Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-01-02
2004-08-10
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06774245
ABSTRACT:
TECHNICAL FIELD
The present invention relates to 3-hydroxymethyl-benzo[b]thiophene derivatives which are important as starting materials for the production of compounds useful in the pharmaceutical field, and methods for producing them.
BACKGROUND ART
3-Hydroxymethyl-benzo[b]thiophene derivatives represented by the formula (II):
wherein, R
1
to R
3
are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group, are very important as intermediates for the production of pharmacologically active compounds.
For example, a compound in which a hydroxyl group has been replaced with a bromine atom in a compound represented by the formula (II) can be a starting material for a synthetic intermediate of benzimidazole derivatives described in the specification of WO 01/53291, and can be said to be very important as an intermediate for the production of pharmacologically active compounds.
However, the production of benzothiophene derivatives having a hydroxymethyl group at the position 3 and having other substituents in a position-selective manner as in the compounds represented by the formula (II) is very difficult, and none have been suitable for industrial production. For example, there are a method in which benzo[b]thiophene is subjected to the Vilsmeier reaction etc. to synthesize 3-formyl-benzo[b]thiophene (J. Org. Chem., 72:1422 (1957)) which is then reduced, a method in which benzo[b]thiophene is subjected to the Friedel-Crafts reaction to synthesize a 3-trichloroacetyl-benzo[b]thiophene derivative (J. Chem. Soc., Perkin Trans. 2:1250 (197u3)) as a starting material candidate, which is hydrolyzed and then reduced, and the like. In any of them, however, depending on the type and the position of the originally retained substituents, at both positions 2 and 3 or any position from positions 2 to 7 on the benzo[b]thiophene ring, a substitution reaction proceeds wherein position-selectivity in the reaction highly tends to depend on the substrates and the reaction conditions used, and thus selectivity is not always high. Furthermore, the isolation of the desired compound from these mixtures is very difficult.
Furthermore, J. Chem. Soc., Chem. Comm., 848 (1974) reports a reaction in which, a propargyl group was introduced into a benzenethiol derivative, which is then subjected to an oxidation reaction to obtain a compound represented by the formula (VIII):
wherein R
6
and R
7
are all hydrogen atoms, or R
6
and R
7
together form a benzene ring, which is then subjected to a heat transfer reaction to obtain a compound represented by the formula (IX):
wherein R
6
and R
7
are all hydrogen atoms, or R
6
and R
7
together form a benzene ring, which is then subjected to a heat transfer reaction in water-dioxane in the presence of p-toluenesulfonic acid to obtain a compound represented by the formula (X):
wherein R
6
and R
7
are all hydrogen atoms, or R
6
and R
7
together form a benzene ring. In this reaction, however, reaction may occur at both ortho positions of the sulfur atom in the compound represented by the formula (VIII), and thus, depending on the position of substituents on the benzene ring, the selectivity required to obtain the compound of interest may not be obtained. Thus, there may be formed the formula (XI) which is not desired, together with the formula (IX), and the formula (XII) which is not desired, together with the formula (X).
wherein R
6
and R
7
are all hydrogen atoms, or R
6
and R
7
together form a benzene ring.
From the foregoing, there has been a need for a selective method of synthesizing 3-hydroxymethyl-benzo[b]thiophene represented by the formula (II) without the possible concomitant production of isomers.
DISCLOSURE OF THE INVENTION
It is an object of the present invention to resolve the problems encountered in the above conventional methods, and to provide a method of producing 3-hydroxymethyl-benzo[b]thiophene derivatives without the possible concomitant production of isomers.
The present invention provides a method of producing a 3-hydroxymethyl-benzo[b]thiophene derivative represented by the formula (II):
wherein, R
1
to R
3
are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group, by allowing a hydrogenating agent to act on a compound represented by the formula (I):
wherein, R
1
to R
3
are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; and X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons, thereby to attain the selective hydrogenation of the substituent X alone.
In the above method, it is preferred that R
1
to R
3
in the above formula (I) are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, or a trihalomethyl group, and X is a halogen atom.
Furthermore, the present invention provides a method of producing a 3-hydroxymethyl-benzo[b]thiophene derivative represented by the above formula (II), wherein a benzo[b]thiophene derivative represented by the above formula (I) is produced by reducing a compound represented by the formula (IV):
wherein R
1
to R
3
are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons; and R
4
is an acyl group, with a hydrogenating metal complex compound, basic hydrolysis, or acid hydrolysis.
Furthermore, the present invention provides a method of producing a 3-hydroxymethyl-benzo[b]thiophene derivative represented by the above formula (II), wherein a benzo[b]thiophene derivative represented by the above formula (IV) is produced by reacting a compound represented by the formula (III):
wherein R
1
to R
3
are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; and X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons, with one or more of carboxylic acid anhydride or carboxylic acid.
Furthermore, the present invention provides a method of producing a 3-hydroxymethyl-benzo[b]thiophene derivative represented by the above formula (II), wherein a compound represented by the above formula (III) is produced by the following steps (1) to (3):
(1) a step of reacting a propargyl group to a compound represented by the formula (V):
wherein R
1
to R
3
are, same or independently, a hydrogen atom, an alkyl group having 1 to 4 carbons, a trihalomethyl group, an alkoxy group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, or a trihalomethoxy group; X is a halogen atom, a hydroxy group, or an acyloxy group having 1 to 9 carbons; and R
5
is an alkoxythiocarbonyl group, an alkyl group, a hydrogen atom, a halogen atom, a sodium atom, a lithium atom, a potassium atom, a magnesium atom, or a calcium atom, in a substitution reaction to obtain a compound represented by the formula (VI):
wherein R
1
to R
3
and X are as defined in the above formula (V);
(2) a step of oxidizing a compound represented by the formula (VI) to obtain a compound represented by the formula (VII):
wherein R
1
to R
3
and X are as defined in the above formula (V); and
(3) a step of obtaining a compound represented by the formula (III) by subjecting a compound represented by the above formula (VII) to a heat transfer reaction.
Furthermore, the present inve
Mizuno Tsuyoshi
Saitoh Hiroshi
Tsuchiya Naoki
Lambkin Deborah C.
Teijin Limited
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