U.S. patent application number 10/346136 was filed with the patent office on 2003-08-14 for 1,3,4-oxadiazole derivatives and process for producing the same.
This patent application is currently assigned to ONO PHARMACEUTICAL CO., LTD.. Invention is credited to Hachiya, Katsutoshi, Kojima, Tsutomu, Ohmoto, Kazuyuki.
Application Number | 20030153758 10/346136 |
Document ID | / |
Family ID | 13305090 |
Filed Date | 2003-08-14 |
United States Patent
Application |
20030153758 |
Kind Code |
A1 |
Kojima, Tsutomu ; et
al. |
August 14, 2003 |
1,3,4-Oxadiazole derivatives and process for producing the same
Abstract
Oxadiazole derivatives represented by formula (I): 1 (wherein
R.sup.1 represents a hydrogen atom or an amino-protective group;
R.sup.2, R.sup.3, and R.sup.4 each independently represents an
alkyl group, a cycloalkyl group, a phenyl group which may be
substituted, or a 3,4-methylenedioxyphenyl group, or R.sup.3 and
R.sup.4 are taken together to represent a C.sub.2-6 alkylene
group), a process of producing the same, and a process for
producing oxadiazole derivatives represented by formula (II): 2
(wherein all symbols have the same meanings as described above)
using the above derivative. According to the invention, the
compound represented by formula (II) is produced through fewer
steps in a high yield.
Inventors: |
Kojima, Tsutomu; (Fukui,
JP) ; Hachiya, Katsutoshi; (Fukui, JP) ;
Ohmoto, Kazuyuki; (Osaka, JP) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 Pennsylvania Avenue, NW
Washington
DC
20037-3213
US
|
Assignee: |
ONO PHARMACEUTICAL CO.,
LTD.
|
Family ID: |
13305090 |
Appl. No.: |
10/346136 |
Filed: |
January 17, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10346136 |
Jan 17, 2003 |
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09936331 |
Dec 19, 2001 |
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6534658 |
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09936331 |
Dec 19, 2001 |
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PCT/JP00/01464 |
Mar 10, 2000 |
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Current U.S.
Class: |
544/314 ;
548/143 |
Current CPC
Class: |
C07K 5/06139 20130101;
C07D 271/10 20130101; C07D 413/12 20130101; Y02P 20/55 20151101;
C07K 5/0821 20130101 |
Class at
Publication: |
544/314 ;
548/143 |
International
Class: |
C07D 413/02; C07D
271/12 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 12, 1999 |
JP |
1166065 |
Claims
1. A compound represented by formula (I): 46(wherein R.sup.1
represents a hydrogen atom or an amino-protective group; R.sup.2,
R.sup.3 and R.sup.4 each independently represents (1) a C.sub.1-8
alkyl group, (2) a C.sub.3-7 cycloalkyl group, (3) a phenyl group,
(4) a phenyl group substituted with one to three of a C.sub.1-8
alkyl group, a C.sub.1-8 alkoxy group, a halogen atom, a
trifluoromethyl group, and a trifluoromethoxy group, or (5) a
3,4-methylenedioxyphenyl group; or (6) R.sup.3 and R.sup.4 are
taken together to represent a C.sub.2-6 alkylene group), a
non-toxic salt thereof or a hydrate thereof.
2. The compound according to claim 1, wherein R.sup.1 represents a
hydrogen atom in formula (I), said compound being represented by
formula (I-1): 47(wherein R.sup.2, R.sup.3 and R.sup.4 have the
same meanings as in claim 1).
3. The compound according to claim 1, wherein R.sup.1 represents a
benzyloxycarbonyl group, a t-butoxycarbonyl group or a
trifluoroacetyl group in formula (I), said compound being
represented by formula (I-2): 48(wherein R.sup.5 represents a
benzyloxycarbonyl group, a t-butoxycarbonyl group or a
trifluoroacetyl group; and R.sup.2, R.sup.3 and R.sup.4 have the
same meanings as in claim 1).
4. The compound according to claim 1, wherein R.sup.2, R.sup.3 and
R.sup.4 each independently represents a C.sub.1-8 alkyl group, a
phenyl group or a 3,4-methylenedioxyphenyl group, or R.sup.3 and
R.sup.4 are taken together to represent a C.sub.2-5 alkylene group
in formula (I).
5. The compound according to claim 4, wherein R.sup.2, R.sup.3 and
R.sup.4 each represents a methyl group; R.sup.2 represents a methyl
group, and R.sup.3 and R.sup.4 are taken together to represent an
ethylene group; R.sup.2 and R.sup.3 each represents a methyl group,
and R.sup.4 represents a phenyl group; or R.sup.2 and R.sup.3 each
represents a methyl group, and R.sup.4 represents a
3,4-methylenedioxyphenyl group.
6. The compound according to claim 2, which is (1)
1-(2-t-butyl-1,3,4-oxad- iazol-5-ylcarbonyl)-2-methylpropylamine,
or (2) 1-(2-(.alpha.,.alpha.-dime-
thylbenzyl)-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropylamine.
7. The compound according to claim 3, which is (1) t-butyl
N-(1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)carbamate,
or (2) t-butyl
N-(1-(2-(.alpha.,.alpha.-dimethylbenzyl)-1,3,4-oxadiazol-5-
-ylcarbonyl)-2-methylpropyl)carbamate.
8. A process for producing a compound represented by formula (I-2):
49(wherein symbols in the formula have the same meanings as
described below), comprising reacting a compound represented by
formula (V): 50(wherein R.sup.5 has the same meaning as in claim 3)
with a compound represented by formula (VI): 51(wherein R.sup.2,
R.sup.3, and R.sup.4 have the same meanings as in claim 1).
9. A process for producing a compound represented by formula (I-1)
52(wherein symbols in the formula have the same meanings as
described below), comprising subjecting a compound represented by
formula (I-2): 53(wherein R.sup.2, R.sup.3, R.sup.4 and R.sup.5
have the same meanings as in claim 3) to a deprotection reaction of
the amino-protecting group.
10. A process for producing a compound represented by formula
(III): 54(wherein R.sup.2, R.sup.3, R.sup.4 and R.sup.6 have the
same meanings as described below) comprising subjecting a compound
represented by formula (I-2): 55(wherein R.sup.2, R.sup.3, R.sup.4,
and R.sup.5 have the same meanings as described in claim 3) to a
deprotection reaction of the amino-protecting group, and subjecting
the resulting compound represented by formula (I-1): 56(wherein
symbols in the formula have the same meanings as described above)
to an amidation with a compound represented by formula (IV):
57(wherein R.sup.6 represents an amino-protecting group).
11. A process for producing a compound represented by formula (II):
58(wherein symbols in the formula have the same meanings as
described below), comprising subjecting a compound represented by
formula (I-2): 59(wherein R.sup.2, R.sup.3, R.sup.4, and R.sup.5
have the same meanings as in claim 3) to a deprotection reaction of
the amino-protecting group, reacting the resulting compound
represented by formula (I-1): 60(wherein symbols in the formula
have the same meanings as described above) with a compound
represented by formula (IV), and subjecting the resulting compound
represented by formula (III): 61(wherein R.sup.2, R.sup.3,
R.sup.4.sub.1 and R.sup.6 have the same meanings as in claim 10) to
a deprotection reaction of the amino-protecting group.
