DD222591A5 - PROCESS FOR PREPARING 5- (OR 1.5-DI) SUBSTITUTED URACYL DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of 5- or 1,5-di-substituted uracyl derivatives of the formula Iworin, for example: R is an alkyl group having 1-10 carbon atoms, an optionally substituted carboxyl group u. R1, hydrogen, an alkenyl or alkynyl group having 2-10 carbon atoms and the like; a.Ziel the invention is to provide a simple and economical process for the production on an industrial scale. According to the invention, for example, a geminal dihalocarboxylic acid halide of the general formula II is reacted with a urea derivative of the general formula (III) and the resulting acylated urea derivative of the general formula (IV) cyclized in an alkanol having 1-4 carbon atoms with an alkali metal hydroxide under heating dehalogenated

Description

Berlin, 20 · 12, 84 64 352 11/39

Process for the preparation of 5- (or l, 5-di) - substituted uracyl perivates ' ''.',

Field of application of the invention

The invention relates to a novel industrially usable process for the preparation of 5- (or I _r 5-di) -substituted Urazyl derivatives of the general formula (I)

in which ^;

R is an alkyl group having 1-10 carbon atoms »an unsubstituted or optionally halogen, a trifluoromethyl, C _1- . Alkyl C * _s. Alkoxy / hydroxyl, cyano, nitro, amino, mono- or D1- (C _1-6 alkyl) amino. Carboxyl or esterified carboxyl group mono- or polysubstituted phenyl or naphthyl group or a substituted by an above phenyl or naphthyl group alkyl group having 1-4 carbon atoms, ι '- -:.

R is hydrogen _Λ an alkenyl or alkynyl group having 2-10 carbon atoms or is identical to the above meaning of R,

The compounds according to the invention have valuable pharmacological properties, in particular anticarcinogenic «antiviral and antibacterial activity, they are used as medicines»

Characteristics of the known technical solutions

It is well known, Heidelberger: "Cancer Medicine", 0, F "Holland and i £. Frei, eds, Lea and 0, Descamps, P, D * Barr, AS Jones, P, Serafinowski, R, CJ. Walker, G.F., Huang, P, F, Torrence, CL Schmidt, M, P, Mertes, T. KUlikowski and D. Shugar: "Antimetabolites in Biochemistry, Biology and Medicine", 0, Skoda and P. Langen, eds , Pergamon Press, Oxford, 1978, page 275; Proc. Natl _# Acad. Sci., USA, 7j6, 2947 (1979); Biochem. Pharmacol., 25, 1233 (1976); FEBS Letters, 40, Supplement, p. 48 (1974) J7 that single 5-substituted uracyl derivatives have an anticarcinogenic and antiviral activity. Some 5-substituted orotic acid derivatives are also known to inhibit the biosynthesis of pyrimidine / ^ Theoret, Biol., 26, 19 (1970); Collect. Czech, Chem., Commun., 3, 1778 (1968 ₎ , 1J5. On the basis of the biological effect mentioned, these compounds can be used as active ingredients of pharmaceutical preparations having anticarcinogenic, antiviral or antibacterial activity.

-. ' ·.

For the preparation of the compounds falling within the scope of general formula (I), several laboratory methods are known. The specialist article under 0. ACS, jj5, 1733-35 (1933) describes the preparation of Timin (in the general fore-

mel (I) R is a methyl group and R is hydrogen, starting from methyl cyanoacetic acid. It is heated in the presence of acetic anhydride with urea to give methyl cyanoacetyl urea. The methyl cyanoacetylurea is hydrogenated in a warm aqueous medium in the presence of a platinum catalyst, then obtained after filtering off the catalyst, the Timin by acidifying the reaction mixture. The hydrogenation process makes it very difficult to use this process in industry. ''. ' '·'. ·. ' '' ". ''"

The article under O, A, C. S _# , 68 ,, 912-13 (1946) describes an improved process for the preparation of Timin. Diethyl oxalate and ethyl propionate are used to prepare ethyl ethoxycarbonylpropionate by Claisen condensation, which is reduced in the presence of a platinum oxide catalyst in a hydrogen atmosphere, the diethyl 3-methyl malate obtained is hydrolyzed off, then the free 3 Methyl malic acid in fuming sulfuric acid condensed with urea. The realization of this process in the industry is made very difficult both by hydrogenation carried out in the presence of platinum oxide and by condensation in fuming sulfuric acid. "

