HU185613B - Process for preparing n-acyl-n'-/mono- or disubstituted/-carbamides - Google Patents

Abstract

The present invention relates to a novel process for the preparation of N-aryl-N '- (mono- or disubstituted) ureas of the formula (I) wherein Arii is optionally one or more of the same or different halogen, nitro, lower alkyl. phenyl substituted with lower alkoxy, phenoxy, halophenoxy and / or trifluoromethyl; R1 and R2 are independently lower alkyl or lower alkoxy, or R1 and R2 are those listed in the definition of "Arii"; or R 1 and R 2 together with the adjacent nitrogen atom to which they are attached may also form a morpholino group, and one of R 1 and R 2 may also represent hydrogen, provided that when one of R 1 and R 2 represents the groups listed in the definition of "Arii", R 1 and R 2 are only hydrogen , lower alkyl or lower alkoxy); Carbamic acid (lower) alkyl esters of formula (II) and amines of formula (III) or carbamic acid (short chain) alkyl esters of formula (IV) and amines of formula (V) wherein R1, R2 and Ari are and X is a lower alkoxy group) by reaction with a tertiary amine in the presence of a catalyst. For the purposes of the present invention, tertiary amine catalysts comprise a total of at least 6 carbon atoms and at least one tertiary alkylamine containing at least one carbon chain of 4 carbon atoms or more. RJ Arri - NH - C0 - N IC R - hAl · Arri - NH2 (I) (II) (III) Arri - NH - CO - X (IV) (V) -1-

Description

The present invention relates to a novel process for the preparation of N-aryl-N '- (mono- or disubstituted) ureas of formula (I):

Aryl is phenyl optionally substituted with one or more identical or different halogen, nitro, lower alkyl, lower alkoxy, phenoxy, halophenoxy and / or trifluoromethyl substituents;

R ¹ and R ² are independently lower alkyl or lower alkoxy, or R ¹ and R ^{2 are} those defined in the "Ari 1" definition, or R ¹ and R ² , together with the adjacent nitrogen atom to which they are attached, may also form a morpholino group and R 'and R ² represent each a hydrogen atom, with the proviso that when R ¹ and R ² is one of the groups in the term "aryl" determination, R ¹ and R ² other of only hydrogen, may be lower alkyl or lower alkoxy ).

In the compounds of formula (I), R ¹ and R ² may be C 1-4 alkyl as alkyl and C 1-4 alkoxy as alkoxy. The "halogen" may be fluorine, chlorine, bromine or iodine. The term "low carbon" as used herein denotes C 1-4 groups.

Preferably, the nitrogen-containing heterocyclic group in place of the group R'R4 - is morpholine.

Many of the compounds of formula I have herbicidal activity. The herbicidal compounds of formula (I) include, for example, where the term "aryl" represents an optionally substituted phenyl, ^R1 is hydrogen or alkyl, ^Z is R is an alkyl derivative containing an alkoxy group (or R. Wegler: Chemie hoarfrost Pflanzenschutz- und Schadiingsbekampfungsmittel , Springer Veriag, Berlin-HeidelbergNew York, 1970; pages 241-255). Other representatives of the compounds of formula (I), such as, for example, one of R ¹ and R ^{2 having a} hydrogen atom and the other having an "Aryl" group, are used as medicaments or as intermediates in the manufacture of medicaments.

Preferred compounds of formula (I) are the following:

N-phenyl-N ', N'-dimethylurea (fenuron), herbicide;

N-phenyl-N '- (2-methylcyclohexyl) urea (siduron), a herbicide;

N- (4-chlorophenyl) -N ', N'-dimethylcarbaride (monuron), herbicide;

N- (3,4-dichlorophenyl) -N'-methyl-N'-butyl-urea (neburon), a herbicide;

N- (3,4-dichlorophenyl) -N ', N' -dimethylurea (diuron), herbicide;

N- [3- (trifluoromethyl) phenyl] -N ', N'-dimethylurea (flumethuron), herbicide; N- [3-chloro-4- (trifluoromethyl) phenyl] -N ', N'-methylurea, herbicide;

N- (3-chloro-4-methylphenyl) -N ', N'-dimethylurea (chlortoluron), herbicide; N- (4-isopropylphenyl) -N ', N'-dimethylurea (isoprothuron), herbicide;

