DE19609272C2 - Process for the parallel synthesis of large numbers of 2,6-disubstituted quinoline derivatives - Google Patents

Description

The present invention relates to a method for the parallel synthesis of large numbers of 2.6- disubstituted quinoline derivatives.

The quinoline scaffold 1 is found in a variety of pharmacologically interesting substances. Chinchona alkaloids are among the best known derivatives found in nature. The pronounced antitumor effect of camptothecin 2 in a number of animal models makes the interest in this natural pyrroloquinoline and its synthetic modifications understandable (J. Med. Chem. 1991, 34, 98). Further examples from the recent literature describe synthetic quinoline derivatives 3, 4 as inhibitors of dehydroorotate dehydrogenase (J. Heterocyclic Chem. 1995, 32, 963) or as antagonists of the 5HT ₃ receptor (J. Med. Chem. 1995, 38, 2692 ).

Process for the parallel production of large numbers of connections, which then as Libraries ("libraries") are referred to under the keyword "combinatorial Chemistry "is already well known. They are used primarily for the production of peptide Libraries also for the production of large numbers of low molecular weight non-oligomeric ones Molecules used (WO 95/19359; WO 90/15070; WO 92/10092; WO 93/06121; WO 95/16712; WO 95/12608; WO 95/13538; WO 94/08711).  

The object of the present invention is to provide a method which is parallel Production of a large number of different 2,6-disubstituted quinoline derivatives possible. Such a process for 2,6-disubstituted quinoline derivatives is not yet available known.

It was first found that compounds of general formula I are in solution can be produced as shown below for representative 10:

The phenolic hydroxyl group at 5 is about 5-bromovaleric acid or cheaper an ester, here the ethyl ester, in an inert solvent such as acetonitrile, Dimethylformamide (DMF) or tetrahydrofuran (THF) in the presence of a base (e.g. Potassium / cesium carbonate) etherified at elevated temperature, 5 → 6.

The alkylation product is isolated and an aldol addition - here with acetophenone in Acetonitrile, THF or DMF in the presence of a base such as potassium / cesium carbonate cast, 6 → 7. The reaction can take place at room temperature or at elevated Temperature if a shorter reaction time is desired. To form the heterocycle a reducing agent, preferably tin (II) chloride in ethanol, is allowed to rise Apply temperature to the aldol adduct. The reaction product obtained from this Transformation of a mixture of quinoline and the corresponding N-oxide, the the latter predominates (80:20), 7 → 8/9. A second reduction of the raw product, for example with  Titanium (III) chloride in an inert solvent such as dichloromethane gives at room temperature in a uniform form the desired quinoline, 8 → 9.

The last variable building block is then installed by aminolysis of the ester, 9 → 10. Im In the present case, the ester is treated with i-butylamine or 3,4,5-trimethoxyaniline (example 6) in an inert solvent such as toluene in the presence of trimethyl aluminum Room temperature, or slightly above, stirred and the end product after aqueous Processing finally cleaned by chromatography.

An economical production of large numbers of quinoline derivatives according to this scheme requires the synthesis to be transferred to a suitable solid support.

It has now been found that 2,6-disubstituted quinoline derivatives of the general formula I

wherein
A is an amino group -NR ¹ R ² , in which R ¹ and R ² independently of one another for a hydrogen atom or for a straight-chain C ₁ - to C ₂₀ - or branched-chain C ₃ - to C ₂₀ radical, or C ₃ -C ₂₀ cyclic (cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl ring, adamantyl radical), optionally aromatic (phenyl, naphthyl or biphenyl radical; furyl, pyridinyl, thienyl, indolyl, pyrazolyl, imidazolyl, pyrrolyl, oxazolyl, , Isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, pyrimidinyl, pyridazinoyl and pyrazinyl) radical and combinations thereof, each having unsaturations and / or interrupted by one or more oxygen and / or sulfur atoms and / or imino groups = NR ³ and / or can carry one or more -OR ³ , -SR ³ and / or -NR ¹ R ² substituents, or
a hydroxyl or alkoxy group -OR ³ , in which R ^{3 can have the} same meanings as R ¹ or R ² ,
B is a function -C (O) XCH ₂ -, where X for a direct bond or for a straight-chain or branched C ₁ -C ₁₈ radical, the unsaturation and one or more oxygen and / or sulfur atoms and / or imino groups = NR ^{3 can be} interrupted and / or can carry one or more -OR ³ , -SR ³ and / or -NR ¹ R ² substituents,
K is optionally with one or more halogens (fluorine, chlorine, bromine, iodine), C ₁ -C ₆ -alkyl, aryl (phenyl, naphthyl or biphenyl radical; furyl, pyridinyl, thienyl, indolyl, Pyrazolyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, pyrididinyl and pyrimidinyl Pyrazinyl), ester- (-COOR ³ ), amino- (-NR ¹ R ² ), amide- (-C (O) NR ¹ R ² ), cyano-, nitro-, trifluoromethyl-, alkoxy- (-OR ³ ), Thioalkyl (-SR ³ ), sulfonamide (-SO ₂ -NH ₂ ) substituted aryl or heteroaryl (phenyl, naphthyl or biphenyl; furyl, pyridinyl, thienyl, indolyl, pyrazolyl, imidazolyl, , Pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, pyrimidinyl, pyridazinoyl and pyrazinyl radicals
can be produced by either an ω-halocarboxylic acid of the general formula II

Hal-CH ₂ X-COOH (II)

wherein X has the meaning given above and Hal represents a chlorine, bromine or iodine atom,
to a solid support functionalized with esterifiable hydroxy groups (hydroxymethylpolystyrene, hydroxyethylpolystyrene, Wang polystyrenes, graft polymers of the Tentagel type) to obtain an ω-halocarboxylic acid of the formula III fixed to the solid support

where P is the solid support,
bound,
the bond formed from this carrier and the carboxyl component of the general formula II must be sufficiently stable throughout the synthesis, but must be able to be cleaved again in the last reaction step of aminolysis or saponification / transesterification to release the quinoline of the general formula I,
and then III with 5-hydroxy-2-nitrobenzaldehyde 5

with the inclusion of this module in and maintenance of the fixed function IV

implemented
or an ω-halocarboxylic acid or an ω-halocarboxylic acid ester of the general formula IIa

