CS482280A2 - Method of 5 (6)-thiocyanatobenzimidazole's derivatives production - Google Patents

Abstract

1. Process for the preparation of 5(6)-benzimidazole derivatives of general formula I see diagramm : EP0080555,P4,F2 wherein R represents hydrogen, halogen, C1-4 alkyl, C1-3 alkoxy or trifluoromethyl, R**1 represents amino or C1-4 alkoxycarbonylamino, and the salts thereof, characterised in that a compound of general formula II see diagramm : EP0080555,P4,F4 wherein R and R**1 are as hereinbefore defined, is reacted with chlorine gas and a rhodanide of general formula III R**3 -SCN wherein R**3 represents an alkali metal or alkaline earth metal atom or the ammonium group.

Description

derivatives of 5 (6) -tapiocyanato-

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of the benzimidazole of formula I

and

H Π)

1> í? ' in which 1. . A-Z113 represents an alkoxycarbonylmino group having carbon atoms in the alkoxy moiety.

Z- '% í'

r i ..í

The 5 (6) -thiocyanatobesiaidazole derivatives of general formula I are intermediates in the production / derivatives of non-imidazole, known as antbelaintics, of the general formula

B

H ve l. '· R and r! B 1 is an ion-bonded metal, ionically or covalently bonded to hydrogen, alkyl, C 1 -C 6, alkenyl or alkynyl, each having 6 carbon atoms or cyclohexyl, benzyl or 2-phenylethyl. wherein the 5 (6) -thiocyanatobenzimidazole derivative of formula (I) is converted to a compound of formula (I) by treatment with a nucleophilic, organic or inorganic base

♦

H 4. · - 4 - 1.} In which r r 1 B a. B stables above ντζηε® a2 * B represents an ion-bonded metal atom or an ion or covalently bonded hydrogen atom; which is optionally reacted with an alkylating agent of formula (S). - Q 'in which ® 2' B denotes an alkyl group and 1 to 5 carbon atoms,. alkenyl or alkynyl "each with up to 6 carbon atoms, cyclohexyl, benzyl or 2-phenyl ethyl, and Q denoted hydroxyl group, halogen or one, of groups 1/2 SO4, 1/2 P03, It is known that, in order to produce 5 (6) -thiocyanatobenzioidazole derivatives of general formula (I), la®ino-2-nitro-4-thiocyanatobenzene is reduced to 1,2-diaaino-4. the thiocyanatobenzene, and then the compound is reacted by the reaction of 1,2-bis (aethoxycarbonyl) -S-ethylisothiourea to form a benziaidazole ring, but this method is not feasible in the scaling. benzene and e must be carried out in concentrated hydrochloric acid zinc zinc in a large excess at -40 ° C (see

"0 ', Χ ie * r. · 1, 1] and cyclic T. zcz rz: ový ový ový ový ový ový ový ový ový ď ď ď. 4, ύ3ύ'Λο1 ~ / Example 1] and the cyclization with 1,3-bis- (methoxycarbonyD-methylisothiourea) is considered to be related to environmental pollution.

It has now been found that it is possible to prepare 5 (6) -thiocyanatobensimidazole derivatives of formula 1 by selective rhodination, i.e. by reacting compounds of formula II

(II), wherein B 3, has the meaning given under Formula I,

with chlorine gas and rhodanide of formula III

B3 r SCN in which B is an alkali metal or alkaline earth metal or amine group in a high degree of purity and high yield. The process of this method is very simple, so it can be carried out on an industrial scale. The direct rhodium addition of 2-benzimidazolylcarbamates of general formula II has not been known to date. In professional literature (for example, S. Patai: "The Ghemistry of Cyanates and Thfiir Thio Deri")

A vates ", Part 2, Str. 837 (1977), Wiley: Pharmazie 22, (4), p. 195 (1977), discloses the rhodanation of numerous hetero cyclic compounds, but not the rhodanation of benzimidazole derivatives. Anhalogenation of 2-benzimidazolylcarbamates ( halogenation is, as is well known, a reaction that is very close to rhodanation in chemistry, which may be because it may have been expected to have the degradation of a very sensitive carbamate group on the one hand and the formation of undesirable byproducts. 4 (7), since the halogenation of 2-substituted benzimidazoles resulted in a mixture of 4 (7) -halogen and 4 (7} -, 5 (6) - dihalogen products (Chem. Rev ·, 48) 490 (1951)).

It was very surprising that the direct rhodination of the 2-benzimidazolylcarbamates of formula (II) leads selectively to the 5 (6) -thiocyanate derivatives of general formula (I), which have a yield of 90% in 90% purity.