N- (3,4-dichlorophenyl) carbamoylmorpholine, a herbicide;

N- (3-chloro-4-bromophenyl) carbamoylmorpholine, a herbicide;

N- (3-chlorophenyl) carbamoylmorpholine, herbicidal active ingredient;

N- (4-chloro-phenyl) -carbamoyl-morpholine, herbicide;

N- (3-chloro-4-methoxyphenyl) -N ', N'-dimethylurea (methoxuron), herbicide; N- [4- (4-chlorophenoxy) phenyl] -N ', N'-dimethylurea (chloroxuron), herbicide; N- (4-chlorophenyl) -N'-methyl-N'-ethoxyurea (monolinuron), herbicide; N- (4-Bromo-phenyl) -N'-methyl-N'-methoxy-urea (Metobromuron), herbicide; N- (3,4-dichlorophenyl) -N'-methyl-N'-methoxyurea (linuron), a herbicide; N- (3-chloro-4-bromophenyl) -N'-methyl-N'-methoxyurea (chlorobromuron), herbicide; N- (3-fluoro-4-bromophenyl) -N'4'-dimethylurea, a herbicide;

N- (3-fluoro-4-chlorophenyl) -N ', N'-dimethylcarbanide, herbicide;

N- (3-fluoro-4-chlorophenyl) -N '· methyl-N'-methoxycarbamide, herbicide;

N- (3-Fluoro-4-iodophenyl) -Ν'-methyl-N'-methoxyurea, herbicide;

N- (4-chlorophenyl) -N '- (3-methyl-4-chlorophenyl) urea, herbicide;

N- (4-chlorophenyl) -N '- (3,4-dichlorophenyl) urea (trichlocarban), a bacteriostatic agent;

N- (4-nitrophenyl) -N '- (4-nitrophenyl) urea' (nicarbazine), a coccidiostatic agent; N- (4-chlorophenyl) -N '- [3- (trifluoromethyl) -4-chlorophenyl] urea (in chloflucarban), antiseptic.

Compounds of general formula (I) are most commonly prepared by reaction of the appropriate isocyanates with their amines. In one variant of NCO Anríl reacted with isocyanates of general formula HNR'R ² with amines of general formula. Alternatively, R ^f -NCO isocyanates are reacted with amines of general aryl-NH ₂ ; products with R ^{2 are} replaced by hydrogen. Such a procedure is described, for example, in U.S. Patent No. 157,726. the Hungarian patent specification and the publications cited therein, as well as Houben-Weyl: Methoden dér organizchen Chemie; Georg Thieme Veriag, Stuttgart, 1952; VIII. Vol. 157-159. side.

The isocyanates used as starting materials are formed by reaction of the appropriate amines with phosgene (Houben-Weyl, Methoden derorganchen Chemie; Georg Thieme Veriag, Stuttgart, 1952; Vol. VIII, pp. 120-123) or the chloroformic acid esters of the corresponding amines for thermal decomposition. (U.S. Patent Nos. 171,538 and U.S. Patent 3,962,302 and references cited therein), and Houben-Weyl, Id., Vol. VIII, pp. 138-139 and 126-127. ).

It is well known that phosgene is extremely harmful to health and therefore special safety precautions are required to perform phosgene reactions. Another method used to prepare the isocyanates (thermal decomposition of the corresponding carbamic acid esters) is a substance-21

185 613 and energy intensive operations are therefore required. The production of isocyanates used in the production of urea derivatives is thus difficult, complicated and costly and in many cases uneconomical at the large scale.

It is known that urea derivatives can also be prepared by reaction of the corresponding primary or secondary amines with thiolcarbamic acid esters. Such a procedure shall be communicated, inter alia, to n .1. Am. <RTIgt; Hcm, </RTI> Soc, 7, 4458-4463 (1954). However, only thiolcarbamic acid esters, carbamic acid phenyl esters and carbamic acid (substituted phenyl) esters have been reported in the literature to be capable of reacting adequately (see also HoubenWeyl, vol., Vol. 161-162). When carbamate (lower) alkyl esters which are substantially easier to obtain than the carbamic acid phenyl esters and the carbamic acid (substituted phenyl) esters are used as reagents, the reaction will take place only for an unacceptably long period of time and in very poor yields. Therefore, the carbamate (lower) alkyl esters are converted on a large scale into substituted ureas by the thermo-isocyanate formation described above on a large scale only through an energy intensive step.

