DD151447A1 - PROCESS FOR THE PREPARATION OF AMIDINES AND THEIR SALTS - Google Patents

Abstract

The invention relates to a process for the preparation of amidines and their salts, especially of N, N, N'-trisubstituted benz, pival or adamantamidines of the formula I, wherein R & exp1! substituted phenyl, R & exp2! and R & exp3! Alkyl groups with 1 to 4 carbon atoms or an alkylene group (CH & ind2!) & Indn! with n = 2-6 or the oxapentamethylene group. The aim of the invention is the preparation of amidines with biological, especially antiviral effect. These compounds are e.g. by activation of N-substituted carboxylic acid amides of substituted or unsubstituted benzoic acid, pivalic acid or adamantanecarboxylic acid with SOCI & ind2 !, PCI & ind5! or also POCI & ind3! and to obtain further reaction with suitable secundary or primary amines. The free amidines are optionally converted into salts. Formula.

Description

Process for the preparation of amidines and their salts

Field of application of the invention

The invention relates to a process for the preparation of, amidines of the general formula

and their salts, wherein R is phenyl or in possible positions by alkyl, alkoxy, halogen, nitro, hydroxyl, amino or substituted by alkyl and Acylaminogrupρen phenyl, tert-butyl or adamantyl (1) and R is an aryl radical, for example phenyl or in possible positions sub-

2 3

substituted phenyl as indicated at R, R and R ^ denote lower alkyl having 1 to 4 carbon atoms, preferably

2 3

Example, an ethyl group or R and R together with the nitrogen atom of the amidino moiety a ^ heterocyclic

2 3

3- to 7-membered ring in which R, R 1 is a methylene bridge / - (CH ₂ ) - / with η = 2 to 6 or a 3-oxapentamethylene bridge / -CH ₂ -CH ₂ -O-CH ₂ - CH ₂ - / represents. This lT, N, N ^f -trisubstituierten amidines and their salts with an inorganic or suitable organic acid are used as substances with diverse biological activity - particularly anti-viral activity and / or as inhibitors of the respiratory chain - as a means of pest and weed control, as well as in veterinary medicine of interest.

~ 2 - Characteristics of the known technical solutions

It is known that the amidine structure of natural and synthetic substances is often capable of biological interaction, so that many amidine waste products have been included in the therapy (A. Kreutzberger, Portstages d. Arzneimittelforschung, 21, 356-445 (US Pat. 1968)). It falls on _$ that the long-known. 1 ", U, IV trisubstituted amidines of the general formula I with any radicals R, R, R-> H play a relatively minor role, since so far considered at least one hydrogen atom amide nitrogen to form a hydrogen bond for the biological effect as important (eg: JU Grafe, H. Liebig and H. Pfetzing, Arzneim.-Forsch. (Drug Res.) 24 » ¹ 53 (1974).)

Among the known with virustatic effect compounds having an amidine structure, there are no ΪΤ, Η, υ'-trisubstituted representatives, as they are characterized in the formula I. For example, by G.May, D.Peteri u. K.Hummel, Arzneimittel.-Forsch. (Drug Res.) 28, (I), 732 (1978), pointed out that even Κ, ίΤ'-disubstituted adamantane-1-carboxylic acid amidines, in contrast to the ΪΓ-monosubstituted representatives unfold no antiviral activity.

Similar amidine derivatives with spasmolytic and psychostimulant action are described in DE-OS 1768787, special derivatives of butyramidine in DE-OS 2132113 and of acetamidines in DE-OS 2029298, 2029299 for use as medicaments.

In the BE-PS 540870 the representation of basic condensation products by the conversion of ϊϊ-disubstituted acid amides, especially dimethylformamide is described with primary amines a3.s intermediates, for v / eitere syntheses are identified. Next γ / ground in DE-OS 2328341 the aliphatic. Amidines of the structure

attributed therapeutic properties. (Lowering blood sugar levels) »

_ 3 -

Object of the invention.

