Preparation of substituted pyridine N-oxide compounds

Details Preparation of substituted pyridine N-oxide compounds Preparation of substituted pyridine N-oxide compounds

2003-10-01

2004-10-19

Dentz, Bernard (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S155000, C546S345000

Reexamination Certificate

active

06806371

ABSTRACT:

The invention relates to a process for preparing substituted pyridine N-oxide compounds by means of phase transfer catalysis.
Substituted pyridine N-oxide compounds are used in the pharmaceutical industry as intermediates in the preparation of medicaments which are effective, for example, against Helicobacter bacteria or, for instance, for treating and preventing stomach ulcers.
The preparation of substituted pyridine N-oxide compounds from the corresponding chloro derivatives is disclosed, for example, by EP-A-0 268 956, WO 98/28299 or WO 96/02534. However, the syntheses described in these references require the use of a strong base, for instance sodium hydride, in differing solvents such as DMF, DMSO or NMP, or the direct preparation of a sodium alkoxide from metallic sodium and alcohol. In addition, they usually achieve moderate yields.
According to this prior art, the preparation of the desired substituted pyridine N-oxide compounds is also possible without use of a solvent. This does not alleviate the abovementioned disadvantages, especially the use of strong bases, the resulting danger potential and the necessary measures for safe handling of these substances, the necessity, if at all, then to use dry solvent, the formation of hydrogen gas, the deficient selectivity of the conversion, and also parameters which are often required such as high temperature or long reaction time.
EP 0 297 783 discloses the preparation of alkoxy-pyridine 1-oxide compounds from the corresponding nitro derivatives. In this preparation, the appropriate nitropyridine 1-oxide compounds are reacted with a simple alcohol or an alkoxide of the formula ROM in which M is H or an alkali metal, in the presence of a base and of a phase transfer catalyst.
However, the reaction of chloro derivatives with diols, mercapto alcohols, ether alcohols, thioether alcohols, dithiols or thioether thiols, which lead to the substituted pyridine N-oxide compounds disclosed by EP-A-0 268 956, WO 98/28299 or WO 96/02534, has hitherto been effected in a similar manner to the above-described process.
It is an object of the invention to modify the reaction in such a way that the strong bases used are replaced by a less expensive alternative which is neither combustible nor explosive, the use of the solvents which are difficult to recycle, such as DMF and DMSO, is avoided, and a reaction in good selectivity in at least comparable time and at comparable temperatures is achieved.
Unexpectedly, this object could be achieved by the use of phase transfer catalysts.
The present invention therefore provides a process for preparing substituted pyridine N-oxide compounds of the formula
in which R1, R2, R3 and R4 are each independently H, a carboxyl group or a C
1
-C
12
-alkyl radical which may optionally contain one or more atoms from the group of N, O and S, or R1 and R2 and/or R3 and R4 together may each form an optionally substituted C
4
-C
20
-alkylene radical which may contain one or more atoms from the group of N, O and S,
A is benzyl or a (CH
2
)
m
group where
m may be an integer from 1 to 12,
Z
1
and Z
2
are each independently O or S, and Y is H, a C
1
-C
12
-alkyl radical which may optionally contain one or more atoms from the group of N, O and S, a C
6
-C
20
-aryl radical or a C
5
-C
20
-heterocycle, and the radicals may optionally be substituted by halogen, C
1
-C
6
-alkyl, nitro, phenyl or tert-amine,
or Z
2
and Y together may form an optionally substituted ring or an optionally substituted ring system, and the ring or the ring system may contain one or more atoms from the group of N, O and S, from the corresponding 4-halopyridine N-oxide of the formula
in which R1-R4 are each as defined above and X is chlorine, bromine or iodine, which comprises reacting the compound of the formula (II) in the presence of a phase transfer catalyst and of a base with a compound of the formula
