Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-26
2002-06-11
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06403572
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for producing a hydrogen bromide salt of a (Z)-2-aminothiazole derivative which is useful as an intermediate of pharmaceuticals, for example, an intermediate for constructing a side chain part of the antibiotics disclosed in EP467647B1, which corresponds to Japanese Patent No. 2618119.
DESCRIPTION OF THE RELATED ART
A process for producing a hydrogen bromide salt of the (Z)-2-aminothiazole derivative is disclosed in Preparation 6 of EP467647B1, however, the process is not always satisfactory as an industrial production method in that no reproducible particulars on how to control the exothermic reaction is disclosed. Hence an improved process has been desired.
SUMMARY OF THE INVENTION
An object of the invention is to provide a method for producing an acid salt of a (Z)-2-aminothiazole derivative of the formula I as depicted below.
Another object of the invention is to provide an industrially advantageous reaction method, particularly a continuous method, for preferentially producing a Z-isomer of a hydrogen bromide salt of a 2-aminothiazole derivative of the formula (I), while effectively controlling the exothermic reaction on an industrial scale production.
The present invention provides:
1. a process for producing an acid salt of a (Z)-2-aminothiazole compound of the formula (I):
wherein
R
1
and R
2
independently represent an alkyl group having 1 to 5 carbon atoms,
Y represents a halogen atom, —OSO
3
H or —OPO(OH)
2
,
m indicates the valence number of an inorganic acid of HY and
n indicates an integer of 1 or 2,
which process comprises:
reacting an acid salt of a 2-aminothiazole compound of the formula (II):
wherein R
1
and R
2
independently represent an alkyl group having 1 to 5 carbon atoms, the wavy line means that this compound is a mixture of the E- and Z-isomers, and X represents a bromine atom or an iodine atom, with an inorganic acid of the formula (III):
HY (III)
wherein Y represents a halogen atom, —OSO
3
H or —OPO(OH)
2
;
2. a continuous process for preferentially producing a Z-isomer of a hydrogen bromide salt of a 2-aminothiazole derivative of the formula (IV):
wherein R
1
and R
2
independently represent a lower alkyl group having 1 to 5 carbon atoms, and the wavy line means that this compound is a mixture of the E- and Z-isomers,
which process comprises:
continuously feeding thiourea and a 2-alkylidene-4-bromoacetoacetic acid ester of the formula (V):
wherein R
1
and R
2
have the same meaning as defined above, and the wavy line means that this compound is a mixture of the E- and Z-isomers, into a reaction vessel having at least one agitator,
reacting the thiourea and the compound of the formula (V) together in the reaction vessel for a sufficient residence time for the conversion of the compound of the formula (V) to the compound of the formula(IV), and
withdrawing a resulting reaction mixture containing the compound of the formula (IV) from the reaction vessel as an effluent; and
3. a process for preferentially producing a Z-isomer of a hydrogen bromide salt of a 2-aminothiazole derivative of the formula (IV) as defined above,
which process comprises:
reacting thiourea and a 2-alkylidene-4-bromoacetoacetic ester of the formula (V) as defined above, wherein the reaction temperature of the reaction is maintained at a temperature of −10 to +45° C. and the reaction time Rt of the reaction is defined by the following inequality:
60
e
(−0.15T)≦Rt≦
180
e
(−0.1T)
,
wherein “T” means a reaction temperature.
In the present invention the term “Rt” stands for both “Reaction Time” (when reference a batch reaction in a reaction vessel), and “Residence Time” (when reference continuous reaction in a reaction vessel).
DESCRIPTION OF THE PREFERRED EMBODIMENTS
First, a description will be made to the first aspect of the present invention drawn to the process for producing an acid salt of a (Z)-2-aminothiazole compound of the formula (I), which process comprises reacting an acid salt of a 2-aminothiazole compound of the formula (II) with an inorganic acid of the formula (III).
Examples of the lower alkyl group having 1 to 5 carbon atoms for R
1
and R
2
of the formulae (I), (II) and (VI) each independently include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, a n-pentyl group and a neopentyl group.
Examples of the lower alkyl group having 1 to 5 carbon atoms for R
1
and R
2
of the formulae (IV) and (V) described for the second aspect of the present invention also include the same as described above.
The group Y in the acid salt of the (Z)-2-aminothiazole compound of the formulae (I) and (III) represents a halogen atom such as chlorine, bromine and the like, or represents —OSO
3
H or —OPO(OH)
2
.
The X in the acid salt of the 2-aminothiazole compound of the formula (II) represents a bromine atom or an iodine atom.
Examples of the acid salt of the 2-aminothiazole compound of the formula (II) include hydrogen bromide salts or hydrogen iodide salts of the following compounds:
methyl 2-(2-aminothiazole-4-yl)-2-butenoate,
ethyl 2-(2-aminothiazole-4-yl)-2-butenoate,
n-propyl 2-(2-aminothiazole-4-yl)-2-butenoate,
isopropyl 2-(2-aminothiazole-4-yl)-2-butenoate,
n-butyl 2-(2-aminothiazole-4-yl)-2-butenoate,
t-butyl 2-(2-aminothiazole-4-yl)-2-butenoate,
n-pentyl 2-(2-aminothiazole-4-yl)-2-butenoate,
methyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
ethyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
n-propyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
isopropyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
n-butyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
t-butyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
n-pentyl 2-(2-aminothiazole-4-yl)-2-pentenoate,
methyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
ethyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
n-propyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
isopropyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
n-butyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
t-butyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
n-pentyl 2-(2-aminothiazole-4-yl)-2-hexenoate,
methyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
ethyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
n-propyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
isopropyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
n-butyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
t-butyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
n-pentyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,
methyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
ethyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
n-propyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
isopropyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
n-butyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
t-butyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
n-pentyl 2-(2-aminothiazole-4-yl)-2-heptenoate,
methyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
ethyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
n-propyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
isopropyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
n-butyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
t-butyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
n-pentyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,
methyl 2-(2-aminothiazole-4-yl)-2-octenoate,
ethyl 2-(2-aminothiazole-4-yl)-2-octenoate,
n-propyl 2-(2-aminothiazole-4-yl)-2-octenoate,
isopropyl 2-(2-aminothiazole-4-yl)-2-octenoate,
n-butyl 2-(2-aminothiazole-4-yl)-2-octenoate,
t-butyl 2-(2-aminothiazole-4-yl)-2-octenoate and
n-pentyl 2-(2-aminothiazole-4-yl)-2-octenoate,
and mixtures of two or more of these acid salts.
Z-isomer rich hydrogen bromide salts of the above-described 2-aminothiazole derivative are preferably used in the present process and can be obtained by a known method or by the methods of the present invention described below.
Examples of the inorganic acid of the formula (III) include hydrogen halide such as hydrogen chloride and hydrogen bromide, sulfuric acid, phosphoric acid, and the like. Preferred are hydrogen chloride and hydrogen bromid
Aratake Yuichiro
Hirata Norihiko
Kurimoto Isao
Nakamura Akihiko
Birch & Stewart Kolasch & Birch, LLP
Gerstl Robert
Sumitomo Chemical Co,. Ltd.
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