Hal-CH ₂ X-COOR ^a (IIa)

wherein Hal and X have the meanings already given and R ^{a is} a hydrogen atom or has the same meanings as R ³ , with 5-hydroxy-2-nitrobenzaldehyde 5

to obtain an etherified 2-nitrobenzaldehyde of the general formula V

coupled,
and, if R ^{a is} not a hydrogen atom, the radical R ^a to give a compound of the general formula VI

split off with a free carboxyl group and this via this carboxyl group on a solid support functionalized with esterifiable hydroxyl groups (hydroxymethylpolystyrene, hydroxyethylpolystyrene, Wang polystyrenes, graft polymers of the Tentagel type) with retention of the fixed function of the general formula IV already containing the polyfunctional building block on the polymeric support

fixed,
the bond formed from this carrier and the carboxyl component of the general formula II must be sufficiently stable throughout the synthesis, but must be able to be cleaved again in the last reaction step of aminolysis or saponification / transesterification to release the quinoline of the general formula I,
and then the carbaldehyde group of the fixed function with an aryl methyl ketone of the general formula VII

wherein
K has the meaning given in general formula I, to a further fixed compound of general formula VIII

implemented this with a reducing agent (tin (II) chloride, iron (II) salts) to obtain a mixture of the further fixed compounds IX and X

cyclized, this mixture to complete conversion of the N-oxide IX into the quinoline X, if necessary reduced again (titanium (III) chloride) and finally the quinoline of the general formula I which is ultimately aimed for with an amine of the formula XI, HNR ¹ R ² (XI) , or an ammonium salt of the formula H ₂ N ⁺ R ¹ R ² Z ^- (XI '), in which R ¹ and R ^{2 have} the meaning given in formula I, and
Z represents a halogen atom Cl, Br, I or a hydrogen sulfate residue, in the presence of an aluminum alkyl compound (trimethylaluminum) or with a hydroxyl group or an alkoxy group -OR ³ , in which R ^{3 have the} same meanings as R ¹ or R ² can, delivering reagent, is released.

For the straight-chain C ₁ to C ₂₀ or branched-chain C ₃ to C ₂₀ radical or C ₃ -C ₂₀ cyclic, optionally aromatic radical, all radicals conceivable under these definitions are suitable according to the present invention, for example a methyl -, Ethyl, propyl, iso-propyl, n, iso or tert-butyl, pentyl, hexyl and the higher straight-chain and branched-chain homologs up to a C ₂₀ radical. The method according to the invention is a broadly and generally applicable method. In the case of a cyclic representative of R ¹ and / or R ² , all customary C ₃ to C ₂₀ carbocycles and their combinations are possible; in particular, this is a cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl ring. It can also be a carbopolycyclic system such. B. act the Adamantylrest. Both the open-chain and the cyclic structures can contain one or, with a corresponding number of carbon atoms, a number of CC double bonds, to a maximum of enough that a fully conjugated system is formed.

Aromatic radicals for R ¹ and / or R ² are all conceivable carbocyclic and heterocyclic aromatics. These are primarily a phenyl, naphthyl or biphenyl radical; representative of a heteroaryl radical are, for example, the furyl, pyridinyl, thienyl, indolyl, pyrazolyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, Benzothienyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, pyrimidinyl, pyridazinoyl and pyrazinyl.

The same radicals as for the substituents R ¹ and / or R ^{2 are} possible for the substituent R ³ .

The expression "heteroatoms in and / or on the backbones" means that the straight-chain C ₁ - to C ₂₀ - or branched-chain C ₃ - to C ₂₀ -rest or C ₃ -C ₂₀ -cyclic residues by one or more oxygen and / or sulfur atoms and / or imino groups = NR ^{3 are} interrupted and / or carry one or more -OR ³ , -SR ³ and / or -NR ¹ R ² substituents.

If X is a straight-chain or branched C ₁ -C ₁₈ radical, which may have unsaturation or cyclic, optionally aromatic structural elements, this is a methylene or ethylene group or a linear or single or multiple branched - (CH ₂ ) ₃ - bis - (CH ₂ ) ₁₈ group. The residues are analogous to R ¹ and / or R ² , but double-bonded.

With regard to the unsaturation or cyclic, optionally aromatic structural elements and heteroatoms in and / or on these radicals, the statements made for R ¹ and / or R ² also apply.

In the case of the optionally substituted aryl or heteroaryl radical K, the present invention primarily refers to one of the carbocyclic or heterocyclic aryl radicals already mentioned under R ¹ and / or R ² , which can all carry one or more of the substituents mentioned.

Halogens are all halogens, namely fluorine, chlorine, bromine or iodine. All open-chain or cyclic radicals already mentioned under R ¹ and / or R ² are possible for the alkyl substitution at C; in particular a C ₁ to C ₆ alkyl group is intended here. Aryl substituents can all be the carbocyclic or heterocyclic aromatics likewise mentioned under R ¹ or R ² .

For the ester groups as substituents on the aryl radical K, all radicals come into question which come under the definition -COOR ³ , where R ^{3 has} the meaning already given, including the aromatic radicals specified under R ¹ and R ² .

Amino substituents can all be the amino groups -NR ¹ R ² falling under the definition of A.

Amides on the aryl radical K are all radicals which come under the definition -C (O) NR ¹ R ² , where R ¹ and R ^{2 have} the meaning already given, including the aromatic radicals specified under R ¹ and R ² .

If K bears one or more alkoxy and / or thioalkyl substituents, the oxygen or sulfur atom is with one of the straight-chain C ₁ to C ₂₀ or branched chain C ₃ to C ₂₀ radicals given under R ¹ or R ² , or C ₃ -C ₂₀ cyclic, optionally aromatic radicals and combinations thereof, each of which may have unsaturations and / or heteroatoms in or on the backbones. In the event that it is a sulfonamide substituent, all the meanings suitable under the amino group A are suitable for the amino group. The phosphorus-containing radicals which are possible as substituents on the aryl or heteroaryl radical are corresponding monovalent radicals of phosphines, phosphines, phosphites, phosphonates, phosphonic acids and phosphonic acid amides. The hydrogen atoms in these phosphorus-containing substituents can be partially or completely replaced by substituents of the meaning R ¹ or R ² .