In 3. Chem. Soc. 157-161 (1958) a further process for the preparation of uracyl and timin analogues is described. The starting material for this is ß-alkoxy-acryloyl-isocyanate or * ß ~ alkoxy-o <-methyl-acryloyl-isocyanate »These substances are from appropriately substituted acrylic acid chloride with

Silver cyanate produced. The resulting isocyanates are very reactive and unstable. According to the process described, they are reacted with primary amines * and the corresponding N '"(β-alkoxy-acryloyl) -N" -substituted urea is prepared and cyclized in an aqueous methylamine-containing, ammonia or sodium hydroxide medium can not be used industrially, since it becomes very expensive due to the silver cyanate and the instability of the intermediate product can cause significant production losses. "

According to the article under Izv, Akad, Nauk SSSR Ger. Khim » _Ä 1968 (4) ι 918 - 920 or» SU-PS Nr., 197 597 is from urea and ethyl (fö »f ormyl) propionate or, from 'Ethyl - (.beta. F -myl) -butyrate in a fuming sulfuric acid medium, timin or' ethyl-uracyl, with a yield of 50 % and 41 %, respectively. 'The use of the process in industry is effected by the fuming sulfur elic acid medium is very difficult.

According to German Offenlegungsschrift No. 1,250,829, 5-substituted barbituric acid is prepared in the presence of water with phosphorus oxychloride or thionyl chloride-C-chloro-S-substituted-urazyl, then reduced to Tlmin analogues by the known methods. Again, the application in industry by the corrosive medium is questionable.

According to Chem. Ind. (London), 13, 485-86 (1976), the timine is prepared from α-methyl-acryloylurea using a lithium palladium chloride catalyst. The process would be, under industrial conditions, because of the

talysators too expensive ·

DP-OS No. 8,134,671 describes a process starting from ethyl (o <-formyl) -propionate for the production of timin. Accordingly, the ethyl (ot-f ormyl) propionate is reacted in a methanol-salzsaureri medium with urea at a temperature of 50 ⁰ C for 4 hours, then the resulting oil in eihem methanol medium with sodium methylate at a temperature of 100 ⁰ C 4 Heated for hours. The process is complicated by the fact that the reaction with sodium methylate must be carried out in an anhydrous medium.

According to 0.A.C.S., 74, 2432-34 (1952), thiotimine is prepared from ethyl (β, β-diethoxy-methyl) -propionate and thiourea in the presence of sodium ethoxide in an anhydrous medium. The difficulty here too lies in the necessity of the anhydrous medium and in the fact that the product is still free of sulfur - e.g. B, by treatment with hydrogen peroxide - must be.

It is clear that none of the processes known hitherto makes possible an economical, simple industrial preparation of timin or substituted uracyl derivatives of the general formula (I).

Object of the invention

The aim of the invention is to provide a simple and economical process for the preparation of timin or substituted uracyl derivatives of general formula (I) on an industrial scale,

; ' ,. ·.; ^: '.. - 6 -. .._. ···. Loan of the essence of the invention

The object of the invention is to devise such a process which allows the industrial preparation of compounds of the general formula (I) under reaction conditions which are easy to secure.

Surprisingly, it has been found that the compounds of the .all-common formula (I) can be easily prepared industrially, if

a) a geminal dihalo-carboxylic acid halide of the general formula (II)

X ¹ X ¹

CH "- C-CG-X ² (II)

R .. , ...

wherein R is as defined above, X and X are halogen, with a urea derivative of the general formula (III)

H ₂ N - CO - NH - R ¹ (III)

where R is as defined above, reacted in an aprotic polar organic solvent,

then the resulting acylated urea derivative of the general formula (IV),

X ¹ X ¹ . '·' - · ..

- C - CO - NH - CO - NH - R ¹ (IV) R

11 -wherein R, R and X are as defined above - is cyclized in an alkanol of 1-4 carbon atoms with an alkali metal hydroxide dehalogenated with heating, or

b) an acryloylurea derivative of the general formula (V)

CH ₂ = CR - CO-NH-CO-NH - R ¹ (V)

1 '

- wherein R and R are as defined above - is reacted in an inert solvent with a free halogen of general formula Xp.

then the resulting acylated urea derivative of the general

1 1 .. '. '

a formula (IV) - wherein R _# R and R are as defined above - is cyclized in an alkanol having 1-4 carbon atoms dehalogenated with an alkali metal hydroxide with heating, or

 '. i

c) an acyl isocyanate of the general formula (VII)

X ¹

CH ₂ - C - CO - N = C = O (VII)

wherein R and X are as defined above, with a primary amine of general formula (VI)

R ¹ "- NH ₂ (VI)

.-Κ --- ", vl \ / l

-where R ^{1 is} as defined above - is reacted,

then the resulting acylated urea derivative of the general formula (IV) - wherein R ₁ R ¹ and X ^{1 are} as defined above in an alkenol having 1-4 carbon atoms is cyclized dehalogenated with an alkali metal hydroxide with heating.

