HU207302B - Process for producing benzimidazolyl-carbamate derivatives - Google Patents

Abstract

Anthelmintic methyl-(5-propyl)-sulpenyl-imidazole-2-yl)-car bamate is prepd. by the redn. in water of bis(2-methoxy-carbonyl-ami no- benzimidazole - 5- yl) - disulphide, at ph 7-14 and 50-20 deg C in 10-60 mins with a cpd. of general formulae (V) -(not given) where R1 = NHgp or two hydrogen atoms. R2 = -NH2 or -OH gp. M = hydrogen atom, potassium or sodium ion), and by propylating the mercaptanm obtd. (Previously notified in week 9123) - ( hed pa)

Description

The present invention relates to a process for the preparation of methyl (5-propylsulfenylbenzimidazol-2-yl) carbamate of the formula (I), also known as albendazole. Because of its anthelmintic properties, albendazole is known to be a mature active ingredient in human and veterinary pharmaceuticals. (U.S. Patent No. 3,915,986),

One of the most preferred methods for the preparation of the compound and its relatives was to obtain albendazole by propylation from 2- (methoxycarbonylamino) -benzimidazol-5-thiol (III) (hereinafter "thiol") (177 418, 182763, 182782). ).

The thiol of formula (III) is prepared from a sulfur derivative of a higher oxidation state and is then propylated either with or without isolation of one of its salts. Several solutions have been suggested for the reduction (Hungarian Patent Nos. 177418, 182782, 182794, 190705, 192973 and 196185).

In these embodiments, the reduction is generally carried out starting from, or through, the bis (2-methoxycarbonylaminobenzimidazol-5-yl) disulfide of formula (IV) and the product is alkylated with propyl bromide in an alkaline medium. However, there may have been various problems with the cleavage of the sulfur-sulfur bond under industrial conditions, as follows:

Complex metal hydride reduction (sodium tetrahydroborate) provides a pure product and is environmentally and technologically appropriate, but is not economical due to the solvent requirement of the reaction and the need for an inert gas atmosphere (Hungarian Patent No. 177,418).

In the case of reduction with alkali metal salts (nucleophilic exchange, potassium cyanide, sodium sulfide), environmental protection (water pollution, air pollution) was of particular concern (Hungarian Patent Nos. 198794 and 182763). Reductions in the acidic medium with metals and metal salts (U.S. Patent Nos. 182782 and 196,185) eliminated the need for sophisticated solvents and were performed in aqueous or aqueous organic solvents. However, the great difference between the redox potential of the metal / metal ion and the SS / S systems made it difficult to prevent some of the metal from being used for water decomposition, and to produce corrosive and unpleasant odor by-products in the acidic medium, and formed a sensitive thiol in an acidic medium, prior to the alkylation step, the thiol had to be recovered, deprotected from the metal salts, and rendered suitable for the propylation step by alkaline dissolution.

During these operations, some of the thiol could be re-oxidized and had to be purified.

Reduction has also been described by nucleophilic exchange, sulfur-containing organic compounds (Hungarian Patent No. 177,418), and systems made from alkali-sulfite and iodine (Hungarian Patent No. 1,929,773). No. 177,418, for the first time, discloses disulfides of formula (IV) and their reduction. According to one example of the Hungarian patent, the reduction with formamidine sulfinic acid is also described by a reduction method known per se. According to the known method (Synthesis 1975, 529531), disulfides can be reduced with formamidine sulfinic acid in the presence of phase transfer catalysts in an aqueous-organic solvent two-phase system to produce the corresponding thiols. According to the cited publication, the yield in a homogeneous system is significantly reduced or the reduction is barely achievable (30% yield for diphenylsulfide is mentioned). No. 177,418. According to the example of the Hungarian patent, the reduction is carried out in an ethanol suspension with an alcoholic solution of cetylpyridinium bromide or hexadecyl tributylphosphonium chloride under reflux under nitrogen for several hours, after which the crude compound of formula I is obtained in 79% yield. . Due to the long reaction time and high temperature, significant amounts of by-products (e.g., 2-amino-5-propylthiobenzimidazole, 5-propylthiobenzimidazol-one-2) are formed. This is because both the starting material and the thiol of formula (III) as an intermediate and its salt and the final product (I) are insoluble in the system and therefore both reduction and alkylation are carried out at the phase boundary and thus the the success and speed of the reactions in terms of diffusion rate, mixing intensity, particle size, etc. It depends. In addition, a significant amount of the disulfide of formula (IV) contaminates the final product, which results both from the unreacted starting material and from the oxidation of a portion of the thiol over a prolonged period of high temperature. It is not significantly helped by boiling the mixture under nitrogen as recommended in the literature. To the best of our knowledge, the method described in the order of a gram has not been enlarged due to the above disadvantages.