Thus, the yield, availability of starting materials, reaction time and operating conditions can be determined. A process for the production of substituted ureas has not yet been developed satisfactorily.

By obviating the drawbacks of the known methods, the present invention provides a novel process for the preparation of ureas of formula (I) which requires readily available starting materials, provides the desired end products in a short and high yield, and eliminates the use of chemicals harmful to health.

The present invention is based on the discovery that carbamate (lower) alkyl esters can be converted directly (i.e. without prior isocyanate formation) to urea derivatives in a short time and with good yields if the carbamate (lower) alkyl esters and longer-chain tertiary alkylamines have been used as catalysts in the reaction of the corresponding amines instead of the conventionally used triethylamine and pyridine.

Relates to a process for the preparation of formula urea compounds (I) of the invention - wherein Aryl, R ¹ and R ² are as defined above - (II) carbamic acid of formula (lower) alkyl esters and (III) amine, or Carbamic acid lower alkyl esters of formula IV and amines of formula V wherein R ¹ , R ² and Ar ¹ are as defined above and X is lower alkoxy by reaction in the presence of a tertiary amine catalyst. According to the present invention, tertiary alkyl amines having a total of at least 6 carbon atoms and at least one carbon chain having 4 carbon atoms or more are used as tertiary amine catalysts.

According to the above definition, tertiary alkylamine catalysts may be used as di- (C 1 -C 3 alkyl) butylamines, however, it is preferred to use catalysts having the longest carbon chain having at least 8 carbon atoms, preferably at least 12 carbon atoms. The other two alkyl groups attached to the nitrogen atom may be shorter groups (such as methyl or ethyl). In our experience, the catalytic action of tertiary alkylamines is the longest: the carbon number of the abb carbon chain! it changes in parallel, and the larger the longest carbon atom is, the shorter the time and the higher the desired urea derivatives are formed. Among the tertiary alkylamine catalysts, the following compounds are particularly preferred: trioctylamine, N, N-dimethyl-N-octylamine, N, N-dimethyl-N-dodecyl-yl-amine, NN-dimethyl-N-hexadeylene aniline and the corresponding Ν, Ν-diethyl and N-methyl-N-ethyl derivatives. These compounds are readily available commercially available materials.

The process according to the invention provides the desired end products in excellent yield (80% or greater) in a short time (a few hours) from carbamate (short-chain) alkyl esters previously considered unsuitable for large-scale urea production.

In the process according to the invention, the carbamate (lower) alkyl esters and amines are suitably used in substantially equimolar amounts according to known methods. The tertiary alkyl smin catalyst is used in an amount of 0.05 to 2 moles, preferably 0.5 to 1.2 moles, per mole of the lower molar amount (i.e., yield). Of course, tertiary alkylamine catalysts may be used in the form of mixtures of several compounds; then the molar ratio given refers to the total amount.

The reaction is usually carried out in a solvent which is inert to the reagents and the final product, such as benzene, toluene or xylene, preferably during the filament of the reaction mixture.

The urea derivatives of formula (I) usually precipitate out of the reaction mixture as an insoluble precipitate and are thus easily isolated. The mother liquor obtained from the isolation of the solid end product, which contains a solvent, a tertiary alkylamine catalyst and a small amount of the dissolved end product, can be used several times as a reaction medium in the process of the invention; Thus, the specific chemical requirement of the process can be significantly reduced.

The following examples further illustrate the process without limiting the invention to the examples.

Example 1

Preparation of N, N'-bis (4-nitrophenyl) urea (nicarbazine)

9.81 g (50 mmol) of methyl N- (4-nitrophenyl) carbamate and 6.9 g (50 mmol) of 4-nitroaniline in 140 mL of xylene are heated to 11.8 g (about 50 mmol) of Genamine CS 302D (dimethyl-C ₁₀ is a mixture of alkyl amines, available from Hoechst AG.) as catalyst, round bottom flask equipped with back drip condenser. From the beginning of the source

By 3 minutes, yellow crystals of the final product have appeared and are rapidly increasing. After half an hour, reflux was discontinued, the dense orange crystalline slurry was filtered off with suction and washed with hot xylene (2020 mL), followed by acetone, and dried in vacuo. The product weighed 12.78 g (85.2%) uniformly by layer chromatography and had a chromatographic image (n-hexane-acetone 3: 1) identical to an authentic sample.