The starting materials used in the process according to the invention, the urea derivatives of the general formula (III) and the primary amines of the general formula (VI) are long known compounds,

The geminal dihalo-carboxylic acid halides of the general formula (II) can be prepared starting from in position aC carrying a substituent R acrylic acid derivative «In the first step, they are reacted with free halogen of the general formula X * - z. B, as described in process b) - and so the corresponding geminal dihalo-carboxylic acid is prepared, reacted in known manner with halogenating agents and so it can be converted into a corresponding acid halide.

The acryloyl-urea derivatives of the general formula (V) can be prepared from appropriately substituted acrylic acid ester and an alkali metal derivative of substituted urea in a manner known per se. * Of course, a correspondingly substituted acrylic acid halide with a substituted urea derivative - z. B "as indicated in process a) - be implemented«

: · · -. ".-. 9 -; >'··.;.>.; _^: · · Κ-

The acyl isocyanates of general formula (VII) can be prepared "B" by reacting geminal dihalocarboxylic acid "halide of general formula (II) and an alkali metal cyanate in an aprotic polar organic solvent.

An alkyl, alkenyl or alkynyl group with ί-IO carbon atoms is understood to mean groups which have a straight or branched carbon chain and carry the free valency at any desired position. The double or triple bond may also be present anywhere in the group his, ·

Prominent examples are the methyl, ethyl _t propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl group or, - where there is the possibility - which straight or branched isomers or whose Called normal, secondary and tertiary representatives.

The advantageous representatives of the alkyl group having 1 to 10 carbon atoms are the alkyl groups having 1 to 4 carbon atoms, These include z, B, the methyl, ethyl, n- and 1-propyl, n-, i-, see, - and tert. ^ butyl groups ·

Advantageous representatives of the alkenyl and alkynyl groups are the vinyl, allyl, the different butenyl, pentenyl, hexenyl and octenyl groups or, the ethinyl, propargyl, the various butynyl, pentynyl, hexynyl and octynyl groups,

The substituents of the phenyl and naphthyl groups optionally substituted at the position of R may be in any desired position. The esterified carboxyl group indicated in the region of the substituents may be replaced by one of the

  - ίο -

esterified alkyl groups with 1-4 carbon atoms given above »

Λ 2

The halogen atoms mentioned in the place of X and X may be advantageously chlorine, or bromine atoms, while the halogen atom is mentioned among the substituents of the property at the point of R phenyl or naphthyl group also be a fluorine s chlorine, bromine or Oodatom can "

The alkenols having 1 to 4 carbon atoms may contain any of the above-identified alkyl groups having 1-4 carbon atoms. Advantageous representatives are methanol and ethanol »

Advantageous representatives of the alkali metal hydroxides are sodium hydroxide and potassium hydroxide.

The aprotic polar solvent used is advantageously acetonitrile »

Example of use

The invention is explained in more detail below with reference to some examples "without the invention being restricted thereto"

example 1

 "*, Ss-Dibromethyl-, methylrpropionyl-hanstt ^ of J [

12.6 g. (0.21 mol) of urea are suspended in 100 ml of acetonitrile, then with stirring at room temperature

26.4 g (o, l MoI) «*. , ß-dibromo-x-methyl-propionyl chloride added dropwise. After the addition, the reaction mixture for 1 hour, then boiled for two hours at room temperature and stirred at 50 ⁰ C for one hour by means of a reflux condenser. Then the solvent is distilled off, the resulting crystal mass stirred with 50 ml of water, filtered, covered with water and ethanol and dried. This gives 24.8 g (86.1 %) of the title compound. Melting point: 134 - 136 ^° C.

