Patent Application
20100216988
The present invention relates to a process for the regioselective synthesis of compounds of the formula (I),
wherein R1; R2; R3; R4; J1; J2; J3; J4 and G have the meanings indicated below and which are useful as intermediates for the preparation of valuable pharmaceutically active ingredients.
The present invention relates to a direct metal catalyzed, regioselective process for the preparation of a wide variety of unsymmetrical, multifunctional annelated benzimidazoles or azabenzimidazoles of the formula (I) starting from 2-halo-nitroarenes and lactames. Preferred metals are palladium and copper. Annelated benzimidazoles play an important role in drug discovery and can certainly be regarded as privileged structures in pharmaceutical research. Several benzimidazole derivatives containing fused ring structures have anti-inflammatory, analgesic, antiarthritic, antitumor activity, or a combination of this activities (A. J. Charlson, J. S. Harrington, Carbohydrate Research 1975, 43, 383-387; P. Bender U.S. Pat. No. 4,186,205, 1980; Chem. Abstr. 1980, 92, 181195; H. G. Alpermann Arzneim.-Forsch. 1966, 16, 1641; R. Zhou, E. B. Skibo J. Med. Chem. 1996, 39, 4321-4331).
In contrast to the great importance of this scaffold no general regioselective route to annelated benzimidazoles and annelated benzimidazoles has been described yet. The few methods available so far are multi-step processes often requiring harsh reaction conditions and are restricted in the substrate range, have poor cost-effectiveness and are thus of limited use (J. R. McLure, J. H. Custer, H. D. Schwarz, D. A. Lill, Synlett, 710-712; E. B. Skibo, I. Islam, W. G. Schulz, R. Zhou, L. Bess, R. Boruah Synlett, 1996, 297-309; F. Aldabbagh, W. R. Bowman Tetrahedron 1999, 55, 4109-4122).
Although palladium-catalyzed protocols for the cross-coupling between aryl halides and lactames have been reported (J. Yin, S. L. Buchwald Org. Lett. 2000, 2, 1101-1104; D. J. Madar, H. Kopecka, D. Pireh, J. Pease, M. Pliushchev, R. J. Sciotti, P. E. Wiedeman, S. W. Djuric Tetrahedron Lett. 2001, 42, 3681-3684), only one example employing a 2-halo-nitroarene derivative has been reported. R. G. Browning, V. Badarinarayana, H. Mahmud, C. J. Lovely, describe in this example the coupling of 1-bromo-2-nitro-benzene and a pyrrolidin-2-one derivative in moderate yield (Tetrahedron 2004, 60, 359-365).
Although copper-catalyzed protocols for the cross-coupling between aryl halides and lactames have been reported, very few examples employing 2-halo-nitroarenes exist. Wei Deng, Ye-Feng Wang, Yan Zou, Lei Liu, Qing-Xiang Guo describe the coupling of 1-iodo-2-nitrobenzene with pyrrolidine-2-one (Tetrahedron Lett. 2004, 45, 2311-2315).
However, no general applicability for the palladium-catalyzed cross-coupling of 2-halo-nitroarenes, in particular 2-chloro-nitroarenes, and lactamas was shown, and in addition no use was made to for the regioselective synthesis of annelated benzimidazoles or azabenzimidazoles.
The limited regioselective access annelated benzimidazoles or azabenzimidazoles often prevents the optimization of a potential drug substance or substance with for example agricultural application and is accompanied by poor cost-effectiveness. Thus the present invention is useful in preparing intermediates or end products of biological active compounds in pharmaceutical and agricultural applications.
The present invention provides a direct metal catalyzed, regioselective synthetic route to a wide variety of unsymmetrical, multifunctional annelated benzimidazoles or azabenzimidazoles of formula I starting from 2-halo-nitroarenes of formula II and lactames of formula III. Preferred metals are palladium and copper. Thus one aspect of the invention is an efficient and general palladium catalyzed coupling method for substituted 2-halo-nitroarenes (step 1) to intermediates of formula IV. In another aspect of the invention, an efficient process is provided for the subsequent reductive aminocyclisation (step 2) of intermediates of formula IV, which can be either performed with the crude reaction mixture of step 1 or optionally after simple filtration through a pad of celite by using a reducing reagent.
The advantages of the provided process are that it comprises a novel, direct regioselective catalytic, mild and general method for the synthesis of annelated benzimidazoles or azabenzimidazoles, which also can be performed as a one-pot procedure. Thus, the process is very time- and cost-effective. Moreover, are the reaction conditions compatible with a broad range of functional groups and a large variety of starting materials, which are easily accessible or even commercially available.
A process for preparing a compound of formula I
and/or all stereoisomeric forms of the compound of formula I, and/or mixtures of these forms in any ratio, and/or a physiologically tolerated salt of the compound of formula I, wherein
wherein R1, R2, R3, R4, J1, J2, J3 and J4 are as defined in formula I and X is Cl, Br, I, triflate or nonaflate, with a compound of formula III
wherein ring G are as defined in formula I,
in the presence of a metal catalyst, a base, a ligand and an aprotic solvent to give a compound of formula IV
and converting the compound of formula IV into a compound of formula I in the presence of a reducing reagent and a second solvent and
optionally the compound of formula I is converted to its physiologically tolerated salt.
The present invention also relates to a process for the preparation of a compound of formula I, wherein palladium or copper are used as a metal catalyst.
The present invention also relates to a process for the preparation of a compound of formula I, wherein
The invention also relates to a process for the preparation of a compound of formula I, which are
The aprotic solvent useful for step 1 in the process of the present invention must be solvent, wherein the compounds of formulae II, III and IV, metal catalyst, base and ligand are soluble or at least partially soluble and compatible and is chemically inert under the reaction conditions and does not contain water or oxygen as impurities. Examples of said aprotic solvents are: benzene, toluene, xylene, mesitylene, acetonitrile, tetrahydrofurane, dimethylformamide, n-methylpyrrolodinone, dimethylacetamide, dimethylsulfoxide, diglyme ((2-methoxyethyl)ether) or pyridine. Preferred is benzene, mesitylene or toluene. Most preferred is toluene.
The base useful in this process of the present invention is a basic organic or inorganic compound and acts as proton acceptor without inhibiting the catalytic activity of the employed metal catalyst e.g. palladium or copper species or preventing the coupled intermediate species of the compound of formula IV to undergo the reductive aminocyclisation. Suitable classes of such bases are for example carbonates, phosphates, fluorides, alkoxides and hydroxides with a suitable metal as counter ion. Carbonates and phosphates are the preferred bases in the process of the present invention. Potassium carbonate or potassium phosphate and in particular caesium carbonate are the preferred bases.
The bases are generally employed in moderate excess based on the 2-halo-nitroarene of the compound of formula II. A useful range is a 1.1 to 2 fold excess based on the 2-halo-nitroarene of the compound of formula II. The base may be favourably employed in a 1.4 fold excess based on the 2-halo-nitroarene of the compound of formula I.
