DE1189980B - Process for the production of urea derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY Int. Cl .:

C07c

GERMAN

PATENT OFFICE

EDITORIAL

German KL: 12 ο -17/03

Number:
File number:
Registration date:
Display day:

1189 980
F31874IVb / 12o
August 13, 1960
April 1, 1965

The German patent specification 1 028 986 describes a process for the production of new urea derivatives, which is characterized in that substituted phenyl isocyanates of the general formula

Cl

in which Cl can also occur several times, with compounds of the general formula

HN

OCH ₃

wherein R is hydrogen or CH ₃ , converts.

In German Auslegeschrift 1 062 059, such urea derivatives become more aromatic by reaction Amines with N-alkyl-N-alkoxy-carbamic acid esters or chlorides in the presence of alcoholates or acid-binding agents or aromatic Isocyanates made with Ο, Ν-dialkyl-hydroxylamine.

These processes have the disadvantage that the N-alkyl-N-alkoxy-carbamic acid esters required as reactants or chlorides as well as the O, N-dialkyl-hydroxylamines are difficult to access.

The German Auslegeschrift 1 076 117 describes a process for the preparation of N-chlorophenyl-N'-alkoxy-N'-alkyl ureas the general formula

Cl

NH - CO - N

OCH ₃

where R denotes a methyl or ethyl group, which is characterized in that O-alkylhydroxylamine is added to chlorinated phenyl isocyanates and the adduct is then added in a mixture of approximately equal amounts of about 10% alkali and an alcohol corresponding to the alkylating agent at 30 to 60 ⁰ C, preferably 30 to 40 ⁰ C, alkylated.

According to the exemplary embodiments, the alkylation on isolated N-chlorophenyl-N'-methoxyureas is carried out carried out.

The invention, however, is a process for the preparation of substituted N-phenyl-N'-alkoxy-N'-alkyl ureas, that enables the desired end products to be obtained in one operation.

Process for the production of urea derivatives

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning, Frankfurt / M.

Named as inventor:

Dr. Otto Scherer, Frankfurt / M.-Höchst;

Dr. Gerhard Hörlein, Frankfurt / M .;

Dr. Rudolf Hübner, Frankfurt / M.-Höchst

There has now been a process for the preparation of urea derivatives of the general formula

(CH ₃ ) ,,

Cl _n '

NH - CO - N

ORi

where Ri is an alkyl radical having 1 to 4 carbon atoms, R _{2 is} a saturated or unsaturated aliphatic radical, optionally substituted by chlorine, having 1 to 12 carbon atoms, η 0 to 3 and m 0 or 1, which is characterized that you can do that from an amine of the general formula

(CH ₃ ) _TOv

Cl /

NH ₂

in which m and η have the above meaning, or its salt and phosgene, obtained in an inert reaction medium corresponding isocyanate without isolation, the excess phosgene optionally being driven off from the reaction mixture with an inert gas, with an alkoxyamine of the general formula

Ri - O - NH ₂

in which Ri has the above meaning, reacts and alkylates the alkoxyurea formed in this way without isolation from the inert reaction medium after addition of a mixture of alkali and an alcohol with an alkylating agent corresponding to _{the above-mentioned R 2.}

509 537/447

So you can ζ. B. N- (4-chlorophenyI) -N'-methoxy- good yields according to the following equation N'-methyl-urea in a simple way and with a lot of gain:

, -α

oc:

NH ₂

+ CH ₃ ONH _{2; C1}

Dimethyl sulfate

N-CO-N-OCH ₃
HH

NaOH

_C, _ / X _NH _ _ _{CQ N}

OCH ₃
^S CH ₃

4-Chlorophenyl isocyanate is obtained from 4-chloroaniline according to V i 11 e η e t, Bl. (3), 21, p. 954 (1899) and an excess of phosgene, the yield is not given. According to H ο u b e η - W e y 1, Methods of Organic Chemistry, IV. Edition, Vol. 8, pp. 119 to 123, the isocyanates both in the phosgenation of the amine chlorohydrates and the free bases in a yield of 85%, based on the amine used, obtained.

