KR20010052929A - Method for producing combinatory amine libraries - Google Patents

Abstract

The present invention relates to a process for producing a compound represented by the following formula (1), which comprises the reaction of an? Component selected from a compound represented by the following general formula (2) and? Components selected from the compounds represented by the following general formulas (3a1, 3a2 or 3b), wherein? Is an integer of 1 or more, alpha < / RTI > ² is greater than or equal to 5), and an amine of formula (1): < EMI ID =

Formula 1

(2)

Formula 3a1

ZR ⁴

Formula 3a2

ZR ⁵

3b

ZR ⁴ -R ⁵ -Z

In this formula,

R ¹ , R ² and R ³ have the meanings given in the specification,

R ⁴ and R ⁵ having the meanings described in the specification, R ⁴ and R ⁵ in the compound of Formula 3b are connected via a bond,

Z is Li or MgX, where X is Hal and Hal is Cl, Br or I.

The reaction is carried out in a solvent in the presence of a titanium, hafnium or zirconium compound and optionally a cocatalyst.

Description

METHOD FOR PRODUCING COMBINATORY AMINE LIBRARIES < RTI ID = 0.0 >

Lead structures that are not peptides but have affinity for the receptor or enzyme are commonly found by mass screening of many compounds. A mixture of natural products or a collection of pure materials made by synthesis has been routinely used as a source of various chemical structures. However, the use of a mixture of natural products is increasingly problematic from an ethical and practical point of view, since organisms derived from mixtures of natural products are often threatened with extinction and studies on new leading structures threaten the survival of the species to which they correspond have. On the other hand, the collection of chemicals initiated by pharmaceutical companies has been limited to structural diversity and categories. In addition, since individual materials were originally produced in connection with a particular biological activity, such collections routinely contain only selected structures among the various possible structures. Finally, a collection of these substances is allowed only to a limited group of people.

It is known to prepare libraries of materials containing mixtures of different reaction products through combination synthesis starting from a number of different starting compounds. On the other hand, by appropriate screening of the library it is possible to identify novel, biologically active, leading structures which can subsequently be made specifically and utilized to the full extent possible. On the other hand, however, the combinatorial library can also be used again in further combinatorial synthesis. Combining these two possibilities, a new leading structure can be found.

A prerequisite for the combined synthesis of a material library containing a lead structure is the simple accessibility to a suitable starting compound that already has a biologically active structural element or forms it by combinatorial synthesis; In order to produce as many possible combinatorial libraries as possible and to avoid the influence of the concentration of the individual compounds in the screening, with as much as possible yield and also with considerable structural diversity, fair; And a simple method for isolating the reaction product in a form usable for screening.

Moreover, the found guiding structure should be suitable for simple and inexpensive forms to be further orally processed, biologically stable, and further processed into clinically available medicaments.

The preparation of combination libraries of peptides is known from the prior art. However, peptides have disadvantages of low bioavailability, low in vivo stability and very high cost. Although a large number of peptides can be produced, structural diversity is limited because the production of amino acid units and linear structures of peptides is simple or natural.

It is known in the prior art to prepare libraries of materials containing compounds of small molecules and the starting compounds must be supported on a solid phase for synthesis. Thus, US-A 5,786,448 discloses a combination library of cyclic urea or thiourea compounds. However, such compounds are derived from peptide structures, so that the possible structural diversity can not be significantly different from the structural diversity of the peptides.

Finally, it is an object of the present invention to provide a process for preparing a useful combination library which contains a non-peptide lead structure with specific structural elements of biological activity and which can be used for screening or further combinatorial synthesis of active compounds, Compounds enable structural diversity and other structural diversity of peptides.

The present invention relates to the discovery of a novel lead structure starting from a combinatorial library. In particular, the invention relates to a process for preparing a combination library of amines.

It is an object of the present invention to provide a process for the preparation of a compound of the formula [3a], a compound of the formula [3a1], a compound of the formula [3a1] or a compound of the formula [3a] (Wherein alpha and beta are integers greater than or equal to 1 and alpha beta ² is greater than or equal to 5, and in particular greater than 7), comprising an amine of the formula:

ZR ⁴

ZR ⁵

ZR ⁴ -R ⁵ -Z

In this formula,

R ^1, R ² and R ³ may be the same or different, hydrogen, a substituted or not alkyl, cycloalkyl, alkenyl are optionally substituted, cycloalkenyl, alkynyl or aryl group, -Si (R) _3, -Sn (R) ₃ , -SR, -OR or -NRR ', or the radicals R ¹ and R ² or R ² and R ³ optionally contain at least one further heteroatom, preferably N, O or S, Lt; RTI ID = 0.0 > cycloalkyl < / RTI > ring,

Radicals R ⁴ and R ⁵ are the same or can be different and is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl or aryl _{group, -Si (R) 3, -Sn} (R) 3 , -SR, -OR or -NRR ', or the radicals R ⁴ and R ⁵ form a cycloalkyl ring which in addition to N may also optionally contain one or more additional heteroatoms, preferably N, O or S, In the case of the compound of formula (3b), the radicals R ⁴ and R ⁵ are connected by a bond,

Z is Li or MgX where X is Hal and Hal is Cl, Br or I,

In the definitions of the radicals R ¹ to R ⁵ , R and R 'may in each case be the same or different and are substituted or unsubstituted alkyl radicals or substituted or unsubstituted aryl radicals.

Due to the specific binding generated by the method of the present invention, compounds with particular structural characteristics which are found to be important for the interaction of the compound with the receptor or enzyme can be readily obtained. That is, the compound has an amine functional group in which the geminal carbon atom contains two or more specific substituents.

On the other hand, for example, branching is also found in natural amino acids. To this extent, there is a basis for structural similarities between the compounds obtainable by the method of the present invention and the amino acids or peptides used in the biological system for interaction with enzymes and receptors.

On the other hand, as in the case of, for example, amino acids, the polar carbonyl functionalities are not included in the same site branching of the amines which can be obtained by the process of the present invention. Conversely, compounds which can be obtained according to the invention have simple, nonpolar and hydrophobic groups at corresponding positions. To this extent, there are fundamental differences between the compounds obtainable according to the invention and the naturally occurring amino acids and peptides related to the electronic state.

Because of the similarities in the structural features of the compounds obtainable according to the present invention and the structural and electronic states for inducing the interaction with the enzyme and the receptor are important, the known active compounds cyclidine (1-diphenylmethyl -4-methylpiperazine), proline (1-benzylbutylpyrrolidine) or methamphetamine.

By the method of the present invention, it is possible to simultaneously, inexpensively and efficiently prepare a plurality of iso substituted amines starting from a simple starting compound, and in the most preferable case, all logically possible reaction products are formed. As a result, the present invention for the first time suggests the possibility of systematically preparing a wide variety of compounds, while retaining the typical structural characteristics of amino acids under fundamentally different electronic conditions.

Thus, the resulting combinatorial libraries can be used as a source of a variety of chemical structures that can be manufactured in a simple and inexpensive manner, from which a novel lead structure with the desired ligand affinity or enzyme-inhibiting activity can be selected, Can be further effectively used using a combination method or a conventional method.

In the present specification, alkyl is preferably C _1-10 -alkyl, more preferably C _1-8 -alkyl. Cycloalkyl is preferably C _3-8 -cycloalkyl, more preferably C _3-7 -cycloalkyl. Alkenyl is preferably C _2-10 -alkenyl, more preferably C _2-8 -alkenyl. Cycloalkenyl is preferably C _3-8 -cycloalkenyl, more preferably C _3-7 -cycloalkenyl. Alkynyl is preferably C _2-10 -alkynyl, more preferably C _2-8 -alkynyl. The aryl is preferably phenyl, naphthyl, anthryl or phenanthryl.

Preferable examples of R ¹ , R ² and R ³ are described below, and halogen is fluorine, chlorine, bromine or iodine.

