DE1468351C - Process for the preparation of hydro chlorides of N aryl and N heteroarlyamines - Google Patents

Description

I 468

It is known that N-Ary! Amidines by reacting a nitrile and an aromatic amine in the presence a metal catalyst such as aluminum chloride or zinc chloride. Further it is known to produce such compounds by reacting the nitrile and the aromatic amine hydrochloride in a solvent such as ether in the absence of metal halide. None however, these methods are entirely satisfactory. The former method has the use of one Metal halides as an additional substance in the reaction mixture with the result that Metal complexes are obtained which have to be decomposed and wherein the metal has to be removed, before pure amidine compounds can be obtained. The second procedure also mentioned gives only low yields of the desired amidine. The 'present invention relates to a method for Production of N-aryl and N-heteroarylamidines that are free from the disadvantages of previous methods and provides the desired products in high yield and in a highly pure form.

The term "heteroaromatics" is used in "Chemie der Heterocyclen", Verlag Chemie GmbH, 1962 explained in more detail on pages 32 ff.

The subject matter of the invention is a process for the preparation of hydrochlorides of N-substituted ones Amidines of the general formula

30;

C-R

HN *

wherein R and R _{1 are} aryl or heteroaryl, by heating a primary amine hydrochloride of the formula

R ₁ NH ₂ -HCI. ■

and a nitrile of the formula RCN, in which R and R _{1 have} the above meanings, under anhydrous conditions in an organic compound as the reaction medium, in which the reaction is carried out in a polychlorinated benzene which is liquid at the reaction temperature and has a boiling point below 222 ° C.

The procedure can be reproduced as follows will:

R ₁ -NH ₂ - HCl + R- ^ CN

^x c-R

NH

HCl

■ ■ ·. . '■■ .- · ■■' ■

wherein R and R _{1 represent} an aryl or heteroaryl radical, for example phenyl, naphthyl, substituted phenyl or naphthyl, or pyridyl and quinolinyl radicals.

A preferred embodiment of the invention is based on the application of the invention Process for the preparation of amidines of the formula

C-R

Il

NH · HCI

Wherein R ₂ denotes a phenyl, substituted phenyl and in particular halophenyl, pyridyl or naphthyl residue or a cyclic 5-membered heteroaromatic radical with at least 2 carbon atoms in the hetero ring and nitrogen, sulfur and / or oxygen as heteroatoms. Typical examples of such heterocyclic radicals are furyl, pyrryl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl or imidazolyl. R ₂ can be hydrogen, a hydrocarbon radical such as lower-alkyl, 'z. B. methyl, ethyl or an aryl radical, e.g. B. phenyl, or a lower alkoxy radical, such as methoxy or ethoxy, or a phenoxy, methylthio or phenylthio radical. It can be seen that such amidines are obtained by reacting aniline hydrochloride or an aniline hydrochloride substituted in the 3-position with the appropriate nitrile. If an N-pyridylamidine is to be produced, an aminopyridine is used instead of: aniline; Such reaction components are known or easily obtainable by methods known per se.

Although the amine is expediently introduced into the reaction mixture in the form of the free base, at least sufficient chlorine _: hydrogen is added to convert all of the amine into the hydrochloride; therefore, as shown in the above scheme, the amine reactant is actually the acid salt. The amidine obtained is obtained as the hydrochloride, but the amidine can be obtained in the form of the free base, if desired, by neutralizing the acid addition salt with a base such as an alkali hydroxide. .

The process is accomplished by heating the aromatic amine hydrochloride and nitrile in one Polychlorobenzene carried out as the reaction medium. It is important that the reaction take place under anhydrous Conditions is carried out. Because the amine. and nitrile react on an equimolar basis, it is sufficient when equimolar amounts of the reaction components are used. But you can also use a molar Use excess of either the amine or the nitrile, preferably about 1 to 10% molar Excess of nitrile, since this results in contamination of the "amidine obtained" with the amine reaction component is reduced to a minimum. .

A further improvement in the yield is made by using an excess of hydrogen chloride obtained in conjunction with the polychlorobenzene solvent;

For best results, at least a 5%, preferably a 1.0 to 50% excess of hydrogen chloride is used used. ■

The addition of excess hydrogen chloride is expediently carried out by a Flow of gas into the reaction mass during most or all of the total reaction Total reaction time is initiated. Alternatively, the total amount of acid used and a weak one positive hydrogen chloride pressure (0.07 to 0.35 aiii) be maintained during the reaction. In this latter case a closed reaction vessel is used used. This is more convenient for a large facility than for small-scale experiments.

For the sake of embarrassment, it is preferred that the Use amine in the form of the free base and that

Hydrochloric! directly in the o-dichlorobenzene reaction medium to build. Good results will be achieved by adding enough acid to achieve this, heating of the mixture of nitrile and amine hydrochloride in o-dichlorobenzene to the reaction temperature and addition of the excess of acid achieved during the response period. If necessary however, all or part of the excess hydrogen chloride can be added at the beginning will.