The subsequent addition of methoxyamine succeeds according to German Patent 1,028,986 in a yield of 93% and the alkylation according to German Auslegeschrift 1 076 117 with 95%.

The literature references cited give an overall yield over all three stages

NH- co - n;

/ CH ₃
^ OCH ₃

35

based on 4-chloroaniline used, of 75% the theory.

Carrying out the alkylation without isolating the intermediates did not appear promising. because it was known that both anilines and alkoxyamines are able to react with alkylating agents.

For example, it was known that chlorine-substituted anilines with alkylating agents such as Allow methyl iodide or dimethyl sulfate to be alkylated (A., 416, p. 190 [1918]; Ber., 49, p. 2201 [1916]; J. Chem. Soc. [1927], p. 2220). It was also known that from O-alkyl-hydroxylamines with alkylating agents O.N-disubstituted hydroxylamines are formed very easily. (A. 252, p. 230 [1889]; J. Chem. Soc. [1952], p. 514; Research (London), 3, p. 190 [1950]; CA., 44, p. 8717).

The starting materials for the present process are free aromatic amines, e.g. B. Aniline and toluidines, as well as chlorine-substituted anilines and toluidines or their salts, e.g. B. the hydrochlorides, in question. The phosgenation of the salts is expediently carried out in suspension, advantageously in elevated temperature, e.g. B. at the boiling point of the selected reaction medium, that of the free Bases are preferably carried out in solution by an excess of phosgene in two temperature stages initially at a lower and then higher, usually be reflux temperature.

Suitable reaction media are carbons, hydrogens, e.g. B. toluene. Xylene, chlorinated hydrocarbons Substances such as chlorobenzene, di- and trichlorobenzene, and chloronaphthalene are used.

The O-alkyl-hydroxylamines required for the reaction according to the present process 1 to 4 carbon atoms are z. B. by alkylation of sodium hydroxylamine disulfonate and then Hydrolysis of the reaction product easily accessible according to the following equation:

NaO-N

SO ₃ Na
SO ₃ Na

Dimethyl sulfate

CH, -O hydrolysis

SO ₃ Na

CH ₃ -O- NH ₂

Dialkyl sulfates, eg. B. dimethyl or diethyl sulfate, saturated or unsaturated alkyl halides, e.g. B. chlorides or bromides, where the alkyl group may optionally be substituted by chlorine, and alkyl toluenesulfonates having 1 to 12 carbon atoms in Consideration.

To carry out the present process one proceeds in such a way that one after the in one the abovementioned reaction media carried out phosgenation of the abovementioned amines or their salts, expediently the excess phosgene with a dry inert gas such as nitrogen, hydrogen, Strips off carbon dioxide or air without isolating and purifying the resulting isocyanate carries out the reaction with the alkoxyamine and the now precipitated phenyl-alkoxy-urea alkylated without isolation.

The alkylation is carried out in such a way that the suspension of the alkoxyurea is removed. after one if appropriate, part of the reaction medium has distilled off. after adding the theoretically required Amount of alkali and an alcohol of the alkylation advantageously corresponding to the alkylating agent subjected to one of the above alkylating agents. The reaction temperature and time are of course dependent on the reactivity of the alkylating agent used.

The process product is advantageously purified by steam distillation. One can but also first pour the reaction mixture into an excess of water and then the

distill off the separated organic phase with steam.

The alkylated alkoxyurea separates out of the residue as oily or crystalline forms on cooling Form and can be further purified by recrystallization or distillation.

The process according to the invention offers the advantage that there is no need to isolate the intermediate stages, which is what makes a technical process possible in the first place. In addition, the yields are noticeably higher than in the prior art when working on the isolated intermediate stages, see above that the reaction product can be separated off in a simple manner and with great purity. The process also offers the advantage that there are no O, N-dialkyl-hydroxylamines which are difficult to obtain is required and, moreover, is able to vary widely in the post-alkylation To introduce alkyl groups which differ from those of the O-alkyl radical.

The compounds obtainable by the process according to the invention have herbicides and acaricides Properties and can be used as a pesticide.

example 1
N- (4-chlorophenyl) -N'-methoxy-N'-methyl-urea

The isocyanate. dissolved in the inert reaction medium, has been produced in a known manner as follows.

