Patent Application
20090186766
The present invention relates to heteroaroyl-substituted alanines of the formula I
in which the variables are as defined below;
Moreover, the invention relates to processes and intermediates for preparing compounds of the formula I, to compositions comprising them and to the use of these derivatives or of the compositions comprising them for controlling harmful plants.
2,ω-Diaminocarbonyl compounds with herbicidal activity are described, inter alia, in WO 03/045878.
Also known from the literature (for example WO 05/061464) are heteroaroyl-substituted phenylalanines which may carry an optionally substituted amino group in the β-position.
However, the herbicidal properties of the prior-art compounds and/or their compatibility with crop plants are not entirely satisfactory.
Accordingly, it is an object of the present invention to provide novel, in particular herbicidally active, compounds having improved properties.
We have found that this object is achieved by the heteroaroyl-substituted alanines of the formula I and their herbicidal action.
Furthermore, we have found herbicidal compositions which comprise the compounds I and have very good herbicidal action. Moreover, we have found processes for preparing these compositions and methods for controlling unwanted vegetation using the compounds I.
Depending on the substitution pattern, the compounds of the formula I comprise two or more centers of chirality, in which case they are present as enantiomers or diastereomer mixtures. The invention provides both the pure enantiomers or diastereomers and their mixtures.
The compounds of the formula I may also be present in the form of their agriculturally useful salts, the nature of the salt generally being immaterial. Suitable salts are, in general, the salts of those cations or the acid addition salts of those acids whose cations and anions, respectively, have no adverse effect on the herbicidal action of the compounds I.
Suitable cations are in particular ions of the alkali metals, preferably lithium, sodium and potassium, of the alkaline earth metals, preferably calcium and magnesium, and of the transition metals, preferably manganese, copper, zinc and iron, and also ammonium, where, if desired, one to four hydrogen atoms may be replaced by C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-C1-C4-alkoxy-C1-C4-alkyl, phenyl or benzyl, preferably ammonium, dimethylammonium, diisopropylammonium, tetramethylammonium, tetrabutylammonium, 2-(2-hydroxyeth-1-oxy)eth-1-yl-ammonium, di-(2-hydroxyeth-1-yl)ammonium, trimethylbenzylammonium, furthermore phosphonium ions, sulfonium ions, preferably tri(C1-C4-alkyl)sulfonium, and sulfoxonium ions, preferably tri(C1-C4alkyl)sulfoxonium.
Anions of useful acid addition salts are primarily chloride, bromide, fluoride, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and the anions of C1-C4-alkanoic acids, preferably formate, acetate, propionate and butyrate.
The organic moieties mentioned for the substituents R1-R16 or as radicals on phenyl, aryl, heteroaryl or heterocyclyl rings are collective terms for individual enumerations of the specific group members.
All hydrocarbon chains, i.e. all alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkoxy, haloalkoxy and alkylthio moieties may be straight-chain or branched.
Unless indicated otherwise, halogenated substituents preferably carry one to five identical or different halogen atoms. The term halogen denotes in each case fluorine, chlorine, bromine or iodine.
Examples of other meanings are:
In a particular embodiment, the variables of the heteroaroyl-substituted alanines of the formula I have the following meanings which, both on their own and in combination with one another, are particular embodiments of the compounds of the formula I:
Preference is given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Preference is also given to the heteroaroyl-substituted alanines of the formula I in which
Particular preference is given to the heteroaroyl-substituted alanines of the formula I in which
Extraordinary preference is given to the compounds of the formula I.a (corresponds to formula I where A=A-1 where R13═H, R14═CF3, R1, R2, R4, R7 and R8═H; R3═CH3), especially the compounds of the formulae I.a.1 to I.a.384 of Table 1, where the definitions of the variables A and R1 to R16 are of particular importance for the compounds according to the invention not only in combination with one another but in each case also on their own.
Most preference is also given to the compounds of the formula I.b, especially the compounds of the formulae I.b.1 to I.b.384 which differ from the corresponding compounds of the formulae I.a.1 to I.a.384 in that A is A1 where R13═CH3 and R14═CF3:
Most preference is also given to the compounds of the formula I.c, especially the compounds of the formulae I.c.1 to I.c.384 which differ from the corresponding compounds of the formulae I.a.1 to I.a.384 in that A is A2 where R13═H and R14═CF3:
Most preference is also given to the compounds of the formula I.d, especially the compounds of the formulae I.d.1 to I.d.384 which differ from the corresponding compounds of the formulae I.a.1 to I.a.384 in that A is A3 where R13═H and R14═CF3:
Most preference is also given to the compounds of the formula I.e, especially the compounds of the formulae I.e.1 to I.e.384 which differ from the corresponding compounds of the formulae I.a.1 to I.a.384 in that A is A3 where R13═CH3 and R14═CF3:
Most preference is also given to the compounds of the formula I.f, especially the compounds of the formulae I.f.1 to I.f.384 which differ from the corresponding compounds of the formulae I.a.1 to I.a.384 in that A is A4 where R13═H and R14═CF3:
Most preference is also given to the compounds of the formula I.g, especially the compounds of the formulae I.g.1 to I.g.384 which differ from the corresponding compounds of the formulae I.a.1 to I.a.384 in that A is A5 where R14═CF3, and R15 and R16═H:
Most preference is also given to the compounds of the formula I.h, especially the compounds of the formulae I.h.1 to I.h.384 which differ from the corresponding compounds of the formulae I.a.1 to I.a.384 in that A is A5 where R14═CF3, R15═H and R16═CH3:
Most preference is also given to the compounds of the formula I.j, especially the compounds of the formulae I.j.1 to I.j.384 which differ from the corresponding compounds of the formulae I.a.1 to I.a.384 in that A is A8 where R13═H and R14═CF3:
Most preference is also given to the compounds of the formula I.k, especially the compounds of the formulae I.k.1 to I.k.384 which differ from the corresponding compounds of the formulae I.a.1 to I.a.384 in that A is A8 where R13═CH3 and R14═CF3:
Most preference is also given to the compounds of the formula I.l, especially the compounds of the formulae I.l.1 to I.l.384 which differ from the corresponding compounds of the formulae I.a.1 to I.a.384 in that A is A10 where R13═CH3 and R14═CF3:
Most preference is also given to the compounds of the formula I.m, especially the compounds of the formulae I.m.1 to I.m.384 which differ from the corresponding compounds of the formulae I.a.1 to I.a.384 in that A is A11 where R13═CH3 and R14═CF3:
The benzoyl-substituted alanines of the formula I can be obtained by different routes, for example by the following processes:
Alanine derivatives of the formula V are initially reacted with heteroaryl acids/heteroaryl acid derivatives of the formula IV to give the corresponding heteroaroyl derivatives of the formula III which then react with amines of the formula II to give the desired heteroaroyl-substituted alanines of the formula I:
L1 is a nucleophilically displaceable leaving group, for example hydroxyl or C1-C6-alkoxy.
L2 is a nucleophilically displaceable leaving group, for example hydroxyl, halogen, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C4-alkylsulfonyl, phosphoryl or isoureyl.