The palladium catalyst useful in this process can be selected from the following classes: Pd-alkanoates, Pd-alkanoate complexes, Pd-acetonates, Pd-halides, Pd-halide complexes, Pd-phosphine complexes. Representative examples include, but are not limited to: palladium (II) acetate, palladium (II) trifluoroacetate, tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, palladium (II) chloride, 2,2′-bis(diphenylphosphino)-1,1′-binaphthylpalladium(II) chloride, acetato(2′-di-tert-butylphosphino-1,1′-biphenyl-2-yl)palladium(II), (1,2-Bis(diphenylphosphino)ethane)dichloropalladium(II), Bis[1,2-bis(diphenylphosphino)ethane]palladium (0), [(2S,3S)-Bis(diphenylphosphino)butane][eta3-allyl]palladium(II) perchlorate, 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium (0) dimer. The preferred catalysts are palladium (II) acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthylpalladium(II) and in particular palladium (II) trifluoroacetate.
The palladium catalyst is generally employed in an amount in the range of 1 to 10 mole percent based on the 2-halo-nitroarene of the compound of formula II. A useful range is 1 to 9 mole percent of palladium catalyst based on the 2-halo-nitroarene of the compound of formula I.
The ligand useful in this process with palladium catalyst is a mono- or bidentate phosphine ligand and can be selected from the following compounds, but are not limited to: (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene, (9,9-dimethyl-9h-xanthene-4,5-diyl)bis[diphenyl phosphine], (R)-(−)-1-[(S)-2-(diphenylphosphino) ferrocenyl]ethyldicyclohexylphosphine, 1,2-Bis(diphenylphosphino)ethane, 1,3-Bis(diphenylphosphino)propane, (R)-(−)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]-ethyldi-tert-butylphosphine, (R)-(+)-1,1′-Bis(diphenylphosphino)-2,2′-bis(N,N-diiisopropylamido)ferrocene, (S,S)-1-[1-(Di-tert-butylphosphino)ethyl]-2-(diphenylphosphino)ferrocene, (1R,2R)-(+)-1,2-Diaminocyclohexane-N,N′-bis(2-diphenylphosphino-1-naphtoyl, (−)-1,2-Bis((2S,5S)-2,5-diiso-propylphospholano)-benzene, Bis[(2-diphenylphosphino)phenyl]ether, (S)-(−)-2,2′-Bis(di-para-tolylphosphino)-1,1′-binaphyl, 4,5-Bis(bis(3,5-bis(trifluoromethyl)phenyl)-phosphino)-9,9-dimethylxanthen, 2,2′-bis[(2′,4′,6′-triisopropyl)dicyclohexylphosphino]-biphenyl, 2,2′-bis(di-tert-butylphosphino)biphenyl, tri-tert-butylphosphine.
Most favourably (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene or (9,9-dimethyl-9h-xanthene-4,5-diyl)bis[diphenyl phosphine] are employed in particular in combination with a palladium source bearing no phosphine itself, like e.g. palladium (II) acetate, palladium (II) trifluoroacetate, tris(dibenzylideneacetone)dipalladium(0), palladium (II) chloride. The most preferred ligand is (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene.
The phosphine ligand is generally employed in an amount in the range of 1 to 10 mole percent based on the 2-halo-nitroarene of the compound of the compound of formula II. A useful range is 1 to 9 mole percent of phosphine ligand based on the 2-halo-nitroarene of the compound of formula II. Most favourably the phosphine ligand is employed in an equimolar ratio with respect to the palladium source.
The copper catalyst useful in this process can be selected from the following classes: copper (I) halogen salts and copper oxides. Representative examples include, but are not limited to: copper (I) chloride, copper (I) bromide, copper (I) iodide and copper (I) oxide. The preferred catalyst is copper (I) iodide.
The copper catalyst is generally employed in an amount in the range of 0.1 to 30 mole percent based on the 2-halo-nitroarene of the compound of formula II. A useful range is 1 to 9 mole percent of copper catalyst based on the 2-halo-nitroarene of the compound of formula I.
The ligands useful in this process with copper catalyst are a mono- or bidentate amine ligand and can be selected from the following compounds, but are not limited to: ethylenediamine, N-methylethylenediamine, N,N′-dimethyl-ethane-1,2-diamine, N,N-dimethyl-ethane-1,2-diamine N-buthylethylenediamine, N,N-dimethylethylenediamine, N,N,N′-trimethylthylenediamine, N,N,N,N′-tetramethylthylenediamine, trans-1,2-cyclohexanodiamine, cis-1,2-cyclohexanodiamine, cis/trans-1,2-cyclohexanodiamine, N,N′-dimethyl-1,2-cyclohexanodiamine, N,N′-diethyl-1,2-cyclohexanodiamine, N,N′-dipropyl-1,2-cyclohexanodiamine, 1,3-propylenediamine, 1,2-benzenediamine, phenanthridine, acridine, acridine orange, 9-aminoacridine, 9-hydroxy-4-methoxyacridine, proflavine, 4-(2-pyriylazo) resorcinol, 1,2-dihydro-1-(2-(2-pyridyl)-ethyl)-3,6-pyridazinedione, [1,10]phenanthroline, 5-nitro-[1,10]phenanthroline, bathophenanthroline, spiramycin, bicinchonic acid sodium salt (bca), 1-(4-pyridyl)pyridinium chloride, 2-pyridylacetic acid hydrochloride, 8-mercaptoquinoline hydrochloride, dimethylamino acetic acid, picolinic acid, 3-hydroxypicolinic acid, 3-hydroxy picolinamide, glycol, pyridine, 2-aminopyridine, 2-hydroxipyridine, 3-cyanopyridine, 4-cyanopyridine, 2-ethylpyridine, 2-amino-6-methylpyridine, 2-(aminomethylpyridine), 2-(hydroximethylpyridine), 2-hydroxi-6-methylpyridine, 2-dimethylaminopyridine, 4-dymethylaminopyridine, 2-(2-hydroxiethyl)pyridine, 4-tert-butylpyridine, 3-acetoxypyridine, 2-phenylpyridine, 4-phenylpyridine, 4-benzoylpyridine, 2-(2-thienyl)pyridine, 2-benzylpyridine, 2-anilinopyridine, 3-pyridinepropanol, 1-(2-pyridyl)piperazine, di-2-pyridyl ketone, ethyl 2-pyridyl acetate, 2-(2-diethylaminoethyl)-pyridine, 4-(2-diethylaminoethyl)pyridine, 2,6-di-tert-butyl pyridine, (S,S)-2,6-bis(4-isopropyl-2-oxazolin-2-yl)pyridine, 2,3-pyridine dicarboxylic acid, 2,6-pyridine dicarboxylic acid, 3,5-pyridine dicarboxylic acid, 1,3-di(4-pyridyl)propane, 2,3-di-3-pyridyl-2,3-butanediol, 2,2′-bipyridine, 2,2-dipyridyl, 4,4′-dimethyl-2,2′-dipyridyl, 3-hydroxypyridine, 2-mercaptopyridine, 2-(2-methylaminoethyl)pyridine, 3-hydroxi picolinamine, 3-hydroxypicolinic acid, 2,2′:6′,2″-terpyridine, 2-picoline, 6,6′-bi-2-picoline, 2,4-lutidine, 2,6-lutidine-α-2,3-diol, 2,6-lutidine 2,4,6-collidine, picolinamide, ethyl picolinate, ethyl isonicotinate, quinoline, 2-phenylquinoline, 8-hydroxyquinoline, 8-acetoxyquinoline, 2-methyl-8-nitroquinoline, 7,8-benzoquinoline, 2-quinolinol, 2-quinolinethiol, quinoline-4-carboxylic acid, 2-phenyl-4-quinoline carboxylic acid, 2,4-hydroxy quinoline monosodium salt, 8-ethoxyquinoline-5-sulfonic acid sodium salt, 8-hydroxy-5-nitroquinoline, 4-chloro-7-(trifluoromethyl) quinoline, 8-hydroxyquinoline-5-sulfonic acid monohydrate, 5-nitroquinaldic acid, isoquinoline, isoquinoline-3-carboxylic acid hydrate, 1,4,5-triazanaphtalene, quinaldine, 4-chloroquinaldine, nicotine, isonicotinamine, neocuproine, glycine, N-methylglycine, N,N-dimethylglycine, glycine hexyl ester, lysine, cystine, α-alanine, arginine, cysteine, β-alanine.