The object of the invention is to provide novel N,! T,! SP-trisubstituted amidines having a variety of biological activities, especially antiviral properties and / or inhibitory effects on the course of the respiratory chain. Such substances are of interest inter alia as pharmaceuticals, as active ingredients in the control of pests and weeds and in veterinary medicine,

Explanation of the essence of the invention

The invention is based on the object, a process for the preparation of hitherto unknown amidines and their. Specify salts, especially of U, Ii, U ¹ -trisubstituted amidines with antiviral activity and / or with an inhibitory effect on the respiratory chain _o According to the invention, a suitably activated carboxylic acid amide R-CO-HHR with the

1 for R and R in the form of an imidic acid or amide acid chloride (H. Ulrich, The Chemistry of Imidoyl Halides, Plenum Press - Hew - York - 19β8.) With a secondary amine HII (R ² R - ⁵ ) with the R ² and R 1 explained importance in the presence of a proton acceptor, for example with triethylamine or pyridine, in an absolute inert solvent or else only in excess triethylamine to give reaction (Houben-Weyl, Methods of Org. Chemistry, Volume 11) / 2, 57ϊ Georg Thieme Verlag Stuttgart).

The activation of the carboxylic acid amide is carried out by conventional reaction with excess thionyl chloride or optionally an equivalent amount of phosphorus pentachloride in an inert solvent with exclusion of moisture, which sometimes beneficial the addition of a few drops of dimethylformamide This resulted in an imidic acid in a few cases, a Aniidsäurechlorid; These Ausgangsverbindvingen are predominantly new or inadequately described, they can also be further processed as raw products.

As a secondary amine is a lower dialkylamine, preferably diethylamine, or an amine such as aziridine cyclisch.es _$ azetidine, pyrrolidine, piperidine, hexamethyleneimine or morpholine is used in particular. The above reaction with these secondary amines to Η, Η, Η'-trisubstituted amidines is conveniently carried out in absolute benzene, toluene or ether in a molar ratio of 1: 1 in the boiling heat in 1 5 hours. Ifach usual workup, the amidines can be isolated by vacuum distillation or by recrystallization or by purification over a salt, for example the sulfate or hydrochloride in pure form. Similar Κ, Ιί, Η'-trisubstituted amidines are obtained when a Η, Η-disubstituted carboxylic acid amide of the general formula R-CO-ER ² R- ³ with the meaning given for R, R ² and R ³ with phosphorus oxychloride in an inert Activated solvent and then with heating with a primary aromatic amine HpHR, optionally in a solvent is reacted. This initially results in a phosphorous-containing intermediate product, from which by treatment with an alkaline solution, sodium hydroxide solution or sodium carbonate solution, for example, the amidine is liberated (H.Bredereck, R.Gomper, K.Klemm H.Rempfer u _{e, e} Chem Ber. 92, 837 (1959)).

R-C

or.

Cl

R-C '

  THEIR

Cl

Cl

^θ HHR ² R ³

A θ

OH

R-C

IJR ² R ³

POCl ^

.0POCl ₂ ^ HR ² R ³ ·

Cl

R-C-OPOCl,

ο 3

It is sometimes convenient first to dissolve the disubstituted carboxylic acid amide and the primary amine together and the phosphorus oxychloride to the boiling solution of both components

_ 5 -

Dilute dilution with a solvent. The resulting phosphorus-containing intermediate is decomposed by alkalization as described. The amidine obtained thereafter is isolated and purified as usual.

The amidines can be conveniently converted into their salts in a solvent with inorganic or suitable organic acids. Particularly suitable are the hydrochlorides, hydrobromides, sulfates, phosphates and the acetates, succinates, salicylates or adamantoates. The amidines according to the invention and their previously unknown salts are unexpectedly characterized by an antiviral activity and / or an inhibitory effect on the respiratory chain. These substantive properties are surprising because hitherto such biological effects were not foreseeable for H, I, F, Ir'-trisubstituted amidines.