Description
TECHNICAL FIELD
[0001] 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.
[0002] More specifically, the invention relates to
[0003] (1) a compound represented by formula (I): 3
[0004] (wherein all symbols have the same meanings as described
below), a non-toxic salt thereof, and a hydrate thereof;
[0005] (2) a process for producing the same, and
[0006] (3) a process for producing a compound represented by
formula (II): 4
[0007] (wherein all symbols have the same meanings as described
below), comprising using the same.
BACKGROUND ART
[0008] WO9824806 discloses that a compound represented by formula
(W-a): 5
[0009] a compound represented by formula (W-b): 6
[0010] and a compound represented by formula (W-c): 7
[0011] (wherein X.sup.w and Y.sup.w independently represent an
oxygen atom, a sulfur atom or a nitrogen atom which may be
substituted; R.sup.1w represents various substituents, such as an
alkyl group which may be substituted, a hydroxyl group, and an
amino group; R.sup.2w and R.sup.3w independently represent a
hydrogen atom or various substituents, such as an alkyl group which
may be substituted; A.sup.w represents a single bond, a --CO--
group, an --NHCO-- group, an --SO.sub.2-- group, or the like;
R.sup.4w represents a hydrogen atom or various substituents, such
as an alkyl group which may be substituted; B.sup.w represents an
--SO.sub.2-- group, a --CO-- group, or the like; and R.sup.11w,
R.sup.12w, and E.sup.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.
[0012] Upon reviewing the specification in detail, it discloses a
compound represented by formula (W-c-1): 8
[0013] (wherein R.sup.1w has the same meaning as described above)
among the compounds represented by general formula (W-c).
[0014] In the specification, various inhibitors are prepared using,
as a key intermediate, a compound represented by formula (W-1):
9
[0015] (wherein R.sup.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.
[0016] In reaction scheme 1, "Cbz" stands for a benzyloxycarbonyl
group; "Py", pyridine; "TEA", triethylamine; "DMSO", dimethyl
sulfoxide; "Ac.sub.2O", 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. 1011
[0017] 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. 12
[0018] 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.
[0019] In reaction scheme 3, "T.sup.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. 13
[0020] 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.
[0021] 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.
[0022] In reaction scheme 4, R.sup.2, R.sup.3 and R.sup.4 each
independently represents:
[0023] (1) a C.sub.1-8 alkyl group,
[0024] (2) a C.sub.3-7 cycloalkyl group,
[0025] (3) a phenyl group,
[0026] (4) a phenyl group substituted with one to three of a
C.sub.1 alkyl group, a C.sub.1-8 alkoxy group, a halogen atom, a
trifluoromethyl group, and a trifluoromethoxy group, or
[0027] (5) a 3,4-methylenedioxyphenyl group; or
[0028] (6) R.sup.3 and R.sup.4 are taken together to represent a
C.sub.2-6 alkylene group; and
[0029] R.sup.5 and R.sup.6 each independently represents an
amino-protective group. 14
[0030] 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.sup.2, R.sup.3 and R.sup.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).
[0031] 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.sup.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.sup.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.sup.6 in the compound represented by formula (IV) and the
compound represented by formula (III).
[0032] 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.
[0033] 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
[0034] The present invention relates to
[0035] 1) a compound represented by general formula (I): 15
[0036] (wherein R.sup.1 represents a hydrogen atom or an
amino-protective group; R.sup.2, R.sup.3 and R.sup.4 each
independently represents
[0037] (1) a C.sub.1-8 alkyl group,
[0038] (2) a C.sub.3-7 cycloalkyl group,
[0039] (3) a phenyl group,
[0040] (4) a phenyl group substituted with one to three of a
C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a halogen atom, a
trifluoromethyl group, and a trifluoromethoxy group, or
[0041] (5) a 3,4-methylenedioxyphenyl group; or
[0042] (6) R.sup.3 and R.sup.4 are taken together to represent a
C.sub.2-6 alkylene group), a non-toxic salt thereof, and a hydrate
thereof,
[0043] 2) a process for producing the compound represented by
formula (I), and
[0044] 3) a process for producing a compound represented by formula
(II): 16
[0045] (wherein all symbols have the same meanings as described
above), comprising using the compound represented by formula
(I).
[0046] The term "C.sub.1-8 alkyl group" as used herein means a
methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl group
or an isomer thereof.
[0047] The term "C.sub.3-7 cycloalkyl group" as used herein means a
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl
group.
[0048] The term "C.sub.1-8 alkoxy group" as used herein means a
methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy or
octyloxy group or an isomer thereof.
[0049] The term "halogen atom" as used herein means fluorine,
chlorine, bromine or iodine.
[0050] The term "C.sub.2-6 alkylene group" as used herein means an
ethylene, trimethylene, tetramethylene, pentamethylene or
hexamethylene group.
[0051] The amino-protective group represented by R.sup.1, R.sup.5
or R.sup.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.
[0052] The amino-protective group represented by R.sup.1 and
R.sup.5 is preferably a t-butoxycarbonyl group or a
benzyloxycarbonyl group, and more preferably a t-butoxycarbonyl
group.
[0053] The amino-protective group represented by R.sup.6 is
preferably a benzyloxycarbonyl group.
[0054] In the present invention, the group represented by 17
[0055] is preferably a group in which R.sup.2, R.sup.3 and R.sup.4
each represents a C.sub.1-8 alkyl group; a group in which R.sup.2
represents a phenyl group, and R.sup.3 and R.sup.4 each represents
a C.sub.1-8 alkyl group; a group in which R.sup.2 represents a
3,4-methylenedioxyphenyl group, and R.sup.3 and R.sup.4 each
represents a C.sub.1-8 alkyl group; and a group in which R.sup.2
represents a C.sub.1-8 alkyl group, and R.sup.3 and R.sup.4 are
taken together to represent a C.sub.2-6 alkylene group;
[0056] more preferably a group in which R.sup.2, R.sup.3, and
R.sup.4 each represents a C.sub.1-4 alkyl group; a group in which
R.sup.2 represents a phenyl group, and R.sup.3 and R.sup.4 each
represents a C.sub.1-4 alkyl group; a group in which R.sup.2
represents a 3,4-methylenedioxyphenyl group, and R.sup.3 and
R.sup.4 each represents a C.sub.1-4 alkyl group; and a group in
which R.sup.2 represents a C.sub.1-4 alkyl group, and R.sup.3 and
R.sup.4 are taken together to represent a C.sub.2-5 alkylene group,
and
[0057] most preferably, the group 18
[0058] represents an
.alpha.,.alpha.-dimethyl-3,4-methylenedioxybenzyl group, a t-butyl
group, an .alpha.,.alpha.-dimethylbenzyl group or a
1-methylcyclopropyl group.