The most preferred ligands are trans-1,2-cyclohexanodiamine and N-methylethylenediamine.
The amine ligand is generally employed in an amount in the range of 0.1 to 60 mole percent based on the 2-halo-nitroarene of the compound of the compound of formula II. A useful range is 5 to 15 mole percent of amine ligand based on the 2-halo-nitroarene of the compound of formula II. Most favourably the amine ligand is employed in a ratio of 2 with respect to the copper source.
The reaction step 1 is carried out in the temperature range 60° C. to 150° C. A useful temperature is from 90° C. to 110° C., preferably from 70° C. to 90° C. Generally the reaction is carried out under the exclusion of air and moisture such as under an inert atmosphere like e.g. in an argon or nitrogen atmosphere at atmospheric pressure. The reaction time for step 1 is in the range of 3 to 48 hours (h).
It is possible to filtrate or to isolate the compound of formula IV before reacting it in the second step. It is also possible to perform reaction step 2 without any separation step in the same reaction vessel.
The solvent useful for step 2 or the second solvent in the process of the present invention is an aprotic or protic solvent, wherein the compounds of formula IV or I are soluble or at least partially soluble and compatible with the reaction conditions and involved structures and reagents. Examples of said aprotic or protic solvents are: methanol, ethanol, propanol, acetic acid, methylene chloride, dimethylformamide, tetrahydrofurane, pyridine, p-xylene, ethylacetate, benzene, toluene, xylene, mesitylene or acetonitrile. Preferred are methanol, ethanol, acetic acid, methylene chloride, dimethylformamide, pyridine, p-xylene and isopropanol. Most preferred is acetic acid.
The reducing reagent useful for the reductive aminocyclisation in step 2 in the process of the present invention can be selected from the following examples, but are not limited to: H2/Raney-N1, H2/Pd—C, H2/PtO2, H2/Ru, NaBH4/NiCl2, NaBH4/FeCl2, H3PO2/Pd—C, Sn/HCl, SnCl2/HCl, Fe/HOAc, Fe/HCl, FeSO4/HCl, Fe/FeSO4, Zn/HCl, Na2S, and Na2S2O4. Favourable is Fe/HOAc as a reagent for the reductive aminocyclisation.
The reaction step 2 is carried out in the temperature range 80° C. to 140° C. A useful temperature is from 110° C. to 120° C.
The reaction time for step 2 is in the range of 15 min to 120 min.
The progress of each reaction step may be monitored by methods known to those skilled in the art, like for example thin layer silica gel chromatography, gas chromatography, nuclear magnetic resonance, infrared spectroscopy, and high pressure liquid chromatography combined with ultraviolet detection or mass spectroscopy. Preferably thin layer silica gel chromatography and high pressure liquid chromatography (HPLC) combined with mass spectroscopy are used. The isolation and purification procedures useful for the compounds obtained by the process of the present invention are well-known to those skilled in the art, like for example filtration through a celite containing cartridge, aqueous work-up, extraction with organic solvents, distillation, crystallisation, chromatography on silica, and high pressure liquid chromatography on normal phase or reversed phase. Preferred methods include, but are not limited to those exemplified.
The term alkyl as used herein expressly includes saturated groups as well as unsaturated groups which latter groups contain one or more, for example one, two or three, double bonds and/or triple bonds. All these statements also apply if an alkyl group occurs as a substituent on another residue, for example in an alkyloxy residue, an alkyloxycarbonyl residue or an arylalkyl residue. Examples of “—(C1-C8)-alkyl” or “—(C1-C8)-alkylene” are alkyl residues containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms are methyl, methylene, ethyl, ethylene, propyl, propylene, butyl, butylene, pentyl, pentylene, hexyl, heptyl or octyl, the n-isomers of all these residues, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tBu, tert-pentyl, sec-butyl, tert-butyl or tert-pentyl. Unsaturated alkyl residues are e.g. alkenyl residues such as vinyl, 1-propenyl, 2-propenyl (=allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl, or alkynyl residues such as ethynyl, 1-propynyl, 2-propynyl (=propargyl) or 2-butynyl. Alkyl residues can also be unsaturated when they are substituted.
The term “—(C3-C8)-cycloalkyl” is understood as cyclic alkyl residues are cycloalkyl residues containing 3, 4, 5, 6, 7 or 8 ring carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyloheptyl or cyclooctyl, which can also be substituted and/or unsaturated. Unsaturated cyclic alkyl groups and unsaturated cycloalkyl groups like, for example, cyclopentenyl or cyclohexenyl can be bonded via any carbon atom.
The term “J1, J2, J3 and J4 are independently from each other selected from carbon or nitrogen atoms and form together with the carbon atoms they are attached to a stable aromatic or heteroaromatic ring” refers to a residue which can be derived from compounds such as benzene pyrazine, pyridazine, pyridine, pyrimidine, triazine or tetrazine.
The term “—(C6-C14)-aryl” is understood as meaning aromatic hydrocarbon radicals containing from 6 to 14 carbon atoms in the ring. Examples of —(C6-C14)-aryl radicals are phenyl, naphthyl, for example 1-naphthyl and 2-naphthyl, biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl. Biphenylyl radicals, naphthyl radicals and, in particular, phenyl radicals are preferred aryl radicals.
The term “monocyclic, bicyclic or tricyclic 4- to 15-membered saturated, or partially unsaturated heterocyclic ring containing in addition to the nitrogen atom of the lactam moiety 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen” refers to any monocyclic or bicyclic 4- to 15-membered heterocyclic ring system containing up to 1, 2, 3 or 4 heteroatoms like for example selected from azetidine, azepane, azocane, aza-bicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, azacyclooctanone, azacyclononanone, aza-tricyclo[4.3.1.1*3,8*]undecane, 4,4-dimethyl-3,5-dioxa-azatricyclo[5.2.1.0*2,6*]-decane, 3,5-dioxa-azatricyclo-[5.2.1.0*2,6*]decane, 4,4-dimethyl-3,5-dioxa-azatricyclo[5.2.1.0*2,6*]decan-9-one, azocane-2-one, azonane, 1,4-diazepane, [1,4]diazocane, [1,2]diazocan-3-one, [1,3]diazocan-2-one, imidazoline, imidazolidine, isothiazolidine, isoxazolidine, ketopiperazine, morpholine, [1,4]oxazocane, [1,3]oxazocan-2-one, piperazine, piperidine, pyrazoline, pyrazolidine, 1,2-dihydro-pyridine, pyrrolidine, pyrrolidinone, 2,3-dihydro-1H-pyrrole, pyrroline, 5,6,7,8-tetrahydro-1H-azocin-2-one, tetrahydropyridine, thiadiazine, thiazolidine, thiazoline or thiomorpholine.
