BE471642A - - Google Patents

Description

       

   <Desc / Clms Page number 1>
 



  "Processes for the preparation of 3-cyanoguanidines-1-substituted and substituted biguanidines 1.5".



   The present invention relates to the preparation of 1-substituted 3-cyanoguanidines and 1,5-substituted s biguanidines.



   According to the present invention, compounds are prepared by reacting dicyanimide or a salt thereof with a predetermined amount of a primary or secondary or a salt thereof to produce a 1-substituted 3-cyanoguanidine, then, if desired, reacting the latter with a new amount of the same primary or secondary amine or a salt thereof, or a different amine, so to produce a 1-substituted biguanidine, a general reaction according to the present invention.

 <Desc / Clms Page number 2>

 
 EMI2.1
 tion making it possible to obtain 1-substituted 3-Cyanoguaaidiaes is given by the following equation (1) in which Rai is hydrogen or an aliphatic radical,

   aromatic or heterouyalic and R 2 is an alipliatic, aromatic or hétroeycliq3e radical:
 EMI2.2
   The present invention also relates to the fact that the s
 EMI2.3
 5-cyanoguanidins can be prepared by reacting a primary or secondary amine salt with a di-azlimid salt. The reaction of these products involves the formation of an inorganic salt and the simultaneous release of
 EMI2.4
 the free amine and the free dieyanimide which reacts alcrs according to equation (1). The complete reaction of the above-mentioned amine and the dieyaaimide salts producing the substituted 5-oyanoguanidine is shown by equation (2):
 EMI2.5
 where R 1 and R2 have the meanings given above, where M is a metal ion and X the anionic part of an alde.



   Previous literature concerning the reaction of
 EMI2.6
 dicyanimide and the preparation of 1-substituted 3-Cyanoguanidlnes is limited. Pellizzarl (Cazz.Chim.Ital.



  53, S84-9a (19a3) shows the treatment of 1-ph6ayl-1-methr3.-iguanide and of ll, -, ipéridylbiuanide with nitrous acid so as to obtain 1-phnyl-mhy1-3-cyanoguanidine and 1,1, -pi, pridyl-3-cyanouanidi.ne, respectively. However, analogous treatment of 1-ph6ayl-biguanide does not provide the corresponding 3-unyl-3-oyau.oguanidine. So the Pellizzari method

 <Desc / Clms Page number 3>

 is limited to the preparation of 3-oyanoguanidines 1.1-di-
 EMI3.1
 substituted and is unable to provide the unsubstituted 3 -Cyanoguanidines.

   As will be apparent from the above discussion, the process of the present invention provides not only the 11-disubstituted 3-oyanoguanidines but also the 1-monosubstituted 3-cyanoguanidin and is therefore of much more general utility. big. 1-substituted 3-cyanoguanidines have already been prepared but the methods used in their preparations are limited.
 EMI3.2
 to the preluetion of l-aryl-3-cyanoguanidines. Wheeler (J.A.C.



  S. 35, 719 (1903) discloses a method in which phenyl isothiooyanate is reacted with cyanamide, the product deprived of the thio ion being reacted with ammonia to give i-phenyl-5-. 9yanoguaniain. Walther and Griashamer (J. Prakt. Hem., 2 &, 209 (1915) indicating the reaction of phenyidiazonium chloride with 3-cyanoguanidine and the subsequent heating removing nitrogen and providing, as well as the l- phenyl-3-oyanoguanidine. Bard (JACS



  50, 192 (1988) indicates the reaction of cyanogen bromide with sodium acid and the subsequent reaction of the product obtained with aniline and hydrogen sulphide leading also
 EMI3.3
 ment to a 1-phenyl derivative. Pohl (J, Prakt. Chem. 77, 533-8 (1908) indicates the reaction of formaldehyde with 3-Cyario-guanidine providing 1-hydroxymethyl-6-oyanoguanidine, a compound which does not come within the scope of the This invention is since the amino compound which would be required according to the process of the present invention cannot be considered as existing per se and therefore cannot be classified as an amine.

   Amines are those compounds in which the carbon atom bonded to nitrogen is itself attached to other carbon or hydrogen atoms and cannot carry negative groups such as oxygen, hydroxyl. , halogen and the like. With regard to the reactions of dicyanimides which are the subject of the pre- '

 <Desc / Clms Page number 4>

 seate invention, researchers prior to slotta (Ber. 62, 1394 (199) indicate that these dicyaninides can only be employed for the preparation of the symmetrical 1.5-substituted aliphatic biguanides, by reaction with the amines.

   Contrary to this proposal, the present invention shows that the preparation of 1-substituted 3-cyanoguanidines is possible by reacting only one of the nitrile groups of dicyanimide with an amine, and for the first time makes possible the preparation of a large number of these 1-substituted 3-cyanoguanidines.



   In practice it is preferred to prepare the 3-cyanoguanidines of the present invention by reacting a salt of a primary or secondary amine with a salt of dicyanimide which is the form in which dioyanimide is usually prepared, recovered. , and kept.



   A general reaction in accordance with the present invention with a view to obtaining the 1.5-substituted biguanides is given by the following equation (3) in which R1 and R have the meanings given above:
 EMI4.1
 in which R1 and R2 have the meanings given above.



   The present invention is also concerned with the fact that the substituted iguanides can be prepared by the reaction of a salt of a primary or secondary amine with a salt of the idcyanimide. The final product obtained by

 <Desc / Clms Page number 5>

 substituted nide and an inorganic salt.



   In practice it is preferred to prepare the substituted biguanides by reacting an aromatic primary or secondary amine salt with a dioyanimide salt, which is the form in which dicyanimide is usually prepared, collected and stored. another general reaction in accordance with the present invention with a view to obtaining 1.5-substituted biguanides is provided by equations (4) and (5) in which R1 and R3 are identical or different aliphatic, aromatic or heterocyclic radicals and R2 and R4 are hydrogen or the same aliphatic, aromatic or heterocyclic radicals, or different radicals:

   
 EMI5.1
 
The same substituted biguanide obtained by equation (4) can also be obtained by the reaction shown by equation (5):
 EMI5.2
 where the letters R have the same meanings previously given.



   The present invention also relates to the fact that the substituted biguanides can be prepared by reacting a salt of a primary or secondary amine with a 1-substituted 3-cyanoguanidin. In many steps it is more convenient - and is often claimed - to use an amine salt in the reaction with the 1-substituted -cyanoguanidin. The mechanism of the reaction is the same as that shown. by equations (4) and (5), except that it is

 <Desc / Clms Page number 6>

 forms a substituted biguanide salt instead of the free base.



  The presence of the salt often facilitated the isolation and recovery of the substituted biguanide because many of the linked bases do not crystallize and / or distill easily.



   Primary and secondary amines which can be used in the present invention can be aliphati-
 EMI6.1
 ques, aromatic and hetiropyalic, and can be saturated or unsaturated. The amines which can be used in the form of their addition salt with an acid, in whole or in part, in the reaction of the present invention, are as follows:
 EMI6.2
 .Aliphatic amines:

   Iethgla.m3.ne, dim6.thyleminee éthyla. "Lline, .0 -hydraxythylamlne, diethylamine, propylamitee, dipropylamine, isopropylamine, diisoprapylamine, Y-methoxypropylamine, butylamine, dibutylamine, hexylamine, dihexylamine, Zamina-thylamine, dihexylamine 2-diethylhexylamine, octylamine, dod4cylamine, ootadecylamine, allylarnine, 0-chlorallyl "lle, diallylamine, octadecenylailline, ethylenediamine, propylenediamine, tetramethylenediamine, hexamethylenediamiae, decahezylenediamoylamine, benzylinaqyloamyloamine-benzylamine, 0-ethylenexylo-amine-benzylamine-benzylamine, 0-ethylenexylo-amoyloylamine-benzylamine, 0-ethylenexylo-amine-benzylamine-benzylamine, 0-ethylene-amine-o-amine-benzylamine hnYlêtlVlami #, naphthylmethylamine.



  Aromatic amines: 1I.niline, 0 <.. -naphthylamine, 0 -naphthylamine, o-aminodiphenyl, sulfanilic acid, sulfanilamide, 2-sulfanilamidopyrimidine, sulfaailylguanidine, 2-sul- fanilamidopyrazine, 2-sulfanilamidopyramidoamidorazine, 2-sulfanil 2-sulfanidoamidoamido - thiazole, aminonap3atalenesulfolic agides, amino-toluenesulfonic acids, aminophenols, aminonaphthols, toluidi # s, xylidines, am1noethyloenzenes, pBényléneàimmines, naphthylene diamines, aminobeazoïlene agides, aminophenols, niline-ethylanila- - anilines, anisidines, diaminoplynols, diaràinonaphthols, diami-
 EMI6.3
 nodip.heaylmethajoe.

 <Desc / Clms Page number 7>

 
 EMI7.1
 



  Het4rocyclic amines: Piperidil, 3-aminopyriaille, morpholine, thiomorpholine, pyrrclidine, piperazine, furfurylecaiae, th.nylamine.



  The amine reacted may contain two substituents or dava-tages, which may be the same or different, such as for example in the enlorotoluidines, cliliroani sidines and the like. of course, these amines can be substituted by various organic radicals, groups or elements which do not prevent reaction with dicyanimides.



  A number of substituents have already been indicated in the above list of amines.



   In the divarses reactions according to the invention,
 EMI7.2
 the reacting amine is generally employed in the form of its diacid salt. In the case of aromatic amines, the reaction proceeds best when the amine is substantially entirely in the form of; salt, while in the case of aliphatic amines it has been found to be preferable that there is a certain amount of free amine present.

   Since the aromatic amine salts dissociate to a much larger extent than the salts of aliphatic amines, it is believed that there is probably a considerable amount of amine.
 EMI7.3
 aromatic free in the reaction mixture in the preferred combinations for the reaction of aromatic amines. The amine salt can be provided by addition to the reaction mixture in the form-mixed state, or by adding acid to the mixture: reaction containing the amine. In the case of amines which contain in their structure acidic groups such as acid \ sulfOL groups, the amine salt is provided by the formation of an internal salt so that there is no need to employ acid.



   The reaction of the present invention can be legalized
 EMI7.4
 in pr4senç? solvent or diluent, or by melting -ao7

 <Desc / Clms Page number 8>

 tifs. One or the other of the methods will be employed according to the particular reagents employed, and more particularly according to the solubilities of the particular reagents in the solvents on the one hand:, on the other hand according to the melting points. particular mixtures of reagents.

   When the reaction is carried out in the presence of a solvent, the amine salt can be provided by adding acid to the amine present in the reaction mixture, or by directly adding the salt of the amine, while That in the method of melting the reactants, it will generally be found more convenient to add the salt of the amine directly because of the fact that it is almost impossible to add the preferred strong mineral acids to the molten mixture.

   On the other hand, acids such as acetic acid, oxalic acid or benzoic acid can be added to the molten mixture, although they are less recommended than the aforementioned strong mineral acids such as hydrochloric acid, sulfuric acid, bromyledric acid, phosphoric acid and the like.



   The use of amine in the salt state is particularly advantageous in the preparation of the substituted biguanides of the present invention. in that it generally facilitates the isolation and the recovery of substituted biguanides, many biguanides not being easily crystallizable and (or) distillable in the free state. Thus, the addition sa-1 of biguanide with an acid corresponding to the particular acid salt of the amine employed in Laotian can also be directly obtained.

   On the other hand, if it is desired to obtain the free biguanide, the salt can be treated with a suitable base such as caustic soda, potash, quicklime or hydrate, sodium carbonate and the like under suitable conditions. neutralization of the acid and allowing the isolation of the free biguanide.



  Likewise, the free biguanide being obtained, addition salts with other acids which may be desired can be obtained.

 <Desc / Clms Page number 9>

 be prepared by treating the free biguanide with the corresponding acid.



