DE2106167A1 - Process for the production of substituted cyanamides - Google Patents

Description

Applicant: Aspro-Nicholas Limited, 2 ^ ί? Bath Road, Slough, Buckinghamshire, England

Process for the preparation of substituted cyanamides

The present invention "relates to a method of manufacture substituted cyanamides as well as certain new substituted biscyanamides which are particularly useful as Intermediate products for the production of pharmacologically active Links. The invention further relates to the production of such pharmacologically active compounds.

The conversion of amines into cyanamides by reacting the amines with cyanide halides is known. This reaction will carried out in such a way that two molecules of amine per molecule of Cy anhalogenide are converted to the released Remove hydrogen halide. The reaction can be represented by the following equation:

2 (R) ₂ KH + CNC1 ^ (R) ₂ NCW + (R) ₂ NH ₂ C1

wherein R represents a substituent of the amine. From this reaction scheme it can be seen that half of the amine is lost and must be recovered by adding a base such as sodium hydroxide. If the reaction is carried out using a diamine, more than half of the nasty amine is lost as three products are obtained ^ -2-

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can, as explained below:

ii

RR Ii it It

-x- KCN, FON -x- KH.HCl, HN -x- NH.LHGl

(x is a divalent radical). It can be seen from this that at If higher polyamines are used, the loss of amine is even greater and the yield of the desired C, yanamide is lower is. If also cias amine can be recovered., This is Procedure time-consuming and technically disadvantageous.

It has now surprisingly been found that secondary amines in the corresponding cyanamides quickly and in excellent Yield can be converted if the reaction is carried out in the presence of ammonia or ammonium hydroxide. This is particularly surprising because e3 began is that ammonia itself reacts with kyanogen halides. Man I therefore had to assume that ammonia interferes with the main reaction.

The present invention accordingly provides a process for the preparation of substituted cyanamides by reacting a secondary amine or ei'c F / .Jzes thereof with a cyanide halide, the process according to the invention being characterized in that this reaction is carried out in the presence of anhydrous ammonia or Ammonium hydroxide is carried out.

The secondary amine can be a mono-, di- or polyamine, so that the process of the present invention is equally useful for making the mono-, di- and polycyanamides.

