WO1998001427A1 - Process for preparing pyrazolone derivatives - Google Patents

Abstract

The invention concerns a process for preparing pyrazolone derivatives and their use as well as a process for the η-alkylation of β-ketoesters in the solid phase, alkylated β-ketoesters in the solid phase, and the use of this process.

Description

 Process for the preparation of pyrazolone derivatives

description

The invention relates to a process for the preparation of pyrazolone derivatives and the use thereof.

The invention further relates to a process for the γ-alkylation of β-keto esters on a solid phase, alkylated β-keto esters on a solid phase and the use of the method.

In classical drug search research, the biological effects of new compounds were tested in a random screening of the whole organism, for example the plant or the microorganism. Biological testing was the limiting factor compared to synthetic chemistry. The situation has changed drastically through the provision of molecular test systems by molecular and cell biology.

A large number of molecular test systems, such as receptor binding assays, enzyme assays and Zeil cell interaction assays, have been and are currently being developed for modern drug discovery research. The automation and miniaturization of these test systems enables high sample throughput. Due to this development, an ever increasing number of chemicals can be tested for their biological effects in random screening and thus for a possible use as a lead structure for an active ingredient in medicine, veterinary medicine or in plant protection.

A modern automated test system enables the screening of 100,000 and more chemicals per year for their biological effects in a mass screening.

This development made classic synthetic chemistry the limiting factor in drug discovery research.

If the performance of these test systems is to be fully exploited, the efficiency of the chemical synthesis of active substances must be increased considerably.

Combinatorial chemistry can make a contribution to this required increase in efficiency, especially if it uses automated solid-phase synthesis methods (see review article J. Med. Chem. 1994, 37, 1233 and 1994, 37, 1385). Combinatorial chemistry enables the synthesis of a wide range Diversity of different chemical compounds, so-called substance libraries. The synthesis on the solid phase has the advantage that by-products and excess reactants can be easily removed, so that no complex cleaning of the products is necessary. The finished synthesis products can be mass-screened directly, ie carrier-bound, or after cleavage from the solid phase. Intermediate products can also be tested in mass screening.

Applications described so far are mainly limited to the peptide and nucleotide field (Lebl et al., Int. J. Pept. Prot. Res. 41, 1993: 203 and WO 92/00091) or their derivatives (WO 96/00391). Since peptides and nucleotides can only be used to a limited extent as pharma due to their unfavorable pharmacological properties. it is desirable that of the peptide and

To use nucleotide chemistry known and proven solid phase synthesis methods for synthetic organic chemistry.

No. 5,288,514 reports on one of the first combinatorial solid-phase syntheses in organic chemistry outside of peptide and nucleotide chemistry. US 5 288 514 describes the sequential synthesis of 1,4-benzodiazepines on a solid phase.

WO 95/16712, WO 95/30642 and WO 96/00148 describe further solid-phase syntheses of potential active substances in combinatorial chemistry.

However, in order to be able to take full advantage of the possibilities of modern test systems in mass screening, it is necessary to continuously feed new compounds with the greatest possible structural diversity into mass screening. This procedure considerably reduces the time to identify and optimize a new drug lead structure.

It is therefore necessary to constantly develop new combinatorial solid-phase syntheses. It makes sense to use biologically active compounds as a guide.

Heterocycles are a component of many pharmaceutical and agrochemical active ingredients, for example pyrazolone derivatives are found in analgesics, anti-inflammatory drugs, anti-rheumatic drugs or anti-pyretic drugs. Heterocycles are therefore sought compounds for the synthesis of active substances. It is therefore important to provide efficient methods for their manufacture, especially on a solid phase. Fields ER et al. (Tetrahedron Lett., Vol 37, No. 7, pp 1003-1006, 1996) describes a first solid phase synthesis of pyrazolone derivatives. The disadvantage of this method is that no acid-labile groups may be present in the synthesized molecule, since they would be destroyed by the resin when they are split off. The monoalkylation described on the α-C atom also hinders the subsequent cyclization to the pyrazolone. After the synthesized products have been split off, the resin cannot be recycled.

The object of the present invention was to provide a fast and efficient process for preparing pyrazolone derivatives on the solid phase which does not have the disadvantages mentioned above and which meets the requirements of combinatorial chemistry.