Allsführungsbeispiele

Imidic acid chlorides - amic acid chlorides

Method A: A B-arylcarboxylic acid amide is boiled with at least t-1.5 equivalents of thionyl chloride in absolute carbon tetrachloride, benzene or even excess thionyl chloride until gas evolution ceases. Tray Removing the solvent i.Vak. The imidic acid chloride can be distilled in vacuo. Often the crude product is suitable for further processing. In some cases, this produces the amic acid chloride, which is more advantageously obtainable by method A / 1.

Method A / 1: The IT-Arylcarbonsäureamid is reacted with 2.5 moles of thionyl chloride with the addition of a few drops of dimethylformamide to accelerate the reaction in the boiling heat and worked up as above.

Method B: An N-arylcarboxylic acid amide is reacted with the equivalent amount of phosphorus pentachloride in absolute benzene or without solvent. The phosphorus oxychloride formed is i.Vak. largely disturbed

  r * £

after and after. Add a little bit of dry benzene or toluene completely removed. The imidic acid chloride is then i.Vak. distilled or used as crude product.

Table 1 Imidic acid chlorides / amic acid chlorides

amidines

Method. To 0.1-0.5 mol of imidic acid chloride in absolute ether, benzene, ethylene chloride or toluene is added 0.1-0.5 mol of an equimolar mixture of secondary amine and triethylamine and heated to boiling for 1-5 hours , It can also, excess triethylamine as. Solvent can be used. It. is sucked from precipitated triethylamine hydrochloride, which is washed with a little ether or the solvent used. After removal of the solvent, the amidines i. Vak. distilled or usually obtained after rubbing as crystalline substances. By recrystallization from ethanol or methanol, also in a mixture, with water, or from hexane, the amidines are obtained pure. Particularly pure amidines are obtained by absorption from the organic phase with dilute sulfuric acid or hydrochloric acid. For this purpose, the aqueous-acid solution of the amidines is optionally made alkaline after filtration and extracted with ether. After drying and distilling off the ether, the amidines remain in the form of mostly rapidly crystallizing oils.

Method B:

a) To the diluted with benzene or toluene solution of a Ή- disubstituted carboxylic acid in phosphorus oxychloride, which is stirred at room temperature for 2-5 hours, is added dropwise a primary aromatic amine or its solution in benzene and heated for 1-5 hours to 70-80 ^J. , The formed lower layer consists of a phosphorus-containing intermediate product which is separated, covered with ether and coated with. Alkali solution or 40% sodium carbonate solution is decomposed with ice to alkaline reaction, lach separating and drying the ethereal extract ¹ v / ird the Amidin by distilling off the solvent by

Distillation i.Vak. or recrystallization from methanol, ethanol - optionally with the addition of water - pure.

Favorable proportions of the components are: HjH-disubst.amide: POCl-: prim.aromat. Amine 1.5 - 3: 1 - 1.3: 1-2 (Xquival.)

b) The solution of 0.1 mol of N-disubstituted carboxylic acid amide and 0.2 mol of primary aromatic amine in about 100 ml of absolute benzene is added dropwise to the boiling solution of 0.13 mol of POClU in 50 ml of absolute benzene and refluxed for a few hours After cooling, the mixture is decomposed with ice and caustic soda to alkaline reaction and taken up with benzene or ether, the amidine and isolated in the usual manner and purified.

The yields given in Table 2 are based on imide acid chloride or amic acid chloride used and pure amidine (pure yield).

Table 2 Amidines Salts of amidines.

The free amidines can be converted in a customary manner into their salts, such as hydrohalides, sulfates or salts of suitable organic acids.

Table 3 Salts of amidines (amidinium salts)

Table 1

Imide acid chlorides R ¹ = C ₆ H ₄ -r

R = r = Sciimp. ° C. ; Sdp, / mmHg-out method / lite

does Ratio use?

