Patent Application
20080071084
The present invention achieves all these objects and provides an attractive method for coupling alcoholates for preparing compounds of the formula (III) by reacting compounds of the formula (II) with a) an alchoholate or b) an alcohol R1-OH and a base
In the presence of a Cu-containing catalyst and of a ligand, where the substituents R1 to R6, X1 to X5 and Hal have the following meaning:
R1 is a substituent from the group: methyl, primary, secondary or tertiary, cyclic or acyclic C1 to C12 alkyl radical, substituted cyclic or acyclic C1 to C12 alkyl radical or a phenyl, substituted phenyl, heteroaryl or substituted heteroaryl radical;
R2-5 are substituents from the group: hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl radical in which one or more hydrogen atoms are optionally replaced by fluorine or chlorine, e.g., CF3, substituted cyclic or acyclic alkyl radicals, alkoxy, dialkylamino, alkylamino, arylamino, diarylamino, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, alkylthio, arylthio, diarylphosphino, dialkylphosphino, alkylarylphosphino, dialkyl-, arylalkyl- or diarylaminocarbonyl, monoalkyl- or monoarylaminocarbonyl, CO2−, alkyl- or aryloxycarbonyl, hydroxyalkyl, alkoxyalkyl, nitro, cyano radicals, or two adjacent radicals R2-5 together form an aromatic, heteroaromatic or aliphatic
fused-on ring; Hal is chlorine, bromine, iodine, alkylsulfonate or arylsulfonate,
X1-5 are independently of one another either carbon or nitrogen, or in each case two adjacent X1R1 linked by formal double bond are together O (furans), S (thiophenes), NRH or Nrl (pyrroles).
The method is distinguished in this connection by the possibility of achieving quantitative reactions, and the reaction times typically being reduced to 8 to 12 h. Compared with conventional variants of C,O coupling, this novel method further exhibits the additional advantage that the oligoglycols and polyglycols or polyamines whatsoever and are typically not classified as dangerous goods. A further advantage of the method is that both the ligands and the copper compounds can be removed without difficulty from the respective coupling products because, on the one hand, they are often very readily soluble in water, in contrast to the organic coupling products, and, on the other hand, they often have high boiling points which prevent contamination of the coupling products during workup by distillation.
The ligands employed are acyclic and/or cyclic oligo- and polyglycols, oligo- and polyamides, or oligo- or polyamino glycols of the general formula (IV).
In this connection, R7-8 in formula (IV) are substituents from the group; hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl radicals in which one or more hydrogen atoms are optionally replaced by fluorine or chlorine, e.g. CF3, substituted cyclic or acyclic alkyl groups. The groups R7 and YR8 may also together form a ring.
k is the number of [CR8] units and n is the number of [X[CR2]k] units, where k is an integer >0 and n is an integer >1.
The heteroatoms X and Y are independently of one another oxygen or nitrogen (NH or NR1), it being possible for them to be either simultaneously both nitrogen (NH or NR1) and both oxygen or separately from one another oxygen or nitrogen (NH or NR1). The radicals R in the formula (IV) are substituents of the [CR2] units from the group: hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl radicals in which one or more hydrogen atoms are optionally replaced by fluorine or chlorine, e.g. CF3, substituted cyclic or acyclic alkyl groups. The substituents R of adjacent [CR2] units may also in this connection together form a double bond or be part of an aromatic ring.
The species employed as catalyst consists of copper powder or a copper compound of oxidation state 0, +1 or +2.
Alcoholates preferably employed are those in which R1 is alkyl radicals such as methyl, ethyl, 2-propyl or tert-butyl. They alcoholate R1-O− is optionally, if commercially available, purchased or generated in a preceding step or (subsequently) formed in the reaction mixture through the presence of base during the reaction. In the latter case, the appropriate alcohols R1—OH are reacted with commercially available bases, for example with carbonates, hydrides, hydroxides or phosphates.
