ZA200505298B - Process for preparing pyridine-substituted amino ketal derivatives - Google Patents

Process for preparing pyridine-substituted amino ketal derivatives Download PDF

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ZA200505298B
ZA200505298B ZA200505298A ZA200505298A ZA200505298B ZA 200505298 B ZA200505298 B ZA 200505298B ZA 200505298 A ZA200505298 A ZA 200505298A ZA 200505298 A ZA200505298 A ZA 200505298A ZA 200505298 B ZA200505298 B ZA 200505298B
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formula
hydroxide
acetylpyridine
chloride
process step
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ZA200505298A
Inventor
Flemming Hans-Wolfram
Korb Gerhard
Mueller-Lehar Juergen
Weber Walter
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Sanofi Aventis Pharma Deutschland Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/51—Acetal radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms

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  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Catalysts (AREA)

Description

Process for preparing pyridine-substituted amino ketal derivatives
The present invention provides a process for preparing pyridinyl-substituted ~ dialkoxyaminoethane derivatives of the formula (I) and intermediates in the process according to the invention.
OR?
AN
”
OR2
N 0
The compounds of the formula (1) are intermediates in the preparation of active 10- pharmaceutical ingredients. For example, US patent 5,792,871 describes the synthesis of derivatives of a compound of the formula (I) in which the pyridine radical is substituted in the 3-position and R’ is (C1-Cg)-alkyl. Starting from these derivatives, according to US 5,792,871, compounds of the formula (It) are obtainable.
OR’
AN N
OR'
NT © : NO, an a.
In addition, compounds of the formula (I) are used as a building block for preparing pyridinoimidazole derivatives of the formula (ll) (J. Am. Soc., 1938, 753-755) ‘a R » . N » j Xx N 7
N (i)
: where R” is H, SH.
Derivatives of the pyridinoimidazole of the formula (lll) were used in tum for preparing novel macrolide antibiotics, for example telithromycin (US 5,635,485).
Known processes for preparing compounds of the formula (I) are based on the action "of alkali metal alkoxides on p-toluenesulfonic esters of ketoximes in alcoholic solution, for example amino ketal derivatives of the formula (I) occur as an intermediate in the preparation of cyclic amino ketones (F. Moller: Amine durch Umlagerungsreaktionen (Neber-Umlagerung) [Amines by rearrangement reactions (Neber rearrangement)],
Houben-Wey! 11/1: Stickstoffverbindungen ll [Nitrogen compounds i} (1957), p. 903- 905).
The preparation of 1-(pyridinyl)-1 ,1-dialkoxy-2-aminoethane derivatives of the formula (1) is described in the US patent 5,792,871 using the example of the 1-(3-pyridinyl)- 1,1-diethoxy-2-aminoethane dihydrochloride of the formula (IV) by the following three- stage process:
OEt rE x 2 HCI
OEt
Nd (IV)
In this method, 3-acetylpyridine of the formula (V) is initially oximated with ] hydroxylammonium chloride in methanol. The resulting 3-acetylpyridine oxime of the : formula (VI) is converted to pyridine by a solvent change and is dried by a plurality of distillation procedures and also by addition of fresh pyridine (water content < 5 mol%).
. o Nek = —_— 7 Xx HCL v) Vi)
Alternatively, the oximation is carried out directly in pyridine and drying is effected.in the same manner. The resulting mixture of the hydrochloride of 3-acetylpyridine oxime of the formula (VI) and pyridine is subsequently reacted with tosyl chloride of the formula (VII) to give 3-acetylpyridine tosyl oxime of the formula (VII1), precipitated from the mixture with water and isolated. ©. oh odo 0 _— ) > oh
N
(v1) vi) vil)
The resulting tosy! oxime of the formula (VIII) is subsequently reacted with potassium ethoxide in ethanol in a Neber rearrangement to give the amino ketal. The resulting p-toluenesulfonic acid potassium salt is filtered after dilution with methyl tert-butyl ether and the filtered solution is admixed with hydrogen chloride dissolved in ether. This precipitates the 1-(3-pyridinyl)-1,1-diethoxy-2-aminoethane dihydrochloride of the : formula (IV) as an orange-colored solid.
I
According to US 5,792,871, the purity of the isolated product could only be estimated with the aid of H and 3c NMR data to > 95% as a consequence of unknown impurities. For the further reaction, the amino ketal dihydrochloride (IV) is suspended
’ in water and admixed with sodium hydroxide solution, in order to prepare the amino ketal as the free base which is required for the further coupling reaction.
