PROCEDURE FOR PREPARING AMINOCETAL DERIVATIVES SUBSTITUTED WITH PYRIDINE
The present invention provides a process for preparing pyridinyl-substituted dialkoxyaminoethane derivatives of formula (I) and intermediates in the process according to the invention.
The compounds of formula (I) are intermediates in the preparation of active pharmaceutical ingredients. For example, U.S. Pat. 5,792,871 describes the synthesis of derivatives of a compound of formula (I) in which the pyridine radical is substituted at the 3-position and R 'is a (C 1 -C 3) alkyl. Based on these derivatives, according to the US document. 5,792,871, the compounds of formula (II) are obtained.
In addition, the compounds of formula (I) are used as a building block for preparing pyridinimidazole derivatives of formula (III) (J. Am. Soc, 1938, 753-755)
where R "is H, SH. Pyridinimidazole derivatives of formula (III) were used in juices to prepare new macrolide antibiotics, for example telithromycin (US Pat. No. 5,635,485) The known procedures for preparing compounds of formula (I) are based on the action of alkali metal alkoxides on p-toluenesulfonic esters of ketoximes in alcoholic solution, for example, derivatives of aminocetals of formula (I) give as an intermediate in the preparation of cyclic amino ketones (F. Moller: Amine durch Umiagemngsreaktionen (Neber-Umlagerung) [Amines by rearrangement reactions (Neber rearrangement)], Houben-Weyl 11/1: Stickstoffverbindungen II [Nitrogen compounds II] (1957), page 903-905). of 1- (pyridinium) -1,1-dialkoxy-2-aminoethane of formula (I) is described in US Patent 5,792,871 using the example of 1- (3-pyridinyl) -1- dihydrochloride -dietoxy-2-aminoethane of formula (IV) by the following procedure Three-stage operation:
In this method, the 3-acetylpyridine of formula (V) is initially oxime with hydroxylammonium chloride in methanol. The resulting 3-acetylpyridin oxime of formula (VI) is converted to pyridine by a change of solvent and dried by a plurality of distillation processes and further by addition of fresh pyridine (water content <5 mol%).
00 (Vi)
Alternatively, the oximation is carried out directly in pyridine and the drying is carried out in the same manner. The resulting mixture of 3-acetylpyridinoxime hydrochloride of formula (VI) and pyridine is further reacted with tosyl chloride of formula (VII) to give the 3-acetylpyridintosiloxime of formula (VIII), precipitated from the mixture with water and isolated
(Vi > (VID (VIII))
The resulting tosyloxime of formula (VIII) is subsequently reacted with potassium ethoxide in ethanol in a Neber regroup to give the aminoketal. The resulting potassium salt of the p-toluenesulfonic acid is filtered after dilution with methyl tert-butyl ether, and the filtered solution is mixed with hydrogen chloride dissolved in ether. This precipitates the 1- (3-pyridinyl) -1,1-diethoxy-2-aminoethane dihydrochloride of formula (IV) as an orange solid. According to the document US 5,792,871, the purity of the isolated product could be estimated only with the aid of 1 H and 13 C a NMR data. 95% as a consequence of unknown impurities. For the further reaction, the aminoketal dihydrochloride (IV) is suspended in water and mixed with sodium hydroxide solution, to prepare the aminoketal as the free base that is required for the additional coupling reaction. The process described above has some disadvantages for the increase on an industrial scale: first, each of the intermediates obtained have to be dried by distillation processes. Second, the 3-acetylpyridintosi-oxime intermediate of formula (VIII) decomposes very easily in case of prolonged storage above room temperature, releasing large amounts of energy (the decomposition energy for 3-acetylpyridintosiloxime is about 1000 J / g, see also the warning regarding the storage of an ester of toluenesulfonicketoxime in F. Moller: Amine durch Umlagerungsreaktionen (Neber Umlagerung), Houben-Weyl 11/1: Stickstoffverbindungen II (1957), p. 903-905). Third, 1- (3-pyridinyl) -1,1-diethoxy-2-aminoethane (IV) dihydrochloride prepared in this manner is contaminated by by-products, which is confirmed by the strong coloration. Fourth, to obtain the free 1- (3-pyridinyl) -1,1-diethoxy-2-aminoethane, the isolated salt (IV) has to be liberated with an auxiliary base in an additional step. Quin-to, there are frequent changes of solvent during the procedure. The solvent mixtures then have to be developed again in a very expensive manner, which causes environmental pollution. It is an object of the present invention to find a more efficient and safe method for synthesizing the compounds of formula (I). The present invention therefore provides a process for preparing 1-pyridinyl-1,1-dialkoxy-2-aminoethane derivatives of formula (I), wherein R1 and R2 are each independently of the other an alkyl (C Ce), wherein the alkyl group may be linear or branched, or wherein R1 and R2 together with the oxygen atoms form a cyclic ketal wherein R1 and R2 together are an alkylidene group (C2-C4), and wherein the pyridine radical is substituted on the position 2, 3 or 4, preferably in position 3, comprising, in step (a) of the process, converting the acetylpyridine of formula (V) using an aqueous solution of a hydroxylammonium compound, for example hydroxylammonium chloride or hydroxylammonium sulfate, or an aqueous solution of hydroxylamine, with the simultaneous or subsequent addition of an inorganic base comprising Mn +, to the metal salt of acetylpyridinoxime of formula (IX), where n is 1 or 2 and Mn + is an ion of alkali metal where n = 1 or an ion of alkaline earth metal where n = 2, preferably Li +, Na +, K * or Ca2 +.
