction mixture of II and III 5 to 80mmol, preferably 5 to 25mmol, an alkali metal bicarbonate added, then heated to 50 to 15O ⁰ C and while returning the indifferent solvent continuously 0.95 to 1, Distilled off 00mol water, the crystallized pyrazolidone (3) -azomethinimin (I) is separated and optionally washed with the indifferent solvent.

2. The method according to claim 1, characterized in that are suitable as indifferent solvent cyclohexane, aromatic hydrocarbons, chlorinated aromatic hydrocarbons and carbon tetrachloride J.

3. Method according to Ansp. 1, characterized in that the indifferent solvent, if it is miscible with water, prior to recycling over a suitable desiccant, preferably via a molecular sieve such as Zeosorb 3 A, is passed.

4. The method according to claim 1, characterized in that the alkali metal salts contained in the crystalline pyrazolidone (3) -azomethiniminen (I) is separated by reacting the pyrazolidone (3) -azomethinimine in suitable solvents, preferably benzene, ethanol , n- or i-propanol, n- or i-butanol, hot dissolves, filtered hot from the undissolved residue and from the filtrate, the finely purified pyrazolidone (3) -azomethinimine (I) crystallized on cooling.

Field of application of the invention

The invention relates to a process for the preparation of pyrazolidone (3) azomethine imines of general formula I

CH -

in the

R 'is phenyl, 4-isopropylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-dimethoxy-phe.iyl, thiophene (2) or furan (2), R ^{2 is} H or methyl,

I ^{3 is} H, methyl or phenyl

mean.

The pyrazolidone (3) azomethine imines of the general formula I are of importance as intermediates for the preparation of medicaments, in particular for cardiovascular and anti-inflammatory drugs.

Characteristic of the known technical solutions

It is known that pyrazolidone (3) -azomethinimines of the general formula I by reaction of equimolar amounts of a pyrazolidone- (3) of the general formula II,

in the

R ² and R ³ are as defined above

and an aldehyde of general formula III,

R'-CHO III

in the

R 'has the meaning given above,

in an organic solvent (H. Dorn and A. Otto, Chem. Ber. 101 [19681, 3287 and H. Dorn and H. Graubaum, J. Biol.

Prakt. Chem. 316 [1974], 886).

This procedure can be used on a laboratory scale, i. at batch sizes of 50 to 200mmol, good yields of pyrazolidone (3) -azomethiniminen I achieve.

However, if one tries to move to larger approaches, ie to seek technical approaches, it turns out, using the known procedure, that the composition and quality of the H>. Ctionsprodukte from equimolar amounts of pyrazolidone (3) (II) and aldehydes (III) vary greatly in previously unpredictable "and uncontrollable manner.

The formation of pyrazoliclone- (3j-azomethine imines of the general formula I according to (A) is a reversible reaction which is accelerated by catalytic amounts of an acid.

" ^H 2 ° II + III = * I

^ ♦ H ₂ O

E '. is to assume that in the laboratory method known this acid of autoxidation of aldehydes, z. B. B snzopersäure unc benzoic acid from benzaldehyde (III, R '= phenyl) was supplied, which either contained in the aldehydes used or durci reaction with atmospheric oxygen are formed.

It is still known. Jaß known compounds which belong to the class of the Azopiethinimine but do not have the structure I, easily dimerize or even in the form of their dimers are isolated (R. Huisgen and co-workers., Angew Chem 72 [19601,416 and 75 [19631, 621 and Tetrahedron Letters 1962, 387; B. Agai and K. Lempert, Tetrahedron 28 [19721, 2069; T.Okamoto et al, Chem Pharm ^Bu: (Tokyo) 14 [1966), 512)...!. One molecule of the latter dimers can, under certain known conditions, undergo the same chemical reactions which would also occur to two molecules of the corresponding azomethine imine itself. The latter is, as yet unknown, a consequence of the symmetry properties of the latter dimers. They are namely centrosymmetric, such as. B. the known dimer IV (Ar = phenyl or substituted phenyl), and they can, according to the geschiängelten line drawn in formula IV, decay intermediately in 2 azomethinimine molecules.

Furthermore, it is known that the pyrazolidone (3) -azomethinimine of the general formula I are stable per se crystalline compounds. On the other hand, it is known that these compounds of the general formula I tend to dimerization reactions, we'che by catalytic amounts of pyrazolidones (3) (II) and acids are caused, d. H. by one of the uses of its preparation per se, namely a pyrazulidone- (3) (II), and by a by-product of the starting feed, e.g.