A process for the preparation of pyrazolone derivatives of the formula I has now been found

in which the substituents have the following meaning:

R ¹ , R ² equal or different

Hydrogen, substituted or unsubstituted -CC ₁₀ alkyl, C ₃ -C ₈ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, aryl,

Aryl (-C-Cιo-alkyl) -, aryl (C ₃ -C ₈ alkenyl) -, aryl (C ₃ -C ₆ alkynyl) -, aryl (C ₃ -C ₈ cycloalkyl) -, hetaryl, hetaryl (Ci-Cio-alkyl) -, hetaryl (C ₃ -C ₈ -alkenyl) -, hetaryl (C ₃ -C ₆ -alkynyl) -, hetaryl (C ₃ -C ₈ - cycloalkyl) -,

R3

Hydrogen, substituted or unsubstituted Ci -Cio alkyl -, C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkynyl -, C ₃ -C ₈ cycloalkyl, aryl, C _j -Cio alkylaryl, Aryl (-C-Cιo-alkyl) -, hetaryl, C -.- C _K - alkyl - hetaryl-, hetaryl (Cι-Cι ₀ alkyl) -,

characterized in that compounds of the formula II

®-

R ^R ; ^{2 (II) <} in which (P) means a solid phase, with compounds of the formula III

H ₂ N NH R ³ (III) to compounds of the formula IV

R ³

NH

reacted and split off from the solid phase with cyclization to give compounds of formula I.

R ¹ and R ² in the formulas I, II and IV denote hydrogen, substituted or unsubstituted Ci-Cio-alkyl -, C ₃ -C ₈ alkenyl, C ₃ -C ₆ alkynyl -, C ₃ -C ₈ - Cycloalkyl -, aryl, aryl (Cι-Cιo-alkyl) -, aryl (C ₃ -C ₈ alkenyl) -, aryl (C ₃ -C ₆ alkynyl) -, aryl (C ₃ -C ₈ cycloalkyl) -, hetaryl, hetaryl (Ci -C ₁₀ alkyl) -, hetaryl (C ₃ -C ₈ alkenyl) -, hetaryl (C ₃ -C ₆ alkynyl) -, hetaryl (C ₃ -C ₈ - cycloalkyl) -,

R ¹ and R ² may be the same or different. The above for R ¹ and R ² have the following meanings, for example:

Alkyl branched or unbranched Cι-Cιo-alkyl chains, such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1-methylbutyl , 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4 -Methylpentyl, 1, 1 -Di ethylbutyl, 1, 2 -Dimethylbutyl, 1, 3 -Dimethylbutyl, 2, 2 -Dimethylbutyl,

2, 3 -dimethylbutyl, 3, 3 -dimethylbutyl, 1 -ethylbutyl, 2 -ethyl-butyl, 1, 1, 2-trimethylpropyl, 1, 2, 2 -trimethylpropyl, 1 -ethyl-1-methylpropyl, 1-ethyl - 2-methylpropyl, n-heptyl, n-octyl, n-nonyl or n-decyl,

Alkenyl branched or unbranched C ₃ -C ₈ alkenyl chains, such as, for example, propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylpropenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- Methyl -1-butenyl, 2-methyl-1-butenyl, 3-methyl -1-butenyl, 1-methyl-2-butenyl, 2-methyl -2-butenyl, 3-methyl -2-butenyl, 1-methyl - 3-butenyl, 2-methyl-3-butenyl, 3-methyl -3-butenyl, 1, 1-dimethyl -2-propenyl, 1, 2-dimethyl - 1 - propenyl, 1,2-dimethyl -2-propenyl, 1-ethyl -1-propenyl,

1- ethyl -2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl - 1 - pentenyl, 4-methyl-1-pentenyl, 1-methyl -2-pentenyl, 2-methyl -2-pentenyl, 3-methyl -2-pentenyl, -Methyl -2-pentenyl, 1-methyl -3-pentenyl, 2 -Methyl -3-pentenyl, 3-methyl-3-pentenyl, 4 -methyl -3-pentenyl, 1-methyl-pentenyl, 2-methyl -4-pentenyl, 3-methyl -4-pentenyl, -Methyl -4 -pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl -3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl -2-butenyl, 1,2-dimethyl -3 -butenyl, 1, 3 -dimethyl - 1-butenyl, 1, 3 -dimethyl -2 -butenyl, 1, -dimethyl - 3 -butenyl, 2, 2 -dimethyl -3 -butenyl, 2, 3 -dimethyl - 1 - butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl -2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl -3-butenyl, 2-ethyl -. -butenyl, 2 -ethyl -2 -butenyl, 2-ethyl-3-butenyl, 1, 1, 2 -tri ethyl -2-propenyl, 1 - ethyl-1-methyl -2-propenyl, 1 -ethyl-2 - ethyl - 1-propenyl, 1-ethyl-2-methyl -2-propenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octeny or 7-octenyl,