The reaction of the alanine derivatives of the formula V with heteroaryl acids/heteroaryl acid derivatives of the formula IV where L2 is hydroxyl to give heteroaroyl derivatives of the formula III is carried out in the presence of an activating agent and a base, usually at temperatures of from 0° C. to the boiling point of the reaction mixture, preferably at from 0° C. to 110° C., particularly preferably at room temperature, in an inert organic solvent [cf. C. Montalbetti et al., Tetrahedron 2005, 61, 10827 and the literature cited therein].
Suitable activating agents are condensing agents, such as, for example, polystyrene-supported dicyclohexylcarbodiimide, diisopropylcarbodiimide, carbonyldiimidazole, chloroformates, such as methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, sec-butyl chloroformate or allyl chloroformate, pivaloyl chloride, polyphosphoric acid, propanephosphonic anhydride, bis(2-oxo-3-oxazolidinyl)-phosphoryl chloride (BOPCl) or sulfonyl chlorides, such as methanesulfonyl chloride, toluenesulfonyl chloride or benzenesulfonyl chloride.
Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons such as benzene, toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran (THF), nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, and also dimethyl sulfoxide, dimethylformamide (DMF), dimethylacetamide (DMA) and N-methylpyrrolidone (NMP) or else in water; particular preference is given to methylene chloride, THF and water.
It is also possible to use mixtures of the solvents mentioned.
Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate, and also alkali metal bicarbonates, such as sodium bicarbonate, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preference is given to sodium hydroxide, triethylamine and pyridine.
The bases are generally employed in equimolar amounts. However, they can also be used in excess or, if appropriate, as solvents.
The starting materials are generally reacted with one another in equimolar amounts. It may be advantageous to employ an excess of IV, based on V.
The reaction mixtures are worked up in a customary manner, for example by mixing with water, separating the phases and, if appropriate, chromatographic purification of the crude products. Some of the intermediates and end products are obtained in the form of viscous oils which are purified or freed from volatile components under reduced pressure and at moderately elevated temperature. If the intermediates and end products are obtained as solids, purification may also be carried out by recrystallization or digestion.
The reaction of the alanine derivatives of the formula V with heteroaryl acids/heteroaryl acid derivatives of the formula IV where L2 is halogen, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C4-alkylsulfonyl, phosphoryl or isoureyl to give heteroaroyl derivatives of the formula III is carried out in the presence of a base, usually at temperatures of from 0° C. to the boiling point of the reaction mixture, preferably at from 0° C. to 100° C., particularly preferably at room temperature, in an inert organic solvent [cf. C. Montalbetti et al., Tetrahedron 2005, 61, 10827 and the literature cited therein].
Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons such as benzene, toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran (THF), nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, and also dimethyl sulfoxide, dimethylformamide (DMF), dimethylacetamide (DMA) and N-methylpyrrolidone (NMP) or else in water; particular preference is given to methylene chloride, THF and water.
It is also possible to use mixtures of the solvents mentioned.
Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate, and also alkali metal bicarbonates, such as sodium bicarbonate, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preference is given to sodium hydroxide, triethylamine and pyridine.
The bases are generally employed in equimolar amounts. However, they can also be used in excess or, if appropriate, as solvents.
The starting materials are generally reacted with one another in equimolar amounts. It may be advantageous to employ an excess of IV, based on V.
Work-up and isolation of the products can be carried out in a manner known per se.
It is, of course, also possible to react initially, in an analogous manner, the alanine derivatives of the formula V with amines of the formula II to give the corresponding amides which then react with heteroaryl acids/heteroaryl acid derivatives of the formula IV to give the desired heteroaroyl-substituted alanines of the formula I.
The alanine derivatives of the formula V (for example where L1═hydroxyl or C1-C6-alkoxy) required for preparing the heteroaroyl derivatives of the formula III are, even in enantiomerically and diastereomerically pure form, known from the literature, or they can be prepared in accordance with the literature cited:
1. Addition of glycine enolate equivalents to nitroolefins:
The heteroaryl acids/heteroaryl acid derivatives of the formula IV required for preparing the heteroaroyl derivatives of the formula III are commercially available or can be prepared analogously to procedures known from the literature [for example Chang-Ling Liu et al., J. of Fluorine Chem. (2004), 125(9), 1287-1290; Manfred Schlosser et al., Europ. J. of Org. Chem. (2002), (17), 2913-2920; Hoh-Gyu Hahn et al., Agricult. Chem. and Biotech. (English Edition) (2002), 45(1), 37-42; Jonatan O Smith et al., J. of Fluorine Chem. (1997), Vol. 1996-1997, 81(2), 123-128; Etsuji Okada et al., Heterocycles (1992), 34(4), 791-798; Aliyu B. Abubakar et al., J. of Fluorine Chem. (1991), 55(2), 189-198; J. Leroy, J. of Fluorine Chem. (1991), 53(1), 61-70; Len F. Lee et al., J. of Heterocyclic Chem. (1990), 27(2), 243-245; Len F. Lee et al., J. of Heterocyclic Chem. (1985), 22(6), 1621-1630; Jacques Leroy et al., Synthesis (1982), (4), 313-315].
The reaction of the heteroaroyl derivatives of the formula III where L1=hydroxyl or salts thereof with amines of the formula II to give the desired heteroaroyl-substituted alanines of the formula I is carried out in the presence of an activating agent and, if appropriate, in the presence of a base, usually at temperatures of from 0° C. to the boiling point of the reaction mixture, preferably at from 0° C. to 100° C., particularly preferably at room temperature, in an inert organic solvent [cf. C. Montalbetti et al., Tetrahedron 2005, 61, 10827 and the literature cited therein].
Suitable activating agents are condensing agents, such as, for example, polystyrene-supported dicyclohexylcarbodiimide, diisopropylcarbodiimide, carbonyldiimidazole, chloroformates, such as methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, sec-butyl chloroformate or allyl chloroformate, pivaloyl chloride, polyphosphoric acid, propanephosphonic anhydride, bis(2-oxo-3-oxazolidinyl)-phosphoryl chloride (BOPCl) or sulfonyl chlorides, such as methanesulfonyl chloride, toluenesulfonyl chloride or benzenesulfonyl chloride.
Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons such as benzene, toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, dioxane, anisole and tetrahydrofuran (THF), nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, and also dimethyl sulfoxide, dimethylformamide (DMF), dimethylacetamide (DMA) and N-methylpyrrolidone (NMP) or else in water; particular preference is given to methylene chloride, THF, methanol, ethanol and water.
It is also possible to use mixtures of the solvents mentioned.
Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate, and also alkali metal bicarbonates, such as sodium bicarbonate, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preference is given to sodium hydroxide, triethylamine, ethyldiisopropylamine, N-methylmorpholine and pyridine.
The bases are generally employed in catalytic amounts; however, they can also be employed in equimolar amounts, in excess or, if appropriate, as solvent.
The starting materials are generally reacted with one another in equimolar amounts. It may be advantageous to employ an excess of II, based on III.
Work-up and isolation of the products can be carried out in a manner known per se.
