CZ297478A3 - Process for preparing 5(6)-thio-benzimidazole derivatives - Google Patents

Description

Technical field

The invention relates to a process for the preparation of 5 (6) -thiobenzimidazole derivatives of the general formula I

wherein R znamená represents a radical or a group of the formula -COO R wherein R ^ represents an alkyl group having from one to four atoms.

Carbon,>

κ známenáívodílo / or halo-alkyl group having one to six carbon atoms, trifluoromethyl group or formula -OR, where five ^watts

R represents an alkyl group of one to four carbon atoms,

R &^lt; 1 > is alkyl of one to four carbon atoms, cycloalkyl of five to seven carbon atoms, alkenyl or alkynyl of three to five carbon atoms, or benzyl or phenyl,

When R ¹ is hydrogen, it is a completely new substances.

2. Background Art

Most of the end products of the process of the invention of formula I are novel compounds. They have valuable anthelmintic properties and are useful in pharmacy and veterinary medicine as anthelmintics ·

Some compounds of formula (I) have already been described in the literature as anthelmintics, see U.S. Patents 3,574,845, 3,915,986 and 3,956,499, German Patent 2,250,469 and French Patent 2,134,558.

It is known that compounds of the following general formula

IA ...... '.....................

-NH-C00r (IA) is a group of compounds of formula (I) wherein C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl or alkynyl are each or a benzyl group, may be prepared by reacting compounds of formula XXI

(III) wherein R ⁹ is as defined above, salt, 3-bis (alkoxycarbonyl) -3-S-alkylisothiomoěovinou formula IV R ⁴ OOC-jl <

/ C-SR ⁴ R ^{4 OOC-Z} and n

H (IV) wherein R ⁴ has the meanings given hereinbefore, according to Reaction Scheme A (German Patent Patent 2,363,351:

or with a compound of formula (V)

HCJÍíUCOOR ⁴ (V) wherein R ⁴ has the above mentioned meanings, according to Scheme B America · sneeze patents 3,915,986 and 3,956,499 t

R ^ S-

+ IC-NH-C00R ⁴ q -> R ^y s

The benzimidazole carbamate cyclic system is formed using the 1,2-diamino * 4-alkylthiobenzene derivatives of formula III, which can only be obtained by a complex multi-step synthesis from relatively expensive starting materials according to reaction schemes C and D.

Reaction Scheme C;

Cl

AND

Ζ '-' Ι

Cl (

Acetylation - _?

NHCOCH-j nitration --->

^K NHC0CH.

hydrolysis

L 11 ..- 1¾ reduction ...

R ⁷ S o ₂ n

RS

/ ------ (byproduct) (III)

-5 Reaction scheme D:

-7 ^ NCS

1¾ acetylation

->

K ⁹ SN ° 2 reduction

Cm)

The reaction procedure in Scheme C involves nitration of m-chloroacetanilide to give two isomers so that the desired isomer is only available in moderate yields, see J. Org. 12, 799 (1947) tox Toxic is used in the next reaction step

-6a malodorous n-sulfaptans (U.S. Pat. Nos. 3,915,986 and 3,956,499) · This reaction can only be performed with really poor yields, see J. Org. 42, 554 (1977). On the basis of these facts, the compounds of the general formula (III) can be isolated only with low yields.

The reaction of Ivo omyoluf of Scheme D is also associated with low yields of compounds of formula III with respect to the seven-step synthesis, see Chem.Ber. 19 ° (1926) and J. Chem.