Alkynyl branched or unbranched C ₃ -CG - alkynyl, such as prop-1 - in-1-yl, prop-2 - in-1-yl, n-but-1-in-1-yl, n-but-l -in-3-yl, n-but-1- in-4 -yl, n-but-2 - in-1 -yl, n-pent-1 - in-l-yl, n-pent-1 - in -3 -yl, n- Pen - 1 - in 4 -yl, n-Pen -1 - in-5-yl, n-Pent-2 - in-1 -yl, n- Pen - 2 - in- 4 -yl, n-Pent-2-in-5-yl, 3-methyl-but-1 - in 3 -yl, 3-methyl-but-1- in-4-yl, n-hex-1 - in - 1 -yl, n-Hex-1 - in 3 -yl, n-Hex-1 - in-4 -yl, n-Hex-l-in-5-yl, n-Hex-1 - in-6 -yl, n-Hex-2 -in-1-yl, n-Hex-2-in-4-yl, n-Hex-2 - in 5 -yl, n-Hex-2 -in-6-yl , n-Hex-3 - in-l-yl, n-Heχ-3-in-2 -yl, 3-methyl-pent-1-in-1 -yl, 3-methyl-pen -1 - in-3 -yl, 3-methyl-pent-1 - in-4 -yl, 3-methyl-pent-1 -in-5-yl, 4-methyl-pent-1-in-1-yl, 4-methyl-pent -2 - in-4 -yl or 4-methyl-pent-2-in-5-yl,

Cycloalkyl branched or unbranched C ₃ -C ₈ cycloalkyl chains with 3 to 8 carbon atoms in the ring, which may optionally contain further heteroatoms in the ring or in the alkyl chain such as N, 0 or S, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, 2-cyclopropyl pentane, 5-cyclopropyl pentane, 2-cyclobutyl butane, 2, 3-dimethyl -3-cyclopropyl propane or 1-methyl -2-cyclopropyl butane, Aryl simple or condensed aromatic ring systems, which may optionally be substituted with one or more radicals such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, thio, alkyl, alkoxy or other saturated or unsaturated non-aromatic rings or ring systems , and are optionally bonded to the basic structure via a Ci -C ₁₀ alkyl, C ₃ -C ₈ alkenyl, C ₃ -C ₆ alkynyl or C ₃ -C ₈ cycloalkyl chain with the abovementioned meaning,

Hetaryl simple or condensed aromatic ring systems with one or more heteroaromatic 3- to 7-membered rings, which may contain one or more heteroatoms such as N, 0 or S, and which may contain one or more residues such as halogen such as fluorine, chlorine or bromine, Cyano, nitro, amino, hydroxy, thio, alkyl, alkoxy or further aromatic or further saturated or unsaturated non-aromatic rings or ring systems can be substituted and optionally via a Ci -Cι ₀ alkyl, C ₃ -C ₈ alkenyl - , C ₃ -C ₆ alkynyl - or C ₃ -C ₈ cycloalkyl chain with the abovementioned meaning are bound to the basic structure.

One or more substituents such as halogen, such as fluorine, chlorine, bromine, cyano, nitro, amino, hydroxy, thio, alkyl, aryl, hetaryl, alkoxy, carboxy, benzyloxy, phenyl, may be used as substituents of the radicals mentioned for R ¹ and R ² or benzyl in question.

R ³ in the formulas I, III or IV denotes hydrogen, substituted or unsubstituted Ci-Cio-alkyl-, C ₂ -C ₈ -alkenyl-, C ₂ -C ₆ -alkynyl -, C ₃ -C ₈ -cycloalkyl -, Aryl, C 1 -C 8 alkylaryl, aryl (C ₁ -C 8 alkyl), hetaryl, C 1 -C ₁₀ alkyl hetaryl, hetaryl (C 1 -C 8 alkyl) -, the said radicals have the following meaning:

Alkyl branched or unbranched Ci -Cirj alkyl chains, such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1-methylbutyl , 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1 -methylpentyl, 2 -methylpentyl, 3 -methylpentyl, - Methylpentyl, 1, 1 -dimethylbutyl,

1,2-dimethylbutyl, 1, 3 -dimethylbutyl, 2, 2 -dimethylbutyl, 2, 3 -dimethylbutyl, 3, 3 -dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1, 1, 2 -trimethylpropyl, 1, 2, 2-trimethyl propyl, 1-ethyl -1-methyl propyl, 1-ethyl -2-methyl propyl, n-heptyl, n-octyl, n-nonyl or n-decyl, Alkenyl branched or unbranched C ₂ -C ₈ alkenyl chains such as, for example, ethenyl, propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -Methyl-1-butenyl, 2-methyl -1-butenyl, 3-methyl-1-butenyl, 1-methyl -2-butenyl, 2-methyl-2-butenyl, 3-methyl -2-butenyl, 1-methyl -3-butenyl, 2-methyl-3-butenyl, 3-methyl -3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl -1-propenyl, 1,2-dimethyl -2-propenyl , 1-ethyl-1-propenyl, 1-ethyl -2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl -1 -pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl , 1-methyl-3-pentenyl, 2-methyl -3-pentenyl, 3-methyl -3-pentenyl, 4-methyl -3-pentenyl, 1-methyl -4-pentenyl, 2-methyl-4-pentenyl, 3 -Methyl - 4-pentenyl, 4 -Methyl -4-pentene yl, 1,1-dimethyl -2-butenyl, 1,1-dimethyl -3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl -3 - butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl , 2,3-dimethyl -2-butenyl, 2,3-dimethyl -3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl -1-butenyl, 1st -Ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 1, 2-tri ethyl -2 - propenyl, 1-ethyl-1-methyl -2 - propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl - 2-methyl -