   Although a large number of solvents can be employed in carrying out the present invention, it is preferred to employ water and organic solvents soluble in water.
 EMI9.1
 water such as dioxane, acetone, t.1-lirue alcohol lt butyl alcohol, "cellosolvas" (mono-ethers of ethylene glycol), "carbitole" (mono-ethers of diethylene glycol) and the like, the solvent or the particular combination of solvent: employed depending on the particular reagents used. Even more preferable are the members
 EMI9.2
 a group comprising water, alcohols or water-soluble alcohol mixtures such as ethanol and butanol,
 EMI9.3
 "oelhsolves" "carbitols" and the like.

   In order to enable a more complete variation of the invention, the following is a detailed description by means of specific examples of the preparation of 1-substituted 3-cyanoguanidines and 1.5-substituted biguanides.
 EMI9.4
 le) Preparation of 1-substituted 3-Qyanonuanidiries.



  Although the reaction of the present invention to produce 1-substituted 3-cyanoguanidines can be carried out within wide temperature limits, it is generally preferable to use a temperature between 50 and 125 C. , significantly higher temperatures causing the formation of appreciable amounts of biguani-
 EMI9.5
 of. however 1-substituted 3-cya.noguanidines can still be obtained, although polluted with substituted biguanides, at higher temperatures, in particular with
 EMI9.6
 shorter reaction times and when the reactive dioyanimide and amine are employed in equimolar amounts.

   Although the temperature limits given above include the temperatures at which virtually all amines can react under the best conditions.

 <Desc / Clms Page number 10>

 tions, the very large majority of these amines and (or) their addition salts with acids react better between about 75 and 115 C, Furthermore experience has shown that in the reaction of the present invention the aromatic amines are much more active and can react at temperatures lower than those required for the reaction of aliphatic amines. Usually aromatic amines and / or their addition salts with acids require temperatures of 75 to 95 C.

   only while the majority of aliphatic amines and / or their addition salts with acids require temperatures in the range of 85-105 C., to obtain the best results.



   If a metal salt of dicyanimide is used for this reaction, it will be understood that any metal salt from which the dicyanimide can be released can be employed. However, it is preferable to use the calcium, sodium and potassium salts of dicyanamide because these compounds are the cheapest and most easily prepared dicyanimide salts.



   If an amine-source apple amine salt is employed for the reaction of the present invention, it will be preferred to employ common salts such as hydrochloride, sulfate and acetate. Any salt from which the amine can be released as a result. - comes to this reaction.



   The following examples show the preparation of typical 1-substituted 3-cyanoguanidines.



    EXAMPLE 1.



   1-phenyl-3-cyanoguanidine.
 EMI10.1
 



     Reagents Molecular proportions Potassium dicyanimide 1.02 Aniline 1.00 Hydrochloric acid 1.00 Water 15.30

 <Desc / Clms Page number 11>

 
A solution of potassium dieyanimide in about three quarters of the water is mixed with the aniline in a reaction apparatus and heated to approximately 90 ° C.



  The hydrochloric acid is diluted with the remainder of the water and this extended acid is added dropwise to the hot stirred reaction mixture. When about half of the acid has been added crystals separate from the solution. Heating of the reaction mixture is continued at substantially 90 ° C for about half the time required for addition of the extended acid.

   The reaction mixture is then cooled and acidified with a small amount of acid, hydrochloric or acetic, and the crystallized solid is collected and washed with water. After drying 1-phenyl-3-cyanoguanidine melts at 194-195 ° C. and is insoluble in water, and extended acids and alkalis, but slightly soluble in ethyl alcohol -, strained. It does not give a color complex by treatment with alkaline copper sulphate.



  EXAMPLE II.



   1-p-sulfophenyl-3-ycanoguanidine.
 EMI11.1
 
 EMI11.2
 
<tb>



  Molecular <SEP> Proportions <SEP> Reagents
<tb>
<tb> Dicyanimide <SEP> pal <SEP> prick <SEP> 0.5
<tb>
<tb> <SEP> sulfanilic acid <SEP> monohydrate <SEP> 1.0
<tb>
<tb> Water <SEP> 17.5
<tb>
 
The solid sulfanilic acid is slowly added to the stirred solution of clacic dicyanimide, the temperature being maintained at substantially 90 ° C. The reaction mixture remains at. the state of a clear solution until the addition of the sulfanilic acid is almost complete, at which point a precipitate begins to form. The reaction mixture is then heated for about two hours, then cooled.

   The calcium salt of 1-p-sulfophenyl-3-cyanoguanidi-

 <Desc / Clms Page number 12>

 does not separate, it is recovered, washed with water and dried in air. This calcium salt is completely insoluble in hot water.

   The free acid can be recovered by treating the calcium salt with cold expanded hydrochloric acid.
 EMI12.1
 di1ùiPL & III. 1-methyl- 1-paeryl-, j- oyanoLanicline ..
 EMI12.2
 
 EMI12.3
 Molecular compounds Dioyenimide calcium J, 5 Methylanl1ine 1.0 Hydrochloric acid 1.0
 EMI12.4
 
<tb> 'Water <SEP> 20.0
<tb>
 
 EMI12.5
 The calcium dioyanimide is dissolved in about three-quarters of the amount of water, and methylaniline is added to this solution. The resulting mixture is then stirred and heated to approximately 80%.

   The hydrochloric acid is spread by means of the last quart of water and the expanded acid solution is slowly added to the reaction mixture, the temperature being maintained at approximately the amine dissolves slowly and it dissolves. separates an oily product from
 EMI12.6
 reaction mixture which is left to cool after complete addition of the acid. This oily product is stirred until crystallization. The 1-metll-1-piuxyl-3-oyanoguanidine thus obtained is r9uper, washed 3t, dried and made to re-pristallize in extended ethyl alcohol; the colorless crystals then melt between 129 and 134 C.



  EXAMPLE IV.
 EMI12.7
 



  1 - o (-naphthyi-3-cyanounidin
 EMI12.8
 

 <Desc / Clms Page number 13>

 
 EMI13.1
 R6aCtil's molecular proportions DiQyanimide caloi.:J.ue 0.5 G {, -na9.1 tyla.mine 1.0 Phlorhydric acid 1.0
 EMI13.2
 
<tb> Water <SEP> 20.0
<tb>
 
 EMI13.3
 A mixture of O <-na., Phthylamine and calcium dicyanimide in water is prepared and heated to about 80 ° C. as shown in Example II. The hydrochloric acid is similarly spread and added slowly to the mixture with stirring at about 80 ° C..



  The rate of addition is such that the pH remains above 4 until the last portions of acid have been added. A purple oil separates during the reaction, which on cooling takes the form of a sticky solid,
 EMI13.4
 1 - <- naphthyl-5-Oyanoguananein crude. By recrystallization from acetone, colorless crystals of 1-- naphthyl-3-oyanoguaniain are obtained, melting at 238.



  ExiimPL- V. l.l '-p-, henylerue-bis-3.3' - Cyauoguanidina,
 EMI13.5
 
 EMI13.6
 Molecular Proportioris Reagents Dioyanimide calcium 1.0 p-phenylenediamine 1, p Clilor hydric acid, 0
 EMI13.7
 
<tb> Water <SEP> 40.0
<tb>
 
A mixture of p-phenylene diamine and calgium diyanimide is prepared according to the method of Example II. The reaction mixture is heated to substantially 80 ° C. with the slow addition of hydrochloric acid extended with a quarter of the total amount of water - The pH is maintained above 4.5 during the addition of 1. 'acidic at the elevated temperature of about 80 C.

   When about half of the acid has been

 <Desc / Clms Page number 14>

 
 EMI14.1
 added, solid products COillm0aCent to precipitate from solution, and when the addition of hydrochloric acid is
 EMI14.2
 complete, the reaction mixture is cooled. The crude l'-p-ahenylene-bis -: "5-eynnoguaidine obtained is soluble in the usual organic solvents with a difficult osrtaine. However, it is sufficiently soluble in the Cllo- solve (3-ethoxyethanol-1). ) so that it is re-crystallized within it and we thus obtain a colorless solid which does not decompose until 314 C.
 EMI14.3
 EXTIlv '[J? LlJ: VI. 1-m- # yàroxyphenyl-6-oyanoguanane.
 EMI14.4
 
 EMI14.5
 
<tb>



  Molecular <SEP> Proportions <SEP> Reagents
<tb>
 
 EMI14.6
 DiQyanimidE) caloic 0.5 m-arai, no phê no 1 1, 0
 EMI14.7
 
<tb> Hydrochloric acid <SEP> <SEP> 1.0
<tb>
<tb> Water <SEP> 20.0
<tb>
 Still following the procedure of Example II, we. add
 EMI14.8
 slowly the hydrochloric acid to the mixture 1 at 83 C and the fold remains above 4.5 until almost all of the acid has been added as the reaction progresses the m-aminophenol dissolves and a light brown solution. When this solution has cooled, the 1-m-
 EMI14.9
 hydroxyphenyl-3-yanQguanidine oristallized and, after recovery, recrystallization from water and drying, melts at 199-200 C.



  EX El, 1PLJ. VI I.



  1-o-hdroxyphenyl-3-Gaaobuanidine,
 EMI14.10
 

 <Desc / Clms Page number 15>

 
 EMI15.1
 Molecular lroporcion reagents Cyaûiwide calsique 0.5 o-emiuophenol 1.0
 EMI15.2
 
<tb> Hydrochloric acid <SEP> <SEP> 1.0
<tb>
<tb> Water <SEP> 20.0
<tb>
 The process followed is essentially the same as
 EMI15.3
 the one used in the example. VI Above. Lto-aminophnol dissolves and precipitates a viscous crude product which slowly crystallizes on cooling of the reaction mixture 1.



  Most of the colored impurities present in this l-o-
 EMI15.4
 Crude hydroxyphéay'L-3-Qyanaguanidine can be extracted by means of hydrochloric acid or acetic acid before its reoristallization in hot water. The brownish needles obtained by this treatment decompose with the release of ammonia at around 173 C.



  EXAMPLE VIII.
 EMI15.5
 1- Cy c lollexyl-3- cyanogu anidine
 EMI15.6
 
 EMI15.7
 (a) Reagents Molecular content Oaloic dipyanimide 0.5 Oyclohexylamine hydrochloride 1.0
 EMI15.8
 
<tb> Water <SEP> 35.0
<tb>
 These reagents are dissolved in water and the pH is adjusted.
 EMI15.9
 at 7 - 7; 5 at medium. of a small quantity of hydrochloric acid, A then heats the reaction mixture :! in a reaction apparatus equipped with a reflux condenser for approximately
 EMI15.10
 24 hours at 95-10000. An oil separates during the reaction, but no ammonia is given off. After dissolving this oil in an extended ethanolic medium, / which /
 EMI15.11
 crude 1-cyclohexyl-3-cyanoguaaîdiae / melts at 1.5-150 C.



  The product is then purified by re-crystallization from extended alcohol to give a crystalline product.
 EMI15.12
 fo.nda: t at 158-160 "C.

 <Desc / Clms Page number 16>

 
 EMI16.1
 
<tb> (b) <SEP> Reagents <SEP> Molecular <SEP> proportions
<tb>
 
 EMI16.2
 Sodium dieyanimide 1.0
 EMI16.3
 
<tb> oyolohexylamine <SEP> hydrochloride <SEP> 1.0
<tb>
<tb> Isopropanol <SEP> 16.5
<tb>
 
A mixture of the above compounds is refluxed for about 4 hours. Sodium dicyanimide is not very soluble in isopropanol so that it is difficult to distinguish it from the sodium chloride which separates during the reaction of dicyani-
 EMI16.4
 mide. The reaction mixture is cooled and the sodium chloride removed.