R ¹ , R ² and R ³ may be the same or different and independently of one another are a hydrogen atom, a C _1-8 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl group, C _1-6 -alkyl groups, C _3-7 - cycloalkenyl groups, C _3-7 - cycloalkyl of C _1-6 substituted by an alkenyl-alkyl group, C _2-8 - alkenyl group, C _{2- 8} - alkynyl group, C _1-6 - alkoxy substituted by a a C _1-6 - alkyl group, C _{2-6-alkenyloxy} substituted by a C _1-6 - alkyl group, C _2-6 - alkynyl C _1-6 -alkyl group substituted by a C _1-6 -alkoxy group, a C _1-6 -alkoxy group substituted by a C _1-6 -alkoxy group, a mono-, di- or _polyhalo -C _1-6 -alkoxy group, a -C _2-6 - alkenyloxy groups substituted by a C _1-6 -alkyl group, a mono-, di- or poly -C _2-6 to be - alkynyloxy groups substituted by C _1-6 -alkyl group, C _1-6 - alkylthio substituted by a C _1-6 - alkyl group, C _1-6 - alkyl substituted by a sulfinyl C _1-6 - alkyl group, C _1-6 - alkyl sulfonic A carbonyl substituted by a C _1-6 -alkyl group, a mono-, di-, or -C _1-6 to be poly-alkyl group, a mono-, di-alkenyl group, - or a -C _2-8 to poly Mono-, di- or polyhalo-C _2-8 -alkynyl group, a C _1-6 -alkyl group substituted by cyano group, a C _2-6 -alkenyl group substituted by cyano group, cyano groups substituted by a C _2-6 - alkynyl group, substituted by a nitro-C _1-6 - alkyl group, a C _2-6 substituted by a nitro-alkenyl group, a C _2-6 substituted by a nitro- alkynyl group, C _1-6 - _1-6 is substituted by a C alkyl-amino-alkyl group, a C _1-6 - alkoxy substituted by an amino-C _1-6 -alkyl group, a di (C _1-3 -alkyl ) an amino substituted by a C _1-6 -alkyl group, N- (C _1-3 -alkyl) -N- (C _1-3 - alkoxy), a C _1-6 substituted by an amino-alkyl group, N- (C _1-6 -alkyl-sulfonyl) -N- (C _1-6 -alkyl), a C _1-6 substituted by an amino-alkyl group, N- (C _1-6 -alkyl-sulfonyl) -N- (C _1-6 - alkoxy) amino group Substituted by C _1-6 -alkyl group, tri -C _1-6 - alkyl silyl groups substituted by C _1-6 -alkyl groups, triarylsilyl groups substituted by a C _1-6 -alkyl group, an aryl group ( Provided that the aryl group may be substituted with at least one substituent selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group), an aryl group , this aryl group is methyl group, halogen atom, trifluoromethyl group, nitro group, C _1-6 - alkyl group and a C _1-6 - may be substituted with one or more substituents selected from the group consisting of a alkoxy) C ₁ is substituted by a _-6 -alkyl group, an aryl group (provided that such an aryl group is substituted with at least one substituent selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group a C _2-7 substituted by may be) -alkenyl group, an aryl group (provided that such a Reel group methyl group, a nitro group, a C _1-6 a halogen atom, a trifluoro-C _1-6 alkyl group, and - may be substituted with one or more substituents selected from the group consisting of alkoxy group) a C _2-6 optionally substituted by An alkynyl group, a phenoxy group (provided that the phenoxy group is at least one substituent selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group) substituted by may be substituted) C _1-6 - alkyl group, an arylthio group (provided that such groups are methyl arylthio group by a halogen atom, a trifluoromethyl, a nitro group, a C _1-6 - alkyl group and a C _{1- 6-a} C _1-6 substituted by may be substituted with one or more substituents selected from the group consisting of a-alkoxy) -alkyl group, an aryl sulfinyl group (provided that such an aryl sulfinyl group is methyl group, halogen atom, trifluoromethyl, A nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group, A C _1-6 -alkyl group, an arylsulfonyl group (provided that such an arylsulfonyl group may be substituted with a halogen atom, a trifluoromethyl group, a nitro group, C _1-6 - alkyl group and a C _1-6 - by a may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _1-6 - alkyl group, a benzyloxy group (provided that such a benzyloxy group the aryl group is a halogen atom, a methyl group, a nitro group, a C _{1-6 trifluoro-1-} substituted by a C may be substituted with one or more substituents selected from the group consisting of a alkoxy) C _1-6 alkyl group and _{A 6} -alkyl group, a benzylthio group (provided that the aryl group of such a benzylthio group is a group selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group May be substituted with the above substituent) Substituted by C _1-6 - alkyl group, a benzyl sulfinyl group (provided that such a benzyl group aryl sulfinyl group is a methyl group, a nitro group, halogen atom, trifluoromethyl, C _1-6 - alkyl group and a C _1-6 - a by may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _1-6 - alkyl group, a benzyl sulfonyl group (provided that such a benzyl aryl sulfonyl group is methyl group, halogen atom, trifluoromethyl group, a nitro group, a C _1-6 - alkyl group and a C _1-6 - by a may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _1-6 - alkyl group, a C _1-4 - C _1-6 -alkyl group substituted by an amino group substituted by an alkylsulfonyl group.

Examples of the ring which, if any radicals R ¹ and R ² or R ² and R ³ have to form a cycloalkyl which can also contain heteroatoms, preferably N, O or S in at least one further optionally added to the N Is 1-pyrrolidinyl, 1-imidazolinyl, 1-pyrazolinyl, 1-piperidyl, 1-piperazinyl, 4-morpholinyl and 4-thiamorpholinyl.

Particularly preferably, the radicals R ¹ and R ² are not hydrogen atoms.

Particularly preferably, the radical R ³ is a hydrogen atom or a methyl group which may be substituted with 1 to 3 fluorine atoms.

Examples of R ⁴ and R ⁵ are as described below, wherein the halogen is fluorine, chlorine, bromine or iodine.

R ⁴ and R ⁵ are the same or may be different, each independently represent a hydrogen atom, C _1-8 - alkyl group, C _3-7 - cycloalkyl group, C _3-7 - cycloalkyl substituted by a C _{1- 6} - alkyl group, C _3-7 - cycloalkenyl groups, C _3-7 - cycloalkyl of C _1-6 substituted by an alkenyl-alkyl group, C _2-8 - alkenyl group, C _2-8 - alkynyl carbonyl group, C _1-6 - alkoxy groups optionally substituted by a C _1-6 -alkyl group, C _2-6 - alkenyloxy groups substituted by a C _1-6 -alkyl group, C _{2-6-alkynyloxy} groups A C _1-6 -alkyl group substituted by a mono-, di- or _polyhalo -C _1-6 -alkoxy group, a mono-, di- or polyhalo-C _2-6 alkenyloxy groups substituted by a C _1-6 -alkyl group, a mono-, di- or poly be -C _2-6 alkynyloxy substituted by a C _1-6 -alkyl group, a C _1-6 di-substituted by a C _1-6 alkylthio-substituted by a C _1-6 alkylsulfinyl--alkyl group, C _1-6 alkyl group, C _{1-6-alkylsulfonyl} A C _1-6 substituted by a-alkyl group, a mono-, di-, or -C _1-8 to be poly-alkyl group, a mono-, di-, or -C _2-8 to be poly-alkenyl group, a mono- -, a di- or polyhalo-C _2-8 -alkynyl group, a C _1-6 -alkyl group substituted by cyano group, a C _2-6 -alkenyl group substituted by cyano group, a cyano group substituted by C _2-6 - alkynyl group, a C _1-6 substituted by a nitro-alkyl group, a nitro groups substituted by C _2-6 -alkenyl group, a nitro substituted by C _2-6 - alkynyl carbonyl group, a C _1-6 - alkylamino groups substituted by a C _1-6 -alkyl group, a C _1-6 - alkoxy substituted by a C _1-6 amino-alkyl group, a di (C _1-3 -alkyl) amino groups substituted by a C _1-6 -alkyl group, N- (C _1-3 -alkyl) -N- (C _1-3 - alkoxy) substituted by an amino-C _1-6 -alkyl group, N- ( C _1-6 - alkylsulfonyl) -N- (C _1-6 - alkyl) amino substituted by a C _1-6 - alkyl group, N- (C _1-6 - alkylsulfonyl) -N- (C _1-6 - alkoxy) amino group of the Substituted C _1-6 -alkyl group, tri -C _1-6 - alkyl silyl groups substituted by C _1-6 -alkyl groups, triarylsilyl groups substituted by a C _1-6 -alkyl group, an aryl group (where , This aryl group may be substituted with at least one substituent selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group), an aryl group the aryl group is a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 - alkyl group and a C _1-6 - may be substituted with one or more substituents selected from the group consisting of a alkoxy) C _1- substituted by a _6-alkyl group, an aryl group (provided that such aryl group is a methyl group, a nitro group, halogen atom, trifluoromethyl, C _1-6 - alkyl group and a C _1-6 - optionally substituted with one or more substituents selected from the group consisting of a alkoxy may be) C-substituted by _2-7 -alkenyl group, an aryl group (provided that such aryl It is a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 - alkyl group and a C _1-6 - by a may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _2-6 - An alkynyl group, a phenoxy group (provided that such a phenoxy group is substituted with at least one substituent selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group A C _1-6 -alkyl group, an arylthio group (provided that such an arylthio group may be substituted by a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkyl group, - a by may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _1-6 - alkyl group, an aryl sulfinyl group (provided that such an aryl sulfinyl group is methyl group, halogen atom, trifluoromethyl, nitro, done alkoxy group-group, C _1-6 - alkyl group and a C _1-6 Substituted by a C may be substituted with one or more substituents selected from the group) _1-6-alkyl group, an arylsulfonyl group (provided that such an arylsulfonyl group as a methyl group halogen atoms, trifluoromethyl, nitro, C _{1 -6-alkyl} group and a C _1-6 - by a may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _1-6 -alkyl group, a benzyloxy group (provided that the aryl group in such benzyloxy groups are methyl group, a nitro group, a C _1-6 a halogen atom, a trifluoro-C _1-6 alkyl group, and a - a by may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _1-6 - An alkyl group, a benzylthio group (provided that the aryl group of the benzylthio group may be substituted with at least one substituent selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group Can be replaced by < RTI ID = 0.0 > Hwandoen C _1-6 - alkyl group, a benzyl sulfinyl group (provided that such a benzyl sulfinyl group of the aryl group is a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 - alkyl group and a C _1-6 - alkoxy substituted by may be substituted with one or more substituents selected from the group consisting of a) C _1-6 - alkyl group, a benzyl sulfonyl group (provided that such aryl group is a methyl group in the benzyl sulfonyl group with a halogen atom, a trifluoromethyl group, a nitro group, C _1-6 - alkyl group and a C _1-6 - by a may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _1-6 - alkyl group, C _1-4 - alkyl sulfonic 0.0 > Ci- ₆ -alkyl < / RTI >