2-propenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6- Octenyl or 7-octenyl,

Alkynyl branched or unbranched C ₂ -C ₆ alkynyl chains, such as, for example, acetylene, prop-1-in-1-yl, prop-2-in-1-yl, n-but-1-in-1-yl, n - But-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-l-yl, n-pent - 1- in-1-yl, n-pent- 1-in-3 -yl, n-pent-1-in-4-yl, n-pent-1-in-5-yl, n-pent-2-in-1-yl, n-pent-2 - in -yl, n-pent-2-yn-5-yl, 3-methyl-but-1-yn-3-yl, 3-methyl-but-1-yn-4-yl, n-hex-1 -in-l-yl, n-Hex-1 -in-3-yl, n-Hex- 1- in -yl, n-Hex-l-in-5-yl, n-Hex-1 -in- 6 -yl, n-Hex-2 - in- 1-yl, n-Hex-2- in-4-yl, n-Hex-2 -in- 5-yl, n-Hex-2 -in-6- yl, n-hex-3-in-1-yl, n-hex-3-in-2-yl, 3-methyl-pent-1-in-1-yl, 3-methyl-pent-1 - in 3-yl, 3-methyl-pent-l-in-4 -yl, 3-methyl -pent -1 -in- 5-yl, 4-methyl-pent-l-in-l-yl, 4-methyl - pent- 2 - in 4 -yl or 4-methyl -pent- 2 -in -5-yl, Cycloalkyl branched or unbranched C ₃ -C ₈ cycloalkyl chains with 3 to 8 carbon atoms in the ring, which may optionally contain further heteroatoms in the ring or in the alkyl chain such as N, O or S, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , Cyclooctyl, 2-cyclopropylpentane, 5-cyclopropylpentane, 2-cyclobutylbutane, 2,3-dimethyl -3-cyclopropylpropane or 1-methyl-2-cyclopropyl-butane,

Aryl simple or condensed aromatic ring systems which may optionally be substituted by one or more radicals such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, thio, alkoxy or other saturated or unsaturated non-aromatic rings or ring systems, or can optionally be substituted with at least one further Ci -Cι ₀ alkyl chain or via a Cx-Cio-alkyl chain, where Ci -Cio "alkyl in both cases has the meaning given above, are bound to the basic structure, are preferred as aryl radical Phenyl and naphthyl,

Hetaryl simple or fused aromatic ring systems with one or more heteroaromatic 3- to 7-membered rings, which can contain one or more heteroatoms such as N, O or S and optionally with one or more residues such as halogen such as fluorine, chlorine or bromine, cyano, nitro , Amino, hydroxyl, thio, alkoxy or further aromatic or further saturated or unsaturated non-aromatic rings or ring systems may be substituted or may optionally be substituted by at least one further Ci-Cio-alkyl chain or via a Cj -Cι ₀ -alkyl chain, where

Ci-Cio-alkyl in both cases has the meaning given above, to which the basic structure is bound.

One or more of the radicals mentioned for R ³ are alkyl, alkenyl, alkynyl or cycloalkyl

Substituents such as halogen such as fluorine, chlorine, bromine, cyano, nitro, amino, hydroxy, thio, alkyl, aryl, ester, hetaryl, alkoxy, carboxy, benzyloxy, phenyl or benzyl in question.

In formula VII Cι-C ⁴ R ₈ alkyl such as branched or unbranched Cι-C _B alkyl chains, such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1 -methylpropyl -, 2-methyl - propyl, 1, 1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methyl-butyl, 3-methylbutyl, 2, 2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2 -Dimethylpropyl, 1 -methylpentyl, 2-methylpentyl, 3 -methylpentyl, -Methylpentyl, 1, 1 -dimethylbutyl, 1, 2 -dimethylbutyl, 1, 3 -dimethylbutyl, 2, 2 -dimethylbutyl, 2, 3 -dimethylbutyl, 3, 3 -dimethylbutyl, 1 -ethylbutyl, 2 -ethylbutyl,

1, 1, 2 -trimethylpropyl, 1, 2, 2 -trimethylpropyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methylpropyl, n-heptyl or n-octyl, preferably tert. -Butyl, or aryl such as simple or condensed aromatic ring systems, which can be substituted with another saturated or unsaturated non-aromatic ring or ring system.

Both radicals mentioned for R ⁴ can optionally be substituted with one or more radicals such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, thio, alkoxy, alkyl, cycloalkyl, aryl, hetaryl or other radicals.

The variable (P) in formulas II, IV or V means a fixed phase.