   After evaporation of the isopropanol solution, a gummy residue is obtained which is purified by dissolution in extended alcohol. We obtain a pro-
 EMI16.5
 crystallized product melting at 155 * 9. of 1-cyolohexyl-3-eyanoguanidine by crystallization of this solution and drying. Further purification raises the melting point to 158-15940. There is no need to remove the sodium chloride by filtration, but it can be leached with water from the residue obtained after evaporation of the isopropanol.
 EMI16.6
 



  (o) Reagents M016euly Proportions
 EMI16.7
 
<tb> Dicyanimide <SEP> sodium <SEP> 1.0
<tb>
 
 EMI16.8
 Oyo1ohexy1- hydrochloride
 EMI16.9
 
<tb> amine <SEP> 1.0
<tb>
 mix the dry salts in an open container and
 EMI16.10
 one heats to 9UG., it forms an eomaeux product, one then raises the temperature appreciably to 100 * 0. and hold it for about an hour. There is no exothermic reaction, nor a release of ammonia.
 EMI16.11
 nias, The reaction mixture is then cooled, the sodium chloride lassivated with water and the residue recrystallized from ethyl alcohol extended so as to give the 1-
 EMI16.12
 Cyclohexyl-3-Qyanoguanidine mp lb8-1g0 '.

 <Desc / Clms Page number 17>

 
 EMI17.1
 
<tb>



  (d) <SEP> Reagents <SEP> Molecular <SEP> proportions
<tb>
<tb> Dioyanimide <SEP> sodium <SEP> 1.0
<tb>
 
 EMI17.2
 Oyolohezylamine hydrochloride 0.9
 EMI17.3
 
<tb> Water <SEP> 5.5
<tb>
 
The above mixture is heated to substantially 10 ° C. for about seven and a half hours. Two liquid phases form after three hours of heating.
 EMI17.4
 about. The oil bed which separates takes on a gummy consistency when the reaction is completed and this product, after recovery and re-oristallization in extended ethyl alcohol, dominates 1-oyalohezyl-3-oyanoguanidine melting at 158- 159 C.
 EMI17.5
 



  EXAMPLE IL 1-butyl-3-oyanoguanidine
 EMI17.6
 
 EMI17.7
 Reaatives Maleoular proportions Dîçyanîmide potassium 1.0
 EMI17.8
 
<tb>
<tb> Butylamine <SEP> hydrochloride <SEP> <SEP> 0.9
<tb>
<tb>
<tb> Water <SEP> 1.4
<tb>
 
 EMI17.9
 These three compounds are mixed and stirred at its laughable 100 C. in a reaction apparatus fitted with a reflux condenser * After about an hour and a half
 EMI17.10
 the reaotiamel mixture loses its homogeneity and after two more hours of heating, it is cooled, water is expanded again and it is left to stand overnight. This insoluble oil does not crystallize easily until it is seeded, but after seeding crystallized 1-butyl-3-oyanoguanidine is obtained.

   This product is then recrystallized from hot water and a colorless crystalline product is obtained, melting at 72-74 ° C.

 <Desc / Clms Page number 18>

 
 EMI18.1
 



  X1'tü'I, iFS 'X. 1-ootyl-3-oyanoguanidine
 EMI18.2
 
 EMI18.3
 Reagents Moleolar proportions Oetylamine 1.0 Phlorhydric acid 1.0
 EMI18.4
 
<tb> Dicyanimide <SEP> sodium <SEP> 0.99
<tb>
 The concomitant hydrochloric acid is added with precaution.
 EMI18.5
 centered on o9tylomine so as to obtain a solution encountered with the salt of the amine. Sodium dicyanimide is then added and the mixture is heated to approximately 100 ° C. in an open container. During the first hour the pH rises from the neutral point to about 8.5 and the water evaporates completely. Heating is continued for a further five to six hours and the final reaction mixture is diluted with water, followed by heating. cooled, acidified and stirred until
 EMI18.6
 obtaining a crystalline product.

   The colorless crystallized 1-optyl-3-pyano-guanidine is recovered and washed with water. After drying it melts at 65-66 C.



  EXAMPLE XI.
 EMI18.7
 l-dodeçyl-3-cyanoguanldine
 EMI18.8
 
 EMI18.9
 
<tb> (a) <SEP> Reactives <SEP> Molecular <SEP> proportions
<tb>
 
 EMI18.10
 Doddoylamine 1.0 Chloride d t anm ont um 1.05
 EMI18.11
 
<tb> Dioyanimide <SEP> sodium <SEP> 1.05
<tb>
 
Deoylamine hydrochloride is first prepared by heating the amine and ammonium chloride in the presence of a small amount of water and ethyl alcohol in an open container at a temperature of about 90 C.
 EMI18.12
 so as to eliminate the ammonia released.

   Sodium diqyanimide and a small portion of water are then added to [alpha] the neutral pasty mass of the amine hydrochloride and this

 <Desc / Clms Page number 19>

 The mixture is heated for about three and a half hours at substantially 100 C. After this heating period the pH is adjusted to 8.5 by means of a small portion of do-decylamine and the heating is continued for a further six hours at substantially 100 C The reaction mixture becomes a fluid oily substance and no tendency to exothermic phenomena is noted. Once heating is complete, the reaction mixture is diluted with cold water and stirred until a crystalline material forms.

   The solid product is filtered off and slurried with water containing a small amount of caustic soda.



  After a second filtration, the wet cake is dissolved in hot ethanol and the slight residual alkalinity is neutralized by means of acetic acid. This alcoholic solution is spread by means of a small amount of water and left to slow cooling. the crystallized 1-dedecyl-3-cyanoguanidine separates and after filtration, washing with water containing a small amount of acetic acid and drying in air, the crystallized product obtained melts at 86-89 C .
 EMI19.1
 
<tb>



  (b) <SEP> Reaotants <SEP> Molecular <SEP> proportions
<tb>
<tb> Dodecylamine <SEP> 1.0
<tb>
<tb> Sulfuric acid <SEP> <SEP> 0.5
<tb>
<tb> Dicyanimide <SEP> sodium <SEP> 1.12
<tb>
<tb> Butanol <SEP> 4.4
<tb>
<tb> Water <SEP> 5.6
<tb>
 
The sulfuric acid is diluted with half of the amount of water indicated above and this solution is carefully added to the butanol solution of dodeoylamine. The pH of the dodecylamine solution thus obtained in the sulphate state is approximately 7 to 8. Sodium dioyanimide is added and the reaction mixture obtained is heated to 95-100 C.

   Water is removed under pressure

 <Desc / Clms Page number 20>

 slightly reduced over 45 minutes, while heating is continued for about two and a half hours. The remaining half of water is then added and then removed as described above. The reaction mixture is further heated for one third hour at approximately 100 C. The presence of a small amount of water in this The reaction facilitates the formation of sodium sulfate and accelerates the reaction. When the above heating is completed, a large volume of water is added and the butanol is separated from the reaction mixture by azeotropic distillation.

   The 1-
 EMI20.1
 doddoyl-3-oyanoguanidine crystallizes in the residual aqueous phase and, after purification and re-oristallization in extended ethyl alcohol as indicated in Example XIa, the product melts at 86-89 C.



  EXAMPLE XII.
 EMI20.2
 1-ootadeoyl-3-oyaaoguanidine.
 EMI20.3
 
 EMI20.4
 
<tb>



  (a) <SEP> Reactants <SEP> Molecular <SEP> proportions
<tb>
<tb> Octa- hydrochloride <SEP>
<tb>
 
 EMI20.5
 decYJ..W! ll.ilG O Dieyan1mide sodium 1.06.
 EMI20.6
 
<tb> Water <SEP> 6.20
<tb>
 
 EMI20.7
 a mixture of redotifs oi-ti3ssus is prepared and it is heated in an open container to approximately 100 C.



  The reaction mixture is stirred and the pH is adjusted to 8-9 with a small amount of octadecylamine. After about an hour the viscous solid turns to a fluid oil and heating is continued for four hours and During the heating the water evaporates from the reaction mixture with the aid of a moderate air stream passing over the surface of said reaction mixture. When the heating is finished, it is spread with water and the product is recovered.

 <Desc / Clms Page number 21>

 resulting solid.

   This is put in the form of a slurry in a large volume of water containing a small amount of caustic soda. After filtering the solid product from this alkaline solution, the wet cake is redissolved in a large volume of hot ethyl alcohol and The residual alkalinity is neutralized by means of aoetic aid. The alcoholic solution is cooled, resulting in crystallization of 1-octadecyl-3-cyanoguanidine. The crystallized product is recovered and after washing with a further quantity of ethyl alcohol and drying, it melts at 95-96 ° C.
 EMI21.1
 
<tb>



  (b) <SEP> Reagents <SEP> Molecular <SEP> proportions¯
<tb>
<tb> Octadecylamine <SEP> 1.0
<tb>
<tb> Acetic <SEP> Acetic <SEP> 1.0
<tb>
<tb> Dioyanimide <SEP> sodium <SEP> 1.05
<tb>
<tb> Water <SEP> 7
<tb>
 
O9tadéeylamine acetate is prepared by dissolving the amine and acetic acid in water. Sodium dicyanimide is then added to the reaction mixture and the temperature is raised to substantially 100 ° C. The process for preparing 1-octadecyl-3-cyanoguanidine is substantially the same as in the case of exempta XIIa. .



  The crystallized solid 1-octadecyl-3-cyanoguanidine melts at the same point as that indicated in the above-mentioned example.
 EMI21.2
 
<tb>



  (c) <SEP> Reagents <SEP> Molecular <SEP> proportions
<tb>
<tb> Octadecylamine <SEP> 1.0
<tb>
<tb> Sulfuric acid <SEP> <SEP> 0.5
<tb>
<tb> Dioyanimide <SEP> sodium <SEP> 1.1
<tb>
<tb> Butanol <SEP> 2.2
<tb>
<tb> Water <SEP> 5, <SEP> 6 <SEP>
<tb>
 
A solution of octadecylamine sulfate is prepared by the cautious addition of extended sulfuric acid.

 <Desc / Clms Page number 22>

 half the amount of water indicated above to a butanol solution of the amine * Sodium dioyanimide is then added to the obtained amine salt and the temperature is raised, and it is maintained at approximately 100 C. The water is removed under slightly reduced pressure while the reaction mixture is heated, which is one and three-quarters hours.

   Two separate layers of water and butanol are then added to the reaction mixture, followed by azotropic distillation. As again in Example XIb, this water serves to facilitate the formation of 1-octadecyl-3-cyanoguanidium and sodium sulfate.



  Each azeotropic distillation and each heating period lasts approximately one hour. The total heating time to 90-100 C is approximately four hours. After heating, a large volume of water is added to the reaction mixture and the butanol azeotropically distilled. The residual oily product crystallizes on cooling, and after recovery and re-crystallization, the 1-octadecyl-3-cyanoguanidine obtained melts at 95-96 C.



  EXAMPLE XIII.



   1.1-cyclopentamethylene-3-cyanoguanidine,
 EMI22.1
 
 EMI22.2
 
<tb> Reagents <SEP> Molecular <SEP> proportions
<tb>
<tb> Piperidine <SEP> 1.0
<tb>
<tb> Hydrochloric acid <SEP> <SEP> 1.0
<tb>
<tb> Dicyanimide <SEP> sodium <SEP> 1.0
<tb>
 
The piperidine is carefully added to the concentrated hydrochloric acid so as to prepare a concentrated solution of piperidine hydrochloride. It may be necessary to provide external cooling of the reaction vessel in which the above solution is prepared.
AT

 <Desc / Clms Page number 23>

 above. Sodium diyanimide is added to the concentrated solution of piperaidine hydrochloride and this reaction mixture is stirred and heated to substantially 100 ° C.