[0059] In the invention, as is apparent to one skilled in the art,
the mark shows that the bond is in front of paper (at the
.beta.-position) unless otherwise indicated; the mark indicates
that the bond is on the other side of paper (at the
.alpha.-position) unless otherwise indicated; the mark shows that
the compound has the bond at the .beta.-position or the
.alpha.-position or the compound is a mixture of these compounds;
and the mark indicates that the compound is a mixture of a compound
having the bond at the .beta.-position and a compound having the
bond at the .alpha.-position.
[0060] In the invention, all conceivable isomers are included in
the scope thereof unless otherwise indicated. For example, an alkyl
group, an alkoxy group and an alkylene group include straight-chain
groups and branched groups. Isomers caused by the presence of an
asymmetric carbon (e.g., R or S-forms, .alpha.- or .beta.forms,
enantiomers, and diastereomers) and optically active compounds
having optical rotation (i.e., D-, L-, d- or I-forms) are all
included within the scope of the invention.
PROCESS OF PRODUCING THE COMPOUND OF INVENTION
[0061] The compound represented by formula (I) can be produced by
processes (1) and (2) described below, the processes according to
Examples described below, or known processes.
[0062] (1) Among the compounds represented by formula (I), a
compound in which R.sup.1 represents an amino-protective group,
i.e., a compound represented by formula (I-2): 19
[0063] (wherein all symbols have the same meanings as described
above) is prepared by reacting a compound represented by formula
(V): 20
[0064] (wherein R.sup.5 has the same meaning as described above)
and a compound represented by formula (VI): 21
[0065] (wherein all symbols have the same meanings as described
above).
[0066] The reaction between the compound represented by formula (V)
and the compound represented by formula (VI) is carried out in an
inert organic solvent (e.g., chloroform, methylene chloride,
diethyl ether, tetrahydrofuran, toluene, dimethylformamide, or the
like) in the presence of a base (e.g., lithium diisopropylamide
(LDA), or the like) and a tertiary amine (e.g.,
tetramethylethylenediamine, or the like) at -78 to 0.degree. C.
[0067] (2) Among the compounds represented by formula (I), a
compound in which R.sup.1 is a hydrogen atom, i.e., a compound
represented by formula (I-1): 22
[0068] (wherein all symbols have the same meanings as described
above) is prepared by subjecting the compound represented by
formula (I-2) to a deprotection reaction of the amino-protecting
group.
[0069] The deprotection reaction for the amino-protecting group
includes, for example,
[0070] 1) a deprotection reaction under alkaline conditions,
[0071] 2) a deprotection reaction under acidic conditions, and
[0072] 3) a deprotection reaction by hydrolysis.
[0073] More specifically,
[0074] 1) the deprotection reaction under alkaline conditions is
carried out, for example, at 0.degree. C. to 40.degree. C. in an
organic solvent (e.g., methanol, tetrahydrofuran, dioxane,
dimethylformamide, or the like) using an alkali metal hydroxide
(e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, or
the like), an alkaline earth metal hydroxide (e.g., barium
hydroxide, calcium hydroxide, or the like), an organic amine (e.g.,
triethylamine, N-methylmorpholine, diisopropylethylamine,
piperidine, or the like) or a quaternary ammonium salt (e.g.,
tetrabutylammonium fluoride, or the like) an aqueous solution
thereof or a mixture thereof.
[0075] 2) The deprotection reaction under acidic conditions is
carried out, for example, at 0.degree. C. to 100.degree. C. in an
organic solvent (e.g., methylene chloride, chloroform, dioxane,
ethyl acetate, anisole, or the like) or without a solvent using an
organic acid (e.g., acetic acid, trifluoroacetic acid,
methanesulfonic acid, trimethylsilyl iodide, or the like) or an
inorganic acid (e.g., hydrochloric acid, sulfuric acid, or the
like), or a mixture thereof (e.g., hydrogen bromide/acetic acid, or
the like).
[0076] 3) The deprotection reaction by hydrolysis is carried out,
for example, in an inert solvent (e.g., ethers (tetrahydrofuran,
dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (methanol,
ethanol, etc.), benzene solvents (benzene, toluene, etc.), ketones
(acetone, methyl ethyl ketone, etc.), nitrites (acetonitrile,
etc.), amides (dimethylformamide, etc.), water, ethyl acetate,
acetic acid, or mixed solvent of two or more thereof) in the
presence of a hydrogenation catalyst (e.g., palladium-carbon,
palladium black, palladium, palladium hydroxide, platinum dioxide,
nickel, Raney nickel, ruthenium chloride, or the like) and in the
presence or absence of an inorganic acid (e.g., hydrochloric acid,
sulfuric acid, hypochloric acid, boric acid, tetrafluoroboric acid,
or the like) or an organic acid (e.g., acetic acid,
p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic
acid, or the like) in a hydrogen atmosphere either under normal
pressure or under pressure or in the presence of ammonium formate
at a 0.degree. C. to 200.degree. C. In using an acid, the acid may
be used in the form of its salt.
[0077] As is easily understood by one skilled in the art, the
desired compound of the invention can be easily obtained by a
proper choice of these reactions.
[0078] The deprotection reaction of the compound represented by
formula (I-2) is preferably carried out by the reaction under
acidic conditions or the reaction by hydrolysis. The reaction under
acidic conditions is more preferred.
[0079] The compound represented by formula (I-1) is allowed to
react with the compound represented by formula (IV): 23
[0080] (wherein R.sup.6 has the same meaning as described above) to
produce the compound represented by formula (III): 24
[0081] (wherein all symbols have the same meanings as described
above). The reaction for producing the compound represented by
formula (III) is an amidation.
[0082] The amidation is known in the art. It includes, for
example,
[0083] 1) a process using an acid halide,
[0084] 2) a process using a mixed acid anhydride, and
[0085] 3) a process using a condensing agent.
[0086] More specifically,
[0087] 1) the process using an acid halide is carried out by, for
example, reacting the compound represented by formula (IV) with an
acid halide (e.g., oxalyl chloride thionyl chloride, or the like)
in an inert organic solvent (e.g., chloroform, methylene chloride,
diethyl ether, tetrahydrofuran, or the like) or without a solvent
at -20.degree. C. to a refluxing temperature and reacting the
resulting acid halide with the compound represented by formula
(I-1) in an inert organic solvent (e.g., chloroform, methylene
chloride, diethyl ether, tetrahydrofuran, or the like) in the
presence of a tertiary amine (e.g., pyridine, triethylamine,
dimethylaniline, dimethylaminopyridine, or the like) at -20.degree.
