DE19601189A1 - High yield and economical preparation of 1,2,4-tri:azolin-3(2H)-one(s) - Google Patents

Abstract

Preparation of 1,2,4-triazolin-3(2H)-ones of formula (I) comprises: (a) reaction of an amide of formula R<1>NHC(=O)CH(R<2>)R<3> (V) with phosgene or thiophosgene (or a substitute for phosgene or thiophosgene) to give a compound of formula (VI); and (b) reaction of (VI) with a compound of formula QNHNHCOR<16> (VII) or its acid addition salt in the presence of a base and finally an acid to give (I). Steps (a) and (b) are optionally conducted in a solvent and step (b) may be at an increased temperature. X = O or S; R<1> = 2-8C alkoxyalkyl, 2-8C haloalkoxyalkyl, 3-8C alkoxycarbonylalkyl, 1-8C alkyl, 1-8C haloalkyl, 1-8C cyanoalkyl, 2-8C alkylthioalkyl, 2-8C alkylsulphinylalkyl, 2-8C alkylsulphonylalkyl, 7-8C arylalkyl (e.g. benzyl), 2-8C alkenyl, 2-8C haloalkenyl, 2-8C alkynyl or 2-8C haloalkynyl; aryl e.g. naphthyl or phenyl optionally substituted by one or more halo, 1-3C alkyl or OCH3; heteroaryl e.g. pyridine optionally substituted by halo; or a group of formula (a)-(c); R<2>, R<3> = H, 1-8C alkyl, 2-8C alkoxyalkyl, 7-8C aryloxyalkyl, 2 -8C alkylthioalkyl, 7-8C arylalkyl (e.g. benzyl), 2-8C alkenyl, 2-8C haloalkenyl, 2-8C alkynyl, 2-8C haloalkynyl, 1-8C cyanoalkyl, naphthyl or phenyl optionally mono- or di-substituted by 1-4C alkyl, 1-4C alkyloxyalkyl, halo or CF3; R<1>, R<2> may also be bonded to a 5-7-membered ring; Q =1-8C alkyl, 1-8C cycloalkyl, CH(Me)CONR<7>R<8>, 1-8C hydroxyalkyl, C(R<7>R<8>)nA or a group of formula (d); R<4> = H, NHCO(1-8C alkyl), halo or NO2; R<5> = H, NO2, NR<7>R<8>, COOR<9>, halo or NHCO(1-4C alkyl); R<6> = H, halo, 1-3C haloalkyl, benzyl or 1-4C alkoxycarbonyl; R<7> = H, 1-4C alkyl or benzyl; R<8> = H or 1-4C alkyl; R<9> = 1-4C alkyl or phenyl optionally substituted by one or more halo or benzyl; A = benzoyl (optionally substituted by one or more halo), CO2R<9> or a group of formula (e); R<10>-R<12> = H or halo; provided that if Q = group (d), then R<1> = groups (a)-(c); R<13> = H, SO2NH(1-6C alkyl), SO2NH(1-6C haloalkyl), SO2NHCOO(1-6C alkyl), SO2NHCO-phenyl optionally mono-, di- or tri-substituted by halo, 1-3C alkyl, 1-3C alkyloxy, 1-3C haloalkyl or 1-3C haloalkyloxy, SO2NHCO-B, 5-tetrazolyl or 1-4C alkoxycarbonyl; R<14> = H, halo or 1-4C alkyl; R<15> = H, halo, 1-4C alkyl or 1-4C alkyloxy; R<16> = H, 1-5C alkyl, 1-5C haloalkyl, 1-5C alkoxy, 1-5C haloalkoxy, 1-8C cycloalkyl, 1-8C cyclohaloalkyl or 1-8C cyclohaloalkoxy; B = furan, thiophene or N-R<7> pyrrole (all substituted by 2 R<12>); n = 1-4; D, E = CH=CH, N=CH or CH=N; Ar = phenyl optionally mono-, di- or tri-substituted by 1-4C alkyl, 1-4C alkyloxy, halo, trifluoromethyl, nitro, cyano or pyridyl optionally substituted by 1-4C alkyloxy.

