EP0829460A1 - Process for preparing molecular libraries - Google Patents

Abstract

Production of a library of molecules comprises contacting a mixture of reactants in the gas phase with a heterogeneous catalyst under conditions such that the reactants react with one another.

Description

The present invention relates to a method for producing molecular libraries and the use of these molecular libraries.

New test methods in molecular biology (e.g. cellular or non-cellular test systems such as enzyme assays or receptor assays) enable the identification of biologically active substances that can be present in small quantities and in a complex product mixture. By automating the test methods, test substances in the order of a few hundred thousand compounds per year can be tested. However, this high number of test substances can no longer be produced with conventional organic synthesis methods with reasonable effort.

With the help of combinatorial chemistry, complex product mixtures, so-called molecular libraries, have recently been generated by combining analog functionalized molecular building blocks, which were then used to search for new active ingredients or lead structures for active ingredients. (Hougthen, Biochemistry 1993, 32, 11035-41, Smith, Bioorganic & Medicinal Chemistry Letters, 1994, Vol. 4, No. 24, 2821-24, Rebek, Angew. Chem. 1994, 106, 2159, Rebeck, Angew. Chem. 1994, 106, 2162, SCIENCE, 1994, vol. 264, 1399, C&EN, 1994, 7, 20).

The variety of the molecules contained in these molecule libraries, as the name already suggests, comes about through combinatorial linking of the molecular building blocks via functional groups of the same type in each case and is thus restricted to precisely predeterminable molecule types with known structural elements.

Despite these possibilities of combinatorial chemistry, however, there was still a need for processes which quickly and reproducibly deliver a large number of chemically different compounds. Since, as a rule, a certain biological activity of a compound is not restricted to a single chemical structure type, there was above all a need for processes which deliver the largest possible number of different chemical structure types.

The present invention achieves the objects described. It relates to a process for the preparation of molecular libraries, which is characterized in that a mixture of starting materials in contact with a heterogeneous catalyst in the gas phase under conditions which allow the reactants to react chemically with one another.

Molecular libraries are understood to mean mixtures of chemically different substances. Molecular libraries are advantageously mixtures in which the molar fraction of the individual substances in the mixture as a whole is of approximately the same order of magnitude or in any case no more than two powers of ten between the fraction of the least represented compound and the most represented compound.

The reaction conditions in which starting materials and heterogeneous catalyst come into contact are chosen so that a large number of secondary and subsequent reactions take place.

This is done, for example, by setting a reaction temperature of more than 200, preferably more than 300 and particularly preferably more than 400 ° C. A very good temperature range for the process according to the invention is the range from 450 to 550 ° C.

• Oxide und Mischoxide, insbesondere Zeolithe, Schichtsilikate, Hydrotalcite, Alumosilikate, supersaure Zirkonoxide oder geträgerte Säuren.
• Metalle und geträgerte Metalle, insbesondere Edelmetalle der 8. Nebengruppe auf oxidischen Trägern.
• Sulfide, Carbide, Nitride und Phosphate.

The following can be used as heterogeneous catalysts:

• Oxides and mixed oxides, in particular zeolites, layered silicates, hydrotalcites, aluminum silicates, super acidic zirconium oxides or supported acids.
• Metals and supported metals, especially noble metals of the 8th subgroup on oxidic supports.
• Sulfides, carbides, nitrides and phosphates.

In particular, heterogeneous catalysts known from the literature, such as, for example, alkylation, acylation, alkoxylation, acetalization, aromatization, decarboxylation, dealkylation, cycloalkylation, cyclocondensation, elimination, disproportionation, metathesis, etherification, esterification, can be used -, Amination, nitration, oligomerization, oxidation, hydrogenation, dehydrogenation, chlorination, hydration and condensation catalysts are used.

The reaction is preferably carried out in a continuous tubular reactor or a pulse reactor.

Educts for the process according to the invention can be taken from a large number of chemical groups. Particularly suitable groups of substances are alcohols, aldehydes, ketones, carboxylic acids, Amines, olefins, alkynes, aromatics, nitriles, esters, carboxylic anhydrides, carboxylic acid chlorides, alkyl halides, isocyanates, carbonates, epoxies, ethers, alkanes, halogens, hydrogen halides, oxides of carbon and nitrogen.

Mixtures within a group of substances, for example different amines, or mixtures of two or more different groups of substances, for example amines and aldehydes, can be used as starting materials. Mixtures of starting materials from two or three different groups of substances are preferably used for the process according to the invention.

Educts such as ammonia, chlorine, bromine, fluorine, HCl, HBr, HF, N ₂ O, NO, NO ₂ , CO, CO ₂ , ethylene, propene, butenes, butadiene, acetylene etc. can also be supplied with the carrier gas stream

The starting materials can be metered in without a solvent or else dissolved in a solvent.

The pressure in the reactor can be varied within a wide range. The process can be carried out at pressures ranging from 1 mbar to the supercritical range of 300 bar.