   This temperature is maintained for about two and a half hours while passing a current of air over the surface of said reaction mixture to aid in the evaporation of the water, the pH ± being kept at 7.5 - 8.5. This reaction mixture is diluted with water, cooled and the solid.
 EMI23.1
 of crystallized is filter. The crude 1,1-cyclopentem6ethylene-3-Qyanoguanidine is recrystallized in a large volume of hot water; the crystallized solid obtained melts at 166-168 C.
 EMI23.2
 



  EX] 1> JIPL XIV. 11-dibut, 1-3-yanouanidina.
 EMI23.3
 
 EMI23.4
 
<tb>



  (a) <SEP> Reagent <SEP> Molecular <SEP> proportions
<tb>
<tb> Dibutylamine <SEP> 1.0
<tb>
 
 EMI23.5
 sodium hydrochloric acid 1.0 D1 Cyan1 ml sodium 1.0
The concentrated aqueous solution of dibutylamine hydrochloride is prepared by carefully adding the acid to the amine. It may be necessary to cool externally to aid in the removal of the heat of neutralization. Sodium dioyanimide is then added to the concentrated solution of the amine salt and the reaction mixture is heated to substantially 100 ° C. The heating time of the reaction mixture is about five and a half hours during which the added water is heated. evaporates, the pH being maintained between 7.5 and 8.5.

   There are two liquid phases before water removal.
 EMI23.6
 The heating being completed, the reaction mixture is

 <Desc / Clms Page number 24>

 extended with water, cooled and stirred until the gummy product crystallizes. we) make the slurry slightly acidic by means of acetic acid and after filtration,
 EMI24.1
 washing and air drying the lel-dibutyl-3-oyanoguanidîne obtained melts at 72-75 C.
 EMI24.2
 
<tb>



  (b) <SEP> Reagents <SEP> Molecular <SEP> proportions
<tb>
<tb> Dibutylamine <SEP> 1.0
<tb>
 
 EMI24.3
 Sulfuric acid 0.5 Sodium diOyanim1 1.1
 EMI24.4
 
<tb> Butanol <SEP> 2.27
<tb>
 A butanol solution of dibutylamine sulfate was prepared by adding sulfuric acid extended to half the above amount of butanol to the dibutylamine dissolved in the remainder of the butanol. Adjust the pH of the mixture to 8 with a small amount of amine and
 EMI24.5
 Add the finely ground sodium dioyanimide, the mixture is heated for five and a half hours at 95-10000, then poured into a large volume of water.

   After cooling the obtained mixture externally with ice-water, the oily product solidified, filtered, washed with water and diluted alkali, and then dried in vacuo.
 EMI24.6
 the crude 1,1-dibutyl-3-oyanaguanidine is re-crystallized from extended ethyl alcohol. It then melts at 72-75 C.



    EXAMPLE XV.
 EMI24.7
 



  1.11-decamethylene-bio-â, 3'oyanoguanidine.
 EMI24.8
 
 EMI24.9
 
<tb> Reagents <SEP> Molecular <SEP> proportions
<tb>
 
 EMI24.10
 Decamethylenediamine (di-
 EMI24.11
 
<tb> Hydrochloride <SEP>) <SEP> 0.46
<tb>
<tb> Dioyanimide <SEP> sodium <SEP> 1.0
<tb>
<tb> Water <SEP> 2.8
<tb>
<tb> Butanol <SEP> 1.37
<tb>
 

 <Desc / Clms Page number 25>

 
 EMI25.1
 The decaadthylenediamine dihydrochloride and sodium dicyanimide are mixed in water and warmed to substantially 100 ° C.

   We breathe in. air at the surface of the mixture to aid in the removal of the water, which is complete after one hour, the butanol is then added to the oily solid residue and a reflux condenser is fitted In the reaction apparatus, the reaction mixture is heated for a further six hours at substantially 100 ° C. At about the end of the second hour of heating, the oily product crystallizes exothermically. When the heating period is over, add a large volume of water and
 EMI25.2
 distils the butanol azdotropically from the reaction mixture.



  The crystallized 1,1deoam6ethylene-bie-3.3t-Qyanoguanidine is filtered, washed with water and acetone and dried. the product can be re-oristallized in an aqueous solution
 EMI25.3
 ethyl dtalçool. The dry product then melts at 180-18500.



  EXAMPLE XVI. tethylene-bis- (l.l-phenylene-3, '- Cyanouanidina,
 EMI25.4
 
 EMI25.5
 Réaet11's. Molecular ports 4, '-d i am inod i pny 72st hane 0.5
 EMI25.6
 
<tb> Hydrochloric acid <SEP> <SEP> to <SEP> 10 <SEP>% <SEP> 1.0
<tb>
<tb> Dioyanimide <SEP> sodium <SEP> 1.13
<tb>
<tb> Ethanol <SEP> 6.4
<tb>
<tb> Water <SEP> 13.8
<tb>
 
All the products, except hydrochloric acid, are placed in a reaction apparatus equipped with a stirrer, a thermometer, and a reflux condenser, as well as
 EMI25.7
 of a device for the slow addition of ae1de. the reaotiortnol mixture is heated to reflux and the aid is added slowly over a period of about one hour.

   The solid product gradually precipitates from the solution as
 EMI25.8
 that the reaction progresses <After cooling, we filter

 <Desc / Clms Page number 26>

 
 EMI26.1
 methylene-bis- (1,1'-p-phnylene-3,51-oyanoguanidine) from the reaction mixture. The solid product is washed thoroughly with water and acetone and a product is obtained.
 EMI26.2
 which, after air drying, decomposes to 873-874 * 0. This product is insoluble in all common solvents.



  EXAMPLE XVII.
 EMI26.3
 1-Benzyl-3-eyanoguanidine.
 EMI26.4
 
 EMI26.5
 React if 'Molecular proportions.
 EMI26.6
 
<tb>



  Benzylamine <SEP> 1.0
<tb>
<tb> Sulfuric acid <SEP> <SEP> 0.56
<tb>
 
 EMI26.7
 Di Oyanim1de {sodium l 7.,
 EMI26.8
 
<tb> Butanol <SEP> 11.7
<tb>
<tb> Water <SEP> 4.1
<tb>
 
After diluting the sulfuric acid in about 21% of the butanol, it is slowly added to a solution of benzylamine dissolved in the remaining 79% of the butanol. The pH of this solution is about 7 to 8. The sodium dL-cyanimide and about 30% of the amount of water indicated above are added to the solution of the amine sulfate.



  The reaction mixture is heated to substantially 100 ° C. for a total time of about six and a half hours.



  During this heating, lte is added several times to the reaction mixture, which is then distilled.
 EMI26.9
 



  When the heating is complete, the mixture is diluted with a large volume of water and the butanol azeotropically distilled. The residual oily product crystallizes on cooling.
 EMI26.10
 This crude 1-bonzyl-3-oyanoguanidine is treated with extended soda and acetic arid to remove
 EMI26.11
 the residual amine. The solid product is then recovered, washed with water and recrystallized in hot water: 1-banzyl-3-oyanoguanidîne is thus obtained, melting at 108-.

 <Desc / Clms Page number 27>

 109 C.
 EMI27.1
 



  EXAMPLE XVIII Example 1-J-snlfel-3-C, anouanidine.
 EMI27.2
 
 EMI27.3
 
<tb>



  Reagents <SEP> molecular proportions <SEP>
<tb>
<tb> Taurine <SEP> 1.0
<tb>
<tb> Dicyanimide <SEP> sodium <SEP> 1.0
<tb>
<tb> Water <SEP> 22.2
<tb>
<tb> Butanol <SEP> 5.5
<tb>
 
Taurine is dissolved in water and the resulting solution is neutralized by means of a small grade of
 EMI27.4
 10% caustic soda solution. Sodium dioyanimide and butanol are then added and the reaction mixture is heated to 90-100 C. This mixture is heated for three to four hours at this temperature while the water is removed. Heating is completed the scat solvents removed. under reduced pressure of the reaction mixture, and an oily residue is obtained which, on cooling, appears in the form of a gummy solid.

   After prolonged drying under vacuum this gummy solid gives crystals of the crude sodium salt of 1-ss -sulfoethyl-3-oyanoguani-
 EMI27.5
 dine which melt at 1C5-180 ° C, 1- (3-sulfot $ yl - cyano-guanidine can be prepared by acidification of its salt
 EMI27.6
 sodium by means of cold hydrochloric acid.



  EDMPLE XIX 1-Isopropyi-3-oyanoguanidine
 EMI27.7
 
 EMI27.8
 Reagents Proportions noiéoulairaa Isopropylacitne 3.47
 EMI27.9
 
<tb> Sulfuric acid <SEP> <SEP> 95 <SEP>% <SEP> 1.24
<tb>
<tb> Water <SEP> 1.5
<tb> -27-
<tb>
 

 <Desc / Clms Page number 28>

 
 EMI28.1
 
<tb> Butanol <SEP> 22.0
<tb>
<tb> Bioyanimide <SEP> sodium <SEP> 2.72
<tb>
 
The isopropylamine is dissolved in butanol, the solution is neutralized by the addition of sulfuric acid, then the water is removed by distillation of about 400 cc. of butanol, in vacuo. Sodium dioyanimide is then added, the pH is adjusted to 7.5 8.5, and the mixture is heated at 90-92 ° C. for 18 hours.

   The solution is then filtered to remove the sodium sulfate, the butanol in turn is removed under reduced pressure and water is then added to ensure the complete removal of the butanol by oo-distillation. The final clear solution with a volume of about 500 oc. Is cooled so as to obtain the 1-iso-
 EMI28.2
 Oristallized propyl-3-eyanoguanidine, collected by filtrate, washed with small portions of cold water (in all approximately 60 units). The product is then air-dried and 217 gr. Is obtained, ie 70% of theory.
 EMI28.3
 1-Isopropyl-3-pyanoguanidine is very soluble in acetone, alcohols including butanol and hot water. The crude product obtained in this way melts at 99-100 ° C.
 EMI28.4
 re-crystallization from hot water, the melting point is 102-104 ç.

   By taking up the mother liquors, a further 15 g are obtained. of crude 3-oyanoguanidine.



  The 1-isopropyl-3-oyanoguanidine can then be reacted with p-chloroanilin to give 1-isopropyl-5-p-ch] .orophenylbiguanide, valuable in pharmacology because of its pronounced anti-malarial action.



  .i:!: X: JlvlPL ':: l #.



  1-p-chlorophenyl-3-cyanoa; uanidin
 EMI28.5
 

 <Desc / Clms Page number 29>

 
 EMI29.1
 
<tb> Reactives <SEP> Molleular <SEP> proportions
<tb>
 
 EMI29.2
 p-ohloroanlliae 1.4 I7ieyanimide calcium 0.75
 EMI29.3
 
<tb> Hydrochloric acid <SEP> <SEP> 1.4
<tb>
<tb> Water <SEP> 45.0
<tb>
 
Hydrochloric acid is extended to 150 cc. by addition of water and added with stirring to the mixture of p-chloroani-
 EMI29.4
 line, of calcium dioyanimide and water, maintained at 8000. The time required for the addition of the acid is about 45 minutes. During the addition of acid, the insoluble oily p-chloroanaline gradually dissolves and it preciates.
 EMI29.5
 pite of crystallized 1-p-chlorophenyl-3-ayanoguanidine.



  After heating for a further fifteen minutes the mixture is cooled and the 3-cyanoguanidine collected by filtration.



  We obtain 253 gr. or 93% of theory. The crude i-p-Chlorophenyl-3-cyanoguanidine obtained in this way melts at 200 ° C. and is only slightly soluble in water, acetone and ethyl alcohol. By crystallization in butanol, the melting point is raised to 205 C,
 EMI29.6
 It is possible to react 1-p-chlorophenyl-3-cyanoguanidine with isopropylamine so as to obtain 1-isopropyl-5-p-chlorophenylbiguaniàe which, as we have discussed above, above, is particularly valuable in pharmacology because of its remarkable activity against malaria.