The above-described process has some disadvantages for the scale-up to the industrial scale: first, the intermediates obtained each have to be dried by distillation procedures. Second, the 3-acetylpyridine tosyl oxime intermediate of the formula (VIil) decomposes very easily in the event of prolonged storage above room temperature to release large amounts of energy (decomposition energy for 3-acetylpyridine tosy! oxime approx. 1000 J/g, see also warning with regard to the storage of a toluene- sulfonic ketoxime ester in F. Moller: Amine durch Umlagerungsreaktionen (Neber-
Umlagerung), Houben-Weyl 11/1: Stickstoffverbindungen Ii (1957), p. 903-905). Third, the 1-(3-pyridinyl)-1,1-diethoxy-2-aminoethane dihydrochloride (IV) prepared in this way is contaminated by by-products, which is confirmed by the strong coloration.
Fourth, in order to obtain the free 1-(3-pyridinyl)-1,1 _diethoxy-2-aminoethane, the isolated salt (IV) has to be released with an auxiliary base in an additional step. Fifth, there are frequent solvent changes during the process. The solvent mixtures then have to be worked up again very expensively, which leads to environmental pollution.
It is an object of the present invention to find a more efficient and safe process for synthesizing the compounds of the formula (1).
The present invention therefore provides a process for preparing 1-pyridinyl- 1,1-dialkoxy-2-aminoethane derivatives of the formula (I) where R and R® are each independently (C1-Cg)-alkyl, where the alkyl group may be straight-chain or branched, } 25 or where R' and RZ together with the oxygen atoms form a cyclic ketal in which R' } and Rr? together are a (C2-C4)-alkylidene group, and where the pyridine radical is substituted in the 2-, 3- or 4-position, preferably in the 3-position, which comprises, in process step (a), converting acetylpyridine of the 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 later addition of an inorganic base comprising mM", to the acetylpyridine oxime metal salt of the formula (IX) where nis 1 or 2 and M™ is an alkali metal metal ion where n=1 or alkaline earth metal ion where n=2, preferably Li, 5 Na”, K* or cat. 0 No
N” N n
Vv) (IX)
R' and R? are preferably each a (C1-Cg)-alkyl radical. Particular preference is given to
R' and R® being the same and each being a (C1-Cg)-alkyl radical. (C1-Cg)-Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or n-hexyl.
The cyclic ketal containing a (C2-Cy)-alkylidene group is, for example, a [1,3]dioxolane or a [1,3]dioxane radical.
The preparation can be effected batchwise or continuously by single- or multicomponent metering. The compound of the formula (IX) can be isolated or further processed as a solution or suspension.
Mis, for example, Li", Na”, K* or ca®*. Inorganic bases comprising Mt are, for example, alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal carbonates or alkali metal or alkaline earth metal hydrogencarbonates or mixtures thereof, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogencarbonate or potassium carbonate.
. For 100 mol of acetylpyridine, preference is given to using 98-120 mol of hydroxylamine or hydroxylammonium compound, more preferably 99-101 mol; and ; also 200-300 mol of an inorganic base comprising mM, more preferably 200-220 mol, or 100-150 mol of an inorganic base comprising m=", more preferably 100-110 mol. .
In process step (b), the aqueous solution, the aqueous suspension or the isolated solid of acetylpyridine metal salt of the formula (IX) is reacted with a solution of a p-toluenesulfonic acid derivative (X) containing a leaving group Y
Y
0x20 : x where Y is F, Cl or Br, preferably Cl, in a suitable solvent which is water-insoluble or sparingly water-soluble to give the acetylpyridine tosyl oxime of the formula (XI)
A nd
N (XI) the reaction proceeding in a biphasic mixture of water and suitable water-insoluble . solvent, and the reaction optionally proceeding with the use of one or more phase transfer catalysts, for example quaternary ammonium or phosphonium salts, preferably a quaternary ammonium salt of the formula (XI) or a phosphonium salt of the formula (XIII) or a hydrate of a salt of the formula (XII) or of the formula (X11)
. R3 . RY + - yi R4 X ope x"
RO R9 (XH) (Xi) where R° to R' are the same or different and are each independently a) (C1-Cop)-alkyl, straight-chain or branched, b) benzyl or c) phenyl, and
X is an anion, for example fluoride, chloride, bromide, iodide, hydroxide, hydrogensulfate, tetrafluoroborate, acetate, trifluoromethanesulfonate, nitrate, hexafluoroantimonate.
The reaction in a biphasic mixture is preferably carried out with the use of one or more phase transfer catalysts, but also proceeds without phase transfer catalyst.