185,613

Example 2

Preparation of N, N'-bis (4-nitrophenyl) urea (nicarbazine)

The procedure of Example 1 is repeated, except that the flask is equipped with a distillation apparatus and the methanol formed in the reaction is continuously distilled from the system under gentle reflux. After 2 hours, the resulting final product was removed by filtration and the reaction mixture containing the catalyst was charged with the same amount of carbamate and 4-nitroaniline as the starting material, and the reaction was repeated. In four successive reactions the following results are obtained:

Cycle- The product Yield song weight (g) (%) Quality First 13.36 89.1 chromium. unified Second 14.30 95.3 chromium. unified Third 13.58 90.5 chromium. unified 4th 14.75 98.3 chrome uniform Average: 14.0 93.3

(The final product cannot be safely classified by its melting point because it is already sublimated near the melting point.)

Example 3

Preparation of N- (4-chlorophenyl) carbamoylmorpholine

9.28 g (50 mmol) of methyl N- (4-chlorophenyl) carbamate and 4.36 g (60 mmol) of morpholine in 100 mL of xylene, 10.6 g (50 mmol) of Ν, Ν-dimethyl- gently boil in the presence of tetradecylamine catalyst to remove methanol formed from the system. After a heating reaction, the heating is stopped and the mixture is allowed to cool. The next morning, the final N- (4-chlorophenyl) carbamoyl-morpholine crystallized, which was then removed by filtration. The dry product weighed 9.1 g, m.p. 196-200 ° C (196-200 ° C), 75.6% yield.

Example 4

N- (4-chlorophenyl) -N ^! - (- 3,4-Dichlorophenyl) urea (triclocarban)

4.61 g (25 mmol) of methyl N- (4-chlorophenyl) -carbamate and 4.07 g (25 mmol) of 3,4-dichloroaniline in 100 mL of methylene chloride. in toluene in the presence of 4.7 g (25 mmol) of Ν, Ν-dimethyl dodecylamine catalyst as described in Example 3 for 20 hours. After cooling, the final crystallized product weighed 4.60 g, yield 58.4%.

Example J.

Preparation of N- (3,4-dichlorophenyl) carbamoylmorpholine

5.50 g (25 mmol) of methyl N- (3,4-dichlorophenyl) carbamate and 2.18 g (25 mmol) of morpholine are reacted with 100 ml of xylene in the presence of Ν, Ν-dimethyldodecylamine catalyst. for 12 hours. After cooling, the precipitated crystalline material is filtered off and the carbamate and morpholine are again weighed into the mother liquor containing the catalyst and the reaction is repeated. The amount of the first final product was 5.0 g (72.7%), the second 6.35 g (92.3%), both melting points 152-155 ° C (literature 157-158 ° C).

This experiment is repeated by using molar equivalents of triethylamine in place of the catalyst of the present invention; After 24 hours, only 3.05 g (44.3%) of product are obtained.

Example 6

Preparation of N- (3,4-dichlorophenyl) -N'methyl-n-butylurea (neburon)

5.50 g (25 mmol) of methyl N- (3,4-dichlorophenyl) carbamate and 2.18 g (25 mmol) of N-butylmethylamine are reacted in 100 ml of white spirit in the presence of N, N-dimethyldodecylamine catalyst. The reaction was repeated for 3 hours, as described in Example 3, and after the product was removed, again weighing the starting materials. The first reaction gave 3.70 g (53.8%) and the second 5.05 g (73.4%) of the final product, mp 108-110 ° C (literature 116-117 ° C).

