Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2001-02-20
2002-09-17
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S411000, C568S425000, C568S812000, C568S768000, C560S226000, C560S227000, C560S229000, C560S254000
Reexamination Certificate
active
06452056
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for producing fluorine-containing benzyl derivatives useful as synthesis intermediates for pharmaceutical drugs and agricultural chemicals. Particularly, the present invention provides a novel production process to produce a fluorine-containing benzylamine derivative, a fluorine-containing benzyl alcohol derivative and a fluorine-containing benzyl ester derivative, with a high purity and a high yield, under industrially advantageous operation conditions in short steps. The present invention further provides a novel fluorine-containing benzyl ester derivative useful as an intermediate for pharmaceutical drugs and agricultural chemicals.
2. Background Art
Heretofore, as a process for producing benzyl alcohol employing benzonitrile as a starting material, the following processes have been disclosed:
(1) A process to obtain benzyl alcohol by converting the nitrile group to a carboxylic acid group, followed by a reduction reaction by using lithium aluminum hydride as a reducing agent.
(2) A process to obtain benzyl alcohol, by converting the nitrile group to a formyl group, followed by reduction.
Further, as a process for producing a benzylamine derivative by reducing a benzonitrile derivative, the following processes have been disclosed:
(3) A process for reducing 2-methylbenzonitrile by lithium aluminum hydride (J. Am. Chem. Soc., Vol. 70, 3738 (1948)).
(4) A process for reducing benzonitrile with sodium borohydride and aluminum chloride (J. Am. Chem. Soc., Vol. 78, 2582 (1956))
(5) A process for reducing m-nitrobenzonitrile with sodium borohydride and boron trifluoride (J. Am. Chem. Soc., Vol. 82, 681 (1960)).
(6) A process to obtain 2,6-difluorobenzylamine, by reacting 2,6-difluorobenzonitrile by using sodium borohydride and dimethyl sulfate in tetrahydrofuran (JP-A-7-53476).
However, in the above-mentioned processes, the following problems have been confirmed.
Lithium aluminum hydride to be used in the processes (1) and (3) is inflammable, its handling is thereby difficult, and it is not suitable for an industrial production with a large capacity. In the process (2), the yield of benzaldehyde is poor, whereby there is a problem to employ the process as an industrial production method. Boron trifluoride to be used in the process (5) and dimethyl sulfate to be used in the process (6) are difficult to handle, whereby they are not suitable for an industrial production with a large capacity. Further, sodium borohydride to be used as a reducing agent in the processes (4), (5) and (6), is relatively expensive, and such is economically disadvantageous for the industrial application. Further, in said processes, a large amount of boron compounds which will be industrial waste, will form due to the reaction, such being problematic.
DISCLOSURE OF THE INVENTION
The present inventors have conducted extensive studies to overcome the above-mentioned problems, and as a result, they have found a novel production route and production process to produce a fluorine-containing benzylamine derivative, a fluorine-containing benzyl alcohol derivative and a fluorine-containing benzyl ester derivative, in short steps with a high yield and with a high purity. Further, the present inventors have found a novel compound as an intermediate for pharmaceutical drugs and agricultural chemicals.
Namely, the present invention provides a process for producing a fluorine-containing benzyl alcohol derivative represented by the following general formula (3), which comprises subjecting a fluorine-containing benzonitrile derivative represented by the following general formula (1) to a reduction reaction to obtain a fluorine-containing benzylamine derivative represented by the following general formula (2), and replacing the amino group in said fluorine-containing benzylamine derivative with a hydroxyl group:
wherein X is a halogen atom, when m is an integer of 2 or more, each X may be the same or different, and m is an integer of from 0 to 4.