Example 2 t *, B-dibromo-ethyl-propionyl-urea

18.6 (0.31 mol) of urea are suspended in 100 ml of acetonitrile, then added dropwise with stirring at room temperature 27.85 g (0.1 mol) of "Χ, ß-dibromo-D ^ -ethyl-propionyl chloride After adding, the reaction mixture is stirred for 2 hours at room temperature and for 2 hours at 50 ⁰ G, then cooked for 5 hours using a reflux condenser. Then the Lösungsijmittel is distilled off, the resulting oily residue with 50 ml recorded and extracted Äthylacetät. The ethyl acetate-containing solution is washed with a saturated sodium bicarbonate solution, then with distilled water, dried over anhydrous sodium sulfate and evaporated. The residual thick oil crystallizes out upon cooling and standing. This gives 26.3 g (87 %) of the title compound. Melting point; 98-103 ⁰ C.

-Ί2 -

^ ur a ζ y 1

The prepared with 240 ml ethanol solution of 28.8 g (P ₄ I mol) * X, B-dibromo-od'-methyl-propio-nyl-harnstof f is added under stirring at a temperature of 40 ⁰ C to 250 The reaction mixture is stirred for one hour at this temperature, then boiled for 2 hours using a reflux condenser. After cooling, the precipitating crystals are filtered off and dissolved in 40 ml of water. The resulting solution is acidified with concentrated hydrochloric acid solution to a pH of 2 and cooled with ice-water. The precipitated crystals of the title compound are filtered off, washed with a little water and ethanol and dried, 8.26 g (65.55 %) of the title compound are obtained * Melting point «318 '-.' 322 ° C». ^: ·. "; .. - .. - ''. ''-',. ·: '- ^ [^ . Λ'. \ ',

Example 4:, ^: . V ^; _: · - '. - '..

5 ~ Methyl-u razyl ..... .... - ": '. : "'. , '

The prepared with 1Ö0 ml methanol solution of 14 g * 4 (o _# 05 mol) Qi, ß-dibromo-oC-methyl-propionyl-harnstof f under stirring at a temperature of 45 ⁰ C to the prepared with 100 ml of methanol solution The reaction mixture is stirred for 1 hour at this temperature, then boiled under reflux for 3 hours, cooled, the deposited salts

are filtered off and dissolved in 30 ml of water. The resulting solution is acidified to pH 2 with concentrated hydrochloric acid solution, cooled, the precipitating title compound is filtered off, washed with a little water, covered with ethanol and dried. This gives 4.9 g (77%) '-' * of the title compound melting point 317-320 ⁰ C. '..' -

Example 5 5-Methyl-urazyl

The solution of 28.8 g (0.l mol) oCβ-dibromo-o-methanol-prppionyl-urea-fium prepared with 240 ml of ethanol is added to the solution prepared with 200 ml of ethanol with stirring at a temperature of 40.degree dropped from 4.6 g of sodium sulfate. The reaction mixture is stirred for 1 hour at this temperature, then boiled for 2 hours using a reflux condenser. On cooling, the precipitating salts are filtered off, dissolved in 30 ml of water and the pH of the solution is adjusted to 2 with concentrated hydrochloric acid solution. The solution is cooled, the precipitated crystals of the title compound are filtered off * washed with a little water and ethanol, dried. This gives 10.52 g of the title compound (83.5 %) »melting point 320 - 322 ⁰ C.

Example 6 5-Methyl-urazyl

The solution of 19.9 g (0.1 mole) of o ( β-dichloro-X-methyl-propionylurea prepared with 200 ml of ethanol is added with stirring and at a temperature of 40 ^° C. to that of 250 ml

; ·; '. , - 14.-. '. , .. ' : '^;'- ·

Ethanol prepared solution of 16.8 g (0.3 mol) of potassium hydroxide added dropwise. The reaction mixture is stirred for one hour at this temperature, then boiled for 2 hours using a reflux condenser. The salts which precipitate due to cooling are filtered off, dissolved in 30 ml of water, and the pH of the solution is adjusted to 2 with concentrated hydrochloric acid solution ., Then, after cooling again, the separated title compound filtered off, washed with a little water and Äthanol'. - 6.82 g (54 _S 1 %) of the title compound are obtained "Melting point 315 - 318 ⁰ C ₈

MJ razy 1

The solution of 19.9 g (o, l mol) & , ß-dichloro-of-methyl-propionyl-hametoff prepared with 100 ml of methanol is added with stirring to the solution of 12 g produced with 150 ml of methanol at a temperature of 45.degree The reaction mixture is stirred for one hour at this temperature, then boiled for 3 hours with the addition of a reflux condenser. The precipitated by cooling salts are filtered off j dissolved in 30 ml of water, the pH of the solution is adjusted with concentrated hydrochloric acid solution to 2, then the precipitated by the repeated cooling crystals of the title compound are filtered off, washed with a little water and ethanol and dried. This gives 7.09 g (56.2%) of the title compound, melting point 316 ~ 320 ⁰ C,

