Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-01-25
2001-03-06
Fan, Jane (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S295000, C546S296000, C546S297000, C546S298000
Reexamination Certificate
active
06197962
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for producing 2-sulfonylpyridine derivatives. The 2-sulfonylpyridine derivatives produced by the present invention are useful as starting materials for synthesis of drugs, agricultural chemicals, etc., such as the synthesis starting materials of drug intermediates, including 5-aminomethyl-2-chloropyridine which is useful as an intermediate for synthesis of chloronicotinyl pesticides, 2,5-dichloropyridine which is an intermediate for synthesis of lazabemide, whose clinical development as an anti-Parkinson's disease drug is being promoted, 2-hydroxypyridine, etc. (refer to U.S. Pat. No. 4,897,488, International Patent Application Laid-open No. WO96/26188, International Patent Application Laid-open No. WO98/11071, and Japanese Patent Application Laid-open No. 9-59254).
Moreover, the present invention relates to a method for producing 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole derivatives. The 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole derivatives obtained by the present invention are useful as, for instance, intermediates of 2-{[(2-pyridyl)methyl]sulfinyl}-1H-benzimidazole derivatives, compounds related to omeprazole, which is useful as an anti-ulcer agent.
2. Related Art of the Invention
Many physiologically active substances with a pyridine skeleton have been discovered in recent years. As methods for producing 2-sulfonylpyridine derivatives that are useful as intermediates for synthesis of these compounds, there are known, for example:
(1) The method in which sulfonyl cyanide is reacted with an acyloxybutadiene derivative (refer to International Patent Application Laid-open No. WO96/26188);
(2) The method in which p-toluenesulfonyl cyanide is reacted with 1-ethoxy-2-methylbutadiene (refer to
Synthesis,
p. 623 (1989) and International Patent Application Laid-Open No. WO98/11071);
(3) The synthesis method in which 2-halogenopyridine is reacted with an alkali metal thiolate to produce sulfenylpyridine, and then the sulfenylpyridine is gradually oxidized (refer to
Journal of the Chemical Society Perkin Transaction
1, page 1839 (1984)).
However, the above-mentioned methods (1) and (2) have problems in that they have to use a diene compound that is thermally unstable, and the above-mentioned method (3) has problems in that there are many steps, the desired product yield is low, etc., and therefore, these methods can not be considered to be industrially efficient methods for producing 2-sulfonylpyridine derivatives.
In addition, the method in which a 2-halomethylpyridine derivative is reacted with a metal salt of a 2-mercapto-1H-benzimidazole derivative is known as a method for producing a 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole derivative, and when this is oxidized, a 2-{[(2-pyridyl)methyl]sulfinyl}-1H-benzimidazole derivative can be obtained (refer to U.S. Pat. No. 4,255,431). The 2-halomethylpyridine derivative that is used as the starting material for this method is produced via many steps using 2,3,5-trimethylpyridine as the starting material (refer to, for instance, U.S. Pat. No. 4,544,750 and Japanese Patent Application Laid-open No. 5-70434).
However, conventional methods for producing 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole derivatives can not be considered to be efficient production methods because many steps are needed to produce the starting 2-halomethylpyridine derivative. Moreover, there are problems in that 2-halomethylpyridine derivatives have poor shelf life and they must therefore be used in the next reaction immediately after synthesis.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a method for producing 2-sulfonylpyridine derivatives industrially with efficiency in a good yield under moderate conditions.
Moreover, another object of the present invention is to provide a novel method for producing, efficiently synthesized in a short process, 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole derivatives, which are precursors of 2-{[(2-pyridyl)methyl]sulfinyl}-1H-benzimidazole derivatives.
The inventors have found that a 2-sulfonylpyridine derivative can be industrially produced efficiently by reacting a sulfonyl cyanide derivative with an &agr;, &bgr;-unsaturated carbonyl compound and that a 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole skeleton can be formed in one step in a good yield by reacting this type of 2-sulfonylpyridine derivative with a 2-methylthio-1H-benzimidazole derivative in the presence of an organolithium compound, and completed the present invention based on these findings.
That is, the present invention provides a method for producing a 2-sulfonylpyridine derivative represented by the formula (III)
(In the formula, R
1
is a hydrogen atom or an alkyl group or an aryl group that may be substituted, R
2
and R
3
are a hydrogen atom, a halogen atom, or an alkyl group or an aryl group that may be substituted, R
4
is a hydrogen atom, a halogen atom, an alkoxyl group, an alkylthio group, a cyano group, an acyloxy group, an alkoxycarbonyl group, a protected amino group that may be substituted, or an alkyl group or an aryl group that may be substituted, and together R
2
and R
3
or R
3
and R
4
can represent —(CH
2
)
n
—(n is 3 or 4.), and R
5
is an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group that may be substituted.), which method comprises:
reacting an &agr;, &bgr;-unsaturated carbonyl compound represented by general formula (I)
(In the formula, R
1
, R
2
, R
3
and R
4
are the same as previously defined.)
with a sulfonyl cyanide represented by general formula (II)
R
5
SO
2
CN (II)
(In the formula, R
5
is the same as previously defined.)
to obtain the 2-sulfonylpyridine derivative represented by general formula (III).
Moreover, the present invention provides a method for producing a 2-{[(4-alkoxy-2-pyridyl)methyl]thio}-1H-benzimidazole derivatives (VII)
(In the formula, R
1
, R
2
and R
4
are the same as previously defined. X is a hydrogen atom, a halogen atom or an alkyl group, an alkenyl group, an aryl group, an aralkyl group or an alkoxyl group that may be substituted, and R
6
is an alkyl group.), which method comprises:
reacting a halogeno-&agr;, &bgr;-unsaturated carbonyl compound represented by general formula (I-1)
(In the formula, R
1
, R
2
and R
4
are the same as previously defined, and R
31
is a halogen atom.)
with a sulfonyl cyanide represented by general formula (II)
R
5
SO
2
CN (II)
(In the formula, R
5
is the same as previously defined.)
to obtain a 4-halogeno-2-sulfonylpyridine derivative represented by general formula (III-1)
(In the formula, R
1
, R
2
, R
31
, R
4
and R
5
are the same as previously defined.),
reacting the obtained derivative of general formula (III-1) in the presence of an organolithium compound with a 2-methylthio-1H-benzimidazole derivative represented by general formula (IV)
(In the formula, X is the same as previously defined.)
to obtain a 2-{[(4-halogeno-2-pyridyl)methyl]thio}-1H-benzimidazole derivative represented by general formula (V)
(In the formula, R
1
, R
2
, R
31
, R
4
and X are the same as previously defined.),
reacting the obtained derivative of general formula (V) with a metal alkoxide represented by general formula (VI)
R
6
OM (VI)
(In the formula, R
6
is the same as defined above, and M is an alkali metal or an alkaline earth metal.),
to obtain the 2-{[(4-alkoxy-2-pyridyl)methyl]thio}-1H-benzimidazole derivative represented by general formula (VII).
In addition, the present invention provides a method for producing a 2-{[(4-halogeno-2-pyridyl)methyl]thio}-1H-benzimidazole derivative represented by general formula (V)
(In the formula, R
1
, R
2
, R
31
, R
4
and X are the same as previously defined.), which method compris
Asanuma Goro
Koyakumaru Ken-ichi
Kuwayama Tomoya
Sugioka Takashi
Fan Jane
Kuraray Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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