The reaction of the heteroaroyl derivatives of the formula III where L1=C1-C6-alkoxy with amines of the formula II to give the desired heteroaroyl-substituted alanines of the formula I is usually carried out at temperatures of from 0° C. to the boiling point of the reaction mixture, preferably at from 0° C. to 10° C., particularly preferably at room temperature, in an inert organic solvent, if appropriate in the presence of a base [cf. C. Montalbetti et al., Tetrahedron 2005, 61, 10827 and the literature cited therein].
Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons such as benzene, toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, dioxane, anisole and tetrahydrofuran (THF), nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, and also dimethyl sulfoxide, dimethylformamide (DMF), dimethylacetamide (DMA) and N-methylpyrrolidone (NMP) or else in water; particular preference is given to methylene chloride, THF, methanol, ethanol and water.
It is also possible to use mixtures of the solvents mentioned.
The reaction can, if appropriate, be carried out in the presence of a base. Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate, and also alkali metal bicarbonates, such as sodium bicarbonate, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preference is given to sodium hydroxide, triethylamine, ethyldiisopropylamine, N-methylmorpholine and pyridine.
The bases are generally employed in catalytic amounts; however, they can also be employed in equimolar amounts, in excess or, if appropriate, as solvent.
The starting materials are generally reacted with one another in equimolar amounts. It may be advantageous to employ an excess of II, based on III.
Work-up and isolation of the products can be carried out in a manner known per se.
The amines of the formula II required for preparing the heteroaroyl-substituted alanines of the formula I are commercially available.
Heteroaroyl derivatives of the formula III where R6═NO2 and R8=hydrogen can also be obtained by condensing acylated glycine derivatives of the formula VIII where the acyl group may be a removable protective group such as benzyloxycarbonyl (cf. VIIIa where Σ=benzyl) or tert-butyloxycarbonyl (cf. VIIIa where Σ=tert-butyl) with nitroolefines VII to give the corresponding addition products VI where R6═NO2 and R8=hydrogen. The protective group is then removed, and the alanine derivative of the formula V formed in this manner where R6═NO2 and R8=hydrogen is acylated with heteroaryl acids/heteroaryl acid derivatives of the formula IV.
Analogously, it is also possible to react an acylated glycine derivative of the formula VIII where the acyl group is a substituted heteroaroyl radical (cf. VIIIb) in the presence of a base with a nitroolefin VII to give the heteroaroyl derivative III where R6═NO2 and R8=hydrogen:
L1 is a nucleophilically displaceable leaving group, for example hydroxyl or C1-C6-alkoxy.
L2 is a nucleophilically displaceable leaving group, for example hydroxyl, halogen, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C4-alkylsulfonyl, phosphoryl or isoureyl.
The reaction of the glycine derivatives VIII with nitroolefins VII to give the corresponding addition product VI where R6═NO2 and R8=hydrogen or heteroaroyl derivative III where R6═NO2 and R8=hydrogen is usually carried out at temperatures of from −100° C. to the boiling point of the reaction mixture, preferably from −80° C. to 20° C., especially preferably from −80° C. to −20° C., in an inert organic solvent in the presence of a base (cf. B. Mendler et al., Organic Lett. 2005, 7 (9), 1715; D. Dixon et al., Organic Lett. 2004, 6 (24), 4427; M. Alcantara et al., Synthesis 1996, (1), 64; M. Rowley et al., Tetrahedron 1992, 48 (17), 3557).
Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, ethers, such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, dioxane, anisole and tetrahydrofuran, and also dimethyl sulfoxide, dimethylformamide and dimethylacetamide, particularly preferably diethyl ether, dioxane and tetrahydrofuran. It is also possible to use mixtures of the solvents mentioned.
Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal amides, such as lithium isopropylamide and lithium hexamethyldisilazide, organometallic compounds, in particular alkali metal alkyls, such as methyllithium, butyllithium and phenyllithium, and also alkali metal and alkaline earth metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, potassium tert-pentoxide and dimethoxymagnesium, moreover organic bases, for example, tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preference is given to sodium hydride, lithium hexamethyldisilazide and lithium diisopropylamide.
The bases are generally employed in equimolar amounts; however, they can also be employed in catalytic amounts, in excess or, if appropriate, as solvent.
The starting materials are generally reacted with one another in equimolar amounts. It may be advantageous to employ an excess of the base and/or the imino compounds VII, based on the glycine derivatives VIII.
Work-up and isolation of the products can be carried out in a manner known per se.
The glycine derivatives of the formula VIII required for preparing the heteroaroyl derivatives III where R6═NO2 and R8=hydrogen are commercially available, known from the literature [for example H. Pessoa-Mahana et al., Synth. Comm. 32, 1437 (2002)] or can be prepared in accordance with the literature cited.
The removal of the protective group Σ to give alanine derivatives of the formula V where R6═NO2 and R8=hydrogen is carried out by methods known from the literature [cf. J.-F. Rousseau et al., J. Org. Chem. 63, 2731-2737 (1998); J. M. Andres, Tetrahedron 56, 1523 (2000)]; in the case of Σ=benzyl by hydrogenolysis, preferably using hydrogen and Pd/C in methanol; in the case of Σ=tert-butyl using acid, preferably using hydrochloric acid in dioxane.
The reaction of the alanine derivatives V where R6═NO2 and R8=hydrogen with heteroaryl acids/heteroaryl acid derivatives IV to give heteroaroyl derivatives III where R6═NO2 and R8=hydrogen is usually carried out analogously to the reaction, mentioned under process A, of the alanine derivatives of the formula V with heteroaryl acids/heteroaryl acid derivatives of the formula IV to give heteroaroyl derivatives III.
The heteroaroyl derivatives, obtainable in this manner, of the formula III where R6═NO2 and R8=hydrogen can be reacted with amines of the formula II analogously to process A to give the desired heteroaroyl-substituted alanines of the formula I where R6═NO2 and R8=hydrogen, which can then, if desired, initially be reduced to give heteroaroyl-substituted alanines of the formula I where R6═NH2 and R8=hydrogen. The heteroaroyl-substituted alanines of the formula I where R6═NH2 and R8=hydrogen obtained in this manner can then be derivatized with compounds IX to give heteroaroyl-substituted alanines of the formula I where R6═NHR10 [cf., for example, Yokokawa, F. et al., Tetrahedron Lett. 42 (34), 5903-5908 (2001); Arrault, A. et al., Tetrahedron Lett. 43(22), 4041-4044 (2002)].
It is also possible to initially reduce the heteroaroyl derivatives of the formula III where R6═NO2 and R8=hydrogen to give further heteroaroyl derivatives of the formula III where R6═NH2 and R8=hydrogen and then, if desired, derivatize with compounds IX to give heteroaroyl derivatives of the formula III where R6═NHR10 and R8=hydrogen [cf., for example, Jung-Hui Sun et al., Heterocycles (2004), 63(7), 585-1599; Christian Lherbet et al., Bioorg. and Med. Chem. Lett. (2003), 13(6), 997-1000; Masami Otsuka et al., Chem. and Pharm. Bull. (1985), 33(2), 509-514; J. R Piper et al., J. of Med. Chem. (1985), 28(8), 1016-1025]. The heteroaroyl derivatives of the formula III where R6═NHR13 and R8=hydrogen obtained in this manner can then be reacted analogously to process A with amines of the formula II to give the desired heteroaroyl-substituted alanines of the formula I where R6═NHR13 and R8=hydrogen:
L1 is a nucleophilically displaceable leaving group, for example hydroxyl or C1-C6-alkoxy.