The term “—(C4-C14)-heteroaryl” refers to mono-, di- or tri-ring systems, wherein one or more of the 4 to 14 ring carbon atoms are replaced by heteroatoms such as nitrogen, oxygen or sulfur. Examples are acridinyl, azaindole (1H-pyrrolopyridinyl), azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydrochinolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 3,3-dioxo[1,3,4]oxathiazinyl, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indanyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolidinyl, isothiazolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxa-thiepanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,4-oxazepinyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, oxetanyl, oxocanyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl, thietanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thietanyl, thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.
The term “a 3- to 7-membered cyclic residue, containing 1, 2, 3 or 4 heteroatoms” refer to structures of heterocycles, which can be derived from compounds such as azepine, azetidine, aziridine, azirine, 1,4 diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirine, dioxazole, dioxazine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazoline, ketomorpholine, ketopiperazine, morpholine, 1,2-oxa-thiepane, 1,2-oxathiolane, 1,4-oxazepane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxaziridine, oxetan, oxirane, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, tetrazole, thiadiazine thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine, thiazoline, thienyl, thietan, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole.
The 3- to 7-membered monocyclic group may be bonded via any ring carbon atom, and in the case of nitrogen heterocycles via any suitable ring nitrogen atom. Thus, for example, a pyrrolyl residue can be 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl, a pyrrolidinyl residue can be pyrrolidin-1-yl (=pyrrolidino), pyrrolidin-2-yl or pyrrolidin-3-yl, a pyridinyl residue can be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, a piperidinyl residue can be piperidin-1-yl (=piperidino), piperidin-2-yl, piperidin-3-yl or piperidin-4-yl. Furyl can be 2-furyl or 3-furyl, thienyl can be 2-thienyl or 3-thienyl, imidazolyl can be imidazol-1-yl, imidazol-2-yl, imidazol-4-yl or imidazol-5-yl, 1,3-oxazolyl can be 1,3-oxazol-2-yl, 1,3-oxazol-4-yl or 1,3-oxazol-5-yl, 1,3-thiazolyl can be 1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl, pyrimidinyl can be pyrimidin-2-yl, pyrimidin-4-yl (=6-pyrimidinyl) or 5-pyrimidinyl, piperazinyl can be piperazin-1-yl (=piperazin-4-yl=piperazino) or piperazin-2-yl.
The term “R1 and R2, R2 and R3 or R3 and R4 form together with the atoms which they are attached to a 5- or 8-membered ring, containing up to 0, 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen” refers to residues which can be derived from compounds such as azepine, azirine, azocane, azocane-2-one, cyloheptyl, cyclohexyl, cyclooctane, cyclooctene, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, [1,2]diazocan-3-one, [1,3]diazocan-2-one, [1,4]diazocane, dioxazine, dioxazole, [1,4]dioxocane, 1,3-dioxolane, dioxole, 1,3-dioxolene, furan, imidazole, imidazolidine, imidazoline, isothiazole, isothiazolidine, isothiazoline, isothiazole, isoxazole, isoxazolidine, isoxazoline, 2-isoxazoline, ketomorpholine, ketopiperazine, morpholine, 1,2-oxa-thiepane, 1,2-oxathiolane, 1,4-oxazepane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxaziridine, [1,4]oxazocane, [1,3]oxazocan-2-one, oxocane, oxocan-2-one, oxazole, piperidine, piperazine, phenyl, pyridazine, pyridine, pyrimidine, pyran, pyrazine, pyrazole, pyrazolepyrrole, pyrazolidine, pyrazoline, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, 5,6,7,8-tetrahydro-1H-azocin-2-one, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, 1,3-thiazole, thiazolidine, thiazoline, thienyl, thietan, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole.
The fact that many of the before-listed names of heterocycles are the chemical names of unsaturated or aromatic ring systems does not imply that the, 4- to 14-membered mono- or polycyclic group could only be derived from the respective unsaturated ring system. The names here only serve to describe the ring system with respect to ring size and the number of the heteroatoms and their relative positions.
As explained above, the 4- to 14-membered mono- or polycyclic group can be saturated or partially unsaturated or aromatic, and can thus be derived not only from the before-listed heterocycles themselves but also from all their partially or completely hydrogenated analogues and also from their more highly unsaturated analogues if applicable. As examples of completely or partially hydrogenated analogues of the before-listed heterocycles from which this group may be derived the following may be mentioned: pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, piperidine, 1,3-dioxolane, 2-imidazoline, imidazolidine, 4,5-dihydro-1,3-oxazol, 1,3-oxazolidine, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine, perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazine (=morpholine), perhydro-1,4-thiazine (=thiomorpholine), perhydroazepine, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline or 1,2,3,4-tetrahydroisoquinoline.
The term “—(C1-C3)-fluoroalkyl” is a partial or totally fluorinated alkyl-residue, which can be derived from residues such as —CF3, —CHF2, —CH2F, —CHF—CF3, —CHF—CHF2,
—CHF—CH2F, —CH2—CF3, —CH2—CHF2, —CH2—CH2F, —CF2—CF3, —CF2—CHF2, —CF2—CH2F, —CH2—CHF—CF3, —CH2—CHF—CHF2, —CH2—CHF—CH2F, —CH2—CH2—CF3,
—CH2—CH2—CHF2, —CH2—CH2—CH2F, —CH2—CF2—CF3, —CH2—CF2—CHF2, —CH2—CF2—CH2F, —CHF—CHF—CF3, —CHF—CHF—CHF2, —CHF—CHF—CH2F, —CHF—CH2—CF3, —CHF—CH2—CHF2, —CHF—CH2—CH2F, —CHF—CF2—CF3, —CHF—CF2—CHF2, —CHF—CF2—CH2F, —CF2—CHF—CF3, —CF2—CHF—CHF2, —CF2—CHF—CH2F, —CF2—CH2—CF3, —CF2—CH2—CHF2, —CF2—CH2—CH2F, —CF2—CF2—CF3, —CF2—CF2—CHF2 or —CF2—CF2—CH2F.
Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, particularly preferably chlorine or bromine.
The term “triflate” refers to trifluoro-methanesulfonic acid ester or trifluoromethanesulfonate.
The term “nonaflate” refers to 1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonic acid ester or 1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonate.
The term “at least one of R1, R2, R3 or R4 are absent in case one or more of J1, J2, J3 or J4 are nitrogen atom,” refers to a residue wherein the nitrogen atom is not substituted by any residue, e.g. in case J1 is nitrogen atom and J2, J3 and J4 are each a carbon atom and R4 is absent and R1, R2 and R3 are each a hydrogen atom the residue pyridine is formed. If R1, R2 and R3 are not each a hydrogen atom but one of the residues specified under b) to x) then a substituted pyridine residue is formed. In case J1 and J2 are each a nitrogen atom and J3 and J4 are each a carbon atom and R4 and R3 are absent and R1 and R2 are each a hydrogen atom the residue pyridazine is formed. If R1 and R2 are not each a hydrogen atom but one of the residues specified under b) to x) then a substituted pyridazine residue is formed.
