Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-20
2004-04-20
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S273400, C546S273700, C514S339000
Reexamination Certificate
active
06723852
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the preparation of derivatives of [[(pyridil substituted)methyl]thio]benzomidazol useful as intermediates in the synthesis of derivatives of [[(pyridil substituted)methyl]sulfinyl]benzomidazol.
BACKGROUND OF THE INVENTION
Certain derivatives of [[(pyridil substituted)methyl]sulfinyl]benzomidazol, among which are omeprazol, 2-[[3,5-dimethyl-4-methoxy-2-pyridil)methyl]sulfinyl]-5-methoxy-1H-benzomidazol, lansoprazol, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridil]methyl]sulfinyl]-1H-benzomidazol, rabeprazol, 2-[[[3-methyl-4-(3-methoxypropoxy)-2-pyridil]methyl]sulfinyl]-1H-benzomidazol, and pantoprazol, 5-difluoromethoxy-2-[[(3,4-dimethoxy-2pyridil)methyl]sulfinyl]-1H-benzomidazol, are anti-ulcerous agents useful in the treatment of stomach and duodenal ulcers, Zollinger-Ellison syndrome and reflux oesophagitis.
One of the key intermediates in the synthesis of said compounds is the derivative of [[(pyridil substituted)methyl]thio]benzimidazole, with the general formula (I)
where
each of R
1
, R
3
and R
4
, independently of each other is hydrogen, an alkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms, or a fluorinated alkoxy group with 1 to 6 carbon atoms, and
R
2
is a nitro group, a halogen, an alkoxy group with 1 to 6 carbon atoms, a halogenated alkoxy group with 1 to 6 carbon atoms, or a group —O—(CH
2
)
n
—OR
8
, where n is an integer between 1 and 6, both inclusive, and R
8
represents hydrogen or an alkyl group with 1 to 6 carbon atoms.
Although many methods have been described for obtaining said compounds with the formula (I), one of the most widely used in the one based on coupling a derivative of 2-methylpyridine (II)
with the corresponding mercaptobenzomidazol (III):
The literature describes compounds with the formula (II), where X is a halogen, as the intermediates usually chosen to perform this reaction.
The synthesis of compounds with the formula (II) can be effected by several methods, such as:
by a radical halogenation of the corresponding methylpyridine [ES 2036948] using as a chlorination reagent trichloroisocyanuric acid, N-chlorosuccinimide, etc.;
from the suitable hydroximethylpyridine, by substitution of the hydroxyl by a halogen [ES 2036948, EP 174726, ES 2036502] using as reagent for example thyonil chloride;
from the N-oxide of the corresponding 2-methylpyridine, compound with formula (IV)
Where R
1
is hydrogen, R
2
is nitro and R
3
is methyl, using as a reagent an alkyl or arylsulfonyl chloride, or a carboxylic acid chloride [ES 2060541]; or
based on the N-oxide of the corresponding 2-methylpyridine, compound with the formula (IV), in two stages, using trichloroisocyanuric acid and later addition of sulfur chloride [ES 2036948].
All of the above methods suffer from important drawbacks:
in general, they require a large number of stages, and in some cases they use very irritating reagents, such as acid chlorides that form hydrochloric acid in the process;
the use of derivatives of 2-halomethylpyridines (compound with the formula (II) where X is a halogen), which usually bring about high levels of irritation, such as the derivatives 4-nitro and 4-(2,2,2-trifluoroethoxy) of 2-chloromethyl-3-methylpyridine and 2-chloromethyl-3,5-dimethyl-4-methoxypyridine; and
in the case of the compound with the formula (IV) where R
2
is a nitro group, during the preparation of the compounds with formulae (I) and (II) byproducts are formed in which R
2
is a halogen, mainly chlorine (as this is the most used derivative), which in the case of low activated pyridines are quite unreactive to nucleophilic substitution in this position. For example, this is the case with omeprazol, where these byproducts are impurities that are difficult to eliminate.
SUMMARY OF THE INVENTION
The invention deals with the problem of developing an alternative method of synthesis of derivatives of [[(pyridil substituted)methyl]thio]benzomidazol, with the general formula (I), which are useful as intermediates of derivatives of [[(pyridil substituted)methyl]sulfinyl]benzomidazol.
The solution disclosed by this invention consists of a process with two stages performed consecutively, and optionally in the same reaction medium, comprising the reaction of the corresponding N-oxide of methylpyridine with the anhydride of activated carboxylic acid or sulfonic acid, and the reaction of the intermediate formed with the corresponding mercaptobenzomidazol.
The method disclosed by this invention has the competitive advantage that it significantly reduces the number of synthesis stages, which implies a great increase of industrial interest as it reduces the cost in comparison with most methods described and reduces the levels of residues formed.
In addition, the intermediates formed after reaction of the corresponding N-oxide of methylpyridine with the activated carboxylic acid or sulfonic acid anhydride produce much lower levels, or nearly inexistent levels, of irritation as compared to the compounds of formula (II), where X is a halogen. Furthermore, the method provided by the invention avoids the handling of these intermediates as they can be made to react in the reaction medium itself.
A further competitive advantage is that the formation is prevented of the corresponding derivative 4-chloro of 2-chloromethylpyridine, which is an important impurity in certain cases, such as in the synthesis of omeprazol.
One object of this invention is a method for obtaining derivatives of [[(pyridil substituted)methyl]thio]benzomidazol, with the general formula (I).
A further object of this invention is a method for obtaining derivatives of [[(pyridil substituted)methyl]sulfinyl]benzomidazol, from compounds with the general formula (I) obtained by the method provided in this invention.
An additional object of this invention are intermediates formed by the reaction of the corresponding N-oxide of methylpyridine with the activated carboxylic acid anhydride of sulfonic acid anhydride, useful as intermediates in the synthesis of derivatives of [[(pyridil substituted)methyl]thio]benzomidazol with the general formula (I). The method for obtaining said intermediates is a further object of this invention.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides a method, hereinafter referred to as the method of the invention, for obtaining derivatives of [[(pyridil substituted)methyl]thio]benzomidazol, with the general formula (I)
where
each one of R
1
, R
3
and R
4
, independently of each other, is hydrogen, an alkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms, or a fluorinated alkoxy group with 1 to 6 carbon atoms, and
R
2
is a nitro group, a halogen, preferably chlorine, an alkoxy group with 1 to 6 carbon atoms, a halogenated alkoxy group, preferably fluorine or chlorine, with 1 to 6 carbon atoms, or a group —O—(CH
2
)
n
—OR
8
, where n is an integer between 1 and 6, both inclusive, and R
8
represents hydrogen or an alkyl group with 1 to 6 carbon atoms,
which comprises:
a) reacting an N-oxide of methylpyridine with the general formula (IV)
and where R
1
, R
2
and R
3
are as described previously;
with (i) an anhydride of activated carboxylic acid with the general formula (R
6
CO)
2
O, where R
6
is a halogenated alkyl group, or (ii) with an anhydride of sulfonic acid with the general formula (R
7
SO
2
)
2
O, where R
7
is an alkyl group, a halogenated alkyl group or an aryl group, optionally substituted with an alkyl group, in an organic solvent, to provide an intermediate with the general formula (V) or the corresponding salt
where
R
1
, R
2
and R
3
are as described previously, and
R
5
is OCOR
6
or OSO
2
R
7
, where R
6
and R
7
are as described previously;
Coppins Janet L
Esteve Quimica S.A.
Ostrolenk Faber Gerb & Soffen, LLP
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