The ω-halocarboxylic acid of the general formula II required for carrying out the process according to the invention is selected from the group of the compounds HOOCXCH ₂ Br, in which X has the prey indicated in claim 1.

The ω-halocarboxylic acid ester of the general formula IIa is selected from the group of compounds

wherein R ^a except for a hydrogen atom have the meanings given in formula IIa and X have the meanings given in formula I in claim 1.

In the compound of the general formulas II and IIa X preferably stands for a direct bond, a - (CH ₂ ) -, - (CH ₂ ) ₂ - or a linear - (CH ₂ ) ₃ - to - (CH ₂ ) ₉ - Group. R ^a in the compounds of general formula IIa is preferably a methyl or ethyl group.

An example of the breadth of the process according to the invention is 5-bromovaleric acid or N- (4-bromobutyl) pyroglutamic acid as a compound of the general formula II or 5- Bromomaleric acid methyl or ethyl ester or  N- (4-bromobutyl) pyroglutamic acid methyl ester as a compound of the general formula IIa used.

The methylaryl ketone of the general formula VII is, for example, from the group of Compounds acetophenone, 4-acetylpyridine, 2-acetylthiophene, 2-acetyl-4-methylfuran, 3- Acetylindol, 1-phenyl-3-acetyl-4-methylpyrazole selected. Again, it should be emphasized that the suitability of the method according to the invention does not apply to these special compounds is limited as possible methyl aryl ketones, but all conceivable methyl aryl ketones have it implemented.

The compounds of general formula VIII are preferably made with tin (II) chloride cyclized. Other reducing agents such as. B. Iron (II) salts can be used. Ethanol, for example, is suitable as a solvent for the cyclization reaction.

The complete conversion of the N-oxide IX to quinoline X is then optionally in accomplished a second reaction step with titanium (III) chloride.

For the release of the ultimately desired quinoline derivative of the general formula I and the incorporation of the third variable function (namely A) into the quinoline framework all common primary and secondary amines or Ammonium salts, summarized under the general formula XI or XI ', in question. This release is in the presence of an aluminum alkyl compound, for example Trimethyl aluminum.

If A is ultimately to be a hydroxyl or an alkoxy group -OR ³ , the quinoline is split off from the support, for example with sodium and / or potassium hydroxide, or the corresponding alcohol R ³ OH and a catalytic amount of base, for example sodium hydride, for generation the corresponding alcoholate.

That the synthesis of 2,6-disubstituted which runs smoothly in solution succeeds Carrying out quinoline derivatives on a solid support is surprising. The selection a suitable carrier is crucial. The carrier must have one hydroxy group functionalized in certain solvents [ether / halogenated carbons hydrogen] soluble or completely insoluble compound and that from the carrier  and the carboxyl component of the general formula II or VI must be bound be sufficiently stable in the course of the entire synthesis, but on the other hand be stable in the last Reaction step, the aminolysis or saponification / transesterification to release the quinoline, let split again.

The successful course of the quinoline synthesis according to the invention was also by no means to be expected because this reaction on the support is in part a multiplicity of heterogeneous reactions since both the support and the basic catalyst K ₂ CO ₃ / Cs ₂ CO ₃ are present in solid form .

The synthesis of the quinoline derivatives according to the invention uses 5-hydroxy-2-nitrobenzaldehyde as the central constant building block and variable components from three groups of substances which are available in large numbers commercially or by methods familiar to the person skilled in the art:
the ω-halogenated fatty acids or esters of the general formula IIa,
the aryl methyl ketones of the general formula VII and
the primary / secondary amines or ammonia or ammonium salts of the general formula (XI) or (XI ').

In the method according to the invention, an ω-halogen fatty acid is first applied to one functionalized carrier bound. The knowledgeable come frequently for this commercially available carriers on organic or inorganic basis, all of them must have esterifiable hydroxyl groups (J. S. Früchtel, G. Jung; Angew. Chem. 1996, 108, 19-46). Examples include hydroxymethylpolystyrene, Hydroxyethyl polystyrene, Wang polystyrenes or graft polymers of the Tentagel type. In the context of the present invention, preference is given to hydroxyethyl polystyrene used.

Preferred reaction conditions for this step require a solvent in which the Carrier swells, such as dichloromethane, a condensation reagent, such as a carbodiimide, and Acceleration of the esterification also DMAP [4- (N, N-dimethylamino) pyridine]. The halogen atom is then replaced by the phenolic one Hydroxyl group of the hydroxyaldehyde in the presence of a base (potassium / cesium carbonate) at elevated temperature.

With regard to the overall yield of quinoline, it may be more favorable to couple ω-halogen fatty acid or ester of the general formula IIa and hydroxyaldehyde 5, followed by purification of the ether by chromatography or crystallization, and then to saponify if R ^{a is} not stands for a hydrogen atom and then to couple to the carrier.

By varying the fatty acid building blocks IIa, the aldol component VII and finally the Amines XI or the ammonium salts XI ', the last step in the detachment from the carrier a large number of derivatives can be produced in parallel.

The compounds can be ent in a parallel manner using the process according to the invention can be synthesized neither as isolated individual substances or as a mixture, and subsequently be screened for biological activity.

Smaller numbers of derivatives can be viewed in parallel as individual isolated items Realize connections with manual (example 15) or automated working methods.

Large numbers of connections are best left through before the splitting step "split-mix" method (also described as a "divide-couple-and-recombine" method) win, so that a mixture of all possible combinations distributed on the carrier results, ideally only one compound to be found per polymer grain. The Aminolysis, like the subsequent biological testing, then has to be pooled respectively.

In the case of the pooled approach, however, the procedure is always that of a targeted reaction per newly added reaction partner takes place.

Such synthesis strategies by "split-mix" methods are described, for example, in: Appl. Chem. 1996, 108, 19-46; J. S. Früchtel and G. Jung; WO 94/08711 and WO 95/13538).

It has become clear that the method according to the invention is suitable for such a parallel synthesis checked experimentally.