The polychlorinated benzene should have a boiling point below 222 ° C. A dichlorobenzene or trichlorobenzene or a mixture of these is preferably used as the solvent. In many cases the commercially available polychlorobenzenes are mixtures of isomers, and such mixtures are satisfactory for the process according to the invention: All members of this group of solvents are well below the reaction temperature, which is preferably between 100 and 165 ° C., in particular 115 to 150 ⁰ C, is liquid (1,3,5-trichlorobenzene from; MP = 63 ° C is the highest melting) and boiling above the preferred reaction temperature (m-dichlorobenzene from MP = 172 ° C is the lowest Boiling), but this is not essential as the reaction can be carried out at the reflux temperature of the solvent or even above the boiling point under pressure. Of the six dichlorobenzenes and trichlorobenzenes, ie o-, m- and p-dichlorobenzene and 1,2,3- ,, 1,2,4- and 1,3,5-trichlorobenzene, o-dichlorobenzene is very particularly preferred Reaction medium used, since excellent yields of amidine hydrochloride are obtained with this,

The amount of solvent used is not critical as long as it is sufficient to keep the reaction mixture liquid. The N-aryl or hydroarylarhidine hydrochloride are practically insoluble in the medium and crystallize as they progress the reaction fail or fail as the reaction proceeds. '

Among the preferred temperature conditions is the formation of N-aryl or N-heteroarylamidiri in _; Virtually complete from 1 to 4 hours, and best results are obtained by performing Procedure Vf for ₁ to 3 hours. Since the amidine hydrochloride is insoluble in the reaction medium, it can easily be obtained in high purity by cooling and filtering the reaction mixture. Alternatively, the amidine hydrochloride can be extracted in water, in which it is highly soluble, and the aqueous solution containing the desired product can be separated from the water-immiscible o-dichlorobenzene or other di- or trichlorobenzenes according to procedures known per se .

In this way, amidines of the formula / '■:

R.

-N

C-R

NH-HCI

wherein R ₁ and R have the meanings given above, are obtained from the suitable aromatic amines and nitriles in very high yield. Buckling of over 90% of theory is usually obtained under the preferred conditions. The amount of readily recoverable amidine is close to the quantitative amount under such preferred conditions, ie when using o-dichlorobenzene solvent and excess hydrogen chloride when the o- Dichlorobenzene is recycled for subsequent experiments, since this eliminates a loss of recoverable product due to a certain poor solubility in the solvent.

B e i s ρ i e I 1

A solution of 41.8 g (0.45 mol) of aniline and 50 g (0.45 mol) of 4-cyanothiazole in 200 ml of o-dichlorobenzene is heated to 14O ⁰ C. 20 g (0.55-mol) of hydrogen chloride are then added within 2 '/ ₂ hours under agitation. During the first half hour, aniline hydrochloride separates out as a solid substance, but it soon liquefies. After the reaction time, the mixture is cooled to 25 ° C. and the. Crystals of N-phenyl- (thi; rzol-4-amidine) hydrochloride are collected by filtration. This gives 105 g (9'6% igc yield) of product, mp = 256 to '259 ⁰ C.

If 0.45 mol of hydrogen chloride is used, so the yield of N-phenyl- (lhiazol-4-amidine) is 80% of theory. ; .

At s ρ ic I 2

1.25 moles of aniline and. 1.25 mol of 4-cyanothiazole are added to 550 ml of o-dichlorobenzene in a 1-liter vessel which is equipped with a thermometer and a gas inlet tube extending below the surface of the liquid. The reaction components are heated to 105 ° C. while stirring, at which point the introduction of dry hydrogen chloride is started. A total of 1.5 mol of gas are added, the temperature rising to 135 to 140 ° C. during this time. After completion of the addition of the gas, the reaction mass with stirring for 2 ¹ ₂ hours at 140 J is heated to l45 ^r C. ■ - - ■ - .. - '' ■■■■

The mixture is then cooled to KK) C and added to 1,200 ml of water. The. pH of the aqueous phase is maintained at 4.5 with concentrated sodium hydroxide. . . ·

After thorough mixing, the mixture is allowed to separate into an aqueous phase and an δ-dichlorobenzene phase. The phases are separated. The aqueous phase contains over 270 g of N-phenyl (thiazol-4-amidine) hydrochloride, as is the case with potentioinetric determination with 0.1 n sodium hydroxide, end point PK ₁ V ₂ = 7.5. indicates. . ■ ■ ' ^v '■;

B e i s ρ ie 1 ... 3-.