R1 and R2 are each preferably an alkyl radical (Ci-Ce).
A particular preference is given to that R1 and R2 are the same and that each is an alkyl radical (?????). The alkyl (?????) is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or n-hexyl. The cyclic ketal containing an alkylidene group (C2-C4) is, for example, a [1,3] dioxolane radical or a [1,3] dioxane radical. The preparation can be carried out batchwise or continuously by means of a single or multi-component meter. The compound of the formula (IX) can be isolated or further processed as a solution or a suspension. n + is, for example, Li \ Na *, K + or Ca2 +. They are inorganic bases comprising Mn +, for example, hydroxides of alkali metals or alkaline earth metals, carbonates of alkali metals or alkaline earth metals or hydrogen carbonates of alkali or alkaline earth metals or mixtures thereof, preferably lithium hydroxide, sodium hydroxide, hydroxide potassium, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate or potassium carbonate. For 100 moles of acetylpyridine preference is given to the use of 98-120 moles of hydroxylamine or a hydroxylammonium compound, more preferably 99-101 moles; and furthermore 200-300 moles of an inorganic base comprising M +, more preferably 200-220 moles, or 100-150 moles of an inorganic base comprising M2 *, more preferably 100-110 moles. In step (b) of the process, the aqueous solution, the aqueous suspension or the isolated solid of acetylpyridine metal salt of formula (IX) is reacted with a solution of a p-toluenesulfonic acid derivative (X) containing a outgoing group Y
where Y is F, CI or Br, preferably Cl, in a suitable solvent that is insoluble in water or soluble in water in moderation, to give the acetylpyridine-siloxime of formula (XI)
The reaction proceeds in a biphasic mixture of water and a suitable water-insoluble solvent, and the reaction optionally continues with the use of one or more phase transfer catalysts, for example quaternary ammonium salts or phosphonium, preferably a quaternary ammonium salt. of formula (XII) or a phosphonium salt of formula (XIII)
(XII) (XIH)
where R3 to R10 are the same or different and are each independently of the other a) (C1-C20) alkyl, straight or branched chain, b) benzyl or c) phenyl, and X "is an anion, for example fluoride, chloride, bromide, iodide, hydroxide, hydrogen sulfate, tetrafluoroborate, acetate, trifluoromethanesulfone-to, nitrate, hexafluoroantimonate The reaction in a biphasic mixture is preferably carried out with the use of one or more phase transfer catalysts, but also continues without phase transfer catalyst Step (b) of the process can be carried out batchwise or continuously, preferably continuously, in which case the concentration of the compound of formula (XI), which is critical from one point of view The resulting mixture of solvent and aqueous phase is subsequently separated by customary phase separation methods.The aqueous phase contains the dissolved metal salts The aqueous phase is fed to a biological purification. Optionally, the aqueous phase can be subsequently washed one or more times with a suitable water-insoluble solvent, and the solvent phases are combined and further processed together.The solvent phase contains the compound of formula (XI). b) of the process, for 100 moles of 3-acetylpyridin oxime salt of formula (IX), preference is given to the use of 0.1-50 moles, preferably 0.2-10 moles, of the phase transfer catalyst. quaternary ammonium salts of formula (XXII) are tetramethylammonium bromide, tetramethylammonium chloride, tetraethylammonium chloride, n-butyltriethylammonium chloride, methyltriisopropylammonium chloride, methyltri-n-butylammonium chloride (Aliquat® 175), methyltri-n-butylammonium bromide, methyltri-n-butylammonium hydrogen sulfate, methyltetra-n-butylammonium chloride, methyltri-n-octylammonium chloride (Aliquat® 336), methyltri-n-octylammonium hydroxide, methyltraprylammonium chloride, methyltraprylammonium hydroxide, dimethylbenzylalkyl chloride (Ce-Cie), tetra-n-propylammonium chloride, triethylhexylammonium chloride, triethyl-n-octyl ammonium chloride, triethyl-n-octylammonium, triethyl-n-decylammonium bromide, triethyl-n-hexadecylammonium bromide, phenyltriethylammonium chloride, ethyltri-n-octylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium hydrogen sulfate, tetramethylammonium