As already explained, the present method uses modules from three different classes of substances. An arbitrary choice of two ω-halogen methyl carboxylic acids, namely 5-bromovaleric acid as a commercially available representative  and N- (4-bromobutyl) pyroglutamic acid as an example synthesized for this purpose, and six aryl methyl ketones, namely acetophenone, 4-acetylpyridine, 2-acetylthiophene, 2- Acetyl-4-methylfuran, 3-acetylindole and 1-phenyl-3-acetyl-4-methylpyrazole, finally two amines, namely iso-butylamine and N- (2-aminoethyl) morpholine, is located Under review.

The actual parallel synthesis begins with the division of a batch of hydroxyethylpo lystyrene in two equal parts and the esterification of one half with 5-bromovaleric acid and the other with the specially synthesized pyroglutamic acid derivative. At both Batches then take place separately but in parallel (at the same time) the formation of the corresponding ones Phenol ether by coupling with 5.

Alternatively, the ethers from 5 and 5-bromovaleric acid ethyl ester or from 5 and Synthesize N- (4-bromobutyl) pyroglutamic acid methyl ester in solution, saponify and then immobilize on the polymer.

The next step in parallel synthesis on the carrier involves the aldol reaction. Since in the present example six arylmethyl ketones are to be brought to the reaction in parallel, the two derivatized polymer batches already present must first be divided into six further batches and with the above-mentioned ketones in the presence of base (K ₂ CO ₃ / Cs ₂ CO ₃ ) to treat.

In this way, twelve differently structured aldol adducts are generated on the carrier, which are / remain spatially separated and in two subsequent steps of a reductive cyclization be subjected to quinoline derivatives.

The final diversification takes place after a final division of all poly batches - here in half - because the final split from the carrier with two Amines should take place.

After aqueous-acidic processing of all reaction solutions, 24 discrete crude are obtained products in a purity between 40-80% (HPLC).

If necessary, the aminolysis products can be analytically pure by chromatography be preserved.

The quinolines obtained by means of the process according to the invention can then either individually or as a mixture in a "screening" for their biological activity (mass Screening). Testing biological activity, individually or in a mixture,  can also be carried out on carrier-bound connections, if that biological target should essentially recognize the quinoline domain.

Compounds identified as biologically relevant can be modified using a variant of the method in Solution without the carrier can then be produced in any quantity. How to proceed for mixtures that show biological activity, for the identification of the active ones Substance (s) or targeted narrowing of combinatorial synthesis to biological Sub-groups showing activity are referred to, for example, WO 95/13538.

The following examples serve to explain the invention in more detail Procedure:  

example 1 5- (3-Formyl-4-nitrophenoxy) ethyl valerate (6)

To a solution of 5.0 g (29.9 mmol) of 5-hydroxy-2-nitro-benzaldehyde 5 and 12.0 ml (74.9 mmol, 2.5 eq.) Of ethyl 5-bromovalerate in 350 ml of CH ₃ CN are given 20.7 g (152.0 mmol, 5 eq.) K ₂ CO ₃ . The orange colored suspension is kept under gentle reflux for 24 hours with vigorous stirring.

Then about 200 ml of the solvent are carefully distilled off in vacuo and the residue is taken up in 300 ml of H ₂ O. After the excess K ₂ CO _{3 has} completely dissolved, it is extracted 3 × with 200 ml of ethyl acetate each time. The combined extracts are in the following sequence 2 × with 200 ml H ₂ O, 2 × with 200 ml 20% aqueous NaOH solution, 2 × with 200 ml H ₂ O and finally 1 × with 100 ml sat. Washed NaCl solution, dried over Na ₂ SO ₄ and freed from the solvent.

The brown, viscous residue is first pre-cleaned by extraction with hexane before the chromatographic purification. For this purpose, the oil is overlaid with 200 ml of hexane in a 1 liter flask and the hexane is briefly heated to boiling with vigorous stirring. After cooling to about 30 ° C, the cloudy, supernatant solution is decanted off. This process is repeated 10 times. The dark brown, glassy residue is discarded. The combined extraction solutions are concentrated to about 250 ml and cooled to 0 ° C. 6.9 g of a dark yellow oil are eliminated, which is purified by chromatography (eluent: CH ₂ Cl ₂ / ethyl acetate, 97: 3, without gradient).

6.0 g (20.0 mmol, 67%) of the desired title compound are obtained, which after some time crystallized (mp: 26-28 ° C).

Example 2 5- (3-formyl-4-nitrophenoxy) valeric acid (11)

42.9 g (max 145 mmol) 6 (crude product) and 250 ml 14% NaOH [in MeOH / H ₂ O / THF 5: 1: 1 (m / v)] are stirred for 4 hours at room temperature.

After saponification, the reaction solution is added to 500 ml of an ice-cooled, 10% aqueous HCl solution with vigorous stirring. The desired carboxylic acid precipitates as a brown oil. After warming to room temperature, the mixture is extracted 4 × with 200 ml of CH ₂ Cl ₂ each. The combined extracts are saturated 3 × with 200 ml H ₂ O and 1 × with 200 ml. Washed NaCl solution, dried over Na ₂ SO ₄ and freed from the solvent.

This leaves 32.2 g of a dark brown, highly viscous residue, which is as follows Process is cleaned: First, the residue is dissolved in 300 ml of boiling acetone. The boiling solution is then swirled with as much boiling hexane until a cloudiness sets in. The solution is allowed to cool slowly, a large proportion of the Oiled out residue (= R1). The supernatant is decanted off and in small portions mixed with hexane until it becomes cloudy again. Generally the desired one crystallizes Title link already out in this step. Should an oily residue form again (= R2) is decanted again and proceed as above. The residues (R1, R2, ...) with about the same degree of purity are summarized in fractions and analogous to that above described procedures cleaned.

In this way, 17.2 g (64 mmol, 44%) of the desired title compound 11 are obtained (Mp: 100-101 ° C, acetone / hexane).

Example 3 5- [3- (1-Hydroxy-3-oxo-3-phenylpropyl) -4-nitrophenoxy] ethyl valerate (7)

A suspension of 4.3 g (14.6 mmol) 6.34 ml (291 mmol, 20 eq.) Acetophenone, 25 ml CH ₃ CN and 8.7 g (63.0 mmol, 4 eq.) K ₂ CO ₃ is stirred vigorously at room temperature for 24 hours.