L3 is a nucleophilically displaceable leaving group, for example halogen, hydroxyl or C1-C6-alkoxy.
The reaction of the heteroaroyl derivatives of the formula III where R6═NO2, NH2 or NHR10 and R8=hydrogen with amines of the formula II to give heteroaroyl-substituted alanines of the formula I where R6═NO2, NH2 or NHR10 and R8=hydrogen usually takes place analogously to the reaction, described under Process A, of the heteroaroyl derivatives of the formula III with amines of the formula II.
The reduction of the heteroaroyl derivatives of the formula III where R6═NO2 and R8=hydrogen to give heteroaroyl derivatives of the formula III where R6═NH2 and R8=hydrogen, and the reduction of the heteroaroyl-substituted alanines of the formula I where R6═NO2 and R8=hydrogen to give heteroaroyl-substituted alanines of the formula I where R6═NH2 and R8=hydrogen is usually carried out at temperatures of from 0° C. to 100° C., preferably at from 10° C. to 50° C., in an inert organic solvent in the presence of a reducing agent.
Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran, nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, and also dimethyl sulfoxide, dimethylformamide and dimethylacetamide, particularly preferably dichloromethane, tert-butylmethyl ether, dioxane and tetrahydrofuran. It is also possible to use mixtures of the solvents mentioned.
Suitable reducing agents are transition metal catalysts (for example Pd/C or Raney-Ni) in combination with hydrogen.
Work-up and isolation of the products can be carried out in a manner known per se.
The reduction of the nitro derivatives of the formula II or I where R6═NO2 is usually carried out at a temperature of from −100° C. to the boiling point of the reaction mixture, preferably at from 0° C. to 100° C., in an inert organic solvent using a reducing agent (cf. V. Burgess et al., Aust. J. of Chem. (1988), 41(7), 1063-1070).
Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, ethers, such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, dioxane, anisole and tetrahydrofuran (THF), nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, and also dimethyl sulfoxide, dimethylformamide and dimethylacetamide, particularly preferably toluene, THF or tert-butylmethyl ether.
Suitable reducing agents are transition metal catalysts (for example Pd/C or Raney-Ni) in combination with hydrogen.
Work-up and isolation of the product can be carried out in a manner known per se.
The reaction of the heteroaroyl derivatives of the formula III where R6═NH2 and R8=hydrogen or of the heteroaroyl-substituted alanines of the formula I where R6═NH2 and R8=hydrogen with compounds of the formula IX to give heteroaroyl derivatives of the formula III where R6═NH2 and R8=hydrogen or heteroaroyl-substituted alanines of the formula I where R6═NH2 and R8=hydrogen is usually carried out at temperatures of from 0° C. to 100° C., preferably at from 10° C. to 50° C., in an inert organic solvent in the presence of a base [cf., for example, Jung-Hui Sun et al., Heterocycles (2004), 63(7), 585-1599; Christian Lherbet et al., Bioorg. and Med. Chem. Lett. (2003), 13(6), 997-1000; Masami Otsuka et al., Chem. and Pharm. Bull. (1985), 33(2), 509-514; J. R Piper et al., J. of Med. Chem. (1985), 28(8), 1016-1025].
Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, dioxane, anisole and tetrahydrofuran, nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, and also dimethyl sulfoxide, dimethylformamide and dimethylacetamide, particularly preferably dichloromethane, tert-butylmethyl ether, dioxane and tetrahydrofuran. It is also possible to use mixtures of the solvents mentioned.
Suitable bases are in general inorganic compounds such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal amides, such as lithium amide, sodium amide and potassium amide, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate and also alkali metal bicarbonates, such as sodium bicarbonate, organometallic compounds, in particular alkali metal alkyls, such as methyllithium, butyllithium and phenyllithium, alkylmagnesium halides, such as methylmagnesium chloride, and also alkali metal and alkaline earth metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, potassium tert-pentoxide and dimethoxymagnesium, moreover organic bases, for example, tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preference is given to sodium hydroxide, sodium hydride and triethylamine.
The bases are generally employed in equimolar amounts; however, they can also be employed in catalytic amounts, in excess or, if appropriate, as solvent.
The starting materials are generally reacted with one another in equimolar amounts. It may be advantageous to employ an excess of base and/or IX, based on III or I.
Work-up and isolation of the products can be carried out in a manner known per se.
Heteroaroyl-substituted alanines of the formula I where R1 and R8=hydrogen and R6═OH can be obtained by converting, in a first step, glycine derivatives of the formula XII with an allyl alcohol derivative of the formula XI in the presence of a transition metal catalyst and a base, and subsequent aqueous-acidic work-up into amino derivatives which can then, in a second and third step, be acylated analogously to process A and converted into an amide X. The double bond of the amide X can then be cleaved oxidatively, and the resulting aldehyde can be reduced to heteroaroyl-substituted alanines of the formula I where R1 and R8=hydrogen and R6═OH. The heteroaroyl-substituted alanines of the formula I where R1 and R8=hydrogen and R6═OH obtained in this manner can for their part be derivatized into further heteroaroyl-substituted alanines of the formula I where R1 and R8=hydrogen and R6═OR9, where R9 is not hydrogen:
L1 is a nucleophilically displaceable leaving group, for example hydroxyl or C1-C6-alkoxy.
L2 is a nucleophilically displaceable leaving group, for example hydroxyl, halogen, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C4-alkylsulfonyl, phosphoryl or isoureyl.
L3 is a nucleophilically displaceable leaving group, for example halogen, hydroxyl or C1-C6-alkoxy.
RY and RZ are hydrogen, C1-C6-alkyl or aryl.
RW is hydrogen or R5.
RX is an acyl group, such as C1-C6-alkylcarbonyl (for example methylcarbonyl) or C1-C6-alkoxycarbonyl (for example methoxycarbonyl).
The reaction of the glycine derivatives of the formula XII with an allyl alcohol derivative of the formula XI is usually carried out at temperatures of from −100° C. to the boiling point of the reaction mixture, preferably from −80° C. to 80° C., especially preferably from −20° C. to 50° C., in an inert organic solvent in the presence of a transition metal catalyst and a base, followed by aqueous-acidic work-up.
Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, dioxane, anisole and tetrahydrofuran, nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, and also dimethyl sulfoxide, dimethylformamide and dimethylacetamide; particular preference is given to toluene, THF and acetonitrile.
It is also possible to use mixtures of the solvents mentioned.
Preferred for use as catalysts are palladium, iridium or molybdenum catalysts, preferably in the presence of a phosphine ligand, such as triphenylphosphine. In the presence of a chiral phosphine ligand, the reaction may also be carried out in an enantioselective manner (cf. D. Ikeda et al., Tetrahedron Lett. 2005, 46(39), 6663; T. Kanayama et al., J. of Org. Chem. 2003, 68(16), 6197; I. Baldwin et al., Tetrahedron Asym. 1995, 6(7), 1515; J. Genet et al., Tetrahedron 1988, 44(17), 5263).