The solid phase (P) used in the process according to the invention can be carriers which are known from solid phase peptide synthesis. As far as they are compatible with the synthetic chemistry used, usable supports can consist of a large number of materials. The size of the straps can be varied widely depending on the material. Particles in the range from 1 μm to 1.5 cm are preferably used as carriers, particularly preferably in the case of polymeric carriers, particles in the range between 1 μm and 500 μm, very particularly preferably 50 μm to 300 μm.

The shape of the carrier is arbitrary, spherical particles are preferred. The size distribution of the carriers can be homogeneous or heterogeneous; homogeneous particle sizes are preferred. Mixtures of carriers can also be used.

Suitable solid phases (P) are, for example, ceramics, glass, latex, crosslinked polystyrenes, crosslinked polyacrylamides, resins, silica gels, natural polymers, gold or colloidal metal particles.

In order to enable the reactants to be attached or to be split off after the synthesis, the support must be suitably functionalized or provided with a linker which has a corresponding functional group. Suitable carriers or carrier-linker conjugates are, for example, chlorobenzyl resin (Merrifield resin), Rink resin (Novabiochem), Sieber resin (Novabiochem), Wang resin (Bachern), tentagel resins (Rapp polymers) or Pega- Resin (Polymer Laboratories). Chlorobenzyl resins or tentagel resins are particularly preferred as carriers. A solid phase can be suitably functionalized, for example, via a linker that a free hydroxyl group for connecting compounds of the

Formula VII can provide. To link a preferred linker (L)

HO © OH

with 2 to 12 carbon atoms on the solid phase, this is optionally modified in a manner known to the person skilled in the art. The linker can be branched or unbranched, chiral or achiral.

Examples of diols are ethylene glycol, 1,3-propanediol, 1,2-propanediol, 1,2-butanediol, 1,3-butanediol, 1,2-butanediol, 2,3-butanediol, 1,2-pentanediol, 1,3 Pentanediol, 1,4-pentanediol, 1,5-pentanediol, 2,4-pentanediol, 2-methyl-1,4-butanediol, 1,2-hexanediol, 1,3-hexanediol, 1,4-hexanediol, 1 , 5-hexanediol, 1, 6-hexanediol, 2, 3-hexanediol, 2, 4-hexanediol, 2, 5-hexanediol, 2-methyl-1, 5-pentanediol or 3-methyl-1, 5-pentanediol.

To determine the concentration of the hydroxyl groups of the linker-linked resin, this is reacted with 3,5-dinitrobenzoyl chloride in pyridine; the nitrogen determination of the ester obtained is a measure of the hydroxyl group concentration. This is in the range of 0.5 to 0.85 mmol hydroxyl groups per gram of resin.

The coupling of the preferred linker to Merrif ield resin can, for example, directly in the double-deprotonated form of the linker (Scheme I) in the presence of aprotic, non-polar or polar solvents such as, for example, diethylformamide (DMF), methylene chloride (CH ₂ C1 ₂ ), dimethyl sulfoxide ( DMSO) or tetrahydrofuran (THF).

Scheme I

© OH + NaO © ONa Lösun ^g smittel ^ Δ

(VIII)

© —o— © ^■ OH (IX)

The connection of the preferred linker to the carrier is carried out between 30 and 150 ° C., preferably between 60 and 100 ° C.

The process according to the invention for the preparation of the pyrazolone derivatives can be carried out in four separate steps in accordance with Scheme II; or all four steps can be carried out together in a successive sequence. The method according to the invention can be carried out in a series of parallel automated synthesis approaches. Mixtures of reactants can also be used in a synthesis approach or parallel synthesis approaches. The method can also be used in a split synthesis (Balkenhohl et al. Angew. Chemie 1996, in press).

Scheme II

In principle, the synthesis can be terminated after each synthesis step (a) to (d) and the products of the synthesis stages can be isolated directly or after cleavage from supports and used in mass screening.

The acetoacetic acid from the β-keto esters (VII) is bound to the solid phase (reaction a) at an elevated temperature in the presence of a solvent. As a solvent in principle, all solvents are suitable, expediently high-boiling solvents such as toluene or xylene are used, in which these are swellable when using resins as carriers. Reaction (a) is carried out in a temperature range between 80 to 5 150 ° C., preferably between 100 to 120 ° C. If resins are used as the solid phase, temperatures which are just below the temperature at which the resin is destroyed can be selected as the maximum reaction temperature. Β-keto esters are preferably used for the attachment to the support, in which the radical R ^{4 is} a secondary or tertiary alcohol, preferably tert. -Butanol. These alcohols have a low nucleophilicity and therefore have only a slight tendency to react back to the ß-ketoester after cleavage and thus favor reaction (a). Reaction (a) can advantageously be further favored by using an excess of β-keto esters.

By adding at least 2 equivalents of an organic Li base per equivalent of β-ketoester, the dianion of the solid-phase-bound β-ketoester is formed. The dianion formed can in principle be alkylated with all alkylating agents known to the person skilled in the art [reaction (b)].

