EP1088029A1 - Amines substituees de maniere geminee - Google Patents

Amines substituees de maniere geminee

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Publication number
EP1088029A1
EP1088029A1 EP99932703A EP99932703A EP1088029A1 EP 1088029 A1 EP1088029 A1 EP 1088029A1 EP 99932703 A EP99932703 A EP 99932703A EP 99932703 A EP99932703 A EP 99932703A EP 1088029 A1 EP1088029 A1 EP 1088029A1
Authority
EP
European Patent Office
Prior art keywords
group
substituted
alkyl
alkyl group
nitro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP99932703A
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German (de)
English (en)
Inventor
Herwig Buchholz
Urs Welz-Biermann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19827161A external-priority patent/DE19827161A1/de
Priority claimed from DE19827163A external-priority patent/DE19827163A1/de
Priority claimed from DE19827165A external-priority patent/DE19827165A1/de
Priority claimed from DE19827166A external-priority patent/DE19827166A1/de
Priority claimed from DE19827164A external-priority patent/DE19827164A1/de
Priority claimed from DE19844194A external-priority patent/DE19844194A1/de
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1088029A1 publication Critical patent/EP1088029A1/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/023—Preparation; Separation; Stabilisation; Use of additives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0201—Oxygen-containing compounds
    • B01J31/0211—Oxygen-containing compounds with a metal-oxygen link
    • B01J31/0212—Alkoxylates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0237—Amines
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
    • B01J31/0274—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 containing silicon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/66—Preparation of compounds containing amino groups bound to a carbon skeleton from or via metallo-organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to geminally substituted amines.
  • the present invention relates to geminally alkylated amines, combinatorial libraries of such amines and special uses of these amines as intermediates in combinatorial active ingredient synthesis or as active ingredients in medicaments.
  • a prerequisite for the combinatorial synthesis of drug libraries is the accessibility of suitable starting compounds which either already contain a biologically active structural element or form this through combinatorial synthesis.
  • the object of the invention is therefore to provide new compounds which contain a special biologically active structural element and which can be used individually or as a library in the combinatorial synthesis of active substances.
  • This object is achieved by providing an amine of the following formula (I) as a pure substance or in a substance library in a mixture with several different amines of the formula (I). It has been found that, surprisingly, the geminal substitution of a preferably tertiary amine can not only provide biological activity, but at the same time also has advantageous properties for combinatorial drug synthesis. A process is also proposed in which a large number of amines of the general formula (I) can be prepared as a substance library.
  • R1 and R ⁇ may be the same or different and each independently represent substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl or trialkylsilyl or R 1 and R ⁇ together with the nitrogen atom to which they are attached have a substituted one or can form unsubstituted cycloalkyl ring which, in addition to the nitrogen atom, can also contain at least one further heteroatom which is selected from the group consisting of nitrogen, oxygen or sulfur,
  • R 3 is selected from hydrogen and methyl, which can optionally be substituted by 1 -3 fluorine atoms,
  • R ⁇ and R5 may be the same or different and each independently represents substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, or alkynyl or a salt, in particular a pharmaceutically acceptable salt thereof
  • the compounds of the present invention are particularly valuable as sympathomimetics
  • Alkyl preferably represents C 1-8 -alkyl, more preferably C2_8-alkyl cycloalkyl preferably stands for C3_3-cycloalkyl, more preferably C3_7-cycloalkyl alkenyl preferably stands for C2_-
  • Nocn more preferably for C2-8" l enyl cycloalkenyl preferably stands for C 3 _ 3-cycloalkenyl, more preferably for C3_7-cycloalkenyl alkynyl preferably stands for C2_ ⁇ n-Al ⁇ nyl, even more preferably for C2-8-alk ⁇ nyl
  • Aryl is preferably phenyl, naphthyl, anthryl or
  • alkyl radical methyl, ethyl propyl butyl pentyl hexyl special
