DE2332323A1 - N-2-aminophenyl N'-alkoxycarbonyl S-alkylisothioureas - prepd. by reacting N-(chloromercaptomethylene)carbamic acid esters with amines - Google Patents

Abstract

Substd. N-2-aminophenyl N'-alkoxycarbonyl S-alkylisothioureas of formula (I): (where X = H is not >6C alkyl or benzoyl; R = is not >12C alk(en)yl, 8C cycloalkyl, or aralkyl opt. substd. with lower alkyl, lower alkoxy and/or halogen; R1 = is not >4C alkyl; R" = H, 18C alkyl (opt. substd. with halogen, cyano lower alkoxy(carbonyl),(halo)phenoxy, lower alkylphenoxy or -alkoxyphenoxy) 8C cycloalkyl, aralkyl with is not >2C alkyl gp. (opt. substd. with halogen, lower alkyl or -alkoxy) furyl, or -NR'''R''''; R''' = H or 4C alkyl R'''' = H is not >18C alkyl (opt. substd. with halogen, cyano or lower alkoxy (carbonyl), is not >8C cycloalkyl, aralkyl with is not >2C alkyl with is not >2C alkyl gp. (opt. substd. with halogen, cyano or lower alkoxy (carbonyl), is not >8C cycloalkyl, aralkyl with is not >2C alkyl gp. (opt. substd. with halogen, lower alkyl, or -alkoxy), phenyl (opt. substd. with halogen, lower alkyl or -alkoxy), aroyl (opt. substd. with halogen or lower alkoxy) arylsulphonyl (opt. substd. with halogen, amino, lower alkyl or -alkoxy) or 4C dialkylamino and R''' + R'''' + N may form a 4-7 membered heterocyclic rihg which may also contain O or S atoms) are prepd. by reacting a cpd. (II): in the presence of an equiv. quantity of acid-binding agent and in inert solvent. (I) have fungicidal and anthelmintic activity.

Description

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Slr / HM ⁵ O ⁹ Leverkusen. Bayerwerk

^{IV a} 2 * June 1973

Process for the preparation of substituted N-2-aminophenyl-N'-alkoxicarbonyl-S-alkyl-isothioureas

The present invention "relates to a chemically peculiar one Process for the preparation of partially known substituted N-2-aminophenyl-N'-alkoxicarbonyl-S-alkylisothioureas, which are known to be used as fungicides. The use of individual according to the invention producible, so far not yet described compounds as anthelmintics is already the subject of a older right.

It has already become known that substituted N-2-aminophenyl-N'-alkoxicarbonyl-S-alkyl-isοthioureas are obtained if substituted N-2-aminophenyl-N ¹ -alkoxicarbonylthioureas are reacted with alkylating agents (see also the German Offenlegungsschriften 2,025,412 and 2,025,413 and similar British patents 1,308,101 and 1,304,655). The thioureas required are obtained in accordance with the state of the art from the corresponding amines and mustard oils (described in German Offenlegungsschriften 1,960,027 and 1,960,029; cf. also US Pat. No. 3,720,682).

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The known sequence of syntheses corresponding to the state of the art is shown by an example:

+ S = C = N-CO-OC ₀ H ₁

NH-CO-CH.

NH-C-NH-CO-OC ₀ H NH-CO-CH

+ CH ₃ I + NaOH

-NaJ -H ₂ O

S-CH ₃
. .N = C-NH-CO-OC ₂ H ₅

NH-CO-CH,

However, this process has a number of disadvantages: Although the sulfur alkylation of the thioureas generally proceeds smoothly and gives good yields, the purity of the product is largely determined by the quality of the thiourea used. The latter is difficult to obtain in pure form when converting the amines and mustard oils. Mustard oils are relatively unstable compounds, which can only be isolated in small quantities, which is why they are prepared for further reactions from alkali metal rhodanides and chloro ant esters in inert solvents and immediately reacted with the amines without being isolated. Because of the instability of the mustard oil and the incomplete conversion of the rhodanide with the chloro ant ester, you have to work with a considerable excess of rhodanide and chloro ant ester, usually around 100 %. First of all, this means a technically and economically highly undesirable waste