Non-nucleophilic bases, preferably non-nucleophilic bulky bases such as LDA (= lithium diisopropylamine), LiHMDS (= lithium hexamethyldisilazide) or LiTMP (= lithium tetraethylpiperidide) are advantageously used as Li -organic bases for reaction (b). Mixtures of the bases mentioned can also be used.

After the monoanion of the β-keto esters has been generated by the aforementioned Li-organic bases, for example by adding at least one equivalent of base per equivalent of β-keto esters, the dianion can also be added by adding another strong base such as n-butyllithium (n-BuLi), sec. -Butyllithium (sec -BuLi) or sodium hydride (NaH) are formed and then alkylated. By removing excess base after formation of the dianion, the mono- γ-alkylated product of the β-keto esters is selectively formed, thereby introducing only one radical R ¹ or R ² .

By adding strong bases again, a dianion can then be formed again, which can be alkylated again, so that two radicals R ¹ and R ² , which may be the same or different, are introduced.

The two substeps described for mono- or dialkylation can also be carried out in one step by adding a multiple excess of base, and the dialkylation product can thus be formed immediately. A can Alkylating agents or a mixture of alkylating agents can be used. When the dianion is formed on the support, the color changes from pale yellow to deep red. The red color disappears again due to the alkylation. This color change can be used as a reaction indicator.

Suitable solvents for reaction (b) are advantageously solvents which are inert to the bases used, for example non-deprotonable solvents such as benzene, THF or petroleum ether.

In principle, all alkylating agents are suitable as alkylating agents VI for the alkylation of the β-keto esters, such as, for example, alkyl halides of chlorine, bromine or iodine, sulfonic acid esters such as nosylates, brosylates, mesylates, tosylates, triflates, tresylates or nonaflates or sulfuric acid esters such as dimethyl sulfate. The alkyl halides are preferred for cost reasons.

If alkenyl or alkynyl radicals are to be transferred in the alkylation reaction - for the introduction of the radicals R ¹ and / or K ² - the carbon atom adjacent to the leaving group, for example to the halide, may advantageously not be part of an aromatic or heteroaromatic ring or part of a double or Be triple bond.

By varying the amount of alkylating agent with the same amount of base, it is also possible to differentiate between mono- and dialkylation, the control under these conditions not being absolute.

The reaction can be driven up to 100% conversion by adding an excess of alkylating agent.

The alkylation is carried out at a temperature of -40 ° C to + 40 ° C, preferably between -10 ° C to + 30 ° C. The reaction is expediently carried out on ice. By adding the alkylating agent, the temperature is allowed to rise up to 25 ° C. during the reaction.

The alkylation takes place exclusively in the γ position. In no case is an alkylation in position observed. After the alkylation, excess base is neutralized and reaction (c) is then carried out.

Reaction (c) introduces a further R ^J radical into the alkylated β-keto esters via hydrazines. Solid phase bound hydrazones are formed. In principle, all aprotic or protic solvents are suitable as solvents; preference is given to protic solvents such as methanol, ethanol, particularly preferably in mixtures with solvents such as THF, which cause the resins to swell well. The reaction 5 is carried out in a temperature range between 0 ° C. to 50 ° C., preferably from 10 ° C. to 35 ° C. In order to achieve complete conversion in reaction (c), it is advantageous to work with a large excess of hydrazines.

10 In reaction (d), the hydrazones are finally cleaved from the solid phase with cyclization to give the corresponding pyrazolone derivatives.

The cleavage with cyclization takes place at elevated temperature 15 in a range from 80 to 150 ° C., preferably between 100 to

120 ° C. In principle, all aprotic and protic solvents are suitable as solvents; preference is given to solvents with a high boiling point such as toluene, xylene or dioxane, particularly preferred solvents which have a high boiling point and can be easily separated from the product such as toluene.

An advantage of the process according to the invention is that the γ-alkylation of the β-keto esters can be stopped selectively at the level of the mono- or dialkylated products. The yields over 25 the entire reaction sequence are between 40 and 76%, depending on the reaction sequence, reactants and product.

The products can be used directly in mass screening without any further cleaning steps. The product purity is over 30 90%. Only the products with structures according to formula IV are split off from the carrier with cyclization. Impurities remain bound to the carrier. The carriers can be reused after the products have been split off.

35 The good yields, the high purity of the products split off and the simple reaction procedure of the process according to the invention make its use in the context of combinatorial synthesis very attractive. It is particularly advantageous in this process, for example, that the use of expensive polymers

40 can be dispensed with, since an inexpensive linker (L) can be connected to any fixed phases for functionalization.

The process is also particularly suitable for the preparation of 5 defined mixtures of pyrazolone derivatives of the formula I, for example in the context of a split synthesis. The solid-phase-bound reaction partner is then reacted with the other reaction partner in accordance with the process described and then, if appropriate, split off from the solid phase with cyclization.