  • cycloalkyl radical examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl special
  • alkenyl radical examples include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl isobutenyl
  • R ⁇ and R ⁇ are described below, where halogen is fluorine, chlorine, bromine or iodine
  • R ⁇ and R ⁇ can be the same or different and independently of one another for a C-
  • Halogen atom a trifluoromethyl group, a nitro group, a C, 6 -alkyl group and a C,
  • a C, 6 -alkoxy group a C, 6 -alkyl group substituted with a phenylsulfinyl group (with the proviso that such a phenylsulfinyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group , a C, ⁇ - alkyl group and a C, 6 - alkoxy group), one with a
  • Phenylsulfonyl group substituted C, 6 - alkyl group (with the proviso that such a
  • Phenylsulfonyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, one
  • Nitro group a C, 6 - alkyl group and a C, 6 - alkoxy group
  • a C, 6 - alkyl group substituted by a benzyloxy group with the proviso that the phenyl group of such
  • Benzyloxy group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C, 6- alkyl group and a C, 6- alkoxy group), a C substituted with a benzylthio group, ⁇ -
  • benzylsulfinyl group can be substituted with one or more substituents which are selected from the group consisting of one
  • Halogen atom a trifluoromethyl group, a nitro group, a C, 6- alkyl group and a C,
  • a C, ⁇ -alkyl group substituted by a benzylsulfonyl group (with the proviso that the phenyl group of such a benzylsulfonyl group may be substituted by one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C, 6 -alkyl group and a C, 6- alkoxy group), a C, g-alkyl group substituted by an amino group which is substituted by a C, 4- alkylsulfonyl group
  • Examples of rings which are present when the radicals R 1 and R 2 form a cycloalkyl ring which may contain, in addition to N, at least one further heteroatom, preferably N, O or S, are as follows: 1-pyrrolidine, 1-imazoleyl, 1 -Pyrazol ⁇ nyl, 1 -P ⁇ per ⁇ dyl, 1 -P ⁇ peraz ⁇ nyl, 4-Morphol ⁇ nyl, 4- Thiamorpholinyl.
  • the radicals R 1 and R 2 are particularly preferably each independently of one another methyl, ethyl, isopropyl, n-butyl, isobutyl, phenyl, benzyl, 2-pyridyl or trimethylsilyl, or together with the nitrogen atom to which they are attached are for 1-Pyrrol ⁇ d ⁇ nyl, 1-P ⁇ per ⁇ dyl, 4-Methylpipendyl, or 4-Morphol ⁇ nyl
  • R 3 particularly preferably represents hydrogen
  • R 4 and R 5 are described below, where halogen is fluorine, chlorine, bromine or iodine:
  • R 4 and R 5 may be the same or different and independently of one another are a C, 8 -alkyl group, a C 3 7 -cycloalkyl group, a C, 6- alkyl group substituted with a C 37 -cycloaikyl group, a C 37 -cycloalkenyl group, one with a C 37 cycloalkenyl group substituted C, 6 alkyl group, a C 2 8 alkenyl group, a C 2 8 alkynyl group, a C, 6 alkoxy group substituted C, 6 alkyl group, one substituted with a C 2 6 alkenyloxy group C, e alkyl group, a C substituted with a C 2 6 -Alk ⁇ nyloxy distr, 6 alkyl group, a with a mono-, di- or polyhalo-C, g alkoxy-substituted C, 6 alkyl group, a, with a mono- di- or polyhalo-C
  • R 4 and R 5 are particularly preferably methyl, ethyl, isopropyl, n-butyl, tert-butyl, ethenyl, Ethynyl, allyl, n-hexyl, trimethylsilylmethyl, cyclopropyl, cyclopentyl, cyclohexyl.
  • the present invention also provides amines of the following general formula (I-a)
  • R ⁇ R 2 , R 4 and R 5 have the meanings indicated above or preferably R 1 and R 2 each independently represent ethyl or hexyl or together with the nitrogen atom to which they are attached represent a piperidinyl group; and R 4 and R 5 are each independently or together hydrogen, methyl, butyl or hexyl.
  • a combinatorial library in the sense of the present invention contains at least five, preferably at least seven different amines of the general formula (I) or (I-a).
  • the preparation of the compounds of the general formula (I) is not particularly restricted. However, it has been found that the compounds of the general formula (I) can preferably be prepared by one of the following processes.
  • R 1 , R 2 and R 3 have the meaning given above and R 3 particularly preferably represents hydrogen or a methyl group, in a suitable solvent with a compound of the general formula (III)
  • R ' for an alkyl radical with C, -C 10 , an aryl radical with C 6 - C 20 or an aryl radical which is mono- to pentasubstituted by fluorine, chlorine, bromine or iodine with C 6 -C 20 , preferably for an iso-propyl radical
  • R 5 has the meaning given above and n is a whole
  • a compound of the general formula (III) is used as the Grignard compound or organolithium compound for the reaction.