Process step (b) can be effected batchwise or continuously, preferably continuously, in which case the concentration of the compound of the formula (XI) which is critical from a safety point of view is kept low. The resulting mixture of solvent and aqueous phase is subsequently separated by the customary methods of phase separation. The aqueous phase contains the dissolved metal salts used. The aqueous phase is fed to a biological purification. Optionally, the aqueous phase can subsequently be washed once or more with a suitable water-insoluble solvent, and the solvent phases combined and further processed together. The solvent phase contains the compound of the } formula (XI). }
In process step (b), for 100 mol of 3-acetylpyridine oxime salt of the formula (IX), preference is given to using 0.1-50 mol, preferably 0.2-10 mol, of the phase transfer catalyst.
: Examples of quaternary ammonium salts of the 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 hydrogensulfate, methyltetra-n-butylammonium chloride, methyltri-n-octylammonium chioride (Aliquat® 336), methyltri- : n-octylammonium hydroxide, methyltricaprylammonium chloride, methyltricaprylammonium hydroxide, dimethylbenzyl (C8 - C18)-alkyl chloride, tetra- n-propylammonium chloride, triethylhexylammonium chloride, triethyl-n-
octylammonium chloride, triethyl-n-octylammonium bromide, triethyl-n-decylammonium bromide, triethyl-n-hexadecylammonium bromide, phenyltriethylammonium chloride, ethyltri-n-octylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butyl- ammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium hydrogensulfate, tetramethylammonium iodide, tetramethylammonium hydroxide pentahydrate, tetramethylammonium hydroxide, methyltriethylammonium bromide, tetramethylammonium chloride monohydrate, tetramethylammonium bromide, tetramethylammonium iodide, tetramethylammonium tetrafluoroborate, (n-hexyl)trimethylammonium bromide, phenyltrimethylammonium chloride, phenyltrimethylammonium iodide, benzyltrimethylammonium chioride, benzyltrimethyl-
ammonium iodide, benzyltrimethylammonium hydroxide, (n-octyl)trimethylammonium bromide, (N-nonyl)trimethylammonium bromide, tetra-n-propylammonium bromide, phenyltriethylammonium iodide, (n-decyl)trimethylammonium bromide,
benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium tetrafluoroborate, benzyltriethylammonium hydroxide, (n-dodecyl)trimethylammonium chloride, (n-dodecyl)trimethylammonium bromide, benzyltri-n-propylammonium chloride, tetra-n-butylammonium bromide, tetra- n-butylammonium iodide, tetra-n-butylammonium acetate, tetra-n-butylammonium hydrogensulfate, tetra-n-butylammonium hydroxide, tetra-n-butylammonium trifluoromethanesulfonate, (n-tetradecyl)trimethylammonium chloride, : (n-tetradecyl)trimethylammonium bromide, (n-hexadecyl)trimethylammonium bromide,
’ tetra-n-pentylammonium chloride, tetra-n-pentylammonium iodide, benzyltri- n-butylammonium chloride, benzyltri-n-butylammonium bromide, (n-hexadecyl)pyridinium chioride monohydrate, (n-hexadecyl)pyridinium bromide monohydrate, tetra-n-hexylammonium bromide, tetra-n-hexylammonium hydrogensulfate, tetra-n-octylammonium bromide, tetra-n-dodecylammonium iodide or tetra-n-dodecylammonium nitrate.
Examples of phosphonium salts of the formula (XIII) are tetra-n-butylphosphonium chloride, tetraphenylphosphonium bromide, methyltri-n-octylphosphonium chloride, methyltriphenylphosphonium bromide, ethyltri-n-octylphosphonium bromide, tetra- n-butylphosphonium bromide, tetraphenylphosphonium chloride, tetraphenylphosphonium iodide, tetraphenylphosphonium hexafluoroantimonate, tetraphenylphosphonium tetrafluoroborate, (n-hexadecyl)tri-n-butylphosphonium bromide or triphenylmethyltriphenylphosphonium chloride.
Suitable solvents which are water-immiscible or sparingly water-soluble or water- insoluble are, for example, aliphatic or aromatic hydrocarbons which are unsubstituted or substituted by one or more (C1-Ca)-alkyl groups, for example methyl, or one or more substituents from the group of fluorine, chlorine and bromine, preferably toluene, xylene (as the pure isomers or mixtures of the isomers), ethylbenzene, heptane or dichloromethane. Also suitable are mixtures of the suitable solvents mentioned.