Optically active carbon atoms present in the compounds of the formula (I) can independently of each other have R configuration or S configuration. The compounds of the formula (I) can be present in the form of pure enantiomers or pure diastereomers or in the form of mixtures of enantiomers and/or diastereomers, for example in the form of racemates. The present invention relates to pure enantiomers and mixtures of enantiomers as well as to pure diastereomers and mixtures of diastereomers. The invention comprises mixtures of two or of more than two stereoisomers of the formula (I), and it comprises all ratios of the stereoisomers in the mixtures. In case the compounds of the formula (I) can be present as E isomers or Z isomers (or cis isomers or trans isomers) the invention relates both to pure E isomers and pure Z isomers and to E/Z mixtures in all ratios. The invention also comprises all tautomeric forms of the compounds of the formula (I).
Diastereomers, including E/Z isomers, can be separated into the individual isomers, for example, by chromatography. Racemates can be separated into the two enantiomers by customary methods, for example by chromatography on chiral phases or by resolution, for example by crystallization of diastereomeric salts obtained with optically active acids or bases. Stereochemically uniform compounds of the formula (I) can also be obtained by employing stereochemically uniform starting materials or by using stereoselective reactions.
The starting materials or building blocks for use in the general synthetic procedures that can be applied in the preparation of the compounds of formula (I) are readily available to one of ordinary skill in the art. In many cases they are commercially available or have been described in the literature. Otherwise they can be prepared from readily available precursor compounds analogously to procedures described in the literature, or by procedures or analogously to procedures described in this application.
Further, in order to obtain the desired substituents in the benzene nucleus and in the heterocyclic nucleus of the benzimidazole or azabenzimidazole ring system in the formula (I), the functional groups introduced into the ring system during the benzimidazole or azabenzimidazole synthesis can be chemically modified. For example, benzimidazoles carrying a hydrogen atom in the 7-position can also be obtained by oxidation of 7-methyl benzimidazole to the benzimidazole-7-carboxylic acid and subsequent decarboxylation or from benzimidazoles carrying an ester group in the respective position. Carboxylic acid groups and acetic acid groups in the 7-position can be converted into their homologues by usual reactions for chain elongation of carboxylic acids.
Especially the groups present in the benzimidazole or azabenzimidazole ring system can be modified by a variety of reactions and thus the desired residues R1, R2, R3, R4 and R5 be obtained. For example, nitro groups can be reduced to amino group with under the described reaction conditions or by various reducing agents, such as sulfides, dithionites, complex hydrides or by catalytic hydrogenation. A reduction of a nitro group may also be carried out at a later stage of the synthesis of a compound of the formula (I), and a reduction of a nitro group to an amino group may also occur simultaneously with the reaction performed on another functional group, for example when reacting a group like a cyano group with hydrogen sulfide or when hydrogenating a group. Ester groups present in the benzene nucleus can be hydrolyzed to the corresponding carboxylic acids, which after activation can then be reacted with amines or alcohols under standard conditions. Ether groups present at the benzene nucleus, for example benzyloxy groups or other easily cleavable ether groups, can be cleaved to give hydroxyl groups which then can be reacted with a variety of agents, for example etherification agents or activating agents allowing replacement of the hydroxyl group by other groups. Sulfur-containing groups can be reacted analogously.
Due to the fact that in the present case the functional groups are attached to an benzimidazole or azabenzimidazole ring it may in certain cases become necessary to specifically adapt reaction conditions or to choose specific reagents from a variety of reagents that can in principle be employed into a conversion reaction, or otherwise to take specific measures for achieving a desired conversion, for example to use protection group techniques. However, finding out suitable reaction variants and reaction conditions in such cases does not cause any problems for one skilled in the art.
In the course of the preparation of the compounds of the formula I it can generally be advantageous or necessary to introduce functional groups which reduce or prevent undesired reactions or side reactions in the respective synthesis step, in the form of precursor groups which are later converted into the desired functional groups, or to temporarily block functional groups by a protective group strategy suited to the synthesis problem. Such strategies are well known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991, or P. Kocienski, Protecting Groups, Thieme 1994). As example of a precursor group cyano groups may be mentioned which can in a later step be transformed into carboxylic acid derivatives or by reduction into aminomethyl groups. Protective groups can also have the meaning of a solid phase, and cleavage from the solid phase stands for the removal of the protective group. The use of such techniques is known to those skilled in the art (Burgess K (Ed.) Solid Phase Organic Synthesis, New York: Wiley, 2000). For example, a phenolic hydroxy group can be attached to a trityl-polystyrene resin, which serves as a protecting group, and the molecule is cleaved from this resin by treatment with trifluoroacetic acid (TFA) at a later stage of the synthesis.
In the course of the synthesis the employment of microwave assistance for speeding-up, facilitating or enabling reactions may be beneficial or even required in many cases. Some reactions are for example described by J. L. Kristenansky, I. Cotteril, Curr. Opin. Drug. Disc. & Development, 4 (2000), 454; Lidstrom, J. Tierney, B. Wathey, J. Westman, Tetrahedron, 57 (2001), 9225; M. Larhed, A. Hallberg, Drug Discovery Today, 8 (2001) 406; S. Caddick, Tetrahedron, 51 (1995) 10403.
Physiologically tolerable salts of the compounds of formula I are nontoxic salts that are physiologically acceptable, in particular, pharmaceutically utilizable salts. Such salts of compounds of formula I containing acidic groups, for example, a carboxyl group (COOH), include, for example, alkali metal salts or alkaline earth metal salts, such as sodium salts, potassium salts, magnesium salts and calcium salts, as well as salts with physiologically tolerable quaternary ammonium ions, such as tetramethylammonium or tetraethylammonium, and acid addition salts with ammonia and physiologically tolerable organic amines, such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine. Basic groups contained in the compounds of formula I, for example, amino groups or guanidino groups, form acid addition salts, for example, with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Compounds of the formula I which simultaneously contain a basic group and an acidic group, for example, a guanidino group and a carboxyl group, can also be present as zwitterions (betaines) which are likewise included in the scope of the present invention.
Salts of compounds of formula I can be obtained by customary methods known to those skilled in the art, for example, by combining a compound of the formula I with an inorganic or organic acid or base in a solvent or dispersant, or from other salts by cation exchange or anion exchange. The present invention also includes all salts of the compounds of formula I which, because of low physiologically tolerability, are not directly suitable for use in pharmaceuticals but are suitable, for example, as intermediates for carrying out further chemical modifications of the compounds of formula I or as starting materials for the preparation of physiologically tolerable salts.
A further aspect of the invention is the use of a compound of the formula I as prepared by the process according to the invention for the production of pharmaceuticals, diagnostic agents, liquid crystals, polymers, herbicides, fungicidals, nematicidals, parasiticides, insecticides, acaricides and arthropodicides.
