CA1122605A - Sulfur-containing benzimidazole derivatives, process for the preparation thereof and intermediates useful in production of the same - Google Patents

Abstract

Abstract of the Disclosure The invention is a process for the preparation of a compound of formula XVII

(XVII) (wherein R21 stands for hydrogen or amino; and if R21 is hydrogen, then R22 is amino and if R21 represents amino, then R22 stands for hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy, aryloxy or aralkoxy) which comprises reacting a compound of the Formula XVIII

(XVIII) (wherein R21 and R22 are as defined above) with dirhodane, chlororhodane, ammonium thiocyanate or an alkali metal thiocyanate in the presence of an oxidizing agent and in an anhydrous medium, an agent capable to introduce a thiocyanate group. Some of the compounds within the scope of formula XVII
are novel. The compounds of formula XVII are useful intermediates in the preparation of compounds having anthelmintic properties.

Description

Tllis application is divided out of our Application Serial No.
303,127, filed on May 11, 1978, which relates to sulfur-containing benzimida-zole derivatives and IO a process for the preparation thereof. This applica-tion relates to intermediates useful in the production of the sulfur-containing benzimidazole compounds of Application Serial No. 303,127.
Most of the end-products which are the subject of Application Serial No. 303,127 (Formula I) are new compounds, never described in litera-ture. The compounds of the Formula I possess useful anthelmintic properties and may be used in human and veterinary therapy as anthelmintic agents.
In the Formula I

R2 ~ ~ ~ N~l - R (I) the various symbols have the following definition: Rl is hydrogen or a group of the Formula -COOR ; R is Cl 4 alkyl; R is hydrogen, halogen, Cl 6 alkyl, trifluoromethyl or a group of the Formula -OR ; R is Cl 4 alkyl, aryl or aralkyl; R4 stands for hydrogen, Cl 6 alkyl, C3_7 cycloalkyl, C3_6 y C3 6 alkynyl, or an aryl or aralkyl group whereby the aryl ring of the aryl or aralkyl group may be optionally substituted by one or more halogeno, Cl 4 alkyl, nitro, hydroxy, Cl 4 alkoxy, Cl 4 alkylthio, carboxy, or cyano substituent(s) or a group of the Formula -S(O)n-R in which R is lower alkyl;
n stands for 0, 1 or 2.
The term "lower alkyl group" - alone or in combinations

- 2 -... .

ll;~Z~05 such as al!coxy, alkyl-.hio etc. - usecl in the speci-FicatiGn rela~es to stra~sht or branched chain sacurated allphatic hydrocarbon ~roups having 1-~, preferably 1-4 carbon atoms (e.~. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobu-tyl, n-amyl etc.). Tl1e ~erm "halogeno a~om" covers all the four halo~ens i.e. fluorine, chlorine, bromine and iodine.
The C3 / cycloalkyl group may be cyclobutyl, cyclopentyl and cyclohexyl preferably. The C~ 6 alkenyl ~roup may be straight or branched chained and is preferably allyl.
The C3 6 allcinyl group may be straight or branched chained and represents preferably propinyl. The term "aryl ~roup"
- used either alone or in combinations such as aralkyl -represents a mono- or bicyclic aromatic ring (e.g. phenyl, naphthyl) which may optionally bear one or more of the conventional substituents of the aromatic rings (e.g.
halogeno atom, lower alkyl, lower alkoxy, lower alkylthio, carboxy, nitro, hydroxy, cyano, alkylsulphinyl, allcyl-sulfonyl, alkylthio etc.~.
Some represen~atives of the compounds of the Formula I
2C are disclosed in prior art as anthelmintic agents (e~g.
US Patents No. 3.574.845l 3,915,985 and 3,956,499; German Federal Republic Patent No. 2,250,453 and French Patent No. 2,134,5~8).
It is Icnown that a certain compound~group of the Formula II

R S ~ ~ ~ _ NH - CoOR5 (II) tfallin9 under the scope of the class of compounds o, the Formula I, wherein ~9 is C1 4 alkyl, C3 7 cycloalkyl, C36 alkenyl~ C3 6 alkinyl or benzyl) may be prepared by reacting an 1,2-diamino-alkylthio-benzene derivative o~
the ~ormula III

R9S~ (III) either with an 1,3-bi~-(alkoxycarbo~yl)-~-alkyl-isothio-urea of the Form~la IV

--C sR5 (German Federal Republic Patent No. 2,363,35~ - reaction scheme A) . ~ , ~ . ~ . ~ + R500C ~ C-SR5 ~ II
R9~_ ~ N~ R500C-NH ~

- or ~nth a Garbalkoxy-cganamide of the Formula V
' -I
. NC - NjH ~ C00 R5 (V) ,' (US Patents No. ~.9,15.986 and 3,956,499 - reaction scheme B).

)5 ~.

g ~ i f NC - NH - CoOR5 - ~ (II) R S ~ NHi (III) ~) ~ he above procedures suf~er from the serio~s ~rawba~
that the be~zimidazole carbama-te ri~g s~stem is formed by using 1~2-diamino-4-alkylthio-benzene deriv~tives of the ~ormula III which can be ebtained by mea~s of a complicated multi-step synthesis from relatively expensive st~rting materials (reaction scheme C) and ~) ).
Reaction scheme C
~ , ~ ~ Cl ~Ha N~-cocH3 - ~a ~t~J ~ 1 Cl --l~ J, ~H-COCH3 Cl -. ~ -NH-COCH3 By-product R~S~

~ N2 ~ . ~ NO~
-~9S ~ H-CO ~ R9S ~ ~E~

~_- ~ , .
R9 ~ ~I~X) -- (; --c Reaction scheme D) ~ NH.
W 2rhodinating NC ~ acetylation~

H-~QCE3 ~ - - NH-COC~3 ~CS ~ nitration ~ ~CS ~ -No2 1C) reduction ~ NH-COC~: -alkylation 9 1 ll 3 h~drol~si.s R S ~ _ ~0~

1~ ~9S ~ ~H~ reduction > (III) -The s~nthesis-route shown ln reaction sche~e C) comprises the nitration of m-chloro-acetanilide which gives rise to the formation of two isomeric compounds.
~herefore the useful o-nitro-acetamido isomer required for the synthesis is available but with moderate yields ~J~ Org. Chem. 12, 799 (1947)7. The further step of the reaction needs toxical mercaptanes of very bad odour (US. Patents No~ 3.915.986 and 3.956.499). ~his reaction can be generally carried only wlth low yields ~. Qrg. Che~.
42, 554 /1977/7. For the reasons stated above the compounds - of the Formula III can be obtained in poor yi~lds.
Reaction schems D) provides the desired compounds of 3o the ~ormula III with the aid of a seven~step synthesis by low yields [Ber. ~9, 190 (1926); J. Chem. Soc. (1928) 1364].
It has been found that the compounds of the Formula I can be prepar-ed by reducing the new benzimidazole-disulfides of the formula VI and if desired subjecting the thiophenol derivatives of the Formula I thus obtained (R is hydrogen = Ia) R2 ~ N NH-Rl (Ia) to selective substitution reaction on the sulfur atom. Thus the compounds of the Formula I are available in a simple manner by very good yields.
The invention of Application Serial No. 303,127 provides a process for the preparation of compounds of the Formula I and salts thereof which comprises subjecting a compound of the Formula VI
L ~ ~ ~ NH-RIi Vl) to reduction (wherein R and R are as stated above) and if desired intro-ducing an R group being other than hydrogen into the compound of the Formula I thus formed (wherein Rl and R2 are as stated above and R4 is hydrogen) and if desired converting a compound of the Formula I thus obtained into its salt.

ll;~Z~05 ~ c~orclillr ~o a preferred embodiMent of our process a compound o, the Formula VI is reacted with a complex me-tal hydride such as lithium aluminium hydride, sodiumborohydr rle-aluminium chloric3e complex, sodium borohydricle or sodium-5 dihydro-bis-~2-methoxy-ethoxy)-aluminate in anhyclrous medium. As reaction medium preferably organic solvents such as dial!<yl ethers, cyclic ethers (e.g. tetrahydrofurane, dioxane), dimethylformamide, dimethylacetamide, hexamethyl-phosphoric triamide, diethylene-glycol dimethyl e~her, lower alcohols etc.) may be used.
When using a sodium borohydride - aluminium chloride complex the reaction may be preferably carriad ou1: in tetra-hydrofurane or dioxane. In this case the reaction talces ~ace at room temperature within 2~3 hours~
When using sodium borohydride the reaction may be carried out in addition to the above solvents also in the mixture of water and a lower allcanol in the presence of an alkali hydroxide. The thiophenol derivative of the formula Ia thus formed can either be isolated or directly converted into other compounds of the Formula I~
The disulfide bond of the compounds of the Formula V
may also be reduced by means of all<ali metals~ The starting material of the Formula VI is suspended in an inert solvent (e.g~ toluene, xylene) and admixed with powdered Z5 potassium or sodium at room tempera~ure or under warmingO
2-4 equivalents of alkali metal are used for 1 equivalent of the compound of the Formula VI~ If ~ equivalents of all<ali are used, the diallcali salt of the compound of the Formula Ia is obtained. The reaction mixture is then acidified and the ~ compound of the Formula Ia can be isolated if desired.