iodide, tetramethylammonium hydroxide pentahydrate, tetramethylammonium hydroxide, methyltriethylammonium bromide, tetramethylammonium chloride monohydrate, tetramethylammonium bromide, I last of tetramethylammonium, tetramethylammonium tetrafluoroborate, (n-hexyl) trimethylammonium bromide, phenyltrimethylammonium chloride, phenyltrimethylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium iodide, benzyltrimethylammonium hydroxide, (n-octyl) trimethylammonium bromide, bromide ( N-nonyl) trimethylammonium, tetra-n-propylammonium bromide, phenyltriethylammonium iodide, (n-decyl) trimethylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium tetrafluoroborate, benzyltriethylammonium hydroxide, chloride (n- dodecyl) trimethylammonium, (n-dodecyl) trimethylammonium bromide, benzyl-tri-n-propylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium acetate, hydrogen sulfate of tetra-n-butylammonium, tetra-n-butylammonium hydroxide, tetra-n-butylammonium trifluoromethanesulfonate, (n-tetradecyl) trimethylammonium chloride, (n-tetradecyl) trimethylammonium bromide, bromur or of (n-hexadecyl) trimethylammonium, tetra-n-pentylammonium chloride, tetra-n-pentylammonium iodide, benzyltri-n-butylammonium chloride, benzyltri-n-butylammonium bromide, (n-hexadecyl) pyridinium chloride monohydrate , (n-hexadecyl) pyridinium bromide monohydrate, tetra-n-hexylammonium bromide, tetra-n-hexylammonium hydrogen sulfate, tetra-n-octylammonium bromide, tetra-n-dodecylammonium iodide or tetra-n-nitrate -Diodecilamonio. Examples of phosphonium salts of formula (XIII) are tert-chloride: n-butylphosphonium, tetraphenylphosphonium bromide, methyltri-n-octylphosphonium chloride, methyltriphenylphosphonium bromide, ethyltri-n-octylphosphonium bromide, tetra-n-bromide. -butylphosphonium, tetraphenylphosphonium chloride, tetraphenylphosphonium iodide, tetraphenylphosphonium hexafluoroantimonate, tetraphenylphosphonium tetrafluoroborate, (n-hexadecyl) tri-n-butylphosphonium bromide or triphenyl-methyltriphenylphosphonium chloride. Suitable solvents which are immiscible in water or moderately water-soluble or water-insoluble are, for example, aliphatic or aromatic hydrocarbons which are unsubstituted or substituted by one or more (C1-C4) alkyl groups, for example methyl, or or more substituents of the group of fluorine, chlorine and bromine, preferably toluene, xylene (as the pure isomers or mixtures of the isomers), ethylbenzene, heptane or dichloromethane. Mixtures of the suitable solvents mentioned are also suitable. For 1 mole of p-toluenesulfonic acid derivative (X), preference is given to the use of 0.6 to 1.1 kg of suitable solvent. In the reaction of 100 moles of acetylpyridinoxime salt of formula (IX), preference is given to the use of 99-150 moles, more preferably 100-110 moles, of p-toluenesulfonic acid derivative (X). The term "biphasic mixture" refers to the mixture of two liquid phases - the aqueous phase comprising the acetylpyridinoxime salt (IX) and the solvent phase comprising the p-toluenesulfonic acid derivative (X). When using a phase transfer catalyst, it may be present either in the aqueous phase or in the solvent phase, or be divided between the phases. The biphasic mixture is stirred and / or mixed by customary batch or continuous process operation methods, so that the good distribution of the phases is ensured. The temperature for the reaction in step (b) of the process in a batch process is preferably 0-50 ° C, more preferably 5-30 ° C, and in a continuous process 0-60 ° C, more preferably 5- 40 ° C. In step (c) of the process, the solvent phase comprises the acetylpyridintosiloxime of formula (XI), after drying or without previous drying, it is measured in a mixture of alkali metal alkoxide, alkali metal hydroxide, alkoxide alkaline earth metal or alkaline earth metal hydroxide and an alcohol, wherein "alkoxide" means R10"and / or R2CT, and wherein alcohol means R1 OH and / or R2OH, and R1 and R2 are as defined in the compound of formula (I) and is converted to the 1- (pyridinyl) -1,1-dialkoxy-2-aminoethane derivative of the formula (I) In step (c) of the process, for 100 moles of the acetylpyridinedhosyloxime of the formula (XI), preference is given to the use of 99-500 moles of an alkali metal alkoxide, more preferably 100-200 moles; or 99-500 moles of an alkali metal hydroxide, more preferably 100-300 moles; or 50-250 