HZ
1
-A-Z
2
-Y  (III)
in which Z
1
, Z
2
, A and Y are each as defined above, at a temperature up to the reflux temperature, to give the corresponding substituted pyridine N-oxide compound of the formula (I).
According to the present invention, substituted pyridine N-oxide compounds of the formula (I) are prepared.
In formula (I), R1, R2, R3 and R4 are each independently H, a carboxyl group or a C
1
-C
12
-alkyl radical which may optionally contain one or more atoms from the group of N, O and S.
In this context, C
1
-C
12
-alkyl radicals are linear, branched or cyclic alkyl radicals, for instance methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, hexyl, cyclohexyl, etc. The alkyl chain may contain one or more atoms from the group of N, S and O.
R1 and R2 and/or R3 and R4 may also together form an optionally substituted C
4
-C
20
-alkylene radical which may contain one or more atoms from the group of N, O and S. The alkylene radical may additionally, depending on the size of the ring formed, also have one or two double bonds.
R1, R2, R3 and R4 are preferably each independently H or C
1
-C
4
-alkyl, more preferably H or methyl.
A may either be benzyl or a (CH
2
)
m
group where m is an integer from 1 to 12, preferably a number from 2 to 6. Z
1
and Z
2
may each independently be O or S, and Y may be H, a C
1
-C
12
-alkyl radical which may optionally contain one or more atoms from the group of N, O and S, a C
6
-C
20
-aryl radical or a C
5
-C
20
-heterocycle, and the radicals may optionally be substituted by halogen, C
1
-C
6
-alkyl, nitro, phenyl or tert-amine.
In this context, C
6
-C
20
-aryl refers, for example, to compounds such as phenyl, biphenyl, naphthyl, etc.
In this context, heterocycle refers to cyclic radicals which contain at least one S, O or N atom in the ring. These are, for example, furyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzoimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, pyrrolyl, quinazolinyl, pyridazinyl, phthalazinyl, morpholinyl, etc.
Z
2
and Y may also together form an optionally substituted ring or an optionally substituted ring system, in which case the ring or the ring system may contain one or more atoms from the group of N, O and S. Examples thereof are 3-nitro[1,2]b-pyridazine, 4-methyl-thiazole, methyltriazole, imidazole, etc.
Preferably, Y is H, a C
1
-C
6
-alkyl radical which may contain one or two atoms from the group of O and S, a C
6
-C
10
-aryl or C
5
-C
10
-heterocycle radical, and the radicals may optionally be substituted by C
1
-C
4
-alkyl, halogen, nitro, tert-amine or phenyl.
Examples of compounds of the formula (I) which can be prepared by the process according to the invention are, for instance, 4-(2-benzyloxyethoxy)-2,3-dimethylpyridine N-oxide, 4-(3-methoxypropoxy)-2,3-dimethylpyridine N-oxide, 4-(2-hydroxyethoxy)-2,3-dimethylpyridine N-oxide, 4-(4-methoxybutoxy)-2-methylpyridine N-oxide, 4-(3-methoxypropoxy)-2-methylpyridine N-oxide, 4-(3-methoxy-propoxy)-2,3,5-dimethylpyridine N-oxide, 2,3-dimethyl-4-(3-hydroxypropylthio)pyridine N-oxide, 2,3-dimethyl-4-(2-hydroxyethylthio)pyridine N-oxide, 2,3-dimethyl-4-(3-hydroxypropylthio)pyridine N-oxide, 4,6-dimethyl-4-(3-hydroxypropylthio)pyridine N-oxide, etc.
The starting compound used is an appropriate 4-halopyridine N-oxide compound of the formula (II) in which R1-R4 are each as defined in formula (I) and X is chlorine, iodine or bromine.
Preferably, X is chlorine.
Suitable compounds of the formula (II) are, for example, 4-chloro-2-methylpyridine N-oxide, 4-chloro-2,3,5-trimethylpyridine N-oxide, 4-chloro-2,3,5,6-tetra-methylpyridine N-oxide, 4-chloro-2,5-dimethylpyridine N-oxide, 4-bromo-3,5-dimethylpyridine N-oxide, etc.
The compound of the formula (II) can be prepared, for example, from the corresponding 4-nitropyridine N-oxide compound, for instance in a similar manner to EP 0 268 956 by reacting with acetyl chloride at −10° C. A further preparation variant is to heat with concentrated hydrochloric acid

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