Example 7

Preparation of N- (3,4-dichlorophenyl) -N'-methyl-N'-butylurea (neburon)

The procedure of Example 6 is followed, except that 100 ml of xylene is used as solvent and the progress of the reaction is monitored by layer chromatography. When the reaction occurs for approx. 90%, based on layer chromatography, the mixture was concentrated in vacuo. A yellowish viscous evaporation residue is obtained which is soluble in standard solvents such as acetone or methyl ethyl ketone and can be used directly for the preparation of herbicidal spray liquors.

Example 8

Preparation of N- (4-chlorophenyl) -Ν, Ν'-dimethylurea (monuron)

12.8 g (0.1 mol) of 4-chloroaniline, 10.3 g (0.1 mol) of methyl N, N-dimethylcarbamic acid, 20 ml of dimethylhexadecylamine and 100 ml of light petroleum distillate (b.p. 160). -180 ° C) as described in Example 7. When the reaction occurs for approx. 90% complete, the reaction is stopped. A solution of N- (4-chlorophenyl) -N ', N'-dimethylurea is obtained which can be used directly in this form as herbicidal compositions such as

185,613, for example, for the production of spray liquors or impregnated granules.

Example 9

Preparation of N- (4-chlorophenyl) -Ν ', N'-dimethylurea (monuron)

A mixture of 4.64 g (0.025 mol) of N- (4-chlorophenyl) -carbamic acid methyl ester and 21.3 ml of Genamine LA 302 D (N, N-dimethyl-C12 μ alkyllatinins, manufactured by Hoechst AG.) In 100 ml Heat in a distillation flask while bubbling dimethylamine gas, keep the temperature at 150-160 ° C for most of the reaction time and allow to rise at the end until the distillate (methanol) is removed. about 2 hours.

The yellowish brown solution precipitated in the form of off-white crystals while cooling, which was collected by filtration, washed three times with 10 ml of n-hexane and then dried. The filtrate was combined with the washing liquid and reused as medium in the next reaction by adding 4.64 g of carbamate again and repeating the above reaction with dimethylamine. During heating, the n-hexane used for the washing is first distilled, which is used separately to wash the next final product.

The reaction is repeated ten times using the same reaction mixture to give the results summarized in Table 1 below:

Table I

Cycle- song Weight (G) Melting point CC) Yield (%) 1 2.70 168-171 54.33 2 3.05 169-171 61.36 3 4.20 170-172 84.51 4 4.50 169-171 90.54 5 4.10 167-169 82.49 6 3.50 167-169 70.42 7 4.50 168-169 90.54 8 3.95 172-173 79.48 9 3.75 172-173 75.45 10 4.55 169-169 91.55 On average: 3.88 169-171 78.07

(The monuron has a literal melting point of 174-175 ° C.)

Example 10

Preparation of N-phenyl-N ', N'-dimethylurea (fenuron)

In the reaction of Example 9, 3.78 g (0.025 mol) of N-phenylcarbamic acid methyl ester was used. The average reaction time is 1.5 hours and the temperature is 140-180 ° C.

The reaction was repeated eight times using the same reaction mixture, and the results were obtained as shown in Table II. are summarized in Table.

Table IL

Cycle- song Weight (G) Product details Melting point (° C) Yield (%) 1 2.10 127-130 51.20 2 3.41 124-127 83.17 3 3.85 125-128 93.90 4 3.75 124-126 91.46 5 1.87 131-133 45.61 6 4.95 124-127 120.73 7 3.05 122-126 74,40 8 3.60 122-126 87.80 average: 3.32. 125-128 81.03

(Fenuron has a literature melting point of 133-134 ° C.)

Example 11

Preparation of N- (3,4-dichlorophenyl) -N'-methoxy-Ν'-methylurea (linuron)

N- (3,4-dichloro-phenyl) -carbamic acid methyl ester (23 ml, approx. 0.075 mol) Genamin arsenal LA 302 (dinietii-C, ₂ -i4 lower alkylamine mixture, produced 5.5 g (0.025 mole) Hoechst AG.) while stirring and heating, and ca. Methoxymethylamine (2.3 g, 0.0375 mol) was bubbled through the mixture for 3 hours while maintaining the temperature at about 200 ° C. The progress of the reaction is monitored by vapor temperature, on the one hand, and by layer chromatography, on the other. When the reaction occurs for approx. 90% complete, the reaction is stopped. A solution of N- (3,4-dichlorophenyl) -N'-methoxy-N'-methylcarbamide was obtained, which was treated with organic solvents, e.g. acetone or methylethylketone can be easily further diluted and can be used directly in this form for the preparation of herbicidal compositions such as sprays or impregnated granules.