A preferred group of amines which may be prepared using the process of the present invention are described below.

In the first group, the amine of the present invention is an amine of the general formula (1) alkylated symmetrically or asymmetrically at the same position,

R ¹ , R ² and R ³ are the same or different and are hydrogen; Alkyl; Mono- or poly-substituted by fluorine, chlorine, bromine or iodine, including perhalogenated alkyl; Cycloalkyl; Cycloalkyl, mono- or poly-substituted by fluorine, chlorine, bromine or iodine; Aryl; Aryl which is mono- to o-substituted by fluorine, chlorine, bromine or iodine; Alkenyl; Alkynyl; -Si (R) ₃ ; -Sn (R) ₃ ; -SR; -OR or -NRR ', or the radicals R ¹ and R ² or R ² and R ³ form a cycloalkyl ring which in addition to N may also optionally contain one or more additional heteroatoms, preferably N, O or S, and,

Radicals R < ⁴ > and R < ⁵ > are the same or different and are alkyl; Mono- or poly-substituted by fluorine, chlorine, bromine or iodine, including perhalogenated alkyl; Cycloalkyl; Cycloalkyl, mono- or poly-substituted by fluorine, chlorine, bromine or iodine; Aryl; Aryl which is mono- to o-substituted by fluorine, chlorine, bromine or iodine; Alkenyl; Alkynyl; Or a radical -C (R ") (R ') CH ₂ R wherein the radical R" is -Si (R) ₃ , -Sn (R) ₃ , -SR, -OR or -NRR'

In the definitions of the radicals R ¹ to R ⁵ , R and R 'may be the same or different in each case and are an alkyl radical; Alkyl radicals mono- or poly-substituted by fluorine, chlorine, bromine or iodine; Alkenyl radicals; Alkynyl radical; Aryl radical; Or an aryl radical which is mono- to o-substituted by fluorine, chlorine, bromine or iodine and the radicals R ⁴ and R ⁵ may in each case have at most one hydrogen atom in the? -Position.

In the second group, the amines of the invention are symmetrically alkylated at the same position with the amine of formula (1)

R ¹ , R ² and R ³ are each independently H, A, Ar, -Si (R ⁶ ) ₃ , -Sn (R ⁶ ) ₃ , -SR ⁷ , -OR ⁷ or -NR ⁸ R ^9, or R ¹ and R ² or R ¹ and R ³ or R ⁸ and R ⁹ are connected to each other to form a carbon number optionally containing at least one additional hetero atom selected from the group consisting of -S-, -O- and -N-, 3 to 8 cyclic rings,

R ⁴ and R ⁵ have the same meaning,

R ⁴ is A, Ar, -Si (R ⁶ ) ₃ , -Sn (R ⁶ ) ₃ , -SR ⁷ , -OR ⁷ or -NR ⁸ R ⁹ wherein R ⁸ and R ⁹ have the meanings given below Or R ⁸ and R ⁹ or R ⁴ and R ⁵ are connected to each other and have, in addition to the nitrogen atom, 3 to 8 carbon atoms optionally containing one or more additional heteroatoms selected from the group consisting of -S-, -O- and -N- To form a cyclic ring of < RTI ID = 0.0 >

R ⁶ , R ⁷ , R ⁸ and R ⁹ independently of one another are A or Ar,

A is a straight or branched alkyl radical having 1 to 10 carbon atoms, a straight or branched alkenyl radical having 2 to 10 carbon atoms, a straight or branched alkynyl radical having 2 to 10 carbon atoms, a substituted or unsubstituted Cycloalkyl radical or a mono- or multi-unsaturated cycloalkyl radical of 3 to 8 carbon atoms,

And Ar is a substituted or unsubstituted aryl radical having 6 to 20 carbon atoms.

In the third group, the amines of the invention are symmetrically alkylated at the same positions with the amine of formula (1)

R ¹ , R ² and R ³ are each independently H, A, Ar, -Si (R ⁶ ) ₃ , -Sn (R ⁶ ) ₃ , -SR ⁷ , -OR ⁷ or -NR ⁸ R ^9, or R ¹ and R ² or R ¹ and R ³ or R ⁸ and R ⁹ are connected to each other to form a carbon number optionally containing at least one additional hetero atom selected from the group consisting of -S-, -O- and -N-, 3 to 8 cyclic rings,

R ⁴ and R ⁵ have the same meaning,

R ⁴ is selected from A, Ar, -Si (R ⁶ ) ₃ , -Sn (R ⁶ ) ₃ , -SR ⁷ , -OR ⁷ , -NR ⁸ R ⁹ wherein R ⁸ and R ⁹ have the meanings given Or R ⁸ and R ⁹ are connected to each other to form a cyclic ring of 3 to 8 carbon atoms, optionally containing at least one further heteroatom selected from the group consisting of -S-, -O- and -N- in addition to nitrogen may ^{be), -C (R 10) (} R 8) CH 2 R 9 ( wherein, R ^8, R ⁹ and R ¹⁰ have the meanings as provided), or R ⁴ and R ⁵ are connected to each other, a nitrogen atom But also a cyclic ring of 3 to 8 carbon atoms, optionally containing one or more heteroatoms selected from the group consisting of -S-, -O- and -N-, with the proviso that R ⁴ and R ⁵ are in each case? Position with at most one hydrogen atom,

R ⁶ , R ⁷ , R ⁸ and R ⁹ independently of one another are A or Ar,

R ¹⁰ is -Si (R ⁶ ) ₃ , -Sn (R ⁶ ) ₃ , -SR ⁷ , -OR ⁷ or -NR ⁸ R ⁹ wherein R ⁸ and R ⁹ have the meanings given above or R ⁸ and R ⁹ are connected to each other to form a cyclic ring having 3 to 8 carbon atoms, optionally containing at least one heteroatom selected from the group consisting of -S-, -O- and -N- in addition to the nitrogen atom,

A is a straight or branched alkyl radical having 1 to 10 carbon atoms, a straight or branched alkenyl radical having 2 to 10 carbon atoms, a straight or branched alkynyl radical having 2 to 10 carbon atoms, a substituted or unsubstituted Cycloalkyl radical or a mono- or multi-unsaturated cycloalkyl radical of 3 to 8 carbon atoms,

And Ar is a substituted or unsubstituted aryl radical having 6 to 20 carbon atoms.