The secondary amine is expediently reacted with the cyanogenide in stoichiometric proportions. However, depending on the purity of the cyanide halide _c e used, as a rule, cyanogen chloride or bromide, an excess of cyanogen

~~~~ 109835/1898 "~

halide can be used. This excess is advantageously about b Ms 11%, but a larger excess can also be used.

In order to achieve particularly advantageous results according to the method of To achieve the invention, at least one mole of ammonia or ammonium hydroxide should be used per mole of cyanide halide. Advantageous up to 1 mol excess of ammonia or ammonium hydroxide are used. It can also be an even bigger one Excess ammonia or ammonium hydroxide can be used. However, if an amine salt is used as the starting compound. is, the addition of an additional equivalent ammonia is expedient in order to add the free amine completely free.

The reaction can be carried out in an aqueous medium, or anhydrous ammonia in an organic solvent can be used. The organic solvent should not react with the ammonia and be a solvent for it. Alternatively, a mixture of water and organic solvent can be used. The ammonia is usually added at the start of the reaction. However, it can if desired, added anytime before half of the cyanide halide has been added. If as The solvent water is used and the secondary amine used as the starting product is not soluble in water, it can be in a suitable inert water-miscible solvent such as alcohol, acetone, dioxane or 2-ethoxyethanol be solved.

If an organic solvent is used, it is possible to use the cyanobromide if this is used as a halide is to be added to the reaction mixture in the form of a solution instead of in solid form. If cyanochloride is used, can the ammonium chloride formed in the reaction with the secondary amine is essentially removed by filtration because ammonium chloride has a low solubility in many organic solvents. Suitable solvents

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21 Q6167

for this purpose are alcohols such as ethanol and ketones such as acetone.

The present invention accordingly relates to a process for the preparation of substituted cyanamides, wherein a secondary amine or a salt thereof with a cyanide halide in the presence of ammonia or ammonium hydroxide, preferably in a stoichiometric excess is, wherein the reaction is advantageously carried out in an aqueous or an organic solvent or a mixture thereof will.

The secondary amine preferably has the formula

NH

R ^

where R is alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl or aralkyl and R is phenyl, alkyl, cycloalkyl, hydroxyalkyl or aralkyl, or R + R ^{1 form} an alicyclic ring which is optionally interrupted by O or N.
Particularly preferred secondary amines are piperazines of the general formula "

R ₁

HN NH

R ₂

wherein R ₁ and Rp, which can be the same or different, stand for hydrogen or a lower alkyl. as

Cyanaalogenides are preferably CNBr or CNCl, with that last is particularly preferred.

In order to achieve optimal yields of substituted cyanamides according to the

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To obtain the method of the present invention, the reaction is preferably carried out at room temperature or below with cooling to remove the heat of reaction. If cyanogen chloride is used, it is preferable the reaction temperature below its boiling point (12 ⁰ C) to hold. When oyan bromide. is used, good yields can be obtained in the order of 60fo characterized in that the reaction temperature is up to 80 ⁰ C increased. If the reaction ^{temperature is reduced below It) 0} C, however, even better yields of up to Ö0% or more are obtained in some cases.

Most of the compounds obtained by this process are known. It can be solid substances that come from the precipitate aqueous or organic reaction medium. Extraction may also be required. Some connections are liquids. These are useful as plasticizers, Solvents for resins and in the manufacture of polymers and lubricating oils, while the solids are used can be used as chemical intermediates in the manufacture of Polymers and drugs.

According to a particular embodiment, the method of The present invention can be used to prepare certain new cyanamides which are used as intermediates for the preparation known biguanide compounds having antibacterial activity are useful by a new method of processing. These new cyanamides, which are also the subject of the present invention, are 1,4-dicyan-unsubstituted and lower alkyl substituted piperazines made according to the process of the present invention thereby can that a corresponding unsubstituted or substituted by lower alkyl piperazine with a cyanide halide is implemented. These compounds correspond to the general formula

