DE2101853A1 - Process for the preparation of benzimidazole carbamates - Google Patents

Description

Process for the preparation of benzimidazole carbamates

The alkyl esters of 2-benzimidazole carbamic acids are suitable as fungicides and also as intermediates in the preparation of other 2-aminobenzimidazole fungicides, d. H. the Dialkyl esters of 1-carboxy-2-benzimidazole carbamic acids according to USA patent 2 933 504- ·

U.S. Patent 3,010,968 describes a process for preparing alkyl esters of 2-benzimidazole carbamic acid by reacting thiourea with dimethyl sulfate to form 2-methylthiopseudourea sulfate. This reaction product is then treated with an alkyl chloroformate and base to form an acylated 2-methylthiopseudourea which is then further reacted with an o-phenylenediamine in the presence of a protonic acid to form the desired compound.

The Belgian patent specification 706 519 describes another process for the preparation of these alkyl esters, in which one

- 1 -109831/2226

Cyanamide or a cyanamide salt with an alkyl chlorofonate in a weakly acidic to basic medium at one temperature between 0 and 105 ° C to form an alkyl cyano carbamate salt reacted, which then with an o-phenylenediamine in an acidic medium at a temperature between 40 and 150 ° C is implemented to form the desired product.

There has now been a process for making alkyl esters the 2-benzimidazole carbamic acid of the formula

found in which R is alkyl having 1 to 4 carbon atoms and Y is hydrogen, halogen, nitro or alkyl having 1 to 4 carbon atoms is.

In this process, cyanamide is first used with mercaptan of the formula R ^ SH, in which R ^ is alkyl of 1 to 4 carbon atoms is converted to a pseudothiourea. The pseudothiourea is made with alkyl chlorofonate of the formula R-OCOCl implemented, wherein R has the above meaning. This reaction is carried out at a pH of 4-9 and gives an acylated pseudothiourea.

The acylated pseudothiourea is then combined with o-phenylenediamine of the formula

1Q9831 / _£ 226

implemented, wherein Y has the above meaning, this stage, which is carried out at a pH of 5 to 8, for Formation of the desired alkyl 2-benzimidazole carbamate and of a mercaptan of the formula ILSH.

The mercaptan obtained can, if desired, be recycled be returned to the first stage.

The method according to the invention offers compared to previous ones Methods for the preparation of alkyl esters of benzimidazole carbamic acids, in particular the process according to U.S. Patent 5,010,968, various advantages. First, the use of toxic dimethyl sulfate is avoided. ™ Second, you can by-product mercaptan from the third Recycle stage and again as starting material in the first stage of the next production batch use and thus achieve economic efficiency with regard to the raw materials and also a serious problem, the elimination an extremely unpleasant material.

Another advantage of the process according to the invention lies in the fact that all three reactions convenient means in a single container of a simple succession of output product additives without intermediate manipulations, such as extraction M tion or filtration can be performed.

The invention thus provides for the three-stage reaction of an alkyl mercaptan, an alkyl chloroformate and a ring-substituted or unsubstituted o-phenylenediamine. These three stages can be explained as follows:

109831/2226

2863-G

1) H ₉ NCTlN + E. SH + HX -> H ₀ NC-NH ⁺ _o . X "

2)

+ C1-C-OR + 2 MOH - ^ HgNC-NC-OR + MCl + MX + ^ O

3) H ₀ NC-NC-OR +

<- It

O H »

N-C-OR + R SH + NH X 1

In here is

E ₁ alkyl with 1 to 4 carbon atoms, R alkyl with 1 to 4 carbon atoms, X Cl, Br, 1/2 SO ₄ , 1/3 PO ₄ ,

O OO

EC-O, H ₂ -NSO ₂ O, HC-O or HOCHgC-O,

M alkali or alkaline earth metal and

Y is hydrogen, halogen, nitro or alkyl having 1 to 4 carbon atoms.

In the first stage, cyanamide is mixed with the mercaptan, preferably in the presence of an equivalent amount of acid, e.g. £. HCl, HBr, CH ₅ COOH, H ₂ SO ₄ and the like, including the salt

«. 4 109831/2 226

2863-G $ 210185 °

of the S-alkylisothiourea intermediate (a pseudothiourea) implemented. This rapid reaction stage also takes place in the absence of acid with the formation of S-allylthiopseudourea. Implementation of cyanamide with a mercaptan in water or alcohol is described in British Patent 296,782.