,~

()5 - sa -Xf only 2 equivaletlts of an acid (e.~. acetic acid) are addec, to the reaction mixture, the solution of- the mono-all<ali salt of the compound of the Formula Ia is formecJ which may be converted into other compourlds of the Formula I clirectly, ll;~Z6~)5 without isolation. ~rhe said reduction may be preferably accnmplished in liquid ammonia at a temperature between -20 C and -~0 C. On evaporating the ammonia solvent the all~ali salt of the compounds of the Formula Ia is obtained as residue, which may be either isolated or subjected to further reactions.
The compovnds of the Formula VI may also be reduced with sulfur-containing inorganic reducing agents such as sodium sulfide, sodium sulfite, sodium dithionite, sodium hydrogen sulfite or potassium pyrosulfite. Sodium hydrogen sulfite and sodium dithionite proved to be particularly suitable for ~his purposeO When using the said reducing agents 2-2,6 moles of all<ali hydroxide and 2-2.2 moles of the reducing agent are applied for 1 mole of a starting material of the formula VI. Reduction may be preferably carried out in an alcoholic solution and/or dimethylformamide containing 10-30 % of water. The reaction is accomplished under heating at 50~80 C,preferably at the boiling point of the reaction mixture. The compounds of the Formula Ia formed are either isolated or directly converted into other compounds of the Formula I.
As reducing agents organic sulfur compounds may be used as well (e.g. mercapto~ethanol or amino-imino-methane sulfinic acid). The solu~ion or su~pension of the starting material of the formula VI in an organic solvent (e.g. lower all<anol or dimethylforrllamide) is reacted with 1-3 equivalents of mercapto-ethanol at 20-~0 C in the presence of a basical catalyst ~e~gO~triethylamine). The compounds of the Formula Ia thus ~med are either directly converted into an other compound of the Formula I or isolated.

~, l~ )S ~-When using amino-imino-methane s~lfinic acid as reducing agent, the solution or suspension of the starting material of the formula VI in a mixture of aqueous alkali and alcohol or a dipolar aprotic solvent (in the la~er case a phase-transmitting catalyst is also added e.g.
cetyl-pyridinium bromide and methyl-capryl-ammonium chloride etc.) is reacted with amino-imino-methane-sulfinic acid at 60-80 C in an inert atmosphere.
One may also proceed by carrying out reduction with glucose. As solvent or diluent a mixture of water and lower alcohols or dimethylformamide may be used. Reductio~
takes place at room temperature within 5-10 hours. It is preferred to subject the aqueous alkaline - alcoholic suspension to strong stirring in the presence of a phase-transmitting ca~yst. This may significantly ~horten the reaction time~ i The reduction of the disulfide bond of the starting materials of the formula VI may also be accomplished with metals in acidic medium. As metal preferably zinc, tin~ , iron or aluminium may be used. One may proceed preferabl~ ¦
by using salts of metals of varying valency in which the metal is in a lower oxidation stage r.g. stannous(II)-chloride, titanium(III)chloride7in acidic medium. ~he suitable pH value may be adjusted by adding a diluted (0.1-2 5 N) inorganic acid such as hydrochlorlc acid or sulfuric acid. As reaction medium water and/or water-miscible organic solvents (e.g. alkanols, glycois, di-methylformamide, dioxane, diethyleneglycol-dimethyl-ether, tetrahydro~urane, preferably lower alkanols) may 3o be u~ed. The reaction may be preferably carried out at a l~ S
-- -'I l --r temperature between ~5 C ~nd 110 C, particularly at the boiling point of the reaction mixture. According to a preferred embodiment of the latter method acetic acid is used which serves both ~s solven-t and for the adjustment of the pH-value~
According to an other method a solution of a com~o~ld Or the formula VI in the mixture of a mineral acid and alkanol or in dimethylformamide is passed through zinc amalgamated in a Jones-reductor. ~9 mineral acid first of all hydro-chloric acid and sulfuric acid may be used~ ~he acidconcentration is preferably 0~-2.5 N~ As solverlt or diluent water-miscible lower alkanols (e~g, methanol~
ethanol or isopropanol) may be used. The above m~thod provides very mild reducing co~ditions and may be very quickly carried out at room temperature too~
According to a preferred form of realisation of the above reducing methods on.e may work in an inert atmosphere particularly under nitrogen. If the reaction is carried o-ut in heterogeneous system it is expedien-t to use a-phase~

transmitting catalyst~
The compounds of the Formula Ia thus obtained may be optionally converted into the thio ethers o~ the ~ormula I
- wherein R4 is other than hydrogen - by transforming the said compounds of the ~ormula Ia into a compound of the Formula Ib .

R2 ~ ~ ~H_~1 (Ib) ? - by reacting wlth a co~pound of the Formula R9~Q; o into a )S

cornpou1ld oF the Formula Ic R~2 ~ _5 ~ NH-R~ (Ic) by reacting with a compound of the Formula X;

_~ ( X) or into a compound of the Formula Id lS R13 ~ ~ R2 ~ ~ NH~R1 (Id) by reacting with a compound of the Formula XI
~0 R14 ~ N2Cl- (XI) or into a compound of the Formula Id, wherein both R~3 and R14 are hydrogen, with chloro-benzene or bromo-ben~ene, in which Formulae R is C~ 6 all<yl; C3 7 cycloalkyl, C3_6 alkenylJ C3 6 all<inyl or arall~yl;
Q is chlorine, bromine or iodine or a group of the Formula ~10-So3_;
R'0 is a phenyl grcup optionally substituted in position ~ by a mèthyl group;
R11 and R~2 are hy~rogen, nitro, cyano~ carboxylic group or a group of the ~ormula -S(0)n-R8;
R a~d n are as stated above;
R1~ and R14 are hydrogen, halogen, C1 4 alkyl, hydroxy, C1_4 alkoxy or alkylthio.
~he compound Ia is at first converted into its alkali salt by dissolving or suspending in an organic solvent and adding an equivalent amount of alkali hydroxide (sodium or potassium hydroxide). ~he solution of this alkali salt - or that of an alkali salt of a compound of the - . . . .
~ For~ula Ia directly formed in the course of one of the reducing methods discussed above - is reacted with a compound of the ~ormula R9-Q (wherein R9 and Q are as stated above). ~he reaction is carrled out at a temperature ~f 10 to 60 C As solvent or suspending medium water-~ miscible orga~ic solven~s (e.g. methanol, ethanol a~d/or 2G dimethylformamidej dimethyIacetamide, or hexamethylphosphorictriamide) may be used. ~hus compounds of the formula Ib are obtained.
~he thioethers o~ the ~ormula Ic may be prepared - ~
~ by reacting a compound of the Formula Ia with a compound of the Formula X~ In this case the compo~nd of ~he ~ormula .. . .
Ia is first converted into its alkali sait as described above~ ~'he reaction takes plaoe a~ room temperature within some hours. ~he reactans are uæed in equimolar amountO
~s~reaction medium preferably water and/or lower alkanols or dimethylformamide may be used~ ~
, .

The compolulds of the Formula Id may be prepared by reacting the alkali salt of a compound of the Formula Ia - prepared as desribed above -with a compound of the Formula XI. One may proceed preferably by pouring the solution of the dia~onium salt of the Formula XI to the solution or suspen-sion of an alkali salt of a compound of the Formula Ia in a lower alkanol or a mixture of water and a lower alkanol, or water, lower alkanol and dimethyl-formamide respectively under boiling. The reaction mixture is diluted with water if necessary whereupon the compound of the Formula Id is recovered by filtration or extraction. The reaction may be optionally carried out in the presence of powdered copper.
Compounds of the Formula Id - wherein both R and R are hydro-gen - may also be prepared by reacting the alkali salt of a compound o the Formula Ia with chloro-benzene or bromo-ben~ene at 100-200C in the presence of 0.1-2.5 equivalents of a heavy metal salt [e.g. cuprous(I)- or cupric(II)-salt such as cupric(II)chloride or cupric(II)bromide].
The conversion of the compounds of the ormula Ia into thioethers of the Formula I (R is other than hydrogen) is carried out in inert atmos-phere preferably under nitrogen. Reactions in heterogenous system are expediently carried out in the presence of a phase transmitting catalyst in order to shorten reaction time and to increase the yield. For this purpose both phosphonium and ammonium type phase transmittants may be readily applied which are generally used in chemistry.
According to a further feature of Application Serial No. 303,127 there {~s are provi.ded new compounds of the Formul.a I and salts the~eo~ (wherein R1, R2 and R4 have the same meaning as stated above with the proviso that R2 is other than hydrogen).
Pre~erable sub-class of the compounds of the Formula I are those derivatives wherein R1 is -CooR5; R5 is lower alkyl, preferably methyl; R4 is lower alkyl, preferably meth~l, ethyl or ~-propyl; allyl, propinyl, benzyl or cyclohexyl and R is halogen preferably chlori~e, bromine or 1~ fluorine; lower alkoxy, preferably methoxy; lower alkylS
preferably methyl î or trifluoromethyl~
Particularly preferable representative~ of the com_ pounds of the Formula I are the ~ollowing derivativess 5(6)-n-propylthio-6(5)-fluoro-benzimidazolyl-2-meth~l--carbamate;
5(6) -n-propylthio-6(5)-chloro benzlmidazolyl-2-methyl~
-carbamate;
5(6)-benzylthio-6(5)-chloro-benzimidazolyl-2-methyl_ -carbamate;
5( 6) allylthio-6(5)-chloro-benzimidazolyl-2-methyl~
-carbamate;
: 5(6)-propynyl-6( 5? -chloro-benzimidazolyl-2-methyl--carbamate;
5(6)-ethylthio 6~5)-chloro-benzimidazolyl-2-me-thyl-~
~ -carbamate 5{6)-cyclohexylthio-6(5)-chloro-benzlmidazolyl-2-methy~--carbamate;
.
5(6)-n-propylthio-6(5)-bromo-benzimidazolyl~2-methyl--carbamate;
5(6)-n-propylthlo-6(5)-methyl-benzlmidazolyl-2-methyl-_ . . _ . _ . _ . . .

