Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-03
2001-03-06
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06197969
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing a substituted alkylamine having a condensed heterocyclic ring or its salt, which is useful as an intermediate for medicines and agricultural chemicals.
BACKGROUND ART
As a substituted alkylamine having a condensed heterocyclic ring, useful for the above usage, there are known 1-(2-benzothiazolyl)alkylamines represented by the following formula:
For synthesis thereof, a process is known which uses a condensation reaction between 2-aminothiophenol derivative and amino acid-N-carboxy anhydride (see JP-A-8-325235).
However, for example, (RS)-1-(6-fluoro-2-benzothiazolyl)ethylamine produced by the above conventional process is low (34%) in yield; moreover, the 2-aminothiophenol derivative used as a raw material is unstable in air and emits an odor and, therefore, has been difficult to handle industrially.
Thus, there has been proposed no industrial process capable of synthesizing a 1-(2-benzothiazolyl)alkylamine from a 2-aminothiophenol derivative at a high yield with easy handling of the derivative.
In view of such a situation of the prior art, the present invention has been completed with an aim of providing an industrial process capable of synthesizing a 1-(2-benzothiazolyl)alkylamine or its salt from a 2-aminothiophenol derivative at a high yield with easy handling of the derivative.
DISCLOSURE OF THE INVENTION
The present inventors surprisingly found out that by using a 2-aminothiophenol derivative metal salt, which is stable in air, emits no odor and accordingly is easy in industrial handling, and by reacting it with an amino acid-N-carboxy anhydride and then cyclizing the reaction product in an acidic condition, a 1-(2-benzothiazolyl)alkylamine or its salt can be obtained at a high yield. A further study by the present inventors has led to the completion of the present invention.
In the present invention, the above aim has been achieved by providing the following inventions [1] to [10]:
[1] A process for producing a substituted alkylamine represented by the following general formula (3):
(wherein X is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a cyano group or a nitro group; n is an integer of 1 to 4; and R
1
and R
2
are each independently a hydrogen atom or an alkyl group which may be substituted with phenyl group, and may together form a 5- or 6-membered ring) or a salt thereof, which process comprises reacting a 2-aminothiophenol derivative metal salt represented by the following general formula (1):
(wherein M is a bivalent metal atom; X has the same definition as given above; and n has the same definition as given above) with an amino acid-N-carboxy anhydride represented by the following general formula (2):
(wherein R
1
and R
2
have the same definitions as given above) and then subjecting the reaction product to cyclization under an acidic condition.
[2] A process for producing a substituted alkylamine or a salt thereof, set forth in [1], wherein the reaction of the 2-aminothiophenol derivative metal salt represented by the general formula (1) with the amino acid-N-carboxy anhydride represented by the general formula (2) is conducted in an amide type aprotic polar solvent.
[3] A process for producing a substituted alkylamine or a salt thereof, set forth in [1] or [2], wherein the 2-aminothiophenol derivative metal salt represented by the general formula (1) is a salt of a Ib or IIb group metal.
[4] A process for producing a substituted alkylamine or a salt thereof, set forth in [3], wherein the 2-A aminothiophenol derivative metal salt represented by the general formula (1) is a zinc salt.
[5] A process for producing a substituted alkylamine or a salt thereof, set forth in [1] or [2], wherein the amino acid-N-carboxy anhydride represented by the formula (2) is DL-alanine-N-carboxy anhydride, D-alanine-N-carboxy anhydride or L-alanine-N-carboxy anhydride.
[6] A process for producing a substituted alkylamine or a salt thereof, set forth in [1] or [2], wherein the reaction of the 2-aminothiophenol derivative metal salt represented by the general formula (1) with the amino acid-N-carboxy anhydride represented by the general formula (2) is conducted in a temperature range of −50 to 60° C.
[7] A process for producing a substituted alkylamine or a salt thereof, set forth in [1] or [2], wherein the reaction of the 2-aminothiophenol derivative metal salt represented by the general formula (1) with the amino acid-N-carboxy anhydride represented by the general formula (2) is conducted in a'temperature range of −30 to 10° C.
[8] A (substituted) benzenesulfonic acid salt of a 1-(6-halogeno-2-benzothiazolyl)ethylamine represented by the following formula:
(wherein Y is a halogen atom).
[9] A (substituted) benzenesulfonic acid salt set forth in [8], wherein the (substituted) benzenesulfonic acid is p-toluenesulfonic acid.
10. A (substituted) benzenesulfonic acid salt set forth in [8] or [9], wherein Y is a fluorine atom.
The (substituted) benzenesulfonic acid salt of a 1-(6-halogeno-2-benzothiazolyl)ethylamine set forth in [8] to [10] includes a pure optical isomer of R-configuration, a pure optical isomer of S-configuration, a racemic modification and a mixture of any proportions of different optically active compounds (R-configuration and S-configuration).
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is described in detail below.
In the process of the present invention, first, a 2-aminothiophenol derivative metal salt represented by the following general formula (1):
is reacted with an amino acid-N-carboxy anhydride represented by the general formula (2).
The 2-aminothiophenol derivative metal salt used as a raw material in the above reaction may be any compound represented by the general formula (1) and has no other restriction. In the formula, M is a bivalent metal atom, and the metal atom can be exemplified by atoms of bivalent transition metals or alkaline earth metals such as zinc, copper, nickel, magnesium, calcium and the like. A Ib or IIb group metal is preferred, and zinc is particularly preferred.
In the formula (1), X is a hydrogen atom; a halogen atom including chlorine, fluorine, bromine or iodine; a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, including methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group or the like; an alkoxy group (—O-alkyl group) whose alkyl moiety is the above-mentioned alkyl group; a cyano group; or a nitro group. The site(s) to which X bonds, is (are) not restricted; and n is an integer of 1 to 4 and refers to the number of X bonding to the aromatic ring of the formula (1).
As the 2-aminothiophenol derivative metal salt represented by the general formula (1) having the above-mentioned M, X and n, which can be used as a raw material in the above reaction, there can be mentioned, for example, bis(2-aminothiophenol) zinc salt, bis(6-fluoro-2-aminothiophenol) zinc salt, bis(6-chloro-2-aminothiophenol) zinc salt, bis(5-fluoro-2-aminothiophenol) zinc salt, bis(5-fluoro-2-aminothiophenol) copper salt, bis(5-fluoro-2-aminothiophenol) nickel salt, bis(5-fluoro-2-aminothiophenol) magnesium salt, bis(5-fluoro-2-aminothiophenol) calcium salt, bis(5-bromo-2-aminothiophenol) zinc salt, bis(5-chloro-2-aminothiophenol) zinc salt, bis(5-methyl-2-aminothiophenol) zinc salt, bis(5-methoxy-2-aminothiophenol) zinc salt, bis(4-fluoro-2-aminothiophenol) zinc salt, bis(4-chloro-2-aminothiophenol) zinc salt, bis(4-cyano-2-aminothiophenol) zinc salt, bis(4-nitro-2-aminothiophenol) zinc salt, bis(4-methyl-2-aminothiophenol) zinc salt, bis(4,5-difluoro-2-aminothiophenol) zinc salt, bis(3-fluoro-2-aminothiophenol) zinc salt, bis(3-bromo-2-aminothioph
Hiyoshi Hidetaka
Ogawa Mahito
Taniguchi Shuji
Umezu Kazuto
Ihara Chemical Industry Co. Ltd.
Kubovcik & Kubovcik
Stockton Laura L.
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