Preferred methods include, but are not limited to those described in the examples. Furthermore, the compounds of the formula I can be used as synthesis intermediates for the preparation of other compounds, in particular of other pharmaceutical active ingredients, which are obtainable from the compounds of the formula I, for example by introduction of substituents or modification of functional groups.
The general synthetic sequences for preparing the compounds useful in the present invention are outlined in the examples given below. Both an explanation of, and the actual procedure for, the various aspects of the present invention are described where appropriate. The following examples are intended to be merely illustrative of the present invention, and not limiting thereof in either scope or spirit. Those with skill in the art will readily understand that known variations of the conditions and processes described in the examples can be used to synthesize the compounds of the present invention.
When in the final step of the synthesis of a compound an acid such as trifluoroacetic acid or acetic acid was used, for example when trifluoroacetic acid was employed to remove a tBu group or when a compound was purified by chromatography using an eluent which contained such an acid, in some cases, depending on the work-up procedure, for example the details of a freeze-drying process, the compound was obtained partially or completely in the form of a salt of the acid used, for example in the form of the acetic acid salt or trifluoroacetic acid salt or hydrochloric acid salt.
Abbreviations used:
(Method A): 1-Iodo-2-nitrobenzene (125 mg, 0.5 mmol), pyrrolidin-2-one (51 mg, 0.6 mmol), palladium trifluoroacetate (13 mg, 0.04 mmol), BINAP (24 mg, 0.08 mmol), and cesium carbonate (212 mg, 0.7 mmol) were placed in a reaction tube, which was the purged with dry argon. Dry toluene (3 mL), was added, and the mixture was heated at 80° C. for 18 h. After cooling to RT, 10 mL of glacial acetic acid and powder iron (279 mg, 5 mmol) were added and the crude was refluxed for 30 min. The acid was removed under reduced pressure and the residue was suspended in saturated sodium bicarbonate solution and extracted with ethyl acetate. The obtained crude was purified by preparative HPLC, affording the title compound as colorless solid (58 mg, 73%). mp 86-88° C. 1H NMR δ 2.75 (t, J=6.9 Hz, 2H), 3.24-3.33 (m, 2H), 4.33 (t, J=7.2 Hz, 2H), 7.46-7.50 (m, 2H), 7.74-7.86 (m, 2H); 13C NMR δ23.7, 25.3, 45.3, 112.7, 115.1, 124.7, 125.0, 128.9, 136.6, 157.0. HRMS (FAB): calc. for C10H11N2 [M+H+]: 159.0922; found: 159.0919.
Method A applied to 2-Chloro-4-methyl-1-nitrobenzene (86 mg, 0.5 mmol) and pyrrolidin-2-one (51 mg, 0.6 mmol) afforded the title compound as a viscous oil (72 mg, 84%). 1H NMR (DMSO) δ 2.73-2.82 (m, 2H), 3.32 (t, J=7.1 Hz), 4.35 (t, J=7.2 Hz, 2H), 7.33 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.69 (d, J=8.3 Hz, 1H); 13C NMR δ 21.0, 23.8, 25.3, 45.6, 112.5, 114.3, 126.4, 127.1, 135.5, 136.1, 157.8.
Method A applied to 1-Chloro-4-methyl-2-nitrobenzene (86 mg, 0.5 mmol) and pyrrolidin-2-one (51 mg, 0.6 mmol) afforded the title compound as a viscous oil (74 mg, 86%). 1H NMR (DMSO) δ 2.55-2.63 (m, 2H), 2.76 (s, 3H), 3.21 (t, J=7.7 Hz, 2H), 3.85 (s, 3H), 4.26 (t, J=7.1 Hz, 2H), 7.56 (d, J=8.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H); 13C NMR δ 21.0, 23.7, 25.2, 45.3, 112.4, 114.5, 126.5, 129.2, 134.8, 137.8, 157.2.
Method A applied to 1-Iodo-4-methoxy-2-nitrobenzene (140 mg, 0.5 mmol) and pyrrolidin-2-one (51 mg, 0.6 mmol) afforded the title compound as a viscous oil (84 mg, 89%). 1H NMR (DMSO) δ 2.74 (t, J=6.9 Hz, 2H), 3.24-3.32 (m, 2H), 3.86 (s, 3H), 4.32 (t, J=7.1 Hz, 2H), 7.09 (d, J=9.1 Hz, 1H), 7.44 (d, J=9.1 Hz, 1H), 7.58 (s, 1H); 13C NMR δ 23.6, 25.3, 45.4, 55.9, 96.0, 114.6, 115.6, 128.7, 129.6, 157.4, 158.2.
Method A applied to 4-Bromo-2-methyl-3-nitrobenzoic acid methyl ester (137 mg, 0.5 mmol) and pyrrolidin-2-one (51 mg, 0.6 mmol) afforded the title compound as a viscous oil (89 mg, 77%). 1H NMR (DMSO) δ 2.55-2.63 (m, 2H), 2.76 (s, 3H), 3.21 (t, J=7.7 Hz, 2H), 3.85 (s, 3H), 4.26 (t, J=7.1 Hz, 2H), 7.56 (d, J=8.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H); 13C NMR δ 14.7, 23.4, 25.4, 44.5, 51.9, 99.1, 109.0, 124.0, 125.6, 129.2, 131.6, 161.6, 167.1.
Method A applied to 2-Chloro-6-methoxy-3-nitropyridine (94 mg, 0.5 mmol) and pyrrolidin-2-one (51 mg, 0.6 mmol) afforded the title compound as a viscous oil (72 mg, 76%). 1H NMR (DMSO) δ 2.68 (p, J=6.9 Hz, 2H), 3.23 (t, J=6.9 Hz, 2H), 3.91 (s, 3H), 4.22 (t, J=6.9 Hz), 6.82 (d, J=8.6 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H).
Method A applied to 2-Chloro-6-methyl-3-nitropyridine (94 mg, 0.5 mmol) and 3-methylpyrrolidin-2-one (59 mg, 0.6 mmol) afforded the title compound as a viscous oil (24 mg, 26%). 1H NMR (DMSO) δ 1.42 (d, J=6.9 Hz, 3H), 2.22-2.32 (m, 1H), 2.55 (s, 3H), 2.86-2.97 (m, 1H), 3.53-2.61 (m, 1H), 4.12-4.38 (m, 2H), 7.27 (d, J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H).
Method A applied to 2-Chloro-6-methyl-3-nitropyridine (94 mg, 0.5 mmol) and (1S,2R,6S,7R)-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.0*2,6*]decan-9-one (110 mg, 0.6 mmol) afforded the title compound as a viscous oil (126 mg, 88%). 1H NMR (DMSO) δ 1.23 (s, 3H), 1.51 (s, 3H), 2.47-2.57 (m, 2H), 2.53 (s, 3H), 3.62 (s, 3H), 4.23 (d, J=4.8 Hz, 1H), 4.35 (d, J=4.8 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H).