The reaction mixture is then mixed with 250 ml of H ₂ O. After the excess K ₂ CO _{3 has} completely dissolved, it is extracted 3 × with 200 ml of ethyl acetate each time. The combined extracts are sat 2 × with 200 ml H ₂ O and 1 × with 200 ml. Washed NaCl solution, dried over Na ₂ SO ₄ and freed from the solvent.

There remain 40.0 g of a yellowish residue. To separate the excess Acetophenone, the product is precipitated by adding hexane. After two Recrystallization from acetone / hexane becomes 4.4 g (10.6 mmol, 73%) of the desired Obtain title compound 7 (mp: 70-71 ° C, acetone / hexane).  

Example 4 5- [6- (1-Oxido-2-phenyl) quinolinyloxy] ethyl valerate (8)

A suspension of 2.0 g (4.8 mmol) 7 and 5.4 g (24.0 mmol, 5 eq.) SnCl ₂ -2 H ₂ O in 80 ml EtOH is boiled at gentle reflux for one hour. The reaction mixture is then ice-cooled in 250 ml. Given Na ₂ CO ₃ solution and extracted 5 × with 100 ml of ethyl acetate. The combined extracts are sat 2 × with 100 ml of 10% aqueous NaOH solution, 2 × with 100 ml of H ₂ O and 1 × with 100 ml. Washed NaCl solution, dried over Na ₂ SO ₄ and freed from the solvent. 1.7 g of a solid, yellowish residue are obtained, which contains both the desired quinoline 9 and the corresponding quinoline N-oxide 8.

The two compounds are separated from one another by chromatography (eluent: CH ₂ Cl ₂ / ethyl acetate, 7: 3). 1.49 g (4.1 mmol, 85%) of the N-oxide 8 are obtained (melting point: 89-90 ° C., hexane / ethyl acetate).

The fractions of the nonpolar quinoline 9 also contain other impurities and must be chromatographed again (eluent: CH ₂ Cl ₂ / ethyl acetate, 95: 5). 0.23 g (0.6 mmol, 11%) 9 are isolated (mp: 78-80 ° C., hexane / ethyl acetate) 9/8 = 1.0: 7.5 (overall yield: 96%).

Example 5 5- [6- (2-phenyl) quinolinyloxy] ethyl valerate (9)

A solution of 150 mg (0.4 mmol) 8 in 2 ml of CH ₂ Cl _{2 was} injected into a solution of 324 mg (2.1 mmol, 5 eq.) Of TiCl ₃ in 3 ml of toluene under inert gas and for 24 hours at room temperature touched.

Then the reaction solution in 25 ml of an ice-cooled sat. Given Na ₂ CO ₃ solution and extracted 3 × with 50 ml of ethyl acetate. The combined extracts are filtered and saturated 2 × with 50 ml H ₂ O and 1 × with 50 ml. Washed NaCl solution, dried over Na ₂ SO ₄ and freed from the solvent. 257 mg of a yellowish, solid residue are obtained, which is purified by chromatography (eluent: hexane / ethyl acetate, 8: 2, without gradient). 135 mg (0.39 mmol, 94%) of the desired title compound 9 are obtained (melting point: 81-82 ° C., hexane / acetone).

Example 6 5- [6- (2-phenyl) quinolinyloxy] valeric acid-3,4,5-trimethoxyanilide (12)

A solution of 213 mg (1.16 mmol, 4 eq.) 3,4,5-trimethoxyaniline in is slowly added to a solution of 4 mmol (14 eq.) AlMe ₃ in 2 ml toluene, which is under inert gas and cooled to -10 ° C 2 ml CH ₂ Cl ₂ injected. After slowly warming to room temperature, a solution of 100 ml (0.29 mmol) 9 in 2 ml CH ₂ Cl _{2 is} added and the mixture is stirred for 24 hours at room temperature. The reaction mixture is then carefully added to 200 ml of H ₂ O (0 ° C.) with vigorous stirring and, after warming to room temperature, extracted twice with 100 ml of ethyl acetate each time. The combined extracts are saturated 2 × with 50 ml H ₂ O and 1 × with 50 ml. Washed NaCl solution, dried over Na ₂ SO ₄ and freed from the solvent.

160 mg of a black-colored oil are obtained. After chromatographic purification (eluent: CH ₂ Cl ₂ / TBME 7: 3, without gradient), 136 mg (0.28 mmol, 96%) 12 are obtained (mp: 147-148 ° C, CH ₂ Cl ₂ / Et ₂ O / hexane).

Example 7 N- (4-bromobutyl) pyroglutamic acid methyl ester (13)

To a suspension of 130 g (0.40 mol, 3 eq.) Cs ₂ CO ₃ and 250 ml (2.1 mol, 15 eq.) 1,4-dibromobutane in 1 l DMF / THF 2: 8 (v / v) a solution of 20 g (0.14 mol) of methyl rac-pyroglutamic acid in 200 ml of THF is added dropwise with vigorous stirring and at a rate of about 1 ml / min. After stirring at 50 ° C. for 24 hours, the THF used is carefully removed under vacuum. The reaction solution is then poured into 1 l of H ₂ O and saturated 3 × with 200 ml of H ₂ O and 2 × with 200 ml each. Washed NaCl solution, dried over Na ₂ SO ₄ and freed from the solvent.

The excess 1,4-dibromobutane is then removed from the residue by distillation (bp 63-65 ° C / 6 mm). 15.5 g of a brown viscous oil are obtained, which is purified by chromatography (eluent: CH ₂ Cl ₂ / acetone 85: 2 → 8: 2). 11.8 g (42.4 mmol, 30%) of the desired title compound are obtained as a pale yellow, viscous oil.

Example 8 N- [4- (3-formyl-4-nitrophenoxy) butyl] pyroglutamic acid methyl ester (14)

To a solution of 14.2 g (85.0 mmol, 2 eq.) 5-hydroxy-2-nitrobenzaldehyde and 11.5 g (41.3 mmol) 13 in 500 ml THF are added 29.4 g (213.0 mmol, 5 eq.) K ₂ CO ₃ . The orange colored suspension is kept under gentle reflux for 24 hours with vigorous stirring. The reaction mixture is then poured into 1 l of an ice-cooled sat. Given NaCl solution and extracted 3 × with 200 ml of ethyl acetate. The combined extracts are in the following sequence 2 × with 200 ml H ₂ O, 2 × with 200 ml 20% aqueous NaOH solution, 2 × with 200 ml H ₂ O and finally 1 × with 100 ml sat. Washed NaCl solution, dried over Na ₂ SO ₄ and freed from the solvent.