moles of an alkaline earth metal alkoxide, more preferably 50-100 moles, or 50-250 moles of an alkaline earth metal hydroxide, more preferably 50-150 moles. In step (c) of the process, preference is given to the use of alkali metal hydroxides or alkoxides, particularly lithium hydroxide, lithium metoxide, lithium ethoxide, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium ethoxide, cesium hydroxide, cesium methoxide or cesium ethoxide. The choice of alkoxide and / or alcohol depends on the introduction of the desired alkoxy groups. For example, for the preparation of 1- (pyridinyl) -1,1-dimethoxy-2-aminoethane, a mixture of an alkali metal or alkaline earth metal methoxide in methanol or an alkali metal hydroxide in methane is used. ! For the preparation of the compound 1- (pyridinyl) -1 - ([1,3] dioxolane) -2-aminoethane in which R1 and R2 together with the oxygen atoms form a cyclic ketal, an alkali metal hydroxide is used in glycol, for example. For 1 mole of acetylpyridin oxime tosylate of formula (XI), preference is given to the use of 0.3-3 kg, preferably 0.5-1.5 kg of the corresponding alcohol. The conversion is effected, for example, within a temperature range of 0-90 ° C, more preferably at 10-60 ° C. After the reaction, a portion of the solvent is distilled initially, so the byproduct of p-toluenesulfonic acid salt precipitates at room temperature. The distillation is carried out by customary methods. The solvent mixture that has been distilled (distilled) can be reused directly for stage (c) of the process. The alkali metal or alkaline earth metal salt of p-toluenesulfonic acid is removed by customary filtration methods. The remaining fractions of solvents are removed by distillation at atmospheric pressure or preferably under reduced pressure, by customary methods. The aminoketal derivative of formula (I) optionally is subsequently isolated in a highly pure form either by vacuum distillation or rectification, or by crystallization from the distillation residue obtained in the above distillation. For example, a compound of formula (I) in which Ri and R2 are each methyl can be purified by distillation. The yield in vacuum distillation or rectification can optionally be improved by adding a flux to the distillation residue. The term "flux" refers to a liquid or a waxy solid whose viscosity is reduced with heating, thus improving the flow properties of the residue to be distilled, but at the same time it has a boiling point considerably higher than that of the product to be distilled. The flux used is, for example, polyethylene glycols having a molecular weight greater than 400 (for example polyethylene glycol 600 or polyethylene glycol 000), paraffins (C n H 2 n + 2 where n> 15), polyhydric alcohols (alcohols having more of an OH group, for example glyce-rol) or asters, for example bis-2-ethyl sebacate. The crystallization can be carried out by customary methods, with or without the use of organic solvents. Fusion or solvent procedures can be used. The advantages of the process according to the invention are, first, the direct isolation of the compounds of formula (I) as a free base of high purity and very good yield; second, that the selected reaction conditions allow oximation and the tosylation reaction to be carried out in a continuous process, which always generates only small amounts of the intermediate of formula (XI) which is relevant from a safety point of view, without isolate the acetylpyridintosiloxes that are critical from a safety standpoint, such as a solid, since, after a short delay time, they are directly converted into a continuous apparatus to the aminocetal of formula (I), which is not critical from a security point of view; the preparation of the compounds of formula (I) with high purity (greater than 97%) and yield (greater than 75% based on the acetylpyridine used), in the form of the free base in a manner that is suitable for the industrial scale; and fourth, the use of a solvent that can be reused directly in the process in pure form or in the form of mixtures, so the environmental implications remain very small. Example 1: Preparation of 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane, method 11 (a) In a reactor, 174 g of 40% hydroxylammonium chloride solution were reacted, 121 g of 3-acetylpyridine and 245 g of 33% sodium hydroxide solution, in a 3-component meter within a temperature range of 15-25 ° C. The sodium salt solution resulting from 3-acetylpyridinoxime was reacted with 2 g of methyltributylammonium chloride. 