You can for faster removal of the products, preferably inert, carrier gas such. B. N ₂ , Ar or He use.

However, it may also be desirable to carry out further chemical reactions such as oxidations or reductions. In these cases it is advisable to use a "carrier gas" which, in addition to being a means of transport, also carries out the desired chemical reaction.

In order to introduce additional functional groups into the products by oxidation, air or an oxygen-containing gas can be used as the carrier gas.

A hydrogen-containing carrier gas can be used to hydrogenate functional groups or aromatic rings by reduction.

The reaction products are cooled, condensed and, if necessary, fed to the biological test after pre-cleaning. The biological test can be carried out both directly with the product mixture as obtained after the reaction and with individual fractions of the product mixture or the components isolated therefrom.

A preliminary or purification of the product mixture obtained can be carried out using customary methods, preferably using chromatographic methods.

The invention further relates to the molecular libraries which can be prepared by the processes described above and the use of these molecular libraries to find active substances or lead structures for active substances, in particular for medicaments and crop protection agents.

The following examples serve to further illustrate the invention

example 1 Preparation of the heterogeneous catalyst

220 g of BETA zeolite from Uetikon (Zeokat-Beta) with the composition SiO ₂ = 91%, Al ₂ O ₃ = 7.8%, Na ₂ O = 0.5%, K ₂ O = 0.7% were mixed with 5% Walocel and 230 g of water in a kneader for 45 minutes. The mass was then shaped into 2 mm strands at a pressure of 70 bar. These were dried at 110 ° C and calcined at 500 ° C for 16 hours. 195 g of these strands were exchanged with 3 liters of 20% NH ₄ Cl solution at 80 ° C. for 2 hours and then washed with 10 l of water. After drying at 110 ° C was calcined at 500 ° C for 5 h.

Preparation of a molecular library by the reaction of aldehydes, ammonia and methanol

10 g of these strands were introduced into a tubular spiral reactor and brought to 450 ° C. under N ₂ . A mixture of 10 g acetaldehyde, 10 g benzaldehyde, 15 g 25% NH ₃ solution and 25 g methanol was passed over the contact at a rate of 10 g / h. The product was condensed and freed from low boilers in a rotary evaporator. The residue was dissolved in DMSO and analyzed by GC.

54 major peaks were found in the area of one- to three-core aromatics. The sample was provided for biological screening.

Example 2 Preparation of a molecular library by the reaction of aldehydes, ammonia and methanol

The experiment from Example 1 was repeated with a mixture of 10 g acetaldehyde, 10 g glutardialdehyde, 15 g 25% NH ₃ solution and 25 g methanol. GC analysis revealed 82 larger peaks in the retention area of the one- to three-core aromatics.

Example 3 Preparation of a molecular library by reaction of glycerin, aniline and methanol

In this experiment, for example 1 analog, an aluminosilicate from BASF with the designation D11-50 was used as catalyst. SiO ₂ / Al ₂ O ₃ (85/15). A mixture of 20 g glycerin, 20 g aniline and 60 g methanol gave a product mixture with 37 larger peaks in the retention area of the one to three-core aromatics.

Claims (13)

Process for the preparation of molecular libraries, characterized in that a mixture of starting materials in the gas phase is brought into contact with a heterogeneous catalyst under conditions which allow the starting materials to react chemically with one another. A method according to claim 1, characterized in that the temperature is chosen so high that a wide product mixture results from a series of parallel and subsequent reactions. Process according to one of the preceding claims, characterized in that a temperature of more than 300 ° C is used. Process according to one of the preceding claims, characterized in that zeolites or layered silicates are used as heterogeneous catalysts. Process according to one of the preceding claims, characterized in that one uses oxides or mixed oxides as heterogeneous catalysts. Process according to one of the preceding claims, characterized in that one uses metals or supported metals as heterogeneous catalysts. Process according to one of the preceding claims, characterized in that one uses carbides, nitrides or silicides as heterogeneous catalysts. Method according to one of the preceding claims, characterized in that one works at a pressure of 0.001 bar to 300 bar. Process according to one of the preceding claims, characterized in that a carrier gas is used. Method according to one of the preceding claims, characterized in that the carrier gas used is N ₂ , air, O ₂ , H ₂ , He, Ar, CO ₂ or NH ₃ . Process according to one of the preceding claims, characterized in that compounds from the alcohol groups, aldehydes, ketones, carboxylic acids, Amines, olefins, alkynes, aromatics, nitriles, esters, carboxylic anhydrides, carboxylic acid chlorides, alkyl halides, isocyanates, carbonates, epoxies, ethers or alkanes and mixtures of compounds used within or between these groups of substances. Use of the molecular libraries, which has been produced by a method according to one of the preceding claims, for finding biological active substances. Use according to claim 12, characterized in that the molecular libraries are used to find drugs or crop protection agents.