For 1 mol of p-toluenesulfonic acid derivative (X), preference is given to using from 0.6 to 1.1 kg of suitable solvent. In the reaction of 100 mol of acetylpyridine oxime salt of the formula (IX), preference is given to using 99-150 mol, more preferably 100- . 110 mol, of p-toluenesulfonic acid derivative (X).
The term biphasic mixture refers to the mixture of two liquid phases - aqueous phase which comprises the acetylpyridine oxime salt (1X) and the solvent phase which comprises the p-toluenesulfonic acid derivative (X). When a phase transfer catalyst is
’ used, it may be present either in the AUEONS phase or in the solvent phase, or be divided between the phases. The biphasic mixture is stirred and/or mixed by customary methods of batchwise or continuous process operation, so that good distribution of the phases is ensured.
The temperature for the reaction in process step (b) in a batchwise procedure is preferably 0-50°C, more preferably 5-30°C, and in a continuous procedure 0-60°C, more preferably 5-40°C.
In process step (c), the solvent phase comprising the acetylpyridine tosy! oxime of the formula (XI), after drying or without preceding drying, is metered into a mixture of alkali ‘metal alkoxide, alkali metal hydroxide, alkaline earth metal alkoxide or alkaline earth metal hydroxide and an alcohol, where “alkoxide” means R'O and/or RO" and where alcohol means ROH and/or R°OH, and R' and R are as defined in the compound of the formula (I), and converted to the 1-(pyridinyl)-1,1-dialkoxy-2-aminoethane derivative of the formula (I).
In process step (c), for 100 mol of the acetylpyridine tosyl oxime of the formula (XI), preference is given to using 99-500 mol of an alkali metal alkoxide, more preferably 100-200 mol; or 99-500 mol of an alkali metal hydroxide, more preferably 100-300 mol; or 50-250 mol of an alkaline earth metal alkoxide, more preferably 50-100 mol, or 50- 250 mol of an alkaline earth metal hydroxide, more preferably 50-150 mol.
In process step (c), preference is given to using alkali metal hydroxides or alkoxides, particularly lithium hydroxide, lithium methoxide, lithium ethoxide, sodium hydroxide, i sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium ethoxide, cesium hydroxide, cesium methoxide or cesium ethoxide.
The choice of the alkoxide and/or of the alcohol depends on the introduction of the desired alkoxy groups. For example, for the preparation of 1-(pyridinyl)-1,1-dimethoxy-

Claims (19)

: What is claimed is:
1. A process for preparing 1-(pyridinyl)-1,1-dialkoxy-1-aminoethane derivatives of the formula (1) OR1 NX ~ OR? N 0) where R' and R are each independently (C1-Cg)-alkyl, where the alkyl group may be straight-chain or branched, or where R' and R? together with the oxygen atoms form a cyclic ketal in which R’ and R? together are a (Co-Cy)-alkylidene group, and where the pyridine radical is substituted in the 2-, 3- or 4-position, preferably in the 3-position, which comprises, in process step (a), converting acetylpyridine of the formula (V) using an aqueous solution of a hydroxylammonium compound or an aqueous solution of hydroxylamine, with the addition of an inorganic base comprising M™, to the acetylpyridine oxime metal salt of the formula (IX) where nis 1 or 2 and M"™" is an alkali metal or alkaline earth metal ion 0 vo . ~ | = N N n v) (IX)
) in process step (b), reacting the acetylpyridine metal salt of the formula (IX) with a solution of a p-toluenesulfonic acid derivative (X) containing a leaving group Y Y 05l20 (X) . where Y is F, Cl or Br, in a suitable solvent which is water-immiscible or sparingly water-soluble or water-insoluble to give the acetylpyridine tosyl oxime of the formula (XI) i 0-5 — N 0 AN Nd Xi xD the reaction proceeding in a biphasic mixture of water and suitable solvent, optionally with the use of one or more phase transfer catalysts, and, in process step (c), converting acetylpyridine tosyl oxime of the formula (XI) to a mixture of an alkali metal alkoxide, an alkali metal hydroxide, an alkaline earth metal alkoxide or an alkaline earth metal hydroxide with an alcohol to a compound of the formula (1), where “alkoxide” means R'O and/or R°O’, and where alcohol means R'OH and/or ROH, and R' and R? are each as defined for the compound of the formula (1), .
: and conducting the process continuously or batchwise independently for each process step (a) to (c).
2. The process as claimed in claim 1, wherein the pyridine radical is substituted in the 3-position.
3. The process as claimed in one of claims 1 or 2, wherein R! and R? are each (C1-Ceg)-alkyl.
4. The process as claimed in one of claims 1 to 3, wherein, in process step (a), hydroxylamine, hydroxylammonium chloride or hydroxylammonium sulfate are used.