The advantage of this solid phase synthesis lies in the rapid generation of a large number of individual compounds, which can then be tested for their effectiveness in test systems.

For this purpose, the substance mixtures can either be separated beforehand or used directly in the form of a mixture. In the second case, a potential active ingredient is identified after testing.

Another object of the invention is the use of the production method according to the invention for bound or free substance of the formulas I, II or IV for the generation of substance libraries.

This includes both the generation of pyrazolongemics described above and the production of a large number of individual substances of the formulas II or IV, for example by carrying out many reactions of the same type in parallel, in each of which one reaction partner has been changed.

The parallel execution of many similar reactions quickly allows the systematic variation of all functional groups in the formulas I, II or IV.

The substance libraries that can be generated in this way can be quickly checked for a certain effectiveness in what is known as mass screening. This greatly speeds up the search for potent active ingredients.

The following examples serve to further illustrate the invention without restricting it in any way. 10

example 1

Synthesis of Acetoacetate Functionalized Resin V

0 0 0 0

© —OH +. ₀ toluene 100 ° C (VIII or IX) ⁽ 2> (V)

5 g of the functionalized resin VIII or IX were swollen in a 250 ml flask in 20 ml of toluene and mixed with 6 ml (42.8 mmol,

10 10 equiv.) Tert. -Butyl -acetoacetate added. The reaction mixture was then heated to 100 ° C. for 3 h. Towards the end of the reaction, the reaction was carried out in an open vessel (removal of ter-butanol by distillation). When using 20 equivalents tert. -Butylacetoacetate was on this measure

15 waived (preferred variant). After the reaction was complete, the resin was filtered off and washed with toluene, methylene chloride and methanol. The polymeric acetoacetate obtained was dried for 24 h at 55 ° C. in a water jet vacuum.

0 (IR: V = 1742, 1718 cm " ¹ )

Example 2 γ-Alkylation of Polymer-Bound Acetoacetate V (Monoalkylation)

5

5 ml of a freshly prepared 0.45 M solution of LDA in THF (2.25 mmol, 6 equiv.) Were placed in a heated 25 ml two-necked flask under a protective gas atmosphere and cooled to 0.degree. 500 mg (swollen in 5 ml of THF) of resin V were added. 0 The suspension was stirred at the same temperature for 1 h. During the deprotonation, the color of the resin changed from yellow-brown to cherry red (color of the dianion). In order to remove the excess of base, the stirring of the suspension was interrupted and, after the resin 4 had settled, the supernatant was "suctioned off". After adding 5 more 5 ml of absolute THF, the resin was "slurried" again and the cleaning process described above was repeated 3 to 5 times until the filtrate was approximately neutral. For the alkylation resin 4 was reacted in the smallest possible amount

Suspended solvent and the corresponding alkyl halides VI were added. Depending on the reactivity, 2 to 5 equivalents were used. The use of reactive alkylating agents led to a sudden disappearance of the red color of the resin, while when using reactive alkyl halides (= R ¹ -Hal) the decolorization is correspondingly slower. In such cases, the reaction mixture was allowed to warm to 25 ° C and stirred for 12 hours. After the reaction had ended, 10 ml of 2N HCl / THF (1/1) were added to protonate the monoanion 6 and the mixture was stirred for 15 min. The resin 7 obtained was then filtered off, washed with THF, methanol and THF and used in the swollen state (THF) for the next reaction. Alternatively, the polymeric carrier could also be dried in vacuo at 55 ° C.

Example 3 γ - Dialkylation of polymer-bound acetoacetate V

0 0 0 0® Λ7 \ n ^ \ ^ \ LDA

THF, 0 ° C,

(V) (4)

θ

0 0 n - BuLi - R ⁱ - Hal (VI) __ -r _^ ^ ^, THF, 0 ° C ** (P) - 0 ^ - ^ ^ R ^l

THF, 0 → 25 ° C

(6)

5 ml of a freshly prepared 0.45 M solution of LDA in THF (2.25 mmol, 6 equiv.) Were placed in a heated 25 ml two-necked flask under a protective gas atmosphere and cooled to 0 ° C. 500 mg (swollen in 5 ml of THF) of resin V were added. The suspension was stirred at the same temperature for 1 h. During the deprotonation, the color of the resin changed from yellow-brown to cherry red (color of the dianion). In order to remove the excess of base, the stirring of the suspension was interrupted and, after the resin 4 had settled, the supernatant was "suctioned off". After adding a further 5 ml of THF, the resin was "slurried" again and the cleaning process described above was repeated 3 to 5 times (until the filtrate was approximately neutral). For the alkylation reaction, resin 4 was suspended in the smallest possible amount of solvent and the corresponding alkyl was added.