C. to 40.degree. C.
[0088] 2) The process using a mixed acid anhydride is carried out
by, for example, reacting the compound represented by formula (IV)
with an acid halide (e.g., pivaloyl chloride, tosyl chloride, mesyl
chloride, or the like) or an acid derivative (e.g., ethyl
chloroformate (ethyl chlorocarbonate), isobutyl chloroformate
(isobutyl chlorocarbonate), or the like) in an inert organic
solvent (e.g., chloroform, methylene chloride, diethyl ether,
tetrahydrofuran, or the like) or without a solvent in the presence
of a tertiary amine (e.g., pyridine, triethylamine,
dimethylaniline, dimethylaminopyridine, N-methylmorpholine, or the
like) at -20.degree. C. to 40.degree. C. and reacting the resulting
mixed acid anhydride with the compound represented by formula (I-1)
in an inert organic solvent (e.g., chloroform, methylene chloride,
diethyl ether, tetrahydrofuran, or the like) at -20.degree. C. to
40.degree. C.
[0089] 3) The process using a condensing agent is conducted by, for
example, reacting the compound represented by formula (IV) with the
compound represented by formula (I-1) in an organic solvent (e.g.,
chloroform, methylene chloride, dimethylformamide, diethyl ether,
tetrahydrofuran, or the like) or without a solvent in the presence
or absence of a tertiary amine (e.g., pyridine, triethylamine,
dimethylaniline, dimethylaminopyridine, or the like) using a
condensing agent (e.g., 1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-[3-(dimethylam- ino)propyl]carbodiimide (EDC),
1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,
or the like) and with or without 1-hydroxybenztriazole (HOBt) at
0.degree. C. to 40.degree. C.
[0090] The reactions 1), 2) and 3) are preferably carried out in an
atmosphere of an inert gas (e.g., argon, nitrogen, or the like)
under anhydrous conditions.
[0091] The amidation between the compound represented by formula
(I-1) and the compound represented by formula (IV) is preferably
carried out by the process using a mixed acid anhydride.
[0092] The reaction for converting the compound represented by
formula (III) into the compound represented by formula (II) can be
carried out by the above deprotection reaction of the
amino-protecting group.
[0093] The deprotection reaction of the amino-protecting group for
converting the compound represented by formula (III) into the
compound represented by formula (II) is preferably carried out by
hydrolysis.
[0094] The compound represented by formula (V) and the compound
represented by formula (VI) are produced by the process described
in WO9824806 or Examples described below.
[0095] The compound represented by formula (IV) is produced by the
process described in EP 528633 (JP-A-5-286946).
[0096] The other starting materials and reagents used in the
present invention are known per se or can be prepared by known
processes.
[0097] As is easily understood by one skilled in the art, the
compounds represented by formulas (I-2), (I-1), (III) and (II) in
their optically active form can be easily produced using an
optically active compound as the compound represented by formula
(V).
[0098] For example, among the compounds represented by formula (V),
t-butyl
N-((1R)-1-(N'-methyl-N'-methoxyaminocarbonyl)-2-methylpropyl)carb-
amate (CAS Registry No. 190260-92-5), t-butyl
N-((1S)-1-(N'-methyl-N'-meth-
oxyaminocarbonyl)-2-methylpropyl)carbamate (CAS Registry No.
160711-20-6), benzyl
N-((1S)-1-(N'-methyl-N'-methoxyaminocarbonyl)-2-methylpropyl)carba-
mate (CAS Registry No. 114744-84-2), and the like are known. Use of
these optically active compounds easily provides, for example,
N-((1R)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-b-
enzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide,
N-((1S)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-b-
enzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide,
and the like among the compounds represented by formula (III); and
N-((1R)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-a-
mino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide,
N-((1S)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-a-
mino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide, and the
like among the compounds represented by formula (II).
[0099] The product of each reaction in the invention is purified
through common purification means, for example, distillation under
normal pressure or reduced pressure, high performance liquid
chromatography using silica gel or magnesium silicate, thin layer
chromatography, column chromatography, washing, recrystallization,
and the like. The purification may be carried out at each reaction
or after completion of several reactions.
[0100] The compound represented by general formula (I) can be
converted into a salt by a known method. The salt is preferably
non-toxic and water-soluble. Examples of suitable salts include
salts with alkali metals (e.g., potassium, sodium, and the like),
salts with alkaline earth metals (e.g., calcium, magnesium, and the
like), ammonium salts, and pharmaceutically acceptable salts with
organic amines (e.g., tetramethylammonium, triethylamine,
methylamine, dimethylamine, cyclopentylamine, benzylamine,
phenethylamine, piperidine, monoethanolamine, diethanolamine,
tris(hydroxymethyl)aminomethane, lysine, arginine,
N-methyl-D-glucamine, and the like).
[0101] The compound represented by formula (I) according to the
present invention can be converted into an acid addition salt by a
known process. The acid addition salt is preferably non-toxic and
water-soluble. Examples of suitable acid addition salts include
inorganic acid salts, such as hydrochlorides, hydrobromides,
sulfates, phosphates, nitrates, and the like; and organic acid
salts, such as acetates, trifluoroacetates, lactates, tartrates,
oxalates, fumarates, maleates, citrates, benzoates,
methanesulfonates, ethanesulfonates, benzenesulfonates,
toluenesulfonates, isethionates, glucuronates, gluconates, and the
like.
[0102] The compound represented by formula (I) according to the
invention or a non-toxic salt thereof can be converted into a
hydrate thereof by a known method.
INDUSTRIAL APPLICABILITY
[0103] The process of the invention provides the compound
represented by formula (II) through a fewer steps using the novel
intermediate represented by formula (I) and is therefore useful as
an efficient industrial process of production.
BEST MODE FOR CARRYING OUT THE INVENTION
[0104] The present invention will now be illustrated in greater
detail by way of Reference Examples, Examples, and Comparative
Examples, but the invention is not limited thereto.
[0105] Solvents in parentheses shown in the part of chromatographic
separation and TLC are eluents or developing solvents used, and
ratios are by volume.
[0106] Solvents in parentheses shown in the part of NMR are
solvents used for the measurement.
Reference Example 1
Synthesis of t-butyl
N-(1-(N'-methyl-N'-methoxyaminocarbonyl)-2-methylprop-
yl)carbamate
[0107] 25
[0108] N,O-Dimethylhydroxylamine hydrochloride (3.37 kg) and
1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (5.73 kg) were
dissolved in pyridine (19 liters (L)) at room temperature in a
nitrogen atmosphere, and 2-t-butoxycarbonylamino-3-methylbutanoic
acid (5.00 kg) was added thereto at 5.degree. C. or lower, followed
by stirring at 20-30.degree. C. for 2 hours. Ice-water (23.8 L) and
toluene (15.8 L) were added to the reaction mixture, and the
resulting layers were separated. The aqueous layer was extracted
with a mixed solvent (toluene:ethyl acetate=1:1, 15.8 L). The
organic layers were combined and washed with 1 N hydrochloric acid
(40 L, twice). Ethyl acetate (7.9 L) was added to the organic
layer, and the mixture was washed with a saturated aqueous solution
of sodium hydrogencarbonate (16 L, twice), water (30 L, twice), and
saturated saline (16 L, twice) successively, followed by
concentration. The residue was dissolved in methanol (12 L) at
40.degree. C., and water (30 L) was added thereto to precipitate a
solid, followed by stirring at 25.degree. C. for 2 hours and then
at 5.degree. C. or lower for 2 at least hours. The precipitated
solid was filtrated and washed with water (5 L). The solid was
dried in vacuo at 30.degree. C. for at least 15 hours to obtain the
title compound (5.16 kg; yield: 86%) having the following physical
properties.