In the fourth group, the amine of the invention R ⁴ and R ⁵ are different and R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, R ^7, R ⁸ and R ⁹ have the second of the present invention Lt; RTI ID = 0.0 > (1) < / RTI > having the same meaning as described for the amine of the group.

In the fifth group, the amines of the present invention are asymmetrically alkylated at the same positions with the amine of formula (1)

R ^1, R ² and R ³ are the same or different and are hydrogen, alkyl, cycloalkyl, aryl, alkenyl, _{alkynyl, -Si (R) 3, -Sn} (R) 3, -SR, -OR or - NRR ', or the radicals R ¹ and R ² or R ² and R ³ form a cycloalkyl ring which in addition to N may also optionally contain one or more additional heteroatoms, preferably N, O or S,

The radicals R ⁴ and R ⁵ are different from one another and are selected from the group consisting of alkyl, cycloalkyl, aryl, alkenyl, alkynyl or radical -C (R ") (R ') CH ₂ R, ₃ , -Sn (R) ₃ , -SR, -OR or -NRR '

In the definitions of the radicals R ¹ to R ⁵ , R and R 'may be the same or different in each case and are alkyl, alkenyl, alkynyl or aryl radicals,

The radicals R < ⁴ > and R < ⁵ > may in each case have at most one hydrogen atom in the [beta] -position.

In the sixth group, the amines of the present invention are asymmetrically identical in the same alkylated alkyl group of the formula 1,

R ^1, R ² and R ³ are the same or different and are hydrogen, alkyl, cycloalkyl, aryl, alkenyl, _{alkynyl, -Si (R) 3, -Sn} (R) 3, -SR, -OR or - NRR ', or the radicals R ¹ and R ² or R ² and R ³ form a cycloalkyl ring which in addition to N may also optionally contain one or more additional heteroatoms, preferably N, O or S,

The radicals R ⁴ and R ⁵ are the same or different, alkyl, cycloalkyl, alkylaryl, alkenyl, alkynyl or a radical -C (R) (R) CH 2 R [ where R is the radical -Si (R) ₃ , -Sn (R) ₃ , -SR, -OR or -NRR '

In the definitions of the radicals R ¹ to R ⁵ , R and R 'may be the same or different in each case and are alkyl, alkenyl, alkynyl or aryl radicals,

The radicals R ⁴ and R ⁵ in each case have two or more hydrogen atoms in the? -Position.

In the first to sixth group of amines, R ³ is particularly preferably hydrogen or a methyl group, or the radicals R ¹ and R ² are not hydrogen atoms.

The present invention also provides useful amines of formula (I)

In this formula,

R ¹ , R ² , R ⁴ and R ⁵ have the meanings given above,

R < ¹ > and R < ² > are in each case independently of each other ethyl or hexyl, or form a piperidinyl group with the nitrogen atom to which they are attached;

R < ⁴ > and R < ⁵ > are in each case independently of one another or all hydrogen, methyl, butyl or hexyl.

The preparation of compounds of formula (I) is inhibited in the process of the invention by the presence of cocatalyst.

Within the meaning of the present invention, the combination library contains more than 5, preferably at least 7 different amines of formula (I) or (I).

The process according to the invention for the preparation of a combinatorial library using the amines of formulas I and 1a is described in detail below.

The first component used in the reaction according to the invention is a compound of formula 2:

(2)

In this formula,

R ¹ , R ² and R ³ have the meanings given above,

R ³ is particularly preferably a hydrogen or a methyl group which may be substituted with 1 to 3 fluorine atoms.

R ³ The compounds of the methyl group formula (II) which may be substituted with hydrogen or from one to three fluorine atoms are the reaction is sterically impaired very little in accordance with the present invention, on the other hand than that for the hydrolysis and concomitant removal of the amine functional group It has an advantage that a stable amine is formed.

According to the process of the present invention, the carboxamide of formula (2) can be reacted with good yields, wherein R ¹ , R ² and R ³ independently of one another can be H or A, Lt; / RTI >

Branched or unbranched carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 10 alkyl; Cycloalkyl having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; Or a corresponding methyl- or ethyl-substituted cycloalkyl group; Mono- or multi-unsaturated cycloalkyl groups such as cyclopentenyl or cyclopentadienyl; Branched or unbranched alkenyl having 2 to 10 carbon atoms such as allyl, vinyl, isopropenyl or propenyl; Branched or unbranched alkynyl of 2 to 10 carbon atoms, such as ethynyl or propynyl; Or NO ₂ , F, Cl, Br, NH ₂ , NHA, NA ₂ , OH and OA wherein A may have the meanings given above and may be mono-, multi- or fully halogenated, preferably fluorinated Unsubstituted or mono- or poly-substituted C 6 -C 20 aryl such as phenyl, naphthyl, anthryl or phenanthryl which is mono- or poly-substituted by a substituent selected from the group consisting of: NO _2, F, Cl, Br, NH _2, NHA, NA _2, OH and OA (here, A may have the significance given above, one may be screen or fully halogenated, preferably fluorinated -, multiple Aralkyl of 7 to 20 carbon atoms, such as benzyl optionally mono- or polysubstituted by a substituent selected from the group of < RTI ID = 0.0 > Or aralkynyl, such as aralkenyl or phenylethynyl, in which case the aryl, alkenyl and alkynyl groups may be considered as having the meanings given above.

R < ¹ > and R < ² > or R < ¹ > and R < ³ > together with a cyclic ring of 3 to 8 carbon atoms containing an additional heteroatom such as -S-, -O- or -N- When used, a particularly good yield is obtained. Herein especially preferred R ¹ and R ² or R ¹ and R by a ^{three-carboxaldehyde} is simple cyclic ring including the nitrogen of an amide form, or R ¹ and R ² or R ¹ and R ³ are as a further hetero atom Is a compound which forms a cyclic ring containing an oxygen atom.

Very preferably, the following compounds are used as the carboxamide of formula (2)

Preferably, 1 to 10, more preferably 1 to 5 different compounds of formula (2) are used.

The second component used in the reaction according to the invention is a compound of formula 3a1, 3a2 or 3b:

Formula 3a1

ZR ⁴

Formula 3a2

ZR ⁵

3b

ZR ⁴ -R ⁵ -Z

In this formula,

R ⁴ and R ⁵ have the meanings given above,

The radical Z is preferably a radical-MgX where X is Cl or Br or lithium.

When R ¹ or R ² is -Si (R) ₃ , this -Si (R) ₃ group can be hydrolyzed briefly to subsequently introduce the hydrogen atom at the corresponding position.

As the nucleophilic reagent, a Grignard or lithium compound of formula 3a1, 3a2 or 3b may be used, wherein each radical has the following meanings:

R ⁴ is preferably a methylene, ethyl, n-propyl, i-propyl, n-sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, An alkyl radical of 1 to 10 carbon atoms; Cycloalkyl having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; A corresponding methyl- or ethyl-substituted cycloalkyl group; Mono- or multi-unsaturated cycloalkyl groups such as cyclopentenyl or cyclopentadienyl; Branched or unbranched alkenyl radicals having from 2 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Branched or unbranched alkynyl radical of 2 to 10 carbon atoms such as ethynyl or propynyl; Or NO ₂ , F, Cl, Br, NH ₂ , NHA, NA ₂ , OH and OA wherein A may have the meanings given above and may be mono-, multi- or fully halogenated, preferably fluorinated Unsubstituted or mono- or poly-substituted aryl radicals having from 6 to 20 carbon atoms, such as phenyl, naphthyl, anthryl or phenanthryl which are mono- or poly-substituted by a substituent selected from the group consisting of: NO _2, F, Cl, Br, NH _2, NHA, NA _2, OH and OA (here, A may have the significance given above, one may be screen or fully halogenated, preferably fluorinated -, multiple An aralkyl radical having 7 to 20 carbon atoms, such as benzyl, optionally mono- or polysubstituted by a substituent selected from the group of < RTI ID = 0.0 > Or phenylethynyl. (In each case, aryl, alkenyl and alkynyl groups may be considered to have the meanings given above).