Description

The invention relates to a new method of manufacture of 1,2,4-triazolin-3 (2H) -ones, also simplified as a result referred to as triazolinones, a class of compounds of Formula (I)

wherein
X = O or S,
R¹ = (C₂-C₈) alkoxyalkyl, (C₂-C₈) haloalkoxyalkyl, (C₃-C₈) alkoxycarbonylalkyl, (C₁-C₈) alkyl, (C₁-C₈) haloalkyl, (C₁-C₈) cyanoalkyl, (C₂-C₈) alkylthioalkyl , (C₂-C₈) alkylsulfinylalkyl, (C₂-C₈) alkylsulfonylalkyl, (C₇-C₈) arylalkyl such as benzyl, (C₂-C₈) alkenyl, (C₂-C₈) haloalkenyl, (C₂-C₈) alkynyl, (C₂-C₈) Haloalkynyl, aryl such as naphthyl or phenyl, which may be substituted one or more times with halogen, (C₁-C₃) alkyl or OCH₃, heteroaryl such as pyridine, which may be substituted with halogen,
or one of the structures (II), (III) or (IV)

means
R² and R³, independently of one another, H, (C₁-C₈) alkyl, (C₂-C₈) alkoxyalkyl, (C₇-C₈) aryloxyalkyl, (C₂-C₈) alkylthioalkyl, (C₇-C₈) arylalkyl such as benzyl, (C₂-C₈ ) Alkenyl, (C₂-C₈) haloalkenyl, (C₂-C₈) alkynyl, (C₂-C₈) haloalkynyl, (C₁-C₈) cyanoalkyl, naphthyl or phenyl optionally substituted with one or two substituents from the group (C₁-C₄) alkyl , (C₁-C₄) alkyloxy, halogen or CF₃,
where R¹ and R² can also be linked to form a 5-, 6- or 7-membered ring,
Q = (C₁-C₈) alkyl, (C₁-C₈) cycloalkyl, CH (Me) CONR⁷R⁸, (C₁-C₈) hydroxyalkyl,
or represents one of the radicals Q-1 or Q-2

wherein
R⁴ = H, NH-CO (C₁-C₈) alkyl, halogen or NO₂,
R⁵ = H, NO₂, NR⁷R⁸, COOR⁹, halogen or NHCO (C₁-C₄) alkyl,
R⁶ = H, halogen, (C₁-C₃) haloalkyl, benzyl or (C₁-C₄) alkoxycarbonyl,
R⁷ = H, (C₁-C₄) alkyl or benzyl,
R⁸ = H or (C₁-C₄) alkyl,
R⁹ = (C₁-C₄) alkyl or phenyl, which can optionally be substituted one or more times by halogen, benzyl,
A = benzoyl, which can optionally be substituted one or more times with halogen, CO₂R⁹,
or for the rest

stands, where
R¹⁰ and R¹¹, independently of one another, represent H or halogen,
with the proviso that if Q = Q-1, then R1 represents one of the structures (II), (III) or (IV),
R ¹² = H or halogen,
R ¹³ = H, SO₂NH (C₁-C₆) alkyl, SO₂NH (C₁-C₆) haloalkyl, SO₂NHCOO (C₁-C₆) alkyl, SO₂NHCO-phenyl, optionally with halogen, (C₁-C₃) alkyl, (C₁-C₃) Alkyloxy, (C₁-C₃) haloalkyl, (C₁-C₃) haloalkyloxy may be monosubstituted, disubstituted or trisubstituted, means SO₂NHCO-B, 5-tetrazolyl or (C₁-C₄) alkoxycarbonyl,
R ¹⁴ = H, halogen or (C₁-C₄) alkyl,
R ¹⁵ = H, halogen, (C₁-C₄) alkyl or (C₁-C₄) alkyloxy,
B represents one of the radicals B-1, B-2 or B-3,

where R⁷ and R¹² has the meaning given above,
n = 1-4,
D = E = CH = CH, N = CH or CH = N,
Ar = phenyl optionally substituted with up to three substituents from the group (C₁-C₄) alkyl, (C₁-C₄) alkyloxy, halogen, trifluoromethyl, nitro, cyano, or pyridyl optionally substituted with (C₁-C₄) alkyloxy,
means.