)S

-carbamate;

5(6)-n-propylthio-6(5)-methoxy-benzimidazolyl-2-methyl-carbamate;
5(6~-n-propylthio-6(5)-n-butyl-benzimidazolyl-2-methyl-carbamate;
5(6)-n-propylthio-6(5)-trifluoromethyl-benzimidazolyl-2-methyl-carbamate.
The compounds of the Formula I possess useful anthelmintic proper-ties and may be used in human and veterinary therapy as anthelmintic agent.
The new compounds of the Formula I and salts thereof are formulated with non-toxical animal veterinary or feed carrier to give a usual anthelmintic composition. The carrier may be a standard animal feed composition based on a feed carrier or an orally ingestible container for the active ingredient for example a hard or soft gelatine capsule. It may also be a pharmaceutical-ly acceptable diluent or excipient of the kind normally used in the produc-tion of medicaments (e.g. starch, lactose, sucrose, calcium phosphate, gelatine, talcum, magnesium stearate, dextrin, agar etc.). As liquid carrier e.g. peanut oil, olive oil, sesame oil and water may be used.
A wide variety of pharmaceutical and veterinary forms ()S

can be elllployed. Thus if a solid carrier is used the composition can be tableted, placed in a hard gelatine capsule, compounded in a salt block, as a powder for drench or gavage use, whole feed or other conventional formula-tions. The compositions are often finished in forms suitable for oral administration (e.g. solution, emulsion, suspension in water or an edible oil). The administration may also be carried out with such forms as bolus, tablet, drench, top dressing etc.
The anthelmintic compositions are made by conventional methods by admixing the active ingredient or a salt thereof with suitable inert solid or liquid carriers or diluents.
The salts of the compounds of the formula I are pharmaceutically acceptable salts.
The dosage of the active ingredient may vary between wide ranges depending on various factors (e.g. seriousness of the infection, condition and weight of the host etc.) and may be generally between about 0.5 mg/kg and 150 mg/kg, preferably 2-20 mg/kg of body weight/dose. The daily active ingredient content may be administered at once or in more doses.
The starting materials of the formula VI and salts thereof are new compounds which are the subject of copending Application Serial No. 370,240 which is also divided out of Application Serial No. 303,127. Application Serial No. 303,127 provides new compounds of the formula VI and salts thereof and a process for their preparation (wherein R , R , R and R3 have the same meaning as stated above). The compounds of the formula VI are use-ful as intermediates in the preparation of the anthelmintic compounds of the formula I while on the other hand they possess ~hemselves fungicidal and anthelmintic properties and can be used in agri-culture as fungicides and in pharmacy as anthelmintics.
The preferred class oE the compounds of the formula VI are those derivatives in which R is hydrogen or methoxycarbonyl and R is hydrogen, chlorine, ~romine, fluorine, trifluoromethyl, methyl, butyl or -OR wherein R is methyl, phenyl or benzyl.
Particularly useful intermediates of the formula VI are the follow-ing derivatives:
bis-~2-amino-benzimidazole-5-yl)-disulfide;
bis-(2-amino-6-methyl-benzimidazole-5-yl)-disulfide;
bis-(2-amino-6-butyl-benzimidazole-5-yl)-disulfide;
bis-(2-amino-6-bromo-benzimidazole-5-yl)-disulfide;
bis-(2-amino-6-chloro-benzimidazole-5-yl)-disulfide;
bis-(2-amino-6-fluoro-benzimidazole-5-yl)-disulfide;
bis-(2-amino-6-trifluoromethyl-benzimidazole-5-yl)-disulfide;
bis-(2-amino-6-methoxy-benzimidazole-5-yl)-disulfide;
bis-(2-amino-6-phenyloxy-benzimidazole-5-yl)-disulfide;
bis-(2-amino-6-benzyloxy-benzimidazole-5-yl)-disulfide;
bis-(2-methoxycarbonylamino-benzimidazole-5-yl)-disulfide;
bis-(2-methoxycarbonylamino-6-methyl-benzimidazole-5-yl)-disulfide;
bis-(2-methoxycarbonylamino-6-butyl-benzimidazole-5-yl)-disulfide;
bis-(2-methoxycarbonylamino-6-bromo-benzimidazole-5-yl)-disulfide;
bis-(2-methoxycarbonylamino-6-chloro-benzimidazole-5-yl)-disulfide~

()5 1 . ~ --bis-(2-m~:hoxycarbonylamino-6-f-luoro-bell~imidazole-5-yl)--disul-Fide;
bis-(2-methoxycarbonylaln:ino-6--~riFluoromethyl-benzimidazolc--5-yl)-disulFide;
bis-(2-methoxycarbonylamino-6-methoxy-benzimidazole-5-yl)--disulfide;
bis-(2-methoxycarbonylamino-6-phenoxy-ben~imidazole-5-yl)--disulfide;
bis-~2-methoxycarbonylamino-6-benzyloxy-benzimidazole-5-yl)--disulfide;
The compounds of the Formula VI may be prepared as follows:
a) for the preparation o, co~pounds of the Formula VI, wherein R1 is hydrogen, reacting a compound of the Formula VII _ _ R2 ~ _ NH (VII) --S ~J NH2 (wherein R2 has the same meaning as stated above) with cyanamide or bromo cyane; or b) for the preparation oF compounds of- the Formula VI, wherein R1 is a group of the Formula ~COOR and R is as stated above, reacting a compound of the Formula VII with a compound of- the Formula XII

R500CN - C - NH - COOR (XII3 or NC - NH - cooP5 (XIII) , . . ~

()S

~ c) to prepare a compound of formula VI in which Rl is a -CooR5 group~ reacting a compound of formula VI in which R is hydrogen with an agent for introducing a group -COOR into the compound of formula VI
and if required, converting a compound of tlle l~ormula VI thus obtained into its salt or setting free the same from its salt.
According to one embodiment of method (a) a compound of the formula VII is reacted with cyanamide. The reaction is accomplished in the presence of a mineral acid (e.g. hydrochloric acid, sulfuric acid, phosphoric acid) in aqueous medium. Thereafter the reaction mixture is treated with an inor-ganic base (e.g. sodium or potassium hydroxide) or an alkali carbonate (e.g.
sodium or potassium carbonate) and the precipitated bis-(2-amino-benzimida-zolyl)-disulfide of the formula VIa ~ R ~ ~ NH~l (VIa) - r s N
~ _ 2 is isolated.
According to another embodiment of method (a) a compound of the formùla VII is reacted with bromo cyane in a lower alkanol (e.g. methanol, etllanol, propanol, isopropanol, preferable in ethanol) at a temperature between 0 C and 40 C~ preferably at 20 C. The reaction mixture is treated with an alkali (e.g. sodium or potassium hydroxide) or an all<ali carbonate (e.g.. sodium or potassium carbonate) to give a compound Of the formula VIa.
Accolding to an embodiment Of method b) of our process a compound Of the Formula VII is reacted with an iso~hiourea derivative of the Formula XII. The process is preferably carried 0ut by heating the components in a protic solvent in the presence of an acid~ As reaction medium water, or organic solvents or a mixture Of water and an organic solvent (e.g. water-ethanol mixture) may be usédO The reaction is preferably eccomplished at a pH value Of 3-6, particularly at an interval Of 3.5-5. The pH is ad;usted with an inorganic ~cid (e.g. hydrochloric acid~ sulfuric acid, phosphoric 15 acid) or en organic acid, e.g. formic acid~ acetic acid~
propionic ecid etc~ preferably acetic acid. The reaction temperature is preferably 50-100 C and one may work ad-vantageously at the boiling point Of the reaction mixture.
Thus compounds Of the Formula VIb 2C) . ~ -~ t ~ ~ Nh~-cooRs ] (VIb) are obtained.
According to an other embodiment Of method b) a compound of the Formula VII is reacted with a carbalkoxy-cydnamide of the formula XIII in 3 water-mi5cible organic solvent 30 (e.gO methanolJ ethanol, acetone, dioxane, pyridine) or a X~

ll'~Z~)S

mixture of water and an organic solvent. The reaction may be accomplished preferably at a temperature between 20C and the boiling point of the reac-tion mixture. Thus compounds of the Formula VIb are obtained.
A compound of the Formula VIa may be converted into the correspond-ing compound of the Formula VIb by reacting with an agent capable for the introduction of a carbalkoxy group. Reaction is carried out preferably in a basical organic solvent (e.g. pyridine) at a temperature of O-100C. As agent capable for the introduction of a carbalkoxy group agents generally used for this purpose ~e.g. alkyl halogeno formiates of the Formula XIV) may be used.
The compounds of the Formula VIa may also be transformed into the corresponding compounds of the Formula VIb by reacting with a dialkyl carbon-ate of the Formula XV in the presence of an equimolar amount of an alkali alcoholate. As solvent preferably an alkanol may be used. One may proceed preferably by using as reaction medium an alcohol which corresponds to the R5 alkyl group of the alkali alcoholate. The reaction temperature amounts to 20-120C, preferably the boiling point of the alcohol solvent used.
It is evident for one skilled in the art that the compounds appear-ing in the examples may be designated in two manners depending on the fact whether the numbering is started from the N-atom or the NH group. Thus bis-(2-methoxycarbonylamino-benzimidazole-5-yl)-disulfide can also be named as bis-(2-methoxycarbonylamino-benzimidazole-6-yl)-disulfide.

