Process for producing 2-hydroxybenzamide derivatives

Details Process for producing 2-hydroxybenzamide derivatives Process for producing 2-hydroxybenzamide derivatives

1999-12-23

2001-03-06

Gerstl, Robert (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06197970

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for producing 2-hydroxybenzamide derivatives which are useful as pharmaceuticals or intermediate products.
BACKGROUND ART
2-Hydroxybenzoylaminothiazole derivatives having a hydroxy group at the 2-position on the benzene ring are known to have effects for the improvement of gastrointestinal dysmotility, which makes them useful as preventive or therapeutic drugs for various types of gastrointestinal dysmotility (WO96/36619). Among such 2-hydroxybenzoylaminothiazole derivatives, 2-[N-(4,5-dimethoxy-2-hydroxybenzoyl)amino]-4-[(2-diisopropylaminoethyl)aminocarbonyl]-1,3-thiazole has particularly excellent effects for the improvement of gastrointestinal dysmotility and thus is useful as a pharmaceutical.
According to the descriptions of the above-described WO96/36619, the 2-hydroxybenzoylaminothiazole derivative is produced through the following procedure. 2-Hydroxybenzoic acid serving as a raw material is subjected to condensation reaction with 2-amino-4-alkoxycarbonyl-1,3-thiazole (step 1). Subsequently, the alkoxycarbonyl group of the thiazole ring is further subjected to amidation (step 2).
However, when the carboxy group of 2-hydroxybenzoic acid is activated by use of a condensing agent or a halogenating agent so as to perform the above-described step 1 reaction, reaction such as polymerization frequently occurs, so make production of the target product difficult. To avoid this problem, a conceivable method in the case of amidation of 2-hydroxybenzoic acid (step 1) is as follows. The hydroxy group at the 2-position of the benzene ring of 2-hydroxybenzoic acid (hereinafter referred to as “the 2-hydroxy group”) is protected and then reacted with a compound having an amino group, after which, deprotection is performed. Examples of the protective group for the 2-hydroxy group used in the present method include known protective groups such as an alkyl group, an allyl group, a benzyl group, a tetrahydropyranyl group, and a silyl group. Of these, an alkyl group is generally used. For deprotection, a known dealkylation reaction may be performed (conversion of an alkoxy group into a 2-hydroxy group). Examples of known dealkylation reactions include those by use of acidic reagents including Br&phgr;nsted acids such as hydrobromic acid, hydriodic acid, and trifluoroacetic acid, Lewis acids such as boron tribromide and aluminum chloride (frequently used singly or in combination with alkyl sulfurs), pyridine hydrochloride, and hydrobromic acid-acetic acid solution; reactions by use of alkaline reagents such as sodium methoxide, sodium cyanide, lithium diphenylphosphine, and lithium chloride; reactions by use of silicon reagents such as trimethylsilyl iodide; and hydrogenation reduction such as catalytic reduction.
However, through these known deprotection reactions, selective dealkylation at the 2-position is difficult for a compound having a substituent such as an alkoxy group or an ester group at a position other than the hydroxy-protected 2-position of the benzene ring at which hydroxy is protected (hereinafter referred to as “the 2-protected hydroxy group”). In addition, particularly in the case of a reaction by use of an alkaline reagent, solvolysis and a side reaction attributable to a base may occur, and, when there is employed an N-thiazolyl-2-substituted benzamide compound containing a catalyst poison such as sulfur atoms in the substrate, hydrogenation reduction cannot be completed. Therefore, there is still need for a process for efficiently producing a 2-hydroxybenzamide derivative, in which the 2-protected hydroxy group is selectively dealkylated without affecting other substituents on the benzene ring and without causing any side reaction.
DISCLOSURE OF THE INVENTION
In view of the foregoing, the present inventors have performed earnest studies on a process for producing a 2-hydroxybenzamide derivative, and have found that when a 2-substituted benzamide compound obtained from the reaction between 2-substituted benzoic acid and a compound having an amino group is reacted with a secondary amine or a tertiary amine, the 2-protected hydroxy group is selectively deprotected and converted into a hydroxy group with other substituents on the benzene ring being not affected—and if there are substituents on locations other than the benzene ring, such substituents also being not affected—or without causing any side reaction. They have also found that when the 2-substituted benzamide compound is reacted with a primary amine in the presence of a polar solvent, deprotection of the 2-protected hydroxy group and amidation proceed in parallel, to thereby industrially and advantageously produce a useful compound serving as the above-described preventive and therapeutic drug for gastrointestinal dysmotility. The present invention has been accomplished based on these findings.
Accordingly, the present invention provides a process for producing a 2-hydroxybenzamide derivative represented by formula (2):
wherein R
2
, R
3
, and R
4
are the same or different and each independently represents a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a lower alkylsulfonyl group, a halogen atom, a nitro group, a cyano group, a mono- or di-lower alkylamino group, or a mono- or di-lower alkylcarbonylamino group, or R
2
and R
3
may join to each other to form a methylenedioxy group; R
5
represents a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a halogen atom, a nitro group, a cyano group, a mono- or di-lower alkylamino group, or a mono- or di-lower alkylcarbonylamino group; and R
6
represents a hydroxy group, a lower alkyl group, or a lower alkoxy group; which process is characterized by reacting a 2-substituted benzamide compound represented by formula (1):
wherein R
1
represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted allyl group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted tetrahydropyranyl group; and R
2
, R
3
, R
4
, R
5
, and R
6
have the same meanings as described above; with a secondary amine or a tertiary amine.
The present invention also provides a process for producing a 2-hydroxybenzamide derivative represented by formula (5):
wherein R
2
, R
3
, R
4
, R
5
have the same meanings as described above; R
7
and R
8
are the same or different and each independently represents a hydrogen atom or a lower alkyl group; and m represents an integer of 1-4 inclusive, which process is characterized by reacting a 2-substituted benzamide compound represented by formula (3):
wherein A represents a hydroxy group or a lower alkoxy group and R
1
, R
2
, R
3
, R
4
, and R
5
have the same meanings as described above with a primary amine represented by formula (4):
wherein m, R
7
, and R
8
have the same meanings as described above, in the presence of a polar solvent.
BEST MODE FOR CARRYING OUT THE INVENTION
In the present invention, the term “lower” means a linear, branched, or cyclic carbon chain having 1 to 6 carbon atoms.
Accordingly, the term “lower alkyl group” refers to linear, branched, or cyclic alkyl groups having 1 to 6 carbon atoms. Specific examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, tert-pentyl, 1,2-dimethylpropyl, neopentyl, 1-ethylpropyl, cyclopentyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methyl-1-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, and cyclohexyl. Among these, linear or branched alkyl groups having 1 to 4 carbon atoms are more preferred.
The term “lower alkoxy group” refers to linear, branched, or cyclic alkoxy groups having 1 to 6 carbon atoms. Specific examples of such alkoxy groups include methoxy, ethoxy, propoxy, cyclopropoxy, isopropox

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