Preferred haloaromatic compounds of the formula (II) which can be reacted by the method of the invention are, for example, benzenes, pyridines, pyrimidines, pyrazines, pyridazines, furans, thiophenes, pyrroles, any N-substituted pyrroles or naphthalenes. Suitable examples are 2-, 3- and 4-bromobenzotrifluoride, 2-, 3- and 4-iodobenzotrifluoride, 2-, 3-bromothiophene, 2-, 3-, 4-bromopyridine, 3,5-dimethylbromobenzene, 3,5-dimethylchlorobenzene, 3,5-dimethyliodobenzene.
Examples of suitable solvents are tetrahydrofuran, dioxane, diethyl ether, di-n-butyl ether, diisopropyl ether or alcohols such as methanol, ethanol, 2-propanol or n-butanol. Methanol, ethanol and 2-propanol are preferably employed.
The preferred reactions temperatures are between +25° C. and +200° C., and temperatures between 60 and 120° C. are particularly preferred.
The compounds employed are preferably those such as copper(I) chloride, copper(I) bromide, copper(I) iodide, copper(I) oxide, copper(II) acetylacetonate, copper(II) bromide, copper(II) iodide, particularly preferably copper(I) chloride and copper(I) bromide. It is possible in most cases to use very small amounts of copper catalyst, the amounts of copper typically employed being typically between 20 and 0.01 mol %, particularly typical amounts being between 5 and 0.05 mol %.
Typical examples of ligands according to formula diagram (IV) are compounds such as hexadecyloxypropanol, octadecyloxyethanol, hexadecyloxypropyl methyl ether, octadecyloxyethyl methyl ether, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 20,000, polyethylene glycol 35,000, polyethylene glycol dimethyl ether 250, polyethylene glycol dimethyl ether 500, polyethylene glycol dimethyl ether 2000, 1,4,10-trioxa-7,13-diazacyclopentadecane, 2-(2-aminoethoxy)ethanol, tetraethylenepentamines, and crown ethers such as 12-crown-4, 18-crown-6, benzo-15-crown-5, benzo-18-crown-6, decyl-18-crown-6, dibenzo-18-crown-6, N-phenylaza-15-crown-6, it being possible to employ one or more compounds together. It is possible in most cases to use very small amounts of ligands, the amounts of ligands typically employed being between 40 and 0.02 mol %, particularly typical amounts being between 10 and 0.1 mol %.
Aqueous workups are generally employed, with either water or aqueous mineral acids being metered in or the reaction mixture being metered into water or aqueous mineral acids. The best yields are achieved here by adjusting the pH or the product to be isolated in each case, i.e. usually a slowly acids, and in the case of heterocycles a slightly alkaline, pH. The reaction mixtures are generally filtered after the addition of water, in order to remove insoluble copper compounds. The reaction products are isolated for example by extraction and concentration of the organic phases. It is alternatively possible to remove the organic solvents from the hydrolysis mixture by distillation and to isolate the product which then precipitates by filtration.
The purities of the products from the methods of the invention are generally high, but for special applications (pharmaceuticals precursors) it is possible also to carry out a further purification step, for example by recrystallization or final distillation. The yields of reaction products are 60 to 99%, and typical yields are in particular 85 to 99%.
The method of the invention opens up a very economical method for transforming aromatic halides and sulfonates into the corresponding alkoxy- or aryloxy-substituted compounds.
The method of the invention is to be explained by the following examples without restricting the invention thereto:
300 g of 2-bromothiophene (1.84 mol) are introduced into a mixture of 2.64 g of copper(I) bromide (CuBr, 1 mol %), 18.4 g of polyethylene glycol dimethyl ether (PEG DME) 500 (2 mol %) and 660 g of sodium methanolate solution in methanol (30% strength) (precursor concentration 30.6%) and heated to 90° C. After the conversion, determined by GC, it is >98% (total) of 8 h), the reaction mixture is added to 500 g of water. It is then filtered through Decalite, and the mixture is extracted twice with 150 g of MTBE each time. Vacuum fractionation of the combined organic phases results in 182 g of 2-methoxythiophene (1.59 mol, 86.4%), GC purity >99% a/a.