  , '' - 15 - '.;': _,

Example 8

5-ethyl-uraz yl Γ

The prepared with 100 ml of ethanol solution of 30.2 g (0.1 mol) of ov, ß-dibromo-rt-ethyl-propionyl-urea is stirred and at a temperature of 40 ⁰ C to the solution prepared with 250 ml of ethanol Of 16.8 g (0.3 mol) of potassium hydroxide added dropwise. The reaction mixture is stirred at this temperature for 1 hour, then boiled for 3 hours using a reflux condenser. The precipitated by cooling salt are filtered off, dissolved in 80 ml of water, the pH of the solution is adjusted to 2 with concentrated hydrochloric acid solution, then the precipitated by repeated cooling crystals of the title compound are filtered off, washed with a little water and ethanol and dried. 8.32 g (59.42 %) of the title compound are obtained. Melting point: 301 - 304 ⁰ C,

Example 9 I

5-ethyl-urazyl

The prepared with 50 ml of methanol solution of 15.1 g (o, O5 mol) ot, ß-dibromo - # - ethyl-propionyl-urea is added with stirring at a temperature of 45 ⁰ C to the prepared with 100 ml of methanol solution of 8.4 g (0.15 mol) of potassium hydroxide are added dropwise. The reaction mixture is stirred for a further hour at this temperature and then boiled for 2 hours using a reflux condenser. It is cooled, the precipitating salts are filtered off, dissolved in 30 ml of water, and the pH of the solution is with

concentrated hydrochloric acid solution adjusted to 2. Repeated cooling separates the title compound. It is filtered, washed with a little water and ethanol and dried. One he keeps _f 3.72 g (53.14%) of the title compound, melting point 304-308 ⁰ C.

Example 10

'''.> -

S-ethyl- urazyl

The prepared with 100 ml methanol solution of 30.2 g. (. P, l mol) of Λ, β-dibromo- o (-äth 1-propionyl-urea is carried out at a temperature of 45 ⁰ C to the tubes with 150 ml The reaction mixture is stirred for 1 hour at this temperature, then boiled under reflux for 3 hours, then it is cooled, the precipitating crystals are filtered off, in 60 The water is dissolved, the pH of the solution is adjusted to 2 with concentrated hydrochloric acid solution and repeatedly cooled. The precipitated crystals of the title compound are filtered off, washed with a little water and ethanol and dried to give 10.96 g (78.2 %) of the . title compound melting point 306-310 ⁰ C,

Example 11

o *, ß-dibromo-oC-isopropyl-propionyl-h- arnstof f

12.6 g (0.21 mol) of urea are suspended in 100 ml of acetonitrile, then stirred at room temperature

.- ¹⁷ -

29.25 g (0.1 mol) *, ß-dibromo - * - isopropyl-propionyl-chloride added dropwise. After adding, the mixture is stirred at room temperature for 1 hour, then at 50 ° C. for 1 hour and under reflux for 2 hours. The solvent is distilled off, the crystalline residue is stirred with 50 ml of water, filtered off, covered with water and ethanol and dried. This gives 25.8 g (81.6 %) of the title compound, melting point: 141-144 ° C.

Example 12 <xβ-Dibromo-methyl-propionyl-urea f

38.4 g of CK-methyl-acryloyl-urea are dissolved with stirring and heating in 200 ml of carbon tetrachloride. 48 g of anhydrous bromine are slowly added dropwise with stirring to the 70 - 72 ⁰ C warm solution, while always paying attention to the disappearance of the color of bromine. At the end of the reaction, the precipitation of crystals begins. After addition of bromine, the reaction mixture is stirred for a further 30 minutes while 75 ml of carbon tetrachloride are added. After cooling the reaction mixture, the deposited crystalline material is filtered off and dried. Thus, 83.2 g (96.5 %) of the title compound are obtained. Melting point: 134 - 136 ^° C.

Example 13

c *, ß-Dibromo - ** -ethyl-propionyl-urea f ,

14.2 g of c * -ethyl-acryloyl-urea are added with stirring and

  - 18 -

Heating dissolved in 100 ml of carbon tetrachloride. With vigorous stirring, 16 g of water are added dropwise to the hot solution. After the reaction has ended, 25 ml of carbon tetrachloride are added to the reaction mixture, the mixture is cooled and the precipitating crystals are filtered off. This gives 29.3 g (97%) of the title compound, mp 99-101 ⁰ C.