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of the two chemicals. However, it is serious in addition to the already indicated contamination of the thioureas. The sparingly soluble Polyrhodane, which as Decomposition products arise, as well as excess rhodanides, which are carried away by the precision of the end product, pollute namely the product in terms of its use as a fungicide in agriculture significantly, in particular because rhodanides are herbicidally active substances (cf. Wegler, "Chemistry of Plant Protection and Pesticides", Volume _2, page 193, Berlin-Heidelbeig-New-York (197O)) in a fungicide can cause undesirable phytotoxic side effects. For the anthelmintic in humans and animals For products to be used orally, exposure to by-products is, of course, all the more unacceptable. A cleaning the thioureas is by reprecipitation or recrystallization because of the extraordinary solubility of these compounds on an industrial scale only very difficult to carry out; The isothioureas obtained from the thioureas are also poorly soluble compounds.

These numerous disadvantages make it appear desirable to develop a process which allows the synthesis of the Isothioureas from the amines bypassing the thioureas allowed.

It has now been found that the partially known substituted N-2-aminophenyl-III '-alkoxicarbonyl-S-alky! -Isothioureas can be used the formula

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SR
^ N = C-NH-CO-OR '

NH-CO-R "

in which

X stands for hydrogen, alkyl with up to 6 carbon atoms and for benzoyl,

R for alkyl and alkenyl with Ms each 12 and for cycloalkyl with up to 8 carbon atoms and for aralkyl (optionally substituted in the aryl part by lower alkyl, lower alkoxy and / or halogen),

R ^{1 represents} alkyl with up to 4 carbon atoms, and

R "represents hydrogen and alkyl of up to 18 carbon atoms (optionally substituted by halogen, cyano, lower alkoxy, lower alkoxycarbonyl, phenoxy, halophenoxy, lower alkylphenoxy, Lower alkoxyphenoxy), also for cycloalkyl with up to 8 carbon atoms, for aralkyl with up to 2 carbon atoms in the alkyl part (optionally on the nucleus by halogen, lower alkyl, Lower alkoxy substituted, for aryl (optionally substituted by halogen, lower alkyl, Lower alkoxy) and for puryl, furthermore for the group

^ R " ¹
^ R " ¹

is where
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R " ^{1 stands} for hydrogen and alkyl with up to 4 carbon atoms and

Run stands _for hydrogen and alkyl with up to 18 carbon atoms (optionally substituted by halogen, cyano, lower alkoxy, lower alkoxycarbonyl), furthermore for cycloalkyl with up to 8 carbon atoms, for aralkyl with up to 2 carbon atoms in the alkyl part (optionally substituted on the nucleus by halogen, lower alkyl , Lower alkoxy), for phenyl (optionally substituted by halogen, lower alkyl, lower alkoxy), for acyl with up to 18 carbon atoms (optionally substituted by halogen, lower alkoxy), for aroyl (optionally substituted by halogen, lower alkyl, lower alkoxy), for aryl sulfonyl (optionally substituted by halogen, amino, lower alkyl, lower alkoxy) and for dialkylamino with a total of up to 4 carbon atoms, and furthermore

R " ¹ and R""together with the connecting nitrogen atom can also stand for a heterocycle with 4 to 7 carbon atoms, where the ring can also optionally contain oxygen or sulfur as further heteroatoms,

obtained when amines of the formula

II -CO-R "

in which

X and R "have the meaning given above,

with N- (chloro-mercapto-methylene) -carbamic acid esters Le A 15 113 - 5 -

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the formula

R-S.

X) = N-CO-OR '

III

in which

R and R ^{1 have} the meaning given above,

in the presence of a diluent and an at least equivalent amount of an acid binder at temperatures between -10 and 100 C.