1364 · p ·? & {$ F o / 7 ^> / f2_IZ

It has now been found that the compounds of formula I can be obtained in a simple manner with excellent yields and in a very pure state. so,. that? The novel disulfide derivatives of formula (XI) are reduced and the compounds of formula (I) are obtained here. already. wherein R is 12

- the hydrogen and R + and R have the same meanings as defined above, - optionally introducing a group R (other than hydrogen) with reagents suitable for sulfur substitution;

The compounds of formula (I) according to the invention can be obtained by reacting a compound of formula (II)

-R ^J (II) __ τ_. 2 -, ____. where R and R are as defined above, they are reduced by treatment with a complex metal hydride, optionally in the presence of Lewis acid, or by treatment with an alkali metal in an alcoholic environment, or with an alkali metal sulfide in an alkali

-7prostředí or by a metal, such as zinc in the presence of an inorganic heaven an organic acid, and the thus obtained product with a compound of Formula ⁵ where R 'has the above meanings and X represents / halogen * ^ ·

According to a preferred embodiment of the process according to the invention, the starting material of the formula II is reduced with a complex metal hydride, for example lithium aluminum hydride, or a complex of sodium borohydride and aluminum chloride or sodium aluminum bis (2-methoxyethoxy) dihydride. solvents, 4,-dialkyl ethers, cyclic ethers such as tetrahydrofuran, dioxane, formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, diethylene glycol dimethyl ether, lower alcohols, etc. ·

When using boron sodium hydride-aluminum chloride complex, the reduction is preferably carried out in tetrahydrofuran or dioxane, in which case it takes place at room temperature within two to three hours.

When sodium borohydride is used as the reducing agent, a mixture of alcohol and water in the presence of an alkali metal hydroxide can be used as reaction medium in addition to the above-mentioned substances. Thus; the thiophenol derivatives obtained can either be isolated or immediately converted to another compound of the formula I

The disulfide bond of the compounds of formula II can also be reduced by alkali metals, in which case the reduced compound is suspended in an inert solvent, e.g.

Of toluene or xylene and after addition of sodium or potassium in powdered form, the reaction mixture is allowed to stand at room temperature, optionally with slight heating. If 2 to 3 equivalents of alkali metal are used per equivalent of starting material II, the alkali metal salt is obtained. When 4 alkali metal equivalents are used, a salt with two alkali metal equivalents is obtained. The reaction mixture is then acidified and the compound can be isolated as such. Addition of only two equivalents of an acid such as acetic acid yields a solution of a simple alkali metal salt and the resulting compound, which can be isolated or immediately converted to another compound of formula (I) above.

The reduction can advantageously be carried out in a liquid ammonia at a temperature between -20 ° C and -40 ° C, and after the ammonia evaporation, the alkali metal salt of the resulting compound remains and can be isolated or immediately converted to another compound of formula I. _

The reduction of the compounds of formula (II) may also be carried out with sulfur inorganic reducing agents, for example sodium sulfide, sodium sulfite, sodium dithionite or sodium bisulfite, with the latter two having the best results. In this case, the alkali metal hydroxide is preferably used in an amount of 2 to 2.6 moles and 2 to 2.2 moles of the reducing agent per 1 mol of the starting compound of formula (II). ^For education, it is advantageously carried out in a solution which is 10 to 30% water and 90 to 70% alkanol and / or dimethylformamide. it is preferably carried out with heating to 50 to 80 ° C, in particular to boiling the reaction mixture. The resulting compounds are either isolated or immediately converted to another compound of formula (I).

Organic sulfur compounds can also be used for the reduction, for example by treating a solution or suspension of the starting material of formula (II) in an organic solvent such as lower alkanol or dlmethylformamide with one to three equivalents of metaptoethanol at 20-80 ° C in the presence a basic catalyst such as triethylamine. The resulting compound can be isolated or immediately converted to another compound of Formula I.

When aminoiminomethanesulfite acid is used for the reduction, e.