Example 5

Synthesis of 1-phenylhydrazone 11

© -0

500 mg of resin 10 were suspended in 10 ml of toluene and the reaction mixture was heated at 100 ° C. for 5 h. The specified reaction time of 5 hours did not necessarily have to be observed in all cases. Compound 11 could often already be detected in the solution after 15 min (TLC control), so that the reaction could be ended after 1 h. In the case of thermally labile compounds, shorter reaction times should therefore be chosen with regard to the purity of the end products. All of the 1-phenylpyrazolones shown were each thermally stable and survived temperatures of 100 ° C. without damage for several hours. After the reaction had ended (TLC control), the resin was filtered off and washed with toluene. The filtrates were concentrated in vacuo and after drying the pyrazolones 11 were obtained as slightly brownish crystalline compounds in the indicated yields (Table I).

Table I: Pyrazolones made by mono- or dialkylation of the γ-position of acetoacetate

*) Yields are calculated on the free hydroxyl groups of the _Q support VIII or IX

5

Claims

claims

1. Process for the preparation of pyrazolone derivatives of the formula I.

_R ^l 3

in which the substituents have the following meaning:

R ¹ , R ² equal or different

Hydrogen, substituted or unsubstituted Cι-Cιo-alkyl, C ₃ -C ₈ alkenyl -, C ₃ -C ₆ alkynyl] -, C ₃ -C ₈ cycloalkyl, aryl, aryl (Ci -Cι ₀ -Alkγl) -, aryl (C ₃ -C ₈ -alkenyl) -, aryl (C ₃ -C ₆ -alkynyl) -, aryl (C -C ₈ -cycloalkyl) -, hetaryl, hetaryl (Cι-Cιo- Alkyl) -, hetaryl (C ₃ -C ₈ alkenyl) -,

Hetaryl (C ₃ -C ₆ alkynyl) -, hetaryl (C ₃ -C ₈ cycloalkyl) -,

R3

Hydrogen, substituted or unsubstituted

-C-Cιo-alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, aryl, Ci -Cι ₀ alkylaryl -, aryl (Ci -Cι ₀ alkyl), hetaryl, C _x -Cι ₀ alkylhetaryl, hetaryl (Ci -Cio-alkyl) -,

characterized in that compounds of the formula II

in which (P) means a solid phase, with compounds of the formula III

H ₂ N NH R ³ (III) to compounds of the formula IV

^ R3

NH

reacted and split off from the solid phase with cyclization to give compounds of formula I.

2. Process for the γ-alkylation of β-keto esters on a solid phase, characterized in that compounds of the formula V

O 0

(V)

®-o

Deprotonated twice with a non-nucleophilic Li-organic base or initially deprotonated with a non-nucleophilic Li-organic base and then deprotonated twice with a strong base and with an alkylating agent VI to introduce the radicals R ¹ or R ² or both radicals R ¹ and R ² to compounds of formula II

in which the substituents and variables have the following meaning:

(P) a solid phase

R ¹ , R ² equal or different

Hydrogen, substituted or unsubstituted Cι-Cιo-alkyl, C ₃ -C ₈ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, aryl, aryl (C _x -C ₁₀ - alkyl) -, aryl (C ₃ -C ₈ -alkenyl) -, aryl (C ₃ -C ₆ -alkynyl) -, aryl (C ₃ -C ₈ -cycloalkyl) -, hetaryl, hetaryl (Ci -Cι _0- alkyl) -, hetaryl (C ₃ -C ₈ -alkenyl) -, hetaryl (C ₃ -C ₆ -alkynyl) -, hetaryl (C ₃ -C ₈ -cycloalkyl) -, is reacted.

3. The method according to claim 2, characterized in that one uses a non-nucleophilic Li-organic base selected from the group LDA, LiHMDS, LiTMP or tert-BuLi.

4. The method according to claim 2 or 3, characterized in that one carries out the γ-alkylation in a temperature range between -40 ° C and + 25 ° C.

5 5. Process according to claims 2 to 4, characterized in that one carries out the γ-alkylation in an aprotic solvent.

6. Process for the preparation of solid-phase-bound β-keto 10 esters, characterized in that compounds of the formula VII

O 0

H - 0 ^IVII > ^*

15 in which R ⁴ is Cι-C _θ alkyl or aryl, at elevated temperature to a solid phase (P) to compounds of formula V

implements.

25 7. The method according to claim 6, characterized in that one carries out the binding of the ß-ketoester in a temperature range between 80 ° C to 150 ° C.

8. Compounds of formula II according to claim 1. 30

9. Compounds of formula IV according to claim 1.

10. Compounds of formula V according to claim 6.

35 11. Compounds of formula II, IV and V according to claims 8 to 10, wherein the solid phase (P) ceramic, glass, latex, cross-linked polystyrenes, cross-linked polyacrylamides, resins, silica gels, natural polymers, gold or colloidal metal particles means.

40

12. Use of a method according to claim 1 for the production of substance libraries.

13. Use of a method according to claim 2 for the production 5 of substance libraries.

14. Use of the substance libraries according to claim 12 or 13 in mass screening.