In addition, the formula 3a1 and 3a2 of the radicals R ⁴ and R ⁵ is _{^{-Si (R 6) 3, -Sn}} (R 6) 3, -SR 7, -OR 7 , or -NR ⁸ R ⁹ or may il (wherein, R ⁶ , R ⁷ , R ⁸ and R ⁹ independently of one another have the meanings given above, or R ⁸ and R ⁹ are connected to each other and, in addition to the nitrogen atom, at least one group selected from the group consisting of -S-, -O- and -N- A cyclic ring having 3 to 8 carbon atoms, which may optionally contain a heteroatom, may be formed together); The two R ⁴ radicals of formula (3b) can be alkyl of 2 to 7 carbon atoms, whereby through the reaction according to the invention a compound of formula (1) is formed in which two radicals R ⁴ form a cyclic ring of 3 to 8 carbon atoms .

Particularly preferably R ⁴ is an alkyl radical such as methyl, ethyl, n-propyl, i-propyl, n-sec-butyl, t-butyl, pentyl or hexyl, or cyclopropyl, cyclobutyl, cyclopentyl or cyclo Cycloalkyl radicals such as hexyl, or aryl radicals such as phenyl, or aralkyl radicals such as benzyl.

Particularly preferably, the following Grignard compounds are used for the reaction as compounds of formula 3a1 or 3a2:

Methylmagnesium bromide, ethylmagnesium bromide, n- or i-propylmagnesium bromide, i-, secondary- or tertiary-butylmagnesium bromide, n-hexylmagnesium bromide, cyclohexylmagnesium chloride, allylmagnesium bromide, vinylmagnesium bromide, Cyclopropylmagnesium bromide, cyclopentylmagnesium bromide, cyclopentylmagnesium chloride, phenylmagnesium bromide, benzylmagnesium chloride or p-fluorophenylmagnesium bromide.

For the reaction, the compound of formula (3a1) or (3a2) should be present in an amount of 1.6 to 2.4 equivalents, preferably 1.8 to 2.2 equivalents, relative to the compound of formula (2) Equivalent < / RTI >

For the reaction, the compounds of formulas 3a1, 3a2 and 3b are used in an amount of 0.7 to 1.2 equivalents, preferably 0.9 to 1.1 equivalents, relative to the compound of formula (2).

The compounds of formulas 3a1, 3a2 and 3b can be prepared by reacting magnesium in the in situ reaction system with compounds of the formulas 3aa1, 3aa2 and 3bb, respectively, when the compounds of formulas 3a1, 3a2 and 3b are Grignard reagents. In the in situ preparation method, magnesium is reacted with the following compounds of the formulas 3aa1, 3aa2 and 3bb:

XR ⁴

XR ⁵

XR ⁴ -R ⁵ -X

In the above formula, the radicals X, R ⁴ and R ⁵ have the meanings given above.

Preferably, in this in-situ preparation method of Grignard compounds, the amount of magnesium is 2 to 4 equivalents, preferably 2.8 to 3.2 equivalents, relative to the compound of formula 3aa1 or 3aa2, and the amount of the compound of formula 3a1 or 3a2 is Is 1.8 to 2.8 equivalents, preferably 2.2 to 2.6 equivalents with respect to the compound of formula (Ib), and when the compound of formula (Ib) is used, the equivalent equivalent in each case is used.

The titanium, hafnium or zirconium compound to be reacted according to the invention is preferably a compound of the formula 4a or 4b:

R ⁵ TiY _3-n (OR ^III ) _n

TiY _4-n (OR ^III ) _n

In this formula,

R < ⁵ > has the meaning given above,

n is an integer of 1 to 3 for Formula 4a and an integer of 1 to 4 for Formula 4b,

Y is Cl, Br or I,

R < ^{III &} gt ^; is the same or different alkyl radical having 1 to 10 carbon atoms or an aryl radical having 6 to 20 carbon atoms.

Preferably, an organotitanium compound wherein R < ^III & gt ^; is isopropyl is used. Particularly preferably, the organotitanium compound used is Ti (OiPr) ₄ (wherein iPr corresponds to an isopropyl radical).

If the reaction is carried out in the presence of an organotitanium compound as a catalyst, it is preferably used in an amount of from 0.5 to 5 mol%, preferably from 1 to 3.5 mol%, based on the compound of the formulas 3a1, 3a2 and 3b.

A nucleophilic reagent of formula 3a1, 3a2 or 3b and a carboxamide of formula 2 are added in the presence of a catalytic amount of titanium dioxide, hafnium dioxide or zirconium dioxide, which are Grignard reagents and are prepared in situ or added to the reaction mixture as prepared, The compound of the formula (1) can be obtained by reacting the compound of the formula (1) in a symmetrically or asymmetrically substituted manner. As a result, the process can be carried out in the presence of a catalytic amount of a metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide, wherein the catalytically active form of the catalyst is produced in situ. In this embodiment, good yields are obtained, especially in the presence of cocatalyst.

The amine compound of formula (1) is preferably prepared in the presence of a titanium, hafnium or zirconium compound as well as in the presence of one of the compounds of the formulas (5) to (7) as cocatalysts:

(R ^IV ) ₃ SiZ

(R ^IV ) ₃ ZSi (CH ₂ ) _o SiZ (R ^IV ) ₂

A ^{m +} (OiPr) _m

In this formula,

R ^IV is the same or different and is an alkyl or aryl radical,

Z is F, Cl, Br or I, preferably Cl,

o is an integer from 1 to 12,

m is an integer of 1 to 4 and represents the oxidation state of the metal,

iPr is isopropyl,

A is Al, Ca, Na, K, Si or Mg, preferably Mg or Na.

It has been found that the reaction starts at room temperature due to the addition of the cocatalyst and leads to complete reaction of the starting material in a relatively short time. A suitable cocatalyst for this reaction is an alkylsilyl halide. In particular, such cocatalysts are alkyl silyl halides of formula 5 or formula 6 described above.

Preferably, alkylsilane halides wherein R is alkyl having 1 to 6 carbon atoms are used. Particularly, a compound wherein R is alkyl having 1 to 3 carbon atoms and X is chlorine is preferable.

It has been found that the addition of 0.7-1.2 moles, especially 0.9-1.1 moles of cocatalyst, per mole of starting material gives improved results such as higher yield, lower reaction temperature or shorter reaction time.

Very preferably, the following compounds are used as cocatalysts:

NaO-iPr, Mg (O- iPr) 2, (CH 3) 3 SiCl, (CH 3) 2 ClSi (CH 2) 2 SiCl (CH 3) 2, (CH 3) 2 ClSi (CH 2) 3 CN, [(CH ₃ ) ₃ Si] ₂ O, [(CH ₃ ) ₃ Si] ₂ NH and [(CH ₃ ) ₃ Si] ₂ .

When a cocatalyst is added to the reaction mixture, it should be used in an amount of 0.7 to 1.2 equivalents, preferably 0.9 to 1.1 equivalents, relative to the compound of formula (2).

The process for preparing the substituted amino compound of the formula (1) is preferably carried out under an atmosphere of an inert gas at a room temperature, that is, at a temperature of 20 to 25 ° C. If the cocatalyst is not further used in the reaction, a temperature of 80 占 폚, preferably 65 占 폚 or lower, may also be set as the reaction temperature. As can be seen from the examples, the complete reaction of carboxamide under the desired conditions occurs even after 1 hour.

The reaction is preferably carried out in a solvent suitable for the compounds of formulas 2, 3a1, 3a2, 3b, 4a or 4b, preferably aliphatic or aromatic hydrocarbons or ethers, preferably toluene, tetrahydrofuran, n-hexane, cyclohexane, Is carried out in a suitable organic solvent such as diethyl ether.

Most preferably, a solution of the compound of formula (2) and (4a) and the co-catalyst is initially introduced and the compound of formula (3) is metered in slowly thereto. It is advantageous if the addition of a Grignard or lithium compound is provided as a solution in the above-mentioned solvent and is preferably added to the reaction mixture by dropwise addition. It is also advantageous to stir the reaction mixture during the entire reaction.