The compounds of the formulas (I) are highly effective Drugs that are active as angiotensin II antagonists and thus new treatments for high blood pressure enable. Compounds of formula (I) also act as Antidepressants or 5 HT2A antagonists. They also serve the treatment of diseases caused by Heliobacter to be triggered. Modern medicine can still do today not specific diseases, such as chronic gastritis, which caused by Heliobacter, satisfactory to treat. Triazolinones, their preparation according to the here claimed methods are extremely potent Remedies for diseases that affect the action of Heliobacter are attributable.

US-A-4,487,773 describes a triazolinone synthesis that of a monosubstituted aliphatic hydrazine that with N-ethoxycarbonylthiopropionamide in an inert Solvent is condensed at elevated temperature. The disubstituted triazolinone is mixed with a Alkylating agent in a separate reaction step to Final molecule implemented. Isolation of the intermediates is necessary with this procedure.

PCT / WO 94/18978 lists a synthesis of triazolinones, which starts from an aromatic phenyl carbamate, which with Hydrazine monohydrate reacts to the hydrazine carboxamide. The Compound is then in with methanimidamide acetate DMF condenses at 160 ° C to the disubstituted triazolinone, that in a further reaction step to trisubstituted end molecule is implemented. This variant  has a large number of synthetic single steps and succeeds in the condensation step to the five-membered ring in only 28% yield.

EP-A2 0 412 594 leads to several processes Triazolinone synthesis. The most important variant includes the use of a carboxyl hydrazide that with a Arylmethyl isocyanate to 1-acyl-4- (arylmethyl) semicarbazide reacted, and base catalyzed to disubstituted Cyclized triazolinone. In the presence of a base U.S. 4,487,773 to the trisubstituted heterocycle alkylated.

Another variant that is also frequently used, see M. Pesson, S. Dupin and M. Antoine, Compt. Rend., 253, 285 (1961) and R. Un, A. Ikizler, Chim. Acta. Turc., 3, 133 (1975), describes the reaction of an imidate, which, from a Produced nitrile, an adduct with carboxyethyl hydrazine provides that with a primary arylmethylamine Cyclized temperatures between 70 and 150 ° C and after separate alkylation, the trisubstituted triazolinone delivers. The condensation step takes place in one Example listed in EP 0 412 594 A2 only with 42% Yield.

The known methods listed have the disadvantages that they only have long synthetic routes, z. T. about Intermediate stages that are complex to manufacture and treat lead, are feasible, moderate yields deliver and create various by-products that result in complex cleaning stages.

The object of the invention is therefore a method for To provide the above disadvantages does not own and is economically more attractive.  

The object of the inventive method for Preparation of compounds of the general formula (I)

wherein
X = O or S,
R¹ = (C₂-C₈) alkoxyalkyl, (C₂-C₈) haloalkoxyalkyl, (C₃-C₈) alkoxycarbonylalkyl, (C₁-C₈) alkyl, (C₁-C₈) haloalkyl, (C₁-C₈) cyanoalkyl, (C₂-C₈) alkylthioalkyl , (C₂-C₈) alkylsulfinylalkyl, (C₂-C₈) alkylsulfonylalkyl, (C₇-C₈) arylalkyl such as benzyl, (C₂-C₈) alkenyl, (C₂-C₈) haloalkenyl, (C₂-C₈) alkynyl, (C₂-C₈) Haloalkynyl, aryl such as naphthyl or phenyl, which may be substituted one or more times with halogen, (C₁-C₃) alkyl or OCH₃, heteroaryl such as pyridine, which may be substituted with halogen,
or one of the structures (II), (III) or (IV)