Method A applied to 1-Iodo-2-nitrobenzene (125 mg, 0.5 mmol) and piperidin-2-one (59 mg, 0.6 mmol) afforded the title compound as pale yellow solid (65 mg, 75%). mp 104-106° C. 1H NMR (DMSO) δ 1.98-2.07 (m, 4H), 3.16-3.23 (m, 2H), 4.30 (t, J=6.9 Hz, 2H), 7.51-7.56 (m, 2H), 7.75-7.92 (m, 2H); 13C NMR δ 17.7, 20.5, 22.3, 43.0, 112.3, 114.2, 124.7, 125.6, 131.5, 151.8, 156.6. HRMS (FAB): cal for C11H13N2 [M+H+]: 173.1079; found: 173.1071.
Method A applied to 2-Chloro-5-methyl-3-nitropyridine (86 mg, 0.5 mmol) and 3-methylpiperidin-2-one (68 mg, 0.6 mmol) afforded the title compound as viscous oil (60 mg, 60%). 1H NMR (DMSO) δ 1.49 (s, 3H), 1.51 (s, 3H), 1.92-2.23 (m, 4H), 3.04-3.20 (m, 2H), 4.75-4.83 (m, 1H), 7.98 (s, 1H), 8.37 (s, 1H).
Method A applied to 2,5-Dichloronitrobenzene (96 mg, 0.5 mmol) and 3,3-diphenylpiperidin-2-one (151 mg, 0.6 mmol) afforded the title compound as a brown solid (63 mg, 35%). 1H NMR (DMSO) δ 1.91-2.02 (m, 2H), 2.76-2.81 (m, 2H), 4.37 (t, J=6.2 Hz, 2H), 7.12-7.49 (m, 11H), 7.64 (d, J=8.8 Hz, 1H), 7.69 (s, 1H).
Method A applied to 1-Iodo-2-nitrobenzene (125 mg, 0.5 mmol) and (S)-3-dimethylaminoazepan-2-one (94 mg, 0.6 mmol) afforded the title compound as a pale yellow solid (84 mg, 73%). mp 164-166° C. 1H NMR (DMSO) δ 1.44-2.46 (m, 6H), 3.03 (s, 6H), 3.96 (dd, J=11.9, 11.6 Hz, 1H), 4.63 (dd, J=14.5, 4.7 Hz, 1H), 5.03 (d, J=10.4 Hz, 1H), 7.26 (t, J=7.3 Hz, 1H), 7.38 (t, J=7.3 Hz, 1H), 7.52-7.72 (m, 5H), 7.79 (d, J=7.8 Hz, 1H); 13C NMR δ 25.2, 26.2, 27.0, 40.6, 43.5, 62.4, 110.3, 118.8, 122.0, 122.8, 135.3, 140.6, 151.1. HRMS (FAB): cal. for C14H20N3 [M+H+]: 230.1657; found: 230.1648.
Method A applied to 2-Chloro-6-methyl-3-nitropyridine (94 mg, 0.5 mmol) and 2-azacyclooctanone (76 mg, 0.6 mmol) afforded the title compound as a viscous oil (74 mg, 69%). 1H NMR (DMSO) δ 1.22-1.88 (m, 8H), 2.62 (s, 3H), 3.19 (t, J=6.5 Hz, 2H), 4.51 (t, J=5.7 Hz, 2H), 7.38 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H).
Method A applied to 2-Chloro-5-methyl-3-nitropyridine (86 mg, 0.5 mmol) and 2-azacyclononanone (85 mg, 0.6 mmol) afforded the title compound as a viscous oil (40 mg, 35%). 1H NMR (DMSO) δ 1.18-1.96 (m, 10H), 2.48 (s, 3H), 3.18 (t, J=6.0 Hz, 2H), 4.54 (t, J=6.5 Hz, 2H), 7.99 (s, 1H), 8.36 (s, 1H).
Method A applied to 2-Chloro-5-methyl-3-nitropyridine (86 mg, 0.5 mmol) and 5,5-diphenyl-piperidin-2-one (151 mg, 0.6 mmol) afforded the title compound as solid (93 mg, 55%). 1H NMR (DMSO) δ 2.48-2.54 (m, 4H), 2.93 (s, 3H), 4.87 (s, 2H), 7.18-7.34 (m, 10H), 7.98 (s, 1H), 8.41 (s, 1H).
Method A applied to 1,2-iodonitrobenzene (125 mg, 0.5 mmol) and (1R,3R,6S,8S)-4-Aza-tricyclo[4.3.1.1*3,8*]undecan-5-one (99 mg, 0.6 mmol) afforded the title compound as a solid (99 mg, 83%). 1H NMR (DMSO) δ 1.84-2.23 (m, 12H), 3.54-3.57 (m, 1H), 5.17 (s, 1H), 7.53-7.58 (m, 2H), 7.80 (d, J=7.2 Hz, 1H), 7.98 (d, J=7.2 Hz, 1H).
A reaction tube containing 2-iodonitrobenzene (125 mg, 0.5 mmol), pyrrolidin-2-one (51 mg, 0.6 mmol), CuI (4.8 mg, 0.025 mmol), N-methylethylenediamine (4.4 μL, 0.05 mmol), potassium phosphate (212 mg, 1 mmol) in dry toluene (3 mL) was purged with dry argon for 3 min. Then the mixture was heated at 100° C. for 18 h. (In other reactions trans-1,2-cyclohexanodiamine was used instead of N-methylethylenediamine). After cooling, the reaction was hydrolyzed with 3 mL of water and filtered through a Varian cartridge Chem Elut 12198007, rinsing with ethyl acetate. The crude mixture was dissolved in 10 mL of glacial acetic acid and refluxed for 30 min in the presence of iron powder (279 mg, 5 mmol). The acid was removed under reduced pressure and the residue was suspended in saturated sodium bicarbonate solution and extracted with ethyl acetate. The obtained crude was purified by preparative HPLC, affording the title compound as a colorless solid (58 mg, 73%). mp 86-88° C. 1H NMR δ 2.75 (t, J=6.9 Hz, 2H), 3.24-3.33 (m, 2H), 4.33 (t, J=7.2 Hz, 2H), 7.46-7.50 (m, 2H), 7.74-7.86 (m, 2H); 13C NMR δ 23.7, 25.3, 45.3, 112.7, 115.1, 124.7, 125.0, 128.9, 136.6, 157.0. HRMS (FAB): cal. for C10H11N2 [M+H+]: 159.0922; found: 159.0919.
The same method was applied to 2-Chloro-4-methyl-1-nitrobenzene (86 mg, 0.5 mmol) and pyrrolidin-2-one (51 mg, 0.6 mmol), using N-methylethylenediamine as ligand (4.4 μL, 0.05 mmol) and afforded the title compound as a viscous oil (72 mg, 84%). 1H NMR (DMSO) δ 2.73-2.82 (m, 2H), 3.32 (t, J=7.1 Hz), 4.35 (t, J=7.2 Hz, 2H), 7.33 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.69 (d, J=8.3 Hz, 1H); 13C NMR δ 21.0, 23.8, 25.3, 45.6, 112.5, 114.3, 126.4, 127.1, 135.5, 136.1, 157.8.