  • the radical R 4 preferably stands for a C, - C 10 alkyl radical, a fluorine or polysubstituted by fluorine, including perfluorinated C, - C, 0 alkyl radical, a C 3 - C 6 cycloalkyl radical, one C 2 - C, 0 alkenyl radical, a C 2 - C, 0 alkynyl radical, or a radical -C (R ") (R ') CH 2 R, where R" is -Si (R) 3 , Sn (R) 3 , -SR, -OR, - NRR ', where R or R', the same or different, represents a C, - C, 0 alkyl radical, a fluorine or polysubstituted, including perfluorinated C, - C, 0 Alkyl radical,
  • the radical M in the general formula (III) preferably stands for a -MgX radical with X for Cl or Br or the radical M stands for lithium.
  • the reaction is preferably also carried out with an organotitanium compound.
  • organotitanium compounds are preferably compounds of the general formula (IV-a) shown above, where n is an integer from 1 to 3, preferably 3, Y is Cl, Br or I, the radicals R "', the same or different, one Alkyl radical with C, - C, 0 or an aryl radical with C 6 - C 20 , preferably isopropyl, and R 5 , identical or different from R 4 , has the meaning given for R 4 .
  • R 5 Ti (OiPr) 3 is particularly preferably used as the organotitanium compound, iPr standing for an isopropyl radical.
  • Methyl, phenyl, cyclopropyl or p-fluorophenyl-tri-isopropyl titanates are very preferred used.
  • the compounds of the general formula (III) and (IV) should each be present in amounts of 0.7 to 1.3, preferably 0.9 to 1.1 equivalents, based on the compound of the general formula (II) .
  • the reaction is preferably carried out in a suitable solvent for the compounds of the general formulas (II) and (III) and (IV-a), preferably in a suitable organic solvent, such as, for. B. an aliphatic or aromatic hydrocarbon or ether, preferably toluene, tetrahydrofuran, n-hexane, cyclohexane, benzene or diethyl ether.
  • a suitable organic solvent such as, for. B. an aliphatic or aromatic hydrocarbon or ether, preferably toluene, tetrahydrofuran, n-hexane, cyclohexane, benzene or diethyl ether.
  • a solution of the compound of the general formula (II) and (IV) and the cocatalyst are very particularly preferably introduced and the compound (III) is metered in slowly. It is advantageous if the addition of the Grignard or lithium compounds is present as a solution in the solvents mentioned and is preferably added to the reaction mixture by dropwise addition. It is also advantageous to stir the reaction mixture during the entire reaction.
  • the process for the preparation of amino compounds of the general formula (I) is preferably carried out at room temperature, i.e. H. at 20 to 25 ° C, carried out under an inert gas atmosphere.
  • the symmetrically or asymmetrically substituted amino compounds can be purified and isolated in the usual way.
  • the products can be used as salts using hydrochloric acid solutions such.
  • hydrochloric acid solutions such as B. 1 molar, ethereal hydrochloric acid solutions, precipitated and filtered off, and, if necessary, purified by recrystallization.
  • reaction product by using the organic solvent removed with the help of vacuum and the remaining residue is separated by column chromatography to isolate the reaction product.
  • Compounds of the present invention can also be prepared by reacting a compound of the general formula (II) shown above, wherein R ⁇ R 2 and R 3 have the meanings given for formula (I), with a nucleophilic reagent of the general formula (III), where R 4 has the meanings given for formula (I), in the presence of catalytic amounts of a metal oxide, selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide.
  • a metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide.
  • the process can also be carried out in the presence of a cocatalyst, where alkylsilyl halides can be used as cocatalysts; namely alkylsilyl halides of the general formula (V)
  • the use of the cocatalyst suppresses the ⁇ and / or ⁇ elimination which is usually observed in titanium alkyls which have ⁇ and / or ⁇ hydrogen atoms. Accordingly, the process can also be carried out by
  • Catalyst selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide, based on the carboxamide, at room temperature under an inert gas atmosphere in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether,
  • carboxamides of the general formula (II) can be reacted with good yields, in which R 1 , R 2 independently of one another have the following
  • a ie branched or unbranched alkyl having 1 to 10 carbon atoms such as methyl, ethyl, n- or i-propyl, n-, sec- or t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyi and their suitable isomers, or cycloalkyl having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or corresponding methyl- or ethyl-substituted cycloalkyl groups or mono- or polyunsaturated cycloalkyl groups, such as cyclocententenyl or cyclopentadienyl or branched or unbranched alkenyl with 2 to 10 C atoms, such as allyl, vinyl, is
  • Aralkenyl or aralkynyl where in each case the aryl, alkenyl and alkynyl group can assume the meanings given, such as. B. in phenylethynyl, and R 3 is hydrogen or methyl.