Due to the high degree of purity, the obtained 5 (6) -thiocyanate-benzimidazole derivatives of general formula (I) can be further processed into the aforementioned anthelmintic without further purification. In a preferred embodiment of the process according to the invention, it is used as the rhodanating agent, which forms the rfaodanide of the formula III and the chlorine gas. It is expedient to make the hydrochloride by reacting rhodanide of the general formula I with chlorine gas in an anhydrous and organic solvent and then added to the solution of the compound of formula II in an organic solvent. However, it is also possible to add a solution of the compound of formula (II) to the chloroform solution.

The process of the invention can also be carried out by introducing chlorine gas into a solution or suspension of the general formulas II and III in an organic solvent. In the process according to the invention, the compound of the general formula II and chlorrhodane is used in a molar ratio of from 1: 1 to 1, 5, preferably from 1 to 1: 3 *. 1 mol of rhodanide of the formula III is added to the 1 mole of the compound of the formula II in an anhydrous organic solvent and then 1 to 4 moles of dry chlorine gas are introduced at a temperature of 15 to 40 ° C. Chlorine gas may be added to the solution or suspension of the compounds of formulas H and III as a solution in an organic solvent. Chlorine gas or its solution is preferably added within a short time. .

As the rhodanide of the formula III, it is possible to use the alkali metal, alkaline earth metal rhodanide and ammonium hydroxide, the preferred rhododium salts being potassium borohydride, sodium rhodanide and ammonium rhodanide. ! As organic solvents and / or diluents, dipolar aprotic solvents can be used in which the reactants are well soluble, such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, lower carboxylic acids, esters, especially acetates or formates, alcohols with 1 to 4 carbon atoms, chlorinated hydrocarbons such as carbon tetrachloride, chloroform, dichloromethane or dichloroethane, further nitromethane or acetonitrile. Of these, acetic acid is a particularly preferred solvent.

The reaction is carried out at a temperature of from 0 ° C to 100 ° C, preferably from 15 ° C to 40 ° C.

The invention is further illustrated by the following examples. Example 1

5.5 g of dry chlorine gas are introduced into a solution of 5 of 2- (methoxycarbonylamino) benzimidazole and 7.5 g of dry potassium rhodanide in 100 ml of acetic acid. The reaction mixture was diluted with 100 ml of a scrubber, the pH of the solution was adjusted to 4 with 5N sodium hydroxide solution, the precipitate was filtered off with suction, washed with water and dried at 60 ° C. There was obtained 5.6% (90% yield) of 5 (6) -thiocyanato-2- (methoxycarbonylamino) 4-benzimidazole, m.p. 252 DEG-254 DEG C. (dec.). EXAMPLE 2 70 ml of carbon tetrachloride containing 5.32 l of chlorine are reacted with a solution of 7.5 g of dry potassium rhodanide in 60 ml of anhydrous acetic acid at 10-15 DEG C. with stirring. The resulting reaction mixture was then stirred for a further 15 minutes before being treated. 5 g of 2- (methoxycarbonylamino) benzimidazole 1 in 25 ml of anhydrous acetic acid are added. After stirring at room temperature, the reaction mixture was poured into water, the carbon dioxide-containing organic phase was separated and the pH of the aqueous phase was adjusted to 4 by the addition of 5 TT of sodium hydroxide solution after decolorizing with charcoal. The precipitate formed is filtered off with suction, washed with water and dried at 60 ° C. There was thus obtained 5 (6) -thiocyanato-2- (methoxycarbonylanino) benzimidazole, m.p. 248 and 250 ° C (dec.).

Claims (3)

I - PATENT CLAIMS 1. Process for the production of 5S-thiocyanatobenzimide & wherein Bx denotes alkoxycarbonylamino having 1 to 4 carbon atoms in the alkosyl moiety, characterized in that the compound of formula II ) H in which B 1 is as defined above is reacted with chlorine gas and rhodide of the formula III-II-ir-scn (ΙΠ), in which ΞΗ represents an alkali metal or alkaline earth metal atom and is an alkali metal atom. ethyl group. 2. A process according to claim 1 wherein the benzimidazole derivative of formula (II) is chlorinated into a solution or suspension of compounds of formulas (II) and (III) or (3e) by reacting the compound of formula (II) with chloro-hexanide formed from rhodanide of formula (III). and chlorine gas. 3. A process according to claim 1, wherein the rhodanide of the formula (III) is potassium rhodanide or sodium rhodanide. '27 .lú.llSo "