Suitable bases are in general inorganic compounds such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate and also alkali metal bicarbonates, such as sodium bicarbonate, alkali metal and alkaline earth metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, potassium tert-pentoxide and dimethoxymagnesium, moreover organic bases, for example, tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preference is given to carbonates, such as Na2CO3.
The bases are generally employed in equimolar amounts; however, they can also be employed in excess or, if appropriate, as solvent.
The subsequent steps 2 and 3 can be carried out analogously to the reaction, described under process A, of alanine derivatives of the formula V with heteroaryl acids/heteroaryl acid derivatives of the formula IV to give the corresponding heteroaroyl derivatives of the formula III and subsequent reaction of the reaction product with amines of the formula II to give the desired heteroaroyl-substituted alanines of the formula I.
The starting materials are generally reacted with one another in equimolar amounts. It may be advantageous to employ an excess of base and/or IX, based on III or I.
Work-up and isolation of the products can be carried out in a manner known per se.
The glycine derivatives of the formula XII required can be obtained analogously to methods known from the literature (cf. Vicky A. Burgess et al., Aust. J. of Chem. (1988), 41(7), 1063-1070).
The required allyl alcohol derivatives of the formula XI are commercially available.
The oxidation of the double bond to the aldehyde is usually carried out at temperatures of from −100° C. to the boiling point of the reaction mixture, preferably from −80° C. to 40° C., especially preferably from −80° C. to 0° C., in an inert organic solvent in the presence of an oxidizing agent.
Preferably, the oxidation is carried out using ozone or by sequential dihydroxylation with osmium catalysts such as OsO4 or permanganates such as KMnO4 and subsequent cleavage of the diol, which is preferably carried out using NalO4 (cf. A. Siebum et al., J. Europ. J. of Org. Chem. 2004, (13), 2905; S. Hanessian et al., J. of Med. Chem. (2001), 44(19), 3074; J. Sabol et al., Tetrahedron Lett. 1997, 38(21), 3687; D. Hallett et al., J. of Chem. Soc., Chem. Comm. 1995, (6), 657).
Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, dioxane, anisole and tetrahydrofuran (THF), nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, and also dimethyl sulfoxide, dimethylformamide and dimethylacetamide; particular preference is given to toluene, THF and acetone.
It is also possible to use mixtures of the solvents mentioned.
Work-up and isolation of the product can be carried out in a manner known per se.
The subsequent reduction to heteroaroyl-substituted alanines of the formula I where R1 and R8=hydrogen and R6═OH is usually carried out at temperatures of from −100° C. to the boiling point of the reaction mixture, preferably from −80° C. to 40° C., especially preferably from −80° C. to 20° C., in an inert organic solvent in the presence of a reducing agent.
Preferred reducing agents are borohydrides such as NaBH4 (cf. A. Siebum et al., J. Europ. J. of Org. Chem. 2004, (13), 2905; S. Hanessian et al., J. of Med. Chem. (2001), 44(19), 3074; J. Sabol et al., Tetrahedron Lett. 1997, 38(21), 3687; D. Hallett et al., J. of Chem. Soc., Chem. Comm. 1995, (6), 657).
Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, ethers, such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, dioxane, anisole and tetrahydrofuran (THF), alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, and also dimethylformamide and dimethylacetamide; particular preference is given to toluene, THF and dioxane.
It is also possible to use mixtures of the solvents mentioned.
Work-up and isolation of the product can be carried out in a manner known per se.
The derivatization of the heteroaroyl-substituted alanines of the formula I where R1 and R8 and R6═OH with compounds of the formula XIII to give heteroaroyl-substituted alanines of the formula I where R1 and R8 and R6═OR9, where R9 is not hydrogen, is usually carried out at temperatures of from 0° C. to 100° C., preferably from 10° C. to 50° C., in an inert organic solvent in the presence of a base [cf., for example, Jung-Hui Sun et al., Heterocycles (2004), 63(7), 585-1599; Christian Lherbet et al., Bioorg. and Med. Chem. Lett. (2003), 13(6), 997-1000; Masami Otsuka et al., Chem. and Pharm. Bull. (1985), 33(2), 509-514; J. R Piper et al., J. of Med. Chem. (1985), 28(8), 1016-1025].
Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran, nitriles, such as acetonitrile and propionitrile, and also dimethyl sulfoxide, dimethylformamide and dimethylacetamide, particularly preferably dichloromethane, tert-butylmethyl ether, dioxane and tetrahydrofuran. It is also possible to use mixtures of the solvents mentioned.
Suitable bases are in general inorganic compounds such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate and also alkali metal bicarbonates, such as sodium bicarbonate, organometallic compounds, in particular alkali metal alkyls, such as methyllithium, butyllithium and phenyllithium, alkylmagnesium halides, such as methylmagnesium chloride, and also organic bases, for example, tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preference is given to sodium carbonate, sodium hydride and triethylamine.
The bases are generally employed in equimolar amounts; however, they can also be employed in catalytic amounts, in excess or, if appropriate, as solvent.
The starting materials are generally reacted with one another in equimolar amounts. It may be advantageous to employ an excess of base and/or XIII, based on I.
Work-up and isolation of the products can be carried out in a manner known per se.
Heteroaroyl derivatives of the formula III
where A, R1 and R4, R5, R6, R7 and R8 are as defined above and L1 is a nucleophilically displaceable leaving group, for example hydroxyl or C1-C6-alkoxy, are also provided by the present invention.
The particularly preferred embodiments of the intermediates with respect to the variables correspond to those of the radicals A, R1 and R4 to R7 of formula I.
Particular preference is given to heteroaroyl derivatives of the formula III in which
The examples below serve to illustrate the invention.
At a temperature of 0° C., 29.4 g (138 mmol) of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was added dropwise to a solution of 34.9 g (138 mmol) of ethyl (2RS,3SR)-2-amino-4-nitro-3-phenylbutyrate (prepared according to M. Rowley et al., Tetrahedron 1992, 48, 3557-3570) and 12.0 g (152 mmol) of pyridine in dichloromethane (400 ml). The reaction mixture obtained was stirred at room temperature for a further 16 hours, and dilute hydrochloric acid (2 M) was then added. Filtration with suction and drying of the resulting precipitate gave 8.0 g of the title compound. The organic phase of the filtrate was washed with dilute aqueous sodium hydroxide solution (2 M), dried and concentrated. By chromatographic purification (silica gel, cyclohexane/ethyl acetate), it was possible to obtain another 11.2 g of the title compound. This gave a total of 19.2 g (32.5% of theory) of the title compound.
1H-NMR (CDCl3): δ=1.10 (t, 3H); 3.95 (s, 3H); 3.95-4.10 (m, 3H); 4.85-4.95 (m, 2H); 5.10 (t, 1H); 6.60 (d, 1H); 7.15-7.35 (m, 5H); 7.95 (s, 1H).
At a temperature of 0° C., methylamine was introduced into a solution of 19.2 g (44.8 mmol) of ethyl (2RS,3SR)-2-({[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)-4-nitro-3-phenylbutyrate in methanol (200 ml) until the solution was saturated. The reaction mixture obtained was stirred at room temperature for a further 16 hours. Subsequent removal of the solvent gave 18.8 g of the title compound (100% of theory; diastereomer mixture, threo/erythro >5:1) which were used without further purification for the next step.