According to the synthesis method, it is possible to produce the amino compound of the formula (1) symmetrically or asymmetrically substituted in a suitable yield within a suitable reaction time, and it is possible to produce an amino compound of the formula (1) Most of the reaction is avoided.

In particular,

a) at least one carboxamide of formula 2, from 1 to 15 mol%, based on the carboxamide, of a metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide, and optionally co-catalyst, Is initially introduced into a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether under an inert gas atmosphere,

b) dropwise adding a solution containing the nucleophilic reagent of formula 3a1, 3a2 or 3b,

c) reacting the mixture with stirring and post-treating the mixture in the usual manner after the reaction is complete, or, if Z is MgX,

a metal magnesium oxide selected from the group consisting of magnesium carbide, carboxamide of Formula 2, titanium oxide, hafnium dioxide and zirconium dioxide in an amount of 1 to 15 mol% based on the carboxamide, at room temperature under an inert gas atmosphere Is initially introduced into a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether,

b ') dropwise the alkyl halide of formula 3aa or 3bb dissolved in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether;

c ') reacting the mixture with stirring, and after the reaction has ended, the mixture is worked up in the usual manner:

Formula 3aa

XR ⁴

3bb

XR ⁴ -R ⁴ -X

Wherein R ⁴ and X have the meanings given above.

To carry out the process according to the invention, commercially available metal oxides selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide can be used as catalysts. Preferably, powdered titanium dioxide (TiO ₂ ) (IV) is used. In the simplest case, the titanium dioxide may be of an industrial grade. It is advantageous to choose a grade that is not too fine to simply separate after the reaction has ended.

Pre-dried metal oxides by heating, preferably titanium dioxide, are likewise used as suspensions in pre-dried, suitable solvents. Suitable solvents are, for example, aliphatic or aromatic hydrocarbons or ethers. Preferably, solvents selected from the group consisting of toluene, tetrahydrofuran, n-hexane, cyclohexane, benzene and diethyl ether which can be dried before reaction by methods known to those skilled in the art are used. Drying can be carried out using magnesium sulfate, calcium chloride, sodium, KOH or by other methods.

In order to carry out the process according to the invention, titanium dioxide (TiO ₂ ) (IV) is added in an amount of from 1 to 15 mol%, preferably from 3 to 13 mol%, based on the amount of the amide reactant, in toluene, (THF), hexane, benzene and diethyl ether in a suitable anhydrous solvent. The suspension is adjusted to a temperature of 15 to 30 캜, preferably about 20 캜. The starting material in the liquid form itself or in the form dissolved in a solvent selected from the group consisting of tetrahydrofuran (THF), toluene, hexane, benzene and diethyl ether under an atmosphere of an inert gas (nitrogen or argon) Gradually drop it. The cocatalyst dissolved in an anhydrous solvent is added dropwise in an amount corresponding to the amount of the starting material to be reacted. The obtained reaction mixture is stirred at a constant temperature for a short time, that is, several minutes. The mixture of the same amount of two different Grignard reagents is then added to the reaction mixture obtained so that the temperature of the reaction mixture does not exceed 50 ° C. In order to carry out the complete reaction of the possible starting materials, in each case the Grignard reagent is added in excess. Preferably, the Grignard reagent is used in an amount of 1.05 to 1.5 moles per mole of the starting material, respectively. In particular, Grignard reagents are used in an amount of 1.1 to 1.3 moles per mole of starting material. After completing the addition of the Grignard reagent, stirring is continued for a certain period of time at a constant temperature for the complete reaction of the reaction mixture obtained.

For example, 5 mmol of the starting material are added to a suspension of 3 mol% titanium (IV) oxide in 40 mL anhydrous tetrahydrofuran under an inert gas atmosphere at 20 < 0 > C with stirring. Similarly, 5 mmol of the cocatalyst dissolved in anhydrous tetrahydrofuran is slowly added to the mixture with stirring. Subsequently, after stirring for 5 minutes at 20 DEG C, 6 mmol of two different Grignard reagents were added slowly so that the temperature of the reaction mixture did not exceed 50 DEG C. [ Additional stirring was continued for 1 hour until the reaction was complete.

The titanium oxide (IV) used as the catalyst is used in an amount of 1 to 15 mol%, preferably 1.5 to 14 mol%, more preferably 2 to 10 mol%, and very preferably 3 To 6 mol% and is initially introduced in the form of a suspension and is adjusted to a temperature of 10 to 30 캜, preferably 15 to 25 캜, particularly preferably about 20 캜, Lt; / RTI > The starting material is dissolved in the liquid form itself or in a dissolved form in a solvent selected from the group consisting of toluene, tetrahydrofuran, n-hexane, cyclohexane, benzene and diethyl ether under an atmosphere of an inert gas (nitrogen or argon) It is gradually added dropwise with stirring. The cocatalyst is then added dropwise in an amount corresponding to the amount of starting material to be reacted, optionally dissolved in a solvent. The obtained reaction mixture is stirred for a short period of time, that is, at a constant temperature for several minutes. Substitution of a sufficient amount of a nucleophilic reagent of formula 3a1, 3a2 or 3b, in particular for the replacement of the same carbonyl C-atom by two identical substituents, i. E. Symmetrical substitution of the carbonyl C- The Grignard reagent is slowly added to the resulting reaction mixture. Addition of a nucleophilic reagent according to the present invention prepared by methods generally known to those skilled in the art should be carried out such that the temperature of the reaction mixture does not exceed 50 캜. It is advantageous to carry out the addition of the nucleophilic reagent, that is to say the Grignard reagent or the lithium compound, under complete mixing, preferably with vigorous stirring. To transfer the reaction equilibrium towards the desired symmetrically substituted product, the nucleophilic reagent used, preferably the Grignard reagent, is added in an amount of 2.1 to 3 moles per mole of starting material involved in the reaction. Preferably, the Grignard reagent is added in an amount of from 2.2 to 2.6 moles per mole of the starting material. When a nucleophilic reagent or a Grignard reagent of Formula 3b is used for the reaction, the reagent is added to the reaction solution in only equimolar amounts based on the starting material used according to the double reactive group.

After completing the addition of the Grignard reagent, the reaction mixture is continuously stirred at constant temperature for a certain period of time until the reaction is complete.

A further variant of the process according to the invention comprises preparing magnesium Grignard reagents in situ by reacting magnesium with a compound of formula 3aa or 3bb in which R ⁴ and X have the meanings given above. In the in situ preparation of the Grignard compound, the amount of magnesium is preferably 2 to 5 times, preferably 2.8 to 3.2 times, based on the amount of the compound of formula (2) used as the starting material, and the amount of the compound of formula Is 2 to 3.8 times, preferably 2.2 to 2.6 times, based on the compound of formula (2).

In the general description that follows the given method, the Grignard reagent may also be replaced by the corresponding lithium compound. Similar to Grignard reagents, the corresponding lithium compounds can be prepared by methods generally known to those skilled in the art, which can be reacted in accordance with the invention in a similar manner as described above.

After the reaction, symmetrically or asymmetrically substituted amino compounds can be purified and isolated in the conventional manner.

In this case, the product can be precipitated with a hydrochloric acid solution, for example a salt, with 1 mol of an etheric hydrochloric acid solution which is filtered and optionally purified by recrystallization.

The product is extracted from the organic phase with an acid solution, preferably an aqueous hydrochloric acid solution, and the obtained extract is adjusted to a pH greater than 10 with an alkali substance, preferably a sodium hydroxide solution, , Preferably several times. The organic phase obtained herein containing the reaction product can optionally be dried (by potassium carbonate) and the organic solvent removed under vacuum.

It is also possible to isolate the reaction product by removing the organic solvent by vacuum and separating the remaining residue by column chromatography in order to isolate the reaction product.

On the other hand, compounds of formula (I) can be prepared without the use of cocatalyst in the process described above.

After the reaction, symmetrically or asymmetrically substituted amino compounds may be purified and isolated in the manner described above in the conventional manner.

In the combined synthesis of the amines of formula 1, one or more different compounds of formula 2 and / or a number of different compounds of formula 3a1 or 3a2, and optionally compounds of formula 3b or 3c are used. In this way, it has been found that a combinatorial library containing multiple amines of the formula (1) as a mixture can be obtained. Preferably, from 1 to 10 different compounds of formula 2 react with two or more compounds of formula 3a1, 3a2 or 3b.