   Examples 1 to XX illustrate the types of 1-substituted 3-cyanoguanidins which can be prepared. The substituent
 EMI29.7
 on 3-oyanoguanidine is determined by the amine which reacts with d1cyantmide. It is thus possible by a judicious choice of the primary or secondary amine to prepare a wide variety of 1-substituted 3-oyaaoguanidines amid the method of the present invention.



  The 1-substituted 6-oyanoguanidines of the present invention are valuable new organic chemical intermediates for the preparation of pharmaceuticals,

 <Desc / Clms Page number 30>

 dyes, insecticides, oxidation inhibitors, vulcanization accelerators, plasticizers, resin generators or modifiers, ion exchange resins, leather treatment agents, papers, and textiles, and the like.



   2 - Preparation of 1,5-substituted biguanides.
 EMI30.1
 



  Rl MI E i9H Il Il 1 li 1 of the type:: R2li -0 -N- 0 - zi zip2 typo: R2 N \ R2
Although the reaction of the present invention for the production of 1.5-substituted biguanides of the type indicated can be carried out within wide temperature limits, in general it is preferable to use a temperature between 80 and 150 ° C., use lower temperatures require a longer reaction time and much higher temperatures being unnecessary and further smoldering lead to the formation of undesirable by-products.



    Experience has further shown that in the reaction of the present invention the aromatic amines are much more active and can react at temperatures lower than those required for the reaction of the aliphatic amines. In general, aromatic amines and (or) their addition salts with acids react best at temperatures between 80 and 105 C., while aliphatic amines and (or) their addition salts with acids require a temperature between 120 and 150 C. for best results.



   If this reaction is carried out with a metal salt of dicyanimide, it is understood that any metal salt from which the dicyanimide can be released can be used. However, it is preferred to use the calcium, sodium and potassium salts of dicyanimide because of this

 <Desc / Clms Page number 31>

 that they are the cheapest and most easily preparable compounds of dicyanimide.



   If an amine salt comma amine source is employed for the reaction of the present invention, the use of common salts such as hydrochloride, sulfate and acetate is preferable. Any salt from which the amine is releasable is suitable for this reaction.



   The following examples show the preparation of typical 1.5-substituted biganides in accordance with the present invention; EXAMPLE XXI
1.5-diphenylbiguanide
 EMI31.1
 
 EMI31.2
 
<tb> Reagents <SEP> Molecular <SEP> proportions <SEP> s
<tb>
 
 EMI31.3
 Caloic dicyanimide 0.45
 EMI31.4
 
<tb> aniline <SEP> 2.0
<tb>
<tb> Hydrochloric acid <SEP> <SEP> conc. <SEP> 2.0
<tb>
<tb> Water <SEP> 24.0
<tb>
 
Half of the above amount of aniline is added to the dioyanimide calcium solution in about one third of the amount of water indicated above.

   The hydrochloric acid is diluted with the remaining quantity of water and this solution is added slowly at substantially 80 ° C. to the stirred mixture containing aniline and calcium dicyanimide.



  When about half of the hydrochloric acid has been added, the rest of the aniline is added. Crystals of 1.5-diphenylbiguanide hydrochloride separated soon after the addition of hydrochloric acid was completed. The reaction mixture is heated for an additional 30 to 60 minutes, then cooled and filtered. the crystals are washed in cold water and air dried. Hydrochloride

 <Desc / Clms Page number 32>

 
 EMI32.1
 1.5-diphenylbiguanid3 melts at 3-H5 C. The base can be obtained by treating the hydrochloride with substantially stohiometric amounts of 10 or 20% aqueous sodium hydroxide solution. the insoluble precipitate obtained is recovered, washed and dried. 1.5-Diphenylbiguani- melts at 148-149 C.



  EXAMPLE XXII.
 EMI32.2
 



  1.5-di-p-sulfophenylbiguanide
 EMI32.3
 
 EMI32.4
 Reagents Molecular ion ratio Caloic dioyanhnide 0.45
 EMI32.5
 
<tb> <SEP> sulfanilic acid <SEP> 2.0
<tb>
<tb> Water <SEP> 35.0
<tb>
 Calcium dicyanimide is dissolved in water and
 EMI32.6
 carefully add gulfauilic acid to the stirred mixture; however that the temperature is raised from 60 to 100 C. approximately. The reaction mixture remains as a clear solution and is refluxed for a period of? hour. It is cooled to about 50 ° C. and acidified with acid.
 EMI32.7
 of extended hydrochloric acid. The liberated product which is 1,5-di-p-sulfohenylbiuanid $ is then precipitated from the aqueous solution containing its soluble calcium salt.



  The colorless solid product is collected.
 EMI32.8
 M-1111PL.-i XXIII * 5-dim-ethyl-1.5-diphenylbiguanide.
 EMI32.9
 
 EMI32.10
 
<tb>



  Molecular <SEP> Proportions <SEP> Reagents
<tb>
<tb> Dioyanimide <SEP> calcium <SEP> 0.45
<tb>
 
 EMI32.11
 Methylaniline 2, p
 EMI32.12
 
<tb> Hydrochloric acid <SEP> <SEP> Cone. <SEP> 2.0
<tb>
<tb> Water <SEP> 33.0
<tb>
 

 <Desc / Clms Page number 33>

 Carefully mix methylaniline, acid
 EMI33.1
 hydrochloric acid and about 40% of the above amount of water so as to form an aqueous solution of methyl ethylene hydrochloride. Alaloic dioyanimide dissolved in the remainder of the water is carefully added to the 90-100% aqueous solution of the amine hydrochloride.

   We x $ oewôe act; the mixture and heated for about an hour after the addition of the calcium dicyanimide solution has been completed. the solution is acidified and after standing it separates crystals of 1.5. dimethyl hydrochloride
 EMI33.2
 l.5-aiphenylbiguaniàe. the product is filtered, washed and dried. It decomposes at 2ù9- & la c, and becomes a clear liquid at 315 "C. This product gives a hydrate which loses its water of crystallization slowly below.
 EMI33.3
 of 100 ° C., and even less if the dehydration takes place under vacuum. The free base is obtained by treating the hydrochloride with an aqueous solution of caustic soda.



  EXAMPLE XXIV
 EMI33.4
 1 "5-di- -naphthyloiguanide
 EMI33.5
 
 EMI33.6
 
<tb> Reagents <SEP> Molecular <SEP> proportions
<tb>
<tb> Dicyanimide <SEP> sodium <SEP> 1.0
<tb>
 
 EMI33.7
 0-Naphthylamine 2.0
 EMI33.8
 
<tb> Hydrochloric acid <SEP> <SEP> 10 <SEP>% <SEP> 2.0
<tb>
<tb> Water <SEP> 13.9
<tb>
 
 EMI33.9
 2-etÀoxyethaàol-1 1310
 EMI33.10
 The sodium dicyanimide and the β -napntyl amine are mixed in aqueous β-ethoxyethanol -1 and the mixture is heated with stirring to approximately 95-100 C. The mixture is added with caution, hydrochloric itacido and an appropriate precipitate.
 EMI33.11
 soon ralt in the originally clear solution. after

 <Desc / Clms Page number 34>

 heating for a total of one to two hours at substantially 95-100 ° C., the precipitate is removed from the hot reaction mixture.

   After washing and drying, 1.5-di- -naphthybiguanide hydrochloride decomposes at 268 C.



  After cooling the original filtrate, a further portion of the hydrochloride can be recovered. Co salt is insoluble or only slightly soluble in usual organic solvents and also in hot water. The base can be prepared from its hydrochloride by suspending it in ethyl alcohol and adding a slight excess of an alkali over the theoretical amount required. The free base is recovered, washed and dried ... It deoomposes at 175-177 C. and is insoluble in water, and only slightly soluble in hot ethyl alcohol. The acetate can be prepared from said free base and is insoluble in hot water, but soluble in hot ethyl alcohol.



   The substituted biguanides of the present invention of the type indicated are valuable chemicals as intermediates in the preparation of chemotherapeutic agents, pharmaceuticals, textiles, rubber, plastics, resins and the like.



   3 - Preparation of 1.5-substituted biguanides
 EMI34.1
 R 1H H NH R of the type: 1> 1 \ 1 - C - \ 1 h - 1 \ 1 C - N <: 5 R
Although the reaction of the present invention to produce the 1.5-substituted biguanides of the type indicated can be carried out over wide temperature limits, it is in general preferable to employ temperatures between 80 and 150 ° C. , the use of lower temperatures requiring a longer reaction time

 <Desc / Clms Page number 35>

 and much higher temperatures being unnecessary and can lead to the formation of undesirable by-products.

   furthermore, experience has shown that in the reaction of the present invention the aromatic amines are much more active and can react at temperatures lower than those required for the reaction of aliphatic amines. In general, aromatic amines and (or) their addition salts with acids react under the best conditions between 80 and 105 C. while the great majority of aliphatic amines and (or) their salts of addition with acids requires
 EMI35.1
 temperatures of the order of 1Q to 150 ° C. to give the best results.



   If an amine salt is employed as the amine source for this reaction, the use of common salts such as the hydrochloride, sulfate and acetate will be preferred.



  Any salt from which the amine can be released is suitable for the reaction.



   The following examples show the preparation of
 EMI35.2
 1.5-substituted biguanides of the type indicated conform to the present invention.
 EMI35.3
 



  M2Ìàil? LE hvv. 1.5-dlphenylbdguanide
 EMI35.4
 
 EMI35.5
 
<tb> (a) <SEP> Reagents <SEP> Molecular <SEP> proportions
<tb>
 
 EMI35.6
 1-Phenyl-S-Oyanoguanidine 1.0
 EMI35.7
 
<tb> Aniline <SEP> 1.0
<tb>
<tb> Hydrochloric acid <SEP> <SEP> cone. <SEP> 1.0
<tb>
<tb> Water <SEP> 48.0
<tb>
 
 EMI35.8
 Approximately 0% mixture of anili and 1-phenyl-to-oyanoguanidine is stirred in approximately 80 to 90% of the above amount of water with stirring. We extend the Bide

 <Desc / Clms Page number 36>

   hydrochloric acid with the remaining 10 or 20% of the water and this solution is carefully added to the hot reaction mixture. The addition of the acid being complete, the reaction mixture is heated to reflux.

   The reflux is maintained for 30 to 60 minutes: during this time a clear solution closes. This solution is cooled and the hydrochloride of 1.5-diphenylbiguanide oristallized. The product is filtered, washed and dried. 1.5-Diphenylbiguanide hydrochloride melts at 223-225 ° C. The free base can be obtained by treating the hydrochloride with substantially stohiometric amounts of 10 or 20 l of caustic soda. The insoluble precipitate obtained is collected, washed and dried. 1.5-Diphenylbiguanide melts at 148-149 C.
 EMI36.1
 
<tb>



  (b) <SEP> Reagents <SEP> Molecular <SEP> proportions
<tb>
<tb> Dicyanimide <SEP> calcium <SEP> 0.45
<tb>
<tb> Aniline <SEP> 2.0
<tb>
<tb> Hydrochloric acid <SEP> <SEP> 2.0
<tb>
<tb> Water <SEP> 24.0
<tb>
 
One-half of the above-mentioned amount of aniline is added to a solution of aloiic dicyanimide in about two-thirds of the amount of water. The hydrochloric acid is spread with the rest of the water and this solution is slowly added to the stirred mixture containing aniline and calcium dicyanimide, at approximately 80 ° C. When about half of the acid is added, the mixture is stirred. add the rest of the aniline. The temperature is raised to approximately 100 ° C. and the remainder of the acid is carefully added.

