Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-07
2003-02-04
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S290000, C546S340000, C514S345000, C514S354000
Reexamination Certificate
active
06515134
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method of producing optically active beta-3 adrenaline receptor agonist intermediates which are important in producing medicinals, and to those important intermediates.
BACKGROUND ART
Known in the art for the production of optically active dihydroxyethylpyridine derivatives or optically active oxirane derivatives which are intermediates of optically active beta-3 adrenaline receptor agonists and are represented by the general formula (14):
in the formula, X represents a hydrogen, a halogen, an acyloxy group containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, an amino group or a substituted amino group; or by the general formula (16):
in the formula, X is as defined above, are:
(i) the process which involves the catalytic asymmetric dihydroxylation reaction of vinylpyridine derivatives (WO9821184),
(ii) the process which involves the asymmetric reduction of halo acetylpyridine derivatives with diisopinocamphenylborane chloride (U.S. Pat. No. 556142, U.S. Pat. No. 5714506), and (iii) the process which involves the asymmetric reduction of aminoacetylpyridine derivatives using a microorganism (WO9803672).
However, the process (i) uses highly toxic osmium oxide and further requires an expensive asymmetric ligand, hence have problems from the industrial utilization viewpoint.
The process (ii) requires the use of a stoichiometric amount of diisopinocamphenylborane chloride, which is an expensive asymmetric reducing agent, hence has a problem from the commercial viewpoint. Further, the halo acetylpyridine derivative unsubstituted or substituted by chlorine in position 2, which is used as the substrate for asymmetric reduction, is produced by halogenation of the methyl group of the corresponding methyl ketone. However, the methyl ketone is difficult to obtain and it is necessary to synthesize the same using diazomethane, which is difficult to handle on an industrial scale because of its toxicity and explosiveness.
The process (iii) is only applicable to derivatives having no substituent on the pyridine ring [namely compounds of the general formula (7) or (9) shown below in which X is a hydrogen] and there is no disclosure about the method of producing pyridine derivatives substituted in position 2 such as 2-amino pyridine derivatives.
Those substituted acetylpyridine derivatives substituted by an amino group in position 2 which are represented by the general formula (1):
in the formula, R
1
and R
2
each independently represents a hydrogen, an alkyl group containing 1 to 10 carbon atoms, an aralkyl group containing 1 to 10 carbon atoms, an acyl group containing 1 to 10 carbon atoms, or an alkyloxycarbonyl group containing 1 to 10 carbon atoms and Y
1
represents a halogen, a hydroxyl group, an acyloxy group containing 1 to 10 carbon atoms, a sulfonyloxy group containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, an amino group, an alkylamino group containing 1 to 15 carbon atoms, an aralkyl amino group containing 1 to 15 carbon atoms, a sulfanyl group, an alkyl sulfanyl group containing 1 to 10 carbon atoms, or an aralkyl sulfanyl group containing 1 to 10 carbon atoms, are expected to be important compounds in the production of intermediates of optically active beta-3 adrenaline receptor agonists. However, they are unknown in the literature.
Those pivaloyloxyacetylpyridine derivatives represented by the general formula (2):
in the formula, X represents a hydrogen, a halogen, a hydroxyl group, an acyloxy group containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, an amino group or a substituted amino group, are also expected to be important compounds in the production of intermediates of optically active beta-3 adrenaline receptor agonists. They are, however, unknown in the literature.
Further, those optically active pivaloyloxy-hydroxyethyl derivatives represented by the general formula (3):
in the formula, X represents a hydrogen, a halogen, a hydroxyl group, an acyloxy group containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, an amino group or a substituted amino group, are also expected to be important compounds in the production of intermediates of optically active beta-3 adrenaline receptor agonists. They are, however, unknown in the literature.
Furthermore, those optically active dihydroxy-ethylpyridine derivatives represented by the formula (4):
or a salt thereof is also expected to be an important compound in the production of intermediates of optically active beta-3 adrenaline receptor agonists. It is, however, unknown in the literature.
SUMMARY OF INVENTION
In view of the current state of the art as mentioned above, it is an object of the invention to produce an optically active dihydroxyethylpyridine derivative and an optically active oxirane derivative, which is an important intermediate in producing an optically active beta-3 adrenaline receptor agonist (as described, for example, in WO9821184 and U.S. Pat. No. 5,561,142) represented by the following general formula (17):
which can readily be converted to the above-mentioned compounds (17) by expedient methods known in the art, from readily available raw materials in a safe and efficient manner and, further, in an industrially advantageous manner.
Thus, the present invention provides a substituted acetylpyridine derivative substituted by an amino group in position 2 which is represented by the general formula (1):
in the formula, R
1
and R
2
each independently represents a hydrogen, an alkyl group containing 1 to 10 carbon atoms, an aralkyl group containing 1 to 10 carbon atoms, an acyl group containing 1 to 10 carbon atoms or an alkyloxycarbonyl group containing 1 to 10 carbon atoms and Yl represents a halogen, a hydroxyl group, an acyloxy group containing 1 to 10 carbon atoms, a sulfonyloxy group containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, an amino group, an alkylamino group containing 1 to 15 carbon atoms, an aralkyl amino group containing 1 to 15 carbon atoms, a sulfanyl group, an alkyl sulfanyl group containing 1 to 10 carbon atoms or an aralkyl sulfanyl group containing 1 to 10 carbon atoms.
The invention further provides a pivaloyloxy-acetylpyridine derivative represented by the general formula (2):
in the formula, X represents a hydrogen, a halogen, or a hydroxyl group, an acyloxy group containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, an amino group or a substituted amino group.
The invention further provides an optically active pivaloyloxyhydroxyethylpyridine derivative represented by the general formula (3):
in the formula, X represents a hydrogen, a halogen, a hydroxyl group, an acyloxy group containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, an amino group or a substituted amino group.
The invention also provides an optically active dihydroxyethylpyridine derivative represented by the formula (4):
or a salt thereof.
The invention further provides a production method of a substituted acetylpyridine derivative represented by the general formula (7):
in the formula, Y
2
represents a halogen and X represents a hydrogen, a halogen, a hydroxyl group, an acyloxy group containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, an amino group or a substituted amino group,
which comprises reacting, with a base, a haloacetic acid derivative represented by the general formula (5):
in the formula, Y
2
is as defined above and Z represents a hydrogen, an alkali metal, a halogenated alkaline earth metal or a silyl group containing 1 to 10 carbon atoms,
to prepare an enolate,
reacting the same with a substituted nicotinic acid ester represented by the general formula (6):
in the formula, X is as defined above and R
3
represents an alkyl group containing 1 to 10 carbon atoms or an aralkyl group containing 1 to 10 carbon atoms,
and then subjecting the reaction product to acid treatment.
The invention further provi
Amano Susumu
Inoue Kenji
Mitsuda Masaru
Taoka Naoaki
Armstrong Westerman & Hattori, LLP
Desai Rita
Rotman Alan L.
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