It is possible to screen a library of amines of formula (1) for biological activity to isolate and identify amines having the characteristics of a particular active compound.

The amine of formula 1 may be used as a pure material or a number of different amines may be used as a combinatorial library in combination synthesis in which one or more reactants and an amine are reacted to produce a modified amine of formula 1. Preferably, the structural elements of the in-situ substitution of the amine are maintained.

In combination syntheses for the preparation of the modified amines of formula (I), amines which have proven to be active in the biological screening process can be advantageously used. By using amines of formula (I) having biological activity in the preparation of modified amines, there is a possibility that improved activity can be obtained through combination synthesis.

By the repeated screening and synthesis steps, the activity of the amine of formula (I) can be increased in particular.

The combinatorial libraries of the synthesis according to the invention offer the following advantages, in particular:

- Contains a very large number of different amines present in the library in similar amounts.

- < / RTI > catalytic reaction.

It is not necessary to support the starting compound for preparing the library, as in the case of standard combination synthesis starting from, for example, an amino acid.

- readily available starting compounds can be used.

The invention is described with reference to the following examples.

Examples 1 to 3

A library containing the amine of formula (1) was prepared according to the following general experimental procedure and verified by mass spectrometry.

5 mmol of the starting material (compound of Formula 2) in solution in tetrahydrofuran or tetrahydrofuran was added to a solution of Ti (OiPr) ₄ (3 mol% or 100 mol, based on the amide used) in 40 mL anhydrous tetrahydrofuran under an inert gas atmosphere at 20 & Mol%) in tetrahydrofuran. In the case of the material of formula (I), ₅ moles of cocatalyst (CH ₃ ) ₃ SiCl were further added to the reaction mixture. This was stirred at 20 < 0 > C for 5 minutes. Next, 12 millimoles of Grignard reagent (compound of formula (III)) was added to the reaction mixture as much as possible so that the mixture was not heated above 50 ° C. This was stirred at room temperature for 1 hour. 15 mL of saturated ammonium chloride solution and 15 mL of water were added and the mixture was further stirred vigorously for 1 to 3 hours. The resulting precipitate was removed and washed with a small amount of anhydrous diethyl ether. The filtrate was made basic (pH > 10) by adding 15% sodium hydroxide solution. The phases were then separated and the aqueous layer was extracted three times with 30 mL each of diethyl ether. The combined organic layers were washed with 15 mL saturated solution of sodium chloride, dried over potassium carbonate and filtered.

The product can be purified by one of the following methods:

1. The product is precipitated as a hydrochloride salt using 1 M ethereal hydrochloric acid solution and filtered (the product obtained is purified by recrystallization as required).

2. Extract the organic layer twice with 40 mL of 0.5 M HCl solution. The extract is adjusted to pH> 10 using 2M NaOH solution and extracted again three times with 30 mL of anhydrous diethyl ether. The combined organic layers are dried over potassium carbonate and the solvent is removed in vacuo.

3. The solvent is removed in vacuo and the residue is isolated by column chromatography.

4. The solvent is removed under vacuum and the residue is distilled under vacuum.

The results are shown in Tables 1 to 3, and the percentage of product found in the mixture of post-treated products was shown in each case.

Claims (6)