1 (b) Subsequently, this solution was reacted in a continuous process (recycling method by means of static mixers with partial removal) with a solution of 193 g of p-toluenesulfonyl chloride and 655 g of toluene, up to a temperature internal temperature of 35-38 ° C. The resulting biphasic mixture was then passed through a separation zone and the solvent phase was separated from the aqueous phase. 1 (c) The solvent phase was allowed to run directly in an initially charged solution of 940 g of methanol (or methanol / toluene mixture of the first solvent distillation, see below) and 216 g of 30% sodium methoxide solution. The temperature was maintained within the range of 20-40 ° C. The reaction solution was allowed to continue reacting for another 5-10 hours. The methanol was distilled from the reaction mixture as an azeotropic mixture together with toluene (first distillation of solvent) at 70-90 ° C and atmospheric pressure. The azeotropic mixture of solvents could be reutilized in the reaction described above (see above). After distillation, the distillation residue was cooled to 25 ° C and the sodium salt of p-toluenesulfonic acid was subsequently filtered and washed with 85 g of toluene. The filtrate was subsequently concentrated by distillation under reduced pressure (approximately 100-200 mbar) to an internal temperature of approximately 120-130 ° C. Subsequently, 10-20 g of polyethylene glycol 600 were added to the distillation residue and the 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane was distilled by means of a short column as a water-free liquid at 1 g. -10 mbar at an internal evaporator temperature of 100-160 ° C. 157.3 g of 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane having a purity of 98-99% (determined as compared to a reference standard by means of titration, HPLC-MS were obtained. and RN). This corresponds to a yield of 85% of the theory, based on the 3-acetylpyridine used. Example 2: Preparation of 1- (3-pyridyl) -1,1-dimethoxy-2-aminoethane, method 2 (a) 174 g of 40% hydroxylammonium chloride solution were reacted in a reactor. , 121 g of 3-acetylpyridine and 245 g of 33% sodium hydroxide solution in a 3-component meter within a temperature range of 5-25 ° C. The resulting sodium salt solution of 3-acetylpyridinoxime was added with 2 g of methyl-tributylammonium chloride. 2 (b) Subsequently, this solution was reacted in a continuous process (recycling method by means of stationary mixers with partial removal) with a solution of 193 g of p-toluenesulfonyl chloride and 655 g of toluene, until an internal temperature of 35-38 ° C. The resulting biphasic mixture was then passed through a separation zone and the solvent phase was separated from the aqueous phase. 2 (c) The solvent phase was allowed to run directly in an initially charged solution of 940 g of methanol (or methanol toluene mixture of the first solvent distillation, see below) and 48 g of sodium hydroxide. The temperature was maintained within a range of 20-40 ° C. The reaction solution was allowed to continue reacting for another 5-10 hours. The methanol was distilled from the reaction mixture as an azeotropic mixture together with toluene (first distillation of solvent). The azeotropic mixture of di-solvent could be reused in the reaction described above (see above). After the distillation, the distillation residue was cooled to 25 ° C and the sodium salt of p-toluenesulfonic acid was subsequently filtered and washed with 85 g of toluene. The filtrate was subsequently concentrated by distillation under reduced pressure (about 100-200 mbar) to an in ternal temperature of about 120-130 ° C. Subsequently, 10-20 g of polyethylene glycol 600 were added to the distillation residue and the 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane was distilled by means of a short column as a water-free liquid at 1 g. -10 mbar at an internal evaporator temperature of 100-160 ° C. 148 g of 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane was obtained having a purity of 98-99% (determined in comparison to a reference standard by means of titration, HPLC-MS and NMR ). This corresponds to a yield of 80% of the theory, based on the 3-acetylpyridine used.