6 5 H 4o-41 ° 96 A 1,3,5,6 tt 2-CH ₃ 125-13o%, 6 73 A tt 3-GH ₃ 15o-155 ° / o, 5; 49-5o ° 7o A CM ti 4-CH ₃ 188 ° / 12; .51-52 ° 80 A 2 It 4-Br 192-195% 75 A It 4-MO ₂ 118-12o ° 7o A 3 4-CH ₃ -C ₆ H 4 ^H 49-52 ° 54 FROM 1,3,5,1o. tt 4-CH ₃ 53-55 ° 9o A 11 tt 2-Cl 158-164%, 3 66 A tt 3-Cl 168-174%, 5 77 A tt 4-Cl 174-178%, 5 86 A 4-CH ₃ OC ₆ H ₄ H 183-185%; 73-76 ° 80 FROM 1,3,5,9,11 It 3-CH ₃ 158-162%, 5 52 FROM tt 4-CH ₃ 54-55 ° 80 A, B 4-PC ₆ E ₄ 3-GH ₃ 50-53 ° 83 A tt 4-CH ₃ 60-65 ° 74 A tt 3-SO ₂ 99-1o3 ° 69 A It 4-HO ₂ Oil (raw) 9o A 4-Cl-C ₆ H ₄ H 139.5%, 5; 67-69 ° 82 FROM 1,4,5,8 » 3-GH ₃ 21o ~ 215 ° / 2o 80 A 4-Br-C ₆ H ₄ H 272-275% lme Vak .; becomes crystalline 151-154%, 1; 76-78 ° 78 81 - A, B A, B 1,7,9 » 3-CH ₃ 1-60-164 ° / 2.5 62 A tt 4-CH-, 9o-91 ° 9o A

Mp. ⁰ C.; Sdp «/ mmHg

Off Method / Lit.

TC ₆ H ₄ H

tr

Adamantyl H

12Ό-121 ¹

140-144 3-Cl 125-128 ° H 55-58%, 2

3-CH "72-78%, o3

55-6o ⁽

86 A 68 A 95 A 84 A 85 A 89 A

1,3,5,7

Amidsäurechloride

MH-R "

R-C

 egg

Cl

Mp. C.

Aus method / literature

^ H. 4-CIL ₅ -CrH, b 4 3 o 4 gH ₄ 4-Cl-C ₆ H ₄

117-120 117-119 ⁽

A, A1 A1, B

12

1) KoZieloff, H. Paul u. G. Heyday, Chem. Ber. 92, 357 (1966); K. Zieloff, Dissert. Humboldt Univ. to Berlin I966.

2) F.Just, Ber. dt sch. former Ges. 1 [9, 980 (1886); CS Gibson u. JOA Johnson, J. Chem. Soc. / London / 1929 , 2743.

3) I.Ugi, F.Beck u. U. Fetzer, Chem. 35_ _t 126 (1962).

4) G.H.Colemann u. R.E.PyIe, J.Amer.chem.Soc. 68,2007 (1947).

5) H. Ulrich, The Chemistry of Imidoyl Halides; Plenary Press, Few York 1968, 76.

6) J.v.Braun u. W. Pinkernelle, Ber.dtsch.chem.Ges. 67th, 1218 (1934)

7) R, C.Shah u. JSChaubal, J. Chem. Soc. / London / 1932 , 65Ο. 8) AV / Chapman, J. Chem. Soc. / London / 1927 , 1743.

9) HLWheeler u. TBJohnson, Amer.chem.Soc. 2 °. * ² 4 ( ¹ 9O3).

10) K.D.Kulkarni u. R.C. Shah, J. Indian chem. Soc. 2 ^ 6,171 (1949).

11) LH Briggs, RCCamtie, J.Ch.Dean et al. PS Rutledge, Austr. J. Chem. 1976 , (29), 357.

12) I.Gfattermann u. CNeuberg, Ber.dtsch.ehem.Ges. 25,1082 (1892).