11.5 g of a brown, viscous residue are obtained, which is purified by chromatography (eluent: CH ₂ Cl ₂ / ethyl acetate 10: 1 → 8: 2). 9.9 g (27.1 mmol, 66%) of the desired title compound 14 are obtained as a pale yellow oil.

Example 9 N- [4- (3-formyl-4-nitrophenoxy) butyl] pyroglutamic acid (15)

9.9 g (27.1 mmol) 14 and 60 ml 14% NaOH [in MeOH / H ₂ O 3: 1 (m / v)] is stirred for 2 hours at room temperature. After saponification, the reaction solution is added to 1 l of an ice-cooled, 10% aqueous HCl solution with vigorous stirring. The desired carboxylic acid precipitates as a brown, viscous oil. After warming to room temperature, the mixture is extracted 3 × with 500 ml of ethyl acetate. The combined extracts are sat 3 × with 200 ml. Washed NaCl solution, dried over Na ₂ SO ₄ and freed from the solvent. This leaves 9.3 g (26.5 mmol, 98%) of a dark brown, highly viscous residue which is pure by NMR spectroscopy and is therefore reacted without further purification.

Example 10 (16)

To a suspension of 20.0 g of hydroxyethyl polystyrene (occupation density B = 1 mmol / g, company Rapp) cooled to 0 ° C, 8.0 g (30.0 mmol) 11 and 0.4 g (3.2 mmol) 4 - (N, N-Dimethylamino) pyridine (DMAP) in 500 ml of CH ₂ Cl ₂ , 8 ml (51.0 mmol) of diisopropylcarbodiimide (DIPC) is added dropwise with vigorous stirring. After 15 minutes, the mixture is slowly warmed to room temperature and stirred for 24 hours.

The polymer is filtered off under reduced pressure through a D3 frit and on the frit in the following order 2 × with 100 ml DMSO, 2 × with 100 ml DMF, 3 × with 200 ml H ₂ O, again 2 × with 100 each ml DMF and 2 × with 200 ml H ₂ O, then 3 × with 200 ml EtOH, 2 × with 200 ml ethyl acetate, 3 × with 200 ml acetone, 2 × with 200 ml CH ₂ Cl ₂ and finally washed 2 × with 200 ml Et ₂ O each.

By applying a vacuum to the frit outlet, the polymer becomes solvent leftover and dried (30 min).

27.8 g of the desired pale yellow polymer 16 are obtained.

Example 11 (17)

20 ml (171 mmol) of acetophenone are added to a suspension of 4.0 g of 16 and 8.9 g (64.4 mmol) of finely ground K ₂ CO ₃ in 80 ml of CH ₂ Cl ₂ / THF (1: 1) and 36 Stirred for hours at room temperature. The polymer is then filtered off under reduced pressure through a D3 frit and on the frit in the following order 3 × with 200 ml H ₂ O, 3 × with 100 ml acetone / EtOH (1: 1), again 3 × with 200 ml H ₂ O and 3 × with 100 ml acetone / EtOH (1: 1), then 1 × with 100 ml EtOH, 2 × with 100 ml acetone, 1 × with 100 ml ethyl acetate, 2 × with 200 ml CH ₂ Cl ₂ and finally washed 2 × with 100 ml Et ₂ O each. By applying a vacuum to the frit outlet, the polymer is freed from solvent residues and dried (30 minutes).

4.5 g of the desired ocher polymer 17 are obtained.

Example 12 (18)

A suspension of 4.51 g 17 and 7.5 g (33.2 mmol) SnCl ₂ . H ₂ O in 75 ml EtOH / CH ₂ Cl ₂ (4: 1) is gently refluxed for 4 hours with vigorous stirring. The polymer is first filtered through a D3 frit and washed 3 × on the frit with H ₂ O (50 ° C) then transferred to a beaker, there in 200 ml EtOH / H ₂ O (1: 1, 50 ° C) suspended and treated with ultrasound for 5 minutes. The washing process is then placed on the frit. It is in the following order 1 × with H ₂ O (50 ° C), 4 × with 100 ml of 20% aqueous NaOH solution, 2 × with 100 ml H ₂ O (50 ° C), 2 × with 100 each ml EtOH, washed 2 × with 100 ml acetone, 1 × with 100 ml ethyl acetate, 2 × with 200 ml CH ₂ Cl ₂ and finally 2 × with 100 ml Et ₂ O.

By applying a vacuum to the frit outlet, the polymer becomes solvent leftover and dried (30 minutes).

5.6 g of the desired ocher polymer 18 are obtained.

Example 13 (19)

2.5 g (16.2 mmol) of TiCl ₃ (in bulk) are added to a suspension of 5.6 g of 18 in 30 ml of CH ₂ Cl ₂ / THF (2: 1) which is under inert gas and the mixture is stirred for 24 hours at room temperature .

The polymer is first filtered off on a D3 frit and there 1 × with CH ₂ Cl ₂ / THF (1: 1), 1 × with 100 ml acetone, 1 × with 200 ml H ₂ O, 2 × with 200 ml sat . Na ₂ CO ₃ solution (50 ° C) and washed 3 × with 200 ml H ₂ O (50 ° C) each, then transferred to a beaker, there in 200 ml EtOH / H ₂ O (1: 1, 50 ° C) suspended and treated with ultrasound for 3 minutes. The washing process is then placed on the frit. It is in the following order 1 × with 100 ml of H ₂ O (50 ° C), 3 × with 100 ml of 20% aqueous NaOH solution, 2 × with 100 ml of H ₂ O (50 ° C), 2 × with 100 ml of EtOH, 2 × with 100 ml of acetone, 1 × with 100 ml of ethyl acetate, 2 × with 200 ml of CH ₂ Cl ₂ and finally 2 × with 100 ml of Et ₂ O washed.

By applying a vacuum to the frit outlet, the polymer becomes solvent leftover and dried (30 minutes).

5.10 g of the desired ocher polymer 19 are obtained.