[0109] TLC: Rf 0.49 (hexane:ethyl acetate=2:1)
[0110] NMR (CDCl.sub.3): .delta.5.13 (brd, 1H), 4.57 (brt, 1H),
3.77 (s, 3H), 3.22 (s, 3H), 1.97 (m, 1H), 1.44 (s, 9H), 0.96 (d,
J=6.8 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H).
Reference Example 2
Synthesis of Pivaloylhydrazine
[0111] 26
[0112] Methyl pivalate (1040 ml) and hydrazine monohydrate (760 ml)
were heated under reflux for 14.5 hours in an argon stream. The
reaction mixture was cooled to room temperature and concentrated.
The residue was cooled with ice, and the precipitated crystals were
collected by filtration. The filtered material was washed with
hexane (250 ml, twice; and 300 ml, once) to obtain the title
compound. Furthermore, the mother liquid (510 g) was cooled with
ice, and the precipitated crystals were collected by filtration.
The filtered material was washed with hexane (100 ml, twice; and
200 ml, once) to obtain the title compound having the following
physical properties (total yield: 571.8 g, 63%).
[0113] TLC: Rf 0.59 (chloroform:methanol=10:1)
[0114] NMR (CDCl.sub.3): .delta.7.06 (brs, 1H), 3.87 (brs, 2H),
1.21 (s, 9H)
Reference Exmaple 3
Synthesis of 2-t-butyl-1,3,4-oxadiazole
[0115] 27
[0116] A mixture of the compound produced in Reference Example 2
(570 g), methyl orthoformate (805 ml) and p-toluenesulfonic acid
monohydrate (14.0 g) was heated under stirring for 9 hours while
distilling off produced methanol. The reaction mixture was cooled
to room temperature and distilled under reduced pressure to obtain
a compound of the invention (538.4 g; 86%) having the following
physical properties.
[0117] TLC: Rf 0.68 (chloroform:methanol=10:1)
[0118] NMR (CDCl.sub.3): .delta.8.33 (s, 1H), 1.45 (s, 9H)
Reference Exmalpe 4
Synthesis of
N-hydroxy-1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydropy-
rimidin-5-ylcarboxamide
[0119] 28
[0120] Triethylamine (49.4 ml) was added to a solution of
1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-ylcarboxylic
acid (97.3 g) in tetrahydrofuran (800 ml) in an ice bath in an
argon atmosphere, and isobutyl chlorocarbonate (45.6 ml) was added
dropwise thereto at 5.degree. C. or lower, followed by stirring at
the same temperature for 1 hour. To the reaction mixture was added
a 50% hydroxylamine aqueous solution (422 ml), followed by stirring
for 20 minutes. The reaction mixture was separated to layers. The
aqueous layer was extracted with ethyl acetate (200 ml). The
organic layers were combined, washed with saturated saline (200
ml), and concentrated. To the residue was added toluene (200 ml),
followed by concentration. The resulting crude crystals were washed
with isopropyl ether (1000 ml) by heating under reflux for 10
minutes, cooled to room temperature, and crystals were collected by
filtration. The collected crystals were dried in vacuo at room
temperature overnight to obtain the title compound (93.3 g; yield:
91%) having the following physical properties.
[0121] TLC: RF 0.5 (ethyl acetate);
[0122] NMR (CDCl.sub.3): .delta.8.95 (s, 1H), 7.62-7.45 (m, 5H),
4.76 (t, J=5.8 Hz, 1H), 4.21 (2H, d, J=5.8 Hz), 3.30 (6H, s).
Reference Example 5
Synthesis of
N-acetyloxy-1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydro-
pyrimidin-5-ylcarboxamide
[0123] 29
[0124] Pyridine (5.66 ml) was added to a suspension of the compound
produced in Reference Example 4 (15.95 g) in tetrahydrofuran (50
ml) at room temperature in an argon atmosphere, and acetic
anhydride (5.19 ml) was added dropwise thereto, followed by
stirring for 20 minutes. Ethyl acetate (150 ml) and 1N hydrochloric
acid (84 ml) were added to the reaction mixture, and the resulting
layers were separated. The organic layer was washed with an aqueous
sodium chloride solution (saturated saline (50 ml) and water (50
ml)) and a mixed solution (saturated saline (50 ml) and a saturated
aqueous solution of sodium hydrogencarbonate (50 ml)) successively,
followed by concentration to obtain the title compound (16.9 g;
crude product) having the following physical properties.
[0125] TLC: Rf 0.44 (toluene:acetone=4:1)
[0126] NMR (CDCl.sub.3): .delta.8.99 (s, 1H), 7.62-7.45 (m, 5H),
4.79 (t, J=5.4 Hz, 1H), 4.22 (d, J=5.4 Hz, 2H), 3.30 (s, 6H), 2.30
(s, 3H).
Reference Example 6
Synthesis of
5-amino-1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydropyri-
midine
[0127] 30
[0128] A suspension of the compound produced in Reference Example 5
(16.9 g) in tetrahydrofuran (200 ml) was heated to obtain a
solution. Water (18 ml) was added thereto at 40.degree. C., and
1,8-diazabicyclo[5.4.0]-7-und- ecene (9.35 ml) was added thereto at
50.degree. C., followed by heating under reflux for 1 hour. After
cooling the reaction mixture to room temperature, toluene (100 ml)
and a saturated aqueous solution of ammonium chloride (100 ml) were
added thereto, and the resulting layers were separated. The organic
layer was washed with a saturated aqueous ammonium chloride
solution and saturated saline (100 ml) successively and
concentrated to obtain the title compound (15.7 g; crude product)
having the following physical properties.
[0129] TLC: Rf 0.26 (toluene:acetone=4:1)
[0130] NMR (CDCl.sub.3): .delta.7.55-7.38 (m, 6H), 4.77 (t, J=5.6
Hz, 1H), 4.14 (d, J=5.6 Hz, 2H), 4.02 (brs, 2H), 3.27 (s, 6H)
Reference Example 7
Synthesis of
5-benzyloxycarbonylamino-1-(2,2-dimethoxyethyl)-6-oxo-2-pheny-
l-1,6-dihydropyrimidine
[0131] 31
[0132] A mixture of the compound produced in Reference Example 6
(15.7 g), tetrahydrofuran (75 ml), water (75 ml), and sodium
hydrogencarbonate (5.88 g) was cooled with ice, and
benzyloxycarbonyl chloride (8.56 ml) was added dropwise thereto at
5.degree. C. or lower, followed by stirring at 5.degree. C.
overnight. Ethyl acetate (100 ml) was added to the reaction
mixture, and the resulting layers were separated. The organic layer
was washed with saturated saline (100 ml), followed by
concentration to obtain the title compound (22.0 g; crude product)
having the following physical properties.