Table 2

R-C

MR

R = r = C ₂ H ₅ Mp. ° C. /Sdp.C/mmHg Yield% Method / literature 1 O ₆ H ₅ H <CH ₂ ) ₂ / 18o-182 ° / 11 72 A It H (CH ₂ ) ₂ O (CH 56 to 57.5 ° 60 A It H CH _{3 2} ) ₂ 72-75 ° 67 A tt 2-CH ₃ C ₂ H ₅ / 13o ° / 1 56 A tt It ⁱ ~ ^C 4 ^H 9 33-34 ° 61 A li It CC ₆ H ₁₁ 65-68 ° , 80 A lt tt (CHg) ₄ 142-145 ° 32 A It It 63-65 ° 40 A It It 47-48 ° 48 A I! It C ₂ H _{5 2} ) ₂ 89-9o ° 59 A It's it it \ RLp Jry 33-37 ° / 132%, 2 139-141 ° _v 35 3o A A » tt { OW ^ / 137-145 ° / o, 5 42 A Il η (CTJ ^ Ci ( C ¹ TT / 24o-244 ° '/ o, l 4o A It π C ₂ H _{5 2} ) ₂ I06-I07 ⁰ 72 A 2 It 4-CH ₃ CC ₆ H ₁₁ 43 ° 63 A It It (CH ₂ ) ₂ O (CH 128 ° 42 A It It C ₂ H _{5 2} ) ₂ I1o-111 ° 61 A H 4-Br (CH ₂ J) ₂ O (CH 69-7o ° 15 B tt tt (CBL) _{0 2} ) ₂ 117-118 ° 42 A 3 tf 4-ΪΤ0 132-134 ° 76 A

- 11 - Z. Z 1 VA!