Example 14 5- [6- (2-phenyl) quinolinyloxy] valeric acid isobutylamide (10)

20 ml (40 mmol) of AlMe ₃ (c = 2 M in toluene) and then 3.2 are added to a suspension of 2.5 g of 19 and in 30 ml of CH ₂ Cl ₂ , which is under inert gas and cooled to -10 ° C. ml (31.9 mmol) of isobutylamine was added dropwise. After 15 minutes, the mixture is slowly warmed to room temperature. The mixture is left to stir at room temperature for 24 hours, the reaction solution being treated with ultrasound for 2 minutes every 30 minutes for the first 3 hours. Ultrasound is applied again for 5 minutes immediately before working up. The reaction mixture is carefully added to 250 ml of H ₂ O (0 ° C.) with vigorous stirring and, after warming to room temperature, extracted 4 × with 100 ml of ethyl acetate each time. The combined extracts are sat 2 × with 100 ml H ₂ O and 1 × with 100 ml. Washed NaCl solution, dried over Na ₂ SO ₄ and freed from the solvent.

548 mg of a yellow solid are obtained. After chromatographic purification (eluent: CH ₂ Cl ₂ / ethyl acetate 8: 2, without gradient), 388 mg (1.04 mmol, 65%) 10 are obtained (mp: 140-142 ° C., acetone / hexane).

Example 15

The exemplary parallel synthesis of 24 quinoline derivatives is carried out simultaneously based on the reaction conditions listed in the individual examples 10-14 in the split process. The following are used as variable building blocks:
5-bromovaleric acid, N- (4-bromobutyl) pyroglutamic acid;
Acetophenone, 4-acetylpyridine, 2-acetylthiophene, 2-acetyl-4-methylfuran, 3-acetylindole, 1-phenyl-3-acetyl-4-methylpyrazole;
iso-butylamine and N- (2-aminoethyl) morpholine.

A representative list of ultimately obtained products which were subjected to a final chromatographic purification on silica gel proves the performance of the process according to the invention:

5- [6- (2-phenyl) quinolinyloxy] valeric acid isobutylamide (10) (yield 65%) mp: 141-142 ° C (acetone / hexane)
5- [6- [2- (4-pyridinyl)] quinolinyloxy] valeric acid isobutylamide (yield 45%) mp: 158-159 ° C (acetone / hexane)
5- [6- [2- (2-thienyl) quinolinyloxy] valeric acid isobutylamide (yield 62%) mp: 147-148 ° C. (acetone / hexane)
5- [6- [2- (4-Methylfuran-2-yl)] quinolinyloxy] valeric acid isobutylamide (yield 35%) mp: 116-117 ° C (acetone / hexane)
5- [6- [2- (3-indolyl)] quinolinyloxy] valeric acid isobutylamide (yield 21%) mp: 184-185 ° C (acetone / hexane)
5- [6- [2- (5-Methyl-1-phenylpyrazol-4-yl)] quinolinyloxy] valeric acid isobutylamide (yield 52%) mp: 138-139 ° C (dichloromethane / hexane)
5- [6- (2-phenyl) quinolinyloxy] valeric acid 2- (N-morpholino) ethylamide (yield 63%) mp: 125-126 ° C (acetone / hexane)
5- [6- [2- (4-pyridinyl) quinolinyloxy] valeric acid-2- (N-morpholino) ethylamide (yield 40%) mp: 145-146 ° C (acetone / hexane)
5- [6- [2- (2-thienyl) quinolinyloxy] valeric acid-2- (N-morpholino) ethylamide (yield 60%) mp: 121-122 ° C (acetone / hexane)
5- [6- [2- (4-Methylfuran-2-yl)] quinolinyloxy] valeric acid 2- (N-morpholino) ethylamide (yield 35%) mp: 132-134 ° C (acetone / hexane)
5- [6- [2- (3-indoyl)] quinolinyloxy] valeric acid 2- (N-morpholino) ethylamide (yield 15%) mp: 196-197 ° C (acetone / hexane)
5- [6- [2- (5-Methyl-1-phenylpyrazol-4-yl)] quinolinyloxy] valeric acid-2- (N-morpholino) ethylamide (yield 50%) mp: 169-170 ° C (dichloromethane / Hexane)
N- [4 - [(2-phenyl) quinolinyl-6-oxy] butyl-pyroglutamic acid isobutylamide (yield 34%) and all other compounds analogous to the above valeric acid amides.

Claims (18)