  • R 1 and R 2 together form a cyclic ring with 3 to 8 carbon atoms which, in addition to nitrogen, contains further heteroatoms, such as - S -, - O - or - N -.
  • Particularly preferred here are compounds in which R 1 and R 2 form a simple cyclic ring which includes the nitrogen of the carboxamide or in which R 1 and R 2 form a cyclic ring which has an oxygen atom as a further Contains heteroatom.
  • R 4 preferably represents an alkyl radical having 1 to 10 carbon atoms, such as methyl, ethyl, n- or i-propyl, n-, sec- or t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like suitable isomers, or cycloalkyl having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or corresponding methyl- or ethyl-substituted cycloalkyl groups or mono- or polyunsaturated cycloalkyl groups, such as cyciopentenyl or cyclopentadienyl or
  • alkenyl radicals with 2 to 10 carbon atoms such as allyl, vinyl, isopropenyl, propenyl or
  • alkynyl radicals having 2 to 10 carbon atoms, such as ethynyl or propynyl.
  • Grignard compounds such as methyl magnesium bromide, ethyl magnesium bromide, n- or i-propyl magnesium bromide, i-, sec-, or tert-butyl magnesium bromide, n-hexyl mag nesi umb romid, cyclohexyl mag nesium mchloride, al lyl mag nesmium bromide, bromide are particularly preferred Cyclopentylmagnesiumbromid, Cyclopentylmagnesiumchlorid, Allylmagnesiumbromid used for the reactions.
  • Alkylsilyl halides are suitable as co-catalysts in this reaction.
  • these are the alkylsilyl halides described above of the general formula (V) or of the general formula (VI).
  • Alkylsilane halides are preferably used, in which R ⁇ v is alkyl having 1 to 6 carbon atoms. Particularly preferred are those in which R ⁇ v is alkyl having 1 to 3 carbon atoms and X is chlorine.
  • Dried commercially available metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide, can be used as the catalyst for carrying out the process.
  • Powdery titanium (IV) ox ⁇ d (Ti0 2 ) is preferably used. In the simplest case, this can be a technical quality. In order to be able to ensure simple separation after the reaction has taken place, it is advantageous to choose a quality which is not too finely divided.
  • the metal oxide preferably titanium dioxide, which has been predried by heating, is used as a suspension in a suitable, likewise predried organic solvent.
  • suitable solvents are e.g. B. aliphatic or aromatic hydrocarbons or ethers.
  • Solvents selected from the group consisting of toluene, tetrahydrofuran, n-hexane, cyclohexane, benzene and diethyl ether are preferably used, which are dried before the reaction by methods known to those skilled in the art. Drying can be carried out using magnesium sulfate, calcium chloride, sodium, KOH or by other methods.
  • a preferred embodiment of the method is that the titanium (IV) oxide used as catalyst in an amount of 1-15, preferably 1.5 to 14, in particular 2 to 10, and very particularly preferably 3-6 mol%, based on a mole of the amide used as starting material is introduced in the form of a suspension which is set to a temperature of 10-30 ° C., preferably 15-25 ° C., particularly preferably a temperature of approximately 20 ° C.
  • the starting material is slowly added dropwise either as such in liquid form or dissolved in a solvent selected from the group consisting of toluene, tetrahydrofuran, n-hexane, cyclohexane, benzene and diethyl ether with stirring. Then an amount of cocatalyst corresponding to the amount of starting material to be reacted, if necessary also taken up in a solvent, is added dropwise. The reaction mixture obtained is stirred for a short time, ie for a few minutes, at a constant temperature.
  • nucleophilic reagent of the general formula (III), in particular a Grignard reagent is slowly added in excess to the reaction mixture thus obtained that a substitution of the geminal carbonyl carbon atom by two identical substituents, that is to say a symmetrical substitution of the geminal carbonyl -C atom can take place.
  • a nucleophilic reagent according to the invention produced according to methods well known to the person skilled in the art, should take place so slowly that the temperature of the reaction mixture does not exceed 50 ° C. It is advantageous if the nucleophilic reagent, ie the Grignard reagent or the lithium compound, is added with thorough mixing, preferably with intensive stirring.
  • the nucleophilic reagent used preferably a Grignard reagent
  • the nucleophilic reagent used is added in an amount of 2.1 to 3 moles per mole of reactant reactant.
