Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-23
2002-01-01
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S174000, C546S176000, C546S180000
Reexamination Certificate
active
06335449
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing the quinoline derivative represented by formula (3) which can be a useful intermediate of cholesterol reducing agents (HMG-CoA reductase inhibitors)
BACKGROUND ART
The quinoline compound represented by formula (4) is disclosed in JP-A-1-279866, EP-A-304063 and U.S. Pat. No. 5,011,930 as a useful cholesterol reducing agent (HMG-CoA reductase inhibitor).
The quinoline compound represented by formula (4) is obtained in the above-mentioned patents as shown below by converting the aldehyde compound (2) into the &agr;,&bgr;-unsaturated carboxylic acid ester compound (5) followed by reduction into the alcohol compound (6) and oxidation into the desired quinoline compound (3). Though direct reduction of the &agr;,&bgr;-unsaturated carboxylic acid ester compound into the desired quinoline compound (3) would improve production efficiency, the problem is the difficulty of its control.
DISCLOSURE OF THE INVENTION
As a result of their extensive research to solve the above-mentioned problem, the present inventors found one-step preparation of the desired quinoline compound (3) via the nitrile compound (1) obtained by reacting the aldehyde compound represented by formula (2) with diethyl cyanomethylphosphonate.
Namely, the present invention relates to a process for producing the quinoline derivative (3) via the nitrile compound (1) obtained by reacting the aldehyde compound represented by formula (2) with diethyl cyanomethylphosphonate and its intermediate (1).
One-step preparation of the desired quinoline compound (3) can be attained via the nitrile compound (formula (1)) obtained by reacting the aldehyde compound represented by formula (2) with diethyl cyanomethylphosphonate.
BEST MODE FOR CARRYING OUT THE INVENTION
Now, the process of the present invention will be described.
Preparation of Nitrile Compound (1)
As the solvent used in the reaction, an aromatic hydrocarbon such as toluene or xylene, an ethereal solvent such as tetrahydrofuran or dioxane or a halogenated solvent such as dichloroethane or o-dichlorobenzene may be mentioned.
From 0.5 to 5 times as many moles, preferably from 0.9 to 1.5 times as many moles, of diethyl cyanomethylphosphonate is used.
A base such as sodium hydride, sodium hydroxide, potassium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide or potassium carbonate may be used in an amount of from 0.5 to 10 times as many moles, depending on the solvent and the type of the base. A phase transfer catalyst such as Aliquat 336 may be used optionally, for example, when toluene as the solvent is combined with (aqueous) sodium hydroxide as the base.
The reaction temperature is within the range of from −20 to 80° C., preferably within the range of from 20 to 40° C.
Preparation of Quinoline Derivative (3)
Use of diisobutylaluminum hydride as a reducing agent and an aromatic hydrocarbon such as toluene or xylene as the solvent in the reaction gives good results. Diisobutylaluminum hydride is used in an amount of from 0.5 to 5 times as many moles, preferably from 0.9 to 1.5 times as many moles, and the reaction temperature is within the range of from −50 to 50° C., preferably within the range of from −30 to 5° C. Reduction with Raney nickel in formic acid as the solvent is also available.
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patent: 5856336 (1999-01-01), Fujikawa et al.
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patent: 3905908 (1990-09-01), None
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U.S. application No. 09/436,789, filed Nov. 8, 1999, pending.*
U.S. application No. 09/743,810, filed Jan. 22, 2001, pending.*
U.S. application No. 09/764,994, filed Jan. 23, 2001, pending.
Ohara Yoshio
Suzuki Mikio
Takada Yasutaka
Yanagawa Yoshinobu
Nissan Chemical Industries Ltd.
Seaman D. Margaret
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