Our goal was to eliminate the remaining operational problems by improving the known procedures, which are already very advanced.

The present invention relates to a process for the preparation of methyl (5-propylsulfenylbenzimidazol-2-yl) carbamate of the formula (I) with the bis (2-methoxycarbonylaminobenzimidazol-5-yl) disulfide of the formula IV or its salt and propyl bromide by reaction with a compound of formula (V) or a salt thereof as a solvent in water at pH 7-14, preferably at 8-11 for 10-60 minutes at 20-50 ° C. - in the formula

R ¹ = NH or two hydrogen atoms,

R ² is -MH ₂ or -OH,

M is hydrogen, potassium or sodium ion moiety is propylated without isolation of the resulting 2- (methoxycarbonylamino) -benzimidazole-5-thiol of formula (III). In the present description, the variable substituents in the general formulas are always as defined above and are therefore not repeated.

The present invention is based on the discovery that the sulfur bond in the water-insoluble disulfide derivative (IV), which is practically insoluble in water, can be selectively and very rapidly cleaved by organic sulfinic acids in the absence of a phase transfer catalyst.

HU 207 302 B

In a preferred embodiment of the present invention, the reduction is carried out with a formamidine sulfinic acid of formula VI or a salt thereof. However, hydroxymethane sulfinic acid of formula (VII) or its salts are also very useful for the reduction.

The latter reagent has so far been used in the textile industry to disrupt disulfide bonds (CA. 415,312 f).

It is preferred that the sulfinic acid derivative (V) or its salt is freshly prepared prior to reduction and reacted directly without isolation.

The reduction is carried out at 20-50 ° C, preferably at 20-40 ° C. The pH range for the reduction is in the range of 7-14, most preferably the pH is in the range of pH = 8-11.

Particularly preferred is the method of reducing the final thiol or sodium salt thereof with propyl bromide, which is freshly prepared in the same reactor, directly to the final product in a single apparatus with very good yields.

From a technological, manufacturing point of view, it is very advantageous for the present invention that, due to the use of an aqueous solvent, the process can be carried out not only from the isolated and de-solvented disulfide compound IV, but also from the high water content of the crude product.

It is a further advantage that the sulfur-sulfur bond cleavage and dusting is performed in a single vessel without isolation of the thiol of formula (III).

It is also economically advantageous that the sulfinic acid derivatives of formula (V) can be readily formed and used without reduction for the isolation.

such ^as formamidine sulfinic acid of formula (VI) with thiourea and hydrogen peroxide in the reaction of the formula hydroxy methane sulfinic acid, formaldehyde (VI) and sodium dithionite is formed by reacting, without isolation, and then the same reactor, reacting the disulfide of formula (IV).

It is significant for the purity of the product that, due to the reductive medium, no reoxidation occurs after the cleavage of the sulfur-sulfur bond despite the alkaline pH. Thus the thiol of formula (III) or its alkaline salt remains stable in solution under operating conditions. This avoids the need to clean the end product of unwanted contamination. Our method does not require any special equipment, heat energy, is not corrosive, the environment is not polluting and it is easy to carry out.

Studying the reduction of the disulfide of formula (IV) drew our attention to the importance of quality. It has been found that the by-products of the incompletely performed chlorosulfonation reaction can cause confusion in the following. It is therefore advisable to dispose of by-products early in the synthesis. It has been found that one of the decisive moments of this is that the chlorosulfonation reaction proceeds perfectly in the desired main reaction and another important moment is that the disulfide of formula (IV) is optionally isolated from the system in the form of its salt.