   The levels of 1.5-diphenyloiguanide hydrochloride separated off shortly after the addition of the hydrochloric acid was complete. The reaction mixture is heated for a further

 <Desc / Clms Page number 37>

 30 to 60 minutes, cool and filter. the crystals are washed in cold water and air dried.
 EMI37.1
 1.5-Diphenylbiguanide hydrochloride melts at -5 ° C. The free base can be retained by treatment of the chlorine hydrate using a medium. in substantially stoichiometric quantities of 10 to 2% caustic soda solution, the insoluble precipitate obtained is collected, washed and dried. 1.5-Diphenylbiguanide melts at ln = 8-149 C.



  ... x.i! lVIPL xx. VI 1-phc., Zl-5-p-sulP..p.W: ¯, rlii; aani.;. E
 EMI37.2
 
 EMI37.3
 
<tb> Reagents <SEP> Molecular <SEP> proportions
<tb>
 
 EMI37.4
 Í-phenyl-6-cyanou8Llidine 1.0 Sulfanilic acid 1.0
 EMI37.5
 
<tb> Water <SEP> 70,
<tb>
 
The aqueous solution of the above reagents is stirred and heated under reflux for 30 to 60 minutes.
 EMI37.6
 The reaction mixture becomes clear after 15 to 4 minutes, then the crystallized luphenyl-5-P-sulfophenylbtguanide begins to precipitate. After cooling the reaction mixture, the solid product is collected.
 EMI37.7
 colorless, wash it with water and dry it? the air.



  1-Phenyl-5-p-sulfophenyl guanide has a value of: 54-85 C. Ia can also be prepared. I-phenyl-5-p-sulfopre nyl-biguanide by reaction of 1-p-sulfophéAyl-3-oyenogénidine with aniline.
 EMI37.8
 



  .riJ #: MPL.lli XXVII ..lt-diphênrl-bis-5.5'-p-phen lenebiuanide,
 EMI37.9
 
 EMI37.10
 Reactants molecular proport ion 1-hén31-3-cyanogua.id ie 1.0 d
 EMI37.11
 
<tb>
<tb>
 

 <Desc / Clms Page number 38>

 
 EMI38.1
 p-pàenylenediamine 0.5 Hydrochloric acid cone. 1.0
 EMI38.2
 
<tb> Water <SEP> 60.0 <SEP> 0
<tb>
 it is heated to approximately 100 C. the mixture acts
 EMI38.3
 of p-phenylenediamine and 1-phenyl-3-oyanoguaniditB in about 80 to 90% of the amount of water indicated above. The hydrochloric acid is spread with the rest of the water and added slowly; to the reaction mixture so that the pH reaches 3 at the end of the reaction.

   This reaction mixture is heated for about an hour and is treated with decolorizing charcoal for about the last quarter of an hour of heating. After removing the decolourising charcoal, the solution is cooled.
 EMI38.4
 tion so that the 1.1'-31-Phnyl-bis-5.5'-p-phenyleebiguanide dihydrochloride crystallizes. The solid product is collected, washed with frcjde water and acetone and dried in air. The dichlorh-yd spleen from 1, α'-diphenyl-bis-5.5'-p-folded = 1; aenebijuaniàe melts at
233 C., after crystallization in water. The free base can be obtained by treating the hydrochloride with substantially stoichiometric amounts of sodium hydroxide.
 EMI38.5
 YT / Caustic.

   1,1'-dilWrayl-bis-5,5 'lhênylGnebi; uaride
 EMI38.6
 melts at .19-0 C, it is insoluble, in cold acetone ethyl alcohol, water and extended sulfuric acid.



  It is soluble in glacial acetic acid, extended acetic acid and extended hydrochloric acid.
 EMI38.7
 ; I PI, XXv'111 1-bubyl-5-oot, y.loijguaniàe
 EMI38.8
 
 EMI38.9
 Reactive rrolecular proportions 1-octyl-3-cyaQGuDnidine 1,
 EMI38.10
 
<tb> Butylamine <SEP> hydrochloride <SEP> <SEP> 1.1
<tb> J
<tb>
 

 <Desc / Clms Page number 39>

 
 EMI39.1
 These two products are mixed and they are stirred meoally during; about three to four hours to sensitive-
 EMI39.2
 ment at 6o-135 C. The mixture becomes homogeneous without showing any strongly exothermic phenomena. After cooling the reaction mixture, the hydrochloride of 1 - tyl-5-ootylbiguanide is dissolved in water so as to form an opalescent solution similar to an el.

   This tolerance is treated with an excess of sodium sulfate over the theoretical amount required and insoluble 1-butyl-5-octylbisuanide sulfate precipitates. The crude salt is collected and washed with acetone. It was made to reo ri set up in isopropanol contained a small amount of water, and the sulphate of 1-butyl-5-octylbiguanide
 EMI39.3
 thus recovered then melts at. 1-; l.i l, The free base P3 must be obtained by treatment of the sulfate by means of quanti-
 EMI39.4
 Stohiometric alkali tees. It is a g # urBuse material at room temperature.

   Chlorbidrate can be prepared by adding Chlo acid, rhyric to the binder base; after recovery, it is in the form of a waxing solid which is very soluble in water.
 EMI39.5
 



  1-r..tyl-5-octyloiuani- can also be prepared in an analogous manner by reacting 1-butyl-3-cyano-
 EMI39.6
 guanidine with oatylam3ne, EXAMPLE: 2 ± 1-dodeoyl-5-ethylbiguanide.
 EMI39.7
 
 EMI39.8
 
<tb>



  Molecular <SEP> Proportions <SEP> Reagents
<tb>
 
 EMI39.9
 1-doleoyl-5-oyanQguaaidine ijo Ethylamine hydrochloride 0.9 The above two reagents are heated for
 EMI39.10
 about four hours at a temperature of 125-10 ° C., substantially. After cooling the reaction mixture, the 1-dddeqyl-5- hydrochloride is dissolved in water.

 <Desc / Clms Page number 40>

 
 EMI40.1
 crude ethylbiguanide obtained. The aqueous solution obtained
 EMI40.2
 is processed by a. excess of sodium sulphate over the theoretical amount required, and the sulphate of 1-
 EMI40.3
 dodecyl-5-etiïylbi; uanide precipitates. After recovery
 EMI40.4
 and reoristallization within isopropanol Containing a
 EMI40.5
 In a small amount of water, 1-aodecyl-5-3ttvlbiguanide sulfate sintered at 1 :, G, and melted at .31 -;:; 14 ::.

   The free base is a waxy solid obtained by treating the sulfate with substantially stoichiometric amounts of sodium hydroxide.
 EMI40.6
 caustic. The hydrochloride is obtained by acidification of the free base with hydrochloric acid, it is also
 EMI40.7
 waxy solid uri which gives a solution with water
 EMI40.8
 cloudy and foamy.
 EMI40.9
 



  1-Dodecyl-5-ethylbiguanide can also be prepared in an analogous manner by reacting 1-ethyl-, -cyanoguanidine with dodepylartilae.



  1GT PL¯, Xxi 1-butyl-5-phenyloiguanide.
 EMI40.10
 
 EMI40.11
 



  (a): 3 reagents Proportion =: moléoulaires l-butyl-6-oyanoguanidine j sniline 1, J .. ", hydrochloric acid 1.0
 EMI40.12
 The above three reagents are carefully mixed and stirred, however they are heated to sensitively 90 ° C. for about two hours. After cooling the reaction mixture, 1-butyl-5-phenylbiguanide hydrate crystallizes from solution. The solid product is collected, washed and dried. 0 9 and after re-crystallization in water, it melts at: 31D-11C.



  The lore base is prepared by the addition of a sensi-

 <Desc / Clms Page number 41>

 stoichiometrically of alkali, and after removal
 EMI41.1
 From sodium chloride, 1-butyl-5-phenylbig> Janide is obtained in the form of an incrystallizable gum. The nitrate can be prepared from the free base by adding a substantially stoichiometric amount of nitric acid.



  It melts at 152-154 C.
 EMI41.2
 



  (b) Reagents Molecular Proportions 1-phenyl-3-oyanoguanidine 1,0 Butylamine hydrochloride 1, Z-ethoxyethanal-1 0, The above mixture of the three reagents is heated
 EMI41.3
 at substantially 160-140 0. for three to four hours. After cooling the reaction mixture, the mixture is cooled with water at room temperature. The aqueous extract is basified and the gummy 1-butyl-5-phenylbisuanide preeipitates. This free base is converted to hydrochloride and recrystallized to give 1-butyl-s-phenylbiguanide hydrochloride, m.p. 210-211 C.



  EXAMPLE XXXI
 EMI41.4
 1-oyalohexyl-5-p-sulfophenylbiguanide.
 EMI41.5
 
 EMI41.6
 



  Reactives I: 'ropor t; 10 Molecular ± 1S 1-oyolonexyl-to-cyanoguanidine 1.3 Sulf8.nLlic acid 1.0
 EMI41.7
 
<tb> Water <SEP> 42.0
<tb>
 
The aqueous mixture of the above reagents is stirred and heated to reflux: for two to three hours. Jn first obtains a clear solution, then a tile separates which then solidifies. After cooling, we collect
 EMI41.8
 crude solid 1-oyoloaexyl-5-p-sulfophenylbiguanide. We

 <Desc / Clms Page number 42>

 purifies it by dissolving it in extended alkali and then reproipitation by adding an acid. By repeating this purification process in alcohol, 1-cy-
 EMI42.1
 Clohexyl-5-p-sulfopiiénylbiguanide crystallized which, after recovery and drying, melts at 58-s59 L.



  1-oyolohe # yl-5-p-sulfophenyl'oiguanide can also be prepared by reacting 1-ps-ulfopliényl-3- cyai.o, -, uanidine with oyclohexylamil1E: following carefully the same process as that described in 8.xBmp1e XXXb.



  EXAMPLE XXXII
 EMI42.2
 I-dode oy1- 5-pheuylbiguanide
 EMI42.3
 
 EMI42.4
 
<tb> Reagents <SEP> Molecular <SEP> proportions
<tb>
 
 EMI42.5
 1-dods Crl- ;; e; ano, ôuan.dine 1, ù Aniline 1.0 Cillorl1ydrique acid 10 d I) J2 Rthanol 1,
This mixture is heated to approximately 90 ° C. for three and a half hours. The resulting clear solution is diluted with water, and after removing the alcohol by distillation, a gel-like residue is obtained. This residue is extended by means of a large excess of water and the resulting solution is filtered while it is still
 EMI42.6
 When hot, after cooling the filtrate of 1-dodeoyl-5-phenylbijuanide precipitates as a hydrochloride. J, i recover this solid product, we wash it and we dry it $ it. f, oad then at 173-174 C.



  1-Dodecyl-5-phenylbiguanide can also be prepared by reacting 1-phenyl-3-oyanoguanidine with dodecylamine as described in Example XXXb.

 <Desc / Clms Page number 43>

 
 EMI43.1
 RX3'.IIPL XXXIII 1-dodecyl-5-p-sulfophéaylbi3uaQid3
 EMI43.2
 
 EMI43.3
 Reagents Proport ioiis mo1écula j-ce 1-dod6CY.L -, - oyaaoguaaidin 1, 0
 EMI43.4
 
<tb> <SEP> sulfanilic acid <SEP> 1.04
<tb>
<tb> Water <SEP> 100.0
<tb>
 
 EMI43.5
 -tlzoJetyiaxol-1 3.1
 EMI43.6
 the above reagents are mixed, stirred and heated = substantially; loooc. for eavi ron CL1Q hours.



  After about two hours, the sulfanilic acid is completely dissolved and a heavy oily material appears. When the heating is complete, the reaction mixture is cooled and the oil solidifies into a trap. solid
 EMI43.7
 waxy. Ji collects 1-dodecyl-5-p-sulfophenylbiuanide, washed and dried; a waxy solid is obtained: soluble in alkalis and in ethyl alcohol. Addition of copper sulfate to an alkaline solution of 1-
 EMI43.8
 dodecyl-5-p-sulfophenylbiguanide results in the formation of a purple colored solution.