i{)5 The compounds of the lormula VII are useful on the one hand as intermediates in the preparation of anthelmintic agents of the Formula I
while on tlle other they possess valuable fungicidal and anthelmintic proper-ties and may be used as fungicides in agriculture and anthelmintics in pharmacy.
All of the compounds of the Formula VII are new except the deriva-tive in which R is hydrogen. In prior art a very complicated and circum-stantial seven-step synthesis is disclosed for the preparation of this com-pound in which aniline is rhodinated, the amino group is protected by intro-ducing an acetyl group, the product is subjected to nitration and hydrolysis, whereupon the product obtained is converted into a disulfide, which is then cleaved into 2-amino-4-mercapto-aniline and finally a disulfide is formed [Ber. 59, 190 (1926); J. Chem. Soc. 1928, 1364; Pharmazie 3, 151 ~1948);
Arzneimittelforschung 2, 455 (1952)]. In view of the complicated steps and the low yield this process is unsuitable for industrial scale production.
The compound of the Formula VII, wherein R is hydrogen, was only known as a laboratory product of theoretical interest.
It has been found that the compounds of the Formula VII are valu-able intermediates in the preparation of biologically active derivatives by further reactions of the active amino groups. Thus they are suitable for the preparation of various heterocyclic compounds, e.g. dibenzimidazolyl-disulfide derivatives. The following preparation of the compounds of the Formula VII
can be readily carried out on ()5 - 2~ -industrial scale. Practically nQ by--products are formed.
The compounds of the Formula VII may be prepar-~J by heating a compound oF the Formula XVI.
S
~2 ~ NH~ ~XVI) I~C ~ NHi The reac~ion m~y be carried out pre~erably by haating th2 starting material of the Formula XVI in a sui~able solvent in the presence of a catalys~.
As solvent water or lower alkanols (e.g. methanol, ethanol~ propanol) or a mixture of water and the above allcar,ols ~ may be used. The catalyst may be an inorganic base (preferably sodium hydroxide, potassium hydroxide), an alkali carbonate (e.g. sodium carbon3te, potassium carbonate) or - preferably - ammonium hydroxide.
One may proceed particularly prefersbly by heatlng a 0 conipound of the Formula XVI with 8 3.5 % aqueouR ammonium hydroxide solution. The reaction temperature is preferably 20-100~, advantageously 80 ~C, The reaction 4 takes place within 1~5 hours, preferably 3 hours.
According to an other embodiment of this process a co~pound of the Formula XVI i~ heated in the mixture of 26 a lower alkanoic acid (e.g. acetic ~cid) and a tertiary - - ; aminc (e~g. triethylamine, dimethylaniline~pyridine)~
Particularly preferable class of compounds are those derivatives of the Formula VII wherein R2 is methyl, butyl~
chlorine, bromine~ fluorine, trifluoromethyl or -oR3 and - R3 is methyl, benzyl or phenyl. ~ -... . .

)5 Particularly preferred representatives of the compounds of the Formula VII are the following compounds:
2,2'-dimethyl-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-dibutyl-4~4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-dibromo-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-dichloro-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-difluoro-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-di-(trifluoromethyl)-4,4',5,5'-tetra.amino-diphenyl-disulfide;
2,2'-dimethoxy-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-diphenoxy-4,4',5J5'-tetraamino-diphenyl-disulfide;
2,2'-di-(benzyloxy)-4,4',5,5'-tetraamino-diphenyl-disulfide.
This present application provides compounds of the formula XVII

~ R21 (XVII) NCS

salts thereof and a process for the prepa.ration of the same.
ln the compounds of the Formula XVII R 1 stands for hydrogen or amino; and if R21 is hydrogen, then R is amino and if R21 represents amino, then R stands for hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy, aryloxy or aralkoxy.
The compounds of the Formula XVII and salts thereof are prepared by reacting a compound of the Formula XVIII

.~ -0~

N}12 ~ R21 (XVIII) (wherein R 1 and R are as defined above) with dirhodane (NCS-SCN), chlororhodane (Cl-SCN), ammonium thiocyanate or an alkali metal thiocyanate in the presence of an oxidizing agent and in an anhydrous medium and, if required, converting a compound of the Formula XVII into its salt or setting free the same from its salt.
The compounds of the Formula XVII are useful intermediates which may be used in the preparation of biologically active compounds, particularly pharmaceuticals and products for application in agriculture such as pesti-cides, e.g. fungicides.
One of the compounds of the Formula XVII - the 1,2-diamino-4-thiocyanato-benzene - has been described as intermediate without disclosing its physical constants (rlungarian laid open patent application Serial No.
SI-1367). According to the known process l-amino-2-nitro-4-thiocyanato- .
benzene (J. Chem. Soc. 1928, 1364 - a compound which is with difficulty available on industrial scale - is reduced with stannous (II)chloride at -40C. (Reaction scheme E) Nll NHAc I ~ ~ cc. HN03 2. Ac20/ 2 4 SCN

NHAc NH2 HCl SCN
SCN

SnC12 ~ NH2 cc. HCl ~ J

SCN

It is known ~J. Gen. Chem. (USSR), ~, 183 (1933); C.A. 28, 1677 (1934)] that 1,3-diamino-benzene may be rhodinated (thiocyanated) with the aid of N,N'-dichloro-urea and ammonium rhodanide (ammonium thiocyanate) in aqueous acetic acid. The authors stated however that this method does not lead to the desired result when diamino-benzene derivatives sensiblc against oxidation (such as p-phenylene-diamine) are used. A recently published summarizing monography about rhodinating was silent in teaching the rhodina-tion of such diamino-benzene derivatives [Die Pharmazie 32, 195 (1977)].
It has been found surprisingly that the diamino-thiocyanato benzene derivatives of the Formula XVII may be prepared by excellent yields from the compounds of the - 2~ -Formula ~VXII by direc~ rhodination in moderately acidic anhydrous medium.
Accordin~ ~o the process of the present invention as rhodinating agent preferably cornpouncls of the Formula XIX
R4 - SCN (XIX3 may be used (wherein R4 is a metal atom, preferably an alkali metal atom, alkaline earth metal atom or a heavy metal atom or an ammonium ion) in the presence or in the absence of an oxidizing agent - depending on the definition of R~.
1~hese rhodinating agents provide under ~he reaction conditions used the desired compounds of the Formula XVII in a simple manner, by excellent yields and in high purity, One may proceed preferably by preparing in advance the ~5 active rhodinating agent and adding the same to the solution of the starti.ng material of the Formula XVIII. The active rhodinatinJ agent may also be prepared by reac~ing a compound of the Formula XIX with an oxidizing ayent. In this reaction both inorganic and organic oxidizing agents may be used~ From the oxidizing agents e.g. organic N~
halogeno compounds, such as Chloramine-T, N-bromo-succinimicle, N,N'-dichloro-urea;peroxides e.g~ hydrogen peroxide;
alkali hypochlorites, all<ali bromates, all<ali'iodates;
ions of heavy metals of suitable oxidation grade e.g.
ions of lead, mangsnese and chromium; furtheron silver oxide and elementary halogens such as chlorine and bromine may be used.
One may also proceed by adding the above oxidizing agent at a suitable rate to the solution of the compounds of the Formulae XVIII and XIXo In the case of rhodanides )5 ~Q ~