The reaction can take place in an alcoholic or aqueous medium or in a mixture of water and alcohol, the alcohol containing 1 to 4 carbon atoms, preferably methyl or ethyl alcohol. The pH value μ

this reaction should generally be between about 6 and 11, preferably 8 and 10.

The starting materials for this are 50% aqueous cyanamide commercial or 100% cyanamide crystals.

Suitable mercaptans are those of the formula B ,, SH, where E ^. Is alkyl of 1 to 4 carbon atoms.

The acids include inorganic acids in the form of HCl, Η, ΡΟ ^ and ^ SO ^ or organic acids such as sulfamic, formic, acetic and propionic acids. \

The concentration of the starting materials in the reaction mixture is not critical, but high concentrations will usually be chosen for economic reasons. The concentration of the cyanamide in water or alcohol can be in the range from 5 to 65 % , and since cyanamide is now commercially available as a 50% aqueous solution, such a solution is preferably used.

The temperature and pressure of the first stage are not critical within comfortable working ranges} usually a temperature between 0 and 60 ° C and a pressure close to atmospheric pressure will be preferred. The choice of these conditions

1 0 9 & M / 2 2 2 6

gen depends in part on the volatility of the mercaptan used. It is only necessary that the conditions are favorable for an adequate concentration of mercaptan in solution and thus an adequate reaction rate is possible. If desired, this stage can be carried out at higher temperatures up to 100 ° C, but in the case of the more volatile mercaptans, such as methyl and ethyl mercaptan, one must apply pressure to get enough mercaptan keep in solution.

The order in which the ingredients are added is not critical, but there is less tendency for cyanamides to dimerize if the cyanamide is gradually converted into the mercaptan instead of the other way around. The reaction is rapid and the product is stable in the reaction medium; the reaction time is therefore not critical, and the product can be used directly in the second stage or a Time to be left to itself. In general, the reaction time can vary depending on the rate of heat transfer 1/2 to $ hour.

The molecular ratio of mercaptan to cyanamide should preferably be in the range from 1.0 to 2.0, in particular more preferably Wise 1.05 to 1.2, so that there is a sufficient excess of mercaptan to the reaction in reasonable Time to drive to completion, while time, heat and cooling, which one does not convert to recovery Mercaptans are required, are not inflated.

In the second stage, the solution of the intermediate product alkyl chloroformate and alkali metal or alkaline earth metal hydroxide as the base are added to the solution of the intermediate product obtained in the first reaction. The alkali hydroxide is added as an aqueous solution at the same time as the alkyl chloroformate, in order to keep the pH of the solution in the preferred range of 4 to 9 * .

1 0 9 <! i 1 / ^ ζδ

7 to 9 1 hold. On the other hand, instead of the alkali metal hydroxide, an alkaline earth metal hydroxide can be added as an aqueous slurry simultaneously or alternately with the alkyl chloroformate or in finely divided solid form all at once at the beginning or intermittently during the addition of the alkyl chloroformate.

The temperature in the second stage is not critical and is in the range from 0 to 105 ° C, in general a range of 25 to 60 ° C is preferred.

The reaction occurs rapidly, and the product is stable in the reaction medium tion%. Thus, the time is not decisive, and the product can be used directly in the third stage or a time can be left to itself. The reaction time generally depends on the rate of heat transfer and can generally be from 5 minutes to 2 hours.

The base concentration is not critical. It is possible to work with concentrations of 5 to 60 % , a range of 25 to 50 % being preferred. For economic reasons, the bases used are preferably sodium, potassium or calcium hydroxide. A.

In the third stage, 0.5 to 2, preferably Λ molecular equivalents of o-phenylenediamine are added to the reaction product of the second stage, it being possible for the addition to take place gradually or all at once and also while the product of the second stage is at its reaction temperature .

To carry out the condensation and the ring closure and the simultaneous release and recovery of alkyl mercaptan during the third reaction you should adjust the pH by adding acid in the loading

109 831/2226

range from 1 to 7, preferably 2.5 "to 4.5, hold. The The pH value can be kept in the desired range by adding any acid, e.g. B. Ant, vinegar, salt, Sulfuric, phosphoric, hydroxyacetic acid and the like · If desired, the o-phenylenediamine can be in the form of a Add mineral acid salt as a solid or melt or as a solution in water. When using o-phenylenediamine salts the amount of acid required to achieve the desired pH is reduced accordingly.