  1-DodeGyl-5-p-sulfophér.ylbiJuani3e can also be prepared by reacting 1-sulPopi-enyl-3-cyanoguanidine with dodeçylam1ae as in Example XXXb.



  BX2L \ IPL ":: XXKIV 1-d.oderyl5-p-sulfoaraidophenylbiuaa.ide
 EMI43.9
 
 EMI43.10
 
<tb> Reagents <SEP> Proporti <SEP> Molecular <SEP> cases
<tb>
 
 EMI43.11
 1-year :, 1 -. Üranouanidicle 1, J Sulfanilariine 1.05% Hydrochloric acid 10% 1.0,; t hanca 1 4, 3
 EMI43.12
 
<tb> Water <SEP> 7.0
<tb> ¯il
<tb>
 

 <Desc / Clms Page number 44>

 
 EMI44.1
 Ja heats by stirring the melan? of 1-àodeoyl-3- cyano; u8aidin and sulfanilamiéle in alcohol and water, at 80-9'J C. 3n added at the beginning of the M.: the r1 2 réa and ton l the extended hydrous a- and after completion of the addition the clear solution is taken and heated to reflux for a further about an hour and a half. The alcohol is then distilled off and the clear solution is diluted with a large excess of water.

   This solution is treated with a sufficient quantity of sodium chloride to cause precipitation of the
 EMI44.2
 1-Dodeoyl-5-p-sulfonamldophenylbiguanide ohrzydrate. .b .. cLaud, this mixture is presented under. the form of a gummy solid, but it crystallizes on cooling. We collect the hydrochloride, we wash it, we dry it.
 EMI44.3
 then melts at 128-160 ';. Sulfate prepared from l-dodea, yl-5-p-aulfonamidophenylbiguanide in the form of hydrochloride by addition of sodium sulfate is insoluble
 EMI44.4
 in white water and slightly dissolved in acetone.



    The free base prepared from the above salts is a waxy, gummy product.
 EMI44.5
 uli can prepare 1-dodecyl-5-p-sulfonamidobiguanide by reacting 1-p-sulfonamidophenyl-α-cyanoga anidine with dodecylamine as in Example XXXb.



  "r, '3F. :: iPh XXY, 6.V. l.l-dibutyl-5-phenylbiguanide
 EMI44.6
 
 EMI44.7
 
<tb> Reagents <SEP> Molecular <SEP> proportions
<tb>
 
 EMI44.8
 l.l-dibutyl-; 5-CJaaoduanidine 1.0
 EMI44.9
 
<tb> Aniline <SEP> 1.0
<tb>
 
 EMI44.10
 Hydrochloric acid 1.1
 EMI44.11
 
<tb> Water <SEP> 13.9
<tb>
<tb> Dioxane <SEP> 4.7
<tb>
 

 <Desc / Clms Page number 45>

 
 EMI45.1
 the 1teK8.1t the hydrochloric acid 2 extended to the methyl, ..; e of 1.1-diDUGyl-J-Oy8Clop ;; uarJ.idi # and aniline in the aqueous dioxaae were added, the temperature being maintained at 90- 1000Ç. The actiaineL mixture is heated for about 1 to 3 hours, and during the last part of heating about 78-80% of aqueous dioxane is removed. The residual clear solution is diluted with a further quantity of water and cooled.

   L, 1-ib.Jtyl-5-pAenylbiguaaie forms hydrochloride and gives a gummy precipitate. this reaction mixture is trout by means of a slight excess of caustic solution so as to form the free base which is also a gummy product. The addition of substantially stoichiometric quantities of extended sulfuric acid causes the formation of neutral sulphate in the crystalline form.
 EMI45.2
 The neutral sulphate constitutes a hydrate which melts at 69-71 ° C. and loses its water of hydration at 95-10500. under the pressure at, our-
 EMI45.3
 pherical.

   Neutral 1-dibutyl-5-'phenylblguanide sulfate is insoluble in water and acetone and soluble in mehanol.
 EMI45.4
 1ill (1! MPL. & XAXVI ieth le: e-bis-1.1 '.. -phenz lene-5,5'-ot lbi ucnide,
 EMI45.5
 
 EMI45.6
 
<tb> Reactants <SEP> Molecular <SEP> proportions
<tb>
 
 EMI45.7
 1-octyl - cyanogania 3.8 4.4'-diaminoàiphenylmethane 1to
 EMI45.8
 
<tb> Hydrochloric acid <SEP> <SEP> 2.0
<tb>
<tb> Water <SEP> 27.8
<tb>
 
 EMI45.9
 Ethanol 8.6
 EMI45.10
 The hydrochloric acid extended to the hydro-alecolic solution of 1-octyl-5- is carefully added.

 <Desc / Clms Page number 46>

 
 EMI46.1
 oyanoguanidine and 4'-diaziinoaipheiiyl; .iethan <P. The reaction mixture is heated for about 4 hours after which the main bulk of the alcohol is removed by distillation.

   The residual clear solution is diluted with water and a gOI11J.lleux precipitate forms. This di (, IlilnrlVdrate de methylene-ois- (l.l'-p-phenylene-5.5'-octylbiguanide) which is first of all in the gummy state when it is precipitated from the hot solution, crystallizes by cooling sen- The crude dihydrochloride is collected, washed with water and acetone, and dissolved at room temperature.
 EMI46.2
 dry. The methylene-is- (1,1'-p-phenylene-5.5'-octylbiguanide) dihydrochloride obtained xarest converted into. ll1bre base by treatment with an excess of talcali in a hydroracthanolic solution, the free base is a product gcmia3U !!: which, on continuing stirring, solidif-ie cold.

   This solid product is recovered, washed and dried under vacuum:
 EMI46.3
 methylene-bis- (1,1'-p-pïéaylèae-5.5i-octyl-biu8nide) is ootient, melting at 11-133 ° C.
 EMI46.4
 ',; ±' 'PL.'s WXII
 EMI46.5
 Iethlene-bis (1.1'- phenylèe-5,5'-phyylbihuanie),
 EMI46.6
 
 EMI46.7
 Reagents Moleolar proportions I-phenyl-3-cyai10guanidin <.; , 18 4.4'-dia; linoHphenylmethane 1, J
 EMI46.8
 
<tb> Hydrochloric acid <SEP>
<tb>
<tb> Water <SEP> 55, J
<tb>
 
 EMI46.9
 -ethoayetnanol-1 3,4 we slowly add extended hydrochloric acid -to the
 EMI46.10
 stirred mixture of 1-phenyl-3-cyanoguanidlne, 3t of 4.4'-d4ami- D.o-diphenylrriéthanc in aqueous medium and of 8-ethoxysthafD 1-1, at approximately 100 ° C..

   Heating the reaction mixture lasts

 <Desc / Clms Page number 47>

 about two hours, and towards the end of this heating period a crystallized precipitate of methylene-bis- (l.l'-
 EMI47.1
 p-phenylene-5,5-phenylbiguanide) as hydrochloride begins to form. When the reaction is complete, it is cooled
 EMI47.2
 the reaction mixture and the crystallized dighloryldrate is collected, washed with water and dried. After recrystallization from water, methylene dihydrochloride
 EMI47.3
 bis- (1,1'-p-ph ± nyléne-5.5'-phenylbisuaniàe) melts at 249-25100 The free base is prepared by suspending the dichlorhydrate in a mixture of water and methyl alcohol and treating with a slight excess of caustic soda, relative to the required stoichiometric proportions.

   Methy-
 EMI47.4
 The resulting insoluble lene-bis- (1.11-e-phenylene-5.5t-phenylbiguanide) melts at E5-r; 6 ° C. , it is not very soluble in water or alcohol,
 EMI47.5
 EXAMPLE III, - - r A.- -. -. i- - ¯0. & -. ¯.¯ ¯¯
 EMI47.6
 t'Ol meTnyj.ene-Eiis.J .'- p-pnonyj.ene- &. 5- (ie? A.meT: ny.eaeoigua- nide)]
 EMI47.7
 
 EMI47.8
 
<tb> Reagents <SEP> Molecular <SEP> proportions
<tb>
 
 EMI47.9
 1.1'-àoàé9amethylene-bis 3.3t-yanauanidiu 1.0 4.41-diaminodiphenylmethane 1.0 Hydrochloric acid 10% 2.0
 EMI47.10
 
<tb> Water <SEP> 18.5
<tb>
<tb> Ethanol <SEP> 17.5
<tb>
 
 EMI47.11
 Extended hydrochloric acid is added slowly for 1 second to a stirred mixture of 1,14-dodecamethylene-bis-3.31-oyanoguanidine and 4,4'-aliaminoaiphenylne% hane in a mixture of ethyl alcohol and water.

   The addition of the extended acid being completed, a clear solution is obtained. The alcohol is then removed by distillation and the mixture is slowly raised.

 <Desc / Clms Page number 48>

 temperature at 90-100 C which is maintained for about four hours, At the end of this time the reaction mixture is somewhat gelatinous; diluted with a large volume of water, it becomes a clear solution. Hydrochloride
 EMI48.1
 Oly methylene-bls- (1,1-p-hnylene-5,5'-dámethylenobiguanide) 1 is precipitated from the cold reaction mixture by addition of a concentrated salt solution. the solid product is collected, washed and dried; the polymer
 EMI48.2
 obtained softens slightly at 205-22000.

   This hydrochloride m. Polyethylene-bis- (1.1'-p-phenylene-5.5'-desamethylenebigua nide) gives a clear solution in water at low concentrations but at high concentrations an opalescent gel is formed. The free base can be prepared by treating the hydrochloride with an equivalent amount of caustic soda. This linear polymer is an amorphous white solid, resinous at elevated temperature.



    EXAMPLE XXXIX
 EMI48.3
 1-isoPropl-5-P-chlorophd lbiuani8e
 EMI48.4
 
 EMI48.5
 
<tb> Reagents <SEP> Molecular <SEP> proportions
<tb>
 
 EMI48.6
 1-isopropyl-3-cyanoguanidine 0.52
 EMI48.7
 
<tb> p-ohloroaniline <SEP> 0.5
<tb>
<tb> Hydrochloric acid <SEP> <SEP> 0.5
<tb>
<tb> Water <SEP> 22.0
<tb>
 
The hydrochloric acid is extended by means of 75 cc. of water and added to a mixture of 1-isopropyl-3-cyano-guanidine, p-chloroaniline and water at 97 ° C., said addition requiring half an hour. Towards the end of
 EMI48.8
 the addition of the acid, the biguanide hydrochloride, starts to precipitate.

   Heating and stirring are continued for a further half an hour, the mixture is cooled, acidified with 5 cc. acetic acid and we collect

 <Desc / Clms Page number 49>

 The biguanide salt by filtration, washed with cold water and acetone and dried in air. The yield
 EMI49.1
 of l-isopropyl-5-p-Phlorophenylbiguanide hydrochloride is 120 gr., ie 83% of theory. A second harvest is recovered from the mother liquors amounting to 6 gr.
 EMI49.2
 



  1-Isopropyl-5-p-chlorophenylbiguanide hydrochloride is only slightly soluble in hot water but it is more soluble in alcohols. The product obtained from
 EMI49.3
 this way melts at a46eO ,, s * re-crystallizing in water does not raise its melting point.



   Biguanide hydrochloride is transformed into base
 EMI49.4
 free by dissolution in a.loo3. spreading and treatment by means of a slight excess of a hydrate of an aloaline metal, resulting in the precipitation of the free biguanide.
 EMI49.5
 The air dried product melts at 100-105 ° C. and apparently a monohydrate its drying at 60 ° C. for a few hours removes only one molecule of water; the melting point is 128-132 C.
 EMI49.6
 



  L-isopropyl-5-p-ohlorophenylbiguanide can likewise be prepared by treating 1-p-ohlorophenyl-3-oyano-guanidine by means of isopropylamine, by operating under the Conditions of Example XXXb in which one react
 EMI49.7
 l-phenyl-3-eyanoguanidine with butylamine. 1-isopropyl-5-chlorophenylbiguanide is particularly valuable in pharmacology because of its high antimalarial activity.
 EMI49.8
 



  The 1.5-substituted biguanides of the present invention of the type indicated constitute valuable chemicals as intermediates in the preparation of chemotherapeutic agents, pharmaceuticals, textiles, dyes, insecticides, rubber products, plastics. , resins and the like.