means
R² and R³, independently of one another, H, (C₁-C₈) alkyl, (C₂-C₈) alkoxyalkyl, (C₇-C₈) aryloxyalkyl, (C₂-C₈) alkylthioalkyl, (C₇-C₈) arylalkyl such as benzyl, (C₂-C₈ ) Alkenyl, (C₂-C₈) haloalkenyl, (C₂-C₈) alkynyl, (C₂-C₈) haloalkynyl, (C₁-C₈) cyanoalkyl, naphthyl or phenyl optionally substituted with one or two substituents from the group (C₁-C₄) alkyl , (C₁-C₄) alkyloxy, halogen or CF₃,
where R¹ and R² can also be linked to form a 5-, 6- or 7-membered ring,
Q = (C₁-C₈) alkyl, (C₁-C₈) cycloalkyl, CH (Me) CONR⁷R⁸, (C₁-C₈) hydroxyalkyl,
or represents one of the radicals Q-1 or Q-2

wherein
R⁴ = H, NH-CO (C₁-C₈) alkyl, halogen or NO₂,
R⁵ = H, NO₂, NR⁷R⁸, COOR⁹, halogen or NHCO (C₁-C₄) alkyl,
R⁶ = H, halogen, (C₁-C₃) haloalkyl, benzyl or (C₁-C₄) alkoxycarbonyl,
R⁷ = H, (C₁-C₄) alkyl or benzyl,
R⁸ = H or (C₁-C₄) alkyl,
R⁹ = (C₁-C₄) alkyl or phenyl, which can optionally be substituted one or more times by halogen, benzyl,
mean,
A = benzoyl, which can optionally be substituted one or more times with halogen, CO₂R⁹,
or for the rest

stands, where
R¹⁰ and R¹¹, independently of one another, represent H or halogen,
with the proviso that if Q = Q-1, then R1 represents one of the structures (II), (III) or (IV),
R¹² = H or halogen,
R¹³ = H, SO₂NH (C₁-C₆) alkyl, SO₂NH (C₁-C₆) haloalkyl, SO₂NHCOO (C₁-C₆) alkyl, SO₂NHCO-phenyl, optionally with halogen, (C₁-C₃) alkyl, (C₁-C₃) alkyloxy , (C₁-C₃) haloalkyl, (C₁-C₃) haloalkyloxy may be monosubstituted, disubstituted or trisubstituted, means SO₂NHCO-B, 5-tetrazolyl or (C₁-C₄) alkoxycarbonyl,
R¹⁴ = H, halogen or (C₁-C₄) alkyl,
R¹⁵ = H, halogen, (C₁-C₄) alkyl or (C₁-C₄) alkyloxy,
B represents one of the radicals B-1, B-2 or B-3,

where R⁷ and R¹² has the meaning given above,
n = 1-4,
D = E = CH = CH, N = CH or CH = N,
Ar = phenyl optionally substituted with up to three substituents from the group (C₁-C₄) alkyl, (C₁-C₄) alkyloxy, halogen, trifluoromethyl, nitro, cyano, or pyridyl optionally substituted with (C₁-C₄) alkyloxy,
means
is solved by using amides of the general formula (V),

wherein R¹, R² and R³ have the meaning given above, with phosgene or thiophosgene, or a phosgene substitute or Thiophosgene substitute, optionally in a solvent a compound of the formula (VI),

wherein X, R¹, R² and R³ have the meaning given above own, react and this compound of formula (VI) then with a compound of formula (VII) or an acid addition salt of (VII)

Q-NH-NH-CO-R¹⁶ (VII)

wherein Q has the meaning given above, and R¹⁶ for H, (C₁-C₅) alkyl, (C₁-C₅) haloalkyl, (C₁-C₅) alkoxy, (C₁-C₅) Haloalkoxy, (C₁-C₈) cycloalkyl, (C₁-C₈) cyclohaloalkyl, (C₁-C₈) cycloalkoxy, (C₁-C₈) cyclohaloalkoxy, optionally in the presence of a diluent and optionally first in the presence of a base and then in the presence of an acid and optionally through Temperature increase to a compound of the formulas (I) implements.

Advantageous variants of the method according to the invention are in the claims referring back to claim 1 Protection.