5. The process as claimed in one of claims 1 to 4, wherein, in process step (a), MT means Lit, Na", K* or ca®t.
6. The process as claimed in one of claims 110 5, wherein, in process step (a), the inorganic base comprising M™ is lithium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium hydroxide, potassium carbonate or calcium hydroxide.
7. The process as claimed in one of claims 1 to 6, wherein, in process step (b), the leaving group Y is Cl.
8. The process as claimed in one of claims 1 to 7, wherein, in process step (b), the ’ 25 phase transfer catalyst is a quaternary ammonium salt of the formula (XII) ora phosphonium salt of the formula (XIll)
R3 : R7 Pa R4 X~ 0 leg Xx ls ly : (Xi) : (xin where R® to R'° are the same or different and are each independently a) (C4-Cop)-alkyl, straight-chain or branched, b) benzyl or ¢) phenyl, and X is an anion, for example fluoride, chloride, bromide, iodide, hydroxide, hydrogensulfate, tetrafluoroborate, acetate, trifluoromethanesulfonate, nitrate, hexafluoroantimonate, preferably methyitributylammonium chloride.
~
9. The process as claimed in one of claims 1 to 8, wherein, in process step (c), lithium hydroxide, lithium methoxide, lithium ethoxide, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium ethoxide, cesium hydroxide, cesium methoxide or cesium ethoxide are used.
10. The process as claimed in one of claims 1 to 9, wherein, in process step (c), the acetylpyridine tosyl oxime of the formula (XI) is used without preceding drying.
11. The process for preparing an acetylpyridine oxime metal salt of the formula (1X) . 20 C XX | Mn N Tom where nis 1 or 2 and Mm is an alkali metal ion or alkaline earth metal ion, and where the pyridine radical is substituted in the 2-, 3- or 4-position, which comprises converting acetyipyridine of the formula (V) O IAN NG V) : using an aqueous solution of hydroxylamine or of a hydroxylammonium compound, with the addition of an inorganic base comprising mM, to the acetylpyridine oxime metal salt of the formula (IX), and conducting the process continuously or batchwise.
12. The process as claimed in claim 11, wherein the pyridine radical is substituted in the 3-position. . . . . n+ . tt + +
13. The process as claimed in one of claims 11 or 12, wherein M isLi ,Na ,K or 2+
Ca .
14. The process as claimed in one of claims 11 to 13, wherein the inorganic base comprising MT is lithium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium hydroxide, potassium carbonate or calcium hydroxide,
15. The process as claimed in claim 11 to 14, which is conducted continuously.
16. A process for preparing the compound of the formula (XI) 0 I 4 ) NO O Sr ~ N (XI) where the pyridine radical is substituted in the 2-, 3- or 4-position, which comprises reacting the acetyipyridine metal salt of the formula (1X)
ed A | mn = N AE where nis 1 or 2 and M™ is an alkali metal ion or alkaline earth metal ion with a solution of a p-toluenesulfonic acid derivative (VII) containing a leaving group Y
~ Y O50 (X) where Y is F, Cl or Br, in a suitable solvent which is water-insoluble or sparingly water- soluble to give the acetylpyridine tosyl oxime of the formula (Xl), the reaction proceeding in a biphasic mixture of water and suitable water-insoluble solvent, and the reaction proceeding optionally with the use of one or more phase transfer catalysts, and conducting the process continuously or batchwise.
17. The process as claimed in claim 16, which proceeds with the use of one or more phase transfer catalysts, and wherein the phase transfer catalyst is a quaternary ammonium salt of the formula (XII) or a phosphonium salt of the formula (XIII) on a R4 X° RT RB X (X11) (Xin 3 10 . . where R™ to R ~~ are the same or different and are each independently . a) (C4-Cop)-alkyl, straight-chain or branched, b) benzyl or
> c) phenyl, and X is an anion, for example fluoride, chloride, bromide, iodide, hydroxide, hydrogensulfate, tetrafluoroborate, acetate, trifluoromethanesulfonate, nitrate, hexafluoroantimonate, preferably methyltributylammonium chloride.
18. The process as claimed in claim 16 or 17, wherein the pyridine radical is substituted in the 3-position.
19. The process as claimed in one of claims 16 to 18, which is conducted continuously.
ZA200505298A 2003-02-11 2005-06-30 Process for preparing pyridine-substituted amino ketal derivatives ZA200505298B (en)

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