It can be described as extremely surprising that the new synthesis of the isothiureas of the formula I is good Yield and high purity supplies; Surprising, because the chlorine of the carbamic acid ester only selectively in the reaction occurs in reaction, although analogous substitutions of the mercapto group by amines have become known in similar syntheses (see U.S. Patent 3,562,290). This risk of side reactions by substituting the mercapto group of the Carbamic acid esters of the formula III is particularly clear when using those esters of the formula III in which R '= aryl. If, for example, 2-aminoacetanilide and N- (chloro-2-phenylmercaptomethylene) carbamic acid methyl ester are left according to the following equation react with one another in the presence of a diluent and a base, the corresponding one is obtained even under mild reaction conditions Benzimidazole derivative:

2 + NH-CO-CH.,

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C = N-COOCH

Cl

! -CO-OCH,

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Show the limits that are imposed on the new process as a function of the substituents on the reactants thus clearly the chemical peculiarity of the process, which could not be foreseen in its surprising course.

The new process offers a number of technical advantages: With its help, the isothioureas are obtained in high yields and in a pure form, in particular free from additions which are directly harmful for their subsequent use. The process also allows the technically readily available starting materials to be used in an economical way Way, with excess waste being avoided by the approximately stoichiometric conversion.

Use 2-aminoacetanilide and methyl N- (chloromethylmercaptomethylene) carbamic acid as starting products, the course of the reaction can be represented by the following equation:

NS,

C = N-CO-OCH,

NH-C = N-CO-OCH,

+ HCl

NH-CO-CH.

The amines to be used as starting materials are by the Formula II generally defined. In this formula, X preferably stands for hydrogen, for alkyl with up to 4 carbon atoms, especially for methyl and butyl, and for benzoyl; R "preferably represents alkyl of up to 5 Carbon atoms, optionally preferably substituted

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by methoxy, ethoxy, phenoxy and chlorine, furthermore preferably for cycloalkyl with up to 6 carbon atoms, for phenylmethyl, phenylethyl, then preferably for Phenyl, Tolyl, Chlorophenyl, Methoxyphenyl, and Furyl for the group

.R "'
-TST
\

RUH "

In the latter, R " ¹ preferably represents hydrogen, methyl and ethyl; R""preferably represents alkyl with up to 6 carbon atoms, optionally substituted, preferably by cyano, methoxy and ethoxy, further preferably benzyl and phenyl. Preferred R" - Substituents may be mentioned in particular: methyl, ethyl, n-propyl, iso-propyl, η-butyl, iso-butyl, iso-amyl, cyclopentyl, cyclohexyl, benzyl, phenoxymethyl, phenyl, p-tolyl, methylamino, propylamino-butylamino, - ur-Cyanpentylamino, 2-Methoxyäthylamino, 3-Äthoxypropylamino, Benzylamino, Phenylamino.

As examples of the amines to be used according to the invention of formula II are:

2-aminoacetanilide

2-aminopropionanilide

2-aminobutyranilide

2-aminoisobutyranilide

2-amino-cyclohexylcarbonanilide

2-Amino-phenoxyethylanilide

2-amino-benzanilide

2-amino (p-chloro-benz) anilide

2-Amino-4-n-butyl-acetanilide

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2-Amino-4-n-butyl-propionanilide 2-Amino-4-n-butyl-butyranilide 2-Amino-4-n-butyl-isobutyranilide 2-Amino-4-n-butyl-cyclohexylcarbonanilide 2-Amino-4- n-butyl-phenoxiacetylanilide 2-amino-4-n-butyl-benzanilide 2-amino-4-n-butyl- (p-chlorobenz) -anilide 2-amino-phenylurea N-2-aminophenyl-N ¹ -methylurea N-2-aminophenyl-N ', N'-dinethylurea N-2-aminophenyl-N'-buty-urea N-2-aminophenyl-N ¹ -octylurea N-2-aminophenyl-N ¹ -dodecylurea N-2-aminophenyl -K ^l -tnP-cyanophenylurea N-2-aminophenyl-N'-2-methoxy-ethylurea N-2-aminophenyl-N ¹ -benzylurea N-2-aminophenyl-N ¹ -phenylurea N-2-aminophenyl-N ¹ , N ¹ -tetramethyleneurea N-2-aminophenyl-N ¹ -acetylurea N-2-aminophenyl-N'-benzoylurea N-2-aminophenyl-N ¹ -p-toluenesulfonylurea 2-amino-4-benzoyl-acetanilide 2- Amino-4-benzoyl-propionanilide 2-amino <-4-benzoyl-butyranilide 2-amino-4-benzoyl-isobutyranilide 2-amino-4-benzoyl-valeranilide 2-amino-4-benzoyl-iso-valeranilide 2-amino- 4-benzoyl-capronane ilid 2-Amino-4-benzoyl-iso-capronane ± lid 2-amino-4-benzoyl-cyclopentancaΓbonanilid 2-amino-4-benzoyl-cyclohexanecarbonanilide 2-amino-4-benzoyl-phenylacetanilide 2-amino-4-benzoyl-phenoxyacetanilide