It is then carried out using a solution or suspension of the starting material of the formula (II) in a mixture of an aqueous solution, an alkali metal hydroxide and an alkanol or in a dipolar, aprotic solvent, and subsequently added. also a phase transfer catalyst such as cetylpyridinium bromide or methylcaprylammonium chloride and the reaction is carried out at a temperature of 60 to 80 ° C under an inert atmosphere. _This reduction can also be accomplished by treatment with some metals in an acidic environment, and zinc, tin, iron, aluminum, etc. can also be used. Metal salts of different valencies can also be used if the metal is in a lower oxidation state The pH is preferably adjusted with dilute inorganic acid, for example 0.1 to 2.5% hydrochloric or sulfuric acid. Water and / or water-miscible organic solvents, for example alkanols, glycols, dimethylformamide, dioxane, diethylene glycol dimethyl ether, tetrahydrofuran, preferably lower alkenols, can be used as the medium. The reaction is carried out at a temperature of 25 to 110 ° C, in particular at the boiling point of the reaction mixture. It is preferred to use acetic acid which has both a solvent and a pH adjustment.

According to another embodiment, the reduction can be carried out in a mixture of alkanol or dimethylformamide with zinc amalgamated in a Jones reactor. The mineral acids are preferably hydrochloric and sulfuric acid, preferably at a concentration of 1 to 2.5 R. which is mixed with water, such as a lower alkanol, for example methanol, ethanol or isopropyl alcohol. This is a very gentle procedure, even at room temperature ·

The abovementioned reduction processes are preferably carried out in an inert medium, for example under nitrogen. When working in a heterogeneous phase, the catalyst is preferably used as a phase transfer agent.

The compounds of the formula I thus obtained can be converted to _jiné to other compounds of the formula I in which Ir represents a different substituent .beta.f hydrogen. In doing so, a compound of the formula I is reacted in which R and R have the meanings given above and is hydrogen, a compound of formula (I) wherein R Att has the meanings given above and X is chloro, bromo. or iodine ....... ........

The compound of formula (I) is first dissolved or suspended in an organic solvent and the addition of an equivalent amount of an alkali metal hydroxide such as potassium,

The press is converted into the corresponding salt. The solution of this salt is then treated with a compound of formula R X, preferably at a temperature of 10 to 60 ° C in a water-miscible organic solvent such as methanol, ethyl alcohol and / or dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide. The expected compounds of formula (I) are thus obtained

Such a reaction is preferably carried out in an inert atmosphere, for example under nitrogen. When operating in a heterogeneous phase, a phase transfer catalyst is preferably used with a view to shortening the reaction time and increasing the yield. Phosphonium or ammonium type reagents are used.

** · - ΤΚΛ - X - -1 .lit T_. _1L -ι-nu .Ι ^ _{ί ·.}

Particularly preferred compounds of formula I are the following derivatives and their salts:

5 (6) -n-propylthio-6 (5) -fluorobenzimidazolyl-2-methylcarbamate, -5 (6) -n-propylthio-6 (5) -chlorobenzimidazolyl-2-methylcarbamate, 5 (6) -benzylthio-6 ( (5) -chlorobenzimidazolyl-2-methylcarbamate,

5 (6) -allylthio-6 (5) -chlorobenzimidazolyl-2-methylcarbamate,

5 (6) -Propinylthio-6 (5) -chlorobenzimidazolyl-2-methylcarbamate,

5 (6) -ethylthio-6 (5) -chlorobenzimidazolyl-2-methylcarbamate,

5 (6) -cyclohexylthio-6 (-5) -chlorobenzimidazolyl-2-methylcarbamate,

5 (6) -n-propylthio-6 (5) -bromobenzimidazolyl-2-methylcarbamate,

5 (6) -n-propylthio-6 (5) -methylbenzimidazolyl-2-methylcarbamate, (6) -n-propyl hio-6 (5) -methoxybenzidine and from 1-2-methyl hxlkar t b t AMA, 5 (6) -n-propylthio-6 (5) -n-butylbenzimidazolyl fithylkarbamát-2, 5 (6) - _n -p _-O pylthio-6 (5) -trifluormethylbenzimidazolyl-2-methylcarbamate .

The compounds of the formula I and their salts are suitable for the production of onthelmintic preparations which contain the usual inert, non-toxic, solid or liquid formulations.

carriers or diluents.