-6-

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NCN

- 6

-4 ^

NCN J

in which E- ubö. H ₂ , the gielefc. or can be different, each denotes hydrogen or lower alkyl ". The cyanamides obtained can then be reacted with cyanamide to obtain the corresponding 1,4-biscyanamidino compounds, which in turn are reacted with a substituted (or unsubstituted) aniline to to obtain the biguanides with anti-bacterial activity, which are disclosed in British patent specification 855,017 (cf. DBP 1,292,65b and OS 1,795,443)

The reaction between 1,4-dicyanopiperazine and cyanamide is preferably carried out in the presence of a "basic catalyst and in an organic solvent." Particularly preferred as the solvent is butanol, in particular secondary butanoic bis biguanide, which is produced by reacting the 1,4-biscyanamidino- Verbindurigen werüer obtained with a substituted or urxsubstituierten aniline. _f correspond asr following formula allgsi.einen

HH-G - NH

HH

C-N

C-NH- C-NH-

fl I

NH NH

in which the symbols R ₅ , which in each case can be the same or different and can be present one or more times, stand for halogens, lower alkyl or lower alkoxy groups. The anilines mentioned are preferably substituted anilines: in particular p-chloroaniline. In the reaction to produce the biguanides, a molar proportion of cyanamide is preferably reacted with at least two molar proportions of the aniline compound in an essentially inert organic liquid in which the reaction components are dissolved or suspended

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The following examples illustrate the invention.

example 1

4.3 g (1/20 mol) piperazine were dissolved in 25 ml (5/40 mol) 5N ammonia and 35 ml water and cooled to 5 G in an ice bath. 11.7 g (10% excess) of cyanogen bromide were during 11? Min. Added in portions with stirring. The mixture was stirred for an additional 3 minutes. The Dicyanpiperazin which separated was collected, washed with water and dried at 105 ⁰ C. Yield 5.9 g (ö75 *>) of white crystals, mp 170.5-172.5 ⁰ C.

Example 2

310 l of water, 80.3 kg of piperazine hexahydrate and 90 l of aqueous ammonia with a specific gravity of 0.880 were placed in a 450 l vessel, which was provided with a stirrer and a jacket through which cold glycol circulated. The mixture was stirred until the amine had dissolved and the temperature of the liquid was 5 ^° C. Then liquid cyanogen chloride was added with stirring at a rate such that the 'temperature did not rise above 15 ⁰ C, were added to 58.2 kg (5JB excess). The mixture was stirred overnight, the temperature falling to -3 ° C. The 1,4-dicyanopiperazine was collected in a centrifuge, washed with water and dried in a fluid bed dryer. Yield 28 kg, 93 6 fi

Example 3

Cyanobromide (117 g) was added in portions to a cooled solution of dimethy lamin (45 g) and 5N ammonia (250 ml) in water (350 ml). After the addition was complete, the resulting mixture was stirred for 2 hours and then extracted completely with ether. The ether extract was washed with water, dried, and the ether was distilled off. When the remaining liquid was distilled, di- _ ₈ _

835 /

1 e

i V

methylcyanamide, b.p. 50-55 ° C / 14 mm Hg (yield $ 85).

Example 4

5.2 g (0.05 mol) of trans-2,5-dimethylpiperazine were dissolved in 4U ml of water and 15 ml of ammonia (specific gravity 0.88) and in a. Ice bath cooled ^{to 5 ° C.} 11.1 g (0.105 mol) of cyanogen bromide were added in portions with stirring so that the temperature did not exceed 15.degree. Stirring was continued for 30 minutes after the addition was complete. The deposited 1,4-Dieyan-25-dimethylpiperazine was collected, washed with cold water and ^{dried at 60 0} C, whereby a white pest material was obtained, F. 129-5 ⁰ O. Yield 6.5 g (84 · 5 $) .

Example 5

Following the procedure described in Example 4, 1,4-dicyano-2-methylpiperazine was prepared from 2-methylpiperazine (4 x 5 g). Yield 2.8 g (40%), m.p. 61 ^° C.

Example 6

8.5 g (0.1 mol) of piperazine were in 40 ml of water and 15 ml Dissolved ammonia (specific gravity 0.88) and treated with 11.1 g (0.105 mol) of cyanogen bromide as described in Example 4. The reaction mixture was then extracted with ether. The ether extract was washed with water and over magnesium sulfate dried. The desiccant was removed by filtration and the ether was stripped off on a water bath, 1-Cyanpiperazine remaining as an oil. Yield 9.8 g Bp. 107 ° C / 14 mm Hg.

Example 7

Following the procedure of Example 6, 1-oyanmorpholine was prepared from morpholine (8.8 g). Yield 3.9 g ($ 35) bp. 117 ^° C / 14 mm Hg.

Example 8