Thus, in a preferred embodiment of the process, the starting material is the disulfide salt of formula IV prepared by preparing benzimidazole methyl carbamate of formula VIII with 4-5 moles of chlorosulfonic acid and 0.1-0.2 moles of phosphorus. Trichloride is quenched with the resulting chlorosulfonic acid derivative (IX) with water, the resulting aqueous suspension is reduced in the presence of iodide with alkaline hydrogen sulfite in the presence of iodide, and the disulfide salt of formula (IV) is isolated in crystalline form. The disulfide salt of formula (IV) is defined as at least 98% content.

It is also very advantageous for the purity of the final product to isolate the product of the formula I obtained after the propolisation of the thiol (III) in the form of its acid salt, dissolved in an alkanolic medium, preferably methanol.

The following examples illustrate the details of our procedure.

Examples

Example 1

Formamidine sulfinic acid (10.8 g, 0.1 mole) was dissolved in water (50 mL) and bis (2-methoxycarbonylaminobenzimidazol-5-yl) disulfide (35.5 g, 0.08 mole) was suspended in the solution for approx. For 1/2 hour. To the homogeneous suspension were added 70 ml of water and 153 g of 34.6% potassium hydroxide solution at 20-40 ° C. Within 30 minutes a clear solution was obtained. Proceeding as above but at 20 ° C, the reaction takes 60 minutes to dissolve. The solution was clarified using 1 g of charcoal, filtered and a solution of 23.6 g of propyl bromide in 70 cm ^{3 of} methanol was added to the crude straw yellow solution with stirring. The precipitation of the final product starts immediately, after approx. After stirring for 2 hours, filter, wash, and dry.

36.0 g (85%) of ethyl (5-propylthio-benzimidazol-2-yl) -carbamate melting at 211-213 ° C are obtained.

Example 2

To a mixture of 150 cin ^{3 of} water and 26.2 g (313 mg / cm ³ ) of hydrogen peroxide was added 7.6 g of thiourea at 8-15 ° C, and the excess hydrogen peroxide was quenched with aqueous sodium hydrogen sulfite until the negative iodine reaction. To this aqueous mixture was added 35.5 g of bis (2-methoxycarbonylaminobenzimidazol-5-yl) disulfide and the procedure described in Example 1 below was identical.

Example 3

To the aqueous mixture of the formamidine sulfinic acid of the previous example was added a crude wet bis (2-methoxycarbonylaminobenzimidazol-5-yl) disulfide (0.08 mol). In the following, the first two examples are followed by adjusting the total volume to 200 cm ^{3 with} water after adding potassium hydroxide. The result is the same.

HU 207 302 Β

Example 4

The procedure of Example 2 or 3 is followed up to the potassium hydroxide decomposition phase, but the reduction is carried out at 40 ° C.

Once a solution is obtained (about 10 minutes), propyl bromide is added with gentle cooling at 40 ° C over 15 minutes.

The product precipitates in crystalline form. After stirring at 20-25 ° C for a further 90 minutes, proceed as in Example 1. 40 g (94%) of crude methyl (5-propylthiobenzimidazol-2-yl) carbamate are obtained, from which 37 g of pure product are isolated by crystallization from acetic acid. The same result is obtained by recrystallization with formic acid.

Example 5

To 120 ml of water was added 22 g (34%) of formaldehyde solution followed by 22 g of sodium dithionite with stirring. The mixture was maintained at 25-27 ° C and had a pH of 8.6-8.7. It is made basic with 5 g of 42% potassium hydroxide solution and 35.5 g (0.08 mol) of bis (2-methoxycarbonylaminobenzimidazol-5-yl) disulphide is added, wet (40-60% moisture) ) in the form of a substance.

To the suspension cooled to 20 ° C is added 155 g of 42% potassium hydroxide solution at a temperature such that the temperature does not exceed 30 ° C. The resulting solution was clarified with 0.5 g of charcoal and filtered. A solution of 22.9 g (0.168 mol) of propyl bromide in 70 ml of ethyl alcohol was added to the filtrate with stirring at 30 ° C. The precipitate was filtered off, washed with potassium hydroxide in ethanol, water, formic acid water and then again with water to neutralize and dried.

g (86%) of methyl 5-propylthio (benzimidazol-2-yl) carbamate is obtained.