The compounds of formula X have anthelmintic properties and can be used as anthelmintics in human and veterinary medicine. The active compounds of the formula I are prepared in a manner known per se. The active compounds are mixed with conventional non-toxic carriers, for example, incorporated into animal feed or drinking water. The carrier may consist of conventional compound feed - or substances which can be administered orally, for example in the form of hard or soft gelatin capsules. It is also possible to use the usual ones in the art

pharmaceutical carriers or diluents, such as starch, clactose, glucose, calcium salts. phosphoric acid, gelatin, talc, magnesium stearate, dextrin agar and the like. Of the liquid diluents, various animal oils, such as nut, olive, sesame and the like, can advantageously be used. not water.

The active ingredient can be formulated into various pharmaceutical forms. The solid preparations may be, for example, tablets, capsules, salt blocks, powdered mixtures, etc., and the liquid preparations may be solutions, suspensions, emulsions, etc. The preparations are often formulated for oral administration, for example, as solutions in water or in edible solutions such as suspensions, tablets and the like salts of the compounds of formula I are pharmaceutically acceptable salts.

The dosage can be varied within wide ranges and depends on the qq. on various factors such as the type of infection, condition and. yáhag individual-a t £. The amount of active ingredient administered is.

usually from 0.5 to 1.50 mg / kg body weight per dose. The daily amount can be administered at one time or in several doses.

Examples of embodiments of the invention

Example 1

44.4 g of 2- (methoxycarbonylamino) -benzimidazole-5 (6) -yldisulphide are dissolved in 800 ml of hexanethyltrinamide phosphoric acid and added with vigorous stirring over a period of 1 to 1.5 hours at 20 to 25 ° C under nitrogen 8 g of boric sodium hydride. Already after adding the first portion of the reducing agent, the light yellow color turns brown.

After two hours, a solution of 24.6 g of propyl bromide in 600 ml of absolute ethanol is added and the mixture is stirred at room temperature under nitrogen for a further 3 hours. The reaction mixture is then diluted by adding 1 liter of water, the precipitated product is filtered off. ,. Wash with water and recrystallize. from propanol. There was thus obtained 40.7 g (77%) of 5- (6-methylthiobenzimidazolyl-2-methylcarbamate), mp 214-215 ° C.

Example

Dissolve in 60 ml of dimethylformamide as a girl

4.4 g of 2- (methoxycarbonylamino) -benzimidazole-8 (6) -yldisulfide, the solution was cooled to room temperature under nitrogen, and 0.8 g of sodium borohydride was added portionwise under vigorous stirring over one hour under nitrogen. Stirring is continued for 90 minutes under constant nitrogen, then a solution of 2.5 g propyl bromide in 50 ml alcohol is added. The reaction mixture is stirred at room temperature for a further 3 hours, diluted with 120 ml of water, the precipitated product is filtered off, washed thoroughly with water and dried. 4.9 g (92.5%) of 5 (6) -propylthiobensimidazolyl-2-methylcarbamate, m.p. 208-211 [deg.] C., are obtained after crystallization with propanol, m.p. Mp 214-215 ° C.

-14Primes 3

The procedures of Examples 1 and 2 are followed, but instead of n-propyl bromide, allybromide, propargyl bromide, benzyl chloride, 4-nitrofluorobenzene or 2,4-dinitrochlorobenzene are used.

Using this procedure, the following compounds are obtained:

5 (6) -allylthiobeuzimidazolyl-2-methylcarbamate,

5 (6) - (Propyn-2-ylthio) -benzimidazolyl-2-methylcarbamate, 5 (6) -benzylthiobenzinidazolyl-2-methylcarbamate, mp, 215-217 ° 0.5 (6) - (4-nitrophenylthip) -benzimidazolyl 2-methylcarbamate, 5 (6) - (2,4-Dinitrophenylthio) -benzimicazolyl-2-methylcarbamate;

Example .4 ..... .................. - -. ........... .. «. The suspension is suspended in 30 ml of methanol.