Further, the present invention provides a process for producing a fluorine-containing benzyl ester derivative represented by the following general formula (5) and a fluorine-containing benzyl alcohol derivative represented by the following general formula (3), which comprises subjecting a fluorine-containing benzonitrile derivative represented by the following general formula (1) to a reduction reaction to obtain a fluorine-containing benzylamine derivative represented by the following general formula (2), and reacting said fluorine-containing benzylamine derivative with a carboxylic acid compound represented by the following general formula (4) and an alkali nitrite:
wherein X is a halogen atom, when m is an integer of 2 or more, each X may be the same or different, m is an integer of from 0 to 4, and R is a linear alkyl group which may have a substituent, or a branched alkyl group which may have a substituent.
Still further, the present invention provides a 2,6-difluorobenzyl ester represented by the following general formula (5A):
wherein R is a linear alkyl group which may have a substituent, or a branched alkyl group which may have a substituent.
In the present specification, the fluorine-containing benzonitrile derivative represented by the general formula (1), the fluorine-containing benzylamine derivative represented by the general formula (2), the fluorine-containing benzyl alcohol represented by the general formula (3), the carboxylic acid compound represented by the general formula (4) and the fluorine-containing benzyl ester derivative represented by the general formula (5) are referred to as compound (1), compound (2), compound (3), compound (4) and compound (5), respectively.
The compound (1) is commercially available, and it is a compound readily available. X in the compound (1) is a halogen atom, and the bonding position is not limited. As said halogen atom, a fluorine atom, a chlorine atom or a bromine atom may be mentioned, and a fluorine atom is preferred.
In the compound (1), m represents the number of X, and is an integer of from 0 to 4. When m is 0, no X is present. Further, when m is an integer of 2 or more, each X may be the same or different. The structure of the compound (1) may optionally be changed depending upon the structure of the desired compound. As the compound (1), a commercially available one as a reagent, or one available for industrial use, can directly be used, and the purity is not particularly limited.
As specific examples of the compound (1), the following compounds may be mentioned.
2-fluorobenzonitrile, 2,3-difluorobenzonitrile, 2,4-difluorobenzonitrile, 2,5-difluorobenzonitrile, 2,6-difluorobenzonitrile, 2,3,4-trifluorobenzonitrile, 2,3,5-trifluorobenzonitrile, 2,3,6-trifluorobenzonitrile, 2,4,5-trifluorobenzonitrile, 2,4,6-trifluorobenzonitrile, 2,3,4,5-tetrafluorobenzonitrile, 2,3,4,5,6-pentafluorobenzonitrile, 3-fluorobenzonitrile, 3,4-difluorobenzonitrile, 3,5-difluorobenzonitrile, 3,4,5-trifluorobenzonitrile, 4-fluorobenzonitrile, 3-chloro-2-fluorobenzonitrile, 4-chloro-2-fluorobenzonitrile, 5-chloro-2-fluorobenzonitrile, 2-chloro-6-fluorobenzonitrile, 3-bromo-2-fluorobenzonitrile, 4-bromo-2-fluorobenzonitrile, 5-bromo-2-fluorobenzonitrile, 2-bromo-6-flubrobenzonitrile, 3,4-dichloro-2,6-difluorobenzonitrile, etc.
As the compound (1), in view of usefulness of the desired compound, reactivity or the like, a compound represented by the following general formula (6) wherein a fluorine atom is attached to the 2-position and a halogen atom (X
1
) is attached to the 6-position:
wherein each of X
1
and X
2
which are the same or different is a halogen atom, provided that when n is 2 or 3 in the compound (6), the plurality of X
2
may be the same or different, and n is an integer of from 0 to 3.
As specific examples of the compound (6), the following compounds may be mentioned.
2,6-difluorobenzonitrile, 2,3,6-trifluorobenzonitrile, 2,4,6-trifluorobenzonitrile, 2,3,4,5,6-pentafluorobenzonitrile, 2-chloro-6-fluorobenzonitrile, 2-bromo-6-fluo
Kawanobe Tsuneo
Takazawa Osamu
Watanabe Hiroyuki
Yoshikawa Keisuke
Asahi Glass Company Limited
Killos Paul J.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Reyes Hector
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