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2-amino-4-benzoyl-benzanilide

N- (2-Amino-4-benzoy1-phenyl) -N'-methyl-urine t of f N- (2-Amino-4-benzoy1-phenyl) -N'-ethy1-urine toff N- (2- Amino-4-benzoy 1-phenyl) -II '-buty1-urine N- (2-Amino-4-benzoyl-phenyl) -N' -uj-cyanpenty 1-urine N- (2-Amino-4- benzoy1-phenyl) -N'-ß-methoxyethy1-urea N- (2-Amino-4-benzoyl-phenyl) -N ^l -benzyl-urea N- (2-amino-4-benzoyl-phenyl) -II '-pheny 1-urine toff

The amines to be used as starting materials are for Part known (see Beistein's "Handbuch der Organic Chemie", Volume 13, Pages 20-32, Berlin (1930); Volume 13,

1st supplementary work, pages 8-10, Berlin (1933); Volume 13 «

2. Supplementary work, pages 14-23, Berlin-Göttingen-Heidelberg (195O)); still new connections can just as well as the known ones can be prepared by reducing the nitro compounds, using standard laboratory procedures (e.g. reduction with nasal hydrogen, obtained from tin or iron and hydrochloric acid).

The N- (chloro-mercaptomethylene) -carbamic acid esters to be used as starting materials are generally defined by the formula III. In this formula, R preferably represents alkyl and alkenyl with up to 6 carbon atoms, furthermore preferably cyclohexyl and benzyl. R ¹ preferably represents alkyl with up to 3 carbon atoms. The compounds of the formula III are not yet known. They can (as described in the experimental section) be prepared from alkali mercaptides and N-dichloromethylene carbamic acid esters in inert solvents (eg in toluene).

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All inert organic solvents can be used as diluents. These include hydrocarbons such as chloroform or chlorobenzene, ethers such as diethyl ether or dioxane.

Tertiary organic bases are mainly used as acid binders, especially triethylamine, N-dimethylbenzylamine, N-diethylaniline and pyridine.

The reaction temperatures can be varied over a wide range. In general, the reaction is preferably carried out from -10 to 100 C, between 0 ° and 80 ⁰ C.

When carrying out the process according to the invention, 1 mole of amine is reacted in the presence of at least 1 mole of acid binder with 1 mole of N-CChlor-mercaptitaiethylenJ-carbamic acid ester. Above or below these ratios by up to 20 % can be carried out without any significant reduction in yield.

Some of the compounds that can be prepared according to the invention are known as such, and the good fungicidal action of several substituted N-2-aminophenyl-N'-alkoxycarbonyl-S-alkyl-isothioureas against phytopathogenic fungi is also known (cf. German Offenlegungsschriften 2 025 412 and 2 025 413 and similar British patents 1 308 101 and 1 304 655). Individual compounds of the general formula I are not yet known, for example compounds in which the substituent X is benzoyl; however, these compounds and their use as anthelmintics are the subject of an earlier protection request (German patent application P 23 04 764 * 5 / Le A 14 713.7).