(amino) -benzimidazole-5 (6) -yl disulphide] a solution of 1.12 g of potassium hydroxide in 15 ml of methanol is added, followed by stirring under nitrogen for 30 minutes at 25 ° C in portions of 2.5 g of propyl bromide and 0.6 g of sodium borohydride. The reaction mixture is stirred for 3 hours, diluted with the addition of ml of water, the precipitated product, once settled, is filtered off.

washed and dried. Thus, 3.0 g of crude 5 (6) -propylthiobenzimidazolyl-2-methylcarbamate, m.p. Mp 206-208 ° C. Yield: 57%, after crystallization from propanol, mp, 214-215 ° C. The product thus obtained is identical to the products of Examples 1 and 2.

Example 5 '

4.4 g of 2- (methoxycarbonylamino) -benzimidazol-5 * (6) -yl disulfide are suspended in 30 ml of methanol and a solution of 1.2 g of potassium hydroxide in 15 ml of methanol is added while hot.

-pod - sus-kera. - To the obtained r-is added under nitrogen kine .....

0.8 g of boron hydride over 30-40 minutes, after stirring for 30 minutes add 1.2 ml of acetic acid, followed by a solution

2.5 g of propyl bromide in 10 ml of methanol and the mixture ^* * ^· ·

-15 Stir for another 2 hours. After dilution with 50 ml of water, the precipitated product is filtered off with suction, washed and dried. There was thus obtained 5 (6) -propylthiobenzimidazolyl-2-methylcarbamate (3.9 g, 73.5%), m.p. Mp 212-214 ° C.

Example 6

To a suspension of 2.2 g of 2- (methoxycarbonylamino) -benzimidazolyl-5 (6) -yl disulfide in 20 ml of alcohol was added 1.2 ml of triethylamine, then 0.8 g of 2-mercaptoethanol, and the mixture was stirred under nitrogen for 5 hours. 0.56 g of potassium hydroxide in 10 ml of absolute alcohol was added to the reaction mixture, followed by 1.3 g of propyl bromide, and the reaction mixture was stirred at room temperature for 2 to 3 hours. After dilution with 30 ml of water, the precipitated product is filtered off, washed and dried. 1.4 g (53%) of 5 (6) -propylthiobenzimidazolyl-2-methylcarbamate are obtained, m.p. Mp 211-213 ° C.

Example 7

After a suspension of 4.4 g of 2- (methoxycarbonylamino) benzimidazolyl-5 (S) -yl-di-sulfide in 100 ml of hot alcohol, a solution of 11.2 g of sodium hydroxide in 15 ml of water is added, followed by a solution of crystalline sodium sulfide under nitrogen. within 30-45 minutes. A solution of phenyldiasonium chloride prepared from 1.9 g of aniline and stabilized with sodium acetate is added to the hot reaction mixture over a period of 10 to 15 minutes. Strong foaming ceases after 15 to 20 minutes, the pH of the mixture was adjusted to 6.5, the precipitated product was filtered off, washed and dried. There was thus obtained 5 (6) -phenylthiobenzimidazolyl-2-methylcarbamate (1.8 g, 68%), m.p. 243 ° 0 (dec.) Example 8

2.2 g of 2- (methoxycarbonylamino) -benzimidazolyl-5 (6) -disulfide are dissolved in 60 ml of hot acetic acid, then 0.8 g of zinc dust is added in portions under nitrogen, after complete dissolution of the zinc, the reaction mixture is dissolved.

Concentrate to dryness in vacuo and stir with an alcoholic potassium hydroxide solution for one hour under nitrogen. After filtration, 1.3 g propyl bromide is added to the alcoholic solution, the mixture is allowed to stand at room temperature for 2 hours, diluted with water, the precipitated product is filtered off with suction, washed and dried to give 1.8 g (68%). 6) -propylthiobenzimidazolyl-2-methylcarbamate, m.p. M.p. -211-214 ° C.