1. Process for the preparation of 2,6-disubstituted quinoline derivatives of the general formula I
wherein
A is an amino group -NR ¹ R ² , in which R ¹ and R ² independently of one another for a hydrogen atom or for a straight-chain C ₁ - to C ₂₀ - or branched-chain C ₃ - to C ₂₀ radical, or C ₃ -C ₂₀ cyclic (cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl ring, adamantyl radical), optionally aromatic (phenyl, naphthyl or biphenyl radical; furyl, pyridinyl, thienyl, indolyl, pyrazolyl, imidazolyl, pyrrolyl, oxazolyl, , Isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, pyrimidinyl, pyridazinoyl and pyrazinyl) radical and combinations thereof, each having unsaturations and / or interrupted by one or more oxygen and / or sulfur atoms and / or imino groups = NR ³ and / or can carry one or more -OR ³ , -SR ³ and / or -NR ¹ R ² substituents, or
a hydroxyl or alkoxy group -OR ³ , in which R ^{3 can have the} same meanings as R ¹ or R ² ,
B is a function -C (O) XCH ₂ -, where X for a direct bond or for a straight-chain or branched C ₁ -C ₁₈ radical, the unsaturation and one or more oxygen and / or sulfur atoms and / or imino groups = NR ^{3 can be} interrupted and / or can carry one or more -OR ³ , -SR ³ and / or -NR ¹ R ² substituents,
K is optionally with one or more halogens (fluorine, chlorine, bromine, iodine), C ₁ -C ₆ -alkyl, aryl (phenyl, naphthyl or biphenyl radical; furyl, pyridinyl, thienyl, indolyl, Pyrazolyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, pyrididinyl and pyrimidinyl Pyrazinyl), ester- (-COOR ³ ), amino- (-NR ¹ R ² ), amide- (-C (O) NR ¹ R ² ), cyano-, nitro-, trifluoromethyl-, alkoxy- (-OR ³ ), Thioalkyl (-SR ³ ), sulfonamide (-SO ₂ -NH ₂ ) substituted aryl or heteroaryl (phenyl, naphthyl or biphenyl; furyl, pyridinyl, thienyl, indolyl, pyrazolyl, imidazolyl, , Pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, pyrimidinyl, pyridazinoyl and pyrazinyl radicals
characterized in that either an ω-halocarboxylic acid of the general formula II
Hal-CH ₂ X-COOH (II)
wherein X has the meaning given above and Hal represents a chlorine, bromine or iodine atom,
to a solid support functionalized with esterifiable hydroxy groups (hydroxymethylpolystyrene, hydroxyethylpolystyrene, Wang polystyrenes, graft polymers of the Tentagel type) to obtain an ω-halocarboxylic acid of the formula III fixed to the solid support
where P is the solid support,
bound,
the bond formed from this carrier and the carboxyl component of the general formula II must be sufficiently stable throughout the synthesis, but must be able to be cleaved again in the last reaction step of aminolysis or saponification / transesterification to release the quinoline of the general formula I,
and then III with 5-hydroxy-2-nitrobenzaldehyde 5
with the inclusion of this module in and maintenance of the fixed function IV
implemented
or an ω-halocarboxylic acid or an ω-halocarboxylic acid ester of the general formula IIa
Hal-CH ₂ X-COOR ^a (IIa)
wherein Hal and X have the meanings already given and R ^{a is} a hydrogen atom or has the same meanings as R ³ , with 5-hydroxy-2-nitrobenzaldehyde 5
to obtain an etherified 2-nitrobenzaldehyde of the general formula V
coupled,
and, if R ^{a is} not a hydrogen atom, the radical R ^a to give a compound of the general formula VI
split off with a free carboxyl group and this via this carboxyl group on a solid support functionalized with esterifiable hydroxyl groups (hydroxymethylpolystyrene, hydroxyethylpolystyrene, Wang polystyrenes, graft polymers of the Tentagel type) with retention of the fixed function of the general formula IV already containing the polyfunctional building block on the polymeric support
fixed,
the bond formed from this carrier and the carboxyl component of the general formula II being sufficiently stable throughout the synthesis, but must be able to be cleaved again in the last reaction step of aminolysis or saponification / transesterification to release the quinoline of the general formula I,
and then the carbaldehyde group of the fixed function with an aryl methyl ketone of the general formula VII
wherein
K has the meaning given in general formula I, to a further fixed compound of general formula VIII
implemented this with a reducing agent (tin (II) chloride, iron (II) salts) to obtain a mixture of the further fixed compounds IX and X
cyclized, this mixture to complete conversion of the N-oxide IX into the quinoline X, if necessary reduced again (titanium (III) chloride) and finally the quinoline of the general formula I which is ultimately aimed for with an amine of the formula XI, HNR ¹ R ² (XI) , or an ammonium salt of the formula H ₂ N ⁺ R ¹ R ² Z ^- (XI '), in which R ¹ and R ^{2 have} the meaning given in formula I, and
Z represents a halogen atom Cl, Br, I or a hydrogen sulfate residue, in the presence of an aluminum alkyl compound (trimethylaluminum) or with a hydroxyl group or an alkoxy group -OR ³ , in which R ^{3 have the} same meanings as R ¹ or R ² can, delivering reagent, is released. 2. The method according to claim 1, characterized in that the ω-halocarboxylic acid of the general formula II is selected from the group of compounds HOOCXCH ₂ Br, wherein X has the prey specified in claim 1. 3. The method according to claim 1, characterized in that the ω-halocarbonate of the general formula IIa is selected from the group of compounds
wherein R ^a except for a hydrogen atom have the meanings given in formula IIa in claim 1 and X have the meanings given in formula I in claim 1. 4. The method according to claim 2, characterized in that reacting with a compound of general formula II, wherein X is a direct bond, a - (CH ₂ ) -, - (CH ₂ ) ₂ - or a linear - (CH ₂ ) ₃ - to - (CH ₂ ) ₉ group means. 5. The method according to claim 2, characterized in that with N- (4-bromobutyl) pyroglutamic acid is reacted. 6. The method according to claim 4, characterized in that with 5-bromovaleric acid is implemented. 7. The method according to claim 3, characterized in that reacting with a compound of general formula IIa, wherein R ^{a is} a methyl or ethyl group and X is a direct bond, a - (CH ₂ ) -, - (CH ₂ ) ₂ - or a linear - (CH ₂ ) ₃ - to - (CH ₂ ) ₉ group. 8. The method according to claim 3, characterized in that with N- (4-bromobutyl) pyroglutamic acid methyl ester is reacted. 9. The method according to claim 7, characterized in that with 5-bromovaleric acid ethyl or methyl ester is implemented.   10. The method according to claim 1, characterized in that with hydroxyl groups Functionalized polymer is hydroxyethyl polystyrene. 11. The method according to claim 1, characterized in that the methylaryl ketone general formula VII is selected from the group of the compounds acetophenone, 4- Acetylpyridine, 2-acetylthiophene, 2-acetyl-4-methylfuran, 3-acetylindole, 1-phenyl-3-acetyl- 4-methylpyrazole. 12. The method according to claim 1, characterized in that the compounds of general formula VIII is cyclized with tin (II) chloride. 13. The method according to claim 12, characterized in that is cyclized in ethanol. 14. The method according to claim 1, characterized in that for complete Conversion of the N-oxide IX to quinoline X is reduced with titanium (III) chloride. 15. The method according to claim 1, characterized in that with iso-butylamine or N- (2-Aminoethyl) morpholine as the amine of formula XI the desired quinoline is released. 16. The method according to claim 1, characterized in that the quinoline general formula I in the presence of the aluminum alkyl compound trimethyl aluminum is released. 17. The method according to claim 1, characterized in that when A is ultimately for there should be a hydroxy group, the cleavage of the quinoline from the carrier with sodium and / or potassium hydroxide. 18. The method according to claim 1, characterized in that when A is ultimately to stand for an alkoxy group -OR ³ , the quinoline is split off from the carrier with the corresponding alcohol R ³ OH and a catalytic amount of base to produce the corresponding alcoholate.