Reacting a? Component selected from a compound represented by the following formula (2) and a? Component selected from the following formula (3a1), (3a2) or (3b) in a solvent in the presence of a cocatalyst and a compound selected from the group consisting of titanium, hafnium and zirconium compounds, (Wherein alpha is an integer of 1 or more, beta is an integer of 1 or more and alpha beta ² is 5 or more), an amine of formula (1) Formula 1 (2) Formula 3a1 ZR ⁴ Formula 3a2 ZR ⁵ 3b ZR ⁴ -R ⁵ -Z In this formula, R ^1, R ² and R ³ may be the same or different, hydrogen, a substituted or not alkyl, cycloalkyl, alkenyl are optionally substituted, cycloalkenyl, alkynyl or aryl group, -Si (R) _3, -Sn (R) ₃ , -SR, -OR or -NRR ', or the radicals R ¹ and R ² or R ² and R ³ may optionally contain, in addition to N, one or more further heteroatoms selected from N, O and S To form a cycloalkyl ring, Radicals R ⁴ and R ⁵ are the same or different, substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl or aryl _{group, -Si (R) 3, -Sn} (R) 3, - SR, -OR or -NRR ', or the radicals R ⁴ and R ⁵ form a cycloalkyl ring which may optionally contain, in addition to N, at least one further heteroatom selected from N, O and S, , The radicals R < ⁴ > and R < ⁵ > are connected by a bond, Z is Li or MgX where X is Hal and Hal is Cl, Br or I, In the definitions of the radicals R ¹ to R ⁵ , R and R 'may in each case be the same or different and are substituted or unsubstituted alkyl radicals or substituted or unsubstituted aryl radicals. The method according to claim 1, Wherein the radicals R < ¹ > and R < ² > are not hydrogen atoms. 3. The method according to claim 1 or 2, Wherein the radical R < ³ > is a hydrogen atom or a methyl group which may be substituted by 1 to 3 fluorine atoms. 4. The method according to any one of claims 1 to 3, R ¹ , R ² and R ³ , which may be the same or different, are each independently of the others a hydrogen atom, a C _1-8 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl group C _1-6 -alkyl groups, C _3-7 - cycloalkenyl groups, C _3-7 - cycloalkyl of C _1-6 substituted by an alkenyl-alkyl group, C _2-8 - alkenyl group, C _{2- 8} - alkynyl group, C _1-6 - alkoxy substituted by a a C _1-6 - alkyl group, C _{2-6-alkenyloxy} substituted by a C _1-6 - alkyl group, C _2-6 - alkynyl C _1-6 -alkyl group substituted by a C _1-6 -alkoxy group, a C _1-6 -alkoxy group substituted by a C _1-6 -alkoxy group, a mono-, di- or _polyhalo -C _1-6 -alkoxy group, a -C _2-6 - alkenyloxy groups substituted by a C _1-6 -alkyl group, a mono-, di- or poly -C _2-6 to be - alkynyloxy groups substituted by C _1-6 -alkyl group, C _1-6 - alkylthio substituted by a C _1-6 - alkyl group, C _1-6 - alkyl substituted by a sulfinyl C _1-6 - alkyl group, C _1-6 - alkyl sulfonic A carbonyl substituted by a C _1-6 -alkyl group, a mono-, di-, or -C _1-6 to be poly-alkyl group, a mono-, di-alkenyl group, - or a -C _2-8 to poly Mono-, di- or polyhalo-C _2-8 -alkynyl group, a C _1-6 -alkyl group substituted by cyano group, a C _2-6 -alkenyl group substituted by cyano group, cyano groups substituted by a C _2-6 - alkynyl group, substituted by a nitro-C _1-6 - alkyl group, a C _2-6 substituted by a nitro-alkenyl group, a C _2-6 substituted by a nitro- alkynyl group, C _1-6 - _1-6 is substituted by a C alkyl-amino-alkyl group, a C _1-6 - alkoxy substituted by an amino-C _1-6 -alkyl group, a di (C _1-3 -alkyl ) an amino substituted by a C _1-6 -alkyl group, N- (C _1-3 -alkyl) -N- (C _1-3 - alkoxy), a C _1-6 substituted by an amino-alkyl group, N- (C _{1-6-alkylsulfonyl)} -N- (C _1-6 -alkyl), a C _1-6 substituted by an amino-alkyl group, N- (C _1-6 -alkyl-sulfonyl) -N- ( C _1-6 -alkoxy) amino group Substituted by C _1-6 -alkyl group, tri -C _1-6 - alkyl silyl groups substituted by C _1-6 -alkyl groups, triarylsilyl groups substituted by a C _1-6 -alkyl group, an aryl group ( Provided that the aryl group may be substituted with at least one substituent selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group), an aryl group , this aryl group is methyl group, halogen atom, trifluoromethyl group, nitro group, C _1-6 - alkyl group and a C _1-6 - may be substituted with one or more substituents selected from the group consisting of a alkoxy) C ₁ is substituted by a _-6 -alkyl group, an aryl group (provided that such an aryl group is substituted with at least one substituent selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group A C _2-7 -alkenyl group, an aryl group (provided that such a Reel group methyl group, a nitro group, a C _1-6 a halogen atom, a trifluoro-C _1-6 alkyl group, and - may be substituted with one or more substituents selected from the group consisting of alkoxy group) a C _2-6 optionally substituted by An alkynyl group, a phenoxy group (provided that the phenoxy group is at least one substituent selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group) substituted by may be substituted) C _1-6 - alkyl group, an arylthio group (provided that such groups are methyl arylthio group by a halogen atom, a trifluoromethyl, a nitro group, a C _1-6 - alkyl group and a C _{1- 6-a} C _1-6 substituted by may be substituted with one or more substituents selected from the group consisting of a-alkoxy) -alkyl group, an aryl sulfinyl group (provided that such an aryl sulfinyl group is methyl group, halogen atom, trifluoromethyl, the alkoxy group-nitro group, C _1-6 - alkyl group and a C _1-6 May be substituted with one or more substituents selected from the group eojin) a C _1-6 substituted by a-alkyl group, an arylsulfonyl group (provided that such groups are methyl arylsulfonyl group, a nitro group, halogen atom, trifluoromethyl, C _1-6-alkyl group and a C _1-6 - a C _1-6 substituted by may be substituted with one or more substituents selected from the group consisting of a alkoxy) - an alkyl group, a benzyloxy group (provided that such a benzyloxy group aryl-methyl group, a nitro group, a C _1-6 a halogen atom, a trifluoro-C _1-6 alkyl group, and - may be substituted with one or more substituents selected from the group consisting of alkoxy group) a C _1-6 optionally substituted by An alkyl group, a benzylthio group (provided that the aryl group of the benzylthio group is at least one group selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group Lt; / RTI >< RTI ID = 0.0 > Substituted by C _1-6 - alkyl group, a benzyl sulfinyl group (provided that such a benzyl group aryl sulfinyl group is a methyl group, a nitro group, halogen atom, trifluoromethyl, C _1-6 - alkyl group and a C _1-6 - a by may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _1-6 - alkyl group, a benzyl sulfonyl group (provided that such a benzyl aryl sulfonyl group is methyl group, halogen atom, trifluoromethyl group, a nitro group, a C _1-6 - alkyl group and a C _1-6 - by a may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _1-6 - alkyl group, a C _1-4 - A C _1-6 -alkyl group substituted by an amino group substituted by an alkylsulfonyl group, or the radicals R ¹ and R ² or R ² and R ³ are optionally substituted by one or more additional 1-pyrrolidinyl, 1-imidazolinyl, 1-pyrazolyl which may optionally also contain heteroatoms , 1-piperidyl, 1-possess piperazinyl, 4-morpholinyl and 4-morpholino-thiazol method for forming a cycloalkyl ring selected from the group consisting of carbonyl. 5. The method according to any one of claims 1 to 4, R ⁴ and R ⁵ that may be the same or different and independently represent a hydrogen atom, C _1-8 each other alkyl groups, C _3-7 - cycloalkyl group, C _3-7 - cycloalkyl substituted by a C _{1- 6} - alkyl group, C _3-7 - cycloalkenyl groups, C _3-7 - cycloalkyl of C _1-6 substituted by an alkenyl-alkyl group, C _2-8 - alkenyl group, C _2-8 - alkynyl carbonyl group, C _1-6 - alkoxy groups optionally substituted by a C _1-6 -alkyl group, C _2-6 - alkenyloxy groups substituted by a C _1-6 -alkyl group, C _{2-6-alkynyloxy} groups A C _1-6 -alkyl group substituted by a mono-, di- or _polyhalo -C _1-6 -alkoxy group, a mono-, di- or polyhalo-C _2-6 alkenyloxy groups substituted by a C _1-6 -alkyl group, a mono-, di- or poly be -C _2-6 alkynyloxy substituted by a C _1-6 -alkyl group, a C _1-6 di-substituted by a C _1-6 alkylthio-substituted by a C _1-6 alkylsulfinyl--alkyl group, C _1-6 alkyl group, C _{1-6-alkylsulfonyl} A C _1-6 substituted by a-alkyl group, a mono-, di-, or -C _1-8 to be poly-alkyl group, a mono-, di-, or -C _2-8 to be poly-alkenyl group, a mono- -, a di- or polyhalo-C _2-8 -alkynyl group, a C _1-6 -alkyl group substituted by cyano group, a C _2-6 -alkenyl group substituted by cyano group, a cyano group substituted by C _2-6 - alkynyl group, a C _1-6 substituted by a nitro-alkyl group, a nitro groups substituted by C _2-6 -alkenyl group, a nitro substituted by C _2-6 - alkynyl carbonyl group, a C _1-6 - alkylamino groups substituted by a C _1-6 -alkyl group, a C _1-6 - alkoxy substituted by a C _1-6 amino-alkyl group, a di (C _1-3 -alkyl) amino groups substituted by a C _1-6 -alkyl group, N- (C _1-3 -alkyl) -N- (C _1-3 - alkoxy) substituted by an amino-C _1-6 -alkyl group, N- ( C _1-6 - alkylsulfonyl) -N- (C _1-6 - alkyl) amino substituted by a C _1-6 - alkyl group, N- (C _1-6 - alkylsulfonyl) -N- (C _1-6 - alkoxy) amino group of the Substituted C _1-6 -alkyl group, tri -C _1-6 - alkyl silyl groups substituted by C _1-6 -alkyl groups, triarylsilyl groups substituted by a C _1-6 -alkyl group, an aryl group (where , This aryl group may be substituted with at least one substituent selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group), an aryl group the aryl group is a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 - alkyl group and a C _1-6 - may be substituted with one or more substituents selected from the group consisting of a alkoxy) C _1- substituted by a _6-alkyl group, an aryl group (provided that such aryl group is a methyl group, a nitro group, halogen atom, trifluoromethyl, C _1-6 - alkyl group and a C _1-6 - optionally substituted with one or more substituents selected from the group consisting of a alkoxy may be) C-substituted by _2-7 -alkenyl group, an aryl group (provided that such aryl It is a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 - alkyl group and a C _1-6 - by a may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _2-6 - An alkynyl group, a phenoxy group (provided that such a phenoxy group is substituted with at least one substituent selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group A C _1-6 -alkyl group, an arylthio group (provided that such an arylthio group may be substituted by a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkyl group, - a by may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _1-6 - alkyl group, an aryl sulfinyl group (provided that such an aryl sulfinyl group is methyl group, halogen atom, trifluoromethyl, nitro, done alkoxy group-group, C _1-6 - alkyl group and a C _1-6 Substituted by a C may be substituted with one or more substituents selected from the group) _1-6-alkyl group, an arylsulfonyl group (provided that such an arylsulfonyl group as a methyl group halogen atoms, trifluoromethyl, nitro, C _{1 -6-alkyl} group and a C _1-6 - by a may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _1-6 -alkyl group, a benzyloxy group (provided that the aryl group in such benzyloxy groups are methyl group, a nitro group, a C _1-6 a halogen atom, a trifluoro-C _1-6 alkyl group, and a - a by may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _1-6 - An alkyl group, a benzylthio group (provided that the aryl group of the benzylthio group may be substituted with at least one substituent selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group Can be replaced by < RTI ID = 0.0 > Hwandoen C _1-6 - alkyl group, a benzyl sulfinyl group (provided that such a benzyl sulfinyl group of the aryl group is a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 - alkyl group and a C _1-6 - alkoxy substituted by may be substituted with one or more substituents selected from the group consisting of a) C _1-6 - alkyl group, a benzyl sulfonyl group (provided that such aryl group is a methyl group in the benzyl sulfonyl group with a halogen atom, a trifluoromethyl group, a nitro group, C _1-6 - alkyl group and a C _1-6 - by a may be substituted with one or more substituents selected from the group consisting of a alkoxy), optionally substituted C _1-6 - alkyl group, C _1-4 - alkyl sulfonic Lt; RTI ID = 0.0 > Cl ₆ -alkyl < / RTI > 6. The method according to any one of claims 1 to 5, A? ² is greater than 7.