1H-NMR (DMSO) for the threo isomer: δ=2.35 (d, 3H); 3.95 (s, 3H); 3.90-4.05 (m, 1H); 4.75 (dd, 1H); 4.90 (dd, 1H); 5.10 (dd, 1H); 7.15-7.40 (m, 5H); 7.90 (br q, 1H); 8.50 (s, 1H); 8.55 (d, 1H).
1.5 g (30.0 mmol) of hydrazine hydrate were added to a suspension von 5.0 g (12.1 mmol) of 1-methyl-N-{(1RS,2SR)-1-[(methylamino)carbonyl]-3-nitro-2-phenylpropyl}-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide in methanol (100 ml). At a temperature of 40° C., about 0.5 g of Raney nickel were then added a little at a time as a methanolic suspension. The reaction mixture obtained was stirred at 40° C. for a further 2 hours. After cooling, the precipitate was filtered off and washed with methanol. The filtrate gave, after removal of the solvent, 2.7 g of the title compound (58.3% of theory, diastereomer mixture, threo/erythro >5:1) which were used without further purification for the subsequent reaction.
1H-NMR (DMSO) for the threo isomer: δ=2.35 (d, 3H); 2.85 (d, 2H); 3.05-3.15 (m, 1H); 3.95 (s, 3H); 4.65 (d, 1H); 7.10-7.40 (m, 5H); 7.85 (br q, 1H); 8.50 (s, 1H); 8.75 (br s, 1H).
0.24 g (1.14 mmol) of trifluoroacetic anhydride was added to a solution of 0.40 g (1.04 mmol) of N-{(1RS,2RS)-3-amino-1-[(methylamino)carbonyl]-2-phenylpropyl}-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide and 0.12 g (1.19 mmol) of triethylamine in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for a further 16 hours, and dilute hydrochloric acid (2 M) was then added. The resulting precipitate was filtered off with suction and washed successively with dilute aqueous sodium hydroxide solution (2 M) and distilled water. Drying of the solid gave 0.35 g (70.2% of theory) of the title compound as a diastereomerically pure compound.
1H-NMR (DMSO): δ=2.40 (d, 3H); 3.40-3.75 (m, 3H); 3.95 (s, 3H); 4.80 (t, 1H); 7.10-7.30 (m, 5H); 7.95 (br q, 1H); 8.45 (d, 1H); 8.50 (s, 1H); 9.20 (br t, 1H).
Solution A: At −60° C., 44 g (0.103 mol) of n-butyllithium (15% strength in hexane) were added dropwise to a solution of 10.4 g (0.103 mol) of diisopropylamine in 500 ml of THF. The mixture was stirred at −20° C. for 30 min and then again cooled to −60° C. A solution of 27.5 g (0.103 mol) of ethyl (benzhydrylideneamino)acetate in 30 ml of THF was added dropwise, and the mixture was stirred at −60° C. for 1 h.
Solution B: 26 g (0.103 mol) of (E)-1,3-diphenylallyl acetate (prepared according to J. Chem. Soc., Perkin Trans. 1, 2001, 2588-2594), 5.4 g (0.021 mol) of triphenylphosphine and 1.9 g (0.0052 mol) of [Pd(allyl)Cl]2 were dissolved in 40 ml of THF.
At −60° C., solution B was added dropwise to solution A, and the mixture was stirred at this temperature for 3 h and then warmed to room temperature. Sat. NH4Cl solution was added, and the mixture was extracted with MTBE. The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was dissolved in 200 ml of THF, and 200 ml of hydrochloric acid (20% strength) were added. After 24 h at room temperature, the solvent was removed under reduced pressure, and twice in each case 500 ml of methanol were added to the residue and the mixture was reconcentrated under reduced pressure. The crude product was triturated with diethyl ether/CH2Cl2, and the solid was filtered off with suction and dried. This gave 32.8 g (96% of theory) of the title compound (diastereomer mixture) as a yellow solid of m.p. 174-176° C.
15 g (0.045 mol) of (E)-1-ethoxycarbonyl-2,4-diphenylbut-3-enylammonium chloride and 10.119 g (0.1 mol) of triethylamine were dissolved in 500 ml of CH2Cl2. At room temperature, 9.608 g (0.045 mol) of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride were added dropwise to this solution. The mixture was stirred at room temperature for 16 h, washed with H2O, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified chromatographically on silica gel (CH2Cl2/ethyl acetate 9:1) The ethyl (E)-2-[(1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]-3,5-diphenylpent-4-enoate obtained (18 g, 0.038 mol) was dissolved in 190 ml of methanol, and 59.3 g (0.764 mol) of a solution of methylamine in methanol (40% strength) were added. The mixture was stirred at room temperature for 16 h, the same amount of methylamine in methanol (40% strength) was added and the mixture was stirred at room temperature for 3 d. The precipitated solid was filtered off and dried. This gave 7.4 g of the title compound (diastereomer 1) as a colorless solid of m.p. 192-194° C. The mother liquor was concentrated and stirred with diethyl ether, and the solid was filtered off and dried. This gave 8.5 g of the title compound (diastereomer 2:diastereomer 1=3:2) as a colorless solid of m.p. 239-241° C. The total yield was 15.9 g (77% of theory over two steps).
1H-NMR (d6-DMSO, diastereomer 1): δ=2.50 (d, 3H), 3.85 (m, 1H), 3.90 (s, 3H), 4.90 (dd, 1H), 6.35 (d, 1H), 6.50 (dd, 1H), 7.15-7.40 (m, 10H), 8.20 (m, 2H), 8.35 (d, 1H).
At −60° C., ozone was introduced with stirring into a solution of 6 g (13.14 mmol) of N-((E)-1-methylcarbamoyl-2,4-diphenylbut-3-enyl)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxamide (diastereomer ratio 3:2) in 450 ml of methanol/CH2Cl2 2:1 until the solution was saturated (40 g/m3, about 50 l/h). The blueish solution was stirred at −60° C. for about another 45 min (complete conversion) and then flushed with N2, 4.84 g (63.63 mmol) of NaBH4 were added and the mixture was stirred at room temperature for 16 h. After filtration, the mother liquor was concentrated, and the residue was dissolved in CH2Cl2/THF 4:1, washed with dil. HCl, dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with diethyl ether and filtered off, and the solid was dried. This gave 3.1 g (61% of theory) of the title compound (diastereomer ratio 3:2) as a colorless solid.
To separate the diastereomers, acetone was added to the residue and the mixture was stirred at 50° C., and the solid was filtered off and dried. This gave 0.5 g of the title compound (diastereomer 1) as a colorless solid. The mother liquor was concentrated and triturated with methanol, and the solid was filtered off and dried. This gave 0.9 g of the title compound (diastereomer 2:diastereomer 1=6:1) as a colorless solid of m.p. 202° C. The mother liquor was reconcentrated and triturated with a little methanol, and the solid was filtered off and dried. This gave 1.1 g of the title compound (diastereomer ratio 1:1) as a colorless solid of m.p. 194° C.