Benzoic acid and / or benzoic acid from the aldehyde (III, R ¹ = phenyl) (H. Dorn and R. Ozegowski, J. prak. Chem. 319 [1977],

The diners of the pyrazolidone (3) azomethine imines (I) have the formula V in which R ¹ , R ² and R ^{3 have} the abovementioned meanings. The Dii..aren V are not centrosymmetric. In contrast to the above-mentioned dimers IV of azomethine imines other than I, the dimers V are neither reversibly capable of providing fyrazolidone (3) azomethine imines I nor of reacting as chemically as 2 molecules of pyrazolidone (3) azomethinimine I.

From a technical point of view, dimers V of pyrazolidone (3) azimethylimine I are undesirable interfering reaction products.

The dimers V are difficult to remove from the pyrazolidone (3) azomethiniines by elaborate and / or lossy separation operations, generally by column separation with silica gel or repeated recrystallization from alcohols or benzene.

So far, no technically applicable method is known with which pyrazolidone (3) -azomethinimine of general formula I in high yield and at the same time in reproducible quality, d. H. especially free of dimers of the general formula V can produce.

Object of the invention

The invention is based on the object of developing a technically feasible process which gives reproducible and high yield pyrazolidone (3) azomethine imines (I) in a technically simple manner without producing uncontrollable amounts of interfering dimers V.

Explanation of the essence of the invention

The object of the invention is achieved by means of a process for the preparation of pyrazolium idon (3) azomethine imines of general formula I in which

R 'is phenyl, 4-isopropyl-phenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, thiophene (2) or furan (2), R ^{2 is} H or methyl,

R ^{3 is} H, methyl or phenyl

mean,

by reacting equimolar amounts of a pyrazolidone- (3) of general formula II,

in the

-4- 263 941

² and R ^{3 have} the abovementioned meanings, with a - :: aldehyde of the general formula III,

R'-CHO III

in the

R ^{1 has} the meaning given above,

by according to the invention in an inert solvent to the reaction mixture of II and III 5 to 80mmol, preferably 5 to 25mmol, an alkali metal bicarbonate added, then heated to 50 to 15O ⁰ C and while returning the indifferent solvent continuously from 0.95 to 1.00 mol of water distilled off, the crystallized Pyrazolidon- (3) -azomethinimin (I) abused or centrifuged and washed with the indifferent solvent. As indifferent solvents are suitable according to the invention cyclohexane, aromatic hydrocarbons, chlorinated aromatic hydrocarbons and carbon tetrachloride.

If the inert solvent is miscible with water, it may be passed through a suitable desiccant, preferably via a molecular sieve such as Zeosorb 3A, prior to recycle.

The alkali metal salts contained in the pyrazolidone (3) azomethine imines (I) which are obtained in crystalline form without further purification may optionally be separated by reacting the pyrazolidone (3) azomethine imines in suitable solvents, preferably benzene, ethanol, n- or i-propanol, n- or i-butanol, dissolves hot, from the undissolved residue hot precipitated or filtered off and then on cooling the filtrate crystallizing Pyrazo ' ^: don- (3) -azomethinimine abrutscht or centrifuged off and dried. For many further processing of pyrazolidone 3) -azomethinimine this fine cleaning is not required.

Apparatus for continuously distilling off the water formed are described in the exemplary embodiments. By means of thin-layer chromatography, it is demonstrated that the pyrazolidone (3) -azazoniethynimines prepared according to the invention are free of dimers V even without fine purification.

The process according to the invention makes it possible, for the first time, to obtain crystalline pyrazolidone (3) -azomsthynimines (I) which contain no dimers V in industrial batch sizes. This eliminates a costly separation of such previously unavoidable in unpredictable amount uncontrollable accumulating dimer V, which represent disturbing and yield-reducing impurities.

The preparation according to the invention of crystalline, dimeric (V) -free pyrazolidone (3) azomethine imines (I) is based on the novel combination of two technically simple measures, namely per se of other processes, e.g. Preparation of esters of acids and alcohols, known continuous removal of water from the mixture of a pyrazolidone- (3) (II), an aldehyde (III) and an inert solvent and the novel maintenance of a low hydrogen ion concentration. Surprisingly, this second measure has no negative effect on the yield of Fyrazolidon- (3) -azoi-ethiniminen (I). The erfir.dungsgemäße combination of the above measures allows the production of any amount of crystalline pyrazolidone (b) -azomethinimine (I) in short reaction times.

embodiments

Beispiß! 1

550 ml of carbon tetrachloride (another 50 ml of CCI ₄ are used in the reaction vessel (RG) in succession to prefill the separators described below), 200.2 g (2.00 mol) of 4-methyl-pyrazolidon- (3) (II: R ² = Me, R ³ = H), 1.68 g (20 mmol) of NaHCO ₃ and 212.2 g (2.00 mol) of benzaldehyde (III: R ¹ = Ph) and mixed by shaking or stirring, after 10 to 20 minutes a homogeneous reaction mixture is formed. On the reaction vessel is vertically upwards a thermally insulated tube and thereupon as a bridge a descending radiator, such as a Liebig radiator with open neck for vacuum connection, mounted. The vertical downwards drain of the cooler is connected to the separator (TV).