  • the Grignard reagent is preferably added in an amount of 2.2 to 2.6 mol based on 1 mol of starting material.
  • the reaction mixture is stirred for a while at a constant temperature until the reaction is complete.
  • the Grignard reagent is prepared in situ by reacting magnesium with an appropriate halide.
  • the amount of magnesium is preferably 2 to 5 times the molar amount, preferably 2.8 to 3.2 times the molar amount, based on the compounds of the general formula (II) used as starting material and the amount of the halide is 2 to 3.8 times the molar amount, preferably 2.2 to 2.6 times the molar amount, based on the compound of the general formula (II).
  • the reaction temperature can be adjusted to approximately 80 ° C., preferably 60 to 70 ° C., in particular 75 ° C., after the addition of the nucleophilic reagent has been completed and thorough mixing has taken place.
  • reaction mixture can be worked up in a manner known to those skilled in the art.
  • the products can be used as salts with the help of hydrochloric acid solutions, e.g. B. 1 molar ethereal hydrochloric acid solutions, precipitated and filtered, and if necessary, purified by recrystallization.
  • hydrochloric acid solutions e.g. B. 1 molar ethereal hydrochloric acid solutions
  • a suitable amount of saturated ammonium chloride solution and water can be added, for example, and stirring is continued intensively for several hours (1-3 hours).
  • the resulting precipitate is separated off and washed with a little dried ether, preferably diethyl ether.
  • the filtrate is made basic (pH> 10) by adding a suitable alkali, such as a NaOH, KOH, sodium or potassium carbonate solution, preferably sodium hydroxide solution.
  • the phases which form are then separated and the aqueous phase is extracted several times (for example three times with 30 ml each in the above case) with diethyl ether.
  • the combined organic phases are washed with (e.g. 15 ml) saturated sodium chloride solution and can be dried over potassium carbonate, magnesium sulfate or sodium sulfate and filtered.
  • the products can be purified in various ways according to methods known to the person skilled in the art, such as e.g. B. in the manner described above.
  • the Grignard reagents can also be replaced by the corresponding lithium compounds.
  • the corresponding lithium compounds can, like the Grignard compounds, after Methods generally known to those skilled in the art can be prepared and can be implemented in the same manner as described above.
  • the reaction can also take place in the presence of an organotitanium compound.
  • the reaction takes place in the presence of an organotitanium compound as a catalyst, which is used in an amount of 0.5 to 5 mol%, preferably 1 to 3.5 mol%, based on the compound of the general formula (II).
  • n is an integer from 1 to 4,
  • R v is an alkyl radical with 1 to 10 C atoms or an aryl radical with 6 to 20
  • organotitanium compounds in which R v is isopropyl are preferably used.
  • the organotitanium compound used is particularly preferably Ti (Oi-Pr) 4 , where i-Pr corresponds to an isopropyl radical.
  • the symmetrically substituted amine compounds of the general formula (I) prepared are preferably not only in the presence of a catalyst, but can also be in the presence of a compound of one of the general formulas (V) or (VI) shown above or a compound of the general formula (VII )
  • M ' is Al, Ca, Na, K, Si or Mg, preferably Mg or Na
  • m is an integer from 1 to 4 and the oxidation state of the metal, prepared as a cocatalyst.
  • a cocatalyst is added to the reaction mixture, it should be used in amounts of 0.7 to 1.2, preferably 0.9 to 1.1 equivalents, based on the compound of the general formula (II).
  • R 4 and R 5 have the meanings given above, where,
  • titanium dioxide Group of titanium dioxide, hafnium dioxide and zirconium dioxide.
  • the catalyst is preferably used in the presence of a cocatalyst, in particular in the presence of an alkylsilane halide as cocatalyst.
  • Suitable alkylsilane halides are the compounds of the general formula (V) or of the general formula (VI) described above.
  • titanium dioxide is used as the catalyst for carrying out the process. The process is characterized in that one
  • Metal oxide selected from the group titanium (IV) oxide, hafnium dioxide, zirconium dioxide, based on the carboxamide, at a temperature of 10 to 30 ° C. of the group toluene,
  • THF THF, hexanes, benzene and diethyl ether, b ') at least two different in a solvent selected from the group toluene,
  • R 4 and R 5 have the meanings given above, added dropwise, c ') can be re-reacted with stirring and, after the reaction has ended, worked up in a conventional manner.
  • Process step a) or a ') is carried out at a temperature of 15 to 25 ° C, preferably at room temperature.