Example 9

2.2 g of 2- (methoxycarbonylamino) -benzimidazol-5 (6) -yl disulphide are dissolved in 40 ml of an alcohol solution of 0.6 g of potassium hydroxide and a solution is added to the hot solution. .1 g glucose. In 15 ml. water. The mixture is maintained in the water. boiling for an additional _______ minutes, then filtered under nitrogen and pressure, the alcoholic solution is cooled to room temperature, and after addition of 1.3 g of propyl bromide, after a further 3 hours the reaction mixture is diluted with 40 ml of water. The precipitated product is washed and dried after filtration. There was thus obtained 5 (6) -propylthiobenzimidazolyl-2-methylcarbumate (1.6 g, 60%), m.p. 210-213 ° C.

Example 10

2.2 g of 2- (methoxycarbonylamino) -benzimidazol-5 (6) -yl disulfide are suspended in 10 ml of ethanol in the presence of

1.6 g of potassium hydroxide, 2 g of aminoiminomethanesulfonic acid and 1 drop of a solution of cetylpyridiniumbroinide (or hexadecyltributylphosphonium chloride) in alcohol are added. The reaction mixture is heated at reflux for 2-3 hours, then cooled to room temperature and 1.3 g of propyl bromide are added. After 3 hours, the reaction mixture is diluted with 40 ml of water, the pH is adjusted to 6, the precipitated product is filtered off, washed and dried.

There was thus obtained 5 (u) -propylthiobenaimidazolyl-2-methylcarbamate in a yield of 2.1 g (79%), m.p. 210-212 ° C.

Examples 11 to 22

In a similar manner as described in Examples 1 to 10, the following compounds of Formula I (R ¹ is methoxycarbonyl) can be prepared and used using the appropriate starting materials:

Example R ² R ³ mp ° C 11 fluorine n-propyl 252-253 12 chlorine n-propyl 266-269 13 chlorine benayl 234-236 - 14 chlorine . aiiyi 203-205 15 ------- ............. chlorine ' propynyl - * 305-307— - 16 chlorine ethyl 237-238 17 chlorine cyclohexyl 294-295 18 bromine n-propyl 191-193 19 Dec methyl n-propyl 230-232 (rc 20 ’ methoxy n-propyl 296-298 21 butyl n-propyl 202-204 22nd trifluoromethyl n-propyl 252 Example 23 For room temperature and under nitrogen with dissolve in

0 ml of dimethylformamide 3.3 g of bis- (2-aminobenaimidaaol-5-yl) -isulfide are added, with vigorous stirring, in portions of 0.8 g of boron hydride in portions. The reaction mixture is stirred for a further 90 minutes while introducing nitrogen, then a solution of 2.5 g of propyl bromide in 50 ml of alcohol is added.

The mixture is stirred for a further 3 hours at room temperature, diluted with 120 ml of water, the precipitated product is filtered off, washed thoroughly with water and dried to give 3.5 g of 2-amino-5 (6) -propylthiobenzimidazole, m.p. Mp 173-175 ° C.

Claims (1)

Process for the preparation of 5 (δ) -thiobenzimidazole derivatives of the general formula I .. O-NH-R ¹ N (I) 1,4 wherein R ^x is * a hydrogenated group of the formula -COOR, wherein, 4 R represents an alkyl group ^of one to four carbon atoms, / wherein R is hydrogen or halogens furthermore an alkyl group of one to six carbon atoms, trifluoromethyl ... - _{from a} - 5 group or a group of the formula -OR, R ^ represents an alkyl group 3 of one to four carbon atoms, a (C 1 -C 4) alkyl group, (C 5 -C 7) cycloalkyl, (C 3 -C 5) alkenyl or alkynyl group, or a benzyl or phenyl group, characterized in that the compound of formula (II) -II-S 1 H% C-NH-R ¹ (II) Wherein R and R are as defined above, reduced by treatment with a complex metal hydride, optionally in the presence of Levjisic acid, or by treatment with an alkali metal in an alcoholic environment; by treatment with an alkali metal air-alkali or zinc in the presence of an inorganic or organic acid, and the product thus obtained is treated with a compound of the formula R ³ wherein X is as defined above and X represents halogen