185 g of 3-bromothiophene (1.13 mol) are introduced into a mixture of 3.24 g of copper(I) bromide (CuBr, 2 mol %), 14.1 g of PEG DME 250 (5 mol %) and 407 g of sodium methanolate solution in methanol (30% strength) (precursor concentration 30.4) and heated to 90° C. After the conversion, determined by GC, it is >98% (total of 10 h), the reaction mixture is added to 300 g of water. It is subsequently filtered through decalite, and the mixture is extracted twice with 120 g of MTBE each time. Vacuum fractionation of the combined organic phases results in 117.4 g of 3-methoxylthiophene (1.03 mol, 91%), GC purity >99% a/a.
25 g of 1-bromo-3,5-bis(trifluoromethyl)benzene (85 mmol) are introduced into a mixture of 366 mg of copper(I) bromide (CuBr, 3 mol %), 1.57 g of 18-crown-6 (7 mol %) and 92.3 g of sodium methanolate solution in methanol (30% strength) (precursor concentration 21%) and heated to 105° C. After the conversion, determined by GC, it is >97% (total of 22 h), the reaction mixture is added to 175 g of water. The mixture is brought to pH 5-6 by metering in hydrochloric acid and is then filtered through decalite. The mixture if extracted twice with 150 g of dichloromethane each time. Vacuum fractionation of the combined organic phases results in 16.5 g of 3,5-bis(trifluoromethyl)anisole (68 mmol, 79.4%), GC purity >98.5% a/a.
45 g of 2-bromo-3-(trifluoromethyl)pyridine (0.2 mol) are introduced into a mixture of 574 mg of copper(I) bromide (CuBr, 2 mol %), 2 g (4 mol %) of polyethylene glycol dimethyl ether 250 and 136 g of sodium ethanolate solution in ethanol (20% strength) (precursor concentration 24.5%) and heated to 100° C. After the conversion, determined by GC, it is >99% (total of 9 h), the reaction mixture is added to 125 g of water. The mixture is brought to pH 9 by metering in hydrochloric acid and then filtered through decalite. The mixture is extracted twice with 135 g of toluene each time. Vacuum fractionation of the combined organic phases results in 32.1 g of 2-ethoxy-3-(trifluoromethyl)pyridine (0.17 mmol, 84%) GC purity >99% a/a.
250 g of 2-bromo-5-methylpyridine (1.45 mol) are introduced into a mixture of 2.1 g of copper(I) bromide (CuBr, 1 mol %), 14.5 g (2 mol %) of polyethylene glycol dimethyl ether 500 and 457 g of sodium methanolate solution in methanol (30% strength) (precursor concentration 14.5%) and heated to 90° C. After the conversion, determined by GC, it is >98.5% (total of 17 h), the reaction mixture is added to 750 g of water. The mixture is brought to pH 9 by metering in hydrochloric acid and is then filtered through decalite. The mixture is extracted twice with 350 g of MTBE each time. Vacuum fractionation of the combined organic phases results in 162.8 g of 2-methoxy-5-methylpyridine (1.32 mol, 91%), GC purity >98% a/a.
45 g of 2-bromo-3-methylthiophene (0.25 mol) are introduced into a mixture of 1.79 g of copper(I) bromide (CuBr, 5 mol %), 7.5 g (12 mol %) of polyethylene glycol dimethyl ether 250 and 255 g of sodium methanolate solution in ethanol (20% strength) (precursor concentration 14.5%) and heated to 110° C. After the conversion, determined by GC, it is >98.5% (total of 17 h), the reaction mixture is added to 600 g of water. It is then filtered through decalite, and the mixture is extracted twice with 350 g of MTBE (methyl tert-butyl ether) each time. Vacuum fractionation of the combined organic phases results in 31.3 g of 2-ethoxy-3-methylthiophene (0.22 mol, 87%), GC purity >99% a/a.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2006 026 431.2 | Jun 2006 | DE | national |