4.3 g (0.05 mol) piperazine and 2.12 g (0.125 mol)

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Ammonia were dissolved in 50 ml of ethanol and cooled ^{to 3 ° C. in an ice bath.} 11.1 g (5 $ excess) of cyanogen bromide dissolved in 25 ml of ethanol were -Perform dropwise during 30 min. Was added, the temperature being kept below 10 ⁰ C. The mixture was stirred for an additional 80 minutes and then allowed to warm to room temperature. The ethanol was distilled off and the residue was treated with cold water. The deposited Dicyanpiperazin was filtered off and dried at 80 ⁰ O. Yield 6 g ($ 88),!. 171-173 °.

Example 9

10.7 g (0.1 mole) of Sr-methylaniline and 2.55g (0.1b mol) of dried egg * were dissolved in 50 ml Ätnanol and in an ice bath at 3 ⁰ C cooled. 11.1 g (5 $ excess) of cyanobromide dissolved in 12 ml of ethanol were added dropwise with stirring over the course of one hour. The temperature was kept below 10 ° C. during this process. Stirring was then continued for an hour in the ice bath. The separated ammonium bromide was filtered off and the PiI-entered was evaporated. The residue was taken up in ether and 1N hydrochloric acid solution. The ether was separated off, washed with water and dried with MgSO ^. After evaporation of the ether, 11.9 g ($ 90) of methylphenyl cyanide remained. This was recrystallized from an ether / petroleum ether mixture, shiny flakes being obtained. P. 30-31 ⁰ C. * Ammonia

Example 10

12.1 g (0.1 mol) of N-methylbenzylamine and 2.55 g (0.15 mol) of dry ammonia were dissolved in 90 ml of acetone and cooled to 1 ° C. in an ice bath. 11.1 g (5 $ excess) of cyanogen bromide in 50 ml of acetone were added dropwise over the course of 45 minutes with stirring, the temperature being kept below 10 ^° C. Stirring was then continued for 1 hour in the ice bath. The precipitated ammonium bromide was filtered off and the PiI step was evaporated. The residue was taken up in ether and 1N salic acid. The ether layer was separated, with

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? 1Dfi1fi7

Washed with water and dried with MgSO. After removing the The ether remained benzylmethyleyanamide (6 back, boiling point 145 ° C / it> mm Hg.

than oil

Example 11

12.7 g (2Qfo excess) cyanogen bromide in 2 !? ml of isopropanol were added dropwise over one hour with stirring to 7 «5 g (0.1 mole) of 2-methylaminoethanol and 3» 4 g (0.2 mol) of anhydrous ammonia in 50 ml of isopropanol, whereby the temperature with an ice bath below 10 ⁰ C held became. After the addition was complete, the mixture was stirred for a further hour in an electric bath and then filtered. The filtrate was evaporated and the residue was extracted with cold acetone. The acetone was removed under reduced pressure at room temperature, leaving 2 ~ H5 ^? aroxyät-i "ylmethyleyanamid as

20 pale yellow mobile oil remained. (5.3 g, b3f <>) n ^ 1.4939. When heated for four hours on a Was3ex bath, this polymerized to a -viskoson oil,

Example 12

■ !! ■ II IWlIlIl ίΤ m \\\ ■ !!! ■■■ I! ■■

11.1 g (5 $ excess) cyanbroinide ir; 20 ml of dimethylformamide were added dropwise over one hour of stirring to a solution of 12.1 g (0.1 mol) of N-ethylanilidine and 2.i>i> g (0.1b mol) of troclmem .. ammonia in 70 ml of dimethylformamide. The temperature was maintained with an ice bath during the addition below 10 ⁰ C, and stirring was continued = 1 hour after completion of addition. The solvent was distilled off under reduced bridge and the residue was taken up in ether and 1N hydrochloric acid. The separated ether layer was washed with water and dried over MgSO 4. After evaporation of the ether, a brown oil (9.1 g> 62 $) remained, b.p. H1 ° C / ii> mm Hg.

As stated above, the new cyanamides according to the present invention are useful for practice

-11

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5/1698

of a new process for the production of biguanides with antibacterial effectiveness. The present invention accordingly also provides a process for the preparation of the biguanides of the formula

H ₁

HH-C-KH-CN'NC-HH-C-HH NH NH ^ -j- 'L · IH

where E ₁ and R ₂ , which can be identical or different, stand for hydrogen or lower alkyl, and the symbol R. ,, which can be present once or several times and can in each case have the same or different meanings, stands for halogen, lower alkyl or lower alkoxy stands,

and of acid addition salts thereof, characterized in that a) a 1,4-dicyanopiperazine of the formula

NCN, HCH

wherein R ₁ and Rg have the same meaning as above, reacted with cyanamide and

b) the 1,4-biscyanamidino compound obtained is then reacted with an R 1 -substituted aniline or an acid addition salt, where R _{5 has} the same meaning as above.