The third reaction occurs at temperatures above 40 ° C. Preferably, the propellant is heated during this stage the implementation to the full process by driving off the released mercaptan. The heat input is important because the implementation of the deräritten_ level at would be too slow at low temperatures. The J reaction mix should gradually be brought to reflux temperature, preferably 60 to 105 ° C. The third reaction stage can also be carried out under pressure or reduced pressure, if so desired. When working under pressure, the temperature can rise to 130 ° C. The flow management continues until mercaptan no longer evolves.

The desired product precipitates during the heating stage. The completeness of the precipitation is thus also an indication that the reaction mixture has been heated long enough for the reaction to be complete. The time is not critical and depends on temperature and pH. For example, the reaction time at a pH of 2.5 to 4.5 and a temperature between 70 and 105 ° C can be 5 to 5 minutes. When working at lower temperatures, the time is longer, and if a pH value in the range from 1 to 7 is not maintained, a very slow reaction or no reaction at all will be obtained.

1098 31/2226

Han can then obtain the desired product using any of the conventional working methods, e.g. B. by spray drying, Filter or spin, or transfer to another liquid medium by distilling off the water.

During the heating step, the alkyl mercaptan separates from the carbamic acid molecule as a vapor. It leads the steam and water and also, if present, contains alcohol, an appropriately-cooled condenser to and collects the condensate and uses it to provide the Mercaptanbedarfs the first reaction of the next process duktxonsansatz m. If desired, the mercaptan obtained can be distilled in order to remove alcohol and water, which would otherwise have to be recycled, or to reduce their quantities. If a volatile acid such as hydrochloric acid or formic acid is used in the third stage, some of this acid can also be present in the condensate. This acid can, if desired, be neutralized with alkali metal hydroxide, but this is not a requirement.

The following examples in which, parts, if not different said, parts by weight are used for further explanation j

of the advantages according to the invention. M.

example 1

A reaction vessel is charged, with agitation, with 74-5 parts of ethyl mercaptan and 10 parts of water, whereupon 100 parts of a 50% strength by weight solution of cyanamide in water are slowly added. The pH is kept in the range from 8 to 9 by adding 37% strength aqueous hydrochloric acid and the temperature is kept at 35 to 37 ° C., the temperature of refluxing ethyl mercaptan. The reaction is complete when all of the cyanamide solution has been added and no further acid addition is necessary to adjust the pH

109831/2226

to hold on 9 * 00. You need to fully implement it 80 min.

Then the pH value is lowered to 1.5 by adding more acid. The product mixture is heated to a small To distill off the amount of unreacted ethyl mercaptan, which is condensed and recovered.

The pH is then adjusted to 7 and then, in the course of 55 minutes, methyl chloroformate is added in an amount of 125.5 parts. The pH value is increased to 7 by the simultaneous addition of 50% sodium hydroxide solution and the temperature is kept at 55.degree. After the addition of the methyl chloroformate, the reaction mass is heated for a further 10 minutes with stirring, at the end of this period it can be seen that no further reaction takes place, since no further addition of sodium hydroxide is required to keep the pH constant at 7.

The reaction mass is cooled to 23 ° O ₁ , 130 parts of o-phenylenediamine are added, the pH is adjusted to 4 by adding 37% strength aqueous hydrochloric acid while gradually increasing the temperature to 94 ° C, and the ethyl mercaptan which is formed is condensed and collected. collects the benzimidazole carbamate which precipitates out of the solution on a filter, washes with hot water and then cold acetone and subjects the product to vacuum drying (dry weight 117 »7 parts). The ethyl mercaptan obtained, to which a small amount of additional mercaptan is added to compensate for manipulatory losses, serves as the starting material for the production of another approach.

Example 2

A reaction vessel is charged with agitation with 74.5 parts ethylmercaptan, after which in the course of

-10 -

10983 1 /? 226

2863-G '^ 21 ol

37 min. Gradually add a solution containing 50 parts of cyanamide, 25 parts of ethanol and 25 parts of water. The pH value is kept between 7 and 9-5 by adding hydrochloric acid. In the same way as in Example 1, this reaction is completed and methyl chloroformate is added.

119 parts of o-phenylenediamine are now added, which increases Temperature with the gradual addition of hydrochloric acid to maintain a pH value of 2.9 to 4.5 at 93 »5 ° C and the product precipitated from the solution (108 parts) is recovered as in Example 1 by filtering, washing and drying. ^ j The ethyl mercaptan by-product is condensed separately and used as a component for a subsequent preparation of the methyl ester the benzimidazole carbamic acid used.