  • a catalyst system consisting of a metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide and a co-catalyst of the general formula (V) or (VI) described above has proven particularly advantageous.
  • This catalyst system preferably contains a compound selected from the group
  • a catalyst system containing titanium dioxide as the metal oxide is very particularly preferably used.
  • titanium (IV) oxide (Ti0 2 ) as a suspension in a suitable, dried solvent is selected from the group consisting of toluene, tetrahydrofuran (THF), hexanes, benzene and diethyl ether in an amount of 1 to 15 mol%, preferably 3-13 mol%, based on the amount of the reacting amide.
  • the suspension is adjusted to a temperature of 15 to 30 ° C, preferably to about 20 ° C.
  • the starting material either as such in liquid form or dissolved in a solvent, selected from the group consisting of tetrahydrofuran, toluene, tetrahydrofuran (THF), hexanes, benzene and diethyl ether, is slowly added dropwise with stirring.
  • a solvent selected from the group consisting of tetrahydrofuran, toluene, tetrahydrofuran (THF), hexanes, benzene and diethyl ether
  • An amount of cocatalyst corresponding to the amount of starting material to be reacted, likewise taken up in a dried solvent, is added dropwise.
  • the reaction mixture obtained is stirred for a short time, ie for a few minutes, while maintaining the temperature.
  • a mixture consisting of is then added to the reaction mixture obtained equal amounts of two different Grignard reagents, added so slowly that the temperature of the reaction mixture does not rise above 50 ° C.
  • the Grignard reagents are added in excess.
  • the Grignard reagents are preferably used in an amount of at least 1.05 mol to 1.5 mol per 1 mol of educt.
  • the Grignard reagents are used in an amount of 1.1 to 1.3 mol, based on 1 mol of starting material.
  • Compounds of the present invention are advantageously prepared by reacting a compound of the general formula (II) shown above, where R 1 , R 2 and R 3 have the meaning given above, in a suitable solvent with at least one compound of the general formula (II la) and (III-b) in the presence of an organotitanium compound of the general formula (IV-b) as a catalyst.
  • Carboxylic acid amides in which the radicals R 1 and R 2 , the same or different, for hydrogen, an alkyl radical with C, -C, 0 , a cycloalkyl radical with C 3 -C 8 , an aryl radical with C 6 - C 20 , an alkenyl radical with C 2 -C, 0 , an alkynyl radical with C 2 -C, 0 , a cycloalkyl ring from the radicals R 1 and R 2 or R 2 and R 3 with C 3 -C 8 , which in addition to nitrogen optionally may contain a nitrogen, oxygen or sulfur atom as a further heteroatom, and the radicals R and R 'for an alkyl radical with C, -C, 0 , a cycloalkyl radical with C 3 -C 6 or an aryl radical with C 6 -C 20 stand.
  • organotitanium compounds used are particularly preferably Ti (OiPr), where iPr stands for an isopropyl radical.
  • the asymmetrically substituted amine compounds of the general formula (I) prepared according to the invention are preferably not only in the presence of a catalyst, but also in Presence of a compound according to one of the general formulas (V), (VI) or (VII) prepared as a cocatalyst.
  • the process for the preparation of symmetrically or asymmetrically substituted amino compounds of the general formula (I) is preferably carried out at room temperature, i.e. H. at 20 to 25 ° C, carried out under an inert gas atmosphere.
  • the compounds of the general formula (I-a) can be prepared by using no cocatalyst in the process described above.
  • the symmetrically or asymmetrically substituted amino compounds can be purified and isolated in a conventional manner, such as. B. described above.
  • the amides of the general formula (II) are initially introduced in THF under argon with the catalyst (for example Ti (OiPr) 4 ) and the cocatalyst (for example (CH 3 ) 3 SiCl).
  • the various Grignard reagents are then added as simultaneously as possible.
  • the mixture is stirred further and worked up as described above.
  • the synthesis thus corresponds to the already known individual syntheses, only that several amides are initially introduced and / or several different Grignard reagents are added simultaneously if possible.
  • the amount of substance should are chosen so that the addition of all amides corresponds to the molar amount of the addition of all Grignard reagents. This ensures that all products that are legally possible can be obtained.
  • the amines of the general formula (I) can be used as pure substances or a number of different ones can be used as a combinatorial library in a combinatorial synthesis in which the amines are reacted with one or more reactants in order to create modified amines of the general formula (I).