1H-NMR (d6-DMSO, diastereomer 1): δ=2.60 (d, 3H), 3.20 (m, 1H), 3.60 (m, 2H), 3.85 (s, 3H), 4.55 (t, 1H), 4.75 (t, 1H), 7.15 (m, 1H), 7.25 (m, 4H), 8.00 (d, 1H), 8.05 (m, 1H), 8.15 (s, 1H).
1H-NMR (d6-DMSO, diastereomer 2): δ=2.35 (d, 3H), 3.20 (m, 1H), 3.70 (m, 1H), 3.75 (m, 1H), 3.95 (s, 3H), 4.55 (t, 1H), 4.70 (t, 1H), 7.15 (m, 1H), 7.22-7.28 (m, 4H), 7.78 (m, 1H), 8.33 (d, 1H), 8.48 (s, 1H).
157 mg (2 mmol) of acetyl chloride were added dropwise to a solution of 400 mg (1.04 mmol) of N-(3-hydroxy-1-methylcarbamoyl-2-phenylpropyl)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxamide (diastereomer 1) and 202 mg (2 mmol) of triethylamine in 20 ml of CH2Cl2/THF 1:1, and the mixture was stirred at room temperature for 1 h. The reaction mixture was washed with H2O and dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, filtered through silica gel and concentrated. The residue was triturated with diethyl ether and filtered off, and the solid was dried. This gave 200 mg (45% of theory) of the title compound as a colorless solid of m.p. 175° C. (diastereomer 1).
1H-NMR (d6-DMSO, diastereomer 1): δ=1.89 (s, 3H), 2.62 (d, 3H), 3.45 (m, 1H), 3.88 (s, 3H), 4.17 (dd, 1H), 4.24 (dd, 1H), 4.81 (t, 1H), 7.19 (m, 1H), 7.27 (m, 4H), 8.21 (m, 3H).
Analogously to the procedure above, N-(3-hydroxy-1-methylcarbamoyl-2-phenylpropyl)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxamide (diastereomer 2:diastereomer 1=6:1) gave the compound 3.8 (diastereomer 2:diastereomer 1=6:1) as a colorless solid of m.p. 204° C.
1H-NMR (d6-DMSO, diastereomer 2): δ=1.86 (s, 3H), 2.35 (d, 3H), 3.47 (m, 1H), 3.95 (s, 3H), 4.16 (dd, 1H), 4.42 (dd, 1H), 4.83 (t, 1H), 7.20 (m, 1H), 7.25-7.30 (m, 4H), 7.90 (m, 1H), 8.48 (d, 1H), 8.50 (s, 1H).
In addition to the compounds above, Tables 2 to 5 below list further heteroaroyl derivatives of the formula III and also heteroaroyl-substituted alanines of the formula I which were prepared or are preparable in a manner analogous to the processes described above.
where R1 and R4 = H, R6 = NO2
where R1, R2 and R4 = H, R3 = CH3, R6 = OR9
where R1, R2 and R4 = H, R3 = CH3, R6 = NR10R11 = H
where R1, R2 and R4 = H, R3 = CH3, R6 = NO2
The heteroaroyl-substituted alanines of the formula I and their agriculturally useful salts are suitable, both in the form of isomer mixtures and in the form of the pure isomers, as herbicides. The herbicidal compositions comprising compounds of the formula I control vegetation on non-crop areas very efficiently, especially at high rates of application. They act against broad-leaved weeds and grass weeds in crops such as wheat, rice, maize, soya and cotton without causing any significant damage to the crop plants. This effect is mainly observed at low rates of application.
Depending on the application method in question, the compounds of the formula I, or herbicidal compositions comprising them, can additionally be employed in a further number of crop plants for eliminating undesirable plants. Examples of suitable crops are the following:
Allium cepa, Ananas comosus, Arachis hypogaea, Asparagus officinalis, Beta vulgaris spec. altissima, Beta vulgaris spec. rapa, Brassica napus var. napus, Brassica napus var. napobrassica, Brassica rapa var. silvestris, Camellia sinensis, Carthamus tinctorius, Carya illinoinensis, Citrus limon, Citrus sinensis, Coffea arabica (Coffea canephora, Coffea liberica), Cucumis sativus, Cynodon dactylon, Daucus carota, Elaeis guineensis, Fragaria vesca, Glycine max, Gossypium hirsutum, (Gossypium arboreum, Gossypium herbaceum, Gossypium vitifolium), Helianthus annuus, Hevea brasiliensis, Hordeum vulgare, Humulus lupulus, Ipomoea batatas, Juglans regia, Lens culinaris, Linum usitatissimum, Lycopersicon lycopersicum, Malus spec., Manihot esculenta, Medicago sativa, Musa spec., Nicotiana tabacum (N.rustica), Olea europaea, Oryza sativa, Phaseolus lunatus, Phaseolus vulgaris, Picea abies, Pinus spec., Pisum sativum, Prunus avium, Prunus persica, Pyrus communis, Ribes sylvestre, Ricinus communis, Saccharum officinarum, Secale cereale, Solanum tuberosum, Sorghum bicolor (s. vulgare), Theobroma cacao, Trifolium pratense, Triticum aestivum, Triticum durum, Vicia faba, Vitis vinifera and Zea mays.
In addition, the compounds of the formula I may also be used in crops which tolerate the action of herbicides owing to breeding, including genetic engineering methods.
In addition, the compounds of the formula I may also be used in crops which tolerate attack by fungi or insects owing to breeding, including genetic engineering methods.
The compounds of the formula I, or the herbicidal compositions comprising them, can be used for example in the form of ready-to-spray aqueous solutions, powders, suspensions, also highly concentrated aqueous, oily or other suspensions or dispersions, emulsions, oil dispersions, pastes, dusts, materials for broadcasting, or granules, by means of spraying, atomizing, dusting, spreading or watering. The use forms depend on the intended purpose; in any case, they should ensure the finest possible distribution of the active compounds according to the invention.
The herbicidal compositions comprise a herbicidally effective amount of at least one compound of the formula I or an agriculturally useful salt of I, and auxiliaries which are customary for the formulation of crop protection agents.
Suitable as inert auxiliaries are essentially the following:
mineral oil fractions of medium to high boiling point, such as kerosene and diesel oil, furthermore coal tar oils and oils of vegetable or animal origin, aliphatic, cyclic and aromatic hydrocarbons, for example paraffins, tetrahydronaphthalene, alkylated naphthalenes and their derivatives, alkylated benzenes and their derivatives, alcohols such as methanol, ethanol, propanol, butanol and cyclohexanol, ketones such as cyclohexanone, strongly polar solvents, for example amines such as N-methylpyrrolidone, and water.
Aqueous use forms can be prepared from emulsion concentrates, suspensions, pastes, wettable powders or water-dispersible granules by adding water. To prepare emulsions, pastes or oil dispersions, the substrates, either as such or dissolved in an oil or solvent, can be homogenized in water by means of a wetting agent, tackifier, dispersant or emulsifier. Alternatively, it is also possible to prepare concentrates comprising active substance, wetting agent, tackifier, dispersant or emulsifier and, if desired, solvent or oil, which are suitable for dilution with water.
