Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-19
2003-03-18
Berch, Mark (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S153000, C546S209000, C546S269100, C548S110000, C544S319000, C544S171000
Reexamination Certificate
active
06534658
ABSTRACT:
TECHNICAL FIELD
The invention relates to oxadiazole derivatives useful as intermediates for producing pharmaceuticals, a process for producing the same, and a process for producing 1,3,4-oxadiazole derivatives by using the intermediate.
More specifically, the invention relates to
(1) a compound represented by formula (I):
(wherein all symbols have the same meanings as described below), a non-toxic salt thereof, and a hydrate thereof;
(2) a process for producing the same, and
(3) a process for producing a compound represented by formula (II):
(wherein all symbols have the same meanings as described below), comprising using the same.
BACKGROUND ART
WO9824806 discloses that a compound represented by formula (W-a):
a compound represented by formula (W-b):
and a compound represented by formula (W-c):
(wherein X
w
and Y
w
independently represent an oxygen atom, a sulfur atom or a nitrogen atom which may be substituted; R
1w
represents various substituents, such as an alkyl group which may be substituted, a hydroxyl group, and an amino group; R
2w
and R
3w
independently represent a hydrogen atom or various substituents, such as an alkyl group which may be substituted; A
w
represents a single bond, a —CO— group, an —NHCO— group, an —SO
2
— group, or the like; R
4w
represents a hydrogen atom or various substituents, such as an alkyl group which may be substituted; B
w
represents an —SO
2
— group, a —CO— group, or the like; and R
11w
, R
12w
, and E
w
are taken together to form a ring, with the proviso that these definitions are abstracts from the disclosure are useful as a serine protease (especially an elastase) inhibitor.
Upon reviewing the specification in detail, it discloses a compound represented by formula (W-c-1):
(wherein R
1w
has the same meaning as described above) among the compounds represented by general formula (W-c).
In the specification, various inhibitors are prepared using, as a key intermediate, a compound represented by formula (W-1):
(wherein R
1w
has the same meaning as described above). According to the specification, the compound represented by formula (W-1) is produced in accordance with reaction scheme 1 or 2 shown below.
In reaction scheme 1, “Cbz” stands for a benzyloxycarbonyl group; “Py”, pyridine; “TEA”, triethylamine; “DMSO”, dimethyl sulfoxide; “Ac
2
O”, acetic anhydride; “EDC”, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride; “HOBt”, 1-hydroxybenzotriazole; “DMF”, dimethylformamide; “NMM”, N-methylmorpholine; “Ts”, a tosyl group; “TFA”, trifluoroacetic acid; “Me”, a methyl group; and “Et”, an ethyl group.
In reaction scheme 2, “Boc” stands for a t-butoxycarbonyl group; “iBu”, an isobutyl group; “DIBAL”, diisobutylaluminum hydride; and “n-BuLi”, n-butyl lithium. Other symbols have the same meanings as described above.
The specification also discloses that the compound represented by formula (W-c-1) among the compounds represented by formula (W-c) is produced using the compound represented by formula (W-1) in accordance with reaction scheme 3 shown below.
In reaction scheme 3, “T
2w
” represents a hydrogen atom or a benzyloxycarbonylamino group, and other symbols are as defined above. The oxidation using the Dess-Martin reagent and the Swern oxidation are known oxidations.
The process according to reaction scheme 1 involves a number of steps (10 steps) for producing the compound represented by formula (W-1) so that it is insufficient in efficiency.
The present inventors have conducted extensive studies seeking an efficient process for producing the compounds represented by formula (W-c-1) that are promising as pharmaceuticals. As a result, they have found a process for producing the compound represented by formula (II) shown in reaction scheme 4, in which novel compounds represented by formulae (I-1) and (I-2), namely, the compounds represented by formula (I) are used as a key intermediate.