R = r = R ² , R ³ = m.p. ⁰ C. Aus method /

/Sdp.°C/mmHg loot literature

-C _fi H _A H CpH ^ 78-79 ° 57 Α, Β

₂ H ₅

52-55 ° 11 B

»» · (CH ₂ ) ₂ 0 (CH2) ₂ 92-95 ° 12 B

«4-CH ₃ C ₂ H ₅ . 64-65 ° 15 B

(CH ^ OtCH ^ 124-125 ^υ 33 A

»2-Cl (CE ₂ ) ₂ 0 (CE ₂ ) ₂ 8o-81 ° 64 A

«3-Cl C ₂ H ₅ 68-68.5 ° 60 A

ⁿ "(σΗ2) ₂ 0 (0Η ₂ ) ₂ 133-134,5 ° '46 A

ⁿ 4-Cl C ₂ H ₅ 113-114.5 ° 42 A

" ⁿ (CH ^ OtCH ^ 115-116.5 ° 72 A

4-CH ₃ O-CgH ₄ HC ₂ H ₅ 65-67 ° 61 Α, Β

»3-CH ₃ C ₂ H ₅ / 178-182%, 5 27 B

»4-CH ^ CpH. 36-37 ° _N 47 A

³²⁵ / 2o5-2o9%, 5

"" 11-C ₃ H ₇ / 17o-175%, 5 56 A

124-125,5 ° 94 A

4-F-CgH ₄ 3 -CH ₃ C ₂ H ₅ - 120-123 ° 58 A

η it ίηπ 1 nfmr 1 137-138 ° 9o A

"4-CH ₃ C ₂ H ₅ / 140-142%, o5 80 A

»» (CH ₂ ) ₂ O (CH ₂ ) ₂ 133-134 ° 94 A

"3-CO ₂ C ₂ H ₅ / 166-174%, o5 58 A

1o6-1o7 ° 51 A

130-132 ° 75 A

76-77 ° 5o A

63-67 ° 31 A

142-143 ° 67 Α, Β

135-138 ° 76 Α, Β

C _O H _C 67-68 ° 5o A

4-Cl-CgH ₄ H It H η H It 3-CH ₃ It 4-CH ₃

R - r = e B R ² , R ³ = Mp. ° C. /Sdp.°C/mmEg Method / bag literature A 4-Cl-C ₆ E ₄ 4-CB ₃ e H '(CH ₂ ) ₂ 110-113 ° 44 A. It It 3-CE ₃ e (CB ₂ ) ₂ 0 (CE ₂ ) ₂ 125-127 ° 68 A 4-Br-C ₆ E ₄ η e C ₂ E ₅ 86-88 ° 69 A η 4-CE ₃ e (CE ₂ ) ₂ 0 (CB ₂ ) ₂ I59-I60 ⁰ 64 A It It 3-CE ₃ C ₂ E ₅ 57-59 ° 43 A tr H (CE ₂ ) ₂ 0 (CE ₂ ) ₂ 150-151 ° 47 A it It C ₂ H ₅ 74-75 ° 62 A tt 4-CE ₃ (CH2) ₂ 0 (CH _{2) 2} 148 to 148.5 ° 66 A 4-O ₂ UC ₆ B ₄ It C ₂ H ₅ 83 to 84.5 ° 68 A 3 tt η (Chg ^ 94t96 ° 44 A It tt (CH ₂ ) ₄ 125-127 ° 71 A. ft 3-Cl Il (CE ₂ ) ₅ 83-84 ° 24 A It It (CE ₂ ) ₂ 0 (CE ₂ ) ₂ 158-160 ° 19 A tt 4-Cl C ₂ E ₅ 85-86 ° 18 A It It (CE ₂ ) ₂ 89-9o ° 37 A It It (CE ₂ ) ₂ 0 (CH ₂ ) ₂ 110-111 ° 74 A It C ₂ E ₅ 92-93 ° 35 A It (CB ₂ ) ₂ 123-125 ° 63 A It (CHg) ₅ • I05-I06 ⁰ 52 A tt (CE ₂ ) ₂ 0 (CE ₂ ) ₂ 136-137 ° 49 A A It d C ₂ E ₅ (CE ₂ ) ₂ 7 °° / 198-2o3 ° / o, 5 86-92 ° 32 39 A It (CE ₂ ) ₂ 0 (CE ₂ ) ₂ 141-142 ° 74 A tr C ₂ H ₅ 113-115 ° 37 A It (CHg) ₂ 162.5 to 164 ° 86 A It (CE ₂ ) ₂ 0 (CE ₂ ) 180-181 ° 74

- .13 -

R = r = H R ^ R- ³ = Slimp. ⁰ C./Sdp.oc/mmHg Yield% method (CH ₃ ) ₃ σ H H C ₂ H ₅ / 145- 15o%, 8 3o A · η H H (CH ₂ ) ₂ / 72-78 / 0, o2 60 A η η H 3-CH ₃ (CH2) ₂ 0 (CE _{2) 2} C ₂ H ₅ V 35-40 ° / 1o8-113 / o, o5 / 145-150%, 8 25 3o A A It η Il It (CH ₂ ) g (CHg) ₅ / 88-94%, 05 / 128-13o%, 4 51 16 A A η It (CHg) ₂ O (CHg) ₂ / 86-87%, o5 2o A adamantyl C ₂ H ₅ 68-70 ° 27 A η (CH ₂ O ₂ 83-85 ° 45 A η (0 ^) ^ (0 ^) 2 91 to 93.5 ° 4o A

T) J.v.Braun, Ber.dtsch.ehem.Ges. _27,, 2682 (19o4).

2) G.Hilgetag, L.Paul u. A. Draeger, Chem. 96. » ¹ 697 (1963).

3) H.W.Heine u. H. S. Bender, J.org. Chemistry 2_5., 461 (196).

it

Table 3 Amidinium salts

* HX.

R = E ¹ = R ² , R ³ = acid Scümp ^ C.

