Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
1998-05-19
2001-01-23
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
Reexamination Certificate
active
06177587
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a industrially useful production method of an aminobenzene compound represented by the formula (IV) shown below which is of value as synthetic intermediates for the production of medicines.
BACKGROUND OF THE INVENTION
In Japanese Patent Laid-open Publication No. 364171/1992 (EP-A-459136), it is disclosed that benzimidazole derivatives including 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate, which have AII (angiotensin II) antagonizing activity and anti-hypertensive activity and which are of value as a therapeutic drug for circulatory diseases such as hypertension, heart diseases (e.g. heart hypertrophy, heart failure, myocardial infarction, etc.), cerebral stroke, nephritis, etc., and it is described that a compound represented by the formula (IV), which is important as a synthetic intermediate of the benzimidazole derivatives, is produced by the reaction of an aminobenzoate derivative represented by the formula (III) shown below with a mono-halogenoalkylbiphenyl compound (4-bromomethylbiphenyl (BMB), etc.) represented by the formula (II) shown below. Also, in Japanese Patent Laid-open Publication No. 192170/1994 (EP-A-553879), it is described that 4-bromomethylbiphenyl (BMB) is produced by brominating 4-methylbiphenyl (MPB) in the presence of an azobis compound.
According to a known production method of a compound or a salt thereof represented by the formula (II), it was believed that it was advantageous to isolate and purify a final product which was used as a material of a drug, since a perhalogenated compound represented by the formula (II′) shown below was produced in the yield of about 10-20% at the time of halogenation of a compound or a salt thereof represented by the formula (I) shown below. Therefore, it was essential to increase purity (usually more than 99%) of a compound or a salt thereof represented by the formula (II) by crystallizing said compound after the halogenating reaction. In addition, in order to recover loss while crystallizing the first crystals and to raise purification effect, it was necessary to isolate the second crystals from mother liquor and dry after isolating and drying the first crystals. So far, the thus purified compound or a salt thereof represented by the formula (II) has been used as a material in the next steps. However, according to the above method, it was necessary to isolate the crystallized compound or a salt thereof represented by the formula (II) by a centrifuge, etc. and thereafter to dry by a drier, etc.
On the other hand, a compound or a salt thereof represented by the formula (II) is useful as an intermediate compound for producing a drug such as anti-hypertensive agent. However, since a compound of the formula (II) wherein R
1
is a cyano group, X is a direct bond and Y is a bromine atom is recognized to be strongly mutagenic and cause chromosomal aberrations, it was necessary to prevent the compound of the formula (II) from being exposed to workers producing the compound of the formula (II) and the environment.
According to a known method for producing a compound or a salt thereof represented by the formula (II), in order to prevent an isolated and purified compound or a salt thereof represented by the formula (II) from being exposed to the environment, a plant for producing said compound must be kept in isolation and, in order to prevent an isolated and purified compound or a salt thereof represented by the formula (II) from being exposed to the workers producing said compound, it was necessary to install an airtight centrifuge and drier, etc. However, it is very disadvantageous in view of industrial production to install such a special apparatus, etc. Moreover, according to a known method for producing a compound or a salt thereof represented by the formula (II), yield from a compound or a salt thereof represented by the formula (I) to a compound or a salt thereof represented by the formula (IV) is low and therefore not satisfactory as an industrial production method.
OBJECT OF THE INVENTION
The production method of the present invention is to provide an industrially advantageous method for producing a compound or a salt thereof represented by the formula (IV) by subjecting a compound or a salt thereof represented by the formula (I) to halogenation reaction and reacting the obtained reaction mixture with a compound or a salt thereof represented by the formula (III) without isolating or purifying a compound or a salt thereof represented by the formula (II).
SUMMARY OF THE INVENTION
The present inventors found that when a reaction mixture containing a compound or a salt thereof represented by the formula (II′) and a compound or a salt thereof represented by the formula (II), which are obtained by halogenating reaction of a compound or a salt thereof represented by the formula (I), is subjected to reaction with a compound or a salt thereof represented by the formula (III), a compound or a salt thereof represented by the formula (II′) does not react with a compound or a salt thereof represented by the formula (III) and that a compound or a salt thereof represented by the formula (IV) is selectively produced. Moreover, they found that when a compound or a salt thereof represented by the formula (IV) wherein R
3
is hydrogen atom, which is obtained by subjecting a compound or a salt thereof represented by the formula (IV) to hydrolysis reaction with a mineral acid such as hydrochloric acid, etc., is crystallized and a compound or a salt thereof represented by the formula (II′) is removed in a mother liquor. Since a compound or a salt thereof represented by the formula (II′) which does not react with a compound or a salt thereof represented by the formula (I) is easily removed, a compound or a salt thereof represented by the formula (IV) can be synthesized at a low price, in a good yield and advantageously in view of an industrial production without isolating and purifying a compound or a salt thereof represented by the formula (II), that is, without exposing a compound or a salt thereof represented by the formula (II) to the workers and environment. According to these findings, the present inventors have completed the present invention.
The present invention relates to
(1) a method for producing an aminobenzene compound of the formula (IV):
wherein the ring A is a benzene ring which may have an optional substituent in addition to the group R
2
, the nitro group and the group of the formula:
R
1
is a group capable of forming an anion or transformable thereinto;
R
2
is a group capable of forming an anion or transformable thereinto;
R
3
is an acyl group; and
X is a chemical bond or a spacer having a chain length of 1 to 2 atoms as the linear moiety between the adjoining phenylene group and phenyl group; or a salt thereof, which comprises reacting a mixture containing
(i) a mono-halogeno compound of the formula (II):
wherein Y is a halogen atom and the other symbols are as defined above, or a salt thereof and
(ii) a di-halogeno compound of the formula (II′):
wherein each symbol is as defined above, or a salt thereof with a compound of the formula (III):
wherein the ring A is a benzene ring which may have an optional substituent in addition to the group R
2
, the nitro group and the group of the formula: —NHR
3
and the other symbols are as defined above, or a salt thereof;
(2) a method of the above (1), wherein said reaction is carried out in acetonitrile;
(3) a method according (1), wherein the mixture is a reaction mixture which is obtained by subjecting a compound of the formula (I):
wherein R
1
is a group capable of forming an anion or transformable thereinto; and X is a chemical bond or a spacer having a chain length of 1 to 2 atoms as the linear moiety between the adjoining phenylene group and phenyl group; or a salt thereof to halogenation;
(4) a method of the above (1), wherein Y is a bromine atom
Hanaoka Tadashi
Hashimoto Hideo
Kato Masayasu
Kifle Bruck
Shah Mukund J.
Takeda Chemical Industries Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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