Example 12

Preparation of N, Ν'-bis (4-nitrophenyl) urea (nicarbazine)

The procedure of Example 2 was repeated, except that 6 ml (25 mmol) of tri-n-butylamine was used as the catalyst. Half an hour after the start of boiling, the desired product begins to precipitate. The heating was turned off after refluxing for a total of 1 hour, and after cooling, the crystals were filtered, washed twice with 20 ml xylene and once with 20 ml n-hexane. 14.36 g (95%) of the title compound are obtained in a single layer.

185,613

Example 13

Claims (3)

Preparation of N- (3-chloro-4-methylphenyl) -N ', Ν'-dimethylurea (chlorotoluron) 4.99 g (25 mmol) of methyl N- (3-chloromethyl-phenyl) -carbamate, 6.74 g (25 mmol) of Armeens DMI6D as catalyst (product of Ν, Ν-dimethylhexadecylamine tech.) (Akzo Chemie Italia Spa) and 25 ml of xylene are reacted with dimethylamine in 5 consecutive reactions as described in Example 9, the results of which are summarized in the following table: Cycle- song Weight (G) Product details Melting point (° C) Yield (%) 1 3.56 143-146 66.92 2 4.00 144-146 75.19 3 4.10 144-146 77.07 4 5.35 144-146 100.56 5 4.35 144-146 81.77 average: 4.27 144-146 80.36 (Chlortoluron has a literature melting point of 147-148 ° C.) Example 14 Preparation of N- (4-isopropylphenyl) -N ', Ν'-dimethylurea (isoprothuron) 14.50 g (75 mmol) of methyl N- (4-isopropylphenyl) -carbamate, 6.04 g (25 mmol) of Armeens DM14D as catalyst (tech. N, N-dimethyltetradecylamine) are prepared by Akzo Chemie Italia Spa) and 25 ml of white spirit are reacted at 140-150 ° C in the same manner as in the previous example with continuous introduction of dimethylamine gas. After one hour of reaction, heating and gas supply are stopped. Upon cooling, the final product begins to precipitate at about 80 ° C. The product was filtered at room temperature, washed twice with 20 ml of white spirit and then with hexane. The dry title compound weighed 7.60 g (49.13%), m.p. 153-155 ° C (reference 155156 ° C). A process for the preparation of N-aryl-N '- (mono or disubstituted) ureas of formula (I). Aryl is optionally one or more of the same or different halo, nitro, C 1-4 alkyl, Phenyl substituted with C 1-4 alkoxy, phenoxy, halophenoxy 10 and / or trifluoromethyl; R 1 and R ² are independently C 1 -C 4 alkyl or C 1 -C 4 alkoxy, or R ¹ and R ^{2 are} the groups listed in the definition of "Ari ¹ " or R ¹ and R ² together with the adjacent nitrogen to which they are attached, can form a morpholino, and R ¹ and R ² represent each a hydrogen atom, With the proviso that when one of R ¹ and R ² is one of the groups listed in the definition of "Ari 1", the other of R ¹ and R ² is hydrogen, C 1-4 alkyl, or C 1-4 alkoxy) 25 C 1 -C 4 alkyl carbamate esters of formula II and amines of formula III, or C 1 -C 4 alkyl esters of carbamic acid formula IV and amines of formula V wherein Aryl, R ¹ and R ² are as defined above and 30 X represents a (1-4C) alkoxy group in the presence of a tertiary amine, wherein the tertiary amine catalyst is a total of at least 6 carbon atoms and at least one tertiary alkyl amine having at least 4 carbon atoms. 2. A process according to claim 1, wherein the tertiary alkylamine catalyst is used which has at least one carbon or 8 carbon atom. It has an alkyl chain length of 40 or more. 3. A process according to claim 1 or 2 wherein the tertiary alkylamine catalyst is present in a lower molar amount of the reagent. 0.05 to 2 moles, preferably 0.5 to 0.5 moles per 1 mole 1.2 moles. 1 figure