3.0 mol (384 g) of 4-chloroaniline, dissolved in 2000 ml of chlorobenzene, are allowed to flow into a solution of 2000 ml of dried chlorobenzene and 800 g of phosgene with stirring at room temperature. Under the temperature rises to about 50 ^'C a precipitate is formed. In the course of 6 hours, phosgene is passed in and the mixture is heated to the reflux temperature and this temperature is maintained until it is completely dissolved. The excess phosgene is then blown off at the same temperature by a stream of dry nitrogen into a receiver filled with chlorobenzene and used again.

After cooling, 3.0 mol of (141 g) methoxyamine was added at room temperature, whereupon the temperature rises to about 50 ⁰ C. A mixture of 500 ml of methanol and a solution of 3 mol (120 g) of sodium hydroxide in 240 ml of water is added to the precipitated addition product. With vigorous stirring, 3 mol (378 g) of dimethyl sulfate are run in at 30 to 40 ^{° C. and the temperature is maintained at 50 °} C. for a further hour. The unreacted dimethyl sulfate is hydrolyzed and the chlorobenzene and methanol are distilled off by subsequent steam distillation. The remaining oil solidifies on cooling and is dried

The yield is 535 g of N- (4-chlorophenyl) -N'-methoxy-N'-methyl-urea (85% of theory, based on the 4-chloroaniline used).

A sample recrystallized from petroleum ether has a melting point of 76 to 78 ° C. The mixed melting point with one by addition of O.N-dimethyl-hydroxylamine product made of 4-chlorophenyl isocyanate does not give depression.

Examples 2 to 8

Examples 2 to 8 listed in Table I are prepared according to that given in Example 1 Procedure. The yields in Examples 2 to 8 are between 80 and 85% of the Theory, based on the amine used. The connections can be recrystallized from petroleum ether. Those described in Examples 2-5 and 7 Compounds are identical to those produced by the addition of O.N-dimethyl-hydroxylamine to the appropriately substituted phenyl isocyanates.

Table I.

at
game End product Aromatic
Amine Alkylation
middle Reaction
medium 81 Fp.
C. 83 Analyzes N 13.0%
Cl 16.6%
N 13.1%
Cl 16.9% 2 N- (3-chlorophenyl) -
N'-methyl-
N'-methoxy-
urea 3-chloroaniline Dimethyl
sulfate Chlorobenzene-
Methanol 90 until 91 Calculated
Found N 11.2%
Cl 28.5%
N 11.0%
Cl 28.2% 3 N- (3,4-dichloro-
phenyl) -
N'-methyl-
N'-methoxy-
urea 3,4-dichloro
aniline Dimethyl
sulfate Chlorobenzene-
Methanol 95 until 96 Calculated
Found N 9.9%
Cl 37.6%
N 9.8%
Cl 37.6% 4th N- (2,4,5-trichloro-
phenyl) -
N'-methyl-
N'-methoxy-
urea 2,4,5-trichloro
aniline Dimethyl
sulfate Chlorobenzene-
Methanol 66 until 67 Calculated
Found N 12.2%
Cl 15.5%
N 12.2%
Cl 15.5% 5 N- (2-methyl-
4-chlorophenyl) -
N'-methyl-
N'-methoxy-
urea 2-methyl
4-chloroaniline Dimethyl
sulfate Chlorobenzene-
Methanol until Calculated
Found

continuation

at
game End product Aromatic
Amine Alkylation
middle Reaction
medium Fp.
C. Analyzes 6th N- (4-chlorophenyl) -
N'-ethyl
N'-methoxy-
urea 4-chloroaniline Diethyl
sulfate Chlorobenzene-
Ethanol 90 to 91 Calculated C 52.6%
H 5.7%
Found C 52.9%
H 5.6% 7th N-phenyl-
N'-methyl
N'-methoxy-
urea aniline Dimethyl
sulfate Chlorobenzene-
Methanol 59 to 60 Calculated N 15.5%
Found N 15.2% 8th N-phenyl-
N'-ethyl
N'-methoxy-
urea aniline Diethyl
sulfate Chlorobenzene-
Ethanol 92 to 93 Calculated N 14.4%
Found N 14.4%

Example 9

20th

The isocyanate, dissolved in the inert reaction medium, is prepared in a known manner as follows been.