(HX)

O ₆ E ₅ C ₂ H ₅ HCl 145-147 °

"""^ SO ₄ 155-160 °

"" (CHg) ₂ O (CEg) ₂ HCl 195-200 °

"3-CH ₃ -CgH ₄ C ₂ H ₅ HCl 170-176 °

• "'' -» (CEg) ₅ HCl 186-189 °

"4-CH ₃ -CgH ₄ C ₂ H ₅ 'HCl hygrosk. Krist,

4-CH ₃ -CgH ₄ C ₆ H ₅ C ₂ H ₅ HCl »«

"2-Cl-CgH ₄ (OYi ₂ ) ₂ O (VR ₂ ) ₂ HCl 211-212 °

»3-Cl-CgH ₄ C ₂ H ₅ HCl 194-197 °

""? (CH ₂ ) ₂ O (CH ₂ ) ₂ HCl 2o4-2o7 °

π 4-Cl-C ^ H. C ₀ H ^ HCl 210-211 °

«» (CH ₂ ) ₂ 0 (CH ₂ ) ₂ HCl 246-247 °

4-CH ~ 0-CrH "C ^ H ₁ - C ₀ H ₁ - HCl 177-179 °

4-Cl-CgH ₄ 4 -CH ₃ -CgH ₄ (CH ₂ ) ₂ O (C 1) ₂ HCl 185 ° (dec.)

4-O ₀ IT CrH. »(CH _o ) _o 0 (CH _o ) _o HCl 2o6-21o °

d D, 4 C. d dd

246-248 °

Claims (2)

- 15 invention claim. Process for the preparation of amidines of the general formula R-C * and their salts, wherein R is phenyl or in possible positions by. Alkyl, alkoxy, halogen, Uitro-, hydroxyl, amino or substituted by alkyl and acylamino phenyl, tertiary butyl or adamantyl- (1) and R is an aryl radical, for example phenyl or phenyl substituted in possible positions as in R is R and R "^ lower alkyl having 1 to 4 carbon atoms, preferably 2 3 a Bthylgruppe or R and R together with the nitrogen atom of Amidingruppierung mean a U-heterocyclic 2 3 form a 3- to 7-membered ring in which R, R * is a methylene bridge / - (CH ₂ ) - / with, η - 2 to 6 or a 3-oxapentamethylene bridge / -CH ₉ -CH ₉ -O- CH ₉ -CH ₉ - /, characterized in that in a manner known per se a suitably activated IT-monosubstituted carboxamides of the general formula R-CO-KHR having the meaning given above for R, R in the form of an imidic acid or amide acid chloride, which is from the carboxylic acid amide by reaction with excess thionyl chloride or an equivalent amount of phosphorus pentachloride, optionally; with the addition of dimethylformamide in an absolute inert solvent or without solvent, in the presence of a proton acceptor such as, for example, triethylamine or pyridine in an absolute inert solvent or in excess triethylamine with a secundary amine. 2 3 example, with a lower dialkylamine HIiR R with the 2 3 for R and R, in particular, with diethylamine or with a secundary cyclic amine such as aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneimine or preferably with. Morpholine condensed, separated from the precipitated salt of the tertiary base and the amidine is isolated or that an E-disubstituted. Carboxylic acid amide of the general formula R-CO-IiR ² R ³ having the meaning given for R and R ³ after activation at room temperature with phosphorus oxychloride in an inert solvent in the boiling heat with a primary aromatic amine ELKR reacted with the meaning given for R, or that the E-disubstituted Garbonsäureamid and the primary amine heated in an inert solvent, added to this solution phosphorus chloride, optionally with dilution in portions, and the phosphorus-containing formed in both cases After the reaction has ended, the intermediate product is converted into the amidine by alkalization and this is treated, if appropriate, with an inorganic or suitable organic acid such as HCl, HBr, HpSO.sub.2, H.sub.2 PO. or acetic, succinic, salicylic or adamantane (1) carboxylic acid in a solvent or water.