Example 6

In 140 ml of water was suspended 35.5 g (0.08 mol) of bis (2-methoxycarbonylaminobenzimidazol-5-yl) disulfide and 5 g of 42% potassium hydroxide, 22 g at 8-10 ° C. Formaldehyde (34%) solution and sodium dithionite (22 g) were added to the suspension. The temperature of the mixture rises to 15-17 ° C.

155 g of a 42% potassium hydroxide solution are added at 20 ° C. It is kept at this temperature for a further one and a half hours and then heated to 25 ° C. As a solution is obtained, the solution is clarified and filtered. In the following, the procedure of Example 5 is followed.

Example 7

A solution of 15001 water and 246 kg of 35% hydrogen peroxide was cooled to 0 ° C and 76 kg of thiourea were added with vigorous stirring and cooling with brine at such a rate that the temperature was between 15-20 ° C. With vigorous cooling, the addition takes 30 minutes. After resting for 30 minutes (no further analysis of thiourea by vrk analysis), excess hydrogen peroxide was decomposed by addition of sodium bisulfite. 311 kg of bis (2-methoxycarbonylaminobenzimidazol-2-yl) -disulphide are added in the form of a jug (40-60% humidity) and after 10 minutes suspension, 1060 kg of 50% potassium hydroxide are added. to the suspension without allowing the temperature to exceed 45 ° C. A solution is obtained within 30 minutes by adding a solution of 206 kg of propyl bromide in 560 kg of methanol cooled to 0 ° C over 30 minutes at 30-45 ° C. The precipitation of the final product begins immediately. Cool to 20 ° C, centrifuge, wash, and dry.

352 kg (95%) of (5-propylthiobenzimidazol-2-yl) methylcarbamate were obtained, m.p. 210-212 ° C.

The crude product, which contains mainly mechanical contamination, is purified by one-pass or acid-aqueous precipitation. Cleaning loss approx. 5%. M.p. 212-214 ° C.

Organic impurities <1% ash content <0.5% active ingredient (by perchloric acid titration or spectrophotometry)> 99.0%

Example 8

To 206 g of chlorosulfonic acid is added 45 g of methyl benzimidazol-2-ylcarbamate at 40 ° C, and after stirring for 2 hours, 5 cm ^{3 of} phosphorus dichloride is added. After stirring for another hour, it was cooled to 20 ° C and poured into 300 g of crushed ice. Sodium iodide (4 g) and cetyltrimethylammonium bromide (1 g) were added and an aqueous solution of sodium bisulfite (75 g) was added at 60-65 ° C. A solution was formed to which 1 g of Selecton B ₂ and 0.5 g of activated carbon were added and filtered. Addition of water and cooling to 0 ° C precipitates 66 g of crystalline bis (2-methoxycarbonylaminobenzimidazol-5-yl) disulfide sulfate dihydrate which decomposes at 265270 ° C.

Analysis:

Calculated: C, 37.3; H, 3.83; S, 16.64; Found: C, 37.07; H, 3.84; S, 16.10.

The product can be used directly for the reduction step without further purification, either directly in the wet (40-60% moisture content) or dried (Example 7). The fuged-wet albendazole thus prepared is suspended in methanol, taken up in 50% sulfuric acid solution, filtered and precipitated with ammonium hydroxide-methanol. It is washed with deionized water, covered with methanol and dried. 56 g of a high quality product are obtained, m.p. 212-214 ° C.

Example 9

To 1263 kg of chlorosulfonic acid was added 276 kg of methyl benzimidazol-2-ylcarbamate at 40 ° C, and after stirring for 2 hours, 48 kg of phosphorus trichloride were added. After stirring for another hour, it was cooled to 20 ° C and poured onto 1850 kg of crushed ice. Sodium iodide (24.5 kg) and cetyltrimethylammonium bromide (6 kg) were added and an aqueous solution of sodium bisulfite (460 kg) was added dropwise at 60-65 ° C. A solution is formed to which is added 6 kg of Electron B ₂ and 3 kg of activated carbon. After filtration, 800 kg of bis (2-methoxycarbonylaminobenzimidazol-5-yl) disulfide sulfate dihydrate was diluted with water and cooled to 0 ° C. Solids content 420 kg, m.p. 265-270 ° C (dec.)