of heavy metals however this embodiment of the process i9 less preferable.
According to a paeticularly preferable embodiment of our process the oxi~iizing agent or a solution thereof is added at a suitable rate to the solution of a compound of the Formula XVIII and a rhodanide of the Formula XIX
wherein R is ammonium, sodium or potassium ion, preferably ammonium ion. One may use preferably an elementary halogen, particularly bromine or chlorine.
~0 As reaction medium organic solvents may be used in which the components are readily soluble such as dipolar aprotic solvents (e.g. dimethylformamide, dimethylsulfoxide, hexa-methylphosphoric triamide, lower fatty acids, esters of alcohols formed acetic acid or formic acid and alkanols having 1-4 carbon atoms. It is preferred to use methanol or ethanol in which most organic rhodanides are easily :
soluble. Methanol proved to give the best results. In the case of the preparation of compounds of the Formula X~II whereln R21 lS amino and R22 is alkyl~ alkoxy, aryloxy ZO ~r aralkoxy, the reaction is carried out under the addition of an acid. For this purpose organic acids may be very advantageously used which act also as solvent (e.g. acetic acid or formic acid). One may proceed partlcularly preferably by using methanol or ethanol as solvent and adding 0-2 moles of acetic acid - related to the diamino-benzene derivative of the Formula XVIII - to the reaction mixture.
- The reaction temperature depends on the solvent and the reactants used and is from about -20 C to about ~200 QC.
The process may be particularly advantageously accomplished by reacting a compound of the Formula XVIII in a mlxture of )5 methanol and acetic acid at a temperature between -10C and +25C with a rhodinating agent formed from ammonium rhodanide and elementary bromine or chlorine.
The above novel process opens a new way in tAe synthesis of sulfur-containing diamino-benzene derivatives. The process is very simple, the starting materials are cheap and easily available in great quantities too and the desired diamino-thiocyanato-benzene derivatives are obtained in one step with excellent yields.
It is evident for one skilled in the art that the numbering of the substituents may be started from either amino group. Thus 1,2-diamino-4-chloro-5-thiocyanato-benzene may be designated as 1,2-diamino-4-thiocyanato-5-chloro-benzene as well.
Preferred representatives of the compounds of the formula XVII are the following derivatives:
1,2-diamino-4-methyl-5-thiocyanato-benzene;
1,4-diamino-2-thiocyanato-benzene;
1,2-diamino-4-chloro-5-thiocyanato-benzene~
1,2-diamino-4-bromo-5-thiocyanato-benzene, -1,2-diamino-4-fluoro-5-thiocyanato-benzene;
1,2-diamino-4-trifluoro-ethyl-5-thiocyanato-benzene 1,2-diamino-4-methoxy-5-thiocyanato-benzene;
1,2-diamino-4-phenoxy-5-thiocyanato-benzene;
1,2-diamino-4-benzyloxy-5-thiocyanato-benzene;
1,2-diamino-4-n-butyl-5-thiocyanato-benzene.
The compounds of the Formula I and salts thereof ; -30-;: .

ll'~'~ti()S

~whereill R , R , R ancl R and R5 are as stated above) may be thus prepared from the diamino-benzene derivatives of the formula XVIII by the following reaction series: reacting a compound of the Formula XVIII (wherein R is amino and R stands for hydrogen, halogen~ trifluoromethyl, lower alkyl, lower alkxoy, aryloxy or aralkoxy) with an agent capable of introducing a thiocyanato-group (SCN); thereafter heating the compound of the Formula XVI thus formed (wherein R2 has the same meaning as stated in claim 1);
thereafter reacting the compound of the Formula VII thus formed (wherein R2 has the same meaning as stated in claim l)(with cyanamide, bromo cyane or a compound of the Formula XII or XIII (wherein R is as stated in claim 1) and if desired reacting a compound of the Formula VI thus formed (wherein R is as stated in claim l; Rl is hydrogen) with a compound of the Formula XIV or XV (wherein R is as stated above and X is halogen) to give a compound of the Formula VI wherein R is as stated above and R is a group of the Formula -CooR5, in which formula R5 is as stated above);
and thereafter subjecting a compound of the Formula VI to reduction (wherein Rl and R2 are as stated in claim 1) and if desired introducing an R group being other than hydrogen into a compound of the Formula I thus formed (wherein R and R are as stated above and R4 is hydrogen) and if desired converting a compound of the Formula I thus obtained into its salt.
According to a particularly preferred aspect of the invention of Application Serial No. 303,127 there is provided a new process for the preparation of 5(6)-n-propylthio-benzimidazolyl-2-methyl carbamate ~a well-known anthelmintic agent - a compound of the Formula I
wherein R is methoxycarbonyl; R is hydrogen and R is n-propyl) which com-prises reacting o-phenylene-diamine with an agent capable of introducing a thiocyanato group (SCN); heating the compound of the Formula (XVI) thus obtained (wherein R is hydrogen); reacting the compound of the Formula VII
thus obtained (wherein R is hydrogen) with cyanamide, bromocyane or a com-pound of the Formula XII or XIII (wherein R is methyl) - whereby if cyanamide or bromo cyane is used, the product thus obtained is reacted with a compound of the Formula XIV or XV (wherein R is methyl); reducing the compound of the Formula VI thus obtained (wherein R is hydrogen; R is -CooR5 and R is methyl) and reacting the compound of the Formula I thus obtained (in which R2 and R are hydrogen; R is -COOR and R5 is hydrogen) with a propylating agent.
Further details of ~he present invention and also of the i.nventions of our Applications Serial Nos. 303,127 and 370,240 are to be found in the Examples without limiting the scope of our invention to the Examples )5 Exan~e .____ 10.8 9 of o-~henylene diamine and 1~.2 9 of ammonium rh~dar7i.de ar~ d.issolved in a mixture or 30 ml of methyl alcohol and lO ml o~ acetic aci.d and to the mixture cooled at a temF)erature of 10 C a solution of 6.5 ml o-F bromine in 20 ml oF methyl alcohol is ad~Jed while stirring in 30-G0 minutes and the temperature i.s maintained at 10 C while stirring until t~le reacti.on is finished (5 to 30 minutes).
The final point of the reacti.on is determined by thinlayer chromatographic analysis (Layer: Polyram Sil G., ~acherey Nagel Co.: Development with: benzene-ethylaceta~e-methyl alcoholic ammonium solution 8~ eveloper : Iodine)~
The reaction finished the mixture is poured into water and the acid is neutralized by adding a 20 yO ammonium hydroxide solution, pH value 7-7-5D The precipitated crystalline 1,2~d:iamino-4-thio-cyanato-benzene is filtered.
Weight: 13.2 9 (yield 80 %). Melting point 123 C
(recrystallized From ben~ene~.
Example 2 10.8 g.of phenylene diamine and 50 g of potassium rhodanide are dissolved in1~00 ml of methyl alcohol and ~o the solution at a temperature of 10 C a solution of 7.0 ml of bromine in 30 ml of methyl alcohol is added while stirring vigorously in 30-60 minutes. The final point of the reaction is detennined by the method set forth in Example 1.
After pouring the mix~ure into water snd ad;usting the-pH value, the product is isolated by extraction with chloroform. After drying and evaporating the solvent 13.5 9 of 1~2-diamino-4-thiocyanat~o-benzene are obtained.
Mp. 123 C (from benzene).

ll~ S

Example 3 15.9 9 of bromine are added dropwise while stirring into a solution of ~0 9 of potassium rhodanide in 100 ml of methyl alcohol at a temperature o-f -10C. The obtained yellowish birhodane solution is added to a solution of 10.8 9 of o-phenylene diamine in 40 ml of a mixture from acetic acid-methyl .alcohol 1:~ while stirring at a temperature of 5-10 C. Processing the reac~ion mixture as set forth in Example 1 the 1,2-diamino-4~thiocyanato-benzene is obtained~ melting at 123 C.

rO a solution of 14~2 9 of 4(5)-chloro-o-phenylene diamine and 38 9 of ammonium rhodanide in 120 ml of methyl alc~hol 5 ml of acetic acid are added, whereafter a solution of 7.2 ml o~ bromine in 20 ml of methyl alcohol is added at a temperature of 15-17 C in 30-60 minutes.
- The mixture is diluted with water and after adjusting tha pH value to 8, 1,2-diamino-4~chloro-5-thiocyanato-~ benzene is obtained, melting at 108-110 C.
: Example 5 To a solution of 13~8 9 of 4(5)-methoxy-o-phenylene diamine and 38 g of ammonium rhodanide in 80 ml of methyl ~lcohol and 15 ml of acetic acid a solution of 6.5 ml of bromine in 20 ml o~ methyl alcohol is added dropwise within z5 40-60 minutes ~t a temperature of 5-10 C. Processing the reaction mixture as set forth in Example 1 the . 1,2-diamino-4 methoxy-5-thiocyanato-benzene is obbined.
Mp.: 112-114 C.
Example 6 21.4 9 of 4~5)-benzyloxy-o-phenylene diamine and 50 9 .