1.0 mol (93 g) aniline, dissolved in 650 ml toluene, it is left with stirring at room temperature to a solution of 650 ml of dried toluene and 250 g Phosgene flow in. The reaction mixture is heated to reflux temperature within about 6 hours high and maintains this temperature until it is completely dissolved. The excess phosgene is, as in Example 1 executed, removed.

After cooling, 1.0 mol (89 g) of n-butoxyamine are added at room temperature. A mixture of 170 ml of methanol and a solution of 1 mol (40 g) of sodium hydroxide in 80 ecm of water is added to the precipitated addition product. While stirring vigorously, 1 mol (126 g) of dimethyl sulfate is run in at 30 to 40 ^{° C. and the temperature is kept at about 50 °} C. for a further hour. The toluene and methanol are driven off by subsequent steam distillation and the reaction product is obtained as an oily residue. which is taken up in methylene chloride. After drying and removal of the solvent, the residue is distilled under reduced pressure.

Distill below 8 mm Hg at 138 to 140 ° C 120 g of N-phenyl-N'-n-butoxy-N'-methyl urea (54% of theory, based on "aniline used).

Analysis: Ci ₂ HiSN ₂ O ₂ (molecular weight 222).

Calculated ... C 64.8%, H 8.1%, N 12.6%;
found ... C 64.4%, H 8.1%, N 12.4%.

Example 10
N-phenyl-N'-methoxy-N'-n-butyl urea

N-phenyl-N'-methoxy urea is analogous to the Process described in Example 1, starting from 1 mol of aniline, obtained as a suspended addition product. It is made with a mixture 250 ml of n-butanol and a solution of 1 mol (40 g) of sodium hydroxide in 80 ml of water are added.

At 60 to 7O ⁰ C allowed to 1 mol (137 g) of n-butylbromide flow to and heated 3 hours at reflux temperature. Steam distillation gives an oily residue which is taken up in methylene chloride, dried and distilled.

At a pressure of 3 mm Hg, 145 g of N-phenyl-N'-methoxy-N'-n-butylurea (65% of theory, based on the aniline used) ^{pass over at 118 to 120 ° C.}

Analysis: Ci ₂ Hi ₈ O ₂ N ₂ (molecular weight 222).

Calculated ... C 64.8%. H 8.1%;
found ... C 65.2%. H 8.0%.

Examples 11-23

Examples 11 to 23 listed in Table II are prepared in such a way that the Methoxyphenyl ureas accessible according to Example 1 with the alkyl halides listed in column 3 according to the procedure given in Example 10.

Table II

at
game End product Aroma
table
Amine Alkylation
middle Reaction
medium Fp.
° C Yield,
based on
Alkylation
step Analyzes 11 N- (4-chlorophenyl) -
N'-methoxy-
N'-isopropyl
urea 4-chlorine
aniline Isopropyl
bromide i-propanol-
Chlorobenzene 93 to 94 70% Calculated N 11.9%
C 54.3%
H 6.2%
Found N 12.0%
C 54.2%
H 5.8%