Example 3

A reaction vessel is charged with 50 parts of ethanol and 79 parts of methyl mercaptan with agitation, whereupon a cyanamide solution containing 63 parts each of cyanamide and water is gradually added over the course of 5 hours and during this period the pH is adjusted by adding 50% iger, aqueous sulfuric acid between 9 »0 and · 10.0. J After a constant pH value ™ without the addition of any acid shows that the reaction has stopped, the mixture consisting of a slurry of white crystals in a clear solution is heated to 40 ° C to drive off unreacted mercaptan into a cold storage tank, which is collected after cooling to 0 ° C the crystals on a filter, washed with a little ethanol and air-dried, 140.5 g crystals of 2-methylpseudothiourea sulfate with a melting point of 246 ° C are obtained. After evaporation of the filtrate and washing , a further yield of 15.7 6 of product is obtained.

- 11 -

10 9 8 3 1 /? 2 7 6

A 139 ml portion of the above intermediate is slurried in 100 parts of water and treated with 106 parts of methyl chloroformate at pH 7 and 48 to 55.degree in the manner described in the previous examples.

The mixture is cooled to 80 ° C. and 108 parts of o-phenylenediamine are added. While gradually increasing the temperature to 92.5 ° C., the pH is controlled with hydrochloric acid in the range from 1.4 to 5 »0. If no further methyl mercaptan condensate is obtained in the cooled condenser, the slurry is cooled and the product is cooled (129 Λ parts) isolated as in the earlier examples.

Example 4

This example explains an optional embodiment of the first process stage according to the invention. The product this stage can be implemented further in the manner described above.

A stirred tank equipped with pH probes is charged with 77.6 parts of cyanamide and 42.7 parts of water. Of the The pH of this mixture is 6.5. After cooling to 3 ° C., 94.5 parts of methyl mercaptan and 67 are added at the same time Parts of 20% hydrochloric acid are added while the pH is kept between 3 and 9 »5 and the reaction temperature is kept below 28 ° C will. The acidic reaction mixture (pH 3) is evaporated to dryness in vacuo, 61 parts of 2-methylthiopseudourea, M.p. 72 to 76 ° C; Product yield 79.5 #, based on cyanamide.

Example 5

A correspondingly equipped reaction flask is charged with 77.6 parts of oyanamide and 42.7 parts of water . The mixture is cooled to 3 bis with stirring

- 12 109 8 31/2226

5 ° C and simultaneously pour 124 parts of methyl mercaptan into the flask and 130 parts of 20% hydrochloric acid to bring the pH to 6 to 9 and the temperature between 3 and 9 ° C to steer. After acidifying the reaction mixture, the temperature is increased to 20 ° 0 and excess methyl mercaptan is left escape, which is cooled and recovered in liquid form.

94.4 parts of methyl chloroformate and 121 parts of 50% strength sodium hydroxide solution are added to this aqueous solution of 2-methylthiopseudo-urea. The pH of the solution is kept between 6 and 8 by regulating the supply of hydroxide, while the reaction temperature is kept below 55 ° C. by cooling from the outside. After this addition, 55 parts of o-phenylenediamine are added and the pH of the reaction mass is continuously adjusted to 3 to 5 with 37% strength hydrochloric acid, the temperature being gradually increased to 95.degree. After the addition of 89.5 parts of 37% hydrochloric acid, the pH of the reaction mass stabilizes at 4. The product slurry becomes 30 to 60 Hin. kept at pH 4. During the addition of acid and the residence time, methyl mercaptan is released, which is condensed and recovered. After cooling the reaction mass to 40 ° C., the pest product is filtered off, washed with water and dried. The yield obtained is 40.6 parts of the methyl ester of 2-benzimidazole carbamic acid or 73 »8 #» based on the o-phenylenediamine used . The product identified by NAT and IR analysis shows a purity of over 99 % - (NAT non-aqueous titration)

Example 6

The excess methyl mercaptan released and recovered after formation of the 2-methylthiopseudourea in Example 5 and methyl mercaptan released and recovered during the addition of o-phenylenediamine and acid is used in the

- 13 -

10 9 8 31/2226

Recirculation to a basic approach ^> 0% ± ger cyanymide solution in order to form 2-methylthiopseudourea in situ. To this, methyl chloroformate and alkali are added in the same way as in Example 5 and then, with appropriate pH and temperature control, o- Phenylenediamine and acid. The amount of methyl ester of 2-benzimidazole carbamic acid obtained corresponds to Example 5.