  • the structural element of the geminal substitution of the amines is preferably obtained.
  • modified amines of the general formula (I) it is advantageously possible to use those amines which have already been found to be effective in a biological screening process.
  • amines of the general formula (I) with biological activity in the creation of modified amines, it is possible to achieve an improved activity by combinatorial synthesis.
  • the process can be carried out catalytically.
  • the compounds of general formula (I) or (la) and their physiologically acceptable salts can therefore be used for the production of pharmaceutical preparations by combining them with at least one carrier or auxiliary and, if desired, with one or more further active ingredients brings the appropriate dosage form.
  • the preparations thus obtained can be used as pharmaceuticals in human or veterinary medicine.
  • Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g.
  • oral or rectal or parenteral application or for application in the form of an inhalation spray and do not react with the new compounds, for example water, vegetable oils, Benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose.
  • Tablets, coated tablets, capsules, syrups, juices or drops are used in particular for oral use; of particular interest are coated tablets and capsules with enteric coatings or capsule shells.
  • Suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants for parenteral administration.
  • sprays can be used which contain the active ingredient either dissolved or suspended in a propellant gas mixture (e.g. chlorofluorocarbons).
  • a propellant gas mixture e.g. chlorofluorocarbons
  • the active ingredient is expediently used in micronized form, it being possible for one or more additional physiologically acceptable solvents to be present, for. B. ethanol.
  • Inhalation solutions can be administered using standard inhalers.
  • the active ingredients claimed according to the invention can also be lyophilized and the lyophilizates obtained, for. B. can be used for the preparation of injectables.
  • the specified preparations can be sterilized and / or contain auxiliaries such as preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and / or flavorings. If desired, they can also contain one or more other active ingredients, e.g. B. one or more vitamins, diuretics, anti-inflammatory drugs.
  • the compounds of the formula (I) or (Ia) according to the invention are generally administered in analogy to other known, commercially available preparations, but in particular in analogy to the compounds described in US Pat. No. 4,880,804, preferably in doses between about 1 mg and 1 g, in particular between 50 and 500 mg per dosage unit.
  • the daily dosage is preferably between about 0.1 and 50 mg / kg, in particular 1 and 10 mg / kg body weight.
  • the specific dose for each individual patient depends on a variety of factors, for example on the effectiveness of the special compound used, on the age, body weight, general health, gender, on the diet, the time and route of administration, the rate of excretion, the combination of drugs and the severity of the disease to which the therapy applies. Oral application is preferred.
  • Titanium (IV) oxide induced symmetric diaikylation of carboxylic acid amides with Gricnardre aqenzien.
  • the compound listed in Table 3 was prepared by titanium (IV) oxide-induced asymmetrical disubstitution of carboxylic acid amides.
  • reaction products are worked up as in Examples 1-5.
  • the organic phase is extracted twice with 40 ml of a 0.5 M HCl solution. This extract is adjusted to pH> 10 with 2 M NaOH solution and extracted again with three times 30 ml of dried diethyl ether. The combined organic phases are dried over potassium carbonate and the solvent is removed under vacuum.
  • REPLACEMENT SHEET (RESEL 26) 3 "Diethyl- (1 -hexyl- C ⁇ 7 H 37 N 255.5 256 (16) [M + ], 171 (100) heptyl) amine [M + - C 6 H 13 ], 86 (6) [C 5 H , 2 N + ].

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

L'invention concerne une amine de la formule générale (I), où R1 et R2 peuvent être identiques ou différents et désignent dans chaque cas indépendamment l'un de l'autre alkyle substitué ou non substitué, cycloalkyle, alkényle, cycloalkényle, alkinyle, aryle ou trialkylsilyle ou R1 et R2 peuvent former conjointement avec l'atome d'azote auquel ils sont liés, un composé cycloalkyle substitué ou non substitué qui, outre l'atome d'azote, peut contenir au moins un autre hétéroatome, sélectionné dans le groupe comprenant azote, oxygène ou soufre; R3 est sélectionné parmi hydrogène et méthyle pouvant éventuellement être substitué par 1 à 3 atomes de fluor; R4 et R5 peuvent être identiques ou différents et désignent dans chaque cas indépendamment l'un de l'autre, alkyle substitué ou non substitué, cycloalkyle, alkényle, cycloalkényle ou alkinyle, ou un de leurs sels.