The same method was applied to 1-Chloro-4-methyl-2-nitrobenzene (86 mg, 0.5 mmol) and pyrrolidin-2-one (51 mg, 0.6 mmol), using N-methylethylenediamine (4.4 μL, 0.05 mmol) as ligand, and afforded the title compound as a viscous oil (74 mg, 86%). 1H NMR (DMSO) δ 2.55-2.63 (m, 2H), 2.76 (s, 3H), 3.21 (t, J=7.7 Hz, 2H), 3.85 (s, 3H), 4.26 (t, J=7.1 Hz, 2H), 7.56 (d, J=8.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H); 13C NMR δ 21.0, 23.7, 25.2, 45.3, 112.4, 114.5, 126.5, 129.2, 134.8, 137.8, 157.2.
The same method was applied to 1-Iodo-4-methoxy-2-nitrobenzene (140 mg, 0.5 mmol) and pyrrolidin-2-one (51 mg, 0.6 mmol), using N-methylethylenediamine (4.4 μL, 0.05 mmol) as ligand, and afforded the title compound as a viscous oil (84 mg, 89%). 1H NMR (DMSO) δ 2.74 (t, J=6.9 Hz, 2H), 3.24-3.32 (m, 2H), 3.86 (s, 3H), 4.32 (t, J=7.1 Hz, 2H), 7.09 (d, J=9.1 Hz, 1H), 7.44 (d, J=9.1 Hz, 1H), 7.58 (s, 1H); 13C NMR δ 23.6, 25.3, 45.4, 55.9, 96.0, 114.6, 115.6, 128.7, 129.6, 157.4, 158.2.
The same method was applied to 4-Bromo-2-methyl-3-nitrobenzoic acid methyl ester (137 mg, 0.5 mmol) and pyrrolidin-2-one (51 mg, 0.6 mmol), using N-methylethylene-diamine (4.4 μL, 0.05 mmol) as ligand, and afforded the title compound as a viscous oil (89 mg, 77%). 1H NMR (DMSO) δ 2.55-2.63 (m, 2H), 2.76 (s, 3H), 3.21 (t, J=7.7 Hz, 2H), 3.85 (s, 3H), 4.26 (t, J=7.1 Hz, 2H), 7.56 (d, J=8.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H); 13C NMR δ 14.7, 23.4, 25.4, 44.5, 51.9, 99.1, 109.0, 124.0, 125.6, 129.2, 131.6, 161.6, 167.1.
The same method was applied to 2-Chloro-6-methoxy-3-nitropyridine (94 mg, 0.5 mmol) and pyrrolidin-2-one (51 mg, 0.6 mmol), using trans-1,2-cyclohexanodiamine as ligand (6 μL, 0.05 mmol), and afforded the title compound as a viscous oil (28 mg, 30%). 1H NMR (DMSO) δ 2.68 (p, J=6.9 Hz, 2H), 3.23 (t, J=6.9 Hz, 2H), 3.91 (s, 3H), 4.22 (t, J=6.9 Hz), 6.82 (d, J=8.6 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H).
The same method was applied to 2-Bromo-6-methyl-3-nitropyridine (109 mg, 0.5 mmol) and 3-methylpyrrolidin-2-one (59 mg, 0.6 mmol), using trans-1,2-cyclohexanodiamine as ligand (6 μL, 0.05 mmol), and afforded the title compound as a viscous oil (77 mg, 83%). 1H NMR (DMSO) δ 1.42 (d, J=6.9 Hz, 3H), 2.22-2.32 (m, 1H), 2.55 (s, 3H), 2.86-2.97 (m, 1H), 3.53-2.61 (m, 1H), 4.12-4.38 (m, 2H), 7.27 (d, J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H).
The same method was applied to 2-Bromo-3-nitropyridine (101 mg, 0.5 mmol) and (1S,2R,6S,7R)-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.0*2,6*]decan-9-one (110 mg, 0.6 mmol), using trans-1,2-cyclohexanodiamine as ligand (6 μL, 0.05 mmol), and afforded the title compound as a viscous oil (57 mg, 44%). 1H NMR (DMSO) δ 1.23 (s, 3H), 1.48 (s, 3H), 2.47-2.57 (m, 2H), 2.53 (s, 3H), 3.64 (s, 3H), 4.22 (d, J=4.8 Hz, 1H), 4.34 (d, J=4.8 Hz, 1H), 7.22 (dd, J=7.9, 5.2 Hz, 1H), 7.99 (d, J=7.9 Hz, 1H), 8.27 (d, J=5.2 Hz, 1H).
The same method was applied to 1-Iodo-2-nitrobenzene (125 mg, 0.5 mmol) and piperidin-2-one (59 mg, 0.6 mmol), using N-methylethylenediamine (4.4 μL, 0.05 mmol) as ligand, and afforded the title compound as pale yellow solid (65 mg, 75%). mp 104-106° C. 1H NMR (DMSO) δ 1.98-2.07 (m, 4H), 3.16-3.23 (m, 2H), 4.30 (t, J=6.9 Hz, 2H), 7.51-7.56 (m, 2H), 7.75-7.92 (m, 2H); 13C NMR δ 17.7, 20.5, 22.3, 43.0, 112.3, 114.2, 124.7, 125.6, 131.5, 151.8, 156.6. HRMS (FAB): cal. for C11H13N2 [M+H+]: 173.1079; found: 173.1071.
The same method was applied to 2-Bromo-6-methyl-3-nitropyridine (86 mg, 0.5 mmol) and 5,5-diphenylpiperidin-2-one (151 mg, 0.6 mmol), using trans-1,2-cyclohexano-diamine as ligand (6 μL, 0.05 mmol), and afforded the title compound as solid (87 mg, 51%). 1H NMR (DMSO) δ 2.68 (s, 3H), 2.88-2.97 (m, 4H), 4.82 (s, 2H), 7.21-7.33 (m, 10H), 7.38 (d, J=8.2 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H).
The same method was applied to 3-Bromo-2-nitropyridine (102 mg, 0.5 mmol) and 2-azacyclooctanone (76 mg, 0.6 mmol), using trans-1,2-cyclohexanodiamine as ligand (6 μL, 0.05 mmol), and afforded the title compound as a viscous oil (20 mg, 20%). 1H NMR (DMSO) δ 1.16-1.25 (m, 2H), 1.41-1.52 (m, 2H), 1.82-1.91 (m, 4H), 3.26 (t, J=6.2 Hz, 2H), 4.61 (t, J=6.1 Hz, 2H), 7.59 (dd, J=8.2, 5.5 Hz, 1H), 8.48 (d, J=8.2 Hz, 1H), 8.62 (d, J=5.5 Hz, 1H).
The same method was applied to 3-Iodo-4-nitroanisole (140 mg, 0.5 mmol) and 2-azacyclononanone (85 mg, 0.6 mmol), using N-methylethylenediamine (4.4 μL, 0.05 mmol) as ligand, and afforded the title compound as brown solid (70 mg, 57%). 1H NMR (DMSO) δ 1.18-1.96 (m, 10H), 3.23 (t, J=6.4 Hz, 2H), 3.88 (s, 3H), 4.61 (t, J=6.1 Hz, 2H), 7.17 (dd, J=8.6, 3.1 Hz, 1H), 7.52 (d, J=3.1 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H).
| Number | Date | Country | Kind |
|---|---|---|---|
| 07290801.5 | Jun 2007 | EP | regional |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/EP2008/004638 | Jun 2008 | US |
| Child | 12644379 | US |