Example 7

The following samples are prepared according to the procedure of Example 1, the alkyl chloroformate, reaction medium, acids and base for pH control and mercaptan corresponding to the following table. The amounts of the starting materials correspond to those of Example 1 on a molecular basis.

109831/2226

OO CaJI

Reaction medium Mercaptan Tabel I. ■ in stage 3 IV)
Oa • i pH handlebar 2 CH ₂ COOH C?
VX sample water CH ₂ SH Alkylchlor 1 LiOH HBr Q Methanol CH ₂ SH formate CH ₂ COOH LiOH HgSO ₄ 1 Water plus methanol CH ₂ SH Methyl- HBr KOH HCl 2 Ethanol CgH ₅ SH Methyl- HgSO ₄ KOH HCl 3 water C ₂ H ₅ SH Methyl- HOCHgCOOH KOH H ₂ SO ₄ 4- Methanol CH ₃ SH Methyl- H ₃ PO ₄ NaOH H ₃ PO ₄ 5 water C ₃ H ₅ SH Ethyl HCl NaOH H ₂ SO ₄ 6th Isopropanol CH ₃ SH Butyl H ₃ PO ₄ NaOH HgSO ₄ 7th i-butanol CgH ₅ SH Methyl- HgSO ₄ NaOH HCl 8th water CgH ₅ SH Methyl- HgSO ₄ Ca (OH) ₂ HCl 9 water C ₄ H ₉ SH Butyl HCl KOH HCl 10 water CH ₂ SH Methyl- HCl NaOH 11 Methyl- NHgSO ₂ H 12th Ethyl

Claims (1)

Claims Y is hydrogen, halogen, nitro or alkyl with "1 to 4 Carbon atoms is characterized in that one a) Oyanamide with a mercaptan of the formula E ^ SH, in which E ,. Is alkyl of 1 to 4 · carbon atoms converts a pseudo thiourea, b) the pseudothiourea with alkyl chloroformate of the formula E-OCOCl, where E is alkyl of 1 to 4 carbon atoms, is reacted at a pH of 4 to 9 to an acylated pseudothiourea and c) the acylated pseudothiourea with o-phenylenediamine of the formula wherein Y is hydrogen, halogen, nitro, or alkyl of 1 to 4 carbon atoms, at pH - 16 - 109831/2226 converts from Λ "to 7 to the alkyl 2-benzimidazole carbamate. 2. The method according to claim 1, characterized in that cyanamide and mercaptan in the presence of acid, in particular acid from the group of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, sulfamic acid, formic acid, HOCHgCOOH or II ₅ COOH, where H, alkyl with 1 to 4 · carbon atoms is converted. 5. The method according to claim 1 or 2, characterized in that ' net that the reaction in stage (a) is carried out at from 0 to 100.degree. 4 ·. The method according to one or more of claims 1 to 3, characterized in that in step (b) for Maintaining the pH base begins. 5 · Method according to one or more of claims 1 to 4 ·, characterized in that the Eeaktion in stage (b) is carried out at Ö to 105 ° C. 6. Method according to one or more of Claims 1 to M 5, characterized in that in stage (c) to Maintaining the pH value acid sets in. 7. The method according to one or more of claims 1 to 6, characterized in that the reaction in stage (c) is carried out at 40 to 130 ° C. 8. The method according to one or more of claims 1 to 7, characterized in that one gains the obtained in stage (c) mercaptan, run in particular in the circuit for use in step (a) leads back. - 17 - _n 109 8 31/2226 ²⁸⁶⁵ - ^G. 9 · A method according to one or more of claims 1 bit 8, characterized in that one works with Y equal to hydrogen and R is methyl. 10. The method according to claim 1 for the preparation of the methyl ester of 2-benzimidazole carbamic acid, characterized in that cyanmide with methyl or ethyl mercaptan at a molar ratio of mercaptan to cyanamide of 1.05: 1 to 1.2: 1 in the presence of one of the maintenance a pH of 8 to 10 corresponding amount of hydrochloric acid at a temperature of 0 to 60 ° C, the methyl pseudothiourea thus obtained with methyl chloroformate and the maintenance of a pH between 7 and 9 corresponding amount of sodium or potassium hydroxide at a Temperature between 25 and 60 ° C and the resulting methyl ester of methylpseudothioureacarboxylic acid with o-phenylenediamine and a maintenance of the pH in the range from 2.5 to 4.5 amount of hydrochloric acid at a temperature between 60 and 105 ° C implements. - 18 - 109831/2 ^ 26