Under the designation "alkyl groups" are both "straight-chain" as well as "branched" alkyl groups understand. Under the name "straight chain alkyl group" are, for example, residues such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, under "branched alkyl group" Residues such as isopropyl or tert-butyl understand. "Cycloalkyl" includes residues such as, for example Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or Understand cycloheptyl. The term halogen stands for Fluorine, chlorine, bromine or iodine. The term "alkoxy group" represents residues such as methoxy, ethoxy, propoxy, Butoxy, isopropoxy, isobutoxy or pentoxy.

Can preferably with the inventive method the following compounds a) to n) are produced:

• a) 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl- 2,4-dihydro-4- (2-phenoxyethyl) -3H-1,2,4-triazol-3-one- Hydrochloride
• b) 5-acetyl-2- [3- [4- (3-chlorophenyl) piperazin-1-yl] propyl] - 4- (2-phenoxyethyl) -3,4-dihydro-2H-1,2,4-triazol-3-one  
• c) 5-Butyl-2- (2-chlorophenyl) -4- [2 ′ - (1H-tetrazole-5- yl) biphenyl-4-ylmethyl] -3,4-dihydro-2H-1,2,4-triazole-3- one
• d) N- [4-bromo-3- [4- (2 ′ - (tert-butoxycarbonylaminosulfonyl) - 3-fluorobiphenyl-4-ylmethyl] -3-ethyl-5-oxo-4,5-dihydro- 1H-1,2,4-triazol-1-yl] phenyl] pentanamide
• e) 4- [2 ′ - (N-benzoylsulfamoyl) biphenyl-4-ylmethyl] -5-butyl- 2- [2- (trifluoromethyl) phenyl] -3,4-dihydro-2H-1,2,4- triazol-3-one
• f) N- [4 ′ - [3-butyl-5-oxo-1- [5-propionamido-2- (trifluoromethyl) phenyl] -4,5-dihydro-1H-1,2,4-triazole- 4-ylmethyl] biphenyl-2-ylsulfonyl] carbamic acid tert-butyl ester
• g) 5- [3-butyl-5-oxo-4- [2 ′ - (1H-tetrazol-5-yl) biphenyl-4- ylmethyl] -4,5-dihydro-1H-1,2,4-triazole-1- yl] methyl pentanoate
• h) 4- [2 ′ - [N- (tert-butoxycarbonyl) sulfamoyl] -5- propylbiphenyl-4-ylmethyl] -5-butyl-2- [2- (trifluoromethyl) phenyl] -3,4-dihydro-2H-1,2,4-triazole- 3-one
• i) N- [4 ′ - [3-butyl-5-oxo-1- [2- (trifluoromethyl) phenyl] -4.5- dihydro-1H-1,2,4-triazol-4-ylmethyl] biphenyl-2- ylsulfonyl] -3-chlorothiophene-2-carboxamide
• j) 2- [5-acetamido-2-chlorophenyl) -5-butyl-4- [3-fluoro-2- [N- (2-fluorobenzoyl) sulfamoyl] -5-propylbiphenyl-4- ylmethyl] -3,4-dihydro-2H-1,2,4-triazol-3-one
• k) 2,5-dibutyl-4- [2 ′ - (1H-tetrazol-5-yl) biphenyl-4- ylmethyl] -3,4-dihydro-2H-1,2,4-triazol-3-one
• l) 5-butyl-4- (2 ′ - [N- (2-chlorobenzoyl) sulfamoylibiphenyl-4- ylmethyl] -2- [2- (trifluoromethyl) phenyl] -3,4-dihydro-2H- 1,2,4-triazol-3-one potassium salt  
• m) 4 ′ - [5-butyl-3-oxo-2- [2- (trifluoromethyl) phenyl] -3,4- dihydro-2H-1,2,4-triazol-4-ylmethyl] -N- (2- chlorobenzoyl) biphenyl-2-sulfonamide potassium salt
• n) N- [4 ′ - [3-butyl-5-oxo-1- [2- (trifluoromethyl) phenyl] -4,5- dihydro-1H-1,2,4-triazol-4-ylmethyl] biphenyl-2- ylsulfonyl] carbamic acid tert.butyl ester.