In reaction scheme 4, R
2
, R
3
and R
4
each independently represents:
(1) a C
1-8
alkyl group,
(2) a C
3-7
cycloalkyl group,
(3) a phenyl group,
(4) a phenyl group substituted with one to three of a C
1-8
alkyl group, a C
1-8
alkoxy group, a halogen atom, a trifluoromethyl group, and a trifluoromethoxy group, or
(5) a 3,4-methylenedioxyphenyl group; or
(6) R
3
and R
4
are taken together to represent a C
2-6
alkylene group; and
R
5
and R
6
each independently represents an amino-protective group.
The inventors have experimented the conventional processes shown in reaction schemes 2 and 3 to find that the overall synthesis yield of a compound represented by formula (II) in which R
2
, R
3
and R
4
all represent a methyl group was 18% through six steps (see Comparative Examples described below, in which a compound represented by formula (W-XI) was used as a starting material.). In the Comparative Examples, the Swern oxidation was used as an oxidation to produce a compound represented by formula (W-XVII).
According to the process of the invention shown in reaction scheme 4, on the other hand, the overall synthesis yield of a compound represented by formula (II) wherein R
1w
is a t-butyl group was 65% through four steps (see Examples described below). In the Examples, a t-butoxycarbonyl group was used as an amino-protective group R
5
in the compound represented by formulae (V) and the compound represented by formula (I-2), and a benzyloxycarbonyl group was used as an amino-protective group R
6
in the compound represented by formula (IV) and the compound represented by formula (III).
Hence, the process of the invention makes it possible to obtain the compound represented by formula (II) through fewer steps in a higher yield. In other words, the process of the invention provides a desired compound through steps less by two in a three- to four-fold yield.
The present inventors have found that the compound represented by formula (II) can be prepared efficiently by the process represented by reaction scheme 4 which uses the novel compounds represented by formula (I) and thus completed the present invention.
DISCLOSURE OF THE INVENTION
The present invention relates to
1) a compound represented by general formula (I):
(wherein
R
1
represents a hydrogen atom or an amino-protective group;
R
2
, R
3
and R
4
each independently represents
(1) a C
1-8
alkyl group,
(2) a C
3-7
cycloalkyl group,
(3) a phenyl group,
(4) a phenyl group substituted with one to three of a C
1-8
alkyl group, a C
1-8
alkoxy group, a halogen atom, a trifluoromethyl group, and a trifluoromethoxy group, or
(5) a 3,4-methylenedioxyphenyl group; or
(6) R
3
and R
4
are taken together to represent a C
2-6
alkylene group), a non-toxic salt thereof, and a hydrate thereof,
2) a process for producing the compound represented by formula (I), and
3) a process for producing a compound represented by formula (II):
(wherein all symbols have the same meanings as described above), comprising using the compound represented by formula (I).
The term “C
1-8
alkyl group” as used herein means a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl group or an isomer thereof.
The term “C
3-7
cycloalkyl group” as used herein means a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.
The term “C
1-8
alkoxy group” as used herein means a methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy or octyloxy group or an isomer thereof.
The term “halogen atom” as used herein means fluorine, chlorine, bromine or iodine.
The term “C
2-6
alkylene group” as used herein means an ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene group.
The amino-protective group represented by R
1
, R
5
or R
6
in the invention includes a benzyloxycarbonyl group, a t-butoxycarbonyl group, a trifluoroacetyl group and the like, but is not limited thereto, so long as it is a group which is easily and selectively removable. For example, those described in T. W. Greene,
Protective Groups in Organic Synthesis,
Wiley, New York (1991) are useful, such as methoxycarbonyl, ethoxycarbonyl, 9-fluorenylmethyloxycarbon
Hachiya Katsutoshi
Kojima Tsutomu
Ohmoto Kazuyuki
Berch Mark
Habte Kahsay
Ono Pharmaceutical Co. Ltd.
LandOfFree
1,3,4-oxadiazole derivatives and process for producing the same does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 1,3,4-oxadiazole derivatives and process for producing the same, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 1,3,4-oxadiazole derivatives and process for producing the same will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3033965