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Production examples ^ / »

NS,

Example 1: » ■> .NH-C = N-CO-OCH ₃

NH-CO-CH ₃

1.5 kg (10 mol) of 2-amino-acetanilide are placed in 5 chloroform. Is added dropwise under ice cooling (temperature below 20 ⁰ C) 1675 g of N- (chloro-methylmercaptomethylen) -carbamic acid methyl ester, and then 1,010 g (in each case 10 mol) of triethylamine. The mixture is subsequently stirred at room temperature for 3 hours. Solution briefly occurs during the reaction, but the end product soon precipitates. After suctioning off, the product is stirred with plenty of water, suctioned off and dried. 2240 g are obtained; A further 300 g of product can be isolated from the mother liquor in the usual way, which can be purified by crystallization from glycol monomethyl ether acetate. The pure compound melts with decomposition at 154-158 ° C. The yield is 90 ° /> of theory of N-2-acetylaminophenyl-N'-methoxycarbonyl-S-methyl-isothiourea.

Manufacture of the preliminary product:

(V 1) CH, -S

⁰ ^ C = N-CO-OCH,

936 g (6 mol) of methoxycarbonyl isocyanide dichloride are placed in 2 liters of toluene, with vigorous stirring 1.5 liters of a 4N sodium thiomethylate solution are cooled (6 mol) are added within 40 minutes in such a way that the temperature reaches a maximum of 10.degree. It will be 15 minutes after

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touched. Then the layers are separated and the toluene phase is extracted twice with water. After drying the solution with calcium chloride, filtration and removal of the solvent remain 971 g of N- (Chlormethylmercapto-methylenj-carbainidsäure-methylester, distillation in vacuo gives 680 g of boiling. ,, 97-100 ⁰ C. The yield is 68 $ the theory.

The following precursors were obtained in a similar manner

.Cl

(V2) CH _x O-OC-N = C. Kp. _ 138-41

³ ^ SC.H _n

4 9

^ Cl

(V 3) CH 1 O -OC-N = C bp 135-142

\ / = x 1-1.5

.Cl (V 4) C ₂ H ₅ O-OC-N = C bp ₁₂ 103-108

NS,

Example 2:

25.4 g (0.1 mol) of 2-acetamido-5-benzoyl-aniline (melting point 136 °) and 10.1 g (0.1 mol) of triethylamine are placed in 300 ecm of dry chloroform and slowly ^{stirred at 0 ° C} 16.7 g

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(0.1 mol) with N- (chloromethylmercaptomethylene) carbamic acid methyl ester offset at 0 G. It is allowed to come to room temperature within 2 hours. That partially crystallized The reaction product is left with the evaporation residue Chloroform solution extracted well with water. The resulting N- (2-acetamido-5-benzoylphenyl) -N'-methoxicarbonyl-S-methyl-isothiourea can be used for further purification be redissolved from ethanol. 20.5 g of melting point 172 g are then obtained (with decomposition).

In a similar way, the following compounds were made:

Example no. Formula

Pp- ( ⁰ C)

CH

-COOCH.

H-COC ₀ H

SCH ₃ ^^ N = C-NH-COO C ₀ H

SCH = C-NH-C00CH,

h-co- / h \

SCH »3

NH-CO

130

126-129 151-152 149 (decomp.)

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SCH, NH-C = N-COOCH,

H-CO

- 14 -

157-159 (decomp.)

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Example no,

Formula Fp- ( ⁰ C)

NS,

NH-CO-C ₃ H ₇ 115-6

SC ₄ H ₉ HG = N-COOCH,

H-COCH. 136-9

10

SCH, N = C-NH-COOCH,

-CO-NH-CH, 146-7 (dec.)

11

SCH ₃ C-NH-C00C _o H

-CO-NH-C ₄ H ₉ 116-20

12th

NS,

NH-CO-NH

154-6

13th

NS

NH-CO-CH. 143

14th

SCH ₃ N = C-NH-COOCH,

NH-COC ₂ H ₅ 133

Example no.

formula

Fp- ( ⁰ C)

15th

₃ CH _qVV N = C-NH-COOCH

^y Ti I

: -coc, H, 116

16

SCH ₅ N = C-NH-COOCH ₅

H-CO

148-50

17th

-CO

SCH , N = C-NH-COOCH,

NHCOC ₅ H ₇ 158 (decomp.)