The separation device used to continuously separate water from an inert solvent that is specifically heavier than water, e.g. Carbon tetrachloride, consists of the separation space (TR), e.g. a tube with the diameter a and the height h ,, followed by a U-tube (UR) with the diameter 0.18 a to 0.36 a connected vertically downwards. The separation chamber is provided with an obliquely downwardly pointing side drain pipe (AR) with the diameter 0.25 a to 0.4 a. The drain pipe is attached to the separation space that at the point of the drain pipe to the separation space, the lower wall of the drain pipe to 0.33 h, higher than the starting point of the U-tube to the separation space. The "free", ie not connected to the separation space leg of the U-tube is bent obliquely downwards at an angle greater than 90 °, the height of the "free" leg of the U-tube, calculated from the lowest point of the lower U-tube -Wandung to the lower U-tube wall at the point of the above turn of the U-tube, h <2.

The height of the attached to the separation space bottom leg of the U-tube, calculated from the lowest point of the lower U-tube wall to the starting point of the U-tube to the separation space is h ₃ , where h _{3 is} at least 0.9 h. The height h ₂ is (h ₃ + 0.33 h,) - h ₄ , and the height difference h _{4 of} the two outflow points of the separator is 0.12 a to 0.36 a.

In the separation space, a funnel (TRI) is mounted, whose diameter is slightly smaller than the diameter a of the separation space. The lower end of the funnel outlet pipe ends at the height h ₂ above the lowest point of the lower U-tube wall.

The bent "free" leg of the U-tube of the separator is connected to the reaction vessel via a short tube of material resident to the solvent, eg of Teflon for CCI ₄ , with a short Tiückflußkühler between the reaction vessel and this tube (RK) is switched.

For approaches up to 12 mol each pyrazolidone (3) (II) and aldehyde (III) commercially available glass grinding equipment can be used. The reaction vessel is then a two-necked flask or a Drcihalskolben, the third neck for an internal thermometer or a stirrer is available. The separator then consists of glass with a = 26mm, h, = 44mm and h ₃ = 49mm. At the top of the glass separating chamber, a standard grounding sleeve NS 29 is mounted in the top, and in the separating space 3 glass bumpers are located above the drainage pipe

fed, who carry the funnel. For larger approaches, a proportionally enlarged separator is * jlas. Teflon or metal used.

Instead of the above-described apparatus including the separation device, in the use of an inert solvent which is specifically heavier than water, such as. B. CCI ₄ , also in Ullmann's Encyclopedia of techn. Chemistry,

Volume 1, page 446 (Verlag Urban and Schwarzenberg, Munich-Berlin 1951) shown column head (Fig. 6931 .c.) As such with closed left lower and upper right open upper tap or one of the latter similar device without the lower left Cock are aufgesotzt on the reaction vessel.

The mixture is heated in the reaction vessel gradually to boiling (bp CCI ₄ : 76.7 ° C, b.p. of the azeotrope with water: 66 ⁰ C), the temperature of the heating bath without affecting the quality of the product to 140 to 150 ⁰ C may be increased, but not necessarily (see boiling point above) is required. During this, CCI ₄ and water distill off, with CCI ₄ continuously flowing back into the reaction vessel, for. B. over the bent "free" leg of the U-tube of the separator, Teflon tube and reflux condenser, and continuously runs off water, eg., Via the drain pipe of the separation chamber of the separator.

Within 25 to 50 minutes after the start of heating 63 to 75% of the theoretically expected amount of water (36ml, 2.00mol) are already distilled off. It is still boiling for 2 to 3 hours, after which the water separation is complete.

The hot reaction mixture is cooled either in the reaction vessel or in another vessel, in which it is still hot, for example a beaker, with stirring to room temperature, the almost colorless crystallizing 1-benzylidene-4-methyl-pyrazolidone (3) -azomethinimin (l: R '= Ph, R * = Me, R ³ = H), covered with CCI ₄ , then stirred with 500 to 600 ml of CCl ₄ from 30 to 35 ⁰ C for 15 minutes, cooled to 20 to 25 ° C, the white, crystalline i -Benzyliden-4-methyl-pyrazolidone- (3) -azomethinimin suction filtered, with CCI ₄ gei'nckt and dried at 8O ⁰ C. This gives 331.2 to 361,3g (88 to 96% d. Th.) Of mp. 137-139 ⁰ C.

