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
- 4 -
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
R500C -
(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
~.
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.
- 7 -
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 ~-
- 10 -
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
12
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
- 14 -
{~s
- 15 -
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
- 16 -
()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
05
~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~
- 18 -
()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
SR5
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
- 20 -
21
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.
- 22 -
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
- 23 -
()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
NH2
~ R21 (XVII)
NCS
R22
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
- 25 -
.~ -
0~
N}12
~ R21 (XVIII)
R22
(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)
- 26 -
Nll NHAc
I ~ ~ cc. HN03
2. Ac20/ 2 4
SCN
NHAc NH2
HCl
CH30H
SCN
SCN
NH2
SnC12 ~ NH2
cc. HCl ~ J
-40C
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
- 7 -
- 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
- 31 -
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
-- 33 -- --
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
..... . . ..
- 36 -
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
- 37 -
)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 ~-
- 41 -
.
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