18th

SCH N = C-NH-COOCH-

NH-COV H

140 (decomp.)

19th

-CO

SCH, 1 3 N = C-NH-COOCH,

NH-CO

139

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Comparative example:
Implementation:

\ —NH-CO-

OCH ₃

16.5 g (0.1 mol) of 2-aminopropionanilide are placed in 50 ml of chloroform, and 23 g (0.1 mol) of methyl N- (phenylmercapto-chloromethylene-carbamate) are added dropwise g (0.1 mol) of triethylamine, a temperature of not more than 10 ^° C. being obtained by slight cooling, the mixture is then allowed to come to room temperature and stirred for 3 hours, giving 7 g of plague product, which is filtered off with suction, washed with chloroform and dried The product proves to be identical to the known benzimidazole-2-carbamido acid methyl ester (cf. US Pat. No. 2,933,502). The yield is 35% of theory.

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Claims (3)

Claims; 1) Process for the preparation of substituted N-2-aminophenyl-N'-alkoxicarbonyl-S-alkyl-isothioureas, characterized in that amines of the formula H-CO-R " in which X stands for hydrogen, alkyl with up to 6 carbon atoms and for benzoyl, and R "for hydrogen and alkyl of up to 18 carbon atoms stands (optionally substituted by halogen, cyano, lower alkoxy, lower alkoxycarbonyl, Phenoxy, halophenoxy, lower alkylphenoxy, lower alkoxyphenoxy), also for cycloalkyl with up to 8 carbon atoms, for aralkyl with up to 2 carbon atoms in the alkyl part (optionally substituted on the nucleus by halogen, lower alkyl, lower alkoxy), for aryl (optionally substituted by halogen, lower alkyl, lower alkoxy) and for furyl, furthermore for the group R " ^f -N is where R ^{IM stands} for hydrogen and alkyl with up to 4 carbon atoms and Le A 15 113 - 18 - 409884 / U19 R "" represents hydrogen and alkyl with up to 18 carbon atoms (optionally substituted by halogen, cyano, lower alkoxy, lower alkoxycarbonyl), furthermore for cycloalkyl with up to 8 carbon atoms, for aralkyl with up to 2 carbon atoms in the alkyl part (optionally substituted on the nucleus by halogen, lower alkyl, lower alkoxy), for phenyl (optionally substituted by halogen, lower alkyl, lower alkoxy), for acyl with up to 18 carbon atoms (optionally substituted by halogen, lower alkoxy), for aroyl (optionally substituted by halogen, lower alkyl, lower alkoxy), for arylsulfonyl (optionally substituted by halogen, amino, lower alkyl, lower alkoxy) and for dialkylamino with a total of up to 4 carbon atoms, and furthermore R "'and R" "also together with the connecting nitrogen atom for a heterocycle with 4 · to 7 Can stand carbon atoms, the ring also optionally containing oxygen or sulfur may contain other heteroatoms, with N- (chloro-mercapto-methylene) -carbamic acid esters of formula R-S ^ C = N-CO-OR ' Cl in which
Le A 15 113 - 19 - 409884/1419 R stands for alkyl and alkenyl each with up to 12 and for cycloalkyl with up to 8 carbon atoms and for aralkyl (optionally substituted in the aryl part by lower alkyl, lower alkoxy and / or halogen) and R ^! represents alkyl with up to 4 carbon atoms, in the presence of a diluent and of an at least equivalent amount of an acid binder is reacted at temperatures between -10 ° and 100 ⁰ G. 2) Method according to claim 1, characterized in that the implementation in T <
is carried out. the reaction in the temperature range between 0 and 80 C. 3) Method according to claim 1, characterized in that that triethylamine is used as an acid binder. Le A 15 113 - 20 - 409884/1419