A synthesis variant is preferred in which the Compounds of the formulas (VI)

by conversion of the amides (V)

with 2-6 molar equivalents of phosgene or phosgene substitute, in an inert organic solvent, for example in an aromatic solvent such as toluene, chlorobenzene, a halogenated hydrocarbon such as chloroform, Methylene chloride, an ether such as diisopropyl ether, tert. Butyl methyl ether, tetrahydrofuran or diethyl ether, Acetonitrile or carboxylic acid esters, for example Ethyl acetate, methyl acetate or Isopropyl acetate, at temperatures between -20 ° C to + 120 ° C, preferably -20 ° C to + 70 ° C in  known in literature according to US-A-3,080,358 in high Yield is obtained and then with the compound of formula (VII) or an acid addition salt, such as for example an HCl or H₂SO₄ salt

Q-NH-NH-CO-R¹⁶ (VII)

in the same solvent or in another, above mentioned solvents optionally in the presence of a Acid acceptor, for example an organic base such as Triethylamine, tetramethylpiperidine, tributylamine or Pyridine or an inorganic base such as NaOH, KOH, Ca (OH) ₂, Na₂CO₃, K₂CO₃, CaCO₃, CaO, NaHCO₃, KHCO₃ or Alcoholates such as NaOCH₃ or NaOC₂H₅₁ is combined, wherein first the compound (VIII) is formed,

which then optionally in the presence of an organic or inorganic acid such as HCl, H₂SO₄ HNO₃, HCO₂H, p-toluenesulfonic acid, acetic acid, camphorsulfonic acid or H₃PO₄ or an acidic ion exchanger and / or with an increase in temperature, for example up to the boiling point of the solvent used, in the compounds of the Formula (I) is transferred. Preferably the Cyclization of (VIII) to (I) with acid catalysis and / or Temperature increase carried out. Follow-up reactions, such as for example alkylations or acylations optionally without intermediate insulation in the same solvent respectively.  

In the implementation of the compounds (VIII) preferably 1-4 molar equivalents of base, particularly preferred 1.5-3.5 molar equivalents of base were added, with 1 mole equivalent of base is used from the acyl used phenylhydrazine · HCl the corresponding acylphenylhydrazine release. For transferring (cyclizing) the connection (VIII) in (I) a certain excess of acid is necessary. It shows that the reaction accelerates all the more becomes, the larger the excess acid. The amount of added acid is based on that previously used Amount of base. Particularly preferred acids are H₂SO₄ and HCl.

The amides of the general structure (V) are commercial available or can be represented analogously to Houben-Weyl, "Methods der Organic Chemistry ", ES, part 2, p. 934ff.

In the method according to the invention is skillful Reaction management of the amide unit (V) over the economical very interesting phosgenation or thiophosgenation in a step activated twice, so that a procedurally and economically much more complex, step-by-step activation is avoided. Also done in the method according to the invention, the cyclization to (I) starting from (VI) and (VII) in one process step, without in the meantime necessary processing, in which desired way. That means opposite known methods a clear, procedural The advantage of this is that coupling, splitting off the Protecting group and cyclization to the compound of formula (I) can be implemented in just one step.

Through the procedure described, the reaction starting from (VI) and (VII) in the one-pot process and without Isolation of intermediate stages take place, so that complex Refurbishment techniques are avoided and at process according to the invention a smooth course of the reaction is made possible and a by-product formation largely  avoided and the overall yield of (I) is increased. Likewise can the reaction with isolation of the respective intermediates (VIII) respectively.

The invention is further illustrated by the embodiments explained, but is not limited to this.