The product is free of dimer V (R ¹ = Ph, R ² = Me, R ³ = H), which can be controlled in the following way: A sample of the above product is applied to a TLC plate with silica gel G. For comparison, a sample of the mixture of diastereomers of dimer V (R ¹ = Ph ₁ R ² = Me ₁ R ³ = H) or a sample of diastereomer V obtainable by recrystallization from i-propanol (R ¹ = Ph, R ² = Me, R ³ = H) of mp. 204 to 205 ° C (the diastereomeric mixture and the pure diastereomer of mp. 204 to 205 ⁰ C of the dimer V have the same Rf values under the conditions described). The pyrazolidone (3) -azomethinimine (I) and the dimer (V) are separated with the mobile phase ethanol and developed with iodine:

Rf (MR ¹ = Ph ₁ R ² = Me, R ³ = H) = 0.41;

R _F (V: R ¹ = Ph, R ² = Me, R ³ = H) = 0.64.

Already the absence of a second spot on a TLC control with higher R _F than that of pyrazolidone (3) azomethine imine (I) carried out according to the above information indicates the absence of dimer (V).

The pyrazolidone (3) azomethinimine I (R ¹ = Ph, R ² -Me, R ³ = H) can be finely purified by recrystallization from 3 to 4 times the amount of benzene, mp 139-141 ° C.

Example 2

1100 ml of benzene, 200.2 g (2.00 mol) of 4-methyl-pyrazolidone (3) (II: R ² = Me, R ³ = H), 4.20 g (50 mmol) of NaHCO ₃ and 212, are added to the reaction vessel. 2 g (2.00 mol) of benzaldehyde (III: R ¹ = Ph) and then heated with stirring gradually to boiling (bp Sb: 80.2 ° C, b.p. of the azeotrope with water: 69.2 ° C). Within 3 to 4 hours, 34.5ml of water separate.

The reaction vessel is equipped with a mechanical stirrer, internal thermometer and a conventional attachment for the refluxing separation of water and solvents which are specifically lighter than water. After the end of the separation of water, the water collected at the bottom can be let out of the water separation tube, then the reaction vessel is allowed to sit a short column packed with stranded or spherical molecular sieve A3 and a reflux condenser and allowed to boil for a further 20 to 40 minutes.

The hot reaction mixture is allowed to cool either with stirring, or you put her 200 to 300 ml of benzene and filtered hot. 319.9 to 353.8 g of 1-8-cylidene-4-methyl-pyrazolidone (3) -azomethinimine are separated at room temperature (I: R ¹ = Ph, R ² = Me, R ³ = H) (85 to 94%) Th.) As a white, crystalline product, which is covered with benzene and dried at 80 ⁰ C, mp 137 to 139 ⁰ C.

The TLC control described in Example 1 shows that the above product is free of dimer V (R ¹ = Ph, R ² = Me, R ³ = H).

Example 3

Analogously to Example 1 and 2 are prepared:

a) 1- (4-isopropyl-benzylidene) -pyrazolidone- (3) -azomethinimine (I: R ¹ = 4-Me ₂ CH-C ₆ H ₄ , R ² = R ³ = H), m.p. 153-154 ⁰ C.

b) 1- (4-Chloro-benzylidene) -pyrazolidone- (3) -azomethinimine (I: R ¹ = 4-CI-C ₆ H ₄ , R ² ρ R ³ = H), mp 214-217 ° C ,

c) 1- (4-methoxy-benzylidene) -pyrazolidone- (3) -azomethinimine (I: R ¹ = 4-MeO-C ₆ H ₄ , R ² = R ³ = h), m.p. 187-189 ° C ,

d) 1- (3,4-dimethoxy-benzylidene) -pyrazolidone- (3) -azomethinimine (I: R ¹ = 3,4- (MeO) ₂ -C ₆ H ₃₁ R ² = R ³ = H), m.p. 171 to 172 ⁰ C.

e) 1-Thenylidene-pyrazolidone- (3) -azomethinimiri (1: R ¹ = thiophene (2), R ² = R ³ = H), mp 239-241 ° C.

f) 1-furfurylidene-pyrazolidone (3) -azomethinimin (I: R ¹ = furan (2), R ² = R ³ = H), mp 214-216 ⁰ C..

g) 1 benzylidene-5-methyl-pyrazolidone (3) -azomethinimin (I: R ¹ = Ph, R ² = H, R ³ = Me), mp 161-162 ⁰ C. h) 1-benzylidene. 5-Phenyl-pyrollzolidone- (3) -azomethinimine (I: R ¹ = R ³ = Ph, R ² = H), m.p. 200-220 ° C.

Claims (1)

Invention claim: 1. Process for the preparation of pyrazolidone- (3) -azomethine-imines of general formula 1, in the R ^{1 is} phenyl, 4-isopropyl-phenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, Thiophene (2) or furan (2),
R ^{2 is} H or methyl,
R ^{3 is} H, methyl or phenyl
mean,
by reacting equimolar amounts of a pyrazolidone- (3) of general formula II,