[0133] TLC: Rf 0.67 (toluene:acetone=4:1)
[0134] NMR (CDCl.sub.3): .delta.8.73 (brs, 1H), 7.60-7.30 (m, 10H),
5.24 (s, 2H), 4.71 (t, J=5.5 Hz, 1H), 4.15 (d, J=5.5 Hz, 2H), 3.26
(s, 6H)
Reference Example 8
Synthesis of
5-benzyloxycarbonylamino-1-formylmethyl-6-oxo-2-phenyl-1,6-di-
hydropyrimidine
[0135] 32
[0136] A mixture of the compound produced in Reference Example 7
(22.0 g), 1N hydrochloric acid (10 ml), and acetic acid (30 ml) was
heated to 70-77.degree. C., followed by stirring for 2 hours. The
reaction mixture was cooled to room temperature, water (75 ml) and
a mixed solvent (toluene:ethyl acetate=4:1, 60 ml) were added
thereto, and the resulting layers were separated. The aqueous layer
was extracted with a mixed solvent (toluene:ethyl acetate=4:1, two
30 ml portions). The organic layers were combined and washed with
water (50 ml), a saturated aqueous solution of sodium
hydrogencarbonate (50 ml), and saturated saline (50 ml)
successively, and dried over anhydrous magnesium sulfate, followed
by concentration to obtain the title compound (16.8 g; crude
product) having the following physical properties.
[0137] TLC: Rf 0.36 (hexane:ethyl acetate=1:1)
[0138] NMR (CDCl.sub.3): .delta.9.59 (s, 1H), 8.79 (brs, 1H),
7.60-7.10 (m, 10H), 5.24 (s, 2H), 4.77 (s, 2H)
Reference Example 9
Synthesis of
5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin--
1-ylmethylcarboxylic Acid
[0139] 33
[0140] An aqueous solution (20 ml) of sodium dihydrogenphosphate
(7.20 g) was added to a solution of the compound produced in
Reference Example 8 (16.8 g) in a mixed solvent
(t-butanol:water=4:1, 100 ml), followed by cooling with ice. To the
reaction mixture was added 2-methyl-2-butene (23.8 ml), and an
aqueous solution (32 ml) of sodium chlorite (19.78 g) was added
dropwise thereto, followed by stirring at room temperature for 3
hours. Ethyl acetate (30 ml) was added to the reaction mixture, and
the resulting layers were separated. To the organic layer were
added a saturated aqueous sodium chloride solution (60 ml) and
ethyl acetate (30 ml), and the resulting layers were separated. The
organic layer was washed with a 10% aqueous solution of sodium
hydrogensulfite (60 ml). The aqueous layer was extracted with ethyl
acetate (50 ml). The organic layers were combined and washed with
1N hydrochloric acid (60 ml) and saturated saline (60 ml)
successively, and dried over anhydrous magnesium sulfate, followed
by concentration. Ethyl acetate (50 ml) was added to the residue,
followed by concentration. Ethyl acetate (50 ml) was further added
to the residue, followed by concentration. To the resulting crude
crystals was added ethyl acetate (35 ml), followed by heating under
reflux for 15 minutes. Isopropyl ether (17.5 ml) was added,
followed by heating under reflux for further 15 minutes. The
solution was cooled to room temperature, followed by stirring at
5.degree. C. overnight. The precipitated crystals were collected by
filtration, and washed with isopropyl ether (50 ml). The crystals
were dried in vacuo to obtain the compound of the invention (11.99
g; yield: 63%) having the following physical properties.
[0141] TLC: Rf 0.55 (chloroform:methanol:acetic acid=18:1:1)
[0142] NMR (CD.sub.3OD): .delta.8.65 (s, 1H), 7.60-7.25 (m, 10H),
5.23 (s, 2H), 4.60 (s, 2H)
EXAMPLE 1
Synthesis of t-butyl
N-(1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methy-
lpropyl)carbamate
[0143] 34
[0144] A 2.0 M solution of lithium diiospropylamide (19.65 kg) was
added dropwise to a solution of the compound produced in Reference
Example 1 (2.52 kg), the compound produced in Reference Example 3
(6.10 kg), and tetramethylethylenediamine (5.62 kg) in
tetrahydrofuran (25.2 L) at -65.degree. C. or less in an argon
stream, followed by stirring at -25.degree. C. to -20.degree. C.
for 3 to 5 hours. The reaction mixture was poured into a cool 10%
aqueous citric acid solution (93 L) and extracted with ethyl
acetate. To the organic layer was added 1N hydrochloric acid (96.8
L), followed by stirring for 1 hour, and the resulting layers were
separated. The organic layer was washed with a 5% aqueous potassium
carbonate solution (50.4 L), water (25.2 L, twice), and saturated
saline (8.4 L) successively, and dried over anhydrous magnesium
sulfate. The anhydrous magnesium sulfate was separated by
filtration and washed with tetrahydrofuran (2.8 L). The organic
layer was concentrated to obtain the compound of the invention
(3.69 kg, crude product) having the following physical
properties.
[0145] TLC: Rf 0.70 (hexane:ethyl acetate=2:1)
[0146] NMR (CDCl.sub.3): .delta.5.30-5.05 (m, 2H), 2.46 (m, 1H),
1.48 (s, 9H), 1.43 (s, 9H), 1.09 (d, J=6.9 Hz, 3H), 0.88 (d, J=6.9
Hz, 3H).
EXAMPLE 1(1)
Synthesis of t-butyl
N-((2S)-1-(2-.alpha.,.alpha.-dimethylbenzyl)-1,3,4-ox-
adiazol-5-ylcarbonyl)-2-methylpropyl)carbamate
[0147] 35
[0148] The compound of the invention having the following physical
properties was obtained in the same manner as in Example 1, except
for replacing the compound produced in Reference Example 3 with a
corresponding oxadiazole derivative and replacing the compound
produced in Reference Example 1 with t-butyl
N-((2S)-1-(N'-methyl-N'-methoxyaminoc-
arbonyl)-2-methylpropyl)carbamate.
[0149] TLC: Rf 0.50 (ethyl acetate:n-hexane=1:2)
[0150] NMR (CDCl.sub.3): .delta.7.32 (m, 5H), 5.16 (m, 2H), 2.45
(m, 1H), 1.89 (s, 6H), 1.43 (s, 9H), 1.07 (d, 3H, J=6.8 Hz), 0.86
(d, 3H, J=7.2 Hz) cl EXAMPLE 2
Synthesis of
1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropylamin- e
Hydrochloride
[0151] 36
[0152] A solution of the compound produced in Example 1 (3.15 kg)
in ethyl acetate (4.3 L) was added dropwise to a 4N hydrogen
chloride-ethyl acetate solution (9.7 L) at 10-20.degree. C. in a
nitrogen stream, followed by stirring for 1.5-2 hours. A 4N
hydrogen chloride-ethyl acetate solution (4.8 L) was added to the
reaction mixture at 10-20.degree. C., followed by stirring for 1
hour. The reaction mixture was concentrated, ethyl acetate (8.8 L)
was added thereto, followed by concentration. Ethyl acetate (8.8 L)
was again added to the concentrate, followed by concentration.
t-Butyl methyl ether (29.0 L) was added to the concentrate,
followed by stirring at 5.degree. C. or lower for at least 2 hours.