EP99932703A 1998-06-18 1999-06-18 Amines substituees de maniere geminee Ceased EP1088029A1 (fr)

Applications Claiming Priority (15)

Application Number Priority Date Filing Date Title
DE19827166 1998-06-18
DE19827161A DE19827161A1 (de) 1998-06-18 1998-06-18 Verfahren zur katalytischen, symmetrischen Disubstitution von Carbonsäureamiden mit Grignardreagenzien
DE19827163 1998-06-18
DE19827163A DE19827163A1 (de) 1998-06-18 1998-06-18 Verfahren zur katalytischen, unsymmetrischen Disubstitution von Carbonsäureamiden mit 2 unterschiedlichen Grignardreagenzien
DE19827164 1998-06-18
DE19827165A DE19827165A1 (de) 1998-06-18 1998-06-18 Katalytisch Titan(IV)-oxid-vermittelte geminale unsymmetrische Dialkylierung von Carbonsäureamiden
DE19827161 1998-06-18
DE19827167 1998-06-18
DE19827166A DE19827166A1 (de) 1998-06-18 1998-06-18 Verfahren zur katalytischen Disubstitution von Carbonsäureamiden mit wenigstens einem Grignardreagenz
DE19827167 1998-06-18
DE19827165 1998-06-18
DE19827164A DE19827164A1 (de) 1998-06-18 1998-06-18 Katalytisch Titan(IV)-oxid vermittelte geminale symmetrische Dialkylierung von Carbonsäureamiden
DE19844194 1998-09-26
DE19844194A DE19844194A1 (de) 1998-06-18 1998-09-26 Verfahren zur symmetrischen oder unsymmetrischen Disubstitution von Carbonsäureamiden mit Organotitanaten und Grignardreagenzien
PCT/EP1999/004256 WO1999065318A2 (fr) 1998-06-18 1999-06-18 Amines substituees de maniere geminee

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EP1088029A1 true EP1088029A1 (fr) 2001-04-04

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EP99929282A Withdrawn EP1087929A1 (fr) 1998-06-18 1999-06-18 Procede pour preparer des bibliotheques combinatoires d'amines
EP99932703A Ceased EP1088029A1 (fr) 1998-06-18 1999-06-18 Amines substituees de maniere geminee

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Publication number Priority date Publication date Assignee Title
DE19960377A1 (de) * 1999-12-14 2001-06-21 Merck Patent Gmbh Verfahren zur Herstellung kombinatorischer Aminbibliotheken
DE19961372A1 (de) * 1999-12-17 2001-06-21 Merck Patent Gmbh Verfahren zur Herstellung kombinatorischer Bibliotheken arylsubstituierter Amine
EP3144015B1 (fr) * 2010-09-20 2021-06-02 Sirna Therapeutics, Inc. Lipides cationiques de faible poids moléculaire pour l'apport d'oligonucléotides
GB201208775D0 (en) 2012-05-18 2012-07-04 Uni I Oslo Chemical compounds

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Publication number Priority date Publication date Assignee Title
GB807835A (en) * 1955-07-01 1959-01-21 Thomae Gmbh Dr K New tertiary amines and their salts and process for their preparation
US3067101A (en) * 1959-11-25 1962-12-04 Lilly Co Eli Method for controlling hypertension
US4020059A (en) * 1975-06-02 1977-04-26 Nippon Shokubai Kagaku Kogyo Co., Ltd. Process for preparing tertiary amines
BE842528R (fr) * 1976-06-03 1976-12-03 Derives actifs de methylamine, compositions therapeutiques les contenant ainsi que les procedes de preparation de ces derives et compositions
DE2657476A1 (de) * 1976-12-18 1978-06-22 Basf Ag Morpholinderivate
CA2207137A1 (fr) * 1996-06-14 1997-12-14 James Erwin Fritz Procede combinatoire a l'aide d'agent d'elimination pour la preparation de banques d'amine secondaire
AU3718397A (en) * 1996-06-28 1998-01-21 University Of Southern California Method for the synthesis of amines and amino acids with organoboron derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9965318A2 *

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JP2002518366A (ja) 2002-06-25
WO1999065863A1 (fr) 1999-12-23
JP2003524588A (ja) 2003-08-19
WO1999065318A3 (fr) 2003-04-17
WO1999065318A2 (fr) 1999-12-23
WO1999065864A2 (fr) 1999-12-23
EP1087929A1 (fr) 2001-04-04
WO1999065855A2 (fr) 1999-12-23
WO1999065864A3 (fr) 2003-05-22
WO1999065855A3 (fr) 2003-12-11

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