The biguanides can optionally onssalae in their acid addition and the acid addition salts are converted into various free biguanides.

The step (a. ^{J of} the above reaction is carried out by a basic

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? 1ΩΒ167

Catalyst catalyzed and, as the reaction rate by which the strength of the base is affected is the use a basic catalyst is preferred. The reaction time can be between about 24 hours if no catalyst is used and about 1-6 hours if a strongly basic catalyst is used such as an alkali or alkaline earth metal salt or a quaternary ammonium compound, vary. Preferred catalysts are sodium or potassium carbonates or hydroxide 'and quaternary alkyl or aralky lammoni umhy dr oxides or alkoxy. such as benzyl trimethylammonium hydroxide or methoxide and Tetraethylammonium hydroxide or methoxide.

The reaction with cyanamide is usually carried out in a suitable reaction solvent. The cyanamide is preferred present in excess amounts of up to $ 00, and the The reaction is preferably carried out at the boiling point of the reaction medium. Suitable solvents are for example Amyl acetate, diethyl carbitol and water. Particularly beneficial is the use of an alkanol with 2 to 4 carbon atoms, in particular n-butanol and sea-butane oil, as a solvent tel.

Step (b) of the above reaction is carried out in that a molar proportion of cyanamidine from step (a) with at least 2 molar proportions of the substituted aniline required, usually in the form of an acid addition salt, is implemented. the The reaction is usually carried out in an inert organic liquid in which the reaction components are dissolved or can be suspended. Examples of suitable solvents are 2-ethoxyethanol, Bu'oanol and dioxane.

The following examples explain the reaction steps (a) and (b).

Example 13

19 g of anhydrous cyanamide were in 700 ml of secondary butanol

-13-

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dissolved by stirring and heating to 35 ° C in a 2 l flask, which is equipped with a reflux condenser and a thermometer was. 100 g of dieyanpiperazine were added and then 2 g of potassium hydroxide dissolved in 300 ml of secondary butanol. That Mixture was stirred and heated until the temperature reached $ 5 ° C would have. Then the heating Trv was continued and the Heat of reaction raised the temperature to the boiling point and caused the mixture to reflux for 15 minutes. That Heating was then restarted and refluxing continued for an additional 5 hours. Then the mixture became cooled, filtered and the residue was washed twice with boiling water. The remaining 1,4-biscyanamidinopiperazine was dried at 10 ° C. Yield 132 g, ($ 81.5) · The infrared spectrum of this product was identical to that of a material which, according to known methods, is produced from piperazine hydrochloride and sodium dicyanimide had been.

Example 14

The procedure described in Example 13 was repeated, with either no catalyst or different catalysts, different solvents, different reaction conditions etc. were applied. The results obtained are summarized in the table below.

Solvent% excess catalyst conc.

Cyanamide

Time yield hrs.

water
water
water
water
n-butanol

62 62 62 4ö 62

Example 8, unless otherwise stated

Na ₂ CO ₅

Na acetate

Na ₂ HPO ₄

KOH

no

5.5
2
22nd

56 45 49 53 62

-14

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- 14 - ammonia 0.01 η 21 HR1 R7 ! at temperatures procedure over 340 ^o C zer - f -1 b ~ Sät ^ 0.1 η 1,4-Dicy an-2-5-dime thy Ipi perazine I. solvent Triton B Time is up prey from ; b-dimethylpiperazine J ^1. ] \
was under \ ^ Excess catalyst conc. Na ₂ CO ₅ Hours. 1,4-Dicyan-2-methylpiperazine the 1,4-Biscyanainidini-2-fflethylpi ' \ described the 1,4-bis «' n-butanol Cyanamide NaOH 0.05 n Vf 63 perazin produced that > 300 ° G obtained. n-butanol 62 KOH 0.3 η Vi 63 sat. n-butanol 62 KOH 0.3 η 4th 66.1 Example 16 n-butanol 62 K acetate 0.03 η 2 78.4 n-butanol 62 NaOH 0.03 η 10 86 n-butanol 62 KOE 0.03 η 4th 64th D. According to example 13 n-butanol 62 KOH 0.01!) II 1ό 78 use of sec-butanol 62 KOH 0.03 η V ( Ib. 3 cyanamidino-2, sec-butanol • 62 KOH 0.03 η 17th 84 sec-butanol 62 KOH 2 79Ο sec-butanol 62 KOH b 83.3 sec-butanol 62 KOH 4th 82.3 sec-butanol 48 KOH 4th 78.3 sec-butanol 48 KOH Example 13 was made under b.b & 1.i> sec-butanol 48 Triton B b 77.6 sec-butanol 43 no 4th 70 sec-butanol 43 Na ₂ CO ₅ b 61.8 sec-butanol 37 16 bl Diglyme 10 6th 48.!? Amyl acetate 5 b 42 Ethyl carbitol 62 1.5 Example 15 40 use According to the procedure of

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Example 17