11~ )5

- 3~ -- of potassium rhodanide are dissolved in a mixture of 100 ml of methyl alcohol and 20 ml of acetic acid and to the solution obtained a solution of 6.5 ml of bromine in 30 ml of methyl alcohol is added at a temperature of 5~10 C
in 30-60 minutes. Processing the mixture as set forth in Example 1 the 1J2-diamino-3-benzyloxy-4-thiocyanato-benzene is obtained.
Example 7 To a solution of 10~8 9. of p-phenylene-diamine and 38 9 of ammonium rhodanide in 100 ml of methyl alohol and 15 ml of acetic acid a solution of 6.5 ml of bromine in 25 ml of methyl alcohol is added while stirring at a temperature of 8-10 C. Processing the reaction mixture as set forth in Example 1 the 1,4-diamino-2-thiocyanato-bel1zene is obtained.
Example 8 - ~
In an analogous manner to the process described in ~Example 1 to 3, tha followin3 compounds are prepared:
1,2-diamino-4-methyl-5-thiocyanato~ben~ene, mp.: 117 C, i - ~ .
1,2-diamino-4-chloro-5-thiocyanato-benzene; mp.: 108-110 C;
: , 1,2-diamino-4-bromo-5-thiocyanato-benzene, mp.: 99-100 C;
1,2-diamino;~4-~uoro-5-thiocyanato-benzene, mp.: 104-106 C;
2-diamino-4-trifluoromethyl-i5-thiocyanato-benzene, mp.:
154-156 C; ~ ~
1J2-diamino-4-n-butyl-5-thiocyanato-benzene, mp.: 109-110 C, - Example 9 \ j .
22.0 g of 1,2-diamino-4-thiocyanato-benzene are d~sso~ed in 100 ml. of methyl alcohol and to the solution 100 ml. of a 25 % ammonium hydroxide solution and 1000 ml 3~ of we-ter are addsd. The mixture is kept a-t a temperature ..... . . ..

of 80--85 C for 3-4 hours. The final point of the reaction is determined by thinlayer chromatographic analysis.
(Layer: Machel-ey-Nagel Polygram Sil. G. Developtment with: benzene-ethylacetate - a 10 % alcoholic ammonia solution 8:1:1. Developer: Iodine Rf 0.48).
The reaction finished, the mixtu~e is cooIed, let to stand overnight in a refrigerator and the precipitated product is filtered, washed with water and dried. 16.1 9 of 3~3',4,4'-tetraamino-diphenyl-disulfide are obtained (Yield 87 %), melting point: 161-162 C.
~ .
16.5 9 of 1,2-diamino-4-thiocyanato-benzene are dissolved in 20 ml of acetic acid and efter adding 4 9 of pyridine catalyst the reaction mixture is boiled. The final point of the reaction is determined by thinlayer chromatogr~phic - analysis (see Example 1). The mixture is poured on 200 9 of 1ee-water, whereafter is made alkaline by adding a 4 N sodium hydroxide solution (pH value 7.5-8).
After standing for a half hour the product is filtered, washed with water and dried. 11.1 9 (yield 81 %) of 3,3'4,4' tetraamino-diphenyl-disulfide are obtained. Mp. 161-162 C.
~
One proceeds in the sams way as in Examples 9 or 10~
withIthe difference~ that instead of 1l2-diamino-4-thiocyanato 2~ benzene an equivalent amount of a compound of the general formula XVI is used, wherein R2 represents a methyl-, butyl , bromine-~ chlorine-J fluorine-, triFluoromethyl-~ methoxy-J
phenoxy- or benzyloxy group.
By this way the follow ng comp-ounds-of the general formula VII are prepared:

()5 ,2'-dimetllyl-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 174-175C;
2,2'-dibutyl-4,4',5,5'-tetraamino-dipllerlyl-disulfide, mp.: 205-207C;
2,2'-dibromo-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 179-180C;
2,2'-dichloro-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 182-183C;
2,2'-difluoro-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 172-173C;
2,2'-di~trifluoromethyl)-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 194-196C;
2,2'-dimethoxy-4,4',5,5'-tetraamino-diphenyl-disulfide, mp.: 190-192C;
2,2'-diphenoxy-4,4',5,5'-tetraamino-diphenyl-disulfide, 2,2'-di-benzyloxy-4,4',5,5'-tetraamino-diphenyl-disulfide.
Example 12 2.78 g of 3,3',4,4'-tetraamino-diphenyl-disulfide and 6.0 g of S-methyl-N,N'-bis(methoxycarbonyl)-isothiourea-diurethane are dissolved in 100 ml of a 50 vol % alcohol and 1 ml of acetic acid is added, the mixture is boiled until the methyl mercaptane evolution ceases ~about 3 hours), whereafter the precipitated bis-~2-methoxycarbonyl-benzimidazole-5-yl)-disulfide is filtered, washed and dried. 4.2 g of the product are obtained ~95%), melting point 328C ~decomposition).
Example 13 8.8 g OL sodium hydroxide are dissolved in 50 ml of water and

4.2 g of cyanamide are added. The mixture is cooled to 10C and 9.4 g of chloro-formic acid methyl ester )5 -- 3~ --are ~ ecl dropwise in 30-45 minutes, The mixture is stirrer~
for a ~urt~ler balf hour, then added to a solution of 13.
g of 3~3',1,4'-tetraamino-diphenyl-disLIlfide in 200 ml oF
a 75 vol% alcohol. The reaction rnixture is boiled and the pll value is maintained between 3-4 by adding some concc--tratell hydroch1oric acid at intervals. AFter boilin~
for 90 minut~s the mixture is cooled to room temperature ~nd the precipitated product is isolated by filtration.
19 ~ 9 of the bis(2-methoxycarbonylamino-benzimidazole-5-yl)-1n dis~lfide are obtained. Meltin~ pointj 325 C (decomposition)0 Examples 14 to 22_ One proceeds according to the process eF tbe Examples 12 to 13 by using the following o-phenylene diamine derivatives:
- 15 2,2'-dimethyl-4,4' J5,5 I-tetraamino-diphenyl-disulfide, 2,2'-dibut yl-4,4'~5,~'-tetraamino-diphenyl-disulfide, 2,2'-dibromo-4,4',5~5'-tetraamino-diphenyl-disulfide, 2,2'-dichloro-4,4',5,5'-tetra~mino-diphenyl-disulfide, 2,2'-difluoro-4,4',5,5'-tetraamino-diphenyl-disulfide t 2,2'-di(trifluoromethyl)-4,4'5,5'-tetraamino-diphenyl-~ -disulfide~
2,2'-dimethoxy-4,4',5,5'-tetraamino-diphenyl-disulfide, 2,2'-diphenoxy-4,4'-5,5'-tetraamino~diphenyl-disulfide, 2,2'-dibenzyloxy-4,4',5,5'-tetraamino-diphenyl-disulfida.
This way the following products were obta~ned:
bis(2-methoxycanbonyl-amino-6-methyl-benzimidazole-5-yl)--disulfide, mp.: ~05-10 C;
bis(2-methoxycarbonyl-amino-6-butyl-benzimidazcle-5-yl)--disulfide, mp- 295-8 C
bis(2-methoxycarbonyl-amino-6-bromo-benzim1da~ole-5-yl~--disulfide, mp.: 310C(d).

-- ~3c~ ~
bis(2-methoxycarijonyl-amino-~-chloro-l~enzimit.:azole-5-yl)--isulfide, mp. 3()5-10 C (d) .
bis~2-methoxycarbonyl-amino~ fluoro-benzimidazole-5-yl)~
-disulfide, mp. 285-8 C.

5 bis~2-methoxycarbonyl-amino-6-trifluoromethyl-berlzilTIid azole--5-yl)-disulfide, mp r: above 340 C, bis~2 methoxycarbonyl-amino-6-methoxy-benzimiclazole-5-yl)--disulfide, mp . 297-300 C (b) .
l~is(2-methoxycarbonyl-amino-6-phenoxy-benzimidazole-5-yl)~
-disulFide bis(2-methoxycarbonyl-amino-6-benzyloxy-benzimidazole-5-yl)--disulfide.

2.7E3 gO of 3,3t,4,4'~-tetraamino-diphenyl-disulfide are dissolved in 70 ml OT alcohol and to the solution 2.12 9 of bromocyane dissolved in 10 ml alcohol are added. The mixture is allowed to stand overnight, whereafter the alcohol is distilled off and the residue is dissolved in water and made alkaline with sodium hydroxide. 3~09 (S0 ~) of the bis(2-amino-benzimidazole-5-yl-disulfide are obtained, melcing at 245 C by decompositio n~

Example 24 2.78 g of 3,3t,~"4t-tetraamino-diphenyl-disulfide are dissolved in 1,7 ml of a 37 ;~0 hydrochloric acid and a solution of 0.92 9 of cyanamide in 1 ml of water is added dropwise~, The reaction mixture is kep~ for 60 minutes at a temperature of 100 C, 0.9 9 of sodium hydroxide are added in the form of a 40 5~ solution 9 until the ammonia evolution has ceasec' the mixture is heated at a temperature of 100 C. After cooling the bis(2-amino-benzimida~ole-5-yl)-disulfide is . . .
~ .

.