The precipitated solid was collected by filtration. The filtered
solid was washed with a mixed solvent (t-butyl methyl ether (3.84
L) and ethyl acetate (0.96 L)) and dried in vacuo at 30.degree. C.
for at least 15 hours to obtain the compound of the invention (2.16
kg; yield through the two steps: 86%) having the following physical
properties.
[0153] TLC: Rf 0.90 (chloroform:methanol=10:1)
[0154] NMR (CD.sub.3OD): .delta.5.05 (d, J=3.8 Hz, 1H), 2.85 (m,
1H), 1.48 (s, 9H), 1.35 (d, J=6.9 Hz, 3H), 1.10 (d, J=6.9 Hz,
3H)
EXAMPLE 2(1)
Synthesis of
(2S)-1-(2-(.alpha.,.alpha.-dimethylbenzyl)-1,3,4-oxadiazol-5--
ylcarbonyl)-2-methylpropylamine hydrochloride
[0155] 37
[0156] The compound of the invention having the following physical
properties was obtained in the same manner as in Example 2, except
for replacing the compound produced in Example 1 with the compound
produced in
EXAMPLE 1(1)
[0157] TLC: Rf 0.50 (chloroform:methanol=10:1)
[0158] NMR (CDCl.sub.3): .delta.9.05 (brs, 2H), 7.28 (m, 5H), 4.96
(m, 1H), 2.79 (m, 1H), 1.87 (s, 6H), 1.29 (d, J=6.8 Hz, 3H), 1.02
(d, J=7.2 Hz, 3H)
EXAMPLE 3
Synthesis of
N-((1RS)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylp-
ropyl)-2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-y-
l)acetamide
[0159] 38
[0160] N-Methylmorpholine (634 g) was added to a solution of the
compound produced in Reference Example 9 (2.38 kg) in
tetrahydrofuran (12.9 L) at -5.degree. C. or lower in an argon
stream, ethyl chlorocarbonate (680 g) was added dropwise thereto at
-2.degree. C. or lower, and the reaction mixture was stirred at
-5.degree. C. or lower for 30 minutes. The compound produced in
Example 2 (1.64 kg) was added to the reaction mixture at -5.degree.
C. or lower, followed by stirring for 30 minutes. To the reaction
mixture was added N-methylmorpholine (634 g) at -5.degree. C. or
lower, followed by stirring for 30 minutes. t-Butyl methyl ether
(24.8 L) and 1N hydrochloric acid (12.9 L) were added to the
reaction mixture, and the resulting layers were separated. The
organic layer was washed with a 5% aqueous sodium hydrogencarbonate
solution (12.9 L), a 5% aqueous potassium carbonate solution (12.9
L), 1N hydrochloric acid (12.9 L), water (12.9 L), and saturated
saline (12.9 L) successively, and dried over anhydrous magnesium
sulfate. The magnesium sulfate was separated by filtration and
washed with tetrahydrofuran (18 L). The organic layer was
concentrated to obtain the compound of the invention (3.61 kg;
yield: 98%) having the following physical properties.
[0161] TLC: Rf 0.33 (hexane:ethyl acetate=1:1)
[0162] NMR (CDCl.sub.3): .delta.8.78 (s, 1H), 7.60-7.30 (m, 10H),
6.74 (d, J=8.5 Hz, 1H), 5.43 (dd, J=8.5, 5.2 Hz, 1H), 5.23 (s, 2H),
4.64 (d, J=15.3 Hz, 1H), 4.60 (d, J=15.3 Hz, 1H), 2.50 (m, 1H),
1.47 (s, 9H), 1.06 (d, J=6.8 Hz, 3H), 0.87 (d, J=6.8 Hz, 3H).
EXAMPLE 4
Synthesis of
N-((1RS)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylp-
ropyl)-2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide
[0163] 39
[0164] To a solution of the compound produced in Example 3 (1.61
kg) in methanol (27 L) was added 10% palladium-carbon (water
content: 50%; 274 g) at room temperature in an argon atmosphere.
Argon substitution was carried out three times, and then hydrogen
substitution was carried out three times. The reaction mixture was
stirred at 25.degree. C. and 3 atm for 25 minutes. After argon
substitution was carried out three times, the reaction mixture was
filtered, and the filtrate was concentrated. The residue was
dissolved in methanol (54.8 L), followed by filtration. Water (54.8
L) was added to the filtrate, and seed crystals (12.4 g) were added
to thereto, followed by stirring overnight and then stirring at
5-10.degree. C. for 1 hour. The precipitated crystals were
collected by filtration, washed with water (30 L), and dried in
vacuo at 60.degree. C. for at least 38 hours to obtain the compound
of the invention (1.90 kg; yield: 77%) having the following
physical properties.
[0165] TLC: Rf 0.45 (methylene chloride:ethyl
acetate:ethanol=10:10:1)
[0166] NMR (CDCl.sub.3): .delta.7.58-7.35 (m, 6H), 6.94 (d, J=8.4
Hz, 1H), 5.44 (dd, J=8.4, 4.9 Hz, 1H), 4.66 (d, J=15.4 Hz, 1H),
4.60 (d, J=15.4 Hz, 1H), 4.06 (brs, 2H), 2.51 (m, 1H), 1.48 (s,
9H), 1.07 (d, J=6.9 Hz, 3H), 0.87 (d, J=6.9 Hz, 1H)
Comparative Examples
[0167] Among the compounds represented by formula (W-c-1), a
compound in which R.sup.1w is a t-butyl group was produced by the
processes shown in the previously described reaction schemes 2 and
3.
Comparative Example 1
Synthesis of t-butyl N-(1-formyl-2-methylpropyl)carbamate
[0168] 40
[0169] Diisobutylaluminum hydride (1.0 M toluene solution, 80 ml)
was added dropwise to a solution of the compound produced in
Reference Example 1 (9.0 g) in anhydrous tetrahydrofuran (500 ml)
at -78.degree. C. in an argon stream, followed by stirring for 30
minutes. Methanol (100 ml) was added to the reaction mixture, the
temperature was raised to 0.degree. C., and a saturated aqueous
ammonium chloride solution (100 ml) was added thereto. The reaction
mixture was filtered, and the filtrate was concentrated. The
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=19:1.fwdarw.4:1) to obtain the title compound
(5.4 g; yield: 78%) having the following physical properties.