Examples 1) Formic acid N '- (2,4-dichloro) hydrazide sodium salt

2,4-Dichlorophenylhydrazine hydrochloride (10.7 g, 0.05 mol) is added at RT to a solution of a 30% methanolic solution of sodium methoxide (22.5 g, 0.125 mol) in methanol. A suspension is formed to which methyl formate (62 ml, 1 mol) is added at the same temperature. The mixture is then stirred at 40-50 ° C for 1.5 h and then at RT overnight. The product is filtered off, washed and concentrated. The residue is taken up in toluene and when concentrated, a light brown powder forms, which is combined with the filter residue mentioned above.
Yield: 11.6 g (= 99%)

2) 2- [2,4-dichlorophenyl] -5,6,7,8-tetrahydro-1,2,4-triazo-1,2,4- [4,3- a] pyridin-3 (2H) -one

To a stirred suspension of formic acid N '- (2,4-dichlorophenyl) hydrazide (4.12 g, 0.02 mol) in 250 ml of acetonitrile is N-chlorocarbonyl-2-chloro at 0-10 ° C in 20 min -1,4,5,6-tetrahydropyridine (4.32 g, 0.024 mol) dissolved in 20 ml of acetonitrile. Triethylamine (4.04 g, 0.04 mol), dissolved in 20 ml of acetonitrile, is then added. The mixture is stirred at 5-10 ° C. for 1 h and a colorless precipitate precipitates out. The mixture is heated to 50-55 ° C. for 3.5 h and then stirred at RT for one night. The mixture is mixed with 30 ml of 6N hydrochloric acid and stirred at 50 ° C for 1 h. The solvent is removed and the residue is digested with ice water. The resulting light gray precipitate is separated off by filtration, washed with water and dried at 50-60 ° C.
Yield: 5.2 g (= 95%)

Claims (10)