The product from Example 13 (8.6 g) and p-chloroaniline hydrochloride (U g) were heated under reflux for 4 hours in 2-ethoxyethanol (60 ml). The mixture was cooled. The product was filtered, dried and then recrystallized from water to give 1,4-bis (N ⁴ '-p-chlorphenylamidinoamidinyl) -piperazindihydrochlorid, F., was obtained 274 ⁰ G.

Example 1b

Following the procedure of Example 17 using the product of Example 1 !? (9.2 g) obtained after recrystallization from 'aqueous 2-ethoxyethanol 1,4-BiS- (N ⁴ »-p-chlorophenylamidinoamidinyl) -2-methylpiperazine dihydrochloride, mp 2b1-2t) 3 ° C.

Example 19

After proceeding with Example 17 using the product from Example 16 (10.0 g), the 1,4-BIs- (N ⁴ '-p-chlorophenylamidinoamidinyl) -2, ^ -dimethylpiperazine dihydrochloride, mp 257-6 ° C., was obtained .

Example 20

10.0 g (0.04t) mol) 1,4-bis (cyanoamidino) -piperazine and 13.7 g (O.o9i> mol) p-toluidine hydrochloride were refluxed in 130 ml (1.32 mol) 2-ethoxyethanol for 12 hours. The mixture was filtered off and filtered and the residue was dried. The product, 1,4-BiS- (N ⁴ '-p-tolylamidinoamidinyl) -piperazine dihydrochloride was recrystallized from a mixture of ethyl acetate and glacial acetic acid and then had a melting point of 21 ° C «

Example 2 1

The reaction between 10.0 g (0.04t) mol) of 14-bis (cyanoamidino) piperazine and 15-6 g (0.092 mol) m-chloraliiline hydrochloride was carried out in a manner similar to that in Example 11? described carried out. The product, 1,4-bis- (N ⁴ '-m-chlorophenylamidinoamidine;,. 1) - -16-

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piperazine dihydrochloride, was recrystallized from ethanol. M.p. 234-23i3 ° C.

Example 22

The condensation between 10 g (0.04i> mol) 1,4-bis (cyanoamidino) piperazine and. 15 x 2 g (0.095 mol) of p-amisfiine hydrochloride was prepared in a manner similar to that described in Example 20. The product, 1,4-bis (N '-p-methoxyphenylamidinoamidinyl) -piperazine dihydrochloride, was obtained from 80% acetic acid umkristailisiert and had the melting point 260 to 261 ⁰ C.

Example 23

10 g (0.04I? Mol) of 1,4-bis (cyanoamidino) piperazine and 19 * 9 g (0.102 mol) of p-bromoaniline hydrochloride were heated under reflux in 1? 0 ml (1-3 mol) of 2-ethoxyethanol for hours, '(b ml of the solvent were then distilled off under reduced pressure on a water bath. The residue was cooled, mixed with 100 ml of ether and filtered. The residue was dried, dissolved in hot 70% aqueous ethanol, by boiling for 10 min Decolorizing charcoal was clarified, then filtered and the filtrate was allowed to cool, and the crystals that separated out were filtered off, washed and dried to give 1,4-BiS- (N'-p-bromophenylamidinoamidinyl) -piperazine dihydrochloride which at 27i ? -2bO ° C melts.

Example 24

10 g (0.04b mol) 1,4-bis (cyanoamidino) piperazine and 19 g (0.096 mol) 3,4-dichloroaniline hydrochloride were refluxed in 200 ml 2-ethoxyethanol for 18 hours. 100 ml of the solvent was then distilled off under reduced pressure on a water bath. The residue was cooled, mixed with 100 ml of ether and filtered. The residue was dried, dissolved in hot water, clarified by boiling with decolorizing charcoal for 10 minutes and filtered. The piltrate was ab- _Λη

- I ι -

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left to cool. The deposited crystals were filtered, washed and dried to give ^1,4-bis-Cn> - is (3 ", 4 ⁿ dichlorophenyl) amidinoamidinyl ^ J -piperazindihydrochlorid obtained, which melts at 253-255 ⁰ C.

Example 25

To p-fluoroaniline (10.6 g) in ether, ethereal HCl was added Excess added. The ether was removed on a water bath. 10 g of 1,4-bis (cyanoamidi} io) piperazine, 100 ml of 2-ethoxyethanol and 2 ml of concentrated KCl were added, and that The mixture was refluxed with stirring for 24 hours. To After cooling, the deposited product was collected, washed with Xther and recrystallized from SO ^ strength ethanol, where- "with 1,4-bis- (U '-p ~ fluorophenylamidinoaiaidinyl) -piperazine dihydrochloride, P. 273 ° 0 was obtained.

The acid addition salts obtained according to the IT experience of Examples 12-20 can be converted into the ei7.tspreeoK.e-i '"".';"-ti'f ^ n bases by treatment with a suitable BuM ^ _:. For example aqueous ammonium hydroxide The free bases obtained in this way can, if desired, be converted into various pharmaceutically acceptable acid addition salts by treatment with the desired acid or a derivative thereof *

The following examples illustrate the preparation of such free bases and other acid addition salts.

Example 26

180 g of 1,4-BiS- (N ^ '- p-chlorophenylamidinoamidinyl) -piperazine dihydrochloride were shaken with 1 l of ammonium hydroxide solution (500 ml of ammonium hydroxide with a specific gravity of 0.88G, 500 ml of water) for 22 hours. Bas Gemisoh was filtered. The solids were seen and washed with water. im '' afcuuin at