Suitable surfactants (adjuvants) are the alkali metal salts, alkaline earth metal salts and ammonium salts of aromatic sulfonic acids, for example ligno-, phenol-, naphthalene- and dibutylnaphthalenesulfonic acid, and of fatty acids, alkyl- and alkylarylsulfonates, alkyl sulfates, lauryl ether sulfates and fatty alcohol sulfates, and salts of sulfated hexa-, hepta- and octadecanols, and also of fatty alcohol glycol ethers, condensates of sulfonated naphthalene and its derivatives with formaldehyde, condensates of naphthalene or of the naphthalenesulfonic acids with phenol and formaldehyde, polyoxyethylene octylphenol ether, ethoxylated isooctyl-, octyl- or nonylphenol, alkylphenyl or tributylphenyl polyglycol ether, alkylaryl polyether alcohols, isotridecyl alcohol, fatty alcohol/ethylene oxide condensates, ethoxylated castor oil, polyoxyethylene alkyl ethers or polyoxypropylene alkyl ethers, lauryl alcohol polyglycol ether acetate, sorbitol esters, lignosulfite waste liquors or methylcellulose.
Powders, materials for broadcasting and dusts can be prepared by mixing or grinding the active compounds together with a solid carrier.
Granules, for example coated granules, impregnated granules and homogeneous granules, can be prepared by binding the active compounds to solid carriers. Solid carriers are mineral earths such as silicas, silica gels, silicates, talc, kaolin, limestone, lime, chalk, bole, loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesium sulfate and magnesium oxide, ground synthetic materials, fertilizers such as ammonium sulfate, ammonium phosphate, ammonium nitrate and ureas, and products of vegetable origin, such as cereal meal, tree bark meal, wood meal and nutshell meal, cellulose powders, or other solid carriers.
The concentrations of the compounds of the formula I in the ready-to-use preparations can be varied within wide ranges. In general, the formulations comprise approximately from 0.001 to 98% by weight, preferably 0.01 to 95% by weight, of at least one active compound. The active compounds are employed in a purity of from 90% to 100%, preferably 95% to 100% (according to NMR spectrum).
The formulation examples below illustrate the preparation of such preparations:
The compounds of the formula I or the herbicidal compositions can be applied pre- or post-emergence. If the active compounds are less well tolerated by certain crop plants, application techniques may be used in which the herbicidal compositions are sprayed, with the aid of the spraying equipment, in such a way that as far as possible they do not come into contact with the leaves of the sensitive crop plants, while the active compounds reach the leaves of undesirable plants growing underneath, or the bare soil surface (post-directed, lay-by).
The rates of application of the compound of the formula I are from 0.001 to 3.0, preferably 0.01 to 1.0, kg/ha of active substance (a.s.), depending on the control target, the season, the target plants and the growth stage.
To widen the spectrum of action and to achieve synergistic effects, the heteroaroyl-substituted serineamides of the formula I may be mixed with a large number of representatives of other herbicidal or growth-regulating active compound groups and then applied concomitantly. Suitable components for mixtures are, for example, 1,2,4-thiadiazoles, 1,3,4-thiadiazoles, amides, aminophosphoric acid and its derivatives, aminotriazoles, anilides, (het)aryloxyalkanoic acids and their derivatives, benzoic acid and its derivatives, benzothiadiazinones, 2-(het)aroyl-1,3-cyclohexanediones, hetaryl aryl ketones, benzylisoxazolidinones, meta-CF3-phenyl derivatives, carbamates, quinolinecarboxylic acid and its derivatives, chloroacetanilides, cyclohexenone oxime ether derivatives, diazines, dichloropropionic acid and its derivatives, dihydrobenzofurans, dihydrofuran-3-ones, dinitroanilines, dinitrophenols, diphenyl ethers, dipyridyls, halocarboxylic acids and their derivatives, ureas, 3-phenyluracils, imidazoles, imidazolinones, N-phenyl-3,4,5,6-tetrahydrophthalimides, oxadiazoles, oxiranes, phenols, aryloxy- and hetaryloxyphenoxypropionic esters, phenylacetic acid and its derivatives, 2-phenylpropionic acid and its derivatives, pyrazoles, phenylpyrazoles, pyridazines, pyridinecarboxylic acid and its derivatives, pyrimidyl ethers, sulfonamides, sulfonylureas, triazines, triazinones, triazolinones, triazolecarboxamides and uracils.
It may furthermore be beneficial to apply the compounds of the formula I alone or in combination with other herbicides, or in the form of a mixture with other crop protection agents, for example together with agents for controlling pests or phytopathogenic fungi or bacteria. Also of interest is the miscibility with mineral salt solutions, which are employed for treating nutritional and trace element deficiencies. Non-phytotoxic oils and oil concentrates may also be added.
The herbicidal activity of the heteroaroyl-substituted alanines of the formula I was demonstrated by the following greenhouse experiments:
The culture containers used were plastic flowerpots containing loamy sand with approximately 3.0% of humus as the substrate. The seeds of the test plants were sown separately for each species.
For the pre-emergence treatment, the active compounds, which had been suspended or emulsified in water, were applied directly after sowing by means of finely distributing nozzles. The containers were irrigated gently to promote germination and growth and subsequently covered with transparent plastic hoods until the plants had rooted. This cover causes uniform germination of the test plants, unless this has been impaired by the active compounds.
For the post-emergence treatment, the test plants were first grown to a height of 3 to 15 cm, depending on the plant habit, and only then treated with the active compounds which had been suspended or emulsified in water. For this purpose, the test plants were either sown directly and grown in the same containers, or they were first grown separately as seedlings and transplanted into the test containers a few days prior to treatment. The rate of application for the post-emergence treatment was 1.0 kg/ha of a.s. (active substance).
Depending on the species, the plants were kept at 10-25° C. or 20-35° C. The test period extended over 2 to 4 weeks. During this time, the plants were tended, and their response to the individual treatments was evaluated.
Evaluation was carried out using a scale from 0 to 100. 100 means no emergence of the plants, or complete destruction of at least the aerial parts, and 0 means no damage, or normal course of growth.
The plants used in the greenhouse experiments belonged to the following species:
Amaranthus retroflexus
Chenopodium album
Galium aparine
Setaria viridis
At application rates of 1 kg/ha, the compounds 3.1, 3.2, 3.7 and 3.14 (Table 3) and the compounds 4.8, 4.10, 4.11, 4.12, 4.13, 4.14, 4.15, 4.22, 4.23, 4.26, 4.27, 4.28 and 4.29 (Table 4) showed very good post-emergence action against the unwanted plants Amaranthus retroflexus, Chenopodium album and Setaria viridis.
Furthermore, at application rates of 1 kg/ha, the compounds 5.1 and 5.4 (Table 5) and, at application rates of 0.25 kg/ha, the compound 5.3 showed very good post-emergence action against the unwanted plants Amaranthus retroflexus, Chenopodium album and Galium aparine.
At application rates of 1 kg/ha, the compound 5.5 (Table 5) showed very good post-emergence action against the unwanted plants Amaranthus retroflexus and Chenopodium album, and good action against Galium aparine.
| Number | Date | Country | Kind |
|---|---|---|---|
| 06114239.4 | May 2006 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP07/54562 | 5/11/2007 | WO | 00 | 11/14/2008 |