)S

~,, precipitated. Weight: 2.70 9 (81 %). Melting point:
245 C (decomposition).
Examples 25 to 33 One proceeds according to the pro~ess of the Examples 23 or 24, using the following o-phenylene-dialnine derivatives:
2,2'-dimethyl-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-dibut~yl-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-dibromo-4,4',5,5'-tetraamino-diphenyl-disulfide;
2,2'-dichloro-4,4',5,5'-tetr~amino-diphenyl-disulfide;
2,2'-difluoro-4,4'~5,5'-tetraamino-diphenyl-disulfide;
2,2'-di(trifluoromethyl)-4,4',5,5'-tetraamino-diphenyl--disulfide;
2,2'-dimethoxy-4,4',5,5'-tetraamino-diphenyI-disulfide;
2,2'-diphenoxy-4~4'J5,5'-tetraamino-diphenyl-disulfide;
2,2'-diphenyloxy-4,4'~5,5'-tetraamino-diphenyl-disulfide.
~ This was the following products are obtained:
bis(2-amino-6-methyl-benzimidazole-5-yl)-disulfide;
bis(2-amino-6-butyyl-benzimidazQle-5-yl)-disulfide;
bis(2-amino-6-bromo-benzimidazole-5-yl)-disulfide;
bis(2-amino-6-chloro--benzimidazole-5-yl)-disulfide, - bis(2-amino-6-fluoro-benzi~idazole-5-yl)-disulfide;
bis(2-amino-6-trifluoromethyl benzimidazole-5~yl~-di-sulfide; ~ ;
bis~2-amino-6-methoxy-benzimidazole-5-yl)-disulfide;
bis(2-amino-6-phenoxy-benzimidazole-5-yl)-disulfide;
bis(2-amino-6-b'enzyloxy-benzimidazole-5-yl)-disulfide~
Example 34 3r32 9 of bis(2-amino-benzimidazole-5-yl)-disulfide .
are dissolved in 300 ml of pyridine and 2~0 9 chloro-lJ~ )S ~-.

formic acid methylester are added while cooling. The mixture is allowed to stand overnight, whereafter it is heated on a hot water-bath for 90-120 minutes. The pyridine is distilled of in vacuo and water is poured on the residue and the precipitated crystals are flltered, washed and dried. 3.4 9 of the bis(2-methoxy-carbonyl-amino-benzimidazole 5-yl)-disulfide are obtained. Yield 78 ~ Melting point:
325 C (decomposition).
Example 35 3.32 g of bie~(2-~r,~ino-benzilnidazole-5-yl)-disulfide are dissolved in 30 ml of methyl alcohol and to the solution ~80 g dimethyl carbonate and 0.46 9 of metallic sodium dissolved in 30 ml of methyl alcohol are added. The ~ mixture is boiled for 1 hour. Thereafter the reaction ~mixture is acidified with acetic acid (pH value between 5.5-6) and the precipitated bis(2-methoxycarbonyl-amino-benkzimidazole-5-yl)-disulfide is filtered off. Weight:
4.1 9 (92.5 %). Melting point 325 C (decomposition)~
Example 36- to 44 One proceeds according to the process of Examples 34 or ~5 using the following bis(2-amino-benzimidazole-5-yl)~
-disulfide derivatives:
bis(2-amino-6-methyl-benzimidazole-5-yl)-disulfide;
bis(2-amino-6-buthyl-benzimidazole-5-yl)-disulfide~ ;
bis(2-amino-6-bromo-benzimidazole-5-yl)-disulfide;
bis(2-amlno-6-chloro--benzimidazole-5-yl) -disulfide;
bis(~-amino-6-fluoro-benzimidazole-5-yl)-disulfide;
bis(2-amino 6-trifluoromethyl-benzimidazole-5-yl~-disl;lfi~e, bis(2-amino-6-methoxy-benzimidazole-5-yl)-disulfide;
bis(2-amino-5-phenoxy benzimidazole-5-yl)-disulfide, )5 - ~2 ~-bis(2-arllino-o-benzyloxy-benzimidazole~5~yl)-disulfide.
This way the following products were ot)tained:
bis~2-me~:hoxycarbonyl-amino-6-me~hyl-benzimidazole-5-yl)--disulfide~
bis(2-methoxycarbonyl-amino-6-buthyl-benzimidazole-5-yl)--disulfide;
bis(2-methoxycarbonyl-amino-6-bromo-benzimidazole-5-yl)--disulfide;
bis(2-methoxycarbonyl-amino-6-chloro-benzimidazole-5-yl)--disulfide;
bis(2-me~hoxycarbonyl-amino-6-fluoro-benzimidazole-5~yl)--disulfide;
bis(2-methoxycarbonyl-amino-6-trifluoromethyl-benzimidazole--5-yl)-disulfide;
bis(2-methoxycarbonyl-amino-6~methoxy-benzimidazole-5-yl~--disul~ide',' bis(2-methoxycarbonyl-amino-6-phenoxy-benzimidazole-5-yl) -disulfide;
bis(2-methoxycarbonyl-amino-6-benzyloxy-benzimidazole-5-yl)--disulfide.
xam~e 45 ~ 4.4 9 of 2-~methoxycarbonyl-amino)-benzimiadzole-5(6)-yl-disulfide are dissolved in 800 ml of hexamethyl-phosphoric acid triamide and while stirring vigorously, in a nitrogen atmosphere 8 g of sodium borohydride are added in 60-90 minutes at a ~emperature of 20-25 C. After addition of the first parts of the reducing agent the Faint yellowish colour of the solution becomes brown.
After 2 hours a solution of 24.6 9 of propylbromide in 600 ml oF anhydrous alcohol is aclded and the reaction 05 ~-~~3 -,oxt-u-~ is stirred in a nitrogen atmosphere for furt~ler llours at room temperature. Thereafter tbe mixture is dilllted with l lit. of water and the precipitated prodlJct is lilLered, w~hed wlth water and recrystallized from n-propanol. 4(~.7 g (77 %) of the 5(6)-propylthio-ben~imidazolyl-2-metllyl-carbamate are obtained. Melting p~ t 214-215 C.
Example 46 .
4.4 9 ol 2-(metho~ycar~nyl-amino)-benzimidazole-5(6)-yl-disulfide are dissolved in 60 ml of hot dimethyl-forlnamide, whereafter the solution is cooled to room temperature and in a nitrogen atmosphere~ while s~irring vigoro~usly 0.8 9 of sodium borohydride ars added inpor~ions in 30 ninutes~
The stirring and introduction of nitrogen is contin~ d for further 90 minutes, whereafter 2.5 9 of propylbromide dissolved in 50 ml of alcollol are ~dded to the reaction ~ mixture. The mixture is stirred for further 3 hours at room temperature and is diluted with 120 ml of water. The precipi~ated product is filtered, washed thoroughly with water and dried. 4.9 9 of the 5(6~-propylthio-benzimidazolyl-2-methyl-corbamate are ohtained.; Yield 92.5 ~, melting point 208-211 C. After recrystallizstion from n-propanol the product melts at 215 C.
Examp le 47 . .
~5 One proceeds according to Examples 45 or 46, but ,(instead o~ n-propylbromide) allylbromide. propargylbromide, benzylchloride, 4-nitro-fluorobenzene snd 2~4-dinitro-chloro-benzene are used . This way the following compounds are obt~ ned:
~30 6(6)-allylthio-benzimidazolyl-2-methylcarbamate;

f r - 5(G)-propin-2-ylthio- benzimidaz~lyl-2-methylcarbarnate;
5(6)-benzylthio-benzimidazolyl-2-methylcarbamate;
5~6)-(4-nitropheny.lthio)-benzirnidazoly-2-methylcarbalnate;
5(6)-(2,4~dinitrophenylthio)~ben~imidazolyl~2~methylcarbamate~' Example 48 4.4 g of 2-(methoxycarbonyl-amino~benzimidazol-5(6)~
yl~disulfide are suspended ir 30 ml. of methyl alcohol and a solution of 1.12 9 of potassium hydroxide in 15 ml of methyl alcohol i9 added~ To ~I-e solution thus obtained, while continuously stirring, in a nitro~en atmosphere 2.5 9 of propylbromide, thereafter 0,6 of sodium borohydride are added in 30 minutes at a temperature of 25 CC in portions.
The mixture is stirred for further 3 hours, whereafter is diluted with 50 ml of water. After standing the precipitated product is filtered, washed and dried. 3 9 (57 %) of the crude 5(6)-propylthio-benzimidazolyl-2-methylcarbamate are obtained. Melting point after recrystallisation from n-propanol is 214-215 C. The product obtained is identic with that obtained in Examples 45 and 46.
Exa~le 49 4.4 9 of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)-yl-disulfide are suspended in 30 ml of methyl alcohol, and a hot solution of 1.12 g of potassium hydroxide in 15 ml of methyl alcohol is added in nitrogen atmosphere. To the solution obtained 0.~ 9 of sodium borohydride are added at room temperature in 30-40 minutes. After stirring for 30 minutes 1.2 ml of acetic acid, then a solution of 2.~ 9 propylbromide in 10 ml of methyl alcohol is added to the reaction mixture. Stirring is continued for further 2 hoursO Thereafter the mixture is diluted with 50 ml of ~ls water~ and after standing for a while the precipitated product is filtered, washed and dried. 3.9 g of the 5(6)-propyl~hio-benzimidazolyl-2-methylcarbamate is obtained.
Melting point 211-213 C, yield 53 %.
~
2.2 9 of 2-(methoxycarbonyl-amino)-benzimidazol-5(6~-yl-disulfide are suspended in 20 ml of alcohol and 1~2 ml of triethylamine/ then 0.8 9 of 2-mercapto-ethanol are added~ The reaction mixture is stirred for 5 hours. There-10 after a solution of 0.56 9 of potassium hydroxide in 10 ml of anhydrous alcohol and 173 9 of propylbromide are added.
Stirring is c~ontinued for further 2-3 hours at room temperature~ Finally the mixture is diluted with 30 ml of water and the precipitated product is filtered, 15 washed and dried. 1.4 g (53 %) of the 5~6)-propylthio-benzimidazolyl-2-mè~hylcarbamate are obtained. Melting point: 211~213 C.
xample 51 4.4 g of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)-~o yl-disulfide are suspended in 100 ml of hot alcohol and to the suspension a solution of 1.12 g potassium hydroxide in 15 ml of water is added, then a solution of 12 9 of crystalline sodium sulfide in 15 ml of water is added in portions in a nitrogen atmosphere, in 30-45 minutes. There~
25 after a phenyl-diazonium-chloride solution prepared from-1.9 9 of aniline and buffered with sod~m acetate is added to the hot rea,ctibn mix~ure in 10-15 minutes. A vigorous foaming begins, which :.eases 15-20 minutes after dosage.
The pH value of the mixture is ad~usted tc 6.5 and the 30 precipitated product is filtered, washed and dried. 3.3 9 i)S