  The calcium salt of dicyanimide which is used

 <Desc / Clms Page number 50>

 apple reagent in Some of the previous examples of the invention can be prepared by reacting water with calcium cyanamide and cyanogen chloride; The reaction is in accordance with the following equation:
 EMI50.1
 
Dicyanimide calcium is a new salt of dioyanimide and its preparation involves the use of inexpensive raw materials. The reaction temperature can be kept within the limits of 0 to 50 ° C. substantially, but it is usually preferred to prepare calcium dicyanimide between 20 and 30 C. Calcium cyanimide of 10 to 100% purity can be prepared. employee .

   The commercial grade of calcium cyanamide which has a mixture of lime, graphite and traces of sodium chloride has a cyanamide content of 50 to 70%. This product is ideally suited for the above reaction.



   The recovery of crystallized calcium dicyanimide is somewhat complicated because of its high solubility in water. If there are only small amounts of inorganic salts in solution with calcium dicyanimide, the water can be evaporated to obtain crystallized celcic dicyanimide in a relatively pure state. But if, for example, crude calcium cyanamide is used as the raw material, the presence of inorganic salts in solution with calcium dicyanimide can result in the recovery obtaining a low quality product by evaporation of the calcium. water.

   It may then be good to remove from the dicyanimide the mineral compounds which contaminate it. this can be done by precipitation of an insoluble dicyanimide salt such as the follow or zinc salt and recovery of these salts deprived of mineral impurities. The dioyanimide calcium can then be regenerated by reacting an aqueous slurry

 <Desc / Clms Page number 51>

 of the above-mentioned insoluble salts of dicyanimide on hydrated lime. This results in the formation of an insoluble hydrate of zinc or copper which can be removed from the aqueous solution of clacic dioyanimide. Pure calcium dioyanimide can then be recovered by evaporation of the water. Here is a typical example of the above reaction for the preparation of calcium cyanimide.



  EXAMPLE XL
 EMI51.1
 
<tb> Reagents <SEP> Molecular <SEP> proportions
<tb>
<tb> <SEP> cyanogen <SEP> chloride <SEP> 1.0
<tb>
<tb> Cyanimide <SEP> (soil, <SEP> aq. <SEP> 10 <SEP>%) <SEP> 1.0
<tb>
<tb> Lime <SEP> hydrated <SEP> 1.2
<tb>
<tb> Water <SEP> 11.1
<tb>
 
Lime hydrate is carefully added to the cyansimide solution with stirring, preventing any tendency to heat up by cooling. the cyanogen chloride is then slowly added while stirring the reaction mixture vigorously; it is then easily absorbed. The temperature should not be allowed to rise significantly above 30 ° C. When the addition of cyanogen chloride is complete, the reaction mixture is stirred until the reaction no longer tends to exotherm.

   The reaction mixture is neutralized with a small amount of hydrochloric acid and filtered to remove any insolubles. The clear filtrate is concentrated and the calcium dicyanimide recovered.



   Calcium dioyanimide forms a dihydrate which pard its water of crystallization to ¯sensibly 100 * 0. and practically does not fade below 315 C. Voioi, in turn characterizing this solid, its optical and oristallographic properties. Calcium dicyanimide dihydrate crystallizes in elongated prisms with development of domes and needles; it has a cleavage parallel to the "b" axis

 <Desc / Clms Page number 52>

 and is optically positive, My refractive indigos are
 EMI52.1
 the following: 01 * 1.05 0.005; - 1.480 0.005; <3 about 1.82.

   The apparent optical axial angle observed in air is 86, and the true optical axial angle calculated from it is 55. The optical axial plane or the main optical section is perpendicular to the plane (Olo). The crystals are oriented in such a way that the main direction of vibration [alpha] is parallel to "b", the elongated axis of the crystal.



   The water of hydration is removed either by heating the dioyanimide calcium dihydrate to approximately 100 ° C., or by drying at a lower temperature under vacuum,
The alkali metal salts of alcoal dicyanimide are used as reactants in some of the foregoing examples of the present invention; they can be
 EMI52.2
 prepared by reacting alkali metal salt with an alkaline metal salt, the anionic part of this salt giving a substantially insoluble salt with calcium. The general reaction is given by the following equation:
 EMI52.3
 where A is an alkali metal and AX is a salt of an alkali metal, the anionic part of which X together with calcium gives a practically insoluble salt.



   Here is a typical example of the above reaction for the preparation of the alkali salts of dicyanimide: EXAMPLE XLI
 EMI52.4
 A solution of alcoal cyanimide obtained by the reaction of calcium cyanimide with oyanogen chloride gives sodium dicyanimide by treatment with sodium carbonate or sulfate or sodium hydroxide.
 EMI52.5
 oaustic. In addition to 14 val4ic oyanimide, ae méiange * aotionÔ

 <Desc / Clms Page number 53>

 nel contains calcium chloride. The calcium is completely precipitated by sufficient addition of 15-20% sodium carbonate solution to ensure combination with the calcium ions of the dioyanimide and the chloride.



  The practically insoluble calcium carbonate is removed by filtration and the aqueous filtrate containing similarly sodium chloride and sodium dicyanimide is concentrated. As the removal of water progresses to the point that the sodium chloride concentration is 25-35%, sodium dioyanimide readily crystallizes and is recovered as colorless crystals which do not melt until 315 C .



   To characterize this solid, here are its properties
 EMI53.1
 optical and crystallographica: sodium dioyanimide crystallizes in lamellae and is optically positive. The main refractive indices observed in white light
 EMI53.2
 ohe are the following: o - 1,410 ..t. 0.003; ) = 1.484 + 0.003. The apparent optical axial angle observed in air is 86. and The true axial optical angle calculated from it is 55.



   It is understood that various modifications can be introduced into the particular methods described without departing from the scope of the present invention.



    RESALE.
 EMI53.3
 



  1. Process for the preparation of 3-oyanoguanidinesl-subati- and 1.5-substituted biguanides, characterized in that the dioyanimide or a salt thereof is reacted with a predetermined amount of a primary amine or -
 EMI53.4
 condaire gu one of its salts under conditions 7t such that a 1-substituted 3-oyanoguanidine is formed ,,, in this / the latter / which is then reacted, if desired with a new quantity the same primary or secondary amine or a different amine so as to produce a 1.5-substituted biganide;

   

 <Desc / Clms Page number 54>

 2. Process according to claim 1, for the preparation
 EMI54.1
 ration of a 1-substituted 3-cyanoguanidine, characterized in that dioyanimide or a salt thereof is heated with a primary or secondary amine or one of its salts under conditions such that it substantially reacts a molecule - the dicyanimide with an amine molecule.



   3. Process according to claim 2, characterized in that the reaction mixture is heated to a temperature of between 50 and 125 C approximately.



     4 :. A process according to claim 2, characterized in that, if an amine or a salt thereof is employed, the reaction mixture is heated to a temperature of about 75 to 95 C.



   5. A method according to claim 2, characterized in that, if 1 ', an alphatic amine or one of its salts is used, the reaction mixture is heated to a temperature of between 85 and 105 C. approximately.



   6. The method of claim 2 for the preparation
 EMI54.2
 ration of l-isopropyl-5-oyanoguanidine, characterized in that isopropylamine or a salt thereof is heated with dioyanimide or one of its salts at a temperature between approximately 85 and 105 ° C..



   7. The method of claim 2 for the preparation
 EMI54.3
 ration of 1p-ahlorophnyJ..3-yanoguanidine, earactris in that p-ohloroaniline or one of its salts with dioyanimide or one of its salts is heated to a temperature of about 75 to 95 C.



   8. A process according to claim 1 for the preparation
 EMI54.4
 tion of a biguanide-1,5-substituted by heating dicyanimide or "a salt thereof with a primary or secondary amine or a salt thereof under conditions such that it substantially reacts a molecule of dicyanimide with two molecules of the amine.



   9. A method according to claim 8, characterized in that the reaction mixture is heated to a temperature '

 <Desc / Clms Page number 55>

 o between 80 and 150 C.



   10. A process according to claim 8, characterized in that, if an aromatic amine or one of its salts is employed, the reaction mixture is heated to a temperature between about 80 and 105 ° C.



   11. The method of claim 8, characterized in that virtually one employs an aliphatic amine or a salt thereof, the reaction mixture is heated to a temperature between about 120 and 150 C.



   12. The method of claim 1 for the preparation
 EMI55.1
 rat, ion of a 1.5-substituted biguanide by heating a 1-substituted 3-oyaaoguanidine with a primary or secondary amine or one of its salts under conditions such that it substantially reacts a cyanoguanidine molecule with an amine molecule.



   13. The method of claim 12, characterized in that the reaction mixture is heated to a temperature between 80 and 150 C.



   14. A process according to claim 18, characterized in that, if an aromatic amine or one of its salts is employed, the reaction mixture is heated to a temperature between about 80 and 105 0.
 EMI55.2
 



  15. The process according to Claim 1, 9> araQt4risé / if / in that an aliphatic amine or a salt thereof is employed, the reaction mixture is heated to a temperature between about 120 and 150 ° C.



   16. The method of claim 12 for the pre-
 EMI55.3
 paration of 1-isopropyl-5-p-chlorophenylbiguanide, charac- t4ris6 in that 1-isogropyl-3-oyaaogua- nidine or a salt thereof is reacted with p-phloroaniline or a salt thereof. a temperature of between 80 and 105 C.



     17. The method of claim 12 for the preparation
 EMI55.4
 ration of 1-isopropyi.-5-p-Chloroph $ nylbiguanide, Character $ ris $

 <Desc / Clms Page number 56>

 
 EMI56.1
 in that 1-p-ohlorophdayl-3-Qyaaoguanidine or a salt thereof is heated with isopropylamine or one of its salts at a temperature of substantially between 120 and 150 C.



   18. A method according to any one of claims 1 to 11, characterized in that the dioyanimide is used in the ton of its calcium salt prepared by reacting an aqueous slurry of calcium cyanimide with chloride. cyanogen at a temperature between about 0 C and 50 C.



   19. A method according to any one of claims 1 to 11, characterized in that the dicyanimide is used in the form of one of its alkali metal salts prepared by reaction in water of the calcium salt. dioyanimide with a salt of an alkali metal, the ionic part of which forms with calcium a practically insoluble salt,
20. 3-oyanoguanidine-1-substituted, wherein at least one substituent is an aliphatic or heterocyclic radical.
 EMI56.2
 



  Si.1-dode cyl-3-cyanoguanidine. ha, 1-oyelohexyl-3-oyanoguanidine. 23. 1,11-Deamethylene-bis-3,31-eyaaoguanidine.



  24. 1,5-Substituted Biguanides of the formula
 EMI56.3
 in which R1 and R3 are aromatic aliphatic radicals
 EMI56.4
 ticks or heterooyclics and IL. and Rj are hydrogen or aliphatic, aromatic or heterocyclic radicals.



   25. 1,5-Diphenylbiguanide.
 EMI56.5
 



  26. 1-Dodeeyl-5-phenylbiguanide.

 <Desc / Clms Page number 57>

 
 EMI57.1
 



  8T. 1-Dodepyl-5-sthylbiguanide.



  28. 1-Isopropyl-5-p-ohlorophenylbiguanide.



  Zg. 1-isoprogyl-3-ryanoguanidine.



  30. 1-p-Chloraph6nyl-3-ayanoguanidiue.