HU 207 302 Β

analysis:

C: 37.3; H: 3.83; S: 16.64 (calc.)

C: 37.1 H: 3.84 S: 16.1 (Found)

A solution of 1500 liters of water and 246 kg of 35% hydrogen peroxide was cooled to 0 ° C and 76 kg of thiourea were added with vigorous stirring and cooling to a temperature of max. 20 ° C. Addition takes 30 minutes. After 30 minutes of rest, the excess hydrogen peroxide is decomposed by the addition of sodium bisulfite. 800 kg of fuganized wet bis (2-methoxycarbonylaminobenzimidazol-2-yl) disulfide sulfate dihydrate was suspended in the solution and after 10 1/2 hours, 1060 kg of 50% potassium hydroxide was added to the suspension at a temperature of do not rise above 45 ° C. After 30 minutes, a solution of propyl bromide (206 kg) and methanol (560 kg) cooled to 0 ° C was added over 30 minutes at 30-45 ° C. Product precipitates immediately. Cool to 20 ° C, centrifuge, wash. The jet-wet material (40-60% moisture content) was suspended in 1500 l of methanol and brought to a solution by addition of 95 kg of 50% sulfuric acid. It is filtered and the solution is adjusted to pH 6.8-7 with anunium hydroxide-methanol, the product is precipitated, washed with deionized water, covered with methanol and dried. 308 kg of high-quality methyl (5-propylthio-benzimidazol-2-yl) -carbamate melting at 212-214 ° C. Determination of drug content by perchloric acid titration or spectrophotometric determination 99%.

Foreign organic pollution is 1%.

Claims (8)

A process for the preparation of methyl (5-propylsulfenylbenzimidazol-2-yl) carbamate of the formula (I): bis (2-methoxycarbonylaminobenzimidazol-5-yl) disulfide of the formula IV or an organic sulfinic acid salt thereof. with propyl bromide, characterized in that the reduction is carried out in water at pH 7-14, preferably 8-11, at 10-60 ° C with a compound of formula (V) or a salt thereof. let's do it - in the formula R ¹ = NH or two hydrogen atoms, R ₂ is -NH ₂ or -OH, M is hydrogen, potassium or sodium, and the resulting 2- (methoxycarbonylamino) -benzimidazole-5-thiol of formula (III) is propylated without isolation. Priority: 1989.05. 18th Process according to claim 1, characterized in that the reduction is carried out with a formamidine sulfinic acid of the formula (VI) or a salt thereof. Priority: May 18, 1989 3. The process according to claim 1, wherein the reduction is carried out with a hydroxymethane sulfinic acid of formula VII or a salt thereof. Priority: 1989.05. 18th 4. A process according to any one of claims 1 to 3, characterized in that the sulfinic acid derivative of the formula (V) is used R ¹ , R ² and M are as defined above, or the salt thereof is prepared immediately before reduction and is reacted directly without isolation. Priority: 1989.05. 18th 5. Process according to any one of claims 1 to 3, characterized in that the disulfide (IV) is used in the form of a salt for the reduction. Priority: 21.03.1991 6. A process according to claim 5 wherein the sulfate salt of the disulfide is used. Priority: 21.03.1991 7. A process according to any one of claims 1 to 4, wherein the disulfide salt of formula (IV) is prepared by reacting benzimidazole methylcarbamate of formula (VIII) with 4-5 moles of chlorosulfonic acid and 0.1-0.2 moles of phosphorus trichloride. The reaction mixture containing the resulting chlorosulfonic acid derivative (IX) is quenched with water, the resulting aqueous suspension is reduced with alkali hydrogen sulfite in the presence of iodide, and the disulfide salt (IV) is isolated in crystalline form. Priority: 21.03.1991 8. Process according to any one of claims 1 to 3, characterized in that the product of the formula I obtained after the propolisation of the thiol (III) is isolated from the impurities present in the form of an acid salt thereof in an alkanolic medium, preferably methanol. Priority: 21.03.1991