1. Process for the preparation of compounds of the formulas (I) wherein
X = O or S,
R¹ = (C₂-C₈) alkoxyalkyl, (C₂-C₈) haloalkoxyalkyl, (C₃-C₈) alkoxycarbonylalkyl, (C₁-C₈) alkyl, (C₁-C₈) haloalkyl, (C₁-C₈) cyanoalkyl, (C₂-C₈) alkylthioalkyl , (C₂-C₈) alkylsulfinylalkyl, (C₂-C₈) alkylsulfonylalkyl, (C₇-C₈) arylalkyl such as benzyl, (C₂-C₈) alkenyl, (C₂-C₈) haloalkenyl, (C₂-C₈) alkynyl, (C₂-C₈) Haloalkynyl, aryl such as naphthyl or phenyl, which may be substituted one or more times with halogen, (C₁-C₃) alkyl or OCH₃, heteroaryl such as pyridine, which may be substituted with halogen,
or one of the structures (II), (III) or (IV) means
R² and R³, independently of one another, H, (C₁-C₈) alkyl, (C₂-C₈) alkoxyalkyl, (C₇-C₈) aryloxyalkyl, (C₂-C₈) alkylthioalkyl, (C₇-C₈) arylalkyl such as benzyl, (C₂-C₈ ) Alkenyl, (C₂-C₈) haloalkenyl, (C₂-C₈) alkynyl, (C₂-C₈) haloalkynyl, (C₁-C₈) cyanoalkyl, naphthyl or phenyl optionally substituted with one or two substituents from the group (C₁-C₄) alkyl , (C₁-C₄) alkyloxy, halogen or CF₃,
where R¹ and R² can also be linked to form a 5-, 6- or 7-membered ring,
Q = (C₁-C₈) alkyl, (C₁-C₈) cycloalkyl, CH (Me) CONR⁷R⁸, (C₁-C₈) hydroxyalkyl,
or represents one of the radicals Q-1 or Q-2 wherein
R⁴ = H, NH-CO (C₁-C₈) alkyl, halogen or NO₂,
R⁵ = H, NO₂, NR⁷R⁸, COOR⁹, halogen or NHCO (C₁- C₄) alkyl,
R⁶ = H, halogen, (C₁-C₃) haloalkyl, benzyl or (C₁-C₄) alkoxycarbonyl,
R = H, (C₁-C₄) alkyl or benzyl,
R⁸ = H or (C₁-C₄) alkyl,
R⁹ = (C₁-C₄) alkyl or phenyl, which can optionally be substituted one or more times by halogen, benzyl,
mean,
A = benzoyl, which can optionally be substituted one or more times with halogen, CO₂R⁹, or for the rest stands, where
R¹⁰ and R¹¹, independently of one another, represent H or halogen,
with the proviso that if Q = Q-1, then R1 represents one of the structures (II), (III) or (IV),
R¹² = H or halogen,
R¹³ = H, SO₂NH (C₁-C₆) alkyl, SO₂NH (C₁-C₆) haloalkyl, SO₂NHCOO (C₁-C₆) alkyl, SO₂NHCO-phenyl, optionally with halogen, (C₁-C₃) alkyl, (C₁-C₃) alkyloxy , (C₁-C₃) haloalkyl, (C₁-C₃) haloalkyloxy may be monosubstituted, disubstituted or trisubstituted, means SO₂NHCO-B, 5-tetrazolyl or (C₁-C₄) alkoxycarbonyl,
R¹⁴ = H, halogen or (C₁-C₄) alkyl,
R¹⁵ = H, halogen, (C₁-C₄) alkyl or (C₁-C₄) alkyloxy,
R¹⁶ = H, (C₁-C₅) alkyl, (C₁-C₅) haloalkyl, (C₁-C₅) alkoxy, (C₁-C₅) haloalkoxy, (C₁-C₈) cycloalkyl, (C₁-C₈) cyclohaloalkyl, (C₁-C₈ ) Cycloalkoxy or (C₁-C₈) cyclohaloalkoxy means
B represents one of the radicals B-1, B-2 or B-3, where R⁷ and R¹² has the meaning given above,
n = 1-4,
D = E = CH = CH, N = CH or CH = N,
Ar = phenyl optionally substituted with up to three substituents from the group (C₁-C₄) alkyl, (C₁-C₄) alkyloxy, halogen, trifluoromethyl, nitro, cyano, or pyridyl optionally substituted with (C₁-C₄) alkyloxy,
means
characterized,
that amides of the general formula (V), wherein R¹, R² and R³ have the meaning given above, with phosgene or thiophosgene, or a phosgene substitute or thiophosgene substitute, optionally in a solvent to give a compound of the formula (VI) wherein X, R¹, R² and R³ have the meaning given above, and this compound of the formula (VI) is then reacted with a compound of the formula (VII) or an acid addition salt of (VII) Q-NH-NH-CO-R¹⁶ (VII ) wherein Q and R¹⁶ have the meaning given above, optionally in the presence of a diluent and optionally first in the presence of a base and then in the presence of an acid and optionally by increasing the temperature to give a compound of the formulas (I). 2. The method according to claim 1, characterized, that the synthesis sequence based on the compounds of the formula (VI) and (VII) without intermediate insulation in a reaction vessel to (I). 3. The method according to claim 2, characterized, that the synthesis sequence without changing the solvent respectively. 4. The method according to claim 1, characterized, that as acid organic or inorganic acids such as for example HCl, H₂SO₄ HNO₃, HCO₂H,  p-toluenesulfonic acid, acetic acid, camphorsulfonic acid or H₃PO₄ or an acidic ion exchanger used will. 5. The method according to claim 4, characterized, that as acid hydrochloric acid, sulfuric acid or Phosphoric acid is used. 6. The method according to claim 2, characterized, that the reaction sequence at a temperature between -20 ° C and 120 ° C, preferably between -20 ° C and 80 ° C, is carried out. 7. The method according to claim 2, characterized, that as a solvent, ethyl acetate or Acetonitrile or mixtures of the two can be used. 8. The method according to claim 1, characterized, that as a base an organic base, an inorganic Base or an alcoholate is used. 9. The method according to claim 8, characterized, that as base preferably triethylamine, tributylamine, Pyridine, tetramethylpiperidine, NaOH, KOH, Ca (OH) ₂, Na₂CO₃, K₂CO₃, CaCO₃, NaHCO₃, KHCO₃, NaOCH₃ or NaOC₂H₅ is used. 10. The method according to claim 9, characterized, that as a base particularly preferably K₂CO₃, Na₂CO₃, Triethylamine or tributylamine can be used.