1βθ g ■ i _i i "= i-ia- {i7 ^i: '-'''- r'-cfc.3i-3rpi: 3n ;; - lar:' i-

■ j

Example 27

105 g of 1,4- (or 1,5-) gluconolactone were dissolved in 3 x 5 1 of water at 7O ⁰ C, 140 g of 1,4-bis (N ⁴ "-p-chlorphenylamidinoamidinyI) piperazine were added with stirring portionwise added. The resulting solution was filtered and allowed to cool, forming a gel "containing about 4 wt. # Of the base as diglueoiiate. This gel is ideal for use in aqueous or creamy pharmaceutical preparations. The solid bigluconate can be removed from the gel of the water in vacuum at 50-10O ⁰ C are prepared the digluconate obtained softens at 105 ^C melts at 153-140 C and ⁰ C υηΐ-:. 'leichteie decomposition.

Example 28

Its aqueous solution of the product from Example 17 (1 mol) r: kd. Katriumsulpliaoetamiä (2 moles) were killed together. The Go- ^; The mixture was cooled and the precipitated disulphacetaiidir-ss' i was filtered off. Ψ, 139-142 ⁰ O.

Example 29

The following salts were prepared from the digluoonate you example by using an aqueous solution of the desired acid (Sch. added to a solution of the digiueonate which had been heated to a temperature above its gel point. The precipitated salt was filtered off.

Salt E.C

Disulfate dinitrate Ditoluenesulfonate Bibensoat

Bis & lioylate

230-40 dec. 252-4 Zers, 254-7

235-7 dec. 213-5
225-8 sera.

Patent claims:

^; : 03835/1698

Claims (1)

Claims 1. Process for the preparation of substituted cyanamides by Reaction of a secondary amine or a pig »thereof with a cyanide halide, characterized in that that the reaction is carried out in the presence of anhydrous ammonia or ammonium hydroxide. 2. The method according to claim 1, characterized in that A secondary amine of the formula is used as the starting product wherein R is alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl or aralkyl and R denotes phenyl, alkyl, cycloalkyl, hydroxyalkyl or aralkyl or R + R form an alicyclic ring, which can optionally be interrupted by 0 or N, is used. >. Method according to claims 1-2, characterized in that that the reaction in water or in an organic solvent or in a mixture of water and a organic solvent is carried out. 4. Process according to Claims 1-3, characterized in that cyanobromide or cyanochloride is used as the cyanide halide will. !?. Process according to claims 1-4, characterized in that that the ammonia or the ammonium hydroxide in the reaction mixture in an excess based on the stoichiometric Amount is available. 6. The method according to claims 1-b, characterized in that that the reaction at or below room temperature by-_2Q_ 109835/1698 - 20 is performed. 7. The method according to AM claims 1-6, characterized in that, that the secondary amine is a piperazine of the general formula ^ 1 ^ -T "X NH NH wherein R. and Rp »are the same or different can, mean hydrogen or lower alkyl, is used, the end product being an unsubstituted or 1,4-dieyanopiperazine substituted by lower alkyl the general formula NCN 'NCN is obtained. ^ 2 ö. The method according to claim 7 »characterized in that the substituted dicyanamide reaction product with cyanamide is reacted _ to the corresponding 1,4-biscyanoamidino compound aerz us share. y. Method according to Claim 8, characterized in that the reaction with cyanamide is carried out in the presence of a basic catalyst. 10. The method according to claims 8-9 »characterized, that the reaction is carried out in the presence of a solvent. 11. The method according to claims 8-10, characterized in that that the solvent used is n-butanol or sec-butanol will. 12. The method according to claims 8-11, characterized in, that the 1,4-biscyanoamidiD compound is substituted with an IU Aniline or an acid addition salt thereof is implemented, where the substituent R 1 may be present once or more and have the same or different meanings and represents halogen, lower alkyl or lower alkoxy, with a biguanide of the general formula NH-C-NH-C-N .U | v NH NH N-C-NH-C-NH NH is obtained. 13. The method according to claim 12, characterized in that p-chloroaniline is used as R 1 -substituted aniline. Method according to claims 12-13, characterized in that that a molar proportion of the cyanoamidine compound with not less than 2 molar proportions of the aniline compound in one essentially inert organic solvent is unset by dissolving or suspending the starting materials are. 1,4-Dicyanpiperazire of the general formula NCN NCN where R ₁ and Rp », which can be identical or different, represent hydrogen or lower alkyl. 109835/1 698 ORIGfHAL! HSPECTEO