Drier gaseous. Hydrogen chloride is added in an amount of 7.2 milliequivalents per minute a stirred solution of 20.6 g (0.187 moles) of 4-cyanothiazole and 16.9 g (0.182 mol) of aniline in 80 ml of o-dichlorobenzene admitted. The o-dichlorobenzene contains some of the isomeric p-dichlorobenzene. After 25 minutes all aniline is converted into aniline hydrochloride and the temperature rises from 25 to 45 C. The supply of hydrogen chloride is stopped and the mixture is stirred for 95 minutes, during which Time the temperature drops to 25 C.

The mixture is then heated to 140 ° C. for 1 hour, during which time gaseous hydrogen chloride is used in an amount of 0.6 milliequivalents

is fed per minute. The reaction mixture will 2 1/2 hours with further addition of hydrogen chloride held at .140 to 145 ° C. In total, an approximately 40% excess of acid is added. To this cell is N-phenyl- (thiazol-4-amidine) hydrochloride in the reaction mixture in the form of crystals present. The mixture is cooled to 30 ° C. and 200 ml of water are added to to dissolve the amidine hydrochloride. The resulting mixture is stirred vigorously while the pH value adjusted to 4.5 with 34% sodium hydroxide. Stop stirring and leave the layers separate. The upper aqueous layer is separated from the o-dichlorobenzene layer. It contains 41 g N-phenyl- (thiazol-4-amidine) hydrochloride as shown by ultraviolet testing (94% yield).

B e i s ρ i e I 4

16.9 g (0.182 mol) of aniline and 19.3 g (0.187 MoI) ■ Bcnzonilril are added to 90 ml o-dichlorobenzene at 25 to 3O ⁰ C. 6.65 g (0.182 mol) of gaseous dry hydrogen chloride are introduced into the mixture within about 30 minutes / The mixture is then heated to 140 to 145 ° C for 30 minutes, during which time 2.7 g of dry hydrogen chloride are fed mixture was 2 '/ ₂ hours at 140 heated to 145 ° C and then cooled to 25 to 30 "C. the solid crystalline N-Phcnylbcnzamidinhydrochlorid (yield about 86% of theory) is filtered off and dried. After recrystallization from methanol-ether has it has a melting point of 231 to 232 ⁰ C..

B e i s ρ ie I 5

10.5 g (0.112 mol) of 3-aminopyridine and 12.3 g (0.112 mol) of 4-cyanothiazole are added to 50 ml of o-dichlorobenzene at about room temperature. 4.1 g (0.112 mol) of dry hydrogen chloride are introduced into the mixture obtained in order to convert the 2-aminopyridine into the acid salt. The mixture obtained is ^{heated to 135 to 140 °} C., and a further 2.0 g of dry hydrogen chloride are introduced. The reaction mixture is stirred for 3 hours at 135 to 140 ⁰ C, during which time N- (3-pyridyl) -thiazol-4-amidine hydrochloride crystallized. The mixture is cooled to about 2O ⁰ C and filtered the amidine. Recrystallization from methanol-ether gives the pure material with a melting point of 223 to 225 ° C. in a yield of 85% of theory. _:

In an analogous manner, the corresponding nitriles are obtained using the nitriles mixed in below N-phenylamidine hydrochloride.

Nilril-KeaktioMskomponcnlc Iiiulprodnkl 1,2,3-thiadiazoI-4-nitrile N-phenyl- (1,2,3-thiadi- ■ azoI-4-amidine) -hydro- chloride Thiophene-2-nitrile N-phenyl- (thiophene- 2-amidine) hydrochloride Thiophen-3-nitrile N-PhenyI- (thiophene- - 3-amidine) hydrochloride Pyridine-3-nitrile N-phenyl- (pyridine- 3-amidine) hydrochloride Furan-2-nitrile N-PhenyI- (furan- 2-amidine)

Those obtainable by the process according to the invention Amidine hydrochloride have a wide variety of uses, but are in particular as Intermediates for the preparation of benzimidazoles substituted in the 2-position !! and azabenzimidazoles suitable that are effective as anthelmintic agents. '

Claims (4)

Patent claims: 1. Process for the preparation of hydrochlorides of N-substituted amidines of the general formula C-R wherein R and R ₁ mean aryl or heteroaryl, by heating a primary amine hydrochloride of the formula ^v "■ R ₁ NH ₂ • HCl and a nitrile of the formula RCN, in which R and R _{1 have} the above meanings, under anhydrous conditions in an organic compound as the reaction medium, characterized in that the reaction is carried out in a polychlorinated benzene which is liquid at the reaction temperature and has a boiling point below 222 ° C undertakes. 2. The method according to claim 1, characterized in that in the presence of excess Hydrogen chloride works. 3. The method according to claim 1 or 2, characterized in that the reaction medium is a di- or trichlorobenzene, especially o-dichlorobenzene, begins. 4. The method according to one or more of claims 1 to 3, characterized in that one works at 100 to 165 ° C.