[0170] TLC: Rf 0.55 (hexane:ethyl acetate=4:1)
[0171] NMR (CDCl.sub.3): .delta.9.62 (s, 1H), 5.16 (brs, 1H), 4.25
(brs, 1H), 2.27 (m, 1H), 1.43 (s, 9H), 1.03 (d, J=6.6 Hz, 3H), 0.96
(d, J=6.6 Hz, 3H)
Comparative Example 2
Synthesis of t-butyl
N-(1-(2-t-butyl-1,3,4-oxadiazol-5-yl)hydroxymethyl)-2-
-methylpropyl)carbamate
[0172] 41
[0173] n-Butyl lithium (1.6 M hexane solution, 308 ml) was added
dropwise to a solution of the compound produced in Reference
Example 3 (62.1 g) in tetrahydrofuran (1.65 L) at -70.degree. C. in
an argon atmosphere, followed by stirring for 40 minutes. Magnesium
bromide diethyl etherate (127 g) was added to the reaction mixture,
and the temperature was raised to -45.degree. C., followed by
stirring for 1.5 hours. A solution of the compound prepared in
Comparative Example 1 (90.0 g) in tetrahydrofuran (60 ml) was added
to the reaction mixture, and the temperature was raised to
-20.degree. C., followed by stirring for 3.5 hours. A saturated
aqueous solution of ammonia chloride (1.5 L) was added to the
reaction mixture, followed by extraction with ethyl acetate (1.8
L). The organic layer was washed with water (1 L, three times) and
saturated saline (1 L) successively, dried over anhydrous sodium
sulfate, and concentrated. The residue was purified by silica gel
column chromatography (ethyl acetate:hexane=1:20.fwdarw.1:1) to
obtain the title compound (76.8 g; yield: 53%) having the following
physical properties.
[0174] TLC: Rf 0.42 (ethyl acetate:hexane=1:1).
[0175] NMR (CDCl.sub.3): .delta.5.18-4.90 (m, 2H), 4.51 and 4.12
(each m, totally 1H), 3.91 and 3.66 (each m, totally 1H), 1.95 (m,
1H), 1.42, 1.41 and 1.34 (each s, totally 18H), 1.15-0.90 (m,
6H).
Comparative Example 3
Synthesis of
1-(2-t-butyl-1,3,4-oxadiazol-5-yl)hydroxymethyl-2-methylpropy-
lamine hydrochloride
[0176] 42
[0177] A solution of the compound produced in Comparative Example 2
(76.3 g) and a 4N hydrogen chloride-dioxane solution (1 L) in
dioxane (200 ml) was vigorously stirred at room temperature for 2
hours, followed by concentration. The residue was solidified with
diethyl ether and subjected to azeotropy with benzene to
quantitatively obtain the title compound (66.1 g) having the
following physical properties.
[0178] TLC: Rf 0.30 and 0.26 (methanol:chloroform=1:10)
[0179] NMR (CDCl.sub.3): .delta.8.34 and 8.24 (each br, each 1H),
5.60 (br, 1H), 3.97-3.60 (m, 2H), 2.08 (m, 1H), 1.42 and 1.41 (each
s, totally 9H), 1.25-0.95 (m, 6H).
Comparative Example 4
Synthesis of
N-(1-(2-t-butyl-1,3,4-oxadiazol-5-yl)hydroxymetyl-2-methylpro-
pyl)-2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-
acetamide
[0180] 43
[0181] To a solution of the compound produced in Reference Example
9 (10.0 g) and the compound produced in Comparative Example 3 (8.16
g) in anhydrous dimethylformamide (88 ml) were added
1-hydroxybenzotriazole monohydrate (4.44 g) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.62
g) in an argon stream under cooling with ice, and
N-methylmorpholine (3.19 ml) was added dropwise thereto. The
reaction mixture was stirred under ice-cooling for 20 minutes and
then at room temperature for 6.5 hours, followed by concentration.
Ethyl acetate (100 ml) and water (100 ml) were added to the
residue, and the resulting layers were separated. The organic layer
was washed with a saturated aqueous solution of ammonium chloride
(60 ml, twice), a saturated aqueous solution of sodium
hydrogencarbonate (60 ml, twice), water (60 ml), and saturated
saline (60 ml) successively, dried over anhydrous sodium sulfate,
and concentrated. The resulting solid (14.7 g; yield: 95%) was used
in the subsequent reaction without purification.
[0182] TLC: Rf 0.60 and 0.55 (chloroform:methanol=9:1)
[0183] NMR (CDCl.sub.3): .delta.8.80 and 8.71 (each brs, total 1H),
7.64-7.24 (m, 11H), 7.15 and 6.79 (each brd, J=9.8 Hz, total 1H),
5.28-4.98 (m, ca. 1.5H), 5.20 (s, 2H), 4.69 (brs, ca. 0.5H), 4.58
and 4.46 (each brs, total 2H), 4.30 and 4.05 (each m, total 1H),
2.05-1.65 (m, 1H), 1.38 and 1.34 (each s, total 9H), 1.08, 0.96,
0.92, and 0.91 (each d, J=6.4 Hz, total 6H).
Comparative Example 5
Synthesis of
N-(1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-
-2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acet-
amide
[0184] 44
[0185] A solution of dimethyl sulfoxide (7.1 ml) in anhydrous
methylene chloride (100 ml) was added dropwise to a solution of
oxalyl chloride (4.4 ml) in anhydrous methylene chloride (100 ml)
at -60.degree. C. or lower in an argon stream, followed by stirring
for 40 minutes. A solution of the compound produced in Comparative
Example 4 (14.7 g) in a mixed solvent (anhydrous methylene chloride
(75 ml) and dimethyl sulfoxide (10 ml)) was added dropwise to the
reaction mixture at -60.degree. C. or lower, followed by stirring
for 2 hours. Triethylamine (69.8 ml) was added dropwise to the
reaction mixture at -60.degree. C. or lower, followed by stirring
at room temperature overnight. The reaction mixture was cooled with
ice, and 2N hydrochloric acid (200 ml) was added dropwise thereto.
The organic layer was washed with 1 N hydrochloric acid (150 ml),
water (150 ml), and saturated saline (150 ml) successively, dried
over anhydrous magnesium sulfate, and concentrated. The resulting
solid (14.6 g; yield: 100%) was used in the subsequent reaction
without purification.
Comparative Example 6
Synthesis of
N-(1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-
-2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide
[0186] 45
[0187] A solution of aluminum chloride (20.0 g) in nitromethane (70
ml) was added to a solution of the compound produced in Comparative
Example 5 (14.4 g) and anisole (16.0 ml) in nitromethane (70 ml)
under cooling with ice, followed by stirring under ice cooling for
10 minutes and then stirring at room temperature for 14 hours. The
reaction mixture was poured into ice-water (200 ml) and extracted
with ethyl acetate (120 ml and 40 ml). The organic layer was washed
with a sodium chloride aqueous solution (a saturated sodium
chloride aqueous solution (100 ml)+water (100 ml)) and saturated
saline (200 ml) successively, dried over anhydrous magnesium
sulfate, and concentrated. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate=1:2.fwdarw.0:1) to
obtain a solid (6.7 g). The solid was washed with a mixed solvent
(hexane:ethyl acetate=1:3) to obtain the title compound (5.2 g;
yield: 46%).
* * * * *