According to Examples 1-13, the following compounds are also prepared:

5- (n-propyl) -urazyl, Melting point: 294-297 ⁰ C;

5- (n ~ butyl) -urazyl, melting point 290-292 ⁰ C;

5 ~ (n-hexyl) -urazyl, melting point 271-273 ⁰ C;

5 ~ (i-propyl) -urazyl, Melting point: 308-310 ⁰ C;

5-benzyl-urazyl, Melting point: 293-296 ⁰ C;

5-phenyl-urazyl, melting point: above 350 ⁰ C.

As a further identifier for the latter connection, the calculated and measured composition will indicate:

Analysis for the formula ^C io ^H 8 ^N 2 ° 2 ^!

Calculated: C = 63.82 % H = 4.25 % N = 14.89 % Found: C = 63.28 % H * 4.82 % N = 14.73 %.

Claims (2)

wherein R is an alkyl group having 1-10 carbon atoms, an unsubstituted or optionally halogen, trifluoromethyl, an alkyl group having 1-4 carbon atoms, an alkoxy group having 1-4 carbon atoms, hydroxyl, cyano, nitro, amino, Μοήο- or di- (C ₁ ) alkyl) -amino, carboxyl or an esterified carboxyl group is mono- or polysubstituted phenyl or naphthyl group or an alkyl group having 1-4 carbon atoms substituted by an above phenyl or naphthyl group, 1
R is hydrogen, an alkenyl or alkynyl group having 2-10 carbon atoms or is identical to the above meaning of R, characterized in that a) a geminal dihalo-carboxylic acid halide of the general formula (II) 11 X X. • · CH ₀ - C - CO - X ^{2 2} · (II) wherein R is as defined above, X and X are halogen - with a urea derivative of general formula (III) H ₂ N - CO-NH-R ¹ (HI) -where Rr is as defined above - is reacted in an aprotic polar organic solvent, then the resulting acylated urea derivative of the general formula (IV) X ¹ X ¹
··. · CH ₀ -C-CO-NH-CO-NH-R ¹ (IV)  , '' R 11 Wherein R, R and X are as defined above - in alkali nol is cyclized with 1-4 carbon atoms dehalogenated with an alkali metal hydroxide with heating, or b) an acryloyl-urea derivative of the general formula (V) CH = CR - CO - NH - CO - NH - R ¹ (V) wherein R and R are as defined above - in one inert organic solvent is reacted with free halogen of general formula X ", then the resulting acylated urea derivative of general formula (IV) - wherein R, R and X are as defined above - is cyclized in an alkanol of 1-4 carbon atoms dehalogenated with an alkali metal hydroxide under heating, or c) an acyl isocyanate of the general formula (VII) X ¹ X ¹ CH ₀ - C - CO - N = C = O (VII) R 1
- wherein R and X are as defined above - with a primary amine of general formula VI R ¹ - NH ₂ (VI) - wherein R is as defined above - reacted and then the resulting acylated urea derivative of the general formula (IV) - wherein R, R ¹ and X are as defined above - is cyclized in an alkanol having 1-4 carbon atoms with an alkali metal hydroxide under heating dehalogenated , 2 »Method according to item la), characterized in that acetonitrile is used as the aprotic polar solvent. is used » 3, process according to point la), Ib) or Ic), characterized in that methanol is used as the alkanol having 1 to 4 carbon atoms, 4, process according to point la), Ib) or Ic), characterized in that ethanol is used as alkanol with 1-4 carbon atoms « 5, Method according to one of the items 1 to 4, characterized in that is used as the alkali metal hydroxide sodium hydroxide. 6 _e Process according to one of the items 1 to 4, characterized in that potassium hydroxide is used as the alkali metal hydroxide. 7. Method according to one of the items 1 to 6 _e, characterized in that cyclization taking place during the dehalogenation is carried out at a temperature between 40 ^° C. and the boiling point of the reaction mixture, 8. The method according to any one of items 1 to 7, characterized in that during the cyclization occurring during the dehalogenation acylated urea derivatives of the general formula (IV) wherein R and R are as defined in item 1, which contain a chlorine atom at the position of X ¹ . Process according to one of the items 1 to 7, characterized in that acylated urea derivatives of the general formula (IV) are added to the cyclization occurring during the dehalogenation wherein R and R are as defined in item 1, which contain a bromine atom at the position of X.