continuation

10

at
spat End product Aroma
table
Amine Alkylation
middle Reaction
medium Fp.
⁰ C Yield,
based on
Alkylation
step Analyzes 12th N- (4-chlorophenyl) -
N'-methoxy-
N'-n-butyl-
urea 4-chlorine
aniline n-butyl
bromide n-butanol-
Chlorobenzo 70% Calculated C 56.1%
H 6.6o / o
Found C 56.1%
H 6.8% 13th N- (4-chlorophenyl) -
N'-methoxy-
N '- (2-methyl-
propyl) urea 4-chlorine
aniline 2-methyl
propyl
bromide i-butanol-
Chlorobenzene 98 to 100 600/0 Calculated N 11.3%
Found N 11.3% 14th N- (4-chlorophenyl) -
N'-methoxy-
N '- (l-methyl-
propyl) urea 4-chlorine
aniline 1-methyl
propyl
bromide sec.Butanol—
Chlorobenzo] 73 to 75 55% Calculated N 10.8%
Found N 10.6% 15th N- (4-chlorophenyl) -
N'-methoxy-
N '- (3-methyl-
butyl) urea 4-chlorine
aniline 3-methyl-
butyl
bromide Ethanol--
Chlorobenzo] 41 to 42 55% Calculated N 10.4%
Cl 13.1%
Found N 10.5%
Cl 13.4% 16 N- (4-chlorophenyl) -
N'-methoxy-
N'-alkyl urea 4-chlorine
aniline Allyl
bromide Allyl
alcohol-
Chlorobenzo] 79 to 80 80% Calculated N 11.6%
C 55.0%
H 5.4%
Found N 11.5%
C 54.8%
H 5.4% 17th N- (4-chlorophenyl) -
N'-methoxy-
N '- (3,3-dichloro-
allyl) urea 4-chlorine
aniline 3,3-Di
chlorine-
allyl
chloride Ethanol--
Chlorobenzene 95 to 96 750/0 Calculated C 42.7%
H 3.6%
Found C 42.9%
H 3.6o / o 18th N- (4-chlorophenyl) -
N'-methoxy-
N'-dodecyl-
urea 4-chlorine
aniline Dodedyl
bromide n-butanol-
Chlorobenzo] 34 to 35 900/0 Calculated N 7.6%
Cl 9.6%
Found N 7.2%
Cl 9.7% 19th N- (2-chlorophenyl) -
N'-methoxy-
N'-n-butyl-
urea 2-chlorine
aniline n-butyl
bromide Ethanol--
Chlorobenzene Kp.il42bis
145 70% Calculated Cl 13.8%
Found Cl 14.2% 20th N- (2,4-dichloro-
phenyl) -
N'-methoxy-
N'-n-butyl-
urea 2,4-di
chlorine-
aniline n-butyl
bromide Butanol-
Chlorobenzene fluid
not
distilled 700/0 Calculated N 9.6%
Found N 9.5% 21 N- (2,4,5-trichloro-
phenyl) -
N'-methoxy-
N'-n-butyl-
urea 2,4,6-tri-
chlorine-
aniline n-butyl
bromide Butanol-
Chlorobenzene fluid
not
distilled 650/0 Calculated N 9.0%
Vl 34, io / o
Found N 8.4%
Cl 33.6% 22nd N- (2-methyl-
4-chlorophenyl) -
N'-methoxy-
N'-n-butyl-
urea 2-methyl
4-chlorine
aniline n-butyl
bromide Butanol-
Chlorobenzene fluid
not
distilled 550/0 Calculated N 10.4%
Cl 13.2%
Found N 11.0%
Cl 12.8% 23 N- (4-methyl-
phenyl) -
N'-methoxy-
N'-n-butyl-
urea 4-methyl-
aniline n-butyl
bromide Butanol-
Chlorobenzene Mp. 56 to 58 60% Calculated N 11.9%
Found N 12.3%

Claims (1)

Claim:
Process for the production of urea derivatives of the general formula
(CH ₃ U Y, ^ NH-co -n; Cl _n , ORi wherein Ri is an alkyl radical having 1 to 4 carbon atoms, R _{2 is} a saturated or unsaturated aliphatic radical, optionally substituted by chlorine, having 1 to 12 carbon atoms, η O to 3 and m O to 1, characterized in that the from an amine of the general formula (CH ₃ ), Cl _n ' NH ₂ its salt and phosgene obtained in an inert reaction medium corresponding isocyanate without isolation, optionally removing the excess phosgene with an inert gas the reaction mixture drives off, with an alkoxyamine of the general formula Ri - O - NH ₂ wherein Ri has the above meaning, and the alkoxy urea thus formed is alkylated without isolation from the inert reaction medium after adding a mixture of alkali and an alcohol with an alkylating agent corresponding to _{the above-mentioned R 2.} where m and η have the above meanings, or publications under consideration: German Auslegeschriften No. 1 028 986, 062 059, 076 117; Bulletin de Ia Societe Chimique de France, [3] 21, 954. 509 537MH7 3. 65 Bundesdruckerei Berlin