(60 %) of the 5(6)-phenylthio~benzimidazolyl 2-methyl-carbamate are obtained. Melting point: 243 C (de-composing)~
Ex_mple 5?
2 2 9 of 2-(methoxycarbonyl-amino)-benlzimidazol-5(6)-yl-disulfide are dissolved in 60 ml of hot acetic acid and in a nitrogen atmosphere 0.8 9 of zinc dust is added in portions. After complete dissolving of thez zinc the reaction mixture is evaporated to dryness in vacuo and is stirred in nitrogen atmosphere for 1 hour with an alcohdic potassium hydroxide solution. The reaction mixture is filtered and to the alcoholic solution 1.3 g of propylbromide are added. The rèaction mixture is let to stand for 2 hours at room temperature, whereafter it is diluted with water and the precipitated product is filtered, washed and dried.
1~8 9 (68 %) of the 5(6)-propylthio-benzimidazolyl-2-methyl-carbamate are obtained, melting at 211-214 C.
Example 53 2.2 9 of 2-(methoxycarbonyl-amino)-benzimidazol-5(6)-yl-disulfide are dissolvèd in 40 ml of alcohol containing 0.6 9 of potassium hydroxide and to the hot solution a solution of 1.0 9 of glucose in 15 ml of water is added in 60 minutes. The reaction mixture is boiled vigorously for further 45 minutes, whereafter it is filtered by a pressure-filter in a nitrogen atmosphere. The alcoholic solutionis cooled to room temperature and 1.3 9 of propylbromide are added. ~ter 3 hours the reaction mixture is diluted with water, the precipitated product is ~iltered, washed and dried. 1.6 g (60 %) of the 5(6)-propylthio-benzimidazolyl-2-methylcarbamate are obtained. Melting point: 210-213 C.

S

- A.;7 _ _ E~ample 54 2.2 9 of 2-(metl1oxycarbonyl-arllino)-ber1zimidaz~l-5(6)-yl-disulfide are susper1ded in e~hyl alcohol cont~ining 1.6 9 of potassium hydroxide and 2 9 of amino-imino-methane-sulfinic acid and 1 drop of an alcoholic cetIy-pyridir~ium-bromide solution (or hexadecyl-tributyl-phosphonium-chloride are added. The reaction mixture is boiled in nitrogen at-mosphere for 2-3 hours, whereafter it is cooled to room temperature and 1.3 9 of propylbromide are added. After 3 hours the reaction mixture is diluted with 40 ml of water and the pH value is adjusted to 6, the precipitated product is filtered, washed and dried. 2~ (J (79 %) of the 5(6)-propylthio-benzimidazolyl-2-methylcarbamate are obtained.
Meltin~ point: 210-Z12 C.
Examples 55 to 66 In an analogous manner to Examples 45 to 54 by using the following starting materials the following compounds o~
the Formula I are prepared (R1 is always methoxycarbonyl):
Example ~2 R4 Mp C
fluorine n-propyl - 252-253 56 chlorine n-propyl 266-269 57 chlorine benzyl 234-236 58 chlorine allyl 203-205 59 chlorine propinyl 305-307 chlorine ethyl 237-238 61 chlorine cyc]ohexyl 294-295 62 bromine n-propyl 191-193 63 methyl n-propyl 230-232 (d) 64 methoxy n-propyl 296-298 butyl n-propyl 202~204 66 - trifluoromethyl n-propyl 252

Claims (26)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the Formula XVII

(XVII) (wherein R21 stands for hydrogen or amino; and if R21 is hydrogen, then R22 is amino and if R21 represents amino, then R22 stands for hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy, aryloxy or aralkoxy) which com-prises reacting a compound of the Formula XVIII

(XVIII) (wherein R21 and R22 are as defined above) with dirhodane, chlororhodane, ammonium thiocyanate or an alkali metal thiocyanate in the presence of an oxidizing agent and in an anhydrous medium, to introduce a thiocyanate group (SCN) and, if required, converting the compound of formula XVII into a salt thereof or setting free a compound of formula XVII from a salt thereof.

2. A process according to claim 1 wherein the oxidizing agent is elementary bromine or chlorine, hydrogen peroxide, N,N'-dichloro-urea or N-bromo-succinimide.

3. A process according to claim 1 wherein the reaction is carried out in the presence of a water-miscible organic solvent.

4. A process according to claim 1 wherein the reaction is carried out in the presence of from 0 to 2 moles of organic acid, based on the amount of the compound of Formula XVIII present.

5. A process according to claim 4 wherein the organic acid is acetic acid.

6. A process according to claim 1 wherein R21 is amino and R22 is hydrogen.

7. A process according to claim 1 wherein R21 stands for hydrogen or amino and if R21 is hydrogen then R22 is amino and if R21 is amino then R22 is halogen, trifluoromethyl, lower alkyl, lower alkoxy, aryloxy or aralkoxy.

8. A compound of Formula XVII

(XVII) wherein R21 and R22 are as defined in claim 7, when prepared by a process according to claim 7 or an obvious chemical equivalent thereof.

9. A process according to claim 1 wherein R22 is amino and R21 is methyl, chlorine, bromine, fluorine, trifluoromethyl, methoxy, phenoxy, benzyloxy or n-butyl.

10. A process according to claim 1 wherein R21 is hydrogen and R is amino.

11. A process for preparing 1,4- diamino-2-thiocyanato-benzene which comprises reacting p-phenylene diamine with ammonium thiocyanate in the presence of methanol, acetic acid and bromine.

12. The compound 1,4-diamino-2-thiocyanato-benzene whenever prepared by a process according to claim 11 or an obvious chemical equivalent thereof.

13. A process for preparing 1,2-diamino-4-methyl-5-thiocyanato-benzene which comprises reacting 4(5)-chloro-0-phenylene diamine with ammonium thiocyanate in the presence of methyl alcohol, acetic acid and bromine.

14. The compound 1,2-diamino-4-methyl-5-thiocyanato-benzene whenever prepared by a process according to claim 13 or an obvious chemical equivalent thereof.

15. A process for preparing 1,2-diamino-4-chloro-5-thiocyanato-benzene which comprises reacting 4(5)-chloro-0-phenylene diamine with ammonium thiocyanate in the presence of methyl alcohol, acetic acid and bromine.

16. The compound 1,2-diamino-4-chloro-5-thiocyanato-benzene whenever prepared by a process according to claim 15 or an obvious chemical equivalent thereof.

17. A process for preparing 1,2-diamino-4-bromo-5-thiocyanato-benzene which comprises reacting 4(5)-bromo-0-phenylene diamine with ammonium thiocyanate in the presence of methyl alcohol, acetic acid and bromine.

18. The compound 1,2- diamino-4-bromo-5-thiocyanato-benzene whenever prepared by a process according to claim 17 or an obvious chemical equivalent thereof.

19. A process for preparing 1,2-diamino-4-fluoro-5-thiocyanato-benzene which comprises reacting 4(5)-fluoro-0-phenylene diamine with ammonium thiocyanate in the presence of methyl alcohol, acetic acid and bromine.

20. The compound 1,2-diamino-4-fluoro-5-thiocyanato-benzene whenever prepared by a process according to claim 19 or an obvious chemical equivalent thereof.

21. A process for preparing 1,2-diamino-4-trifluoromethyl-5-thiocyanato-benzene which comprises reacting 4(5)-trifluoro-methyl-0-phenylene diamine with ammonium thiocyanate in the presence of methyl alcohol, acetic acid and bromine.

22. The compound 1,2-diamino-4-trifluoromethyl-5-thiocyanato-benzene whenever prepared by a process according to claim 21 or an obvious chemical equivalent thereof.

23. A process for preparing 1,2-diamino-4-methoxy-5-thiocyanato-benzene which comprises reacting 4(5)-methoxy-0-phenylene diamine with ammonium thiocyanate in the presence of methyl alcohol, acetic acid and bromine.

24. The compound 1,2-diamino-4-methoxy-5-thiocyanato-benzene whenever prepared by a process according to claim 23 or an obvious chemical equivalent thereof.

25. A process for preparing 1,2-diamino-4-n-butyl-5-thiocyanato-benzene which comprises reacting 4(5)-n-butyl-0-phenylene diamine with ammonium thiocyanate in the presence of methyl alcohol, acetic acid and bromine.

26. The compound 1,2-diamino-4-n-butyl-5-thiocyanato-benzene whenever prepared by a process according to claim 25 or an obvious chemical equivalent thereof.